APRN21 • Advanced Practice Nurses 2021 (Includes 30 Pharmacology Hours)

Table of Contents

APRN21 • Advanced Practice Nurses 2021 (Includes 30 Pharmacology Hours)

How to Receive Credit

NetCE 10 Hour Course #90200 • Botulinum Toxin and Dermal Fillers for Facial Aging

90200 • Botulinum Toxin and Dermal Fillers for Facial Aging

1. INTRODUCTION

2. TERMINOLOGY

3. BACKGROUND

4. THE PROCESSES OF FACIAL AGING

5. BOTULINUM TOXIN

6. SOFT TISSUE (DERMAL) FILLERS

7. DEOXYCHOLIC ACID

8. INDIVIDUALIZED ASSESSMENT AND TREATMENT PLANNING

9. THE MINIMALLY INVASIVE TREATMENT APPROACH

10. PATIENT SELECTION AND EVALUATION

11. ADVERSE EFFECTS

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #95323 • Diabetes Pharmacology

95323 • Diabetes Pharmacology

1. INTRODUCTION

2. DIABETES EPIDEMIOLOGY

3. PATHOGENESIS OF DIABETES

4. DIABETES RESEARCH

5. DIAGNOSIS OF DIABETES

6. SULFONYLUREA THERAPY: FIRST AND SECOND GENERATIONS

7. NONSULFONYLUREA SECRETAGOGUE (GLINIDE) THERAPY

8. ALPHA-GLUCOSIDASE INHIBITOR THERAPY

9. BIGUANIDE THERAPY

10. THIAZOLIDINEDIONE THERAPY

11. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITOR THERAPY

12. SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

13. COMBINATION ORAL MEDICATION PREPARATIONS

14. BOLUS INSULIN THERAPY

15. BASAL INSULIN

16. COMBINATION INSULIN PREPARATIONS

17. INCRETIN MIMETICS

18. AMYLIN ANALOGS

19. PATIENT EDUCATION

20. CASE STUDIES

21. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #30463 • Moderate Sedation/Analgesia

30463 • Moderate Sedation/Analgesia

1. INTRODUCTION

2. PATIENT CARE

3. PHARMACOLOGY AND DRUG ADMINISTRATION

4. DRUG CLASSES AND MEDICATIONS

5. PATIENT MONITORING DURING MODERATE SEDATION

6. DOCUMENTATION OF MODERATE SEDATION

7. COMPLICATIONS DURING MODERATE SEDATION

8. MODERATE SEDATION OF THE PEDIATRIC PATIENT

9. MODERATE SEDATION OF THE GERIATRIC PATIENT

10. MODERATE SEDATION OF THE OBSTETRIC PATIENT

11. SEDATION OF THE CRITICALLY ILL PATIENT

12. PATIENTS UNDERGOING PROCEDURAL INTERVENTIONS

13. CASE STUDIES

14. PRACTICE ISSUES

15. SUMMARY

Works Cited

Evidence-Based Practice Recommendations Citations

APRN21 • Advanced Practice Nurses 2021 (Includes 30 Pharmacology Hours)

Mark Rose, BS, MA, LP

Diane Thompson, RN, MSN, CDE, CLNC

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

APRN21 • Advanced Practice Nurses 2021 (Includes 30 Pharmacology Hours)

Expiration Date: 01/31/2022

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

90200 • Botulinum Toxin and Dermal Fillers for Facial Aging

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2021 NetCE, All rights reserved.

The importance for primary care clinicians to understand aesthetic medicine, patient variables, and market factors is brought to light by the increasing rates of aesthetic injections performed by non-board-certified physicians, nurses, and minimally trained aestheticians at inadequately equipped clinics, office settings, and spas. Primary care providers are well-placed to importantly inform their patients about many aspects related to aesthetic medicine but benefit from educational intervention to become most effective in this role.

Table of Contents

90200 • Botulinum Toxin and Dermal Fillers for Facial Aging

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. TERMINOLOGY

3. BACKGROUND

INCREASING CONCERNS

4. THE PROCESSES OF FACIAL AGING

THE TWO-DIMENSIONAL MODEL

THE 3-D MODEL: NORMAL ANATOMY OF FACIAL TISSUE

THE INTEGRATIVE AND AESTHETIC UNITS PERSPECTIVES

5. BOTULINUM TOXIN

DISCOVERY AND DEVELOPMENT

MECHANISM OF ACTION

AVAILABLE PRODUCTS AND FORMULATIONS

CLINICAL USE OF BOTULINUM TOXIN

6. SOFT TISSUE (DERMAL) FILLERS

HYALURONIC ACID

CALCIUM HYDROXYLAPATITE

POLY-L-LACTIC ACID

POLYMETHYLMETHACRYLATE MICROSPHERES

FILLER SELECTION

7. DEOXYCHOLIC ACID

8. INDIVIDUALIZED ASSESSMENT AND TREATMENT PLANNING

KEY ASSESSMENT ELEMENTS

ETHNIC CONSIDERATIONS

GENDER CONSIDERATIONS

AGE CONSIDERATIONS

9. THE MINIMALLY INVASIVE TREATMENT APPROACH

RECOMMENDED THERAPY COMBINATIONS

RECOMMENDED THERAPY SEQUENCE

PATIENT-TAILORED TREATMENT

THE TRI-VECTOR TECHNIQUE

THE UPPER FACE

THE MIDFACE

THE LOWER FACE AND NECK

THE NECK

10. PATIENT SELECTION AND EVALUATION

SCREENING AND SELECTION

PATIENT EVALUATION AND CONSENT

11. ADVERSE EFFECTS

PREVENTION AND RISK REDUCTION

COMMON ACUTE SIDE EFFECTS

INFREQUENT ACUTE ADVERSE EVENTS

VASCULAR COMPROMISE

ALLERGIC/HYPERSENSITIVITY REACTIONS

DELAYED COMPLICATIONS: INFLAMMATION OR INFECTION?

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

90200 • Botulinum Toxin and Dermal Fillers for Facial Aging

Education Category. Medical / Surgical

Release Date. 04/01/2021

Expiration Date. 03/31/2024

Course Overview

The importance for primary care clinicians to understand aesthetic medicine, patient variables, and market factors is brought to light by the increasing rates of aesthetic injections performed by non-board-certified physicians, nurses, and minimally trained aestheticians at inadequately equipped clinics, office settings, and spas. Primary care providers are well-placed to importantly inform their patients about many aspects related to aesthetic medicine but benefit from educational intervention to become most effective in this role.

Audience

This course is designed for physicians, nurses, and other healthcare professionals who may administer or care for patients who have undergone aesthetic procedures.

Course Objective

This course is designed to provide clinicians with the knowledge necessary to provide minimally invasive aesthetic procedures and to care for patients who have undergone these procedures.

Learning Objectives

Upon completion of this course, you should be able to:

1. Outline the background of aesthetic medicine and botulinum toxin/filler use.

2. Describe the process of usual facial aging.

3. Discuss the mechanism of action and clinical use of botulinum toxin for the treatment of facial aging.

4. Compare and contrast the classes of dermal filling agents available.

5. Analyze components that affect the appropriate selection of dermal filling agent.

6. Describe key aspects of individualized assessment of patients seeking aesthetic treatments for facial aging.

7. Outline the minimally invasive approach to the treatment of facial aging.

8. Evaluate patient-related factors affecting suitability for various aesthetic treatments.

9. Identify acute and potentially severe side effects of botulinum toxin/filler use.

10. Discuss the role of biofilm infections in delayed reactions to dermal fillers.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Visibly apparent aging and loss of youthful appearance are frequent concerns of patients seeking cosmetic treatment. Botulinum toxin and dermal (soft tissue) fillers are minimally invasive (i.e., injection-delivered) therapies that, along with knowledge advances, have revolutionized cosmetic treatment of aging features.

The clinical features of aging are the result of bone resorption; ligament laxity; redistribution, volume loss, and descent of facial soft tissue; and formation of lines and folds in inelastic, sagging skin. This complexity is not amenable to single-modality treatment; current practice combines botulinum toxin and fillers as the core approach, with other therapies added. Filling isolated lines or creases is de-emphasized.

In carefully selected patients with strict adherence to safety standards, desired results can be achieved with a low risk to safety. With increasing consumer demand, injector backgrounds and settings have expanded beyond oversight. Rises in catastrophic complications are largely unknown, as the "risk-free" perception of botulinum toxin and fillers continues. Clinicians and patients may be unaware of the range of U.S. Food and Drug Administration (FDA)-approved minimally invasive options, advances in the understanding and addressing facial aging with these therapies, and the potential of serious complications with incorrect use. These areas are the focus of this course.

Beyond the scope of this course are cosmetic surgery (e.g., rhinoplasty, face-lift), reconstructive or rehabilitative surgery, cosmetic concerns of systemic origin (e.g., lipoatrophy from antiretroviral therapy), and nonfacial cosmetic concerns. Laser, energy, and topical therapies are noninvasive interventions for sun-damaged, aged skin and acne scars, but they will not be the focus of this course. Cosmetic medicine is a point of convergence for diverse psychological, social, cultural, and racial factors, all of which should be considered for each patient. The properties of products discussed in this course are unique. This requires reference by commercial brand, but should not be construed as endorsement of any commercial product.

2. TERMINOLOGY

Plastic surgery includes subfields of reconstructive or rehabilitative surgery for congenital malformations or acquired disfigurements, and cosmetic surgery for correction, restoration, or enhancement of appearance [1]. "Aesthetic medicine" was coined to replace "cosmetic medicine/surgery," but the terms remain interchangeable [2].

The cosmetic medicine literature describes features with terms (e.g., defect, defective, deformity, deformation) that carry different meanings outside of this highly specialized professional audience. It is not the intent of this course to imply that normal aging of the face or skin is in any way a defect aside from the patient's perception or desires in terms of appearance. Beauty is a standard that varies by culture, time, age, and personal experiences, and there is no one standard for any facial feature or individual.

Therapeutic goals are variously described as volumizing, re-volumizing, rejuvenation, restoration, harmonization, resurfacing, correction, and others, with little consistency. This course will not attempt to modify terminology used in the published literature, except to improve logical consistency.

3. BACKGROUND

Until the 1990s, facial aging was attributed to gravitational effects that required surgical lifting and tightening to defy soft-tissue descent. Facial aging as a multi-tissue process of descent, volume loss, and resorption was first described in 1965 but remained obscure, and the focus on superficial tissue descent and correction persisted [3,4,5,6].

Botulinum toxin and dermal fillers were introduced to correct cosmetic defects without the need for surgery. Earlier use to spot-correct isolated wrinkles and creases led to temporary but limited benefits, with no advantage over surgical facelift for persons with moderate or advanced aging features [4,5,6,7].

Studies identified soft tissue volume loss and hard tissue resorption as causal to facial aging. This prompted filler injection into deep tissue for re-volumizing; new fillers designed for specific tissue placement; use of lower-dose botulinum toxin to improve outcomes; advances in lasers and energy devices for resurfacing or tightening with minimal recovery time; and evidence of synergistic efficacy and superior cosmetic outcomes with combined therapies [6,7,8]. These advances brought a paradigm shift from "wrinkle-chasing," with isolated clinical benefit, to recognition of facial aging as a complex interaction of extrinsic and intrinsic factors across multiple tissue planes requiring a three-dimensional, multilayered treatment approach [9,10]. Surgical facelift requires patients to wait until visible aging is sufficient to warrant surgery, often with sudden, sometimes unnatural, changes in appearance. Minimally invasive therapy offers a more gradual, natural-looking harmonization preferred by many patients [7].

Botulinum toxin and dermal filler injection techniques are constantly evolving; what was considered state-of-the-art 5 to 10 years ago no longer represents a practice standard [11]. Every year, the American Society of Plastic Surgeons (ASPS) and the American Society for Dermatologic Surgery (ASDS) separately publish the number of procedures performed by their board-certified members. In 2019, ASPS members performed 18.1 million cosmetic procedures—16.3 million nonsurgical (82% female)—at a total cost of $16.7 billion. Among patients who received cosmetic procedures, 70% were Caucasian, 11% were Hispanic, 9% were African American, 7% were Asian, and 3% were other [12]. The 7.7 million botulinum toxin and 2.7 million dermal filler procedures reported by ASPS in 2019 represent an increase of 878% and 312%, respectively, compared with 2000 [12]. ASDS members in 2019 performed an additional 2.3 million botulinum toxin (88% female) and 1.6 million filler (90% female) procedures, a 60% and 78% increase from 2012, respectively [13].

Between 2012 and 2017, there was a 50% increase in cosmetic procedure requests by persons younger than 30 years of age (90% female), and in 2016, more than 229,000 cosmetic procedures were performed in patients 18 years of age or younger [14,15]. The annual figures by ASPS/ASDS are considered the benchmark for cosmetic procedures, trends, and demand, but they significantly under-represent the actual number of minimally invasive procedures performed outside of their membership [16,17,18,19,20].

INCREASING CONCERNS

As cosmetic treatment methods have evolved, provider backgrounds expanded from specialists in plastic surgery (traditional) to dermatology, ophthalmology, and otolaryngology, then to dentists and registered nurses, followed by licensed aestheticians, unsanctioned medical personnel (e.g., medical assistants), and lay practitioners [17]. As such, the experience and qualifications of injectors is increasingly questionable and unpredictable. A large and growing proportion is performed in medical spas, spas, hair salons, other commercial settings, and at "Botox and filler parties" in private homes by non-healthcare professionals, sometimes without written informed consent [16,17].

There is an increasing number of filler complications from intravascular injection, an immediate, severe event that can result in blindness, tissue necrosis, or stroke, and from bacterial biofilm infection, when filler injection seeds skin-surface bacteria into tissue with the filler product [19]. Biofilm infections may become disfiguring, are often antibiotic-resistant, and are potentially a methicillin-resistant Staphylococcus aureus (MRSA) infection [21]. The increasingly unregulated state of botulinum toxin and filler injection practice, the absence of a universal adverse event reporting mechanism, and potentially powerful financial incentives to conceal complications have prompted calls for greater regulation of providers and practice and for relabeling of filler injections as "dermal implants" to accurately reflect the risks inherent in placing an inanimate object into human tissue [16,17,18,22,23].

The face ages in a unique but relatively consistent manner, creating a distinct but recognizable ''aged'' appearance. As people age, many are left with the feeling that their physical appearance is no longer an accurate representation of their mental state. Some opt to pursue cosmetic procedures for ''matching their outsides with their insides'' [24]. In skilled hands with diligent execution of precautions, the results attainable without surgery can be impressive, with a good safety margin. Improper patient selection, preparation, or technique invites problems ranging from patient dissatisfaction and poor cosmetic outcomes to increased risks of serious and potentially catastrophic complications of intravascular injection or delayed bacterial infections. The idea that botulinum toxin and fillers are risk-free cosmetic treatments is thoroughly dispelled.

4. THE PROCESSES OF FACIAL AGING

In the face, the process of aging that culminates in cosmetic concerns is complex. Changes of the facial skeleton, soft tissue, retaining ligaments, fat compartments, and the skin contribute to the features of facial aging in varying degrees, influenced by intrinsic (e.g., genetic) and extrinsic (e.g., sun exposure) factors [25]. To understand facial aging and appropriate interventions requires multidimensional knowledge of the normal anatomy and physiology of facial tissue layers, age-related changes in histology and morphology in each plane, and their multilevel interactions to form cosmetic features of aging.

Perceptual models used in cosmetic medicine can assist in conceptualizing these changes. Each model views facial aging from a different perspective. Presented in sequence, the models break down the complex, dynamic, multidimensional process into its dimensional components. The predominant models are [4,26,27,28,29,30,31,32]:

- The two-dimensional (2-D) model: Organizes the surface anatomy and superficial cosmetic defects into horizontal zones that anchor morphologic features to familiar anatomic boundaries

- The three-dimensional (3-D) model: Delineates facial anatomy into its underlying tissue layers to describe normal and age-related changes in structure/function at each facial tissue level

- The integrative model: "Zooms out" from the 3-D model to describe how tissue-level changes interact to form the visible features of facial aging

- The aesthetic zones/units model: Describes cosmetic defects of facial aging as changes in underlying and surrounding tissue within anatomically compartmentalized units

All four models will be used later in this course to describe the cosmetic features of facial aging and recommended minimally invasive interventions.

THE TWO-DIMENSIONAL MODEL

To describe the anatomic locations of common cosmetic concerns widely referenced in this course (Table 1), the face is divided into three horizontal zones with defined anatomic boundaries [4,30,31,32]:

- The upper face: Forehead, glabella (smooth area between eyebrows), periocular (lateral to the eyes) areas, and temples

- The midface: Between the glabella and tip of nose, lateral to the zygoma (cheekbone). The malar area is highly relevant, as the malar is the cheekbone prominence. The submalar is the bony area underneath the cheekbone.

- The lower face: The perioral area (lips), mandible, chin, and neck

Table 1: FACIAL AGING FEATURES

Zone

Cosmetic feature

Description

Upper face

Glabellar rhytides

Vertical lines between the eyebrows

Horizontal forehead rhytides

Horizontal creases on the forehead, exacerbated during brow elevation

Lateral canthal rhytides ("crow's feet")

Multiple periocular lines and wrinkles that radiate lateral to the eye, more prominent when smiling

Brow ptosis (drooping)

Tissue descent that can mimic angry or scowling expressions

Temporal fossa wasting

Concavity of the temple area

Midface

Nasojugal fold (tear trough depression)

Depression between the rim of the orbital bone and the nasal sidewall

"Bunny lines"

Wrinkles on the dorsal and lateral nose during contraction of the upper nasalis muscle

Nasolabial foldsa

Creases extending from the lateral nasal alae to the lateral mouth

Lower face

Perioral lip rhytides ("whistler's wrinkles")

Vertical wrinkles extending from the lip border

Mouth frown

A downward turn of the corners of the mouth

Melomental folds ("marionette lines")

Facial lines extending from the corners of the mouth to the mandible (jaw)

Mental crease

A horizontal groove present on the chin

Peau d'orange chin

Multiple dimples on the chin during contraction of the mentalis muscle

Masseteric hypertrophy

Square appearance to the jawline

Gingival (gummy) smile

Significant upper gum display during smilingb

Neckc

Platysmal bands

Vertical linear bands present on the anterior neck

Horizontal neck lines

Horizontal bands present on the upper neck

aSometimes assigned to the lower face.

bNot necessarily age-related.

cThe neck is usually included in the lower face for three horizontal zones.

Source: [10,33,34]

THE 3-D MODEL: NORMAL ANATOMY OF FACIAL TISSUE

The two-dimensional model is a good descriptive framework for cosmetic concerns but does not describe the aging processes of underlying facial tissue that inform their minimally invasive correction. This area is addressed by the three-dimensional model.

The Skin

The skin consists of the epidermis and dermis, mutually dependent layers that rest on the superficial fat layer [35].

Epidermis

The epidermis is the most superficial layer, composed of stratified squamous cells or keratinocytes (90%) and melanocytes (approximately 8%). The epidermis is directly exposed to the environment and its damaging effects. To replace damaged cells, new cells must constantly form and migrate to the surface over two to four weeks [35,36].

Melanocytes produce melanin, which gives pigment to the skin and absorbs ultraviolet (UV) light to prevent DNA damage. Absolute numbers of melanocytes are constant across races. The amount of melanin produced, size of melanosomes, and extent of aggregation account for differences in pigmentation. Epidermal melanocyte density declines with aging [35,36,37].

Dermis

The superficial papillary dermis (20% of the dermis) is loose connective tissue with capillaries, reticular fibers, and some collagen. Small projections (dermal papillae) into the epidermis maintain adhesion between the layers and nourish the epidermis [35,36].

The deeper reticular dermis is dense connective tissue, and the deepest level borders the superficial fat layer. Collagen makes up most of the dermis (75% is collagen type I), providing strength and structure to the skin. Elastin fibers, synthesized by fibroblasts and keratinocytes, give elasticity and resilience. Fibroblasts, the major cell type of the dermis, produce procollagen and elastin fibers [35].

Filling the spaces between collagen and elastin fibers is an extracellular matrix of glycosaminoglycans (hyaluronic acid), chondroitin sulfates, and glycoproteins (carbohydrates or amino sugars linked to a protein) [35,36,38].

The Superficial Fat Layer

The superficial fat layer, consisting of adipose tissue and collagen network, contributes to thermoregulation, shock absorption, wound healing, and immune function. The adipocytes can transform into myofibroblasts to influence local collagen synthesis [39]. Fibrous partitions separate the superficial fat into perioral (around the lips), nasolabial, cheek, and periorbital (around the eye sockets) compartments [40].

In the midface, the malar fat is composed of superficial fat compartments that lie above the superficial fascia. From medial to lateral, they are [25,41]:

- The nasolabial fat

- The superficial medial cheek, middle cheek, and lateral temporal cheek fat

- The inferior infraorbital fat, where under-eye "bags" appear, above the superficial medial cheek

Superficial Musculo-Aponeurotic System

The soft tissue is complex, because active movement over and around the orbital and oral cavities requires a muscle layer within soft tissues that connects with the overlying skin [42]. The superficial musculo-aponeurotic system is an organized fibrous network comprised of the platysma muscle, parotid fascia, and fibromuscular layer covering the cheek. The superficial musculo-aponeurotic system divides the deep and superficial fat, connects the facial muscles to the dermis in a moveable continuous plane, and functions to transmit, distribute, and amplify the activity of all facial muscles [43,44].

Muscles and Ligaments

Muscles of facial expression and muscles that facilitate chewing, smiling, speaking, and blinking alter the tension in adjacent skin, unlike other muscles that attach to bones or tendons. Muscles of facial expression significantly impact facial aesthetics, as repeated contraction can form dynamic rhytids and static lines [44,45,46,47].

The Deep Fat Layer

The deep fat layer is separated from superficial fat by the superficial musculo-aponeurotic system in the midface, platysma in the neck, and superficial temporal fascia in the temples, forming deep fat pads with fibrous ligament partitions [39,40]. Deep fat compartments in the midface are [25,41]:

- The deep cheek fat, which divides into medial (deep and medial to nasolabial fat) and lateral (deep to superficial medial cheek fat) parts. The deep medial cheek extends medially almost to the lateral incisor tooth.

- Medial portion of the buccal fat pad, just lateral to the deep lateral cheek

- The medial and lateral suborbicularis oculi fat, deep to the orbicularis oculi muscle of the lower eyelid

The Deep Fascia

The deep fascia layers are interconnected and secured to the facial skeleton in specific areas by a network of retaining ligaments, perpendicular to the layers and connect all layers to the deep fascia. The deep fascia provides the attachment for ligament origins and is formed by the periosteum on the facial skeleton and by deep muscle fascia where the skeleton is overlain by the masticatory structures [42].

The Facial Skeleton

The facial skeleton forms the scaffold on which soft tissues are draped and has a substantial effect on appearance. The primary bones of the facial skeleton by horizontal zone are [31,46,48]:

- Upper face: The frontal bone (forehead), bordered below by the glabella (smooth area between eyebrows) and frontonasal groove, and laterally by the supra-orbital (above-eye) ridges.

- Midface: Medial and middle thirds of the midface skeleton formed by the maxilla (houses roof of the mouth, extends upward to orbital floor). The lateral third is formed by the zygoma (cheekbone) body and arch.

- Lower face: The mandible (jaw bone) is the primary bone.

The 3-D Model: Age-Related Alteration

Age-related physiologic processes lead to morphologic changes of the facial skeleton, soft tissue, retaining ligaments, fat compartments, and skin. The three-dimensional alterations of facial aging require accurate evaluation to provide patients the optimal aesthetic strategy [25,30,42].

The Facial Skeleton

From prominent bone formation in youth, age-related changes in the relative dynamics of bone expansion and bone loss lead to predominant bone resorption in the aging craniofacial skeleton, an important contributor to facial aging [42,49]. Skeletal resorption and atrophy is uneven, and bone reduction is greatest in facial areas where prominent aging stigmata appear [4,25,31,42,50]. The maxilla has the greatest resorption; substantial reduction in its anterior projection largely contributes to aged appearance. The periorbital bones and anterior and inferior mandible (prejowl area) resorb extensively; the chin becomes shorter. The posterior and superior mandible undergo bone formation, increasing the mandible angle from 97º in younger skulls to 135º in older skulls. Maxilla and mandible resorption appreciably reduces the facial height. The midface recedes, but the forehead continuously expands.

Local changes in soft tissue and mechanical needs can also induce bone remodeling [50]. Mechano-transduction transforms mechanical energy into electro-chemical signaling to tissues or cells. Through this process, chronic facial muscle tension or overuse contributes to skeletal changes by impacting molecular signaling pathways, which alters bone remodeling patterns [51].

Reduction of anterior projection in the aging facial skeleton occurs immediately beneath the periosteum attached to the bone surface. The periosteum recedes with the bone; ligament origins recede with the periosteum [42].

Facial Fat

Superficial and deep facial fat is highly compartmentalized. Aging significantly alters the volume, structure, and position of facial fat compartments. Typically, deep fat atrophies and superficial fat may be unchanged or hypertrophy. Assessment of the fat depletion pattern is crucial for volumetric restoration. With attention to ligament involvement, the pattern is fairly predictable [8,25,30,41,42,50,53]. It occurs first in the periorbital and malar fat. The most extensive loss of deep fat occurs in the lateral and medial orbital fat and medial cheek fat. Likewise, the most extensive loss of superficial fat occurs with lateral temporal and preauricular fat.

Ligaments

Ligaments confine the fat areas; retaining ligaments anchor and stabilize the skin and facial fascia. With aging, medial ligaments of the center face keep their strength with strong fixation points, but lateral ligaments weaken and lose ability to prevent movement of fat compartments (though they may retain the borders). With loss of lateral fat volume and ligament support, the malar fat moves inferomedially and the superficial nasolabial and superior/inferior jowl fat move medially.

Superficial Musculo-Aponeurotic System and Muscles

The ligaments also transmit the effect of skeleton resorption by strongly connecting the skeleton with the superficial musculo-aponeurotic system. Glabella and masseter muscles can become hypo- or hypertonic. Chronic muscle use in facial expressions can aggravate some features of aging. Atrophy is prominent in masticatory muscles.

Epidermis and Dermis

Aging substantially alters the skin. Dermal collagen content declines by roughly 1% every year starting at around 40 years of age in women and 50 years of age in men. The remaining collagen fibers become disorganized, compact, and fragmented. Elastic fibers decrease in number and diameter. Epidermal thinning, collagen loss, and dermal elastosis contribute to fine rhytids of the aging face. Loss of muscle tone, skin elasticity, and thickness leads to sagging [41,49].

These dermal changes trigger a cascade of secondary events that greatly influence surrounding tissues. Wrinkles and furrows, a main focus of patients seeking cosmetic treatment for aging, develop from a slow, progressive alteration of all facial structures [49]. UV radiation from sun exposure substantially contributes to skin changes in aging.

THE INTEGRATIVE AND AESTHETIC UNITS PERSPECTIVES

The two- and three-dimensional models describe age-related changes within facial tissue layers. However, the integrative and aesthetic units models describe how these changes interact and combine into the cosmetic features of facial aging [4,25,30,41,42,52].

As noted, bone resorption is extensive in orbital and periorbital, malar, submalar, and mandibular areas. Soft tissue loss occurs in periorbital, forehead, glabellar, temporal, malar, perioral, mandibular, and mental areas. Retaining ligaments of fat compartments weaken; facial fat and soft tissue descent forms malar bags, folds, and sagging in nasolabial, jowl, and submental areas.

Increased orbit size and posterior maxillary resorption promote inferior displacement of the malar fat, accentuation of nasolabial folds, a blunted midface, and loss of support for periorbital tissues that contributes to perioral lines. Infraorbital volume loss exposes the inferior border of the orbicularis oculi muscle that helps form a malar crescent over the zygomatic eminence (lateral) and the nasojugal fold (medial); formerly concealed infraorbital fat pads ("palpebral bags") emerge.

Periorbital and perioral skin wrinkling from repeated muscle action progress from dynamic rhytids to static rhytids as the skin changes become permanent. Volume loss, distributional changes, and sagging disrupt the defining arcs and convexities of youth and contribute to the distinct morphology of the aging face.

Youthful Appearance and Aging

Loss of youthful features and development of aging features are frequent cosmetic concerns of patients. Expert plastic surgeons and cosmetic dermatologists are broadly uniform in characterizing youthful features and age-related changes. The following section specifically describes female features; male features will discussed later in the course [4,29,32,49,54,55,56,57,58].

The youthful face has a diffuse, balanced distribution of superficial and deep fat, conferring a smooth, three-dimensional topography delineated by a series of arcs and convexities, without clear distinction between temple, eyelid, and malar areas. On frontal view, the primary arc of the jawline, convexities of the temples, and multiple smaller secondary arcs of the lips are evident. In profile, the definitive features of youth are the lateral cheek projection, extending as an unbroken convex line from the lower eyelid to the cheek (the "ogee" curve).

Youthful features converge on the malar area. Prominent malar eminences are a hallmark of beauty in many cultures, and malar area convexity (roundness) is a defining feature of a youthful face. With aging, the malar fat position over the zygoma and orbital rim diminishes and descends. Ptotic cheek fat, and descent of malar soft tissue, produces sunken cheeks and shadows, leaving behind a cheek concavity accentuated by depletion of malar fullness.

From the front, the jawline appears scalloped; the temporal, buccal, and suborbital areas hollow; and the lips straight and angular. In profile, the primary arc of the cheek is broken, the mandibular arc replaced by a jowl line, and the forehead and brow lose their anterior projection.

Youthful features and age-related changes have agreement, but the extent of cosmetic correction is debated. A multinational panel of cosmetic medicine experts recommended an age-appropriate approach as the criterion standard, with a conservative approach preferable [52].

The Facial Aesthetic Units Perspective

The aesthetic units perspective informs how some visibly apparent aging features develop and directs cosmetic intervention. The surface and subsurface structural changes in skin thickness, composition of subcutaneous tissue, contour of the facial skeleton, and location and integrity of retaining ligaments contribute to variability of bony landmarks, formation of lines and wrinkles, variable skin pigmentation, and overall discontinuity of the facial region, termed "facial aesthetic units" [28].

In younger persons, facial aesthetic units flow together, appearing as a smoothly contoured, single dynamic structure without perceptible division. With aging, the redistribution of facial fat, loss of tissue volume, and retention of ligament borders induce a demarcation of the underlying facial structures. The compartmentalized aesthetic units become distinct as changes within and between distinct aesthetic units collectively contribute to an overall aged facial appearance [4,28].

A strong correlation was found between observer judgment of age and visually obvious separation of facial aesthetic units, suggesting it may serve as a psychophysical cue fundamental to perception of facial aging. This finding also aligns with current practice. Facial rejuvenation can include creation of more homogeneous skin tones, texture, and facial symmetry, and smooth contours between anatomical regions by blending the transition of facial aesthetic units for a harmonious and youthful facial appearance [28].

5. BOTULINUM TOXIN

DISCOVERY AND DEVELOPMENT

Botulinum toxin is derived from neurotoxins produced by Clostridium botulinum, the gram-positive bacillus that causes botulism. Subsequent to the 1897 discovery of C. botulinum as etiologic agent of botulism, seven botulinum toxin serotypes (A, B, C1, D, E, F, and G) with differing pharmacologic properties have been identified. Only serotypes A and B are used clinically, with type A (botulinum toxin-A) the most widely used for both medical and aesthetic indications [59].

During the late 1960s and early 1970s, the clinical value of botulinum toxin became evident in the treatment of strabismus. This was followed by demonstrated benefit in blepharospasm, hemifacial spasm, cervical dystonia, and other disorders of muscle hyperactivity and spasticity. From the first report of botulinum toxin-A injection for a cosmetic indication (glabellar frown lines) in 1992, its use has expanded to become the most requested procedure in aesthetic medicine. One commercial brand of botulinum toxin-A, Botox, has become popularized as the generic reference for all cosmetic botulinum toxin [60,61].

Botulinum toxin-A is the primary form used for cosmetic treatment. While less extensively studied for cosmetic indications, botulinum toxin-B also appears to be effective [59].

MECHANISM OF ACTION

Botulinum toxins block the release of acetylcholine from motor neurons at the neuromuscular junction. By inhibiting acetylcholine neurotransmission between peripheral nerve endings and muscle fibers, botulinum toxin weakens or paralyzes skeletal muscle and, in aesthetic medicine, weakens muscular contraction [10].

Botulinum toxin blocks presynaptic acetylcholine release, causing reduced or diminished muscle contraction. This results in temporary improvement in the appearance of the areas affected by lines and wrinkles, for facial contouring and improving the skin [62]. The inhibitory effect is temporary; recovery of muscular function is often evident by three months, but the cosmetic effect may persist longer [10,33].

AVAILABLE PRODUCTS AND FORMULATIONS

Four botulinum toxin formulations are approved by the FDA for aesthetic use (Table 2). The FDA recommends using specific names (e.g., ONA or ABO, Botox or Dysport), instead of serotypes (e.g., botulinum toxin-A), to prevent confusion between products [59]. Discussion in this course is limited to the four serotype A botulinum toxin products approved for cosmetic use; the off-label use of RIMA will not be explored. Unless a specific product is described, botulinum toxin is used to broadly reference the use of FDA-approved botulinum toxin-A formulations.

Table 2: BOTULINUM TOXIN PRODUCTS AND FORMULATIONS

Name, Serotype

Commercial Product

FDA-Approved Indications

Comments

ONA type-A

Botox

Botox Cosmetic

Vistabel

Vistabex

Vacuum-dried powder (50 or 100 U/vial)

Glabellar, lateral canthal, and forehead lines

The original, most-studied formulation. Widely used off-label for treating other lines and facial contouring.

ABO type-A

Dysport (300 or 500 U/vial)

Glabellar lines

First marketed in Europe

INCO type-A

Bocouture or Xeomin (as lyophilized powder in 50 or 100 U)

Glabellar lines

Newer formulation. Free of complexing proteins. May reduce risks of sensitization and antibody formation.

PRA type-A

Jeuveau (4 U [0.1 mL] IM in each of five sites)

Glabellar lines

Newer formulation. Similar in efficacy to ONA.

RIMA type-B

Myobloc, in liquid (5,000 U/mL)

No cosmetic indications

Less studied than type-A. Used in off-label facial lines. Distributed in the United States and Canada.

ABO = abobotulinumtoxinA, INCO = incobotulinumtoxinA, ONA = onabotulinumtoxinA, PRA = prabotulinumtoxinA, RIMA = rimabotulinumtoxinB, U = units.

Source: [59]

ONA, ABO, PRA, and INCO must be reconstituted before using, with sterile, non-preserved saline recommended by their respective makers. In practice, many clinicians reconstitute these products in saline containing benzyl alcohol to reduce injection-site pain [63]. Compelling evidence now suggests that reconstitution using preserved saline dramatically improves patient comfort without compromising efficacy [18].

The formulations (i.e., ONA, INCO, PRA, and ABO) are not interchangeable. The products differ in units, chemical properties, biologic activities, weight, and manufacturing process. Production process and conditions such as pH, temperature, formulation, and concentration are crucial; alterations in any can increase the likelihood of formation of inactivated toxoid proteins, which in turn may be immunogenic [62].

Dose conversions are not standardized. Dosing is not interchangeable, and the products and procedures should be selected and prescribed according to individual needs and aims of treatment [62].

CLINICAL USE OF BOTULINUM TOXIN

With aging, decreased skin elasticity and repeated muscle contraction cause hyper-functional facial lines, particularly in the glabellar and periorbital regions. Depressor muscles overpower the levators to result in ptosis of the brow and mid-cheek groove, and patients develop horizontal forehead rhytides, glabellar frown lines, or lateral canthal "crow's feet," indications for botulinum toxin use [64].

Botulinum toxin is also extensively used off-label for brow shaping, eyebrow lifting, opening the aperture of the eye, decreasing mouth frown, defining the jaw line, increasing lip show, decreasing gummy smile, reducing "bar-code" lines around the mouth, eliminating "golf ball" chin, reducing platysma bands, and softening a squared, masculine jaw [65].

Patients treated with botulinum toxin for aesthetic purposes can expect their results to last at least three months, but effects can persist four to five months depending on the area treated, dose, and formulation used. The results may last longer for some patients, especially after repeated treatment [62].

Long-term outcome data support practice trends in decreased dosing and increased botulinum toxin injection intervals. Patients treated for glabellar lines over an average of nine years reported high levels of satisfaction sustained by repeated treatment and greater reductions in their perceived age with increasingly longer treatment durations [6].

While botulinum toxin monotherapy of dynamic rhytides is effective, current practice favors botulinum toxin combined with fillers, lasers, and/or light- or energy-based devices for synergistic effects and superior and more durable improvements [10,33,59].

Dilution of FDA-approved botulinum toxin for off-label intradermal injection is used for reducing surface wrinkling by weakening superficial facial muscle activity but sparing deeper muscle function. This approach is also used for reducing upper face rhytides without affecting brow muscles [64,66].

Safe and effective use of botulinum toxin requires the understanding of anatomy, movement of muscles in isolation and in relation to other muscles, the concept of compensatory strengthening, and observant evaluation of the patient at rest (static) and with normal and exaggerated animation (dynamic). Every patient is unique, and inter-patient differences can be vast [65].

Patient Selection

To help determine botulinum toxin suitability, assess facial muscle function and tone in static and dynamic states looking for signs of stronger contraction (e.g., greater dynamic movement, deeper lines, larger apparent mass during use) [67]. Observing dynamic movement of the skin can help identify areas of stronger or weaker muscle contraction, why certain wrinkles are formed, and which muscles are creating them. The findings assign patients to one of the following categories [67]:

- Kinetic: Regular muscle contraction and wrinkles during active expression, but not at rest. Botulinum toxin very likely effective.

- Hyperkinetic: More excessive muscle contraction. May require more frequent, higher-dose botulinum toxin to achieve the desired effect.

- Hypertonic: Inability to relax specific muscles, visible wrinkles at rest. Some benefits may be possible with botulinum toxin, but adding filler injections may be necessary.

- Deep static lines with loss of skin elasticity: Unsuitable for botulinum toxin injection.

Side Effects and Safety

Compared with dermal fillers, prevention of botulinum toxin adverse effects is more straight-forward [18,33,59,62]. Common acute side effects include transient swelling, bruising, and headache. Ice or cooling is commonly used for post-injection comfort and to prevent bruising. Temperature seems to influence botulinum toxin uptake, suggesting that cooling the area might undermine efficacy.

Poor treatment response can result from insufficient or incorrect dosing, anatomical variation, or errors in drug handling during preparation, storage, or administration. Diffusion of toxin to untargeted areas from improper injection placement can result in excessive muscle weakness, cosmetic disfigurement, and/or functional deficits that persist for months.

Contraindications

Evidence Based Practice Recommendation

The Australasian College of Dermatologists strongly recommends that botulinum toxin-A treatment be avoided during pregnancy and breastfeeding owing to the lack of adequate data on the developmental risk to a human fetus from the use of these agents in pregnant women and evidence of reproductive toxicity in animal studies.

https://onlinelibrary.wiley.com/doi/full/10.1111/ajd.13273

Last Accessed: March 26, 2021

Level of Evidence: Expert Opinion/Consensus Statement

Injection-site infection, known hypersensitivity to any product component, and allergy to cow milk proteins for ABO only are all contraindications to botulinum toxin treatment [59]. Perioral botulinum toxin injections in professional speaker, vocalist, or musician patients require discussion of the potential functional impact from weakened or impaired muscle tone, a possible contraindication.

6. SOFT TISSUE (DERMAL) FILLERS

A variety of injectable soft tissue (dermal) filling agents are available for correction of prominent skin lines, fat atrophy, volume lost, and other contour changes of facial soft tissue (Table 3) [68]. Fillers are classed on different variables that inform appropriate selection and potential complications: biodegradability, longevity in the tissue, and histologic reaction [69,70,71].

Table 3: FDA-APPROVED DERMAL FILLERS AND CLINICAL USE

Product, Year Approved

Approved Indications

Hyaluronic acid: Galderma Labs

Restylanea, 2003

Correction of moderate-to-severe facial rhytides and/or folds

Lip augmentation

Restylane-L, 2012

Restylane Silk, 2014

Lip augmentation

Correction of perioral rhytides

Restylane Lyft, 2015

Correction of moderate-to-severe deep facial rhytides and folds

Restylane Defyne, 2016

Correction of moderate-to-severe facial rhytides and folds with age-related volume loss

Restylane Refyne, 2016

Correction of moderate-to-severe facial rhytides and folds

Hyaluronic acid: Allergan

Juvéderm XC, 2006

Correction of moderate-to-severe facial rhytides and folds

Juvéderm Ultra XC, 2006

Juvéderm Ultra Plus XC, 2006

Juvéderm Ultra Plus XC, 2015

Lip augmentation

Correction of perioral rhytides

Juvéderm Voluma XC, 2013

Correction of age-related volume deficit in the midface

Cheek augmentation

Juvéderm Volbella XC, 2016

Lip augmentation

Correction of perioral rhytides

Juvéderm Vollure XC, 2017

Injection into the mid-to-deep dermis for correction of moderate-to-severe facial wrinkles and folds (e.g., nasolabial folds)

Hyaluronic acid: Merz Aesthetics

Belotero Balance, 2011

Correction of facial rhytides and folds, especially around the nose and mouth

Hyaluronic acid: Teoxane S.A.

RHA 2 and RHA 3, 2017

Injection into the mid-to-deep dermis for correction of moderate-to-severe dynamic facial wrinkles and folds (e.g., nasolabial folds)

RHA 4, 2017

Injection in deep dermis to superficial subcutaneous tissue for correction of moderate-to-severe dynamic facial wrinkles and folds (e.g., nasolabial folds)

Hyaluronic acid: Prollenium Medical Technologies, Inc.

Revanesse Versa, 2018

Injection in mid to deep dermis for correction of moderate-to-severe facial wrinkles and folds (e.g., nasolabial folds)

Calcium hydroxylapatite (CaHA): Merz Aesthetics

Radiessea, 2006

Correction of moderate-to-severe facial rhytides and folds

Radiesse(+), 2015

Poly-L-lactic acid (PLLA): Galderma Labs

Sculptra Aesthetic, 2009

Correction of shallow-to-deep nasolabial fold contour deficiencies and other facial rhytides

Polymethylmethacrylate (PMMA): Suneva Medical

Bellafill, 2006

Correction of volume deficits around the mouth (e.g., nasolabial folds)

Bellafill, 2015

Correction of acne scars

aDoes not contain lidocaine.

Source: [72,73]

The FDA designates fillers as either absorbable/temporary (e.g., hyaluronic acid, calcium hydroxyapatite [CaHA], poly-L-lactic acid [PLLA]) or non-absorbable/permanent (e.g., polymethylmethacrylate [PMMA]) based on the agent's biodegradability. If an agent absorbs within 18 months, it is considered temporary; if it does not absorb within 24 months, it is considered permanent. Some agents combine absorbable material for immediate effect and carrier until a nonabsorbable material induces fibroblast stimulatory effects (in more than 18 months). These agents are considered semipermanent. Agents with minimal tissue response are considered volumizers, while those that induce a strong tissue reaction are considered stimulators.

Temporary fillers use FDA-approved biodegradable materials absorbed by the body over time. Permanent fillers persist indefinitely in tissue. Some FDA-approved fillers, such as collagen-based products or avian-derived hyaluronic acid (Hylaform), remain available but are largely replaced by hyaluronic acid fillers with superior clinical properties and/or negligible allergenic potential [68,73,74].

Most acute side effects and potential serious adverse effects of FDA-approved dermal fillers are common across fillers. All filler agents are contraindicated in patients with known hypersensitivity to any product component specific to the product. There are a variety of other contraindications to the use of various dermal fillers (Table 4).

Table 4: CONTRAINDICATIONS TO DERMAL FILLERS

Contraindication

Specific Conditions

Relative and absolute contraindications

Allergic history

Multiple severe allergies

Anaphylaxis

Heightened immune responses to common inhaled and food allergens (atopy)

Allergy to latex, hyaluronic acid products, streptococcal/other gram-positive bacterial proteins, or lidocaine

Desensitization therapy during filler treatment

Scar-related

History of hypertrophic scarring or keloid formation

Scars at intended treatment site

Bleeding-related

Current anticoagulant or antiplatelet therapy

History of bleeding, clotting (hemophilia), or connective tissue disorders

Active autoimmune disease

Systemic lupus erythematosus

Rheumatoid arthritis

Hashimoto thyroiditis

Patient-related factors

Unattainable expectations

Pregnancy

Lactation

Contraindications unless fully resolved with treatment

Inflammatory skin diseases

Atopic dermatitis

Seborrheic dermatitis

Acne

Rosacea

Psoriasis

Skin infection or any unhealed facial wound

Impetigo

Folliculitis

Propionibacterium acnes

Viral warts

Perioral HPV

Molluscum contagiosa

Streptococci or staphylococci bacterial infections

Candida (yeast) infections

Local infection

ENT, oral cavity, or dental infections or abscess

Remote infection

Intestinal tract, urinary tract, or bladder infection

Inflammatory processes

Pimples

Hives

Rashes

Cysts

ENT = ear, nose, or throat, HPV = human papillomavirus.

Source: [19,75]

With all fillers, treatment should undercorrect the defect and avoid overcorrection. All treatment sites should be massaged immediately after injection to facilitate an even distribution.

HYALURONIC ACID

Hyaluronic acid is a glycosaminoglycan disaccharide and natural constituent of the dermal extracellular matrix, cartilage, and connective tissue. Hyaluronic acid is highly hydrophilic, enabling dermal hyaluronic acid to hydrate and cushion the skin and fill empty spaces within the extracellular matrix. Dermal hyaluronic acid content declines with skin aging, which reduces water-binding capacity and elasticity, induces volume loss, and promotes the development of rhytids and other aging features [72,73,76,77].

Unmodified hyaluronic acid readily dissolves in water to form a viscous gel, but injected into the dermis, it is quickly degraded by hyaluronidase and free radicals in the skin [76]. Most FDA-approved hyaluronic acid fillers use nonanimal stabilized hyaluronic acid synthesized from Streptococcus equi bacteria. Liquid nonanimal stabilized hyaluronic acid, as with native hyaluronic acid, is rapidly broken down [72,77]. To increase stability and longevity, manufacturers use crosslinking agents to bind hyaluronic acid polymer chains to each other, resulting in a gel that resists enzymatic and free radical breakdown. Most fillers use 1,4-butanediol diglycidyl ether (BDDE) as a cross-linker [76,77]. The hyaluronic acid modification process, proprietary to each maker, allows a portfolio of hyaluronic acid filler consistencies with varied rheologic properties (e.g., viscosity, gel hardness, lifting ability, tissue integration) that determine optimal tissue placement depth and product longevity [19,78,79].

Hyaluronic acid can bind 1,000 times its volume in water. This water-binding and space-filling effect underlies the volumizing efficacy of hyaluronic acid fillers [76]. Efficacy has been observed to persist beyond a time frame explained by space-filling effects alone. This led to research of other mechanisms, which identified induction of adipogenesis, neocollagenesis through mechanical tension on fibroblasts, and periosteal stem cell activation followed by new tissue formation with periosteal filler placement [52,80,81].

Hyaluronic acid fillers combined with botulinum toxin act synergistically to produce superior, more durable effects than either monotherapy. For example, the longevity of effects is improved when treating sites of dynamic wrinkles, such as glabellar lines. Reduced filler deformation due to botulinum-toxin induced local muscle relaxation at least partially accounts for this effect [68].

CALCIUM HYDROXYLAPATITE

Calcium hydroxylapatite (CaHA) is a mineral commonly found in human teeth and bones that functions as a scaffold for collagen ingrowth. CaHA filler contains CaHA microspheres as biodegradable particles suspended in an aqueous carboxymethylcellulose gel carrier. Once injected, the carrier gel gradually resorbs; the microspheres stimulate a fibroblastic response resulting in active physiologic remodeling of the extracellular matrix and long-term collagen deposition around the implant that promotes volumizing. The microspheres eventually degrade into calcium and phosphate ions and are excreted. The effects last around 18 months [10,73,79].

Radiesse (formerly Radiance) is the only FDA-approved CaHA filler, indicated for correcting moderate-to-severe soft-tissue defects, facial folds, and wrinkles, including nasolabial folds [72]. The viscoelastic filler is well suited for supraperiosteal and deep fat placement. When injected more superficially, it should be diluted 1:1 or 1:2 [10,68]. Radiesse(+), formulated with 0.3% lidocaine, was approved in 2015 to reduce pain without needing to premix before injection [82].

Radiesse is contraindicated in patients with a history of anaphylaxis or multiple severe allergies [68]. Radiesse injection of the lips risks forming nodules and should be avoided. Radiesse is visible on x-ray and may obscure underlying features [73].

POLY-L-LACTIC ACID

Poly-L-lactic acid (PLLA) is a biodegradable, biocompatible, synthetic polymer used for decades in resorbable sutures, orthopedic plates, and urologic stents. First approved in 1999 as a dermal filler in Europe, PLLA received FDA approval in 2004 for the treatment of HIV-associated lipoatrophy (Sculptra) and in 2009 for aesthetic treatment in immunocompetent patients (Sculptra Aesthetic) [49,72,73].

PLLA induces a subclinical inflammatory response that stimulates fibroblast proliferation, neocollagenesis, and type I collagen formation, leading to a progressive increase in dermal volume [68,72]. Each PLLA injection produces a gradual treatment effect with limited correction. Three injection sessions at six-week intervals are generally required, but improvements after the final injection can last up to two years. Patients should be counseled that final results can take months to achieve [83,84].

Treatment should aim to undercorrect, because the results progressively improve over time. Injections should be spaced at least three weeks apart because transient post-injection edema can mimic a full correction [68].

Injections should be placed into the deep dermis or subcutaneous fat. The lip and periorbital region should be avoided due to risk for nodule formation. Subcutaneous papules are a common adverse effect [68].

POLYMETHYLMETHACRYLATE MICROSPHERES

Polymethylmethacrylate (PMMA) is a non-biodegradable, biocompatible, synthetic polymer used in medical devices such as bone cement and intraocular lenses. As a soft tissue filler, PMMA microspheres are tiny, round, smooth particles suspended in a gel-like solution containing lidocaine and bovine collagen [73].

The collagen gel gives an initial volume but is resorbed over one to three months. The microspheres stimulate a local inflammatory reaction, followed by deposition of granulation tissue that encapsulate the microspheres and mature into connective tissue. By three months post-injection, the microspheres are surrounded by newly formed collagen, accounting for the observed volume-filling effect [74,79,84]. Tissue encapsulation of PMMA microspheres makes the results irreversible.

The PMMA filler Bellafill is the only FDA-approved permanent filler. Treatment of nasolabial folds and facial acne scars are the only approved cosmetic indications, but Bellafill is used off-label to volumize other mid- and lower-face contour defects [74,85].

The bovine collagen carries potential immunogenic issues. Clearance for Bellafill injection requires non-reactive response to skin-testing for bovine collagen hypersensitivity one month pre-procedure [74,79].

Good PMMA candidates are patients with well-defined lines and furrows and minimal excess skin [74,85]. PMMA use is not recommended in areas of thin skin (e.g., lower eyelid, neck), the lips, and in patients with generally thin, loose skin [74].

Bellafill is intended for deep tissue placement. A series of conservative injections can be required for optimal results, with touch-up injections performed one to three months after initial treatment [74]. Optimal results require 3 to 12 months for sufficient new collagen synthesis, and additional improvement beyond 12 months may occur [86].

FILLER SELECTION

Hyaluronic Acid Fillers

Unlike CaHA (Radiesse), PLLA (Sculptra), and PMMA (Bellafill) fillers, availability of numerous hyaluronic acid products requires judicious product selection based on rheologic properties. Each facial area and anatomic plane subjects filler to biomechanical stressors of compression, stretching, and lateral shearing from skin tension, muscle activity, and fat volume of varying intensity and frequency [78,87].

Rheology studies the flow and deformation of filler material subjected to biomechanical stressors to understand their clinical properties and behavior. Manufacturers crosslink and modify hyaluronic acid products (e.g., Hylacross, Vycross) using methods that determine gel rheology. The rheologic properties leverage the distinct tissue distribution patterns and clinical behaviors of hyaluronic acid products [76,77].

The clinical behavior of Radiesse is influenced by the same rheologic factors as hyaluronic acid fillers. Rheologic properties are unique to each hyaluronic acid and CaHA product, between filler families. The major rheologic properties are [9,29,52,76,78,88,89,90]:

- Shearing: Force pushing one part of a body in one direction and another part in the opposite direction

- Elasticity: Ability to resist deformation by external forces

- Viscosity: Ability to resist shearing forces

- Cohesivity: Ability to resist vertical compression and stretching

- Hydrophilicity (water-binding ability): Capacity to attract water and expand

- Particle size: Contributes to overall lifting and filling power

- Particle concentration and crosslinking: Influences durability by resisting enzymatic degradation.

Clinically, the elasticity of filler reflects the gel's firmness. The level of viscosity will determine the pattern and extent of tissue integration. High-viscosity agents resist tissue spread and shearing. Low-viscosity agents are ideal for superficial placement to treat shallow folds and lines and are best used where spread and softness is more important than volume (e.g., the lips) [52,76,77,78]. Conversely, high-elasticity and high-viscosity gels are best suited for deep placement to treat deep folds and restore volume loss by creating volume and lift in the mid- and lower face.

Cohesivity is spreading related to tissue depth and ability to hold form or shape under stress by overlying/underlying muscle and skin compression. Cohesivity increases with degree of cross-linking and hyaluronic acid concentration. Low-cohesivity gels are easier to mold and spread evenly in the skin, making them suited for correcting small rhytides. High-cohesivity gels are suited for revolumizing large areas of volume loss.

Restylane Lyft is an example of a high-elasticity, large-particle gel with greater filling power and resistance to degradation in deep-tissue volumizing. Juvéderm products use elasticity from highest to lowest in gels intended for deep (Voluma), midlevel (Vollure), and superficial (Volbella) tissue placement.

Calcium Hydroxylapatite

With a high lift capacity and results that last more than one year, Radiesse works well to fill volume loss in the midface and is placed in a manner similar to injection of hyaluronic acid products [84]. The use of Radiesse for melomental folds ("marionette lines") has been reported extensively, with effective and durable results [58].

Of note, Radiesse may be more likely than other fillers to result in intra-arterial complications, skin necrosis, and blindness. The increased propensity to cause vascular compromise could be related to particle size, with larger particles resulting in more proximal vessel obstruction. Certain particles may also stimulate the clotting cascade, ultimately resulting in skin necrosis [16]. This seems to elevate precautions in using this product near vascular danger zones.

Poly-L-Lactic Acid (Sculptra)

PLLA volumizes soft tissue in a gradual, progressive, and predictable manner, providing natural-looking restoration of facial volume [91]. Although it is categorized as biodegradable by the FDA, the duration of action is 12 to 24 months and, with repeat treatment, several years. As noted, PLLA is more accurately classed as a semipermanent dermal filler [84,92].

PLLA should be avoided in perioral and periocular areas; in the neck where thin skin requires superficial injection; and in mandibular ligament/platysma muscles [49,58]. Superficial injection in the dermis is also inappropriate. PLAA injection is recommended for the supraperiosteal in the temples, lateral brow, zygomatic area, maxillary area, mandibular area, and mental area [93]. It may also be used in the subcutaneous fat in the mid-cheek regions and preauricular area. More specifically, recommended PLLA injection sites are [49,58,93]:

- Temporal fossa: Supraperiosteal at the temporal muscle origin

- Lateral brow: Supraperiosteal at the tail of the brow

- Medial malar region: Supraperiosteal on the zygomatic bone, maxilla, and pyriform fossa

- Submalar/mid-cheek: Deep subcutaneous plane where bony background is absent

- Lateral third of the mandible/mandibular angle and lower lateral cheek: Superficial subcutaneous fat above the parotid gland and masseter muscle

- Mandible/chin: Supraperiosteal over the menton and prejowl sulcus

Sculptra may provide global volume restoration in lean patients who are too depleted for space-occupying fillers, an alternative to deep volumizing hyaluronic acid fillers that could be too expensive and difficult to use as scaffolding [94].

Polymethylmethacrylate (Bellafill)

Used as a deep tissue filler for mid- and lower-face volume loss, Bellafill seems comparable to other filler types in efficacy [84]. This shifts the basis for Bellafill selection to patient preference and appropriateness [34,74].

Persistent effects, possibly with a single treatment (or with minor touch-ups), can make Bellafill attractive, but treatment with permanent fillers requires careful screening. Patients who have histories of unsubstantiated dissatisfaction with cosmetic results, are unsure of their desired outcome, or are new to fillers are poor candidates for Bellafill [34,74].

Other Considerations in Filler Selection

Clinician experience influences the choice of filler. Improper use can result in an unacceptably high risk for adverse effects, and clinicians not trained in using specific fillers should refrain from their use [34,74]. Complications or unfavorable cosmetic results with permanent fillers may require surgical intervention and may be impossible to completely reverse.

The desired duration of effect should be considered. Fillers that eventually degrade in tissue (e.g., hyaluronic acid) offer the advantage of reversibility but require multiple subsequent treatments to maintain the desired effect. Adverse effects of products may not become apparent until post-market, making it prudent to select products with an established safety/adverse event profile from clinical use [95].

7. DEOXYCHOLIC ACID

Deoxycholic acid (Kybella) is FDA-approved for treatment of moderate-to-severe submental fullness/convexity ("double chin"). Injection into the subcutaneous fat below the chin area causes focal adipolysis and necrosis. This induces macrophages to clear cell membrane fragments, recruit fibroblasts, and stimulate neocollagenesis. Once destroyed, adipocytes cannot store or accumulate fat. Submental appearance is improved through subcutaneous fat reduction and tissue tightening [96,97].

Kybella is an alternative to liposuction for achieving an aesthetically pleasing jawline by submental fat reduction, but comparisons in clinical trials are lacking. Kybella is given in 0.2-mL injections, spaced 1 cm apart, until all sites in the planned treatment area are injected. Up to 50 injections, or 10 mL, are allowed per session. Several sessions spaced at least four weeks apart are usually required. In phase 3 clinical trials, the drug was effective and safe, although a significant number of patients experienced pain, transient bruising, edema, and numbness [98,99].

In the phase 3 trials, patients were injected with a mean 186 mg of drug as treatment. Cosmetic surgeons reported charging a mean $691 per 20-mg vial of deoxycholic acid, which would have cost the average study participant $6,426.35. In contrast, the average patient cost for submental liposuction is $2,976.56. While Kybella is cost-effective only for patients with mild-to-moderate submental liposis who require fewer injections and treatments, the avoidance of surgery for some patients may outweigh the greater expense [99].

With 65,800 procedures performed in 2019, Kybella uptake into cosmetic practice seems limited following its 2015 FDA approval [12].

8. INDIVIDUALIZED ASSESSMENT AND TREATMENT PLANNING

KEY ASSESSMENT ELEMENTS

Optimal assessment of facial aging begins with a thorough patient history and examination that assesses anatomical structure and age-related changes to the bone, fat, muscle, and skin. Specifically, this should include [10,49]:

- Skeletal changes

- Degree and location of volume loss

- Muscle anatomy and movement

- Appearance of lines and wrinkles

- Skin quality

- General facial appearance, symmetry, or any imbalance in facial proportions

The use of photonumeric scales are recommended for the objective assessment of facial aging features. Photonumeric scales have the advantage of providing a consistent visual frame of reference that minimizes variability in perception and subjectivity [100].

With these scales, assessment of the upper, mid, and lower face is performed, with specific aging features rated using a 0–4 scale (0: absent; 4: advanced) [101,102,103]. The score helps inform the appropriate level of intervention [10]:

- Early intervention: Individuals with minimal evidence of facial aging (Levels 0–1)

- Restoration: Individuals with moderate to advanced signs of aging (Levels 2–4)

The assessment lays the foundation for a detailed, individualized treatment plan that balances clinical experience with patient desires and expectations [10]. In this initial period, it is important to discuss treatment goals and ensure the patient understands the progressive nature of the aging process. Costs should also be reviewed, and in patients with limited financial means, treatment should focus on areas that will have the greatest impact. When the individualized treatment plan is formulated, the extent and sequence of procedures and/or treatments should be discussed. Clinicians should ensure the patient understands the maintenance involved in any type of facial restoration and that overtreatment and unnatural results (and likewise undertreatment and suboptimal results) will be avoided.

ETHNIC CONSIDERATIONS

Fundamental to individualized patient assessment is careful consideration of racial/ethnic and gender variation in facial aging features. In this course, the terms used to reference ancestry are Caucasian (European, North African, southwest Asian/Middle Eastern), African (sub-Saharan Africa), Latino/Hispanic (Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture), East Asian (China, Korea, Japan), Southeast Asian (Thailand, Singapore, Indonesia), and South Asian (the Indian subcontinent) [104].

People of all races have distinct ethnic features, yet cultural standards of beauty share remarkable similarity around the world, such as balance, proportion, and symmetry of facial features, and clear, unblemished, and youthful skin [105,106].

The aging process may manifest differently among various ethnic/racial group; aging promotes and accentuates intrinsic differences of facial morphology and structure. This leads to variations in aged features, such as "Caucasian corners" of lips that develop into marionette lines [94,105].

Relative to other ethnic/racial groups, the earlier onset and more extensive facial aging common in Caucasian patients reflects the interaction of morphologic features and skin quality. Bony remodeling, facial fat and soft tissue volume loss, deflation, and descent give rise to the same common signs of aging in all ethnic groups, making restoration of volume and correction of related sequelae fundamental strategies for every patient [52,105].

Skin Phototype

A powerful determinant of skin aging is the amount of melanin pigment in skin, which determines skin color or phototype. The Fitzpatrick Scale is a classification system that assigns individuals to one of six distinct phototypes based on skin complexion and response to UV radiation exposure (Table 5) [35,107]. Phototype is more tied to the equatorial proximity of one's ancestors than to specific ethnicity.

Table 5: FITZPATRICK SKIN PHOTOTYPES

Phototype

Unexposed Skin Color

Sun Exposure Responsea

Examples

I

Pale white

Always burns, never tans

Red hair with freckles

II

White

Burns easily, minimal tan

Fair-haired Caucasian, Northeast Asian

III

Olive to light brown

Burns minimally, gradually tans

Mediterranean Caucasian, East Asians

IV

Moderate brown

Burns minimally, tans well

Some Southwest Asian (Middle East) Caucasian, South Asian, Hispanic

V

Dark brown

Rarely burns, tans profusely

Darker Hispanic, some African

VI

Deeply pigmented dark brown to black

Never burns, tans deeply

Darker African, Indigenous Australian

aAfter one hour on sun-shielded, untanned skin.

Source: [107,108,109]

Variations in Aging Features

In phototypes IV–VI, the thicker, more compact dermis and higher melanin content delays the onset of skin aging, skin laxity, and sagging. In these individuals, aged skin presents with muscular or expressive lines instead of early fine wrinkling [10].

