GCA18O1 • Nurses

Table of Contents

GCA18O1 • Nurses

How to Receive Credit

NetCE 15 Hour Course #38821 • Pathophysiology: The Respiratory System

38821 • Pathophysiology: The Respiratory System

1. INTRODUCTION

2. THE RESPIRATORY SYSTEM IN HEALTH AND ILLNESS: STRUCTURAL AND FUNCTIONAL INTER-RELATIONSHIPS

3. PATHOPHYSIOLOGIC INFLUENCES AND EFFECTS

4. RELATED SYSTEM INFLUENCES AND EFFECTS

5. PSYCHOSOCIAL/LIFESTYLE INFLUENCES AND EFFECTS

6. NURSING ASSESSMENT: ESTABLISHING THE DATA BASE

7. NURSING DIAGNOSES, PLANNING, AND IMPLEMENTATION

8. DISORDERS OF THE UPPER RESPIRATORY SYSTEM

9. DISORDERS OF THE LOWER RESPIRATORY SYSTEM

10. TRAUMATIC DISORDERS

11. RESPIRATORY SURGERY OF THE UPPER AIRWAY

12. THORACIC SURGERY

13. CONCLUSION

14. CASE STUDIES

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 2 Hour Course #34942 • Diabetes and Stroke: Making the Connection

34942 • Diabetes and Stroke: Making the Connection

1. INTRODUCTION

2. AN OVERVIEW OF DIABETES

3. DIAGNOSIS OF DIABETES

4. CEREBROVASCULAR DISEASE AND DIABETES

5. TREATMENT OF STROKE

6. PREVENTION

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #98771 • Parkinson Disease

98771 • Parkinson Disease

1. INTRODUCTION

2. BACKGROUND

3. EPIDEMIOLOGY

4. RISK FACTORS AND ETIOLOGY

5. PATHOPHYSIOLOGY

6. DIAGNOSTIC WORKUP

7. TREATMENT OF PARKINSON DISEASE

8. CONCLUSION

9. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 3 Hour Course #95150 • Responsible and Effective Opioid Prescribing

95150 • Responsible and Effective Opioid Prescribing

1. INTRODUCTION

2. SCOPE OF THE PROBLEM

3. PAIN MANAGEMENT APPROACHES

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

8. MANAGEMENT OF OPIOID USE DISORDER

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

GCA18O1 • Nurses

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

Diane Thompson, RN, MSN, CDE, CLNC

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

GCA18O1 • Nurses

Expiration Date: 04/30/2021

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.

38821 • Pathophysiology: The Respiratory System

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

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

Pathophysiology is the study of disordered and altered functions affecting the body's dynamic homeostasis and the concepts of illness development and progression. This course is designed to broaden the nurse's understanding of respiratory pathophysiology by exploring causes, alterations and physiology adaptations, manifestations, and resolution of disease states. Pathophysiologic symptoms and signs are described in relation to the patient's clinical presentation, allowing the nurse can monitor physical changes and relate them directly to the illness process. Appropriate diagnostic tests and treatments for each problem are included to provide information about disease progression, remission, and resolution.

Table of Contents

38821 • Pathophysiology: The Respiratory System

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. THE RESPIRATORY SYSTEM IN HEALTH AND ILLNESS: STRUCTURAL AND FUNCTIONAL INTER-RELATIONSHIPS

THE UPPER RESPIRATORY TRACT

THE LOWER RESPIRATORY TRACT

THE PULMONARY CIRCULATION

THE PROCESS OF VENTILATION

MECHANISMS OF RESPIRATORY CONTROL

THE COUGH REFLEX

3. PATHOPHYSIOLOGIC INFLUENCES AND EFFECTS

HYPOVENTILATION

DIFFUSION IMPAIRMENT

VENTILATION-PERFUSION ABNORMALITIES

4. RELATED SYSTEM INFLUENCES AND EFFECTS

NEUROLOGIC SYSTEM

CARDIOVASCULAR SYSTEM

OTHER RELATED SYSTEMS

5. PSYCHOSOCIAL/LIFESTYLE INFLUENCES AND EFFECTS

SMOKING

ENVIRONMENTAL ALLERGENS AND POLLUTION

OCCUPATIONAL AND ECONOMIC FACTORS

SOCIAL FACTORS

6. NURSING ASSESSMENT: ESTABLISHING THE DATA BASE

SUBJECTIVE DATA

OBJECTIVE DATA

DIAGNOSTIC STUDIES

7. NURSING DIAGNOSES, PLANNING, AND IMPLEMENTATION

INEFFECTIVE AIRWAY CLEARANCE

INEFFECTIVE BREATHING PATTERN

IMPAIRED GAS EXCHANGE

8. DISORDERS OF THE UPPER RESPIRATORY SYSTEM

LARYNGEAL EDEMA

FOREIGN BODY IN THE LARYNX

UPPER RESPIRATORY INFECTION

NEOPLASMS OF THE LARYNX

TRAUMATIC DISORDERS

9. DISORDERS OF THE LOWER RESPIRATORY SYSTEM

OCCUPATIONAL LUNG DISEASES (PNEUMOCONIOSES)

ACUTE RESPIRATORY DISTRESS SYNDROME

ACUTE TRACHEOBRONCHITIS

ACUTE BRONCHITIS

PNEUMONIA

TUBERCULOSIS

LUNG ABSCESS

EMPYEMA

HISTOPLASMOSIS

BRONCHIECTASIS

ASTHMA

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

ACUTE RESPIRATORY FAILURE

LUNG CANCERS

10. TRAUMATIC DISORDERS

FLAIL CHEST

PNEUMOTHORAX

HEMOTHORAX

CARBON MONOXIDE POISONING

11. RESPIRATORY SURGERY OF THE UPPER AIRWAY

TRACHEOTOMY

CRICOTHYROIDOTOMY

LARYNGECTOMY

12. THORACIC SURGERY

TYPES OF THORACIC SURGERY

PHYSIOLOGIC IMPLICATIONS

PREOPERATIVE CARE

POSTOPERATIVE CARE

13. CONCLUSION

14. CASE STUDIES

ASTHMA

COPD

Works Cited

Evidence-Based Practice Recommendations Citations

38821 • Pathophysiology: The Respiratory System

Education Category. Infection Control / Internal Medicine

Release Date. 09/01/2020

Expiration Date. 08/31/2023

Course Overview

Pathophysiology is the study of disordered and altered functions affecting the body's dynamic homeostasis and the concepts of illness development and progression. This course is designed to broaden the nurse's understanding of respiratory pathophysiology by exploring causes, alterations and physiology adaptations, manifestations, and resolution of disease states. Pathophysiologic symptoms and signs are described in relation to the patient's clinical presentation, allowing the nurse can monitor physical changes and relate them directly to the illness process. Appropriate diagnostic tests and treatments for each problem are included to provide information about disease progression, remission, and resolution.

Audience

This course is designed for nurses working in critical care and general and specialty medical-surgical units in which patients with multiple organ system problems are found.

Course Objective

As health care becomes more complex, it is essential that the theoretical concepts of the basis of illness (pathophysiology) be well understood. The purpose of this course is to reinforce the scientific rationales for the interventions nurses perform and the decisions nurses make as patients move through the ever-changing struggle with their respiratory illness.

Learning Objectives

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

1. Identify the key structures and functional inter-relationships in the respiratory system.

2. Describe the components and functions of pulmonary circulation.

3. Discuss the pathophysiologic and environmental influences and effects on the respiratory system.

4. Outline the role of subjective data in completing a full nursing assessment of the respiratory system.

5. Describe objective data compiled during a nursing assessment of the respiratory system.

6. Identify diagnostic tests used in the identification and classification of respiratory diseases.

7. Outline the nursing diagnoses, planning, and management of conditions related to respiratory dysfunction.

8. Discuss clinical manifestations of infectious diseases of the upper respiratory system.

9. Review signs and symptoms of upper respiratory neoplasms and related nursing actions.

10. Describe the common causes, appearances, and treatment of traumatic disorders of the upper respiratory disorders.

11. Analyze the presentation and nursing management of occupational lung diseases.

12. Evaluate pathologic causes and manifestations of disorders of the lower respiratory tract.

13. Discuss the pathophysiology and clinical manifestations of traumatic respiratory disorders.

14. Outline the concepts and information the nurse should provide for the patient during the health teaching and discharge planning process after respiratory surgery.

15. Describe key concepts related to caring for patients who receive thoracic surgery.

Faculty

Jane C. Norman, RN, MSN, CNE, PhD, received her undergraduate education at the University of Tennessee, Knoxville campus. There she completed a double major in Sociology and English. She completed an Associate of Science in Nursing at the University of Tennessee, Nashville campus and began her nursing career at Vanderbilt University Medical Center. Jane received her Masters in Medical-Surgical Nursing from Vanderbilt University. In 1978, she took her first faculty position and served as program director for an associate degree program. In 1982, she received her PhD in Higher Education Administration from Peabody College of Vanderbilt University. In 1988, Dr. Norman took a position at Tennessee State University. There she has achieved tenure and full professor status. She is a member of Sigma Theta Tau National Nursing Honors Society. In 2005, she began her current position as Director of the Masters of Science in Nursing Program.

Faculty Disclosure

Contributing faculty, Jane C. Norman, RN, MSN, CNE, PhD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Sharon Cannon, RN, EdD, ANEF

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

Respiratory diseases are among the most common long-term conditions affecting patients in the United States, and the identification, assessment, diagnosis, and treatment of most respiratory diseases is an essential component of patient care. Socioeconomics, ethnicity, age, and gender have a significant effect on both the development of respiratory disease and its outcome. In addition, the impact of respiratory disease on patients, families, health services, and society is significant. When caring for patients with respiratory illness, there are key nursing skills involved in interpreting diagnostic testing, identifying comorbidities, and effectively managing care.

Respiratory disease affects patients of all ages. It also brings specific challenges in the diagnosis and treatment of various groups including children, some occupational and ethnic groups, those with social and mental health conditions, and those nearing the end of life. This course is designed to broaden the nurse's understanding of the pathophysiology of respiratory illness by exploring causes, alterations and physiologic adaptations, manifestations, and resolution of disease states. Pathophysiologic symptoms and signs are described in relation to the patient's clinical presentation, so the nurse can monitor physical changes and relate them directly to the illness process. Appropriate diagnostic tests and treatments for each problem are included, along with the nurse's responsibilities for patient teaching.

2. THE RESPIRATORY SYSTEM IN HEALTH AND ILLNESS: STRUCTURAL AND FUNCTIONAL INTER-RELATIONSHIPS

Every cell in the body requires oxygen to carry out its metabolic functions. Likewise, every cell in the body must rid itself of carbon dioxide (CO_2), a waste product of cellular metabolism. The process of transporting oxygen to the cells and removing CO_2 is called respiration. Any disease or trauma that interferes with respiration injures body cells. The body can survive without food for weeks and without water for days; without oxygen, it dies within minutes.

Respiration involves two major body systems: the cardiovascular system and the respiratory system, both regulated by the nervous system. Oxygen and CO_2 are conveyed to and from tissues and organs by the cardiovascular system. The respiratory system delivers oxygen from the atmosphere to the bloodstream and delivers CO_2 from the blood to the atmosphere. This gas exchange takes place in specialized structures of the lungs.

Although the respiratory airways and the anatomic structures where gas exchange takes place are continuous, their components are classified anatomically and functionally as belonging to either the upper or lower respiratory tracts. The muscles of the chest wall and diaphragm also participate in respiration.

THE UPPER RESPIRATORY TRACT

The upper respiratory tract is primarily an air delivery system. It warms, moistens, and filters inspired atmospheric air on its way to the lungs. Structures of the upper respiratory tract also expel foreign matter and excess secretions from the system. The principal structures of the upper respiratory tract are the nose, the paranasal sinuses, the pharynx, and the larynx.

The Nose

Air enters the system first through the nares or nostrils into the nasal fossae. The nasal septum separates the two fossae. The nose is composed of both bone and cartilage, and its interior surface has ridges called turbinates. The ridged configuration increases the effective surface of the nasal mucosa. An extensive bed of capillaries transfers body heat to the inspired air. Because of this rich vascularity, bleeding from injured nasal tissue can be profuse.

Mucus secreted by the membrane that lines the nose helps humidify inspired air, which attains a relative humidity of more than 90% as it passes through the nares. Hairs that line the nose filter out large foreign particles, and a sticky mucus secreted by the serous glands in the mucosa traps finer dirt, dust, and micro-organisms. Hairlike structures of the mucous membrane called cilia constantly propel trapped particles toward the pharynx, from which they can be expelled by sneezing or coughing [1,2].

In addition to its respiratory functions, the nose is the organ of olfaction. Sensory receptors sensitive to various odors are concentrated in the roof of the nasal fossae. Along with the paranasal sinuses, the nose functions as a resonance chamber for phonation; if the mucosa of these structures becomes edematous or clogged with secretions, a flat, nonresonant sound occurs [2].

The Paranasal Sinuses

The paranasal sinuses are air-filled cavities within bony structures adjacent to the nasal cavity. These sinuses—the ethmoid, frontal, sphenoid, and maxillary sinuses—drain through the nasal cavity. All are lined with ciliated columnar epithelium that is continuous with the lining of the nose. Because the mucosa is continuous, infection in the nasal passages can readily spread to the sinuses.

The paranasal sinuses have a variety of functions, including lightening the weight of the head, humidifying and heating inhaled air, increasing the resonance of speech, and serving as an insulate to help protect vital structures in the event of facial trauma [3,4]. Like all structures of the upper respiratory tract, the sinuses can trap foreign matter and, by ciliary movement, expel it [5].

The Pharynx

The pharynx begins at the base of the skull and ends opposite the lowest cartilaginous rings of the larynx. Its three sections, from superior to inferior, are the nasopharynx, the oropharynx, and the laryngopharynx. The nasopharynx contains the adenoids (paired lymphatic structures) and the Eustachian tubes, which maintain appropriate air pressure within the middle ear. Functional Eustachian tubes are essential for hearing and crucial to the mechanism by which the body maintains balance.

Air and food both enter the body through the oropharynx. The palatine tonsils, which are composed of lymphatic tissue, are located in the oropharynx. The laryngopharynx contains the lingual tonsils and the epiglottis, a small flap of tissue that covers the larynx during swallowing to prevent food or liquid from being aspirated into the lower airway [6,7].

The lining of the pharynx, like the lining of the structures that precede it, consists of mucous membrane that traps foreign particles and humidifies and warms the inspired air. The lymphatic tissue of the tonsils also traps micro-organisms and disposes of them by phagocytes before they can continue further in the respiratory tract, another line of defense against infection [7].

THE LOWER RESPIRATORY TRACT

The lower respiratory tract consists of the trachea, the bronchi and their branches, and the various structures of the lungs, which are protected by the chest wall. The structures of the trachea and bronchi are best visualized as an inverted tree. The tracheobronchial tree is composed of a main "trunk" (the trachea) that bifurcates into two major branches (the right and left primary bronchi). These divide in turn into secondary and then tertiary bronchi, which branch again and again into "twigs" (the bronchioles). At the tiny outermost tips of the "twigs" are the respiratory bronchioles, from which air passes through alveolar ducts into the alveoli, the "leaves" where gas exchange actually takes place [6,8].

The Trachea

The air passage of the trachea, or windpipe, is kept open by C-shaped cartilaginous rings in the tracheal wall. The mucus-bathed ciliary epithelium that lines the trachea sweeps foreign material up into the pharynx, where the cough reflex expels it. The trachea, like the upper respiratory passages, warms and humidifies inspired air.

The Bronchi and Bronchioles

The left primary bronchus exits from the trachea at a more acute angle than the right bronchus. Because of the obtuse angle, foreign material is more often aspirated into the right lung than the left. The cellular structure of the bronchial lining at this point is similar to that of the trachea.

The bronchi contain sensory receptors of the parasympathetic and sympathetic nervous systems. If these nerve endings are stimulated (for example, by an allergen), impulses transmitted to the respiratory centers of the brain by cranial nerves initiate constriction of the bronchi, the secretion of mucus, and/or the cough reflex.

The right primary bronchus divides into three secondary bronchi that supply the three lobes (superior, middle, and inferior) of the right lung. The left bronchus bifurcates, each segment going to one of the two lobes of the left lung.

The primary bronchi, like the trachea, are supported by partial rings of cartilage. As the airways become narrower, the proportion of smooth muscle to cartilage increases and the number of serous glands lining the bronchiolar walls decreases. At approximately the point where a bronchiole narrows to 1 mm in diameter, the walls are entirely surrounded by smooth muscle. Thus, when the muscles of the bronchioles spasm, as in an asthma attack, the lack of cartilaginous support causes air passages to collapse and breathing becomes extremely difficult.

The terminal bronchioles mark the end of the air conduction system and open into the respiratory bronchioles. Each of these in turn branches into several alveolar ducts, which open into grapelike clusters of air-filled sacs called alveoli. The respiratory bronchioles, alveolar ducts, and alveoli form the terminal respiratory units of the lungs, called acini [6].

The Lungs

The lungs are paired structures that lie in the thoracic cavity on either side of the mediastinum. The bases of the lungs rest on the diaphragm. As noted, the right lung has three lobes; the left has two. The lobes are further subdivided into smaller bronchopulmonary segments. This segmental structure makes it possible to remove a relatively small portion of the lung if surgical resection is necessary [9].

The lungs lie free within the pleural cavities of the thorax, except at the hilus on the medial surface. The bronchi and blood vessels enter and exit through the hilus, and the sternum forms the anterior border of the thorax. The lateral boundaries of the thorax are composed of the twelve ribs, or costae, which are attached to the sternum by the costal cartilages interiorly and the vertebral column posteriorly. This bony thoracic cage protects the vital structures within the mediastinum and the fragile, spongy tissue of the lungs. The ability of the lungs to stretch to accommodate increases in volume is termed compliance [9].

The diaphragm is an important muscle of respiration and separates the thorax from the abdominal cavity. Each half of the diaphragm is innervated by a phrenic nerve. An injury to one of the phrenic nerves results in a unilateral diaphragmatic paralysis with elevation of half of the diaphragm [10,11].

The Pleura

The visceral pleura covering the lungs is continuous with the parietal pleura, which lines the thoracic cavity. Both pleurae are formed of serous membrane that secretes pleural fluid into the extremely narrow pleural cavity between the two layers. This fluid lubricates the two layers, reducing friction as the lungs and thorax move during respiration. The pleural fluid also couples the parietal and visceral pleurae and the structures to which they are attached [9]. Inflammation of the pleural membrane (pleurisy) causes the membrane to become dry and fibrous. The ensuing friction makes breathing painful.

Intrapleural Pressure

Because of changes that occur when breathing begins after birth, air pressure within the pleural cavity (intrapleural pressure) is lower than air pressure within the lungs (intrapulmonary pressure). This lower pressure keeps the lung expanded because of its tendency to be drawn toward the area of subatmospheric pressure. If the lung or chest wall is punctured, air rushes into the area of lower pressure—the pleural space—destroying the vacuum that keeps the lung expanded. In severe injury, the amount of air entering the intrapleural space may be sufficient to cause equalization of intrapleural pressure and atmospheric pressure. The result is collapse of the lung on the affected side [6,11].

THE PULMONARY CIRCULATION

The lungs have a dual blood supply: the tracheobronchial circulation and the pulmonary circulation. The right and left bronchial arteries branch from the descending aorta and supply blood to the trachea and bronchi to the level of the respiratory bronchioles. The terminal respiratory units of the lungs are nourished via the pulmonary circulation.

The pulmonary circulation is where oxygenation of blood occurs. The entire output of the right ventricle leaves the heart via the pulmonary artery, which divides into the right and left pulmonary arteries. This poorly oxygenated blood circulates through the capillaries of the alveoli, where gas exchange takes place. Oxygenated blood is then returned to the left atrium via the pulmonary veins [6,11].

The Alveoli and Gas Exchange

Each terminal bronchiole supplies its own unit of several alveoli, called the acinus. Essentially, each alveolus is a tiny air space enclosed by a thin wall (the alveolar septum) that consists of a network of pulmonary capillaries held together by connective-tissue fibers and lined with squamous epithelium that contains secretory cells. The tissue of an adult lung contains more than 300 million alveoli [12].

The secretory glands of the alveolar wall produce pulmonary surfactant, which reduces the surface tension of the pleural fluid. If surface tension were to pull alveolar walls together, expansion of the lungs during inspiration would be hindered, and the alveoli would tend to collapse during expiration. Pulmonary surfactant also contains macrophages that destroy foreign material that has passed through the upper-airway defenses [13,14].

Within the alveoli, air is separated from blood by the respiratory membrane, which is formed by the basement membrane of the alveolar and capillary epithelia. This membrane is less than 1-mm thick, and gases move across it in accordance with the principle of diffusion. Dyspnea is a symptom of an increasing capillary wedge pressure [12].

The venous blood returning from the tissues is high in CO_2 and low in oxygen; the air in the alveolar space is higher in oxygen and lower in CO_2 than the blood. Under normal conditions, the approximate partial pressures of oxygen in the alveoli and the capillaries are 105 mm Hg and 40 mm Hg, respectively. The partial pressure of CO_2 is 45 mm Hg in the capillaries and 35 mm Hg in the alveoli.

In essence, gas exchange depends on adequate flow of blood (perfusion) and adequate flow of air (ventilation) to and from alveoli [9]. For efficient gas exchange, a large number of capillaries must be in contact with the inspired air. The many-sectioned structure of lung tissue normally provides maximum capillary surface. If alveolar septa are destroyed by a disease process, however, and alveoli coalesce, the surface available for diffusion is reduced. In addition, if the alveolar membrane becomes fibrous and thickened by scaring, diffusion will be impeded.

Pulmonary blood flow must also be normal for efficient gas exchange. If an embolus obstructs blood flow to a portion of the lung, gas exchange will be impaired. In addition, alveoli must be in normal condition. If alveoli are filled with inflammatory exudates from infection, air cannot reach the respiratory membrane.

THE PROCESS OF VENTILATION

Ventilation is the exchange of air between the atmosphere and the alveoli. At rest and at sea level, intrapulmonary pressure and atmospheric pressure are equal—760 mm Hg. During inspiration, the muscles of the diaphragm and the intercostal muscles contract, lowering the diaphragm and raising the rib cage. The volume of the intrathoracic space expands and intrapleural and intrapulmonary pressures decrease, until the intrapulmonary pressure is lower than atmospheric pressure. Air moves along the concentration gradient (from higher concentration to lower) into the upper respiratory tract, through the tracheobronchial tree, and into the alveolar tissue of the lungs. Air moves into the lungs until intrapulmonary pressure and atmospheric pressure are equal.

Neuronal receptors sensitive to stretch respond to the expansion of the thoracic cage, stimulating a rebound action of the muscles and connective-tissue fibers of the lungs. The ribs become more vertical and the diaphragm rises, causing intrapulmonary pressure to rise above atmospheric pressure. Air moves passively out of the lungs along the reversed concentration gradients, carrying out CO_2 (and other waste gases) that have been exchanged for oxygen from the inspired air. This expiration continues until the intrapulmonary pressure is again lower than atmospheric pressure, and the cycle begins again [15].

During normal inspiration, most of the work is accomplished by the diaphragm, with some participation by the intercostal muscles. Movement of the rib cage may be barely perceptible during quiet respiration, as during sleep. As exertion increases, oxygen demand increases proportionately, and the intercostal muscles are called upon to an increasing extent. During forced or labored respiration, additional chest muscles and even abdominal muscles are employed in moving the thoracic cage [15].

MECHANISMS OF RESPIRATORY CONTROL

The rate and extent of inspiration and expiration are governed by nervous pathways that respond to various stimuli that signal increased or diminished oxygen requirements or CO_2 levels. Requirements are greater during exertion and least during sleep. Like other mechanisms vital to survival, respiration proceeds without conscious control [1,2].

Cerebral control of the respiratory mechanisms is believed to be centered in the pons and the medulla oblongata, both located in the brain stem. The apneustic and pneumotaxic centers of the pons apparently control and modify the activities of the medulla center through stimulation and inhibition, respectively. The cerebral centers receive impulses from a wide array of nerve endings, some sensitive to chemical stimuli and some to mechanical stimuli. Certain chemicals that accumulate in muscle tissue during exertion initiate impulse sequences that increase the respiration rate. If circulating CO_2 increases, hydrogen ions increase and pH decreases; these chemical changes stimulate neurologic pathways that ultimately effect increases in both the rate and depth of ventilation. Fear or anxiety initiate response mechanisms that increase both heart rate and respirations to prepare the body for "fight or flight." Chemoreceptors in the aortic arch and the bifurcation of the internal and external carotid arteries detect changes in oxygen content of the blood and send impulses via neuronal networks to the respiratory centers to increase the ventilation rate as required [2].

Clearly, then, there are many prerequisites for normal respiration. The muscles of respiration must be capable of normal movement, and the chest wall must be mobile. The neurologic pathways and centers affecting respiration must be intact and functional. Any number of alterations in the internal or external environment may adversely affect respiratory functions [2].

THE COUGH REFLEX

The cough reflex is initiated when a foreign substance (e.g., a dust particle) irritates specialized nerve endings within the larynx, trachea, or major bronchi. Nerve impulses are sent to contract muscles that close the vocal cords and simultaneously contract abdominal muscle and muscle fibers within the respiratory tract itself. Air pressure builds up in the lower airways, and when the vocal cords reopen, a sudden rush of air carries mucus and foreign matter up to be expectorated. Because the vocal cords are crucial to the cough reflex, persons whose larynxes have been removed cannot cough and thus are deprived of an important defense against airway obstruction.

3. PATHOPHYSIOLOGIC INFLUENCES AND EFFECTS

The basic abnormalities of oxygen-CO_2 exchange are hypoventilation, diffusion impairment, and ventilation-perfusion inequality, including shunt.

HYPOVENTILATION

Ventilation below the level needed to maintain normal arterial CO_2 tension is called hypoventilation. If a patient is hypoventilating, arterial blood levels of CO_2 will be above normal (hypercapnia or hypercarbia), because alveolar ventilation is not keeping pace with body metabolism. As arterial CO_2 rises, the partial pressure of arterial oxygen (PO_2) falls; this condition is called hypoxemia. Although hypercapnia is caused only by hypoventilation, hypoxemia may be caused by several other conditions as well [5].

Hypoventilation is related to many conditions; airway obstruction is one of the most common. The upper airway, especially the pharynx and larynx, may be obstructed by inflamed, edematous mucosal linings or by hypertrophic tonsils or adenoids. Alternatively, polyps, tumors, or foreign bodies may partially block the airway. Impairment of the lower respiratory tract or the alveoli can have even more serious effects. Retained secretions, mucosal edema, and bronchospasm can narrow or collapse some or all of the airways. Obstructive diseases such as emphysema cause hypoventilation because they impair air flow [5].

Functional alterations in the central nervous system, as well as neuromuscular or skeletal abnormalities, can also play a part in hypoventilation. Hypoventilation may also occur as a consequence of immobility or inappropriate positioning for extended periods.

DIFFUSION IMPAIRMENT

As discussed, oxygen and CO_2 molecules are transported between the alveolar air spaces and the capillary beds of the alveolar septum by diffusion. The effectiveness of the diffusion process is influenced by the condition of the alveolar and capillary epithelia, the interstitial fluid, and the erythrocyte membrane, as well as by the secretion of pulmonary surfactant. However, there is a wide margin of safety. Because blood in the alveolar capillaries can reach the gas tension levels prevalent in the alveolar space, approximately one-third of the time it remains there. Diffusion can be reduced for some time before abnormalities become apparent [15,16].

Significant diffusion abnormalities can interfere with the passage of inspired oxygen from the alveoli into the blood. Because CO_2 diffuses readily, the partial pressure of CO_2 is generally unaffected by diffusion impairment. Hypoxemia may lead to hyperventilation, however, and this, rather than diffusion impairment itself, may lower partial pressure of CO_2 (PCO_2) [15,16].

Any condition that thickens the alveolar septum can impair diffusion. For example, metastatic carcinoma may invade the interstitial spaces. Pulmonary edema hampers oxygen diffusion because of the increased amount of fluid in the alveoli and the interstitial spaces. If the amount of functioning lung tissue is reduced because of emphysema, pneumonectomy, or tumor growth, diffusion will also be impaired [17].

In the early stages of diffusion impairment, hypoxemia may occur only during exertion. As the condition progresses, hypoxemia and related symptoms (e.g., dyspnea, restlessness, tachycardia) may occur even when the patient is resting.

VENTILATION-PERFUSION ABNORMALITIES

Efficient exchange of CO_2 for oxygen requires equality of alveolar ventilation and perfusion. Slight imbalances occur in healthy individuals, but excessive ventilation perfusion imbalances are the most common causes of hypoxemia. Such abnormalities may be classified as [18]:

- Normal ventilation to no perfusion

- No ventilation to normal perfusion

- No ventilation to no perfusion

Normal Ventilation to No Perfusion (Dead Space Unit)

Without perfusion, gas exchange cannot take place. This condition is called wasted ventilation, because ventilation of the alveoli brings about no exchange of CO_2 for oxygen. Conditions related to wasted ventilation include a decrease in total blood volume (in hemorrhage or dehydration), pulmonary embolism, and chronic obstructive pulmonary disease (COPD). Emphysema may also destroy both alveoli and capillaries within portions of the lungs, so neither ventilation nor perfusion can take place. If large areas of the lungs are affected by wasted ventilation, hypoxemia and hypercapnia with related respiratory acidosis can occur [18].

No Ventilation to Normal Perfusion (Shunt Unit)

In shunting, the alveolus is perfused but not ventilated (wasted perfusion). Any pathologic condition that obstructs the alveoli can lead to a low ventilation-to-perfusion ratio. For example, a patient who is in pain from upper abdominal surgery may take shallow breaths, resulting in atelectasis. Then unoxygenated blood from the collapsed area mixes with oxygenated blood from the unaffected areas, lowering the level of oxygen in the arterial blood. In addition, insufficient CO_2 is eliminated. Arterial hypoxemia occurs, but hypercapnia may not occur unless the lungs are severely compromised [18].

No Ventilation to No Perfusion (Silent Unit)

Conditions leading to diminished or absent ventilation of some alveolar units include pneumonia, atelectasis, pulmonary edema, and COPD. Conditions leading to diminished or absent perfusion of some alveolar units include compression of intrathoracic blood vessels by a neoplasm; occlusion of blood vessel by emboli or thrombi; and collapse of blood vessels because of decreased perfusion pressure, shock, or hypotension. The severity of patient symptoms depends on the extent of alveolar units involved [18].

4. RELATED SYSTEM INFLUENCES AND EFFECTS

In addition to abnormalities of the lungs and upper respiratory structures, physiologic processes involving other body systems can adversely affect respiratory functions. Conversely, because oxygen is a primary need of every body cell, dysfunction of the respiratory systems can have extensive repercussions in any body system. The two body systems closely related to respiratory function are the neurologic and cardiovascular systems [19].

NEUROLOGIC SYSTEM

The neurologic system regulates normal ventilation, and the cerebral cortex can consciously control respiration. As such, drugs or disease processes affecting the nervous system will inevitability affect respiration to some extent. Anesthetic agents are a major example of drugs having respiratory side effects. Infections, tumors, diseases of the peripheral nervous system (e.g., Guillain-Barré syndrome), and neuromuscular diseases (e.g., myasthenia gravis) may also affect respiration in various ways. The respiratory system may respond to these influences by hyperventilation, hypoventilation, a combination of the two (Cheyne-Stokes respiration), or apnea. If the brain or spinal cord is damaged, respiratory function may be greatly impaired or even totally destroyed, depending on the location and severity of the damage [19,20].

CARDIOVASCULAR SYSTEM

The heart not only moves blood to the pulmonary arteries for exchange of oxygen and CO_2 but also supplies oxygenated blood to the lung tissue itself. Consequently, functional alterations in the cardiovascular system affect respiratory function as well.

If severe hemorrhage depletes the volume of circulating blood, the supply of oxygen and nutrients for the airways and terminal respiratory units will also be diminished. The oxygen and nutrient deficit will be greater in pulmonary tissue because, even under normal conditions, pressure in the pulmonary circulation is lower than pressure in the systematic circulation. As the lungs are adjacent to the heart, little pressure is normally required for pumping blood to them [19].

Failure of the right side of the heart related to certain disease states may affect the volume of pulmonary blood circulation. Conversely, certain disorders of the respiratory system are closely related to right-sided heart failure. Left-sided heart failure also affects pulmonary function as a result of a backup of blood in the pulmonary vasculature and related pulmonary edema. If the volume of blood circulating either to or from the lungs is compromised for any reason, oxygen, CO_2, and acid-base abnormalities may occur [19,21].

Oxygen obtained during gas exchange in the pulmonary circulation must combine with hemoglobin to be transported to the tissues. Normally, the circulation contains approximately 15 g of hemoglobin to carry about 20 mL of oxygen at any given time. If the hemoglobin concentration is less than normal (i.e., anemia), the capacity of the blood to transport oxygen will be reduced [18,22].

OTHER RELATED SYSTEMS

Diseases and deformities of the skeletal system can also alter respiratory functioning, generally by restricting movement of the thoracic cage (e.g., scoliosis). Problems in the gastrointestinal tract (e.g., hiatal hernia) can interfere with lung expansion. Extreme obesity can restrict movement of the thoracic cage and place an abnormal load on the respiratory system by increasing the exertion required for ordinary activities [19].

Surgery of the gastrointestinal tract, especially procedures such as cholecystectomy that have a high abdominal incision, can be associated with pulmonary complications in the postoperative period. Pain at the surgical site inhibits adequate deep breathing and coughing, resulting in inadequate expansion of the lungs. Atelectasis or pneumonia can be the consequence [19].

5. PSYCHOSOCIAL/LIFESTYLE INFLUENCES AND EFFECTS

Long-term impairment of respiratory function has serious effects on patients and their families. An acute respiratory infection or chest injury can severely incapacitate an individual, but after the infection is controlled or the injury healed, the patient can usually resume daily activities. Cancer of the respiratory system, on the other hand, is a progressive disease, often with a poor prognosis. Chronic disabling respiratory disorders of long duration, such as COPD, also have far-reaching psychosocial effects. These long-term disabilities have become more prevalent as the U.S. population has aged and as once-deadly acute infectious diseases have become more easily managed. Similarly, attention to environmental hazards that can lead to long-term pathologic changes in the respiratory system, such as smoking, has increased.

SMOKING

More than 480,000 Americans die prematurely each year from disorders related to smoking; millions of others lead restricted lives because of pulmonary damage and cardiovascular impairment [23]. The chemical agents in tobacco smoke reduce and eventually destroy ciliary movement in the bronchial mucosa, making the lungs more susceptible to infection. The hot smoke dries and inflames the delicate tissues of the mouth, larynx, trachea, and lungs. Carbon monoxide in cigarette smoke combines with hemoglobin more readily than oxygen; this competition reduces the amount of oxygen available to body tissues. Nicotine is a vasoconstrictor, and vasoconstriction also reduces oxygen supply. Sensors in the blood and the tissues thus signal the heart to beat faster to make up the deficit. Perhaps most well known, tar in cigarette smoke cause cancerous lesions in the lungs [24].

ENVIRONMENTAL ALLERGENS AND POLLUTION

Airborne allergens can cause or aggravate respiratory disease. The most common respiratory disease associated with allergens is extrinsic asthma, which can affect children and adults. Such well-known and widespread environmental allergens as ragweed pollen and animal dander are related to allergic rhinitis [25].

Pollution of the air by industrial and agricultural chemicals can increase the severity of numerous respiratory conditions, including long-term obstructive disorders. Individuals who have such conditions may have to change their residence or stay indoors when pollution levels are high. Although increasing public awareness of pollution hazards has stimulated efforts by government and industry to reduce the quantity of pollutants released into the air, new technology is needed and much remains to be done [25].

OCCUPATIONAL AND ECONOMIC FACTORS

Occupation is a significant factor in the development of some respiratory disorders. "Black lung disease," which affects coal miners, is a well-publicized example; asbestosis is another. Solvents in paints and varnishes have also been implicated in respiratory disorders, not only among factory workers and professional painters, but among hobbyists as well. A timely question about recent craft or hobby projects cans yield a valuable diagnostic clue about respiratory ailments. Clerks in dry cleaning establishments and beauticians exposed to permanent wave solutions (ammonia) and hair dyes may also develop respiratory abnormalities [25].

Existing respiratory problems can be made worse by exposure to chemical pollutants at work. The trend toward tightly insulated buildings to conserve energy has raised concerns about chemical pollution in office environments that formerly were relatively hazard free. By being alert to occupational information in the patient's history, the nurse can help identify individuals at risk and can counsel patients with respiratory disorders about possible hazards in their working environments [25].

SOCIAL FACTORS

A disease that affects an activity as fundamental as breathing necessarily influences all aspects of the patient's life, from intimate relationships to casual social contacts. Fear, anxiety, and anger related to symptoms and restrictions of activity place added burdens on an already compromised respiratory system and on personal relationships. Tensions rise, and depression is common.

If work activities are restricted, an individual may see his/her position and value in his/her family and community as being threatened or destroyed. When sports or hobbies are abandoned because they require more energy than the damaged respiratory system can supply, the social relationships accompanying these activities are also lost [25].

6. NURSING ASSESSMENT: ESTABLISHING THE DATA BASE

SUBJECTIVE DATA

Patients with disorders of the upper and lower airway may describe a variety of symptoms. These symptoms vary primarily with the location and severity of the disorder.

Principle Symptoms

Airway Problems

A common symptom in patients with respiratory disorders is difficult breathing, or dyspnea. Dyspnea is more often caused by disorders of the lower respiratory tract, such as COPD and carcinoma of the lung, than of the upper respiratory tract. However, occlusion of the upper airway by inflammation or obstruction by a foreign body or tumor may also result in dyspnea. Metabolic acidosis causes deep and labored breathing (Kussmaul breathing). Patients should be asked whether they are short of breath during rest or exertion and what factors aggravate and alleviate the symptoms, if present.

Another common symptom of respiratory disorders is a cough. Cough can result from irritation or from retained secretions that obstruct part of the airway. Causative disorders in the upper airway include sinusitis (leading to postnasal drip) and infections of the pharynx; causative disorders in the lower respiratory tract include bronchitis, bronchiectasis, and pneumonia. The patient should be asked whether the cough is productive or nonproductive. If the cough is productive, ask about the color, amount, odor, and consistency of the sputum. Inquire also about precipitating factors and the frequency of the cough.

Bronchospasm, retained secretions, edema, and obstruction by foreign objects can result in complaints of wheezing. This may be the chief concern of patients with asthma or allergic rhinitis. The patient should be questioned about the frequency of wheezing and any precipitating factors [26].

Chest Pain

Patients with respiratory dysfunction often describe sensations of pain and tenderness. Discomfort in the upper airway can result from an infection such as rhinitis, sinusitis, or pharyngitis. Trauma to the head and neck area can also cause pain in the upper respiratory tract. Although chest pain is not uncommon for patients with respiratory dysfunction, it can also result from cardiovascular, gastrointestinal, hepatic-biliary, genitourinary, and musculoskeletal disorders. Stress, anxiety, and panic can also contribute to chest pain. A careful history and physical examination are necessary to determine the origin of the pain so proper interventions can be carried out. Some disorders that cause chest pain, such as myocardial infarction or a punctured lung, can be fatal if not treated appropriately and promptly [27].

Voice Change

Having determined that chest pain does not stem from a disorder demanding immediate intervention, ask whether the patient has experienced any voice change. This symptom can be caused by infections of the pharynx, vocal nodules, laryngeal paralysis, and laryngeal tumors. Laryngeal paralysis results from damage to the recurrent or superior laryngeal nerve or the vagus nerve (e.g., due to bronchogenic carcinoma or an aortic aneurysm). Ask the patient how long ago the voice change occurred and whether it is associated with pain when speaking or swallowing.

Dysphagia

Dysphagia, defined as a decrease in a patient's ability to swallow, drink, and eat, may result from disorders such as pharyngitis, infectious mononucleosis, peritonsillar abscess, and tumors of the oropharynx and laryngopharynx. If present, ask patients how long they have experienced this symptom, if they experience pain when attempting to swallow, and if a sensation of choking or gagging occurs. Whether any difficulty has significantly affected nutritional intake should also be assessed [27].

Fatigue

Patients with respiratory illness may also complain of generalized feelings of malaise and fatigue. This may result from respiratory infections or other conditions that alter the normal levels of oxygen and CO_2 in the body. Neoplastic disorders also cause fatigue from increased metabolic demands. Furthermore, fatigue may result in patients using respiratory accessory muscles to breathe.

Weight Change

It is important to determine whether patients with respiratory disease have had a weight change. Weight loss may be the result from a neoplastic process or COPD. A weight gain may indicate fluid retention secondary to pulmonary edema or congestive heart failure. Ask how much weight was lost or gained, over what period of time, and whether the patient's appetite increased or decreased during the change.

Other General Symptoms

Many disorders of the respiratory tract may lead to an alteration in CO_2 and oxygen levels in the blood. This imbalance may manifest itself as respiratory acidosis or alkalosis. Patients in an acidotic state may complain of headache, double vision, weakness, drowsiness, and difficulty in breathing. These symptoms may result from hypoxia and/or hypercapnia. Patients who are in an alkalotic state may report they are dizzy and have a tingling sensation in the fingers and toes; these subjective complaints are the result of hypercapnia [28].

Tobacco Use

It is crucial to obtain a detailed smoking and tobacco use history from the patient. Cigars, pipes, and chewing tobacco should be included along with cigarettes. Smoking has been implicated as a risk factor in the development of lung cancer, cancer of the head and neck, and COPD. Smoking also aggravates upper respiratory symptoms such as rhinorrhea, sinusitis, and pharyngitis, because it damages the cilia and mucous membranes. The longer a person has smoked and the greater the number of cigarettes, the greater the risk of developing respiratory disorders. Patients who smoke should be asked how many cigarettes they smoke each day, what brand and type, and how long they have been smoking (i.e., age at initiation). Patients who have stopped smoking should be asked the date they quit in addition to the previous questions. The patient's smoking history is recorded in pack years, which is calculated as the number of packs (i.e., 20 cigarettes) per day multiplied by the number of years they smoked. For example, a patient who has smoked two packs per day for 10 years has a 20 pack-year smoking history [28].

Patients should also be asked if they use chewing tobacco, as this has been implicated as a factor in the development of cancers of the mouth, larynx, throat, and esophagus. How long the patient has chewed tobacco and how frequently it is used should be noted.

Alcohol Use

An excessive use of alcohol has been implicated as a predisposing factor in the development of tuberculosis, pneumonia, and cancers of the mouth, larynx, throat, esophagus, and liver. Patients should be questioned specifically about what they drink, how much per day, and how long they have been drinking. Patients may minimize their drinking, so a careful, sensitive, nonjudgmental approach is needed when asking questions related to alcohol intake [28].

Past Health History

A thorough history of past respiratory, face, neck, and thoracic problems should be obtained. This includes history of maxillofacial trauma or rib fractures, scoliosis or thoracic deformity, a positive tuberculosis skin test or abnormal chest x-ray, and respiratory complications following general anesthesia or surgery. A history of any of these could contribute to the current health problem of the patient [28].

Allergy and Medication History

The patient should also be questioned about any history of allergies, which can cause sinusitis, allergic rhinitis, and asthma. If the patient has a history of allergies, ask how long the allergic symptoms have been present, what the symptoms are (e.g., difficulty breathing, rhinitis), if allergy testing been done, if specific allergens have been identified, if the patient is receiving immunotherapy, and what specific medications relieve the symptoms.

Patients should be asked to list all medications they are taking (including over-the-counter medications and herbal supplements) and why. Note if patients are using medications as prescribed and if they seem to provide the desired effects [28]. Drug allergies should also be ascertained.

Occupational and Travel History

Because exposure to certain chemical agents and other irritants can result in respiratory disorders, a thorough occupational history should be obtained. Patients should be asked if they work or have ever worked in a job that exposed them to chemical fumes, dust, smoke, or asbestos or in an environment with people who smoke. The specifics of the work environment (e.g., recirculated air) should be noted. The patient's recent travel history is also important, because some infectious diseases affecting the respiratory system are endemic to certain geographic regions [28].

Family History

Information should be gathered on respiratory problems in relatives. Any family history of allergies, asthma, chronic bronchitis, emphysema, tuberculosis, or malignancy should be documented. Whether the patient grew up in a smoking household or currently lives with a smoker should be noted. It is also important to know if anyone in the home or in the family has symptoms like the patient's [28].

OBJECTIVE DATA

Physical Assessment

When performing a physical assessment of patients suspected of having a respiratory disorder, nurses use the skills of inspection, palpation, percussion, and auscultation.

Inspection

Inspection of the nose may reveal polyps, tumors, enlarged turbinates, a foreign body, secretions, or a combination of these. The size and shape of the nose should be noted. An alteration in its shape may be the result of trauma or a tumor in or near the nose. Characteristics of the nasal mucosa and the appearance of the nasal septum are important. The mucosa may be swollen, reddened, and/or covered with secretions. Patients with allergic rhinitis often have pale nasal mucosa rather than the usual pink. Most adults have some degree of nasal septal deviation, but any deviation that narrows or blocks the nasal airway should be noted [29].

The characteristics of the nasal secretions should be assessed. They may be watery, mucoid, mucopurulent, purulent, or bloody. Watery discharge is usually of viral origin, while secretions that are mucoid or mucopurulent may result from inflammation, an acute bacterial rhinitis, or allergic rhinitis. Purulent discharge is usually of bacterial origin. Blood may drain from the nares because of irritation or trauma.

The appearance of the inferior and middle turbinates should be assessed. Tissue overlying the turbinates may become hypertrophied in conditions such as chronic allergic rhinitis. Sinusitis may result in a decrease in transillumination of the frontal and maxillary sinuses. Skin over these areas may also appear reddened in the presence of an infection [30].

Structures of the oropharynx may be enlarged, reddened, and/or covered with secretions. The color of the oral mucosa should be noted. White patches or spots on the mucous membrane of the cheek or tongue (leukoplakia) may indicate a premalignant lesion. Inflammation and secretions are often present with infections such as pharyngitis. Bleeding, restrictions, or distortion of the area may be from a neoplasm of the oropharynx or an infection. Inspect the uvula, fauces, and pharyngeal tonsils as part of the examination. These areas may be distorted in disorders such as peritonsillar abscess, infectious mononucleosis, and tumors of the pharynx [30]. Enlarged lymph nodes in the neck may be the result of common upper respiratory infections, mononucleosis, lymphoma, or metastatic cancer.

Inspection of the chest may reveal thoracic deformities such as kyphoscoliosis or an increased anteroposterior diameter (i.e., "barrel chest"). Kyphoscoliosis reduces thoracic movement and limits lung expansion. "Barrel chest" is a common finding in patients with COPD. Asymmetrical chest expansion can result from trauma (e.g., pneumothorax, hemothorax, flail chest). General overall appearance, such as facial expression, posture, and ease of movement, should also be assessed. Patients with COPD may have to sit up or lean forward in a chair in order to breathe [30].

Examination of sputum may reveal thick, tenacious secretions; mucus plugs; or purulent, bloody, or blood-tinged sputum (hemoptysis). Secretions that are yellow-green or foul smelling may indicate an infection. Sputum that is pink or rust-colored may indicate bleeding, which can result from irritation, infection, or neoplasm.

The pattern and character of respirations should be observed, including the rate and depth of breathing. Labored breathing may be marked by nasal flaring, the use of neck and accessory chest muscles, asymmetry of chest expansion, and/or an increase in respiratory rate. This occurs in conditions such as airway obstruction, COPD, and mediastinal shift. Pursed-lip breathing (a slow, relaxed expiration against pursed lips) is characteristic of patients with emphysema and prevents collapse of small bronchioles and reduces the amount of trapped air. Chest trauma may result in subcutaneous emphysema (air under the skin), which can compromise the airway [30].

When inspecting patients with respiratory disorders, also observe for signs of respiratory acidosis, respiratory alkalosis, and hypoxemia. Disorders that can lead to acidosis include COPD, pneumonia, or respiratory depression due to trauma or medications/illicit drugs. Clinical manifestations of respiratory acidosis or hypercapnia include confusion, drowsiness, dizziness, tetany, and asterixis. Tachycardia and dysrhythmias may be present. Late signs of hypercapnia are convulsions and coma [30].

Respiratory alkalosis occurs in conditions that may lead to hyperventilation, including brain injury, central nervous system tumors, gram-negative sepsis, acute asthma attacks, and extreme anxiety. Manifestations of respiratory alkalosis are related to stimulation of the nervous system. The nurse may observe muscle spasms in these patients, including carpopedal spasm—contractions of the hands and feet. Severe spasms can progress to tetany or continuous muscle contractions. Diaphoresis and cardiac dysrhythmias may occur. The patient will be tachypneic and may lose consciousness [30].

When the respiratory system is affected by disease, the ability to deliver oxygen to the tissues may become impaired, resulting in hypoxia (inadequate tissue oxygen) or hypoxemia (inadequate blood oxygen levels). Conditions that limit the volume of air entering the lungs result in inadequate amounts of available oxygen at the alveolar level. Disorders leading to hypoxia or hypoxemia include restrictive lung diseases (such as pulmonary fibrosis, occupational lung disease, and sarcoidosis), obstructive lung diseases (such as asthma, chronic bronchitis, and emphysema), and occasionally morbid obesity. Any disorder that lowers the oxygen-carrying capacity of the hemoglobin in the blood will also produce tissue hypoxia [30].

The symptoms manifested by acute hypoxia are reflected in the neurologic, cardiovascular, and respiratory systems. Deprivation of oxygen to the brain causes signs of restlessness, irritability, and mental confusion. Effects on the cardiovascular system include tachycardia, hypertension, and cardiac dysrhythmias. Manifestations of chronic hypoxia include exercise intolerance, a general feeling of fatigue, and clubbing of the fingers [30].

Palpation

Palpation of structures of the upper respiratory tract may reveal swelling due to neoplasms or an infection. Palpate the areas over the frontal and maxillary sinuses. With sinusitis, this may elicit complaints of tenderness or pressure. The neck should also be palpated for the presence of enlarged lymph nodes.

Fluid-filled or solid structures transmit vibrations better than structures filled with air. With palpation over the chest, vocal fremitus will be increased with excessive secretions, tumors, or pneumonia. A decrease in vocal fremitus is present in pleural effusion, because it slows the transmission of sound.

Crepitus may be palpated in cases of subcutaneous emphysemas; touching the area results in a crackling sensation. Intercostal bulging may be noted in a patient who has lung abscesses, tumors, or rib fractures. A deviation of the trachea may be palpated in conditions such as tension pneumothorax and neck masses [30].

Percussion

Percussion of the chest produces sounds that can help locate abnormalities in the lungs. The sound heard over normal lung tissue is called resonance. Hyper-resonance is noted when air trapping occurs, as in emphysema or a pneumothorax. Dullness may be heard in the presence of a small pleural effusion, atelectasis, or hemothorax. Flatness (the same sound transmitted with percussion over the thigh) may be heard with massive consolidation or a large pleural effusion. Consolidation refers to an area of the lung that has become more dense either because air is not reaching the alveoli or because the alveoli are filled with fluid or secretions. When fluid is present in the frontal or maxillary sinuses, as in sinusitis, percussion over the sinus produces a dull sound.

Auscultation

Auscultation of the lungs is performed to determine the presence or absence of abnormal breath sounds. Bronchial/tracheal, bronchovesicular, and vesicular breath sounds are normal respiratory sounds in certain areas of the lungs. However, auscultation of these sounds in areas where they are not normally heard may indicate pathology. For example, the presence of bronchial or tracheal sounds over the periphery of the lung may be an indication of atelectasis or consolidation. Although soft rustling (vesicular) sounds heard primarily during inspiration over the peripheral lung fields are normal, decreased vesicular sounds may be present in early pneumonia or emphysema [30].

Adventitious or abnormal breath sounds may also be heard during auscultation. These can include fine-to-medium rales, medium-to-coarse rales, rhonchi, wheezing, crackles, and friction rubs. Crackles are the result of air flowing through moisture in lung passages. Fine-to-medium rales may indicate pneumonia, while medium-to-coarse rales are heard in bronchitis, pneumonia, bronchiectasis, emphysema, and pleural effusion. Wheezing may be noted in patients with asthma or COPD. Rhonchi indicate an obstructive mass or secretions in the large airways. A friction rub is described as "grating after coughing" and may be heard in patients with pneumonia, lung cancer, pleurisy, or tuberculosis [30].

DIAGNOSTIC STUDIES

Pulmonary Function Tests

Pulmonary function tests measure the functional ability of the lungs. More specifically, they:

- Provide objective evidence of the presence, type, and degree of lung abnormality

- Monitor the course of a disease process over time

- Evaluate the effectiveness of various interventions on breathing function

- Help determine the risk of respiratory complications or surgical procedures

Spirometry

Evidence Based Practice Recommendation

The Department of Veterans Affairs and the Department of Defense recommend that spirometry, demonstrating airflow obstruction, be used to confirm all initial diagnoses of COPD.

https://www.healthquality.va.gov/guidelines/CD/copd/VADoDCOPDCPG2014.pdf

Last Accessed: August 10, 2020

Level of Evidence: Consensus Statement and/or Expert Opinion

In routine pulmonary function studies, the patient's lung size and breathing ability are compared with values for healthy individuals who are similar to the patient in age, sex, height, and race. The spirometer is the primary instrument used in this test. Spirometry provides an easy and inexpensive method to measure lung volume with relatively little risk to the patient. Several different types of spirometers are used to measure lung volumes [31,32].

Pulmonary function study results can show a restriction, an obstruction, or a combination of these states. Disease conditions that commonly result in a restriction of airflow include certain neuromuscular disorders (e.g., myasthenia gravis), thoracic deformities (e.g., kyphoscoliosis), restrictions to lung expansion (e.g., pneumothorax, fibrosis), or infiltrative diseases (e.g., tuberculosis, lung cancer). These restrictive conditions cause a reduction in lung compliance, decreasing chest expansion and the volume of air inspired and expired. Disorders that result in pathologic changes of the airways or alveoli obstruct airflow into and out of the lungs. These include chronic bronchitis, emphysema, asthma, and bronchiectasis [31].

Spirometry is able to measure tidal volume, inspiratory reserve volume, and expiratory reserve volume. Tidal volume is the amount of air inspired and expired with each normal breath. The normal value is approximately 500 mL. Inspiratory reserve volume is the additional volume of air that can be inspired beyond the normal tidal volume. It amounts to approximately 3,000 mL. Expiratory reserve volume is the volume of air that can be forcefully expired at the end of the normal tidal expiration. This is about 1,100 mL in healthy individuals. Residual volume consists of the amount of air that remains in the lungs after a forceful expiration. This usually equals about 1,200 mL.

