30100 • Understanding Postoperative Cognitive Dysfunction

Table of Contents

30100 • Understanding Postoperative Cognitive Dysfunction

How to Receive Credit

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

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. EXECUTIVE FUNCTION AND ITS RELATIONSHIP TO POCD

3. A REVIEW OF ANESTHETICS

INTRAVENOUS AGENTS: FOCUS ON PROPOFOL AND KETAMINE

INHALED AGENTS: FOCUS ON DESFLURANE, ISOFLURANE, AND SEVOFLURANE

4. OVERVIEW OF POSTOPERATIVE COGNITIVE DYSFUNCTION

POSTOPERATIVE NEUROLOGIC SYNDROMES VERSUS POCD

POCD RISK BY TYPE OF SURGERY

POSSIBLE MECHANISMS UNDERLYING POCD

5. PROGNOSIS AND TREATMENT FOR THE PATIENT WITH POCD

ANESTHESIA AND SURGICAL TECHNIQUES TO DECREASE RISK OR EFFECTS OF POCD

APPROACHES TO TREATMENT

6. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

30100 • Understanding Postoperative Cognitive Dysfunction

Richard E. Haas, BSN, MSN, EdM, PhD, CRNA, LTC US Army Nurse Corps (Retired)

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

Postoperative cognitive dysfunction (POCD) is a significant and sometimes devastating complication that can occur in the hours, days, or even months following surgery. Although biomarkers may help identify when POCD has occurred, there are currently no routinely used preoperative predictors that are both highly sensitive and specific. Additionally, therapeutic interventions remain limited, and no gold-standard pharmacologic or neurocognitive treatment has been established. While many patients experience only transient cognitive changes, a subset may suffer prolonged executive function impairment, leading to decreased productivity, impaired activities of daily living, social challenges, increased morbidity, and higher mortality risk. This course provides an in-depth overview of POCD, including its pathophysiology, clinical manifestations, duration patterns, and modifiable and nonmodifiable risk factors. Participants will examine the current state of evidence regarding biomarkers, prevention strategies, and supportive management approaches. Emphasis will be placed on the critical role nurses play across care settings in early recognition, patient and family education, environmental safety, risk mitigation, and interdisciplinary collaboration.

30100 • Understanding Postoperative Cognitive Dysfunction

Education Category. Medical / Surgical

Release Date. 03/01/2026

Expiration Date. 02/28/2029

How to Receive Credit

To complete this course for continuing education credit please go to http://www.netce.com/course/3409 in your browser.

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

Course Overview

Postoperative cognitive dysfunction (POCD) is a significant and sometimes devastating complication that can occur in the hours, days, or even months following surgery. Although biomarkers may help identify when POCD has occurred, there are currently no routinely used preoperative predictors that are both highly sensitive and specific. Additionally, therapeutic interventions remain limited, and no gold-standard pharmacologic or neurocognitive treatment has been established. While many patients experience only transient cognitive changes, a subset may suffer prolonged executive function impairment, leading to decreased productivity, impaired activities of daily living, social challenges, increased morbidity, and higher mortality risk. This course provides an in-depth overview of POCD, including its pathophysiology, clinical manifestations, duration patterns, and modifiable and nonmodifiable risk factors. Participants will examine the current state of evidence regarding biomarkers, prevention strategies, and supportive management approaches. Emphasis will be placed on the critical role nurses play across care settings in early recognition, patient and family education, environmental safety, risk mitigation, and interdisciplinary collaboration.

Audience

This course is designed for nurses involved in the care of patients before and after operative procedures.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

NetCE designates this continuing education activity for 5 ANCC contact hour(s). NetCE designates this continuing education activity for 1 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 6 hours for Alabama nurses. NetCE is authorized by IACET to offer 0.5 CEU(s) for this program. AACN Synergy CERP Category A.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 30, 2029); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2027; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Course Objective

The purpose of this course is to enhance nurse's understanding of postoperative cognitive dysfunction (POCD) by reviewing its clinical presentation, risk factors, and current evidence regarding biomarkers, prevention, and management, while identifying supportive care strategies to mitigate functional impact and promote patient recovery.

Learning Objectives

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

1. Review the concept of executive function and its relation to postoperative cognitive dysfunction (POCD).

2. Identify tools available to assess neuropsychologic function.

3. Compare and contrast the available intravenous anesthetics, particularly ketamine and propofol.

4. Describe the mechanism or action of the inhaled anesthetics.

5. Distinguish between POCD and other postoperative neurologic conditions.

6. Discuss the POCD risk associated with various operative procedures.

7. Analyze the possible mechanisms underlying POCD.

8. Outline the treatment and prognosis of POCD.

Faculty

Richard E. Haas, BSN, MSN, EdM, PhD, CRNA, LTC US Army Nurse Corps (Retired), is a retired nurse anesthetist and prehospital registered nurse (instructor) who has published extensively in various areas of healthcare research while providing clinical care in arenas ranging from academic medical centers to austere environments in the third world during both wartime and peacetime. He has a bachelor’s degree in nursing from Georgetown University, Master’s degrees in education (Boston University) and nursing specializing in anesthesia (State University of New York in Buffalo and U.S. Army), and a PhD from the University of South Carolina. He is a retired lieutenant colonel in the U.S. Army Nurse Corps. He has taught nursing anesthesia, pharmacology, and physiology; mentored students in doctoral programs; and used advanced patient simulation to train students. Dr. Haas has worked in clinical, administrative, education, and research roles. He continues to work as an independent consultant, while taking more time to enjoy life with his wife of nearly 50 years and their children and grandchildren.