Craniofacial measurements of diverse racial/ethnic groups were originally compiled for reconstructive surgeons, who required normative data in treating congenital or post-traumatic facial disfigurements. These data inform cosmetic practice in diverse patients who age differently [111,112]. Unless otherwise stated, Caucasian facial characteristics are the point of reference for ethnic/racial variations discussed in the following sections [104]. This is the literature standard and should be taken as a guide rather than a determinate of beauty or value.

African

Compared with Caucasians, persons of African decent have skin that maintains its structural integrity and youthful appearance. This bestows lower rates of facial rhytides, brow ptosis, lip aging, lip volume loss, and perioral rhytides formation [104,112].

Facial aging tends to show more prominently in the periorbital region and midface. Patients with African ancestry can exhibit pronounced sagging of the malar fat pads, soft-tissue laxity, and jowl formation of the midface. Unlike the laxity and descent of Caucasian skin, the thickness and weight of skin contribute to jowling in these patients [104].

Aging Black patients often have fewer issues requiring soft-tissue augmentation but may seek to restore the youthful fullness of their lips. Typically the upper lip alone is treated, as the lower lip usually maintains its volume [112].

Latino/Hispanic

This heterogeneous group encompasses individuals with any combination of Caucasian, Native American, and/or African-American features. For patients with predominately Native American characteristics, approaches for East Asians are recommended; when Caucasian characteristics predominate, approaches appropriate for this group are used [112].

Patients of Mexican or Central or South American origin tend to have rounder faces with heavy eyelids, a prominent malar eminence and midface area, broader nose, abbreviated nasal length, and a recessed chin. With aging, the mid-cheek area becomes thicker and heavier, with fat pad accumulation and more prominent nasolabial folds, along with eyebrow and eyelid drooping and lower lid fat accumulation [104].

East Asian

East Asians tend to have a wider face with wider bitemporal and bizygomatic width, shorter in vertical height, lower structural projection of the midface, and lack of brow, nasal, and chin projection. Aging is likely to present as central face retrusion; flattening of the anteromedial midface; recessed piriform fossa; and a flatter forehead. A flatter facial skeletal framework promotes greater soft-tissue descent of the midface, malar fat pad ptosis, and tear trough formation [52,105].

These features account for the prevalence of fillers of the medial midface, nose, chin, and forehead of younger Asian patients. In older patients, these regions are a priority, along with correcting age-related disharmonies. Volumizing is limited to the medial maxilla area to enhance central projection and to avoid further widening the midface. Lip augmentation is usually not needed, especially in patients of Southeast Asian origin who present greater lip fullness and may more likely desire lip reduction to balance the lower third of the face [52,104,112].

South Asian

South-Asian populations differ from Caucasian and East Asians, with smaller width of the malar prominences, smaller mandibular width and height, a much shorter lower third of the face compared with the middle and upper thirds, and smaller facial skeletal width compared with Caucasians. The downward medial descent of soft tissue is more aggressive due to higher volumes of facial fat pad over a smaller bone framework [56].

Bony changes and loss of lateral temple and cheek fat are best approached by volumizing the anterior mid-cheek and nasolabial fat pads, avoiding the deep medial midface fat pads. Nasolabial and medial midface correction should be very conservative, with emphasis on deep fat volumizer placement in lateral zones [56].

A concern of some patients is of repeated filler treatment producing an overtreated appearance and unsatisfying outcome. To address this concern, avoid volumizing the medial midface where soft tissue descent aggregates, compensating for this pattern by focusing on lateral midface volumizing [56].

GENDER CONSIDERATIONS

Men represent a small but growing proportion of cosmetic patients and distinctly differ from women in facial anatomy, physiology, and aging. Knowledge of sexual dimorphism (phenotypic differences between sexes) of the entire facial form, including the skeletal structure, musculature, vasculature, soft tissue, and skin is vital for aesthetic outcomes. Female facial characteristics remain the frame of reference for male variations [50,110,113,114,117].

Sexual dimorphism of skull characteristics is foundational to gender differences in facial features (Table 6). The facial vasculature of men is greater in density. Men have increased facial muscle mass, including the mimetic muscles, greater facial muscle movement, and greater upward vertical movement capacity in facial expressions (e.g., smiling, puckering of lips). Unlike the more curvilinear cheekbone in women, the male midface is more angled due to strong muscle insertions. Facial movement contributes to rhytid formation. Men have greater severity and distribution of facial rhytides; the perioral area is the only exception.

Table 6: SEXUAL DIMORPHISM OF THE SKULL

Area of the Face

Female

Male

Forehead

More straight

More oblique

Glabella

Curved and subtle

Frontonasal suture is more prominent

Supraorbital rim

Less conspicuous

More striking

Midface

Subtle angles

Irregular surface and little anterior projection

Zygoma

More prominent and curvilinear

Less prominent

Mandible

Lighter, with subtle angles

Larger, stronger, with clear-cut angles

Chin

Smaller and rounded shape

Larger and square-shaped

Source: [50]

Facial subcutaneous fat exhibits sexual dimorphism. The subcutaneous fat is 1.5 times thicker in the medial malar fat compartment of women, but the distribution is uniform in men. Men have less soft tissue in the cheek area overall, and the subcutaneous fat layer is thinner in men regardless of age.

The loss of subcutaneous fat, thicker skin, and more prominent facial musculature results in deeper expression lines and contributes to the greater severity of male rhytides. The prominent volume loss makes men appear older than their age, relative to women. Aging also causes a more significant downward shift of the lower eyelid in men.

Treatment Considerations

Understanding sexual dimorphism is crucial to prevent unwanted feminization of male features, a primary concern of male patients seeking aesthetic treatment [52,114,115,116]. In addition, cosmetic intervention that produces an exaggeration, rather than restoration, of typical male features can result in an aggressive or threatening appearance [117]. Of course, some men do wish to attain a more feminine or masculine appearance, but this is beyond the scope of this course, which focuses on cosmetic procedures to address unwanted facial changes associated with aging.

General approaches to minimally invasive correction of cosmetic concerns in older men vary by the area of the face [52,113,114,115,116].

Upper Face

Overfilling the temple should be avoided, because temporal hollowing is aesthetically appealing in many men. With botulinum toxin for rhytides, the lateral frontalis muscle is injected to prevent lateral brow arching and to maintain the flat male brow position. The frontalis may require more injections due to the larger forehead area. In a brow already lower with age, inferior frontalis injection requires caution to avoid ptosis (when brow position falls below the orbital rim) [52,113,114,115,116].

Midface

In the subcutaneous medial cheek fat compartment, uniform injection of filler replaces volume loss while maintaining a flatter and more angular cheek contour. The structural support may also improve the tear trough and palpebral malar groove. Fillers should be injected laterally along the zygomatic arch, avoiding a feminizing convexity from overvolumizing the anterior and medial cheeks [52,113,114,115,116].

Lower Face

Filler injections can restore or enhance the projection of the chin; increasing its forward projection helps tighten the jawline area, and increasing its lateral borders helps to square a recessed chin and add definition to the jawline. To restore volume or enhance shape, the supraperiosteal temporal-buccal fat pad is injected, which will project the jaw laterally and strengthen the jawline if a more square jaw is desired [52,113,114,115,116].

AGE CONSIDERATIONS

Aesthetic medicine professionals are confronted by increasing demand for cosmetic treatments by young patients. Treating this age group can be difficult to justify, but standard physiologic aging and individual concerns can guide age-appropriate cosmetic counseling, prevention, and intervention [118].

In patients younger than 20 years of age, minimally invasive cosmetic procedures are generally inappropriate. Emphasis is placed on prevention counseling (e.g., protection against sun damage) and addressing age-independent congenital characteristics or acquired disharmonies (e.g., acne scars) [52,118]. Cumulative exposures to UV radiation, smoking, and pollution can initiate early collagen decline, leading to noticeable fine lines and wrinkles in some patients in their 20s. Appropriate treatment includes noninvasive modalities or botulinum toxin, which is FDA-approved for rhytides in patients 18 years of age and older [118,119].

The typical age of patients who seek cosmetic procedures is between 30 and 50 years. When clinically indicated, fillers and toxin can demonstrably benefit older and younger patients. Patients between 30 and 50 years of age often achieve the most benefit from botulinum toxin treatment; a greater proportion of rhytides in older patients may be due to loss of skin elasticity, which is not alleviated by botulinum toxin [33]. There is no upper limit for age beyond which benefits cease, assuming that dose and injection sites are tailored to muscle mass and function [52].

9. THE MINIMALLY INVASIVE TREATMENT APPROACH

In the recommended practice of minimally invasive therapy for aging features, discussion begins with an overview of evidence that informs practice and the sequence of treatment delivery. Next, for each horizontal zone, the clinical features of aging are briefly reviewed and corresponding interventions are described.

The practice standard for facial aging is volume replacement, tissue tightening, and skin rejuvenation (resurfacing). Therapies for skin resurfacing include lasers/light (e.g., intense pulsed light, fractional laser), energy (e.g., microfocused ultrasound with visualization, radiofrequency) and topical (e.g., microdermabrasion, chemical peels) modalities. These mostly noninvasive therapies are mentioned by necessity as recommended components of multimodal treatment, but specifics of their use are beyond the scope of this course.

RECOMMENDED THERAPY COMBINATIONS

Improved understanding of facial aging and mechanisms of therapies inform their combination and sequence of use. With superior outcomes repeatedly demonstrated with combination therapy over monotherapy, this approach is now recommended for most patients [6,10,33,34,52,120].

Botulinum Toxin Plus Hyaluronic Acid Fillers

Botulinum toxin and hyaluronic acid fillers act synergistically for superior improvements and duration [34,52,79,87,120]. Recognition that hyperdynamic muscle activity leads to both soft tissue volume loss and rhytides has prompted botulinum toxin injection one to two weeks before fillers. Botulinum toxin increases filler efficacy by diminishing the dynamic muscle component of the target, and improves longevity by preventing filler breakdown from repetitive muscle activity. Fillers can extend botulinum toxin efficacy to six months.

Botulinum toxin is less effective in deep lines and creases (e.g., glabellar or forehead rhytides), and repetitive muscle contraction degrades filler efficacy to soften the appearance. Botulinum toxin/fillers overcome the respective monotherapy limitations to produce superior extent and duration of improvement, without increased bothersome or significant side effects. Outcomes are optimized by treating aesthetic units.

Botulinum Toxin/Hyaluronic Acid Fillers Plus Lasers/Light Therapies

Combined with energy-based therapies, the efficacy of botulinum toxin/fillers is superior to monotherapy, without increased spread of botulinum toxin, filler migration, or other untoward effects [10,94]. Botulinum toxin before laser resurfacing improves post-laser healing, collagen remodeling, and aesthetic results, while post-laser botulinum toxin reduces wrinkle recurrence, prolonging resurfacing efficacy.

Botulinum toxin added to intense pulsed-light treatment of photoaging increases overall aesthetic benefits. Microfocused ultrasound and radiofrequency stimulate fibroblast proliferation and new collagen for efficacy in cutaneous sagging, wrinkling, and marionette lines. Outcomes are usually more satisfactory combined with hyaluronic acid fillers.

RECOMMENDED THERAPY SEQUENCE

Ideally, all treatments should be spaced apart at least two weeks, with botulinum toxin given two weeks before filler injections in areas of static lines, dynamic rhytides, or deep folds. However, patients may prefer same-day botulinum toxin and filler injection for convenience. This is thought to be safe, with botulinum toxin injection before fillers to avoid toxin spread beyond the treated area [8,10,11,29,30,52,71]. In the four weeks before and after filler injection, lasers, intense pulsed light, chemical peels, microdermabrasion, and over-the-counter or prescription wrinkle treatments should be avoided. It is also important to avoid concurrent botulinum toxin with laser resurfacing or microfocused ultrasound; increased blood flow and edema may promote toxin diffusion and side effect risks.

The midface is treated first. Patients with nasolabial fold complaints may require education that correcting midface volume naturally and effectively treats overall aging features. The filler injection sequence is lateral, then middle, then medial fat compartments; in some cases, a sequence from deep to superficial tissue planes is suitable. New filler injection over previous fillers ("layering") is discouraged due to greater risk of potentially serious complications [8,10,11,29,30,52,71].

PATIENT-TAILORED TREATMENT

While minimally invasive procedures can improve facial texture and volumize, reduce, contour, lift, or reinforce soft tissue, optimal safety and aesthetic outcomes require individualized treatment planning based on assessment of skin changes, tissue quality, extent and pattern of muscle contraction, and soft/hard tissue volume loss [2,52]. These principles become obscured when rigid adherence to algorithms or cutaneous landmarks (which shift with age) supersedes a patient-tailored approach [52].

Declining tissue quality and skin laxity are indications for combining fillers with lasers or energy-based devices. In older patients, fewer injection sites and smaller toxin doses at each site may be indicated if muscle mass or function is reduced [52].

THE TRI-VECTOR TECHNIQUE

Patients present with varying levels of lipoatrophy regardless of age, and the tri-vector technique adapts practice standards into an easily patient-tailored framework [121]. In each horizontal zone, this approach initiates filler injections in lateral compartments, working from lateral to medial.

In this approach, step one is supra-periosteal filler injections. In the upper face, injections are made in the temporal fossa to address forehead atrophy, brow ptosis, and temporal volume loss. Filler in the midface addresses volume loss of preauricular (in front of ear) lateral cheek and mid-cheek fat, tear trough, and infra-nasal lines/folds; in the jawline, injections can address mandibular angle changes and maxilla and mandibular fat volume loss (also marionette lines).

The second step consists of deep dermis filler injections at three ligament support sites to provide fibrous fixation points and restrain facial skin against gravitational changes. These sites are:

- McGregor patch (posterior to zygomaticus minor muscle)

- Pyriform aperture (superior part of nasolabial fold)

- Modiolus (lateral to inferior part of nasolabial fold)

The final step in this approach is patient-specific. It may include filler injection in dermal or superficial fat layers to contour the face, soften any sharp angles (especially in jawline area), or address focal superficial lipoatrophy sites [121].

THE UPPER FACE

In each horizontal facial zone, there are compartmentalized anatomic regions that undergo changes and/or loss of volume and tissue integrity with age. Differences in underlying bony structure, weight, and soft-tissue quality influence inter-patient variations in specific aging changes [29,49].

The youthful upper face is characterized by a subtle convexity of the temple, forehead, and lateral brow and upper eyelid fullness [29]. The aged forehead skin, with loss of bone and fat support, is pulled by repetitive activity of depressor muscles and mimetic musculature to form horizontal rhytides. With temporal and forehead volume loss, glabellar rhytides deepen and lateral canthal rhytides (crow's feet) develop at rest and at smile [10].

The eyebrows, a powerful and versatile facial feature, greatly contribute to the perception of facial attractiveness, and fundamentally inform sexual dimorphism, facial recognition, and nonverbal communication [122]. Low medial brows, even without furrowed wrinkles, signal hostility and anger [65]. Brow ptosis develops as periorbital bone remodeling and temporal deep fat loss erode the support and fullness of the upper lid, causing the brow to descend to the superior orbital rim [4,29]. Fixed glabellar frown lines, transverse forehead furrows, temporal hollowing, skeletonized supraorbital rim, brow ptosis, and redundant upper eyelid skin combine to form an aged appearance to the upper face [4,29].

The forehead, glabella, and temples are treated as one aesthetic unit, with botulinum toxin for muscle modulation, fillers to improve temporal hollowing and contours of the forehead, and microfocused ultrasound to lift the ptotic brow and tighten the skin [10,11]. This "aesthetic unit" principle is underscored by inter-relationships of the brow elevator (frontalis) and depressor (corrugator, procerus, orbicularis oculi) muscles. With antagonistic function, botulinum toxin injection in one muscle causes unopposed strength in another [11,79].

Botulinum Toxin Treatment

Lines, furrows, and creases develop over time from hyperactive, repetitive use and contraction of various muscles. Botulinum toxin injection into culpable muscles can smooth vertical glabellar rhytides (glabellar complex muscles), horizontal forehead rhytides (frontalis muscle), and periorbital lateral canthal rhytides (lateral orbicularis oculi muscle) [33].

Horizontal Forehead Rhytides

The frontalis, the sole elevator muscle in the upper face, contracts to raise the eyebrows and upper eyelid to express surprise or fright. Frontalis contraction eventually forms horizontal forehead rhytides [33,67].

Horizontal forehead rhytides require simultaneous botulinum toxin injections of the frontalis and brow depressors. With frontalis muscle injection alone, unopposed activity of depressor muscles will induce a lowered, angry-looking brow ptosis. Frontalis injections are 2–3 cm above the brows; closer brow placement risks inhibition of facial expression and brow ptosis [11,33].

Glabellar Rhytides

Treatment of glabellar frown lines is an integral part of harmonizing the brow shape and eyebrow position. Glabellar lines are caused by contraction of the corrugator and orbicularis oculi muscles (move the brow medially) and the procerus and depressor supercilii muscles (pull the brow inferiorly). Botulinum toxin injection of corrugator and procerus muscles weakens the brow depressors to improve glabellar rhytides. Injections are made above the supraorbital rim to avoid upper eyelid ptosis. Men typically require higher doses due to greater muscle mass in this area [33].

Lateral Canthal Rhytides

Contraction of the lateral orbicularis oculi muscle produces lines (crow's feet) that radiate from the lateral canthus. These lines initially appear on smiling or squinting (dynamic) but can become static (at rest) due of aging, photodamage, and skin remodeling. Crow's feet are treated with multiple botulinum toxin injections into the lateral orbicularis oculi muscle, lateral to the orbital rim with the facial musculature at rest [11,33,79].

Brow Lift

Brow ptosis, a common feature of aging, can produce facial features at rest that mimic angry or scowling expressions. Brow shape and height are controlled by the opposing action of brow elevator (frontalis) and depressor muscles [33]. Botulinum toxin is injected as in treating glabellar lines (above), the lateral orbicularis oculi, and in the lateral corrugators 1–2 cm above the orbital rim to avoid the Mephisto or Spock eyebrow (quizzical look). Injections limited to the superolateral orbicularis oculi muscle (tail of the eyebrow) can give a lateral eyebrow elevation [10,11,33,79].

Hypertrophic Orbicularis Oculi

Botulinum toxin injection can widen the ocular aperture by weakening the orbicularis oculi muscle complex, producing a wider, rounder eye during smiling and at rest [33].

Dermal Fillers

Given the substantial variability in anatomy and aging of the upper face, reversible (hyaluronic acid) fillers may be preferred; clinicians with experience and a level of comfort may consider stimulatory (PLLA) fillers [10,11].

Fillers for temple and upper brow volume loss require elevated elasticity and viscosity for periosteal placement, to give structural and lifting support to overlying tissues with low risk of displacement (e.g., Restylane Lyft, Radiesse, Juvéderm Voluma-XC, Juvéderm Ultra Plus XC) [29]. Fillers for volumizing the upper lid, forehead, and crow's feet should have lower elasticity and viscosity for superficial placement (e.g., Restylane-L, Restylane-Silk, Belotero Balance, Juvéderm Ultra XC) [29].

The anatomic order of contouring influences the ultimate outcome of facial volumization. Augmenting the temple alone may provide lateral brow support and should be addressed before moving more caudally [29]. The upper face is a challenging area for fillers because of risk for serious complications [11].

Temple Volumization

Fillers for temporal volume loss and hollowing intend to eliminate concavity and achieve a uniform or slightly convex contour between the temporal fusion line and the zygomatic arch. Severe volume loss may require multiple treatment sessions [8,11].

Brow and Upper Lid

Volume loss occurs in bone and more superficial tissues including subcutaneous fat and the retro-orbicularis oculi fat pad. To correct this deficit, the initial filler injection is directly onto periosteum 1 cm superior to the upper lateral orbital rim or just above the superior lateral brow hairline [29].

Eyebrow Shaping

The position and/or shape of the eyebrow often changes with aging. Fillers can enhance eyebrow contour and volume and may improve elevation of the eyebrow tail when botulinum toxin provides insufficient eyebrow lifting [11].

Forehead Contouring

Dynamic forehead lines are usually treated with botulinum toxin, but fillers can treat deep horizontal lines to create a smooth contour across the forehead. The filler is injected at least 2 cm above the eyebrow, with the needle tip on bone [11]. For tightening eyelid skin, radiofrequency is preferred because of its efficacy and built-in safety features [10].

THE MIDFACE

In facial aesthetics, the midface is a main determinant of perceptions of facial attractiveness, influenced by synergy of the eyes, nose, lips, and cheekbones (central facial triangle). It is also the focal point for restoration of a youthful topography. As such, the midface should be treated first [4,10,122].

Degenerative changes occur in nearly all anatomic components of the midface. The mid-cheek manifests the most complex soft tissue changes with aging, and volume loss of the deep mid-facial fat is a primary determinant of an aged appearance. Fat within each compartment changes independently over time, losing volume and shifting as the facial ligaments attenuate and the bony skeleton recedes [10,31].

Loss of maxilla projection and skeletal support and inferior displacement of soft tissues contribute to the tear-trough deformity, malar mounds, and prominent nasolabial fold and groove. The cheeks lose projection to assume a sunken appearance. Prominent transitions between cheek fat pads and flattening of the malar prominence mark the deflated midface; the heart-shaped face of youth becomes distinctly pear shaped [10,29,31].

Accurate assessment of midface volume loss is the single most important factor for appropriate correction of facial volume; precise restoration may rejuvenate the upper and lower face [29]. To define these midface areas, draw one line from the lateral canthus to the lateral oral commissure and a second line from the tragus to the nasal ala. The lines intersect to form quadrants. Examine the upper-outer (zygomatico-malar region), upper-inner (anteromedial cheek), and lower-outer (submalar region) quadrants for volume loss and treat accordingly [84,123,124].

The medial suborbicularis oculi fat migrates inferiorly with aging. The medial part of the deep medial cheek fat extends almost to the lateral incisor tooth. Volumizing both medial fat pads is crucial for correcting cheek sagging—a major contributor to deep nasolabial folds [2,40].

Fillers are used for volumization and contouring the upper cheek and lid-cheek junction, the submalar and preauricular areas. Botulinum toxin plays a limited role [125]. Recommendations for the midface advise treating the malar area first; volumizing the malar and restoring its contours gives a lifting effect that may reduce or negate the need for filling other midface areas [30,55]. Careful attention should be paid to restorative effects on the lower lid, nasolabial fold, nasal base, and upper lip during malar augmentation [29].

Malar Area

Fillers are injected to create vertical pillars over the bone to support and lift the malar area. The following injection sequence is lateral to medial, to achieve a tenting effect with less filler needed for medial injection [8,30,94]:

- In the lateral midface, the zygomatic (cheekbone) arch and prominence (crucial for optimal cheek restoration)

- Lateral compartment of the superficial cheek fat pad and the preauricular superficial fat compartment

- Middle compartment of the superficial cheek fat (medial sub-orbicularis oculi fat)

A variety of fillers can volumize the malar/lateral cheek region with good results (e.g., hyaluronic acid, CaHA, PLLA, PMMA) [84].

Lower Lid

Volume restoration of tear trough deformity with filler injection is a difficult technique in a danger zone for vascular complications and should only be performed by experts [84].

Deep Medial Cheek

Volumizing the deep medial cheek fat increases anterior projection, reduces the nasolabial fold, and recreates a youthful cheek within its natural boundaries [25,40]. Juvéderm Voluma XC, Juvéderm Ultra Plus XC, Restylane Lyft, Radiesse, PLLA, and PMMA are all suited for deep midface volumizing [29,84]. Patients with significant orbital fat herniation may benefit more from surgery; fillers alone may be inadequate to reduce the transition between protuberant fat pad and concave tear trough [84].

Nasal Tip and Upper Nasolabial Fold

Deep volumizing of the nasal sill can provide support to the aging nasal tip, a natural correction of the upper nasolabial fold, and a minor lift to the upper lip. Treatment requires periosteal placement of high-elasticity, large-particle fillers [29].

Botulinum toxin can correct "bunny lines"—horizontal rhytides that traverse the nasal bridge and the downward slope of the nose when the patient is smiling—and elevation of the nasal tip [10,125]. In the midface, nasolabial folds are treated last [10].

Nasolabial Folds

Most fillers are indicated for treating nasolabial folds by the FDA, but unlike other midface areas, nasolabial folds hypertrophy with age. Thus, fillers are suggested to soften a prominent fold, not to volumize. First correct deficient malar volume, then soften residual nasolabial folds conservatively using moderate-elasticity and -viscosity filler (e.g., Restylane-L, Juvéderm Ultra XC) injections in the superficial fat just to the dermis [29].

Low-dose botulinum toxin into each lip elevator complex above the nasofacial groove can collapse the upper nasolabial fold but may vertically lengthen the upper lip, an aging-related feature. Botulinum toxin should not be directly injected into nasolabial folds, as this may result in an asymmetrical smile or lip ptosis [33].

After addressing volume loss, microfocused ultrasound treatment of the overlying superficial musculo-aponeurotic system and skin envelope addresses laxity and bridges the aesthetic unit compartments to create a smooth cheek contour [10,126].

THE LOWER FACE AND NECK

During the aging process, bony and soft-tissue structures in the lower face undergo significant alterations [4,10,29,58]. Malar and perioral fat volume loss, bone resorption, and ligament laxity cause increasingly lax skin to droop downward over a changing lower face structure. The general widening and loss of integrity of the lower face can appear as a relative increase in jowl volume with decreased jawline strength and perioral/lip volume.

Jowling is one of the most unwanted effects of aging and a primary concern of aging patients. The jowls become prominent with deflation of superficial fat exposing deeper fat pads, descent of deep fat pads, and increased septal laxity. Loss of volume in the prejowl sulcus, posterior jawline, and inferior preauricular region exacerbates the appearance of jowls.

Superficial and deep atrophy of the perioral area manifests as a lengthening and flattening of the upper lip complex, loss of vermillion and vermillion border volume, and formation of vertical perioral rhytides. The oral commissures turn down, and the mentalis region flattens or becomes ptotic. Protrusion of the central chin results from loss of lateral and inferior volume. These changes are superimposed on and intensified by mandibular bony changes that result in decreased vertical ramus height, a widening mandibular angle, and loss of anterior mandibular (mental) projection. Platysma muscle contraction from support of deeper neck and floor of mouth structures promotes vertical fibrous bands on the neck; laxity in overlying skin creates horizontal rhytides.

Botulinum toxin and filler combinations are especially effective in the lower face to address dynamic musculature, loss of volume and support, and skin laxity [10]. Some believe that fillers are more important than botulinum toxin and should be used first to provide structure and support before considering botulinum toxin for dynamic lines [127].

Jawline

Structural volumizing of the lower face should begin with correction of the jawline, using fillers with high elasticity (Restylane Lyft, Radiesse, Juvéderm Voluma XC, or Juvéderm Ultra Plus XC) [29]. Injector preference/experience will also determine filler choice [10].

Mandibular shrinkage and redistribution of fat leads to the emergence of jowls and loss of jawline definition. To smooth the jawline and camouflage the prejowl, the inferior mandibular border is injected in the supraperiosteal plane. Injection under the mandibular rim improves the prejowl concavity. The jowl is not directly injected, to avoid blood vessels [8,58].

A technique referred to as the "Nefertiti lift" involves small amounts of botulinum toxin injected along the jaw and into the lateral, upper platysmal band to improve the appearance of pouches. With skin laxity, the addition of microfocused ultrasound helps lift the jowls for a tighter appearance [10].

In women, an overly squared jaw can be undesired. If sagging is not an issue, botulinum toxin injection of the masseter results in a softening of the determined, clenched appearance and a more feminine face [65].

Chin

Botulinum toxin injections just anterior to the bony mentum on each side of the midline weaken the mentalis muscle contraction responsible for mental crease, and injections into the mentalis muscle at the prominence of the chin can help reduce a peau d'orange chin [33,65]. Fillers create definition and fill residual depressions. Injection is placed on the periosteum and deep subcutaneous tissue to create vertical pillars. Fillers with greater lift are preferred [8,58].

The perioral region is considered one aesthetic unit, comprising the lips, oral commissures, and melomental folds (marionette lines). Botulinum toxin is commonly used for perioral rhytides but requires caution, as improper injection may result in a flaccid cheek, an incompetent mouth, an asymmetrical smile, or speech pathology [10,79]. Perioral volumization may independently restore and support the lips by enhancing lip volume and should be precede direct mucosal lip volumizing in an aging face [29].

Moderate-elasticity fillers (e.g., Restylane-L, Restylane-L Silk, Juvéderm Ultra XC, Belotero Balance) are injected in the subcutaneous plane, first in the oral commissure until a subtle upturning is achieved, then in the upper and lower lip columns for volumizing support. This will improve the appearance of vertical lip rhytides and philtral columns [29].

Vertical perioral rhytides are common cosmetic concerns, induced or exacerbated by repetitive orbicularis oris muscle contraction. With fillers, a short-lived improvement and fairly rapid recurrence is likely caused by normal perioral animation. Low-dose botulinum toxin is injected adjacent to the vermillion border in the areas of rhytides, and lateral to the Cupid's bow area of the lip. Avoid injecting the oral commissures (corners of the lip) and the midline area to reduce the risk of a drooping lateral lip [33].

Mouth frown results when the depressor anguli oris muscle pulls the corners of the mouth downward, in opposition to the action of zygomaticus major/minor muscles, producing a frowning expression. Botulinum toxin injection weakens the depressor anguli oris, allowing the zygomaticus to elevate the corners of the mouth, which return to a horizontal position. Botulinum toxin is injected into the insertion point of the mentalis muscle, because upward pull of the mentalis contributes to mouth frown [33].

Melomental folds (marionette lines) are exacerbated by contraction of the depressor anguli oris muscle. This is treated by botulinum toxin injection into the posterior margin of each depressor anguli oris immediately above the mandible [33].

THE NECK

Platysmal bands, often the first sign of aging of the neck, appear as two vertical, bulky cords from the lower border of the mandible to the suprasternal region. Formerly thought to result from skin laxity and loss of platysma muscle tone, these vertical muscular bands are now attributed to platysma muscle activity, treated by denervating the platysma muscle with botulinum toxin instead of tightening the skin [128]. Very-low-dose botulinum toxin is injected superficially into only specific platysmal bands, to avoid dysphagia [79]. Improvement of the overall appearance of the neck requires fillers for structural support of the chin and jawline and botulinum toxin for the masseter, platysmal bands, or horizontal neck lines [33,127].

10. PATIENT SELECTION AND EVALUATION

As discussed, the careful assessment of patients forms the basis of individualized treatment planning. Because aesthetic procedures are elective, the benefits must clearly outweigh the risks. Healthcare providers have a responsibility to refuse requests in which the risk-benefit ratio is not in the patient's best interest, and to refer patients elsewhere for consideration of treatments the clinician cannot or prefers not to perform. Patients rely on the healthcare provider to act as a "learned intermediary" and to exercise fiduciary responsibility in advising the patient on the best course of action [95].

Patients should be carefully selected by thorough assessment of medical history, motivation, and expectations to identify contraindications. The increasing incidence of serious dermal filler complications has expanded the cutaneous and systemic contraindications to filler treatment, relevant to botulinum toxin because combined therapy is common.

Following screening, careful discussion addresses the specific cosmetic concerns and possible benefits and risks across a range of available options. A treatment plan is arrived at through shared decision-making; informed consent and documentation are made.

For those who are not proficient in English, it is important that the patient history and information regarding the risks associated with the use of botulinum toxin/dermal fillers be obtained in the patient's native language, if possible. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

SCREENING AND SELECTION

Screening and Assessment of Medical Contraindications

The patient may request a cosmetic therapy, but the aesthetic provider should ultimately "select" the patient. Most complications stem from inappropriate patient selection, inadequate antiseptic preparation, or improper treatment technique. Selecting appropriate patients, or perhaps more importantly, not treating inappropriate patients, is the first crucial step in avoiding complications [71].

A thorough history of skin conditions, allergies, systemic disease, current medication use, and previous cosmetic procedures is mandatory. Patients may not see important aspects of their history as relevant. To help ensure disclosure, assess skin-related and systemic conditions by linking to potential adverse effects [19,71].

Some skin disorders and local or remote infections can promote injection seeding of infective agents that populate the filler site, or hematogenous spread to implanted fillers and later biofilm formation or transition from infection to hypersensitivity [19,129,130]. These conditions require careful screening. Fillers have risks of injection-site keloid formation or hyperpigmentation; patients with these conditions should avoid fillers [75].

Screening may identify conditions whereby filler therapy is contraindicated, deferred until resolution, or considered cautiously. Significant comorbidity, polypharmacy, or use of immunomodulatory drugs can greatly complicate adverse effect management if it becomes necessary [22].

Screening and Assessment of Psychological Contraindications

Understanding the motivations for cosmetic treatment is vital to minimizing inappropriate patient selection. Unrealistic expectations, which are contraindications to cosmetic treatment, are prevalent in some psychological conditions [19,75]. Low self-esteem can lead to unrealistic goals and expectations. High neuroticism and/or anxiety may influence expectations, and outcomes tend to be poorer [131]. The most important mental disorder consideration is body dysmorphic disorder.

Body dysmorphic disorder is a psychiatric disorder characterized by preoccupation with an imagined defect in appearance or distorted perception of one's body image. These patients may be unduly invested in the cosmetic procedure as the solution to other life problems. Unrealistic expectations are followed by dissatisfaction with results that do not correlate with objective outcomes [132,133]. Dissatisfied patients with body dysmorphic disorder have been reported to retaliate against their cosmetic providers with lawsuits, threats of violence, physical assault, and in rare cases, homicide [134,135].

Compulsive behaviors have been described in patients who, driven by the quest for physical perfection, demand and obtain multiple sequential cosmetic injections despite the increasing risk. Compulsive demand for cosmetic procedures falls on a spectrum of dysmorphophobic behaviors [136,137]. Body dysmorphic disorder is also associated with "doctor-shopping" [131].

Whether the diagnostic threshold for body dysmorphic disorder is a contraindication to nonsurgical cosmetic procedures is unresolved, but many consider signs of body dysmorphic disorder a firm contraindication to cosmetic treatment [19,131,132,138]. Appropriate onward referral may be required when psychopathology is apparent [131,139].

PATIENT EVALUATION AND CONSENT

After the patient has been screened for medical and psychological contraindications to cosmetic treatment, the next step is to determine if treatment expectations can be met or managed with education and counseling. Following this, treatment options are explored and a plan is developed and documented.

Patient Motivation and Treatment Expectations

American healthcare consumers are both aging and youth-oriented [94]. A majority of the population is dissatisfied with their appearance, rates of cosmetic interventions continue to increase, and the expectations of many patients have risen proportionately [131].

Patient motivation for cosmetic therapy, benefits anticipated, and satisfaction with the outcome are closely inter-related. The expectations and motives for seeking treatment are complex and diverse. Patient dissatisfaction usually derives from failing to manage or meet expectations, underscoring the importance of identifying expectations at the first consultation and documenting this discussion [131]. The clinician should establish underlying motivations, differentiate patient wants from needs, and temper expectations within realistic goals [19].

Patient motivation is considered external when expecting physical changes to influence some aspect of their life (e.g., partner will love them more, career success). Unrealistic expectations with external motivation require discussion, as these patients are more likely to be dissatisfied with outcomes. In contrast, internally motivated patients (driven by a desire to look better for themselves) are good candidates [131,138].

Other factors can influence expectations [94,131]. Younger patients can be especially sensitive to peer group acceptance and social media images, but correction of an objectively undesired feature can also be therapeutic. Traditional and digital media promote unrealistic expectations of an idealized appearance, and along with marketing, this has led some patients to believe a youthful appearance can be maintained indefinitely, has a quick fix, or is guaranteed with a "miracle treatment." Partners, families, and friends can exert strong influences that can be helpful to separate from the patient's own expectations. Expectations tend to be higher among more educated patients.

Expectation Management

Patient expectations should be managed so they do not envisage an unrealistic outcome. The treatment of inadequately informed patients is fraught with potential problems and risks of dissatisfaction [71].

Patient education on the risks, potential benefits, and limitations of cosmetic procedures may modify expectations. Good information is associated with better outcomes, and hearing these details may lead the patient to prefer a different course of treatment than first proposed [131].

A 2016 guideline stresses the importance of giving prospective cosmetic patients time to reflect on what they learned during the initial consultation—a "cooling-off period" [140]. However, a 2015 consensus statement suggested initiating at least part of the treatment plan the same day to build patient confidence in aesthetic procedures and in the clinician [94]. It may be best to assess on a patient-by-patient basis which approach is appropriate.

The FACE-Q is a validated screening instrument that measures patient expectations of cosmetic treatment, such as appearance-related psychosocial distress and how they expect their appearance and quality of life to change after cosmetic treatment [141]. Use of the FACE-Q can help augment, but not replace, patient-clinician discussions of factors that influence expectations of cosmetic treatments [131].

An effective approach to expectation management is the mnemonic STEP [94]:

- Stress what can and cannot be done with minimally invasive aesthetic treatments.

- Target specific areas of patient concern.

- Envision what the effect of the aesthetic outcome would be like to the patient.

- Preframe the patient to the expected outcome.

Developing a Treatment Plan

The clinician should be both probing and empathetic. Patients may be ashamed they look older than their peers but too embarrassed to directly discuss it. Others may see their concerns as vain and frivolous. Many patients are unaware of the range and versatility of cosmetic procedures or believe their concerns are beyond remediation [94]. Keep the focus on cosmetic concerns rather than any preconceived treatment approach.

Educate the patient to focus on the underlying cause, not the superficial manifestation, of her/his cosmetic complaint. For example, sagging skin is often caused by volume loss, making volume augmentation the appropriate treatment [94].

Discuss realistic expectations for the results of specific treatments. For example, if a patient requests a specific treatment for prominent nasolabial folds with the goal of looking younger, explain that nasolabial folds can be treated directly, but would not produce a more youthful appearance—correcting the underlying volume loss could restore a youthful appearance, even with some residual folds [94].

Many patients have concerns about several facial areas. Asking: "If you could fix only one thing today, what would it be?" can help clarify their relative priorities to base a reasonable sequence of procedures [94].

Clarify expectations of time frame to determine what is realistic and feasible when patients require the desired effects before an important event, such as a wedding. Other patients may want progressive, rather than immediate, aesthetic improvement. Also understand the degree of patient risk tolerance in treatment selection [94].

Discuss the implications of botulinum toxin treatment of the orbicularis oris muscle. The reduction of fine motor control around the mouth may be detrimental to professional speakers, vocalists, or musicians [94].

Informed Consent and Documentation

The risk of malpractice claims is highest in cosmetic medicine. Most result from inadequate informed consent instead of procedural failures [16]. To fully inform decision-making and consent to treatment of patients, carefully discuss the possible benefits, disadvantages, and limitations over a broad range of options [7,95].

Beyond an unnatural look, the three main patient concerns are pain, complications, and costs. It is essential to discuss treatment costs, obtain financial consent, and plan over the long term to obviate financial stress. Addressing these issues upfront is instrumental in establishing the trust that underpins true patient satisfaction [19].

Shared decision-making, an essential element of evidence-based medicine, explores available treatment options, possible benefits and harms of each option, and best match to the patient's characteristics and preferences [142]. Obtaining signed informed consent is crucial in creating awareness and acceptance of potential complications. An informed consent document confirms patient understanding of the potential adverse effects and expected treatment outcome. The document should outline common and uncommon but serious adverse events. Supplying written pre- and post-instructions during the initial consultation can help to establish realistic expectations and minimize dissatisfaction [19,34].

Photographic documentation is essential for medico-legal purposes and appraisal of results. To ensure good quality pre- and post-treatment photographs, the patient should remove all makeup and jewelry and pull hair back or up using a hairband; a black/dark background is preferred. Multiple images at rest and during animation are recommended, including anterior, oblique, and lateral views with the head in a neutral, neck-extended, and neck-flexed position. Proper lighting, consistent angles, and a fixed camera distance are mandatory. A single-lens reflex camera and tripod are recommended instead of smartphones [19].

11. ADVERSE EFFECTS

As mentioned, there is increasing concern of serious adverse events involving dermal filler injections. Some experts noted that by 2010, the increasingly sophisticated training in nonsurgical cosmetic treatment was already neglecting adverse events and their management [22]. With the rapid growth in consumer demand for injection cosmetic therapies, the quality of training, skill, and credentialing of injectors and facilities are increasingly unclear. Along with inadequate regulation, the net effect is described as compromising not only patient safety but the reputation of the field [19,20,23].

With serious adverse events a focus of concern, there is an expansion of recommended measures to prevent, reduce, and manage adverse events before they become disastrous complications.

PREVENTION AND RISK REDUCTION

Several approaches are recommended before injection therapy to prevent or reduce complications by mitigating patient, clinician, or procedure risk factors.

Pretreatment Patient Management

Some complications may be prevented by careful pre-treatment patient management. Filler injection can reactivate latent herpes simplex virus (HSV) infection. Prophylactic antivirals (e.g., acyclovir, valaciclovir, famciclovir) are recommended with patient history of HSV in the intended injection area. Patients with a current outbreak of HSV should receive antivirals, with fillers deferred until resolution of herpes lesions [143,144]. For two to four weeks before and after filler treatment, patients should be counseled to avoid [92,143,144]:

- Dental procedures, oral hygienist visits, tooth bleaching/whitening

- Immunizations/vaccinations

- Other medical procedures

- Any facial procedure inducing inflammation or skin barrier disruption

In addition, products with blood-thinning effects should be avoided the week before filler treatment. This includes food/beverages (e.g., red wine, dark chocolate, grapefruit) and certain supplements/over-the-counter medications (e.g., vitamin E, gingko biloba, fish oils, St. John's wort, nonsteroidal anti-inflammatory drugs [NSAIDs]). Prescribed anticoagulants (e.g., aspirin, warfarin, clopidogrel, apixaban, rivaroxaban, dabigatran) should also be withheld, but only when cleared by the prescribing physician [92,143,144].

A pretreatment checklist should be provided to the patient that includes these points and explains the importance of having any infective or inflammatory conditions treated before the procedure; the treatment should be rescheduled if the pretreatment checklist is incomplete. The patient should receive the checklist with sufficient time to plan relevant medical visits around the treatment date. Contact patients one week pretreatment to ensure they possess and understand the checklist and have no precluding factors [19].

Procedure- and Clinician-Related Factors

Knowing previous surgical (e.g., rhinoplasty) or nonsurgical cosmetic procedures and locations is vital to prevent complications. Fixation, scarring, or alteration of underlying vasculature and anatomy at procedure sites can facilitate intravascular filler injection. "Layering" new fillers over a previously injected semi/fully intact filler can provoke dormant biofilm or inflammatory response [19,71,145].

Vascular Complications

Vascular occlusion from injected filler material may lead to potentially catastrophic complications of tissue necrosis, blindness, or stroke. Even with advanced knowledge of facial anatomy, vascular injury cannot be avoided with 100% certainty. However, measures can be taken to help reduce risks and mitigate intravascular adverse events if they develop. A key step is understanding the danger zones for vascular occlusion, areas where arteries have little or no collateral circulation, extensive anastomoses with the internal carotid artery, or are prone to external compression. Risk factors for vascular occlusion are summarized in Table 7 [19,146,147]. Table 8 outlines strategies to mitigate these potential complications.

Table 7: RISK FACTORS FOR VASCULAR COMPLICATIONS DURING FILLER INJECTION

Factor

Description

Injection site danger zones

Injections to the nose, nasolabial fold, forehead, and glabella are at increased risk for blindness.

Injections to the glabellar region, nasal tip/alar triangle, and lips increase the risk for necrosis.

Injected volume

Bolus injections near danger zones increase risk of necrosis.

Filler type

Non-hyaluronic acid fillers cannot be dissolved.

Necrosis is more common with denser or more permanent fillers.

Needle gauge

Sharp needles puncture arteries more easily. Aspiration before injecting is suggested, but unreliable. Blunt cannulas are less likely to puncture vessels.

Scarring

Scarring from prior cosmetic procedures or trauma can alter the local vascular pattern.

Source: [70,145,146,147,148,149,150]

Table 8: RISK MITIGATION STRATEGIES FOR FILLER-RELATED VASCULAR COMPLICATIONS

Step

Recommended Strategy

Knowledge

Know injection-site vascular anatomy, and be aware of inter-patient variations.

"Go easy"

Inject slowly, and apply the least amount of pressure necessary. Keep the needle moving. Restrict bolus injections to periosteal plane.

Monitor closely

Watch for blanching or any changes in skin color.

Be aware

In a vascular occlusion, epinephrine can mask skin blanching, and local anesthetic or lidocaine can mask pain.

Listen to your patient

Immediately stop injecting if resistance is encountered, or if patient reports pain, discomfort, or changes in vision.

Have a plan

Onsite protocols for immediate, early, and late adverse events should be easily accessible.

Discharge instructions

Describe in writing the signs/symptoms of vessel occlusion and where and why to seek medical attention.

Staff education

Educate clinic staff on accurate assessment and appropriate referral of patients who report filler adverse events.

Report the incident

Report vascular compromise adverse events to the FDA and filler manufacturer.

Source: [70,145,146,147,148,149,150]

Infection Risk

To minimize infection, stringent aseptic technique is mandatory [19,151]. Prior to any intervention, it is vital to clean, degrease, and disinfect the patient's skin. Remove makeup and cleanse carefully with 2% chlorhexidine in 70% alcohol, avoiding ocular exposure. When treating the perioral area, consider antiseptic mouthwash containing chlorhexidine or povidone-iodine for sterilizing the oral cavity.

The clinician should remove all jewelry, wash hands with antiseptic cleanser, and use gloves for all injections. Once the syringe is held, sterility is lost and aseptic technique is crucial. Not touching any needle or cannula component that penetrates the skin may further reduce infective complications. Cleansing a broad area avoids infective risk from inadvertently resting a cannula on adjacent uncleaned skin. Frequently change needles/cannula when using multiple entry points.

Biopsy can play a crucial role in diagnosing and treating filler-related adverse events, but cosmetic patients strongly resist facial biopsy unless absolutely necessary. A medicolegal process is always justified [152].

After treatment is administered, it is important to assess the patient's response. Clinicians should routinely check perfusion in treated and watershed (e.g., glabella, nasal tip, upper lip) areas [19]. Consider that makeup can obscure skin tone and signs of vascular compromise. Patients should be furnished with written post-treatment instructions and contact numbers. A follow-up call to the patient should be made within 24 hours, and the clinician/clinic should be available by phone for 48 hours postprocedure [19].

All facilities should have easily accessible protocols for early and delayed-onset reactions [19]. Resuscitation measures (e.g., epinephrine, IV access, fluids) and an adequate supply of hyaluronidase should be kept on hand, with regular checks of expiration dates on emergency drugs. In addition, contact information for an ophthalmologist or oculoplastic surgeon experienced in treating retinal artery occlusion should be maintained.

Anesthesia/Analgesia

Pain control is crucial to ensuring a positive experience for patients [76]. Topical anesthetics or local nerve blocks are commonly used to reduce pain, although many fillers are also formulated with lidocaine. To reduce pain, use the smallest suitable needle, slow infiltration, and the least needle punctures necessary. Other measures to help reduce pain include ice application, skin vibration, patient distraction, and a relaxed, soothing treatment environment [34].

COMMON ACUTE SIDE EFFECTS

Pain, bruising, redness, itching, and swelling are common, self-limiting side effects following dermal filler injections. Persistence beyond seven days should be closely assessed [144].

Pain

Pain is relatively common and is more likely with multiple needle punctures. However, pain may also be a sign of impending vascular compromise, discussed in detail later in this course. Pain can be minimized by using slow needle introduction, ice anesthesia, and filler warmed to body temperature [70].

Erythema

Erythema (redness) usually resolves without treatment. Longer-lasting or persistent erythema suggests hypersensitivity reaction or infection and requires careful evaluation. Oral tetracycline, isotretinoin, topical tacrolimus, or medium-strength topical steroids are suggested for persistent erythema; long-term, high-potency topical steroids should be avoided. In severe cases, oral propranolol (20 mg) can make erythema less evident [70,143].

Edema

Evidence Based Practice Recommendation

If ice is used to control pain following botulinum toxin or dermal filler injection, the Australasian College of Dermatologists recommends placing it inside either a sterile glove or a nonsterile glove, then wiping the glove with alcohol or chlorhexidine to sterilize it, as ice is not sterile. Alternatively, frozen gel packs may be used in the same way.

https://onlinelibrary.wiley.com/doi/full/10.1111/ajd.13273

Last Accessed: March 26, 2021

Level of Evidence: Expert Opinion/Consensus Statement

Edema (swelling) in the first few days is normal with all fillers and can be managed by gentle pressure and ice packs [83]. Episodic swelling and edema following filler injection can occur after sun exposure, exercise, or saunas. It is important not to confuse normal edema with allergic reaction; manage with ice packs, topical steroids, and avoidance of vasodilating stimuli [70].

Ice is recommended and commonly applied on the injection site to prevent and manage pain and edema, but it has also been associated with infection. An Oregon plastic surgery clinic described an outbreak of facial Mycobacterium chelonae infection (presenting as swollen skin nodules with drainage or discoloration three to six weeks after inoculation) following filler injections. The infections required three to four months of multiple oral or IV antimicrobial agents to resolve. The source was traced to clinic tap water, used for ice applied immediately pre- or post-injection [153]. As such, cold packs rather than ice may be safer options.

Bruising

Bruising, hematoma, and ecchymosis can result from needle pricks and bleeding. This can be minimized by firm pressure on the needle insertion site and prevented by cessation of alcohol and supplements with anticoagulant effects one week before treatment. Intense pulsed light and vascular lasers have been used to treat persistent symptoms [70].

Lesions

Papulopustular lesions occur when filler injected too superficially in the papillary dermis occludes, or extrudes through, sebaceous or sweat gland openings and mimics bacterial infection or acneiform eruption. Post-injection massage can help in prevention, and topical astringents can help in their resolution [70].

Overcorrection can appear as bumps, nodules, or irregularities when too much material is injected. In these cases, hyaluronic acid products should be resolved using hyaluronidase. With non-hyaluronic acid fillers, puncture and drainage of excess product may suffice [70].

INFREQUENT ACUTE ADVERSE EVENTS

Dysesthesias and Paresthesia

Dysesthesias and paresthesia are symptoms of nerve injury following direct trauma, injection of filler into a nerve, or tissue compression by the product. Nerve damage is usually transient and reversible, infrequently permanent, with the infraorbital nerve the most common site [143].

Intracranial Penetration

For deep periosteal or supraperiosteal injections, the needle is advanced to the level of the bone and retracted slightly. Accidental intracranial penetration is a demonstrated risk, but the prevalence is unknown [70].

VASCULAR COMPROMISE

Vascular compromise is the result of vascular occlusion following inadvertent intravascular filler injection or vascular compression by adjacent filler material. Embolism occurs when filler material enters the vasculature, impeding blood flow. Vascular compromise can involve arterial or venous occlusion [70,143,150].

Areas at highest risk of embolism have minimal collateral circulation (the nose), terminal blood supply (the glabella), large vessels (the nasal artery), or large areas (forehead) supplied by a vessel with minimal collateral circulation (terminal supratrochlear artery) [154]. Embolization of filler material is a potentially catastrophic complication with possible sequelae of tissue necrosis, blindness, or cerebrovascular accident. The literature is replete with examples of permanent blindness following hyaluronic acid, PLLA, or CaHA filler injections [122,155]. Intravascular injection occurs more frequently than assumed. In a study of expert aesthetic physicians, 62% reported inducing one or more such events [156].

Tissue Necrosis

With embolism induced by intra-arterial injection, damage to endothelial cells leads to ischemic changes in the skin, tissue degradation, and necrosis [71]. Cells undergoing necrosis swell and then burst, releasing their contents to trigger a local inflammatory reaction, with swelling, pain, heat, and redness. Intra-arterial injection can lead to embolism, platelet aggregation, subsequent occlusion in a terminal branch, and delayed-onset necrosis [145].

Necrosis can follow vascular occlusion due to vessel compression by filler material or filler-induced tissue swelling, and onset can be delayed. Tissue necrosis can occur with all dermal filler types but is more likely with particulate fillers [83,145]. With blood supply reliant on a single arterial branch, the glabella, nasal ala, and nasolabial folds are most vulnerable to necrosis [70,83].

The cardinal features of vascular occlusion and necrosis are changes in skin color and pain [70,71,145,150]. Skin blanching and severe pain are immediate with arterial occlusion. However, epinephrine use may mask blanching, and pain may not fully appear until local anesthetic or nerve block wears off. If not swiftly resolved, the affected skin will develop reticulated erythema, purpura, ulceration, and scarring.

With venous occlusion, red/bluish skin color changes appear immediately to hours later, with or without pain, progressing to blisters, pustules, and tissue necrosis within a few days.

Blindness

The most feared complication of filler injections is blindness following occlusion of the central retinal artery, the final branch of the ophthalmic artery. Comparing average diameters, injected hyaluronic acid filler particles (400 mcm) easily move through the ophthalmic artery (2 mm) to block the central retinal artery (160 mcm) [122,154,157].

The routes to occlusion and blindness vary by proximal branch of the ophthalmic artery inadvertently injected. When the force of injection exceeds intra-arterial pressure, the injectate can move proximally in the angular artery and then proximal of the origin of the central retinal artery. With pressure on the syringe released, the material moves distally into the retinal artery. Central retinal artery occlusion follows injection into the glabellar region (through the supratrochlear artery into the supraorbital artery) or the nasolabial fold (in any anastomosis of the dorsal nasal artery from the ophthalmic artery) [154]. Blindness, visual field deficit, or blurring is instant, often with excruciating ocular pain [70,83,143].

Stroke

With greater pressure on the plunger or for a longer time, the filler may travel into the internal carotid artery and then enter cerebral circulation, producing a stroke [122,150]. Unilateral blindness and left-sided hemiplegia immediately following glabellar area injections are reported. However, these effects are rare with dermal fillers and more likely with autologous fat injections [70]. Pulmonary embolism and panophthalmoplegia have also been reported with filler injections [19].

Management of Vascular Compromise

Intense pain is considered an initial sign of intravascular filler injection, but as noted, it may be obscured by lidocaine in fillers or by local anesthetic. Vigilance for skin color change is mandatory [19]. With any suspicion of vascular occlusion from inappropriate pain, skin blanching, or mottled discoloration, immediately stop injecting and aspirate any product when withdrawing the needle (if possible). It is vital to facilitate an immediate, aggressive response to remove the product and promote blood flow [19,71].

Hyaluronidase Reversal

With hyaluronic acid fillers, hyaluronidase injection is the foundation of emergent therapy for most adverse events, a powerful advantage of these products, as no other dermal filler material has a reversing agent [19]. Hyaluronidase injection enzymatically dissolves the hyaluronic acid filler material [68].

Hyaluronidase is indispensable in resolving acute hyaluronic acid filler adverse events. All clinicians who provide hyaluronic acid filler injection should always have an adequate supply of hyaluronidase in the office for emergencies and regularly check the product expiration date [122].

Evidence Based Practice Recommendation

Hyaluronidase has also been shown to diffuse into the lumen of blood vessels even when injected external to it. According to the Aesthetic Complications Expert Group, for potential cases of necrosis due to intravascular deposition of hyaluronic acid, it is not essential to inject directly into the vessel—injection into the surrounding area is also likely to result in dissolution of the product.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057733

Last Accessed: March 26, 2021

Level of Evidence: Expert Opinion/Consensus Statement

Hyaluronidase is recommended in vascular compromise from all filler types to reduce edema and potentially decrease vessel-occluding pressure. When injected immediately, hyaluronidase degrades hyaluronan, a potent proinflammatory mediator associated with tissue necrosis [58,71].

High-dose hyaluronidase (500–1,000 IU) mixed with lidocaine is injected in the affected vessel, the surrounding path of the vessel, and its terminal branch; a large-bore cannula avoids bruising that obscures signs of improving skin color. Doses up to 1,500 U may be used if needed; the consequences of inadequate dosing are dire. Repeat hourly for three to four hours and daily for at least four days or as long as signs of ischemia persist [71,146,158,159].

Injecting high-dose hyaluronidase diluted with lidocaine induces vasodilation and hyaluronic acid dispersion and, with saline, allows coverage of a larger area [71]. Vigorously massage the treated area during and after all hyaluronidase injections to optimize the results and aid mechanical breakdown [158].

Because anaphylaxis is a potential side effect of hyaluronidase and skin testing for hypersensitivity reaction is not an option in emergencies, risk mitigation requires full resuscitation equipment on site and training in its use [34,95,158].

Promote Blood Flow to the Affected Area

Evidence Based Practice Recommendation

For necrosis following dermal filler injection, nitroglycerin paste (rectal paste, used off label) can be applied under an occlusive dressing for several days. The Aesthetic Complications Expert Group recommends applying for 12 hours and then removing for 12 hours until clinical improvement is seen or until it is no longer tolerated.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057733

Last Accessed: March 26, 2021

Level of Evidence: Expert Opinion/Consensus Statement

Apply warm compresses, and vigorously massage or tap the area. To limit platelet aggregation, clot formation, and further compromise, the patient should be administered two tablets (650 mg) of aspirin to chew and swallow, followed by 75 mg per day until necrosis resolves [19,71,145].

Some experts recommend nitroglycerin paste 2% to promote vasodilation [70,145,160,161]. However, others caution against its use before the hyaluronic acid has dissolved with two or three days of treatment, as dilation of adjacent unobstructed vascular pathways may propagate the embolus toward the orbital area [19]. Low-molecular-weight heparin has also been used in the management of patients with filler-induced vascular occlusion [34].

Additional Recommendations

Necrotic cells and tissue invite opportunistic infection. The measures needed to promote healing and prevent further complications depend on the extent of necrosis and range from appropriate dressing and wound care with topical and/or oral antibiotics to surgical debridement for removal of dead tissue. Susceptible patients may require antiherpetic medication with perioral-area necrosis [145].

Necrosis can be very painful, and pain management should be considered. While over-the-counter analgesics may be adequate in some cases, more severe pain can require opioids [145]. Because necrosis can cause significant scarring and distress to patients, practitioners should prepare for a possible malpractice claim filed by the patient [145].

Ophthalmic Events

An ophthalmic event is a medical emergency, with 60 to 90 minutes the absolute time window for saving vision. Blindness from central retinal artery occlusion is resolvable following hyaluronic acid filler injection only with rapid intervention by retrobulbar injection of hyaluronidase. Occlusion longer than 60 to 90 minutes is irreversible [19].

An ophthalmologist or oculoplastic surgeon should be contacted immediately and the patient transported to the clinic. The general emergency department is inappropriate [122].

To save vision, a needle is advanced in the inferotemporal quadrant of the orbit, inferior and lateral to the optic nerve, with hyaluronidase 2–4 cc (150–200 U/mL) injected into the inferolateral orbit [122]. Attempt rapid ocular pulsed massage. Having the patient hyperventilate in a paper bag may promote retinal vessel dilation. If possible, annotate the time of the vascular event and the visual acuity if lack of light perception or loss of vision occurs [19].

ALLERGIC/HYPERSENSITIVITY REACTIONS

Acute infections appear as acute inflammation or abscesses at the injection site. If left untreated, the initial reddening and hardening can result in fistula formation, discharge of pus and filler, and potentially permanent disfigurement [162].

Hypersensitivity/allergic reactions occur when injected filler material triggers an immune response. Etiology differs by post-injection onset: acute (minutes to hours) or delayed (within days) [19,71,143,163].

Acute Hypersensitivity Reaction

Type I hypersensitivity reactions, mediated by immunoglobulin E (IgE), may present with angioedema or anaphylaxis. Check vital signs; anaphylactic shock is a medical emergency. Angioedema can also progress to airway obstruction. Any systemic manifestation should be considered impending anaphylaxis and treat as such. This involves immediately administering IV epinephrine; if insufficient to maintain perfusion, consider additional vasopressor agents (e.g., dopamine, norepinephrine, glucagon). H1-receptor antagonists (plus cimetidine) are recommended for histamine-induced hypotension.

Hospital admission should be considered for more severe cases, as late-phase reactions may occur more than 36 hours after onset. If possible, remove the dermal filler using hyaluronidase as needed.

Delayed Hypersensitivity Reaction

Type IV hypersensitivity reactions, mediated by T lymphocytes and not antibodies, usually present with induration, erythema, edema, or various types of skin lesions, including painful erythematous nodules. Management consists of cold compresses for localized angioedema and H1-receptor antagonists for histamine-induced hypotension and pruritus. H2-receptor antagonists, oral corticosteroids, and ibuprofen are additional measures.

DELAYED COMPLICATIONS: INFLAMMATION OR INFECTION?

Understanding of delayed dermal filler adverse events and pathogenesis has been a slowly evolving process, impeded by the inconsistent terminology describing these adverse events [148,152]. Delayed filler adverse events have long been considered foreign body immune responses or type IV immunologic reactions to filler materials or contaminants from production, reinforced by negative bacterial culture tests of pus from nodules and the low-grade nature of most inflammations [69,144,150,164]. Sporadic findings of bacterial infection in late-onset nodules were often ascribed to departures from antiseptic standards in skin prep or handling of fillers [165,166]. However, steroid or high-dose NSAID therapy to suppress a presumed inflammatory/immune response led to worsened inflammation and abscesses in some patients, who often required IV antibiotics or surgery [22,162].

In 2009, molecular diagnostics with fluorescence in situ hybridization and advanced imaging established bacterial colonization of tissue and filler material as the causality of chronic inflammation and nodules [165,167,168]. In 2010, the role of biofilm in late filler complications gained attention, helping explain adverse reactions to steroid therapy. These dense bacterial colonies on surfaces secrete extracellular polymers, forming a protective matrix against host defenses and antibiotics. Knowledge of biofilm involvement improved the characterization of filler adverse events [152,162].

A foreign body granuloma results when immune response, unable to enzymatically degrade a foreign body, forms lymphocytic inflammation and fibrosis entrapping the body, preventing its migration. Foreign body granulomas are histologically distinct from inflammatory nodules [70,71,150].

Foreign body granuloma formation can involve biofilm which, protected from host immune response, remains semidormant until activated months or years later by host conditions that favor replication (e.g., new filler injection, dental/medical surgery, local or remote infection, trauma). Activated biofilm can cause an immune response, granulomatous inflammation, abscesses, or nodules, and flu-like illness can precede late-onset nodules [19,22,69].

Thus, late-onset nodules or granuloma may represent an immune/inflammatory response secondary to biofilm-colonized filler. Clinical differentiation is challenging. Foreign material in the dermis or sub-dermis can lead to sterile abscesses, granulomas, cellulitis, or nodules. Infection months or years after injection may have similar signs, varying from erythema, edema, inflammatory nodules, and pain/itching to systemic responses [165].