When discussing the pulmonary cycle, it is often helpful to consider two or more of the pulmonary volumes together. These combinations are referred to as pulmonary capacities. Inspiratory capacity is the volume of air that a person can inspire from a resting level. This equals the tidal volume plus the inspiratory reserve volume, and typically amounts to about 3,500 mL. Vital capacity is the maximum volume of air that can be exhaled forcefully from the lungs following a maximal inspiration. This is equal to the inspiratory reserve volume, the expiratory reserve volume, and the tidal volume, and should total about 4,600 mL. Total lung capacity refers to the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort. It equals the vital capacity plus the residual volume and is approximately 5,900 mL [21,33].

Pulmonary volumes are measured in time intervals. Forced vital capacity (also referred to as forced expiratory volume) is the maximum pulmonary volume the patient has for ventilation. The patient inhales the maximum amount of air and then forcefully exhales as fast as possible. The amount of air the patient can forcefully exhale within a specific time period is calculated. The usual time periods are one, two, and three seconds. A healthy individual can usually exhale approximately 75% of vital capacity in one second and 100% by three seconds.

Minute respiratory volume is the amount of air moved into the respiratory passages each minute. This consists of the tidal volume multiplied by the respiratory rate. The normal finding is approximately 6 L/minute [21,33].

To allay anxieties, patients should be told how spirometry tests will be conducted and what will be expected of them. It is important to explain that pulmonary tests are not painful or harmful. Some patients may need to be reassured that the degree of exertion necessary to complete the test will not cause injury to their lungs. Others may fear their lungs will burst or that they will be unable to catch their breath. Explain the technique and equipment to patients in terms they can understand. This will aid in lowering patient anxiety and increasing cooperation. Patients should be told their noses will be clamped intermittently and they will be asked to breathe in and out through a mouthpiece connected to a machine. It is important that patients understand that accurate results can be obtained only by following instructions carefully. Because gastric distention may impair ability to expand the lungs, tests should be performed before meals. Medications that may alter respiratory function, such as bronchodilators, should be withheld unless otherwise indicated by the physician [30].

Before the test, the patient is asked to loosen any constricting clothing that might interfere with chest expansion. The patient may be either sitting or standing. The patient should be told to seal both lips around the mouthpiece and keep the nose clip on to prevent air leakage. The patient is then asked to breathe as normally as possible through the spirometer; the next step is not initiated until he or she is comfortable with breathing normally on the machine. At the completion of four or five normal breaths, the patient is told to breathe in as much air as possible, to fill the lungs far more than usual, and then to blow out all the air from the lungs. The volumes breathed in and out are the measures, along with the time needed for expiration.

Gas Dilution Methods

Functional residual capacity cannot be calculated using simple spirometry; a method of gas dilution is used to obtain this value. Functional residual capacity is the volume of air remaining in the lungs after a normal expiration. It equals the expiratory reserve volume plus the residual volume and is approximately 2,300 mL in healthy adults. After this value is obtained, the residual volume can be calculated.

Gas dilution methods include the helium dilution and nitrogen washout techniques. With the nitrogen washout technique, after a normal expiration, the person changes from breathing normal air to breathing 100% oxygen for several minutes. This serves to remove (wash out) all of the nitrogen into the expired air (as dry atmospheric air contains approximately 78% nitrogen and 21% oxygen). By determining how much nitrogen was in the expired air, the amount of air in the lungs at the beginning of the test can be calculated. This value is the functional residual capacity. Residual volume may then be calculated by subtracting the expiratory reserve volume from the functional residual capacity [21].

Another technique is the helium dilution method. This consists of the use of a spirometer filled with a solution of helium and oxygen. The patient takes normal breaths, and the difference in helium concentration before and after the test is used to calculate the patient's functional residual capacity.

Lung Plethysmography

In some cases, a specialist may order lung plethysmography in order to assess patients with upper respiratory problems. This tests consists of the patient sitting in a small, air-tight room (also referred to as a "body box") and blowing into a mouthpiece in both the open and closed positions.

X-Rays

Chest X-Ray

Chest x-ray, one of the most common procedures used to evaluate the lungs, is part of the evaluation of most patients suspected of having pulmonary disease, except during pregnancy. The evaluation should include a posteroanterior view and at least one lateral film.

In posteroanterior views, the upright position is used because the diaphragm is lower and the lungs are larger. The patient is asked to take a deep breath and hold it for a few seconds while an x-ray beam is projected from the back to the front of the patient. Individuals who are very ill, infants, and young children are usually x-rayed lying down in the supine or anteroposterior position [33].

Evidence Based Practice Recommendation

According to the American College of Radiology, despite inconsistent data regarding the sensitivity of chest radiographs for bacterial pneumonia, it still plays a role as the primary modality for making or excluding the diagnosis of bacterial pneumonia in patients presenting with acute respiratory illness.

https://acsearch.acr.org/docs/69446/Narrative

Last Accessed: August 10, 2020

Level of Evidence: Expert Opinion/Consensus Statement

Lateral views add information about areas of the lungs that cannot be viewed well in the posteroanterior position, such as the anterior part of the lung close to the mediastinum. A lateral film is always taken whenever chest disease is suspected or for patients older than 40 years of age. Oblique views are beneficial in delineating pulmonary or mediastinal masses or lesions and pleural effusion that may not be well-demonstrated on posteroanterior or lateral views [33].

The lateral decubitus view is used to detect a small amount of free pleural fluid, pneumothorax, cavitations, or lung abscess. This view is taken with the patient in the side-lying position. The x-ray beam is aimed parallel to the floor and the area of concern is positioned closest to the film. Lordotic views are also taken to better evaluate the apical portions of the lungs, to assist in recognizing collapse of the middle lobe, and to determine if a lesion is anterior or posterior. Abnormal findings evident on chest x-ray include areas of density (potentially related to atelectasis, pneumonia, or pneumothorax), hypersecretion, masses, and increased vascular marking [33].

Paranasal Sinus Films

Patients suspected of having sinusitis may benefit from evaluation with paranasal sinus films. X-ray examination of the paranasal sinuses may also be employed for patients with head trauma and those suspected of having sinus neoplasm.

Traditional x-ray assessment of the paranasal sinuses often necessitates a series of different views, typically Caldwell's view, Water's view, lateral view, submentovertical view, and right and left oblique orbital views.

An area of density on x-ray film may indicate a foreign body, stone, cyst, polyp, or osteoma in the paranasal sinus. Osteolysis (abnormal resorption or absorption of bone) may be evident. In the absence of disease, the mucosal lining of the sinuses does not show up on x-ray films. An infection of the sinus may be evident if it causes edema of the mucosal lining. Clouding of the sinus may indicate edema or accumulated fluid. When fluid is present but does not fill the entire cavity, an air-fluid level may be seen. Fluid may be present as the result of sinusitis or hemorrhage secondary to trauma.

Facial Films

The traditional x-ray examination to detect injury after maxillofacial trauma consists of the four views, with the addition of the panorex view of the mandible. This shows the entire mandible fairly well in one view so that breaks in the bones and edema of tissues may be seen. If the patient has severe maxillofacial trauma, the nurse will need to provide emotional support in addition to technical skill maintaining a patent airway and closely monitoring vital signs.

Nursing Implications

The x-ray procedure should be explained in terms that the patient can understand. In a chest x-ray, a beam passes through the body to a film. The films obtained will provide the radiologist with information about the structure and function of the lungs. Patients may have misconceptions about the physiologic effects of exposure to diagnostic radiation. Allow the patient to verbalize these fears and then provide correct information. If the patient is pregnant, x-rays are avoided unless absolutely necessary. If critical illness of a pregnant woman necessitates a chest x-ray, the abdomen is protected with a lead shield [30].

When patients are acutely ill, portable chest x-rays may be necessary. The quality of a chest film taken with a portable x-ray is not as good as the film taken in the radiology department, because the patient and equipment cannot be positioned for the best view. To increase the quality of these films, the patient should be sitting completely upright. Visitors and other staff members should be asked to leave the immediate area, and personnel who must remain in the room should be protected by lead aprons. A pregnant nurse or visitor should never be exposed to x-rays [21].

If sinus x-ray is necessary, patients should be told that films will be taken from different views, and that the process will not cause them much, if any, discomfort. Patients will be asked to hold the head in certain positions against the x-ray plate. The nurse might find it helpful to compare the process to a chest x-ray, as many patients have had that experience [21].

Lung Scans

A lung scan may be classified as either a perfusion scan or a ventilation scan; usually, both types are done together. To obtain a perfusion scan, radioactive dye is administered intravenously. When the dye is injected, the patient should be supine and breathing normally to produce a uniform distribution of radioactive particles in the pulmonary capillary bed. The scan may begin immediately after injection of the dye. Anterior, posterior, both lateral views, and both posterior oblique views are obtained. An x-ray of the lung may be obtained at the same time so comparisons can be made [33].

Ventilation scans are usually performed using radioactive tracer gas or mist. The patient should be sitting or supine. Patients will usually wear a tightly fitting facial mask that allows them to breathe radioactive gas for a few minutes. Depending on the type of gas, patients may need only to breathe through a nasal cannula.

Ventilation and perfusion scanning are used most often to diagnose pulmonary embolism, but they may also be used in the work-up of lung cancer, COPD, pulmonary edema, and pulmonary infections. Unlike most pulmonary function tests, the lung scan can measure regional lung functions. This makes possible the diagnosis of pulmonary diseases at an earlier stage, before other parameters of respiratory function become impaired [33].

Nursing Implications

When preparing patients for lung scans, the first step is to explain the purpose of the test (to determine if all of the patient's lung tissue has adequate circulation and if air is reaching areas as it should). Patients should know they will receive radioactive dye IV for a perfusion scan. Any history of an allergic reaction to dye used in diagnostic tests should be documented and brought to the attention of the physician. The nurse should stress that patients should try to relax and breathe normally during the test. Patients should be told that a machine will move over the chest to obtain different views of the lungs. A conventional chest x-ray may also be taken at that time [30].

Patients should be informed that during a ventilation scan they will be asked to breathe a mixture of gases through a mask or nasal cannula so the air flowing in and out of their lungs can be traced. Inhalation of this gaseous mixture should not cause them discomfort.

Arterial Blood Gas Analysis

Arterial blood is collected for analysis of pH, PCO_2, PO_2, oxygen saturation, bicarbonate level, and base excess. These values show how well the patient's lungs are delivering oxygen to the bloodstream and eliminating the waste products of cellular metabolism [34].

pH

The normal pH of arterial blood is 7.35 to 7.45. Values less than 7.35 indicate acidemia, while those greater than 7.45 are indicative of alkalemia. The normal pH range is maintained primarily by two buffers: carbonic acid and bicarbonate [34].

The normal ratio of carbonic acid to bicarbonate (1:20) must be maintained; otherwise, the pH will not be within the normal range. The lungs control the carbonic acid level by selectively retaining or ventilating CO_2, which combines with water to form the carbonic acid's hydrogen ion. The bicarbonate portion of the balance is controlled by the kidneys, which excrete either alkaline or acidic urine [35].

The normal range of PCO_2 in the arterial blood is 35 to 45 mm Hg. A PCO_2 level greater than 45 mm Hg may be indicative of compensated metabolic alkalosis or hypoventilation, which results in respiratory acidosis. A PCO_2 value less than 35 mm Hg may arise from compensatory metabolic acidosis or hyperventilation, which can result in respiratory alkalosis [34,35].

The normal pressure of PO_2 in arterial blood is 80 to 100 mm Hg. This value has no direct bearing on the pH, but it is an important indication of whether adequate oxygen is available for cellular metabolism. A PO_2 elevation may be seen in patients who are receiving a high-liter flow of oxygen. Prolonged elevations in PO_2 levels can result in damage to the pulmonary tissue [34,35].

Oxygen Saturation

The extent of oxygen saturation (the amount of hemoglobin combined with oxygen) is expressed as a percentage of the blood's capacity for full saturation. The normal value is 95% to 98% in arterial blood [34,35].

Bicarbonate Ion

The negative ion of bicarbonate is normally present in arterial blood at a value of 22–26 mEq/L. A lower value is indicative of metabolic acidosis or compensation for respiratory alkalosis. A value greater than 26 mEq/L is indicative of metabolic alkalosis or compensated respiratory acidosis [34,35].

Base Excess

The base excess represents an increase or a decrease in the total amount of buffer bases available. The normal range is -2 to +2 mEq/L in arterial blood. This value is considered a more reliable indication of the true metabolic makeup of an acid-base disturbance than the bicarbonate value. As with the other measures, an increase indicates metabolic alkalosis or compensated respiratory acidosis; a decrease indicates metabolic acidosis or compensated respiratory alkalosis [34,35].

Nursing Implications

For arterial blood gas tests, the patient should be advised that a small amount of blood will be obtained from an artery to determine how well the lungs are functioning. Equipment necessary includes a heparinized syringe, an alcohol swab, and a piece of gauze. Many facilities use prepared syringes with dry electrolyte-balanced heparin. Heparinization may also be achieved "in house" by drawing up 0.5 mL of heparin (1:1,000) into the syringe and wetting the entire barrel by moving the plunger up and down. Excess heparin is ejected, leaving the syringe free of air bubbles, and the needle filled with heparin. This will prevent clotting of the blood sample [30].

Common sites for obtaining an arterial blood gas sample are the radial, brachial, and femoral arteries. The puncture site should be thoroughly cleansed with alcohol or an antiseptic solution. The location of the artery is ascertained by palpation of the pulse. A sterile 5-mL heparinized syringe fitted with a wide-bore needle (20 to 21 gauge) will allow the easy flow of blood into the syringe. However, a smaller gauge needle results in less trauma to the artery.

Cultures

A culture involves growing bacteria or other micro-organisms from a specimen of blood or material obtained in an aseptic manner or using sterile technique. The specimen is placed in an environment that promotes the growth of organisms. When the micro-organisms increase, laboratory personnel can isolate and identify the pathogen. Sensitivity studies may also be done to determine which antimicrobial drug is effective against the organism to help guide drug therapy.

Specimens are examined in stained and unstained direct smears. The most frequent staining test is Gram stain, which distinguishes among bacteria with similar morphology by classifying them as gram-negative or gram-positive. Some organisms, such as mycobacteria, cannot be stained using this method and require acid-fast staining techniques [1,10].

Nursing Implications

Obtaining a nose or throat culture rarely causes the patient discomfort, but the patient should be told that a cotton swab will be inserted into the nose or throat to obtain a specimen. The purpose of obtaining the specimen—to identify organisms present and susceptibility to specific drugs—should be explained.

For cultures from the nares, the swab should be introduced as far back as possible (without bending) and rotated gently. Cultures from the pharynx are obtained while avoiding touching the tongue or teeth, which would result in contamination. Depress the tongue with a tongue blade, and swab the interior wall of the pharynx below the level of the uvula. The swab should be rotated over any involved or inflamed areas. The specimen collected on the swab should be placed in the appropriate container and taken to the laboratory as soon as possible to prevent drying.

Sputum cultures are often indicated for patients with suspected respiratory disease. Other culture specimens (e.g., from abscesses in the lungs) are obtained during bronchoscopy [29,36].

Sputum Cytology

Sputum cytology involves the detailed examination of the cellular structures of sputum. This is primarily done to assist in the identification of malignant cells in individuals suspected of having lung cancer.

Nursing Implications

The optimal time to obtain a sputum specimen is early in the morning. The first sputum expectorated will contain secretions that have pooled in the patient's lungs during the night, giving a more productive sample. To decrease contamination of the sputum, the patient should rinse out the mouth without swallowing, brush the teeth, or both.

For a true sputum sample (not saliva), the patient should take several deep breaths and then cough forcefully. Respiratory secretions are more easily expelled if the patient is well-hydrated and breathes humidified air.

If the patient is not able to produce a sputum sample, it can be obtained by postural drainage, inhalation of cold steam or nebulized vapor, or suctioning. If suctioning is used, a sputum collection trap is used to obtain a sterile sample. When cultures are being obtained, the specimens should be collected in sterile containers using sterile technique prior to beginning antibiotic therapy [33].

Skin Tests

Tuberculin Skin Testing

Evidence Based Practice Recommendation

The World Health Organization recommends that household contacts and other close contacts of TB cases, people living with HIV, and current and former workers in workplaces with silica exposure should be systematically screened for active TB.

https://www.who.int/tb/tbscreening/en/

Last Accessed: August 10, 2020

Strength of Recommendation/Level of Evidence: Strong recommendation, low-quality evidence

One way to perform tuberculosis screenings is to use the Mantoux method of skin testing [37]. The test indicates those who have been infected with the organism as soon as 2 to 10 weeks after exposure.

With the Mantoux technique, 0.1 mL of purified protein derivative (PPD), containing 5 tuberculin units (TU), is injected intradermally into the volar or dorsal surface of the forearm. Using a 26- or 27-gauge needle, the tuberculin syringe should be held close to the skin so the needle hub touches it as the needle is inserted into the skin, with the bevel up. This decreases the needle angle at the skin surface and helps to ensure the fluid is injected just beneath the surface of the skin into the dermis to form a wheal, taking care not to inject subcutaneously.

The site of the injection should be circled with a pen and the location documented on the patient's medical record (in case the pen circle should wash off). Examine the site of the Mantoux intradermal injection within 48 to 72 hours of injection. Always use sufficient lighting to examine the area. Use a pen to outline the diameter of induration (firm-to-hard zone of elevation or swelling). The area of erythema is not measured, and erythema without induration is of no significance. Use a standard centimeter ruler or a clear plastic ruler that has been marked with circles of various diameters. Place the ruler over the outlined induration to measure its diameter. The presence and degree of induration is an indicator of prior tuberculosis infection and, to some extent, the probability of current active tuberculosis.

A reaction of <5 mm is negative. Reactions >10 mm are "positive." An intermediate reaction of 5–10 mm is suspicious for prior infection in high-risk persons.

In suspect cases, the significance of a negative tuberculin skin test can be further assessed by testing for anergy. A control test is done using antigens to which virtually all adults have been previously exposed to determine if there is any cellular immune response. The antigens most commonly used as controls are Candida albicans, Trichophyton, mumps virus, and tetanus. They are administered using the same Mantoux technique.

Two blood tests are also available for tuberculosis diagnosis (the QuantiFERON-TB Gold In-Tube and T-SPOT.TB tests), and these options have the advantages of being done in one patient visit with results available in 24 hours. As such, they are usually the preferred option for diagnosis (rather than screening).

Coccidioidomycosis Skin Testing

Skin testing for coccidioidomycosis, a respiratory fungal disease also known as Valley fever, can be performed with mycelium-derived antigen coccidioidin or the newer, more sensitive spherulin (produced from the parasitic spherule). The procedure for administering the test is similar to that described for the Mantoux tuberculin test; the test is read in 24 to 48 hours [38]. A positive reaction (0.5 mm or more of induration) indicates past infection. This test becomes diagnostic only when conversion to positive occurs during the course of the clinical illness. A positive skin test indicates intact cell-medicated immunity. This immunity is frequently lost during the course of dissemination of the disease and means a poor prognosis. As with tuberculosis, blood testing may be preferred over skin testing for diagnostic purposes.

Immunoglobulins

Immunoglobulins are serum proteins, produced by lymphocytes and plasma cells, that function as antibodies in the body's immune defense system. Immunoglobulins can be separated for study by electrophoresis. The five main immunoglobulin serum proteins are IgG, IgA, IgM, IgI, and IgE. The levels of one or more immunoglobulin fractions may change in allergy, pneumonia, tuberculosis, and pulmonary fungal infections (e.g., coccidioidomycosis). For this test, only a blood sample is necessary [1].

Indirect Laryngoscopy

Indirect laryngoscopy allows the examiner to view the vocal cords and other laryngeal structures. Patients are usually positioned so they are sitting all the way back in the chair with the head and shoulders forward. Mirrors of different sizes can be used, depending on the amount of space between the tonsils. Various surgical procedures can be performed using indirect laryngoscopy if the patient is cooperative, including injection laryngoplasty (to treat unilateral vocal cord paralysis) and removal of vocal nodules [19].

Nursing Implications

Laryngoscopic examination is easier and more information is gained if the patient is relaxed and knows what to expect. Position the patient correctly and explain the importance of remaining in that position. It is helpful if patients know that they will be instructed to say "ah" or make other sounds while being examined [30].

If surgical procedures are performed using this approach, the patient is usually given a sedative. In this case, the nurse would assist the patient in maintaining the desired position. The nurse also assesses the patient for changes in appearance or vital signs and abnormal bleeding.

Direct Laryngoscopy

With direct laryngoscopy, the physician inserts a fiber-optic laryngoscope to view the larynx directly under magnification. A variety of types of instruments can be used. Microlaryngoscopic instruments with binocular magnification allow the physician to view changes that cannot be seen with indirect laryngoscopy.

Direct laryngoscopy is used to investigate signs and symptoms associated with the larynx (e.g., when a patient complains of hoarseness for more than two weeks) when indirect laryngoscopy shows no abnormality. In addition, direct laryngoscopy is frequently used for minor surgical procedures, such as biopsy of a growth on the larynx, removal of laryngeal polyps and vocal cord nodules, and removal of foreign bodies from the larynx. Trauma victims may require direct laryngoscopy to assess the extent and severity of injuries [19].

Nursing Implications

Direct laryngoscopy can be performed using either local or general anesthesia. Patients should be assured that they should not experience pain during the procedure and that the airway will be maintained throughout. Preoperative medications may be administered to help the patient relax if local anesthesia is employed. The patient should not drink or eat for several hours before the procedure, and any dentures should be removed.

After the procedure, the patient will be allowed to drink soon after waking up. If a local anesthetic was used, the nurse must ensure that the patient's gag reflex has returned and that he or she can swallow. A sore or irritated throat is not uncommon following laryngoscope, but the patient should be observed for signs and symptoms of respiratory distress from laryngeal edema or spasm. After the removal of laryngeal polyps or vocal cord nodules, the patient should rest the voice for several days. Clearing the throat and coughing should be avoided, if possible [30].

Bronchoscopy

Bronchoscopy is the direct viewing of the trachea and tracheobronchial tree by means of a standard or fiber-optic bronchoscope. The fiber-optic bronchoscope is a slender, flexible tube with mirrors and a light at the distal end. A brush, biopsy forceps, or catheter may be passed through the bronchoscope to obtain samples for cytologic examination.

The fiber-optic bronchoscope is most commonly used because it is small and flexible, allowing better visualization of the segmental and subsegmental bronchi. There is also less risk of trauma from intubations with this approach [19].

Bronchoscopy is performed with the patient sitting or supine, with the bronchoscope inserted either through the patient's nose or mouth [19]. Bronchoscopy is used in the diagnosis of such conditions as hemoptysis, lesions, masses, and abnormalities seen on chest x-ray. The procedure may also be used to treat lung abscesses, pneumonia, and aspiration; to debride mucosal eschar resulting from burns and other inhalation injuries; and to remove foreign bodies. Bronchoscopy can aid in removal of excessive tenacious secretions when nasotracheal suctioning is ineffective.

Nursing Implications

Bronchoscopy entails a certain amount of patient discomfort. The patient is likely to be anxious, not only about pain but also about the findings, especially if the procedure is being performed to assess suspected malignancy. Nurses should take time to explain the procedure and to answer any questions the patient may have and allay any anxieties based on misconceptions. Patients should be told that they will receive an intravenous sedative to help them relax and that a local anesthetic will be sprayed into the nose and mouth to suppress the gag reflex. This will produce the sensation of a dry mouth, swollen tongue, and swollen throat, and will make the patient unable to swallow. Patients should be reassured that they will be able to breathe during the procedure [30].

Following bronchoscopy, vital signs are monitored. Conscious patients are placed in a semi-Fowler's position; unconscious patients are positioned on their side with the head of the bed slightly elevated. An emesis basin should be provided and the patient instructed to expectorate secretions into the basin rather than swallowing them. Patients should be advised that clearing the throat or coughing could dislodge a clot and possibly cause hemorrhage. Watch for subcutaneous emphysema, which may indicate tracheal or bronchial perforation. Foods and fluids are restricted until the gag reflex returns. Hoarseness and a sore throat can be relieved by gargles and throat lozenges. Nurses should assess for any breathing difficulty (from laryngeal edema or laryngospasm), hemoptysis, symptoms of a pneumothorax, and bronchospasm.

Mediastinoscopy

With mediastinoscopy, an incision is made over the mediastinum and a scope inserted to explore the area. The mediastinum is the area in which the esophagus, trachea, great vessels, and heart are located. Mediastinoscopy is also used to obtain biopsies of lymph nodes or other masses, to determine the presence of lymphoma or lymph node metastases due to bronchogenic carcinoma, and to diagnose intrathoracic sarcoidosis. A common approach is through an incision in the suprasternal notch, which allows for endoscopic examination of the upper half of the mediastinum, including the proximal part of the major bronchi [1].

Nursing Implications

Mediastinoscopy can be performed under either local or general anesthesia. Patients should be advised that the procedure will leave a small incision and that the incision site might be somewhat sore for a few days. The patient should not eat or drink anything for several hours prior to the procedure. Patients are given a full explanation of the procedure and its purpose in terms they can understand. A signed consent is necessary [30].

Postoperative nursing care includes monitoring vital signs, observing for bleeding from the incision site, and alleviating discomfort by supportive measures or administering prescribed pain medication, as appropriate. The nurse should also observe the wound for signs and symptoms of infection. Possible complications, in addition to hemorrhage and wound infection, include right recurrent laryngeal nerve paralysis and esophageal perforation.

Bronchography

On a chest x-ray, a small portion of the bronchial tree beyond the first two major divisions is visible. To diagnose abnormalities of the smaller sections of the bronchial tree, bronchography may be performed. This diagnostic test begins with instillation of radiopaque contrast medium through a catheter into the lumen of the trachea and bronchial tree. Chest x-rays are then taken. Bronchography is primarily indicated for diagnosing bronchiectasis and ascertaining its location before surgical resection. Bronchography may also aid in diagnosing compression, obstruction, and presence of a foreign body or a lesion in the trachea or larger bronchi [1].

Nursing Implications

A full explanation of the procedure should be given, including informing patients that they will be placed in various positions to aid in distribution of the dye. Question the patient and also check the chart for known hypersensitivity to the dye used for the procedure. Proper visualization requires that the airways be as free of secretions as possible. To achieve this, bronchial drainage, nasotracheal suctioning, or both may be necessary. The patient should have nothing by mouth for several hours prior to the procedure [30].

After completion of the procedure, the patient's vital signs should be monitored. To facilitate removal of the contrast medium, deep breathing and sighing, postural drainage, and nasotracheal suctioning are usually necessary. Before allowing the patient to drink, check for return of the gag reflex by stimulating the posterior pharynx with a swab or tongue blade.

Thoracentesis

Thoracentesis, employed for years to aid in the identification of diseases involving the pleura, consists of the insertion of a needle into the intrapleural space to remove fluid. It may be done to obtain a specimen for diagnostic purposes or to remove fluid from a pleural effusion. After the selected area is cleaned, a local anesthetic is injected into the skin. The needle is then inserted and fluid aspirated. The amount, color, odor, and character of the fluid should be noted. The fluid may be described as serous, serosanguineous, or turbid. Serous fluid may be obtained from patients who have disorders of nontraumatic origin, including congestive heart failure, pleural effusion due to a malignancy, glaucomatous diseases, and disorders resulting in inflammation. Blood in the fluid is usually due to trauma to the lungs, but it may also be seen in patients with advanced malignancy. Turbid fluid in the intrapleural space is most commonly from an infection [1,10]. Rarely, hyperalimentation solution may be present in the fluid. This occurs when a central venous line is placed (and the solution is infused) into the intrapleural space instead of the vena cava.

No more than 1,000–1,500 mL of fluid should be removed at any one time because of the danger of hypotension. The specimen is sent to the laboratory, where it is assessed for red blood cell count, white blood cell count with differential, protein, glucose, lactic acid, dehydrogenate, amylase, pH, cultures, bacteriologic stains, and pleural fluid cytology.

Nursing Implications

Although thoracentesis is a relatively simple procedure, it can be frightening to patients. The basic steps should be explained to the patient calmly and completely. Patients should be warned to expect a sensation of pressure or discomfort when the needle is inserted. In some cases, medication may be prescribed to calm a frightened patient [30].

Proper positioning of the patient is essential for the procedure. The patient should either be sitting and leaning over a bedside table or, if unable to sit, lying on his/her affected side with the ipsilateral arm over the head and access available to the midaxillary line. These positions give the patient support and stability and allow for elevation of the ribs. Patients should be encouraged to remain still to avoid trauma to the lung tissue. If the patient has a frequent cough, a cough suppressant may be administered to avoid excessive movement while the needle is in the intrapleural space.

A nurse will remain with the patient throughout the procedure to provide support and monitor vital signs. Complications of thoracentesis are relatively rare and include hemorrhage, pain, and pneumothorax. After the procedure, monitor the patient's vital signs and respiratory status to detect any adverse reactions. The insertion site should be observed for swelling that could result from bleeding into the area [10].

Lung Biopsy

Both open and closed approaches are used to obtain lung tissue for cytologic analysis and culture. Closed approaches include fine-needle aspiration, biopsy via a percutaneous cutting needle, and biopsy via fiber-optic bronchoscope. All closed procedures are done under local anesthesia with fluoroscopic guidance. Open biopsy requires a thoracotomy. This approach provides the largest volume of tissue, but general anesthesia is needed. Lung biopsy is indicated when the patient's diagnosis remains unclear despite a complete work-up [12,32].

Nursing Implications

If only local anesthetic is used, patients should be told that the area will be numbed, but they will probably still feel some pressure or discomfort when the biopsy is taken. Patients may be asked not to eat or drink anything for a few hours prior to the procedure. When the biopsy is completed, observe the site for swelling or bleeding, and watch the patient for approximately 24 hours for any signs and symptoms of pneumothorax, air embolism, or hemorrhage [30].

7. NURSING DIAGNOSES, PLANNING, AND IMPLEMENTATION

Assessment of patients with respiratory dysfunction involves obtaining the history, conducting a physical examination, and reviewing the results of diagnostic studies. The three major nursing diagnoses are ineffective airway clearance, ineffective breathing pattern, and impaired gas exchange. Various nursing interventions may be implemented to address these diagnoses.

INEFFECTIVE AIRWAY CLEARANCE

The nursing diagnosis of ineffective airway clearance is frequently used. The degree may range from mild to severe and may be related to the upper or lower respiratory system or both. Patients may experience difficulty maintaining normal airflow into and out of the lungs because of structural obstruction, the presence of foreign bodies, or the presence of excessive tenacious nasal or bronchial secretions. For example, patients with acute rhinitis or sinusitis may have nasal and sinus secretions that make it difficult or impossible to breathe through the nose. The presence of nasal polyps or turbinates enlarged as a result of an allergic response will also decrease the airflow through the nasal passage. Inadequate draining of the paranasal sinuses can result in chronic infectious sinusitis that may necessitate surgical intervention. Secretions may be present in the oropharynx from postnasal drip or an infection such as pharyngitis or tonsillitis and may impair the patient's ability to swallow, speak, or breathe. These symptoms can also be caused by a tumor in the oropharynx or laryngopharynx that blocks the flow of sputum when the patient coughs. Enlargement of structures in the oropharynx (e.g., the tonsils) may also block attempts to expel sputum. Foreign bodies in the oropharynx or laryngopharynx may block the flow of secretions as well as the flow of air and can be fatal [26,27].

COPD is a common cause of ineffective airway clearance in the lower respiratory system. Patients with COPD often have excessive pulmonary secretions and have difficulty expelling the sputum. Infections such as pneumonia may also cause the accumulation of excessive secretions in the lower respiratory system.

A variety of nursing interventions may be employed when the nursing diagnosis is ineffective airway clearance. The most useful include pursed-lip breathing, diaphragmatic breathing, postural drainage, and nasotracheal suctioning. In severe disorders, the patient may require intubation mechanical ventilation [26].

Pursed-Lip Breathing

Pursed-lip breathing—a slow, even expiration against pursed lips—prevents collapse of small bronchioles, reduces the amount of trapped air in the lungs, and promotes CO_2 elimination. To assume the proper lip position for pursed-lip breathing, have the patient in a sitting position pretend to blow out a candle. As noted, patients with emphysema can use pursed-lip breathing to maximize expiration.

Diaphragmatic Breathing

Diaphragmatic breathing (also known as abdominal breathing) facilitates maximum use of the diaphragm in breathing. This is particularly helpful for patients who have had thoracic surgery and those with COPD. Ask the patient in a sitting position to take a deep, slow breath through the nose, concentrating on maximum expansion of the abdomen. Place the patient's hand on the abdomen to feel it rise. Then, have the patient exhale slowly through pursed lips while contracting the abdominal muscles. The patient should place manual pressure on the abdomen during expiration. Use of this breathing pattern should be encouraged during daily activities so it becomes an automatic approach to breathing during periods of respiratory difficulty [27].

Postural Drainage

Postural drainage combines the force of gravity with normal ciliary action to move secretions from smaller to larger airways, where they can be removed by coughing or suctioning. The patient's lungs should be auscultated prior to postural drainage to determine which segments require drainage, and after drainage to determine effectiveness of the therapy. Postural drainage can be directed to any segment of the lung.

Percussion and vibrating techniques are often used with postural drainage. Percussion with a cupped hand helps loosen secretions and stimulate coughing. The patient should use diaphragmatic breathing during percussion. Vibration involves manual pressure on the chest using a vibrating movement of the hand during expiration. The loosening and mobilizing of mucous secretions are increased with vibration.

Percussion and vibration are directed to the specific lung segments involved. To loosen secretions in the right middle lobe, percuss over the anterior and lateral right chest from the midaxillary line to the sternum for about two minutes. Then, perform three to five vibrations over the same area during expiration only. The patient should cough after the procedure.

Extremely ill or elderly patients may not be able to tolerate some of the positions for postural drainage, particularly those with the head lower than the feet. Individual modifications of position will be necessary, based on the patient's condition. Postural drainage exercises should be scheduled before meals, because sputum will be minimal and the risk for vomiting and aspiration minimized. Postural drainage is generally done two to four times per day [26,27].

Nasotracheal Suctioning

Patients who are not intubated may require suctioning of the tracheobronchial tree. It is important to explain the procedure to the patient to allay anxiety and gain as much cooperation as possible. An explanation is important even if patients are unresponsive, because they may still be aware of activities.

The patient is positioned at a 45-degree angle (unless contraindicated). Patients should be hyperoxygenated before suctioning; if they are receiving oxygen, the flow rate is increased during the procedure. Nurses should limit suctioning to 5 to 10 seconds, and a rest period should be provided before repeating the procedure [26,27].

Nasal Packing

Patients with epistaxis may have a nursing diagnosis of ineffective airway clearance. Some will have difficulty breathing because of the drainage of blood thorough the nasopharynx into the oropharynx. These patients may also have difficulty expectorating the blood and may swallow a significant amount, causing nausea and vomiting. Nasal packing (e.g., a balloon catheter) is inserted by the physician in an effort to control the bleeding.

Nasal packing may be either anterior, posterior, or both. When bleeding from the anterior portion of the nose cannot be controlled by either local application of vasoconstrictor drugs or cauterization, packing is inserted. Bleeding from the posterior portion of the nose is often more severe, and a posterior pack is inserted to control the bleeding. Patients with anterior nasal packing are often sent home; however, patients who require posterior packing may be admitted to the hospital for observation because of the risk of obstruction [29].

Patients sent home with nasal packing should be instructed to observe for bloody drainage. If bleeding begins and the gauze becomes blood soaked, the patient should call his or her physician immediately. When bleeding recurs, the patient is usually instructed to return to the office or hospital. Patients should also avoid tampering with or unnecessary touching of the packing or nose and should apply a lubricant around the nares to prevent drying and crusting of secretions and skin. Because mouth breathing is necessary, frequent oral hygiene should be given to prevent drying of the oral mucosa. Lubricants may be applied to the lips to prevent drying or cracking [36].

For patients with posterior packing, the posterior pharynx should be inspected often, with good lighting, to check for bleeding and to ensure that the packing has not moved. Misplacement of the packing into the oral pharynx could obstruct the upper airway. The patient should be told that swallowing may be difficult and will bring a sucking sensation in the back of the throat. Due to this, a liquid or soft diet is best tolerated [29].

Nurse and patient should be alert for renewed or increased bleeding, which can result in tachycardia and hypotension. Stools may be tarry if bleeding has lasted for a few days. These patients may also be prescribed prophylactic antibiotics to prevent sinus infection.

Nursing Evaluation

Nursing interventions related to excessive excretions in the respiratory system are successful when the patient can move air in and out of the upper and lower respiratory tracts without difficulty. Subjective and objective findings that verify these outcomes include a normal appearance (or a decrease in inflammation and swelling) of structures in the nose, oropharynx, and hypopharynx; absence of inflammation, redness, and tenderness over the paranasal sinuses; return of the patient's voice to normal; absence of purulent, tenacious discharge or sputum; normal breath sounds on auscultation; absence of adventitious breath sounds; patient verbalization or verification that dysphasia, cough, headache, and/or sore throat have disappeared; and good skin turgor, with intake and output within acceptable limits. In addition, the patient's vital signs, chest x-ray, and arterial blood gas analysis should ideally be within normal limits [26,27]. However, these expected outcomes may never be reached by some patients with respiratory disorders. For example, a patient with COPD will likely continue to have abnormal arterial blood gas values and a productive cough.

Patients with upper or lower respiratory tract infection may require education on actions to facilitate resolution of the infection and to prevent transmission. Signs that instruction was effective include observations that the patient has taken action to prevent the spread of infection (e.g., covering mouth and nose when coughing and sneezing); uses correct method of coughing and blowing nose; follows proper administration of decongestants/antihistamines; knows the benefits of and techniques for adequate hydration and humidification; correctly performs breathing exercises; and uses oxygen equipment appropriately. Family members and/or caregivers should also have an understanding of all information presented [26,27].

INEFFECTIVE BREATHING PATTERN

Patients who have chest trauma, chest or abdominal pain, or pathology of the pulmonary tissue or who have undergone thoracic surgery are diagnosed as having an ineffective breathing pattern. Trauma to the thorax resulting in pneumothorax, hemothorax, flail chest, tension pneumothorax, or mediastinal shift may cause various abnormal breathing patterns leading to ineffective ventilation. When the condition prevents air from moving in and out of the lungs effectively, various signs of respiratory distress may be observed, such as dyspnea, cyanosis, or use of accessory muscles for breathing.

Patients experiencing pain in the chest or abdomen tend to "guard" by breathing as little as possible to avoid increasing the pain. This hypoventilation in turn leads to impaired gas exchange over a period of days.

Patients with pathology of the pulmonary tissue often show signs that they are having difficulty moving air in and out of their lungs. For example, patients with emphysema experience "air trapping" in the alveoli and have difficulty exhaling fully. These patients often lean forward and purse their lips to facilitate movement of air.

Patients with asthma or allergic reactions may experience bronchospasm and have difficulty ventilating. Wheezing can often be heard when the lungs of these patients are auscultated [26,27].

Several nursing interventions may be employed when the nursing diagnosis is ineffective breathing pattern, including artificial airway (i.e., endotracheal, tracheotomy, or laryngectomy tube), chest tubes, and mechanical ventilation. These patients may also require deep breathing, coughing and breathing exercises, postural drainage, and nasotracheal suctioning if they are not intubated [27].

Incentive spirometry may be used to promote optimal breathing. With this approach, the patient is encouraged by visual feedback from a spirometer to execute sustained maximal inhalation. Patients usually perform 10 to 20 sustained deep breath exercises per hour until they can achieve their predicted inspiratory reserve volume. This method encourages voluntary deep breathing and reduces the risk of atelectasis and pulmonary consolidation.

Nursing Evaluation

Nursing interventions employed to improve the patient's breathing pattern are successful when the lungs are aerated adequately. Findings verifying this outcome in patients who have experienced chest pain or trauma include normal breath sounds, normal chest x-ray, normal arterial blood gas values, vital signs within normal limits, symmetrical chest expansion, and normal pulmonary function studies. When evaluating patients with a chest tube, note that the chest tube is in place, secured, and covered by a sterile dressing. The chest drainage collection receptacle should also be observed to see that it is functioning properly. If the patient is on a ventilator, the function of the ventilator should be monitored in addition to the condition of the patient [26].

Findings indicating that the nursing intervention for patients with pathophysiology of lung tissue has been successful include a return to baseline values for the arterial blood gas analysis, normal chest x-ray, and normal findings on pulmonary function studies. Improved lung sounds should be audible upon auscultation, and sputum production should decrease [26].

Respiratory disorders can significantly alter a patient's ability to perform activities of daily living, as seen in many patients with COPD. The physiologic changes can result in stress and emotional turmoil for patients and family. With knowledgeable and caring nursing interventions, both patients and family members should be able to cope more effectively with limitations imposed by the respiratory disorder. Examples of effective coping behavior include active participation in developing the plan of care and performing activities of daily living. Expression of fears and anxieties related to the illness and its effects is an integral part of the coping process. Successful adaptation to the limitations imposed by the illness is evidenced by an interest in functioning at an optimal level. For some, this may mean adjusting to a change in occupation and/or a decrease in social activities [27].

Patients who require long-term management of their illness need to learn new techniques and skills. Instruction is successful if the patient and family members are able to incorporate learned health behaviors into their everyday life.

IMPAIRED GAS EXCHANGE

Any disorder of the respiratory system may result in a nursing diagnosis of impaired gas exchange, depending on the degree to which it interferes with ventilation and perfusion. This state, although abnormal, is "normal" for certain patients with respiratory disorders. For example, some patients with COPD have a higher PCO_2 and lower PO_2 than patients without a respiratory disorder. The diagnosis of impaired gas exchange may refer to three different abnormalities: respiratory acidosis, respiratory alkalosis, or hypoxia [26,27].

Respiratory Acidosis (Hypercapnia)

Respiratory acidosis occurs when a disorder results in interference with gas exchange or decreases the amount of effective alveolar ventilation. The underlying cause of this abnormal state is always related to hypoventilation. Respiratory acidosis is observed in certain patients with COPD, pneumonia, or decreased respiratory function as a result of medication/illicit drugs or trauma. Patients in respiratory acidosis may exhibit confusion, drowsiness, headache, dizziness, tetany, asterixis, tachycardia, dysrhythmias, convulsions, and/or coma [34,35].

Respiratory Alkalosis (Hypocapnia)

Respiratory alkalosis is the result of a low level of CO_2 or a high level of bicarbonate in the blood, usually due to hyperventilation. Any respiratory illness that leads to shortness of breath may result in this condition. Over time, hypocapnia may result in metabolic abnormalities (e.g., mild lactic acidosis), cardiac arrhythmias, and GI dysfunction.

Hypoxia

Disorders that limit the volume of air entering the lungs and produce hypoventilation result in inadequate amounts of available oxygen at the alveolar level and an impaired ability to deliver oxygen to the tissues, resulting in hypoxia. Conditions that can lead to hypoxia include restrictive lung diseases (e.g., pulmonary fibrosis), occupational lung diseases, and sarcoidosis. Hypoxia can also result from obstructive lung diseases such as asthma, chronic bronchitis, and emphysema. Signs and symptoms of hypoxia are similar to those experienced by persons at high altitudes and include headache, restlessness, irritability, fatigue, tachycardia, hypertension, cardiac dysrhythmias, tachypnea, dyspnea, exercise intolerance, clubbing of the fingers, mental confusion, and coma. Treatment is to initiate oxygen therapy [34,35].

Numerous nursing measures can be employed in an effort to improve the exchange of CO_2 and oxygen. These patients often require highly skilled nursing care with the assistance of mechanical ventilation. Other nursing measures that may be employed when caring for these patients include deep breathing and coughing exercises, administration of oxygen, postural drainage, and suctioning.

Nursing Evaluation

Nursing interventions for patients with gas exchange abnormalities focus on adequate oxygenation for cellular metabolism and return of arterial CO_2 levels to within the normal range [28].

When caring for the patient with hypoxia, nursing interventions are successful when there is improvement in cerebral, cardiovascular, and respiratory signs and symptoms, including an absence of (or decrease in) restlessness, irritability, impaired judgment, central cyanosis, diaphoresis, labored breathing, tachypnea, and tachycardia. Blood pressure and level of consciousness should return to the normal range for the patient, providing brain injury did not occur. Interpretation of arterial blood gas values will reveal a return to baseline normal PO_2 and oxygen saturation. A complete blood count will also show hemoglobin values within normal limits [28].

If the hypoxic state is a chronic condition, patients and caregivers will need to learn to cope effectively with the lowered oxygen level. For example, the patient and family may need to plan daily activities with adequate time for rest periods.

As with hypoxia, nursing measures for patients with hypercapnia and/or hypocapnia are successful if signs and symptoms of cerebral, cardiovascular, and respiratory impairment improve. This involves an absence of (or decrease in) confusion, drowsiness, headache, dizziness, tetany, muscle spasm/asterixis, tachycardia, and cardiac dysrhythmias. The patient will no longer experience convulsions, and the level of consciousness will improve or return to normal. Analysis of arterial blood gases will show a pH of 7.35 to 7.45 [39].

Patients with impaired gas exchange will require nursing measures to orient the patient and assist the family in coping with changes in cognition. Measures are considered successful if patients are able to provide their names, the date, the time, and the place. Family members and caregivers should have good knowledge of measures necessary to prevent the patient from self-injury [39].

8. DISORDERS OF THE UPPER RESPIRATORY SYSTEM

LARYNGEAL EDEMA

Edema of the laryngeal tissue may be acute or chronic. The rapidity of onset varies, depending on the underlying etiology and the response of the individual. Infections that involve the larynx may cause some degree of edema. Edema may also be related to irradiation of the neck, neoplastic diseases involving the larynx or adjacent region, or infections that alter the lymphatic drainage of the area. Laryngeal edema may also be secondary to iatrogenic injury in connection with intubation or surgical procedures. In some instances, edema occurs as a result of systemic diseases that alter capillary permeability or disturb the oncotic pressures of the plasma. Angioedema can develop as an allergic response of the tissues of the larynx. It can occur rapidly with an allergic reaction to inhalants, injected substances (including contrast media), transfusions, insect bites, foods, or medications [29].

Clinical Manifestations

The initial symptom of laryngeal edema is often hoarseness. As the condition progresses, the patient may lose the ability to speak. When inspected by indirect mirror laryngoscopy, the laryngeal structures and vocal cords may appear swollen. As obstruction becomes more severe, dyspnea, stridor, tachypnea, and cyanosis may occur. With the exception of angioedema, onset of the edema is usually gradual and involves structures other than the larynx. In the case of angioedema, symptoms and signs of laryngeal obstruction develop rapidly and the condition can progress to total obstruction and death [36].

Therapeutic Measures

Laryngeal edema is considered a medical emergency. For patients with angioedema, intravenous administration of epinephrine usually brings about rapid decrease in inflammation; corticosteroids may also be used. Tracheotomy or intubation may be required to maintain a patent airway, particularly in cases of acute onset. Laryngeal edema related to systemic disorders responds to treatments directed at the underlying condition. Serum protein and electrolyte levels may be monitored and corrected, if necessary [36].

Specific Nursing Measures

Nursing responsibilities involve obtaining a history from the patient of known allergies and documenting them in the nursing care plan and the patient's chart. Patients who have been intubated should be monitored for evidence of laryngeal edema. Emergency medications and a tracheotomy setup should be generally accessible.

FOREIGN BODY IN THE LARYNX

Foreign substances lodged in the throat may have been put into the mouth and accidentally displaced backward into the throat, or they may consist of large pieces of food or substances contained in food, such as bone. Many people hold objects in their mouths while working (e.g., pins, tacks, nails) and accidentally swallow or aspirate them when distracted. Intoxicated individuals, or those taking sedative drugs, may aspirate gastric contents or food because their protective reflexes are impaired. People who talk while eating or eat hurriedly without chewing their food sufficiently are at increased risk, as are the elderly, patients with neurologic disorders, and those who may have poor dentition and cannot chew effectively [29,36].

Clinical Manifestations

Any foreign body that becomes lodged in the larynx will impair respiration to some extent. If complete obstruction occurs, the victim will be unable to talk and may indicate choking by clutching the neck—the universal sign of choking. If the airway is incompletely obstructed, the victim will exhibit signs of respiratory distress; coughing, choking, or gagging indicates that some air is moving through the respiratory tract [36].

Therapeutic Measures

Total obstruction of the airway is an emergency; victims can sustain brain damage or even die in minutes if a patent airway is not restored. The Heimlich maneuver is recommended in this situation. If the maneuver is unsuccessful, a cricothyroidotomy should be performed. If the larynx is only partially blocked, endoscopic removal of the obstruction should be performed by direct laryngoscopy as soon as possible, as the object blocking the airway could shift and cause a total obstruction [36].

UPPER RESPIRATORY INFECTION

Evidence Based Practice Recommendation

The Advisory Committee on Immunization Practices asserts that routine annual influenza vaccination is recommended for all persons 6 months of age and older.

https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html

Last Accessed: August 10, 2020

Level of Evidence: Consensus Statement and/or Expert Opinion

Upper respiratory infection encompasses infections of the nose and paranasal sinuses, nasopharynx, middle ear and Eustachian tube, pharynx, and larynx. Upper respiratory infections are among the most common infections and are responsible for 80% of all missed school days and 40% of lost workdays. In some cases, more severe disorders accompany upper respiratory infections. On occasion, an upper respiratory infection may spread to the lower respiratory tract [29].

Most of these infections are minor and self-limiting, but inflammation of the epiglottis is considered an emergency because it can rapidly lead to total obstruction of the airway. This serious infection is most often caused by Haemophilus influenzae type B organism, but the infection has also been associated with Staphylococcus aureus, group A beta-hemolytic streptococcus, Neisseria catarrhalis, and Streptococcus pneumoniae [36].

Clinical Manifestations of Epiglottitis

Typically, epiglottitis is manifested by sore throat of short duration (less than 12 hours) and rapidly increasing severity, pain in the area of the hyoid at the base of the tongue, significant dysphagia, and elevation of temperature that may reach 103 degrees F. Secretions may be so copious that the patient drools. Hoarseness is minimal, but the patient's voice may have a muffled quality. Respiratory obstruction becomes evident as the inflammation progresses. Although the enlarged, cherry red epiglottis may be seen by means of indirect laryngoscopy, lateral x-rays of the neck taken with the patient in an upright position are a less hazardous means of diagnosis. Manipulation can aggravate edema, leading to sudden total occlusion of the airway. Cultures of blood and secretions may be used to isolate the causative organism. A leukocyte count of 18,000–24,000 cells/mcL is common [36].

Therapeutic Measures

The patient with epiglottitis should be hospitalized, because respiratory obstruction can rapidly occur. Restlessness, stridor, cyanosis, and retraction of the supraclavicular and intercostal spaces indicate a need for immediate tracheotomy. Antibiotic therapy appropriate to the organism identified by culture studies is prescribed and administered. Recovery usually follows 24 to 48 hours after treatment is initiated. Failure to recognize the seriousness of the disorder can lead to death in up to 20% of patients [29,36].

NEOPLASMS OF THE LARYNX

Neoplasia of the upper respiratory tract can have diverse consequences. Benign tumors can have serious adverse effects related to expansion and obstruction; malignant neoplasms damage tissue by infiltration and metastasis. Any diagnosis of cancer is frightening to the patient, but neoplastic disease affecting the head and neck can be especially devastating psychologically because sensory functions (e.g., olfaction, vision) may be disturbed, and physical appearance may be seriously affected.

Although benign neoplasms of the larynx do occur, they are usually small, easily removed papillomas. Malignant laryngeal neoplasms may be classified according to locus of origin as:

- Glottic (arising from the larynx)

- Supraglottic (arising above the larynx)

- Subglottic (arising below the larynx)

- Transglottic

Glottic carcinoma is the most common and has the most favorable prognosis. Supraglottic lesions are more often associated with lymphatic metastasis and thus have a poorer prognosis. Subglottic lesions, the rarest of the four types, are less aggressive than supraglottic lesions but more so than glottic cancers. Transglottic cancer is highly invasive and tends to metastasize extensively [29]. Laryngeal cancer has a high rate of cure when detected early, but patients have consulted an average of three physicians about persistent hoarseness over a period of eight months by the time the condition is diagnosed [29].

Cigarette smoking and ingestion of alcohol are believed to be major factors in the development of laryngeal cancer. Environmental pollution (particularly air pollution), occupational exposure to radiation, and chronic pharyngeal infection have also been implicated. Although laryngeal carcinoma predominantly affects men 50 to 70 years of age, the incidence in women has been rising [36].

Clinical Manifestations

The most common symptom of benign laryngeal neoplasm is hoarseness, sometimes accompanied by dysphasia if the lesion is large. Other symptoms of laryngeal carcinoma vary according to the type of lesion [29].

Glottic Carcinoma

With glottic carcinoma, hoarseness occurs early in the course of the disorder. Pain may be felt in the latter stages, as are dyspnea and inability to speak (aphonia) [29].

Supraglottic Carcinoma

Hoarseness is uncommon with supraglottic carcinoma. Patients may report a sensation of "something in the throat" or a change in voice quality. The throat may burn when hot or acidic liquid is ingested. The patient may notice a lump in the neck, which may be the reason for consulting a healthcare provider. Pain unrelated to ulceration may occur, as may referred otalgia. Later symptoms include pain, hoarseness, and dyspnea related to obstruction of the airway [29].

Subglottic and Transglottic Carcinomas

In subglottic carcinoma, dyspnea may be the initial reported symptom; hoarseness is rare. Transglottic tumors have invaded various sections of the larynx; thus, a variety of symptoms described for the other types may occur. Lesions involving one of both vocal cords may be seen by indirect mirror laryngoscopy; supraglottic lesions are more likely to ulcerate than glottic lesions. Visualization of the subglottic area requires direct laryngoscopy. Cervical nodes may be palpable if the lesion has metastasized. X-ray examinations will aid in determining the extent of the disease, and biopsy specimens may be removed under local or general anesthesia [29].

Therapeutic Measures

A radical neck dissection may be necessary in conjunction with total or supraglottic laryngectomy, but partial laryngectomy has the most favorable prognosis. In cases of localized carcinomas involving only one vocal cord, radiation therapy may be effective and will have less effect on voice quality than surgical excision. Radiotherapy is least effective with advanced lesions because the level of irradiation required to destroy the neoplasm causes damage to the surrounding tissues. Adjuvant chemotherapy may be employed in an attempt to shrink the tumor and eradicate micrometastases [29,36].

TRAUMATIC DISORDERS

Trauma of the head and neck may be related to motor vehicle accidents, abuse or assaults, falls, sports activities, or occupational accidents. Trauma to the head and neck is a leading cause of morbidity and mortality in the United States. Such trauma is serious, as it can lead to sensory impairment, permanent disability, disfigurement, and death [29,40,41].

Maxillofacial trauma may cause extensive damage to soft tissue, bone, and cartilage. Because the nose protrudes from the center of the face, it is injured more frequently than other areas of the body. Maxillofacial trauma is related to some kind of direct blow [36,40,41].

Laryngotracheal trauma may be classified as open or closed and may be accompanied by neural and vascular trauma of the head and neck. Fracture of the cervical spine commonly co-occurs with this kind of injury.

Automobile accidents in which an individual is thrown against the steering wheel or dashboard at a high rate of speed are the most common cause of blunt laryngotracheal trauma. Penetrating injuries are often caused by sharp objects (e.g., stab wounds). Iatrogenic laryngeal injury can occur in relation to endoscopy, endotracheal intubation, or tracheotomy; improper endoscopic technique can dislocate the larynx or tear the laryngeal mucosa. Pressure exerted by the cuff of an endotracheal or tracheostomy tube against the arytenoid cartilage may result in formation of scar tissue (arytenoid stenosis), although this occurs less frequently with the introduction of low-pressure cuffs [36,40,41].

General Nursing Implications

Patients with facial, skull, or neck fractures require surgical intervention to reduce, stabilize, and immobilize the injured part. Proper nursing care of these patients can greatly facilitate healing and help avoid complications. Many head and neck injuries have psychologic consequences related to changed appearance and an inability to carry out normal activities. Patients with such injuries can benefit from instructions and support during recovery and rehabilitation [36]. In addition, nurses working in the community should advocate for safety features such as automobile seat belts and helmets while riding bicycles and motorcycles.

Assessment

Patients with upper respiratory trauma should be assessed for possible damage to the cervical spine prior to any manipulation, except emergency lifesaving measures, to prevent additional neurologic damage. Assessment of cranial nerves II through X should be performed. Visual disturbances such as diplopia or decreased acuity may occur. Alteration in sensation may range from pain to hypoesthesia [36,40,41]. Symptoms of a fat embolus include petechial hemorrhages on the thorax.

Inspection for hemorrhage and drainage should be routine; edema and ecchymosis may occur in relation to profuse bleeding. Drainage from the nares should be evaluated for the presence of cerebrospinal fluid (CSF), which is transparent, contains glucose, and dries as a yellow, halo-like ring and does not crust as do other types of secretions. Lacerations may be noted, with foreign debris in the wound or surrounding area. The patient may experience difficulty swallowing or speaking [30,40,41].

Nursing Intervention

It is important that cardiopulmonary function is maintained post-trauma. The oral cavity should be inspected, and dried blood, tooth fragments, bone splinters, and other foreign matter should be removed by suction. A tracheotomy tray should be readily available, and the nurse should be prepared to assist with intubation or tracheotomy [28].

Patients should be positioned to reduce edema and avoid asphyxiation. Elevating the head of the bed, if not otherwise contraindicated, helps decrease edema of the head and neck; application of ice is helpful during the first 24 hours after injury, with warm applications used thereafter to promote vasodilation. Blood transfusions and intravenous fluids may be given [28].

Wound care should be meticulous. This may involve cleansing and application of antimicrobial ointments. Dressings may be necessary, depending on the nature of the injury. The nurse should continually observe for signs of infection [28].

Adequate nutritional intake is crucial to healing. Depending on the patient's ability to eat, a liquid diet or intravenous fluids may be used initially. If the nature of the injury permits, nasogastric feedings may be administered. A baseline weight should be obtained upon admission, so nutritional status can be monitored.

Patients should be encouraged to take part in self-care to the maximum extent possible; doing so helps them re-establish a sense of control over their lives. Emotional support is of utmost importance for these patients, who may face long-term rehabilitation and major changes in appearance and lifestyle. Patients with disfiguring injuries may appreciate receiving information about plastic surgery [42].

9. DISORDERS OF THE LOWER RESPIRATORY SYSTEM

Problems of the lower respiratory tract constitute a major concern in patient care. These disorders can range from a minor bout of acute bronchitis to major life-threatening conditions such as respiratory failure. Many lower respiratory system disorders are chronic and debilitating, making it necessary for patients and their families to make long-term adjustments in lifestyle. Patients admitted to a hospital with other debilitating conditions frequently develop respiratory difficulties in the form of atelectasis, retained secretions, and pneumonia. A majority of these are preventable with good medical and nursing care.

Interpersonal nursing intervention skills are also required. Dysfunction of the lower respiratory system can arouse many disturbing feelings and concerns, including anxiety, helplessness, fear, despair, and depression. Air hunger is a primal drive—stronger even than hunger and thirst. Nurses should be equipped to deal with the problems these feelings produce and assist patients and their families to cope.

OCCUPATIONAL LUNG DISEASES (PNEUMOCONIOSES)

Occupational lung diseases result from exposure to offending respiratory agents in the workplace. The pathogenic agents can be classified as mineral (inorganic) fibers or dusts, organic fibers and dusts, or irritant gases and chemicals [29].

Pneumoconioses are lung diseases resulting from inhalation of inorganic dusts. Silicosis, asbestosis, and coal workers' pneumoconiosis fall into this category.

Clinical Manifestations

The clinical manifestations of various pneumoconioses are similar, and all can lead to pulmonary fibrosis. This condition causes the lungs to become stiff and non-elastic, reducing lung volume. The development of a thickened pulmonary membrane can interfere with gas exchange [29,36].

Silicosis

Silicosis may occur in various forms. The most common is chronic or classic silicosis, which occurs in individuals who have inhaled relatively low concentrations of dust over long periods (i.e., 10 to 20 years). Initially, the accumulated dust and tissue reaction result in the development of scattered nodules throughout the lungs and shortness of breath upon exertion. Over time, silicosis may become more serious, resulting in increased shortness of breath, cough, and sputum production. In complicated silicosis, fibrosis of the lung occurs, leading to restriction in lung function and right-sided heart failure. Respiratory impairment is severe.

Those with silicosis may also develop tuberculosis and/or Caplan syndrome, characterized by rheumatoid arthritis and concomitant fibrotic lesions. Acute silicosis, most commonly due to exposure to high concentrations of silica dust (as with sand blasting), is a rapidly progressive disease leading to severe disability and high mortality within five years of diagnosis [29,36].

Asbestosis

Asbestosis is a diffuse interstitial fibrosis of the lungs resulting from the impact and deposition of asbestos fibers on the alveolar walls. As the fibrosis becomes widespread, the elasticity and compliance of the lung are reduced. Fibrosis results in a thickening of the alveolar walls and interstitial space, which in turn reduces the oxygen diffusion to the pulmonary capillary bed. Pulmonary function studies show a reduced forced vital capacity. X-rays reveal linear opacities, especially in the lower lung fields. Unfortunately, there are few physical symptoms and signs until the disease is relatively advanced. Individuals may seek help for a productive cough, shortness of breath, and/or weight loss. Asbestosis has no cure and is associated with a high mortality rate.

Lung cancer is also associated with all types of asbestos inhalation. Malignant mesothelioma, a cancer that usually affects the pleura, is a significant cause of death among high-risk workers (e.g., dock workers) [29,36].

Coal Workers' Pneumoconiosis

Coal workers' pneumoconiosis results from the inhalation and accumulation of coal dust in the lungs, also known by the name "black lung disease." Simple coal workers' pneumoconiosis is not complicated by other lung conditions and causes no symptoms or respiratory difficultly. A small percentage of patients develop progressive massive fibrosis with large lesions consisting of fibrous tissue, coal dust, and central cavitation. Patients may produce thick, black sputum and suffer from shortness of breath and dyspnea. X-ray reveals large opacities, and pulmonary function studies indicate an obstructive deficit. The large-mass lesions may eventually lead to pulmonary hypertension, cor pulmonale, and death from congestive heart failure [29,36].

Therapeutic Measures

Thorough patient history, pulmonary function studies, and chest x-ray assist in the assessment and diagnosis of pneumoconioses. Therapeutic measures are supportive rather than curative. Superimposed respiratory tract infections are treated with antibiotics. Antituberculosis medications are administered if tuberculosis develops, and bronchodilators may be beneficial when there is evidence of a reversible obstructive component [29,36].

Oxygen therapy may be necessary for individuals with low PO_2 levels; however, administering O_2 at too high a flow rate may depress the patient's stimulus to breathe. Cardiotonic drugs may be prescribed if the cardiovascular system has been affected. Bronchial hygiene measures, such a deep breathing, coughing, and postural drainage, are often indicated [36].

Specific Nursing Measures

Nursing management of patients with pneumoconioses is generally supportive. It is important to stress the importance of avoiding further exposure to the harmful agent(s) and other irritating substances, including cigarette smoke. Answering patient questions, describing the disease process, and explaining treatments will empower patients to be involved in their own care.

Even in the face of serious disease, many people will be reticent to leave their occupation, especially after years of commitment and specialized training. Others, unable to leave a geographic area and with responsibility for a family, will feel their options are limited. Some may choose to stay in a job even though it interferes with their health. If nurses acknowledge the reality of the patient's situation, health teaching efforts may be more readily accepted [36].

ACUTE RESPIRATORY DISTRESS SYNDROME

Acute respiratory distress syndrome (ARDS) is a pathophysiologic state best recognized in patients with no previous underlying lung disease who experience a sudden, catastrophic, often multisystem insult that leads to the development of severe dyspnea, hypoxemia, loss of pulmonary compliance, and noncardiogenic pulmonary edema. ARDS is not a clearly defined disease, but is rather an umbrella term for a group of conditions of different etiology having similar manifestations. Many factors can lead to the development of ARDS, including major insults such as shock, multisystem trauma, aspiration, overwhelming systemic infections (sepsis), drug overdose, and inhaled toxic substances. ARDS has also been called shock lung, white lung, Da Nang lung, adult hyaline membrane disease, stiff lung syndrome, and wet lung.

Estimates of the incidence of ARDS in the United States range from 64.2 to 78.9 cases per 100,000 persons [43]. Twenty-five percent of ARDS cases are initially classified as mild and 75% as moderate or severe. Approximately one-third of mild cases progress to moderate or severe disease. The morality rate of ARDS is commensurate to the severity of disease—27% for mild disease, 32% for moderate disease, and 45% for severe disease [43].

Clinical Manifestations

There is often a latent period of 12 to 48 hours between the initial injury or insult and the development of ARDS. The pathophysiology is the result of diffuse damage to either side of the alveolar-capillary membrane. Whether the initial damage is alveolar or capillary, the result is an increase in vascular permeability with edema and hemorrhage. Fluid and red blood cells leak into the interstitial space and the alveoli. The resulting pulmonary edema leads to decreased lung volume and impaired oxygenation. The presence of fluid in the alveoli causes a decrease in surfactant activity, leading to an increased tendency of the alveoli to collapse. In alveoli that are collapsed or filled with edema fluid, little or no ventilation can take place. Because oxygen-poor blood is still perfused to these non-ventilated alveoli, the result is an abnormally low ventilation-to-perfusion ratio, with an increased right-to-left intrapulmonary shunt. This is responsible for the severe hypoxemia associated with ARDS that is refractory to increases in inspired oxygen concentrations [39].

Therapeutic Measures

Prevention and early identification are key, and the first step is identifying patients who are at risk for developing ARDS. These patients should be closely monitored for early signs of abnormal lung functioning so preventive measures can be instituted. Treatment of ARDS requires that the patient's ventilation be supported and adequate inspired oxygen be delivered to correct the life-threatening hypoxemia [39].

After ARDS has been diagnosed, nursing care becomes complex. The patient's airway requires suctioning and postural drainage, and proper management of the endotracheal or tracheostomy tube is necessary. Close attention should be paid to arterial blood gas values and fluid balance. Daily weights and accurate intake and output records are important. Electrolyte imbalances should be assessed and addressed as necessary [39].

The cardiovascular system may be affected by the various therapeutic interventions. Measurements of central venous pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure are frequently made in the intensive care setting. Because these patients are acutely ill, they and their families require emotional support [39].

ACUTE TRACHEOBRONCHITIS

Of all infectious diseases, lung infections are the most common life-threatening diseases, accounting for significant morbidity and mortality. A variety of organisms (e.g., viruses, bacteria, fungi) can cause respiratory infections. One such infection is acute tracheobronchitis, a condition involving inflammation of the trachea, bronchi, or both. Although it is usually the result of an infection, it can also be due to an irritant or allergic reaction. Symptoms include cough, wheezing, and sore throat.

Therapeutic Measures

Treatment focuses on palliation of symptoms, because the condition is generally self-limited and resolves relatively quickly. In some cases, antibiotics are prescribed to prevent infection spreading through the respiratory tract into the larger bronchi [44].

ACUTE BRONCHITIS

Acute bronchitis is primarily an infection of the larger bronchi in patients whose airways are otherwise normal. This infection is most commonly viral in etiology and usually starts as an extension of an upper respiratory infection.

Clinical Manifestations

The major symptoms of acute bronchitis include cough, a burning substernal sensation (often aggravated by a deep breath), and sputum production. As the infection progresses, sputum becomes mucoid or purulent. The patient may or may not have an elevated temperature. Malaise, muscle aches, and headache are common. Chest auscultation reveals rales, rhonchi, and wheezes. The disease is self-limiting, and the duration depends on the underlying causative organism. Smoking tends to prolong and aggravate the condition [44].

Therapeutic Measures

Treatment of acute bronchitis is aimed at relieving the symptoms. Bed rest, hot or cold steam inhalation, and intermittent positive pressure breathing will loosen secretions so they can be more easily expectorated. Antipyretics (e.g., aspirin) may be ordered if temperature is elevated; expectorants or antitussives may be necessary to loosen secretions or to quiet a chronic, nonproductive cough. Lozenges may be used to soothe an irritated throat. Antibiotics are not routinely given unless sputum cultures identify a bacterial infection [44].

In more debilitated patients who have a poor cough reflex, suctioning may be necessary. Increased fluid intake of at least 2–3 L/day should be encouraged (unless contraindicated) to help prevent dehydration and to keep respiratory tract secretions more easily expectorated. Nutritional management should include light meals that are easily tolerated and digested to meet caloric needs [42].

PNEUMONIA

Pneumonia is an infection of the lower respiratory tract that is usually accompanied by cough, fever, malaise, and chest x-ray abnormalities. Sputum production, dyspnea, hypoxia, and hemoptysis may be present in some individuals with pneumonia, depending on the causative organism. The disease is further classified as community-acquired, healthcare-associated, or hospital-acquired according to how and where it was contracted.

The Infectious Diseases Society of America (IDSA) defines community-acquired pneumonia (CAP) as an acute infection of the pulmonary parenchyma frequently associated with at least two symptoms of active infection occurring in individuals who have not been hospitalized or resided in a long-term care facility for 14 days before the onset of symptoms [45]. In most cases of CAP, diagnosis is made by history and physical examination; identification of the etiologic agent is not always necessary. The most clear-cut indication for extensive diagnostic testing is in the critically ill patient with CAP [46]. Although the list of organisms causing CAP is long and increasing, relatively few organisms are responsible for most cases of pneumonia [46].

Hospital-acquired pneumonia (HAP) is defined as any pneumonia in a patient who has been hospitalized 48 hours prior to onset of symptoms and that was not incubating prior to admission [47]. Ventilator-associated pneumonia (VAP) refers to a pneumonia that develops at least 48 hours after intubation and the initiation of mechanical ventilation. An additional subtype of pneumonia is healthcare-associated pneumonia (HCAP), which refers to pneumonia in patients who are not hospitalized but have had contact with the healthcare system. Guidelines for patients with HCAP were previously included with those for HAP and VAP due to patients' contact with the healthcare system and the presumed high risk of multidrug-resistant pathogens. However, recommendations specific to HCAP were removed from the updated 2016 IDSA guidelines for the management of HAP and VAP due to increasing evidence that patients defined as having HCAP are not necessarily at high risk for multidrug-resistant pathogens. Although interaction with the healthcare system potentially puts patients at risk for these pathogens, underlying patient characteristics are important independent determinants of risk [47].

As stated, multidrug-resistant bacterial pathogens are very often a cause of HAP and VAP. Pathogens responsible for multidrug-resistant pneumonias can include Pseudomonas aeruginosa, Acinetobacter spp., and methicillin-resistant Staphylococcus aureus (MRSA).

Aspiration pneumonia is an infectious process caused by inhalation of oropharyngeal secretions that are colonized with bacteria. Aspiration pneumonia is distinct from aspiration pneumonitis (caused by the inhalation of sterile gastric contents), but the syndromes can overlap. This type of pneumonia is a major cause of morbidity and mortality in both nursing home residents and hospitalized patients [48].

Atypical pneumonia is a term used to refer to pneumonia caused by bacteria and nonbacterial organisms that do not share characteristics commonly found in patients with pneumonia. Causative agents include Legionella spp., Mycoplasma pneumoniae, Chlamydophila spp., and Coxiella burnetii[47].

The most common cause of bacterial pneumonia is the gram-positive bacterium Streptococcus pneumoniae, estimated to be the cause of 20% to 60% of pneumonia cases [49]. Possible gram-negative infective organisms include Haemophilus influenzae, Klebsiella pneumoniae, and Moraxella catarrhalis. K. pneumoniae infections are more commonly diagnosed when there is co-existent alcoholism [45,47]. S. aureus and H. influenzae infections often occur after a primary influenza infection. M. catarrhalis, an organism not thought to be pathogenic, is most commonly found in those with chronic lung conditions, such as COPD [50]. It is also found in patients with diabetes, who are taking steroids, or who have other underlying chronic lung conditions or malignancy [50].

Another organism known to cause pneumonia is Legionella pneumophila. This organism was first implicated in 1976 after 182 people became ill in Philadelphia while attending an American Legion convention [51]. The organism is a gram-negative bacillus that survives in water and soil. Infection with the organism is acquired through inhalation of aerosolized droplets, making air-conditioning ventilating systems an obvious reservoir.

Potential atypical and nonbacterial organisms responsible for pneumonia include M. pneumoniae, Chlamydia pneumoniae (the Taiwan acute respiratory [TWAR] strain), and multiple viruses. Mycoplasma organisms lack cell walls and cannot be stained and visualized by conventional methods. Infection with these organisms usually causes disease in younger individuals and follows a milder course than that seen in patients with bacterial pneumonia. Chlamydial infection also manifests as a mild infection spread from person to person by aerosolized droplet secretions.

Pneumonia remains one of the leading causes of morbidity and mortality in the United States, especially in older adults and in those with underlying chronic disease. It is the leading cause of death from infectious disease and the eighth most common cause of death overall in the United States (along with influenza) [52]. It is estimated that 4 million episodes of pneumonia are diagnosed in the United States every year, with a total of 30 million days of disability [53,54]. The World Health Organization (WHO) estimates that 54 million people die from pneumonia every year, with a bimodal distribution of mortality, with peaks in children younger than 5 years of age and adults older than 75 years of age [55]. Worldwide, pneumonia killed an estimated 808,694 children younger than 5 years of age in 2017, with the majority of these deaths occurring in South Asia and sub-Saharan Africa [56]. These are surprising statistics given the advent of broad-spectrum antibiotics, a multivalent pneumococcal vaccine, and sophisticated hospital care.

The elderly have the highest rates of CAP in the United States [57,58,59]. Aging is associated with a variety of declines in immune function (immune senescence) and prevalent comorbidities. As a result, the elderly constitute the largest immunocompromised population in the United States, putting them at risk for new infectious agents. Pathogens that are not typical causative agents of pneumonia must be considered as possible etiologic agents in the elderly. As a result, older adults are more likely to have CAP caused by a resistant organism or tuberculosis and to require hospital admission [60].

Therapeutic Measures

The successful treatment of pneumonia depends on the correct empiric antibiotic selection and knowledge of its proven effectiveness in vivo. A working knowledge of the organisms that most commonly infect different age-groups and the habits or characteristics that put an individual at risk for specific etiologic agents is essential. Polyvalent pneumococcal vaccine can be used to prevent the development of pneumococcal pneumonia, providing protection for at least three years against 23 serotypes causing 75% of this type of pneumonia [61].

Antipyretics and analgesics such as acetylsalicylic acid or acetaminophen may be given. Narcotics may be required if chest pain is severe; codeine is most frequently given. Expectorants are given to reduce the viscosity of pulmonary secretions; terpin hydrate may be given orally or acetylcysteine by nebulization. Antitussives may be ordered to treat nonproductive cough [62,63].

Patients with more severe disease may require bed rest or hospitalization. Intermittent positive pressure breathing along with other pulmonary hygiene measures, such as postural drainage, may be ordered. Supplemental oxygen may be necessary if PO_2 levels become too low. Hospitalized patients may receive intravenous fluids to replace fluid and electrolyte loss caused by an elevated temperature, increased cellular metabolism, tachypnea, and diaphoresis. Between 3 and 4 L of fluid per day are required unless contraindicated. If the patient is unable to eat, nasogastric feedings or hyperalimentation may be ordered. If respiratory failure occurs, intubation and mechanical ventilation are required. Depending on the infectious agent, patients may have to be placed in respiratory isolation. If a pleural effusion develops, a thoracentesis may be performed [33].

Specific Nursing Measures

Although the etiology and signs/symptoms of pneumonias vary, the overall nursing care is similar. Care for hospitalized patients should be organized to allow periods of uninterrupted rest combined with turning, range of motion exercises, coughing, and deep breathing at least every two hours. Postural drainage measures may also be needed. If patients are not able to expectorate secretions effectively, tracheal suctioning may be required [64].

Careful monitoring and assessment of respirations is necessary to identify improvements or deteriorations in the patient's condition. Nurses should remain alert to potential pulmonary complications of pneumonia, including pleurisy, pleural effusion, empyema, lung abscess, and pulmonary edema (which may lead to respiratory failure). Monitoring for systemic complications (e.g., septicemia, septic shock, meningitis, endocarditis, renal and liver involvement) is also important to ensure early recognition and treatment [65].

Because sputum specimens play an important part in identifying the causative organism, efforts should be made to collect an adequate sample. Tracheal suctioning may be required for patients who cannot cough effectively. If the patient has an elevated temperature and is diaphoretic, tepid baths and frequent changes of bed linen are needed as comfort measures and to prevent chilling [66].

As noted, keeping the patient hydrated is important. In hospitalized patients, fluid intake should be closely monitored, and set amounts should be given for each shift. Urinary output is a good indicator of hydration. If patients can eat, good oral care may help to improve the appetite. Splinting the chest during coughing and deep breathing exercises will help to reduce chest pain.

Discharge planning involves reviewing medication actions and side effects with the patient and family. Patients with an underlying chronic debilitating condition should be advised of their increased susceptibility to respiratory tract infections and techniques to avoid infections that may lead to further pneumonia. If these measures are not at least attempted, the risk of recurrence is increased [64,65].

Specific nursing measures should be employed to prevent aspiration. Patients with altered consciousness should be placed on their side with the foot of the bed elevated 6–9 inches unless contraindicated. The head of the bed should be elevated at least 30 degrees during and for one hour after feeding. Gag and cough reflexes should also be checked before feeding. Before administering a nasogastric feeding, check for proper placement of the tube in the stomach. Aspirate for stomach contents, and if 100 mL or more is withdrawn, hold the feeding and consult with the physician. The tube feeding should be administered slowly over 30 minutes. If tube feeding is continuous, the head of the bed should be kept elevated. Frequent oral care and removal of secretions that accumulate in the back of the throat will help to prevent the aspiration of organisms into the lower respiratory tract [66].

TUBERCULOSIS

TB, also historically called the "white plague" and "consumption," is a disease that has plagued the citizens of nearly every nation in the world for centuries. It has produced acute, chronic, and latent diseases involving every organ in the body, although the lungs remain the primary site of infection. The disease is caused by a group of similar bacilli, most commonly Mycobacterium tuberculosis, which is often abbreviated as M. tuberculosis or as MTB.

In a global perspective, the effect of TB on the health and economy of the world is staggering. It has been estimated that 2 to 3 billion people worldwide have become infected with M. tuberculosis and are therefore at risk for developing active clinical disease within their lifetime. This represents more than one-third of the world's population. In 2018 alone, 10.0 million new cases of active clinical disease and 1.2 million deaths from TB-related causes were reported by the WHO [67]. TB ranks as a leading cause of death among individuals with HIV or acquired immune deficiency syndrome (AIDS) worldwide, and 251,000 TB deaths are among HIV-positive individuals [67].

In 2018, a total of 9,025 TB cases were reported in the United States, a 0.7% decline from the 2017 rate, continuing the decrease in incidence rates for more than 20 years [68]. This represents an incidence of 2.8 per 100,000 population. Incidence varied significantly among states, from 0.3 per 100,000 population in West Virginia to 8.5 per 100,000 in Alaska [68]. Overall, the incidence of TB remained the same from 2017 to 2018; however, the nation has not yet achieved the 2025 national target of less than 1.3 TB cases per 100,000. In 2018, 42 states reported incidences at or below the national average of 2.8 cases per 100,000 [68]. California, Florida, New York, and Texas combined account for more than half of all cases in the United States [68].

Clinical Manifestations

There are three stages of infection seen in persons with pulmonary TB: primary or initial infection; latent or dormant (asymptomatic) infection; and secondary or reactivation infection. All three must be considered and treated when patients present with TB-specific symptoms.

The early symptoms of active pulmonary TB are often so subtle as to be missed at first by most patients. Because of this, they will frequently have difficulty pinpointing exactly when their illness began. Some patients without obvious symptoms are diagnosed solely by a routine chest x-ray. For those who do have symptoms, the most common manifestations are gradual onset and progression of fever, malaise, cough, anorexia, and weight loss. The fever is one that is not so high as to be noticed or to be disquieting. When the fever breaks during the early morning hours, it is often associated with "night sweats." Weight loss may result from the infectious process itself, or it can be a sign that malnutrition and depletion of immune reserves preceded, and to some extent caused, the infection.

Cough is generally nonproductive at first, then later productive of purulent sputum. With progressive cavitation in the lung, the patient develops hemoptysis. Bleeding results from the necrosing walls of cavitary lesions in the lungs or from the rupture of small venules in the walls of inflamed bronchi.

Chest pain, usually pleuritic in nature, arises from infection of the pleural surface and the resulting effusion. If there is extensive lung destruction, dyspnea will also occur, which eventually leads to respiratory failure and death.

Therapeutic Measures

With appropriate antibiotic treatment, TB can be cured in most people. Six drugs (isoniazid, rifampin, rifabutin [off-label], rifapentine, pyrazinamide, and ethambutol) are rated as first-line because they are frequently effective and have low toxicity for most patients with TB. A successful treatment outcome depends greatly on patient compliance with the prescribed combination of drugs. Patient noncompliance with the prescribed regimen may lead to failed resolution, early relapse, and the emergence of resistant strains. Successful treatment of drug-resistant TB is difficult and involves the use of less effective, potentially more toxic medications that must be administered for as long as two years. Even more severe is extensively drug-resistant TB, which is caused by a strain that resists even the second-line agents [69,70].

In cases of ineffective breathing, the patient may have decreased lung volume and lung capacity due to the TB. Increased metabolism may also be a factor in patients with high fevers. Some patients may have a frequent productive cough and hemoptysis. These issues are defined by increased respiratory rate, the use of accessory muscles to breathe, retractions, diaphoresis, and tachycardia. The therapeutic interventions are to administer oxygen as necessary, push fluids and promote hydration to liquefy secretions, and maintain semi-Fowler's position to ease breathing.

Specific Nursing Measures

Patients with TB who require hospitalization are routinely placed in isolation in negative air pressure rooms, if available. Careful handling and disposal of secretions, the avoidance of direct face-to-face contact, and the use of respirators are recommended. The patient's room should be properly ventilated with non-recirculating air. Laminar flow or ultraviolet lighting will accomplish the same purpose as non-recirculating ventilation. Patients should be instructed to cover their nose and mouth when they cough or sneeze. Patients unable to cover their mouths should be masked when direct care is given. Within two weeks after chemotherapy is begun, the possibility of transmitting the disease is markedly reduced [71].

Because strict adherence to the medication schedule is required for effective treatment, patients should receive extensive education on prescribed medications and the need to continue taking medications for six to nine months. The importance of follow-up should be stressed, not only so progress can be monitored but also to check for possible side effects from the medications and to make sure drug resistance has not developed. Patients should be instructed to see a physician immediately if symptoms of TB recur or if they develop any medication side effects [65].

LUNG ABSCESS

A lung abscess is a circumscribed suppressive area of inflamed and infected lung parenchyma associated with central tissue necrosis. Communication with the bronchial tree results in the eventual expectoration of purulent material.

Single lung abscesses usually result from an inflammatory response to a bronchial obstruction. The aspiration of foreign material, such as food, gastric contents, or blood, can lead to obstruction. Benign or malignant tumors or large amounts of thick, sticky secretions can also obstruct an airway. Pneumonia, although not as common a cause of lung abscess formation, may be a causative factor in some cases. The organisms most frequently responsible for lung abscess formation are S. aureus, K. pneumoniae, some strains of mycobacteria, Bacteroides spp., and certain fungi and parasites, such as the lung fluke. Immunosuppressive therapy and alcohol abuse are predisposing factors in the development of lung abscesses [71].

Clinical Manifestations

The most common symptoms of lung abscess include fever, chills, malaise, anorexia, cough, and pleuritic chest pain. When the abscess ruptures into a bronchus, the cough is productive of copious amounts of purulent sputum, which may be foul smelling, bloody, and dark brown in color. Cavitary lesions that result from abscess formation are visible on chest x-ray. The prognosis of lung abscess, if not complicated by an underlying malignancy or other progressive lung disease, is generally good if the organism responsible is treated [71].

Therapeutic Measures

In cases of lung abscess of bacterial origin, standard therapy consists of clindamycin 600 mg IV every eight hours. Alternatives include penicillin, lincomycin, or erythromycin; in some cases, streptomycin or tetracycline may be added. Antibiotics are usually given for at least six weeks [21].

Bronchoscopy is indicated for removal of foreign matter that may be blocking a bronchus or to obtain a specimen for diagnostic purposes. Pulmonary hygiene measures, such as postural drainage and suctioning, may be ordered. Surgical drainage of an abscess by means of a thoracotomy or chest tube is rarely performed today but may be done if the abscess is resistant to antibiotic therapy or is larger than 6 cm in diameter [21].

Specific Nursing Measures

Nursing measures for patients with lung abscess include coughing and deep breathing exercises, tracheal suctioning, and postural drainage. Good oral hygiene in patients who are unconscious is important because bacterial growth in the oral cavity can worsen infections.

EMPYEMA

Empyema is the accumulation of pus in the pleural space or a purulent pleural effusion. The use of antibiotics in the treatment of lung infections has greatly reduced the occurrence of empyema, but it can develop as a complication of a penetrating chest wound or thoracic surgery [71].

Clinical Manifestations

Fibrous adhesions between the lung and the chest wall can develop as part of the inflammatory process. Common symptoms include fever, pleuritic chest pain, dyspnea, and anorexia. Breath sounds are absent over the affected area, and there is dullness to percussion. There may be a productive cough; blood-stained sputum can result from the development of a bronchopleural fistula. The prognosis for individuals with empyema is good if it is properly and promptly treated with antibiotics and/or surgery [71].

Therapeutic and Nursing Measures

Antibiotic therapy is selected on the basis of Gram stain and culture and sensitivity reports. Surgery is also usually required. A thoracentesis is usually performed to make a definitive diagnosis. A chest tube is then inserted to drain the pleural space. Repeated needle aspirations may be performed in lieu of chest tube insertion [21].

Nurses should provide education and support to patients with empyema. Oral care should be conducted before and after meals. Because empyema is an infectious disease, it is crucial to maintain a clean environment and to teach patients proper cough/sneeze cover and disposal of used tissues.

HISTOPLASMOSIS

Fungal infections (mycoses) of the lungs are generally the result of infectious spores that are inhaled into the distal air spaces, where they multiply and cause an inflammatory response. The infection can then spread from the lungs to other organs, including the skin, bones, and the central nervous system. Many fungi can cause respiratory diseases, all of which have similar pathologic findings, symptomatology, and treatment. Coccidioidomycosis, histoplasmosis, and blastomycosis are three of the most common endemic fungal infections in the United States, with prevalence varying by region [71].

Histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum. It occurs worldwide, but in the United States, it is more prevalent in the Mississippi and Ohio River valleys. The organism flourishes in a temperate climate, and its growth is enhanced in soil that contains chicken, starling, or blackbird droppings or bat guano. The fungi become airborne and may be inhaled when the soil is disturbed; transmission from person to person does not occur [71].

Clinical Manifestations

After the spores of H. capsulatum are implanted in the lungs, they mature and rupture, releasing yeast forms of the organism. These yeast forms are surrounded and engulfed by macrophages, similar to the process seen with tuberculosis. Caseating granulomas form, and delayed hypersensitivity develops. Invariably, the organism invades the bloodstream, spreading to various organs, especially the liver and spleen. In most cases, the disease is self-limited. Histoplasmosis can be asymptomatic, acute, or chronic. Acute histoplasmosis is most common in infants and small children; acute histoplasmosis in adults is most often a reinfection with a large number of fungi. Symptoms include fever, chills, malaise, dry cough, and muscle aches. Pulmonary infiltrates plus hilar and mediastinal lymphadenopathy are visible on x-ray. Symptoms of this form of histoplasmosis usually persist for five to seven days. Lesions on the lung eventually calcify, leaving a so-called "buck shot" appearance. In some cases, a severe pneumonia results. Acute disseminated histoplasmosis is rare. Patients who are immunosuppressed and young children are more likely to develop this form of histoplasmosis [71].

Therapeutic Measures

A Histoplasma antigen skin test is available for diagnosis. However, skin testing is of limited value because of the high rate of false-positive and false-negative results. Serologic tests can be done, but they are often made positive by the histoplasmin skin test, so blood should be drawn prior to the skin test. The organism can be better identified from cultures of sputum, blood, urine, and tissue biopsy. No antifungal medication is required for primary histoplasmosis under most circumstances. However, in cases of chronic progressive pulmonary disease and acute disseminated disease, IV amphotericin B is recommended, followed by an extended course of itraconazole [23]. Surgery is rarely performed but may be done to resect compressing nodes, if necessary [21].

Specific Nursing Measures

Nursing care for patients with pulmonary mycoses focuses on explaining the disease and treatment and monitoring for potential side effects of treatment. Patients and their families may be apprehensive that the disease is contagious, so it is important to explain that person-to-person transmission does not occur.

Because the primary drug used in the treatment of histoplasmosis, amphotericin B, can cause kidney damage and other adverse effects (e.g., liver damage, severe chilling, hypotension), the administration of this medication should be monitored closely. Patients should be questioned about any side effects experienced, and laboratory tests of hepatic and renal function may be ordered. The color and consistency of urine should also be monitored and urinary output measured. The patient's skin should be inspected in natural light to detect any jaundice [64,65].

BRONCHIECTASIS

Bronchiectasis is a permanent abnormal dilation of one or more large bronchi caused by destruction of the elastic and muscular components of the bronchial wall. While the number of people developing bronchiectasis as a complication of severe pulmonary infection is decreasing, bronchiectasis remains a common complication of certain systemic disorders, particularly cystic fibrosis [71].

The basic disturbance in bronchiectasis is a congenital or acquired weakness of the bronchial wall. Anomalies of the bronchial system can lead to bronchiectasis by promoting infection in the involved airways. For example, immotile cilia syndrome, a genetic disorder causing immobility of cilia in the respiratory tract, leads to recurrent sinus and bronchial infections and eventually bronchiectasis. Certain hereditary immunodeficiency diseases are also frequently complicated by bronchiectasis because affected patients are predisposed to infections of the upper and lower airways [71]. Occasionally, bronchiectasis may follow the aspiration of corrosive chemicals or gastric fluid.

Most forms of bronchiectasis are associated with prolonged respiratory tract infections and bronchial obstruction. At times, it is difficult to determine whether the infections caused the bronchiectasis or if the infection is superimposed on an underlying congenital, hereditary, or local obstruction. Those most likely to develop bronchiectasis have disorders with diffuse airway involvement such as cystic fibrosis, bronchial asthma, chronic bronchitis, and ciliary immobility disorders [71].

Clinical Manifestations

The primary clinical feature of bronchiectasis is a chronic, loose cough that is usually productive of large amounts of mucopurulent, often foul-smelling sputum. Hemoptysis is a frequent occurrence, and recurrent bronchopulmonary infections are common. Patients may develop dyspnea, chronic malnutrition, fatigue, and anemia as the disease progresses.

Auscultation of the chest usually reveals rales. Chest x-ray may show chronic inflammatory changes, including recognizable dilations. Arterial blood gas values reveal a reduced PO_2 because of perfusion of poorly ventilated alveoli; PCO_2 is often normal. The prognosis of severe untreated bronchiectasis is generally poor, but the use of antibiotics has improved the outlook for this disease [71].

Therapeutic Measures

The cornerstone of treatment in bronchiectasis is daily bronchial hygiene with postural drainage, which usually has to be continued for life. Adequate hydration and humidification along with intermittent positive pressure breathing are necessary to assist in the liquefaction of bronchial secretions. Bronchodilators are indicated when bronchospasm compounds the problem [1,10].

Antibiotic therapy is necessary if an infection develops in association with bronchiectasis. The choice of antibiotic is guided by results of sputum culture. However, prolonged use of antibiotics, especially multiple antibiotics, should be avoided. Treatment of accompanying sinusitis with decongestants and humidified air is also important [63,72].

Specific Nursing Measures

Because bronchiectasis is a chronic condition, patients and their families will require instruction on long-term care, including how to perform deep breathing and coughing exercises and bronchial drainage. Adequate fluid intake and humidified air may also help. Patients should avoid exposure to infectious diseases and other situations, such as smoke or heavy smog, that could aggravate their conditions.

Nutritional management should be stressed, because patients with bronchiectasis are often anorexic. A nutritious diet is necessary for patients' immune systems to ward off respiratory tract infections [36]. Good oral hygiene and adequate rest are also important. Bronchial hygiene measures before meal times may help reduce coughing and expectoration during eating. Patients should be encouraged to receive appropriate immunizations, particularly influenza and pneumococcal vaccines [42].

ASTHMA

Asthma is considered a chronic, albeit reversible, respiratory disorder. This inflammatory condition produces hyper-reactive and hyper-responsive airway and lungs, causing episodic, reversible airway obstruction through bronchospasms, increased mucus secretions, and mucosal edema [73,74,75]. The hyper-reactive lungs of patients with asthma are more sensitive than most individuals' and may become inflamed or edematous when exposed to irritants, such as cold air, animal dander, dust, tobacco smoke, or grass [74,75]. The patient's immune system over-reacts to these irritants, constricting the airways and filling them with mucus; constricted airways interfere with the movement of air in and out of the lungs, making breathing difficult [74,75].

Asthma is marked by recurrent episodes of wheezing, breathlessness, chest tightness, and/or coughing. Usually, these periods are associated with widespread but variable airflow obstruction followed by a period of relief, either spontaneously or in response to treatment [76]. Asthma has many puzzling aspects, and its symptoms may wax and wane, especially seasonally [74]. Unlike other respiratory diseases, such as COPD and emphysema, in which air trapping and hyperinflation of the lungs also occur, asthma is reversible with the use of proper medications and therapies. Long-term lung tissue damage can occur when asthma attacks occur frequently or when the disorder is poorly controlled. Permanent damage would require many instances of severe attacks. In children, whose lungs are still developing, the risk of long-term damage is greater.

In 2016, an estimated 339 million people worldwide had asthma. Most asthma-related deaths occur in low and lower-middle income countries. According to the World Health Organization, there were 417,918 deaths due to asthma worldwide in 2016 [77].

The global increase in asthma incidence and its impact on public health are also evidenced in the United States. In 2018, it was estimated that 7.7% of Americans (approximately 24.7 million people) had asthma [78]. The number of individuals diagnosed with asthma increased from 7.3% in 2001 to 7.9% in 2017 [79]. As of 2018, current asthma prevalence in the United States is 7.7% (19.2 million) among adults and 7.5% (5.5 million) among children [80].

The cause of the proliferation of asthma in the last few decades is not yet known, although some have attributed the rise to environmental factors and expansion of the condition's diagnostic criteria. The National Health Survey questions, from which most of the statistics on asthma prevalence are obtained, changed slightly after 1997, causing a shift in how the condition and associated statistics were reported [81,82]. In 2001, the CDC introduced a more precise measurement of asthma. Since then, the trend has remained stable at historically high levels [82].

Clinical Manifestations

There are essentially five key elements of an asthma attack: muscle spasm, excess mucus, coughing, wheezing, and fatigue. While not all five elements are present for all patients, they are the most common physical manifestations of an episodic attack of the condition and should be evaluated and treated urgently.

Muscle Spasm

In response to irritation and immune response, muscles on the outer layer of the bronchi contract, causing a bronchospasm. Tightened muscles restrict the movement of air. Depending on the degree of airway narrowing, which differs for each patient and with the severity of the attack, the characteristic breathing difficulty, chest tightness, wheezing, and coughing will follow [74].

Excess Mucus

Inflammation can produce excess mucus as a protective mechanism. During an asthma attack, glands secrete excessive amounts of thick mucus to compensate for the increased amount of irritants or allergens. The excess mucus clumps together in the airways, further narrowing the bronchial tubes by partially blocking the passageway and hindering breathing. This increased amount of mucus can also form plugs that clog very small airways. During an asthma episode, some patients attempt to clear their airways by coughing up what seems to be a mucus plug. However, patients may produce many plugs; consequently, they may have a continuous, irritating hacking cough. If left untreated, mucus plugs can prolong asthma episodes and increase the risk of infection [74].

Coughing

When secretions become too thick for cilia to handle, the system responds by coughing to remove the unwanted substance. Dry coughs in patients with asthma are generally the product of extra-thick mucus plugs or bronchioles so blocked that the mucus cannot be removed or moved through. Nasal and sinus drainage, a common symptom of allergies, may also irritate airways and produce a nagging, unproductive cough [74]. If a patient has been mouth breathing, the airways may become dry and have decreased elasticity, making it more difficult to clear them. If this is the case, the patient should be encouraged to take frequent sips of water or isotonic fluids (e.g., electrolyte replacement drinks).

Wheezing

Wheezing is considered to be a trademark of asthma, but it is not a definite indicator. The wheezing sound associated with asthma results from a forceful rush of air pushing through narrowed, constricted airway lumens. The surge of air causes vibrations that make the wheezing sound. In some cases, airways can be so constricted that the air flowing past a blockage is not sufficient to produce a wheeze. In very severe attacks, the absence of wheezing is a worrisome sign.

It is important to note that patients with severe asthma have acute airway inflammation during an episode, and patients with chronic asthma have continuous symptoms of airway inflammation, which can eventually destroy airway tissue and alter lung function. Prolonged inflammation may result in permanent obstruction as a result of alteration of the bronchial walls. Unfortunately, after this change occurs, the airways may not respond to treatment as quickly or at all. This is why it is important to use medication to reduce airway inflammation, subsequently preventing permanent obstruction [74].

Fatigue

Breathing with asthma can fatigue the body. As exhalation is blocked and air is trapped in the lungs, more force is required to maintain adequate oxygen supply. To aid in exhalation, accessory muscles become involved, which can deplete the body of energy. Untreated asthma can produce severe degrees of fatigue for the patient, and this can become a critical situation warranting immediate intervention [74]. Lethargy, decreased response time, and weakness are all late signs of fatigue.

Therapeutic Measures

The treatment of asthma is generally divided into one of two categories: short- or long-term management. Short-term treatments are used only in the case of an asthma attack for immediate relief from the devastating symptoms. The focus of treatment for stable asthma is long-term prevention, planning ahead for emergencies, and being alert to increased symptoms [74]. Asthma may be controlled with early, accurate diagnosis and a treatment plan that involves a patient's, and perhaps an entire family's, active participation.

Evidence Based Practice Recommendation

In patients with severe allergic asthma, the American Thoracic Society and the European Respiratory Society suggest a therapeutic trial of omalizumab both in adults and in children.

https://www.thoracic.org/statements/resources/allergy-asthma/Severe-Asthma-CPG-ERJ.pdf

Last Accessed: August 10, 2020

Strength of Recommendation/Level of Evidence: Conditional recommendation, low quality evidence

When considering pharmacologic treatment of asthma, the dosage, timing, and type of medication should be tailored to individual needs. Optimal treatment should include methods to reverse airflow barriers, stop symptoms from occurring, prevent serious attacks and need for emergency care and hospitalization, keep asthma from interfering with activities of daily living, minimize side effects, and control symptoms with the least amount of medication [74]. As with the approach to management, medication therapy generally adheres to two possible uses: to relieve symptoms quickly with the use of bronchodilators or to reduce chronic airway inflammation with anti-inflammatory medications, preventing asthma from recurring in the future.

Asthma exacerbations can be frightening experiences for both patients and their caregivers, especially the first time an attack occurs. A thorough explanation of all the treatments administered will better educate patients for future attacks and prepare them for future treatment.

Specific Nursing Measures

Although patients may have been through the experience many times, each asthma attack generates the fear of dying. To help allay the feeling of suffocation, patients may prefer not to be closed in (e.g., by bedside curtains). A quiet environment with as few interruptions as possible should be maintained. Patients should be protected from drafts and chills; wet linen from diaphoresis should be changed quickly.

Because shortness of breath interferes with the ability to talk, patients should not be fatigued further by taking an in-depth history or asking nonessential questions. Needed information can often be obtained more easily from family members [36].

Fluid intake and output should be monitored; unless contraindicated, patients should receive 3–4 L per day. The nutritional intake of patients with asthma can be severely hampered if shortness of breath makes them unable to eat. It may be necessary to monitor food and fluid intake and provide or recommend high-nutrient liquid supplements.

Breathing exercises along with bronchial drainage are important aspects of care. These exercises can help reduce the amount of residual volume of air in the lungs during an attack, and bronchial drainage can help to prevent the buildup of secretions [29,36,83]. Suctioning may be required if secretions cannot be expectorated. The sputum expectorate should be observed and charted for amount, consistency, odor, and color [29,36].

Respiratory and cardiac assessment is an ongoing responsibility, as is careful monitoring of arterial blood gas values and pulmonary function studies. Cardiac dysrhythmias, tachycardia, tremors, nervousness, nausea, and headache are possible adverse effects from the beta-adrenergic stimulators as well as from aminophylline and theophylline. Sudden absence of wheezing indicates a progression to respiratory failure [29,36].

Because asthma is a chronic condition, patients, their families, and significant others require instructions in its cause, care, and treatment. If possible, help patients to identify precipitating factors (triggers) in the development of their attacks and take measures to avoid them. Environmental irritants, such as cigarette smoke, aerosol sprays, overly dry air, and extremes in temperatures, should be avoided. Patients should be encouraged to seek medical care at the first sign of a respiratory tract infection, tonsillitis, or sinusitis [29,36].

Patients with asthma should be encouraged to maintain as active and as normal a life as possible. Sufficient rest is important, as fatigue may make it more difficult for these patients to handle daily stress.

Patients should be aware of the nature, proper administration, and effects of the medications they are taking. Propranolol should not be given to patients with asthma because of its potential to cause bronchoconstriction. Antihistamines and decongestants should be avoided because of the tendency to dry airway secretions, making expectoration difficult [72].

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

COPD is as a common preventable disease characterized by airflow limitation that is usually progressive and is associated with an abnormal inflammatory response in the airways and the lung to inhaled noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients [84]. Clinically and pathologically, COPD is comprised of two overlapping disease processes: chronic bronchitis and emphysema.

Chronic bronchitis is defined as a cough with sputum production on most days for at least three months of a year for two consecutive years [85]. Patients with chronic bronchitis have a characteristic hyperplasia and hypertrophy of the goblet cells and mucous glands of the airway, leading to excessive mucus secretion narrowing the airways, which results in repeated cough with sputum. The airway walls are infiltrated with inflammatory cells, and persistent inflammation results in thickening of the wall and airway narrowing. Progression of chronic bronchitis results in fibrosis and squamous metaplasia, which limits airflow [86]. Chronic bronchitis is a recurrent and irreversible condition, which differentiates it from acute bronchitis. Acute bronchitis is an inflammation of the large bronchi in the lungs typically caused by viruses or bacteria that may last several days or weeks [87].

Emphysema is an enlargement of the air spaces distal to the terminal bronchioles, with destruction of their walls [85]. The destruction of air space walls reduces elastic recoil and the surface area available for the exchange of oxygen and CO_2 during breathing. These airways can collapse, leading to further limitation in airflow. Emphysema can be classified by location as panacinar/panlobular and centriacinar/centrilobular [88].

Panacinar emphysema results in enlargement of respiratory bronchiole to alveoli and includes entire respiratory acini. It usually involves all lung fields, particularly the bases and anterior margins of the lungs. This type of emphysema is common in individuals with alpha-1 antitrypsin deficiency.

Centriacinar emphysema predominantly occurs in the upper lobes, resulting in enlargement of the respiratory bronchiole (i.e., the proximal and central part of the acinus); however, the distal acinus and alveoli are unaffected. This type of emphysema is common in smokers. Emphysema can also be classified as distal acinar emphysema, irregular emphysema, or congenital lobar emphysema (CLE). Distal acinar emphysema preferentially involves the distal airway structures, alveolar ducts, and alveolar sacs. CLE is a rare congenital disorder characterized by hyperinflation of one or more of the pulmonary lobes. Irregular emphysema is a fibrotic form of the disease that shows no consistent relationship to any portion of the acinus. Scarring is very common in patients with irregular emphysema.

Clinical Manifestations

The cardinal signs and symptoms of COPD are chronic cough, sputum production, breathlessness (shortness of breath and dyspnea), and limited exercise tolerance. Other common signs that may be present in COPD include:

- Tachypnea

- Pursed lips breathing

- Prolonged expiration phase of breathing (compared with inspiration)

- Active use of neck muscles during breathing

- Increased resonance of the chest (by percussion) caused by hyperaeration and emphysematous change

- Increased anteroposterior diameter of the chest ("barrel chest")

In established and late-stage disease, systemic complications can develop, including skeletal muscle wasting and weakness, poor exercise capacity, weight loss, depression and anxiety, osteoporosis, cor pulmonale, and polycythemia.

Treatment Measures

The management of stable COPD is characterized by a stepwise increase in treatment guided by the overall health and clinical status of the patient and the severity of the disease. Pharmacotherapy is used to both control and prevent COPD symptoms. Effective treatment will reduce the frequency and severity of COPD exacerbations, increase exercise capacity, and improve overall health status. Currently, there is no medication for COPD that can prevent the long-term deterioration in lung function that is the hallmark of the disease. However, there are many drugs that can improve symptoms and provide relief to the patient, including bronchodilators (i.e., beta2-agonists, muscarinic antagonists, and methylxanthines), corticosteroids, and phosphodiesterase-4 inhibitors. Each individual responds differently to treatment and will experience a varying degree of side effects. Careful monitoring is required to ensure that the goal of treatment is met.

Influenza and pneumococcal vaccines are effective in preventing some of the infections that cause COPD exacerbations and should be administered to all patients with COPD. Pulmonary rehabilitation is a multidisciplinary and comprehensive intervention that is individually tailored for patients with COPD. Its principal goals are to:

- Reduce COPD symptoms

- Optimize physical and emotional status

- Reduce healthcare costs by controlling and reversing various dysfunctions (reducing the need for hospitalization)

- Improve overall quality of life

- Improve activities of daily living

Pulmonary rehabilitation can address nonpulmonary conditions that are not addressed by the medical management of COPD, including:

- Muscle weakness and wasting

- Exercise deconditioning

- Depression

- Relative social isolation

- Weight loss

Addressing and treating such problems can disrupt the "vicious circle" in COPD, leading to overall improvement in all aspects of COPD. Patients involved in pulmonary rehabilitation experience an 11% increase in peak oxygen consumption, an 18% increase in peak workload, and an 87% increase in endurance time [89].

Specific Nursing Measures

Evidence Based Practice Recommendation

The American College of Chest Physicians and the Canadian Thoracic Society suggest including smoking cessation counseling and treatment using best practices as a component of a comprehensive clinical strategy to prevent acute exacerbations of COPD.

https://europepmc.org/article/med/25321320

Last Accessed: August 10, 2020

Strength of Recommendation/Level of Evidence: 2C (Weak recommendation, low- or very-low-quality evidence)

Patients with chronic lung conditions like COPD may feel angry, depressed, or anxious over their condition and its effect on their life. It is important that patients understand which aspects of their condition are reversible, such as accumulation of secretions and bronchospasm, and which are not. The potential for reversibility is greatest in treating chronic bronchitis and least in treating emphysema [29].

Patients with COPD should be instructed to take steps to avoid respiratory tract infections and to contact their physician if they become ill. Patients should also avoid exposure to irritants and high pollution levels.

Bronchial hygiene is an important aspect of patient teaching. Topics should include effective cough technique, breathing exercises, and pursed lip breathing to promote CO_2 elimination. Bronchial drainage may be necessary to facilitate the expectoration of secretions and reduce bronchospasm; an intermittent positive pressure breathing machine may be ordered for use at home. Saline and medications such as isoetharine may be added to the nebulizer to loosen secretions and reduce bronchospasm. Steam inhalation may also be helpful [29].

Continuous home oxygen therapy may be required if the patient's PO_2 level is low. Because those with COPD may have a hypoxic drive to breathe, continuous low-flow oxygen therapy should be carefully monitored with regular arterial blood gas levels. Patients and caregivers should be instructed to use only the flow of oxygen ordered by the physician and not to increase the flow [36].

Signs and symptoms of hypoxia and hypercapnia (e.g., shortness of breath, restlessness, lethargy, headache, confusion) should be reviewed with the patient and family members and/or caregivers, as these symptoms may signify impending respiratory failure. Patients should weigh themselves daily, because a significant weight gain in a short period could indicate fluid retention from right-sided heart failure.

Hydration is an important aspect of COPD care, because water helps to liquefy secretions in the lungs. Unless contraindicated, patients should be instructed to drink 8 to 10 glasses of fluids daily. Coffee and tea have a diuretic effect and should not be counted as fluid intake [36].

High-calorie meals are necessary for patients with COPD who are underweight and undernourished. Small, frequent meals may be more easily tolerated by those who are short of breath; eating large meals requires more energy to consume and digest. Salt-restricted diets may be necessary for those with right-sided heart failure. Foods high in potassium are important for patients taking diuretics. Teaching materials and handouts are available through the American Lung Association [42].