Therapy for late-onset nodules or granuloma consists of [19,68,69,150]:

- Oral antibiotics with immunomodulatory and anti-inflammatory efficacy, with a macrolide (e.g., clarithromycin) or a tetracycline (e.g., minocycline or doxycycline)

- Systematic and intralesional corticosteroids

- Topical tacrolimus (0.1%) or pimecrolimus (1%)

- Intralesional 5-fluorouracil

- Laser treatment

- Surgical excision

Biofilm in Dermal Filler Infections

Biofilm as an increasing concern is reflected in surgical and infectious disease practice guidelines; uptake in cosmetic/aesthetic medicine is more recent. The skin is understood as a microbiota ecosystem, colonized by diverse micro-organisms. In normal skin flora, most bacterial constituents are harmless. Some are beneficial, such as Staphylococcus epidermidis, which inhibits the growth of pathogenic Staphylococcus aureus [169,170].

S. aureus, the most commonly isolated pathogenic bacteria in surgical-site infections, colonizes tissue and artificial surfaces and is found on 30% to 60% of healthy Americans. A disturbed balance of the skin ecosystem can favor S. aureus proliferation and biofilm [171,172,173,174].

Evidence Based Practice Recommendation

To minimize the risk of contamination and infection, the Australasian College of Dermatologists asserts that stringent hygiene, including the use of antiseptic non-touch technique at all times, is essential when fillers are injected. Because filler injections necessitate using hands to stabilize or pinch the skin, clinicians should perform antisepsis frequently during the procedure. They also note that sterile gloves may provide a false sense of security; therefore, they advocate changing gloves after preparing syringes for injection and marking the face.

https://onlinelibrary.wiley.com/doi/full/10.1111/ajd.13273

Last Accessed: March 26, 2021

Level of Evidence: Expert Opinion/Consensus Statement

On unbroken skin, S. aureus can remain asymptomatic; on injection sites, it can seed infections. The needle breaks the skin barrier, picking up bacteria that are delivered into the dermal filler and setting up infection in the tissue. Preoperative skin preparation for open surgery fails to remove 20% of resident skin flora [21,165,175].

Dermal filler skin prep is less stringent than presurgical site prep. However, it is important to remember that Isopropyl alcohol, chlorhexidine, and povidone iodine are demonstrably insufficient in preventing S. aureus biofilm transfer to tissue during filler injection [165,170].

S. aureus biofilm-seeded hyaluronic acid injections have been linked to bacterial infection in studies comparing subjects who developed late infection to complication-free subjects, matched on age and hyaluronic acid treatment (e.g., filler properties, injections, volume). Bacterial skin flora were cultured from nasal swabs in both groups and filler injection sites in patients with late bacterial infection repeatedly over 12 months [164]. S. epidermidis dominated the bacterial flora on facial skin in 100% of subjects without complications, but pathogenic S. aureus and Klebsiella spp. dominated the bacterial flora on the facial skin of subjects with late bacterial infection. Late bacterial infection was diagnosed a mean 5.5 months after filler injection; pus and inflammatory tissue cultures were negative for bacterial growth. No subjects consented to biopsy, but exhaustive exclusion of other etiologies suggested bacterial biofilm infection [164].

Concerns of Antibiotic Resistance

Bacteria in a biofilm matrix exchange DNA mutations to spread antibiotic-resistant genes and biodiversity. As biofilms mature, antibiotic and antimicrobial resistance strengthens [162,172,173,175]. A lack of biofilm-specific biomarkers has made noninvasive detection and diagnosis very difficult [174].

Biofilms are very difficult to treat and can require antibiotic concentration over 32 times that necessary for planktonic bacteria. Even the highest tolerable antibiotic dose can be insufficient [176]. Filler explant may be needed, putting the patient at risk for tissue scarring, deformity, and nerve or structural damage. Minimally biodegradable fillers have higher rates of delayed-onset infection [165].

MRSA is a serious concern because few remaining antibiotics are effective. Vancomycin-resistant S. aureus has also emerged—a potentially incurable infection [174]. In the general U.S. population, 20% are persistently colonized with S. aureus (i.e., carriers) and 2% are MRSA carriers. MRSA carriage among surgical staff (4.5%) and healthcare workers (5%) is higher, and many studies support MRSA transmission from healthcare workers to patients [170,177]. As such, MRSA carriage screening and decolonization of surgical staff and patients can reduce MRSA surgical infections. However, no protocols or data are available on plastic surgeon MRSA carriage, association with filler-site infections, or decolonization [178,179].

Management of biofilm infection consists of oral antibiotics with immunomodulatory and anti-inflammatory efficacy [19,22,143,150]. The first-line choice is a macrolide (e.g., clarithromycin) or a tetracycline (e.g., minocycline or doxycycline) for two weeks. Second-line therapy is dual macrolide- and tetracycline-class therapy. The addition of a quinolone (e.g., ciprofloxacin) is reserved as third-line therapy due to potential serious class-wide adverse events. Patients with systemic symptoms or more severe local infection may require hospitalization and IV antibiotics.

Additional treatment options include hyaluronidase, laser, surgical drainage of the abscess, and filler excision. Note that intralesional hyaluronidase requires extreme caution, as it can facilitate the spread of active infection into adjacent tissues.

Another strategy for treating biofilm is low-dose triamcinolone injection mixed with 5-fluorouracil at regular intervals until resolution. The efficacy of 5-fluorouracil may involve its interaction with ariR, a regulatory gene that inhibits biofilm formation [34].

12. CONCLUSION

The importance for primary care clinicians to understand aesthetic medicine, patient variables, and market factors is brought to light by the increasing rates of aesthetic injections performed by non-board-certified physicians, nurses, and minimally trained aestheticians at inadequately equipped clinics, office settings, and spas [20]. Primary care providers are well-placed to importantly inform their patients about many aspects related to aesthetic medicine but benefit from educational intervention to become most effective in this role.

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130. Chiang YZ, Pierone G, Al-Niaimi F. Dermal Fillers: pathophysiology, prevention and treatment of complications. J Eur Acad Dermatol Venereol. 2017;31(3):405-413.

131. Robson SJ. Managing expectations associated with cosmetic intervention. JCAD. 2017;4.

132. Higgins S, Wysong A. Cosmetic surgery and body dysmorphic disorder: an update. Int J Womens Dermatol. 2018;4(1):43-48.

133. Yazdandoost RY, Hayatbini N, Asgharnejad Farid AA, Gharaee B, Latifi NA. The body image dissatisfaction and psychological symptoms among invasive and minimally invasive aesthetic surgery patients. World J Plast Surg. 2016;5(2):148-153.

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135. Sweis IE, Spitz J, Jr Barry DR, Cohen M. A review of body dysmorphic disorder in aesthetic surgery patients and the legal implications. Aesthetic Plast Surg. 2017;41(4):949-954.

136. Rongioletti F, Atzori L, Ferreli C, et al. Granulomatous reactions after injections of multiple aesthetic micro-implants in temporal combinations: a complication of filler addiction. J Eur Acad Dermatol Venereol. 2015;29(6):1188-1192.

137. Lin CH, Chiang CP, Wu BY, Gao HW. Filler migration to the forehead due to multiple filler injections in a patient addicted to cosmetic fillers. J Cosmet Laser Ther. 2017;19(2):124-126.

138. Urdiales-Galvez F, Delgado NE, Figueiredo V, et al. Preventing the complications associated with the use of dermal fillers in facial aesthetic procedures: an expert group consensus report. Aesthetic Plast Surg. 2017;41(3):667-677.

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145. King M. This month's guideline: management of necrosis. J Clin Aesthet Dermatol. 2018;11(7):E53-E57.

146. Allen S. Anatomic Danger Zones for Facial Injection of Soft Tissue Fillers. Available at https://www.uptodate.com/contents/anatomic-danger-zones-for-facial-injection-of-soft-tissue-fillers. Last accessed March 15, 2021.

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148. DeLorenzi C. Complications of injectable fillers, part 1. Aesthetics Surg J. 2013;33(4):561-575.

149. DeLorenzi C. Complications of injectable fillers, part 2: vascular complications. Aesthet Surg J. 2014;34(4):584-600.

150. Abduljabbar MH, Basendwh MA. Complications of hyaluronic acid fillers and their managements. Journal of Dermatology and Dermatologic Surgery. 2016;20(2):100-106.

151. Saththianathan M, Johani K, Taylor A, et al. The role of bacterial biofilm in adverse soft-tissue filler reactions: a combined laboratory and clinical study. Plast Reconstr Surg. 2017;139(3):613-621.

152. Almeida A, Banegas R, Martinez C, et al. Diagnosis and treatment of hyaluronic acid adverse events: Latin American expert panel consensus recommendations. Surg Cosmet Dermatol. 2017;9(3):204-213.

153. Rodriguez JM, Xie YL, Winthrop KL, et al. Mycobacterium chelonae facial infections following injection of dermal filler. Aesthet Surg J. 2013;33(2):265-269.

154. Balczun J. Dermal Fillers: All the Things that Can Go Wrong. Available at http://www.prime-journal.com/dermal-fillers-all-the-things-that-can-go-wrong. Last accessed March 15, 2021.

155. Prado G, Rodríguez-Feliz J. Ocular pain and impending blindness during facial cosmetic injections: is your office prepared? Aesthetic Plast Surg. 2017;41(1):199-203.

156. Goodman GJ, Roberts S, Callan P. Experience and management of intravascular injection with facial fillers: results of a multinational survey of experienced injectors. Aesthetic Plast Surg. 2016;40(4):549-555.

157. Beleznay K, Carruthers JDA, Humphrey S, Jones D. Avoiding and treating blindness from fillers: a review of the world literature. Dermatol Surg. 2015;41(10):1097-1117.

158. King M, Convery C, Davies E. This month's guideline: the use of hyaluronidase in aesthetic practice (v2.4). J Clin Aesthet Dermatol. 2018;11(6):E61-E68.

159. Signorini M, Liew S, Sundaram H, et al. Global Aesthetics Consensus: avoidance and management of complications from hyaluronic acid fillers: evidence- and opinion-based review and consensus recommendations. Plast Reconstr Surg. 2016;137(6):961e-971e.

160. Beer K, Downie J, Beer J. A treatment protocol for vascular occlusion from particulate soft tissue augmentation. J Clin Aesthet Dermatol. 2012;5(5):44-47.

161. Sclafani AP, Fagien S. 2009. Treatment of injectable soft tissue filler complications. Dermatol Surg. 2009;35(Suppl 2):1672-1680.

162. Alhede M, Bjarnsholt T. Are biofilms responsible for the adverse effects experienced following soft-tissue fillers? Future Microbiol. 2014;9(8):931-933.

163. Bhojani-Lynch T. Late-onset inflammatory response to hyaluronic acid dermal fillers. Plast Reconstr Surg Glob Open. 2017;5(12):e1532.

164. Netsvyetayeva I, Marusza W, Olszanski R, et al. Skin bacterial flora as a potential risk factor predisposing to late bacterial infection after cross-linked hyaluronic acid gel augmentation. Infect Drug Resist. 2018;11:213-222.

165. Wang Y, Leng V, Patel V, Phillips KS. Injections through skin colonized with Staphylococcus aureus biofilm introduce contamination despite standard antimicrobial preparation procedures. Sci Rep. 2017;7:45070.

166. Dumitraşcu DI, Georgescu AV. The management of biofilm formation after hyaluronic acid gel filler injections: a review. Clujul Med. 2013;86(3):192-195.

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Evidence-Based Practice Recommendations Citations

1. Goodman GJ, Liew S, Callan P, Hart S. Facial aesthetic injections in clinical practice: pretreatment and posttreatment consensus recommendations to minimise adverse outcomes. Australas J Dermatol. 2020;61(3):217-225. Available at https://onlinelibrary.wiley.com/doi/full/10.1111/ajd.13273. Last accessed March 26, 2021.

2. King M. This month's guideline: management of necrosis. J Clin Aesthet Dermatol. 2018;11(7):E53-E57. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057733. Last accessed March 26, 2021

95323 • Diabetes Pharmacology

Diane Thompson, RN, MSN, CDE, CLNC

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Diabetes is a serious and growing problem in the United States. Behavior change, diet, and exercise are first in the line of treatment for this chronic disease. However, diabetes is a progressive disease, and these techniques will only work for a small portion of patients. Oral medications will eventually be necessarily incorporated into treatment plans in order to preserve control of the disease at an optimal level, and injectable medications are started in the second tier of therapy when glucose levels are significantly greater than the goal range. Healthcare professionals are required to sustain a fundamental understanding of diabetes medication classes, including action, maximal safe dosing, and side effects, when caring for their patients. Oral medications for diabetes impact individuals to differing degrees and maintain various safe practice recommendations. Furthermore, although insulin and other injectable medications are beneficial, patient acceptance of injectable medications continues to be a significant barrier to achieving optimal blood glucose control. The emotional stressors can be a substantial barrier to success for individuals and their significant others and/or caregivers. These emotional interferences include needle fears and phobias, ignorance, and time constraints. Patients' responses to the medications, laboratory results for safe, efficacious dosing, and drug effects must all be monitored.

Table of Contents

95323 • Diabetes Pharmacology

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. DIABETES EPIDEMIOLOGY

3. PATHOGENESIS OF DIABETES

PHYSIOLOGY OF INSULIN RELEASE IN FUEL METABOLISM

4. DIABETES RESEARCH

THE DIABETES PREVENTION PROGRAM

THE DIABETES COMPLICATION AND CONTROL TRIAL

THE UNITED KINGDOM PROSPECTIVE DIABETES STUDY

TREAT-TO-TARGET TRIAL

4-T TRIAL

ORIGIN TRIAL

CAROLINA TRIAL

5. DIAGNOSIS OF DIABETES

TYPES OF DIABETES

SCREENING FOR DIABETES

DIAGNOSTIC CRITERIA

6. SULFONYLUREA THERAPY: FIRST AND SECOND GENERATIONS

FIRST-GENERATION AGENTS

SECOND-GENERATION AGENTS

POTENTIAL SIDE EFFECTS

CASE STUDY

7. NONSULFONYLUREA SECRETAGOGUE (GLINIDE) THERAPY

REPAGLINIDE

NATEGLINIDE

POTENTIAL SIDE EFFECTS

CASE STUDY

8. ALPHA-GLUCOSIDASE INHIBITOR THERAPY

ACARBOSE

MIGLITOL

POTENTIAL SIDE EFFECTS

CASE STUDY

9. BIGUANIDE THERAPY

POTENTIAL SIDE EFFECTS

CASE STUDY

10. THIAZOLIDINEDIONE THERAPY

PIOGLITAZONE

ROSIGLITAZONE

POTENTIAL SIDE EFFECTS

CASE STUDY

11. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITOR THERAPY

SITAGLIPTIN

SAXAGLIPTIN

LINAGLIPTIN

ALOGLIPTIN

CASE STUDY

12. SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

POTENTIAL SIDE EFFECTS

13. COMBINATION ORAL MEDICATION PREPARATIONS

CASE STUDY

14. BOLUS INSULIN THERAPY

INSULIN ASPART

INSULIN LISPRO

INSULIN GLULISINE

REGULAR INSULIN

HYPERGLYCEMIC CRISES

15. BASAL INSULIN

NPH (INTERMEDIATE-ACTING) INSULIN

INSULIN GLARGINE

INSULIN DETEMIR

POTENTIAL SIDE EFFECTS

16. COMBINATION INSULIN PREPARATIONS

17. INCRETIN MIMETICS

CASE STUDY

18. AMYLIN ANALOGS

19. PATIENT EDUCATION

ORAL DIABETES MEDICATIONS

HYPOGLYCEMIA

TIMING OF MEDICATIONS AND OTHER CONSIDERATIONS

INSULIN AND NONINSULIN INJECTABLES

20. CASE STUDIES

CASE STUDY 1

CASE STUDY 2

CASE STUDY 3

21. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95323 • Diabetes Pharmacology

Education Category. Pharmacology

Release Date. 11/01/2019

Expiration Date. 10/31/2022

Course Overview

Diabetes is a serious and growing problem in the United States. Behavior change, diet, and exercise are first in the line of treatment for this chronic disease. However, diabetes is a progressive disease, and these techniques will only work for a small portion of patients. Oral medications will eventually be necessarily incorporated into treatment plans in order to preserve control of the disease at an optimal level, and injectable medications are started in the second tier of therapy when glucose levels are significantly greater than the goal range. Healthcare professionals are required to sustain a fundamental understanding of diabetes medication classes, including action, maximal safe dosing, and side effects, when caring for their patients. Oral medications for diabetes impact individuals to differing degrees and maintain various safe practice recommendations. Furthermore, although insulin and other injectable medications are beneficial, patient acceptance of injectable medications continues to be a significant barrier to achieving optimal blood glucose control. The emotional stressors can be a substantial barrier to success for individuals and their significant others and/or caregivers. These emotional interferences include needle fears and phobias, ignorance, and time constraints. Patients' responses to the medications, laboratory results for safe, efficacious dosing, and drug effects must all be monitored.

Audience

This course is designed for pharmacy professionals and nurses in any practice setting with a desire to familiarize themselves with the medications used in the treatment of type 2 diabetes.

Course Objective

The purpose of this course is to meet the needs of healthcare professionals seeking a better understanding of the actions, dosages, onset of action, and adverse effects of diabetes medications in order to provide optimal care to their patient population.

Learning Objectives

Upon completion of this course, you should be able to:

1. Outline the epidemiology of diabetes in the United States.

2. Describe normal fuel metabolism and the pathogenesis of type 1 and type 2 diabetes.

3. Analyze the current state of diabetes research.

4. Identify the diagnostic criteria and screening guidelines for diabetes.

5. Discuss the role of sulfonylureas in the treatment of diabetes, including potential side effects.

6. Review the pharmacology of nonsulfonylurea secretagogues.

7. Compare and contrast the alpha-glucosidase inhibitors available for the treatment of diabetes.

8. Describe the role of metformin in diabetes management.

9. Assess the strengths and weaknesses of thiazolidinediones and dipeptidyl peptidase-4 inhibitors to control blood glucose levels.

10. Identify various bolus insulin options, and outline the risk and response to related hyperglycemic crises.

11. Discuss the importance of basal insulin in the treatment of type 1 and type 2 diabetes.

12. Compare the efficacy and actions of incretin mimetics and amylin analogs.

13. Choose key topics that should be included in patient education plans for individuals being treated with oral or injectable diabetes medications.

Faculty

Diane Thompson, RN, MSN, CDE, CLNC, has an extensive history in nursing and nursing education. She possesses a strong background in diabetes and cardiac care, starting her professional career at the cardiac care area of the Cleveland Clinic in Cleveland, Ohio. Ms. Thompson took the knowledge and experience she learned from the Cleveland Clinic and transferred it into the home health arena in rural Ohio, after which she moved to Florida and obtained further knowledge while working as a PRN nurse in all areas, including medical/surgical, intensive care, emergency, critical care, and cardiology. With a desire to have a specific area to concentrate her profession, Ms. Thompson accepted a position as a pneumonia case manager, which led into a diabetes case manager career.

Ms. Thompson has been employed in diabetes care since 2001, when she was hired as a diabetes case manager. After the completion of 1,000 hours of education to diabetes patients, Ms. Thompson earned her certification as a diabetes educator in 2003. From 2006 to 2018, Ms. Thompson was the Director of Diabetes Healthways at Munroe Regional Medical Center in Ocala, Florida. As the director of the diabetes center, Ms. Thompson was responsible for the hospital diabetes clinicians, hospital wound care clinicians, and out-patient education program. Today, she is the nurse manager of a heart, vascular, and pulmonary ambulatory clinic at Metro Health System in Cleveland, Ohio. Ms. Thompson has also lectured at the local, state, and national level regarding diabetes and the hospital management of hyperglycemia. Ms. Thompson is a member of the ADA, AADE, Florida Nurses Association, and the National Alliance of Certified Legal Nurse Consultants.

Ms. Thompson acknowledges her family as her greatest accomplishment. She is a wife of more than 30 years and a mother of a daughter and son, of which she is very proud. Ms. Thompson credits her husband for the support needed to set a goal and achieve it. He has been by her side through nursing school and completion of her Bachelor's degree and Master's degree, which she was awarded in 2015 from Jacksonville University in Florida.

Faculty Disclosure

Contributing faculty, Diane Thompson, RN, MSN, CDE, CLNC, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

Jane C. Norman, RN, MSN, CNE, PhD

Abimbola Farinde, PharmD, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Diabetes is a serious and growing problem in the United States. Behavior change, diet, and exercise are first in the line of treatment for this chronic disease. However, diabetes is a progressive disease, and these techniques will only work for a small portion of patients. Oral medications will eventually be necessarily incorporated into treatment plans in order to preserve control of the disease at an optimal level, and injectable medications are started in the second tier of therapy when glucose levels are significantly greater than the goal range [1]. Healthcare professionals are required to sustain a fundamental understanding of diabetes medication classes, including action, maximal safe dosing, and side effects, when caring for their patients. Oral medications for diabetes impact individuals to differing degrees and are associated with differing safe practice recommendations. Furthermore, although insulin and other injectable medications are beneficial, patient acceptance of injectable medications continues to be a significant barrier to achieving optimal blood glucose control [2]. Laboratory results, drug effects, and patient response to treatment should all be monitored.

2. DIABETES EPIDEMIOLOGY

Diabetes, known clinically as diabetes mellitus, is a progressive disease process affecting the fuel metabolism functioning within the body [3]. According to the Centers for Disease Control and Prevention (CDC), the prevalence of diagnosed diabetes has increased from less than 1% of the U.S. population in 1958 to more than 7% in 2014 [4]. As of 2017, 9.4% of the U.S. population, or 30.3 million Americans, have diabetes. Unfortunately, 7.2 million of these individuals are unaware of their diabetes diagnosis [5,6]. Diabetes has been considered epidemic since the 1970s, and the percentage of Americans expected to have diabetes or impaired glucose tolerance (IGT) is estimated to reach 15% to 20% by the year 2025 [7].

The scope of the problem is vast and diverse. From 1994 through 2015, the prevalence of diagnosed diabetes increased across all states. In 1994, only one state had a prevalence greater than 6.0%. In 2015, all states had prevalences greater than 6.0%, and 27 exceeded 9.0% [8]. According to data from the Behavioral Risk Factor Surveillance System, West Virginia has the highest rate of adults with diabetes (16.2%). Nine of the 10 states with the highest rates (12% to 15.9%) are in the South. Colorado ranked last at 7.1% [8]. Genetics, race, age, and lifestyle influence the onset and progression of the disease process significantly [9]. According to 2013–2016 national survey data, diabetes was higher among non-Hispanic black (17.9%) and Hispanic (19.8%) adults compared with non-Hispanic white (12.4%) adults. The prevalence of diagnosed diabetes was higher in Hispanic (13.6%) and non-Hispanic black (13.9%) adults compared with non-Hispanic Asian (10.2%) and non-Hispanic white (8.5%) adults. The prevalence of undiagnosed diabetes is higher in Hispanic (6.2%) adults compared with non-Hispanic white (3.9%) and non-Hispanic black (4.0%) adults [10]. Native Americans/Alaskan Natives present the greatest risk for the development of type 2 diabetes; their risk is more than two times greater than that of white Americans. It is estimated that 15.1% of Native Americans/Alaskan Natives older than 20 years of age have diabetes [6]. The highest prevalence of diabetes in the United States is observed in Native Americans in southern Arizona, where an estimated 22% of the population has developed diabetes [6].

The most rapid increase in prevalence in the last decade has been among adolescents. Historically, children and adolescents with hyperglycemia have been diagnosed with type 1 diabetes, a result of the body being unable to produce adequate amounts of insulin. However, in 2012, researchers from the SEARCH for Diabetes in Youth study released data showing a 21% increase in type 2 diabetes between 2001 and 2009 in youth 10 to 19 years of age, with the number of cases rising faster among girls than boys [11]. Approximately 5,300 children and adolescents were newly diagnosed with type 2 diabetes during 2011–2012. Those who were members of racial or ethnic minority groups had the highest rates of new cases [6]. It has been predicted that children born in this millennium will have a one in three chance of developing diabetes in their lifetime; among high-risk ethnic groups, the estimate is as high as one in two [12].

3. PATHOGENESIS OF DIABETES

Individuals with type 1 diabetes typically present to their primary care office or hospital emergency department with a sudden weight loss and severe hyperglycemia [13]. The consequences of the disease can take years to impact the body if optimally controlled. In contrast, an individual with type 2 diabetes may be unaware of the disease process for years prior to being diagnosed. The onset of type 2 diabetes is insidious, with the loss of first-phase insulin response to postprandial levels. The first elevation may be detected at the time of screening as prediabetes or IGT [7]. During this time, the disease progression and hyperglycemia are ravening the body's micro- and macrovascular systems [3].

In a healthy body, carbohydrate consumption results in an initial swell in serum glucose levels and hyperglycemia. In response to this escalation, the body releases insulin from pancreatic beta cells into the circulatory system to assist with glucose transport into muscle, liver, and adipose tissues; this causes a lowering of the blood glucose levels.

In the case of type 1 diabetes, pancreatic beta cells fail to produce and release insulin, and the only treatment option is exogenous insulin and other appropriate injectables [7]. However, the pathogenesis of type 2 diabetes is more complex. Virtually all individuals diagnosed with type 2 diabetes have insulin resistance in conjunction with some degree of insulin deficiency [14]. In response, the body's inability to react to the mounting glucose level is magnified by insulin deficiency in the functioning pancreatic beta cells, insulin resistance in the muscular tissue, or both [3]. Unlike the therapy for type 1 diabetes, type 2 diabetes is initially treated with lifestyle modification therapy (e.g., medical nutrition therapy, exercise, behavior change) and frequently with an oral medication, such as a biguanide. Within five years of type 2 diabetes diagnosis, it is estimated that as many as 90% of people will fail this initial therapy and require further oral medications or injectables to achieve adequate glucose control. As a result of this failure rate, medication therapy is initiated early (in the prediabetes stage) in diabetes medical treatment algorithms [15].

PHYSIOLOGY OF INSULIN RELEASE IN FUEL METABOLISM

In order to fully comprehend the action of exogenous insulin, healthcare providers require a solid understanding of insulin physiology. Glucose regulation is maintained by a sophisticated mechanism of regulatory and counter-regulatory reactions. When an individual consumes food, specifically carbohydrates, sugars are released into the blood circulatory system [16]. The chemical reactions to this sugar introduction help maintain homeostasis in the body.

Phases of Insulin Response

The concentration of plasma glucose is dependent on the rate glucose enters the circulation in contrast to the rate it is removed [17]. Fuel homeostasis within the body can be explained in a five-phase approach [18]. Phase 1, or the fed state, occurs immediately and up to 3.9 hours after consumption of food. During this phase, the circulating glucose is predominantly from an exogenous source. Plasma insulin levels are elevated, glucagon levels are minimal, and triglycerides are synthesized in the liver. Insulin impedes the breakdown of glycogen and triglyceride reservoirs. The brain and other glucose-dependent organs utilize some of the glucose absorbed from the intestinal tract, and the excess glucose is stored in the liver, muscle, adipose tissue, and other tissues for use later.

Phase 2 occurs 4 to 15.9 hours after consumption of food and is referred to as the postabsorptive state. In phase 2, blood glucose originates from the breakdown of glycogen and hepatic gluconeogenesis. There is a decrease in plasma insulin levels, and glucagon levels begin to increase. Anabolism (energy storage) ends in this phase and catabolism (energy production) begins. There is a mobilization of carbohydrate and lipid stores. Hepatic glycogen breakdown provides maintenance of circulating plasma glucose to ensure an adequate supply of glucose to the brain and other organs. Adipocyte triglyceride begins to break down, and free fatty acids are released into the circulatory system for use by the liver and skeletal muscle as the primary energy source and as a substrate for gluconeogenesis. The brain continues to utilize glucose, provided mainly by gluconeogenesis, due to its inability to use free fatty acids.

Phase 3 is the early starvation state. About 16 to 47.9 hours after the consumption of food, the blood glucose is generated from hepatic gluconeogenesis and glycogenolysis. Gluconeogenesis continues to generate most of the hepatic glucose. In this phase of starvation, lactate makes up half of the gluconeogenesis substrate along with amino acids (specifically alanine) and glycerol. The secretion of insulin is suppressed, and counter-regulatory hormone (i.e., glucagon, cortisol, growth hormone, epinephrine) secretion is stimulated.

Phase 4 begins 48 hours to 23 days after food consumption. During this preliminary prolonged starvation state, blood glucose originates from hepatic and renal gluconeogenesis. Within 60 hours of starvation, gluconeogenesis provides more than 97% of hepatic glucose output. The secretion of insulin is distinctly diminished and counter-regulatory hormone secretion is stimulated.

Phase 5, or the secondary prolonged starvation state, begins 24 days after food consumption. Blood glucose during this phase originates from hepatic and renal gluconeogenesis, just as in phase 4. However, in phase 5 the rate of glucose being utilized by the brain and the rate of gluconeogenesis diminishes.

The relationship between the glucoregulatory and the counter-regulatory hormones and the many factors that contribute to the fuel metabolism should be considered. There is a sophisticated relationship between the metabolic-regulatory hormones insulin (a glucoregulatory hormone), glucagon, and epinephrine. When insulin is elevated, glucagon and epinephrine are suppressed [19]. This process occurs to prevent the continued rise of endogenous glucose levels. Conversely, when insulin levels decline in response to diminished circulating glucose levels, glucagon and epinephrine respond by increasing. These relationships are maintained when normal homeostasis is present. In patients with diabetes, there is a disruption of this homeostasis [20].

4. DIABETES RESEARCH

A strong focus has been placed on the area of prevention and treatment of type 2 diabetes with oral medications, lifestyle modification, and/or injectable medications. As the body of research grows, clinicians gain insights into possible treatment approaches and best practices.

THE DIABETES PREVENTION PROGRAM

The National Institute of Health's sponsored study, the Diabetes Prevention Program (DPP), was sanctioned to determine if diabetes could be prevented or delayed through the use of various interventions. The study was conducted in 27 centers throughout the United States, and the study participants were randomized into one of four treatment groups [21]. Treatment groups included lifestyle and behavior change or therapy with metformin, troglitazone, or placebo [21].

All 3,234 study participants were 25 years of age or older, overweight, and had IGT and elevated fasting plasma glucose, which are risk factors for the development of type 2 diabetes. In addition, 45% of the participants were from minority groups—African American, Alaskan Native, Native American, Asian American, Hispanic/Latino, or Pacific Islander—and 20% were 65 years of age or older. The study lasted more than three years but was halted earlier than expected due to 25 of the 27 centers demonstrating remarkable findings proving the hypothesis [21].

The first group, referred to as the lifestyle intervention group, received intensive education and counseling pertaining to diet, physical activity, and behavior modification. For individuals in this group, the overall goal was to maintain a loss of 7% of total body weight by consuming a decreased amount of fat and fewer calories and engaging in 150 minutes of exercise per week. The metformin treatment group was prescribed 850 mg of metformin twice per day, while the placebo group received placebo pills twice per day. Both the metformin and placebo groups also received education regarding lifestyle interventions (e.g., diet, exercise) but not intensive counseling. The troglitazone group was prescribed 400 mg of the drug daily, but this arm of the study was discontinued due to concerns that troglitazone was associated with liver toxicity. Participants in the troglitazone group continued to be followed but were not included as one of the intervention groups [21]. Troglitazone was removed from the U.S. market in 2000 [22].

The researchers found that participants who lost a modest amount of weight through dietary changes and increased physical activity sharply reduced their chances of developing diabetes [21]. The metformin treatment group also displayed a reduced risk for the development of diabetes, but the decrease was less dramatic.

THE DIABETES COMPLICATION AND CONTROL TRIAL

Research has also proven that tight glycemic control can prevent the development of chronic microvascular complications in diabetic patients. Initial research in the Diabetes Complication and Control Trial (DCCT) focused on the benefits of conventional versus intensive therapy for the prevention of complications related to type 1 diabetes [14,23]. The study involved 1441 individuals and demonstrated enough statistical power to unequivocally demonstrate the importance of glycemic control with utilization of multiple daily insulin injections [23,24].

This randomized controlled trial found that the risk of microvascular complications was reduced by intensive glycemic control in patients with type 1 diabetes. Participants in the intensively treated group (goal glycosylated hemoglobin [HbA1c]: <6.05%; mean achieved HbA1c: approximately 7%) demonstrated an approximately 60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy compared to the standard group (mean achieved HbA1c: approximately 9%) over an average of 6.5 years. The relationship between glucose control and risk of complications was linear and extended down to the normal HbA1c range (<6%) with no threshold noted [25].

When the DCCT ended in 1993, researchers began a follow-up study called the Epidemiology of Diabetes Interventions and Complications (EDIC). The EDIC continues to follow more than 90% of DCCT participants, assessing the incidence and predictors of cardiovascular disease events (e.g., heart attack, stroke, needed heart surgery) and diabetic complications related to the eye, kidney, and nerves. For example, the EDIC has shown that an individualized eye exam schedule results in fewer eye exams, lower costs, and faster diagnosis and treatment of advanced diabetic eye disease [26]. The EDIC also is examining the impact of intensive versus standard control on participants' quality of life [23].

THE UNITED KINGDOM PROSPECTIVE DIABETES STUDY

Research from the DCCT trial was further substantiated in the United Kingdom Prospective Diabetes Study (UKPDS), a clinical trial of patients with newly diagnosed type 2 diabetes conducted between 1977 and 1997. Once more, the groups were separated into a conventional therapy study arm or an intensive therapy arm to determine the efficacy and outcomes of the differing treatments [14]. Intensive blood glucose control was achieved utilizing sulfonylurea medications or insulin in normal-weight people and metformin in participants who were overweight. The UKPDS aimed to treat patients using only a single medication even if blood glucose became quite high because, at the time, there were some concerns that utilizing multiple medications had the potential of being harmful. In the conventional therapy cohort, lifestyle alone was used to control blood glucose. This was the first study to establish the now well-known association between level of glucose control and the reduction of microvascular complications (i.e., retinopathy, nephropathy, neuropathy) in individuals with type 2 diabetes [27].

When researchers revisited the participants of the UKPDS after 10 years, it was found that those who had been in the tight glycemic control arm during the trial had a lower risk of myocardial infarction and death than those who participated in the conventional glycemic control arm [28]. This finding was somewhat surprising because within one year of UKPDS ending, differences in HbA1c levels between the intensive and conventional treatment groups had disappeared. However, 10 years later, the follow-up study reported that myocardial infarction risk was reduced 15% in the sulfonylurea/insulin group and 33% in the metformin group, while overall risk of death was reduced 13% and 27%, respectively [28]. With this knowledge, the goal for diabetes treatment is striving for euglycemia by utilizing behavior change, meal planning, and lifestyle change followed by medication management [7].

TREAT-TO-TARGET TRIAL

The Treat-to-Target Trial was designed to determine if the addition of basal insulin at bedtime to an existing oral therapy regimen could improve achievement of the recommended 7% HbA1c target. Its secondary goal was to assess the efficacy and safety of glargine compared to neutral protamine Hagedorn (NPH) insulin as the basal insulin of choice in this treatment approach [29].

Researchers found that the addition of bolus insulin at bedtime (either glargine or NPH) reduced the average HbA1c level from 8.6% to 7%, with almost 60% of patients reaching 7% or less [29]. This high success rate may be attributed to the fact that the average baseline HbA1c was lower than in most other studies, the majority of study participants had advanced diabetes (suggested by poor glucose control on two oral agents), and more than 90% of participants adhered to the treatment, indicating it was an easy regimen to follow. Researchers also systematically titrated the insulin dosage to target [29].

Although fasting glucose and HbA1c levels were similar with both types of insulin, glargine was associated with fewer symptoms of hypoglycemia and less variability in fasting glucose levels [29]. Rates of severe hypoglycemia were low for both insulins, but nocturnal hypoglycemia was significantly more likely with NPH insulin. Nocturnal hypoglycemia was reduced from 42% to 48% in the glargine group, indicating that this insulin's lower peak of action would make it a better choice for this treatment approach [29].

4-T TRIAL

The Treating to Target Type 2 Diabetes, or 4-T, Trial was established to determine the effects of adding biphasic, prandial, or basal insulin to oral therapy for type 2 diabetes [30]. Participants in the trial had suboptimally controlled diabetes (mean HbA1c: 8.5%) despite treatment with sulfonylurea plus metformin. Subjects were randomized into three treatment groups: biphasic insulin aspart (twice daily), prandial insulin aspart (three times daily), or basal insulin detemir (once or twice daily, as required). All patients continued their established oral therapy, and dose titration, glucose monitoring, and follow-up visits were provided for all. After one year, the mean HbA1c level had decreased in all treatment groups, to 7.3% with biphasic insulin, 7.2% with prandial insulin, and 7.6% with basal insulin. However, no group met the goal of 6.5% or less; only 17%, 23.9%, and 8.1% of participants, respectively, met the goal. Although biphasic and prandial insulin more effectively lowered mean HbA1c levels, they were associated with greater risks of hypoglycemia and weight gain [30]. The authors concluded, based on a comparison of the risks and benefits of each approach, that the treatment of choice would be adding once-daily basal insulin to an established oral medication regimen for type 2 diabetes patients [30,31]. Three years after the study concluded, the majority of patients in each group were receiving a second type of insulin (67.7% of the biphasic group, 81.6% of the prandial group, and 73.6% of the basal group) [30].

ORIGIN TRIAL

The Outcome Reduction with Initial Glargine Intervention (ORIGIN) Trial was a large study attempting to identify the advantages of insulin glargine therapy and omega-3 fatty acids (fish oil) in managing type 2 diabetes and associated cardiovascular risks. The trial was completed in 2013 [32]. Because the majority of individuals who experience a myocardial infarction have impaired fasting glucose and/or IGT, investigators believed that achieving lower blood glucose levels (using insulin) might reduce the risk of cardiovascular events. The ORIGIN Trial randomized participants into groups receiving standard insulin glargine or variable-dose glargine, and further into subgroups receiving 865 mg of omega-3 fatty acid or placebo. The trial followed 12,500 individuals to determine the effect on the incidence of cardiovascular events [32]. Results indicated no difference in the incidence of cardiovascular events between the insulin glargine and standard care groups. Additionally, there was no difference in the incidence of cardiovascular death between the omega-3 fatty acid supplement and placebo groups. Insulin glargine provided better glucose control and lower risk of new diabetes. Side effects included a small increase in risk of hypoglycemia and weight gain of approximately 1.6 kg over a period of more than six years [33].

CAROLINA TRIAL

The Cardiovascular Outcome Study of Linagliptin versus glimepiride (CAROLINA) trial was a randomized, noninferiority clinical trial that compared the effect of linagliptin with glimepiride on major cardiovascular events in more than 6,000 participants with type 2 diabetes and elevated cardiovascular risk [34]. Participants were randomized to receive 5 mg of linagliptin once daily or 1–4 mg of glimepiride once daily in addition to usual care. The primary outcomes were time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The median duration of follow-up was 6.3 years. A cardiovascular event occurred in 356 (11.8%) participants in the linagliptin group and 362 (12%) participants in the glimepiride group. Results indicated that the use of linagliptin compared with glimepiride resulted in a noninferior risk of composite cardiovascular outcome [34].

5. DIAGNOSIS OF DIABETES

TYPES OF DIABETES

As discussed, the most common types of diabetes are type 1 and type 2. However, gestational diabetes is also relatively common and is a source of significant morbidity and mortality. Gestational diabetes is first recognized in pregnancy, usually around the 24th week of gestation, and typically resolves after the birth of the child. Gestational diabetes is estimated to affect 10% of pregnancies [35,36]. Patients with gestational diabetes present special challenges, and the need for tight glycemic control often necessitates the use of insulin therapy. After conception and early in the first trimester, the risk of hypoglycemia is amplified as a result of increases in the peripheral utilization and storage of glucose. Late in the third trimester, overnight hypoglycemia can occur if a bedtime snack is insufficient to meet the intensified fetal demands for glucose. Lastly, during the postpartum period, the risk of hypoglycemia results from the loss of placental hormones [37].

Adequate glucose control should be maintained in order to prevent adverse effects to fetal health. Potential adverse effects include hyperbilirubinemia (jaundice), respiratory distress syndrome, hypocalcemia, polycythemia, macrosomia, and neonatal hypoglycemia [37,38].

Macrosomia occurs when a high level of glucose in the maternal blood results in the elevated glucose to the fetus. Sensing this elevation, the fetal pancreas begins producing insulin to normalize the glucose levels. The result of this is increased adipose tissue in the organs, chest, and abdomen, leading to disproportionate size of the trunk and shoulders in relationship to the head. These infants are often large for gestational age, increasing likelihood of cesarean delivery, vaginal tearing, and other birth traumas, such as shoulder dystocia, brachial plexus injury, Erb palsy, and asphyxia [38].

If the fetal pancreas has been overproducing insulin in response to elevated maternal blood glucose levels, hypoglycemia will occur when the umbilical cord is clamped and glucose-rich maternal blood is no longer circulating in the neonate. Neonatal hypoglycemia occurs in the first 12 hours of life and resolves with infusions or oral administration of glucose until euglycemia is restored. The risks associated with neonatal hypoglycemia include seizure, cerebral damage, and death [38].

The first-line treatment for gestational diabetes is conventional therapy of diet, exercise, and other lifestyle changes [39]. The goals for blood glucose levels during this period of pregnancy are very strict [40]:

- Before meals and at bedtime: less than 95 mg/dL

- One-hour postprandial: less than 140 mg/dL

- Two-hour postprandial: less than 120 mg/dL

When these goals are not being met, insulin therapy should be initiated, if needed, to achieve glycemic targets [41]. Insulin is the preferred medication, as it does not cross the placenta to a measurable extent. Metformin and glyburide should not be used as first-line agents, as they do cross the placenta. All oral agents lack long-term safety data [41].

Other less common types of diabetes do occur, and it is important to have a basic understanding of these forms as well. Less common types of diabetes include [7,14]:

- Maturity-onset diabetes of the young (MODY): A genetic, autosomal-dominant defect of the pancreatic beta cells that results in insulin deficiency and decreased insulin release without the presence of insulin resistance and obesity. This form of diabetes typically develops in patients younger than 25 years of age. This is a different clinical entity than type 2 diabetes of the adolescent, which presents with insulin resistance.

- Diabetes related to diseases of the exocrine pancreas, such as cystic fibrosis, and various endocrine diseases, such as Cushing syndrome, acromegaly, and chromocytoma

- Drug-induced diabetes resulting from the use of certain medications, particularly high-dose corticosteroids

SCREENING FOR DIABETES

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends screening for abnormal blood glucose as part of cardiovascular risk assessment in adults 40 to 70 years of age who are overweight or obese.

https://annals.org/aim/fullarticle/2466368

Last Accessed: October 22, 2019

Strength of Recommendation: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

All adults older than 45 years of age should be screened for diabetes every three years or every two years if they have any risk factors for type 2 diabetes [14,41,42]. In addition, individuals of any age who are at risk or are suspect of having diabetes should be screened. Established risk factors for type 2 diabetes include [41,43,44]:

- Age older than 45 years

- Body mass index (BMI) greater than or equal to 25 kg/m^2

- Family history of type 2 diabetes

- Habitual physical inactivity

- Race/ethnicity (e.g., African American, Hispanic American, Native American, Alaskan Native, Pacific Islander)

- IGT or elevated fasting glucose

- Previous history of gestational diabetes or giving birth to a child weighing more than 9 pounds

- Hypertension (blood pressure greater than 140/90 mm Hg in adults)

- Abnormal lipid levels (high-density lipoprotein [HDL] level <35 mg/dL and/or triglyceride level >250 mg/dL)

- Polycystic ovarian syndrome

- History of vascular disease

- Acanthosis nigricans (most common among individuals of African descent)

DIAGNOSTIC CRITERIA

The diagnostic criteria for type 2 diabetes are fairly straightforward and are based on fasting plasma glucose and plasma glucose levels (Table 1). After a diagnosis of type 2 diabetes has been definitively made, education on self-care management is necessary in order to obtain euglycemia and prevent complications related to the detrimental effects of hyperglycemia [3]. The healthcare team involved in providing care should include, at a minimum, the primary care physician, certified diabetes educator, dietitian, and support person/system. Education should focus on healthy eating habits, blood glucose monitoring, exercise planning, medication management, risk reduction, and healthy coping techniques [45]. As previously stated, it is estimated that as many as 90% of patients with type 2 diabetes will require oral medications to achieve adequate glucose control within five years of diagnosis [15]. When glucose levels cannot be adequately controlled with oral medications, the use of injectable medications is necessary. If elevated blood glucose levels are untreated and continue to rise, the result can be hyperosmolar hyperglycemia syndrome (HHS) and ultimately death [2].

Table 1: DIAGNOSTIC CRITERIA FOR DIABETES

Stage

Fasting Plasma Glucose Levels

Two-Hour Postprandial Plasma Glucose Levels

Euglycemia

<100 mg/dL

<140 mg/dL

Prediabetes

>100 mg/dL but <126 mg/dL

>140 mg/dL but <200 mg/dL

Diabetes

≥126 mg/dL

≥200 mg/dL

Source: [14,45]

6. SULFONYLUREA THERAPY: FIRST AND SECOND GENERATIONS

Historically, there were few options to achieve control of blood glucose levels, and pharmacologic management was limited to the sulfonylureas [3]. Today, sulfonylurea medications are categorized as either first- or second-generation (Table 2). These medications are typically used as primary or secondary agents in the treatment of type 2 diabetes. Sulfonylureas can be rapid-acting, intermediate-acting, or long-acting based on their onset and duration of action. For sulfonylureas to be effective, the individual must have functioning pancreatic beta cells. Thus, they are not useful for patients with type 1 diabetes [46]. Some individuals will not respond to initial sulfonylurea therapy, and over time, most will experience failure with this therapy as the disease progresses. The ideal candidate for sulfonylurea therapy is a patient with [47]:

- Type 2 diabetes without dyslipidemia

- Normal weight

- Hyperglycemia despite following meal planning and an exercise program

- Ability and willingness to follow a reasonable dietary program

- Hyperglycemia for less than five years

- Age older than 30 years

Table 2: SULFONYLUREAS

Drug Name

Trade Name

Dose Range

Maximum Daily Dose

Frequency

Onset of Action

Duration of Action

First-Generation

Chlorpropamide

Diabinese

100–500 mg daily

500 mg

Daily

1 hour

24 hours

Second-Generation

Glimepiride

Amaryl

1–2 mg daily

8 mg

Once or twice daily

2 to 3 hours

24 hours

Glipizide

Glucotrol

2–40 mg daily

40 mg

Three times daily

3.5 to 6 hours

12 to 16 hours

Glucotrol XL (extended-release)

20 mg daily

20 mg

Daily

3.5 to 6 hours

12 to 16 hours

Glyburide

Diabeta, Micronase

2.5–20 mg daily

20 mg

Once or twice daily

1.5 hours

16 to 24 hours

Glyburide (micronized)

Glynase

0.75–12 mg daily

12 mg

Once or twice daily

1.5 hours

12 to 24 hours

Source: [3,48,49,50,51]

Sulfonylurea preparations act to stimulate the release of insulin from functioning beta cells in the islets of Langerhans in the pancreas, which results in lowered blood glucose [46,49,52]. These agents close the energy-sensitive potassium channel in the cell membrane of the pancreatic beta cell. By accomplishing this, there is an increased amount of available insulin for action within the body [3]. It is important to keep in mind that individuals with impaired first-phase insulin release will experience a diminished effect from sulfonylurea therapy [53]. Duration of action is generally rapid, fairly complete, and basically unaffected by food, with the exception of glipizide [48].

FIRST-GENERATION AGENTS

The original sulfonylurea agents are now known as the first-generation sulfonylureas. Although effective in controlling hyperglycemia, first-generation sulfonylureas were hindered by the frequency of hypoglycemia related to therapy and high dosage requirements. The second-generation sulfonylureas have improved on the effectiveness of the earlier agents by requiring smaller doses and demonstrating a lower incidence of side effects [3,46]. Although the only currently utilized first-generation sulfonylurea agent in the United States is chlorpropamide, it is important to have an understanding of all medications within this category in the rare case a patient presents with a history of having taken one of these agents.

Chlorpropamide

Chlorpropamide is typically prescribed at 100–250 mg/day for stable diabetics; those with more severe disease may take up to the maximum safe dose of 500 mg/day [49]. Adjusting doses up or down should be accomplished by increasing or decreasing by 50–125 mg/day over three to five days. Chlorpropamide has an onset of action of one hour, a half-life of less than 36 hours, and a duration of action of 24 hours [49]. Chlorpropamide is primarily metabolized in the liver and excreted via the kidneys. This medication does cross the placenta and has been found in breast milk, and women of childbearing age should be educated regarding possible effects to their fetus or infant [7,49].

Discontinued Medications

Acetohexamide

Acetohexamide has a prescribing dose range from 250–1,500 mg daily, with a maximum safe dosage of 1,500 mg/day [46]. Acetohexamide may be taken in two divided doses per day to obtain maximum efficacy of the medication. It has an onset of action of 1 hour, and the duration of action is anywhere from 12 to 24 hours [54].

Tolazamide

Tolazamide has a prescribing dose range of 100 mg to a maximum safe dose of 1,000 mg daily and may be given in divided doses [46]. The onset of action for tolazamide is four to six hours, with a half-life of seven hours. The duration of action ranges between 10 and 14 hours. This medication is metabolized in the liver with excretion via the kidneys. Like chlorpropamide, tolazamide crosses the placenta [49].

Tolbutamide

Tolbutamide has a prescribing dose range of 500 mg to a maximum 3,000 mg/day [49]. A prescribed dose of tolbutamide is given in three divided doses in order to reach maximum efficacy. A larger dose is typically required to be effective. The onset of action for tolbutamide is 1 hour, with a half-life of 6 to 8 hours; the duration of action ranges from 12 to 18 hours. Tolbutamide is metabolized in the liver with excretion via the renal system [49]. It is important to note that levels of tolbutamide are not reduced by hemodialysis [7].

SECOND-GENERATION AGENTS

The second generation of sulfonylureas was developed to include a shorter duration of action and shorter half-lives, which decrease the frequency and severity of side effects related to medication therapy [3]. These agents are most commonly used in the treatment of type 2 diabetes today.

Glimepiride

Glimepiride is typically prescribed at a maintenance dose of 1–4 mg/day, with a maximum safe dose of 8 mg daily [49]. Glimepiride is usually taken once daily with breakfast or the first main meal. The onset of action is two to three hours, with a half-life of five to nine hours. The maximum effect is experienced within 2 to 6 hours, but the duration of action is 24 hours.

After oral administration, glimepiride is completely metabolized by oxidative biotransformation into the major metabolites cyclohexyl hydroxy methyl derivative (M1) and carboxyl derivative (M2). Cytochrome P450 2C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is about one-third as pharmacologically active as its parent; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear. When glimepiride is given orally, approximately 60% of the total radioactivity is recovered in the urine in seven days, and M1 (predominant) and M2 account for 80% to 90% of that recovered in the urine [49,52]. Because this medication can pass through the placenta to the fetus, care should be taken when treating women of childbearing age [7,49]. Agents other than glimepiride are currently recommended to treat diabetes in pregnant women [49]. Due to its different action and lack of effects on the coronary arteries, some have classified glimepiride as the first third-generation sulfonylurea.

Glipizide

Glipizide is initially prescribed at a dose of 2.5 mg/day, which may be titrated up in 2.5–5 mg increments until desired effects are achieved [49]. The maximum safe dose is 40 mg/day for the standard preparation and 20 mg/day for the extended-release formula [49]. The standard dose of glipizide is taken three times per day to obtain optimal effect; the extended-release formula is taken only once per day. The onset of action for both preparations is 3.5 to 6 hours, with the maximum effect obtained in 1 hour [7]. The duration of action for glipizide is 12 to 24 hours, and it has a half-life of approximately 2 to 5 hours [49]. Glipizide is extensively metabolized in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine [55]. As with other sulfonylureas, the medication crosses the placenta and may affect the fetus [7,49].

Glyburide

Glyburide is available in regular and micronized forms, and dosing will depend on the form prescribed [49]. The initial dose of the regular form is 2.5–5 mg/day, which may be increased weekly to desired effect or a maximum of 20 mg daily. The initial dose for the micronized tablets is 1.5–3 mg/day, which can also be titrated weekly. The maximum micronized dose is 12 mg/day [49].

The onset of action for glyburide is 90 minutes, with maximum effect noted at 60 minutes for micronized preparations and two to four hours for the nonmicronized formula. The half-life of glyburide is 10 hours regardless of micronization, and the drug has a duration of action of 12 to 24 hours (micronized) or 16 to 24 hours (nonmicronized) [48,49]. Glyburide is excreted as metabolites in the bile and urine. This dual excretory pathway is different from that of other sulfonylureas, which are excreted primarily in the urine [49,56]. Glyburide does cross the placenta, and precautions with women of childbearing age should be taken [7,49].

POTENTIAL SIDE EFFECTS

As with any drug therapy, a hypersensitivity reaction can potentially occur with sulfonylurea therapy. However, hypersensitivity to one agent does not necessarily indicate a cross-sensitivity with other sulfonamide agents. Care should be taken when treating geriatric, malnourished, or debilitated patients, as these groups are at particular risk for hypoglycemia. Furthermore, any person with adrenal, pituitary, or hepatic insufficiency who is particularly susceptible to the hypoglycemic effects of glucose-lowering agents should be closely monitored while on a sulfonylurea therapy regimen [3]. Alteration in hepatic enzyme activity may also alter the clearance of sulfonylurea agents.

A secondary side effect of sulfonylurea therapy is weight gain as a result of a greater amount of circulating insulin [49]. This increase results in a greater amount of circulating glucose being stored as adipose tissue. Less commonly seen sulfonylurea side effects include [49]:

- Skin rash (2%)

- Gastrointestinal disturbances (5%)

- Metabolic disorders (e.g., syndrome of inappropriate antidiuretic hormone hypersecretion associated with chlorpropamide use) (4%)

It is important to mention that there is ongoing research regarding a possible correlation between sulfonylurea therapy and suspected deaths in patients with a past myocardial infarction [57,58]. Although a causal relationship has not been established, it is important to understand this concept and to counsel patients to discuss any concerns with their primary care physician [59].

Sulfonylurea agents may also interact with a variety of other medications. These interactions have the potential to affect the action of the sulfonylurea agent, the other medication, or both. Drug-drug interactions are more commonly seen with the first-generation sulfonylurea agents [60]. One of the primary causes for drug interactions is a competition for protein binding sites, which results in a greater amount of circulating sulfonylurea agent in the bloodstream and can increase the hypoglycemic effect, seen more often with the longer acting agents (e.g., chlorpropamide, glibenclamide [i.e., glyburide]) [61]. Medications that may interact with sulfonylureas include beta blockers, corticosteroids, thiazide diuretics, cyclic antidepressants, and antifungals [49,61].

CASE STUDY

Patient M is a white woman, 32 years of age, presenting to her primary care physician with complaints of polyuria for the past four weeks. Further assessment reveals an upcoming appointment with her optometrist for new onset blurred vision. The patient is 5 feet 5 inches tall and weighs 142 pounds; her calculated BMI is 23.6 kg/m^2. She confirms a family history of diabetes on her father's side and admits to a generally sedentary occupation and lifestyle. A random finger stick reveals a blood glucose level of 257 mg/dL.

Rationale and comments : Patient M's evaluation has resulted in adequate findings to diagnose diabetes. Any random blood glucose greater than 200 mg/dL with additional symptoms (in this case, polyuria and blurred vision) is considered diagnostic for diabetes.

Patient M is referred for fasting blood work, which reveals the following results:

- HbA1c: 8.5% (estimated average glucose: 197 mg/dL)

- Fasting blood glucose: 147 mg/dL

- Two-hour glucose level (after 75 g oral glucose tolerance test): 240 mg/dL

- Triglycerides: 152 mg/dL

- Low-density lipoprotein (LDL): 97 mg/dL

- HDL: 35 mg/dL

- Liver function tests: Within normal limits

- Renal function: Within normal limits

Patient M is referred to an ADA-recognized diabetes education program for further education in diabetes self-management, self-monitoring of blood glucose (SMBG), and exercise and meal planning education [62].

Patient M returns to her primary care physician after three months. Her follow-up HbA1c demonstrates minimal change, with a result of 8.2% (estimated average glucose: 189 mg/dL) and a fasting blood glucose level of 156 mg/dL. SMBG records reveal blood glucose levels consistently between 135 mg/dL and 160 mg/dL fasting and between 230 mg/dL and 300 mg/dL postprandial. Patient M states that she is following her meal and exercise planning goals with little success.

The patient's physician evaluates all of her blood work and patient history information and determines that the best course of treatment would be to initiate sulfonylurea therapy. Patient M is started on glipizide 5 mg each morning, and continuation with her meal and exercise plans is emphasized.

Rationale and comments : This is an appropriate treatment plan for Patient M because, although she has a sedentary occupation, she is not considered obese. She has been adherent to her meal and exercise plan without success. Her fasting blood glucose levels are elevated, but it is the postprandial levels that have instigated the elevated HbA1c levels. The sulfonylurea secretagogue glipizide should improve the high postprandial levels resulting from loss of first-phase insulin release.

7. NONSULFONYLUREA SECRETAGOGUE (GLINIDE) THERAPY

The nonsulfonylurea secretagogues, more commonly known as meglitinides or glinides, are hypoglycemic agents that predominantly affect postprandial glucose levels (Table 3). There are two medications considered to be within this classification of hypoglycemic agents: repaglinide and nateglinide [7]. The ideal candidate for glinide therapy would have type 2 diabetes for which medical nutrition therapy and exercise has not achieved euglycemia, alone or in combination with other agents. In contrast, this therapy is not a viable option for patients with [3]:

- Type 1 diabetes

- Ketoacidosis

- Known hypersensitivity to either drug

- Severe infection

- Surgery

- Trauma

Table 3: NONSULFONYLUREA SECRETAGOGUES (GLINIDES)

Drug Name

Trade Name

Dose Range

Maximum Daily Dose

Frequency

Onset of Action

Duration of Action

Repaglinide

Prandin

0.5–4.0 mg before meals

16 mg

Three times daily

25 to 30 minutes

4 to 6 hours

Nateglinide

Starlix

60–120 mg before meals

360 mg

Three times daily

Within 20 minutes

4 hours

Source: [3,48,49,50,51]

REPAGLINIDE

Repaglinide stimulates the release of insulin from functioning beta cells in the pancreatic islets. Repaglinide closes adenosine triphosphate (ATP)-dependent potassium channels in the beta-cell membrane, which depolarizes the beta cell and leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion [49]. This action is highly tissue selective, with low affinity for heart and skeletal muscle [63]. Results with repaglinide therapy are best achieved when taken within 15 to 30 minutes of a meal [7,49]. This results in a greater insulin release from the pancreas during the first phase. The onset of action is rapid (usually within 15 to 60 minutes), and the drug possesses a short half-life (about one hour), resulting in a low plasma level of the medication [3,49]. Excretion of repaglinide is completed via the intestinal system in the form of feces [7,49]. Repaglinide can be utilized as a monotherapy agent or in conjunction with a biguanide, thiazolidinedione (TZD), or both [49,50].

NATEGLINIDE

Nateglinide is a very rapid acting amino-acid derivative known as D-phenylalanine. Nateglinide interacts with the ATP-sensitive potassium channel on pancreatic beta cells to produce calcium influx and insulin secretion. As with repaglinide, the extent of insulin release is glucose dependent and diminishes at low glucose levels [49,64]. Nateglinide is rapidly absorbed, and the onset of action is approximately within 20 minutes of ingestion. This medication is taken just prior to a meal due to this mechanism of action [7,49]. Due to the short half-life (1.5 hours), nateglinide stops acting on the pancreatic beta cells shortly after the meal, decreasing the possibility of hypoglycemia. This medication is excreted in the feces after it is metabolized in the intestinal tract [7]. Nateglinide can be used as monotherapy or in combination with metformin, TZD, or both. It is important to note that if adequate control is not achieved using a sulfonylurea agent, it is unlikely that nateglinide will be effective [49].

POTENTIAL SIDE EFFECTS

As with all medications, there are precautions when considering glinide therapy. These medications should not be used during pregnancy, in women who are breastfeeding, or in children [41]. Repaglinide should be used cautiously in persons with hepatic dysfunction, and routine, close monitoring of liver function is necessary. Individuals who are elderly, malnourished, debilitated, or have adrenal or pituitary dysfunction are particularly susceptible to hypoglycemia, the most common side effect related to this class of medication (<10%). The key measure for preventing hypoglycemia in patients taking glinides is patient education stressing the need to omit the medication if a meal is not going to be consumed [49].

Aside from hypoglycemia, there are less common side effects associated with glinides, including [3]:

- Bronchitis, sinusitis, rhinitis (<10%)

- Nausea/vomiting, diarrhea, constipation (2% to 5%)

- Headache, chest pain, urinary tract infection, back pain (2% to 9%)

- Dizziness (3.6%)

As with any pharmaceutical preparation, healthcare professionals should be aware of potential interactions between medications that an individual is prescribed. In the case of both sulfonylureas and nonsulfonylurea secretagogues, potential effects of drug-to-drug interactions include [50]:

- Drug level and/or effect decreased by: carbamazepine, charcoal, corticosteroids, estrogens, isoniazid, nicotinic acid, nonsteroidal anti-inflammatory drugs, oral contraceptives, phenobarbital, primidone, rifampin, sympathomimetics, thiazide and other diuretics, thyroid products, urinary alkalinizers

- Drug level and/or effect increased by: beta blockers, chloramphenicol, cimetidine, delavirdine, diclofenac, fibric acid derivatives, fluconazole, gemfibrozil, ketoconazole, nicardipine, salicylates, sulfonamides, telithromycin, tricyclic antidepressants

Herbs that may increase the effects of secretagogues include burdock, dandelion, eucalyptus, and marshmallow. As noted, it is imperative to understand these interactions and the impact they have on blood glucose levels. Rapid identification of hypoglycemic or hyperglycemic emergencies utilizing blood glucose monitoring and assessment skills is also critical [50].

CASE STUDY

Patient L is an African American man, 52 years of age, presenting to his primary care physician with complaints of frequent urination and excessive thirst, particularly in the late afternoon and early evening. He is a truck driver and works 12 hours each day. Patient L is 6 feet 1 inch tall and weighs 215 pounds, with a calculated BMI of 28.4 kg/m^2. He confirms a family history of diabetes on both his father's and mother's sides. A random finger stick results in a blood glucose level of 243 mg/dL.

Rationale and comments : The information gained from Patient L's initial examination indicates diabetes. Again, any random blood glucose greater than 200 mg/dL, accompanied by symptoms (polyuria and excessive thirst for this patient), is considered diagnostic for diabetes.