ACUTE RESPIRATORY FAILURE

Acute respiratory failure is defined as the sudden inability of the respiratory system and the heart to maintain adequate arterial oxygenation and CO_2 elimination. The marked increases in CO_2 levels associated with acute respiratory failure depress the central nervous system, leading to symptoms of drowsiness, muscle twitching, a gradual loss of consciousness, and coma. Clinical manifestations of hypoxemia affect the nervous system first, because it is most sensitive to oxygen deprivation. The four most common signs of acute respiratory failure are restlessness, headache, confusion, and tachycardia [44].

Treatment Measures

If necessary, bronchodilators such as aminophylline may be used in the treatment of respiratory failure to decrease edema of the airways and bronchospasm. Corticosteroids may be administered to reduce bronchial inflammation and bronchospasm. Antibiotics may also be necessary if underlying infection is present. Cardiac medications are given if cardiac failure or dysrhythmias occur. Sodium bicarbonate is administered if respiratory acidosis is present [44].

Acute respiratory failure can be a medical emergency requiring lifesaving measures such as intubation and mechanical ventilation. Three general indications for endotracheal intubation and mechanical ventilation are unconsciousness, copious secretions that cannot be cleared by coughing, and severe hypoxemia or respiratory acidosis that does not respond promptly to other measures [39,44].

Specific Nursing Measures

Patients with respiratory failure should be carefully observed for signs and symptoms of hypoxia and hypercapnia. Individuals who are difficult to arouse from sleep or irritable may be exhibiting signs of hypercapnia. Besides monitoring respiratory status, the patient's cardiac status should also be assessed; hypoxia, hypercapnia, and acidosis can lead to cardiac dysrhythmias and depressed myocardial contractility. Serum electrolyte values also require close monitoring [39].

Healthcare professionals should be alert to the possibility of CO_2 narcosis, especially in those with COPD. This condition occurs when the level of CO_2 in the arterial blood becomes so elevated that it no longer provides a stimulus to breathe. This can lead to respiratory arrest [39].

Bronchial hygiene instruction is necessary. If patients cannot clear secretions effectively, tracheobronchial suctioning may be necessary. Psychologic support is also important. Many of the lifesaving measures employed in the treatment of acute respiratory failure can cause anxiety and fear.

LUNG CANCERS

Lung cancer is the second most common cancer affecting both men and women in the United States, accounting for an estimated 12.5% of all new cancer diagnoses [90,91]. Although it has been linked primarily to smoking and environmental factors, this disease can affect patients regardless of their occupation or lifestyle. Within the general diagnosis of lung cancer, there are several types, each with its own clinical course and prognosis.

There are two main categories of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancers and is further divided into two types: non-squamous carcinoma (this includes adenocarcinoma, large cell carcinoma, and other cell types) and squamous cell (epidermoid) carcinoma, each with distinct histologic and clinical characteristics [92,93,94,95]. It is important that healthcare professionals understand these differences as they care for patients with the diagnosis of lung carcinoma.

Clinical Manifestations

Evidence Based Practice Recommendation

According to the American College of Chest Physicians, all patients with lung cancer who have troublesome cough without a treatable cause should be prescribed opioids to suppress the cough.

https://journal.chestnet.org/article/S0012-3692(13)60305-0/fulltext

Last Accessed: August 10, 2020

Strength of Recommendation: 1B (Strong recommendation based on moderate evidence that the benefits outweigh the risks/burdens)

Lung cancer rarely gives an early indication of its presence. It may be detected accidentally, when viewing a routine chest x-ray, or it may be suspected by symptoms presented by the patient.

One of the most common symptoms experienced by patients with lung cancer is cough, which occurs when the airways become irritated (as from smoking) [91,93,96]. Those patients who have a cough related to their smoking may recognize a change in the type of cough but are not as likely to realize the significance of that change, particularly if the change occurs slowly over decades [96]. The cough may be more frequent, more irritating, of a different tone, or may feel as if it is arising from a different site than a normal cough. A cough that has always been dry may suddenly become productive as the obstructed bronchus develops an infection [91,96,97]. Persistent wheezing that occurs in one location in a smoker may also indicate lung cancer [96,97].

Pain that arises from lung abscess or tumor is often difficult to describe. It may not be severe, if present at all. With metastasis to the chest wall or lymph nodes, the patient may feel some tightness or a constant ache, which may be mistaken for a pulled muscle related to coughing. When a tumor invades the brachial plexus, there is usually pain in the arm and shoulder. Pain that originates in the chest wall may worsen with deep breathing or coughing [96,97,98].

Therapeutic Measures

After the tissue type has been confirmed and the stage has been determined, treatment options may be discussed with the patient and the patient's family. It is critical that all healthcare professionals thoroughly understand each type of treatment in order to answer questions posed by the patient and family as they work through the decision-making process. Patients commonly ask about the quality of life that can be anticipated after the treatment decision has been made. The components of treatment, such as discomfort, pain, nausea, hospitalization, and loss of time with friends and family, should all be weighed against the possibility of a longer life. The course of treatment is ultimately the patient's decision, and it is helpful to answer questions and provide acceptance no matter what choice is made.

Surgery is a frequent and logical choice for removing a cancer. Many patients respond to their diagnosis with comments indicating that they want the cancer removed from their body immediately. While this is not always an option, it is the best choice for many patients with early-stage disease [92,99]. In general, the type of surgery performed depends upon the extent of the disease [92].

The patient with NSCLC may receive chemotherapy in combination with radiation and/or surgery, as determined by the stage of the disease and the patient's overall health status [100]. Research has indicated that adjunctive chemotherapy, in addition to surgery, radical radiotherapy, or supportive care, is effective in improving overall survival rates and disease-related symptoms [100].

Radiation therapy is defined as the use of ionizing radiation to kill cancer cells. It is usually considered local therapy because it treats only the cells at which the radiation is directed; however, systemic radiation therapy, or introduction of radioactive material (i.e., radiopharmaceuticals) into the circulatory system, is also available. When healthy cells surrounding the cancerous lesion are exposed to radiation, they may also be destroyed; however, they are better able to repair DNA damage than are cancer cells. Radiation treatments may be administered intravenously or orally, whichever is determined most effective to treat the specific tumor type and magnitude [101,102].

Aside from these modalities, several alternative modalities, such as stem cell and bone marrow transplantation, are in clinical trials to determine their effectiveness in the treatment of lung cancer.

Specific Nursing Measures

Patient education is a crucial aspect of the care of those with lung cancer. Patients require an understanding of the various diagnostic procedures, therapeutic interventions, and associated side effects [103].

One of the primary concerns voiced by patients who are given a diagnosis of cancer is that they will be in severe pain. Some patients are so certain their diagnosis equates to suffering that they are willing to forego treatment that would prolong their life. It is vital that patients and their families be assured that pain, if experienced, will be relieved effectively.

Nausea, vomiting, and weight loss are often linked to treatment with either radiation or chemotherapy but may occur solely from the cancer. For patients experiencing nausea, soda crackers and ginger ale may help settle their stomachs. For some patients, simply eliminating spicy foods or foods with strong odors may make a difference. Encouraging the family to eat with the patient and making it a social event can be helpful. Antiemetics taken regularly before meals can often relieve symptoms of nausea and vomiting. Simple counseling may be very helpful. Dietitians can suggest ways to increase the caloric content of simple foods without requiring the patient to eat a great deal more food. Adding dry milk powder to milk, ice cream, or puddings, for example, can substantially increase calorie intake.

Lung cancer generally does not have a good prognosis. As previously noted, many patients with lung cancer have metastases at the time of diagnosis, which decreases survival time. For these patients, dealing with impending death is a reality to be considered. This is not to say that patients should not be fighting the disease and, indeed, some do win the battle. Unfortunately, the overall five-year survival rate for lung cancer is only about 19% [91].

While patients with terminal lung cancer face psychologic and emotional anguish, it may also be a time for connection and personal growth [104,105]. The time of life when lung cancer is diagnosed may be relevant to the degree of grace the patient exhibits. When occurring so as to interrupt plans of travel, marriage, child rearing, career, or other major events, the impact of cancer may be even more devastating to the patient and the patient's family. When hope begins to fade and it becomes apparent that the end is approaching, changes will occur in the patient and the patient's family. Ideally, this is a time when they can realize how important they are to one another and express their feelings and wishes.

10. TRAUMATIC DISORDERS

Chest trauma results from penetrating or blunt trauma to the chest. Penetrating chest injuries, also referred to as "open chest" trauma, may be caused by gunshot wounds, stab wounds, and wounds from other penetrating objects. Blunt chest trauma—nonpenetrating injury to the chest—is primarily caused by traffic accidents, but other causes include falls, blasts, explosions, and assault. Blunt chest trauma is by far the most common type of injury to the chest. Chest injuries may involve the bony framework of the chest, the heart, the great vessels, the lungs, or a combination of these structures. Damage to the liver and spleen may also occur. Of all deaths resulting from trauma, approximately 75% involve chest injury [106,107].

Trauma victims require close monitoring because the full extent of their injuries may not always be initially evident. When caring for a patient with chest trauma, remember the ABC(CC)s: airway, breathing, circulation, cervical spine, and consciousness [107].

Breathing in patients with chest trauma may be accompanied by pain, dyspnea, asymmetrical chest movement, paradoxical chest movement, a sucking sound, poor tidal volume, and/or symptoms of hypoxia or hypercapnia. Cyanosis may be a later manifestation. Circulation may be affected and may be detected by such signs as jugular venous distention, tachycardia, dysrhythmias, hypovolemic shock, and cardiogenic shock. It is always assumed that victims of chest trauma have suffered a spinal cord injury until x-rays prove otherwise. Patients with chest trauma may fall at any point on the spectrum between alert/oriented and comatose; if alert, they may be very apprehensive [106,107].

If a patient with a penetrating chest wound has retained the instrument (e.g., knife), it should not be removed until he or she is in a position to be stabilized. In most situations, the object serves as a mechanical barrier for the lacerated vessels, and removing the instrument may result in hemorrhage.

The control of pain is important for all trauma patients. If analgesics are ordered, the nurse should monitor the patient for depressive respiratory side effects [106,107,108].

FLAIL CHEST

A flail chest occurs when multiple adjacent rib fractures and/or costosternal separations result in "floating" of a segment of the rib cage. It is the result of blunt trauma in which there is crushing injury to the chest [107].

Clinical Manifestations

A primary symptom of flail chest is the paradoxical motion of the chest wall during inspiration and expiration. Flail chest may also be accompanied by a pneumothorax, a hemothorax, or both. Mediastinal structures may shift toward the uninjured lung, compressing it and reducing the amount of ventilation the unaffected lung can provide. This mediastinal shift may also cause kinking and obstruction of major vessels. Patients complain of pain, often severe, that results in limited respiratory effort and an ineffective cough. Other manifestations include dyspnea, tachycardia, restlessness, and cyanosis [106,107].

Therapeutic Measures

As a first-aid measure, the flail segment can initially be stabilized by exerting firm but gentle pressure on the segment with the palm of the hand. Supplemental oxygen and nerve blocks to decrease pain may also be employed. If the patient's ventilation becomes more severely compromised (i.e., hypoxemia and hypercapnia develop), the treatment of choice is intubation and mechanical ventilation. Mechanical ventilation is usually continued only until the patient can maintain adequate spontaneous ventilation. Closed chest drainage may be necessary if a pneumothorax or hemothorax is present [107].

Specific Nursing Measures

Coughing and deep breathing are imperative to prevent atelectasis and pneumonia. Suctioning may be required. The patient's level of pain should be assessed and the effects of analgesics monitored. Close observation of vital signs and level of consciousness is necessary [39].

PNEUMOTHORAX

A pneumothorax occurs when there is a leak of air into the pleural space, with resultant loss of the negative intrapleural pressure causing partial or total collapse of the lung. A pneumothorax may be open or closed. In an open pneumothorax, an injury creates an opening in the chest wall, allowing air to flow into the pleural cavity. The increased intrapleural pressure causes a partial or total collapse of the lung [106]. In closed pneumothorax, also called spontaneous pneumothorax, the chest wall remains intact and air enters the pleural space from the lung surface. A closed pneumothorax may be caused by blunt chest trauma, in which a fractured rib pierces the lung [107].

Clinical Manifestations

A patient with a pneumothorax may complain of pain with breathing and may also exhibit dyspnea, tachypnea, and unilateral diminished breath sounds. The respiratory movement on the affected side may be diminished or absent. With a tension pneumothorax, air enters the pleural cavity during inspiration but is unable to escape during expiration. With each inspiratory cycle, the amount of air increases, causing progressive compression of the lung. The high intrathoracic pressure on the affected side causes a shift of the mediastinum (along with the heart, trachea, esophagus, and great vessels) to the unaffected side. This mediastinal shift compresses the unaffected lung, further decreasing ventilation. Distortion of the vena cava impairs venous return to the heart, with a resulting decease in cardiac output. Symptoms include marked dyspnea, severe chest pain, restlessness, agitation, hypotension, and cyanosis [44].

Therapeutic Measures

Diagnosis of pneumothorax is confirmed by chest x-ray, which also shows the extent of lung collapse. Treatment of a pneumothorax involves the insertion of chest tubes in the pleural space to evacuate the air; a thoracentesis may be performed. If a tension pneumothorax has developed, emergency performance of a needle thoracotomy or insertion of a flutter valve or chest tube is done to relieve the life-threatening pressure in the pleural cavity [44,108].

Specific Nursing Measures

Careful assessment of the respiratory and cardiac status of the patient with pneumothorax is imperative. Be on the alert for signs and symptoms of a tension pneumothorax.

Positioning the patient in a semi-Fowler's position may facilitate breathing. Deep breathing and coughing should be encouraged. In cases of penetrating injuries, the possibility of infection introduced by the penetrating object should be considered. Be prepared to assist the physician in a thoracotomy and insertion of chest tubes [39].

HEMOTHORAX

A hemothorax is defined as the accumulation of blood in the pleural space. It may result from either blunt or (more commonly) penetrating trauma to the chest. A hemothorax should be considered in severe blunt or decelerating accidents (e.g., motor vehicle accidents), which can result in ruptured intrathoracic vessels and cause aortic tears. Fractured ribs caused by blunt trauma are commonly responsible for lacerations leading to hemothorax [44,108].

Clinical Manifestations

A hemothorax may result not only in respiratory and cardiac impairments, but also in hypovolemic shock if large amounts of blood are lost. The total accumulation of blood can range from less than 300 mL in a small hemothorax to more than 1,500 mL in a severe hemothorax. With a small hemothorax, the patient may be asymptomatic. With more severe bleeding, partial or total lung collapse may occur as blood accumulates in the pleural cavity. There may be increasing dyspnea, asymmetric chest movement, chest tightness, ecchymosis over the affected lung, and hemoptysis. Tachycardia, restlessness, hypotension, and hypovolemic shock may occur [44,108].

Therapeutic and Specific Nursing Measures

Chest x-ray confirms the diagnosis of hemothorax. Patients with a small hemothorax often require no treatment, as the absorptive power of the pleura may resolve the problem. In symptomatic cases, a thoracentesis may be performed initially, but chest tube drainage is the most effective treatment. Replacement of lost blood volume is indicated, and a thoracotomy may be necessary in cases in which there is a large amount of recurrent bleeding. The nursing measures are comparable to those of pneumothorax. The emphasis is on monitoring for hypovolemic shock and carrying out fluid and blood replacement therapy [39].

CARBON MONOXIDE POISONING

Carbon monoxide is a toxic but colorless, odorless, tasteless, and initially non-irritating gas produced by the incomplete combustion of organic matter due to insufficient oxygen supply. It is often produced in domestic or industrial settings by motor vehicles that run on gasoline, diesel, methane, or other carbon-based fuels and from tools, gas heaters, and cooking equipment that are powered by carbon-based fuels such as propane and butane. Exposure at 100 ppm or greater can be dangerous to human health [44,108].

Clinical Manifestations

Carbon monoxide mainly causes adverse effects in humans by combining with hemoglobin to form carboxyhemoglobin (HbCO_2) in the blood. This effectively reduces the oxygen-carrying capacity of the blood, leading to hypoxia. Myoglobin and HbCO_2 can revert to hemoglobin, but the recovery takes time because the HbCO_2 complex is fairly stable [44,108].

Symptoms of mild acute poisoning include light-headedness, confusion, headache, vertigo, and flu-like symptoms; larger exposures can lead to significant toxicity of the central nervous system and heart and eventually loss of consciousness and death. Following acute poisoning, long-term sequelae often occur. Chronic exposure to low levels of carbon monoxide can lead to depression, confusion, and memory loss.

Therapeutic and Nursing Measures

Treatment of carbon monoxide poisoning largely consists of administering 100% oxygen or providing hyperbaric oxygen therapy, although the optimum treatment remains controversial. Oxygen increases the removal of carbon monoxide from hemoglobin, providing the body with normal levels of oxygen.

The prevention of carbon monoxide poisoning is a significant public health issue. Carbon monoxide poisoning is the most common type of fatal poisoning in many countries and has been used as a method to commit suicide. Domestic poisoning can be prevented by early detection with the use of household carbon monoxide detectors. Modern automobiles, even with electronically controlled combustion and catalytic converters, can still produce potentially lethal levels of carbon monoxide in an enclosed space or if the tailpipe is obstructed (e.g., by snow) [44,108]. These risks should be relayed to the public.

11. RESPIRATORY SURGERY OF THE UPPER AIRWAY

Patients who undergo surgery of the respiratory system (and their families or caregivers) often require teaching, support, and encouragement to cope with the significant alterations in lifestyle that may result. To be effective, the healthcare professional who cares for these patients should blend technical competence with human sensitivity.

As with any surgery, these patients should be monitored for complications. Aspiration and postoperative bleeding should be considered. Patients having surgery of the upper airway show signs of postoperative hemorrhage by repeated swallowing attempts.

TRACHEOTOMY

Tracheotomy is performed to obtain a temporary opening into the trachea. If the trachea is sutured to make a permanent opening, it is a tracheostomy. This technique is performed to provide access for aspiration of the bronchial tree or to relieve upper airway obstruction. It may be employed when a patient is unable to cough effectively and expel secretions. Indications for a tracheotomy include [108]:

- Mechanical ventilation for more than 7 to 10 days

- An artificial airway is required but the patient is not a candidate for orotracheal or nasotracheal intubation (because of severe facial injuries)

- Weakness or critical illness making breathing difficult

- A neurologic disorder paralyzing the chest muscles and diaphragm

- An obstructed upper airway caused by a tumor of the trachea or pharynx

A tracheotomy is not recommended in an emergency; in these cases, a cricothyroidotomy should be performed [108].

Physiologic Implications

Possible complications of tracheotomy during the early postoperative period include hemorrhage, tear of the trachea, extra-tracheal intubation (i.e., placement of the tube anterior to the trachea in a false passage), and subcutaneous emphysema [108]. Some patients are unable to swallow effectively following tracheotomy (even when the cuff of the tracheostomy tube is deflated) and may require the placement of a nasogastric feeding tube. Patients often experience postoperative discomfort and pain requiring analgesics. Opioids should be avoided or administered at the lowest possible dose to prevent respiratory depression. Humidified air or supplementary oxygen is necessary to avoid irritation to the mucosal lining. Even so, an increase in mucus production is likely.

Nursing Implications

Patients undergoing tracheotomy should be prepared for the effects of the operation, particularly if a tracheostomy is created—breathing through the stoma in the neck and loss of ability to speak while the stoma is open. Nurses should frequently assess respiratory rate and breathing patterns.

Tracheal suctioning should be performed as needed, depending on the status of the patient. The need for suctioning is determined by auscultation of lung sounds, the degree of the patient's respiratory distress, arterial blood gas levels, and chest x-rays. Cleansing of the area around the stoma and the tracheostomy tube is necessary [29].

Discharge Teaching

Patients who have a tracheostomy will need to learn how to care for themselves at home. The patient and at least one family member should demonstrate competence at suctioning and cleansing the tube prior to discharge. Patients should be assured that accidental occlusion of the opening during sleep will awaken them. Water poses a risk, however; patients should be reminded to cover the stoma when bathing. Some experts advise against all water sports, while others indicate that patients can engage in certain water sports if cautious. Drowning can occur rapidly, and patients should be extremely careful if they choose to engage in boating or fishing [29].

CRICOTHYROIDOTOMY

Cricothyroidotomy consists of the creation of an opening between the thyroid and cricoid cartilages into the trachea. Cricothyroidotomy is the procedure of choice in an emergency to establish an airway when orotracheal or nasotracheal intubation is not possible [108].

In many cases, cricothyroidotomy is done in the field or emergency department, often without the benefit of anesthesia. If the procedure is elective, local anesthesia is given. A short transverse incision is made in the neck immediately below the thyroid cartilage to expose the cricothyroid membrane. An incision is made through this membrane, and a small tracheostomy tube is inserted to establish the airway. If the patient requires intubation for more than a few days, the cricothyroidotomy should be converted to a standard tracheotomy. The implications for patient care are the same as for a tracheotomy [108].

LARYNGECTOMY

Laryngectomy is an option for some patients with laryngeal cancer. Partial laryngectomy using the laryngofissure approach is recommended for patients in whom the cancerous growth is limited. Partial laryngectomy approaches have the advantage of preserving the normal airway and the patient's ability to speak [108]. Total laryngectomy is appropriate for the removal of neoplasms too extensive to be removed by a partial or supraglottic laryngectomy [108].

Physiologic Implications

A total laryngectomy results in permanent changes in the patient's airway and speech. During ventilation, air enters through the tracheostoma instead of the nose, which results in anosmia and lack of humidification. Because taste depends on smell, patients may also experience a permanent alteration of their ability to taste. Potential complications include hemorrhage, nerve damage, fistula formation, and carotid artery rupture. Mucus secretion is often copious after surgery, and the patient cannot cough effectively without a glottis to close to increase intrathoracic pressure. However, patients can still expel secretions (often forcefully) through the stoma. Patients can no longer blow their noses or use a straw when drinking; they may experience difficulty swallowing initially, but this usually subsides after healing. The change that affects individuals the most is loss of the ability to talk (with total laryngectomy only). Fear of being unable to communicate can cause anxiety and negatively impact quality of life [108].

Preoperative Care

Preoperative teaching should focus on the permanent alterations in breathing and communication. When planning preoperative counseling, consider individual differences [39]. Speech therapists, mental health professionals, and other allied healthcare providers should establish contact before the procedure is done.

Postoperative Care

In the postoperative period, priority should be given to maintaining a patent airway. The trachea should be suctioned to remove secretions, and humidified air or oxygen may be administered initially. Most surgeons prefer to have the patient wear a laryngectomy tube for one to two weeks or until the stoma maintains its size. After the tube has been permanently removed, the patient should wear a lightweight stoma covering or bib. This allows movement of air into and out of the stoma but prevents foreign particles from entering. Moistening the bib with sterile saline provides some humidification [39].

If thick secretions are a problem, the patient should be taught to instill a few drops of normal saline into the stoma, followed by suctioning. A mucous plug that obstructs the trachea can usually be removed by suctioning, which stimulates the patient to cough. If these measures are unsuccessful, the physician should be notified. Measures should be taken to promote wound healing and prevent infection [39].

Discharge Teaching

Patients should be advised that the stoma should be covered when bathing to avoid aspiration. A scarf or high collar can be worn for warmth and to prevent foreign-body aspiration. Patients should be encouraged to carry a wallet card or bracelet indicating that they have undergone a laryngectomy.

Most patients will return as outpatients for continued instruction and evaluation of the method they choose for voice production. In the early postoperative period, patients may rely on gesturing and/or writing. Other options for communication include esophageal speech, artificial speech aids, and surgical-prosthetic voice restorations. Multimedia resources and written material are available through organizations such as the American Cancer Society.

12. THORACIC SURGERY

Thoracic surgery refers to any surgical procedure involving the chest wall or any organ between the diaphragm and clavicles. A variety of incisions may be employed in thoracic surgery; the posterolateral and anterolateral approaches are used often in general thoracic surgery, whereas median sternotomy is employed for certain cardiothoracic procedures [108].

Opening the thorax disrupts the normal negative pressure in the intrapleural space. During surgery, the loss of negative intrapleural pressure is compensated for—the patient is intubated and mechanically ventilated. Chest tubes are placed prior to closure of the thorax to restore the negative intrapleural pressure and assist in re-expansion of the lungs. After most pulmonary resections, tubes are placed to allow for drainage of fluid and removal of air from the intrapleural space [108].

TYPES OF THORACIC SURGERY

Closed Tube Thoracotomy

Closed tube thoracotomy refers to percutaneous insertion of a chest tube into the intrapleural space to evacuate blood or other fluid caused by trauma, surgery, malignancy, or infection or to re-expand the lung in patients who have a pneumothorax with more than 10% collapse [108].

Chest tubes are removed when fluid drainage is less than 80–100 mL per day, when an air leak is no longer present, or when the tube is occluded. A chest x-ray is done after removal of a chest tube to evaluate lung expansion. The patient should be observed for symptoms and signs of a recurrent pneumothorax or hemothorax [108].

Open Thoracotomy

Open thoracotomy consists of opening the thorax for the purpose of inspecting, repairing, or removing tissue. It may be performed as an elective or emergency procedure. It has also been used when patients develop cardiac tamponade or other bleeding cardiopulmonary wounds. Emergency thoracotomy allows rapid access to perform open heart massage in an effort to maintain an adequate cardiac output [108].

Decortication

Decortication involves the removal of pathologically thickened pleura that restricts lung expansion [108]. If the intercostal space is fused, this procedure may be very difficult or impossible.

Lung Transplantation

Lung transplantation was developed for patients with end-stage pulmonary disease. Techniques have been developed to transplant one lung, both lungs, or the heart with both of the lungs [108]. Long-term immunosuppression is necessary to prevent rejection of the transplanted organ.

Pulmonary Resection

There are many different types of pulmonary resection, usually categorized by the location and/or extent of the resection. Pneumonectomy refers to the removal of a lung, and a radical pneumonectomy also includes the removal of anterior and posterior mediastinal lymph nodes [108]. Lobectomy is the removal of one lobe from either the right or left lung [108]. The removal of a portion of a lobe is referred to as a segmentectomy or wedge resection [108].

PHYSIOLOGIC IMPLICATIONS

Thoracic surgery is generally associated with some pain, the degree of which varies with the type of procedure. This often causes patients to guard the area and hyperventilate, which increases the risk for atelectasis (i.e., collapse of a section of the lung).

Other possible complications following thoracic surgery include hemorrhage, hypotension, infection, cardiac dysrhythmia, respiratory failure, pulmonary edema, subcutaneous emphysema, residual pleural space, persistent air leak, bronchopleural fistula, and emphysema [108]. With pulmonary resection, there is a permanent decrease in pulmonary function [108].

PREOPERATIVE CARE

Candidates for thoracic surgery usually undergo extensive evaluation to ensure they can withstand the stress of the procedure. In addition to routine preoperative tests, patients' nutritional status and cardiac, pulmonary, and adrenal function are assessed. The results of pulmonary function tests and arterial blood gas analyses allow evaluation of respiratory status. Aggressive measures may be employed in an attempt to improve the patient's nutritional or pulmonary status prior to surgery, including hyperalimentation or enteral (tube) feedings [39].

Family members should be included in preoperative preparation. All patients should be prepared to engage in breathing, walking, and shoulder exercises after surgery. Teaching the procedure for incentive spirometry should be included in preoperative care. Psychologic preparation of the patient and family may include a preoperative visit to the intensive care unit. Patients may have an endotracheal tube, pulmonary artery catheter (Swan-Ganz catheter), central venous pressure (CVP) line, arterial line, peripheral intravenous lines, chest tubes, and a urinary catheter inserted during surgery. Preoperative teaching about the function of tubes inserted during surgery is also helpful [39].

POSTOPERATIVE CARE

Arm and shoulder exercises prevent stiffening of the shoulder and loss of muscle strength. The patient should be taught (and should demonstrate) shoulder exercises and the proper technique for coughing and deep breathing. Patients should also be instructed to ask for analgesics if they are experiencing pain. Nursing goals for patients who have undergone thoracic surgery include maintenance of adequate cardiac output, promotion of optimal pulmonary ventilation, maintenance of normal fluid and electrolyte balance, relief from pain, promotion of optimal wound healing, promotion of recovery without residual dysfunction, and emotional support and encouragement [39].

Maintaining Adequate Cardiac Output

Immediately upon arrival from surgery, the patient's blood pressure should be obtained and electrodes fixed to the chest to facilitate continuous monitoring of the cardiac rhythm. CVP readings should be taken hourly. Pulmonary capillary wedge pressures may be ordered every one to two hours. A change in body temperature alters the metabolic requirement and, thus, affects the cardiac output. If the patient's temperature is greater than 102 degrees F (39 degrees C), an antipyretic is prescribed. If the temperature rises above 104 degrees F (40 degrees C), the patient is placed on a cooling pad [39].

Drainage from the chest tubes should be monitored hourly. During the immediate postoperative period, it is wise to note the amount every 15 minutes. Persistent drainage of more than 200 mL per hour may require re-exploration to achieve hemostasis. Patients should be encouraged to move their legs frequently while in bed to promote venous return to the heart and prevent the formation of clots [39].

Promoting Optimal Pulmonary Ventilation

After thoracic surgery, humidified oxygen is administered either by endotracheal tube or by mask to prevent hypoxia and to liquefy secretions. The patient's color, respiration, and other vital signs should be assessed and documented. Auscultate the chest for a full respiratory cycle at each placement point of the stethoscope to determine the respiratory quality of function. Frequent analysis of arterial blood gas levels may be necessary.

It is crucial to ensure that chest tubes remain in the intrapleural space, are patent, and are connected to a collection receptacle. As soon as the patient regains consciousness, encourage coughing and deep breathing every hour for the first 24 hours. Coughing is more effective if the patient is assisted to a sitting position with the feet elevated. The incision should be supported anteriorly and posteriorly during coughing to minimize pain [39].

The patient should change position every one to two hours. In general, it is recommended that patients who have undergone pneumonectomy not be turned to the nonoperative side to allow maximum ventilation of the remaining lung. Patients who undergo lobectomy or a segmental resection should be positioned so their operated side is up to facilitate expansion of the remaining tissue in the lung. After one or two days, these patients can usually be turned to either side. Patients who undergo other types of thoracic surgery can usually be turned from their back to either side [39].

Maintaining Normal Fluid and Electrolyte Balance

Weight should be measured daily post-thoracic surgery. Urine output is closely monitored and should amount to at least 30 mL per hour. It is important not to administer fluids too rapidly, as this can lead to complications such as pulmonary edema.

If the abdominal cavity was not entered during surgery, patients can take fluids by mouth as soon as they are alert. Patients should be encouraged to drink a minimum of 1.5–2 L each day unless contraindicated. The patient can usually be advanced to the prescribed diet by the third postoperative day [39].

Relief From Pain

An opioid analgesic such as meperidine or morphine is prescribed to be given every two to three hours, as needed, after surgery. However, caution should be used when administering opioid analgesics because they can lead to respiratory depression. Later, medications such as aspirin or acetaminophen should be sufficient to manage postoperative pain [39,65].

Promoting Recovery without Residual Dysfunction

Altered sensation around the surgical wound can last for months, and patients often avoid moving the arm on the affected side because of the discomfort it causes. To combat these factors, the patient should engage in regular arm and shoulder exercises, starting with passive range-of-motion exercises performed a few hours after surgery. Patients often require encouragement to carry out these exercises [39].

Emotional Support and Encouragement

The hospital environment, the presence of numerous tubes, and pain can be emotionally exhausting for patients. The patient and family members will require explanations and reassurances [39].

13. CONCLUSION

With knowledge of respiratory structure and function and the dynamic pathology that impedes normal function, nurses can readily provide quality and even lifesaving care. An appreciation of the underlying causes of respiratory signs and symptoms leads to quicker reporting of changes in the patient's condition. The nurse can also perform immediate interventions based on standing orders and recognition of the appropriate actions to provide safe, quality care. Understanding the pathophysiology of the respiratory system transforms technical care to professional care through the use of solid decision-making skills.

14. CASE STUDIES

ASTHMA

Patient A is a woman, 42 years of age, admitted to the critical care unit (CCU) for an acute asthmatic attack. For three weeks prior to admission, the patient had increasing difficulty with cough with thick, white sputum, shortness of breath, syncope episodes associated with wheezing, and intermittent fevers up to 101 degrees F (37.8 degrees C).

Patient A is married and has two children in college. Although she has no smoking history, she was forced to retire from her job four years ago because of her chronic obstructive lung disease.

Past Medical History

Patient A reports allergies to erythromycin and penicillin. She has a history of asthma precipitated by dust, pollens, fumes, and air pollution requiring multiple emergency department visits and hospital admissions over the past 10 years. She also reports thrombophlebitis and hypertensive syncope accompanied by seizure activity for one year.

Past surgical procedures include left brachial artery embolectomy done 4 years previously, right knee repair completed 10 years previously, remote hemorrhoidectomy, and remote tonsillectomy and adenoidectomy in childhood. She is currently taking sustained-release theophylline, prednisone, phenytoin, warfarin, terbutaline sulfate, and metaproterenol sulfate inhaler.

Assessment and Diagnosis

Upon admittance to the CCU, a full physical exam is conducted (Table 1). An ECG is done and shows sinus tachycardia with incomplete right bundle branch block. Several laboratory tests are ordered, with the following results:

- White blood cell count: 9.5 x 10^9/L

- Hemoglobin: 18.2 g/dL

- Hematocrit: 53.2%

Table 1: PATIENT A'S PHYSICAL EXAM RESULTS

Parameter

Findings

General appearance

Heavy-set, agitated, diaphoretic woman breathing with pursed lips

Height: 5 feet 2 inches (157.5 cm)

Weight: 187 pounds (85 kg)

Head and eyes

Normocephalic

Pupils equal, round, reactive to light, accommodation

Ears

Tympanic membranes intact and clear

Neck

Supple, without masses or thyromegaly

Jugular-vein distention to 7 cm while sitting up 45 degrees

Chest

Dyspnea with rib retractions

Unable to complete a sentence without taking a breath

Fair inspiratory effort

A few diffuse inspiratory wheezes, marked expiratory wheezing

Abdomen

Rounded with active bowel sounds

Soft and nontender to palpation

Extremities

Peripheral pulses full, equal, and without bruits

Genitourinary system

Within normal limits

Neurologic status

Oriented to person, place, and time

Cranial nerves II–XII grossly intact

Sensory and motor function intact

Cardiovascular system

Point of maximal impulse not palpable

Heart sounds very difficult to hear

Peripheral pulses present and thready

Left radial pulse barely palpable

Vital Signs

Blood pressure

100/60 mm Hg

Temperature

101° F

Heart rate

155 beats per minute

Respiratory rate

18 breaths per minute

Source: Author

Based on the results of the assessment, Patient A is diagnosed with acute asthma attack.

Management

Patient A's ventilation and oxygenation are managed and monitored by arterial blood gas results. Pulmonary spirometry is also used to evaluate her progress, and there is marked improvement with a bronchodilator. Patient A is transferred out of the CCU on the fourth day and discharged on the seventh day.

Study Questions

1. Why is asthma considered an obstructive pulmonary disease?

2. What nursing interventions will help calm a hypoxic, agitated patient?

3. How do you recognize and treat asthma?

4. What should you think if a patient with acute asthma stops hyperventilating or has a normal CO_2 level?

5. The arterial blood gas level of a patient with asthma has changed from alkalotic to normal, and the patient seems to be sleeping. Is the patient ready to go home from the hospital?

COPD

Patient B, 69 years of age with advanced COPD, is admitted to the CCU for progressive respiratory distress. His respiratory status began deteriorating three months prior to admission following an upper respiratory tract infection. Since then, he has used oxygen at home, intermittently produced large amounts of purulent, non-bloody sputum, and lost 10 pounds. Patient B works as the owner of a movie theater and is involved in his Greek Orthodox church. He had been a heavy cigarette smoker and exposed to toxic chemicals during his working life.

Past Medical History

Patient B has a history of spring "hay fever" and rare asthma since puberty. For the past 18 years, he has had progressive emphysema with a reversible component. Two years previously, he was diagnosed with adenocarcinoma of the lung. He also reports an allergy to penicillin.

At 12 years of age, Patient B underwent right inguinal herniorrhaphy. Sixteen years ago, he underwent gastrojejunal anastomosis, followed by right upper lobotomy requiring tracheotomy, and right upper lobotomy for benign organized pneumonitic process. Nine years previously, an appendectomy and repair of perforated sigmoid disarticulates with peritonitis were performed.

Assessment and Diagnosis

Upon admittance to the CCU, a full physical exam is conducted (Table 2). Complete blood count, electrolytes, and urinalysis are all within normal limits.

Table 2: PATIENT B'S PHYSICAL EXAM RESULTS

Parameter

Findings

General appearance

Thin, wasted, tired-looking man in acute respiratory distress

Height: 5 feet 9 inches (175 cm)

Weight: 152 pounds (69 kg)

Head and eyes

Normocephalic

Pupils equal, round, reactive to light, accommodation

Foul odor to breath

Ears

Tympanic membranes intact and clear

Neck

Supple, without masses or thyromegaly

Jugular venous pulse not visualized

Chest

Increased anteroposterior diameter

Decreased breath sounds in the right lower lobe posteriorly and anteriorly with scattered loud wheezes, rhonchi, and rales

Prolonged expiratory time and rib retractions with dyspnea and tachypnea

Abdomen

Scaphoid, with several mature scars

Bowel sounds active in all quadrants

Soft, nontender without masses

Lower liver edge palpable 2 cm below right costal margin

Extremities

Peripheral pulses full, equal, and without bruits

Pitting edema (2+) noted on lower extremities and sacrum

Genitourinary system

Within normal limits

Neurologic status

Oriented to person, place, and time

Cranial nerves II–XII grossly intact

Sensory and motor function intact

Patient fatigues quickly

Cardiovascular system

Sinus tachycardia

Faint heart sounds

Normal S1 and S2 with summation gallop

Skin warm and moist

Vital Signs

Blood pressure

140/100 mm Hg

Temperature

97.8° F

Heart rate

134 beats per minute

Respiratory rate

40 breaths per minute

Source: Author

Based on the results of the assessment, Patient B is diagnosed with:

- Acute respiratory failure

- COPD

- Adenocarcinoma of the lung

Management

Patient B is given aerosolized bronchodilators every one to two hours initially. An aminophylline infusion is administered as well. The frequency of the aerosol treatments is gradually reduced to every four hours, with supplemental oxygen administered by nasal cannula. Patient B's ventilation and oxygenation are managed and monitored by arterial blood gas results (Table 3).

Table 3: PATIENT B'S ARTERIAL BLOOD GAS RESULTS

Time

O_2

pH

PCO_2

PaO_2

CaO_2

0 hours (admission)

2 L/minute

7.06

92.8

30

8.8

2 hours

4 L/minute

7.18

66.2

62

20.0

4 hours

6 L/minute

7.21

72.3

69

21.4

6 hours

4 L/minute

7.28

60.8

55

19.9

9 hours

4 L/minute

7.35

52.8

48

19.6

24 hours

4 L/minute

7.37

52.2

62

21.7

Discharge

2 L/minute

7.4

57.8

66

21.3

Source: Author

The nurses work with a dietitian to provide small, frequent, high-calorie and high-protein meals. This approach, adapted to his anorexia, dyspnea, and previous gastric surgery, improves Patient B's nutritional status. Patient B is transferred out of the CCU on the second hospital day and discharged five days after admission.

One month after discharge, Patient B is readmitted in acute respiratory failure. He and his family decide no resuscitation should be performed, and he dies two days after readmission.

Study Questions

1. Discuss the etiology of COPD. What lifestyle restrictions does the patient face?

2. Describe the pathophysiology of Patient B's chronic respiratory failure. What changes occur when acute respiratory failure is superimposed?

3. According to the arterial blood gas results, was Patient B improved at discharge?

4. If it is not possible to achieve normal arterial blood gas levels in a patient with respiratory failure, what levels are considered acceptable?

5. Identify Patient B's nursing problems. What outcomes are appropriate for him in view of his end-stage respiratory failure?

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73. Willis L. Professional Guide to Diseases. 11th ed. Ambler, PA: Lippincott Williams and Wilkins; 2019.

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76. McMillan JA, DeAngelis CD, Feigin RD, Jones MD (eds). Oski's Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.

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78. Centers for Disease Control and Prevention. Asthma: Data, Statistics, and Surveillance: Asthma Surveillance Data. Available at https://www.cdc.gov/asthma/asthmadata.htm. Last accessed July 8, 2020.

79. Centers for Disease Control and Prevention. Asthma: Data, Statistics, and Surveillance. Asthma Prevalence in the U.S. Available at https://www.cdc.gov/asthma/asthmadata.htm. last accessed July 17, 2020.

80. Centers for Disease Control and Prevention. National Center for Health Statistics. Asthma. Available at https://www.cdc.gov/nchs/fastats/asthma.htm. Last accessed July 17, 2020.

81. Moorman JE, Zahran H, Truman BI, Molla MT. Current asthma prevalence—United States, 2006–2008. MMWR. 2011;60(1):84-86.

82. Centers for Disease Control and Prevention. State of Childhood Asthma, United States: 1980–2005. Available at https://www.cdc.gov/nchs/pressroom/06facts/asthma1980-2005.htm. Last accessed July 17, 2020.

83. Ehrman J, Gordon P, Visich P, Keteyian S. Clinical Exercise Physiology. 3rd ed. Champaign, IL: Human Kinetics; 2013.

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85. Wilkinson I, Raine T, Wiles K, Goodhart A, Hall C, O'Neill H. Oxford Handbook of Clinical Medicine. 10th ed. Oxford: Oxford University Press; 2017.

86. Feather A, Randall D, Waterhouse (eds). Kumar and Clark's Clinical Medicine. 10th ed. Edinburgh: Elsevier Saunders; 2020.

87. Wenzel RP, Fowler AA. Clinical practice: acute bronchitis. N Engl J Med. 2006;355(20):2125-2130.

88. Lodish H, Berk A, Kaiser CA, et al. Molecular Cell Biology. 8th ed. New York, NY: WH Freeman; 2016.

89. Troosters T, Casaburi R, Gosselink R, Decramer M. Pulmonary rehabilitation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;172(1):19-38.

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Evidence-Based Practice Recommendations Citations

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34942 • Diabetes and Stroke: Making the Connection

Diane Thompson, RN, MSN, CDE, CLNC

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Every year, thousands of individuals will die as a result of their diabetes complications, and stroke is one of the leading causes of death in this population. Good control of diabetes and of other signs of cerebrovascular disease can reduce the associated morbidity and mortality and improve patients' quality of life. Healthcare professionals play a crucial role in identifying diabetic patients at risk for stroke and intervening to address modifiable factors. This course is intended to raise nurses' awareness of the connection between diabetes and stroke in order to improve patient care.

Table of Contents

34942 • Diabetes and Stroke: Making the Connection

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. AN OVERVIEW OF DIABETES

EPIDEMIOLOGY

3. DIAGNOSIS OF DIABETES

4. CEREBROVASCULAR DISEASE AND DIABETES

TYPES OF CEREBROVASCULAR ACCIDENTS

RISK FACTORS

SIGNS AND SYMPTOMS

5. TREATMENT OF STROKE

MECHANICAL EMBOLECTOMY

ANTICOAGULANTS

ANTIPLATELETS

6. PREVENTION

KNOWLEDGE OF STROKE WARNING SIGNS

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

34942 • Diabetes and Stroke: Making the Connection

Education Category. Infection Control / Internal Medicine

Release Date. 06/01/2019

Expiration Date. 05/31/2022

Course Overview

Every year, thousands of individuals will die as a result of their diabetes complications, and stroke is one of the leading causes of death in this population. Good control of diabetes and of other signs of cerebrovascular disease can reduce the associated morbidity and mortality and improve patients' quality of life. Healthcare professionals play a crucial role in identifying diabetic patients at risk for stroke and intervening to address modifiable factors. This course is intended to raise nurses' awareness of the connection between diabetes and stroke in order to improve patient care.

Audience

This course is designed for nurses in all practice settings who care for patients with diabetes.

Course Objective

Due to the widespread and potentially life-threatening nature of this issue, having a firm understanding of the implications of diabetes and how they relate to stroke is paramount. The purpose of this course is to provide nurses with the information necessary to identify patients with diabetes who are at risk for stroke and intervene early.

Learning Objectives

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

1. Outline the prevalence and diagnosis of diabetes.

2. Evaluate the etiology and presentation of stroke in patients with diabetes.

3. Identify treatment options for acute stroke.

4. Describe primary stroke prevention strategies for patients with diabetes.

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 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.

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

Both diabetes and stroke are major public health issues in the United States. An estimated 30.3 million American children and adults, or 9.4% of the total population, have diabetes [1]. Cerebrovascular disease is one of the most common complications of diabetes and is an area of serious concern as the population ages and the trend for diabetes to be diagnosed at an earlier age continues.

The risk of stroke is two to four times greater for individuals with diabetes compared to those without. As of 2014, stroke was documented as the cause of death in approximately 8% of all diabetes-related deaths among individuals 18 years of age and older [1]. Due to the widespread and potentially life-threatening nature of this issue, having a firm understanding of the implications of diabetes and how they relate to stroke is paramount.

2. AN OVERVIEW OF DIABETES

EPIDEMIOLOGY

Diabetes is a progressive disease process influencing fuel metabolism [2]. Carbohydrate, protein, and fat metabolism are altered when insulin, the mediator of fuel, is not available. This insulin deficiency can result from defects in insulin secretion and/or diminished tissue response to insulin, resulting in hyperglycemia [3]. The chronic metabolic dysregulation associated with diabetes can result in long-standing damage to various organs, including the eyes, kidneys, nerves, heart, and blood vessels [2].

According to the American Diabetes Association (ADA), the prevalence of diabetes increased 382% between 1988 and 2014 [4]. As stated, 9.4% of the U.S. population, or 30.3 million Americans, have a diagnosis of diabetes. In addition, an estimated 7.2 million people have diabetes but remain undiagnosed [1]. By 2025, it is predicted that 15% to 20% of all Americans will be diagnosed with diabetes or impaired glucose tolerance [5].

The scope of the diabetes problem is vast and diverse, particularly among geographical regions. In 2016, the prevalence of diabetes in the United States varied from 6.2% in Colorado to 13.2% in Alabama [6]. Genetics, race, age, and lifestyle significantly influence the onset and progression of the disease process [1]. Although all races and ethnicities can develop diabetes, the prevalence is greatest (15.1%) among Native Americans/Alaska Natives. This group also has a risk for development of type 2 diabetes that is more than two times greater than that of white Americans [1]. The prevalence of diabetes is 12.7% in non-Hispanic black Americans, 12.1% in Hispanic Americans, 8.0% in Asian Americans/Pacific Islanders, and 7.4% in non-Hispanic white Americans [1]. Compared to non-Hispanic whites, African Americans and Hispanics are 50% more likely to have diabetes [4]. The highest prevalence of diabetes in the United States is observed in Native Americans in certain areas of the Southwest, where an estimated 22.2% of the population has the disease [1].

Diabetes is considered to be one of the most important risk factors for ischemic stroke, especially in individuals younger than 65 years of age. Individuals with diabetes who experience an ischemic stroke are typically younger than those without diabetes and often also have signs of hypertension, myocardial infarction, and hyperlipidemia [7]. In 2016, after adjusting for age, the percentage of adults with diabetes who reported stroke was lowest among Hispanics (7.3%) compared with whites (7.6%) or blacks (9.4%) [8].

3. DIAGNOSIS OF DIABETES

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 after 27 weeks' gestation, and typically resolves after the birth of the child [9]. Other less common types of diabetes include [5,10]:

- Maturity-onset diabetes of the young: A genetic, autosomal-dominant defect of the pancreatic beta cells resulting 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. It 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

Evidence Based Practice Recommendation

The Institute for Clinical Systems Improvement recommends diagnosing a patient with type 2 diabetes through the use of an A1c test with a threshold ≥6.5%, fasting plasma glucose ≥126 mg/dL, or a two-hour plasma glucose ≥200 mg/dL on a 75-g oral glucose tolerance test. Additionally, if a patient has symptoms of hyperglycemia and casual plasma glucose ≥200 mg/dL, diabetes may be diagnosed.

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

Last Accessed: May 1, 2019

Strength of Recommendation/Level of Evidence: Strong/Low

All adults older than 45 years of age should be screened for type 2 diabetes every three years or every two years in the presence of risk factors [9]. In addition, individuals of any age who are at risk for or are suspected of having diabetes should be screened. Established risk factors for type 2 diabetes include [9]:

- Age older than 45 years

- Body mass index (BMI) greater than or equal to 25

- Family history of type 2 diabetes

- Habitual physical inactivity

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

- Impaired glucose tolerance or elevated fasting glucose

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

- Hypertension (i.e., blood pressure greater than 140/90 mm Hg in adults)

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

- Polycystic ovary syndrome

- History of vascular disease

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

The diagnostic criteria for type 2 diabetes are fairly straightforward and are based on fasting plasma glucose and postprandial 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 [9]. 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 [9]. 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 hyperglycemic nonketotic syndrome and ultimately death [11].

Table 1: DIAGNOSTIC CRITERIA FOR TYPE 2 DIABETES

Stage

Fasting Plasma Glucose Level

Two-Hour Postprandial Plasma Glucose Level

Glycated Hemoglobin (HbA1c)

Euglycemia

≤100 mg/dL

<140 mg/dL

<5.7%

Prediabetes

>100 mg/dL but <126 mg/dL

≥140 mg/dL but <200 mg/dL

5.7% to 6.4%

Diabetesa

≥126 mg/dL

≥200 mg/dL

≥6.5%

aA random blood glucose level ≥200 mg/dL with symptoms of hyperglycemia is also indicative of diabetes.

Source: [9,10,11]

4. CEREBROVASCULAR DISEASE AND DIABETES

The main cause of cerebrovascular disease in patients with diabetes is atherosclerosis, or thickening of artery walls. It is generally believed that patients with diabetes are at an increased risk for atherosclerosis due to endothelial dysfunction. The endothelium is the biologically active lining of the blood vessel that functions to [12]:

- Provide a mechanical lining

- Maintain vascular patency

- Prevent platelet aggregation and thrombosis

- Promote fibrinolysis

Endothelial dysfunction is the earliest vascular abnormality seen in patients with diabetes and is associated with blood vessel constriction, aggregation of platelets, and a proinflammatory state, with the accumulation of leukocytes and coagulation products on the endothelium [12]. This inflammatory response is mainly caused by the chronic effects of hyperglycemia and specifically the formation of biologically active glycated proteins and lipids that promote inflammation [13]. Visceral obesity, hypertension, and hyperlipidemia also contribute to oxidative stress, which can damage the endothelium [14].

The normal metabolic response to a glucose load is an increase in free fatty acids and insulin. These changes result in a transient decrease in endothelium-derived nitric oxide production and in endothelium-mediated vasoconstriction. In persons without diabetes, endothelial nitric oxide production and vasodilation returns to normal within two hours. In the presence of diabetes, endothelial-mediated vasoconstriction extends for hours [15].

In addition to vasoconstriction, aggregation of platelets and an increase in leukocytes and coagulation products on the endothelium also occur. Fibrinolysis is decreased, and thrombosis is increased. As the secretion of prostacyclin and nitric oxide induce vasoconstriction, plasma cytokine and prothrombin levels increase, making the plasma markedly procoagulant and antifibrolytic and promoting atherosclerosis [12]. These changes at the microvascular and macrovascular levels lead to reduced vascular reactivity and impaired blood flow to end organs [15].

Defects in endothelial function may be further compounded by the hypercoagulable state of the patient with diabetes. Plasminogen activator inhibitor-1, antithrombin III (which inhibits fibrinolysis), and tissue plasminogen activator antigen (a marker of impaired fibrinolysis) are consistently elevated in individuals with diabetes or insulin resistance [16]. Over time, these changes may lead atheromatous plaques to form at branching and curves in the cerebral circulation. The smooth stenotic area can degenerate, resulting in an ulcerated area of the vessel wall. Platelets and fibrin adhere to the damaged wall and a clot forms, gradually occluding the artery and eventually causing a stroke [17].

TYPES OF CEREBROVASCULAR ACCIDENTS

The two primary types of stroke are ischemic and hemorrhagic. In the United States, approximately 87% of all strokes are ischemic and 13% are hemorrhagic [18]. An ischemic stroke occurs when any artery that supplies the brain with oxygen becomes stenosed or occluded, resulting in infarction [19]. In the case of hemorrhagic stroke, bleeding occurs below the arachnoid, the location of the brain's blood supply, allowing blood to directly contact and damage brain tissue. Research has linked diabetes (particularly poorly controlled type 2 diabetes) with ischemic stroke, a result of the disease's impact on vascular health and predisposition for atherosclerosis, as discussed [20]. The link between diabetes and hemorrhagic stroke is not well established. Therefore, the focus of this course will be on ischemic stroke.

Ischemic stroke can be further classified as either thrombolic or embolic depending on its origin. A thrombotic stroke occurs when a thrombus impairs cerebral blood flow by further narrowing or blocking an artery, typically around an atherosclerotic plaque. The stenosed or occluded artery may be a large vessel (e.g., carotid artery systems, vertebral arteries, the circle of Willis) or a small vessel (e.g., branches of the circle of Willis, the posterior circulation). Approximately 21% to 27% of ischemic strokes arise from atherosclerotic disease of the large vessels [21,22]. In these cases, the cerebral artery branch points, especially those of the internal carotid artery, are the most vulnerable [23]. Small-vessel disease is associated with 21% to 25% of ischemic strokes [21,22]. Thrombotic strokes caused by small-vessel disease are traditionally associated with lacunar infarcts, small, deep, subcortical lesions 15 mm or less in diameter resulting from occlusion of a single penetrating artery [24,25]. As many as 20% of older individuals who are otherwise healthy have asymptomatic lacunar infarcts unrelated to an ictal event [26]. These silent infarctions were previously believed to be benign with a good long-term prognosis. However, they now have been linked to increased risks of stroke and death and can lead to debilitating cognitive impairments such as vascular dementia [26,27]. Independent risk factors for lacunar infarcts include hypertension, gender, age, diabetes, smoking, and a history of transient ischemic attack (TIA) [26,28].

An embolic stroke occurs when an embolus (i.e., any circulating clot or particle originating from a distal point) blocks an artery that supplies oxygen to the brain. Stroke registries indicate that 26% to 29% of ischemic strokes are embolic [21,22]. Emboli include blood clots, fatty deposits, atherosclerotic plaque fragments, and cancerous cells or infectious materials emanating from conditions such as atrial myxoma and endocarditis, respectively. Clinical symptoms of the resulting infarct correspond to the location of the embolus, not its type. The region of the middle cerebral artery is most frequently blocked by emboli [29].