Patient L is referred for fasting blood work, which reveals the following:

- HbA1c: 9.1% (estimated average glucose: 214 mg/dL)

- Fasting blood glucose: 132 mg/dL

- Two-hour glucose level (after 75 g oral glucose tolerance test): 310 mg/dL

- Triglycerides: 147 mg/dL

- LDL: 102 mg/dL

- HDL: 46 mg/dL

- Liver function tests: Within normal limits

- Renal function: Within normal limits

Patient L is diagnosed with type 2 diabetes and is referred to an ADA-recognized diabetes education program. A follow-up appointment in three months is scheduled.

Upon the follow-up primary care appointment, Patient L's HbA1c shows minimal change, with a result of 8.8% (estimated average glucose: 206 mg/dL) and a fasting blood glucose level of 148 mg/dL. The patient's SMBG records reveal fasting blood glucose levels consistently between 150 mg/dL and 165 mg/dL and postprandial levels steadily between 230 mg/dL and 290 mg/dL. Patient L states that he has difficulty eating meals at consistent times due to his profession and exercises when he is able. There has been little change in his weight since his last visit.

Patient L's physician determines that the best course of therapy would be to initiate nonsulfonylurea secretagogue therapy. The patient is started on repaglinide 2 mg 15 minutes prior to his first three main meals. He is advised not to take the medication if he does not eat the meal. He is strongly encouraged to continue with his meal and exercise plans.

Rationale and comments : This is an appropriate choice of medication for Patient L due to his inconsistent eating habits and continued postprandial hyperglycemia, his sedentary occupation, and his weight (not considered obese). His postprandial levels are the problematic factor, and repaglinide will allow Patient L the freedom to adjust his medication therapy to his eating schedule.

8. ALPHA-GLUCOSIDASE INHIBITOR THERAPY

There are two available oral antihyperglycemic agents in the category of alpha-glucosidase inhibitors: acarbose and miglitol (Table 4). In contrast to sulfonylureas, alpha-glucosidase inhibitors do not enhance insulin secretion. The antihyperglycemic action of these agents is a result of a reversible inhibition of membrane-bound intestinal alpha-glucoside hydrolase enzymes. In addition, acarbose inhibits pancreatic alpha-amylase. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine; membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. When these factors are inhibited, glucose absorption is delayed and postprandial blood glucose levels remain within the normal range. Because their mechanism of action is different, alpha-glucosidase inhibitors enhance glycemic control achieved by sulfonylureas, insulin, or metformin when used in combination. In addition, alpha-glucosidase inhibitors diminish the insulinotropic and weight-increasing effects of sulfonylureas [65].

Table 4: ALPHA-GLUCOSIDASE INHIBITORS

Drug Name

Trade Name

Dose Range

Maximum Daily Dose

Frequency

Onset of Action

Duration of Action

Acarbose

Precose

25–100 mg before meals

300 mg

Three times daily

Immediate

6 hours

Miglitol

Glyset

25–100 mg before meals

300 mg

Three times daily

Rapid

Less than 4 hours

Source: [3,46,47,48,49]

An ideal candidate for alpha-glucosidase therapy will have:

- Dyslipidemia

- Obesity

- Symptoms suggesting postprandial hyperglycemia

ACARBOSE

Acarbose is prescribed in doses of 25–100 mg, with a maximum daily dose of 300 mg [7,49]. Acarbose should be taken in equal doses three times a day for maximum efficacy [7]. The onset of action of acarbose is immediate, with peak effect seen in one hour. Acarbose has a half-life of two hours and a duration of action of approximately six hours [49,50]. Acarbose is excreted via the renal and fecal routes without being metabolized [7].

MIGLITOL

Miglitol has a dose range of 25–100 mg taken at the beginning of each meal, up to a maximum of 300 mg/day. Miglitol has a rapid onset of action, and peak effect is reached in about two to three hours. The half-life is roughly two hours, and the duration of action is believed to be less than four hours [49,50]. No metabolites have been detected in plasma, urine, or feces, indicating a lack of either systemic or presystemic metabolism [49,66]. The drug is excreted via the renal route [7,49].

POTENTIAL SIDE EFFECTS

Due to the location and mechanism of action, alpha-glucosidase inhibitors are not well absorbed in the intestinal tract. Elevated plasma levels of acarbose have been found in persons with a creatinine clearance of less than 25 mL per minute, suggesting accumulation. With this in mind, caution should be used in these patients. In addition, use of alpha-glucosidase inhibitors is contraindicated in patients with [49]:

- Small bowel disease

- Colonic ulceration

- Obstructive bowel disorder

- Chronic intestinal disorders of digestion or absorption

- Cirrhosis of the liver

- Elevated creatinine levels >2.0 mg/mL

Furthermore, women who are pregnant or breastfeeding and children should not use these agents [49].

Side effects for alpha-glucosidase inhibitors are typically confined to the gastrointestinal system and usually occur during initiation of therapy or when adjustments to the dose are made [49]. Potential side effects of alpha-glucosidase inhibitors include [49]:

- Gastrointestinal effects

- Abdominal pain: 12% to 21%

- Diarrhea: 29% to 33%

- Flatulence: 42% to 77%

- Increased plasma concentration relative to the degree of renal dysfunction

- Elevation in transaminases with acarbose (believed to be related to the use of higher-than-recommended dosages)

These side effects are generally self-limiting and transient and can be minimized by starting with a lower dosage and titrating up to desired effect or maximum therapeutic dose [49,50]. When caring for a patient being treated with alpha-glucosidase inhibitors, two-hour postprandial blood glucose levels should be monitored to identify effectiveness of the therapy [3,49]. Studies have demonstrated elevations in serum transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]), so liver function should also be monitored periodically.

Lastly, alpha-glucosidase inhibitors' effects have the potential to be altered by charcoal products and may diminish the bioavailability of ranitidine, propranolol, and digoxin [49,67].

Potential drug-drug interactions with the use of acarbose include decreased drug levels and/or efficacy when taken in combination with calcium channel blockers, corticosteroids, estrogens, fosphenytoin, hormonal contraceptives, isoniazid, nicotinic acid, phenothiazine, phenytoin, sympathomimetics, thiazides and other diuretics, and thyroid products [49]. Digestive enzyme preparations containing carbohydrate-splitting enzymes (e.g., amylase, pancreatin) and intestinal absorbents (e.g., activated charcoal) may reduce the effects of acarbose [49]. As mentioned, digoxin levels may be reduced when taken in combination with acarbose.

Although in the same category as acarbose, miglitol has different drug interactions including [49,50,67]:

- Digoxin, propranolol, and ranitidine, which may decrease the bioavailability of miglitol

- Charcoal and digestive enzyme preparations such as amylase and pancreatin, which reduce the effect of miglitol

CASE STUDY

Patient V is a Hispanic man, 61 years of age, presenting to the primary care physician with complaints of polydipsia, polyphagia, and fatigue for the past month. Upon further assessment, he states that he has recently had his eyeglass prescription adjusted due to blurred vision. He is 5 feet 10 inches tall and weighs 245 pounds; his calculated BMI is 35.2 kg/m^2. The patient reveals a family history of diabetes on both sides. He works a physical job in a warehouse lifting 50-pound boxes. A random finger stick reveals a blood glucose level of 220 mg/dL. As previously discussed, this is sufficient information to diagnose diabetes.

Patient V's fasting blood work reveals the following:

- HbA1c: 8.7% (estimated average glucose: 203 mg/dL)

- Fasting blood glucose: 151 mg/dL

- Two-hour glucose level (after 75 g oral glucose tolerance test): 233 mg/dL

- Triglycerides: 210 mg/dL

- LDL: 112 mg/dL

- HDL: 35 mg/dL

- Liver function tests: Within normal limits

- Renal function: Within normal limits

Patient V is referred to an ADA-recognized diabetes education program and is instructed to return for follow-up in three months.

When the patient returns to his primary care physician, his follow-up HbA1c demonstrates minimal change with the result of 8.2% (estimated average glucose: 189 mg/dL) and a fasting blood glucose level of 156 mg/dL. SMBG records reveal fasting blood glucose levels consistently between 135 mg/dL and 160 mg/dL and postprandial levels steadily between 220 mg/dL and 248 mg/dL. His lipid levels remain greater than goal as well. Patient V indicates that he has been following his meal and exercise planning goals but has experienced minimal success.

After evaluation of the patient's blood work, history, and progress to date, the physician decides to utilize the alpha-glucosidase inhibitor, acarbose. Patient V is started on acarbose 25 mg with each meal, and adherence to his culturally specific meal and exercise plans is stressed.

Rationale and comments : Although not commonly utilized, acarbose is appropriate for Patient V due to his elevated lipid levels and postprandial hyperglycemia. His fasting blood glucose levels are above normal, and the physician has determined that his postprandial levels are the cause of the elevated HbA1c levels. Acarbose should improve the patient's postprandial glucose levels and his lipid levels.

9. BIGUANIDE THERAPY

Biguanides are popular medications in diabetes treatment. Primitive versions of guanidines were used historically, in the form of extracts of Galega officinalis (goat's rue or French lilac), for blood glucose control [7]. The modern form was first introduced in Europe in the late 1950s. There is only one agent, metformin, available in this class of diabetes medications (Table 5) [49].

Table 5: BIGUANIDES

Drug Name

Trade Name(s)

Dose Range

Maximum Daily Dose

Frequency

Onset of Action

Duration of Action

Metformin

Glucophage, Fortamet

500 mg twice daily or 850 mg once daily

2,550 mg

Two or three times daily

Within days

6 hours

Glucophage XL (extended-release)

500–2,000 mg daily with evening meal or 1,000 mg two times daily

2,500 mg

Once or twice daily

Within days

Up to 24 hours

Metformin liquid

Riomet

500 mg twice daily or 850 mg once daily

1,000 mg

Twice daily

—

—

Source: [3,48,49,50,51]

Evidence Based Practice Recommendation

The Institute for Clinical Systems Improvement recommends clinicians should initiate metformin as first-line pharmacotherapy for patients with type 2 diabetes, unless medically contraindicated.

https://www.icsi.org/wp-content/uploads/2019/02/Diabetes.pdf

Last Accessed: October 22, 2019

Level of Evidence/Strength of Recommendation: High/Strong

Metformin therapy is now frequently utilized due to the lack of hypoglycemia as a side effect [68]. If not contraindicated and if tolerated, metformin is the ADA-preferred initial pharmacologic agent for management of type 2 diabetes [41]. It is an antihyperglycemic agent that lowers both basal and postprandial plasma glucose and improves glucose tolerance. Metformin acts in several ways to achieve this effect, including inhibiting hepatic glucose production and intestinal absorption of glucose [68]. It also increases peripheral glucose uptake and utilization [49]. Unlike sulfonylureas, metformin does not increase the risk of hypoglycemia and does not cause hyperinsulinemia [69]. Insulin secretion remains unchanged using metformin, but fasting plasma insulin levels and day-long plasma insulin response may actually decrease [3].

Metformin therapy has been extensively studied, and a meta-analysis of randomized controlled trials supports the benefit of metformin use in comparison to sulfonylureas [7]. Patients on metformin therapy demonstrated greater fasting blood glucose reduction and improvement in weight [7]. Compared with treatment with a sulfonylurea, monotherapy treatment with metformin is associated with a lower risk of major adverse cardiovascular events among patients with diabetes and reduced kidney function [70]. Although the benefits are well-documented, metformin therapy may not be the treatment of choice in all cases. The optimal candidate would present with:

- Type 2 diabetes

- Dyslipidemia

- Obesity or a genetic factor increasing the potential for insulin resistance

- Elevated fasting blood glucose level

- Tendency for hypoglycemia with sulfonylurea therapy

Additionally, metformin is approved for use in children 10 years of age and older [49]. It is the only oral diabetes medication approved for children.

Metformin is available in both immediate-release and extended-release tablets. The initial recommended dose for adults is 500 mg once or twice daily or 850 mg once daily, which may be titrated up every one to two weeks to a maximum safe dose of 2,550 mg/day [48,49]. In general, doses of at least 1,500 mg/day are necessary to produce clinically significant effects. Although the maximum safe dose is 2,250 mg/day, most preparations contain a maximum of 2,000 mg of active ingredient [71]. Metformin should be started in the evening and can be taken in two or three divided doses to improve efficacy [7]. The extended-release formulation is initially prescribed at dosages of 500–1,000/day, which may be titrated weekly to a maximum dose of 2,000 mg daily [49].

The onset of action for metformin is within days, but the peak effect of the immediate-release form is typically seen in two to four hours [50]. Peak effect with the use of the extended-release form is in four to eight hours. The duration of action is approximately 6 hours for immediate-release metformin, while the extended-release preparation is up to 24 hours [48]. The drug has a plasma half-life of four to nine hours [49].

Metformin is not metabolized by the liver [49]. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the unchanged drug is excreted in the urine [69].

Metformin is used both as a single agent and in combination with other therapies. It has been formulated into a multitude of combination preparations to increase the efficacy of both medications. The use of these combination formulations is cost effective and results in improvements in patient adherence to their medication regimen.

POTENTIAL SIDE EFFECTS

Although metformin is beneficial for many people, it should be used with caution in some populations. Women who are pregnant or breastfeeding should not utilize metformin therapy. There have been no formal studies to show benefit or risk analysis when metformin is used during pregnancy. Metformin use should also be temporarily halted in patients who are acutely ill or who are predisposed to acute renal failure or tissue hypoperfusion. Lastly, metformin should be withheld for a minimum of two days or until renal function has returned following any radiologic test utilizing iodinated contrast media [49]. Examples of such tests include urograms, angiography, intravenous cholangiography, and any scans using intravascular contrast media.

Metformin therapy is contraindicated in patients for whom the adverse effects may be life-threatening. This includes patients with elevated serum creatinine levels greater than 1.5 mg/dL for men or greater than 1.4 mg/dL for women, abnormal creatinine clearance from any cause, and patients with an eGFR <30 mL/minute/1.73 m^2 [7,49,72]. Because metformin is excreted through the kidneys, accumulation of the medication can occur in the presence of renal dysfunction. In 2016, the FDA issued a drug safety communication, new recommendations, and a label change requirement for metformin and metformin-containing medications for use in certain patients with mild-to-moderate renal impairment. The new FDA recommendations include [72]:

- Obtain eGFR prior to initiating metformin therapy.

- Initiate metformin in patients with an eGFR between 30–45 mL/minute/1.73 m^2 is not recommended.

- Obtain an eGFR at least annually in all patients taking metformin; assess renal function more frequently in patients at increased risk for renal impairment (e.g., the elderly).

- Assess the benefits of continuing metformin treatment in patients whose eGFR falls below 45 mL/minute/1.73 m^2; discontinue if the eGFR falls below 30/mL/minute/1.73 m^2.

Individuals with hepatic dysfunction who are receiving biguanide therapy can be predisposed to lactic acidosis [49]. Due to the potential damaging effects of alcohol on the liver, any individual with a history of alcohol abuse or binge drinking would not be a good candidate for metformin therapy. Finally, individuals with a history of chronic obstructive pulmonary disease or cardiac function impairment should not be prescribed metformin due to the potential of lactate accumulation in these hypoxic conditions [7,49].

Side effects of metformin are relatively mild and self-limiting, with the exception of lactic acidosis. Typically, the side effects are gastrointestinal in nature and resolve within the first few weeks of therapy. Potential side effects include [49]:

- Lactic acidosis (0.03/1,000 patient years)

- Diarrhea, nausea/vomiting, flatulence, bloating, anorexia (>10% during initiation)

- Metallic taste (3% during initiation)

- Decrease of vitamin B12 to subnormal levels (7% in one study)

- Impaired hepatic function

Biguanide therapy rarely causes serious side effects, but lactic acidosis has occurred in some cases and is an important consideration for patients taking metformin [49]. Lactic acidosis, although rare, is a potentially fatal metabolic complication. Persons at risk include those with renal insufficiency and those with acute or unstable heart failure who are at risk for hypoperfusion and hypoxemia. Characteristics of lactic acidosis include:

- Serum lactate levels greater than 5 mmol/L

- Decreased blood pH

- Electrolyte abnormalities resulting in an elevated anion gap

- Increased lactate/pyruvate ratio

The onset of lactic acidosis symptoms are generally vague and subtle at presentation [3]. The person's symptoms may include malaise, myalgia, nonspecific abdominal pain, increased somnolence, and/or respiratory distress. Serum lactate levels should be monitored periodically or when a patient is at risk for lactate accumulation [67]. If a patient develops symptoms of lactic acidosis while taking metformin, the agent should be discontinued immediately [49,67].

Metformin can interact with other medications and herbs. Knowledge of these interactions is necessary to ensure appropriate patient care. If taken with metformin, beta blockers may potentiate hypoglycemia. There are many medications that may potentiate hyperglycemia, including [50]:

- Calcium channel blockers

- Corticosteroids

- Estrogens

- Fosphenytoin

- Hormonal contraceptives

- Isoniazid

- Nicotinic acid

- Phenothiazines

- Phenytoin

- Sympathomimetics

- Thiazides and other diuretics

- Thyroid drugs

Several medications compete for the same renal tubular transport systems as metformin, which can increase the serum levels of both drugs. Medications with this effect include amiloride, cimetidine, digoxin, morphine, nifedipine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin [49]. In addition to these interactions, consumption of guar gum may decrease hypoglycemic effect of metformin.

CASE STUDY

Patient K is a white woman, 71 years of age, presenting to her primary care physician with complaints of fatigue, polyuria, polyphagia, and polydipsia for the past few months. She is 5 feet 4 inches tall and weighs 205 pounds, with a calculated BMI of 35.3 kg/m^2. She confirms a family history of diabetes on her mother's side, a personal history of having given birth to a child weighing more than 9 pounds, and arthritis of her bilateral knees. A finger stick reveals a blood glucose level of 198 mg/dL.

Rationale and comments : Based on the information gathered during the initial examination, Patient K cannot be definitively diagnosed with diabetes. Although symptoms of diabetes are present, a blood glucose level of 198 mg/dL is not diagnostic unless further laboratory testing is completed.

In order to gain additional information, Patient K is referred for a complete blood work-up. The results of this work-up reveal:

- HbA1c: 8.0% (estimated average glucose: 183 mg/dL)

- Fasting blood glucose: 195 mg/dL

- Two-hour glucose level (after 75 g oral glucose tolerance test): 160 mg/dL

- Triglycerides: 167 mg/dL

- LDL: 123 mg/dL

- HDL: 29 mg/dL

- Liver function tests: Within normal limits

- Renal function: Within normal limits

Based on this additional information, Patient K is diagnosed with type 2 diabetes and is referred to an ADA-recognized diabetes education program. At her three-month follow-up appointment, the patient's HbA1c level has increased to 8.6% (estimated average glucose: 200 mg/dL) and her fasting blood glucose level is 205 mg/dL. Sporadic SMBG records reveal fasting levels consistently between 180 mg/dL and 210 mg/dL and postprandial levels between 150 mg/dL and 170 mg/dL. Patient K states she did not attend the education class as recommended but has attempted to limit her sugar intake. She denies starting an exercise program because of the pain she experiences in her knees when she tries to walk.

It is determined, taking into account Patient K's blood glucose level and failure to make lifestyle changes, that the best course of treatment is medication therapy utilizing metformin. The patient is prescribed metformin 500 mg each evening and water aerobics for exercise. Her physician again stresses the importance of SMBG and participation in diabetes self-management education.

Rationale and comments : The therapy prescribed is appropriate for Patient K for many reasons. Her fasting blood glucose levels are higher than normal, her postprandial levels are slightly elevated, and she is suspected to have insulin resistance. She is obese and has been non-adherent to her meal and exercise plans. Her SMBG has been erratic. Metformin will positively impact the patient's fasting blood glucose levels by decreasing the liver's production of endogenous glucose, decreasing insulin resistance, and decreasing the reabsorption of carbohydrates in the gut.

10. THIAZOLIDINEDIONE THERAPY

The group of antihyperglycemic agents referred to as the thiazolidinediones, or TZDs, is one of the more modern classes of diabetes medications (Table 6). These agents improve blood glucose levels by increasing the body's sensitivity to insulin [3]. TZDs are not hypoglycemic agents and do not precipitate hypoglycemia, but when used in combination with a sulfonylurea, there is a synergistic effect to improve glucose tolerance by complimentary mechanisms [67].

Table 6: THIAZOLIDINEDIONES

Drug Name

Trade Name

Dose Range

Maximum Daily Dose

Frequency

Onset of Action

Duration of Action

Pioglitazone

Actos

15–45 mg daily

45 mg

Once daily

Days

Unknown

Rosiglitazone

Avandia

4–8 mg daily

8 mg

Once or twice daily

Days to weeks

Unknown

Source: [3,48,49,50,51]

TZDs depend on the presence of insulin to act. Insulin resistance is decreased in the periphery and in the liver when TZD therapy is utilized, resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. TZDs are a potent agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action, such as adipose tissue, skeletal muscle, and the liver, and also in the vascular endothelium, macrophages and other cell types [7,49,67]. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism [49,67].

TZDs have been found to reduce the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by TZDs result in increased responsiveness of insulin-dependent tissues [67,73]. TZDs enhance the action of insulin at the receptor or post-receptor level in the peripheral hepatic tissues, reversing or partially reversing insulin resistance [74]. In addition, TZDs improve insulin sensitivity within the muscle and adipose tissues, further improving blood glucose levels [50].

In addition to their blood glucose-regulating effects, TZDs can improve the efficiency of the cardiac work load [3]. Adipose tissue expression of adiponectin is lowered in the presence of insulin resistance. As a result, lower plasma levels have been documented in humans with obesity, type 2 diabetes, and/or coronary artery disease. Research and trials have also demonstrated a close correlation between changes in adiponectin plasma levels after TZD treatment and measures of insulin-mediated glucose metabolism and adipose tissue distribution [7].

TZDs can be utilized as a monotherapy or in combination with metformin, a sulfonylurea, a secretagogue, and/or insulin. They should be used as monotherapy agents only when insulin production appears to be adequate [3]. Due to the adiponectin relationship, this is an ideal medication regimen for patients with type 2 diabetes complicated by obesity and/or coronary artery disease. However, TZD therapy is contraindicated in some cases, including for patients with [49,67]:

- Acute liver disease or ALT levels greater than 2.5 times the upper limit

- Symptomatic class III or IV heart failure (black box warning)

- Jaundice

- Hypersensitivity to the medication

- Type 1 diabetes

- Diabetic ketoacidosis

Although TZDs are contraindicated for the treatment of type 1 diabetes, research is being done to identify the risks and benefits associated with TZD therapy in type 1 diabetics with a BMI greater than 27 kg/m^2 [7].

PIOGLITAZONE

Pioglitazone is initially prescribed at a dose of 15–30 mg once daily, which may be increased to the desired response up to a maximum of 45 mg/day [49]. The exact onset of action of pioglitazone is unknown, but peak effect is reached in approximately two hours, a time that may be delayed with food. The half-life of pioglitazone is 16 to 24 hours [49,50]. Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Following oral administration, approximately 15% to 30% of the dose is excreted in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces [73].

ROSIGLITAZONE

Rosiglitazone should be started at an initial daily dose of 4 mg, regardless of whether it is being used as monotherapy or as part of combination therapy [49]. After several weeks, the dose may be titrated up, if necessary, to a maximum of 8 mg/day. Rosiglitazone may be taken in two divided doses [48,49]. The onset of action for rosiglitazone is unknown; maximum effects may not be present for up to 12 weeks. The drug has a peak action time of about one hour with a half-life of three to four hours [49,50]. Rosiglitazone is extensively metabolized, and the major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than the parent drug and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone. The majority of rosiglitazone metabolites are eliminated in the urine (64%) and the feces (23%) [49,75].

POTENTIAL SIDE EFFECTS

Weight gain is the most recognized side effect with TZD therapy and is thought to be a result of plasma volume expansion leading to edema [49]. As a result of this plasma volume expansion, there is also a small reduction in hemoglobin, hematocrit, and neutrophil counts [7]. Other notable side effects include [3,49]:

- Increased total serum cholesterol

- Fluid retention (5% with monotherapy and 15% with insulin therapy)

- Headache, arthralgia, back pain (5% to 14%)

- Nausea and diarrhea (4% to 6%)

- Small decrease in hemoglobin, hematocrit, and neutrophil counts (5%)

- Elevation in ALT levels (1.9%)

In addition, rosiglitazone is associated with specific adverse effect risks, such as [3,49]:

- Bone fracture in women

- Decreased efficacy of oral contraceptives

- Resumption of ovulation in premenopausal anovulatory women

- Potential increased risk of heart failure

TZD therapy has several known drug-drug interactions, including [50,67]:

- Atorvastatin: may decrease atorvastatin and pioglitazone levels

- Hormonal contraceptives in conjunction with pioglitazone may decrease the level of hormonal contraceptives, reducing the effectiveness of the contraceptive

- Ketoconazole may inhibit pioglitazone metabolism

The concurrent administration of certain herbs, such as burdock, dandelion, eucalyptus, and marshmallow, can result in potentiation of TZDs' hypoglycemic effects.

CASE STUDY

Patient H is an African American woman, 38 years of age, presenting to her primary care physician for a routine physical with complaints of fatigue and constant hunger. She is 5 feet 7 inches tall and weighs 235 pounds, with a calculated BMI of 36.9 kg/m^2. She has a strong history of diabetes and coronary artery disease on both sides of her family, a personal history of gestational diabetes with her last two children, and is employed as a legal secretary. A finger stick reveals a blood glucose level of 213 mg/dL. A diagnosis of diabetes is made, and the patient is referred for fasting blood work, which reveals:

- HbA1c: 7.8% (estimated average glucose: 177 mg/dL)

- Fasting blood glucose: 137 mg/dL

- Two-hour glucose level (after 75 g oral glucose tolerance test): 187 mg/dL

- Triglycerides: 178 mg/dL

- LDL: 131 mg/dL

- HDL: 21 mg/dL

The physician refers Patient H to an ADA-recognized diabetes education program so she may receive information regarding blood glucose monitoring and exercise and meal planning. At her follow-up appointment, the patient's HbA1c has not significantly changed, with a result of 7.7% (estimated average glucose: 174 mg/dL) and a fasting blood glucose level of 172 mg/dL. SMBG records reveal fasting blood glucose levels consistently between 155 mg/dL and 190 mg/dL and postprandial levels steadily between 190 mg/dL and 213 mg/dL. Patient H claims to be adherent to her meal and exercise planning goals but is struggling with weight loss and hunger. As a result, her physician initiates her on TZD therapy. The patient is prescribed pioglitazone 15 mg each morning, and she is advised to continue with her meal and exercise plans. Patient H is also given instructions to report any signs of sudden weight gain, shortness of breath, or chest pains, as these could be signs of excessive fluid retention related to TZD therapy.

Rationale and comments : Patient H has been adherent to her meal and exercise plan with little success and growing frustration. Her morning and postprandial blood glucose levels are above normal, and both contribute to the elevated HbA1c levels. TZD therapy is indicated for Patient H because of her family history of coronary heart disease, obesity, and suspected insulin resistance.

11. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITOR THERAPY

A more recent addition to the available treatments for type 2 diabetes is the dipeptidyl peptidase-4 (DPP-4) inhibitor, of which there are four approved medications: sitagliptin, linagliptin, saxagliptin, and alogliptin (Table 7). This discovery has launched a new era in the management of hyperglycemia. The two well-characterized incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both cause an increase in insulin synthesis and release from pancreatic beta cells in response to normal or increased blood glucose levels [76,77]. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic adenosine monophosphate. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production [51]. DPP-4 inhibitors are believed to exert their action in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by these agents, thereby strengthening and prolonging their action. GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4.

Table 7: DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

Drug Name

Trade Name

Dose Range

Maximum Daily Dose

Frequency

Onset of Action

Duration of Action

Sitagliptin

Januvia

25–100 mg daily

100 mg

Once daily

1 to 4 hours

24 hours

Linagliptin

Tradjenta

5 mg daily

5 mg

Once daily

1.5 hours

24 hours

Saxagliptin

Onglyza

2.5–5 mg daily

5 mg

Once daily

2 hours

24 hours

Alogliptin

Nesina

12.5–25 mg daily

25 mg

Once daily

—

24 hours

Source: [3,48,49,50,51,78]

SITAGLIPTIN

Sitagliptin is generally dosed at 100 mg/day, with decreased doses necessary for patients with renal impairment [49]. It is given once daily and may be used alone or with other medications to obtain the best results. The drug is rapidly absorbed, with time to peak action within one to four hours after ingestion. Sitagliptin has a half-life of 12 hours, with a duration of action equaling 24 hours. Metabolism is a minor pathway of elimination [49]. Six metabolites have been detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. Following administration of sitagliptin, approximately all of the active drug was eliminated in feces (13%) or urine (87%) within one week of dosing, and renal clearance is approximately 350 mL/minute [51]. An estimated 79% of sitagliptin that is excreted in the urine is unchanged drug [49].

Sitagliptin is indicated for patients with type 2 diabetes who are not achieving adequate blood glucose control with medical nutrition therapy and exercise alone. It can be utilized as a monotherapy or in combination with metformin, a secretagogue, or a TZD [7,49]. Sitagliptin may be used for a person with mild renal insufficiency at the full dosage. For patients with moderate renal insufficiency (creatinine clearance of 30–50 mL/minute), the dose should be 50 mg, and for those with a creatinine clearance of less than 30 mL/minute or end-stage renal disease and hemodialysis, the dosage should be 25 mg [48,49].

Side Effects

The most common adverse effect associated with sitagliptin monotherapy is nasopharyngitis, which occurs in 5% of patients [49]. Additional adverse effects include [67]:

- Upper respiratory infection (6.2% in combination therapy)

- Headache (5.9%)

- Abdominal pain (2.2%)

- Diarrhea (2.4%)

- Nausea (1.3%)

When caring for an individual receiving sitagliptin therapy, it is also important to be aware of reports to the U.S. Food and Drug Administration (FDA) regarding 88 post-marketing cases of pancreatitis, 2 of which were hemorrhagic or necrotizing, in patients receiving sitagliptin therapy. These cases of pancreatitis were reported to the FDA between October 2006 and February 2009 [79]. In 2009, the FDA issued a special alert regarding the possible association of sitagliptin/metformin combination with acute pancreatitis [79]. A study that examined insurance records found that the use of sitagliptin could double the risk of developing acute pancreatitis [80]. Additionally, in 2013 the FDA announced that it is evaluating unpublished findings that suggest precancerous cellular changes (i.e., pancreatic duct metaplasia) in patients with type 2 diabetes treated with sitagliptin. The findings are based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes [81]. Patients taking sitagliptin should be advised regarding symptoms of pancreatitis (i.e., persistent severe abdominal pain, anorexia, nausea, vomiting) and instructed to contact their physician should they experience these symptoms. In the case of sitagliptin, there are no known significant drug-herb interactions [50].

SAXAGLIPTIN

Saxagliptin is dosed at 2.5–5mg/day, with a lower dose used in patients with moderate or severe renal impairment or when the agent is prescribed in conjunction with a strong cytochrome P450 3A4 inhibitor [49,82]. This agent is approved for use with other drugs or as monotherapy for the treatment of type 2 diabetes in adults. The time to peak action for saxagliptin is approximately two hours, and the drug is metabolized hepatically to 5-hydroxy saxagliptin, an active metabolite [82]. The majority of the drug and the metabolite are excreted in the urine (75%) and the feces (22%) [49].

Saxagliptin may be initiated as a single therapy or in conjunction with metformin, under the brand name Kombiglyze XR. It may also be added on to an ongoing metformin, sulfonylurea, or TZD regimen. No adjustment of dosage is necessary for BMI, gender, or age. For patients with a creatinine clearance of 50 mL/minute or less, the recommended dosage is 2.5 mg once daily; for those with end-stage renal disease, a dose of 2.5 mg should be given once daily after dialysis [49].

Side Effects

The most common adverse reactions associated with saxagliptin are upper respiratory tract infection (7.7%), headache (6.5%), nasopharyngitis (6.9%), and urinary tract infection (6.8%) [67,83]. Anyone with a hypersensitivity reaction should discontinue the drug immediately. There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin [67,83]. After initiating treatment, observe patients carefully for signs and symptoms of pancreatitis. An FDA safety review also has found that saxagliptin may increase the risk of heart failure, particularly in patients with heart or kidney disease [84]. As a result, the agency has added new warnings to drug labels.

LINAGLIPTIN

Linagliptin was approved by the FDA in 2011 for the treatment of patients with type 2 diabetes that is uncontrolled by diet modification and exercise [82]. In addition to monotherapy, it has also been studied as add-on therapy with metformin, pioglitazone, and a sulfonylurea. When used with a secretagogue, the dose of the secretagogue should be lowered in order to reduce the risk of hypoglycemia [67,85]. Linagliptin is absorbed rapidly, with an onset of action of about 1.5 hours [49]. It is primarily excreted as unchanged drug in the feces (80%) and urine (5%) [49].

No dosage adjustment is necessary for patients with renal or hepatic impairment. Concurrent use of linagliptin with either insulin or a secretagogue is associated with an increased risk for hypoglycemia [49]. The medication may be taken with or without food, and the only significant contraindication is allergy or hypersensitivity to linagliptin [49,82].

Side Effects

Side effects most commonly associated with linagliptin include headache (6%), nasopharyngitis (6% to 7%), arthralgia (6%), and back pain (6%) [49]. Drug interactions are also possible. Clinicians should consider using an alternative to any strong cytochrome P450 3A4 inducer in patients who are being treated with linagliptin, as the combination can reduce the effectiveness of linagliptin [49]. The FDA has advised of postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin [85,86]. If pancreatitis is suspected, the drug should be promptly discontinued.

ALOGLIPTIN

Approved by the FDA in 2013, alogliptin is now available in the United States. It is usually dosed at 12.5–25 mg/day and is available in fixed-dose formulations with metformin (brand name Kazano) and with pioglitazone (brand name Oseni) [78]. Alogliptin is approved for use with diet and exercise to improve blood sugar control in adult patients with type 2 diabetes.

Alogliptin or its combination formulations may be added to an ongoing regimen. It has been shown to be safe and effective in reducing HbA1c in 14 clinical trials involving more than 8,500 patients [78]. The most common side effects are nasal congestion, headache, and upper respiratory tract infection [49]. In 2013, the FDA requested that the manufacturer complete postmarking studies related to the safety of the drug, including a cardiovascular outcomes trial, a study monitoring for liver abnormalities, and three pediatric studies [78]. A safety review published by the agency in 2016 found that alogliptin may increase the risk of heart failure, particularly in patients with heart or kidney disease [84]. As a result, the agency has added new warnings to drug labels.

CASE STUDY

Patient B is a Pacific Islander woman, 64 years of age, presenting to the primary care physician with complaints of a urinary tract infection (UTI) and fatigue. She attributes the fatigue to waking frequently at night due to the UTI. The patient denies any recent history of febrile states or pain with urination. She is 5 feet 1 inch tall and weighs 170 pounds, with a calculated BMI of 32.2 kg/m^2. She confirms a family history of diabetes on her mother's side and admits to a sedentary lifestyle.

Patient B's urine sample is negative for infection. A random finger stick reveals a blood glucose level of 207 mg/dL. She is diagnosed with type 2 diabetes based on her blood glucose level and the characteristic symptoms (polyuria and fatigue).

In order to gain additional information, Patient B is referred for fasting blood work. The results of this blood work indicate:

- HbA1c: 7.8% (estimated average glucose: 177 mg/dL)

- Fasting blood glucose: 147 mg/dL

- Triglycerides: 167 mg/dL

- LDL: 199 mg/dL

- HDL: 32 mg/dL

Patient B is referred to an ADA-recognized diabetes education program and is initiated on treatment for dyslipidemia based on her very high LDL level and borderline high triglycerides.

When Patient B returns for her three-month follow-up appointment, she acknowledges compliance to her meal and exercise planning goals with very little success. Her repeat HbA1c demonstrates minimal change with a result of 7.6% (estimated average glucose: 171 mg/dL) and a fasting blood glucose level of 165 mg/dL. Her fasting levels during SMBG are generally between 145 mg/dL and 170 mg/dL; her postprandial levels are between 170 mg/dL and 190 mg/dL.

DPP-4 therapy is determined to be the best treatment choice to control Patient B's diabetes. She is started on sitagliptin 100 mg each morning and continues her meal plan and exercise program.

Rationale and comments : Patient B's higher than normal fasting and postprandial blood glucose levels are contributing to the elevated HbA1c levels, and she has been adherent to her meal plan and exercise program with minimal success. This treatment is appropriate for Patient B because DPP-4 therapy assists in weight loss while impacting blood glucose levels.

12. SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

Canagliflozin, the first in the new class of diabetes medications referred to as sodium-glucose co-transporter 2 (SGLT2) inhibitors, was approved by the FDA in 2013, with two additional agents, dapaglifozin and empagliflozin, approved in 2014, and another, ertugliflozin, approved in 2017 (Table 8) [87,88,89]. This class of drugs acts by inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, which reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose. SGLT2 is the main site of filtered glucose reabsorption, and reduction of filtered glucose reabsorption and lowering the renal threshold result in increased urinary excretion of glucose and improved plasma glucose concentrations [49].

Table 8: SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

Drug Name

Trade Name

Dose Range

Maximum Daily Dose

Frequency

Time to Peak Action

Duration of Action

Canagliflozin

Invokana

100–300 mg daily

300 mg

Daily

1–2 hours

24 hours

Dapagliflozin

Farxiga

5–10 mg daily

10 mg

Daily

2 hours

24 hours

Empagliflozin

Jardiance

10–25 mg daily

25 mg

Daily

1.5 hours

24 hours

Ertugliflozin

Steglatro

5–15 mg daily

15 mg

Daily

1–2 hours

24 hours

Source: [49,87,88,89]

The recommended initial dose of canagliflozin is 100 mg once daily prior to the first meal of the day [49,87]. The dose may be increased up to 300 mg/day, unless the patient has impaired renal function. Dapagliflozin is dosed at 5 mg once daily in the morning and may be increased to 10 mg/day, while empagliflozin is started at 10 mg daily and may be increased to 25 mg per day, if necessary [49,88,89]. Ertugliflozin is started at a dose of 5 mg daily, with possible titration up to 15 mg/day [49]. These agents are approved for use with diet and exercise to improve the control of type 2 diabetes in adult patients. They have been studied for use as monotherapy and in combination with other antidiabetics, including metformin, sulfonylureas, pioglitazone, and insulin [87].

POTENTIAL SIDE EFFECTS

The most common side effects associated with SGLT2 inhibitors are vulvovaginal candidiasis and urinary tract infection [87]. Other possible adverse effects include increased serum potassium, renal insufficiency, and hypoglycemia [49]. In 2013, the FDA requested that the manufacturer of canagliflozin complete postmarking studies, including a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, liver abnormalities, pancreatitis, hypersensitivity reactions, photosensitivity reactions, and adverse pregnancy outcomes; a bone safety trial; and two pediatric studies [87].

In 2015, the FDA issued a warning that canagliflozin, dapagliflozin, and empagliflozin may lead to ketoacidosis. The warning was based on the identification of 20 cases of diabetic ketoacidosis requiring hospitalization in patients treated with SGLT2 inhibitors between March 2013 and June 2014. Later in the year, the FDA revised the labels of SGLT2 inhibitors, warning about the risks of ketoacidosis as well as serious urinary tract infections. Additionally, the FDA is requiring manufacturers of the drugs to conduct enhanced pharmacovigilance studies to evaluate spontaneous reports of ketoacidosis in patients treated with SGLT2 inhibitors. The enhanced studies include a five-year period of specialized follow-up to collect additional information [90,91,92].

In 2016, the FDA alerted the public about interim safety results from an ongoing clinical trial that found an increase in leg and foot amputations, mostly affecting the toes, in patients treated with canagliflozin. Also in 2016, the FDA strengthened the existing warning about the risk of acute kidney injury with canagliflozin and dapagliflozin. The warning was based on reports of 101 confirmable cases of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin or dapagliflozin use [94].

In 2017, based on data from two large clinical trials, the FDA confirmed the increased risk of leg and foot amputations with canagliflozin and issued requirements for a new boxed warning [93]. In 2018, the FDA issued a warning about rare but serious necrotizing fasciitis of the perineum associated with SGLT2 inhibitor therapy [95].

13. COMBINATION ORAL MEDICATION PREPARATIONS

Due to the success of using multiple agents concurrently to combat diabetes, many medications have been combined into one preparation to provide the benefits of both drugs and lessen the number of pills necessary (Table 9) [7]. Research has demonstrated a greater level of success utilizing combination therapy as opposed to separate prescriptions [96]. The ideal candidate for combination preparations is being treated with separate classifications of antihyperglycemic agents for which a single, combination form is available. However, combination therapy is not without risks. When formulations are combined, the adverse effects and contraindications associated with both must be taken into consideration [49]. Combination medications are only available in fixed dosages and may not meet the needs of every individual. Furthermore, in some instances, these combined formulas may be more expensive than the separate agents [3].

Table 9: COMBINATION PREPARATIONS OF ORAL DIABETES MEDICATIONS

Agents

Brand Name

Available Dosages

Pioglitazone and metformin

Actoplus Met

15 mg/500 mg

15 mg/850 mg

Pioglitazone and metformin

Actoplus Met XR

15 mg/1,000 mg

30 mg/1,000 mg

Pioglitazone and glimepiride

Duetact

30 mg/2 mg

30 mg/4 mg

Glyburide and metformin

Glucovance

1.25mg/250 mg

2.5 mg/500 mg

5 mg/500 mg

Sitagliptin and metformin

Janumet

50 mg/500 mg

50 mg/1,000 mg

Sitagliptin and metformin

Janumet XR

50 mg/500 mg

50 mg/1,000 mg

100 mg/1,000 mg

Glipizide and metformin

Metaglip

2.5 mg/250 mg

2.5 mg/500 mg

5 mg/500 mg

Alogliptin and metformin

Kazano

12.5 mg/500 mg

12.5 mg/1,000 mg

Alogliptin and pioglitazone

Oseni

12.5 mg/15 mg

12.5 mg/30 mg

12.5 mg/45 mg

25 mg/15 mg

25 mg/30 mg

25 mg/45 mg

Dapagliflozin and metformin

Xigduo

5 mg/500 mg

5 mg/1,000 mg

10 mg/500 mg

10 mg/1,000 mg

Canagliflozin and metformin

Invokamet

50 mg/500 mg

50 mg/1,000 mg

150 mg/500 mg

150 mg/1,000 mg

Linagliptin and metformin

Jentadueto

2.5 mg/500 mg

2.5 mg/1,000 mg

Linagliptin and metformin

Jentadueto XR

5 mg/1,000 mg

5 mg/2,000 mg

Saxagliptin and metformin

Kombiglyze XR

5 mg/500 mg

5 mg/1,000 mg

2.5 mg/1,000 mg

Empagliflozin and metformin

Synjardy

5 mg/500 mg

5 mg/1,000 mg

12.5 mg/500 mg

12.5 mg/1,000 mg

Empagliflozin and metformin

Synjardy XR

5 mg/1,000 mg

10 mg/1,000 mg

12.5 mg/1,000 mg

25 mg/1,000 mg

Ertugliflozin and metformin

Segluromet

2.5 mg/500 mg

2.5 mg/1,000 mg

7 mg/500 mg

7 mg/1,000 mg

Dapagliflozin and saxagliptin

Qtern

10 mg/5 mg

Ertugliflozin and sitagliptin

Steglujan

5 mg/100 mg

15 mg/100 mg

Empagliflozin and linagliptin

Glyxambi

10 mg/5 mg

25 mg/5 mg

Empagliflozin, linagliptin, and metformin

Trijardy XR

5 mg/2.5 mg/1,000 mg

10 mg/5 mg/1,000 mg

12.5 mg/2.5 mg/1,000 mg

25 mg/5 mg/1,000 mg

Source: [3,48,49,50,51,78,97]

CASE STUDY

Let us revisit Patient K, who has been taking metformin to control her type 2 diabetes. One year ago, Patient K was started on metformin 500 mg each evening with recommendations to attend diabetes self-management education. Since then, her dosage has been titrated up, and she currently takes metformin 1,000 mg twice per day. At her scheduled appointment, Patient K has an HbA1c level of 8.8% (estimated average glucose: 206 mg/dL) and claims to be adherent with her meal and exercise plan the majority of the time. Occasional SMBG indicates fasting levels between 145 mg/dL and 170 mg/dL and postprandial levels between 180 mg/dL and 230 mg/dL. Although the metformin achieved a small decrease in Patient K's blood glucose levels, she has not obtained satisfactory results. More intensive therapy, with a second antihyperglycemic agent, is necessary, and the physician prescribes glyburide 2.5 mg daily. Upon hearing this, the patient becomes teary-eyed and expresses concerns about the cost of the new medication. She states she is on a fixed income and can barely make ends meet. The physician offers to prescribe a combination medication that is less expensive than the two agents separately. Patient K agrees and is prescribed Glucovance 2.5 mg/500 mg in the morning and continues with metformin 1,000 mg in the evening.

Patient K returns for a three-month follow-up. Her HbA1c demonstrates a decrease, with the result of 8.1% (estimated average glucose: 186 mg/dL) and a fasting blood glucose level of 110 mg/dL. SMBG records show fasting blood glucose levels consistently between 98 mg/dL and 120 mg/dL and postprandial levels between 160 mg/dL and 200 mg/dL. The patient has also made great improvements in adhering to meal plans, exercise goals, and SMBG. However, the physician stresses the need for Patient K's HbA1c level to be less than 7.0%, and they agree to change therapy to Glucovance 2.5 mg/500 mg twice per day. The patient agrees to wake at 3 a.m. at least twice in the first week to test her morning blood glucose level to assess for nocturnal hypoglycemia.

Rationale and comments : Patient K's morning blood glucose levels are close to optimal, but her postprandial levels remain elevated and her HbA1c level remains suboptimal. She has demonstrated greater adherence to her meal, exercise, and SMBG plans. Metformin will continue to impact her fasting and mid-day blood glucose levels by decreasing the liver's production of endogenous glucose, decreasing insulin resistance, and decreasing the reabsorption of carbohydrates in the gut. In addition, glyburide will assist the pancreas in the production of insulin. Patient K will require education regarding the importance of determining the presence of nocturnal hypoglycemia, signs and symptoms of hypoglycemia, and conditions that require communication with her primary care physician.

14. BOLUS INSULIN THERAPY

A bolus of insulin refers to the administration of insulin over a short period of time, usually after ingestion of carbohydrates (meal bolus) or in reaction to an elevated glucose level (correction bolus) [98]. Bolus insulin therapy can be administered via a single injection, an insulin pump, or inhaled mist and is used in the treatment of both type 1 and type 2 diabetes [2]. In 2016, the FDA approved the first automated insulin delivery device for individuals 14 years of age and older with type 1 diabetes. The device is a hybrid closed-loop system that automatically monitors glucose and provides appropriate basal insulin doses [99].

Evidence Based Practice Recommendation

According to the Institute for Clinical Systems Improvement, insulin dosing schedules should be individualized based on a variety of factors, including the severity of diabetes, oral intake, severity of illness, and other concurrent diabetic medication. It is not feasible to design a single algorithm for determining an insulin regimen in every patient.

https://www.icsi.org/wp-content/uploads/2019/02/Diabetes.pdf

Last Accessed: October 22, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Meal bolus therapy provides more flexibility to individuals with diabetes, but it requires competency in carbohydrate counting and a working knowledge of the rapid-acting insulin analog's impact within the body [100]. When administering a meal bolus, the dosage of insulin is determined by the amount of carbohydrates to be ingested. This amount is divided by the insulin-to-carbohydrate ratio (the number of grams of carbohydrate that one unit of insulin covers). The ratio must be individualized and will vary among patients [98]. For example, a patient may have an insulin-to-carbohydrate ratio requiring 1 unit of insulin for every 15 g of carbohydrate. If this patient consumed a meal containing 60 g carbohydrates, 4 units of insulin would be needed. Alternatively, if this patient attends a party and chooses to consume a piece of cake with ice cream for a total of 120 g carbohydrate, the flexibility provided by meal bolus insulin therapy will allow the patient to administer the insulin needed (8 units).

Correction bolus is an infusion or injection of insulin delivered quickly to bring high blood glucose levels back within a goal range [101]. The dose of insulin administered for a correction bolus is determined by the sensitivity factor (the amount the blood glucose level will decrease with 1 unit of insulin). As with the meal bolus, the correction bolus will vary depending on certain factors, including an individual's weight. The sensitivity factor is calculated by dividing 2,000 (2,200 for less tight control, 1,800 for tighter control) by the individual's total daily dose of insulin [98]. For example, if a patient takes an average of 100 units of insulin each day, his or her sensitivity factor would be 20, meaning 1 unit of insulin would decrease the blood glucose level by 20 mg/dL. If this same patient has a target blood glucose level of 110 mg/dL and a blood glucose test indicating a current blood glucose level of 240 mg/dL, he or she could utilize a correction bolus to lower the blood glucose level by 130 mg/dL to the target. The necessary dose is calculated by dividing the difference (130 mg/dL) by the correction factor of 20 to determine the amount of insulin needed—6.5 units of insulin in this case.

Several insulin preparations may be administered via bolus for use in meal or correction bolus therapy. The most commonly used types will be discussed in length in the following sections.

INSULIN ASPART

One available insulin analog that may be administered in bolus therapy is insulin aspart (recombinant DNA [rDNA] origin). This type of insulin is rapid-acting and is nearly homologous with regular human insulin. It is produced using Pichia pastoris or Saccharomyces cerevisiae, also known as baker's yeast [102]. A slight change in the insulin chain makes insulin aspart more rapidly absorbed than regular insulin. Insulin aspart is available in a concentration of 100 units/mL (U100). Its onset of action is 5 to 15 minutes, and the peak of action is one to three hours. The effective duration of action for insulin aspart is less than five hours [48,49]. Unlike oral antihypoglycemic agents, insulin aspart does not have a maximum dosage, but is specific to the individual [103].

Insulin aspart is available in 10 mL vials containing U100 insulin aspart and in prefilled and cartridge pens containing 3 mL of U100 insulin. These preparations can be stored unopened until the expiration date; however, once opened or punctured, insulin aspart will expire in 28 days regardless of storage location [49,50]. If stored in a refrigerator, it is important to allow the insulin aspart to warm to room temperature before administration for greater absorption rates and comfort [102]. It is important to note that although refrigeration is permissible, cartridges should not be refrigerated after they are punctured [50,102]. Although cartridge pens have been available for several years, in 2010 and 2011 the manufacturer began to discontinue these pens in favor of the prefilled types.

INSULIN LISPRO

Insulin lispro (rDNA origin) is also a rapid-acting human insulin analog. This type of insulin is created from a non-pathogenic strain of Escherichia coli that has been genetically altered by the addition of the gene for insulin lispro [104]. Like insulin aspart, insulin lispro is available in a U100 concentration and has no labeled maximum dose [103]. Its onset of action is 15 to 30 minutes, and peak effect is experienced in 30 minutes to 2.5 hours. Insulin lispro has an effective duration of action of less than five hours [48,49].

Insulin lispro is available in 10 mL vials for subcutaneous injection, intravenous injection, or infusion via insulin pump. It can be stored at room temperature or refrigerated unopened until the expiration date [49,50]. After the vial has been opened, it must be used within 28 days. If the vial is stored in the refrigerator, it should be allowed to warm to room temperature prior to use [104].

INSULIN GLULISINE

Insulin glulisine (rDNA origin) is another rapid-acting insulin analog. As with insulin lispro, insulin glulisine is synthesized from non-pathogenic E. coli. It is available in U100 concentration in 10 mL vials or 3 mL cartridges [48,49,50]. The onset of action for insulin glulisine is 15 to 30 minutes, with peak action reached within approximately 1.5 to 2.5 and a duration of action of three to four hours [49].

Insulin glulisine may be administered via subcutaneous injection, intravenous injection, or insulin pump. Like other insulin analogs, opened vials of insulin glulisine must be used within 28 days and may be stored at room temperature or refrigerated. Refrigerated vials should be brought to room temperature before use [49]. Preparations mixed for intravenous use are stable at room temperature for 48 hours [49].

REGULAR INSULIN

There are two preparations of regular human insulin on the market: Humulin R and Novolin R. Both preparations are similar in action but differ in chemical make-up. Both have an onset of action of 15 to 30 minutes, and peak action is noted at 2.5 to 5 hours. The effective duration of action is between 2 to 12 hours [49]. Regular insulin can be utilized as a subcutaneous injection, intravenous infusion, insulin pump infusion, or inhaled mist, although insulin analogs are now more widely used [98,105].

Humulin R is created in a non-pathogenic strain of E. coli and consists of zinc-insulin crystals dissolved in a clear fluid. It is a sterile solution and is for subcutaneous, not intramuscular, injection [106]. The concentration of Humulin R is U100 or U500 [49,50].

Novolin R (rDNA origin) is structurally identical to natural human insulin and is produced utilizing S. cerevisiae [107]. Novolin R is only available in the U100 concentration in 10 mL vials [50]. Humulin R and Novolin R may be stored at room temperature until expiration or up to 31 days after the vial is opened [49].

HYPERGLYCEMIC CRISES

In addition to their use in the everyday management of diabetes, the action and short half-life of these insulins, both regular and analogs, makes them well suited for use in the treatment of hyperglycemic states resulting from metabolic changes in response to system stresses, such as surgery, trauma, and sepsis. Hyperglycemia and insulin resistance are common in critically ill patients, even when glucose homeostasis has previously been normal. This effect is amplified in diabetics because diabetic patients cannot increase insulin production to counteract the effect of the increase in catabolic hormones. In some patients, the insulin requirements may increase more than 10-fold [108]. Many critically ill patients are also receiving high-carbohydrate feedings in the form of hyperalimentation or enteral feeding, which can contribute to increased blood glucose levels. Therefore, providing adequate amounts of insulin to promote euglycemia and enough nutrition to avoid hypoglycemia, proteolysis, and lipolysis is a challenge in critically ill patients [109]. When this balance is not maintained, either due to poor diabetes control or illness/trauma, hyperglycemic crises, such as diabetic ketoacidosis or HHS, may develop.

Diabetic Ketoacidosis

Diabetic ketoacidosis is caused by the body's inability to utilize glucose due to a lack of insulin. Because glucose is unavailable for energy needs, fat is used as a fuel source. The byproducts of this fat metabolism (i.e., ketones) accumulate, and electrolyte disturbances, acidosis, and severe dehydration result [110]. It occurs most often in persons with type 1 diabetes, but it can occur in patients with type 2 diabetes as well [111]. Children younger than 5 years of age and those without ready access to health care are at the greatest risk to develop diabetic ketoacidosis [112]. Factors that can precipitate the development of this disorder include [98,111]:

- Severe infection

- Serious illness, such as myocardial infarction

- Inappropriate dosing or skipped or missed doses of insulin

- Continuous subcutaneous insulin infusion failure

- Leaving insulin pump infusion sets intact for longer than the manufacturer recommendation

- Growth spurts in children and adolescents

- Steroid therapy

- Stress

The diagnostic criteria for diabetic ketoacidosis includes a plasma glucose level greater than 250 mg/dL and an arterial pH less than 7.3 [113]. It is further classified based on arterial pH level and mental status as mild (pH 7.25–7.3, alert), moderate (pH 7–7.24, alert/drowsy), or severe (pH <7, stupor/coma). Conditions associated with diabetic ketoacidosis requiring prompt treatment and correction include [2]:

- Chronic hyperglycemia and glucotoxicity

- Acidosis

- Low blood volume

- Hyperosmolality and associated potassium loss

Diabetic ketoacidosis is considered a medical emergency, and if left untreated, it can result in death. Healthcare professionals require the knowledge and critical thinking skills to swiftly recognize the signs and symptoms of diabetic ketoacidosis and provide rapid treatment [111].

Evidence Based Practice Recommendation

The Institute for Clinical Systems Improvement recommends that for insulin-deficient patients, despite reductions or the absence of caloric intake, basal insulin must be provided to prevent diabetic ketoacidosis.

https://www.icsi.org/wp-content/uploads/2019/02/Diabetes.pdf

Last Accessed: October 22, 2019

Level of Evidence: Expert Opinion/Consensus Statement

In critically ill patients, symptoms of diabetic ketoacidosis can prevent the treatment of the triggering condition. The early signs of ketoacidosis, such as unexplained hyperglycemia, nausea, weakness, fatigue, and confusion, can prevent the individual from partaking in SMBG and insulin administration [98,111].

A successful outcome is based on the recognition and prompt treatment of this medical emergency, initiation of intensive therapy, and careful clinical follow-up. Goals for treatment include rehydration, providing adequate insulin to restore normal glucose metabolism, and correction of electrolyte deficiencies and acidosis [111,114].

Fluid Replacement

The partial correction of dehydration within the first few hours of therapy is necessary to significantly reduce hyperglycemia and ketonemia. This is accomplished by fluid replacement [113]. Adults with diabetic ketoacidosis may present with a deficit of more than 6 liters of fluid [115]. Initial fluid replacement consists of 50% normal saline or 100% normal saline, depending on serum sodium levels, urine output, and the individual's state of dehydration [113,114].

Phosphate concentration decreases with insulin therapy. Although studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in diabetic ketoacidosis, the ADA states that phosphate replacement may be indicated in patients with cardiac dysfunction, anemia, or respiratory depression, or in patients whose serum phosphate concentration is less than 1.0 mg/dL. The ADA recommends that 20–30 mEq/L potassium phosphate be added to replacement fluids when needed [113].

Insulin Replacement

All individuals with diabetic ketoacidosis require insulin therapy. This is best accomplished by a continuous insulin infusion of rapid- or short-acting insulin [111,114]. Intravenous insulin is the most effective route in this case because it can be adjusted rapidly and is not dependent on tissue perfusion for absorption, as is subcutaneous delivery [111,113]. The initial intravenous bolus of regular insulin or insulin analog is 0.1–0.15 units/kg. This is followed by an infusion of 0.1 units/kg/hour, which is titrated to lower blood glucose 50–75 mg/dL/hour. A decrease in blood glucose greater than 75 mg/dL/hour is associated with the potential complication of cerebral edema [111,114]. Insulin therapy should continue until metabolic control is achieved [111].

Correction of Electrolyte Imbalances

It is necessary to provide aggressive potassium supplementation for all individuals with diabetic ketoacidosis, as depletion of potassium can lead to cardiac dysrhythmias. However, renal function must be replaced prior to the administration of potassium [115]. If the potassium level is 4.5–6 mEq/L, administer 10 mEq/h of potassium chloride. If the level is 3–4.5 mEq/L, administer 20 mEq/h of potassium chloride. Supplementation is not needed if the potassium level is greater than 6 mEq/L. Monitor serum potassium levels hourly and stop if the level is greater than 5 mEq/L [111].

The use of bicarbonate for the treatment of acidosis is no longer routine unless the metabolic acidosis is severe [111,113,114,115]. If bicarbonate therapy is utilized, 1–2 mEq/kg should be administered over two hours followed by an assessment of plasma bicarbonate levels until the venous pH is >7.0 [113]. Total bicarbonate treatment should not exceed 5 mEq/kg in a 12-hour period [116].

Prevention

The prevention of diabetic ketoacidosis can often be accomplished with patient education regarding the condition and recognition of the initial signs and symptoms. Patients with type 1 diabetes or ketosis-prone type 2 diabetes should be educated and assessed for understanding regarding the recognition of the early warning signs. Individuals with infections or who are on injection or infusion insulin therapy may benefit from regularly measuring urine ketones and adjusting insulin doses and diet in accordance with findings [117].

Hyperosmolar Hyperglycemic Syndrome

HHS is an acute metabolic complication characterized by insulin deficiency. The condition was formerly referred to as hyperosmolar hyperglycemic nonketotic syndrome, but the terminology was changed because coma is found in fewer than 20% of patients with HHS. It is a life-threatening crisis with a high rate of mortality [118,119]. The syndrome is typically seen in individuals with undiagnosed diabetes, patients who are diagnosed after a long period of hyperglycemia, and elderly patients with type 2 diabetes, especially those who reside in long-term care facilities [2]. Blood glucose levels increase in response to a precipitating stressful situation or event. As the stress continues, the hyperglycemia is exacerbated and the evolution of HHS begins [118]. If untreated, blood glucose levels will exceed 180 mg/dL, the level at which the kidneys are no longer able to reabsorb glucose. At the same time, water loss reduces renal perfusion and causes further dehydration. This cascade of events results in more extreme levels of hyperglycemia and osmolarity with HHS than those found with diabetic ketoacidosis [114,118]. As the patient becomes increasingly dehydrated and hyperosmolar, mental status will be impaired. Like diabetic ketoacidosis, HHS will result in death if left untreated [118].

Patients experiencing HHS may present to the emergency department with seizures or symptoms that mimic a cerebrovascular accident. In most cases, physical examination will demonstrate evidence of extreme dehydration, orthostatic hypotension, and a frank hypovolemic shock. The plasma glucose level is typically greater than 600 mg/dL, with a serum osmolality level greater than 320 mOsm/kg [118]. Anything that elevates blood glucose levels or reduces hydration can contribute to the development of HHS, including [114,118]:

- Infection (the precipitating factor in 60% of cases)

- Surgery

- Myocardial infarction

- Gastrointestinal hemorrhage

- Pancreatitis

- Pulmonary embolism

- Medications that impact carbohydrate metabolism (e.g., glucocorticoids, thiazides, phenytoin, beta blockers)

Fluid and Electrolyte Replacement

The main goal in the treatment of HHS is providing adequate fluids for rehydration [114]. Aggressive fluid replacement is crucial, as patients have an average fluid loss of 9 liters [118]. The guideline for fluid replacement is to infuse half of the fluid deficit over the initial 12 hours and the remainder during the subsequent 12 to 24 hours [114,118]. When administering hypertonic solutions, it is important to be alert to the potential of cerebral edema due to the rapid decrease in serum osmolality [118].

Laboratory values provide critical information to guide electrolyte replacement decisions. The potassium replacement strategy is similar to that with diabetic ketoacidosis, and evidence of the deficit may be initially evident by an electrocardiogram [114]. The total body potassium loss is significant and can equal 4–6 mEq/kg. Furthermore, after insulin therapy is initiated, the potassium level may drop even further [118]. For this reason, insulin therapy should be withheld if the serum potassium is less than 3.3 mEq/L [114].

Insulin Therapy

After hydration is re-established, insulin therapy is usually, but not always, required to obtain euglycemia. The treatment of acidosis is not a part of the treatment plan of HHS; therefore, insulin requirements are not as high [114]. The initial insulin intravenous bolus should be 0.1 units/kg of rapid- or short-acting insulin followed by a consistent infusion at the same rate. When glucose levels reach 300 mg/dL, the infusion may be decreased to 0.05 units/kg. The infusion should be maintained to keep the glucose level between 250–300 mg/dL until the osmolality is less than 315 mOsm/kg and the individual is alert [118].