RISK FACTORS

As discussed, diabetes is a well-established risk factor for stroke, particularly ischemic stroke, and cerebrovascular disease. In addition to diabetes, other risk factors include [17,30,31]:

- Advanced age (older than 65 years)

- Positive family history

- Arterial hypertension (elevated systolic and/or diastolic blood pressure)

- Carotid artery disease

- Cigarette or cigar use

- Physical inactivity

- Hyperlipidemia

- Obesity

- Atrial fibrillation

- Cardiac conditions other than atrial fibrillation

- History of myocardial infarction or TIA

- Asymptomatic carotid stenosis

- Atherosclerosis of the aortic arch

- Postmenopausal hormone replacement therapy

- Polycythemia and thrombocythemia

- Alcohol or drug abuse

- Sleep-disordered breathing

SIGNS AND SYMPTOMS

The National Institute of Neurological Disorders and Stroke has identified the following signs and symptoms of stroke [17,30,32]:

- Sudden unilateral weakness or numbness of the face, arm, or leg

- Sudden loss of vision or dimming of vision

- Sudden aphasia or confusion

- Sudden severe headache

- Sudden falling, gait disturbance, or dizziness

- Hemiparesis or paralysis

- Homonymous hemianopia

The physical signs, symptoms, and sequelae of ischemic stroke are usually unilateral because of the circulatory anatomy of the brain (Table 2).

Table 2: GENERAL REGIONS OF ISCHEMIC STROKE AND CORRESPONDING NEUROLOGIC DEFICITS

Affected Region

Common Signs and Potential Sequelae

Left anterior hemisphere

Aphasia (esp. difficulty reading, writing, and calculating)

Right limb weakness and sensory loss

Right field visual defect

Right anterior hemisphere

Limb motor weakness or loss

Left field visual neglect

Unable to determine two-point stimuli on left side

Left posterior cerebral artery

Aphasia (esp. difficulty reading and naming objects)

Right visual field defect

Occasionally, right-sided numbness

Right posterior cerebral artery

Left limb sensory loss

Left-sided neglect

Left field visual defect

Vertebrobasilar territory (posterior circulation)

Bilateral vision disturbances and nystagmus

Dysarthria and dysphagia

Ataxia

Dizziness, vomiting, headache

No cortical deficits (e.g., aphasia and cognitive impairments)

Caudate nucleus, thalamus, frontal lobe (anterior circulation)

Sudden abnormal behavior

Thalamus (posterior circulation)

Numbness, decreased sensation in the face, arm, leg on same side

Source: [33,34]

Because neurons surrounding the ischemic or infarcted tissues undergo changes that disrupt the plasma membranes, cellular edema ensues, resulting in further compression of capillaries. Cerebral edema reaches its maximum in about 72 hours and takes about two weeks to subside. Most individuals survive an initial hemispheric ischemic stroke cerebral vascular accident unless there is massive cerebral edema, which is typically fatal [17].

5. TREATMENT OF STROKE

Individuals who present with symptoms of cerebrovascular accident should have a full neurologic assessment by a physician [30]. After etiology is determined, treatment related to the causative source may be initiated. In thrombotic strokes, treatment is directed at prevention of ischemic injury [15]. Occlusions treated within 90 minutes of the onset of symptoms show the most improvement. Tissue plasminogen activator (t-PA) is recommended for select patients who may be treated within three hours after the onset of symptoms [31,35]. In 2009, the American Heart Association/American Stroke Association (AHA/ASA) revised guidelines for administration of rt-PA after acute stroke, expanding the window of treatment from 3 hours to 4.5 hours. Eligibility criteria for treatment during this later period are similar to those for treatment within three hours, but also include the following exclusion criteria [35,36,37,38]:

- Age older than 80 years

- Use of oral anticoagulants, regardless of the INR

- Baseline score on the National Institutes of Health Stroke Scale (NIHSS) >25

- History of stroke and diabetes

As time goes on, there is a diminishing effect of treatment, and there may be almost no benefit when treatment is initiated more than six hours after onset [35,39].

Between 31% and 50% of patients treated with rt-PA have a 4-point or greater NIHSS score improvement by three months after the stroke [24]. These clinical improvements do not recede for at least one year after the stroke. In general, the best response to rt-PA has been found for patients who are younger than 75 years of age and have a baseline NIHSS score greater than 20 [24].

The most common serious medical complication of rt-PA is secondary brain hemorrhage, which occurs in 6% of patients [35,40]. Yet, the risk does not outweigh the benefits of rt-PA [41,42]. In most cases, the mortality rate for patients receiving treatment or placebo is comparable at three months (17% compared with 20%) and one year (24% compared with 28%) [43,44]. Other dangerous complications of rt-PA, although rare, are angioedema, anaphylaxis, systemic hemorrhage, and if rt-PA is administered soon after an acute MI, myocardial rupture [45].

MECHANICAL EMBOLECTOMY

Mechanical embolectomy may be an option for patients with acute stroke who are ineligible for intravenous rt-PA or who fail to respond to intravenous rt-PA [32,46]. This procedure consists of a device that is threaded through the artery to remove the thrombus and restore blood flow. Mechanical embolectomy can remove a clot in a matter of minutes, compared with pharmaceuticals, which may take as long as two hours to dissolve a thrombus [47]. The procedure is effective for up to eight hours after the onset of symptoms [46]. Several different devices are available, and more are under review [32].

In 2004, the Merci Retriever became the first mechanical stroke device to be approved by the U.S. Food and Drug Administration (FDA) [47]. Although the Merci is still in use, in 2015, and again in 2018, the AHA/ASA issued updated guidelines for treatment of acute stroke, recommending the use of stent retrievers due to higher recanalization rates and better outcomes than those seen with the Merci [47,48,49]. Newer stent retrievers include [47,50,51]:

- The Penumbra System

- The Stryker Trevo stent retriever

- The Solitaire stent retriever system

ANTICOAGULANTS

The AHA Task Force reviewed and discussed several studies addressing the use of heparin or low-molecular-weight heparin and danaparoid as an adjunct to a thrombolytic agent in the treatment of stroke [35]. In general, the Task Force concluded that early administration of heparin or low-molecular-weight heparin and danaparoid is inadvisable partly due to the increased risk of bleeding complications, especially the hemorrhagic transformation of ischemic strokes. Additionally, early administration has not been shown to prevent recurrent stroke, lessen the risk of neurologic worsening, or improve patient outcomes [35].

ANTIPLATELETS

Data combined from two large clinical trials suggest that administration of aspirin (160–300 mg) within 48 hours after the onset of stroke slightly reduces mortality and morbidity by preventing early recurrent stroke in some patients [52,53]. A 2014 Cochrane review found that the daily administration of aspirin (160–300 mg) within 48 hours of onset of stroke reduced the risk of early recurrent stroke without a major risk of early hemorrhagic complications. Long-term outcomes were also improved [54]. Although no new data have emerged since the publication of these results, the 2018 AHA guideline recommendations for antiplatelet therapy have changed to include the administration of aspirin in patients with acute ischemic stroke within 24 to 48 hours after onset. For patients treated with IV alteplase, aspirin administration is generally delayed until 24 hours later but might be considered in select patients [24,35]. Other oral antiplatelet therapies (e.g., ticlopidine, clopidogrel, dipyridamole) have not been tested sufficiently in the setting of acute ischemic stroke. The efficacy of intravenous glycoprotein IIb/IIIa receptor blockers in combination with other interventions or alone is under investigation. These agents may accelerate spontaneous recanalization and improve microvascular patency [55]. If administered alone, these agents have been shown to have an adequate safety profile [56].

6. PREVENTION

Primary stroke prevention relies primarily on lifestyle changes to reduce the impact of modifiable risk factors, and this should be a part of the treatment plan for all patients with diabetes. Elimination of tobacco use via cigarettes or cigars should be stressed. In addition to smoking cessation, stress management techniques should be investigated to attempt to control hypertension. If these techniques do not succeed, medications may be necessary [12]. The combination of hyperglycemia and hypertension is thought to increase the risk of stroke [57]. The AHA recommends that the target blood pressure for individuals with diabetes be less than 130/80 mm Hg [57]. Pharmacologic therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has been shown to be safe and effective in this population [57]. A low-cholesterol diet should be encouraged in order to address dyslipidemia [46]. In addition, lipid-lowering statins reduce the risk of first-time strokes in patients with diabetes, irrespective of the baseline lipid levels, pre-existing vascular conditions, or glycemic control [58]. Niacin, bile acid sequestrants, ezetimibe, or fibric acid derivatives may also be considered for individuals with known coronary heart disease and low levels of HDL cholesterol, such as people in whom target cholesterol levels cannot be achieved with statins or tolerate statin therapy; however, their effectiveness in decreasing stroke risk has not been established [58].

Obesity and excess weight place pressure on the entire circulatory system and are associated with hyperlipidemia, hypertension, and diabetes—all of which create an increased risk for cerebrovascular accidents. Adopting healthy eating habits and increasing physical activity can help reduce stroke risk in these patients [46].

Glycemic control is also essential in the prevention of stroke or extension of the injury. Intracellular acidosis resulting from hyperglycemia increases lactate, leading to glial and neuronal membrane damage due to reactive oxygen species generation and impaired vasodilatation. Potentially viable neurons in the ischemic penumbra are more likely to infarct under conditions of hyperglycemia, and research has demonstrated a disruption of the blood brain barrier associated with greater degrees of hemorrhage and cerebral edema. Hyperglycemia with or without a diagnosis of diabetes is associated with transformation from ischemic to hemorrhagic stroke [59]. Therefore, patients with diabetes should be encouraged to monitor their blood glucose levels regularly and remain compliant with prescribed medications.

KNOWLEDGE OF STROKE WARNING SIGNS

Although public knowledge regarding the warning signs and risks of stroke has improved, the majority of the general public is still unaware that early treatment can prevent severe disability and death [60,61]. According to one estimate, five out of six people are unable to name the signs that signify a stroke [62]. Estimates vary widely, however. The International Stroke Trial found that only 4% of patients suffering an acute ischemic stroke arrive at the emergency department (ED) within three hours after the onset of symptoms, and a separate study found that 21% to 25% of individuals with acute ischemic stroke arrive at an ED within the same timeframe [63,64]. Of these individuals, 2% to 4% receive thrombolytic treatment [65,66]. It has been estimated that if all individuals called for emergency help at the onset of symptoms, as many as 29% could realistically receive treatment within three hours [65]. If all patients arrived at the ED within one hour after known symptom onset and received optimal treatment, the projected rate of thrombolysis would be 57%.

To improve the rate of early arrival in the ED, public education campaigns designed to help individuals recognize a stroke and seek early treatment often use the "five sudden warning signs" devised by the Brain Attack Coalition or "FAST," a mnemonic device created by study investigators on the basis of the Cincinnati Prehospital Stroke Scale [67,68]. FAST was designed to focus on fewer common signs of stroke onset (face numbness, arm numbness, and slurred speech) and to include an action component (time) for lay persons who may have trouble recalling the warning signs and the appropriate action. A retrospective study exploring the capacity of the FAST campaign to facilitate the recognition of stroke suggests that it leads to the identification of approximately 89% of individuals who have a stroke or TIA [68]. The most common stroke symptoms were related to the face, arm, and speech/language. The same study found that a modified version of FAST (with removal of the word "numbness") decreased the number of TIAs identified and targeted ischemic stroke more readily than hemorrhagic stroke. Ultimately, it is unknown whether the general public is more likely to remember FAST or the five sudden warning signs.

Another education program—Hip-Hop Stroke (HHS)—is a school-based, child-mediated, stroke communication intervention designed to improve stroke literacy among school-aged children and their parents in low-income urban communities [69]. Researchers recruited 3,070 fourth- through sixth-grade schoolchildren and 1,144 parents from 22 schools, randomized to the HHS intervention or attentional control (i.e., nutritional classes) [70]. Among the children, an estimated 1% of controls and 2% of the intervention group demonstrated optimal stroke preparedness (i.e., perfect scores on the knowledge/preparedness test) at baseline. This increased to 57% immediately following the program in the intervention group compared with 1% among controls. At three-month follow-up, 24% of the intervention group retained optimal preparedness, compared with 2% of controls. Only 3% of parents in the intervention group could identify all four letters of the stroke FAST acronym at baseline, which increased to 20% immediately post-test and to 17% at three months post-test. There were no significant changes among controls. Among children in the intervention group, four called 911 for real-life stroke symptoms, in one instance over-ruling a parent's wait-and-see approach [70].

7. CONCLUSION

Every year, thousands of individuals will die as a result of their diabetes complications, and stroke is one of the leading causes of death in this population. Good control of diabetes and of other causes of cerebrovascular disease can reduce the associated morbidity and mortality and improve patients' quality of life. Healthcare professionals play a crucial role in identifying patients with diabetes who are at risk for stroke and intervening to address modifiable factors. This course is intended to raise nurses' awareness of the connection between diabetes and stroke in order to improve patient care.

Works Cited

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20. Hyvärinen M, Tuomilehto J, Mähönen M, et al. Hyperglycemia and incidence of ischemic and hemorrhagic stroke: comparison between fasting and 2-hour glucose criteria. Stroke. 2009;40(5):1633-1637.

21. Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O'Fallon WM, Wiebers DO. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke. 1999;30(12):2513-2516.

22. Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German Stroke Data Bank. Stroke. 2001;32(11):2559-2566.

23. Frishman W, Ismail A. Role of infection in atherosclerosis and coronary artery disease: a new therapeutic target? Cardiol Rev. 2002;10(4):199-210.

24. Adams H Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Circulation. 2007;115(20):e478-e534.

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26. Vermeer SE, Longstreth WT Jr, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol. 2007;6(7):611-619.

27. Bokura H, Kobayashi S, Yamaguchi S, et al. Silent brain infarction and subcortical white matter lesions increase the risk of stroke and mortality: a prospective cohort study. J Stroke Cerebrovasc Dis. 2006;15(2):57-63.

28. Tuttolomondo A, Pinto A, Salemi G, et al. Diabetic and non-diabetic subjects with ischemic stroke: differences, subtype distribution and outcome. Nutr Metab Cardiovasc Dis. 2008;18(2):152-157.

29. Olsen TS. Regional cerebral blood flow after occlusion of the middle cerebral artery. Acta Neurol Scand. 1986;73(4):321-337.

30. Venes D (ed). Taber's Cyclopedic Medical Dictionary. 22nd ed. Philadelphia, PA: FA Davis Company; 2013.

31. Jauch EC. Ischemic Stroke Treatment and Management: Mechanical Thrombectomy. Available at https://emedicine.medscape.com/article/1916852-treatment#d15. Last accessed April 16, 2019.

32. National Institute of Neurological Disorders and Stroke. Transient Ischemic Attack Information Page. Available at https://www.ninds.nih.gov/Disorders/All-Disorders/Transient-Ischemic-Attack-Information-Page. Last accessed April 16, 2019.

33. Hewko C. Acute ischemic stroke: swift assessment and quick action produce optimal outcomes. JAAPA. 2004;17(7):19-25.

34. Savitz SI, Caplan LR. Vertebrobasilar disease. N Engl J Med. 2005;352(25):2618-2626.

35. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110.

36. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329.

37. Del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke. 2009;40(8):2945-2948.

38. Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with alteplase 3–4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet. 2008;372(9646):1303-1309.

39. Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;384(9958):1929-1935.

40. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke. 1997;28(11):2109-2118.

41. Diedler J, Ahmed N, Sykora M, et al. Safety of intravenous thrombolysis for acute ischemic stroke in patients receiving antiplatelet therapy at stroke onset. Stroke. 2010;(2):288-294.

42. Xian Y, Federspiel JJ, Grau-Sepulveda M, et al. Risks and benefits associated with prestroke antiplatelet therapy among patients with acute ischemic stroke treated with intravenous tissue plasminogen activator. JAMA Neurol. 2016;73(1):50-59.

43. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587.

44. Kwiatkowski TG, Libman RB, Frankel M, et al. for the National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group. Effects of tissue plasminogen activator for acute ischemic stroke at one year. N Engl J Med. 1999;340(23):1781-1787.

45. Lyden PD. Thrombolytic Therapy for Acute Stroke. 2nd ed. Totowa, NJ: Humana Press; 2005.

46. National Stroke Association. Stroke Treatments. Available at https://www.stroke.org/we-can-help/survivors/just-experienced-stroke/stroke-treatments. Last accessed April 16, 2019.

47. Lutsep HL. Mechanical Thrombolysis in Acute Stroke. Available at https://emedicine.medscape.com/article/1163240-overview. Last accessed April 16, 2019.

48. Powers WJ, Derdeyn CP, Biller J, et al. 2015 AHA/ASA focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(10):3020-3035.

49. Hassan AE, Aman MM, Chauhdry SA, et al. Value of other endovascular techniques among patients with MERCI device failure during the treatment of acute ischemic stroke: what to do when MERCI fails? J Vasc Interv Neurol. 2013;5(2):27-31.

50. Jeffrey S. Solitaire Device for Stroke Gets FDA Nod. Available at https://www.medscape.com/viewarticle/759773. Last accessed April 16, 2019.

51. Kent C. Stryker Receives FDA Approval for its Trevo Pro Retriever Mechanical Thrombectomy Device. Available at https://www.advisory.com/research/service-line-strategy-advisor/the-pipeline/2012/08/stryker-receives-fda-approval-for-its-trevo-pro-retriever-mechanical-thrombectomy-device. Last accessed April 16, 2019.

52. Chinese Acute Stroke Trial (CAST) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet. 1997;349(9066):1641-1649.

53. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet. 1997;349(9065):1569-1581.

54. Sandercock PA, Counsell C, Tseng MC, Cecconi E. Oral antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev. 2014;3:CD000029.

55. Lapchak PA, Araujo DM. Therapeutic potential of platelet glycoprotein IIb/IIIa receptor antagonists in the management of ischemic stroke. Am J Cardiovasc Drugs. 2003;3(2):87-94.

56. Abciximab Emergent Stroke Treatment Trial (AbESTT) Investigators. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of a randomized phase 2 trial. Stroke. 2005;36(4):880-890.

57. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(2):517-584.

58. Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(12):3754-3832.

59. Bloomgarden ZT. Inpatient diabetes control: approaches to treatment. Diabetes Care. 2004;27(9):2272-2277.

60. Müller-Nordhorn J, Nolte CH, Rossnagel K, et al. Knowledge about risk factors for stroke: a population-based survey with 28,090 participants. Stroke. 2006;37(4):946-950.

61. Schneider AT, Pancioli AM, Khoury JC, et al. Trends in community knowledge of the warning signs and risk factors for stroke. JAMA. 2003;289(3):343-346.

62. Miller-Hoover S. Stroke Awareness: Act F.A.S.T. Available at https://www.rn.com/nursing-news/stroke-awareness-act-fast. Last accessed April 16, 2019.

63. Rosamond WD, Gorton RA, Hinn AR, Hohenhaus SM, Morris DL. Rapid response to stroke symptoms: the Delay in Accessing Stroke Healthcare (DASH) study. Acad Emerg Med. 1998;5(1):45-51.

64. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet. 1997;349(9065):1569-1581.

65. California Acute Stroke Pilot Registry (CASPR) Investigators. Prioritizing interventions to improve rates of thrombolysis for ischemic stroke. Neurology. 2005;64(4):654-659.

66. Wattigney WA, Croft JB, Mensah GA, et al. Establishing data elements for the Paul Coverdell National Acute Stroke Registry. Part 1: proceedings of an expert panel. Stroke. 2003;34(1):151-156.

67. Kothari R, Pancioli A, Liu T, Brott T, Broderick J. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med. 1999;33(4):373-378.

68. Kleindorfer D, Miller R, Moomaw CJ, et al. Designing a message for public education regarding stroke: does FAST capture enough stroke? Stroke. 2007;38(10):2864-2868.

69. Williams O, Leighton-Hermann E, DeSorbo A, et al. Hip Hop Stroke: study protocol for a randomized controlled trial to address stroke literacy. J Clin Trials. 2015;5(5):pii:242.

70. Williams O, Leighton-Herrmann Quinn E, Teresi J, et al. Improving community stroke preparedness in the HHS (Hip-Hop Stroke) randomized clinical trial. Stroke. 2018;49(4):972-979.

Evidence-Based Practice Recommendations Citations

1. 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 May 1, 2019.

98771 • Parkinson Disease

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Parkinson disease (PD) is a neurodegenerative disorder that affects approximately 1% of those older than 60 years of age. Improved recognition of both non-motor and motor symptoms can promote early diagnosis and treatment of PD. Importantly, early intervention leads to better quality of life for the patient, and this may be facilitated by improved understanding of PD pathophysiology, signs and symptoms, differential diagnosis, and therapeutic options. As a chronic condition, patients with PD have ongoing contact with their primary care provider for PD and non-PD related concerns. Additional aspects related to PD are likely to be encountered, including issues with medications prescribed to control PD symptoms, comorbid conditions, and polypharmacy. This course will review all of the relevant aspects of PD diagnosis and treatment necessary for the optimal care of patients with the disease.

Table of Contents

98771 • Parkinson Disease

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. BACKGROUND

DEFINITIONS

3. EPIDEMIOLOGY

PREVALENCE AND INCIDENCE

DEMOGRAPHICS

MORTALITY RATES

4. RISK FACTORS AND ETIOLOGY

RESEARCH

ENVIRONMENTAL RISK FACTORS

GENETIC RISK FACTORS

RISK FACTOR INTERACTIONS

5. PATHOPHYSIOLOGY

DOPAMINERGIC PATHOPHYSIOLOGY AND LOSS OF MOTOR FUNCTION

CORE PATHOLOGIC FEATURES

DEVELOPMENT AND PROGRESSION OF PATHOPHYSIOLOGY

NATURAL HISTORY OF DISEASE PROGRESSION

NON-MOTOR SYMPTOM APPEARANCE AND DISEASE STAGE

PRE-MOTOR SYMPTOMS

ASSESSMENT AND DIAGNOSIS OF PARKINSON DISEASE

CLINICAL FEATURES

6. DIAGNOSTIC WORKUP

DIAGNOSTIC CRITERIA

PATIENT HISTORY

NEUROLOGIC EXAMINATION

DIAGNOSTIC CONFIRMATION

SCREENING TESTS

DIFFERENTIAL DIAGNOSIS

7. TREATMENT OF PARKINSON DISEASE

OVERVIEW OF TREATMENT APPROACHES THROUGH DISEASE PROGRESSION

MEDICATION NON-ADHERENCE

PHARMACOTHERAPIES

MANAGEMENT OF EARLY PARKINSON DISEASE

MANAGEMENT OF LATER PARKINSON DISEASE

MANAGEMENT OF ADVANCED PARKINSON DISEASE

MANAGEMENT OF NON-MOTOR SYMPTOMS

END-STAGE PARKINSON DISEASE

ADJUNCTIVE TREATMENT MODALITIES

PRACTICE CONSIDERATIONS

8. CONCLUSION

9. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

98771 • Parkinson Disease

Education Category. Infection Control / Internal Medicine

Release Date. 05/01/2019

Expiration Date. 04/30/2022

Course Overview

Parkinson disease (PD) is a neurodegenerative disorder that affects approximately 1% of those older than 60 years of age. Improved recognition of both non-motor and motor symptoms can promote early diagnosis and treatment of PD. Importantly, early intervention leads to better quality of life for the patient, and this may be facilitated by improved understanding of PD pathophysiology, signs and symptoms, differential diagnosis, and therapeutic options. As a chronic condition, patients with PD have ongoing contact with their primary care provider for PD and non-PD related concerns. Additional aspects related to PD are likely to be encountered, including issues with medications prescribed to control PD symptoms, comorbid conditions, and polypharmacy. This course will review all of the relevant aspects of PD diagnosis and treatment necessary for the optimal care of patients with the disease.

Audience

This course is designed for all healthcare providers in the primary care setting who may encounter patients with Parkinson disease.

Course Objective

The purpose of this course is to provide physicians, nurses, and other members of the interprofessional healthcare team a review of current concepts of pathogenesis, disease progression, diagnosis, and management of Parkinson disease, in order to improve patient care and quality of life.

Learning Objectives

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

1. Outline the history, epidemiology, and clinical signs/symptoms of Parkinson disease (PD) and scientific developments related to recognition of the disease.

2. Describe the assessment and management of PD.

3. Assess motor and non-motor symptoms and signs in relation to pathophysiology of PD.

4. Anticipate the time course of symptom development in patients with PD, and use this to assess clinical probability and to inform follow-up of a patient in whom the diagnosis is unclear.

5. Refine history and clinical examination skills in order to detect the early motor and non-motor signs and symptoms of PD.

6. Develop a strategy for the initial workup of patients with suspected PD that conforms with diagnostic and clinical staging criteria.

7. Compare and contrast syndromes that may mimic PD and their differential diagnosis.

8. Devise a treatment strategy and select an appropriate drug regimen for the management of PD.

9. Create an approach to the management of PD based on stage of the disease, severity of symptoms, and rate of progression.

10. Discuss the role of non-motor symptoms of PD and devise a strategy for treatment.

11. Outline a long-term plan for monitoring the course of illness, including patient and family education and safety precautions.

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

John V. Jurica, MD, MPH

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

Alice Yick Flanagan, PhD, MSW

Abimbola Farinde, PharmD, PhD

James Trent, PhD

Division Planners Disclosure

The division planners have 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

Parkinson disease (PD) is a neurodegenerative disorder that affects approximately 1% of those older than 60 years of age [1,2]. Improved recognition of both non-motor and motor symptoms can promote early diagnosis and treatment of PD. Importantly, early intervention leads to better quality of life for the patient, and this may be facilitated by improved understanding of PD pathophysiology, signs and symptoms, differential diagnosis, and therapeutic options [3,4]. As a chronic progressive illness, patients with PD require regular follow-up with their primary care provider working in concert with a neurology consultant and other members of the interprofessional care team. Important aspects of care likely to be encountered include the need to adjust dosage or alter drug treatment, attention to medication side effects/toxicity, management of comorbid conditions, and risk of polypharmacy. This course will review the relevant pathophysiology and clinical aspects of PD, including principles of diagnosis and treatment options in relation to stage of disease and other considerations important to the optimal care of patients.

2. BACKGROUND

The clinical syndrome now known as parkinsonism was first described in 1817 by the English physician James Parkinson as "the shaking palsy" [5]. This disorder is characterized by the motor symptoms of resting tremor, muscle rigidity, and bradykinesia. Over time the non-motor features of PD have been increasingly identified, including sensory, autonomic, and neuropsychiatric symptoms, some of which appear before motor dysfunction is evident. The precise cause of PD is unclear, but disease manifestations are known to result from the disruption of dopaminergic neurotransmission within the central, peripheral, and autonomic nervous systems. The defining pathologic feature of PD is the loss of dopamine-producing cells and the local deposition of aggregates of the protein alpha-synuclein (Lewy bodies) in the substantia nigra region of the brain [8].

The onset of PD is insidious, the course progressive, and neurologic signs are often asymmetrical. The four primary motor symptoms and signs are [8]:

- Tremors of the hands, arms, legs, and jaw

- Stiffness and rigidity of the limbs and trunk

- Bradykinesia (slowness of movement)

- Postural instability caused by impaired balance and coordination

In time, symptoms become more pronounced and the simple tasks of daily living, such as walking, talking, and swallowing, become increasingly difficult. Other, non-specific symptoms of PD include sleep behavior disorder, constipation, labile emotional state, and depression. While the symptoms are amenable to treatment, the disease is slowly progressive and eventually disabling for most patients.

There is no blood test or other laboratory procedure proven to be specific for the diagnosis of PD [8]. The diagnosis rests on clinical findings and pattern of progression, often requiring multiple examinations over time. Laboratory testing and neuroimaging is useful to exclude other diagnostic possibilities. Drug treatment of PD is directed toward replenishing local tissue dopamine levels in an effort to facilitate neurotransmission and improve motor function. Effective long-term management is rendered best by an interprofessional team care approach.

DEFINITIONS

Parkinsonism: A motor disorder syndrome and core clinical feature of PD that includes bradykinesia plus tremor, rigidity, and/or postural instability. Parkinsonism is non-specific, as corticobasal degeneration, multisystem atrophy, and other neurodegenerative disorders may show features of parkinsonism. All patients with PD have parkinsonism, but not all patients with parkinsonism have PD [1,6,7].

Idiopathic Parkinson disease: Synonymous with PD, the most common cause of parkinsonism. Idiopathic means unknown cause, and idiopathic PD refers to parkinsonism not attributed to corticobasal degeneration, multisystem atrophy, or other neurologic disorder and not the direct result of gene mutation [1,6,7].

Sporadic Parkinson disease: PD without direct familial/genetic cause. Synonymous with idiopathic PD.

Bradykinesia: An abnormal degree of slowness when initiating voluntary movement and progressive reduction in speed and amplitude with repetitive movement. The core motor symptom of PD.

Dementia: The progressive decline in cognitive function due to neurologic damage or disease, with decline greater than expected from normal aging.

Dyskinesia: Involuntary movements with a rotatory, writhing appearance that can affect the limbs, trunk, or face. Dyskinesias are typically associated with dopaminergic therapy in later PD.

"On" and "off" states: With long-term levodopa use in later PD, many patients develop fluctuating drug response, termed "on" and "off" motor states. "On" describes optimal motor response to medication (typically levodopa); "on with dyskinesias" describes involuntary writhing movements during medication efficacy. "Off" describes resurgent motor symptoms and impairment, sometimes accompanied by non-motor symptoms such as low mood or fatigue. "Off" episodes commonly occur during loss of medication effect before the next dose [1,6,7].

3. EPIDEMIOLOGY

PREVALENCE AND INCIDENCE

Sporadic (idiopathic) PD is the second most frequent neurodegenerative disorder after Alzheimer disease [8]. The prevalence of diagnosed PD in the United States is estimated to be 500,000, but the actual number is thought to be twice that, as many persons with the condition are as yet undiagnosed or misdiagnosed [8]. Roughly 60,000 new cases are diagnosed each year, the majority of which are persons older than 60 years of age. The population prevalence is 1% in persons 60 years of age or older and up to 4% in those 80 years of age or older. About 10% of patients with PD had onset of illness before 50 years of age. Women develop PD at lower rates and with later onset than men; the delayed onset has been attributed to the neuroprotective effects of estrogen on the nigrostriatal dopaminergic system [1,2]. The variable prevalence of PD throughout the world suggests that environmental and genetic factors interact with ethnic differences in disease pathogenesis [2].

The cost of treating PD in the United States is estimated to be $14 billion annually, and the indirect costs add another $6.3 billion [8]. Because of the aging population, the number of persons with PD is expected to double by 2040.

DEMOGRAPHICS

The incidence of PD varies by age, race, and ethnicity. The ratio of men to women is roughly 2:1 [9]. As noted, the incidence is markedly higher in each decade after 60 years of age, peaking after 80 years of age. The rate is highest among Hispanic individuals, followed by non-Hispanic whites, Asians, and black persons [9]. However, there is some variation in the incidence in each racial/ethnic group when divided by sex, with black men and Asian women at greater risk than their other-sex counterparts.

MORTALITY RATES

The United States has the fourth highest annual death rate from PD in the world. In 2011, 23,111 people died from PD, the 14th most common cause of death in the United States. From 1999 to 2011, there was a 30% increase in the annual death rate from PD (from 5.2 to 7.4 per 100,000 persons) [10]. Between 2000 and 2013, age-adjusted death rates from PD per 100,000 increased for men (8.8 to 11.0) and women (3.9 to 4.8) [11].

4. RISK FACTORS AND ETIOLOGY

Idiopathic PD, like other neurodegenerative diseases, has a complex pathogenesis involving the interaction of several genetic contributions, each with minor impact, with environmental factors [12]. Risk factors associated with the development of PD include other medical conditions, abnormal physiologic processes, and exposure to specific substances and environmental toxins. Genetic associations are less robust, but several gene mutations confer greater risk of PD (Table 1).

Table 1: RISK AND GENETIC FACTORS ASSOCIATED WITH PARKINSON DISEASE

Category

Risk Factors

Medical conditions and lifestyle factors

Post-infection states

Head trauma

Elevated cholesterol

High caloric intake

Substance use

Methcathinone (manganese content)

Methamphetamine and amphetamines

Environmental toxins

Herbicides
and pesticides

Methanol and organic solvents

Carbon disulfide

Cyanide

Inflammatory, immune, and oxidative processes

Inflammation with microglia activation

Mitochondrial dysfunction

Nitric oxide toxicity

Oxidative stress

Signal-mediated apoptosis

Gene mutations

Alpha-synuclein gene (SNCA)

Eukaryotic translation initiation factor 4 gamma 1 gene (EIF4G1)

Glucocerebrosidase gene (GBA)

Leucine-rich repeat kinase 2 (LRRK2) gene loci

PTEN-induced putative kinase 1 (PINK1) gene loci

Superoxide dismutase 2 gene (SOD2)

Vacuolar protein sorting 35 homolog gene (VPS35)

Source: [1]

RESEARCH

Current understanding of how environmental factors increase or mitigate risk of developing PD was accelerated by a series of studies from two distinct lines of investigation. These investigations identified specific protective and risk factors, greatly contributing to the knowledge of pathogenesis and pathophysiology in PD.

Identification of Factors Protective Against PD

The first line of investigation began in the early 1960s, with an unexpected finding that linked cigarette smoking with protection against PD. This association between smoking and neuroprotection from PD has been replicated in numerous epidemiologic, pre-clinical, and case-control studies. These studies also identified coffee drinking (and caffeine) as a factor that reduced risk of developing PD [13].

In these studies, risk of developing PD is shown as odds ratio (OR), where the odds of developing PD in cigarette or coffee users was compared to non-user reference groups. An OR of 1.00 signifies no difference from the reference group, while a number greater than 1 means increased odds of developing PD and a number less than 1 indicates decreased odds of PD.

In one study, smoking, other lifestyle behaviors, family history of PD, and their interaction were examined for possible association with risk of PD diagnosis by comparing 1,808 patients in Denmark with PD diagnosis with 1,876 matched population controls [14]. Strong inverse associations were found between cigarette smoking and risk of PD, even in smokers who quit 10 years before PD diagnosis. Compared with never-smokers without PD family history, the OR was 2.81 in never smokers with family history, versus 1.60 in smokers with family history. Duration had the greatest effect in modulating the smoking-PD relationship. Current smokers who smoked 40 years or more had ORs as low as 0.30. Unlike the correlation between longer smoking and lower PD odds, smoking more than 10 cigarettes per day did not further reduce odds.

Moderate coffee intake (3.1 to 5 cups per day) (vs. no coffee intake) showed an OR of 0.45. Moderate alcohol intake (3.1 to 7 units per week) (vs. no alcohol use) was associated with an OR of 0.60; higher daily alcohol did not further reduce the odds of developing PD. Stronger negative OR for PD was found in smokers with medium-high coffee or moderate alcohol intake than with each alone. Coffee intake association with lower PD odds was found in men and women; only men showed lower risk estimates with caffeine and alcohol, largely attributed to beer consumption [14].

These findings were consistent with numerous prior studies, including publications from the prospective NIH-AARP Diet and Health Study [7,15]. In this study, 306,895 participants (58.8% male, 50 to 71 years of age) were evaluated in 1995–1996 and again in 2000–2006 for development of PD.

One NIH-AARP study examined caffeine intake, risk of PD, and whether smoking affected this relationship [15]. Higher caffeine use in 1995–1996 was associated with lower risk of PD diagnosis in 2000–2006 for men (OR=0.75) and women (OR=0.60). The linear trend for lower odds with higher caffeine was significant for both sexes [15].

The authors also performed a meta-analysis, which confirmed the inverse association between caffeine intake and risk for PD in men and women. Together with the study findings, this data led the researchers to conclude that gender differences do not influence caffeine risk reduction of PD. Smoking and caffeine may act independently to reduce PD risk [15].

Another NIH-AARP study examined cigarette smoking and risk of PD by comparing those who developed PD to those who did not. Odds for developing PD were 0.78 in past smokers and 0.56 in current smokers, with 0.47 in men and 0.74 in women. For few current smokers at baseline who developed PD, other comparisons were not relevant [16]. The greatest reductions in odds for PD were found with current smoking and higher daily amount/duration of past smoking [16].

In the NIH-AARP study, amount and type of alcohol use was studied for risk of PD. Compared to non-drinkers, the odds ratio for developing PD was 0.73 with 1 to 1.99 drinks of beer per day, 1.22 with liquor, and 0.74 with wine. Beer and liquor consumption showed opposite effects [17].

Higher circulating levels of uric acid have also been associated with decreased incidence of PD and with slower rate of decline in patients with PD. This suggests a link to the neuroprotective effects of caffeine and the purinergic system [7,18].

Identification of Environmental Risk Factors

A second line of investigation began when the first environmental risk factor was identified. In the early 1980s, a parkinsonism syndrome developed in persons who used a tainted street drug. An illicit lab produced a meperidine (Demerol) analog that contained 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxic impurity. MPTP crosses the blood-brain barrier and is oxidized to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO)-B. MPP+ is a neurotoxin that, following dopamine neuron uptake via the dopamine transporter, destroys striatal dopamine neurons by inhibiting mitochondrial complex I activity. Ten persons who ingested this batch developed a severe, irreversible parkinsonism syndrome [19,20]. Extensive evaluation of these patients at onset and over time led to many breakthroughs in the understanding of PD and related conditions. Also identified were several persons with MPP+ exposure who developed mild-to-moderate, but not severe, parkinsonism. For the first time, an environmental factor was linked to PD pathogenesis, initiating environmental risk factor research. The variable consequences from exposure also helped prompt research into protective factors [19,21,22,23].

ENVIRONMENTAL RISK FACTORS

Pesticides (i.e., herbicides, insecticides, fungicides, and rodenticides) that increase the risk for developing PD include paraquat and rotenone. Neurotoxic mechanisms have been proposed based on findings that substances such as MPTP cause selective damage to dopaminergic neurons in the nigrostriatal pathway through mitochondrial complex I toxicity [7].

Paraquat exposure induces reactive oxygen species formation, and while not shown to stimulate Lewy body formation, it accelerates alpha-synuclein misfolding, disrupts membrane conductance, and accelerates protein aggregation [24,25]. Rotenone inhibits mitochondrial complex I, enhances alpha-synuclein fibril formation, and increases alpha-synuclein aggregation, modification, misfolding, and toxicity [26,27]. The data suggest environmental factors that increase oxidative stress or inhibit mitochondrial function can lead to alpha-synuclein misfolding and nigrostriatal damage, processes that underlie PD [7].

A retrospective study of methamphetamine or amphetamine use as a risk factor for PD/parkinsonism/essential tremor was performed by examining statewide medical records in Utah (1996 through 2011) for all persons 30 years of age and older. A methamphetamine/amphetamine cohort and cocaine cohort were compared to a population control cohort unexposed to drugs or alcohol. Methamphetamine/amphetamine users showed increased risk compared to population controls; cocaine users did not exhibit elevated risk of PD compared to controls. The nearly three-fold increased risk of PD in methamphetamine/amphetamine users confirmed prior observations and suggests PD risk in users may be higher than previous estimates. A suggestion that female and male users may differ in PD susceptibility warrants further study [28].

Pre-clinical research identified nicotine exposure as a possible protective factor against methamphetamine-induced dopaminergic deficits [29]. Using oral nicotine, researchers found that nicotine exposure from adolescence through mid-adulthood attenuated methamphetamine-induced striatal dopaminergic deficits associated with drug use in early adulthood. High-dose nicotine attenuated the negative effects of methamphetamine in late adolescence, but the protective effects did not persist. High-dose nicotine from post-adolescence to early adulthood did not protect against methamphetamine in very early adulthood, but high-dose nicotine from post-adolescence to full adulthood did protect against methamphetamine in mid-adulthood.

Nicotine neuroprotection is not due to nicotine alteration of methamphetamine pharmacology but from nicotine effects on nicotinic acetylcholine receptors (nAChRs). Imaging analysis found that nicotine increased striatal α4β2 nAChR expression, while methamphetamine and nicotine decreased striatal α6β2 nAChR expression. This suggests that nicotine protects against methamphetamine-induced striatal dopaminergic deficits by affecting α4β2 and/or α6β2 expression, with additional influence from nicotine exposure duration and the age of onset [29].

A meta-analysis of data from this study concluded that higher body mass index (BMI) in overweight (BMI 25–29.9) or obese (BMI ≥30) persons had no impact on the risk of developing PD [30].

GENETIC RISK FACTORS

Inherited genetic mutations are responsible for a small proportion of PD, with the most common genetic form of PD, PARK8, accounting for 2% of PD cases in the United States [31]. Penetrance is incomplete in this inherited parkinsonism, and PD manifestation in carriers is determined by environmental exposure or other genetic factors [31].

Idiopathic PD is a sporadic disorder, and twin studies have not shown a strong genetic basis in patients older than 50 years of age. However, genetic mutations have been increasingly mapped, and rare autosomal dominant and recessive familial forms have been identified in small numbers of patients. These include the SNCA, Parkin, PINK-1, DJ-1, GBA, and LRRK2 genes that code various proteins, with some carrying the same name as the mutation and components of the ubiquitin-protease system. In addition, mutations in the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, confer a greater risk of PD [32,33].

The protein alpha-synuclein is a key element in Lewy pathology and contributes to familial and sporadic PD. Duplications and triplications of wild-type SNCA, the gene encoding alpha-synuclein, have been identified in typical and early-onset PD, suggesting SNCA overexpression is related to PD pathogenesis [7].

RISK FACTOR INTERACTIONS

Gene-environment interactions in PD were examined by studying smoking and caffeine use interaction with 10 single nucleotide polymorphisms at or near four PD susceptibility genes in 584 patients with PD and 1,571 controls. Combining smoking and caffeine exposure showed significant interaction with one single nucleotide polymorphism at SLC2A13, near LRRK2. Each A allele was associated with a 35% increase in PD risk in never-smokers with low caffeine intake and a 32% lower risk in smokers with high caffeine intake. This study suggests a potential gene-environment interaction for PD [34].

History of traumatic brain injury also increases PD risk [35]. The SNCA Rep1 variation may mediate the association between brain injury and PD risk. Pooled results from two case-control studies found head injury unrelated to risk of later PD, but relative to subjects with medium-length Rep1 alleles, head injury was strongly associated with PD in those with long Rep1 alleles. Those with both head injury and long Rep1 were diagnosed with PD an average of five years before those with neither risk factor. High levels of alpha-synuclein (as with Rep1 expansion) may initiate and/or accelerate neurodegeneration following head injury [36].

5. PATHOPHYSIOLOGY

Unless otherwise stated, the following discussion pertains to sporadic (idiopathic) PD (i.e., cases lacking heritable/gene mutation cause).

DOPAMINERGIC PATHOPHYSIOLOGY AND LOSS OF MOTOR FUNCTION

PD is the most common neurodegenerative cause of parkinsonism, a syndrome characterized by progressive deterioration in motor abilities resulting from dopaminergic neuron loss in the substantia nigra pars compacta and ventral tegmental area. Dopamine neuron loss is most prominent in the ventral lateral substantia nigra; 60% to 80% of these neurons are lost when motor symptoms emerge and PD is diagnosed [8,12].

Substantia nigra pars compacta dopamine neuron loss and striatal dopaminergic deficits, including nicotinic receptor-mediated dopaminergic signaling, underlie motor symptom development in PD. The results of numerous studies linking cigarette smoking with protection against PD are explained by the actions of nicotine. Acetylcholine influences striatal dopamine release predominantly through action at nAChRs, and nicotine protects against nigrostriatal damage by stimulating nAChRs. Modulation of the nicotinic cholinergic system is an active area of PD research, also fueled by evidence that nAChR drugs may reduce PD progression and levodopa-induced dyskinesias [13,37].

Structural and Functional Pathophysiology

The origin of motor dysregulation in PD is neuronal degeneration in the substantia nigra pars compacta and loss of dopaminergic regulation of the striatum. The striatum is an entry point for cortical projections into the basal ganglia, and the basal ganglia-thalamocortical motor circuit modulates the cortical output required for normal movement. Cortical signaling enters the striatum and is processed through the basal motor circuit; motor circuit output is relayed through the internal globus pallidus and the substantia nigra pars reticulata. The basal ganglia circuit involves two dopaminergic pathways:

- The direct pathway of striatal neurons with dopamine D1 receptors, projecting to the globus pallidus and substantia nigra reticulata

- The indirect pathway of striatal neurons with D2 receptors, projecting to the striatum/external globus pallidus connection and the external globus pallidus/subthalamic nucleus connection

In PD, striatal dopamine depletion deactivates the excitatory D1 direct pathway and hyperactivates the inhibitory D2 indirect pathway. Alterations in these two pathways inhibit voluntary movement [7,8,12].

Pathogenic Mechanisms

There is a consistent line of evidence linking PD to a neurodegenerative process involving oxidative stress, mitochondrial dysfunction, and neuroinflammation. Environmental and genetic factors induce mitochondrial dysfunction, resulting in abnormal accumulation of miscoded proteins (mostly alpha-synuclein) and generation of oxidative stress in enteric, peripheral, and central nervous systems. In turn, oxidative stress, excitotoxicity, and mitochondrial dysfunction promote the destruction of dopamine neurons and dopaminergic function in midbrain systems [12,38,39,40].

CORE PATHOLOGIC FEATURES

Along with substantia nigra dopamine neuron loss, postmortem confirmation of PD diagnosis requires the presence of Lewy body pathology—intraneuronal aggregates of misfolded (pathogenic) forms of the protein alpha-synuclein. In addition to other pathologic effects, alpha-synuclein aggregates are associated with axonal and neuronal dysfunction, sequestration of vital neurotransmitter enzymes, and reduction or loss of cytoplasmic tyrosine hydroxylase and choline acetyltransferase. These effects compromise cellular integrity and fuel degeneration and contribute to neuronal death [41].

A third pathologic feature of PD is increased gliosis. Gliosis refers to an increased number and activation state of astrocytes and microglia, glial cell types that respond to injury or damage with altered morphology and production of inflammatory molecules. Increased gliosis is found in areas of neurodegeneration, which is not limited to the nigrostriatal pathway but evident throughout the brain to suggest a generalized neuroinflammation. Misfolded alpha-synuclein aggregates directly activate microglia, further linking alpha-synuclein and neuroinflammation to PD. These findings support a role of the innate immune system in the neurodegenerative process of PD [7].

DEVELOPMENT AND PROGRESSION OF PATHOPHYSIOLOGY

Neuroscience findings have transformed the concept of PD, now recognized as a disease with pathology distributed throughout the enteric, peripheral, and central nervous systems. Nigrostriatal motor pathology is one pathophysiologic phase on a continuum of processes that begin long before motor symptoms emerge [7,12,42].

An essential initiating event for PD is induction of alpha-synuclein misfolding. This is followed by aggregation of misfolded alpha-synuclein and initial formation of alpha-synuclein aggregates in neurons. Very few neuron types are vulnerable to alpha-synuclein inclusions; the most vulnerable are projection neurons with long, thin, sparsely myelinated axons. Glutamatergic, gamma aminobutyric acid-ergic, dopaminergic, noradrenergic, serotonergic, histaminergic, and cholinergic projection cells can become involved, but within neurotransmitter types, some subgroups are selectively vulnerable (dopaminergic substantia nigra pars compacta neurons) while others are not (dopaminergic hypothalamic neurons) [43].

Neurons with the greatest exposure to potentially hostile environmental factors are selectively vulnerable to alpha-synuclein inclusions. Aggregates form in these enteric, peripheral, and central neurons and propagate trans-synaptically from neuron to neuron. A regional distribution pattern of aggregated alpha-synuclein emerges through specific involvement of susceptible and axonally interconnected projection neurons within the nervous system [41].

Evidence indicates that PD originates in structures outside the brain, including the enteric nervous system of the gastrointestinal tract and salivary glands. The olfactory bulb has very early involvement. A primary route of disease progression is through enteric nervous system neuronal connections to the vagal nerve motor nucleus in the lower brainstem. The pathology then spreads through visceromotor and somatomotor brainstem centers to the locus coeruleus, basal forebrain, striatum, basal ganglia-thalamocortical motor circuit, central amygdala, and cortical structures. Other routes are through spinal cord centers via descending projections from lower brainstem nuclei and from autonomic projections connecting the enteric nervous system with spinal cord peripheral ganglia and preganglionic nuclei [7,8,41].

A classification method was developed to identify the extent of postmortem pathology resulting from PD. This system uses six stages to roughly demarcate the sequence of anatomic involvement and symptom emergence throughout the disease course (Table 2). The stages occur in two phases: the pre-clinical phase (stages 1 through 3) and the clinical, or motor, phase (stages 4 through 6). Each stage includes newly affected regions along with those involved in previous stages [8,41,42,44,45].

Table 2: STAGES OF PARKINSON DISEASE

Stage

Description

Preclinical phase

1

Lesions (Lewy body pathology/alpha-synuclein aggregates) develop in olfactory structures, salivary glands, enteric and peripheral autonomic nervous system, parasympathetic and sympathetic ganglion projection neurons, and lamina I of the spinal cord.

2

The pathologic process enters the lower brainstem, including vagal nerve projection neurons that connect the enteric nervous system with the central nervous system, the lower raphe nuclei, and the locus coeruleus.

3

Lesions spread in the midbrain tegmentum, the basal forebrain, and into the substantia nigra

Clinical (motor) phase

4

The pathology is entrenched in the substantia nigra pars compacta and infiltrates the amygdala, the intralaminar thalamic nuclei, and the hippocampal CA2 sector.

5

Lesions spread in the cingulate
and temporal cortex.

6

Lesions infiltrate the frontal and parietal cortex.

Source: [8,41,42,44,45]

PD is clinically diagnosed by the presence of cardinal motor features, broadly defined as bradykinesia, rest tremor, rigidity, and postural/gait impairment. The inclusion of postural/gait dysfunction in clinical criteria has been challenged, because it typically appears later in the disease course (instead of during the onset of motor symptoms) and is influenced by non-dopaminergic pathology primarily involving cortical cholinergic neurodegeneration [46].

NATURAL HISTORY OF DISEASE PROGRESSION

The progression of disease and disability in PD varies and is partially influenced by patient factors such as age. In general, from the mean age at diagnosis of 61 years, the mean time to death is 14 years overall. Survival time is a mean 24 years for patients diagnosed in their 40s and 9.7 years for patients diagnosed in their 70s [4]. With the onset of subclinical non-motor symptoms decades before diagnosis, pathologic processes that underlie PD are probably active over a 40-year period in many patients [45].

Throughout the disease course, all patients experience deterioration in motor function associated with increased impairment and disability and declining quality of life. The later stages of the disease are characterized by reduced efficacy of oral medication, increased medication-related side effects, dysphagia, cognitive dysfunction with conversion of mild cognitive impairment to dementia, reduced mobility with increased tendency to fall, and in many, dependence on others for activities of daily living. The mode of death often involves respiratory compromise from bronchopneumonia or aspiration [4].

Mild cognitive impairment later progressing to dementia is very prevalent in patients with PD, and roughly 80% of patients develop dementia within 20 years of diagnosis. Cerebrospinal fluid levels of alpha-synuclein predict the progression of cognitive decline in PD [47]. Dementia in PD and Alzheimer disease is associated with central nervous system (CNS) accumulation of protein aggregates such as b-amyloid peptide. B-amyloid peptide deposition in the striatum strongly correlates with dementia, suggesting this accumulation is a contributing factor to the development of cognitive impairment and neurodegeneration in PD [48]. Subjects with PD and dementia show degeneration of several subcortical nuclei, including the cholinergic nucleus basalis of Meynert, the medial substancia nigra, and the noradrenergic locus coeruleus. Presence of secondary neuropathologies may further increase oxidative stress, decrease brain energy, and enhance brain degenerative processes in patients with PD [12].

NON-MOTOR SYMPTOM APPEARANCE AND DISEASE STAGE

PD is typically diagnosed following the onset of motor features (stage 4) that prompts the patient to seek medical attention. Pre-motor prodromal disease can manifest in non-motor features, such as depression, fatigue, rapid eye movement (REM) sleep behavior disorder, anosmia, and constipation, that reflect disease involvement in autonomic, enteric, or somatomotor systems. Visuospatial and cognitive dysfunction, especially mild cognitive impairment with dominant executive dysfunction manifested in diminished multitasking, planning, retrieval, concentration, and attention performance, are increasingly recognized as prevalent in earlier stages [4]. As mentioned, physical appearance, severity, and progression of pre-motor and motor features corresponds to the nervous system and brain areas afflicted by pathologic infiltration [44,49,50,51].

Motor symptoms can also appear long before diagnosis. A prospective study found motor symptom onset 10 years before formal PD diagnosis. In this study, primary care patients were assessed for prodromal PD symptoms at three time points over 10 years. Symptom frequency was compared in patients later diagnosed with PD with those remaining PD-free (controls). Some symptoms were not analyzed [49]. Ten years pre-diagnosis, tremor was 7.6 times more likely and constipation twice as likely in patients who developed PD than in controls. Five years pre-diagnosis, patients who developed PD were more likely to show tremor, balance impairments, constipation, hypotension, erectile dysfunction, urinary dysfunction, dizziness, fatigue, depression, and anxiety than controls.

The progression of non-motor symptoms in PD, and stage of pathophysiologic progression that underlies their emergence, is shown in Table 3 [7,42,52].

Table 3: PATHOLOGY AND NON-MOTOR SYMPTOMS IN VARIOUS STAGES OF PARKINSON DISEASE

Non-Motor Symptoms

Stage

Symptoms/Signs

Affected Nervous System Areas

Sensory

Olfaction

1

Decreased odor detection, identification (hyposmia)

Olfactory bulb

Anterior olfactory nucleus

Pain

2, 3

Vague discomfort

Burning pain or paresthesia

Serotonergic pathways

Dopaminergic pathways

Autonomic

Gastrointestinal

1

Nausea

Constipation

Decreased gastric emptying

Colonic dysmotility

Esophageal dysmotility

Dorsal motor nucleus of the vagus

Enteric ganglia

Genitourinary

2

Urinary frequency, urgency

Incontinence

Erectile dysfunction

Gain setting neurons

Pelvic autonomic ganglia

Cardiovascular

1

Orthostatic hypotension

Dorsal motor nucleus of the vagus

Sympathetic ganglia

Thermoregulatory

3, 4

Hyperhydrosis

Hypohydrosis/anhydrosis

Sympathetic ganglia

Hypothalamus

Neuropsychiatric

Sleep disorders

2, 3

Sleep cycle disruption

Excessive daytime sleeping

REM sleep behavior disorder

Locus ceruleus/subceruleus

Raphe nuclei

Pedunculopontine nucleus

Suprachiasmatic nucleus

Behavioral disorders

2, 3

Apathy

Depression

Anxiety

Locus ceruleus

Raphe nuclei

Ventral tegmental area

Dementia

4, 5, 6

Bradyphrenia

Executive dysfunction

Memory decline

Visuospatial impairment

Dopaminergic (substantia nigra, ventral tegmental area)

Cholinergic (nucleus basalis of Meynert)

Cortical/subcortical pathology

Source: [7,42,52]

It should be noted that PD is heterogeneous, and not all patients exhibit full-blown motor and non-motor syndromes. Some patients exhibit motor features that remain modest in severity for many years, or cognitive and behavioral functions that appear normal or minimally affected. Overall, the clinical features are most easily viewed as motor and non-motor components of the PD phenotype [7].

PRE-MOTOR SYMPTOMS

Several pre-motor symptoms have been studied for their relationship to disease process and PD diagnosis.

REM Sleep Behavior Disorder

REM sleep behavior disorder is characterized by dream enactment behavior during sleep, including yelling, laughing, or crying; complex voluntary movements; falling out of bed; and even violent behaviors with injury. REM sleep behavior disorder is an extremely powerful predictor, or prodromal marker, of developing synuclein-mediated neurodegenerative diseases, which eventually occurs in at least 80% and most frequently involves PD [53,54].

A 16-year follow-up study of men diagnosed with REM sleep behavior disorder found that 80.8% eventually developed parkinsonism/dementia and were diagnosed with PD (62%); dementia with Lewy bodies (14%); multisystem atrophy (9.5%); clinically diagnosed, autopsy-confirmed Alzheimer disease plus Lewy body pathology (9.5%); or profound unspecified dementia (5%) [55]. Of those who progressed to parkinsonism, the mean age of REM sleep behavior disorder onset was 57.7 years; the mean age of parkinsonism/dementia onset was 71.9 years. Overall, the mean interval from REM sleep behavior disorder onset to parkinsonism/dementia onset was 14.2 years (range: 5 to 29 years). In these patients, lower brainstem involvement, particularly the pons, appeared long before the onset of motor features [55].

The first published methodology with high accuracy in predicting PD development used data from patients with REM sleep behavior disorder. These patients were regularly evaluated throughout the 10-year period following their initial REM sleep behavior disorder diagnosis. Using this data, prodromal markers of PD were analyzed for predictive validity. Factors that highly predicted PD when combined were (in descending order of strength) subtle motor dysfunction, nonuse of antidepressants, abnormal color vision, olfactory loss, and advanced age. Factors found non-predictive when aggregated were mild cognitive impairment, depression, "Parkinson personality," treatment with clonazepam or melatonin (for REM sleep behavior disorder), autonomic markers, and male sex [53].

Olfactory Dysfunction

Studies of olfaction in PD have shown abnormalities in up to 100% of patients, making olfactory dysfunction the most robust predictor of developing PD. As noted, many patients complain of declining sense of smell long before parkinsonism onset. As it is not disabling and relatively nonspecific, anosmia has mostly failed to gain traction as a predictive and clinical feature of PD [56].

Constipation

Constipation is a notoriously bothersome and common symptom in PD that results from peripheral autonomic involvement in the early pathogenic process [56]. Compared with middle-aged men who reported more than two bowel movements per day, men who reported fewer than one bowel movement per day were prospectively identified as more than four times more likely to develop PD. This suggests lower bowel involvement is an early sign that, in some patients, predated PD by 15 years or more [57].

Excessive Daytime Sleepiness

Excessive daytime sleepiness has also been identified as a midlife risk factor for PD, suggesting early brainstem involvement and subsequent sleep disturbances as a pre-diagnostic feature [58].

ASSESSMENT AND DIAGNOSIS OF PARKINSON DISEASE

As noted, parkinsonism refers to the motor features of bradykinesia, tremor, rigidity, and postural instability resulting from nigrostriatal dopamine neuron loss in PD, as well as dementia with Lewy bodies, multisystem atrophy, progressive supranuclear palsy, and corticobasal degeneration. PD is the most common neurodegenerative cause of parkinsonism, comprising 80% of cases [59].

The centrality of the motor syndrome remains the core feature that defines clinical PD and by which PD is diagnosed. However, the pathologic process of PD is now established as beginning in non-dopaminergic structures of the brain or peripheral nervous system, during which non-motor features dominate. This is reflected in a new diagnostic classification, prodromal PD, now considered a true stage of PD, and in the 2015 International Parkinson and Movement Disorder Society (MDS) PD diagnostic criteria that incorporate non-motor manifestations of PD [60].

Non-motor symptoms of PD appear before motor symptoms and are usually present at diagnosis or develop and progress in severity through the disease course. Non-motor symptoms may appear as early as three decades before motor features, during the prodromal PD phase. They are present earlier in the neurodegenerative process than motor features, which require 60% to 80% loss of dopaminergic neurons to emerge [42]. Criteria for prodromal PD have been published, and while early detection of PD before the onset of motor features could be immensely valuable, the absence of neuroprotective or disease-modifying therapy against PD, ethical issues from disclosure of disease risk, and the frequently shifting understanding of PD discourage any attempts to clinically diagnose the motor symptom prodrome of PD [61]. Nonetheless, identification and treatment of non-motor symptoms are essential due to their potentially great negative impact on patient well-being [1,8].

CLINICAL FEATURES

Motor Symptoms of PD

In PD, the cardinal motor features of bradykinesia, resting tremor, rigidity, and postural/gait impairment reflect parkinsonism [62]. A mnemonic for the core motor features is TRAP [7]:

- Tremor at rest

- Rigidity

- Akinesia (i.e., bradykinesia and hypokinesia)

- Postural instability

It is important to note that postural instability, while a cardinal motor feature, is seldom a problem early in the course of PD and may not be evident at diagnosis, as it usually appears later in the disease course [60].

Bradykinesia

Bradykinesia, as typically defined, combines the definitions of bradykinesia (slowness) and hypokinesia (decreased movement amplitude) [60]. Bradykinesia is reduced speed in initiating and executing movement, and altered fine motor control and dexterity. It is not just slowness in movements, but slowness in initiating voluntary movement, with progressive fatiguing during repetitive movements that presents in reduced speed and amplitude during finger or foot tapping. Slowness of movements, progressive reduction in speed and amplitude of repeated movements, delay in initiating movements, and freezing gait eventually occur in 80% to 90% of patients with PD [63].

Bradykinesia is the defining feature of parkinsonism and the essential clinical sign because the slowed, disordered motor movements directly correlate with functional abnormality in basal ganglia-cortical neuronal circuits, where aberrant dopamine-mediated firing patterns within indirect and direct pathways inhibit activity in cortical motor system neurons [4,7]. The slowed, small-amplitude movements in bradykinesia interfere with limb control, dexterity in tying shoes or buttoning shirts, and swallowing (dysphagia). It may also present as decreased facial expression and eye blinking (hypomimia), weak voice (hypophonia), and progressively smaller handwriting (micrographia) [4,62,64].

Rigidity

Rigidity is increased muscle tone in flexor and extensor muscle groups at rest and resistance to passive stretch movement in flexor and extensor muscles with the limb relaxed. Rigidity is present in 80% to 90% of patients with PD, usually unilaterally at the onset of motor symptoms. It often, but not always, co-occurs with tremor. Rigidity results from altered firing rates in the basal ganglia, a fundamental feature of parkinsonism. The resultant motor system output reflects inappropriate activation of agonist and antagonist muscles that present in bradykinesia and rigidity [7]. In early-stage disease, rigidity may manifest as pain, such as frozen shoulder or low back pain, obscuring the diagnosis of a CNS disorder [4].

Rest Tremor

Rest tremor, an initial symptom in 70% to 90% of patients, refers to a 4–6 Hz tremor in the fully resting limb, suppressed during movement initiation. Rest tremor is a rhythmic, oscillatory involuntary movement and one of the most characteristic signs in clinical medicine. The most distinguishing rest tremor is the "pill-rolling" type, with rubbing movements of thumb and index fingers against each other. Rest tremor is thought to initiate with nigrostriatal degeneration and subthalamic nucleus or globus pallidus disinhibition, or disrupted thalamo-cortical-cerebellar circuits leading to abnormal thalamic pacemaker cell function [4,7].

Tremor in parkinsonism is distinct from other forms of tremor by its asymmetry, speed, dominance at rest, reduction or cessation during action, re-emergence when maintaining a posture, and increased amplitude during tasks requiring mental concentration [4].

Postural Instability

Postural instability is defined as difficulty adjusting to postural change, and together with gait impairment and postural abnormalities, it comprises the axial motor signs of PD [65]. Postural instability and other axial signs do not usually present in early PD, reflecting pathophysiology beyond dopamine motor neuron loss [7]. As such, the inclusion of axial signals in the cardinal motor features required for the parkinsonism diagnosis in PD has been challenged [60].

Postural and gait impairment result from loss of postural reflexes, which leads patients to adopt a stooped posture. The loss of postural reflexes is also a major contributor to falls [66]. In PD, the gait is slow, with short shuffling steps on a narrow base that appears as if the patient is chasing his or her own center of gravity. Patients show decreased arm swing; turning around is slow, with multiple small steps, and freezing gait can occur, especially in crowded or narrow places. Festination, a very fast succession of steps with the patient only able to stop when meeting an obstacle, may also be present. Walking and turning becomes difficult or impossible in patients with PD when additional cognitive load, such as dual tasking, is imposed [67,68].

Brainstem pathology is now recognized as a major contributor to the clinical features in PD. Postural control problems with imbalance, falls, and freezing gait tend to occur later in PD and reflect cholinergic neuron degeneration and dysfunction outside of the basal ganglia [7]. Persons with parkinsonism or other extrapyramidal neurodegenerative disorders frequently develop problems with balance and may experience frequent falls. The vestibular system controls balance and is synaptically linked to the extrapyramidal system, possibly contributing to posture and balance dysfunction [62].

Non-Motor Symptoms

The frequency and diversity of non-motor symptoms in PD is substantial, and includes autonomic, neuropsychiatric, olfactory, sensory, and sleep disorders that occur in 80% to 90% of patients (Table 4). Non-motor symptoms can manifest before, during, or after motor symptoms and may result in greater impairment of quality of life. The prevalence of cognitive, autonomic, and mood disorders is very high; progression can result in patients requiring care in a supervised environment [7].

Table 4: NON-MOTOR SYMPTOMS IN PARKINSON DISEASE

Category

Symptoms

Autonomic dysfunction

Constipation

Orthostatic hypotension

Sexual dysfunction

Sweating

Urinary retention and urgency

Sialorrhea (also from decreased swallowing movements)

Neuropsychiatric

Apathy

Anxiety, panic attacks

Cognitive deterioration, from mild impairment to dementia

Depression (dysphoria, suicidal ideation)

Impulse-control disorders (e.g., obsessions, hypersexuality, compulsive shopping, binge eating), usually associated with dopamine agonist use

Psychoses (hallucinations, delusions)

Sensory symptoms

Olfactory dysfunction (hyposmia)

Paresthesias (tingling, numbness), other abnormal sensations

Decreased visual contrast and color discrimination

Decreased visual motion perception

Sleep disturbance

Daytime somnolence

Insomnia

REM sleep behavior disorder

Restless legs syndrome

Sleep attacks

Sleep apnea

Other

Fatigue

Pain

Weight loss

Source: [1,4]

A 2010 survey found that up to 62% of patients with PD do not volunteer symptoms such as apathy, pain, sexual dysfunction, bowel incontinence, constipation, or sleep disorders either through embarrassment or unawareness of symptom relevance to PD. Clinicians may not understand that these symptoms require assessment. Their under-reporting has important therapeutic and societal implications, as most are treatable. Left unaddressed, non-motor symptoms detrimentally affect patient quality of life, frequently lead to hospitalization and institutionalization, and quadruple the cost of PD care [69].

6. DIAGNOSTIC WORKUP

Disease-specific screening tests or biomarkers for PD are not yet available, and definitive diagnosis is only possible at autopsy by confirmation of striatal dopamine neuron loss and Lewy body pathology [64]. Idiopathic PD is diagnosed through patient history and physical examination, often performed sequentially over time in order to identify signs of progression and the emergence of defining clinical features. History or physical findings inconsistent with features of idiopathic PD are explored further to rule out or confirm an alternate diagnosis. Clinicians with limited experience caring for patients with PD should consider referring a patient with suspected disease to a physician with expertise in movement disorders to confirm diagnosis [2].

DIAGNOSTIC CRITERIA

Evidence Based Practice Recommendation

According to the European Academy of Neurology and the Movement Disorders Society European Section, only the Brain Bank clinical diagnostic criteria for Parkinson disease have been validated and are therefore recommended as probably effective for clinical practice.

https://www.movementdisorders.org/MDS-Files1/MDS-ES/MDS-ES--EFNS/BerardellietalEFNSMDSESene12022.pdf

Last Accessed: April 11, 2019

Level of Evidence: B (At least one convincing prospective study or overwhelming evidence from retrospective studies)

The UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria have been the most widely used diagnostic criteria for PD, recommended for use in North America and Europe as a straightforward, objective, and accurate approach (Table 5) [4,63,71]. With these criteria, three major steps are required for PD diagnosis. The presence of parkinsonism must be established, but parkinsonism is non-specific to PD and additional steps are required for a PD diagnosis.

Table 5: UK BRAIN BANK CLINICAL DIAGNOSTIC CRITERIA FOR PARKINSON DISEASE

Step

Criteria

Step 1: Diagnosis of parkinsonian syndrome

Bradykinesia and one or more of the following:

- Muscular rigidity

- Resting tremor 4–6 Hz

- Postural instability (not due to primary visual, vestibular, cerebellar, or proprioceptive dysfunction)

Step 2: Exclusion criteria for Parkinson disease

History of repeated strokes with stepwise progression of parkinsonian features

History of repeated head injury

History of definite encephalitis

Oculogyric crises

Neuroleptic treatment at onset of symptoms

More than one affected relative

Sustained remission

Strictly unilateral features after three years

Supranuclear gaze palsy

Cerebellar signs

Early severe autonomic involvement

Early severe dementia with disturbances of memory, language, and praxis

Babinski sign

Cerebral tumor or communicating hydrocephalus on computed tomography scan

Negative response to large-dose levodopa

MPTP exposure

Step 3: Supportive positive criteria of Parkinson diseasea

Unilateral onset

Rest tremor present

Progressive disorder

Persistent asymmetry affecting side of onset most

Excellent levodopa response (70% to 100% symptom reduction)

Severe levodopa-induced chorea

Levodopa response ≥5 years

Clinical course ≥10 years

aThree or more required for diagnosis of definite PD.

Source: [71]

However, the UK Brain Bank diagnostic criteria were established more than 20 years ago (in 1992) and solely address motor symptoms, leading many to consider them outdated. This led to the 2015 publication of new PD diagnostic criteria by the MDS Task Force, comprised of North American and European experts. These criteria better reflect current understanding of PD as a multi-system disorder affecting all parts of the nervous system, often with a genetic component and a very slow progression of neurodegenerative processes reflected in a long prodromal period. These aspects are incorporated in the new criteria [60].

The first essential criterion of the MDS Clinical Diagnostic Criteria for PD is parkinsonism, defined as bradykinesia with rest tremor and/or rigidity [60]. Examination of cardinal motor features should follow as described in the MDS-United Parkinson Disease Rating Scale (UPDRS) [72]. After parkinsonism is diagnosed, PD may be diagnosed as either clinically probable or established based on the presence or absence of absolute exclusion criteria, supportive criteria, and guideline-defined "red flags" (Table 6) [60]. Clinically probable PD diagnosis requires [60]:

- Absence of absolute exclusion criteria

- Presence of no more than two red flags counterbalanced by supportive criteria

- If one red flag is present, there must also be at least one supportive criterion

- If two red flags, at least two supportive criteria are needed

Table 6: MDS CLINICAL DIAGNOSTIC CRITERIA FOR PD

Absolute exclusion criteria

Unequivocal cerebellar abnormalities, such as cerebellar gait, limb ataxia, or cerebellar oculomotor abnormalities (e.g., sustained gaze evoked nystagmus, macro square wave jerks, hypermetric saccades)

Downward vertical supranuclear gaze palsy, or selective slowing of downward vertical saccades

Diagnosis of probable behavioral variant frontotemporal dementia or primary progressive aphasia within the first five years of disease

Parkinsonian features restricted to the lower limbs for more than three years

Treatment with a dopamine receptor blocker or dopamine-depleting agent in a dose and time-course consistent with drug-induced parkinsonism

Absence of observable response to high-dose levodopa despite at least moderate disease severity

Unequivocal cortical sensory loss (i.e., graphesthesia, stereognosis with intact primary sensory modalities), clear limb ideomotor apraxia, or progressive aphasia

Normal functional neuroimaging of the presynaptic dopaminergic systema

Documentation of an alternative condition known to produce parkinsonism and plausibly connected to the patient's symptoms, or the expert evaluating physician, based on the full diagnostic assessment, feels that an alternative syndrome is more likely than PD

Supportive criteria

Clear, dramatic benefit to dopaminergic therapy. During initial treatment, patient returned to normal or near-normal level of function. In the absence of documented initial response, dramatic response can be classified as:

- Marked improvement with dose increases or marked worsening with dose decreases. Mild changes do not qualify. Document objectively (>30% change in MDS-UPDRS) or subjectively (clearly documented history of marked changes from a reliable patient or caregiver)

- Unequivocal and marked on/off fluctuations, which must have at some point included predictable end-of-dose wearing off

Presence of levodopa-induced dyskinesia

Rest tremor of a limb, documented on clinical exam (past or present)

Presence of olfactory loss or cardiac sympathetic denervation on MIBG scintigraphy

"Red flags"

Rapid progression of gait impairment requiring regular use of wheelchair within five years of onset

Total absence of motor symptom/sign progression over five or more years, unless the stability is treatment-related

Early bulbar dysfunction: severe dysphonia or dysarthria (speech unintelligible most of the time) or severe dysphagia (requiring soft food, NG tube, or gastrostomy feeding) within first five years

Inspiratory respiratory dysfunction: either diurnal or nocturnal inspiratory stridor or frequent inspiratory sighs

Severe autonomic failure in the first five years of disease, such as:

- Orthostatic hypotension (orthostatic decrease of blood pressure within three minutes of standing by ≥30 mm Hg systolic or ≥15 mm Hg diastolic) in the absence of dehydration, medication, or other diseases explaining autonomic dysfunction

- Severe urinary retention or incontinence (nonfunctional) in the first five years of disease (excluding long-standing or small-amount stress incontinence in women). In men, urinary retention is not from prostate disease and must be associated with erectile dysfunction

Recurrent (more than once per year) falls from impaired balance within three years of onset

Disproportionate anterocollis (dystonic) or contractures of hand or feet within the first 10 years

Absence of common non-motor PD features, despite five years disease duration. Includes sleep dysfunction (sleep-maintenance insomnia, excessive daytime somnolence, symptoms of REM sleep behavior disorder), autonomic dysfunction (constipation, daytime urinary urgency, symptomatic orthostasis), hyposmia, or psychiatric dysfunction (depression, anxiety, hallucinations)

Otherwise-unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic hyper-reflexia (excluding mild reflex asymmetry and isolated extensor plantar response)

Bilateral symmetric parkinsonism: patient/caregiver report of bilateral symptom onset without side predominance confirmed by objective exam

Prominence of postural instability early in the course of the disease

aExclusion of this criterion does not imply dopaminergic functional imaging is required for diagnosis. If no imaging has been performed, this criterion does not apply.

MDS-UPDRS = Movement Disorder Society-Unified Parkinson Disease Rating Scale, MIBG = meta-iodobenzylguanidine, NG = nasogastric.

Source: [60]

A diagnosis of clinically established PD is made if the patient displays [60]:

- Absence of absolute exclusion criteria

- At least two supportive criteria

- No red flags

The MDS PD criteria note that the establishment of parkinsonism motor features remains the foundation of PD diagnosis, but several pre-motor features are woven into the overall criteria [60]. While postural instability is a feature of parkinsonism, it is not a criterion for parkinsonism in the MDS guideline. Dementia with Lewy bodies is not considered an alternative parkinsonian syndrome; these patients can be diagnosed as PD (dementia with Lewy bodies subtype).

PATIENT HISTORY

Idiopathic PD is diagnosed by history and physical examination. The first step in the diagnostic process is taking a careful history by thoroughly questioning the patient and/or family members regarding [1,4,62]:

- Symptoms that emerged, their sequence, and perceived anatomical involvement, including symptoms that suggest bradykinesia, rigidity, resting tremor, and/or postural instability

- The presence and onset of pre-motor symptoms:

- Neuropsychiatric symptoms

- Autonomic dysfunction

- Sleep disorders

- Sensory symptoms

- Fatigue

- Past and present medical disorders

- Family history, including neurologic disorders and ethnic ancestry, as monogenic forms of PD are more frequent in some ethnic groups (e.g., LRRK2 in Ashkenazi Jews and North African Arabs)

- Exposure to illicit drugs associated with parkinsonism (e.g., methamphetamine, amphetamine)

- Environmental toxin exposure (e.g., manganese in welders)

It is also important to explore the possibility of prescription drug-induced parkinsonism. This is one of few reversible causes of the disorder, and identification by a complete medication evaluation will help avoid inappropriate treatment. The most frequent causes of drug-induced parkinsonism are typical antipsychotics (e.g., haloperidol, chlorpromazine), most atypical antipsychotics (e.g., risperidone, olanzapine), and the gastrointestinal agents prochlorperazine, promethazine, and metoclopramide. Infrequent causes are tetrabenazine, reserpine, methyldopa, flunarizine, cinnarizine, verapamil, valproic acid, and lithium. In one study of 155 cases of drug-induced parkinsonism between 1995 and 2009, 70% of patients developed symptoms within three months of beginning the prescribed medication; the remaining patients all developed symptoms within one year on the offending drug [150]. Recovery from drug-induced parkinsonism can be expected following discontinuation of the medication, though many weeks to months may be required for full resolution of symptoms.

The propensity for antipsychotic drugs to produce parkinsonian side effects has implications for managing patients with PD who experience psychosis as a complication of the disease. For such patients, some have recommended using clozapine, with quetiapine as a second-line option [1].

NEUROLOGIC EXAMINATION

A neurologic examination is performed to provide objective evidence of motor symptoms in the absence of other abnormalities. Simple observation will often reveal a generalized slowness and lack of spontaneous movement. Findings of parkinsonism motor features supported by patient history, confirm a diagnosis of idiopathic PD. Idiopathic PD will demonstrate any combination of the following, and motor symptom findings are usually asymmetrical [63].

Bradykinesia

To assess bradykinesia, ask the patient to perform repetitive movements as quickly and widely as possible, such as opening and closing the hand, tapping thumb and index fingers, or tapping the foot on the ground. Progressive slowness and/or loss of amplitude should emerge and may bring the movement to full arrest (freezing). To globally assess bradykinesia, observe spontaneous movements while the patient is sitting, standing up from a chair, or walking [62,64]. To avoid misdiagnosis, distinguish clinical bradykinesia from simple slowness in patients with decreased muscle power, spasticity, or reduced motivation in depression or in normal elderly populations that reflect non-specific slowness [62,64].

Rigidity

Rigidity refers to "leadpipe" resistance, whereby velocity-independent resistance to passive movement is not influenced by an inability to relax (i.e., distinct from spasticity). This resistance is felt throughout the full range of movement, and unlike spasticity, it does not increase with higher mobilization speed. When resting tremor co-occurs with rigidity, "cog-wheel rigidity" can be felt during passive limb mobilization, especially in the wrist. When assessing rigidity, interruption of passive movement by a "cog-wheel" movement reflects the underlying 4–6 Hz tremor oscillation. In contrast, pyramidal tone (spasticity) is dependent on the velocity of passive movement and is described as ''clasp knife'' in quality because of the higher resistance during early acceleration of the passive movement followed by giving way, such as is seen when opening lock-blade knives [62]. Rigidity is assessed by passive movement of a joint and reinforced by asking the patient to move the opposite limb in a circular motion or open/close a fist.

Tremor

Resting tremor is often observed in patients with PD, and postural tremor and re-emergent resting tremor may be seen with arms outstretched. Resting tremor is best observed in the hands during patient focus on a mental task (e.g., eyes-closed countdown from 100) that facilitates muscle relaxation; in the legs with the patient seated on the edge of an exam table, with legs hanging and feet unsupported; and in the jaw when the patient is engaging another part of the body in activity [4,62].

Gait

Gait may be stooped or shuffling, with reduced arm swing. Patients often turn en bloc, requiring numerous steps to complete a 180° turn. The pull test (briskly pulling the patient backwards while standing) may be used to assess postural reflexes. Loss of postural reflexes generally occurs in later-stage disease.

DIAGNOSTIC CONFIRMATION

Unless signs or symptoms are observed that are inconsistent with idiopathic PD (i.e., MDS absolute exclusion criteria or red flags), no further testing is needed with history and exam findings consistent with idiopathic PD. Imaging tests are used only to confirm absolute exclusion criteria findings or to rule out or confirm red flag findings [60].

Evidence Based Practice Recommendation

The American College of Radiology recommends non-contrast magnetic resonance imaging (MRI) of the head in patients with Parkinson disease with typical clinical features and responsive to levodopa only for problem-solving purposes.

https://acsearch.acr.org/docs/69360/Narrative

Last Accessed: April 11, 2019

Strength of Recommendation: 7 (Usually appropriate)

However, there are a variety of special procedures available that help to confirm diagnosis, obtain additional information on disease type or severity, and differentiate PD from disease mimics (Table 7). Dopaminergic challenge tests that elicit objective improvement in motor function and alleviation of symptoms provide positive evidence for the diagnosis, although support is not universal [63,73]. Olfactory testing can help substantiate a PD diagnosis, is inexpensive, is extensively validated, and contributes to the early diagnosis and differential diagnosis of PD. Although it can help identify patients with pre-motor symptoms of PD, use alone is not diagnostic [1,63,74].

Table 7: EFNS/MDS-ES RECOMMENDATIONS FOR DIAGNOSTIC INSTRUMENT USE IN PARKINSON DISEASE

Diagnostic Modality

Level of Evidence

Indications for Use

Genetic testing

SNCA gene point mutations and multiplication

B

PD families suggestive of dominant inheritance

LRRK2 and known pathogenic variants

B

Typical PD with family history suggestive of dominant inheritance

Sporadic PD from specific populations with known founder effect mutations

GBA mutations

B

Founder effect mutations in PD cases in specific populations (e.g., Ashkenazi Jewish) with or without positive family history

Parkin, PINK1, DJ-1 mutations

B

PD with onset before 50 years with family history suggestive of recessive inheritance

Sporadic PD with onset before 40 years

ATP13A2, PLA2G6, FBX07

B

Very early onset PD cases

Olfactory tests

University of Pennsylvania Smell Identification Test (with other diagnostic tests)

A

PD versus atypical and secondary parkinsonism

A

Idiopathic PD versus recessive PD forms

A

Pre-motor PD

Neuropsychologic testing

Collateral history from a carer, cognitive assessment, and screening of REM sleep behavior disorder, psychosis, severe depression

A

During initial evaluation to exclude other causes of parkinsonism in patients with suspected PD

Transcranial sonography

Use with other diagnostic tests

A

Differential diagnosis of PD from atypical and secondary parkinsonism

A

Early diagnosis of PD

A

Detection of subjects at risk for PD

Magnetic resonance imaging (MRI)
in differential diagnosis

Conventional 1.5-Tesla MRI

A

Differential diagnosis of multisystem atrophy from PD

B

Differential diagnosis of progressive supranuclear palsy from PD (detection of midbrain atrophy and/or SCP atrophy)

C

1.5-Tesla diffusion-weighted MRI

A

Differential diagnosis of multisystem atrophy from PD (identification of putaminal diffusivity changes)

B

Differential diagnosis of progressive supranuclear palsy from PD (identification of SCP diffusivity changes)

Single photon emission tomography (SPECT) in differential diagnosis

123Ioflupane SPECT

A

Differential diagnosis of essential tremor from PD and atypical parkinsonism

123I-MIBG SPECT

A

Differential diagnosis of PD from multisystem atrophy

EFNS/MDS-ES = European Federation of Neurological Associations/Movement Disorders Society–European Section, MIBG = meta-iodobenzylguanidine, SCP = superior cerebellar peduncle.

Levels of evidence: A = effective, B = probably effective, C = possibly effective.

Source: [63]

Recommendations for genetic testing in diagnosing PD are inconsistent. Some view this testing as questionable in benefit due to lack of clarity on which populations to test, the consequences of test results, and cost issues [1]. Others highly recommend use of genetic testing to identify parkinsonism and PD genotypes that differ in clinical course, prognosis, and treatment response from idiopathic PD [63,74].

Some have suggested assessing all patients younger than 40 years of age with suspected PD for Wilson disease. Wilson disease is confirmed by low serum ceruloplasmin, elevated 24-hour urine copper, or the presence of Kayser-Fleischer rings on slit-lamp examination [73].

SCREENING TESTS

Screening tests are used to help identify common comorbidities, including depression and dementia in patients with PD. The American Academy of Neurology (AAN) recommends the following assessment tools when screening for comorbid conditions [75,76]:

- Depression: Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS), Geriatric Depression Scale (GDS)

- Dementia: Cambridge Cognitive Examination (CAMCog), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA)

The MDS-UPDRS is widely used in research and in clinical practice to standardize the neurologic exam and present the findings as a pre-determined Likert scale. The UPDRS can be used to assess the clinical status of patients with PD during follow-up. This instrument assesses motor features, psychologic features, activities of daily living, and treatment complications. Increases of 2.5 and 4.3 points in UPDRS motor and total scores, respectively, indicate clinically relevant change [77,78].

If cognitive impairment is noted on mental status examination, magnetic resonance imaging (MRI) and neuropsychologic testing should be used to distinguish PD with dementia from other neurodegenerative disorders [1].

DIFFERENTIAL DIAGNOSIS

The diagnostic assessment of a patient suspected of having PD should include consideration of other, possibly reversible, disorders that may present with motor signs of parkinsonism. These are often referred to as "atypical" PD or "mimics" of PD and include [62,64]:

- Essential tremor

- Neurodegenerative syndromes

- Multisystem atrophy

- Progressive supranuclear palsy

- Corticobasal degeneration

- Dementia with Lewy bodies

- Symptomatic syndromes of non-neurodegenerative underlying cause:

- Drug-induced parkinsonism

- Vascular parkinsonism (i.e., ischemia/infarcts in the basal ganglia)

- Infectious disease (e.g., acquired immunodeficiency syndrome, subacute sclerosing panencephalitis, postencephalitic parkinsonism, prion disease)

- Neurotoxin exposure (e.g., carbon monoxide, manganese, MPTP)

- Structural disorder (e.g., tumor, hydrocephalus, subdural hematoma, trauma)

- Metabolic disease (e.g., Wilson disease, hypothyroidism)

- Other secondary causes

Assessment

Clues from the medical history and atypical exam findings should prompt a careful work-up to rule out or confirm an alternate diagnosis. The most common syndromes mimicking PD are essential tremor, vascular parkinsonism, Lewy body dementia, progressive supranuclear palsy, multisystem atrophy, corticobasal degeneration, and drug-induced parkinsonism (Table 8). Neurologic consultation and neuroimaging studies are often needed to adequately assess many of these possibilities [1,2,63,79,80].

Table 8: SYNDROMES THAT MAY MIMIC PARKINSON DISEASE

Syndrome

Signs/Symptoms Resembling Parkinson Disease

Differentiating Tests

Essential tremor

Appears or worsens with movement

Symmetrical presentation

Affects distal extremities, head, and voice

Family history common

Improves with alcohol and/or beta-blockers

Dopamine transporter scan

Vascular parkinsonism

Symmetrical lower body manifestation

Gait highly affected

Rest tremor uncommon

Cognitive impairment

Poor levodopa response

Significant small vessel disease or basal ganglia lacunar infarct(s) on brain MRI

Dopamine transporter scan

Drug-induced parkinsonism

Akinesia and bradykinesia

Patient medication history, particularly for dopamine antagonists (e.g., clozapine)

Lewy body dementia

Dementia

Vivid visual hallucinations

Marked fluctuating mental status

History may be sufficient for diagnosis

Neuropsychologic testing to distinguish domains of cognitive deficits

Dopamine transporter scan to distinguish from non-Lewy body dementias (e.g., Alzheimer disease)

Progressive supranuclear palsy

Gaze palsies

Early falls within one year of diagnosis

Neurologic examination findings of vertical gaze palsy and significant postural instability

Evidence of midbrain atrophy on brain MRI (suggestive, not definitive)

Multisystem atrophy

Autonomic dysfunction with symptomatic hypotension, constipation, urinary urge incontinence, fecal incontinence, urinary retention, persistent erectile dysfunction

Speech or bulbar dysfunction

Pyramidal or cerebellar dysfunction

Poor levodopa response

Neurologic examination findings of deficits outside the extrapyramidal system

Pontine and cerebellar atrophy on brain MRI (suggestive, not definitive)

Electromyography findings of denervation and re-innervation of rectal sphincter muscle

Corticobasal degeneration

Apraxia

Alien limb phenomenon

Cortical sensory loss

No tests required

Source: [1,2,63,79,80]

Importance of Establishing a Diagnosis

Defining the presence of parkinsonism is the first step to considering therapeutic options and differentiating PD from other primary central nervous system disorders, such as progressive supranuclear palsy, multisystem atrophy, corticobasal degeneration, and vascular parkinsonism. While these alternative diagnoses will not expand the options for disease-modifying or curative therapies, arriving at a definitive diagnosis is important for purposes of patient and family education, prognosis, reassurance, and options for therapy. A definitive diagnosis gives a name to the condition. This is very important for the patient experience and helps in coming to terms with a chronic disease. An "atypical parkinsonism" or "parkinsonian syndrome" diagnosis leaves patients and family with vague uncertainty and fails to provide a clear basis for management decisions and prognosis. A hierarchical list of diagnostic possibilities should be discussed if definitive diagnosis is elusive. Diagnostic criteria for progressive supranuclear palsy, corticobasal degeneration, and multisystem atrophy allow for possible and probable diagnostic categories, according to diagnostic certainty [4].

7. TREATMENT OF PARKINSON DISEASE

Although no cure for PD is yet available, some degree of disease modification and significant alleviation of motor symptoms can be achieved with drug combinations that enhance tissue levels of dopamine, thereby promoting dopaminergic activity. Treatment strategies for PD are influenced by stage of disease, problematic symptom profile, and patient age. Clinical decision-making should balance possible efficacy with potential side-effect risk for each treatment option. Treatment decisions should be based on the best available evidence for each intervention. Pharmacotherapy should be accompanied by non-medical interventions, as needed, for gait and balance dysfunction, vocal impairment, and other motor, non-motor, and comorbid conditions [74].

Management of PD begins at the time of diagnosis but may not require immediate initiation of drug therapy. Early issues for consideration include information delivery, sources of support, counseling to facilitate a realistic view of what to expect going forward, discussion of prognosis, and potential treatment options. These conversations usually take place over several visits and should include discussion of available medical therapies for PD. When possible, these initial meetings should include family members [4].

OVERVIEW OF TREATMENT APPROACHES THROUGH DISEASE PROGRESSION

Initial treatment of early PD generally involves monotherapy, and motor control problems can be improved in many patients. Treatment of later PD becomes more complicated, with disease progression and prolonged dopaminergic drug administration. Requirements for dopamine replacement therapy become increasingly demanding as motor signs worsen. Patients initially well controlled using dopamine agonists require initiation of levodopa and, over time, increasing amounts given in higher doses with more frequent intervals. Patients initiated on levodopa will require the addition of dopamine agonists and/or other adjuncts that improve response to levodopa [81].

Levodopa therapy is commonly withheld until motor symptoms begin interfering with normal patient functioning. This is based on the assumptions that:

- The period of improved motor control is finite, and levodopa therapy is more valuable in later disease, when symptom improvement is greater.

- Deferring levodopa initiation defers the onset of dyskinesias.

- Early symptomatic treatment has no effect on disease course.

However, there is some evidence that initiating levodopa in early PD and maintaining the dose less than 400 mg/day reduces dyskinesia onset, and early use of levodopa has been shown to be the most effective treatment for motor symptoms, with long-term risk of dyskinesia minimally affected by early use of less than 400 mg/day. It appears that disease stage has a greater influence on the development of levodopa-induced dyskinesia than medication duration [81,82,83].

Some PD motor symptoms show preferential dopaminergic response. For example, bradykinesia and rigidity show the most robust levodopa response. Rest tremor severity correlates poorly with the other cardinal symptoms and extent of dopamine neuron loss and inconsistently responds to dopaminergic therapy. This sign may originate from a trigger in the basal ganglia, with contributions from cerebellothalamic pathways. Freezing gait and imbalance with frequent falls also poorly respond to dopaminergic treatment [7].

Added complexity comes with progression from later to advanced PD. The onset of motor fluctuations and motor complications (e.g., dyskinesia, freezing) create the greatest challenge to treatment efforts to maintain mobility and function in earlier disease. Predicting the onset of motor complications and fluctuations in individual patients is very difficult, but disease duration and stage, dose and duration of levodopa exposure, sex, and body weight are contributing factors [81].

Even if motor symptoms are well controlled, numerous non-motor components of PD will emerge and can be intensely burdensome to patients. Many non-motor symptoms lack response to dopaminergic medications, reflecting progression beyond the dopamine neuron motor system and extensive disease involvement in the cortical and frontal lobes and widespread central neuropathology. Only recently have non-motor symptoms received adequate research attention, and for some of these syndromes, effective treatments have been identified and become available or their final regulatory evaluation is in progress [77,81].

MEDICATION NON-ADHERENCE

An important issue, unaddressed by practice guidelines, is medication non-adherence in patients with PD. While the prevalence of non-adherence broadly varies by assessment method, the figures range from 15% to 20% using patient self-report to 67% or more using pharmacy refill data and pill counts [84]. An important dimension in PD treatment is timing adherence, as dopaminergic medications should be taken at precise and evenly spaced intervals, as instructed by the prescribing physician. Non-adherence to timing of dosage is probably very common and contributes to unwanted dopamine variability implicated in earlier onset of motor fluctuations [85]. The overall consequence of non-adherence is unsatisfactory motor control, with diminishing mobility, greater fluctuations, dyskinesias, and declining quality of life [86].

In chronic diseases, highest medication adherence occurs with once-daily formulations, but this sharply decreases with each added daily dose [87]. Polypharmacy in PD is normative, with most patients taking two or more antiparkinsonian drugs and additional medications for non-motor symptoms and comorbidities. In addition to the risk of non-adherence that directly correlates with the number of prescriptions and daily doses per prescription, many patients with PD experience depression and/or cognitive impairment, both of which are strong independent risk factors for medication non-adherence [86].

Medication non-adherence among patients with PD should be recognized as a common, under-reported, detrimental, and costly cause of suboptimal disease control. Reliance on clinical judgment to identify non-adherence is demonstrably inaccurate, and healthcare professionals should use nonjudgmental interviewing skills that encourage patient admission of their non-adherence without fear or concerns of disapproval or termination of care. Barriers to adherence should be explored and clinical resources applied to surmount them. These include simple explanations of how medications optimally work when taken correctly and referral to non-adherence counseling. To avoid unnecessary dose escalations, adverse effects, and increased patient and healthcare costs, non-adherence should be explored before a drug regimen is deemed ineffective [86].

PHARMACOTHERAPIES

Levodopa

Exogenous dopamine administration is ineffective for treating PD, because circulating dopamine does not cross the blood-brain barrier and is thus unable to reverse brain dopamine depletion. Levodopa is a dopamine prodrug that does cross the blood-brain barrier, where it is converted by aromatic amino acid decarboxylase (AAAD) to dopamine. The regular administration of oral levodopa leads to repletion of dopamine in the substantia nigra pars compacta, and to storage in presynaptic dopamine neurons for subsequent use. The majority of patients treated with levodopa realize significant and prolonged improvement in motor function, though there are side effects and, in time, many patients experience fluctuations in beneficial effects of the drug. Levodopa was introduced for use in PD in the late 1960s, and remains the criterion-standard treatment [7].

The bioavailability of orally administered levodopa is compromised by extensive metabolism to dopamine in the gut. Only 30% of an oral dose reaches systemic circulation for distribution to the brain. For this reason, Levodopa used to treat PD is always combined with carbidopa, a peripherally acting AAAD inhibitor. Carbidopa reduces the peripheral conversion of levodopa to dopamine, which triples levodopa bioavailability and lowers dosage requirements. Carbidopa 75–100 mg/day is required to inhibit peripheral conversion of levodopa to dopamine. Carbidopa also decreases acute peripheral dopamine side effects, such as nausea, vomiting, and hypotension, and improves tolerability [88].

The risk for side effects and toxicity, including troublesome dyskinesia, is high in patients on chronic levodopa therapy. For this reason, careful dose titration and tight adherence to the effective dose is important for PD symptom management. No evidence has been found that using an extended-release levodopa/carbidopa formulation, or adding a catechol-O-methyltransferase (COMT) inhibitor, delays or prevents the development of motor fluctuations [89].

Because levodopa is absorbed in the proximal small intestine, food may delay absorption. Levodopa also competes with dietary proteins for transport into the brain. High-protein meals should be kept separate from levodopa dosing, and daily dietary protein intake should be reduced to approximately 0.8 g/kg (of body weight). Levodopa is metabolized in the gastrointestinal tract, kidneys, and liver, with 70% excreted in the urine. Levodopa half-life is roughly one hour. Dosing should be reduced 10% to 30% when other dopaminergic agents are added to carbidopa/levodopa. Available formulations in the United States are [88]:

- Carbidopa/levodopa tablet (Sinemet)

- Carbidopa/levodopa orally disintegrating tablets (Parcopa ODT)

- Carbidopa/levodopa sustained-release tablet (Sinemet CR)

- Carbidopa/levodopa extended-release tablet (Rytary ER)

- Carbidopa/levodopa enteral suspension (Duopa)

- Carbidopa/levodopa/entacapone (Stalevo)

Potential adverse events associated with levodopa/carbidopa can be generally categorized as CNS, gastrointestinal, or other. Adverse effects involving the CNS include confusion, sedation, vivid dreams, dizziness, hallucinations, psychosis, and depression. Gastrointestinal effects may include nausea, vomiting, and changes in bowel habits. Orthostasis, leg edema, dyskinesia, dystonia, hemolytic anemia, and leukopenia may also occur. All patients taking levodopa should be monitored for changes in blood pressure, pulse, mental status, and clinical response.

With prolonged therapy and disease progression, the duration of benefit from each levodopa dose often becomes increasingly shorter. "End of dose deterioration," "wearing-off," "off periods," or simply "off" refers to the waning or absent effects of levodopa within four hours of the last dose. As "off" periods increase, "on" periods (levodopa-related motor symptom control) decrease [4].

Caregivers monitoring the course of a stable patient on chronic levodopa therapy for PD often face two potential therapeutic challenges. First is the development of dyskinesia, indicative of drug intolerance or excessive dosage. The second is fluctuation in motor symptoms, perhaps indicative of inadequate dosage, failing compliance, or waning therapeutic effectiveness. The frequency, or risk, of dyskinesia and motor fluctuations during chronic levodopa therapy for PD is difficult to predict. One literature review of publications spanning 1966 through 2000 showed that among patients receiving levodopa therapy, the median frequency of dyskinesia was 39%, and after a satisfactory first year of therapy, the frequency of motor fluctuations gradually increased to 40% of patients by four to six years of treatment [151].

Dopamine Agonists

Dopamine D2/3 receptor agonists bind post-synaptic striatal dopamine receptors to increase dopaminergic neurotransmission and reduce parkinsonism symptoms. Ropinirole (oral), pramipexole (oral), and rotigotine (transdermal) are the most widely used agents. In advanced disease, subcutaneous apomorphine is continuously delivered via external pump or is used for rapid rescue therapy (via injection). The ergot derivative dopamine agonists cabergoline, pergolide, and bromocriptine are not recommended as first-line dopamine agonist therapy, and bromocriptine is associated with the development of fibrotic tissue. Ergot derivatives require specialized side effect monitoring, but they remain options for patients lacking benefit or tolerability with other dopamine agonists [74,90].

Dopamine agonists are the second most potent drug class (after levodopa) for motor symptom control in PD and are effective at all stages of the condition. Initial dopaminergic therapy using dopamine agonists (versus levodopa) is associated with reduced/delayed treatment-related complications, such as levodopa-induced dyskinesia and motor fluctuations [7,91].

However, poor tolerability can limit the use of dopamine agonists. While dopamine agonists are less likely to lead to motor fluctuations in early disease than levodopa, they are less effective for motor symptoms and carry greater risk of side effects such hallucinations, psychosis, hypotension, peripheral edema, excessive daytime somnolence, and impulse control disorders. In patients older than 70 years of age, dopamine agonists should be used with caution or avoided entirely [89]. All patients taking ropinirole, pramipexole, or rotigotine should be monitored for changes in blood pressure, daytime alertness, weight, and heart rate [88].

Ropinirole

Ropinirole undergoes hepatic metabolism, with a half-life of about six hours. It is associated with various adverse effects in various systems, including the gastrointestinal system (e.g., nausea, vomiting, dyspepsia, abdominal pain, constipation) and the CNS (e.g., dizziness, somnolence, headache, syncope, confusion, hallucinations, impulse control disorders, sleep attacks). Other potential adverse effects include fatigue, asthenia, dependent/leg edema, viral infection, pain, increased sweating, orthostatic symptoms, pharyngitis, abnormal vision, and urinary tract infection [88].

Pramipexole

Pramipexole is administered orally for PD and is available in immediate- and extended-release formulations. The half-life in healthy adults is about 8 hours, but this is extended to 12 hours in elderly patients. It is excreted in the urine primarily as unchanged drug, and dose adjustment is required in renal impairment. Overnight switch from immediate- to extended-release is successful in 80% of patients [88]. Potential adverse effects include nausea, abdominal pain/discomfort, constipation, dizziness, somnolence, headache, hallucinations, impulse control disorders, dyskinesia, orthostatic hypotension, xerostomia, peripheral edema, and muscle spasms [88].

Rotigotine

Rotigotine is available as a transdermal patch for the treatment of PD. It undergoes extensive metabolism via conjugation and N-dealkylation. The initial half-life is three hours, with the terminal half-life five to seven hours after patch removal. Potential adverse effects have included nausea, vomiting, somnolence, dizziness, application-site reactions, dyskinesia, anorexia, hyperhidrosis, visual disturbance, and peripheral edema, and all patients should be monitored for skin reactions. Patients with sulfa allergy should not be prescribed rotigotine, and patches contain aluminum and should be removed prior to MRI [88].

Apomorphine

Apomorphine for PD is given as a subcutaneous injection into the abdominal wall, upper arm, or upper leg; the injection site should be rotated. It is indicated for hypomobility and "off" episodes associated with PD.

Apomorphine undergoes extensive first-pass metabolism, with a terminal half-life of about 40 minutes. Nausea, vomiting, drowsiness, somnolence, dizziness, orthostatic hypotension, hallucinations, confusion, dyskinesia, rhinorrhea, and edema/swelling of extremities may occur. It is important to avoid use of apomorphine with serotonin blockers, as co-ingestion may cause profound hypotension. All patients taking this agent should be monitored for orthostatic hypotension and drowsiness [88].

Bromocriptine Mesylate

Bromocriptine mesylate is taken orally and is metabolized by the liver. The half-life is approximately 5 to 15 hours. Potential adverse effects include nausea, vomiting, abdominal discomfort, abnormal involuntary movements, ataxia, hallucinations, confusion, "on-off" phenomenon, dizziness, syncope, drowsiness, insomnia, depression, visual disturbance, hypotension, shortness of breath, constipation, vertigo, and asthenia. Long-term treatment with this drug is associated with pleural thickening (fibrosis). As such, patients' pulmonary function should be monitored during treatment [88].

Monoamine Oxidase B Inhibitors

MAO-B is an enzyme that inactivates dopamine by breaking it down into metabolic byproducts. MAO-B inhibitors block the breakdown of dopamine, slowing the loss of dopamine and several of the effects of PD. MAO-B inhibitors are generally considered for initial treatment of early PD as monotherapy and as adjunctive therapy to augment the effects of levodopa in later PD. The preferred agents are selegiline and rasagiline, both of which have shown symptomatic benefit and multiple neuroprotective effects in pre-clinical research [7,89,92].

Selegiline

In the treatment of PD, selegiline may be used as monotherapy or combined with levodopa. This agent blocks the breakdown of dopamine via MAO-B inhibition. It is metabolized via CYP450 enzymes to amphetamines, with a half-life of 10 hours. In high doses, it may precipitate a hypertensive crisis. Other potential adverse effects include nausea, weight loss, dyspepsia, hypotension, decreased heart rate, headache, hallucinations, vivid dreams, dizziness, insomnia, flu-like symptoms, dyskinesias, dystonia, rash, and photosensitivity [93]. All patients undergoing treatment with selegiline should be monitored for rash, drug interactions, and changes in blood pressure, cardiac status, and mental status (i.e., increased anxiety) [93].

In addition to a capsule/tablet, selegiline is available as an orally disintegrating tablet. Pharmacology, potential adverse effects, and monitoring are similar, but metabolism of the disintegrating tablet bypasses the liver to reduce formations of amphetamine metabolites, which reduces the risk of insomnia side effects [93].

Rasagiline

Oral rasagiline may be used in monotherapy or combination therapy for patients with PD. This agent inhibits the breakdown of dopamine via MAO-B inhibition and is metabolized via CYP1A2. The half-life is three hours. The potential adverse effects and patient monitoring requirements are the same as with selegiline [93].

Catechol-O-Methyltransferase Inhibitors

COMT is an enzyme that converts levodopa in peripheral circulation to 3-O-methyl-DOPA (3-OMD). This metabolite cannot be converted to dopamine and accumulates in plasma during levodopa therapy. Inhibition of COMT increases the bioavailability of levodopa, allowing a larger amount of the drug to reach the brain and consequently raise dopamine levels. COMT inhibitors are always taken in combination with levodopa because they lack intrinsic dopaminergic activity. They are used in PD to potentiate levodopa effects when "wearing off" or other motor complications appear during carbidopa/levodopa therapy [93].

Entacapone

As a COMT inhibitor, entacapone inhibits the peripheral metabolism of levodopa. It is metabolized to active isomer and undergoes glucuronidation to inactive metabolites, with a half-life of two hours. Potential adverse effects include exacerbation of levodopa adverse effects, brown/orange urine, and diarrhea. All patients should be monitored for changes in blood pressure and mental status. A fixed-dose combination of entacapone with carbidopa/levodopa is available and reduces the number of tablets needed for treatment, which may improve adherence [93].

Tolcapone

Tolcapone inhibits peripheral and central metabolism of levodopa. It has a half-life of about three hours and is metabolized via glucuronidation and CYP2A6 and CYP3A4 enzymes. The adverse effects are the same as those described for entacapone, plus transient elevations in liver enzymes and fulminant liver failure. In addition to the monitoring recommended for entacapone, these patients should be regularly tested for liver enzymes and function [93].

Opicapone

Opicapone is a novel, once-daily, third-generation COMT inhibitor. Research has compared opicapone with entacapone and placebo as a levodopa adjunct. In a study involving 590 patients with PD-associated motor fluctuations, the mean reduced times in "off" state were 56 minutes for placebo, 96.3 minutes for entacapone, and 116.8 minutes for opicapone after 14 to 15 weeks. Opicapone 50 mg was statistically superior to placebo and non-inferior to entacapone, but lower-dose opicapone did not differ from placebo [94].

The most common adverse events with opicapone are dyskinesia, insomnia, and constipation. Serious adverse events were reported in six patients with placebo, eight with entacapone, and four with opicapone 50 mg. In addition to "off" time efficacy, an advantage of opicapone is the once daily dosing [94].

Anticholinergic Agents

Anticholinergic agents used in PD treatment include benztropine (Cogentin) and trihexyphenidyl. Anticholinergics may be helpful as a symptomatic treatment in younger patients with early PD and severe tremor or dystonia, but they should not be drugs of first choice due to their narrow range of efficacy. Adverse effects from nonselective cholinergic receptor blockade are a major drawback and include CNS-related side effects of cognitive impairment, exacerbation of dementia, delirium, sedation, and hallucinations. Other side effects include constipation, xerostomia, blurred vision, and urinary retention; higher doses may cause or worsen orthostatic hypotension and palpitations. Elderly patients are especially prone to these side effects plus confusion and memory difficulties, and anticholinergic agents are not recommended in this population [89].

Amantadine

Amantadine is an N-methyl-d-aspartate (NMDA) antagonist with modest benefit in early PD and efficacy in suppressing levodopa-induced dyskinesia in later/advanced PD. The mechanism of action is thought to involve augmentation of pre-synaptic dopamine release and NMDA glutamatergic antagonism. Common side effects include pedal edema and livedo reticularis (violet, lace-like coloration) [7].

Amantadine is the only agent demonstrated to suppress levodopa-induced dyskinesia without worsening parkinsonism, and the American Academy of Family Physicians recommends that amantadine should be considered for treatment of dyskinesias in patients with advanced PD [2]. However, use in frail elderly patients with advanced PD may result in confusion, hallucinations, and/or worsening motor symptoms [95].

Acetylcholinesterase Inhibitors

The acetylcholinesterase inhibitor rivastigmine is the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of mild-to-moderate PD dementia. Other approved drugs for dementia, including donepezil, galantamine, and memantine, have been evaluated for the treatment of PD dementia, but their efficacy has not been clearly shown [95].

Rivastigmine has shown significant improvement in PD dementia that was maintained through 48- and 76-week follow-up in different trials. In long-term trials comparing rivastigmine capsules (12 mg/day) versus transdermal patch (9.5 mg/24 hours), the rates of adverse effects from worsening PD were 36.1% with the capsule (tremor in 24.5%) versus 31.9% with the patch (tremor in 9.7%). Both formulations showed a 2.1-point worsening on the UPDRS-III motor scale [96,97].

Novel and Investigational Agents

Istradefylline

In 2019, the FDA approved istradefylline as an add-on treatment to levodopa/carbidopa in adult patients with PD experiencing "off" episodes [155]. This agent is an adenosine receptor antagonist with evidence of significantly decreasing daily “off” time compared with patients receiving a placebo. Potential side effects include dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia [155].