Prevention

The most important tactic in the prevention of hyperglycemic crises is patient and family education regarding the early identification, treatment, and management of illnesses. Patients with a history of HHS are at risk for further episodes [118]. Patients with type 1 diabetes should be taught about urine ketone testing and appropriate steps should the test return a positive result, including communication with a physician, increased non-caloric fluid intake, and insulin therapy [118]. Additionally, increasing the frequency of SMBG can help prevent the progression and potential complications related to diabetic ketoacidosis and HHS. Key patient and family teaching points include [120]:

- Always take diabetes medications as prescribed. Patients having trouble tolerating the medication due to vomiting should notify their primary care provider.

- Monitor blood glucose levels at least four times a day. If a patient is too sick to self-test, a family member, caregiver, or trusted support person should provide assistance.

- Maintain a blood glucose log and keep it readily available in case the primary care provider is called.

- Monitor for ketones any time blood glucose levels are 250 mg/dL or greater. Levels should be recorded.

- Maintain adherence to the normal meal plan whenever possible.

- Drink plenty of sugar-free liquids to prevent dehydration.

Conditions that require the immediate notification of a physician include [120]:

- A fever greater than 38 degrees Celsius (100.5 degrees Fahrenheit)

- Vomiting or diarrhea for more than two hours

- Blood glucose levels of 250 mg/dL or greater after two checks or after additional insulin injections

- Moderate or large urine ketones

Case Study

Patient A is a white man, 19 years of age, with a history of type 1 diabetes. He is currently in the end of his first year of college and studying for his final examinations. He has been unable to exercise due to the amount of time devoted to studying. His eating has been erratic, and he has forgotten to cover his meals with insulin aspart. He presents to the emergency department with a six-hour history of abdominal pain, nausea, and confusion as reported by his roommate. The roommate also recalls a fruity odor to Patient A's breath and knows he has not been consuming alcohol. When asked questions regarding his blood glucose levels, Patient A is confused and unable to recall any past history of testing. The roommate states he did not witness the patient assessing any glucose levels. The patient's laboratory evaluation reveals:

- Blood glucose: 531 mg/dL

- Strong serum ketones

- Bicarbonate: 3 mEq/L

- Arterial pH: 7.1

- Potassium: 5.3

- CO_2: 10 mmol/L

- Liver function tests: Within normal limits

- Renal function: Within normal limits

Rationale and Comments : Diabetic ketoacidosis should be the expected diagnosis. Signs and symptoms that support this diagnosis include:

- History of type 1 diabetes

- High level of stress related to upcoming examinations

- Erratic eating patterns

- Not covering carbohydrates with insulin

- Acetone breath, confusion, nausea

- Laboratory glucose, bicarbonate, pH, CO_2, and serum ketone levels

Based on the laboratory values and patient history, the attending physician diagnoses diabetic ketoacidosis and orders insulin therapy: a bolus of regular insulin at 0.1 units/kg followed by an insulin infusion of 0.1 units/kg/hour. An infusion of 0.9% sodium chloride at 20 mL/kg/hour is administered for the first hour. Blood glucose levels are monitored hourly, and adjustments to the infusion are made based on hospital policy.

Eighteen hours after admission, Patient A awakes. His blood glucose is well controlled on the insulin infusion, and his acidosis is resolved. One hour prior to discontinuation of the insulin infusion, he is started on his home dose of insulin glargine, as his HbA1c level was assessed to be 7.1%. The next morning, the patient remains stable and his glucose status is controlled.

Before Patient A is discharged, important patient education points are reviewed and reinforced. The nurse assesses the patient's insulin administration technique by allowing him to demonstrate drawing up and administering his insulin injections. An overview of the onset, peak action times, and duration of all prescribed insulin preparations is provided. The need for injection site rotation and appropriate storage of insulin vials are stressed. The nurse also provides Patient A with information on stress management techniques. Finally, the nurse gives the patient written information regarding sick day management and encourages him to share the handout with his roommate or anyone else who will be involved with his care or well-being.

15. BASAL INSULIN

Basal insulin refers to the steady background insulin that controls blood glucose levels in the fasting state (overnight and between meals). In nondiabetic individuals, healthy beta cells release insulin into the circulatory system throughout the day [5]. This basal or background insulin enables stored fat and glucose to be released in the appropriate amounts to sustain metabolism during times when fuel is not being consumed and metabolized. A consistent insulin level throughout the day regulates glucose production from the hepatic system, the breakdown and production of fat as fuel, and the entry of amino acids into the cells for the creation of enzymes and structural proteins [98]. Basal insulin can be utilized to successfully control blood glucose levels in individuals with either type 1 or type 2 diabetes, but it is one of the cornerstones of therapy for those with type 1 diabetes [5].

Basal insulin therapy may be administered via an injection or with a continuous subcutaneous insulin infusion. For patients with type 2 diabetes with a less than optimal blood glucose level, basal insulin may be added to oral agents to achieve the most advantageous level of metabolic control [2]. A patient's basal insulin needs can be met using a variety of preparations and routes, including intermediate-acting insulin, long-acting insulin, basal/bolus combination in multiple daily dosages, or continuous subcutaneous insulin infusions via an insulin pump.

NPH (INTERMEDIATE-ACTING) INSULIN

NPH insulin is manufactured by two companies and marketed in the United States as Novolin N or Humulin N [49]. NPH is a zinc insulin suspension that includes the polypeptide protamine. It is produced in a concentration of 100 units/mL and generally appears cloudy or milky [121]. As with some insulin analogs, the insulin in NPH is synthesized using noninfectious E. coli bacteria.

NPH is available only in U100 concentration vials or pre-filled pen preparations [50]. The onset of action is within 1 to 2 hours, with peak effect to be expected within 4 to 12 hours [49]. NPH is considered an intermediate-acting insulin as its effective duration is longer than regular insulin or insulin aspart but not as long as insulin glargine or detemir [48,49]. Due to its wide variation in effective action time, this insulin may be prescribed once or twice per day [2]. As with most insulin preparations, NPH can be stored at room temperature or refrigerated until it expires or for 31 days after it is opened. As with any injectable insulin, it should be room temperature prior to injection [50].

INSULIN GLARGINE

Insulin glargine is a long-acting recombinant human insulin analog. It is available in U100 concentration vials, 3-mL cartridges, or 3-mL disposable devices [50,67]. The onset of action is three to four hours, and glargine is considered to be peakless in terms of action [49]. Insulin glargine was the first insulin to be truly long acting, with an effective duration of action of 20 to 24 hours [48]. The rate of absorption does not differ among various sites of injection, and the pharmacokinetics within various individuals is fairly consistent [2].

In 2021, the first biosimilar insulin (insulin glargine-yfgn) was approved by the FDA [153]. As an agent that is readily interchangeable with insulin glargine, it is hoped that this approval with improve availability and affordability of insulin therapy.

INSULIN DETEMIR

Like insulin glargine, insulin detemir is a long-acting basal insulin analog with up to 24 hours duration of action [67,122]. It was approved in 2005 by the FDA for use in maintaining background insulin in patients with type 1 or type 2 diabetes [123].

Insulin detemir is available in U100 concentration vials, 3-mL cartridges, and 3-mL prefilled syringes [49,50]. The onset of action for insulin detemir ranges from three to eight hours, and it is also considered a peakless insulin. The effective duration of action of insulin detemir is dose-dependent and varies from just under 6 hours to 23 hours [48,49]. The duration is mediated by slow absorption from the injection site and slow distribution to target tissues due to a strong self-association and albumin binding [2].

In 2009, the FDA issued a public health advisory regarding stolen vials of insulin detemir [124]. Stolen vials had reappeared on the market, and because handling and storage of these vials (lots XZF0036, XZF0037, and XZF0038) is unknown, patients should not use them.

Insulin glargine, insulin detemir, and NPH preparations are not appropriate for continuous subcutaneous insulin infusion or intravenous infusions and should only be considered for basal insulin therapy [2]. Subcutaneous injection sites for intermediate- or long-acting insulins include the abdomen, buttocks, posterior-lateral area of the arm, and lateral area of the thigh [125].

POTENTIAL SIDE EFFECTS

As with any other insulin therapy, the greatest side effect risk is hypoglycemia [49]. Hypoglycemia is a result of one of two different issues: hyperinsulinemia (resulting from too much exogenous insulin, an insulin-secreting pancreatic tumor, or excessive diabetes medication) or iatrogenic (alteration in glucose counter-regulation) [126]. In the case of exogenous insulin therapy, hypoglycemia is due to the effects of hyperinsulinemia [101].

The benefits of the intermediate- and long-acting insulins include the benefit of improved blood glucose control with a minimized risk of hypoglycemia [127]. For many patients, the greatest benefit of basal therapy is achieved when used in combination with bolus insulin to more effectively mimic the normal physiology of the pancreas [127].

16. COMBINATION INSULIN PREPARATIONS

Many insulin preparations can be utilized in combination to achieve greater efficacy, coverage, and accuracy [49,67]. Most insulin combinations can be mixed in the same syringe, requiring only one injection rather than two [128]. However, insulins glargine and detemir and injectables exenatide and pramlintide cannot be mixed in the same syringe with additional insulin formulations [50].

Multiple combination insulin preparations are available in premixed solutions in vial or pen form [49,67]. These combinations provide the benefit of NPH and a rapid- or short-acting insulin for greater glycemic control and management [50]. All of the fixed combinations are only available in U100 concentration to prevent potential hypoglycemia. Available fixed combinations include [48,49,67]:

- Humulin or Novolin 70/30 (70% NPH and 30% regular insulin)

- Humalog 75/25 (75% NPH and 25% insulin lispro)

- NovoLog 70/30 (70% NPH and 30% insulin aspart)

17. INCRETIN MIMETICS

The first agent in this category of antihyperglycemics, exenatide, was approved for the adjunctive treatment of diabetes in 2005 [129]. Exendin-4 is a naturally occurring incretin mimetic originally isolated from the salivary secretions of the Heloderma suspectum lizard [2]. The action of exenatide differs from other available diabetes medications. It enhances insulin secretion by pancreatic beta cells, slows gastric emptying, and suppresses glucagon secretion [49]. Exenatide has been shown to bind and activate the GLP-1 receptor, which increases both synthesis and secretion of insulin [130].

As it primarily acts to stimulate insulin secretion, exenatide is approved for patients with type 2 diabetes [49]. For these patients, use of this agent results in improved glycemic control. It is important to note that exenatide does not impair the normal glucagon response to hypoglycemia.

Though mainly used for patients with type 2 diabetes, studies have shown exenatide to be a useful adjunctive therapy for patients with type 1 diabetes, although this is an off-label use. Its effect of delaying gastric emptying has been found to reduce postprandial hyperglycemia in adults and adolescents with type 1 diabetes [131].

Exenatide is available in prefilled injection pens and as a kit containing 2 mg of the drug and a diluent [50,67]. The recommended initial dosage for the pen preparation is 5 mcg twice daily within one hour prior to a meal [49]. The dose may be increased to a maximum of 10 mcg twice per day. The recommended dosage for the 2-mg kit is once every seven days (weekly); it can be administered at any time of day, with or without meals [67]. Exenatide has an onset of action of 30 minutes and effective duration of action of approximately 10 hours [48]. The greatest side effect risk and disadvantage with exenatide is nausea, which is reported by 44% of patients who take the drug [128]. Other possible side effects include vomiting, diarrhea, dizziness, headache, and dyspepsia [128]. However, the drug has the beneficial effects of beta cell rejuvenation, decreased glucagon production, and weight loss [103]. Concurrent use of insulin, metformin, sulfonylureas, or a combination of these medications with exenatide is not recommended [49]. Exenatide is best indicated for individuals who have not achieved adequate control on combination medication therapy [2].

In 2010, a second incretin mimetic, liraglutide (Victoza), was approved by the FDA [132]. Liraglutide is a long-acting GLP-1 analog that acts by suppressing glucagon secretion, stimulating insulin secretion, and inhibiting gastric motility [49,133]. Like exenatide, it has also been linked to weight loss and improvements in beta-cell function and mass. However, because liraglutide has a longer action than exenatide, it may be administered only once per day.

Liraglutide is started at a dose of 0.6 mg/day for one week, administered subcutaneously via a prefilled injectable pen, after which the dose is increased to 1.2 mg/day [49]. The dose may be titrated to a maximum of 1.8 mg/day if necessary. Its peak serum concentration is generally reached within 8 to 12 hours, with a half-life of approximately 13 hours [49].

The most common side effects observed with liraglutide are headache, nausea, vomiting, and diarrhea [49,134]. Other side effects include allergic-like injection site reactions, such as hives. Albiglutide is administered at a dose of 30 mg once weekly, though the dose may be titrated to 50 mg once weekly to effect [135]. The initial dose of dulaglutide is 0.75–1.5 mg once weekly [136]. These weekly medications should be administered on the same day each week. Common side effects include hypoglycemia, diarrhea, nausea, and local site reactions [49]. As with exenatide, these drugs are approved for monotherapy or as an addition to an existing regimen. However, albiglutide, dulaglutide, and liraglutide are considered second-line therapies [41].

Another GLP-1 receptor agonist, lixisenatide, received FDA approval in 2016 [49]. Lixisenatide is administered at a dose of 10 mcg once daily. Lixisenatide is available as a kit containing 10 mcg of the drug and a diluent. Common side effects include nausea, vomiting, and headache [49].

In 2019, the FDA approved semaglutide, the first oral treatment for type 2 diabetes [137]. It is not recommended as first-line therapy and is contraindicated in patients with type 1 diabetes or diabetic ketoacidosis [137]. Semaglutide is administered at a dose of 0.25 mg once per week for four weeks via a prefilled injectable pen, then increased to 0.5 mg once weekly for four weeks. The maximum dose is 1 mg once weekly. Gastrointestinal adverse effects are common [49].

Clinical studies have indicated that the incretin mimetics are associated with an increased risk for the development of thyroid tumors, and their labeling includes a black box warning regarding the increased risk of thyroid C-cell tumors. Therefore, these patients should be assessed for elevated calcitonin concentrations and should be counseled on the risk and symptoms (e.g., neck mass, dysphagia, dyspnea, persistent hoarseness) of thyroid tumors [49]. Patients with a personal or family history of medullary thyroid cancer or with multiple endocrine neoplasia syndrome type 2 should not take liraglutide. In 2013, the FDA began investigating unpublished new findings by a group of researchers that suggest an increased risk of pancreatitis and pancreatic duct metaplasia in patients with type 2 diabetes treated with incretin mimetics [81].

CASE STUDY

Patient T is a defense attorney in a busy prestigious law firm. She has dealt with type 1 diabetes since the age of 13 years. She was started on an insulin pump in order to improve her blood glucose control and her overall health. Patient T has been happy with the results achieved with the pump, with the exception of a recent weight gain of 10 pounds and increases in her postprandial blood glucose levels. She confers with her endocrinologist regarding options to decrease the postprandial levels and alleviate any further weight gain.

The endocrinologist suggests treatment with exenatide. However, Patient T is concerned with returning to a twice-daily injection, which is one reason she appreciates insulin pump therapy. The patient and her endocrinologist discuss this option, and although she is hesitant to return to daily injections, the patient chooses to attempt the therapy. The endocrinologist prescribes exenatide 5 mcg twice daily.

After four weeks of therapy with exenatide, Patient T returns for follow-up. She states that although she initially experienced nausea, her weight is starting to trend down and her postprandial levels are improving. Patient T indicates she would like to continue with the exenatide therapy based on seen benefits.

18. AMYLIN ANALOGS

Like exenatide, pramlintide is another relatively new antihyperglycemic medication available to help obtain and maintain glycemic control [128]. FDA approved in 2005, pramlintide is utilized in combination with insulin therapy for patients with type 1 or type 2 diabetes [49,138]. Pramlintide mimics the human hormone amylin, a neuroendocrine hormone that contributes to glucose control during the postprandial period. As a synthetic analog of amylin, pramlintide primarily acts by promoting satiety, slowing gastric emptying, and decreasing postprandial glucagon secretion. Because use of pramlintide is associated with feelings of fullness and a reduction in caloric intake, one benefit of use is potential weight loss. Slowed gastric emptying, an effect that lasts for approximately three hours following administration, reduces the initial postprandial increase in plasma glucose, but it does not alter absorption of carbohydrates, fats, or other nutrients.

Pramlintide is contraindicated for patients with gastroparesis or who are prescribed medications that affect gastrointestinal motility or slow the absorption of nutrients [49,128]. Potential side effects include nausea, anorexia, dizziness, and pharyngitis, but the greatest risk is the development of hypoglycemia [50]. Particularly among individuals with type 1 diabetes, pramlintide taken in addition to insulin is associated with an increased risk of severe hypoglycemia [49]. When it does occur, severe hypoglycemia usually develops within three hours of administration of pramlintide injection. Complete patient education and monitoring insulin dose response can help prevent this untoward effect [139].

A patient with type 1 diabetes who uses bolus insulin at mealtime and has not achieved optimum glycemic control is a prime candidate for the addition of pramlintide [49,50]. In addition, pramlintide is indicated for patients with type 2 diabetes who utilize bolus insulin at mealtimes and have failed to achieve adequate glycemic control, with or without a concurrent sulfonylurea and/or metformin therapy [49,103].

For the management of type 1 diabetes, pramlintide is started at a dose of 15 mcg before each meal [49]. This can be titrated up every three days in 15 mcg increments to a maximum of 60 mcg. If pramlintide is prescribed for type 2 diabetes, the initial dose is 60 mcg immediately before eating [49]. Again, this can be titrated up to 120 mcg after three to seven days, if necessary [49]. The onset of action for this medication is 30 minutes, with a duration of action of three hours [48,49]. Pramlintide is primarily metabolized in the kidneys to an active metabolite with a short half-life [49,128].

19. PATIENT EDUCATION

ORAL DIABETES MEDICATIONS

Evidence Based Practice Recommendation

According to the Institute for Clinical Systems Improvement, nonadherence with diabetes medications can limit the success of therapy and help to explain why a patient is not achieving treatment goals. To screen for nonadherence, clinicians can ask patients open-ended, non-threatening questions at each office visit.

https://www.icsi.org/wp-content/uploads/2019/02/Diabetes.pdf

Last Accessed: October 22, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Patient education is of the utmost importance when it comes to prevention of adverse effects and detrimental outcomes related to diabetes medication therapy. Each class of diabetes medication requires specific instructions and education. Many healthcare providers leave diabetes self-management education to a certified diabetes educator prepared to provide this type of formal education, which is optimal. However, consistent reinforcement is needed and is best done at every patient interaction in the form of teachable moments [14]. It is important to consider each individual's specific comprehension and comfort level. Encompassing a variety of theories and teaching styles is paramount [3].

Fundamental topics for all individuals taking a medication to prevent and correct hyperglycemia include [3,50]:

- Adherence to the medication regimen

- Adherence to the meal and exercise regimen

- Importance of wearing medical identification at all times

- Symptoms of hypoglycemia and necessary treatment

- Consultation with physician regarding the use of over-the-counter medications and herbal medications

HYPOGLYCEMIA

Any person receiving medication therapy for diabetes should be educated regarding the prevention, signs and symptoms, and treatment of hypoglycemia. Overmedication, meal skipping, alcohol consumption, excessive exercise, drug interactions, illness or infection, and trauma can all precipitate hypoglycemia in patients taking certain medications, particularly insulin secretagogues.

Prevention of hypoglycemia includes not skipping meals and eating prior to exercise. Additionally, patients should be advised regarding what to do in the event of a missed medication dose. Most medication preparations should be taken as soon as the missed dose is realized, with a few exceptions. If the medication is repaglinide or nateglinide, or if it is too close to the time of the next dose, the dose should be skipped altogether [50]. Patients should also know the signs and symptoms of hypoglycemia, which include [140]:

- Dizziness or lightheadedness

- Weakness

- Hunger

- Numbness or tingling around the mouth

- Headache

- Palpitations

- Confusion

- Shakiness

- Sweating

- Irritability or nervousness

In general, patients can manage instances of hypoglycemia using the 15:15 rule. According to this rule, patients should treat low blood glucose with 15 grams of carbohydrate and recheck their blood glucose level in 15 minutes. Fifteen grams of carbohydrate would consist of three to four glucose tablets, 4 ounces of fruit juice, one-half can of regular soda, or one tube of glucose gel. In cases of severe hypoglycemia, when the individual is unable to swallow or has a potential of choking, the treatment includes dextrose 50% intravenously or, if intravenous access is unavailable, an intramuscular injection of glucagon [2].

TIMING OF MEDICATIONS AND OTHER CONSIDERATIONS

Sulfonylureas

Sulfonylurea medications should be taken with breakfast or with the first main meal of the day to maximize effect and safety [50]. In addition, there is a risk for hypoglycemia, and steps should be taken to prevent this complication. This includes spacing meals no more than four hours apart and avoiding situations when meals may be missed [5]. Individuals taking a sulfonylurea should carry a rapid-acting glucose source, such as glucose tablets or gel, in order to swiftly treat the onset of hypoglycemia at the initial signs of low blood glucose [50]. Finally, it is essential to advise these patients regarding safe alcohol practices [3].

Nonsulfonylurea Secretagogues

Timing is essential for the prevention of hypoglycemia while utilizing the nonsulfonylurea secretagogues repaglinide and nateglinide. Patients should be instructed to take the medication no more than 30 minutes prior to the meal [50]. Often, patients are advised to take this medication with the first bite of a meal [3]. If a meal is not going to be consumed, the prescribed doses of the medication should also be skipped [50].

Alpha-Glucosidase Inhibitors

Patients prescribed acarbose or miglitol should be instructed to take the medication immediately before the three main meals of the day [50]. Instruction regarding the action of alpha-glucosidase inhibitors and the need to treat incidents of hypoglycemia with simple sugar sources is imperative. These patients should carry glucose tablets or gel with them at all times to prevent severe hypoglycemia [3].

Biguanides

Metformin should be given with a meal, taking into consideration that maximum doses will be better tolerated if divided into three doses and taken with each main meal [50]. Additional education regarding metformin therapy should include the discontinuation of the medication for 48 hours or until appropriate renal function has been verified following procedures involving iodized contrast media [49]. As stated, the FDA has issued a drug safety communication for metformin and metformin-containing medications for use in certain patients with mild-to-moderate renal impairment [72]. Some individuals may experience a metallic taste, but this should subside in time [3]. Lastly, patients should be instructed to avoid excessive alcohol consumption while utilizing this medication [50].

TZDs

Education regarding TZD therapy should be centered on identification of developing or worsening heart failure. It is essential that patients monitor weight daily and report any weight gain of 5 pounds or more over a two-day period to their physician immediately [50]. Moreover, monitoring liver function to evaluate safe levels is critical [3]. Patients should be instructed to notify their healthcare provider immediately if unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine occurs, as these symptoms may indicate liver problems [50].

DPP-4 Inhibitors

Sitagliptin can be taken during the day regardless of food intake. Patient education regarding sitagliptin should include the nasopharyngeal and upper respiratory side effects discussed previously [49]. Because weight loss is a benefit of DPP-4 therapy, it is imperative to stress that the medication is not a substitute for a healthy diet and exercise, and that the prescribed medical nutrition and exercise therapy should be followed [50]. As discussed, the FDA is evaluating findings that suggest pancreatic duct metaplasia in patients with type 2 diabetes treated with sitagliptin [81].

INSULIN AND NONINSULIN INJECTABLES

Patient selection is critical to the successful use of insulin or noninsulin injectable therapy. The ideal candidate would be motivated, compliant, educable, and without any other medical condition or physical limitations that preclude accurate and reliable SMBG and insulin administration [2]. Caution is required in the elderly population or for any individual who could have difficulty with the identification of signs and symptoms of hypoglycemia. For patients with type 2 diabetes, insulin therapy is most commonly reserved for individuals in whom a sufficient trial of diet, exercise, and oral medication therapy has proven ineffective [2].

Any individual initiating injectable therapy to control diabetes requires specific instructions to safely administer the medications. Necessary education related to injectable therapy includes injection techniques, site rotation, needle disposal, and identification of signs and symptoms of hypoglycemia [141].

Injection Techniques

If insulin is being used, it may be available in a prepared pen or cartridge or the patient may be required to prepare a syringe. Steps to correct syringe preparation for a single type of insulin are:

- Wash hands with soap and water.

- Clean the top of the vial with an alcohol wipe.

- Pull enough air into the syringe to replace the prescribed amount of insulin to be taken from the vacuum-sealed vial.

- Insert the air into the vial, and invert the vial.

- Pull back the total amount of insulin prescribed.

- Assess the syringe for any air pockets.

- If air pockets are present, lightly tap the syringe to elevate the air to the top of the syringe and release the bubble back into the vial.

- Remove the needle from the vial

Vials of suspension preparations, such as NPH, should be rolled gently to mix the components prior to administration. In cases of mixed insulins, most commonly when a rapid- or short-acting insulin is utilized in tandem with NPH insulin, additional steps are required. For example, a patient administering NPH and insulin lispro would complete the following steps [142]:

- Wash hands with soap and water.

- Clean the top of the vial with an alcohol wipe.

- Roll the vial of NPH 10 times on its side to thoroughly combine the active components.

- Pull 10 units of air into the syringe to replace the prescribed amount of NPH insulin to be taken from the vacuum-sealed vial.

- Insert the air into the vial, and invert the vial.

- Remove the needle from the vial of NPH.

- Pull 7 units of air into the syringe to replace the 7 units of insulin lispro to be removed from the vacuum-sealed vial.

- Insert the air, and invert the vial.

- Pull back 7 units of insulin lispro.

- Assess the syringe for any air pockets.

- If air pockets are present, lightly tap the syringe to elevate the air to the top of the syringe and release the bubble back into the vial.

- Remove the needle from the vial.

- Insert the needle into the vial of NPH. Do not insert the insulin lispro into the NPH.

- Pull back 10 units of NPH into the syringe containing the insulin lispro.

- Assess for the presence of air pockets. If present, tap the syringe lightly and release only the air back into the vial.

- Remove the needle.

It is important to note that insulin glargine and insulin detemir cannot be mixed with any other insulin or fluid. Therefore, if glargine or detemir is prescribed with rapid- or short-acting insulin, this will require two separate injections [50]. Furthermore, pramlintide and exenatide should not be combined with any other injectable medication due to the chemical composition [143].

Preparation of the site requires cleaning the area of injection with soap and water. Alcohol can be an alternative when soap and water are unavailable. After the site has dried completely, the patient will pinch the skin into a tent with the non-dominate hand and insert the needle at a 90-degree angle. He or she should then count to three; this will allow time for the insulin to start to disperse. It will also decrease the chance of removing the needle too rapidly, allowing the medication to back out of the subcutaneous tissue along with the needle [142]. The needle should then be disposed of in adherence with local requirements. The patient may utilize a commercial container or something as simple as a detergent bottle. When the container is full to within one inch of the top, recap the container and place strong tape around the top or follow the manufacturer's specific instructions [142].

It is important for patients to not reuse the needle due to the risk of infection and contamination of the medication vial. Patients should also be advised to assess needles prior to use and discard any that appear dull or bent to prevent injury [142]. A new needle should be used with each injection regardless of delivery method (e.g., syringe, pen device). This is a crucial topic of education [128].

Site Selection and Rotation

Injectables should be administered into specific locations to allow for the greatest absorption [128]. The first choice is usually the abdomen, which is considered the most consistent and rapid; the posterior upper arm is the second choice and is considered fast absorbing. The anterior thigh is appropriate, but the absorption is considered slow. Lastly, the buttocks can be utilized but will result in the slowest route of absorption [141].

Injection site rotation is of significant importance due to the potential development of a scar tissue related to overuse of a particular site of injection [141]. Insulin does not absorb into scar tissue; therefore, sites with overuse injuries will be ineffective [141]. For this same reason, it is important for patients to avoid areas where there are surgical or trauma scars. No one particular site-rotation technique is preferred as long as the chosen method is performed consistently by the person responsible for the injections [128].

Hypoglycemia

The development of hypoglycemia is a concern for all individuals on an injectable therapy regimen. Education should include information regarding oral and injectable combination medication management, insulin and injectable medication management, exercise considerations, and specific patient-centered issues to maintain safe use of medications in daily life [5].

Injectable medications alone or in combination with another antihyperglycemic agent increase the potential for an adverse hypoglycemia reaction [50]. Preventative measures include not skipping meals, eating prior to exercise, and appropriately timing insulin bolus therapy [50,98].

With the greater potential for hypoglycemia reactions, caregivers or significant others will require specialized training in the preparation and administration of glucagon. The caregiver should receive instruction on how to prepare the solution. He or she should inject saline from the prefilled syringe into the vial of powdered hormone and shake to assure the complete mixing of the solution. Then the preparation may be drawn back into the syringe for injection into the upper arm, leg, or buttock [98].

Accurate and frequent SMBG is vital. Patients should report frequent blood glucose levels below 70 mg/dL to their primary care provider [144]. Communication among the entire team, including the patient, the certified diabetes educator, and the primary care provider, is an optimal approach to patient education regarding the prevention of hypoglycemia [128]. Individuals should communicate frequent and multiple episodes of hypoglycemia to their primary care provider for adjustments in basal insulin, bolus insulin, or a combination, depending on the timing of the hypoglycemic event(s). This will allow for the fine tuning of the insulin regimen, which should result in optimized glycemic control and reduction of adverse outcomes [145].

For patients on an insulin regimen, exercise can significantly increase the potential for hypoglycemia [41,146]. Education related to exercise should focus on the assessment of pre-exercise blood glucose levels and determination if additional carbohydrates are needed. The patient should have a carbohydrate source available for treatment if signs or symptoms of hypoglycemia develop. Longstanding guidelines recommend consuming 10–15 grams of carbohydrate to prevent exercise-induced hypoglycemia [147]. However, subsequent research has illustrated that carbohydrate supplementation should be individualized to the patient's type of insulin and absorptive state [148,149]. Patient education should include information about how different therapies affect timing of peak insulin levels and duration of insulin action [150]. Patients should not exercise during periods of hypoglycemia and should be advised to avoid exercise for 24 hours after an episode of hypoglycemia [151]. The risk for hypoglycemia increases as the duration or intensity of the activity increases. Patients should be advised to avoid exercise when their insulin is at peak effect. Lastly, patients should avoid injection into the muscle on which exercise will be focused. This is because as a muscle is exercised, blood flow increases the utilization of glucose transport into the skeletal muscle, leading to greater decreases in blood glucose levels [151].

Patients who have or who are suspected to have nocturnal hypoglycemia as a result of insulin therapy should monitor blood glucose levels prior to going to bed. When the blood glucose level is less than 90 mg/dL, the individual should be instructed to consume a snack that includes a carbohydrate and a protein. Specific signs and/or symptoms of nocturnal hypoglycemia should be provided, and patients should be instructed to notify the primary care provider of suspected episodes. When nocturnal hypoglycemia is suspected, patients will be required to test blood glucose levels at 3 a.m.; this will provide vital information for the primary care provider [152].

Storage Issues

As discussed, insulin and injectables should be stored in a cool place or refrigerated until the preparation is used or has expired. If the preparation becomes frozen, it should be discarded [49]. Once opened, vials should be discarded after 31 days. After a pen or cartridge is pierced for the first time, the preparation should be refrigerated [2]. Combination NPH and insulin in the pen or cartridge form should only be used for 10 to 14 days (depending on preparation) prior to replacement. Insulin lispro, insulin glargine, and insulin glulisine pen preparations can be stored at room temperature and utilized for 28 days. Lastly, insulin detemir vials or pens can be utilized for 42 days once opened [49].

20. CASE STUDIES

CASE STUDY 1

Patient W is a Native American woman, 48 years of age, who is admitted to the hospital with complaints of chest pain. She is 5 feet 6 inches tall and weighs 256 pounds; her BMI is 41.4 kg/m^2. Her vital signs are assessed; her heart rate is 122 beats per minute, regular rate and rhythm, blood pressure is 198/101 mm Hg, and oral temperature is 37.4 degrees Celsius. Her past medical history is positive for gestational diabetes with her fourth child (five years previous), bilateral arthritis of the knees, and tobacco use. Patient W denies use of recreational drugs and homeopathic pharmaceuticals, but she does admit to occasional alcohol usage, generally two beers per day on the weekend. Her family history includes diabetes, heart disease, stroke, lung cancer, and alcohol abuse. Although her electrocardiogram is negative for myocardial infarction, her stress test reveals left coronary artery ischemia. Her cardiac enzymes are negative, but other significant laboratory results include:

- Triglycerides: 250 mg/dL

- LDL: 141 mg/dL

- HDL: 22 mg/dL

- Blood urea nitrogen (BUN): 35 mg/dL

- Creatinine: 1.5 mg/dL

- Random blood glucose: 310 mg/dL

- HbA1c: 9.5% (estimated average glucose: 226 mg/dL)

- Liver function tests: Within normal limits

- eGFR: 43 mL/min/1.73 m^2

Patient W is admitted for a cardiac catheterization and further cardiac work-up. She is started on blood glucose monitoring before meals and at bedtime with weight-based insulin correction with analog (rapid-acting) insulin, a calorie-controlled cardiac diet, antihypertensive medication, a statin for lipid management, an angiotensin-converting enzyme inhibitor, and pain medications as needed for chest pain or discomfort.

On hospital day 2, Patient W has a fasting blood glucose of 210 mg/dL. She receives rapid-acting insulin coverage per weight-based protocol even though she is being prepared for cardiac catheterization in the late morning and has not eaten. At approximately 10 a.m., the patient is taken for a cardiac catheterization, which reveals a 90% blockage of the left coronary artery, and subsequently undergoes percutaneous coronary intervention (PCI). A drug-eluting stent is placed. Postprocedure, Patient W returns to her room mildly sedated with an arterial line in place and a blood glucose level of 201 mg/dL, for which she receives weight-based coverage. At 5 p.m., the patient is alert and hungry. Her arterial line is discontinued, and her blood glucose is 220 mg/dL, for which she again receives weight-based coverage. At 9 p.m., Patient W has been pain free throughout the day and is ready to sleep. Her blood glucose level is 201 mg/dL. She is given insulin and is instructed to notify the nurse of any pain, palpitations, sweating, shakiness, and/or dizziness.

On hospital day 3, Patient W awakens with a blood glucose level of 248 mg/dL. Her physician initiates basal insulin to obtain better glucose control. She is cleared for discharge by her cardiologist, but her primary care physician would prefer to monitor her glucose levels for one more day, including her two-hour postprandial level after her evening meal. Throughout the day, the following blood glucose levels are documented:

- 7 a.m.: 248 mg/dL

- 11 a.m.: 121 mg/dL

- 5 p.m.: 118 mg/dL

- 7 p.m. (two-hour postprandial): 210 mg/dL

- 9 p.m.: 178 mg/dL

The following morning, Patient W is discharged to home with a prescription for glyburide 2.5 mg twice a day for her newly diagnosed type 2 diabetes. She is also referred to an ADA-recognized education program. She receives survival skills education prior to leaving the hospital and is encouraged to contact the outpatient education center within the first week after discharge. Patient W agrees with her discharge plan and states understanding of all instructions given.

Rationale and comments : The treatment approach appears appropriate to manage Patient W's diabetes. Patient education will be extensive for this patient given the many new medications and changes associated with the PCI and her various conditions. Education specific to the glyburide should include instructions to eat meals at a consistent time (not skipping meals) and information regarding the signs, symptoms, and treatment of hypoglycemia.

At her follow-up appointment, Patient W has completed her self-management education and set personal behavior change goals for meal planning and exercise. She is demonstrating competent SMBG assessment; her fasting levels are between 140 mg/dL and 170 mg/dL, and her postprandial levels range from 160 mg/dL to 200 mg/dL. The patient's occasional two-hour postprandial readings range from 190 mg/dL to 230 mg/dL. Her fasting laboratory results are as follows:

- Fasting blood glucose: 167 mg/dL

- HbA1c: 8.6% (estimated average glucose: 200 mg/dL)

- Triglycerides: 220 mg/dL

- LDL: 110 mg/dL

- HDL: 33 mg/dL

- BUN: 35 mg/dL

- Creatinine: 1.5 mg/dL

- Liver function tests: Within normal limits

In order to improve Patient W's blood glucose control, her physician chooses to increase her glyburide to 5 mg twice a day with instruction to return for follow-up in one month to assess the efficacy of treatment. In one month, Patient W continues to have difficulties achieving optimal control on monotherapy. The decision is made to start combination therapy with pioglitazone, a TZD.

Rationale and comments : Combination therapy with a TZD is the correct choice for Patient W because her BUN and creatinine levels are too high to safely utilize metformin. Furthermore, her casual use of alcohol on the weekends can be an area of concern with the potential for liver dysfunction. Pioglitazone will address the issue of insulin resistance in the presence of the metabolic syndrome and has beneficial effects on coronary artery disease in the presence of type 2 diabetes.

Prior to leaving the physician's office, the nurse reviews the signs and symptoms of hypoglycemia with Patient W. The patient is instructed to alert her primary care physician of frequent episodes of hypoglycemia. She is also counseled regarding the need to eat meals at spaced intervals throughout the day to decrease the chances of developing hypoglycemia.

The heart failure risks associated with TZD use are discussed as well as the need to report any weight increase of 3 to 5 pounds over a two-day period to her primary care physician. Patient W is also advised to contact her primary care physician if she experiences any symptoms related to liver dysfunction/failure, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Finally, the patient is reminded of the need to monitor her liver function by venipuncture periodically while on pioglitazone.

CASE STUDY 2

Patient O is a Hispanic male, 48 years of age, with a seven-year history of type 2 diabetes. He presents to his primary care physician's office for a routine follow-up appointment to assess his diabetes control. His only complaint at the time of his appointment is an occasional burning sensation in his bilateral lower extremities.

Patient O's past medical history is positive for type 2 diabetes diagnosed at 41 years of age, hypertension for the past two years, and new onset of hyperlipidemia within the past six months. He is negative for renal disease, retinopathy, and peripheral vascular disease. The patient's family history is positive for type 2 diabetes, coronary artery disease, cerebral vascular accident, hyperlipidemia, and obesity.

During the physical assessment, Patient O is alert and oriented. His height (5 feet 10 inches), weight (239 pounds), and BMI (34.4 kg/m^2) are measured and documented. Blood pressure is 128/68 mm Hg on medications, pulse is 74 beats per minute, and oral temperature is 37 degrees Celsius. Lungs are clear to auscultation, and heart sounds are clear without rubs or murmurs. The patient's abdomen is soft and nontender at all quadrants. Peripheral pulses are present at +2 at all extremities, and feet are free from lesions with a positive Babinski reflex. All extremities are warm to touch and responsive to monofilament test.

Patient O's laboratory results include:

- HbA1c: 8.1% (estimated average glucose: 186 mg/dL)

- Fasting blood glucose: 155 mg/dL

- BUN: 24 mg/dL

- Creatinine: 1.3 mg/dL

- ALT: 16 U/L

- HDL: 31 mg/dL

- LDL: 122 mg/dL

- Triglycerides: 201 mg/dL

- Microalbuminuria: 312 mcg/mg

The patient is currently prescribed captopril 25 mg twice a day, simvastatin 40 mg daily at bedtime, metformin 1,000 mg twice per day, and glipizide extended-release 20 mg daily. He has previously met with a registered nurse certified diabetes educator and registered dietitian certified diabetes educator regarding self-care management, blood glucose monitoring, behavior change, meal planning, and goal setting. He tests his blood glucose levels twice a day at various times.

At this visit, Patient O receives the results of his blood work and has expressed concerns regarding his recent SMBG numbers and new onset of burning in his lower extremities. He presents verbalizing frustration and feeling like a failure. It is vital to actively listen to the patient regarding his frustrations and fears related to his diabetes. It is also important to educate him regarding the progressive nature of diabetes, regardless of the attentiveness a person gives to the care of the disease [2].

The nurse reviews Patient O's eating and exercise habits to see if any changes could be made to optimize control. Furthermore, sources of stress are discussed. Patient O is told that worrying about the progression of his diabetes and having anxiety regarding adherence to his meal or exercise plan is normal, but it is possible for this additional stress and anxiety to result in increased blood glucose levels [7]. Patient O states that he was unaware of the impact stress was having on his body.

Due to the continued elevated blood glucose levels, the primary care physician wants to maximize oral medication therapy, most likely by adding a DPP-4 inhibitor, an alpha-glucosidase inhibitor, or a TZD [2]. In order to make a decision regarding the most appropriate agent, each of the classes' benefits and risks should be considered with Patient O in mind. The addition of a DPP-4 inhibitor has been shown to be weight neutral, occasionally demonstrating a reduction in weight. The dose can be decreased for safe use in those individuals who have some renal impairment, such as Patient O [51]. The greatest drawback of DPP-4 inhibitor therapy is the cost.

The addition of an alpha-glucosidase inhibitor is a less expensive option and would benefit Patient O by decreasing the absorption of complex carbohydrates in the intestinal tract. The alpha-glucosidase inhibitors do have objectionable side effects, such as recurrent flatulence, that some patients are unable to tolerate [50]. Patient education needs for those taking alpha-glucosidase inhibitors include timing of medication with meals, gastrointestinal side effects, and the treatment of hypoglycemia [49,50,65].

The addition of a TZD would reduce insulin resistance and reduce cardiovascular risk factors, including markers of vascular inflammation [2]. However, precautions should be taken when this therapy is prescribed. Weight gain and liver damage are possible, and laboratory levels should be regularly monitored. Patient education regarding weight gain and shortness of breath is necessary as these are signs of impending heart failure.

The final option for Patient O would be to continue current therapy and add basal insulin. This would provide long-acting coverage to allow the metformin and extended-release glipizide to have a greater effect. This also has obstacles to acceptance, including fear of injection, fear of acute hypoglycemia, and misconceptions about insulin therapy. All therapy choices would be viable options for Patient O, and as a healthcare provider, understanding of all available agents is needed to support the final decision.

CASE STUDY 3

Patient F is a black female resident of a local long-term care facility. She is 87 years of age and has had type 2 diabetes for the past 25 years. In addition to diabetes, Patient F has a past medical history of hypertension, cardiovascular disease, peripheral neuropathy, and mild Alzheimer disease. Her son and daughter-in-law came to visit and found the patient confused, wet with foul urine, and begging for water. She had a temperature of 38.5 degrees Celsius. The family requested her transfer to the emergency department for evaluation and treatment.

Upon admission to the emergency department, Patient F is increasingly confused and combative, with a body temperature of 38.8 degrees Celsius. She is started on oxygen at 2 liters for an oxygen saturation of 88%. Laboratory samples are obtained, and an infusion of 0.9% sodium chloride is initiated at 75 mL/hour for observed signs of dehydration. The laboratory results indicate:

- Blood glucose: 1179 mg/dL

- Potassium: 5.2 mEq/L

- Phosphorus: 3.4 mmol/L

- Ketones: Minimal

- Serum osmolality: 420 mOsm/kg

- HbA1c: 11.9%

- White blood cell count: 46,000

- Urinalysis: Positive for bacteria

Based on this information, a diagnosis of HHS is made. Because HHS is characterized by profound dehydration, management is initially focused on rehydration. The physician orders an increase in the current 0.9% sodium chloride infusion to 100 mL/hour. Because there are no dysrhythmias noted on the telemetry monitor, the physician continues to monitor the potassium level with subsequent laboratory assessments. Patient F is also started on empirical antibiotic therapy for a suspected UTI until the results of urine and blood culture are known. An additional intravenous access is initiated in order to administer insulin. A regular insulin bolus of 0.1 units/kg followed by an infusion of regular insulin is ordered to run at a rate of 0.1 units/kg/hour.

Patient F's blood glucose levels slowly drop to 275 mg/dL, but her osmolality is 365 mOsm/kg and she remains confused. Because the patient's osmolality remains greater than 350 mOsm/kg and her confusion is unresolved, her blood glucose levels should be maintained between 250 mg/dL and 300 mg/dL. Her potassium level stabilizes without intravenous therapy and is currently 4.2 mEq/L. Her telemetry readings remain in sinus rhythm.

After 36 hours of therapy, Patient F has an osmolality of less than 315 mOsm/kg, and she is back to her baseline mentation. Her blood glucose level is 225 mg/dL, and she is getting prepared to transfer off of the insulin infusion.

Rationale and comments : Several considerations should be made in order to continue to achieve optimal glycemic control. The patient's HbA1c is 11.9%, which is considered uncontrolled. If a long-acting insulin is not started, the glucose levels will rebound. Also, it is vital that hydration status is maintained. Basal insulin should be given at least one hour prior to the discontinuation of the insulin infusion in order to prevent rebound hyperglycemia, which is a risk due to Patient F's continuing UTI and high HbA1c.

Patient F is maintained on 0.9% sodium chloride 75 mL/hour until adequate oral intake is established. She also starts insulin detemir 0.2 units/kg (total dose: 15 units) to be given once per day at night, which should provide weight-based coverage for correction of glucose elevations.

After three days, Patient F's HHS has been resolved, and the team is preparing the patient for discharge. However, she continues to have blood glucose levels between 280 mg/dL and 400 mg/dL.

Rationale and comments : There are several available options for Patient F. Insulin detemir may be continuously increased to desired effect and/or split to a twice daily schedule. If glycemic control is not achieved on the long-acting insulin preparation, addition of bolus insulin therapy may be necessary. Because the patient is a resident of a long-term care facility and has a history of cognitive impairment, the better option for her may be combination therapy.

To combat the consistently high blood glucose levels, Patient F's insulin detemir dose is increased to 15 units twice a day. The next day, the patient has the following glucose results: 146 mg/dL, 175 mg/dL, 188 mg/dL, and 136 mg/dL. Her primary care provider is satisfied with these readings and plans to discharge her the following day.

21. CONCLUSION

As the prevalence of diabetes increases, it is important to have a general understanding of the many options for treatment. Each of the various drug classes has specific contraindications and potential side effects, and all members of the interdisciplinary team should be involved with assessing the efficacy of the treatments and patients' quality of life. This approach is best to ensure optimal outcomes and prevention of long- and short-term complications. With the constant evolutions and advances being made in the management of diabetes, healthcare professionals should frequently review and renew their professional knowledge to ensure the care provided to diabetic patients is the most accurate and up-to-date possible.

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137. U.S. Food and Drug Administration. Press Release: FDA Approves First Oral GLP-1 Treatment for Type 2 Diabetes. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-glp-1-treatment-type-2-diabetes?utm_campaign=092019_PR_FDA%20approves%20first%20oral%20GLP-1%20treatment%20for%20type%202%20diabetes&utm_medium=email&utm_source=Eloqua. Last accessed October 7, 2019.

138. Karl D, Philis-Tsimikas A, Darsow T, et al. Pramlintide as an adjunct to insulin in patients with type 2 diabetes in a clinical practice setting reduced A1C, postprandial glucose excursions, and weight. Diabetes Technol Ther. 2007;9(2):191-199.

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141. Down S, Kirkland F. Injection technique in insulin therapy. Nurs Times. 2012;108(10):18-21.

142. Drugs@FDA. Novolin 70/30. Label information. U.S. Food and Drug Administration Web site. Available at https://www.accessdata.fda.gov/scripts/cder/daf/. Last accessed October 7, 2019.

143. U.S. Food and Drug Administration. Symlin (Pramlintide Acetate): Label Information. Available at https://www.accessdata.fda.gov/scripts/cder/daf/. Last accessed October 7, 2019.

144. Kulkarni K. Diets do not fail: the success of medical nutrition therapy in patients with diabetes. Endocr Pract. 2006;12(Suppl 1):121-123.

145. Centers for Disease Control and Prevention. Take Charge of Your Diabetes. 4th ed. Atlanta, GA: U.S. Department of Health and Human Services; 2007.

146. Zinman B, Ruderman N, Campaigne BN, Devlin JT, Schneider SH. Diabetes Mellitus and Exercise. Available at https://www.medscape.com/viewarticle/717051. Last accessed October 7, 2019.

147. Wasserman DH, Zinman B. Exercise in individuals with IDDM. Diabetes Care. 1994;17(8):924-937.

148. Dubé M-C, Weisnagel SJ, Prud'homme D, Lavoie C. Exercise and newer insulins: how much glucose supplement to avoid hypoglycemia? Med Sci Sports Exerc. 2005;37(8):1276-1282.

149. Francescato MP, Geat M, Fusi S, Stupar G, Noacco C, Cattin L. Carbohydrate requirement and insulin concentration during moderate exercise in type 1 diabetic patients. Metabolism. 2004;53(9):1126–1130.

150. Nagi D (ed). Exercise and Sport in Diabetes. 2nd ed. Chichester: John Wiley and Sons, Ltd; 2005.

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Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force. Screening for abnormal blood glucose and type 2 diabetes mellitus: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015;163(11):861-868. Available at https://annals.org/aim/fullarticle/2466368. Last accessed October 22, 2019.

2. Redmon B, Caccamo D, Flavin P, et al. Diagnosis and Management of Type 2 Diabetes Mellitus in Adults. Bloomington, MN: Institute for Clinical Systems Improvement; 2014. Available at https://www.icsi.org/wp-content/uploads/2019/02/Diabetes.pdf. Last accessed October 22, 2019.

30463 • Moderate Sedation/Analgesia

Susan Engman Lazear, RN, MN

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

Moderate sedation is an exciting field for nurses. As newer, safer sedation medications become available, nurses will be asked to provide moderate sedation on an increasingly frequent basis. Recognition of the goals and objectives of moderate sedation is the first step in providing safe care. Medication administration and knowledge of pharmacologic principles is paramount prior to drug delivery. Providing for patient safety should be the most important aspect of nursing care delivery. Recognition of the nuances of care delivery to specific patient populations must not be overlooked. If these aspects are adhered to throughout moderate sedation, the patient will be provided with safe care before, during, and after sedation.

Table of Contents

30463 • Moderate Sedation/Analgesia

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. PATIENT CARE

PRESEDATION CARE

CARE DURING SEDATION

POSTSEDATION CARE

3. PHARMACOLOGY AND DRUG ADMINISTRATION

ROUTE OF ADMINISTRATION

ADMINISTRATION OF INTRAVENOUS MEDICATIONS

4. DRUG CLASSES AND MEDICATIONS

BENZODIAZEPINES

OPIOIDS

BARBITURATES

OTHER SEDATIVE HYPNOTICS

DISSOCIATIVE AGENTS

ANTAGONISTS

5. PATIENT MONITORING DURING MODERATE SEDATION

PULSE OXIMETRY

END-TIDAL CARBON DIOXIDE MONITORING

CARDIAC MONITORING

NONINVASIVE BLOOD PRESSURE MONITORING

BISPECTRAL INDEX

6. DOCUMENTATION OF MODERATE SEDATION

7. COMPLICATIONS DURING MODERATE SEDATION

OVERSEDATION AND UNDERSEDATION

RESPIRATORY INSUFFICIENCY

COMPROMISED AIRWAY

ASPIRATION

CARDIOVASCULAR COMPLICATIONS

PAIN

NAUSEA AND VOMITING

MALIGNANT HYPERTHERMIA

PARADOXICAL REACTIONS

8. MODERATE SEDATION OF THE PEDIATRIC PATIENT

ANATOMIC AND PHYSIOLOGIC DIFFERENCES

PHARMACOLOGIC CONSIDERATIONS

NURSING CARE

9. MODERATE SEDATION OF THE GERIATRIC PATIENT

ANATOMIC AND PHYSIOLOGIC DIFFERENCES

PHARMACOLOGIC CONSIDERATIONS

NURSING CARE

10. MODERATE SEDATION OF THE OBSTETRIC PATIENT

ANATOMIC AND PHYSIOLOGIC DIFFERENCES

PHARMACOLOGIC CONSIDERATIONS

NURSING CARE

11. SEDATION OF THE CRITICALLY ILL PATIENT

12. PATIENTS UNDERGOING PROCEDURAL INTERVENTIONS

RADIOLOGIC INTERVENTIONS

CARDIAC CATHETERIZATIONS AND ELECTROPHYSIOLOGIC STUDIES

ENDOSCOPIC PROCEDURES

13. CASE STUDIES

PATIENT J

PATIENT D

14. PRACTICE ISSUES

ADVANCED CARDIAC LIFE SUPPORT TRAINING

MEDICAL-LEGAL CONSIDERATIONS

POLICIES AND PROCEDURES

ISSUES IN INTRAVENOUS VS. TRANSMUCOSAL ADMINISTRATION OF MODERATE SEDATION

COMPETENCY ISSUES

15. SUMMARY

Works Cited

Evidence-Based Practice Recommendations Citations

30463 • Moderate Sedation/Analgesia

Education Category. Medical / Surgical

Release Date. 08/01/2020

Expiration Date. 07/31/2023

Course Overview

Moderate sedation is an exciting field for nurses. As newer, safer sedation medications become available, nurses will be asked to provide moderate sedation on an increasingly frequent basis. Recognition of the goals and objectives of moderate sedation is the first step in providing safe care. Medication administration and knowledge of pharmacologic principles is paramount prior to drug delivery. Providing for patient safety should be the most important aspect of nursing care delivery. Recognition of the nuances of care delivery to specific patient populations must not be overlooked. If these aspects are adhered to throughout moderate sedation, the patient will be provided with safe care before, during, and after sedation.

Audience

This course is designed for all nurses, especially those in procedural and diagnostic areas, such as radiology, endoscopy, cardiac cath, outpatient surgery, intensive care, and emergency departments.

Course Objective

The purpose of this course is to provide nurses with the knowledge required for safe drug delivery based on standardized operational guidelines. Preprocedural, intraprocedural, and postprocedural patient care are presented, as well as a thorough review of the drugs used, their advantages and disadvantages, and the safe administration of these agents.

Learning Objectives

Upon completion of this course, you should be able to:

1. Define moderate sedation, including the goals and objectives.

2. Detail the necessary components of the preprocedural patient care period, including patient assessment, selection, and preparation.

3. List the duties and responsibilities of those who provide care for the patient receiving moderate sedation medications.

4. Detail patient care provided during the postsedation period, including the minimal parameters that should be met by the patient prior to discharge after sedation.

5. Present the advantages and disadvantages of the various methods and routes of medication administration.

6. Review the most commonly used pharmacologic agents for moderate sedation.

7. List the advantages, disadvantages, and limitations of pulse oximetry and end-tidal carbon dioxide monitoring in the sedation setting.

8. Describe the various techniques for cardiac monitoring. Explain the advantages of each of these methods.

9. Outline the role of bispectral indexing in moderate sedation patients.

10. Develop a sedation documentation form that includes the appropriate information.

11. Discuss the most common complications occurring during or after moderate sedation.

12. Outline the anatomic and physiologic differences between children and adults and how these differences impact pediatric moderate sedation patients.

13. Describe the anatomic and physiologic differences in the elderly and the impact of these differences on the administration of sedation.

14. Explain how sedation practices should be altered in sedating the obstetric patient.

15. Review issues that impact moderate sedation administration for patients in the intensive care unit or those undergoing procedural interventions.

16. Identify practice issues for nurses administering moderate sedation.

Faculty

Susan Engman Lazear, RN, MN, received her undergraduate education at the Walter Reed Army Institute of Nursing in Washington, D.C. After completing her BSN, she served as an Army Nurse at Letterman Army Medical Center in San Francisco for four years. She then attended the University of Washington School of Nursing and received a Master’s in Nursing, specializing in Burn, Trauma and Emergency Nursing. After receiving her MN, she started Airlift Northwest, the air ambulance service based in Seattle which serves the entire Northwest region, including Alaska. Mrs. Lazear left the air ambulance service to start her own nursing education and consulting business, Specialists in Medical Education. For the past 20 years she has been teaching emergency nursing courses throughout the country. She lives in the Seattle area. Mrs. Lazear continues to teach and publish. She is both an editor and contributing author of Critical Care Nursing, published by W.B. Saunders Company, in June of 1992. She served as an author and reviewer of the Emergency Nursing Core Curriculum 6th Edition, published by W.B. Saunders Company in 2007. She has been named to the Who’s Who in American Healthcare list annually since 1992.

Faculty Disclosure

Contributing faculty, Susan Engman Lazear, RN, MN, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Jane C. Norman, RN, MSN, CNE, PhD

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Moderate sedation/analgesia (formerly referred to as conscious sedation) was once a task performed exclusively by anesthesiologists but is now a common nursing practice in a number of settings. The interest in and use of moderate sedation has dramatically increased as more nurses and care providers become trained in the safe delivery of patient care while administering sedative agents.

In 2001, the Joint Commission developed a new definition of moderate sedation that is now widely accepted and used. The Joint Commission identifies moderate sedation/analgesia as the second level in a continuum between minimal sedation (i.e., anxiolysis) and deep sedation (i.e., anesthesia). Thus, the Joint Commission defines moderate sedation/analgesia as "a drug-induced depression of consciousness during which individuals served respond purposefully to verbal commands either alone or accompanied by light tactile stimulation. No interventions are required to maintain a patent airway, and spontaneous ventilation is adequate. Cardiovascular function is usually maintained" [1]. The Joint Commission has mandated that an institution's sedation practices be monitored and evaluated by the department of anesthesia. In response to this mandate, the American Society of Anesthesiologists (ASA) developed practice guidelines for nonanesthesiologists who provide sedation and analgesia [2,3,4]. The practitioner should recognize that sedation is part of the continuum that progresses from minimal to moderate to deep sedation and eventually reaches the state of general anesthesia. Each individual patient should be closely and continuously monitored to prevent this progression to the deeper sedated states [5]. Practitioners of sedation should have the necessary skills to rescue a patient from a deeper level of sedation than that intended [5].

Much like the Joint Commission, the ASA has defined moderate sedation in the following manner [2]:

- Depression of consciousness is drug-induced.

- Patient responds purposefully to verbal commands, either alone or accompanied by light tactile stimulation.

- Airway is patent without interventions, and spontaneous ventilation is adequate.

- Cardiovascular function is usually maintained.

Moderate sedation/analgesia can be used to achieve a number of objectives. Moderate sedation allows a patient to tolerate an unpleasant procedure while maintaining consciousness and cooperation. Many of the pharmacologic agents used will provide mood alteration and partial amnesia. The patient does not remember the majority of the procedure and awakens in a comfortable, composed state. The choice of medications used depends on the objectives desired; some medications will provide for an elevation in the patient's pain threshold, while others have no analgesic properties. However, it is important to note that the term moderate sedation cannot be used synonymously with pain management, as not all sedating medications will achieve the parameters of pain control. An additional goal of sedation is a rapid return of the patient to his/her presedation state with a decreased risk of resedation. It is imperative for nurses providing moderate sedation to remember that while the goals and objectives of moderate sedation are important, the most critical part of patient care delivery is providing for patient safety during the time that the patient is sedated and recovering from sedation.

Moderate sedation is delivered in a number of settings. The reasons for sedation may vary, but the Joint Commission requires that the patient receive the same level of care regardless of the practice setting. The first reports of the use of moderate sedation can be found in dental literature. Many dental and oral surgery procedures are successfully accomplished on the sedated patient. The emergency department may deliver sedation for a number of reasons, including, but not limited to, the repair of complex lacerations, reduction of fractures and casting, wound care, and abscess incision and drainage. Some patients may require lengthy, uncomfortable radiologic studies necessitating sedation in the radiology suite. Many invasive and diagnostic measures are performed using moderate sedation, such as bronchoscopy, endoscopy, cardiac studies, and pacemaker placement. The outpatient setting has seen an increased use of moderate sedation. It is not uncommon for in vitro fertilization to be performed on a sedated patient. Additionally, moderate sedation has been used as an adjunct to local anesthesia. A vast number of procedures that are uncomfortable and/or painful can be performed safely using moderate sedation [4,6,7,8,9,10,11,12,13,14,15].

As previously mentioned, the use of moderate sedation has increased tremendously. This increase in acceptance and popularity has occurred for a number of reasons. Due to healthcare reform, the financial impact of patient care is under daily scrutiny. Moderate sedation performed by trained nursing staff can greatly reduce the patient's hospital charges, as opposed to sedation performed by an anesthesiologist. A study of cardiac patients undergoing a six-hour electrophysiologic study found a reduction in costs of administering sedation ranging from $1,800 to $2,400 when a patient received moderate sedation administered by a nurse as compared to the patient receiving general anesthesia administered by an anesthesiologist [16]. This reduced cost reflected a number of factors, including shorter recovery times and a rapid return to the presedation state in the patient, thus requiring less expensive nursing care and shorter hospital stays [17,18]. One study investigated the clinical and cost outcomes associated with moderate sedation in patients undergoing transcatheter aortic valve replacement [19]. Of 231 patients initially identified, 225 were included in the study. Compared with general anesthesia, moderate sedation was associated with significantly fewer intensive care unit (ICU) hours (30 vs. 96); fewer total hospital days (4.9 vs. 10.4); a 28% decrease in direct costs; and significant decreases in all cost categories [19].

Patient acceptance and demand for moderate sedation is another reason its use has become more prevalent. The reported rates of patient satisfaction after procedures with moderate sedation have been high [20,21,22]. A knowledgeable patient recognizes that there are medications and techniques available (i.e., moderate sedation/analgesia) that allow the patient to have a procedure performed with a minimal amount of disruption in his/her daily activities. Patients no longer stay overnight after many procedures, and if given short-acting medications, they can return to their jobs and home life within a relatively short period of time.

Additionally, parents and family members do not want to see their loved ones uncomfortable or suffering and will request medications to help ease the pain. This is especially true with the pediatric patient, as many of the invasive procedures performed can be achieved with much less difficulty and pain in a moderately sedated child. The results are improved and the parent is satisfied in knowing that his/her child is not being unnecessarily restrained.

Patient satisfaction varies according to the drug used. There are a number of good, short-acting drugs available that assist in achieving the goals and objectives of moderate sedation. Prior to the 1990s, diazepam had been the drug of choice in most practice settings; however, the side effects were intolerable to many, and patients had longer recovery times. With the advent of newer benzodiazepines and opioids, patients can experience the same benefits without the disadvantages of the older drugs.

Finally, increased use of moderate sedation can be traced to the advent of new technologic innovations. With the development of pulse oximetry and noninvasive blood pressure monitoring, moderate sedation can be delivered safely and noninvasively to provide for maximum patient comfort and care.

The subsequent discussion of moderate sedation will focus on safe patient care delivery. The administration of moderate sedation can be performed using either intravenous (IV) or transmucosal (i.e., oral, intranasal, rectal, sublingual) routes. Each route has advantages and disadvantages, which will be discussed in length at a later point in this course. The issues discussed in the Patient Care section will cover both routes of administration, with special attention to IV sedation when appropriate.

2. PATIENT CARE

Care of the patient receiving sedating medications includes three phases: presedation care (i.e., care prior to the procedure); care during the procedure, and postsedation care (i.e., care after the procedure). Administering moderate sedation/analgesia requires vigilant nursing assessment during all phases to ensure safe drug administration and positive patient outcomes.