Adenosine A2A Receptor Antagonists

A2A receptors are co-localized on dopamine D2 receptors and may be over-activated in PD. Thus, A2A receptor antagonism may reduce PD motor symptoms [98]. Istradefylline was the first A2A antagonist evaluated in PD, but it received a "not approvable" letter from the FDA due to lack of clinical benefit and association with dyskinesias. A subsequent review concluded istradefylline 50 mg had clinical potential as a levodopa adjunct in PD, with support from a clinical trial showing significant reduction in "off" time and good tolerance [95,99].

Riluzole

There has been interest in glutamate receptor antagonists for the treatment of PD based on the finding that PD is linked to glutamate overactivation in basal ganglia circuits, resulting in oxidative stress and cell death. Riluzole, an NMDA receptor antagonist approved for the treatment of amyotrophic lateral sclerosis, was studied in PD, but it lacked significant effects on survival or disease progression [93].

Safinamide

Safinamide is an alpha-aminoamide developed as adjunct therapy to dopamine agonist or levodopa therapy in patients with PD. This drug shows dopaminergic and non-dopaminergic activity, including MAO-B inhibition, sodium channel antagonism, and inhibition of glutamate release. Clinical trials have shown significantly improved motor symptoms versus placebo. In a six-month double blind, placebo-controlled study of patients with mid-to-late stage PD with motor fluctuations, the addition of safinamide 50–100 mg/day was shown to significantly improve "on time" without increasing dyskinesia and to improve motor function, activities of daily living, quality of life measures, and depressive symptoms [152]. Clinical benefit was sustained over an additional 18-month period of continued treatment and observation.

In 2017, the FDA approved safinamide as "add-on" treatment for patients with PD who are taking levodopa/carbidopa and experiencing "off" periods [8].

Cannabidiol

Cannabidiol, the primary non-psychoactive constituent in Cannabis, has been evaluated for treatment efficacy in several non-motor PD conditions. In patients with PD-associated psychoses of at least three months' duration, oral cannabidiol treatment ≤400 mg/day for four weeks significantly reduced psychotic symptoms. No cognitive or motor side effects were found in study participants [101].

A small case series of patients with PD and REM sleep behavior disorder examined treatment response to oral cannabidiol 75 mg/day or 300 mg/day for six weeks. In this sample, symptoms of REM sleep behavior disorder included swearing, laughing, yelling, pushing, kicking, or punching during REM sleep, occurring two to seven times per week. After six weeks of cannabidiol, REM sleep behavior disorder symptom frequency was no times per week in 75% and one time per week in 25% of patients. All patients reported elimination of nightmares. Shortly after cannabidiol cessation, symptom frequency returned to baseline level in all patients. No side effects were observed [102].

Inosine

The antioxidant urate precursor inosine has been associated with lower risk of PD and slower PD progression and was suggested as neuroprotective in laboratory assays. The effects of inosine on PD are currently in phase III clinical trial evaluation in the Safety of Urate Elevation in Parkinson Disease (SURE-PD) study [83].

Agents FDA-Approved for Other Indications

In addition to investigational new drugs, several FDA-approved medications have been studied for their off-label use in the treatment of PD. Calcium-channel blockers are one such group. In one study, the calcium-channel blocker isradipine was found to reduce risk of PD in patients 65 years of age or older [103]. Isradipine, a calcium-channel blocker in use as hypertension therapy, may be neuroprotective in PD. The drug is currently in phase III trials (known as STEADY-PD) to determine its utility in treating early PD [83].

Evidence for the role of neuroinflammation in the pathogenesis of PD have prompted trials of several anti-inflammatory agents. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be protective against PD, but the overall evidence of neuroprotective effect with aspirin or NSAIDs in PD is inconsistent [93].

The stimulant methylphenidate has been found in limited studies to improve gait hypokinesia and freezing in patients with PD receiving deep brain stimulation of the subthalamic nucleus [104].

Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes. In a 12-month trial of 45 patients with moderate PD, subcutaneous exenatide showed clinically relevant improvements in PD across motor and cognitive measures versus untreated controls [105,106].

Zonisamide is an anticonvulsant with neurotransmitter effects, including stimulation of dopamine synthesis, and is approved in Japan for the treatment of PD. Use as an adjunct to levodopa found improvements in "off" time [107].

Beta-blockers are considered a therapeutic option for PD tremor, although some patients may not benefit from or tolerate these agents [108].

MANAGEMENT OF EARLY PARKINSON DISEASE

Evidence Based Practice Recommendation

The European Federation of Neurological Societies asserts that the optimal time frame for onset of therapy for Parkinson disease has not been clearly defined. Once parkinsonian signs start to have an impact on the patient's life, initiation of treatment is recommended.

https://onlinelibrary.wiley.com/doi/abs/10.1002/9781444328394.ch14

Last Accessed: April 11, 2019

Level of Evidence: Expert Opinion/Consensus Statement

The therapeutic objective in patients with early PD is symptomatic treatment of motor symptoms to restore more normalized motor function and to optimize and maintain patients' ability in perform activities of daily living. Therapy initiation is individualized, based on patient age, handedness, employment status, and functional status. Tremor is often the symptom that brings patients to medical attention and diagnosis, but it is dominant at rest and infrequently a source of disability or reason to initiate treatment. Rigidity and bradykinesia are more frequently associated with the functional limitations and mobility impairments that influence a patient to initiate treatment [7]. Initial therapy should also target the most disruptive and impairing symptoms in each patient, which can differ with tremor versus rigidity [109].

Initial therapeutic options for motor symptoms, in descending order by potency of effect, are levodopa, dopamine agonists, and MAO-B inhibitors. Dopaminergic agents (levodopa and dopamine agonists) remain the mainstay of symptom control but are not always first-line treatment. The timing of dopaminergic therapy initiation depends on patient preference, degree of disability, and potential side effects. In general, early dopaminergic treatment is recommended, and the choice, depending on age and overall cognition, is between levodopa preparations, dopamine agonists, and MAO-B inhibitors [4].

The assumption that dyskinesia strictly arose from long-term levodopa use led to the common practice of delaying its initiation until the onset of significant motor symptoms in order to save the window of efficacy before dyskinesia begins. As noted, it is now thought that disease stage has greater influence than medication duration on development of levodopa-induced dyskinesia. This has led to earlier levodopa initiation, although MAO-B inhibitors or dopamine agonists are often preferred as initial early PD therapy [7].

Treatment-Naïve Patients

The initial choice of drug depends on the likelihood of improving motor function (better with levodopa) compared with the risk of motor complications (more common in younger patients, delayed by agonists) and the presence of neuropsychiatric complications (more common in older and cognitively impaired patients, greater with agonists). Levodopa is the mainstay of initial treatment and the most effective drug for improving motor function. One should avoid controlled-release formulations or adding entacapone, as this is not effective for delaying the onset of motor complications. Other treatments include MAO-B inhibitors (e.g., selegiline, rasagiline) or oral or transdermal dopamine agonists (e.g., pramipexole, ropinirole, rotigotine). Initial treatment with an agonist can be recommended in younger patients. Ergot derivatives (e.g., bromocriptine, cabergoline) are not recommended due to the increased risk of fibrotic development [74]. Amantadine and anticholinergic agents are also options. Rehabilitation in early-stage disease has seldom been evaluated, and therefore a recommendation for or against its use cannot be made [74].

Dose adjustments with dopamine agonists and levodopa preparations are made in response to clinical effect, emerging symptoms, and/or side effects. Risks of psychiatric side effects and dyskinesias are greater at higher doses, and treatment with the lowest dose possible to achieve benefit is favored; this better maintains patient function and quality of life. Patients older than 50 years of age who receive levodopa doses greater than 600 mg/day are more likely to develop dyskinesia [4].

Adjustment of Initial Therapy in Patients without Motor Complications

Patients who initiate treatment with an MAO-B inhibitor, anticholinergic agent, amantadine, or their combination will, at some point, require levodopa or a dopamine agonist added. If patients on dopaminergic therapy require treatment intensification, the options are to increase the dose, switch to another agonist, or add levodopa. Patients who are initiated on levodopa may be better managed by an increase in the dose, the addition of an agonist, or the addition of a COMT inhibitor [74]. If significant tremor persists in patients with disabling tremor, add or initiate with [74]:

- Anticholinergic drug

- Clozapine

- Beta-blocker (e.g., propranolol)

- Deep brain stimulation

MANAGEMENT OF LATER PARKINSON DISEASE

Later stage PD is clinically characterized by diminished efficacy of dopaminergic therapy and the emergence of motor fluctuations and dyskinesias. In patients with PD, the initial response to carbidopa/levodopa therapy is usually positive, because dopaminergic systems are relatively intact and produce sufficient endogenous dopamine to "buffer" the exogenous carbidopa/levodopa. With disease progression, combined effects from dopaminergic neuron loss, receptor alteration, modifications in circuitry, and desensitization of receptors lead to inconsistent and unpredictable carbidopa/levodopa response and the development of motor fluctuations. At some point, virtually all patients with PD develop motor fluctuations that include wearing off, delayed onset dyskinesias and dystonias [110,111,112].

Levodopa-Induced Dyskinesias

While early PD can be effectively managed with levodopa for many years, disease progression invariably leads to peak-dose dyskinesias, including tics, tremors, and other involuntary movements [8]. In addition to levodopa, dyskinesias can also develop with dopamine agonists or MAO-B inhibitors. Men and younger patients have higher risk of dyskinesias. Mild dyskinesias do not require specific treatment, but more severe cases may respond to a reduction in levodopa dose or addition of an NMDA antagonist or dopamine receptor agonist [4].

Motor Complications

When patients develop end-of-dose deterioration (symptom relapse) or peak-dose dyskinesias, motor complications begin to dominate the clinical picture. Several potential mechanisms contribute to the development of motor complications. Low plasma levels of dopaminergic drugs lead to "off" periods, while high levels increase peak-dose dyskinesia; the levodopa therapeutic window is narrowed. Motor complications accrue in an estimated 10% of patients with PD per year, with an estimated 50% prevalence with five years of levodopa treatment. Other motor signs and symptoms can emerge, including axial motor symptoms of gait and postural abnormalities, that increase the risks of falling, dysphagia, dysarthria, and cognitive problems [8].

Emergence of Motor Symptoms

Axial motor signs/symptoms of gait impairment, postural instability, and postural abnormalities are common and debilitating in patients with later PD. Unlike the cardinal motor symptoms of rest tremor, bradykinesia, and rigidity, dopaminergic therapy and physiotherapy minimally benefit axial motor symptoms. This is probably due to mediation of motor control of axial and cardinal functions by different anatomical-functional pathways [65].

Freezing gait often appears later in the disease course and can lead to significant declines in quality of life. Walking requires shifting from one leg to the other, and patients with freezing gait experience a sense of falling every time they lift a foot up off the floor. Every step forward resembles a controlled fall. Research has shown that auditory stimuli (e.g., sound of a metronome) or visual cues (e.g., a flash of light or lines on the floor indicating stride length) can reduce episodes of freezing, but how these cues work is unknown [8].

Management

When motor complications emerge, manipulation of levodopa dose or frequency is often the first strategy, but the initial improvement is eventually precluded by the emergence of dyskinesias.

Levodopa Wearing Off

Studies comparing immediate- and modified-release levodopa found roughly 25% less levodopa absorbed with the modified-release formulation, and this should be considered when switching between preparations. Erratic levodopa absorption in later PD and significant reduction in doses per day with modified-release levodopa can result in delayed or no "on" responses. Modified-release levodopa has greatest benefit in reducing overnight wearing-off [4].

The next strategy is adding adjunctive therapies to levodopa to control fluctuating motor response. Wearing-off symptoms can be reduced by adding MAO-B inhibitors, COMT inhibitors, or dopamine agonists. The MAO-B inhibitor rasagiline reduces "off" time by around 1.5 waking hours per day; the same results were found with the COMT inhibitor entacapone [4]. The COMT inhibitors entacapone and tolcapone can improve CNS delivery of levodopa by inhibiting its peripheral degradation to 3-OMD. Entacapone is most widely used due to rare hepatic failure associated with tolcapone, although the latter agent may be more effective [7,74]. COMT inhibitors can increase ''on'' time, but these drugs lack intrinsic antiparkinsonism efficacy as monotherapy [4].

The dopamine agonists pramipexole and ropinirole reduce "off" time by around 15% but can cause problematic side effects, including drowsiness, sudden onset of sleep, and impulse control disorders, in 15% or more of patients. Patients should be screened for pre-existing drowsiness and tendencies toward compulsive disorders (e.g., gambling) before prescribing a dopamine agent. Patients should be monitored for the development of impulse control disorders throughout the course of treatment. Apomorphine can be administered by continuous infusion or intermittently to treat sudden "off" periods unresponsive to other medications [4].

Severe Motor Fluctuations

Deep brain stimulation is effective against motor fluctuations and dyskinesia [74]. However, because the risk for adverse events is elevated, this modality is only recommended in patients younger than 70 years of age without major psychiatric or cognitive problems. Other options include subcutaneous apomorphine administered via penject or pump or intrajejunal levodopa/carbidopa enteric gel administered through percutaneous gastrostomy [74].

Unpredictable "On-Off"

Deep brain stimulation of the subthalamic nucleus is effective to manage unpredictable "on-off" symptoms [74]. In treatment studies for wearing-off, patients with unpredictable "on-off" have been excluded or were uncommon. Thus, there is insufficient evidence to conclude if the results are valid for unpredictable "on-off." The strategies described for dyskinesia and wearing-off should be considered. For delayed "on," dispersible levodopa and subcutaneous apomorphine injections have some value [74]. Reducing or redistributing dietary proteins may be helpful, but a more practical approach is to take levodopa on an empty stomach one hour before, or at least one hour after, each meal.

Freezing

Management options for "off" freezing are the same as for wearing-off. However, freezing during "on" often does not respond to dopaminergic strategies. Visual or auditory cues are empirically useful for facilitating the start of motor acts [74].

Dyskinesias

The first step in managing dyskinesias is to reduce the levodopa dose. This elevates the risk of increasing "off," but it can be compensated for by increasing the number of doses or adding a dopamine agonist. MAO-B or COMT inhibitors should also be reduced or discontinued at the risk of worsening wearing-off [74].

Amantadine (an NMDA antagonist) is the sole effective agent in suppressing levodopa-induced dyskinesia without worsening parkinsonism and should be initiated at 200–400 mg/day [74,95]. In younger patients, an anticholinergic agent may be prescribed [74].

Deep brain stimulation of the subthalamic nucleus also reduces dyskinesia symptoms and dopaminergic dosing. Stimulation of the globus pallidus pars interna may reduce severe dyskinesia.

Clozapine or quetiapine may be added. Clozapine is associated with potential serious adverse events (e.g., agranulocytosis, myocarditis) and requires monitoring. Intrajejunal levodopa infusion is another option. Continuous subcutaneous infusion of apomorphine allows reduction of levodopa [74].

Biphasic Dyskinesia

Biphasic dyskinesias can be very difficult to treat, and well-designed treatment studies are sparse. Deep brain stimulation of the subthalamic nucleus appears effective [74]. The strategies described for managing peak-dose dyskinesias may also be considered.

Another option is increasing the size and frequency of levodopa dosing, at the risk of increasing peak-dose dyskinesia. However, larger and less frequent doses may give more predictable responses. Apomorphine and intrajejunal levodopa infusion may be tried [74].

Off-Period and Early-Morning Dystonias

The strategies for wearing-off can be applied to patients with off-period dystonias. Additional levodopa or dopamine agonist doses at night may be effective if the symptoms are worst in the morning. Deep brain stimulation is recommended, and botulinum toxin injection may be employed [74].

MANAGEMENT OF ADVANCED PARKINSON DISEASE

Advanced PD is defined as the onset of persistent and severe motor complications despite optimized oral pharmacologic and behavioral management [95]. The development of motor complications during later disease progresses to advanced disease. The underlying pathophysiologic mechanisms result in a narrowing therapeutic window whereby low plasma and striatal levels of dopaminergic drugs lead to "off" periods and high levels lead to increases in peak-dose dyskinesia. Patients experience increasing dose failures from absorption problems [7,95]. Dyskinesias become more frequent and severe in advanced disease, appearing in 59% of patients after 10 years of levodopa treatment. Even small dose increases in levodopa to improve motor function may produce dyskinesias. Management of dyskinesias and "off" periods by lowering the levodopa dose and shortening the time intervals between doses becomes increasingly ineffective in advanced disease [89].

Long-acting dopamine agonists taken once daily have become popular with patients. In theory, long-acting dopamine agonists should allow a stable release of drug, with continuous dopaminergic stimulation reducing plasma fluctuations and decrease motor complications. Many experts state this theory is unsupported by observations in clinical practice, and the presumptive advantage of long-acting dopamine agonists has not been proven. Dopamine agonists should not be prescribed to patients with dementia, hallucinations, autonomic dysfunction, or sleep disorders, and impulse control disorders are a potential side effect with this drug class [95].

With disease progression in advanced PD, the development of wearing-off symptoms and dyskinesias can produce severe, disabling motor fluctuations uncontrollable with oral medications. Advanced therapies are considered at this point, including deep brain stimulation or infusional therapies such as subcutaneous apomorphine or intraduodenal levodopa gel infusions. Such therapies are generally reserved for patients who no longer improve with available oral and transdermal therapies and who lack cognitive or psychiatric dysfunction [4].

Apomorphine, intraduodenal levodopa, and deep brain stimulation can substantially improve motor fluctuations by decreasing daily "off" time and dyskinesias. Despite benefits that may continue several years after initiation, the underlying pathology progresses, and even patients with excellent response can experience the emergence of advancing disease with postural instability and falls, cognitive disturbance, autonomic dysfunction, and swallowing and speech dysfunction [4].

While large head-to-head studies comparing invasive procedures are lacking, deep brain stimulation has the highest level of supportive evidence from the largest number of randomized controlled trials. Before any decision is made to use invasive therapies, a multidisciplinary team should examine the patient and carefully weigh the relative risks and potential benefits of each therapy [95].

Pharmacotherapy Interventions

With apomorphine, the rapid onset of action makes it an effective intervention for "off" periods with use as a rescue injection. Apomorphine is also available as a continuous infusion treatment, suggested by clinical trials as effective in treating motor symptoms and some non-motor advanced PD symptoms [95].

With FDA approval in 2015, intestinal gel is the most recent formulation of levodopa/carbidopa to improve its blood concentration consistency and stability. In advanced PD, delayed and unpredictable spontaneous gastric emptying interferes with the passage of oral medication from the stomach to the small intestines for absorption and circulation to the brain. Levodopa/carbidopa intestinal gel (Duodopa) was developed to bypass this problem by delivering the drug directly to the proximal jejunum via a percutaneous endoscopic gastrojejunostomy tube connected to a portable infusion pump [113].

Compared to conventional immediate-release levodopa, levodopa/carbidopa intestinal gel has been found superior in improving motor fluctuations and quality-of-life scores. For example, 71 patients with advanced PD were randomized to levodopa/carbidopa intestinal gel plus oral placebo or oral levodopa/carbidopa plus placebo intestinal gel. After 12 weeks, the levodopa/carbidopa intestinal gel group showed a significant reduction in "off" time (-4.04 hours/day), versus the active oral/placebo gel group (+2.14 hours/day). This extent of improvement was also observed in "on" time without troublesome dyskinesia, and in "on" time without dyskinesia. Most side effects involved complications related to the percutaneous gastrojejunostomy therapy pump [114].

Deep Brain Stimulation Surgery

Evidence Based Practice Recommendation

According to the European Federation of Neurological Societies, deep brain stimulation of the subthalamic nucleus is effective against motor fluctuations and dyskinesia in later-stage PD, but because of the risk for adverse events, the procedure is only recommended for patients younger than 70 years of age without major psychiatric problems or cognitive decline.

https://onlinelibrary.wiley.com/doi/abs/10.1002/9781444328394.ch15

Last Accessed: April 11, 2019

Level of Evidence: A (At least one convincing randomized, controlled clinical trial or at least two consistent, convincing prospective matched-group cohort studies)

Surgical treatment is considered in patients with advanced PD when optimized medical treatment has failed to control motor symptoms. Initial surgical interventions involved lesions to the basal ganglia, with thalamotomy for tremor and pallidotomy for levodopa-induced dyskinesias. Surgical lesions showed a high risk of permanent side effects, and while pallidotomy or thalamotomy remain options in carefully selected patients, deep brain stimulation is now the surgical treatment of choice for patients with advanced PD [2]. Unlike ablative surgery, deep brain stimulation can be modified over time to address changing disease presentation with progression, adverse effects are primarily reversible, and deep brain stimulation can be used bilaterally to improve symptoms [89].

Deep brain stimulation can reduce symptoms of motor fluctuations, dyskinesia, and tremor, but symptoms unresponsive to levodopa in advanced PD (e.g., cognitive impairment, gait instability, mood disorders, speech impairment, autonomic dysfunction) are unlikely to improve and may worsen with deep brain stimulation. Guidelines recommend that deep brain stimulation should only be performed in experienced centers [2].

The primary targets of deep brain stimulation are the subthalamic nucleus and the globus pallidus pars interna. Effectiveness of subthalamic nucleus stimulation in improving levodopa-responsive signs and symptoms has been reported by many short-term and long-term studies. The overall improvement of activities of daily living and motor UPDRS scores averaged 50% compared to pre-surgery. Levodopa-induced dyskinesias have been reduced by an average 69%. The most frequent post-surgical surgery-related adverse effects are infections (6.1%), migration or misplacement of the leads (5.1%), lead fractures (5%), intracranial hemorrhage (3%), and skin erosion (1.3%) [115].

Factors that contribute to deep brain stimulation outcome include clinical indications, patient selection, surgical targeting accuracy, stimulation programming, and medication management. The most frequently reported persistent complications possibly related to deep brain stimulation include eyelid opening apraxia (1.8% to 30%), dysarthria/hypophonia (4% to 17%), gait disturbances (14%), postural instability (12.5%), weight gain (8.4%), and verbal fluency decline (14%) [89,116]. As of 2016, more than 100,000 patients had undergone deep brain stimulation surgery for the treatment of PD and other movement disorders [117].

Timing

While deep brain stimulation was formerly offered only in late-phase disease (mean: 13 to 14 years post-diagnosis), several considerations have now moved the timing for surgery forward [117]. Deep brain stimulation produces motor improvement in symptoms responsive to dopaminergic drugs, but unresponsive features usually predominate in later disease. Performing deep brain stimulation at advanced stages of illness can alleviate some motor dysfunction features but does not benefit ongoing problems in well-being and occupational, social, and role functioning. In addition, older patients are more likely to develop surgical complications and/or worsening of axial motor functions.

Earlier deep brain stimulation surgery was studied by comparing best medical treatment with deep brain stimulation of the subthalamic nucleus in 251 patients with early-stage motor fluctuation (mean: seven years post-diagnosis). Early and sustained improvement was found in quality of life for patients who received deep brain stimulation. Deep brain stimulation of the subthalamic nucleus has been proposed in patients less than four years after diagnosis without motor fluctuation, but this approach is less compelling, as it exposes patients to potentially dangerous side effects without improving motor function or quality of life. The long-term impact is also unclear [117].

Targeting

Several trials comparing subthalamic nucleus and globus pallidus pars intera stimulation have helped define relative advantages between these two targets. While motor benefits are comparable, other parameters show advantages with subthalamic nucleus for more severe on-off symptoms and cost-efficacy, and advantages with globus pallidus pars intera for dyskinesia suppression, long-term stability of effects, and cognitive symptoms [117].

Experimental and clinical observations suggest contribution from the pedunculopontine nucleus to the pathophysiology of gait and stability impairment. However, pedunculopontine nucleus stimulation remains investigational, with several unresolved issues [117].

Long-Term Impact

Early open-label studies reporting long-term (more than 10 years) outcomes in subthalamic nucleus stimulation consistently found durable benefits in motor fluctuation, dyskinesias, and the cardinal symptoms of PD (tremor, rigidity, and to a lesser extent, bradykinesia). A survival advantage was suggested when comparing eligible patients who chose deep brain stimulation versus those who continued medical treatment. However, subthalamic nucleus stimulation does not halt disease progression, and "long-term deep brain stimulation syndrome" with axial motor problems can emerge from long-term therapy. Reappraisal of current targets and investigation of new ones is ongoing [117].

MANAGEMENT OF NON-MOTOR SYMPTOMS

As discussed, patients frequently develop diverse non-motor symptoms and syndromes throughout the clinical course of PD. Most non-motor symptoms cluster into broader groups of abnormality: neuropsychiatric disorders, autonomic dysfunction, sleep disorders, and pain.

Neuropsychiatric Disorders

Psychosis in Parkinson Disease

Psychosis in PD is common and multifactorial in etiology. Up to 60% of patients with PD develop psychosis. Following its onset, PD psychosis remains a persistent, lifelong problem for most patients [118]. Pharmacologic management is challenging, in part because dopaminergic agents required for motor control can exacerbate psychotic symptoms, and antipsychotic agents can exacerbate motor symptoms [119]. The onset of psychosis in PD predicts a poor prognosis, including increased likelihood of nursing home placement and early mortality [120].

The early clinical manifestations of PD-associated psychosis differ from other psychotic disorders in that hallucinations are common and patients initially remain lucid and connected with reality. Visual hallucinations are the most prevalent form. Functional MRI performed on patients with PD who are experiencing visual hallucinations show several abnormalities: altered cortical visual processing; decreased occipital response and increased caudate and frontal cortical activation to visual stimuli; overactive visual association cortex; and decreased primary visual cortex activity [119].

Auditory, tactile, olfactory, and gustatory hallucinations do occur, though less commonly and usually in combination with visual hallucinations. Confusion states, delusions, paranoia, agitation, and delirium may also develop.

The stage of PD at which psychotic features emerge has some diagnostic import. In newly suspected or recently diagnosed (within three months) cases of PD, the appearance of psychotic symptoms suggests early-onset dementia with Lewy bodies, but could also indicate an alternative neuropsychiatric diagnosis, such as Alzheimer disease with extrapyramidal symptoms or underlying functional (psychiatric) psychosis. Differences in the initial presentation of PD-associated psychosis do not substantively change the management approach (with some caveats) [119].

Risk factors for PD-associated psychosis include cognitive impairment, dementia, advanced age, sleep disturbances, and disease duration/severity [121]. Psychosis is unrelated to total dose or duration of dopaminergic medication, and no differences have been found in the incidence rate among patients receiving levodopa versus those on dopamine agonists or anticholinergic drugs [122].

The association between sleep disturbance and PD psychosis is sufficiently robust to suggest REM sleep behavior disorder manifests from an evolving synucleinopathy in patients with PD-associated psychosis or dementia. Both factors may develop from a single epiphenomenon, such as neurodegeneration. Evidence also suggests contribution to PD psychosis from non-dopaminergic neurotransmitters, including serotoninergic or cholinergic systems [119].

Visual hallucinations require medication adjustment and possibly specific therapies if they are troublesome, threatening, or associated with behavioral change [4]. Triggering factors, such as infection, metabolic disorders, fluid/electrolyte imbalance, and sleep disorder, should be controlled. In addition, steps should be taken to reduce polypharmacy. Tricyclic antidepressants and anxiolytics/sedatives should be reduced or stopped. Antiparkinsonism drugs should also be reassessed. Anticholinergics and amantadine should be halted, while dopamine agonists and MAO-B and COMT inhibitors should be reduced or halted. The levodopa dose may be reduced [74,123].

Unfortunately, most commonly used antipsychotic drugs have side effects that exacerbate PD. Consequently, atypical antipsychotics are often key in the management of PD-associated psychosis. Almost all antipsychotic drugs can exacerbate PD. Clozapine is the only antipsychotic with high-level evidence of efficacy; in some patients, it also improves motor function [124]. Clozapine is widely recommended as the first-line choice, but it is associated with potentially fatal agranulocytosis, which develops in 1% of patients and makes routine blood neutrophil counts mandatory. Less serious side effects include sedation, tachycardia, orthostatic hypotension, and sialorrhea. Low-dose clozapine (less than 50 mg) also has efficacy, with less frequent and more tolerable side effects and rare agranulocytosis [125,126].

The AAN states quetiapine can be considered in the treatment of PD-associated psychosis [76]. However, some studies have found quetiapine no better than placebo in antipsychotic effect in this group of patients [127,128]. Despite clozapine superiority, quetiapine is the most frequently used antipsychotic for PD-associated psychosis in the United States, due to better safety and despite inconsistent antipsychotic benefit [75,119].

First-generation antipsychotics (e.g., haloperidol) should not be used. This drug class is a common cause of drug-induced parkinsonism, shows little to no psychotic symptom relief, and can worsen motor symptoms [119]. Other atypical antipsychotic agents (e.g., olanzapine, risperidone) can worsen parkinsonism and should not be used [75]. The FDA requires all atypical antipsychotics to carry black box warnings for increased risk of death in elderly patients with dementia [119].

Adding a cholinesterase inhibitor (e.g., rivastigmine, donepezil) is an option [74]. In patients requiring sedation for severe agitation, non-neuroleptics such as lorazepam should be considered over standard agents like haloperidol [75,76].

Pimavanserin is an investigational drug with a novel mechanism of antipsychotic action as a selective serotonin 5-HT2A receptor inverse agonist. The activity of this drug does not block dopamine receptors and does not adversely affect PD. In clinical trials for the treatment of PD-associated psychosis, pimavanserin has shown efficacy and tolerability, including significant improvements in positive symptoms of psychoses, caregiver burden, and overall clinical improvement without worsening of motor function. No safety signals have emerged [95,129].

Dementia

Dementia is the progressive decline in cognitive function (i.e., thinking, planning, organizing, problem solving) beyond what might be expected from normal aging. The dementia of PD takes two forms: an early, more rapidly progressive dementia characterized pathologically by an abundance of Lewy bodies within the brain (i.e., dementia with Lewy bodies), and a later onset, less rapid form characterized by neurodegenerative change and fewer Lewy bodies (i.e., PD dementia) [8]. The cognitive signs of dementia with Lewy bodies begin within one year of motor symptom onset, while the cognitive problems associated with PD dementia begin one or more years after motor symptom onset.

Dementia affects a substantial portion of people with PD and has virtually no effective treatment [8]. Cognitive impairment, autonomic dysfunction, and falls are all features of PD dementia that substantially affect function and quality of life and incompletely respond to medication manipulation [4].

In patients with typical PD dementia, there is an initial rapid loss of midbrain dopamine neurons followed by slow progression of Lewy body infiltration into the brain over decades. Dementia manifests later when Lewy bodies invade the neocortex. Patients diagnosed with PD after 70 years of age develop dementia earlier in the disease, show more alpha-synuclein-containing Lewy bodies throughout the brain, and often have additional age-related plaque pathology. In contrast, dementia with Lewy bodies occurs with PD diagnosed at a younger age, is more rapidly progressive, and shows substantial amounts of Lewy bodies and Alzheimer-type pathologies infiltrating the brain. These data suggest that age at symptom onset and the extent and type of age-related, Alzheimer-type pathology influence pathologic progression in PD [8].

Management involves discontinuation of potential aggravators, including anticholinergics, amantadine, tricyclic antidepressants, tolterodine, oxybutynin, and benzodiazepines [74,123]. A cholinesterase inhibitor, such as rivastigmine, donepezil, or galantamine, should be initiated. With idiosyncratic clinical response or side effects, an alternate agent may be tried. If cholinesterase inhibitors lack tolerability or efficacy, memantine should be added or substituted.

Depression

As many as 90% of patients with PD experience depression, which can appear in early and advanced disease. This neuropsychiatric problem has a major impact on both patients' and caregivers' quality of life. With many overlapping features between depression and PD before and during dopaminergic treatment (e.g., loss of facial expression, hypophonic speech, slowed movement, reduced appetite, sleep disorders), depression in PD often goes on unrecognized [89,130].

Tricyclic antidepressants may be the best choice for depression treatment in PD, followed by selective serotonin or norepinephrine reuptake inhibitors (SSRIs/SNRIs) or dopaminergic agonist therapy. Cognitive-behavioral therapy also appears promising. Most PD experts use an SSRI, SNRI, or tricyclic antidepressant and follow the patient closely for four to six weeks, adjusting as needed [95,131].

The potential of antidepressants to worsen PD motor symptoms has been debated, but studies show no significant increase in risk of motor deterioration. A review of tricyclic antidepressant and SSRI/SNRI treatment of depression in PD concluded possible efficacy in reducing levodopa-induced dyskinesia [132]. There is a minor risk of impairing levodopa motor control, but this finding is inconsistent. The effect is usually minor when it happens and can be resolved by increasing levodopa dose [132]. Nortriptyline has no effect on dyskinesia or motor symptoms.

Tricyclic antidepressants and SSRIs/SNRIs are probably effective for depression [132]. The strongest evidence is for nortriptyline and paroxetine. SSRIs may not be the preferred drug class when rapid effect is needed, and quicker onset of therapeutic benefit is achieved with noradrenergic antidepressants. Tricyclic antidepressants and SSRIs/SNRIs are also beneficial in treating anxiety in patients with PD.

In other drug classes, the dopamine agonist pramipexole (up to 1 mg three times per day) significantly improved depression compared to placebo, an effect unrelated to motor improvement [95,131]. Depression symptoms confined to "off" time may respond well to any treatment that reduces motor fluctuations and improves "on" time. Electroconvulsive therapy remains a potentially lifesaving treatment in major depression and has been used successfully in PD, but sufficient trials in PD depression do not exist [95,131].

Apathy

Apathy in non-demented and non-depressed patients with PD is not associated with dopamine transporter activity in the striatal sub-regions. It is more likely the result of extra-striatal lesions that accompany PD rather than striatal dopaminergic deficits [133].

No established treatment for apathy is available. Levodopa, selegiline, and antidepressants have been suggested as useful. In a small clinical trial, rivastigmine 9.5 mg/day transdermal significantly improved apathy symptoms beyond placebo response. There was also improvement in activities of daily living and caregiver burden, but not quality of life. Methylphenidate is probably effective in treating apathy and fatigue in later PD [132]. There is a lack of literature on the subject, many experts use a dopamine agonist for severe apathy, but with caution for impulsive behaviors [95,134].

Impulse Control Disorders

Impulse control disorders and aberrant behaviors can develop during dopamine agonist treatment in PD and worsen patient and caregiver quality of life. Often, patients lack insight into the negative consequences of their behavior. Risk factors include male sex, younger age at onset, personality traits of high impulsivity and novelty seeking, and personal or family history of addictive disorders. In predisposed patients, overstimulation of mesocorticolimbic dopamine receptors by dopamine agonists leads to impulse control disorders and compulsive medication use. Impulse control disorders are more likely in early PD with normal-range medication dosing, while compulsive medication use is more commonly associated with fluctuations in advanced disease. Affected patients often lack noteworthy psychiatric histories and cognitive impairment, making identification difficult. Management requires reducing dopaminergic therapy, and psychosocial support is often necessary. SSRIs may help, while atypical antipsychotics have limited benefit. Prevention is based on the identification of at-risk individuals and active monitoring [135].

In a study of 203 patients with PD, the most common impulse control disorders were compulsive eating (14%), hypersexuality (10%), compulsive shopping (6%), and pathologic gambling (3%). Age younger than 68 years and exposure to dopamine agonists or MAO-B inhibitors were identified as risk factors for developing disorders of impulse control. Affected patients on dopamine agonists received a daily dose 60% higher than those without the disorders. Impulse control disorder symptoms showed a nonlinear dose-response relationship with dopamine agonists [136].

Autonomic Dysfunction

Constipation

In patients with PD, constipation may develop due to impaired gastrointestinal motility and medication side effects. Treatment is often behavioral, with a focus on increasing fluid ingestion, fiber intake, and physical activity. If additional treatment is necessary, polyethylene glycol solution, fiber supplements (e.g., psyllium, methylcellulose), and/or osmotic laxatives are recommended. Short-term irritant laxatives may help in selected patients [74,123].

Dysphagia

Management of dysphagia requires optimization of motor control approaches. Speech therapy is indicated for assessment, swallowing advice, and further investigations, if needed. Videofluoroscopy may be conducted in selected cases to exclude silent aspiration. In severe cases, enteral feeding options (e.g., short-term nasogastric tube, percutaneous endoscopic gastrostomy) may be considered [74,123].

Orthostatic Hypotension

Orthostatic hypotension is a symptomatic drop of 20 mm Hg systolic or 10 mm Hg diastolic blood pressure when rising to standing from sitting or lying down. Orthostatic hypotension is associated with lightheadedness, syncope, or nonspecific complaints including fatigue, unsteadiness, headache, neck tightness, or cognitive slowing. Because supine hypertension often accompanies orthostatic hypotension, the first step of treatment should be non-pharmacologic to avoid worsening supine hypertension. Patients should avoid, reduce, or eliminate large meals, alcohol, warm environments, volume depletion, diuretics, antihypertensive drugs, tricyclic antidepressants, nitrates, dopaminergic drugs (if possible), and alpha-blockers used for benign prostatic hypertrophy. Increasing salt intake may also help. Tilting the head of bed at night (30° to 40°) is recommended, as is exercise, as tolerated. Waist-high elastic stockings, abdominal compression bands, and counter-maneuvers (e.g., leg crossing, toe raising, thigh contraction) are effective prevention measures.

Midodrine has the greatest level of evidence in terms of pharmacotherapy. Fludrocortisone is also possibly effective, but it is important to monitor for side effects [74,95,123].

Urinary Dysfunction

Urinary incontinence in patients with PD is thought to result from hyper-reflexia caused by basal ganglia dysfunction. When symptoms appear suddenly, it is important to rule out urinary tract infection. If incontinence occurs mainly at night, fluid intake should be reduced after 6 p.m. and the head of the bed should be tilted up for sleep.

Night-time dopaminergic therapy should be optimized, and if necessary, an anticholinergic drug may be added. Guidelines recommend trospium chloride (10–20 mg two to three times per day) or tolterodine (2 mg twice per day) [74,123]. However, trospium is less able to penetrate the blood-brain barrier, and cognition may worsen. Botulinum toxin type A injected in the detrusor muscle is also an option [74,123].

Sexual Dysfunction

Sexual dysfunction is common in men and women with PD and is a complex problem from diverse etiologies, including motor dysfunction, medication side effects, mood disorders, and autonomic dysfunction manifesting in erectile dysfunction, reduced genital sensitivity and lubrication, and difficulty reaching orgasm [123].

Erectile dysfunction is widespread in PD and affects at least 50% to 75% of men with PD. Good evidence supports the use of sildenafil citrate, and similar drug class members, such as tadalafil and vardenafil, are also likely to be effective [89].

Sleep Disorders

Excessive Sleepiness

Excessive daytime somnolence and sudden sleep onset can originate from the disease process, medications, or other sleep disorders. Excessive daytime somnolence can result from dopaminergic medications—more commonly dopamine agonists than levodopa. Patients with these symptoms should be assessed for nocturnal sleep disturbances. Nocturnal sleep may be improved by reducing akinesia, tremor, and urinary frequency.

Sedative drugs should be reduced or discontinued. All dopaminergic drugs may induce daytime somnolence, so the dose of the current dopamine agonist may be reduced or the patient may switch to another dopamine agonist. Modafinil and/or other wake-promoting agents (e.g., methylphenidate) should be added [74,123]. Patients with excessive daytime somnolence should be advised to stop driving.

Restless Legs Syndrome

Restless legs syndrome (RLS) is a movement disorder of the limbs whereby patients have a bothersome, irresistible urge to move the legs. RLS often interferes with sleep, leading to chronic sleep deprivation and stress. The prevalence of RLS was 12% in one study of patients with PD [137]. Drugs considered the most efficacious for RLS include levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin; second-line options include rotigotine, bromocriptine, oxycodone, carbamazepine, valproic acid, and clonidine [138].

Insomnia

Insomnia in PD may be the result of mood disturbances, persistent tremor, night-time re-emergence of PD symptoms, nocturia, and reversal of sleep patterns [123]. Levodopa/carbidopa may contribute to insomnia while improving sleep-related motor symptoms. Melatonin may be effective in improving patients' perception of sleep quality [123].

REM Sleep Behavior Disorder

As discussed, REM sleep behavior disorder is a type of parasomnia characterized by the behavioral enactment of dreams during REM sleep. REM sleep behavior disorder is one of the most robust predictors of PD development and is very prevalent throughout the motor symptom phase of disease progression. Standard treatment is clonazepam or melatonin [54].

Pain

Among non-motor symptoms, 60% to 83% of patients with PD report pain of heterogeneous presentation and disabling effect on quality of life. Pain has received minimal attention in PD due to its association with the reappearance of motor symptoms and dystonic muscle contraction with dissipation of levodopa dose response. Pain also occurs as skeletal-muscle or neuropathic (peripheral or central) pain. Evidence suggests patients with PD have abnormal nociceptive processing in pain-free states, independent of parkinsonism motor symptom presence, that is unaffected by levodopa stimulation. Few therapeutic strategies for pain management in PD have been developed [139,140].

A concern in using opioids to treat pain in patients with PD is potential exacerbation of constipation, a common, burdensome symptom of autonomic dysfunction. To possibly mitigate this issue, an oral formulation combining prolonged-release oxycodone with naloxone has been evaluated. In an eight-week trial, patients with PD-associated chronic pain received low-dose oxycodone/naloxone (5 mg/2.5 mg) twice daily. Of the 87.5% who completed the trial, significant pain reduction was achieved, no adjustment of dopaminergic therapy was required, no significant changes were observed in bowel function and constipation symptoms, no changes were observed in sleep symptoms, and improvements were recorded in clinician impression of therapeutic effect [141].

END-STAGE PARKINSON DISEASE

A little-studied area of PD has been symptom manifestation with approaching death and factors related to their severity and progression. The course of non-dopaminergic PD symptoms in relation to age and death was prospectively studied in 378 patients with PD over five years. Patients who died (11%) during follow-up had more severe non-dopaminergic symptoms. The progression of cognitive and axial symptoms accelerated in older patients, and the progression of axial, cognitive, and psychotic symptoms accelerated before death. Improving understanding of these factors will hopefully make a positive impact on end-of-life care [142].

End-of-Life Care

During end-stage PD, the focus of care is on palliation of symptoms and comfort. Patients with end-stage PD often exhibit cognitive impairment and progress to the point of requiring assistance with most activities. The best approach for patients with PD at the end of life is multidisciplinary palliative care with adequate physical, psychologic, and spiritual support. In earlier stages, the goal is to maintain patient independence for as long as possible; however, in end-stage PD, the focus is mainly on comfort and supportive care [149].

Non-motor symptoms such as depression, psychosis, urologic dysfunction, pain, and respiratory depression, become more common in end-stage PD. Over time, these symptoms may become the most prominent medical problem, leading to increasing decline in quality of life [149]. The first step in managing these symptoms may be reduction or discontinuing triggering pharmacotherapeutic agents, such as anticholinergics, MAO-B inhibitors, and opioids.

In the last days, the goals of the healthcare team are to ensure a peaceful death for the patient and to support the family during the dying process and throughout grief and mourning. The focus for the patient is management of symptoms and emotional and spiritual ease, and the focus for the family is education to prepare them for the dying process.

ADJUNCTIVE TREATMENT MODALITIES

Evidence Based Practice Recommendation

The American Occupational Therapy Association recommends engagement of patients with PD in exercise and physical activity, specifically multisession, repetitive physical exercise (diachronic) to improve motor and sensory-perceptual performance skills.

https://www.guidelinecentral.com/summaries/occupational-therapy-practice-guidelines-for-adults-with-neurodegenerative-diseases

Last Accessed: April 11, 2019

Level of Evidence: A or B (There is strong or moderate evidence that occupational therapy practitioners should routinely provide the intervention to eligible clients.)

A variety of nonpharmacologic, adjunctive interventions have been evaluated for management of PD. These include exercise programs and occupational, physical, and speech therapies. While clinical study design and control group issues have confounded the quality of evidence, clinical experience suggests that these approaches have value. The American Academy of Family Physicians recommends physical therapy, speech therapy, and occupational therapy be offered to patients with PD as part of an overall strategy for improving or maintaining function [2]. The specific benefits for allied health professional interventions to patients with PD include [143]:

Physical Therapy

- Gait re-education, improving balance and flexibility

- Increasing aerobic capacity

- Improving movement initiation

- Improving independent functioning, mobility, and daily activities

- Advising on safety in the home environment

Occupational Therapy

- Maintaining work and family roles, home care, and leisure activities

- Improving and maintain transfers and mobility

- Improving self-care activities such as eating, drinking, washing, and dressing

- Addressing environmental issues to improve safety and motor function

- Cognitive assessment and appropriate intervention

Speech/Language Therapy

- Improving vocal loudness and pitch range (with programs such as Lee Silverman voice treatment)

- Teaching strategies to optimize speech intelligibility

- Ensuring effective means of communication maintained throughout the disease course, including use of assistive technologies

- Reviewing and managing safe and efficient swallowing to minimize risk of aspiration

When capable of doing so, persons with PD should be encouraged to maintain a regular program of stretching and other physical exercise. In a randomized, controlled trial, tai chi training was seen to be more effective than resistance training or stretching in reducing balance impairments and falls in patients with mild-to-moderate PD [153]. The American Parkinson Disease Association has developed a free, web-based training program designed to teach fitness professionals how to best meet the unique needs of persons with PD [154]. Cognitive training is likely helpful for other patients. Patient and family member education is a key component of PD management, as is the use of support groups [93].

PRACTICE CONSIDERATIONS

Avoiding Inappropriate Medications

Many patients with PD require hospital admission for problems unrelated to motor pathology. Their medical care is typically received on non-neurology wards from staff unfamiliar with PD management, increasing the risk of inappropriate medications that exacerbate PD. Among inpatients with PD, 43.8% received inappropriate anti-dopaminergic medication at some point, primarily haloperidol and metoclopramide. The highest prevalence occurred in patients with PD on chronic antipsychotics [75].

Nausea and vomiting, common adverse effects of levodopa and dopamine agonists, may require antiemetic use. The centrally acting dopamine antagonists metoclopramide and prochlorperazine should not be used; the peripheral dopamine antagonist domperidone is the antiemetic of choice. The serotonin receptor antagonist ondansetron is another option [74,75].

Healthcare professional education is suggested to improve the care of inpatients with PD. Pharmacists can play a key role in identifying inappropriate medications and in educating non-PD specialist professionals [75].

Safety Precautions with Dopaminergic Agents

With disease progression, patients with PD become more reliant on medication to maintain their ability to function. In addition to regular monitoring for drug-specific side effects, clinicians should be careful not to abruptly withdraw dopaminergic medication [89]. Patients and family should be educated on the importance of medication compliance and regular dosing so as to avoid rapid changes in efficacy. Special attention is required during periods of intercurrent illness, such as gastroenteritis or abdominal surgery, which may result in interruption of dosage or poor intestinal absorption. These measures help to avoid the potential development of acute akinesia or neuroleptic malignant syndrome. "Drug holidays" are not recommended due to the risk of developing neuroleptic malignant syndrome.

Considering the risks of sudden changes in dopaminergic medication, patients with PD admitted to hospitals or care facilities should receive their medication at the appropriate times or be allowed self-medication. Medication adjustment should be reserved for specialists in PD management [89].

Clinician-Patient Communication

In managing newly diagnosed patients, healthcare professionals should exhibit great sensitivity and understanding in describing disease symptoms and progression. As it progresses, PD complicates every aspect of daily living. Formerly routine tasks demand full attention and often cause frustration and anxiety. Over time, PD reduces work capacity, erodes earning potential, and may compromise social and family relationships. Disease progression leads to increased dependency and fosters feelings of being a burden to others. Increasing difficulties with writing and speaking, coupled with the loss of independence, often lead to social withdrawal, isolation, depression, frustration, and anger. Access to primary care, speech therapists, exercise programs, and emotional support is critical to managing the disease and living with dignity, and people living with PD require understanding and support as they struggle to maintain independence and adapt to living with a chronic condition [89].

Good communication is the foundation of care between patients with PD, their caregivers, and health professionals. Healthcare professionals' commitment to clear, compassionate communication can make a meaningful difference to their patients. When patients with PD understand healthcare professionals' recommendations, they can know what to expect and are better prepared to navigate the system, ask the right questions, and make the best personal choices [89].

Communicating effectively is more challenging when the patient's primary language differs from that of the practitioner. According to the U.S. Census Bureau, more than 31 million Americans speak a language other than English in the home, with approximately 9.4 million of them (11.7% of the population) speaking English less than "very well" [144]. It has been suggested that when patients are first evaluated, they should be asked what language is spoken at home and if they speak English "very well" [145]. In addition, patients should also be asked what language they prefer for their medical care information, as some patients prefer their native language even though they have said they can understand and discuss symptoms in English [145]. Many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care and that the use of professional interpreters improves communication (errors and comprehension), utilization, clinical outcomes, and patient satisfaction with care [146,147].

"Ad hoc" interpreters (untrained staff members, family members, friends) are often used instead of professional interpreters for a variety of reasons, including convenience and cost. However, the reliability and specificity of information obtained through ad hoc interpreters is less than with professional interpreters [148]. In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members [70]. A systematic review of the literature has shown that the use of professional interpreters facilitates a broader understanding and leads to better clinical care than the use of ad hoc interpreters [147].

Care decisions should be based upon best available evidence and provided by applicable professional standards. Issues to consider when communicating with people with PD and their caregivers include [89]:

- Style, manner, and frequency of communication that is compassionate and respectful

- Ease of access for those receiving information in a timely and appropriate manner throughout the progression of the disease

- Honesty and sensitivity in tailoring information to meet changing medical needs

- Encouragement of self-management to meet individual needs and preferences

- Inclusion of caregivers who are also impacted by PD and require information and support

Hospice

Traditionally, management of PD has focused on drug treatment and interdisciplinary care for a long-term, slowly progressive disorder. Palliative care specialists have not routinely been involved. Due to the long duration of the disease and the difficulty in predicting the time of death, patients with PD are frequently refused access to hospice and palliative care services [89].

8. CONCLUSION

PD is an important, increasingly prevalent neurodegenerative disease of aging. Although the defining motor abnormalities are relatively easy to recognize after the syndrome of parkinsonism is fully manifest, the onset and progression of clinical features are variable and often preceded or followed by non-motor symptoms of disease. The pathogenesis of PD remains vague, but the pathophysiology is clear enough to provide the basis for treating the motor dysfunction of PD and to lend hope for future development of more effective and innovative therapies.

On average, patients with PD live for well over a decade with their disease, which usually follows a slowly progressive and debilitating course. The likelihood of intercurrent complications is high, and at each stage, there are new issues of chronic disease management that challenge healthcare providers and family alike. All involved should have a basic understanding of the clinical features of PD, the sources of suffering, principals of treatment, importance of compliance, and potential for drug-drug interactions and side effects. Best practice outcomes require the coordinated effort of well-informed primary care physician and nurse, subspecialist, pharmacist, and home health provider—an interprofessional healthcare team approach.

9. RESOURCES

National Institute of Neurological Disorders and Stroke

https://www.ninds.nih.gov/Disorders/All-Disorders/Parkinsons-Disease-Information-Page

American Parkinson Disease Association

https://www.apdaparkinson.org

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123. Zesiewicz TA, Sullivan KI, Arnulf I, et al. Practice parameter: treatment of nonmotor symptoms of Parkinson disease. Neurology. 2010;74(11):924-931.

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125. The Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. N Engl J Med. 1999;340(10):757-763.

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129. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540.

130. DeMaagd G, Philip A. Parkinson's disease and its management. Part 5: treatment of nonmotor complications. PT. 2015;40(12): 838-846.

131. Troeung L, Egan SJ, Gasson N. A meta-analysis of randomised placebo-controlled treatment trials for depression and anxiety in Parkinson's disease. PLoS One. 2013;8(11):e79510.

132. Huot P, Fox SH, Brotchie JM. Monoamine reuptake inhibitors in Parkinson's disease. Parkinsons Dis. 2015;2015:609428.

133. Chung SJ, Lee JJ, Ham JH, Lee PH, Sohn YH. Apathy and striatal dopamine defects in non-demented patients with Parkinson's disease. Parkinsonism Relat Disord. 2016;23:62-65.

134. Devos D, Moreau C, Maltete D, et al. Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial. J Neurol Neurosurg Psychiatry. 2014;85(6):668-674.

135. Antonini A, Cilia R. Behavioural adverse effects of dopaminergic treatments in Parkinson's disease: incidence, neurobiological basis, management and prevention. Drug Saf. 2009;32(6):475-88.

136. Santiago P-L, Rey MV, Fabre N, et al. Prevalence and pharmacological factors associated with impulse-control disorder symptoms in patients with Parkinson disease. Clin Neuropharmacol. 2012;35(6):261-265.

137. Nomura T, Inoue Y, Miyake M, Yasui K, Nakashima K. Prevalence and clinical characteristics of restless legs syndrome in Japanese patients with Parkinson's disease. Mov Disord. 2006;21(3):380-384.

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139. Antonini A, Tinazzi M. Targeting pain in Parkinson's disease. Lancet Neurol. 2015;14(12):1144-1145.

140. Tinazzi M, Del Vesco C, Defazio G, et al. Abnormal processing of the nociceptive input in Parkinson's disease: a study with CO2 laser evoked potentials. Pain. 2008;136(1-2):117-124.

141. Madeo G, Schirinzi T, Natoli S, et al. Efficacy and safety profile of prolonged release oxycodone in combination with naloxone (OXN PR) in Parkinson's disease patients with chronic pain. J Neurol. 2015;262(9):2164-2170.

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145. Karliner LS, Napoles-Springer AM, Schillinger D, Bibbins-Domingo K, Pérez-Stable EJ. Identification of limited English proficient patients in clinical care. J Gen Intern Med. 2008;23(10):1555-1560.

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Evidence-Based Practice Recommendations Citations

1. Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES recommendations for the diagnosis of Parkinson's disease. Eur J Neurol. 2013;20(1):16-34. Available at https://www.movementdisorders.org/MDS-Files1/MDS-ES/MDS-ES--EFNS/BerardellietalEFNSMDSESene12022.pdf. Last accessed April 11, 2019.

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4. Oertel WH, Berardelli A, Bloem BR, et al. Late (complicated) Parkinson's disease. In: Gilhus NE, Barnes MP, Brainin M (eds).European Handbook of Neurological Management. 2nd ed. Oxford: Wiley-Blackwell; 2011: 237-267. Available at https://onlinelibrary.wiley.com/doi/abs/10.1002/9781444328394.ch15. Last accessed April 11, 2019.

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95150 • Responsible and Effective Opioid Prescribing

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2017 NetCE, All rights reserved.