PRESEDATION CARE

Patient selection and assessment prior to drug administration is critical to safe patient care both during and after sedation. The goals of presedation selection include the recognition of risk factors that may place the patient at increased risk of complications; the recognition of patients with a high level of anxiety who may not tolerate the sedation process easily; and the recognition of pre-existing comorbidities that will complicate care delivery. For elective procedures, a preprocedure assessment may be done days or weeks in advance; early assessment is essential for allowing time to make any necessary changes, such as the discontinuation of certain medications or herbal supplements [3,4,6,23,24]. Even when an early assessment has been done, the Joint Commission requires that a presedation assessment be performed on each individual prior to beginning moderate sedation and before anesthesia induction [25]. This assessment allows the practitioner to plan and administer sedation to ensure patient safety. The components of presedation assessment include the patient's age, height, weight, and existing medical diagnosis. A physical examination with a review of the cardiac, respiratory, and neurologic systems should be completed. Astute assessment is critical as medications administered during moderate sedation will most significantly affect these body systems, and the patient who may be at risk should be identified.

The patient's past medical history should be reviewed. A history of allergies should be documented, and if necessary, therapeutic reversal agents, such as diphenhydramine and epinephrine, should be prepared. The patient's current medical history should include the reason for sedation and other current factors, including medication(s), alcohol, illicit drug, and/or tobacco use. A review of the patient's history may help to identify patients at risk for complications (Table 1) [6].

Table 1: USING HISTORY TO HELP IDENTIFY PATIENTS AT RISK FOR COMPLICATIONS

Question

Relevance to Moderate Sedation

Is there a history of cardiovascular problems?

The patient may be at increased risk for complications and may require special monitoring.

Is there a history of respiratory problems (emphysema, asthma)?

Risk of complications is greater for patients with emphysema or asthma due to potential respiratory depression.

Is there a history of seizure disorders?

If disorder is treated with benzodiazepines, a benzodiazepine antagonist cannot be used as a reversal agent.

Is there a history of liver disease?

Liver damage may prolong and/or heighten sedative effects of drugs metabolized in the liver.

Is there a history of renal disease?

Potential for problems for patients with renal insufficiency if the sedation drugs used are ones that are excreted in the urine (such as benzodiazepines and opioids).

Is there a history of thyroid disease?

Altered rates of metabolism affect the effective doses of sedation drugs.

Is there a history of substance abuse?

A back-up plan should be made with an anesthesia professional in case the patient becomes combative or uncooperative or if sedation drugs have little effect.

Are there any piercings?

Piercings may need to be removed, depending on location.

What current medications are taken?

Many prescription medications and herbal supplements may increase the risk for complications related to sedation/analgesia and/or an invasive procedure.

Source: [6]

Airway assessment should be conducted and is easily performed using the modified Mallampati scale [26,27,28]. The patient is placed in a comfortable sitting position and asked to open his/her mouth and protrude the tongue. The nurse then assesses the airway, noting the ability to visualize the fauces, anterior and posterior pillars, soft palate, and uvula. The patient with a Class 1 airway has all these structures visible. The pillars are masked by the tongue in a patient with a Class 2 airway. A patient with a Class 3 airway has only the soft palate and base of the uvula visible. A patient for whom only the hard palate is visible has a Class 4 airway [29]. The modified Mallampati scale allows the nurse to recognize which patients may be at risk for difficult airway management, including difficult intubations [28]. It has also been noted that obesity may contribute to airway difficulties [30,31]. In addition to visualization of the airway, neck circumference and body mass index should also be assessed preoperatively and considered in the overall airway assessment.

Baseline vital signs should be obtained, taking into consideration that the patient's "normal" vital signs may be masked by anxiety, pain, and fear. A baseline assessment of the patient's level of consciousness should be achieved to allow for proper assessment during sedation as well as for assessment of readiness for discharge. Additionally, baseline pulse oximetry readings should be achieved prior to initiating oxygen therapy.

An anesthesia history should be obtained, focusing on previous surgical interventions and any known complications. Appropriate laboratory studies can be obtained prior to the procedure.

It is important to accurately and fully assess the patient without performing excessive, superfluous tests. An electrocardiogram (ECG) may be indicated for patients with positive cardiac histories, but not everyone older than 40 to 50 years of age will require a presedation ECG. The performance of unnecessary tests may increase the patient's out-of-pocket costs if, for example, the patient's insurance company determines that the tests were unnecessary and declines to pay for them. Not only is this expensive, it may cause the patient to question the necessity of other important tests that may have been performed at the same time. Therefore, preprocedural tests should be weighed but by no means considered requirements for every patient.

Finally, the setting in which sedation will be administered should be considered in the selection process. The ASA Committee on Standards and Practice Parameters recommends that patients who receive moderate sedation on a scheduled basis should not drink clear fluids for at least two hours or eat solid foods (a light meal) for at least six hours prior to the procedure [32]. However, meeting the fasting requirements for emergently performed procedures is difficult, and guidelines note that when urgent or emergent procedures must be done, recent food intake is not a contraindication for administering procedural sedation/analgesia in adults or children [3,4,23,33,34]. The potential risks of sedation without fasting (e.g., aspiration) should be weighed against the benefit of performing the procedure promptly [4]. The ASA has developed a Physical Status Classification System to determine risk for complications among patients undergoing anesthesia (Table 2). This scale is frequently used in the moderate sedation setting and easily performed on all patients in all settings. Patients in Class 1 and 2 are considered good candidates for moderate sedation procedures; those in Class 3 and Class 4 carry higher risks. Nurses providing sedation should recognize that Class 3 and 4 patients may benefit from sedation and should not be excluded based upon their ASA classification. Sedation is frequently provided to ICU patients, most of whom are in Class 3 or 4, and these patients greatly benefit from the effects of the sedation.

Table 2: AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL STATUS CLASSIFICATION

Physical Status Classa

Definition

1

A normal healthy patient with no systemic disease

2

A patient with mild-to-moderate systemic disease

3

A patient with severe systemic disease

4

A patient with severe systemic disease that is a constant threat to life

5

A moribund patient who is not expected to survive without surgical intervention

6

A declared brain-dead patient whose organs are being removed for donor purposes

aThis number may be followed by an "E" if the surgery is considered an emergency

Source: [35]

A prime example of this dilemma would be a patient, 76 years of age, with a history of unstable angina who is being evaluated for sedation. His history shows that he lives alone and cares for himself. However, he is unable to walk a flight of stairs without stopping to catch his breath; thus, he would be classified as an ASA Class 3 patient. Withholding sedation because of his history may actually increase his risk of compromise if he is found to be extremely anxious about the intended intervention. His anxiety may increase his risk of developing chest pain; relieving this anxiety with sedation medications would reduce the risk of cardiac compromise.

Upon completion of the presedation assessment, a decision should be made as to the acceptability of the patient for moderate sedation. Every nurse providing sedation should recognize the patients who are at risk, and if extenuating circumstances arise, the nurse should be comfortable to say that he/she is not adequately trained in providing sedation to this particular patient. There should be no pressure on the nurse to provide sedation when suitability criteria are not met. If the criteria are met, the patient should be educated regarding the care he/she will receive during and after sedation. The patient should be told what he/she can expect during the procedure, and the nurse should inform the patient about the continuous monitoring that will occur throughout the sedation period. The techniques of noninvasive blood pressure monitoring should be explained, as this may cause momentary pain while the cuff is inflated to its highest level. The pulse oximeter probe should be explained, and the patient should be aware of its placement and use, recognizing that no pain should be experienced from its use. The vital sign assessment schedule should be explained and demonstrated, as patients will often be asked to take deep breaths. If the procedure is painful and a pain scale will be used to assess the patient's level of pain, the patient should be instructed on its use prior to beginning sedation. Finally, discharge instructions should be provided prior to the procedure; the nurse should recognize that the patient may not remember all that is told to him/her in the postsedation period. Reinforcing these instructions during the presedation period will greatly enhance patient compliance in the postsedation period.

Additional responsibilities in the presedation period include the preparation of the equipment to be used and available during the sedation period (Table 3). Patient support equipment, including oxygen and suction, should be tested to ensure proper functioning. If the nurse were to only check to make sure that the equipment is available, problems could ensue if something functioned improperly at a critical point in patient care. Monitoring equipment should be warmed up and calibrated, if necessary. Medications should be available, and determination of proper dosing should be precalculated. Reversal medications should be readily available; drawing an initial dose of the reversal agent is a wise and prudent move. These drugs can be drawn and the syringe labeled for future reference. In addition, medications used for advanced cardiac life support should be readily available.

Table 3: SUGGESTED EQUIPMENT LIST

Standard Equipment

Oxygen delivery system

Method to summon help

Cardiac monitoring system

Policy and Procedure Manual readily available

Pulse oximeter

Documentation forms

Blood pressure monitoring device

Emergency supplies (see below)

IV access equipment

Gloves

Medications appropriate to institution

Emergency Airway Supplies

Nasopharyngeal airways (appropriate sizes)

Magill forceps (adult, pediatric)

Oropharyngeal airways (appropriate sizes)

Sterile lubricant

Tongue blades

Suction equipment

Laryngoscope handle

Yankauer suction catheters

MacIntosh blades (appropriate sizes)

Suction catheters (appropriate sizes)

Miller blades (appropriate sizes)

Oxygen supply

Spare lightbulbs

Bag valve mask device (appropriate sizes)

Endotracheal tubes (appropriate sizes)

Stylets (adults, pediatric)

Emergency Support Equipment

Defibrillator

IV tubing

IV catheters (appropriate sizes)

Pediatric burette

Tourniquets

Extension tubing

Gloves

IV fluid

Alcohol wipes

3-way stopcocks

Adhesive tape

Intraosseous needles (pediatric patients)

Syringes (appropriate sizes)

Emergency Medicationsa

Glucose

Dopamine

Atropine

Sodium bicarbonate

Amiodarone

Naloxone

Epinephrine (1:1,000 and/or 1:10,000)

Flumazenil

Lidocaine

Methylprednisolone

Ammonia spirits

aChoice of medications will vary by institution policy.

Source: [6,36]

A well-stocked crash cart should also be available and within easy access in the event of an emergency. A method to summon additional help should be within arm's reach and tested to ensure accurate functioning. It is also important to ensure that all equipment is age-appropriate and size-appropriate for the patient receiving sedation. Standard adult equipment may not be appropriate for a small female; large child sizes may be more appropriate for this patient. It is imperative that this equipment is located and checked to prepare for complications, should they develop.

Many patients scheduled for moderate sedation are undergoing a planned procedure. If this is the case, the patient should have received preprocedural instructions. These instructions should include the patient's NPO status (if any), the time for arrival, the estimated time for procedure performance, and the estimated time for discharge. If the patient will be discharged to the care of a responsible adult, this person should be notified of his/her responsibilities and time for arrival (if he/she does not accompany the patient to the facility). Additionally, procedure-specific guidelines should be reviewed, including such items as bowel preparations and administration of antibiotics.

Prior to the administration of any sedating agents, the patient should sign an informed consent. Guidelines note that the risks, benefits, and limitations of moderate sedation, as well as possible alternatives (no sedation), should be discussed with patients, enabling them to make an informed decision [37]. If a patient is undergoing a scheduled procedure, this may have been accomplished at the time of preprocedural patient teaching; if the patient is undergoing an emergent procedure, this may have been accomplished during registration in the emergency department. In either case, a separate consent is not necessary [4]. However, informed consent should be present and complete prior to beginning the procedure. It is often the nurse's responsibility to ensure its placement in the patient's chart.

One immediate presedation responsibility includes establishing IV access in the patient receiving IV sedation. (This is a controversial area in the arena of transmucosal sedation and will be addressed at a later point in this course.) If the patient was not NPO, as is the case in emergent patients, medications to decrease gastric contents and stomach acid should be administered. These drugs will help reduce the risk and complications of aspiration, one of the most prevalent complications of moderate sedation. Metoclopramide will speed passage of gastric contents into the bowel, thus reducing gastric volume. The histamine antagonists cimetidine, ranitidine, and famotidine will increase gastric pH, thus reducing complications, should the patient aspirate gastric contents into his or her pulmonary tree.

The Joint Commission requires that heart rate and oxygenation be continuously monitored by pulse oximetry in all patients undergoing moderate sedation [1]. If the patient is to receive supplemental oxygen therapy, a pulse oximetry reading on room air should be documented. After oxygen therapy is initiated, another pulse oximetry reading should be obtained.

The results of all elements of the preprocedure assessment should be clearly documented before sedation is started. A final set of presedation vital signs should be obtained as baseline measures, and the patient's level of consciousness should be evaluated and documented before initiation of sedation. In addition, the patient's name, birth date, and procedure should be confirmed prior to initiating sedation [4,38].

Importance of Effective Communication

Because the history and informed consent are vital components of the preprocedure process and integral to patient safety and satisfaction, effective communication is key. Among the most important factors for effective communication are knowledge of the language preference of the patient, an awareness of the patient's health literacy level, and an understanding of and respect for the patient's and family's cultural values, beliefs, and practices (referred to as cultural competency) [39]. When the nurse and the patient speak different languages, the use of family members and/or friends as interpreters should be avoided if possible, as the patient may not be as forthcoming with information and the family member or friend may not remain objective [40]. Studies have demonstrated that the use of professional interpreters rather than "ad hoc" interpreters (e.g., untrained staff members, family members, friends) facilitates a broader understanding, leads to better outcomes, and is better aligned with patient preferences [41,42,43].

CARE DURING SEDATION

During sedation, the two most important responsibilities of the nurse are to ensure patient safety and monitor the patient's level of sedation. Documentation should be performed throughout the procedure as a record of patient care [44].

Throughout the sedation period, the nurse should remain with the patient at all times. There should be no other responsibilities for the nurse; assisting with the procedure should not be an expectation. It is imperative that all persons involved with moderate sedation be aware of this requirement. The nurse should never be asked to help out "just this once," thus compromising patient safety. The policy and procedure manual for moderate sedation delivery should clearly delineate the nurse's responsibilities and the right to refuse additional tasks during this period.

Evidence Based Practice Recommendation

The American Society of Anesthesiologists recommends that periodic assessment of airway patency, respiratory rate, and oxygen saturation be done during emergence and recovery, with particular attention given to monitoring oxygenation and ventilation.

https://anesthesiology.pubs.asahq.org/article.aspx?articleid=1918686

Last Accessed: July 14, 2020

Level of Evidence: Expert Opinion/Consensus Statement

While the patient is receiving and recovering from sedation, the nurse should judiciously monitor the patient's airway [44]. It is the nurse's responsibility to ensure that during sedation, the patient's spontaneous ventilation is maintained without intervention [1]. Should the patient's level of consciousness deepen to the point that the airway is compromised, the physician should be informed and measures undertaken to reverse the effects of this untoward complication.

The patient may have supplemental oxygen supplied, although the use of prophylactic oxygen therapy is a debatable issue. Many institutions require that all patients undergoing moderate sedation have supplemental oxygen used throughout the sedation period. Other policies require that supplemental oxygen be applied if or when the patient's pulse oximetry reading drops to an unacceptable level, generally ranging from 90% to 94%. The ASA guidelines note that supplemental oxygen should be considered for moderate sedation [44].

Oxygen therapy devices are advantageous, but also disadvantageous, for a number of reasons. First and foremost, supplemental oxygen helps assure that the patient's oxygen level is adequate. However, the use of sedation medications blunts the response to falling levels of oxygen; thus, the patient may not institute compensatory measures during this period. Additionally, the application of oxygen therapy devices may be confining and can actually increase the patient's level of anxiety, which would be counterproductive to the objective of sedation. Whenever using oxygen therapy, it is imperative that the patient be educated regarding its use and purpose.

Oxygen therapy devices used in moderate sedation range from the simple (e.g., nasal cannula) to the more complex (e.g., non-rebreather and Venturi masks). The nurse caring for the patient should understand the importance of the proper application of each device used. For example, the flow rate on the simple face mask should be, at a minimum, 5 L/min. If the oxygen flow rate were less than 5 L/min, carbon dioxide (CO_2) could accumulate within the mask and the patient would rebreathe this CO_2. This would lead to a respiratory acidotic state with further compromise of the patient's ventilatory status. Table 4 summarizes the various oxygen delivery devices used in the moderate sedation setting, and notations are made about each device.

Table 4: OXYGEN THERAPY DEVICES

Type

Fraction of Inspired Oxygen (FiO_2)

Flow (L/min)

Comments

Nasal cannula

24% to 40%

3–6

Comfortable, only increases O_2 level slightly, inexpensive, high flow rate increases problems

Simple face mask

25% to 55%

5–8

Poorly tolerated if too tight

Face tent

30% to 50%

4–10

Less confining, may provide humidification during long procedures

Nonrebreather mask

40% to 100%

6–15

Mask with reservoir and one-way valves, best noninvasive device, requires tight seal to achieve high %

Venturi mask

24% to 55%

2–14

Adjustable FiO_2

Bag valve mask

up to 100%

10–15

Self-inflating, may increase gastric distention

Source: [45] Reprinted from Litwack K. Post Anesthesia Care Nursing. 2nd ed. St. Louis, MO: C.V. Mosby Co.; 1995. With permission from Elsevier.

During sedation, the patient will be monitored for his/her response to the medications used. If a patient demonstrates restlessness and agitation, the nurse should determine the cause and intervene to reverse any untoward events. Restlessness and agitation should always be considered signs of hypoxemia until proven otherwise. However, it is just as possible that these behaviors are secondary to inadequate analgesia, and further assessment should be performed. If the nurse considers hypoxemia as the primary cause and intervenes appropriately, the risk of further hypoxemia is eliminated.

Vital signs may be assessed as frequently as every five minutes and should also be assessed at one minute after each additional dose of IV sedative. This will ensure the recognition of developing cardiovascular and respiratory complications secondary to medication administration. It is also prudent to assess the patient's airway with each vital sign assessment and ask the patient to take a deep breath (unless contraindicated by the procedure). This will ensure safe patient care delivery throughout the procedure.

An additional concern during sedation is the accumulation of secretions in the airway. Certain medications (e.g., ketamine) are more likely to produce secretion formation, and the nurse should maintain constant vigilance of the airway to prevent airway obstruction. Suction should be done using a Yankauer-type device.

Finally, to ensure that the goals of sedation are being met, the nurse should assess the patient's level of consciousness and, again, document this throughout the procedure [4,33,44]. Although several scales and scoring systems have been developed to describe the level of consciousness, none are ideal. The sedation scale should be developed to decrease observer bias. The patient should be able to be assessed by a number of different individuals at the same time and receive the same score with each assessment. The scale should have graded changes that reflect different sedation levels, and similar changes should be noted with different sedating agents. The patient should experience no pain or discomfort, and the scoring should be noninvasive. Furthermore, the scale should be easy to use, interpret, and record.

One recommended tool is the Modified Observer's Assessment of Alertness/Sedation Scale (Table 5) [38]. The patient's response to verbal commands should be monitored routinely, except for patients who are unable to respond (e.g., young children, mentally impaired individuals) or during procedures in which the lack of patient movement is essential [18,28]. For situations in which a verbal response is not possible (e.g., upper endoscopy), the patient and the nurse who is monitoring should determine hand signals before sedation is administered.

Table 5: MODIFIED OBSERVER'S ASSESSMENT OF ALERTNESS/SEDATION SCALE

Responsiveness

Score

Agitated

6

Responds readily to name spoken in normal tone ("alert")

5

Lethargic response to name spoken in normal tone

4

Responds only after name is called loudly and/or repeatedly

3

Responds only after mild prodding or shaking

2

Does not respond to mild prodding or shaking

1

Does not respond to deep stimulus

0

Source: [38] Reprinted from Cohen L, Delegge MH, Aisenberg J, et al. AGA Institute review of endoscopic sedation. Gastroenterology. 2007;133(2):676-701. With permission from Elsevier.

Other commonly used scales include the Ramsay Sedation Scale, the Sedation-Agitation Score, the Richmond Agitation-Sedation Scale (RASS), and the Motor Activity Assessment Scale. All of these scales were developed for use in a variety of settings, including the ICU. The Ramsay Sedation Scale (Table 6) was developed for ICU patients and is one of the scoring systems most widely used during moderate sedation [46,47]. The desirable level of sedation using the Ramsay Sedation Scale is a level of 2 or 3; however, upon inspection of this scoring system, clarity is lacking between these two levels [6]. Many documentation forms use the Modified Aldrete Score for assessing the patient's level of functioning; however, this score was developed for monitoring the patient's readiness for discharge and is not recommended as a method of assessing the patient's level of sedation during the procedure. Other scoring systems exist, some of which include recommendations for frequency of drug administration [6].

Table 6: RAMSAY SEDATION SCALE

Score

Response

1

Patient anxious, agitated/restless, or both.

2

Patient is cooperative, oriented, and tranquil.

3

Patient responds to commands only.

4

Patient exhibits brisk response to light glabellar tap or loud auditory stimulus.

5

Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus.

6

Patient exhibits no response.

Source: [47]

POSTSEDATION CARE

After administration of the sedation medication is complete, patient monitoring should continue until the patient achieves his/her presedation level of consciousness and functioning. The ASA recommends that monitoring continue until the patient is near the baseline level of consciousness and is no longer at increased risk of cardiorespiratory depression [44]. If the patient is to be transferred to a separate recovery area, the nurse administering the sedatives should accompany the patient to the recovery area and give a complete, concise report to the nurse responsible for further patient care. This report should include information regarding the respiratory, circulatory, and neurologic function of the patient before and during the procedure. Measures to control the patient's pain should be shared, as well as the time and effectiveness of pain medications.

Other important items to reference in this report include the total amount of sedative drugs received and the time of reversal agent administration, if given. Information on any untoward complications should be provided, as well as measures undertaken to correct these problems. The patient's fluid status may be important to share, as knowledge of the patient's ability to take oral fluids or to void will impact the length of time for recovery. Finally, a preprocedural level of functioning should have been documented so that discharge can be based on these findings.

During the postsedation period, the patient's vital signs and pulse oximetry readings should be assessed on a regular basis. The time frame for these assessments can vary, depending on the drug, the route, the amount of drug received, and the time since the last dose. Generally, vital signs and pulse oximetry readings are obtained on a 15-minute cycle until stable and then on a regular basis until the time of discharge.

The patient may need reorientation to time and place. The amnesic effects of many of the medications administered will prevent the patient from remembering certain facts about his/her surroundings. As the medications wear off, the patient will need less reorientation.

Another measure that may be necessary in the postsedation period is limitation of stimuli to the patient. The risk of untoward reactions increases with certain medications (e.g., ketamine) and with certain forms of stimuli (e.g., loud noises). Limiting these exposures will ensure a safe, comfortable arousal for the patient.

Discharge of the patient after sedation is a critical part of postsedation care. There are a number of variables that affect discharge of the patient. Most critical is the location and type of the unit to which the patient will be transferred. Many patients are discharged to home, and care of the patient should be well-delineated so that both the patient and the caregiver are comfortable with the expectations of the remaining recovery period.

Other factors that impact discharge of the patient include the type of procedure performed, the type of monitoring used during the procedure, the type and amount of medication received, the patient's preprocedure health status, and the development of any complications. Many of the procedures performed under moderate sedation are those in which rapid recovery and discharge of the patient is an expectation. If a procedure is expected to be lengthy and requires in-depth monitoring and postsedation care, the patient may not be considered a candidate for moderate sedation provided by nursing staff. This decision is made during the presedation assessment.

Typical discharge criteria require that the patient return to his/her preprocedural status. The patient should have adequate respiratory function and stable vital signs. The preprocedural level of consciousness should be reached, without the risk of resedation and a return to a decreased level of functioning. Intact protective reflexes, including gag reflex, are imperative. The patient should have his/her pain under control, and the procedural site should be stable, without evidence of bleeding or other complications. Many facilities also delineate a time period since last receiving medications as a parameter for discharge. Finally, if a patient is to be discharged to home, a responsible adult caregiver should be present to accompany the patient [38,44]. If the patient is a child who still uses a car seat, the American Academy of Pediatrics (AAP) suggests that at least two adults be available to take the child home, so one adult can sit with the child while the other drives [33]. Parents should be told that the child is at risk for airway obstruction if his or her head falls forward while in the car seat [44].

A number of discharge scoring systems are used to assist the staff with identifying patients who are ready for discharge, but there are no established standard discharge criteria; healthcare facilities should establish their own standardized criteria [33,38,44]. The scoring system should provide objective, measurable parameters for the patient to attain (e.g., stable vital signs, alert/oriented status, patent airway, adequate pain control) and should identify the score for discharge. The patient should meet the appropriate criteria to achieve that score [38,44].

One of the most commonly used discharge scoring systems is the Modified Aldrete Score (Table 7). This scoring system is used on a daily basis by postanesthesia care nurses working with ambulatory patients. The easy-to-use, simple scoring mechanisms are very useful for patients undergoing moderate sedation. A score of 18 or higher indicates a patient's readiness for discharge [48,49].

Table 7: MODIFIED ALDRETE SCORE

Domain

Criteria

Score

Activity

Able to move four extremities voluntarily on command

2

Able to move two extremities voluntarily on command

1

Able to move no extremities voluntarily on command

0

Respiration

Able to breathe deeply and cough freely

2

Dyspnea or limited breathing

1

Apneic

0

Circulation

Blood pressure (BP) + 20 of preanesthetic level

2

BP + 22–49 of preanesthetic level

1

BP + 50 of preanesthetic level

0

Consciousness

Fully awake

2

Arousable on calling

1

Not responding

0

Oxygen saturation

Able to maintain O_2 saturation >92% on room air

2

Needs oxygen inhalation to maintain O_2 saturation >90%

1

O_2 saturation <90% even on oxygen supplement

0

Dressing

Dry

2

Wet, but stationary

1

Wet, but growing

0

Pain

Pain free

2

Mild pain

1

Pain requiring parenteral meds

0

Ambulation

Able to stand up and walk straight

2

Vertigo when erect

1

Dizziness when supine

0

Fasting/feeding

Able to drink fluids

2

Nauseated

1

Nausea and vomiting

0

Urine output

Has voided

2

Unable to void, but comfortable

1

Unable to void, but uncomfortable

0

Source: [48] Reprinted from Aldrete J. Discharge criteria. Bailliere's Clin Anaesthesiol. 1994;8(4):763-773. With permission from Elsevier.

Other similar scoring systems are the Post-Anesthesia Discharge Scoring System (PADSS) and the Modified Post-Anesthesia Discharge Scoring System (MPADSS) [50,51,52,53]. These systems have a maximum total score of 10; a patient with a score of 9 or greater is considered fit for discharge [53]. It is important to remember that whichever type of scoring system is used, individual patient requirements should be met to ensure a safe, continued recovery following discharge. Additionally, this score should be incorporated into the documentation record for the patient.

Discharge criteria are used in almost all environments in which moderate sedation is administered; however, these criteria are not without controversy. It is important for facilities to regularly review and update discharge criteria to ensure that current guidelines are being followed. The typical criteria of stable vital signs with a return to presedation values may not be attainable in all patients. Patients with a history of hypertension may not reach their "normal" systolic blood pressure due to the vasoactive effects of the sedating agents used. It may require 24 hours for the patient's vital signs to return to their presedation level. However, this should not prevent this patient from being discharged.

Although the ASA recommends that a mandatory minimum stay not be required, many facilities have a typical time requirement of 30 to 60 minutes after the last sedative dose and/or two hours after the last reversal dose as criteria for discharge [44]. Many healthy adult patients may awaken much faster than this, especially if the total sedative dose was small. On the other hand, elderly patients may need more time for monitoring, as circulation times are slower and the risk of slow release of sedative from the fatty tissue may develop.

The ability to achieve the presedation level of activity may be impossible in a small population. The patient who underwent arthroscopic surgery on a lower extremity and is now required to use crutches for ambulation will not achieve his/her presedation level of activity for a number of weeks.

The absence of nausea and vomiting is often used as a criterion for discharge; however, it should be recognized that certain procedures and medications may increase nausea (and possibly vomiting) for prolonged periods of time. For example, intravenous ketamine may cause vomiting in children for up to two hours after administration. Ensuring a good intact gag reflex so that the child can protect his/her airway is critical in this population. However, keeping the child for an extra two hours for monitoring is generally not accepted, either by parents or staff.

An additional discharge requirement may be to ensure that the patient has taken fluids orally; however, many facilities have eliminated criteria related to the ability to eat or drink before discharge, and the ASA states that this requirement may only be necessary for select patients [38,44]. The problem of using oral fluid intake as a criterion for discharge is that many patients will willingly force fluids so that they may leave the facility. This may be done even though it is not in the best interest of the patient. As an example, patients who are experiencing bouts of nausea may drink fluids just so they can go home. This intake of fluids may be all that is necessary for the patient to vomit, which may, in turn, delay the patient's discharge. The requirement that all patients drink clear fluids prior to discharge has also been eliminated for many patients [44]. Guidelines recommend that toleration of fluids should only be required for specific populations, such as diabetics [44,50]. Patients who are discharged prior to taking fluids should be advised to start drinking clear liquids when they feel ready.

Evidence Based Practice Recommendation

The American Society of Anesthesiologists states that the routine requirement for urination before discharge should not be part of a discharge protocol and may only be necessary for selected patients.

https://anesthesiology.pubs.asahq.org/article.aspx?articleid=1918686

Last Accessed: July 14, 2020

Level of Evidence: Expert Opinion/Consensus Statement

Although it continues to be included in the Modified Aldrete Score, the requirement that all patients void prior to discharge has not been supported by research, and it may lead to delays in patient discharge. As such, many facilities have eliminated this requirement [38,44,50,54]. Assessment of urine output is useful in detecting some postoperative complications, and patients who are at high risk of urinary retention are generally required to void prior to discharge [44]. This includes patients who have had pelvic or genitourinary surgery, rectal or urologic procedures, hernia repairs, perioperative urinary catheterization, a history of urinary retention, or neuraxial anesthesia [50]. However, patients without an urge and no evidence of bladder distension (as shown by ultrasound) may be exempt from the voiding criteria [50,54]. Patients who do not void prior to discharge should be given clear instructions on seeking medical attention if they remain unable to void eight hours after discharge [50].

Discharge criteria are simply measures that provide the practitioner with some parameters for discharge. Each individual patient should be evaluated based on a number of considerations, not just on meeting the outlined criteria [44]. It is the practitioner's responsibility to ensure patient safety at the time of discharge, and this should be documented in the patient's chart at the time the patient leaves the facility. If a patient is unable to meet the required discharge criteria but is discharged, these discrepancies should be noted in the patient chart at the time of discharge.

Prior to leaving, the patient and caregiver should receive postprocedural instructions (Table 8). These should be provided both verbally and in writing [38,44,55]. The instructions should be reviewed with the patient and caregiver, and a signed copy of these instructions should be included in the patient's chart. It is important to remember that not all patients go home immediately after sedation; many are returned to their nursing unit. The same type of discharge instructions provided to the patient and caregiver should also be given to the staff assuming care of the patient in a nursing unit. It cannot be assumed that the floor nursing staff fully comprehends the postsedation care required for moderate sedation recovery.

Table 8: SAMPLE DISCHARGE INSTRUCTIONS

Today you received medications to make you sleepy during your procedure. The medications you received are: _____________________________________________________________________________________________.

The following items are recommendations for your care during the next 24 hours.

1. Do not drive or operate heavy machinery for 8 to 24 hours.

2. Do not consume any alcoholic beverages for 24 hours.

3. Do not make any important decisions for 24 hours.

4. Describe pain management plan and medication use (if appropriate): You will experience pain for the next few hours (or specific time frame). Your doctor provided you with the name of medication to take every three to four hours for pain. If you did not receive pain medications, you can take... (List over-the-counter medications and instructions for use).

5. You may resume your regular diet unless instructed otherwise. If you feel sick to your stomach, you may begin with clear liquids and add items as you feel ready.

6. It is best to rest the remainder of the day.

7. Describe surgical site management (if appropriate).

8. If you are unable to reach your physician, you can call the emergency room at 555-5555.

(Note: These should be provided in written format and signed by the patient and caregiver.)

Source: [56] Reprinted from Odom J. Conscious sedation in the ambulatory setting. Crit Care Nurs Clin North Am. 1997;9(3):361-370. With permission from Elsevier.

Information to include in discharge teaching includes postprocedural diet, level of activity, postprocedural care (e.g., wound care, dressing changes), and patient follow-up for both emergency and normal care. If medications are given, the purpose, name, dosage, route, frequency, duration of use, and significant or expected side effects, if any, should be explained. It is also helpful to provide the patient with the name of the sedating agent(s) that he/she received. If the patient needs to contact someone for further information or emergency treatment, this information may be invaluable.

Discharge instructions provided to the patient should be reiterated to the responsible caregiver who is accompanying the patient from the facility. This individual should understand the importance of following instructions, whether it is to awaken the patient on a regular basis or monitor the patient's procedural site. The caregiver should be instructed how to obtain assistance in the event of an emergency.

As mentioned previously, providing discharge information during the presedation period will assist the patient with remembering and complying with the instructions provided. A patient in the postsedation period may remain slightly amnesic and many items may be forgotten. Reinforcing these instructions both prior to the procedure and in written format following the procedure will help to ensure good patient compliance.

Finally, postprocedural follow-up, in the form of a telephone call, can help improve future patient care. This telephone call should be placed within 24 hours of the patient's discharge and ascertain that the patient is safe and fully recovered from the effects of the medications administered. Information to obtain may include the incidence of complications related to the sedation and/or procedure, recovery time, adequate pain management, compliance with instructions, and patient satisfaction. This information should be recorded and evaluated on a regular basis. Compiling this information will allow for identification of trends in care and measures that can be instituted to improve care, if necessary.

3. PHARMACOLOGY AND DRUG ADMINISTRATION

Medication administration for moderate sedation incorporates a number of issues. The choice of medication(s) depends on the type of procedure being performed and the estimated length of the procedure. The route of administration should be chosen for its efficacy, patient compliance, and method of action. The method of administration depends on the agent being administered, the route of administration, and the actions desired. Unfortunately, there is no one perfect agent that will meet these criteria.

The ideal moderate sedation agent should be one that is rapid acting with limited cardiorespiratory effects. A titratable medication would allow the practitioner to administer drugs in which the length of action is equal to the length of time required for sedation. Providing both analgesia and sedation would be beneficial in many situations and for many procedures. Furthermore, this ideal agent would be eliminated expeditiously for rapid return to the presedation state. And if complications were to occur, a drug that is readily and easily reversed would be optimal.

Because this drug does not exist, the following discussion will focus on the advantages and disadvantages of the routes and methods of administration and on the classes of medications.

ROUTE OF ADMINISTRATION

Transmucosal and intravenous moderate sedation produce sedation in the patient through somewhat different pathways. Most commonly, transmucosal administration includes oral, sublingual, and rectal administration. Other forms of administration include intramuscular, inhalation, subcutaneous, and topical administration. Intravenous sedation will be addressed separately.

Oral administration of moderate sedation agents is safe, economical, and convenient. It is accepted by many patients; however, it does require patient cooperation to ensure adequate drug delivery. Absorption from the oral route generally occurs in the small intestine secondary to its thin lining and large surface area. Thus, drugs must pass through the stomach and into the small intestine. Their absorption is dependent upon blood flow to these organs, the state of the drug (i.e., liquid or solid), and the contents of the gastrointestinal tract. Drug degradation may occur secondary to digestive enzyme activity, consequently limiting the dosage reaching the central circulation. Additionally, the practitioner should consider the level of the patient's anxiety; high levels of anxiety can delay gastric emptying time, delaying onset of action.

Oral administration may precipitate emesis in some patients, especially if the agent is foul tasting and/or smelling. This increases the risk of aspiration and should always be considered when preparing the patient and resuscitation equipment. Additionally, many drugs administered orally go through what is termed "first-pass effect." Once in the vascular space, drugs that are absorbed from the stomach and/or small intestine first pass through the hepatic circulation, where hepatic metabolism occurs. Hence, the amount of the drug undergoing first-pass effect that reaches the central circulation is lower than the actual dose administered by the oral route. Many drugs exhibit this first-pass metabolism; therefore, drug dosing for the oral route is frequently larger on a milligram per kilogram basis.

Sublingual administration is a convenient and easy method of drug delivery. With the advent of oral transmucosal fentanyl, sublingual administration is becoming more commonly used in the pediatric population. The advantage of this route is that no first-pass effect occurs; the blood supply from the oral cavity drains directly into the superior vena cava. The disadvantages are that sublingual absorption requires highly lipid-soluble drugs and patient cooperation. If a patient chews a medication that is to be administered via oral mucosa (e.g., a lozenge), absorption is compromised and total drug dosing is difficult, if not impossible, to calculate.

Another route that is becoming more frequently used is intranasal administration. Some medications can be mixed in normal saline and instilled into the nasal passage. This method is most frequently used when administering midazolam to pediatric patients. The patient rapidly achieves maximum effect, and the length of action is short. The disadvantages include the limit on the volume of medication that is tolerated by this route and the risk of the patient swallowing the medication, thus converting absorption to the oral route. Additionally, the patient may sneeze with this technique, and the volume of medication received is imprecise.

Rectal administration is used in a number of situations. Many adult patients find this route distasteful; however, it is used frequently with the pediatric population. It is also a useful route for patients experiencing significant nausea and vomiting. Drug absorption through the rectal wall is somewhat dependent on where the drug is actually deposited. If the drug is deposited into the proximal rectum, first-pass effect may occur. If the drug is deposited into the distal rectum, the drug will bypass hepatic circulation, thus avoiding the first-pass effect [57]. It is difficult to assess the patient's rectal anatomy to ensure proper placement of the drug. Furthermore, if the drug is irritating to the lining of the rectum, the patient may expel the drug prior to its absorption, hindering drug dosing.

As noted, rectal administration is used most commonly in the pediatric setting. This route provides practitioners with the ability to initially sedate a scared and/or combative child prior to insertion of an IV line.

Administering medications via the intramuscular route is often rejected by patients, if given the choice. Intramuscular injections can cause pain and irritation of the tissues. Intramuscular absorption is dependent on blood flow to the muscle, and the onset of sedation can be quite rapid if blood flow is adequate. However, if blood flow is compromised, onset is slow and length of action may be prolonged as the drug stays sequestered in the muscle and is slowly released. Despite these disadvantages, certain medications, such as ketamine, are being administered more frequently by this route. One complication of intravenous ketamine use is emergence excitement, the incidence of which is greatly reduced with intramuscular or oral administration [58]. Emergence reactions also may be reduced by pretreatment with a benzodiazepine, use of ketamine at the lower end of the dosing range, and minimizing verbal and tactile stimulation of the patient during the recovery period [59].

Inhalation administration is currently limited to the use of nitrous oxide due to the fact that sedation drugs are not prepared in an appropriate form. The inhalation route is easily used, the drugs are rapidly absorbed, and the effects are rapid in onset. Improper use of the inhaler limits the ability to regulate drug dosage, but with minimal teaching, many patients, including children as young as 3 years of age, can be instructed on proper inhaler use. Even children younger than 3 years of age can receive medications by this route, with assistance of the care provider and the use of a spacer device.

Transdermal and subcutaneous administration is generally reserved for sedation and pain management in settings other than moderate sedation. Fentanyl is available for administration in a patch; however, the drug release is slow and the amount of medication is inadequate to achieve the level of sedation desired in moderate sedation settings. Transdermal absorption is dependent on the use of drugs that are lipid soluble, and the dose depends on how much medicine is exposed to the surface skin. Thus, this route is generally not used in the moderate sedation setting.

Finally, moderate sedation may be administered by the IV route. There are a number of controversies surrounding IV and transmucosal routes, and these are addressed in detail later in this course. It is important to remember that intravenous absorption and response is dependent, in part, on circulation times. Intravenous drugs achieve a rapid plasma level and do not undergo first-pass effect. However, the incidence of complications is greater, and these complications can occur immediately after IV administration. Intravenous administration requires careful monitoring to prevent untoward patient responses. The drugs can be delivered in large volumes and, if given by continuous infusion, provide continuous therapeutic drug plasma levels. All the drugs used for sedation are available in the intravenous form and administered by this route in very large numbers.

ADMINISTRATION OF INTRAVENOUS MEDICATIONS

Methods of administration of IV medications include single-dose injection, bolus technique, continuous infusion technique, and drug combination therapy. Each method has distinct advantages and disadvantages, and certain drugs can only be administered by one technique.

Single-dose injection is also known as "titration to effect." The patient is given frequent, small doses of the medication, and the effects are monitored prior to further drug administration. This method requires that the practitioner monitor the patient's vital signs and level of sedation after each drug dose and titrate subsequent doses based upon these responses. Single-dose injection provides for better control of the amount of drug delivered, although repeated doses may prolong the patient's recovery time. Additionally, this route requires more nursing time in order to prepare the drug, administer the drug, and monitor the effects. Yet, it is one of the safest methods for drug delivery. The risk of oversedation or undersedation is minimal.

The bolus technique is the administration of the entire dose, or a large percentage of the drug, all at once, causing a rapid onset of action and allowing the drug to reach a therapeutic level very quickly. Deep, rapid sedation is more common, and the risk of respiratory depression increases. The major disadvantage of this method is that the length of action of the drug may be shorter than the procedural time, causing the patient to be inadequately sedated toward the end of the procedure. Another predicament that may develop with the bolus technique is a rapid onset of complications. This is most often seen with the rapid administration of high doses of fentanyl. Chest wall rigidity develops in these patients, rendering the patient unable to breathe. Efforts to support ventilations are difficult, if not impossible, and the patient must be administered a neuromuscular blocking agent, such as succinylcholine. The patient is then paralyzed for a short period of time, and ventilatory assistance must continue until the return of ventilatory function. In addition, naloxone should be administered to reverse the effects of the narcotics. This complication can be completely avoided with proper drug dosing and drug delivery techniques.

Continuous infusions are advantageous in that they provide a constant plasma level of the drug. Recovery time is often shorter, and the individual begins to awaken as soon as the drug is discontinued. Propofol is administered by this route, as its extremely short length of action makes other methods and routes impractical. This technique does require constant vigilance of the infusion to ensure adequate drug dosing and prevent accidental overdose.

Finally, combination drug therapy may be used. Most commonly, opiates and benzodiazepines are combined to achieve an appropriate level of sedation and pain control. As to be discussed next, benzodiazepines do not provide analgesia, and for any procedure that is painful, another agent should be used. A possible disadvantage of drug combinations is the synergistic, cumulative effects of drugs, producing the risk of profound, deep sedation. The likelihood of side effects increases, and the risk of cross reactions exists. However, with drug combination therapy, the goals and objectives of moderate sedation can be achieved with proper drug dosing.

4. DRUG CLASSES AND MEDICATIONS

The medications used for moderate sedation provide a number of different actions. Medication choice should be made with consideration of a number of factors, including the actions of the drugs, their relative length of action, and the bioavailability of each drug. The two most common medications administered for moderate sedation are midazolam and fentanyl. These drugs, as well as many others, are included in the following discussion. The reader is referred to Table 9 for drug dosing.

Table 9: PHARMACOLOGY OF MODERATE SEDATION MEDICATIONS

Agent

Onset

Peak

Duration

Antagonist

Half-Life

Usual Dosea

Notes

Benzodiazepines

Midazolam (Versed)

IV: 3–5 mins

IM: 5–15 mins

Intranasal: <5 mins

PO: 10–20 mins

IV:3–5 mins

IM: 30–60 mins

Intranasal: 10 mins

PO: 2–6 hrs

IV: <2 hrs

IM: 1–6 hrs

Flumazenil

1–4 hrs

0.5–2 mg over 2 mins, Max 5 mg

(Do NOT exceed 2.5 mg as initial dose or 1.5 mg initially in elderly)

Pediatric doseb:

IV/PO: 0.25–0.5 mg/kg

IM: 0.1–0.15 mg/kg

Nasal: 0.2–0.4 mg/kg (not an approved route)

Give slowly. MR every 5 mins w/0.5 mg; can be given by infusion. Adolescent/pediatric patients may exhibit paradoxic excitement. Decrease dose by 30% (50% in the elderly) if patient is taking other narcotics or CNS depressants.

Diazepam (Valium)

IV: 1–5 mins

PO: 15–60 mins

IV: 1 min

IV: 2–4 hrs

Flumazenil

20–50 hrs

2–10 mg, Max 20 mg

Pediatric dose:

IV: 0.2–0.3 mg/kg/dose

PO: 0.2–0.3 mg/kg/day (Max 10 mg)

MR at 5–10 min intervals w/1 mg.

Increased half-life in neonates, elderly.

Lorazepam (Ativan)

IV: 2–3 mins

IM: 20–30 mins

Up to 2 hrs

6–8 hrs

Flumazenil

10–20 hrs

0.05 mg/kg, Max 2 mg IV, 4 mg IM

Pediatric dose: 0.02–0.09 mg/kg

MR at 5–10 min intervals for prolonged sedation, used in critical care setting.

Opioids (Narcotics)

Fentanyl (Sublimaze)

IV: 1–3 mins

IM: 7–8 mins

TM: 5–15 mins

IV: 5–15 mins

IM: 15–20 mins

TM: 15–30 mins

IV: 30–60 mins

IM:1–2 hrs

TM: 12 hrs

Naloxone

2–4 hrs (longer with TM route)

25–100 mcg IV

Pediatric dose: IV/IM: 0.5–2 mcg/kg/dose

TM: 5–20 mcg/kg

MR 25 mcg every 5 mins.

Give slowly to prevent chest wall rigidity.

Apnea may occur.

Morphine

IV: 5–10 mins

IM: 10–30 mins

PO: 20–40 mins

IV: 10–20 mins

IM: 30–60 mins

PO: 1–2 hrs

IV: 1–4 hrs

IM: 4–5 hrs

PO: 4–24 hrs

Naloxone

2–4 hrs

2.5–10 mg IV slowly

Pediatric dose:

IV: 0.05–0.1 mg/kg

IM: 0.15–0.3 mg/kg

MR 2–5 mg every 5 mins.

Give slowly.

Assess patient's pain level, hypotension, nausea and vomiting.

Meperidine (Demerol)

IV: 2–5mins

IM: 10–15 mins

PO: 10–15 mins

IV:5–7 mins

IM: 35–60 mins

PO: 1 hr

2–4 hrs

Naloxone

2.5–4 hrs

25–50 mg IV over 2 mins, Max 150 mg

Pediatric dose: 1–2 mg/kg/dose

MR 10–15 mg every 5–10 mins.

Use with caution in patients with liver disorders; avoid use in patients with renal impairment. Do not use in patients taking MAO inhibitors.

Remifentanil (Ultiva)

IV:1–3 mins

3–5 mins

Dose dependent,5–15 mins after discontinuing drug

Naloxone

10–20 mins

1 mcg/kg IV bolus followed by an infusion of 0.1 mcg/kg/min titrated for effect

Assess patient's pain after procedure secondary to short length of action.

Sedative Hypnotics

Propofol (Diprivan)

IV: 30–60 secs

1 min

3–10 mins

None

4–7 hrs

Initial: 2–2.5mg/kg

Maintenance: 100–200 mcg/kg/min

Pediatric dose:

Initial: 1–2 mg/kg

Maintenance: 125–300 mcg/kg/min

May cause hypotension, bradycardia, or respiratory depression.

Etomidate (Amidate)

30–60 secs

1 min

3–5 mins

None

2–3 hrs

Initial: 0.1 mg/kg over 30–60 secs

Maintenance: 5–20 mcg/kg/min

Solution may cause pain on injections. Preadministration of lidocaine may be considered.

Chloral hydrate

15–30 mins

30–60 mins

1–2 hrs

None

8–11 hrs (longer in neonates)

500–1,000 mg, Max 2 g/day.

Pediatric dose: 50–75 mg/kg/dose

Induces sleep 1–4 hrs. Monitor airway, O_2 saturations. Sedation failure increases with age. Best used in children younger than 3 years of age.

Dissociatives

Ketamine (Ketalar)

IV: 30–60 secs

IM: 3–4 mins

IV: 1 min

IM/Rectal: 12–25 mins

PO: 30 mins

Intranasal: 10–14 mins

IV:5–10 mins

IM: 12–25 mins

Intranasal: Up to 60 mins

None

10–15 mins

IV: 0.5–1 mg/kg

IM/Rectal: 2–5 mg/kg

PO: 4–6 mg/kg

Pediatric dose:

IV:1–2 mg/kg/dose

IM: 4–5 mg/kg/dose

May cause emergence reactions, including vivid dreams, hallucinations, or delirium.

Barbiturates

Methohexital (Brevital)

IV: 30 sec

Rectal: 5–15 mins

IV: 45 sec

Rectal: 5–10 mins

IV: 5–15 mins

Rectal: 45–60 mins

None

1–4 hrs

Pediatric dose:

IM: 0.5–1mg/kg of a 5% solution

Rectal: 25 mg/kg of a 1% solution

May cause paradoxical excitement in children and elderly.

Thiopental (Pentothal)

IV: 30–60 sec

IV: 30–40 sec

IV: 5–30 mins

None

3–11.5 hrs

Initial: 3–5 mg/kg

Maintenance: 25–100 mg/kg as needed

Pediatric dose:

Initial: 5–6 mg/kg

Maintenance: 1 mg/kg as needed

Tissue necrosis with extravasation.

Repeated dosing may cause cumulative effects.

Pentobarbital (Nembutal)

IV: 1 min

IM: 10–15 mins

IV, IM: 10–15 mins

IV: variable

None

15–50 hrs

IM: 150–200 mg

Pediatric dose: IV: 2 mg/kg

IV no faster than 50 mg/min. Allow time between IV doses for effect. Monitor for prolonged recovery.

Antagonists

Naloxone (Narcan)

IV: 1–2 mins

IM: 2–5 mins

15–30 mins

30–120 mins

N/A

60–90 mins (3–4 hrs neonates)

0.4–2 mg IV

May titrate for reversal (add 0.4 mg in 10 mL syringe: give 1 mL=0.04 mg)

Pediatric dose: 0.1–2 mg/kg

MR every 1 min to max of 10 mg. Observe for resedation. May not reverse cardiovascular effects. May cause noncardiogenic pulmonary edema.

Flumazenil (Romazicon)

1–3 mins

6–10 mins

1 hr

N/A

40–80 mins

0.2 mg IV over 15 sec, Max 3 mg/hr

MR every 1 min to max 1 mg

Pediatric dose: 0.01 mg/kg over 15 sec, MR every 1 min to max 2 mg

Observe for resedation. Use with caution in patients with a history of benzodiazepine abuse or seizures.

Nalmefene (Revex)

IV: 1 min

IM: 5–15 mins

IV: 2 mins

IM: 1.5 hrs

1–10 hrs (dose dependent)

N/A

12.5 hrs

0.25 mcg/kg, MR every 2–5 mins

Dose >1 mcg/kg has no added benefit

Give over 60 seconds to patients with renal failure.

aUsual dose is a safe dose to begin sedation. Higher doses are frequently administered. The practitioner must be aware that the higher the dose, the greater the risk of complications.

bThe pediatric dose is for children >6 months of age.

MR = may repeat, TM = transmucosal.

Source: [6,59,60,61,62,63]

BENZODIAZEPINES

Benzodiazepines are a class of drugs that is very familiar to most nurses. These drugs are used on a daily basis and have actions that are predictable and meet patients' needs. The benzodiazepines to be included in this discussion include midazolam, diazepam, and lorazepam. Other benzodiazepines used less frequently include triazolam, chlordiazepoxide, and alprazolam.

Benzodiazepines facilitate the inhibitory action of gamma-aminobutyric acid (GABA) in the brain, thus reducing excitatory impulses. The drugs are lipid soluble; however, midazolam is available in a water-soluble suspension. The water-soluble suspension reduces the pain on injection that is experienced with diazepam, which is commonly administered in a propylene glycol suspension. Benzodiazepines are classified by their half-lives as short-acting (e.g., midazolam), intermediate-acting (e.g., lorazepam), or long-acting (e.g., diazepam) [64,65].

Benzodiazepines are frequently used in moderate sedation due to their excellent amnesic properties, including antegrade amnesia. The patient's level of anxiety is reduced secondary to the anxiolytic action. Additionally, the patient may achieve some skeletal muscle relaxation [64,66].

The major effect of these drugs is on the respiratory system of the patient. The patient may develop a depressed ventilatory response to increasing carbon dioxide levels with subsequent falling levels of arterial oxygenation. Each 0.1 mg/kg of midazolam is said to reduce the body's response to rising carbon dioxide levels by 50%. In addition, there is a rise in pulmonary airway resistance. As the patient's level of consciousness decreases, the risk of respiratory insufficiency increases greatly [66,67].

Because the patient's compensatory responses are blunted, carbon dioxide levels will continue to rise and oxygen levels will continue to fall unless additional therapeutic measures are undertaken. It is imperative that the nurse administering these drugs is aware of this risk and continuously monitors the patient's respiratory effort and oxygen saturations. With the development of easy-to-use end tidal CO_2 meters, the practitioner is better prepared to monitor for this developing complication.

Benzodiazepines produce a slight decrease in cardiovascular function. The patient may experience a decrease in peripheral vascular resistance and a subsequent drop in blood pressure and cardiac output. Patients with low cardiac output require slower loading times for benzodiazepines to reduce the risk of profound respiratory and cardiovascular depression [68].

The central nervous system effects include a reduction in cerebral blood flow, a decrease in cerebral oxygen consumption, and an elevation in the seizure threshold. The hypnosis provided by this class of drugs helps achieve the relaxation and amnesia for which these drugs are known.

The benzodiazepines should be used with caution in patients with [68]:

- A history of chronic obstructive pulmonary disease or sleep apnea

- Known cardiovascular depression

- Drug and/or alcohol intoxication

- Liver and/or renal disease

- Difficult airways

Furthermore, precautions should be taken for the very young, elderly, and pregnant or lactating patient. Patients on heparin may experience prolonged bleeding times with midazolam use [69]. Certain medications, including metoprolol, propranolol, and digitalis, will have an increased effect of action. Thus, the patient with a slow heart rate secondary to the negative chronotropic effects of digitalis should be closely monitored for the development of symptomatic bradycardia while receiving any of the benzodiazepines.

All the benzodiazepines used in moderate sedation are 97% to 98% protein bound [59]. This is an important consideration in many elderly patients with decreased protein stores. The less body proteins available, the more free-circulating drug exists. Thus, the effects of action are potentiated. It is recommended that long-acting benzodiazepines not be used in elderly patients due to the increased risk for drug metabolite accumulation resulting in excessive sedation, cognitive impairment, and falls [68,70]. If possible, benzodiazepines should be avoided altogether for this population.

Benzodiazepines have the advantage of being reversible with flumazenil. However, this antagonist should be administered intravenously, which limits its use in patients sedated with benzodiazepines by transmucosal routes. (Further information on flumazenil can be found in the Antagonists section).

Midazolam is a drug that is easily administered by a number of routes (i.e., intramuscularly, orally, rectally, intranasally) [71]. Intravenous administration provides rapid onset of action (i.e., three to five minutes), with a duration of less than two hours. It is easily titrated and associated with less pain at the injection site [59,71]. Intranasal midazolam has become popular as a method of achieving moderate sedation in the pediatric population, although this is an off-label use [59,71,72]. This method may also be used to achieve initial sedation in a child prior to insertion of an IV line. Additionally, midazolam can be administered by continuous infusion. The loading dose is 0.5–2.0 mg/kg over two minutes, which may be repeated every two to three minutes, if needed, for a total dose of no more than 5 mg [59].

Because midazolam can be expensive for sedation by continuous infusion, other benzodiazepines may be preferred to reduce the medication costs. One systematic review found no high-quality evidence supporting the use of midazolam over other medications for preprocedural sedation. The authors also found moderate-quality evidence suggesting that oral midazolam produces less effective sedation than chloral hydrate for children undergoing noninvasive diagnostic procedures [73].

Diazepam

Diazepam is the benzodiazepine to which all others are compared. Its long length of action (i.e., two to four hours) may preclude its use for short-term moderate sedation. However, it has the efficacy of a single-dose injection with good outcomes in many patients. Diazepam may be given intravenously, orally, and rectally. Intramuscular injection is quite painful, and this route is avoided. The half-life of diazepam is long, varying from 20 to 50 hours in healthy adults [59]. The elderly, neonates, and those with severe hepatic disorders are more at risk for prolongation of action, and the dosage administered should be reduced in these populations.

Lorazepam

Lorazepam is an intermediate-acting benzodiazepine with a length of action ranging from six to eight hours [59]. It is a popular drug for prolonged sedation and is frequently encountered in the intensive care environment.

OPIOIDS

Opioids, also referred to as narcotics, bind with specific receptors in the central nervous system. These receptors include the mu, kappa, delta, and sigma subtypes. The actions of each receptor type varies; the mu, kappa, and delta receptors all provide some level of analgesia, while the sigma does not. Additionally, narcotics can produce sedation, and in higher doses, will produce a profound decrease in the patient's level of consciousness and a risk of respiratory arrest [57].

The cardiovascular system is significantly affected by this class of drugs. All narcotics, with the exception of meperidine, produce bradycardia. (Meperidine produces tachycardia secondary to its vagolytic effect.) Blood pressure is affected by this decrease in heart rate; the patient may experience a drop in his/her systemic pressure. Morphine and meperidine also induce the release of histamine, leading to a decrease in systemic vascular resistance [57].

The respiratory system is most affected by the narcotics that release histamine (i.e., morphine, meperidine). This histamine release can produce bronchoconstriction in the patient; thus, these drugs should be used with caution in the patient with a history of asthma. Additionally, opioids depress respiratory rate and volume. As with benzodiazepines, a similar, although not as profound, depressed response to rising carbon dioxide levels occurs. As the dose increases, the risk of respiratory depression and apnea increases [57].

Chest wall rigidity is an uncommon, but life-threatening, complication that can occur with the rapid intravenous administration of narcotics, especially fentanyl. The chest wall muscles become tight, and the patient is unable to be ventilated. To successfully resuscitate the patient, the administration of succinylcholine should be performed rapidly and the patient ventilated with a bag-valve-mask device until the respiratory drive returns. Additionally, naloxone should be administered to combat the effects of the narcotics and repeated if necessary. Obviously, with this development, the goals and objectives of moderate sedation are no longer being met and other actions should be undertaken if the procedure is to be continued [57].

Narcotics also impact the central nervous system by producing an increase in cerebral metabolic rate and blood flow. Intracranial pressure may rise, increasing the risk to the neurologically compromised patient. The vomiting center in the brain may be stimulated. Many patients complain of nausea after administration of these drugs, and some may begin to vomit.

Careful administration of narcotics should be considered in any neurologically compromised patient or any patient with a history of chronic obstructive pulmonary disease, asthma, cardiovascular depression, a difficult airway, or morbid obesity. Patients with symptomatic bradycardia should be placed on a cardiac monitor and continually monitored for the cardiovascular depressive effects of these medications [57].

Fentanyl

Fentanyl is a popular narcotic for moderate sedation due to its short length of action. The patient achieves the benefits of sedation and analgesia but is arousable within a short period of time. The drug can be administered intravenously, intramuscularly, and transmucosally. It is reversible with naloxone. The analgesic activity of 100 mcg of fentanyl is equivalent to approximately 10 mg of morphine [59].

Oral administration of fentanyl is available in lozenge, buccal film, buccal tablet, or sublingual tablet form. Fentanyl lozenges were first developed for use in pediatric oncology and have become a popular and desirable method for achieving moderate sedation in children [74]. The lozenge, film, and tablets all have a premeasured dose of fentanyl and are scored to allow administration of varying dosages. The child should be instructed to suck on the medication; if the child chews it, the medication absorption converts from sublingual absorption to gastric absorption and first-pass effect will limit the amount of drug available [59].

Morphine

Morphine is one of the least expensive and most popular of all the medications used for moderate sedation. Nurses and physicians are comfortable with the actions of morphine, the effects are well known, and untoward complications can be avoided with proper administration. The risk of hypotension is great with morphine secondary to the action of histamine upon the vascular system. Therefore, the patient should be continually assessed during administration for profound cardiovascular depression. With slow titration of the drug, these effects can be negligible.

Meperidine

Meperidine was previously used for its analgesic properties. However, the American Pain Society and the Institute for Safe Medication Practices (ISMP) do not recommend the use of meperidine for its analgesic properties, unless the patient experiences acute pain. If the patient experiences acute pain, it is recommended that treatment with meperidine be limited and used with caution in patients with liver and renal disease [59].

Remifentanil

Remifentanil has a very short length of action that is dose dependent and varies from 3 to 10 minutes [59]. It is important to remember that the length of analgesic action is also short, and the patient should be assessed for adequate pain control after the normal length of action time has been surpassed [75].

Other Opioids

There are several other opioids that may be used to induce moderate sedation. For example, hydromorphone has been found to be safe and effective, with a low risk of adverse effects, such as excessive sedation or respiratory depression [76]. The opioids are popular drugs for a number of reasons, as many practitioners feel comfortable with administering these drugs, and their actions are well defined and predictable. The analgesic properties are the best of any of the drugs used in sedation, and whenever a painful procedure is initiated, these drugs should be at the top of the consideration list.

BARBITURATES

Barbiturates have been available for a number of years, and their actions are well known. Ultra-short-acting barbiturates are used in the moderate sedation setting and include methohexital. Thiopental and thiamylal are no longer available in the United States [77]. Pentobarbital, a short-acting barbiturate, is used in young children undergoing radiologic procedures. These drugs are highly lipid soluble and can become rapidly sequestered in fatty tissues. Repeated doses can lead to accumulation of the drug and subsequent prolongation of the length of action.

The actions of the barbiturates include sedation, hypnosis, and anticonvulsant properties. There is no analgesia achieved with these medications; therefore, their use is limited to interventions that are not painful [59].

One of the most profound effects of barbiturates is the precipitous drop in systemic vascular resistance upon intravenous administration. This decreased resistance leads to a significant drop in blood pressure, compensatory tachycardia, and decreased venous return. The patient with a sensitive cardiovascular system or hypovolemia should be closely monitored during drug administration [59].

Respiratory effects include the development of a decreased ventilatory response to falling oxygen and rising carbon dioxide levels, as seen with the benzodiazepines. If the drugs are administered rapidly intravenously, there is a moment of apparent apnea in many patients [59]. This will often be followed by a large gasping respiration, and then the patient begins to breathe normally and comfortably on his/her own. However, there is a moment when the nurse administering these drugs feels uncomfortable with the ominous feeling of having significantly oversedated the patient. Fortunately, this apparent cessation of breathing is short lived, and by the time the nurse is beginning to act, the patient is breathing again. Regardless, it is one of the scariest moments in the moderate sedation setting.

Methohexital can produce bronchospasms in many patients, especially those with a history of asthma or reactive airway disease [59]. Pentobarbital is most commonly used in the radiology setting when a motionless patient (most commonly a child) is necessary to achieve a good study. Administration of this drug requires vigilant assessment, as airway compromise is a common consequence [59].

Central nervous system effects include a decrease in the cerebral metabolic rate, a decrease in cerebral blood flow, and a subsequent drop in intracranial pressure. In low doses, the barbiturates may cause disorientation or excitement, and the patient should be monitored for these effects [59]. Safety measures should be instituted to protect the patient from harm.

The practitioner should be careful in administering these drugs to patients with [59]:

- Hepatic dysfunction

- Cardiovascular depression

- Hypovolemia

- Seizure disorders

- Chronic obstructive pulmonary disease

- Difficult airways

- Alcohol intoxication

- History of sleep apnea

- Morbid obesity

The use of barbiturates is common in many situations. A barbiturate may be administered as a single-dose injection for a short-term procedure, such as cardioversion. The patient is sedated, cardioverted, and arouses within minutes. In many cases, the patient will be completely unaware that the procedure has been completed upon arousal.

Barbiturates can also be useful in combination drug therapy. A dose of 10–20 mg of methohexital may be added to benzodiazepine administration to achieve further sedation. Care should be used in this setting, as the cumulative sedative effects can be compromising to the patient, producing deep sedation [59].

Another concern with the barbiturates is the significant tissue damage that occurs if the drug extravasates into the local tissues. The pH of this class of drug is very high, leading to profound tissue necrosis at the extravasation site [59]. In this event, the affected area should be immediately infiltrated with 5–10 mg of phentolamine, diluted in 10 mL of normal saline [59]. It is imperative that if barbiturates are being used in a facility, one or two vials of phentolamine are available for this untoward complication.

Finally, it is important to remember that there is no antagonist available for the barbiturates. Any complications that develop should be managed with supportive therapies until the sedative effects are cleared.

OTHER SEDATIVE HYPNOTICS

Sedative hypnotics as a class encompass many agents, the most common being barbiturates and benzodiazepines. An additional two medications, propofol and etomidate, are also used in moderate sedation. These ultra-short-acting agents provide no analgesic effects, and pain management requires concomitant use of analgesic agents [59].

Evidence Based Practice Recommendation

According to the American College of Emergency Physicians, propofol can be safely administered to children and adults for procedural sedation and analgesia in the ED.

https://www.acep.org/patient-care/clinical-policies/procedural-sedation-and-analgesia

Last Accessed: July 14, 2020

Strength of Recommendation: A (Generally accepted principle for patient care that reflect a high degree of clinical certainty)

Propofol is a sedative hypnotic that is being used more frequently in the moderate sedation setting. It produces a cortical depression of very short action; the patient awakens very rapidly upon discontinuation of its administration. The drug also has an antiemetic effect, although there are no analgesic properties [59]. Propofol produces negative inotropic effects on the cardiovascular system, leading to a significant drop in the patient's blood pressure after administration. This hypotension is associated with a decrease in cardiac output and arrhythmia development [59]. The therapeutic index of propofol is narrow and the risk for deep sedation is high. Therefore, the ASA recommends that patients who receive propofol (by any route) should receive care that is consistent with that required for deep sedation. Additionally, clinicians who administer propofol should be qualified to rescue patients from any level of sedation, including general anesthesia [78]. Propofol has no antagonist [59].

Respiratory system effects include a dose-dependent respiratory depression, progressing to apnea in higher doses [59]. The patient may experience hiccoughs, wheezing, and coughing [59]. While these effects are not life-threatening, they may be very uncomfortable for the patient.

The patient receiving propofol may complain of a headache or appear confused and/or euphoric. There are a small number of reports from patients describing very sexually explicit dreams while sedated with propofol [79]. Some patients may verbalize these sexual fantasies, and many practitioners who have administered this drug can relate tales of patient's fantasies.

The peak effect of propofol can be achieved within one minute and lasts four to eight minutes; thus, the drug is administered by continuous infusion [59]. It is important to remember that special handling of the drug is required to prevent the risk of multi-system sepsis. Propofol is available as an oil-in-water emulsion that contains egg lecithin, glycerol, soybean oil, and very small amounts of preservative. It is recommended that the drug be used and completed within 6 hours if transferred to a syringe or other container prior to administration, and 12 hours if used directly from a vial or prefilled syringe. When preparing the drug, strict aseptic technique should be used [59]. The vial top should be disinfected with 70% alcohol, a sterile vent spike should be used to withdraw the drug, and the medication should be drawn up into a sterile syringe. Once drug administration is completed, the IV solution and IV tubing should be discarded and replaced with new solutions. If the drug is used for continuous sedation (e.g., as used in an ICU), it is recommended that the IV line and solution be changed every 12 hours [59]. Any patient who receives prolonged sedation with propofol should be monitored for developing signs of infection [59].

It should be noted that in 2010 the manufacturer of propofol, Hospira, announced a voluntary recall of the drug to all healthcare professionals [80]. This recall was related to concerns of particulate matter (i.e., subvisible inert stainless steel particles) that would not dissolve in the patient's blood, potentially blocking blood flow. The recall affected propofol that was distributed both in and outside the United States between March 2008 and April 2010. Healthcare professionals were urged to immediately discontinue use of the drug and monitor patients who may have received it [80].

Propofol has also been associated with several iatrogenic infections [81]. Researchers identified 20 propofol-related outbreaks that occurred during 1989–2014. The outbreaks affected 144 patients and resulted in 10 deaths. Contributing factors included reuse of syringes for multiple patients and prolonged exposure to the environment when vials were left open. Some countries have begun adding antimicrobial drugs to the emulsion to prevent further outbreaks, but no comprehensive information exists on the effectiveness of these measures [81,82].

Etomidate is another ultra-short-acting sedative hypnotic used to induce moderate sedation. Intravenous etomidate has a very rapid onset of action, with peak effect reached within one minute [59]. The sedating effect lasts 5 to 15 minutes. Although this rapid onset and duration of action is similar to propofol, administration of etomidate via continuous infusion has been associated with increased morbidity and mortality as a result of its adrenal suppression [59,83]. This effect on adrenal function is dose dependent and cumulative. Therefore, etomidate is only recommended for short-term sedation, and the patient should be monitored for adverse effects [59].

Etomidate has been found to have a relative lack of significant hemodynamic and respiratory effects, making it an appropriate drug for use in patients with unstable heart disease, difficult airways, or asthma [59,84]. Etomidate has been associated with an increased risk for myoclonus and nausea and vomiting upon emergence from sedation [59,85]. Pretreatment with midazolam has been shown to effectively prevent and lessen the degree of etomidate-induced myoclonus [82].

Etomidate's rapid onset and duration and favorable side effect profile make it especially desirable for procedural sedation in emergency situations, particularly for cardioversion, intubation, dislocation or fraction reduction, and abscess incision and drainage [59,85,86]. When compared to propofol in a randomized trial, etomidate showed comparable safety but a lower rate of procedural success and a very high rate of induced myoclonus in 20% of patients [87]. Intravenous etomidate administered after fentanyl has been shown to be effective for short-duration, painful emergency department procedures in children [34].

Another consideration of administration is that both propofol and etomidate are painful on injection. This can be combated by administering lidocaine. Lidocaine administration can precede the propofol or etomidate (the patient is administered 0.5 mg/kg IV) or lidocaine can be added to the IV solution [59].

Propofol and etomidate have no antagonists. However, the advantage of their use is their short length of action. Should a patient develop complications, these are generally short-lived due to the rapid metabolism. Regardless, during this time period the patient should be supported with appropriate therapeutic interventions.

DISSOCIATIVE AGENTS

Ketamine is an agent that "dissociates" the thalamus from the limbic system [59]. The drug produces a cataleptic state, and onset of sedation is noted when nystagmus and an open-eye gaze develops. During administration of ketamine, the individual remains responsive but not always appropriately so.

The drug provides both analgesia and amnesia [59]. Other than the narcotics mentioned earlier, this is one of the few drugs used for moderate sedation that provides for pain control. Another action that may be undesirable in some patient populations is the skeletal muscle movement that can occur. A patient who is required to lie completely still, like those undergoing MRI, should in most cases not receive ketamine for sedation.

Unlike other sedatives, ketamine produces a stimulation of the sympathetic nervous system, resulting in excitation of the cardiac system. This leads to an increased heart rate, cardiac output, and blood pressure. Myocardial oxygen consumption increases; therefore, patients with a history of coronary artery disease, hypertension, or congestive heart failure are not considered good candidates for its use [59].

The benefit of this drug is on the respiratory system, as it produces bronchodilation and has a minimal effect on the patient's respiratory drive. Therefore, this may be the sedative of choice (assuming there are no other contraindications) for the asthmatic patient [59]. Ketamine is commonly used for procedural sedation and analgesia in children. One systematic review of seven studies evaluated the use of intranasal ketamine in 264 children 0 to 14 years of age [88]. In four of the seven studies, intranasal ketamine provided superior sedation to comparators and resulted in adequate sedation for 85% of the participants. Vomiting was the most common adverse effect (occurring in 10% of patients) [88]. Saliva and mucus production are increased, especially in the pediatric patient. These effects are usually tolerable in the adult, but the child may require the administration of an antisialagogue or an anticholinergic agent to help dry these secretions [59]. Prophylactic anticholinergics were once recommended for adults to reduce the risk of airway-related adverse events (by preventing oral secretions), but studies showed no benefit to this prophylaxis [62].

Cerebral vasodilation occurs with ketamine use, leading to an increase in cerebral blood flow, an increase in intracranial pressure, and an increase in cerebral oxygen consumption. Therefore, ketamine use in the patient with a history of intracranial pathologies should be avoided [59].

An additional central nervous system effect is the development of emergence delirium in the patient awakening from ketamine sedation. This complication occurs in approximately 10% to 30% of adults who receive ketamine [62]. These reactions range from vivid dreams to hallucinations and delirium [62]. Because of the risk for emergence reactions, ketamine is not usually used alone in adults [89]. The concomitant use of midazolam may help reduce this risk [59,62]. Benzodiazepines were once recommended to combat emergence reactions in children, but reactions in this population are rare and prophylaxis is no longer recommended [90].

In the emergency department setting, intravenous administration of ketamine is preferred for adults because of the ease of repeated doses and reduced risk for vomiting [90]. In the event of an inadvertent overdose, no antagonist exists and the effects cannot be reversed [91].

ANTAGONISTS

Antagonists, also known as reversal agents, act on the receptors in the central nervous system to reverse the pharmacologic effects of the medications administered. They have no other pharmacologic properties. Generally, their length of action is short, usually shorter than the length of action of the drug being reversed. Thus, administration requires repeat dosing.

Opioids and benzodiazepines both have antagonists available to reverse their actions. Naloxone is the opioid antagonist, and flumazenil is the benzodiazepine antagonist [59].

The advantage of the antagonists is that they can be administered in small doses, with a goal of reversing deep sedation and respiratory depression. By administering the drugs in this manner, the patient's respiratory drive increases but the effects of the sedative are not completely reversed. In other words, the intervention can proceed and the patient can remain, by definition, moderately sedated. This is more easily achieved with naloxone. Titrating small increments of the drug can be easily accomplished by adding the naloxone to a syringe and giving 1 or 2 mL as needed. (SeeTable 9 for more specific preparation.)

To reverse sedation, flumazenil is administered in 0.2 mg increments, repeating the dose (maximum four doses) at one-minute intervals to a maximum of 1 mg [59]. Eighty percent of the response will be achieved within the first three minutes after administration [59]. If the patient remains in a deep sedated state, additional drug may be necessary [59]. After administration of flumazenil, the patient may complain of flushing, headache, and fatigue. A transient hypertensive episode may be evident [59].

Although these agents are said to have no pharmacologic effect, there is a risk associated with rapid administration, especially with higher doses. Naloxone given rapidly can produce a noncardiogenic pulmonary edema, evidenced by increasing shortness of breath, rales and rhonchi on chest auscultation, and decreasing blood oxygen levels [59]. In acute cases, ventilatory support will be required.

Flumazenil can precipitate seizure activity in the patient with a history of benzodiazepine use or abuse. Many patients under-report their drug use and may falsify their benzodiazepine intake. If flumazenil is administered to these patients, it may produce seizure activity. When administering flumazenil, seizure precautions should be considered [59].

Although the use of antagonists in moderate sedation is a debatable issue, the ASA recommends that, whenever possible, antagonists should be on hand during the use of moderate sedation [44]. Some physicians will order naloxone or flumazenil at the end of the procedure in an effort to rapidly reverse the effects of sedation. In some instances, this is warranted to allow for further evaluation of the patient's neurologic status. On the other hand, reversal for the sake of reversal is not considered by many to be acceptable. Reversal of narcotics will reverse the analgesic effects, and if reversal is abrupt, the patient is not allowed time to slowly reorient to his/her surroundings. In addition, reversal agents are not without complication (as noted previously); the risks of reversal should be considered.

As reversal has a number of detrimental effects, many institutions and practitioners now utilize antagonists as rescue medications. The antagonist is administered in small doses to "rescue" the patient from an unintended deep level of sedation. This allows the patient to return to the moderately sedated level and allows for procedure completion.

Many practitioners think that it is safer for the patient to arouse slowly and comfortably at the end of the procedure. If a drug with a length of action equal to the length of the procedure was chosen and used, arousal should not take long. Patients will appreciate the care they receive and be satisfied with the results. Additionally, many institutions have the requirement that if a patient receives a reversal agent, that patient should be monitored for two hours prior to discharge. Therefore, the patient who is not reversed can be discharged earlier, when he/she is capable of meeting the appropriately assigned discharge criteria.

The ASA guidelines note that other steps should be taken before or concomitantly with pharmacologic reversal in patients who become hypoxemic or apneic during sedation, including [44]:

- Encouragement or stimulation of deep breathing

- Supplemental oxygen

- Positive pressure ventilation if spontaneous ventilation is inadequate

The ASA also recommends that patients be closely monitored after pharmacologic reversal to ensure that sedation and cardiorespiratory depression do not recur [44].

Knowledge of the drug therapy used in moderate sedation is imperative to delivering safe patient care. Until the advent of the ideal agent, nurses should be aware of the uses, contraindications, and considerations of the moderate sedation medications in their facility's formulary.

5. PATIENT MONITORING DURING MODERATE SEDATION

PULSE OXIMETRY

Pulse oximetry monitoring has become the standard for monitoring patients undergoing moderate sedation. The ability to assess oxygen desaturation greatly improves patient care and helps to ensure patient safety. The Joint Commission requires that all patients undergoing moderate sedation be continually monitored with pulse oximetry [1].

Pulse oximeters provide a noninvasive estimation of arterial oxyhemoglobin saturation [92]. A saturation of 90% is equivalent to an arterial oxygen blood gas value of 60 torr. During moderate sedation, many patients develop respiratory insufficiency secondary to sedating medications. If this respiratory compromise continues unchecked, significant tissue hypoxia will develop. The pulse oximeter allows the practitioner to monitor the hemoglobin saturation as a method of early detection of impending hypoxia [61]. Studies have shown that monitoring pulse oximetry greatly improves the practitioner's ability to assess changes in the early stages of hypoxia and initiate interventions to reverse developing complications. It has not been shown to affect the outcome of sedation or length of hospital stay [93,94,95].

An additional advantage of pulse oximetry is the rapid response time between changes in patient status and the reading on the monitor. Monitoring is noninvasive and does not require that the patient be cannulated for a blood gas sample. Furthermore, the advantage of being able to assess the patient who is draped or in a darkened room is clearly optimal to providing safe patient care. Pulse oximeters are said to be accurate within the range of 65% to 95% saturations, with only a 1% to 2% error. A number of patient variables (e.g., hemoglobin level, patient's oxygenation ability, percentage of inspired oxygen) may impact the accuracy of saturation values [96].

Pulse oximeter probes may be placed in a number of locations, including the fingers, toes, earlobes, nose, or forehead. Repetitive research studies have evaluated pulse oximetry monitoring and the results consistently demonstrated that the probes placed on the patient's earlobe are more accurate and have faster response times than probes placed elsewhere [97]. With this in mind, the practitioner should assess the earlobe site for use in probe placement. In certain procedures, as when the patient's head is draped, this location would not be considered appropriate. Proper positioning of the oximeter probe is essential to prevent production of artifactual data (e.g., underestimation or overestimation of oxygen saturation) [5].

Prior to application of the probe, it is critical to ensure that the site is prepared properly. Fingernail polish will prevent accurate measurements and should either be removed or the fingertip ruled out for probe placement [98]. The skin may be gently cleansed to remove accumulated dirt and body oils. The area of probe placement should be checked for proper circulation with good capillary refill. Patients with poor capillary refill secondary to peripheral vascular disease will be better monitored using the earlobes, nose, or forehead locations. After good venous circulation is assured, the probe may be placed. There are a number of types of probes, both permanent and disposable. The practitioner should be able to demonstrate competency in pulse oximetry monitoring prior to using this technique.

It is important to recheck the probe location for good capillary refill, both immediately after probe placement and intermittently during patient monitoring. The probe should not be placed on the same extremity in which blood pressure will be measured. When the cuff inflates, the blood flow to the extremity may be compromised, producing an inaccurate saturation reading.

Disadvantages of pulse oximetry include the fact that there is no information on the patient's ventilatory status, as measured by the partial pressure of carbon dioxide (PaCO_2). In cases when the oxygen saturation is below 65%, the monitor will overestimate the saturation, providing an inaccurate measurement. Pulse oximeters are also prone to motion artifact, which creates a high rate of false alarms. Newer models reduce motion sensitivity, which may result in an increased frequency of missed true alarms [99]. There are a number of situations in which pulse oximetry use is limited, and practitioners should be aware of these drawbacks (Table 10). However, the advantage of monitoring the patient in the moderate sedation setting is that these situations are rarely encountered. If a patient were to be severely hypothermic, for example, he or she would most likely not be considered a good candidate for moderate sedation in the first place. However, there is one consideration that is encountered relatively frequently, as there are a number of situations in the radiology setting in which the patient receives intravascular dyes for various studies. Although the impact of intravascular dyes on pulse oximetry reading is generally considered to be short-lived, it is imperative that the practitioner caring for this patient recognize the possibility of inaccurate readings and use other methods of physical assessment to ensure adequate patient oxygenation [98,100].

Table 10: LIMITATIONS OF PULSE OXIMETRY

Significant hypotension

Anemia poisoning

Vasoconstrictive drug use

Carbon monoxide

Severe hypothermia

Methemoglobinemia

Arterial compression

Intravascular dye use

Pulsating venous blood

Muscular contractions

Source: Compiled by Author

The anemic patient should always be evaluated for signs of hypoxia in addition to the oxygen saturation reading [101]. A patient with a hemoglobin of 8 that is 95% saturated will have a pulse oximetry reading of 95%. Another patient with a hemoglobin of 16 that is 95% saturated will also have a pulse oximetry reading of 95%. Monitoring these two patients will produce the same reading; however, the second patient has twice as much hemoglobin and therefore twice as much oxygen-carrying capacity. The first patient may exhibit signs of tissue hypoxia much more rapidly than the second patient, despite the same pulse oximeter readings.

The practitioner should also be aware that the oxygen-hemoglobin saturation is dependent on the oxyhemoglobin curve. In situations in which the oxyhemoglobin curve is shifted to the left (with an increase in pH, a decrease in body temperature, or a decrease in PaCO_2), the hemoglobin's affinity for oxygen increases. This translates to less oxygen available at the tissue level. Conversely, if the curve is shifted to the right (with a decrease in pH, increase in body temperature, or an increase in PaCO_2), the affinity for oxygen decreases, and more oxygen is readily available at the tissue level. This can be demonstrated in the following example: A patient with an alveolar oxygen partial pressure (PaO_2) of 45 torr has a measured pH of 7.25. This patient's oxygen saturation reading would measure 80% [101]. If this same patient were given sodium bicarbonate (as an example) to elevate the pH to 7.4, but no interventions were undertaken to correct the PaO_2 of 45, the oxygen saturation reading would increase to 88% by simply correcting the pH. A practitioner monitoring this patient would see the improved oxygen saturation and may be inappropriately comforted by this improvement. However, the patient's oxygen level did not change, meaning that the level of hypoxemia was unchanged.

Pulse oximetry has become the standard for monitoring patients undergoing moderate sedation, despite the aforementioned limitations. In the vast majority of patients receiving sedating agents, these limitations are not problematic. However, nurses should remember that even though this monitoring technology exists, physical assessment skills cannot be disregarded. Pulse oximetry is not considered a replacement for direct observation of patient ventilatory function [102].

END-TIDAL CARBON DIOXIDE MONITORING

End-tidal CO_2 monitoring measures expired carbon dioxide and provides information about the patient's ventilation. This type of monitoring is most commonly used with deep sedation and general anesthesia but is becoming commonplace in monitoring patients undergoing moderate sedation [103]. The advantage of this type of monitoring is that it allows early detection of developing hypoventilation and possible airway obstruction. Additionally, if the patient is developing the early stages of malignant hyperthermia, this can be recognized by rising CO_2 levels.

Two techniques are used for measuring expired carbon dioxide. The first uses a photo detector that calculates the CO_2 value as it passes through a transducer. The second method, capnography, actually obtains a sample of expired air and diverts it to a machine (i.e., capnograph) that directly measures the carbon dioxide level. Both techniques are easily accomplished on intubated patients. Measurement of end-tidal CO_2 levels in nonintubated patients is also possible [103]. Using microstream technology, a nasal cannula-type device can be applied to the patient's nares to allow for end-tidal CO_2 measurements. These devices are comfortable for patients and provide the practitioner with additional information regarding the patient's ventilatory status.

Evidence Based Practice Recommendation

The American College of Emergency Physicians states capnography may be used as an adjunct to pulse oximetry and clinical assessment to detect hypoventilation and apnea earlier than pulse oximetry and/or clinical assessment alone in patients undergoing procedural sedation and analgesia in the ED.

https://www.acep.org/patient-care/clinical-policies/procedural-sedation-and-analgesia

Last Accessed: July 14, 2020

Strength of Recommendation: B (Recommendation for patient care that reflects moderate clinical certainty)

Recommendations about noninvasive monitoring of end-tidal carbon dioxide with capnography have evolved. At the time of their guidelines on monitoring during moderate sedation, the ASA, the American Society for Gastrointestinal Endoscopy (ASGE), and the American Gastroenterological Association (AGA) Institute found insufficient evidence to recommend the routine use of capnography, and the American College of Emergency Physicians (ACEP) noted only that procedural monitoring "may include" capnography [4,38,44,55]. However, since the publication of those guidelines, several studies have demonstrated that capnography readings are a more sensitive measure of ventilatory function, detecting hypoventilation earlier than changes in vital signs, clinical observations, or pulse oximetry [104,105,106,107]. In a study in the emergency department setting, capnography had a sensitivity of 100% (specificity 64%) in detecting hypoxia before onset [106]. In addition, a meta-analysis (five studies) demonstrated that respiratory depression was more than 17 times more likely to be detected during procedural sedation when capnography was used than when it was not used [107]. In 2010, the ASA issued updated standards for anesthetic monitoring, stating that monitoring for the presence of exhaled carbon dioxide should be carried out during moderate (or deep) sedation [108]. Use of capnography during sedation is also recommended by the Emergency Nurses Association, and, in a joint position statement, the ASGE, the American Association for the Study of Liver Diseases (AASLD), the ACG, and the AGA Institute acknowledge that capnography reduces the occurrence of apnea and hypoxemia during gastrointestinal endoscopy with propofol sedation [109,110]. In the 2014 revision to its clinical policy on procedural sedation and analgesia in the emergency department, the ACEP states that capnography used as an adjunct to pulse oximetry and clinical assessment may detect hypoventilation and apnea earlier than pulse oximetry and/or clinical assessment alone in patients undergoing procedural sedation in the emergency department [34]. A multisociety-developed curriculum on sedation during gastrointestinal endoscopy notes that proper training should include interpretation of capnography readings [62].

Guidelines from the AAP/American Academy of Pediatric Dentistry support the use of capnography during pediatric sedation. However, it was used by less than half (45%) of practitioners in a large study of high-functioning pediatric sedation systems [33,111].

CARDIAC MONITORING

Cardiac monitoring of patients undergoing moderate sedation provides information regarding heart rate and rhythm. The Joint Commission requires continuous cardiac assessment in all patients undergoing moderate sedation [1]. Cardiac monitoring allows for the early detection of arrhythmias and the development of myocardial ischemia. In some patients, pacemaker function can also be continually assessed. Many policies and procedures recommend cardiac rhythm monitoring for all patients with an ASA Physical Status of 2 or higher [3,112]. Other policies require cardiac rhythm monitoring in all patients receiving intravenous moderate sedation, as the incidence of complications increases with this route of medication administration.

Lead placement techniques vary by institutional guidelines as well as what information is to be obtained. Modified lead II placement provides a waveform that is predominantly upright and easily recognized by most healthcare providers [113]. With modified lead II placement, the positive electrode is placed over the lowest palpable rib in the left midclavicular line. The negative electrode is placed at the first intercostal space at the right sternal border in the midclavicular line. The ground electrode is placed in the first intercostal space at the left sternal border in the midclavicular line. This allows for easy identification of P waves and the development of atrial arrhythmias. The disadvantage of modified lead II is the difficulty in visualizing bundle branch block. However, for the majority of patients who do not have a cardiac history with arrhythmia risk, modified lead II is an easy, recognizable method of cardiac monitoring.

Placement with modified chest lead using V1 (MCL1) produces a waveform that is normally negative; however, with right bundle branch block, the waveform will be upright. Many practitioners do not feel comfortable with this waveform view and therefore have difficulty in recognizing cardiac developments such as ischemia and/or arrhythmias. MCL1 placement requires that the positive electrode be placed in the fourth intercostal space to the right of the sternum. The negative electrode is placed below the left clavicle in the midclavicular line. The ground electrode may be placed in any convenient position [114].

The major advantage of monitoring the patient in MCL1 is that right and left bundle-branch block may be easily identified. Additionally, differentiation of ventricular tachycardia and supraventricular tachycardia with aberrancy is possible [114]. Premature ventricular contractions can be evaluated to determine their origin, either in the right or left ventricle. MCL1 is used frequently in intensive care units as it is equivalent to lead V1 on the 12-lead electrocardiogram. However, it has been shown to differ in QRS morphology in 40% of patients with ventricular tachycardia and is, therefore, not recommended for diagnosing wide QRS complex tachycardia [114].

Modified chest lead using V6 (MCL6) is another lead that may be used. The waveform produced is upright, and it allows identification of intraventricular conduction defects. MCL6 is equivalent to lead V6 on the 12-lead electrocardiogram [115]. With this lead, the positive electrode is placed at the fifth intercostal space in the left midaxillary line. The negative electrode is placed below the left clavicle in the midclavicular line, and the ground electrode is placed in the midclavicular line below the right clavicle.

Cardiac monitoring can be a useful adjunct to patient monitoring, particularly for high-risk patients. Detection of developing hypoxia as evidenced by arrhythmia development is beneficial to all patients, especially the patient with a positive cardiac history. Patients at risk of developing arrhythmias include the elderly, patients with abnormal electrolyte values, patients with a positive cardiac history, and patients experiencing significant hypoxic intervals. The most common arrhythmias that develop during moderate sedation include premature ventricular complexes and atrial dysrhythmias, such as atrial flutter and atrial fibrillation. Fortunately, for the vast majority of patients, these arrhythmias are readily reversed with oxygen therapy and present little danger to the patient's outcome.

Additionally, recognition of myocardial ischemia formation can allow the practitioner to determine if developing ischemia and myocardial injury is occurring. T-wave inversion is seen first with myocardial ischemia. The patient subsequently develops tall, peaked T waves, which are asymmetrical with a wide base. The ST segment becomes elevated, indicating myocardial injury. At this point, the extent of long-term myocardial damage can be reversed with oxygen and nitrate therapy. The development of Q waves can occur at any time, within a few hours or up to days after the infarct. The practitioner monitoring the patient receiving sedation can use the cardiac abnormality to determine the extent of ischemia, and consequently, a decision can be made regarding the necessity of discontinuing the procedure or correcting the ischemia (e.g., with oxygen therapy, nitrates).

The controversy regarding cardiac monitoring lies in the fact that many patients receiving moderate sedation are healthy, and continuous cardiac rhythm monitoring may be unnecessary in a large population of patients. Guidelines from the ASA, the AGA Institute, and the ASGE note that ECG monitoring is not needed for low-risk patients [38,44,55]. The ASA guidelines suggest ECG monitoring to decrease risks for patients who have significant cardiovascular disease or dysrhythmia, and the AGA Institute and the ASGE state that ECG monitoring should be considered for high-risk patients, such as patients with a history of significant cardiac or pulmonary disease [38,44,55]. The AAP recommends that an ECG monitor be readily available [33]. Each institution should develop its own policies and procedures as to which patients are candidates for monitoring and which patient populations do not require this level of care.

NONINVASIVE BLOOD PRESSURE MONITORING

Noninvasive blood pressure monitoring allows for repetitive evaluation of the patient's blood pressure with a minimal amount of nursing time. The monitor will cycle at a preset interval to obtain blood pressure readings and is accurate in a wide variety of settings.

The blood pressure cuff is placed over the brachial artery with the lower edge of the cuff one inch above the antecubital fossa. In a patient with fragile skin, a single layer of cotton padding may be placed around the arm prior to application of the blood pressure cuff. This will protect fragile tissue from repeated injury that may occur with each cuff inflation.

It is important that the practitioner place the cuff appropriately and ensure that the appropriate size cuff is used. A cuff that is too wide will provide a blood pressure reading that is inaccurately low. Conversely, a cuff that is too narrow will provide an inaccurately high reading. A proper cuff is approximately 40% of the circumference of the arm to which the cuff is applied [116]. The American Heart Association has provided recommendations for appropriate cuff sizes based on upper-arm circumference (Table 11).

Table 11: AMERICAN HEART ASSOCIATION RECOMMENDED SIZES FOR BLOOD PRESSURE CUFFS

Patient Parameter

Recommended Cuff Size

Adults (By Arm Circumference)

22–26 cm

12 x 22 cm (small adult)

27–34 cm

16 x 30 cm (adult)

35–44 cm

16 x 36 cm (large adult)

45–52 cm

16 x 42 cm (adult thigh)

Children (By Age)a

Newborns, premature infants

4 x 8 cm

Infants

6 x 12 cm

Older children

9 x 18 cm

aA standard adult cuff, large adult cuff, and thigh cuff should be available for use in measuring a child's leg blood pressure and for children with larger arms.

Source: [117]

Patients may complain of pain as the cuff inflates. Many machines now allow the practitioner to set the maximum cuff inflation pressure. This prevents overinflation of the cuff every time the cuff is used. With this ability to monitor the patient without inflicting undue pain, patient care is maximized.

Many blood pressure monitoring devices provide a digital read-out of the patient's vital signs. These are important records and should be incorporated into the patient's chart. However, it is important to remember that these attachments may become lost and separated from the chart. It is always advisable to document a set of vital signs in the chart and state that the digital read-out is attached. If legal action was to occur and no vital signs recorded and no print-out found, the nurse could face serious consequences for not obtaining vital signs. For example, if no record exists, an attorney may make the assumption that vital signs were not obtained. Additionally, the read-out may fade over time and become illegible. Also, if tape is placed over the ink when attaching the monitoring strip to the chart, the tape has the tendency to make the recording "disappear," and the readout is no longer visible.

Many blood pressure monitoring machines also allow for cardiac monitoring of the patient. Some provide a rhythm strip, and others simply monitor the heart rate. Combining these assessments ensures safe patient care without extra costs incurred for additional pieces of monitoring equipment.

BISPECTRAL INDEX

The bispectral index (BIS) has been developed as a method of objectively determining sedation status via electroencephalogram (EEG) recordings [118]. Based on the index, the sedation level can be determined mathematically based on the patient's EEG pattern. An alert adult would receive a score of 100, while a score of 0 is characterized by an isoelectric EEG pattern [118]. The bispectral index score is a relatively new tool, and research has indicated that it is a valid measure of depth of sedation, in addition to nursing evaluation [44,119,120,121]. However, some studies have found its use to be questionable among some populations, such as pediatric patients, and both the ACEP and the ASGE have found insufficient evidence to recommend routine use of BIS [4,55,62,122,123,124].

6. DOCUMENTATION OF MODERATE SEDATION

Critical to the success of moderate sedation is appropriate documentation of the procedure. Documentation provides other healthcare practitioners with information regarding the patient during the intervention. Additionally, chart reviews can be performed as a component of quality monitoring. Good documentation allows for a review of the medications, patient responses, and any adverse complications that may have developed during the procedure [125,126].

The ideal flow sheet should have three basic sections: the presedation assessment, the intrasedation record, and the postsedation record, which includes the discharge status of the patient. The format of the flow sheet should allow a reviewer to easily determine how the patient responded to therapy and sedation. Graphic flow sheets, which allow for vital sign charting next to medication administration times, allow rapid assessment of the patient and the patient's responses to medications [126].

When developing a flow sheet, input should be obtained from all users of the form. A sample form can be developed and critiqued, with changes made as appropriate. When a sample form is deemed acceptable, the form should be put into use and re-evaluated on a regular basis. It is not often that the ideal form is created during the first phase of development. Usually, it requires refinement a number of times. Unfortunately, too many individuals are resistant to change, and once a form is put into daily use, users do not want to see it changed, regardless of whether it meets their needs.

Current practice allows documentation of moderate sedation in a number of ways. The Joint Commission standards do not specify the elements required for sedation documentation but rather leave this responsibility to each individual organization, which is free to determine its documentation format [125].

The components of the presedation assessment should be easily identified to facilitate review [126]. Because the assessment of cardiac, respiratory, and neurologic components are critical in this phase of care, a section that allows for easy recording of these findings will ensure that the patient is appropriately assessed. A checked box format allows the recorder to document function and lessens the time required to complete the form.

Presedation baseline vital signs and oxygen saturations should be readily identified. If another individual is recovering the patient after sedation, he or she will need to be able to identify the patient's baseline parameters to evaluate readiness for discharge. The patient's ASA physical status and any important history, including medication use, allergies, diagnostic data (e.g., laboratory, ECG, X-ray) and last oral intake, should be included as well [3,126].

Monitoring equipment used may also be documented in a checked box format. If a patient is placed on the cardiac monitor, pulse oximeter, and noninvasive blood pressure monitor, a simple check system will expedite charting as well as act as a reminder to the care provider that these monitors should be considered.

Additional information in the presedation section could include a checklist of tasks to be accomplished during this phase of care. For example, a checklist may include such items as: informed consent obtained; emergency supplies readily available; oxygen and suction present and functional; history and physical reviewed [126]. These act as reminders and ensure that patient safety is always foremost.

The intraprocedural section should include a time-based record of patient assessment information as well as a medication section [126]. The medications should be documented according to their time of administration, the dose administered, the route of administration, and the patient's response. Vital sign assessment obtained one minute after sedative administration may be coordinated to show the effects of medications upon the patient's vital signs. All medications administered should be documented, including premedicants, sedating agents, and reversal agents, and the summary totals of their dosages should be easily identifiable [126].

If the patient is receiving intravenous solutions, these should be documented [126]. Any blood loss should be reported. A postprocedural intake and output calculation may be valuable for a number of patients.

During the procedure, the use of monitoring equipment should be documented [126]. Many noninvasive blood pressure monitors produce a paper strip with a vital sign and heart rhythm summary. These are acceptable methods of documentation. However, as discussed, the nurse should be aware that if the strip is lost or misplaced, there will be no record of vital signs on this patient, which may result in negative legal consequences. Therefore, as previously noted, it is prudent for the nurse caring for the patient to physically write in a set of vital signs and indicate that the rhythm strip is attached. Although this still does not show complete evidence of patient assessment, the nurse is able to demonstrate that he/she obtained vitals as appropriate.

Another important part of the intraprocedural form is the documentation of the patient's level of sedation. Many institutions use sedation scales as a method of documenting changes in the patient's level of responsiveness. This is a widely accepted method of documentation, and one which will stand up under legal scrutiny. The sedation scale selected should be easy to use and document. Many facilities use the Ramsay score; however, as previously discussed, this score lacks clarity in some areas [6]. Many hospitals now use the Modified Observer's Assessment of Alertness/Sedation Scale [38].

Pain assessment should also be included in the intraprocedure section. The Joint Commission requires that all patients be assessed for pain and have their pain managed appropriately. An additional box for documenting a pain score may be added to the vital sign section to ensure that the practitioner is including pain in his/her assessment. If the procedure is not painful, this too should be documented. (It is imperative to remember that if pain continues into the postsedation period, these pain assessments should be continued and documented.)

A summary of the procedure may be included in this intraprocedure section. The start and stop time of the procedure and the condition of the patient at the end of the procedure may be documented. The occurrence of any unusual events during the administration of sedation should be documented. Medication summaries should also be tallied [126].

The last section of the document is the postsedation care section. This includes assessment of the patient during the postsedation period as well as information regarding the patient at the time of discharge. Regular vital sign and pain assessments should be documented, including the patient's level of sedation. A reviewer should be able to identify the progression of the patient's arousal from the sedated state. Any complications should be described, and interventions undertaken should be documented. Pain medications, if administered, should be charted, including an assessment of the effectiveness of such medications [126].

The discharge of the patient should also be included. Depending on the location to which the patient is discharged, varying information should be documented (as previously presented). The location to which the patient is discharged should be clearly identifiable. The discharge criteria used to assess the patient's readiness for discharge should be clearly delineated. If a discharge scoring system is used, the patient's score should be noted, as well as a notation regarding the acceptable score for discharge. The condition of the patient at the time of discharge should be documented. If a patient is being discharged to home, the individual who is accompanying the patient should be identified.

Finally, discharge instructions should be charted [126]. Many facilities use standard discharge instruction worksheets that require signatures from both the patient and the nurse providing these instructions. After review, a copy of these instructions should be signed by both individuals and attached to the patient chart. The nurse(s) caring for the patient should sign the flow sheet prior to inserting the documentation record into the patient's chart.

In summary, documentation of the patient undergoing moderate sedation is an important aspect of good nursing care. The sedation assessment document should be user-friendly for the staff using the form during sedation, as well as any other individuals who may be reviewing the document at a later point. Without documentation of all aspects of the procedure, the assumption is that these activities were not completed. Therefore, it is imperative that documentation be complete, thorough, and easily legible.

7. COMPLICATIONS DURING MODERATE SEDATION

Moderate sedation is not a treatment without consequence. Although the incidence of complications is low, there are risks (Table 12). In many cases, complications are related to pre-existing comorbidities in the patient. With good presedation assessment and selection, the incidence of these problems can be kept to a minimum.

Table 12: COMPLICATIONS OF MODERATE SEDATION

Over- or undersedation

Cardiac arrest

Respiratory insufficiency

Pain

Airway obstruction

Nausea and vomiting

Aspiration

Malignant hyperthermia

Hemodynamic instability

Paradoxical reactions

Dysrhythmias

Source: Compiled by Author

OVERSEDATION AND UNDERSEDATION

Most complications occur because of sedation becoming deeper than intended (oversedation), rather than not reaching adequate sedation [44]. This is especially important for children, as studies have indicated that children often reach a level of sedation that is deeper than intended [33]. Clinicians who administer moderate sedation must be qualified to rescue patients who reach a deep level of sedation [44].

Another common complication of moderate sedation is nonoptimal sedation (undersedation) of the patient [127]. The nurse newly trained in moderate sedation administration may undersedate the patient in an effort to reduce the risk of oversedation. Although undersedation may seem beneficial as compared to oversedation, the effects of undersedation can be just as undesirable. The patient who is undersedated experiences an increased amount of stress, leading to an increased autonomic response [128]. The patient experiences an increase in heart rate and blood pressure, both of which can be detrimental in a variety of patient populations.

Certain populations are at increased risk of oversedation and undersedation, particularly the young, the old, the critically ill, and the obese [3]. Patients with liver and/or renal disease are also at increased risk, especially for oversedation [129]. Patients with high preprocedural levels of anxiety may also be at risk; the heightened anxiety state can prevent the patient from achieving the full benefits of the drug administered. As an example, a patient with a high level of anxiety is scheduled for an MRI. The patient has heard a great deal from friends and family about the claustrophobic environment of the scanner. This patient has a fear of enclosed spaces and becomes fearful that he/she will be unable to tolerate the closed-in feeling in the scanner. The nurse caring for this patient administers a low-dose benzodiazepine in an effort to relax the patient and relieve his/her anxiety. The preprocedural instructions provided to the patient explained the type of sedation and that these medications are administered to relieve the patient's heightened level of anxiety. However, the dosage administered is inadequate to achieve these goals, and the patient enters the scanner without feeling relief. The patient believes that the medication should be working but remains unable to relax. This only further increases the patient's anxiety, and the physiologic responses of an increased heart rate and blood pressure become evident.

Both oversedation and undersedation can be prevented with proper drug dosing, dosing techniques, and recognition of at-risk patients. Administering drugs in small doses on a more frequent, as-needed basis can all but eliminate these problems. Should overdosage become a problem, administration of a reversal agent (if available) may be used.

RESPIRATORY INSUFFICIENCY

Differentiating oversedation from respiratory insufficiency can be challenging. Respiratory insufficiency is a known effect of sedation agents and should also be considered a potential complication of oversedation. Clinical signs of respiratory insufficiency include decreased, shallow, or labored respirations; rocking motion of chest; weak cough; high-pitched noise during inspiration (partial obstruction); no movement of air (complete obstruction); and decreased oxygen saturation [9]. Patients with high respiratory rates, such as the pediatric patient and the obese patient, are at increased risk of respiratory insufficiency secondary to their high minute volumes. If a patient's normal respiratory rate is 30 and drops to a rate of 15/minute, there is a 50% drop in the patient's minute volume. On the other hand, if an adult whose normal respiratory rate is 20 drops to 15/minute, there is only a 25% drop in minute volume. It is clear that the patient with the higher resting respiratory rate is at increased risk for hypoxemia.

Complicating the respiratory insufficiency expected with sedative administration is the response to a developing hypoxemia. Many sedating agents blunt the patient's response to impending hypoxemia, and a vicious cycle is set in motion, the end result being a patient whose respiratory drive is insufficient to meet his/her tissue oxygen demands.

Preventing respiratory insufficiency can be accomplished by monitoring the patient's respirations and oxygen saturations every five minutes. Stimulating the patient to breathe with each vital sign assessment can also ensure adequate ventilatory effort, assuming that such behavior does not adversely interfere with the procedure being undertaken. Providing supplemental oxygen to patients at risk of decreased respiratory effort will prevent the further development of significant hypoxemia [9].

Oximetry has been shown to effectively detect oxygen desaturation and hypoxemia in patients who are administered sedatives. Early detection of hypoxemia through the use of oximetry during sedation can decrease the likelihood of adverse outcomes (e.g., cardiac arrest). Supplemental oxygen also decreases patient risk during moderate sedation [3]. In severe situations, administering a reversal agent (if available) or terminating the procedure may be necessary to reverse this problem [9].

COMPROMISED AIRWAY

Airway obstruction is another common complication that can be prevented with close monitoring. Obstruction of the airway is more common in the young child, whose tongue is larger in proportion to the size of his/her mouth. The modified Mallampati Scale is a useful tool in evaluating patients at risk for airway compromise [26,27,28,31]. This four-level pictorial tool was devised to predict difficult compromised airway and is now widely recommended as a routine screening element before procedural sedation [130]. The scale classifies the patient's airway as Class 1, 2, 3, or 4. The patient with either a Class 3 or 4 airway has an increased risk of airway obstruction in comparison to a patient with a Class 1 airway, as outlined previously. Any patient with a Mallampati Class 2 airway may also be at increased risk. While it is important to anticipate that a patient may have a difficult airway, there is no specific evidence that the Mallampati score improves the baseline clinical judgment of a standard airway evaluation. Variability in grading by independent observers makes it an unreliable assessment when used alone. It also cannot be evaluated in many young children and in patients who cannot cooperate due to an underlying psychologic or medical condition [29,130].

A prospective, observational study was undertaken to compare the rates of adverse events during pediatric procedural sedation in 575 children (median age: 6 years) with Mallampati scores of III/IV versus scores of I/II [131]. The primary reason for sedation was fracture reduction; most sedations involved the use of ketamine. Patients with scores of III/IV were more likely to require repositioning during sedation compared to those with scores of I/II, but, overall, they did not experience a higher proportion of adverse events compared with children with scores of I/II [131].

The airway also may become compromised from accumulated vomitus, blood, or oral secretions. Patients who are sedated without the benefit of gastric emptying will be at increased risk of aspiration. Controlling secretions with suction and head positioning is imperative in this group of patients.

Finally, in the event of developing deep sedation, the patient will lose submandibular muscle tone causing a slack jaw and unprotected airway. It is important to remember that sedation is a continuum; the progression to deep sedation is varied and individualized. The development of a slack jaw can occur at any time, and the patient's muscle tone and airway should be monitored at all times.

In most adult patients, the head-tilt/jaw-thrust maneuver is all that is necessary to open the airway. (Note: It is imperative to remember that in the pediatric patient, a head-tilt is NOT an appropriate airway maneuver; the child should be placed in the sniffing position with the jaw forward.) Insertion of an oral airway is generally contraindicated, as the patient's level of consciousness is not deep enough to allow placement. Placement of an oral airway may actually precipitate laryngospasm in many lightly sedated patients, necessitating intervention [9].

If the airway is compromised with accumulated particulate material, insertion of a nasal trumpet and suctioning will be required. Again, care should be taken to prevent laryngospasm that may occur with vigorous suctioning.

ASPIRATION

Aspiration is the most common cause of death secondary to intravenous moderate sedation [6]. Although the risk of death is increased, the incidence of aspiration remains lower in moderate sedation than in general anesthesia [132]. The most common cause of aspiration is the relaxed cardiac sphincter tone that develops with deeper levels of sedation. Any patient with a history of reflux is at risk, as are obese, obstetric, and elderly patients [6,24,55].

Risk of aspiration may be reduced by administering medications to decrease gastric contents or medications to increase gastric pH. Elevation of the head of the bed may decrease the patient's risk, assuming that such positioning is not contraindicated by the procedure being performed. Finally, if the patient does aspirate, suctioning and airway protection with intubation may be required. The patient may be started on antibiotic therapy and vigorous pulmonary toilet will be instituted. Postaspiration pneumonia carries a high mortality if not recognized and treated early [34,133].

CARDIOVASCULAR COMPLICATIONS

Hypotension

Hemodynamic instability is a common cardiovascular complication occurring during moderate sedation [6]. The direct cardiodepressant effect of many of the sedating drugs causes hypotension in the patient. The patient with a pre-existing compromised circulatory volume is at greatest risk for this complication [55]. Hypovolemia and hemorrhage require aggressive volume and blood replacement to prevent dangerously low circulating pressures. In acute cases, vasoactive drugs may be required to supplement hemodynamic status. Recognition of the patient at risk for hypotension will allow the practitioner to supplement the patient's volume status prior to sedation, thereby circumventing this problem. Hypotension may be an early sign of oversedation.

Other causes of hypotension include pain and the histamine release that occurs with a number of depressant agents. It is imperative that the cause of the hypotension be identified so that proper therapy can be instituted to reverse the cause and correct the problem.

Dysrhythmias

Another cardiovascular complication is the development of dysrhythmias, most commonly in the elderly individual. Most dysrhythmias occur secondary to hypoxia and can be prevented or treated with increasing oxygen percentages; other causes of dysrhythmias include fluid overload, pain, and hypovolemia [134]. The patient at risk should be placed on continuous cardiac monitoring prior to the start of the sedation and continuously monitored both throughout the sedation period and during the recovery phase [24,38,44]. Supplemental oxygen may be recommended prior to beginning the procedure. Antidysrhythmics and defibrillation are rarely required; however, access to these interventions should be readily available.

The type of agent used will affect the type of dysrhythmia that develops. Fentanyl and the barbiturates are associated with bradycardia, while dissociative agents such as ketamine are more commonly associated with tachycardia, myocardial depression, and ventricular ectopy [59,134].

Cardiac Arrest

In the event of significant cardiovascular compromise, the risk of cardiac arrest exits. With good presedation evaluation and risk assessment, the advent of cardiac arrest is rare. However, should this life-threatening event occur, the team caring for the patient should cease procedural interventions and immediately begin full resuscitation efforts. The facility's "code team" may be activated to provide expert back-up assistance in resuscitating the patient; however, the Joint Commission standards require that individuals who administer moderate sedation must also be competent to perform the rescue. A "code team" is considered an additional resource [135]. Those caring for the patient also should be well versed in the American Heart Association's cardiac arrest protocols [136]. Airway, breathing, and circulation should be managed and drug therapy instituted.

PAIN

Pain is a complication that should rarely present itself if the nurse caring for the patient is performing his/her responsibilities. It is an important preprocedural responsibility to instruct the patient regarding pain. The use of pain scales should be demonstrated so that the patient is aware of his/her responsibilities in informing the nurse of any pain. Another important teaching point to address is that there is a difference between pain and discomfort. Analgesics may be provided for pain control; however, discomfort may be a part of the procedure that cannot be eliminated. As an example, a patient undergoing a colonoscopy with moderate sedation may experience discomfort while the abdomen is assessed. This type of discomfort cannot be treated with analgesic therapy. The patient should be aware of these differences, and a path of open communication should be established. Often, nonpharmacologic interventions may be instituted to relieve discomfort, such as padding under the back (if allowed) to relieve pressure and discomfort over the sacral area.

A known painful procedure should be performed using sedating agents that have known analgesic properties. Assessing the patient's level of pain is imperative to provide safe, patient-oriented care. If a patient is experiencing a significant amount of pain, the nurse may be wary of administering further pain medications due to their synergistic effects upon sedation. This issue should be addressed with the physician, and consideration of nonsteroidal anti-inflammatory agents may be considered.

NAUSEA AND VOMITING

Evidence Based Practice Recommendation

According to the American Society of Anesthesiologists, multiple antiemetic agents may be used for the prevention or treatment of postanesthesia nausea and vomiting, when indicated.

https://anesthesiology.pubs.asahq.org/article.aspx?articleid=1918686

Last Accessed: July 14, 2020

Level of Evidence: Expert Opinion/Consensus Statement

Nausea and vomiting are additional complications that put the patient at risk and increase the patient's discomfort. Increased vagal tone can produce the sensation of nausea and potential vomiting. Opiate use is known to produce nausea and vomiting in some cases. Other patients at risk for experiencing these complications include those that are hypovolemic, obese, or in pain. Certain procedural interventions are known to increase the complaints of nausea and vomiting; therefore, assessment for increased risk should take place in the preprocedural period.

Administering antiemetics may be of benefit. However, these drugs can produce additional sedation, and the nurse should exercise caution when giving these drugs to the sedated patient. In the event of significant gastric distension, the use of a nasogastric tube to suction may help reduce the risks. Hypovolemia should be corrected, and pain may be treated with additional analgesics; however, the practitioner should be aware of the synergistic effects of additional analgesics already presented.

MALIGNANT HYPERTHERMIA

Malignant hyperthermia (MH) is another rare but potentially life-threatening complication [137,138]. Once again, taking good presedation history, including risk assessment for MH, can prevent this problem from developing [139]. Patients at risk for developing MH include children and those with a history of anesthetic complications [134,137]. Agents that can precipitate MH include anesthetic gases and succinylcholine [59,140]. Although the majority of these drugs are not used in the moderate sedation realm, the risk of this complication developing should not be overlooked.

The onset of symptoms of MH may begin with the development of masseter muscle spasm (also known as masseter muscle rigidity) and rising CO_2 levels. The patient can develop tachycardia and other ventricular dysrhythmias [134,139]. The patient's core temperature remains normal in the early stages; however, the skin appears flushed and may feel warm to touch. It is imperative that the care provider recognize these symptoms in this early stage. If the syndrome progresses to the state of high fever and muscle rigidity, the incidence of death and long-term sequelae increases [134].

If MH develops, the procedure should be terminated immediately and interventions undertaken to prevent its progression [140]. The patient may be administered dantrolene, and cooling measures should be instituted [134,137]. The Malignant Hyperthermia Association of the United States (MHAUS) recommends that a full supply of dantrolene be available on site to allow for initial stabilization and treatment while more vials are acquired to continue treatment, as needed [140]. Administration of dantrolene requires additional support personnel, as drawing up an adequate dose is time consuming and difficult to perform while instituting other supportive measures.

Children will respond to external cooling measures, such as ice packs to pressure points and cool cloths. The adult patient may require internal cooling, with iced lavage of the peritoneal, gastric, bladder, and rectal cavities [59]. In the event of significant hyperthermia (i.e., temperature greater than 42°C), placing the patient on the heart-lung bypass machine to institute extracorporeal cooling may be required.

Subsequent complications, such as ventricular dysrhythmias, should be treated according to standard protocols. The patient will require increased fluids to prevent the development of acute renal failure secondary to myoglobinuria. Sodium bicarbonate may be administered for severe acidosis, and diuretics may be given to prevent developing renal failure. If the patient is at increased risk of hyperkalemia, a glucose-insulin drip may be ordered to reduce the serum potassium level [59,134].

Additionally, the risk of recurrence exists. The patient should be monitored for up to 48 hours for recurring signs and symptoms. MHAUS guidelines recommend that 2.5 mg/kg of dantrolene be administered with an upper limit of 10 mg/kg [59,140]. It is also imperative that the patient and his/her family be made aware of the complication and further education instituted so that it may be prevented in the future.

PARADOXICAL REACTIONS

Finally, the risk of paradoxical reaction exists. The patient who experiences agitation, dysphoria, and/or confusion, either during sedation or upon recovery, is at risk for self-inflicted injury. These types of reactions are more common in the pediatric and elderly populations and are known side effects of certain medications (e.g., midazolam use in the elderly, benzodiazepine use in children) [141]. If a paradoxical reaction to benzodiazepines is suspected, the offending agent should be discontinued immediately. While management with observation may be sufficient, tranquilization (e.g., with low-dose ketamine, propofol, haloperidol) has been reported to be successful [142,143].

Other causes of paradoxical reactions include hypoxia and undermedication. Hypoxia should always be considered as the primary cause, and measures should be undertaken to reverse this problem. As discussed, undermedication can lead to an increased level of anxiety or provide an inadequate amount of analgesia for the patient, thus precipitating this type of reaction [141]. Treating hypoxia with oxygen administration in this combative patient may be difficult and may only increase the patient's agitation. In this case, blowing oxygen at the patient's face may help reverse the hypoxia. Administering pain medications may help ease the response, but additional sedation may develop.

Another suspected cause of paradoxical excitement is the administration of reversal agents. The rapid arousal of the patient may bring on fear, which subsequently leads to a paradoxical response. If administering a reversal agent to a patient, slow administration and reversal have been found to help decrease the risk of excitement in many patients. Titrating the reversal medications can help achieve this goal.

The risk of complications exists with any type of moderate sedation procedure but can be reduced, if not prevented, with recognition of the patient at risk and vigilant monitoring to detect early signs of patient deterioration.

8. MODERATE SEDATION OF THE PEDIATRIC PATIENT

Administering moderate sedation to the pediatric patient is a safe and effective method of controlling agitation and discomfort in the child. However, a child's ability to control his/her own behavior for purposes of cooperating for a procedure depends on the child's chronologic and developmental age. Children younger than 6 years of age and those with developmental delay often require deep levels of sedation to affect adequate behavior control. It is important to anticipate the need for deep sedation as studies have shown that children commonly pass from the intended level of sedation to a deeper, unintended level [5,144,145,146]. Also, the sedation medication used has a more profound effect on the respiratory drive, patency of the airway, and protective reflexes of a child in this age group. Administration of drug therapy and care of the patient should be modified to take into consideration the anatomic and physiologic differences in children. Institution of appropriate measures will ensure safe drug delivery with successful outcomes. The concept of rescue is particularly essential to the safe sedation of children [5].

ANATOMIC AND PHYSIOLOGIC DIFFERENCES

The child's airway is anatomically different than the adult airway. The larynx is located more cephalad and anterior; thus, head positioning is different in the child. Airway diameter is narrow, with the narrowest section of the trachea located at the cricoid ring. Airway compromise is always a consideration secondary to the large tongue, which can relax and fall back into the airway, causing obstruction.

Children's breathing effort is different in that there is less alveolar space for gas exchange with fewer collateral ventilatory pathways. Oxygen demands are higher secondary to the child's high minute volume. Normal respiratory rates in children are faster than adults; therefore, a decrease in the child's respiratory drive secondary to drug administration can cause significant respiratory insufficiency. Additionally, the sternum and the ribs are more cartilaginous and pliable in the child, making signs of respiratory distress visually identifiable by chest wall retractions and abdominal muscle use.

Heart rate and blood pressures vary by age of the child, and the evaluation of changes should take these variables into consideration. Children's cardiac output is controlled by increasing heart rate, and drugs that slow the heart rate will cause a drop in cardiac output with a subsequent decrease in circulation times. This drop in cardiac output translates into a longer onset and a prolonged length of drug action. Additionally in children, the circulatory response to hypoxia is the development of bradycardia. Therefore, heart rate becomes an important assessment parameter.

Assessing the level of consciousness and arousal in the child should take into consideration the development age of the child. The neurologic system is not well developed until 8 to 10 years of age. Recognizing normal, age-appropriate behaviors in the child will allow the care provider to identify changes in the child's level of functioning.

The hepatic and renal function of a child is not well developed, and this will impact drug metabolism and clearance. The child may have longer length of action of drugs secondary to reduced hepatic function. On the other hand, the child may have a faster clearance time due to the higher circulating volumes. Monitoring the child for drug response is imperative due to this unpredictable medication response.

Additional considerations include fluid volume differences and differences in the distribution of these body fluids. Children have a large body surface area to body mass and are at increased risk for developing hypothermia. While circulating volume is calculated at 80–90 mL/kg, children will require additional maintenance fluids for circulatory support. Maintenance fluids are frequently required for children younger than 8 years of age, as well as children who have been NPO for a significant length of time. Table 13 outlines the formula for pediatric maintenance fluid administration. Typically, the choice of fluids includes a dextrose containing solution, such as 5% dextrose with 0.25% normal saline. This provides the child with the supplemental glucose that is required during times of stress.

Table 13: PEDIATRIC MAINTENANCE FLUID CALCULATIONS

100 mL/kg for 1st 10 kgs

(Ex: 10-kg child = 1,000 mL)

50 mL/kg for 2nd 10 kgs

(Ex: 20-kg child = 1,500 mL)

20 mL/kg for each additional kg

(Ex: 26-kg child = 1,620 mL)

Total calculated volume is divided equally over 24 hours.

Fluid of choice is generally 5% dextrose with 0.25% normal saline.

Source: [60]

PHARMACOLOGIC CONSIDERATIONS

Techniques for the pediatric patient receiving moderate sedation are different from adult patients. Internal factors (i.e., child's age, developmental level, previous experience) and external factors (i.e., parental interactions with the child, preparation, clinical skill, physical setting where procedure is performed) determine how the child will respond. Individualized dosing and titratable agents are, therefore, often necessary [71].

It is more common for children to receive transmucosal medications with excellent results. The oral route is advantageous due to its ease of administration. However, a risk of aspiration may occur, especially with foul-tasting medications. Usually, the taste of these medications is disguised in a sweet, syrupy concoction that greatly improves patient compliance. Many medications are metabolized by first-pass effect, and dosing by the oral route should be increased on a milligram per kilogram basis to achieve the same level of sedation achieved by the intravenous route.

Sublingual administration, such as fentanyl lozenges, is an easy and desirable method. The child should be able to cooperate with instructions to suck on the lozenge rather than chewing it, as chewing prevents complete absorption and compromises proper drug dosing. The advantage of sublingual administration, as previously mentioned, is the lack of first-pass effect.

Nasal administration of sedating agents is gaining popularity, especially for the pediatric population; however, not all agents are approved for this route of administration [147,148]. Midazolam can be mixed with normal saline and dripped into the nasal passages. Many children, especially younger children, tolerate this route quite well [147]. Onset of sedation is rapid, and return to a presedation state is comfortable and quick. The disadvantage of this route is that medications may produce sneezing in the child, making the volume of medication received uncertain [149]. Additionally, if the volume of saline instilled into the nasal passage is large, the child may swallow the medication, converting absorption to the oral route. A study that compared oral midazolam syrup with intranasal midazolam spray for pre-anesthetic sedation in pediatric patients found that the two routes of administration produced similar anxiolysis and sedation, but better drug acceptance and response was noted with oral midazolam [150]. A study that compared the ease of administration of oral midazolam syrup with intranasal midazolam spray as premedication administered by parents to children found that parents reported better ease of administration with the syrup than the spray and that children better accepted the syrup than the spray [151].

Rectal administration of medication is utilized frequently in the child, especially the child who is resistant to intravenous line placement. Initial doses of medications can be given rectally. Once the sedating effects occur, an intravenous line can be placed and further drug dosing accomplished by the intravenous route. The disadvantage of rectal administration in the child is the lack of retention of the drug in the rectum. Some children may bear down and dispel the medication prior to its absorption.

Intramuscular administration is the least desirable route of administration in all populations, especially with the pediatric patient. The advantage of the longer length of action should be weighed against the pain and delayed onset that occurs with this route. Furthermore, if this is the sole route for drug delivery, repeat injections may be required for further sedation, causing additional pain and discomfort in the child.

Intravenous administration has the advantage of providing the most controlled route for drug dosing. There is no question regarding the amount of drug that was administered, which may not be the case with other routes of administration. The risk of rapid onset of complications does exist but can be controlled by the titration of drugs to allow for monitoring of response to medications. Intravenous drug therapy does require intravenous line placement, which is traumatic for a large percentage of children. Thus, use of combined techniques (i.e., rectal, oral, nasal administration) for initial sedation followed by intravenous administration (for prolonged effect) is very beneficial in this population. It is important to note that the potential for adverse outcomes increases when three or more sedating agents are administered. Knowledge of the time of onset, time to peak, duration of each agent, and whether a previous dose of an agent has taken full effect is essential. An agent with a long duration of action requires a longer observation period, even if the child has achieved recovery and discharge criteria. This is especially important for infants and toddlers who are transported home in car seats. These children are at risk of resedation due to residual prolonged drug effects with the potential for airway obstruction [5]. It is essential that the nurse consider the effects of these techniques and choose the most appropriate route or methods based on each individual child's needs.

Pharmacologic effects of drug administration are affected by the higher cardiac outputs and metabolic responses in children. Drug dosing is on a higher milligram per kilogram dosage in children than in adults. The risk of this type of drug dosing is the sequestration of drugs in the fat or muscle of the child, leading to prolonged length of action and risk of resedation as the drug is slowly released from these tissues. The nurse providing sedation should always be aware that the potential for complications is higher in children and have readily available reversal agents, medications, and equipment.

Additionally, certain medications are used exclusively in the pediatric population. Thus, nurses caring for children should be aware of the pharmacology of these drugs. Fentanyl lozenges are most commonly utilized in children.

Chloral hydrate and pentobarbital are used in children undergoing radiologic procedures when a motionless patient is required, as during the MRI. These drugs have different actions in young versus older children. Chloral hydrate has a long duration of action, and residual effects (e.g., motor imbalance, agitation, restlessness) are common and may occur after the child is discharged to home. Most institutions limit the use of these two drugs to children younger than 3 years of age [152]. The nurse administering either of these drugs in the older child should carefully monitor the child for untoward effects.