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat pain patients with opioids. By implementing these tools, clinicians can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Table of Contents

95150 • Responsible and Effective Opioid Prescribing

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. SCOPE OF THE PROBLEM

3. PAIN MANAGEMENT APPROACHES

ACUTE PAIN

CHRONIC PAIN

PALLIATIVE CARE AND PAIN AT THE END OF LIFE

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

RISK ASSESSMENT TOOLS

PERIODIC REVIEW AND MONITORING

CONCURRENT USE OF BENZODIAZEPINES

CONSULTATION AND REFERRAL

MEDICAL RECORDS

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

DISCONTINUING OPIOID THERAPY

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

CONTROLLED SUBSTANCES LAWS/RULES

STATE-SPECIFIC LAWS AND RULES

8. MANAGEMENT OF OPIOID USE DISORDER

CRISIS INTERVENTION

HARM REDUCTION

DETOXIFICATION AND WITHDRAWAL

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

STIGMA OF ADDICTION

PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95150 • Responsible and Effective Opioid Prescribing

Education Category. Pharmacology

Release Date. 05/01/2017

Review Date. 09/15/2019

Expiration Date. 04/30/2021

Course Overview

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat pain patients with opioids. By implementing these tools, clinicians can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Audience

This course is designed for all physicians, osteopaths, physician assistants, and nurses who may alter prescribing practices or intervene to prevent drug diversion and inappropriate opioid use.

Course Objective

The purpose of this course is to provide clinicians who prescribe or distribute opioids with an appreciation for the complexities of opioid prescribing and the dual risks of litigation due to inadequate pain control and drug diversion or misuse in order to provide the best possible patient care and to prevent a growing social problem.

Learning Objectives

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

1. Apply epidemiologic trends in opioid use and misuse to current practice so at-risk patient populations can be more easily identified, assessed, and treated.

2. Create comprehensive treatment plans for patients with pain that address patient needs as well as drug diversion prevention.

3. Evaluate behaviors that may indicate drug seeking or diverting as well as approaches for patients suspected of misusing opioids.

4. Identify state and federal laws governing the proper prescription and monitoring of controlled substances.

5. Describe the available treatment modalities for opioid use disorder.

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

Ronald Runciman, 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.

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

Pain is the leading reason for seeking medical care, and pain management is a large part of many healthcare professionals' practice. Opioid analgesics are approved by the U.S. Food and Drug Administration (FDA) for moderate and severe pain and are broadly accepted in acute pain, cancer pain, and end-of-life care, but are controversial in chronic noncancer pain. In response to the long-standing neglect of severe pain, indications for opioid analgesic prescribing were expanded in the 1990s, followed by inappropriate prescribing and increasing abuse, addiction, diversion, and overdose through the 2000s. In tandem with the continued under-treatment of pain, these practice patterns led to needless suffering from uncontrolled pain, opioid analgesic addiction, and overdose. Opioid analgesic prescribing and associated overdose peaked in 2011 with both now in multi-year decline.

Patients show substantial opioid response variations in analgesia and tolerability and may exhibit a range of psychologic, emotional, and behavioral responses that reflect inadequate pain control, an emerging opioid use problem, or both. Clinician delivery of best possible care to patients with pain requires appreciation of the complexities of opioid prescribing and the dual risks of inadequate pain control and inappropriate use, drug diversion, or overdose. A foundation for appropriate opioid prescribing is the understanding of factual data that clarify the prevalence, causality, and prevention of serious safety concerns with opioid prescribing.

2. SCOPE OF THE PROBLEM

Inappropriate opioid analgesic prescribing for pain is defined as the non-prescribing, inadequate prescribing, excessive prescribing, or continued prescribing despite evidence of ineffectiveness of opioids [1]. Appropriate opioid prescribing is essential to achieve pain control; to minimize patient risk of abuse, addiction, and fatal toxicity; and to minimize societal harms from diversion. The foundation of appropriate opioid prescribing is thorough patient assessment, treatment planning, and follow-up and monitoring. Essential for proper patient assessment and treatment planning is comprehension of the clinical concepts of opioid abuse and addiction, their behavioral manifestations in pain patients, and how these potentially problematic behavioral responses to opioids both resemble and differ from physical dependence and pseudo-dependence. Prescriber knowledge deficit has been identified as a key obstacle to appropriate opioid prescribing and, along with gaps in policy, treatment, attitudes, and research, contributes to widespread inadequate treatment of pain [2].

The current extent of opioid analgesic use in the United States is unprecedented in the country's history and unparalleled anywhere in the world. Before 1990, physicians in the United States were skeptical of prescribing opioids for chronic noncancer pain. But as of 2017, 1 of 25 adults is prescribed an opioid such as oxycodone and hydrocodone for chronic pain, and sales of opioid analgesics now total more than $9 billion each year [3].

Worldwide consumption of opioid analgesics has increased dramatically in the past few decades, with the United States driving a substantial proportion of this increase. For example, the 1990 global consumption of hydrocodone was 4 tons (3,628 kg), compared with the 2009 consumption of 39 tons (35,380 kg); 99% of this was consumed in the United States. Similarly, 3 tons (2,722 kg) of oxycodone were consumed globally in 1990, versus 77 tons (69,853 kg) in 2009, of which 62 tons (56,245 kg or 81%) were consumed in the United States [3]. With only 4.5% of the world's population, the United States annually consumes more than 80% of all opioid supplies, including [4]:

- 99% of all hydrocodone

- 80% of all oxycodone

- 58% of all methadone

- 54% of all hydromorphone

- 49% of all fentanyl

- 43% of all meperidine

This disproportionate rate of opioid consumption reflects sociocultural and economic factors and standards of clinical medicine.

Between 1992 and 2003, the U.S. population increased 14%, while persons abusing opioid analgesics increased 94% and first-time non-medical opioid analgesic users 12 to 17 years of age increased 542% [4]. It is interesting to note that while opioid prescribing has increased precipitously among adults in the United States, the rate remained low and steady for children between 1996 and 2012 [5]. To assist in monitoring the public health problem associated with prescribed opioids, numerous governmental, non-profit, and private sector agencies and organizations are involved in collecting, reporting, and analyzing data on the abuse, addiction, fatal overdose, and treatment admissions related to opioid analgesics.

Before it was halted in 2011, the Drug Abuse Warning Network (DAWN) provided estimates of the health consequences of nonmedical use of individual drugs, including opioid medications [6]. DAWN indicates that opioid abuse is a growing problem in the United States. In 2005 and 2011, hydrocodone and its combinations accounted for 51,225 and 97,183 emergency department visits, respectively. Oxycodone and its combinations resulted in 42,810 visits to the emergency department in 2005; this number increased to 175,229 visits in 2011 [7,8]. Visits for nonmedical use of all opioids increased from 217,594 to 420,040 during the six-year period.

3. PAIN MANAGEMENT APPROACHES

Healthcare professionals should know the best clinical practices in opioid prescribing, including the associated risks of opioids, approaches to the assessment of pain and function, and pain management modalities. Pharmacologic and nonpharmacologic approaches should be used on the basis of current knowledge in the evidence base or best clinical practices. Patients with moderate-to-severe chronic pain who have been assessed and treated, over a period of time, with non-opioid therapy or nonpharmacologic pain therapy without adequate pain relief, are considered to be candidates for a trial of opioid therapy [9,10]. Initial treatment should always be considered individually determined and as a trial of therapy, not a definitive course of treatment [11].

ACUTE PAIN

Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids in a quantity no greater than that needed for the expected duration of severe pain. In most cases, three days or less will be sufficient; more than seven days will rarely be needed [10]. However, it is important to note that this guideline is based on emergency department prescribing guidelines for non-traumatic non-surgical pain [12]. It may be necessary to prescribe for longer periods in patients with acute severe pain.

With postoperative, acute, or intermittent pain, analgesia often requires frequent titration, and the two- to four-hour analgesic duration with short-acting hydrocodone, morphine, and oxycodone is more effective than extended-release formulations. Short-acting opioids are also recommended in patients who are medically unstable or with highly variable pain intensity [13,14,15].

CHRONIC PAIN

Nonpharmacologic therapy and non-opioid pharmacologic therapy are the preferred first-line therapies for chronic pain. Several nonpharmacologic approaches are therapeutic complements to pain-relieving medication, lessening the need for higher doses and perhaps minimizing side effects. These interventions can help decrease pain or distress that may be contributing to the pain sensation. Approaches include palliative radiotherapy, complementary/alternative methods, manipulative and body-based methods, and cognitive/behavioral techniques. The choice of a specific nonpharmacologic intervention is based on the patient's preference, which, in turn, is usually based on a successful experience in the past.

Implantable intrathecal opioid infusion and/or spinal cord stimulation may be options for severe, intractable pain. Both options require that devices or ports be implanted, with associated risks. With intrathecal opioid infusion, the ability to deliver the drug directly into the spine provides pain relief with significantly smaller opioid doses, which can help to minimize side effects (e.g., drowsiness, dizziness, dry mouth, nausea, vomiting, and constipation) that can accompany systemic pain medications that might be delivered orally, transdermally, or through an IV [90]. However, use of opioid infusion has traditionally been limited to cancer pain. With spinal cord stimulation therapy, the most challenging aspect is patient selection. In order for patients to be considered for spinal cord stimulation, other options should have been ineffective or be contraindicated. Spinal cord stimulation is indicated for severe neuropathic pain persisting at least six months [91].

If opioids are used, they should be combined with nonpharmacologic therapy and non-opioid pharmacologic therapy, as appropriate. Clinicians should consider opioid therapy only if expected benefits for pain and function are anticipated to outweigh risks to the patient [10].

Opioid therapy for chronic pain should be presented as a trial for a pre-defined period (e.g., ≤30 days). The goals of treatment should be established with all patients prior to the initiation of opioid therapy, including reasonable improvements in pain, function, depression, anxiety, and avoidance of unnecessary or excessive medication use [1,10]. The treatment plan should describe therapy selection, measures of progress, and other diagnostic evaluations, consultations, referrals, and therapies.

In opioid-naïve patients, start at the lowest possible dose and titrate to effect. Dosages for opioid-tolerant patients should always be individualized and titrated by efficacy and tolerability [1,10]. When starting opioid therapy for chronic pain, clinicians should prescribe short-acting instead of extended-release/long-acting opioid formulations [10].

The need for frequent progress and benefit/risk assessments during the trial should be included in patient education. Patients should also have full knowledge of the warning signs and symptoms of respiratory depression. Prescribers should carefully reassess evidence of benefits and risks when increasing the dosage to ≥50 mg morphine equivalent dose (MED) per day. Decisions to titrate dose to ≥90 mg MED/day should be avoided or carefully justified [10].

Prescribers should be knowledgeable of federal and state opioid prescribing regulations. Issues of equianalgesic dosing, close patient monitoring during all dose changes, and cross-tolerance with opioid conversion should be considered. If necessary, treatment may be augmented, with preference for nonopioid and immediate-release opioids over long-acting/extended-release opioids. Taper opioid dose when no longer needed [16].

PALLIATIVE CARE AND PAIN AT THE END OF LIFE

Unrelieved pain is the greatest fear among people with a life-limiting disease, and the need for an increased understanding of effective pain management is well-documented [27]. Although experts have noted that 75% to 90% of end-of-life pain can be managed effectively, rates of pain are high, even among people receiving palliative care [27,28,29,30,31,32,33,34,35,36].

The inadequate management of pain is the result of several factors related to both patients and clinicians. In a survey of oncologists, patient reluctance to take opioids or to report pain were two of the most important barriers to effective pain relief [37]. This reluctance is related to a variety of attitudes and beliefs [27,37]:

- Fear of addiction to opioids

- Worry that if pain is treated early, there will be no options for treatment of future pain

- Anxiety about unpleasant side effects from pain medications

- Fear that increasing pain means that the disease is getting worse

- Desire to be a "good" patient

- Concern about the high cost of medications

Education and open communication are the keys to overcoming these barriers. Every member of the healthcare team should reinforce accurate information about pain management with patients and families. The clinician should initiate conversations about pain management, especially regarding the use of opioids, as few patients will raise the issue themselves or even express their concerns unless they are specifically asked [38]. It is important to acknowledge patients' fears individually and provide information to help them differentiate fact from fiction. For example, when discussing opioids with a patient who fears addiction, the clinician should explain that the risk of addiction is low [27]. It is also helpful to note the difference between addiction and physical dependence.

There are several other ways clinicians can allay patients' fears about pain medication:

- Assure patients that the availability of pain relievers cannot be exhausted; there will always be medications if pain becomes more severe.

- Acknowledge that side effects may occur but emphasize that they can be managed promptly and safely and that some side effects will abate over time.

- Explain that pain and severity of disease are not necessarily related.

Encouraging patients to be honest about pain and other symptoms is also vital. Clinicians should ensure that patients understand that pain is multidimensional and emphasize the importance of talking to a member of the healthcare team about possible causes of pain, such as emotional or spiritual distress. The healthcare team and patient should explore psychosocial and cultural factors that may affect self-reporting of pain, such as concern about the cost of medication.

Clinicians' attitudes, beliefs, and experiences also influence pain management, with addiction, tolerance, side effects, and regulations being the most important concerns [27,34,37,39,40,41]. A lack of appropriate education and training in the assessment and management of pain has been noted to be a substantial contributor to ineffective pain management [37,39,41,42]. As a result, many clinicians, especially primary care physicians, do not feel confident about their ability to manage pain in their patients [37,39].

Clinicians require a clear understanding of available medications to relieve pain, including appropriate dosing, safety profiles, and side effects. If necessary, clinicians should consult with pain specialists to develop an effective approach.

Strong opioids are used for severe pain at the end of life [30,34,43,44]. Morphine, buprenorphine, oxycodone, hydromorphone, fentanyl, and methadone are the most widely used in the United States [45]. Unlike nonopioids, opioids do not have a ceiling effect, and the dose can be titrated until pain is relieved or side effects become unmanageable. For an opioid-naïve patient or a patient who has been receiving low doses of a weak opioid, the initial dose should be low, and, if pain persists, the dose may be titrated up daily until pain is controlled.

More than one route of opioid administration will be needed by many patients during end-of-life care, but in general, opioids should be given orally, as this route is the most convenient and least expensive. The transdermal route is preferred to the parenteral route, although dosing with a transdermal patch is less flexible and so may not be appropriate for patients with unstable pain [34]. Intramuscular injections should be avoided because injections are painful, drug absorption is unreliable, and the time to peak concentration is long [34].

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

Information obtained by patient history, physical examination, and interview, from family members, a spouse, or state prescription drug monitoring program (PDMP), and from the use of screening and assessment tools can help the clinician to stratify the patient according to level of risk for developing problematic opioid behavioral responses (Table 1). Low-risk patients receive the standard level of monitoring, vigilance, and care. Moderate-risk patients should be considered for an additional level of monitoring and provider contact, and high-risk patients are likely to require intensive and structured monitoring and follow-up contact, additional consultation with psychiatric and addiction medicine specialists, and limited supplies of short-acting opioid formulations [10,26].

Table 1: RISK STRATIFICATION FOR PATIENTS PRESCRIBED OPIOIDS

Low Risk

Definable physical pathology with objective signs and reliable symptoms

Clinical correlation with diagnostic testing, including MRI, physical examination, and interventional diagnostic techniques

With or without mild psychologic comorbidity

With or without minor medical comorbidity

No or well-defined and controlled personal or family history of alcoholism or substance abuse

Age 45 years or older

High levels of pain acceptance and active coping strategies

High motivation and willingness to participate in multimodal therapy and attempting to function at normal levels

Medium Risk

Significant pain problems with objective signs and symptoms confirmed by radiologic evaluation, physical examination, or diagnostic interventions

Moderate psychologic problems, well controlled by therapy

Moderate coexisting medical disorders that are well controlled by medical therapy and are not affected by chronic opioid therapy (e.g., central sleep apnea)

Develops mild tolerance but not hyperalgesia without physical dependence or addiction

Past history of personal or family history of alcoholism or substance abuse

Pain involving more than three regions of the body

Defined pathology with moderate levels of pain acceptance and coping strategies

Willing to participate in multimodal therapy, attempting to function in normal daily life

High Risk

Widespread pain without objective signs and symptoms

Pain involving more than three regions of the body

Aberrant drug-related behavior

History of alcoholism or drug misuse, abuse, addiction, diversion, dependency, tolerance, or hyperalgesia

Major psychologic disorders

Age younger than 45 years

HIV-related pain

High levels of pain exacerbation and low levels of coping strategies

Unwilling to participate in multimodal therapy, not functioning close to a near normal lifestyle

HIV = human immunodeficiency syndrome, MRI = magnetic resonance imaging.

Source: [17]

Evidence Based Practice Recommendation

Despite limited evidence for reliability and accuracy, screening for opioid use is recommended by the American Society of Interventional Pain Physicians, as it will identify opioid abusers and reduce opioid abuse.

https://painphysicianjournal.com/2012/july/2012;%2015;S67-S116.pdf

Last Accessed: September 17, 2019

Level of Evidence: Limited (Evidence is insufficient to assess effects on health outcomes because of limited number or power of studies, large and unexplained inconsistency between higher-quality trials, important flaws in trial design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes.)

Before deciding to prescribe an opioid analgesic, clinicians should perform and document a detailed patient assessment that includes [1]:

- Pain indications for opioid therapy

- Nature and intensity of pain

- Past and current pain treatments and patient response

- Comorbid conditions

- Pain impact on physical and psychologic function

- Social support, housing, and employment

- Home environment (i.e., stressful or supportive)

- Pain impact on sleep, mood, work, relationships, leisure, and substance use

- Patient history of physical, emotional, or sexual abuse

If substance abuse is active, in remission, or in the patient's history, consult an addiction specialist before starting opioids [1]. In active substance abuse, do not prescribe opioids until the patient is engaged in treatment/recovery program or other arrangement made, such as addiction professional co-management and additional monitoring. When considering an opioid analgesic (particularly those that are extended-release or long-acting), one must always weigh the benefits against the risks of overdose, abuse, addiction, physical dependence and tolerance, adverse drug interactions, and accidental exposure by children [10,16].

Screening and assessment tools can help guide patient stratification according to risk level and inform the appropriate degree of structure and monitoring in the treatment plan. It should be noted that despite widespread endorsement of screening tool use to help determine patient risk level, most tools have not been extensively evaluated, validated, or compared to each other, and evidence of their reliability is poor [17].

RISK ASSESSMENT TOOLS

Opioid Risk Tool (ORT)

The Opioid Risk Tool (ORT) is a five-item assessment to help predict aberrant drug-related behavior. The ORT is also used to establish patient risk level through categorization into low, medium, or high levels of risk for aberrant drug-related behaviors based on responses to questions of previous alcohol/drug abuse, psychologic disorders, and other risk factors [18].

Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R)

The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a patient-administered, 24-item screen with questions addressing history of alcohol/substance use, psychologic status, mood, cravings, and stress. Like the ORT, the SOAPP-R helps assess risk level of aberrant drug-related behaviors and the appropriate extent of monitoring [19].

CAGE and CAGE-AID

The original CAGE (Cut down, Annoyed, Guilty, and Eye-opener) Questionnaire consisted of four questions designed to help clinicians determine the likelihood that a patient was misusing or abusing alcohol. These same four questions were modified to create the CAGE-AID (adapted to include drugs), revised to assess the likelihood of current substance abuse [20].

Diagnosis, Intractability, Risk, and Efficacy (DIRE) Tool

The Diagnosis, Intractability, Risk, and Efficacy (DIRE) risk assessment tool is a clinician-rated questionnaire that is used to predict patient compliance with long-term opioid therapy [21]. Patients scoring lower on the DIRE tool are poor candidates for long-term opioid analgesia.

Mental Health Screening Tool

The Mental Health Screening Tool is a five-item screen that asks about a patient's feelings of happiness, calmness, peacefulness, nervousness, and depression in the past month [22]. A lower score on this tool is an indicator that the patient should be referred to a specialist for pain management.

Informed Consent and Treatment Agreements

The initial opioid prescription is preceded by a written informed consent or "treatment agreement" [1]. This agreement should address potential side effects, tolerance and/or physical dependence, drug interactions, motor skill impairment, limited evidence of long-term benefit, misuse, dependence, addiction, and overdose. Informed consent documents should include information regarding the risk/benefit profile for the drug(s) being prescribed. The prescribing policies should be clearly delineated, including the number/frequency of refills, early refills, and procedures for lost or stolen medications.

The treatment agreement also outlines joint physician and patient responsibilities. The patient agrees to using medications safely, refraining from "doctor shopping," and consenting to routine urine drug testing (UDT). The prescriber's responsibility is to address unforeseen problems and prescribe scheduled refills. Reasons for opioid therapy change or discontinuation should be listed. Agreements can also include sections related to follow-up visits, monitoring, and safe storage and disposal of unused drugs.

PERIODIC REVIEW AND MONITORING

When implementing a chronic pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function [1]. This can include input from family members and/or the state PDMP. During the initiation phase and during any changes to the dosage or agent used, patient contact should be increased. At every visit, chronic opioid response may be monitored according to the "5 A's" [1,23]:

- Analgesia

- Activities of daily living

- Adverse or side effects

- Aberrant drug-related behaviors

- Affect (i.e., patient mood)

Signs and symptoms that, if present, may suggest a problematic response to the opioid and interference with the goal of functional improvement include [24]:

- Excessive sleeping or days and nights turned around

- Diminished appetite

- Short attention span or inability to concentrate

- Mood volatility, especially irritability

- Lack of involvement with others

- Impaired functioning due to drug effects

- Use of the opioid to regress instead of re-engaging in life

- Lack of attention to hygiene and appearance

The decision to continue, change, or terminate opioid therapy is based on progress toward treatment objectives and absence of adverse effects and risks of overdose or diversion [1]. Satisfactory therapy is indicated by improvements in pain, function, and quality of life. Brief assessment tools to assess pain and function may be useful, as may UDTs. Treatment plans may include periodic pill counts to confirm adherence and minimize diversion.

Involvement of Family

Family members of the patient can provide the clinician with valuable information that better informs decision making regarding continuing opioid therapy. Family members can observe whether a patient is losing control of his or her life or becoming less functional or more depressed during the course of opioid therapy. They can also provide input regarding positive or negative changes in patient function, attitude, and level of comfort. The following questions can be asked of family members or a spouse to help clarify whether the patient's response to opioid therapy is favorable or unfavorable [24]:

- Is the person's day centered around taking the opioid medication? Response can help clarify long-term risks and benefits of the medication and identify other treatment options.

- Does the person take pain medication only on occasion, perhaps three or four times per week? If yes, the likelihood of addiction is low.

- Have there been any other substance (alcohol or drug) abuse problems in the person's life? An affirmative response should be taken into consideration when prescribing.

- Does the person in pain spend most of the day resting, avoiding activity, or feeling depressed? If so, this suggests the pain medication is failing to promote rehabilitation. Daily activity is essential, and the patient may be considered for enrollment in a graduated exercise program

- Is the person in pain able to function (e.g., work, do household chores, play) with pain medication in a way that is clearly better than without? If yes, this suggests the pain medication is contributing to wellness.

Assessment Tools

VIGIL

VIGIL is the acronym for a five-step risk management strategy designed to empower clinicians to appropriately prescribe opioids for pain by reducing regulatory concerns and to give pharmacists a framework for resolving ambiguous opioid analgesic prescriptions in a manner that preserves legitimate patient need while potentially deterring diverters. The components of VIGIL are:

- Verification: Is this a responsible opioid user?

- Identification: Is the identity of this patient verifiable?

- Generalization: Do we agree on mutual responsibilities and expectations?

- Interpretation: Do I feel comfortable allowing this person to have controlled substances?

- Legalization: Am I acting legally and responsibly?

The foundation of VIGIL is a collaborative physician/pharmacist relationship [25].

Current Opioid Misuse Measure (COMM)

The Current Opioid Misuse Measure (COMM) is a 17-item patient self-report assessment designed to help clinicians identify misuse or abuse in chronic pain patients. Unlike the ORT and the SOAPP-R, the COMM identifies aberrant behaviors associated with opioid misuse in patients already receiving long-term opioid therapy [26]. Sample questions include: In the past 30 days, how often have you had to take more of your medication than prescribed? In the past 30 days, how much of your time was spent thinking about opioid medications (e.g., having enough, taking them, dosing schedule)?

Pain Assessment and Documentation Tool (PADT)

Guidelines by the CDC, the Federation of State Medical Boards (FSMB), and the Joint Commission stress the importance of documentation from both a healthcare quality and medicolegal perspective. Research has found widespread deficits in chart notes and progress documentation with chronic pain patients receiving opioid therapy, and the Pain Assessment and Documentation Tool (PADT) was designed to address these shortcomings [46]. The PADT is a clinician-directed interview, with most sections (e.g., analgesia, activities of daily living, adverse events) consisting of questions asked of the patient. However, the potential aberrant drug-related behavior section must be completed by the physician based on his or her observations of the patient.

The Brief Intervention Tool

The Brief Intervention Tool is a 26-item, "yes-no," patient-administered questionnaire used to identify early signs of opioid abuse or addiction. The items assess the extent of problems related to drug use in several areas, including drug use-related functional impairment [22].

Urine Drug Tests

UDTs may be used to monitor adherence to the prescribed treatment plan and to detect unsanctioned drug use. They should be used more often in patients receiving addiction therapy, but clinical judgment is the ultimate guide to testing frequency (Table 2) [47]. The CDC recommends clinicians should use UDT before starting opioid therapy and consider UDT at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs [10]. However, this recommendation was based on low-quality evidence that indicates little confidence in the effect estimate.

Table 2: PATIENT RISK LEVEL AND FREQUENCY OF MONITORING

Monitoring Tool

Patient Risk Level

Low

Medium

High

Urine drug test

Every 1 to 2 years

Every 6 to 12 months

Every 3 to 6 months

State prescription drug monitoring program

Twice per year

Three times per year

Four times per year

Source: [47]

Initially, testing involves the use of class-specific immunoassay drug panels [1]. If necessary, this may be followed with gas chromatography/mass spectrometry for specific drug or metabolite detection. It is important that testing identifies the specific drug rather than the drug class, and the prescribed opioid should be included in the screen. Any abnormalities should be confirmed with a laboratory toxicologist or clinical pathologist. Immunoassay may be used point-of-care for "on-the-spot" therapy changes, but the high error rate prevents its use in major clinical decisions except with liquid chromatography coupled to tandem mass spectrometry confirmation.

Urine test results suggesting opioid misuse should be discussed with the patient using a positive, supportive approach. The test results and the patient discussion should be documented.

CONCURRENT USE OF BENZODIAZEPINES

In 2015, 23% of persons who died of an opioid overdose also tested positive for benzodiazepines, a class of sedative medication commonly prescribed for anxiety, insomnia, panic attack, and muscle spasm [87]. Benzodiazepines work by raising the level of the neurotransmitter gamma-aminobutyric acid (GABA) in the brain. Common formulations include diazepam, alprazolam, and clonazepam. Combining benzodiazepines with opioids is unsafe because both classes of drug cause central nervous system depression and sedation and can decrease respiratory drive—the usual cause of overdose fatality. Both classes have the potential for drug dependence and addiction.

The CDC recommends that healthcare providers avoid prescribing benzodiazepines concurrently with opioids whenever possible [10]. If a benzodiazepine is to be discontinued, the clinician should taper the medication gradually, because abrupt withdrawal can lead to rebound anxiety and complications such as hallucinations, seizures, delirium tremens, and, in rare instances, death. A commonly used tapering schedule is a reduction of the benzodiazepine dose by 25% every one to two weeks [10].

CONSULTATION AND REFERRAL

It is important to seek consultation or patient referral when input or care from a pain, psychiatry, addiction, or mental health specialist is necessary. Clinicians who prescribe opioids should become familiar with opioid addiction treatment options (including licensed opioid treatment programs for methadone and office-based opioid treatment for buprenorphine) if referral is needed [1].

Ideally, providers should be able to refer patients with active substance abuse who require pain treatment to an addiction professional or specialized program. In reality, these specialized resources are scarce or non-existent in many areas [1]. Therefore, each provider will need to decide whether the risks of continuing opioid treatment while a patient is using illicit drugs outweigh the benefits to the patient in terms of pain control and improved function [48].

MEDICAL RECORDS

As noted, documentation is a necessary aspect of all patient care, but it is of particular importance when opioid prescribing is involved. All clinicians should maintain accurate, complete, and up-to-date medical records, including all written or telephoned prescription orders for opioid analgesics and other controlled substances, all written instructions to the patient for medication use, and the name, telephone number, and address of the patient's pharmacy [1]. Good medical records demonstrate that a service was provided to the patient and that the service was medically necessary. Regardless of the treatment outcome, thorough medical records protect the prescriber.

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

Patients and caregivers should be counseled regarding the safe use and disposal of opioids. As part of its mandatory Risk Evaluation and Mitigation Strategy (REMS) for extended-release/long-acting opioids, the U.S. Food and Drug Administration (FDA) has developed a patient counseling document with information on the patient's specific medications, instructions for emergency situations and incomplete pain control, and warnings not to share medications or take them unprescribed [16]. A copy of this form may be accessed online at https://www.fda.gov/media/86281/download.

When prescribing opioids, clinicians should provide patients with the following information [16]:

- Product-specific information

- Taking the opioid as prescribed

- Importance of dosing regimen adherence, managing missed doses, and prescriber contact if pain is not controlled

- Warning and rationale to never break or chew/crush tablets or cut or tear patches prior to use

- Warning and rationale to avoid other central nervous system depressants, such as sedative-hypnotics, anxiolytics, alcohol, or illicit drugs

- Warning not to abruptly halt or reduce the opioid without physician oversight of safe tapering when discontinuing

- The potential of serious side effects or death

- Risk factors, signs, and symptoms of overdose and opioid-induced respiratory depression, gastrointestinal obstruction, and allergic reactions

- The risks of falls, using heavy machinery, and driving

- Warning and rationale to never share an opioid analgesic

- Rationale for secure opioid storage

- Warning to protect opioids from theft

- Instructions for disposal of unneeded opioids, based on product-specific disposal information

There are no universal recommendations for the proper disposal of unused opioids, and patients are rarely advised of what to do with unused or expired medications [49]. According to the Office of National Drug Control Policy, most medications that are no longer necessary or have expired should be removed from their containers, mixed with undesirable substances (e.g., cat litter, used coffee grounds), and put into an impermeable, nondescript container (e.g., disposable container with a lid or a sealed bag) before throwing in the trash [50]. Any personal information should be obscured or destroyed. The FDA recommends that certain medications, including oxycodone/acetaminophen (Percocet), oxycodone (OxyContin tablets), and transdermal fentanyl (Duragesic Transdermal System), be flushed down the toilet instead of thrown in the trash [50]. Patients should be advised to flush prescription drugs down the toilet only if the label or accompanying patient information specifically instructs doing so.

The American College of Preventive Medicine has established best practices to avoid diversion of unused drugs and educate patients regarding drug disposal [49]:

- Consider writing prescriptions in smaller amounts.

- Educate patients about safe storing and disposal practices.

- Give drug-specific information to patients about the temperature at which they should store their medications. Generally, the bathroom is not the best storage place. It is damp and moist, potentially resulting in potency decrements, and accessible to many people, including children and teens, resulting in potential theft or safety issues.

- Ask patients not to advertise that they are taking these types of medications and to keep their medications secure.

- Refer patients to community "take back" services overseen by law enforcement that collect controlled substances, seal them in plastic bags, and store them in a secure location until they can be incinerated. Contact your state law enforcement agency or visit https://www.dea.gov to determine if a program is available in your area.

DISCONTINUING OPIOID THERAPY

The decision to continue or end opioid prescribing should be based on a physician-patient discussion of the anticipated benefits and risks. An opioid should be discontinued with resolution of the pain condition, intolerable side effects, inadequate analgesia, lack of improvement in quality of life despite dose titration, deteriorating function, or significant aberrant medication use [1,10].

Clinicians should provide physically dependent patients with a safely structured tapering protocol. Withdrawal is managed by the prescribing physician or referral to an addiction specialist. Patients should be reassured that opioid discontinuation is not the end of treatment; continuation of pain management will be undertaken with other modalities through direct care or referral.

As a side note, cannabis use by chronic pain patients receiving opioid therapy has traditionally been viewed as a treatment agreement violation that is grounds for termination of opioid therapy. However, some now argue against cannabis use as a rationale for termination or substantial treatment and monitoring changes, especially considering the increasing legalization of medical use at the state level [48].

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For patients who are not proficient in English, it is important that information regarding the risks associated with the use of opioids and available resources be provided in their 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. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers who ultimately enhance the clinical encounter. In any case in which information regarding treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

Research has more closely defined the location of prescribed opioid diversion into illicit use in the supply chain from the manufacturer to the distributor, retailer, and the end user (the pain patient). This information carries with it substantial public policy and regulatory implications. The 2015 National Survey on Drug Use and Health asked non-medical users of prescription opioids how they obtained their most recently used drugs [51]. Among persons 12 years of age or older, 40.5% obtained their prescription opioids from a friend or relative for free, 34.0% got them through a prescription from one doctor (vs. 17.3% in 2009–2010), 9.4% bought them from a friend or relative, and 3.8% took them from a friend or relative without asking [51]. Less frequent sources included a drug dealer or other stranger (4.9%); multiple doctors (1.7%); and theft from a doctor's office, clinic, hospital, or pharmacy (0.7%) (vs. 0.2% in 2009–2010) [51].

As discussed, UDTs can give insight into patients who are misusing opioids. A random sample of UDT results from 800 pain patients treated at a Veterans Affairs facility found that 25.2% were negative for the prescribed opioid while 19.5% were positive for an illicit drug/unreported opioid [52]. Negative UDT results for the prescribed opioid do not necessarily indicate diversion, but may indicate the patient halted his/her use due to side effects, lack of efficacy, or pain remission. The concern arises over the increasingly stringent climate surrounding clinical decision-making regarding aberrant UDT results and that a negative result for the prescribed opioid or a positive UDT may serve as the pretense to terminate a patient rather than guide him/her into addiction treatment or an alternative pain management program [53].

In addition to aberrant urine screens, there are certain behaviors that are suggestive of an emerging opioid use disorder. The most suggestive behaviors are [48,54,55]:

- Selling medications

- Prescription forgery or alteration

- Injecting medications meant for oral use

- Obtaining medications from nonmedical sources

- Resisting medication change despite worsening function or significant negative effects

- Loss of control over alcohol use

- Using illegal drugs or non-prescribed controlled substances

- Recurrent episodes of:

- Prescription loss or theft

- Obtaining opioids from other providers in violation of a treatment agreement

- Unsanctioned dose escalation

- Running out of medication and requesting early refills

Behaviors with a lower level of evidence for their association with opioid misuse include [48,54,55]:

- Aggressive demands for more drug

- Asking for specific medications

- Stockpiling medications during times when pain is less severe

- Using pain medications to treat other symptoms

- Reluctance to decrease opioid dosing once stable

- In the earlier stages of treatment:

- Increasing medication dosing without provider permission

- Obtaining prescriptions from sources other than the pain provider

- Sharing or borrowing similar medications from friends/family

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

There are a number of actions that prescribers and dispensers can take to prevent or intervene in cases of drug diversion. These actions can be generally categorized based on the various mechanisms of drug diversion.

Prevention is the best approach to addressing drug diversion. As noted, the most common source of nonmedical use of prescribed opioids is from a family member or friend, through sharing, buying, or stealing. To avoid drug sharing among patients, healthcare professionals should educate patients on the dangers of sharing opioids and stress that "doing prescription drugs" is the same as "using street drugs" [49]. In addition, patients should be aware of the many options available to treat chronic pain aside from opioids. To prevent theft, patients should be advised to keep medications in a private place and to refrain from telling others about the medications being used.

Communication among providers and pharmacies can help to avoid inappropriate attainment of prescription drugs through "doctor shopping." Prescribers should keep complete and up-to-date records for all controlled substance prescribing. When possible, electronic medical records should be integrated between pharmacies, hospitals, and managed care organizations [49]. If available, it is also best practice to periodically request a report from the state's prescription reporting program to evaluate the prescribing of opioids to your pahttp://www.netce.com/tients by other providers [49].

When dealing with patients suspected of drug seeking/diversion, first inquire about prescription, over-the-counter, and illicit drug use and perform a thorough examination [49,56]. Pill counting and/or UDT may be necessary to investigate possible drug misuse. Photo identification or other form of identification and social security number may be required prior to dispensing the drug, with proof of identity documented fully. If a patient is displaying suspicious behaviors, consider prescribing for limited quantities [56].

If a patient is found to be abusing prescribed opioids, this is considered a violation of the treatment agreement and the clinician must make the decision whether or not to continue the therapeutic relationship. If the relationship is terminated, it must be done ethically and legally. The most significant issue is the risk of patient abandonment, which is defined as ending a relationship with a patient without consideration of continuity of care and without providing notice to the patient. The American Medical Association Code of Ethics states that physicians have an obligation to support continuity of care for their patients. While physicians have the option of withdrawing from a case, they should notify the patient (or authorized decision maker) long enough in advance to permit the patient to secure another physician and facilitate transfer of care when appropriate [57]. Patients may also be given resources and/or recommendations to help them locate a new clinician.

Patients with chronic pain found to have an ongoing substance abuse problem or addiction should be referred to a pain specialist for continued treatment. Theft or loss of controlled substances is reported to the DEA. If drug diversion has occurred, the activity should be documented and a report to law enforcement should be made [58].

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

In response to the rising incidence in prescription opioid abuse, addiction, diversion, and overdose since the late 1990s, the FDA has mandated opioid-specific REMS to reduce the potential negative patient and societal effects of prescribed opioids. Other elements of opioid risk mitigation include FDA partnering with other governmental agencies, state professional licensing boards, and societies of healthcare professionals to help improve prescriber knowledge of appropriate and safe opioid prescribing and safe home storage and disposal of unused medication [24].

Several regulations and programs at the state level have been enacted in an effort to reduce prescription opioid abuse, diversion, and overdose, including [59]:

- Physical examination required prior to prescribing

- Tamper-resistant prescription forms

- Pain clinic regulatory oversight

- Prescription limits

- Prohibition from obtaining controlled substance prescriptions from multiple providers

- Patient identification required before dispensing

- Immunity from prosecution or mitigation at sentencing for individuals seeking assistance during an overdose

CONTROLLED SUBSTANCES LAWS/RULES

The U.S. Drug Enforcement Administration (DEA) is responsible for formulating federal standards for the handling of controlled substances. In 2011, the DEA began requiring every state to implement electronic databases that track prescribing habits, referred to as PDMPs. Specific policies regarding controlled substances are administered at the state level [60].

According to the DEA, drugs, substances, and certain chemicals used to make drugs are classified into five distinct categories or schedules depending upon the drug's acceptable medical use and the drug's abuse or dependency potential [61]. The abuse rate is a determinate factor in the scheduling of the drug; for example, Schedule I drugs are considered the most dangerous class of drugs with a high potential for abuse and potentially severe psychologic and/or physical dependence.

STATE-SPECIFIC LAWS AND RULES

Most states have established laws and rules governing the prescribing and dispensing of opioid analgesics. It is each prescriber's responsibility to have knowledge of and adhere to the laws and rules of the state in which he or she prescribes.

Arkansas Laws and Rules

An excerpt from the Arkansas Code rules and regulations relating to the regulation of controlled substances is available by clicking here.

Colorado Laws and Rules

An excerpt from the Colorado Revised Statutes relating to the electronic prescription drug monitoring program, and the full Guidelines for the Safe Prescribing and Dispensing of Opioids are available by clicking here.

New Mexico Laws and Rules

An excerpt from the New Mexico Administrative Code Title 16, Chapter 10, Part 14: Management of Pain and Other Conditions with Controlled Substances is available by clicking here.

New York Laws and Rules

An excerpt from the New York Code, Rules, and Regulations relating to the regulation of controlled substances is available by clicking here.

Vermont Laws and Rules

Information on use of the Vermont Prescription Monitoring System (VPMS) is available by clicking here.

Wisconsin Laws and Rules

The Wisconsin Medical Examining Board Opioid Prescribing Guideline is available by clicking here.

Washington Laws and Rules

Laws governing the prescribing of opioids in the state of Washington are available by clicking here.

Michigan Laws and Rules

A summary of 2017 legislation enacted in Michigan to curb substance abuse and drug diversion is available by clicking here.

Nebraska Laws and Rules

An excerpt reprinted from the Nebraska Revised Statutes 71-2454 and 71-2455 is available by clicking here.

8. MANAGEMENT OF OPIOID USE DISORDER

Management of opioid dependence entails different methods to achieve different goals, depending on the health situation and treatment history of the patient. These treatment approaches include [62]:

- Crisis intervention: Directed at immediate survival by reversing the potentially lethal effects of overdose with an opioid antagonist.

- Harm reduction: Intended to reduce morbidity and mortality associated with use of dirty needles and overdose.

- Detoxification/withdrawal: Aims to remove the opioid of abuse from the patient’s body, either through gradual taper and substitution of a long-acting opioid or through ultra-rapid opioid detoxification.

- Maintenance treatment or opioid (agonist) replacement therapy: Aimed at reduction/elimination of illicit opioid use and lifestyle stabilization. Maintenance follows detoxification/withdrawal, whereby the patient is tapered from short-acting opioids and introduced to a long-acting opioid agonist, such as methadone or buprenorphine. Patients remain on agonist therapy short-term, long-term, or indefinitely depending on individual needs.

- Abstinence-oriented therapy: Treatment directed at cure. The patient is tapered off of short-acting opioids during the detoxification/withdrawal process and may be placed on an opioid antagonist with the goal of minimizing relapse.

All treatment approaches share the common goal of improving health outcomes and reducing drug-related criminality and public nuisance [62].

CRISIS INTERVENTION

In response to acute overdose, the short-acting opioid antagonist naloxone is considered the criterion standard. Naloxone is effective in reversing respiratory depression and coma in overdose patients. There is no evidence that subcutaneous or intramuscular use is inferior to intravenous naloxone. This prompted discussion of making naloxone available to the general public for administration outside the healthcare setting to treat acute opioid overdose, and in April 2014, the FDA approved naloxone as an autoinjector dosage form for home use by family members or caregivers [63]. The autoinjector delivers 0.4 mg naloxone intramuscularly or subcutaneously. The autoinjector comes with visual and voice instruction, including directs to seek emergency medical care after use [63]. In November 2015, the FDA approved intranasal naloxone after a fast-track designation and priority review. Intranasal naloxone is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. It is available in a ready-to-use 4-mg single-dose sprayer [64,65].

HARM REDUCTION

Harm reduction measures are primarily employed to minimize the morbidity and mortality from opioid abuse and to reduce public nuisance [66]. As a part of this effort, measures to prevent and minimize the frequency and severity of overdoses have been identified. Enrollment in opioid substitution therapy, with agents such as methadone and buprenorphine, substantially reduces the risk of overdose as well as the risk for infection and other sequelae of illicit opioid use [66].

DETOXIFICATION AND WITHDRAWAL

The process of tapering opioid-dependent patients from agonist therapy is often referred to as detoxification, or more accurately, medically supervised withdrawal [67,68]. Its purpose is to eliminate physical dependence on opioid medications. It can be considered the medically supported transition to a medication-free state or to antagonist therapy. A careful and thorough review of the risks and benefits of detoxification should be provided and informed consent obtained from patients prior to choosing this option [68,69]. Detoxification alone should not be considered a treatment and should only be promoted in the context of a well-planned relapse-prevention program [62,68].

Discontinuation of opioid use must be implemented slowly and cautiously to avoid a marked abstinence syndrome. Withdrawal symptoms may not begin for days after abrupt discontinuation of methadone or buprenorphine given their longer half-lives. Protracted abstinence, or post-acute withdrawal, may last for several months and is characterized by asthenia, depression, and hypotension. Post-acute withdrawal is more likely to occur with methadone than other opioids [67].

The three primary treatment modalities used for detoxification are opioid agonists, non-opioid medications, and rapid and ultra-rapid opioid detoxification [67]. The most frequently employed method of opioid withdrawal is a slow, supervised detoxification during which an opioid agonist, usually methadone, is substituted for the abused opioid [70]. Methadone is the most frequently used opioid agonist due to the convenience of its once-a-day dosing [67]. Methadone is highly bound to plasma proteins and accumulates more readily than heroin in all body tissues. Methadone also has a longer half-life, approximately 22 hours, which makes withdrawal more difficult than from heroin. Substitution therapy with methadone has a high initial dropout rate (30% to 90%) and an early relapse rate. Alternative pharmacologic detoxification choices include clonidine (with or without methadone), midazolam, trazodone, or buprenorphine [70].

Many opioid withdrawal symptoms, such as restlessness, rhinorrhea, lacrimation, diaphoresis, myosis, piloerection, and cardiovascular changes, are mediated through increased sympathetic activation, the result of increased neuron activity in the locus coeruleus. Non-opioid agents (such as clonidine), which inhibit hyperactivation of noradrenergic pathways stemming from the locus coeruleus nucleus, have been used to manage acute withdrawal [70,71]. The first non-opioid treatment approved for the management of opioid withdrawal symptoms is lofexidine [86]. In studies, lofexidine resulted in less severe withdrawal symptoms and greater treatment retention than placebo.

However, some withdrawal symptoms, including anxiety and myalgias, are resistant to clonidine; benzodiazepines and nonsteroidal anti-inflammatory agents may be necessary to treat these symptoms. To mitigate withdrawal symptoms and assist in detoxification, alpha2-agonists, opioid agonist-antagonists, benzodiazepines, and antidepressants have been used [70].

Following detoxification, patients may feel exhausted and weak. Other complications, such as slight variations in hemodynamic status and gastrointestinal tract symptoms, follow quickly and may take several days to resolve. Muscle cramps and low back pain can be treated with nonsteroidal anti-inflammatory drugs. However, the newer cyclooxygenase-2 (COX-2) inhibitors may be advantageous because they produce fewer gastrointestinal side effects [70]. Insomnia is a frequent aspect of acute and protracted withdrawal, as opioids disrupt the normal sleep-wake cycle and many addicts require narcotics to sleep. Although long-term disruption of the normal sleep-wake cycle cannot be corrected rapidly, melatonin (3 mg), benzodiazepines, or antihistamines can be used with beneficial effects. Hypnosis and relaxation techniques are nonpharmacologic methods that may also be used [70]. Psychosocial treatments offered in addition to pharmacologic detoxification treatments positively impact treatment retention and completion, results at follow-up, and compliance [72,73].

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

Two principle treatment modalities are offered for opioid-dependent patients: agonist maintenance or detoxification followed by outpatient or residential drug-free treatment. Both can be effective, with no clear indication for each, although agonist maintenance leads to greater treatment retention [74]. A reasonable approach is initial outpatient or residential treatment referral for patients relatively new to treatment, with agonist maintenance appropriate for patients with history of treatment failures, greater disease severity, or a history of drug overdoses. Naltrexone is best reserved for patients with strong legal incentives to abstain, family involvement to monitor treatment, or concurrent enrollment and involvement in a psychosocial intervention [75].

At present, there are no direct interventions that are capable of reversing the effects of drugs of dependence on learning and motivation systems [76]. Instead, the management of opioid dependence often consists of pharmacotherapy with methadone and buprenorphine, which do not eliminate physical dependence on opioids. These medications instead reduce the use of illicit opioids and produce very strong positive health outcomes as measured by decreased mortality, improved mental and physical health, and reduced risk of disease transmission [76]. Considering the high rate of relapse after detoxification, maintenance therapy with methadone or buprenorphine is currently considered to be the first-line treatment for opioid-dependent patients [62].

Any treatment for opioid dependence must take into consideration the chronic relapsing nature of opioid dependence, characterized by a variable course of relapse and remission in many patients. Treatments should emphasize patient motivation, psychoeducation, continuity of care, integration of pharmacotherapy and psychosocial support, and improved liaison between the treatment staff and the judicial system. Pharmacotherapy must be offered in a comprehensive healthcare context that also addresses the psychosocial aspects of dependence [62]. Opioid-dependent patients frequently suffer from physical and psychiatric disorders, and targeted interventions of psychiatric comorbidity are essential in improving treatment outcome for these patients [62]. Polysubstance abuse is the rule rather than the exception in opioid dependence, and concurrent use of other substances should be carefully monitored and treated when necessary [62]. Incarceration should never automatically result in discontinuation of an existing treatment; imprisonment offers a window of opportunity to initiate or restart treatment with a necessary continuation after release [62].

Agonist Replacement Therapy

The goal of opioid replacement therapy is to reduce illicit drug use and associated health risks, with secondary goals of reducing unsafe sexual practices, improving vocational and psychosocial functioning, and enhancing quality of life [67]. The theoretical basis of opioid replacement stems from the finding that chronic opioid use results in an endogenous opioid deficiency as a result of the down-regulation of opioid production. This creates overwhelming cravings and necessitates interventions that shift the dependent patient’s attention and drive from obsessive preoccupation with the next use of opioids to more adaptive areas of focus, such as work, relationships, and non-drug leisure activities [67].

The neurobiologic changes resulting from prolonged opioid exposure provide a rationale for specific pharmacotherapies, such as long-acting opioid agonists, that are aimed at stabilizing these complex systems [77]. Opioid agonist maintenance treatment stabilizes brain neurochemistry by replacing short-acting opioids, which can create rapid changes in opioid levels in the serum and brain, with a long-acting opioid that has relative steady-state pharmacokinetics. Opioid agonist maintenance treatment is designed to have minimal euphoric effect, block the euphoria associated with administration of exogenous opioids (competitive antagonism), eliminate the risk of infectious disease and health consequences associated with injection drug use, and prevent opioid withdrawal [77].

Successful maintenance treatment entails stabilization of opioid dependence through opioid receptor occupation. Positron emission tomography studies have revealed that only 25% to 35% of brain opioid receptors are occupied during steady-state methadone maintenance, suggesting that unoccupied opioid receptors disrupted during cycles of opioid abuse could normalize during methadone maintenance [67]. Additionally, opioid replacement therapy blocks much of the euphoria from illicit heroin use. Long-term opioid agonist treatment also has a positive impact on public health, through significantly reducing overdose deaths, criminal activity, and the spread of infectious disease [67].

As of 2018, there were 1,519 treatment programs including opioid replacement therapy in the United States [78]. However, this represents only an estimated 19% of all opioid-dependent patients. Although some have criticized the practice of methadone and buprenorphine therapy on the grounds that one opioid is merely being substituted for another, the clinical benefits strongly support this treatment modality [67]. When compared to active street heroin users, these benefits include a four-times lower HIV seroprevalence rates, 70% fewer crime-days per year, and a one-year mortality rate of 1% (versus 8%) [79].

Abstinence-Oriented Therapies

The primary goal of abstinence-oriented interventions is cure, which is defined as long-term, stable abstinence from all opioids. Abstinence is achieved in two phases: detoxification and relapse prevention. Outcomes in abstinence-oriented programs are generally poor [62].

The primary goal of pharmacotherapy during detoxification is to alleviate opioid withdrawal severity and associated distress/medical complications and to enhance patient motivation to continue treatment. Withdrawal can also be reduced by psychosocial measures, such as contingency management or counseling, and as discussed, the addition of psychosocial therapy to pharmacologic treatment increases efficacy. Buprenorphine and clonidine are both used to manage withdrawal symptoms, but buprenorphine’s advantages, compared with clonidine, are related to its favorable side effect profile and positive effects on well-being and psychosocial variables [62].

12-Step/Self-Help Programs

Twelve-step programs for opioid abuse and dependence include Narcotics Anonymous (NA) and Methadone Anonymous (MA) and are modeled after Alcoholics Anonymous (AA), an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA has helped hundreds of thousands of alcoholics achieve sobriety [80]. The 12-step model emphasizes acceptance of dependence as a chronic, progressive disease that can be arrested through abstinence but not cured. Additional elements include spiritual growth, personal responsibility, and helping other addicted persons. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and are a resource for emotional support [80]. Although research on efficacy and patient outcomes in NA and MA is very limited, many prominent researchers emphasize the important role ongoing involvement in 12-step programs plays in recovery from substance abuse [81].

The understanding of drug dependence as a chronic and relapsing disorder has helped professionals gain a better comprehension of the vital role played by 12-step programs. Every patient attempting to recover from a substance use disorder will encounter a time when he or she faces urges to use without the resources or assistance of healthcare professionals. Twelve-step programs are not considered treatment, nor are they intended as substitutes for treatment. Instead, they are organizations that provide ongoing and indefinite support in the achievement and maintenance of abstinence and in personal growth and character development [81].

Part of the effectiveness of NA and MA is related to their ability to provide a competing and alternative reinforcer to drug use. Involvement in 12-step programs can enhance the quality of social support and the social network of the member, a potentially highly reinforcing aspect the person stands to forfeit if they resume drug using. Other reinforcing elements of 12-step involvement include recognition for increasingly durable periods of abstinence and frequent awareness of the consequences of drug and alcohol use through attendance of meetings [82]. Research shows that establishing a pattern of 12-step program attendance early in treatment predicts the level of ongoing involvement. Emphasis and facilitation of early engagement in a 12-step program involvement are key [83].

STIGMA OF ADDICTION

Many terms used in discussions of opioid use and misuse may have ambiguous meanings, and the absence of consensus in the terminology and definitions of substance use, substance use disorders, and addiction has led to considerable confusion and misconceptions. These misconceptions may be harbored by clinicians, patients, family members, and the public and can negatively impact patient interaction, assessment, treatment, and outcomes. This, coupled with pervasive stereotypes about what an opioid addict “looks” like, can negatively impact willingness to receive treatment or seek help and impair the patient’s self-worth and mental health. Correction of these erroneous beliefs and attitudes is important, as is the use of nonpejorative and nonstigmatizing language when describing opioid analgesics, the patients who need them, and patients who develop aberrant behaviors or addiction involving opioids [88,89]. It is important for all healthcare professionals to remember that addiction can affect any patients, regardless of age, sex, socioeconomic status, education, ability, or race.

PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

The relapse rate among patients receiving treatment for opioid dependence and other substance abuse is high (25% to 97%), comparable to that of other patients with chronic relapsing conditions, including hypertension and asthma [84]. Many cases of relapse are attributable to treatment noncompliance and lack of lifestyle modification [85].

Duration of agonist replacement therapy is usually recommended as a minimum of one year, and some patients will receive agonist replacement therapy indefinitely. Longer durations of treatment are associated with higher rates of abstinence from illicit opioids [76].

Much remains unknown about patient outcomes following termination of long-term opioid replacement therapy. Some patients aim to achieve total abstinence from all opioids, but little is known about patient characteristics and strategies used among those who remain abstinent. It is likely that at least some of the patients who remain abstinent from all opioids do so with the help of a 12-step support program, such as NA [76].

9. CONCLUSION

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat patients with opioids. By implementing these tools, the clinician can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

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Evidence-Based Practice Recommendations Citations

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