NURSING CARE

Nursing care of the child receiving moderate sedation requires vigilant monitoring of the child at all times. The onset of complications may be more rapid, and the risk of untoward events is higher. However, careful assessment of the child throughout the procedure ensures that drug administration is safe and the child is comfortable.

Airway management in the child requires head positioning with consideration of anatomic variables. The child with airway compromise should be placed in the "sniffing" position, with the jaw lifted upward and forward. Placing a child in the standard head-tilt/jaw-thrust maneuver can cause inadvertent collapse of the child's airway. Signs of airway obstruction should be evaluated whenever unusual airway sounds are identified, including inspiratory stridor and/or snoring. Additional signs include restlessness secondary to developing hypoxia, intercostal muscle use, tachypnea, and bradycardia. In children 5 years of age and older, presedation assessment should include looking for loose teeth that may fall out and lead to airway obstruction. Immobilization devices (e.g., papoose boards) should be used so as to avoid airway obstruction or chest restriction. If an immobilization device is used, a hand or foot should remain exposed, and the child should never be left unattended [5]. Airway management in children with abnormal airway anatomy or airway obstruction may be accomplished with the use of devices, such as the laryngeal mask airway (LMA). The LMA device is available in a variety of sizes and may even be used in neonates [5].

The child should be administered supplemental oxygen secondary to his/her high oxygen demands. Cooperation with oxygen mask placement can be challenging in the combative and restless child. Enlisting a parent to hold an oxygen mask and blow oxygen at the child's face may be beneficial in the early stages. After the child is adequately sedated, the use of oxygen therapy devices should be continued and is usually easily accomplished. The use of capnography for sedated children is recommended, particularly when other means of assessing the adequacy of ventilation are limited. As noted, guidelines from the AAP/American Academy of Pediatric Dentistry support the use of capnography during pediatric sedation [33,111]. Several manufacturers have produced nasal cannulae that allow simultaneous delivery of oxygen and measurement of expired carbon dioxide values [5].

The child should be placed on a cardiac monitor so that signs of bradycardia are readily identified. If cardiac monitoring is not performed, frequent vital sign assessment of heart rate is imperative to recognize changes from the status quo. If anticholinergic medications, such as atropine, are given to reduce secretion formation, it is imperative that the nurse monitor for additional signs of hypoxia, as bradycardia development will be blocked by these medications.

Children may require additional fluids, especially if the child has been NPO. Generally, children receiving sedation for elective procedures should follow the same fasting guidelines as children receiving general anesthesia. The American Society of Anesthesiologists has developed guidelines for appropriate food and liquid intake for children prior to elective sedation (Table 14). For the child who undergoes sedation for an emergent procedure, the benefits and risks should be evaluated, with consideration given to the amount and type of liquids or solids ingested [32]. Routine preoperative administration of pharmacologic treatment to reduce gastric volume and increase gastric pH in patients who have no apparent increased risk for pulmonary aspiration is not recommended by the ASA [32].

Table 14: APPROPRIATE INTAKE OF FOOD/LIQUIDS BEFORE ELECTIVE SEDATION FOR CHILDREN

Ingested Material

Minimum Fasting Period

Clear liquids (i.e., water, fruit juices without pulp, carbonated beverages)

2 hours

Breast milk

4 hours

Infant formula

6 hours

Nonhuman milk: Because nonhuman milk is similar to solids in gastric emptying time, the amount ingested should be considered when determining an appropriate fasting period.

6 hours

Light meal: A light meal typically consists of toast and clear liquids. Meals that include fried or fatty foods or meat may prolong gastric emptying time. Additional fasting time (e.g., eight hours or more) may be needed in these cases. Both the amount and type of foods ingested should be considered when determining an appropriate fasting period.

6 hours

Source: [32]

Additional considerations for nursing care include keeping the child warm during the procedure. Children should also be monitored for the increased risk of paradoxical excitement and emergent reactions. Parental presence during the recovery phase commonly helps to reduce the severity of emergent excitement in children. However, prior to having a parent present in the recovery area, the nurse should evaluate the parent's level of comfort in dealing with a potentially confused and combative child. Many parents do not feel comfortable watching their child experience these types of reactions, and they should not be forced to do so under the auspices that it is helpful to the child.

Finally, discharge of the child should take into consideration the age-appropriate behaviors in children. Meeting the preprocedural level of functioning is the aim of discharge criteria in the child. A number of children undergoing sedation may not be ambulatory or able to sit without support; however, they should be able to perform those developmental tasks that they were able to accomplish in the preprocedural phase prior to discharge.

It is more common for children to vomit in the postsedation period. The caregiver should be aware of this risk and undertake measures to reduce the risk of aspiration. In addition, the caregiver should be instructed that it is not common for the child to keep vomiting. If this were to occur, the child should be returned to the institution or a follow-up telephone call should be placed.

Discharge instructions for the pediatric population should be given to both the child and the caregiver. Dependent on the age of the child, he or she may not be able to fully comprehend the need to adhere to these instructions.

The challenge in sedating the pediatric patient is achieving an appropriate level of sedation while preventing oversedation and other complications. Appropriate techniques of drug dosing and vigilant monitoring of this patient population will assure competent drug delivery.

9. MODERATE SEDATION OF THE GERIATRIC PATIENT

Sedation of the geriatric patient can provide a calm, comfortable environment for the patient who may be experiencing a high level of anxiety. However, the psychologic needs of this population are great, and the increased risk of complications is readily known to practitioners as well as patients. Allowing for adequate history taking and patient instruction is imperative to providing safe delivery of care.

ANATOMIC AND PHYSIOLOGIC DIFFERENCES

As individuals age, there is a decrease in both laryngeal and pharyngeal reflexes; thus, the patient is at increased risk for airway compromise. The loss of dentition changes the shape of the mouth, and it may become a challenge to achieve proper placement and seal with ventilation masks. Should airway compromise develop, osteoarthritis of the neck may preclude placing the patient in the standard head-tilt/jaw-thrust maneuver. In this instance, positioning the elderly patient's head becomes a formidable task that requires the practitioner to be adaptable and able to work within the confines of the situation. If the head-tilt maneuver is not possible, placing the patient in the left lateral decubitus position may decrease the risk of inadvertent aspiration.

One of the major complications of aging and the use of moderate sedation occurs when benzodiazepines and/or opiates are used. Both of these drug classes produce enhanced depression of the patient's respiratory drive, which is a normal change that occurs with aging. With rising levels of CO_2 and falling levels of oxygenation, the younger person will increase the depth and rate of respirations to ensure adequate tissue oxygenation. This ability to respond to these changes is dampened in the elderly, putting the individual at risk for profound hypoxemia [153]. Concurrently, the blood oxygen levels decrease with age; it is not uncommon for the elderly individual to have blood oxygen levels of 80 torr with oxygen saturations of approximately 93% to 95% [153]. These compounded problems lead to a patient who is at increased risk for hypoxia and hypercapnia, which requires judicious monitoring to prevent their occurrence.

The aging process produces a decrease in cardiac output, leading to decreased renal and hepatic blood flow. By the time an individual is 80 years of age, it is said that their cardiac output is one-half that of an individual 20 years of age [154]. This drop in cardiac output requires slower loading times in the elderly, especially with barbiturates.

In addition, the cardiac conduction system deteriorates, enhancing the risk of dysrhythmia development. Combined with developing hypoxia, it is not uncommon to see dysrhythmias in this patient population [154].

Sedation drugs utilized for moderate sedation affect the central nervous system. For the elderly patient, there is an increased sensitivity to these medications. It is highly recommended that the dosage of sedating agents be decreased in the elderly person to prevent profound, deep sedation [153]. Assessing this individual may also be challenging; as individuals age there may be a decrease in cognitive abilities, memory, and data acquisition. The standard neurologic testing should be done with consideration of these changes.

It is estimated that a large percentage of the elderly population is chronically volume depleted. The frequent use of diuretic therapy presupposes these individuals to circulating volume deficits. Drugs that are water soluble have an enhanced action potential in these volume depleted patients.

Additionally, approximately 6% to 11% of older adults are heavy users of alcohol, many of whom under-report their alcohol ingestion [155]. Furthermore, an estimated 6% to 49% of older persons in hospitals or other healthcare facilities evidence either illness or other serious consequences of alcohol abuse [156]. It is these patients who can present a unique challenge when they decompensate during sedation due to combined effects of the residual alcohol in their blood stream and the sedating medication [155,156].

PHARMACOLOGIC CONSIDERATIONS

Decreases in both hepatic and renal function, which naturally occur with aging, lead to a longer half-life and longer clearance of most medications. This translates to a longer length of action; therefore, recovery from moderate sedation is longer in the elderly than it is in other adult populations [59,154]. Additionally, the elderly patient is at risk for cumulative drug effects, causing altered function of the sedating drugs. This is commonly seen when this patient population is given benzodiazepines and opiates concurrently.

Drug binding is also altered in the elderly patient. Protein-bound drugs attain an increased concentration of circulating drug secondary to the decrease in albumin that occurs with aging [154]. With more circulating drug available, the more profound the drug effects will be. Hence, any sedating drug that is protein bound will produce more profound sedation, increasing the risk of oversedation. The amount of body protein in an individual can be assessed by evaluating the patient's serum albumin level. The lower the albumin level, the lower the amount of body protein. Any patient with a decreased serum albumin would be expected to have the aforementioned risk of profound sedation.

Water-soluble drugs will have a greater amount of drug available at the target site, as the amount of total body water decreases with age [154,156]. As with protein-bound drugs, the risk of increased drug effects occurs. Coupled with the chronic volume-depleted state, the risk of oversedation occurring with water-soluble drugs is greatly increased.

Conversely, fat-soluble drugs have less drug available at the target site secondary to the increase in body fat that accumulates during aging. These drugs are sequestered in the fat and will have a slower release and, therefore, a longer length of action. Any fat-soluble drug given to an elderly individual can be expected to produce a slower, lengthier recovery period [154].

Adverse drug reactions and interactions are more common in this population due to the fact that the number of over-the-counter and prescription drugs and herbal supplements ingested is much higher [156]. Elderly patients should be monitored for adverse drug reactions, and these should be reported to the appropriate agencies. Cardiovascular medications can cause significant compounded cardiovascular instability in the elderly by producing significant bradycardia and hypotension.

Recommended drug dosing in the elderly patient should be done with the following statement in mind: Start Low and Go Slow. Adherence to this advice will greatly reduce the risk of complication development. Dosing of benzodiazepines is generally reduced by 30% to 50% from the normal adult dosage [59]. Barbiturates should be administered slowly due to decreased cardiac output and circulation times. If given too rapidly, profound hypotension and a decreased level of consciousness will occur. Sedative hypnotic doses should also be decreased, and the risk of paradoxical excitement/delirium is more common with these medications [59].

Titrating drug dosages in the elderly should be considered standard practice [59,154]. The risk of complications is high in this population, and the practitioner should undertake measures to reduce these risks.

NURSING CARE

The practitioner providing sedation to the elderly patient should adjust care during the presedation, intrasedation, and postsedation phases. Initially, thorough preprocedural assessment is imperative, including a full evaluation of the patient's airway. Recognition of comorbidities is essential to decrease the risk of complications.

Evidence Based Practice Recommendation

The American Society for Gastrointestinal Endoscopy Practice Committee recommends standard monitoring procedures in the elderly during moderate sedation with heightened awareness of this population's increased response to sedatives.

https://www.asge.org/docs/default-source/education/practice_guidelines/doc-modifications-in-endoscopic-practice-for-the-elderly.pdf?sfvrsn=60c94951_6

Last Accessed: July 14, 2020

Level of Evidence: +++O (Moderate quality)

Presedation vital signs and oxygen saturations should be attained, noting that anxiety and fear may cause these to be inaccurate. Once these parameters are attained, oxygen should be administered, with consideration of the patient with a history of pulmonary disease, which may preclude the use of high oxygen percentages. Cardiac monitoring should be instituted prior to sedation and continued throughout the sedation and recovery periods. Volume replacement may be necessary; however, it is just as important to prevent volume overload in the patient with a positive cardiac history. It is also important to remember that the elderly patient is at risk for developing hypothermia, and the patient should be kept warm during long procedures, especially those interventions with large body surface exposure.

Discharge criteria for the elderly patient may require an adjustment in the ability to meet presedation values. The normally hypertensive patient may remain slightly hypotensive secondary to prolonged cardiovascular effects of the drugs administered. This hypotension may last as long as 24 hours and should not prevent the patient from being discharged.

It is important in managing sedation in the elderly to remember these criteria to deliver safe care. With the increasing incidence of moderate sedation procedures being performed in this population, the practitioner will continue to see these patients on a regular basis.

10. MODERATE SEDATION OF THE OBSTETRIC PATIENT

Moderate sedation in the obstetric setting can be done for a variety of reasons. It is imperative that the pregnant woman be monitored for the effects of sedation on her fetus as well as herself. Many of the changes that occur with pregnancy occur over time; others can occur as soon as the woman conceives. In moderate sedation, these anatomic and physiologic responses should be addressed.

ANATOMIC AND PHYSIOLOGIC DIFFERENCES

Airway changes in the pregnant woman include engorgement of the nasal and mucous membranes leading to a narrowing of the airway. Tidal volume increases by 30% to 35%. The respiratory rate remains relatively constant or increases slightly. In order to meet her and her fetus's oxygen demands, there is a compensatory and significant increase in minute ventilation. However, the patient's vital capacity decreases as the diaphragm becomes elevated [157].

Hemodynamic changes occur during pregnancy as well. There is an increase in heart rate, which reaches a maximal value of 10% to 30% above baseline values by 32 weeks. Cardiac output increases 30% to 50% above baseline levels by 25 weeks and may be affected by position [157]. Systolic blood pressure may drop, and the patient is at risk for developing supine hypotension [157]. It is imperative that the practitioner be aware of these changes as assessment parameters are altered and the recognition of hemodynamic instability is more challenging [158].

In addition, during pregnancy there is an increase in circulating volume. The majority of this increase is in plasma volume. This blood volume increases progressively, peaking at a value of approximately 40% above baseline by the third trimester [157].

PHARMACOLOGIC CONSIDERATIONS

Sedation medications are like any other drug given during pregnancy, and considerations should be made as to the effects of the drug on both the mother and the fetus. The greatest risks occur during the first trimester, when fetal development is most adversely affected. Additional risks occur at the time of delivery, as certain medications can cross the placental barrier, leading to a sedated newborn [59].

Drug dosing in the pregnant patient is the same as for a nonpregnant female. However, the increased circulating volume will affect how water-soluble drugs are distributed and absorbed [158]. These drugs become less concentrated; therefore, onset of action is somewhat slower, although not significantly. The dosage of the drug may need to be increased, although it is safer to start at the normal recommended dosage for a nonpregnant female and increase dosage as needed.

NURSING CARE

The risk of airway compromise is increased in the pregnant patient and astute airway assessment is critical. Statistics show that 1 in 300 pregnant women will have an airway that is difficult to manage [159]. When checking for emergency support supplies, ensure that a smaller-than-anticipated endotracheal tube is available. A pregnant woman with engorged tissues may require an endotracheal tube as small as a 6.0; many of these tubes may not be cuffed, as they are usually used in the pediatric population. Therefore, it is necessary to check that the appropriate equipment is available.

Supplemental oxygen should be readily available and used early. The developing hypoxia affects not only the mother but the fetus as well [158]. Additionally, it is known that hypoxia can precipitate contractions, which should be avoided if at all possible.

Dehydration can also precipitate contractions. Therefore, ensuring adequate volume replacement for the patient who has been kept NPO is imperative. If sedation is performed emergently, assessment of the patient's food and fluid intake should be done with consideration of the fact that gastric emptying time is prolonged during pregnancy. The use of histamine blockers is recommended in this population to reduce the risk of gastric reflux and aspiration [57,158].

Positioning the patient in the left lateral decubitus position will help ensure adequate blood return to the heart. If the patient must be in the flat-lying, recumbent position for the intervention, placing a towel or blanket under the right hip to rotate the hips to the left will help achieve the same objective [59].

Fetal monitoring should be considered in all high-risk patients [158]. Instituting fetal monitoring should be performed by someone skilled in monitor use and the detection of subtle changes. Unless the nurse commonly works in the obstetric setting, an additional individual to monitor the mother and the fetus would be most helpful. When monitoring the fetus, observation of changes in heart rate and rhythm are the most sensitive indicators of fetal well-being. Decelerations in fetal heart rate that are spontaneous or in response to uterine contractions are considered signs of fetal distress [158]. In most instances, administration of oxygen and repositioning the mother may correct this untoward complication.

Although utilized infrequently in the obstetric patient, moderate sedation can be a very beneficial therapy. The mother who is comfortable and anxiety-free can provide the fetus with a safe, supportive environment. It is the nurse's responsibility to ensure that the mother is also in a safe and supportive environment throughout the intervention.

11. SEDATION OF THE CRITICALLY ILL PATIENT

Sedation in the critically ill patient has changed dramatically over time. For many years, the patient in the ICU was deeply sedated and immobile. After years of research, it was concluded that this deep sedation was not beneficial for the patient; in fact, it produced a number of complications. The deeply sedated patient was unable to move or shift positions, leading to an increased risk of pressure sore development. Patients who were mechanically ventilated in the control mode were difficult to wean from the ventilator when the appropriate time came. In addition, family members were unable to interact with their loved ones, leading to significant emotional impact upon these individuals.

Today, the patient in the ICU is lightly sedated, and sedation is used as an adjunct to achieve therapeutic results. Patients are sedated in order to minimize patient discomfort, alleviate anxiety and agitation, attenuate the stress response, facilitate mechanical ventilation, and decrease physiologic demands. Sedation is generally for longer time frames and may be delivered by continuous infusion.

A number of interventions in the ICU are painful and/or produce discomfort. Placement of invasive monitoring lines, endotracheal tube intubation, and Foley catheter placement all increase patient discomfort. Sedatives with analgesic properties, such as narcotics, can help alleviate this pain of intrusion.

Patient's senses in the ICU are assaulted by a number of stimuli, including lights, sounds, and activities. These assaults can greatly increase the patient's level of anxiety and agitation, often leading to an increase in heart rate and blood pressure. Mild sedation can attenuate this response, decreasing the stressors upon the individual's metabolic demands. Patient comfort should be a primary concern [160].

Many modes of ventilatory support are uncomfortable to the patient and may cause the patient to fight the respirator. As an example, permissive hypercapnia is accomplished over the course of a few days, allowing the patient's CO_2 level to rise to higher than normal levels. The normal compensatory response in the healthy individual would be to increase the respiratory rate to express this excess CO_2. The patient is sedated to avoid this compensatory response.

It is well known that the stress response that occurs in an ICU patient greatly increases the patient's physiologic demands. These increased demands have a number of negative outcomes; as an example, wound healing is compromised. In an effort to reduce this stress response, the patient may be sedated to improve physiologic functioning and a return to a normal state of health.

Continuous infusion of medications is a highly popular method of ICU sedation [160]. Some patients may still be sedated on an every four-to-six-hour basis, which, if medication administration is delayed, will produce peak and trough levels of drugs. As patient and family demands are being encouraged and valued, preventing these highs and lows in sedation responses is becoming more important, making drug bolusing a less popular method of drug dosing. However, the practitioner should be aware that prolonged continual infusion of certain drugs can extend the half-life and length of action of these medications. For example, the half-life of morphine sulfate in the non-ICU patient ranges from 1.5 to 4 hours [59]. In the patient on a continuous morphine infusion in the ICU, the half-life can extend to 5.9 to 13 hours [6]. This longer length of action can delay recovery from sedation, prolonging ICU stays. Trying to meet the patient's needs without oversedation is a continual challenge in providing sedation to this population [160].

Concomitantly, sedation in the ICU may be accompanied by the use of neuromuscular blockade [161]. The level of paralysis may vary depending upon patient need and condition. However, the use of blockade may prevent full evaluation of the patient's level of response. Additionally, neuromuscular blockade will prevent using certain sedation scales as patient responses are compromised by the paralysis [161].

It has been recommended that, in addition to the necessity for evaluation in the postsedation period, ICU patients be monitored for sedation status while receiving medications [160]. One study evaluated the use of the RASS to evaluate changes in sedation and analgesia over consecutive days in the ICU. The researchers determined that the RASS was an effective tool and assisted in guiding goal-oriented sedation [160]. Other scales that have been tested for validity in ICU patients include the Ramsay Sedation Score, Sedation-Agitation Scale (SAS) Glasgow Coma Scale, Motor Activity Assessment Scale, Auditory Evoked Potentials, and the Nursing Instrument for the Communication of Sedation [162,163,164]. The use of sedation scales and protocols designed to minimize sedative use are associated with improved ICU patient outcomes, including shortened duration of mechanical ventilation, shortened ICU stay and length of hospital stay, and decreased incidences of delirium and long-term cognitive dysfunction [164].

Many institutions using sedation in the critically ill develop guidelines specifically for this patient population. The goals and objectives of ICU sedation do vary from those previously discussed. If sedation in the ICU is considered "moderate sedation," the policy and procedure for sedation should reflect this change in patient outcomes.

12. PATIENTS UNDERGOING PROCEDURAL INTERVENTIONS

Many patients receive moderate sedation when undergoing procedures in a number of settings, including, but not limited to, cardiac catheterization laboratories, endoscopy settings, gastroenterology settings, radiology settings, and other ambulatory departments. If these patients are young or elderly, the parameters previously discussed should be considered. However, in certain situations with certain procedures, there are other issues that should be addressed, and a brief discussion of these issues will be presented here.

RADIOLOGIC INTERVENTIONS

The patient undergoing radiologic procedures may be administered contrast media that has the potential to alter pulse oximeter readings [98,100]. The dye prevents the passage of the light through the tissues, thus giving inaccurate readings. These effects may last for only a brief period; however, in other situations they may last minutes to hours. Variables include the volume of dye administered, the size of the vessel in which the dye was injected, the patient's cardiac output and circulation time, and the renal function of the patient [98]. The longer the dye is on board, the longer this effect upon pulse oximetry monitoring will be experienced. The disadvantage is that the practitioner is not always able to ascertain when the dye is cleared from the body. Thus, the nurse caring for this patient should use other physical assessment tools to evaluate the oxygenation status of the patient [98].

Additionally, contrast dyes may have high sodium levels that produce a transient hypertensive period, usually followed in 15 to 20 minutes by a diuretic phase. Furthermore, during this time the patient has an increase in cardiac filling pressures. For the patient with a compromised cardiovascular system, these changes in vital signs and cardiovascular volume may not be well tolerated. It is imperative that the practitioner continually monitor these patients and intervene, should the effects be detrimental and/or lengthy in the patient.

Another complication occurring in this setting is the development of allergic or adverse reactions. Although these reactions are characterized by activation of mediators typical of allergic response, they are not antigen mediated and, therefore, are not true allergies [165]. The nurse should monitor the patient for the initial signs of developing anaphylactoid response: flushing, chills, nausea and/or vomiting, and urticaria. Epinephrine and diphenhydramine should be readily available in the setting for management of this complication [165].

For patients undergoing MRI, there are a number of important considerations. The equipment that is used should be determined to be magnetic resonance-compatible. All cables and coils should be checked to insure that there are no loops of cable or wire that can burn the patient or distort the image. Imaging is done inside a large magnet, and access to the patient is minimal. Coupled with this limited access, visibility is compromised; the room lighting is altered, and the observation window is covered with a copper mesh screen. Noise levels can reach 95 decibels and may affect the ability to hear equipment alarms. It is critical that these patients receive diligent monitoring throughout the procedure.

Medications used in children undergoing magnetic imaging require astute patient assessment, which, as noted, is challenging while the patient is in the scanner. Additionally, combination chloral hydrate and pentobarbital can produce profound sedation in the child with the risk of airway compromise and deep sedation. Nurses administering these drugs should be well versed in their actions and uses and provide vigilant monitoring during performance of the study.

Finally, many patients are anxious while undergoing studies in the radiology suite. The procedures may cause pain and discomfort, some of which can be treated with analgesics. Patients who are claustrophobic become highly anxious when an MRI is performed. Continual reassurance and support, in unison with adequate sedation, will help reduce these factors.

CARDIAC CATHETERIZATIONS AND ELECTROPHYSIOLOGIC STUDIES

Patients undergoing cardiac interventional procedures are generally cardiovascularly compromised prior to the start of the procedure. Many of these interventions are done on an elective basis to allow time for optimizing cardiovascular function. However, the patient may require emergent intervention without adequate time for stabilization. Therefore, it is imperative that presedation assessment be thorough to recognize patient risks. Patients with a history of hemodynamic instability may be at risk for significant hypotension immediately after administration of sedation agents, especially narcotics. For this reason, the sedating drug administered should be chosen with consideration of this risk.

Many cardiac studies are quite lengthy and sedation of the patient can last up to six hours or more. Obviously, with this length of procedure, nursing care and documentation is more in-depth. Providing sedation throughout the procedure can be challenging. Administering sedation with continuous infusions can ensure a therapeutic blood level that is difficult to maintain with the bolus technique of administration.

A number of sedating medications affect the cardiac conduction system, and this should be a consideration for any patient undergoing an electrophysiologic study. Also, most antidysrhythmics are discontinued prior to the start of this type of procedure to allow for drug effect evaluation. Therefore, cardiac monitoring of rate and rhythm is imperative to providing safe patient care.

ENDOSCOPIC PROCEDURES

The advantage of the majority of endoscopic procedures is their short procedural time. The use of short-acting sedatives is efficient in this population; thus, repeat drug dosing may not be required. This translates to short recovery times with early discharge [147].

During these procedures, patients may be asked to cooperate with position changes, etc. It is important that the patient's level of consciousness be appropriate to allow the patient to cooperate with these requests. As an example, during endoscopic retrograde cholangiopancreatography (ERCP) the patient is commonly placed in the prone position, which presents additional challenges in the ability to monitor the patient's airway [94,166]. Oversedation of this population is not recommended, as patient compliance and the patient's protective mechanisms are compromised [166].

Manipulation of the endoscope while in the lower esophagus may lead to cardiac dysrhythmia development. Continual cardiac rhythm monitoring should be required for all these patients. If dysrhythmias do develop, repositioning of the scope may avert their progression.

13. CASE STUDIES

The radiology department occasionally performs moderate sedation on patients who exhibit a high level of anxiety prior to a procedure. On today's schedule, there are two patients requiring MRIs. Both patients will require moderate sedation to allow the radiologist and technician to obtain an accurate study.

A nurse from the emergency department is scheduled to administer the moderate sedation agents as no registered nurse is routinely staffed in radiology. Upon arrival, the nurse begins to prepare the radiology suite for the procedure and review the patients' histories and physicals.

PATIENT J

Patient J is a young girl, 2 years of age, with a history of hydrocephalus since birth. She has been brought to the hospital with complaints of continuous vomiting, lethargy, and inappropriate behavior for her age. The pediatric neurologist orders the MRI to evaluate the current status of her cerebral spinal fluid circulation.

The neurologist orders the procedure to be performed under moderate sedation, as Patient J is not cooperative and is easily agitated. The nurse reviews her history, which is otherwise unremarkable. She is not taking any current medications at home, either prescribed or over-the-counter. She had previously been on anticonvulsant medication, which was discontinued more than a week prior to the procedure.

Upon arrival of Patient J in the radiology suite, the nurse performs a presedation assessment. Her cardiac and respiratory systems are within normal limits for her age. However, neurologic assessment of Patient J is challenging due to her decreased mental status. The nurse notes that Patient J responds to her mother, who accompanies her to the department. Although Patient J has had previous MRIs, the nurse discusses the procedure with the mother and patient. She explains what will be happening and that she will be asked to lie still for a number of minutes. Additionally, the nurse explains the use of moderate sedation to the mother and patient, ensuring the mother that Patient J will be comfortable and everything will be done to try and reduce her fear of separation from her mother. When the mother asks to stay in the room with Patient J, the nurse explains that this is neither safe nor allowed.

Additional review of Patient J's chart shows that she was admitted yesterday afternoon and received antiemetics upon admission. Upon admission, her blood pressure was low for her age. Her admission vital signs were: blood pressure, 84/68 mm Hg; pulse, 104 bpm; respiratory rate, 30 breaths/minute; and temperature, 99.7°F. Currently, her blood pressure is 92/64 mm Hg; pulse, 100; and respiratory rate, 30 breaths/minute. She has an IV line infusing 5% dextrose in 0.25% normal saline at a rate of 45 cc/hr. Her admission weight was 25 pounds (approximately 11 kgs). Upon questioning, her mother states that she has lost some weight; her normal weight is about 28 pounds. She has not taken anything by mouth since admission.

After obtaining the presedation assessment, the nurse must prepare the room, equipment, and medications for Patient J. The nurse ensures that a crash cart is located in the radiology department and checks the defibrillator for proper functioning. The oxygen set-up in the scanner is checked, as is the suction. The pulse oximeter and noninvasive blood pressure monitor are warmed up to assure that they will be ready when the sedation is to begin. Furthermore, all equipment should be determined to be MR-compatible to prevent burns during the procedure.

The medication ordered for Patient J includes midazolam 0.02 mg/kg IV or a dose of 0.5 mg/kg orally. (As Patient J has a history of vomiting, the nurse chooses to administer the midazolam via the intravenous route to ensure proper drug dosing and reduce the risk of vomiting.) Also ordered is fentanyl 0.5 mcg/kg, to be given in the event that the midazolam is inadequate in achieving the appropriate level of sedation. The nurse first calculates the correct dose based upon Patient J's weight of 11 kgs. Thus, the dose of midazolam is 0.2 mg, and the dose of fentanyl is 5 mcg. These medications are drawn into syringes and labeled. Additionally, the nurse draws 0.5 mg of naloxone (based on a dose of 0.05 mg/kg); this syringe is also labeled and placed off to the side, where it is easily accessible in the event of oversedation or other complications.

Finally, Patient J is brought into the room with the scanner and hooked up to the oxygen, pulse oximeter, and noninvasive blood pressure monitor. A presedation set of vital signs are obtained, including oxygen saturation measurements before and after oxygen therapy is initiated. The patient's IV is checked for patency and another set of vital signs is obtained. At this point, the mother is asked to leave the room, and Patient J becomes quite agitated. The radiologist orders the nurse to begin administering the sedation medications immediately in order to relax Patient J and prevent any further agitation.

The nurse administers the 0.2 mg of midazolam and monitors Patient J's response to the medication. After one minute, her blood pressure is noted to fall to a systolic pressure of 84 mm Hg. Neurologically, she is less agitated and appears to be relaxing. When asked her name she answers appropriately, but also asks again for her mother. The blood pressure decline is of concern; in response to this, the nurse increases the IV rate to 50 cc/hr. Within five minutes, her blood pressure is back up to its presedation level.

The radiologist is ready to start the scan; however, Patient J continues to move on the scanner table. The radiologist requests the nurse to administer additional medication, and the nurse administers an additional 0.2 mg of midazolam. Within two minutes, Patient J is quiet and calm and the procedure is initiated.

During the procedure, the nurse must leave the room and monitor the patient from the outside viewing area. Patient J's vital signs are continually monitored via the blood pressure monitor cycles. The nurse also observes the pulse oximeter reading as part of the patient assessment. After 10 minutes, the nurse notes that Patient J's pulse oximeter reading has fallen to a level of 91%. The radiologist is informed, and the scan is momentarily terminated to allow the nurse to enter the room and evaluate the patient. The patient's respiratory rate is now 15 breaths/minute, and the pulse oximeter reading has fallen further to 90%. The nurse immediately places Patient J's head into the sniffing position to open her airway and increase the oxygen flow rate. The patient's pulse oximeter reading increases to only 91% with this maneuver, and the nurse decides to administer a reversal agent to prevent the respiratory insufficiency from progressing further.

It is at this point that the nurse realizes that naloxone has been drawn as an antagonist. As the patient has only thus far received midazolam, the naloxone will be ineffective at reversing a benzodiazepine, as it is a narcotic antagonist. Immediately, the nurse draws up a dose of 0.1 mg of flumazenil and administers this through the IV line. Within two minutes, Patient J is breathing at a rate of 25 breaths/minute, her pulse oximeter reading has increased to 94% saturation, and her other vital signs remain within normal limits. However, she is starting to move on the table and the scan cannot be completed until she is sedated adequately to prevent body movement.

Patient J is allowed to stabilize for another five minutes, at which time the radiologist requests further sedation so the scan can be completed. The remaining time to perform the scan is approximately 10 to 12 minutes. The nurse now chooses to administer 2.5 mcg of fentanyl to Patient J and to monitor the drug effects. Although a dose of 5 mcg was ordered, the nurse is concerned that the patient will develop a second episode of respiratory insufficiency. After three minutes, Patient J remains agitated and a second dose of 2.5 mcg of fentanyl is administered.

Throughout administration of the fentanyl, Patient J's vital signs and oxygen saturations remain within normal limits. After the second dose of fentanyl (for a total of 5 mcg), the procedure can continue and is able to be completed without further complication.

Upon completion, Patient J's mother is allowed to return to her daughter's bedside and the effects of the medication are allowed to wear off. No further reversal agents are administered. Based upon the length of action of the midazolam and fentanyl, it is expected that Patient J will remain sedated for another 20 to 30 minutes. During this recovery period, the nurse continues to assess the patient's vital signs and oxygen saturations, and all parameters remain within normal limits.

Due to the fact that Patient J is an inpatient, the recovery and discharge is different than for a patient who is being discharged to home. After 30 minutes, Patient J remains sleepy but opens her eyes and recognizes her mother. When asked her name she answers appropriately. At this point, the nurse finishes documenting the procedure and Patient J is returned to her bed on the pediatric unit.

Discussion

The nurse caring for Patient J performed quite well. The presedation assessment was very thorough; it was important to consider the fact that continuous vomiting can lead to protracted volume status in children, and this could impact her response to medications. The nurse recognized that the intravenous route of medication administration is far more appropriate in this patient than the oral route. Her history of a decreased level of consciousness could hinder oral administration. Additionally, with the patient's history of vomiting, oral drug administration could precipitate a further bout of vomiting.

Preparing the medications was critical to the success of this procedure. The biggest error was in not drawing up a dose of flumazenil. The nurse chose to prepare the naloxone, without considering that the fentanyl may not have been utilized at all. It would have been to everyone's benefit had both the naloxone and flumazenil been prepared initially. However, the outcome was good; this delay did not harm the patient in any manner.

When the radiologist asked to continue the procedure, the nurse administered a dose of fentanyl that was one-half of the ordered dose, most likely based on the fact that Patient J had experienced the previous episode of respiratory insufficiency. This choice was not inappropriate, but in review of the case, it was probably inadequate due to the length of time since the initial administration of the midazolam. Had the nurse recognized that the duration of the midazolam was reached, administering the full 5 mcg of fentanyl most likely would have been safe. However, in this instance, the nurse chose to act cautiously, and no one should find fault with this action.

Finally, the recovery of this patient was uneventful. The patient reached her presedation level of functioning. As she had an altered level of functioning to begin with, this was an appropriate way to evaluate her neurologic status. However, had the nurse not performed a good presedation assessment, recognition of the patient's return to her presedation level of functioning would have been challenging.

PATIENT D

The next patient scheduled for the MRI scanner is Patient D, a man 76 years of age, who fell at home yesterday and has a history of falling. There is point tenderness at the hip joint, and the patient is unable to ambulate. The orthopedic surgeon requests an MRI of the hip and pelvic area to determine what, if any, injury could be causing this pain and dysfunction.

Patient D states that he is very claustrophobic and initially refused the MRI because of the fear of the "tube." After discussion with the surgeon, with a guarantee that he would be sedated and comfortable, Patient D agreed to the scan.

Upon review of the patient's history, it is determined that he has a history of congestive heart failure, smokes two packs of cigarettes a day, and denies alcohol ingestion. The nurse performs a presedation assessment, obtaining baseline vital signs and auscultates the patient's heart and lungs. The patient is asked to open his mouth wide, and a Mallampati score of 2 is assigned to the patient. The patient is questioned about any dentures or partials, which he denies. An anesthesia history is obtained; the patient has had two previous surgeries under general anesthesia. He denies any complications with either procedure.

Due to the patient's history of congestive heart failure, the nurse reviews the chart for a current 12-lead electrocardiogram and finds that one was obtained yesterday on admission. Additionally, Patient D's admission laboratory values are reviewed. The only abnormality is a potassium level of 3.3 mEq. The nurse determines that the patient is a Class 3 on the ASA Risk Classification score. The nurse also reviews the patient's current medication use, which includes digoxin, furosemide, and naproxen for arthritic pain control.

Although the surgeon reviewed the moderate sedation procedure with the patient, the nurse conducts patient education as well. The nurse explains that the patient will be receiving medications to help him relax and decrease his fears about the scanner. Patient D responds, "Just knock me out. I don't want to remember or feel a thing!" The nurse then proceeds to offer further information; it is imperative that the patient recognize that he will not be asleep. The patient may be asked to respond to questions throughout the procedure to adequately assess the level of sedation. Additionally, the nurse explains that the medications can help alleviate some of the patient's pain, but there is discomfort that is experienced from lying on a hard table. The patient is assured that everything will be done to make the patient as comfortable as possible, but the procedure is not discomfort-free.

At this point, Patient D reconsiders his decision to have the procedure performed. When he agreed to the procedure it was his understanding that he would be asleep, similar to what occurs with general anesthesia. It is unfortunate that the surgeon allowed the patient to develop this misunderstanding; it not only delayed the start of the procedure but backfired in that the patient's level of anxiety was heightened. It took the nurse more than 20 minutes to educate the patient and receive his permission to continue with the scan.

In preparing the room for Patient D, the nurse has only recently finished sedating the first patient and knows the equipment was functional. She places the patient on the monitor, pulse oximeter, and oxygen by face mask. Presedation vital signs are obtained and compared to the vital signs obtained on the inpatient unit. An oxygen saturation of 91% is obtained prior to initiating oxygen therapy, as is expected. With oxygen, the saturation increases to only 93%. The existing IV line is checked for patency.

The medications ordered for Patient D include midazolam 2 mg IV, fentanyl 50 mcg IV, and methohexital 10 mg IV, as needed. The nurse draws the appropriate dosages into syringes and labels each. Learning from the first patient, the nurse draws both flumazenil (0.2 mg) and naloxone (1 mg) and labels these syringes as well.

The radiologist orders the sedation to be initiated, and the nurse administers 2 mg midazolam IV over one minute. The patient demonstrates a slight drop in blood pressure; however, it is within acceptable limits. The patient remains quite agitated, asking when the medication is going to work. At this point, the nurse administers 25 mcg fentanyl IV. Patient D's blood pressure starts to fall after the dose of fentanyl, and the IV rate is increased. The patient continues to complain of discomfort and fear. His heart rate increases to a rate of 90 bpm (from a normal of 62 bpm). The radiologist requests additional sedation medication in an attempt to achieve an appropriate level of sedation in this patient.

The nurse then administers an additional 2 mg IV of midazolam. Patient D appears to relax, and he is moved into the "tube." Immediately upon entering the tube, the patient becomes severely agitated, asking to get out, and calling out, "Somebody help me." It is obvious that the patient's level of sedation is inadequate at this point, and the patient is removed from the scanner. The nurse enters the room and notes that the patient is very confused; he is unable to answer appropriately to his name, he is calling for his wife (who had died three years before), and his blood pressure, pulse, and respiratory rate are all quite high.

The radiologist orders an additional 3 mg IV of midazolam, which the nurse administers. At this point, Patient D appears more relaxed; however, when the nurse approaches the patient to listen to his heart and lungs, the patient starts thrashing about on the table. Obviously, Patient D is at risk of further injury, especially at the injured hip joint. The radiologist orders an additional 3 mg IV midazolam. However, the nurse refuses to administer this dose based upon concern of oversedation, common to the elderly individual. The nurse expresses this concern, and the order is changed to fentanyl 50 mcg IV. The nurse agrees to administer the fentanyl, and upon administration, the patient experiences a short burst of ventricular tachycardia that spontaneously converts to the patient's normal rhythm.

At this point, the radiologist decides to cancel the procedure until such time that the patient can be appropriately sedated. It is obvious that the radiologist blames the nurse for the patient's deterioration.

Despite the apparent animosity, the nurse's responsibility is to stay with Patient D and provide for his safety. The patient's oxygen flow rate is increased, after which the patient becomes quite agitated and removes the oxygen mask. While the nurse is preparing an amiodarone bolus to prevent further episodes of ventricular tachycardia, the patient becomes agitated to the point of requiring restraints. The nurse looks for assistance from other staff members but has been left alone with Patient D.

At this point, the nurse remembers the naloxone and administers 1 mg IV, hoping to see a reduction in the patient's level of agitation. However, this is not accomplished. Subsequently, flumazenil (0.2 mg IV) is administered, and the patient begins to appear more relaxed, with improving vital signs.

After three minutes, the nurse administers a second dose of flumazenil, and Patient D is able to answer questions appropriately. Throughout this time period, the nurse continues to assess Patient D's vital signs, which are slowly returning to normal.

Once the patient reaches his presedation level of functioning, the nurse transfers the patient back to the inpatient unit. Upon moving the patient into his bed, he asks, "What did they find?" Patient D is unaware that the procedure had not been completed.

Discussion

A number of mistakes were made in preparing and sedating Patient D. However, the nurse did perform a good presedation assessment. All the appropriate information was obtained from the patient, and the patient was assessed fully. One omission was putting the information to use. Elderly patients with a history of cardiac disease, especially congestive heart failure, are at increased risk of poor circulation and low cardiac outputs. These patients need special care when administering sedating agents. Additionally, the patient was on digoxin with a low potassium level, increasing the risk of dysrhythmia development. Had the nurse considered the risks involved in this patient, the incidence of ventricular tachycardia may have been avoided by further stabilization measures prior to the start of the sedation.

It was an error on the surgeon's part to assure Patient D that he would be comfortable throughout the procedure. With this false assurance, the patient was at risk for agitation when his expectations were not met. As soon as Patient D entered the scanner, this anxiety level was enhanced. Thus, the medication effects were inadequate to meet the patient's needs.

In preparing the room for this second patient, the nurse assumed that the equipment was functioning properly because it had done so during the last case. This assumption can be deadly; the equipment should always be re-tested prior to the start of a subsequent procedure. In this case, there were no apparent equipment failures, but had this occurred, the outcome could have been disastrous.

The medications ordered for Patient D were probably not the best for an elderly patient with a history of congestive heart failure. Midazolam is known to precipitate an episode of paradoxical excitement in the elderly, which became quite apparent throughout this case study. Of all the narcotics, fentanyl has the least effect upon the cardiovascular system; however, patients with a history of cardiac disease are at risk of hemodynamic instability with any of the sedating drugs. Methohexital, a barbiturate, can precipitate a profound drop in the patient's blood pressure, and although the dosage ordered was quite low, this may have been a risk for Patient D had he received this medication.

Throughout the procedure, the sedating drug of choice was midazolam. The initial dose was tolerated by the patient; however, subsequent doses caused further patient compromise. After the second dose of midazolam, Patient D was moved into the scanner, and this is when he began to exhibit signs of paradoxical excitement and confusion. Rather than treating this with flumazenil, Patient D was administered an additional 3 mg of midazolam, which caused a further decline in his level of functioning and his vital signs.

The nurse was appropriate in refusing to administer the next 3 mg dose of midazolam. However, in its place, fentanyl was administered. Prior to administering the fentanyl, the patient should have been evaluated and the cause of his agitation further investigated.

This dose of fentanyl most likely precipitated a fall in the patient's blood pressure, leading to a decreased coronary artery blood flow and precipitating the run of ventricular tachycardia. Fortunately, the dysrhythmia was self-limiting and the patient did not experience further cardiac failure, including ventricular fibrillation or asystole.

It was at this point that the radiologist canceled the procedure and left the room. Patient D was definitely not stable at this point, and additional backup should have been called. Instead, the nurse continued to support the patient alone. Fortunately, the nurse was able to handle the developments as they arose; however, had the patient developed a second bout of ventricular tachycardia or other life-threatening complications, it would have been difficult to access additional backup support.

Eventually, the nurse remembered the antagonists that were available. The dose of naloxone was appropriate to reverse the effects of the fentanyl; however, Patient D's greatest problem was the agitation secondary to the midazolam. It may have been wiser to administer the flumazenil first, followed by the naloxone, if needed.

During this difficult period, the nurse and the radiologist's relationship deteriorated to the point of becoming ineffective. Early attempts at communication and a collegial discussion of why the patient was deteriorating may have reduced the number of complications experienced by Patient D. It is imperative that the nurse and physician in charge of the procedure communicate regarding patient condition and work together to achieve a successful outcome.

When Patient D returned to his inpatient unit, he did not remember that the MRI was not performed. This is a common occurrence after the administration of benzodiazepines. The antegrade amnesia prevents the patient from remembering details. In many cases, this is a desirable effect; in this case, it may only lead to further patient mistrust. He was told that he would not remember, but at the same time, the procedure was not accomplished.

This case study demonstrates a number of the risks involved in providing moderate sedation to the elderly. This patient population is at increased risk of complications. In addition, they exhibit varying responses to the "typical" sedating medications. Prior to initiating sedation in this population, it is wise to review the risks, consider the causes, and evaluate the potential effectiveness of interventions. Then, if the patient does develop untoward complications, the cause can be more easily identified and therapies instituted earlier.

14. PRACTICE ISSUES

There are a number of issues that remain unresolved regarding the delivery of moderate sedation by nurses. Nurses are concerned about their legal status, training, competencies, and moral obligations in providing safe and competent care. With time and experience, many of these issues will resolve themselves. Others should be evaluated and policies and procedures developed to protect nurses' rights and responsibilities.

The following discussion will focus on these practice issues. At the present time, there is no right or wrong answer in solving these questions; nurses administering moderate sedation should make it their responsibility to determine what they believe to be safe care and adhere to these standards.

ADVANCED CARDIAC LIFE SUPPORT TRAINING

Many questions frequently arise when developing a moderate sedation program. Do nurses need to be Advanced Cardiac Life Support (ACLS) certified? If indeed life-threatening complications arise, should the nurse administering sedating medications be trained in the advanced management of these risks?

Many professional organizations, hospitals, and State Boards of Nursing have examined the issue of cardiac life support training. Some states and institutions have developed policies that clearly state that nurses administering moderate sedation must maintain current ACLS certification or equivalent [167,168]. The advantages of this training are far-reaching. The patient who develops a complication, such as loss of airway or dysrhythmia development, will receive immediate corrective action performed by a trained, certified nurse. It is well documented that the faster the corrective action is undertaken, the better the chance of achieving a full and complete recovery.

Additionally, the algorithms used in ACLS offer a framework for interventional guidelines. Interventions are clearly spelled out and sequenced in a step-by-step manner to alleviate the anxiety that develops when an untoward event occurs. The nurse knows immediately which actions should be performed, and there is no doubt or question as to the course of action.

Despite the apparent benefits of ACLS training, mandatory certification is not supported by a number of organizations. The ASA states that "an individual with advanced life support skills should be immediately available (within five minutes)" [3]. The Joint Commission minimally requires that the physician responsible for prescribing and ordering moderate sedation be competent in managing the patient in the event of complications; basic cardiac life support (BCLS) is required [1]. ACLS certification of the responsible physician is strongly encouraged by the Joint Commission [1]. Neither organization supports the need for ACLS certification by all members of the moderate sedation team. The "scope of practice" for certified sedation registered nurses outlined by the American Association of Moderate Sedation Nurses (AAMSN) states that ACLS training "may" be included as an additional responsibility within the expertise of the individual certified sedation registered nurse [168].

Institutions that require certification in ACLS skills should provide this type of training. The costs of producing an ACLS course are high, training the staff is expensive, and many institutions find this type of training to be unnecessary in providing safe care during moderate sedation.

In response to those who desire ACLS training, an ACLS equivalent training program can be instituted. This course would provide similar information that could be attained in an ACLS course but without providing the certification from the American Heart Association. This ACLS equivalent course would require the individual to demonstrate competency in the following areas: advanced airway management, identification of dysrhythmias, pharmacologic therapy for life-threatening dysrhythmias, and the use of a defibrillator to defibrillate, cardiovert, and institute external pacing, if appropriate. Such a course could be tailored to the institution providing the training to ensure safe care throughout the facility.

The advantage of equivalency training is that, in order to successfully pass the course, the individual must demonstrate competency in the defined areas. ACLS training also requires a demonstration of learned behaviors; however, as those who have previously attained ACLS certification know, the quality of ACLS courses can vary greatly. Learning to intubate a mannequin is nothing like intubating an individual with a compromised airway. Therefore, this equivalency training can be even more favorable to successful outcomes if it is presented appropriately.

These issues will most likely continue to be a source of debate. Those who strongly believe that ACLS certification is beneficial are not inappropriate in striving for certification. On the other hand, equivalency training may be adequate for the vast majority of moderate sedation providers. Regardless of the type of training, the important issue that should always be considered prior to the start of any sedating procedure is the immediate availability of backup assistance.

MEDICAL-LEGAL CONSIDERATIONS

In determining the nurse's scope of practice in regards to sedation administration, a number of resources should be accessed. The State Board of Nursing should be consulted as to nurses' legal scope of practice [169]. The State Boards of Nursing in all 50 states address the administration of moderate sedation, and it is imperative that the nurse be aware of these legal limitations. Some Boards of Nursing have developed fairly stringent guidelines for sedation administration. Others have more loose definitions of nurses' responsibilities that allow the nurse and the institution to develop their own policies regarding drug delivery.

Another organization that should be consulted prior to developing a moderate sedation policy is the Joint Commission. Historically, in each subsequent yearly manual, more rules and regulations regarding the delivery of moderate sedation are delineated. The Joint Commission states that the same standards of care should be met throughout the healthcare facility [1]. In other words, moderate sedation delivery in the operating room should meet the same standards as moderate sedation delivery in the radiology suite. The need to maintain current practice is critical to maintaining accreditation.

Additionally, a number of professional organizations have developed position statements regarding nursing delivery of sedation medications. The American Nurses Association first published their position statement in September 1991, and this position statement has been endorsed by twenty-three other nurses' organizations [170]. The AAMSN was founded in 2008 to foster patient safety through education for nonanesthetist RNs and to promote adherence to ANA, AANA, and ASA standards and guidelines for RNs who practice moderate sedation [171]. A number of medical organizations have also developed position statements. The American Academy of Pediatrics (AAP) has published guidelines for pediatric sedation [5]. Many, including the Joint Commission, consider these AAP guidelines as the standard for pediatric sedation delivery.

Determining the scope of practice for sedation delivery is not an easy task. Variations in practice settings, procedural interventions, and clinical situations can all present challenges to developing one set of guidelines. However, it is critical that these guidelines be well thought out and detailed in order to protect the legal practice of the nurses delivering moderate sedation.

POLICIES AND PROCEDURES

The scope of practice should be spelled out in the facility's policies and procedures for moderate sedation. These policies and procedures should be developed by a multidisciplinary team. They should identify the methods of authority, responsibility, and accountability for safe sedation care. Areas to be addressed include nursing care, patient care, and administrative concerns. The policies and procedures should be readily available in the unit where the sedation is being administered in the event that questions concerning responsibilities of care arise.

The policy should begin with a definition of the scope of practice. The intent of sedation should be detailed, including a definition of moderate sedation. The purpose of the policy should be clearly outlined.

Sample Moderate Sedation Policy

Policy

University Medical Center provides moderate sedation to patients in multiple settings, including but not limited to: the operating room, the endoscopy laboratory, the cardiac catheterization laboratory, cardioversion, the emergency department, the diagnostic imaging department, and the obstetric department. In all of these locations, a patient with the same health status can expect a comparable level of preprocedure, intraprocedure, and postprocedure care provided by equivalently trained personnel.

Purpose

1. To provide patient safety and early detection of problems that may arise during and after the administration of moderate sedation.

2. To outline responsibilities for monitoring and caring for the patient receiving moderate sedation.

3. To provide that only professionals who have demonstrated competency in moderate sedation may administer medications, including IV, and monitor patients receiving said medications.

Definitions

1. Moderate sedation/analgesia: a drug-induced depression of consciousness during which the individual responds purposefully to verbal commands, either alone or accompanied by light tactile stimulation. No interventions are required to maintain a patent airway, and spontaneous ventilation is adequate. Cardiovascular function is usually maintained.

2. Loss of protective reflexes: the inability to handle secretions without aspiration or to maintain a patent airway independently.

3. Deep sedation: loss of protective reflexes induced by sedation medications.

Guidelines

These guidelines are designed to provide specific recommendations for the safe care of patients during the delivery of medications for sedation and analgesia by nonanesthesiologists during medical procedures.

These guidelines are NOT intended to apply to the routine administration of narcotics or sedative medications for pain or anxiety relief in an ICU, post-anesthesia care unit, or emergency department.

The policies and procedures should then continue with sections regarding patient care, including but not limited to: patient selection; patient assessment criteria; patient care preprocedure, intraprocedure, and postprocedure; patient monitoring; and criteria for discharge. Classification systems, if used, can be presented as either part of the policy or as attachments. Additionally, documentation of the procedure should be outlined, specifically addressing the minimum time between vital sign and level of sedation assessment. These minimally delineated times should be strictly adhered to; however, it is always acceptable to assess and document on a more frequent, as-needed basis.

The medication section of the policies and procedures should include a listing of the medications that are considered acceptable at the institution. As discussed previously, there is a great deal of debate regarding the use of specific medications (i.e., ketamine, propofol). Drug dosing should be clearly delineated for those medications approved for moderate sedation use. A drug table can be developed and attached to the policy. It is important to remember that this drug table will be used throughout the facility and parameters of drug dosages should be acceptable in all settings.

Some of the best sedation policies include not only the drugs and appropriate dosing, but the maximum dose allowed within a set time frame. One of the more common conflicts that develop during sedation is that the physician will ask for additional sedation medication to be administered prior to the time in which the nurse administering the drug thinks it is safe to do so. For example, a patient has received 100 mcg of fentanyl for a bronchoscopy. The nurse is assessing the patient's vital signs and level of sedation and notes a quiescent patient with a blood pressure that has dropped greater than 20 points below baseline. The nurse continues to monitor the patient for loss of protective reflexes to ensure that a deeper level of sedation is not developing. However, during the procedure, the patient moves during manipulation of the scope and the physician requests that an additional 50 mcg of fentanyl be administered. The nurse is uncomfortable with administering this additional sedative at the present time. If the policy outlines that no more than 100 mcg of fentanyl may be administered within a 10-minute time frame, the nurse can refuse to administer the sedation until that time window has passed. However, if the policy has no such time frame, the nurse should either choose to administer the drug or refuse to do so and accept the consequences for refusal. In the best of all worlds, the physician will accept this limitation on drug delivery and wait until the patient is appropriately and safely sedated. Unfortunately, what often occurs is that the physician will order the medication, the nurse will refuse to administer, and the physician will then pre-empt the nurse and take the syringe in hand and administer the additional sedation. The nurse should then continue to monitor the patient and prepare for the development of oversedation, loss of airway, or any other potential complication that can develop secondary to administration of large doses of narcotics in a short time frame. Regardless of who administered the drug, the nurse caring for the patient is responsible for continuing to provide safe care. With a detailed drug chart developed by physicians, nurses, and anesthesiologists together, these problems can be diminished.

Administrative concerns should also be presented in the policies and procedures. The standards of care should be clearly outlined, ensuring that both state and Joint Commission standards are maintained. Personnel requirements can be addressed, as well as training and competencies of the personnel administering moderate sedation.

One standard of care that is critical to safe drug delivery is that the physician be physically present in the room prior to drug administration. Many institutions neglect to spell out this requirement, and the nurse is asked to administer sedation without appropriate backup personnel. As an example, a physician telephones the endoscopy suite and orders the nurse to administer 5 mg IV midazolam, informing the nurse that he/she would like the patient sedated and ready to begin the procedure when he/she arrives in three to four minutes. The nurse may administer the drug as ordered; however, the physician may be inadvertently delayed by a telephone call, a stuck elevator, or for any number of reasons. The nurse is now caring for a sedated patient without sufficient backup. If the policy states that the medications will only be administered once the physician is present, this risk will be avoided. The Joint Commission requires that, in addition to the individual performing the sedation procedure, sufficient numbers of qualified staff be present to evaluate, monitor, administer medication, assist with the procedure, and recover the patient, if needed [125].

Finally, the policy should finish with a section concerning continuous quality improvement measures. Each department's responsibilities in record keeping and evaluation of care delivery should be clearly stated. Any adverse patient outcomes should be documented, addressed, and subsequently reviewed at a quarterly review of moderate sedation patient care.

The more comprehensive the policies and procedures, the better protected the facility and nursing staff is from legal action, should a problem arise. The policies will allow the nurses to deliver safe care before, during, and after the procedure. The policies and procedures should be updated on an annual basis to ensure compliance with changing standards of care and standards outlined by changing Nurse Practice Acts and Joint Commission requirements.

ISSUES IN INTRAVENOUS VS. TRANSMUCOSAL ADMINISTRATION OF MODERATE SEDATION

There are many issues that arise in considering the method of drug delivery, either by intravenous or transmucosal administration. It would seem to be a straightforward issue; however, on a daily basis there are a number of questions that arise. The Joint Commission moderate sedation standards state that the care standards apply "in any setting, for any purpose, and by any route" [1]. This may help to resolve some of the previous dilemmas. However, a well-developed policy and procedure manual can help resolve other specific issues, a few of which will be discussed here.

If a patient receives medications by the transmucosal route, does that patient require a patent IV line or heparin lock? Or, should the patient be cared for by someone with IV skills? Flumazenil, the benzodiazepine antagonist, should be administered intravenously. If a patient receives transmucosal midazolam, as an example, and requires an antagonist and no line has been placed, the administration of this drug is delayed while IV access is secured. Therefore, any patient receiving moderate sedation should have a patent IV line, regardless of the method of original administration.

Is the length of observation time shorter (or longer) for patients receiving transmucosal medications? Many individuals inappropriately believe that if a patient receives transmucosal medications, their recovery time is shorter. In fact, the length of action of the drug may be longer due to slower absorption.

Can individuals who receive transmucosal medications go home earlier than patients receiving intravenous medications? Can they drive themselves home and go home alone? Do they need the same type of discharge instructions as does the patient receiving intravenous medications? The answers to these questions are well accepted if the patient receives intravenous medications. There are well-developed standards of practice for intravenous drug delivery. The nurse administering sedation by the transmucosal route should answer these questions prior to drug delivery.

One of the most important things to remember is: What are the goals and objectives of moderate sedation? If the goals and objectives are the same whether the patient is receiving the sedation by the intravenous or the transmucosal route, is there a difference in care? It is definitely a point to ponder and one that should be answered by the individual and the institution and delineated in the policy and procedure for moderate sedation.

COMPETENCY ISSUES

Competency verification is a critical part in the delivery of safe patient care. A mechanism for the evaluation of the nurse's skills and knowledge should be an integral part of the moderate sedation program. Areas for moderate sedation competency evaluation include [6,168]:

- Scope of practice

- Presedation assessment

- Pharmacology of moderate sedation medications

- Intraprocedural and postsedation care

- Monitoring skills

- Complication recognition

- Complication management

- Documentation

- Discharge criteria

- Patient education

- Emergency resuscitation techniques

- Special considerations for specific populations

This is by no means considered to be a comprehensive listing; additional items can be added to it as facility policy dictates.

Ensuring competency should be done on a regular basis. Knowledge performance measures usually require that the individual meets the criteria 90% of the time, at a minimum. All nurses should strive to meet these criteria 100% of the time; however, there are times when perfection is a goal and not an achievable endpoint.

Achieving competency varies with the frequency of moderate sedation administration. Some larger institutions have a moderate sedation team whose sole responsibility is to provide sedation in various settings throughout the institution. The individuals who work on this team are able to perform a number of sedation procedures on a regular basis. Their level of competency is commonly high. However, just because an individual performs sedation frequently does not guarantee competency. On the other hand, the staff of the emergency department may be trained in moderate sedation but only perform the procedure on an as-needed basis, with the possibility of long time periods between procedures. Regardless of the frequency of sedation administration, the same standards should be met by all individuals performing sedation.

Annual or biannual evaluations should be undertaken for all individuals administering sedation, including nurses and physicians. Commonly, physicians are verified by the Department of Anesthesiology. The same stringent guidelines met by the nurses should also be met by the physicians.

Ensuring safe care delivery during sedation is paramount to a successful moderate sedation program in any facility. All the issues discussed here should be addressed and can provide an opportunity for expansion in policy development. The answers may not be readily apparent at the present time; with more experience and practice, many of these issues may become moot points as moderate sedation practice becomes more sophisticated.

15. SUMMARY

Moderate sedation is an exciting field for nurses. As newer, safer sedation medications become available, nurses will be asked to provide moderate sedation on an increasingly frequent basis. Recognition of the goals and objectives of moderate sedation is the first step in providing safe care. Medication administration and knowledge of pharmacologic principles are paramount prior to drug delivery. Providing for patient safety should be the most important aspect of nursing care delivery. Recognition of the nuances of care delivery to specific patient populations should not be overlooked. If these aspects are adhered to throughout moderate sedation, the patient will be provided with safe care before, during, and after sedation.

Works Cited

1. The Joint Commission. Comprehensive Accreditation Manual for Hospitals (CAMH). Oakbrook Terrace, IL: Joint Commission Resources; 2020.

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165. Maddox TG. Adverse reactions to contrast material: recognition, prevention, and treatment. Am Fam Physician. 2002;66(7):1229-1235.

166. Pannu HK, Fishman EK. Complications of endoscopic retrograde cholangiopancreatography: spectrum of abnormalities demonstrated with CT. Radiographics. 2001;21(6):1441-1453.

167. North Dakota Board of Nursing. Practice Statements: Role of Registered Nurse (RN) in the Management of Patients Receiving Moderate Sedation/Analgesia for Therapeutic, Diagnostic, or Surgical Procedures. Available at https://www.ndbon.org/RegulationsPractice/PracticeStatements/Mgmt-ModerateSedation.asp. Last accessed July 6, 2020.

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Evidence-Based Practice Recommendations Citations

1. Apfelbaum JL, Task Force on Postanesthetic Care. Practice guidelines for postanesthetic care: an updated report by the American Society of Anesthesiologists Task Force on Postanesthetic Care. Anesthesiology. 2013;118(2):291-307. Available at https://anesthesiology.pubs.asahq.org/article.aspx?articleid=1918686. Last accessed July 14, 2020.

2. Godwin SA, Burton JH, Gerardo CJ, et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med. 2014;63(2):247-258. Available at https://www.acep.org/patient-care/clinical-policies/procedural-sedation-and-analgesia. Last accessed July 14, 2020.

3. ASGE Standards of Practice Committee, Early DS, Acosta RD, et al. Modifications in endoscopic practice for the elderly. Gastrointest Endosc. 2013;78(1):1-7. Available at https://www.asge.org/docs/default-source/education/practice_guidelines/doc-modifications-in-endoscopic-practice-for-the-elderly.pdf?sfvrsn=60c94951_6. Last accessed July 14, 2020.