Faculty Disclosure

Contributing faculty, Richard E. Haas, BSN, MSN, EdM, PhD, CRNA, LTC US Army Nurse Corps (Retired), has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Mary Franks, MSN, APRN, FNP-C

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

Postoperative cognitive dysfunction (POCD) is a complex, often under-recognized postoperative complication characterized by changes in cognition that can affect attention, memory, learning, orientation, and—most notably—executive function. Unlike clearly defined neurologic injuries, POCD is not tied to a single anatomic lesion or universally accepted diagnostic criteria, which can make it challenging to identify, measure, and discuss with patients and families. Yet for the individuals who experience it, even a subtle decline in "normal" thinking and daily functioning can be disruptive, and in some cases profoundly distressing.

2. EXECUTIVE FUNCTION AND ITS RELATIONSHIP TO POCD

Before studying any process seen as "abnormal," it is important to understand what "normal" looks like and how a state of normalcy is measured. This is particularly important in POCD, when the area affected is neither anatomic nor pathophysiologic, but an acute and/or chronic degradation of what is referred to as executive function. In order to understand the devastation that may accompany POCD, it is important to understand the concept of executive function. Each day, individuals go about usual activities of daily living in the midst of a conscious state using what is referred to as executive function [1,2,3]. As we are insensitive to the air that surrounds us, so we are insensitive to executive functioning each day. Both air and executive function have another thing in common: if either one goes bad or missing, it instantly becomes a priority. Baddeley noted this first in 1983 through a term he referred to as "working memory" [1]. He described this as a "temporary storage of information" that was transactional in nature (i.e., used to get things done).

Since Baddeley's description in 1983, other researchers have sought to further hone this concept. Their research reflects the fact that executive function is inextricably linked to brain physiology, and the determination of the specific neuroanatomic sites in which these physiologic interactions take place, thus allowing executive function to occur. Executive function is defined as functions necessary to successfully complete instrumental activities of daily living (IADLs) (e.g., grocery shopping, public transportation use, work- or school-related tasks) and are essential for completion of goal-directed behavior [3]. Okutemo and Nakamura have a useful description of executive function [4]:

Experts identify three main areas: working memory, inhibitory control and cognitive flexibility. Indeed, when we want to do something, whether it is solving a math exercise, making a declaration of love, learning to play the piano or learning a dance step; we need three so-called executive skills: we need a good working memory, which allows us to keep information in memory and organize it; a good inhibitory control, which allows us to inhibit distractions to stay focused, to control our impulses, our emotions, or inappropriate actions; and finally, we need cognitive flexibility, to be creative and adjust our strategies in case of mistakes.

Executive function therefore hinges on these three linchpins: good working memory, good inhibitory control, and cognitive flexibility [4]. POCD's primary manifestation is impaired executive function in the postoperative patient. One can easily see the problems arising in patients with POCD secondary to the degradation of any or all these three crucial faculties.

Patients may have many forms of mental disabilities that preclude them from effectively engaging in executive function, including traumatic brain injury, stroke, psychosis, aging, inflammation of the central nervous system, Alzheimer disease/dementia, and other neurologic conditions [5,6,7,8]. Indeed, the practicing clinician often sees decreased executive functioning in the acute or chronically ill patient, despite having no identifiable central nervous system pathology. This likely results from a stress response activating glucorticoid receptors in the brain, which in turn decreases brain function, resulting in diminished executive function [9].

Evidence Based Practice Recommendation

In patients at risk for postoperative dysfunction, the American Society of Anesthesiologists (ASA) Perioperative Brain Health Initiative recommends clinicians conduct or direct the conduct of a baseline cognitive screen using validated tests and an assessment of additional risk factors for perioperative neurocognitive disorders.

https://www.bjanaesthesia.org/article/S0007-0912(20)30925-9/fulltext

Last Accessed: February 28, 2026

Level of Evidence: Expert Opinion/Consensus Statement

It is clear that the concept of executive function is both real and measurable. For various reasons, executive function may be degraded, temporarily or permanently, in large groups of patients, some unrelated to surgery. Therefore, clinicians require techniques and tools to measure the degree of degradation of this function. A review of all available neuropsychologic tests is beyond the purview of this course; however, the most common is the Mini-Mental State Exam (MMSE). The MMSE is a bedside evaluation tool that can be used to help evaluate patients with suspected executive function degradation [10]. It was invented in 1975 to provide a quick indication of cognitive function, with the authors noting that it can be administered in as little as 5 to 10 minutes [10]. Since its release in the 1970s, the tool has been used across populations and cultures, as well as in the presence of many types of organic and injury-induced central nervous system trauma [11]. The maximum score one can receive on the test is 30 points, and any score greater than 24 is considered "normal" [11]. In the original study, researchers reported scores of 20 or less only in patients with dementia, delirium, schizophrenia, or affective disorder—not in healthy older adults or in patients with a primary diagnosis of neurosis and personality disorder [10]. As this course progresses, please keep these numbers in mind as indicators of the degree of executive functioning, with a score of 20 or less seen as indicative of diminished function.

3. A REVIEW OF ANESTHETICS

The purpose of anesthetics is to render the patient unresponsive to surgical stimulus and induce a hypnotic state of unconsciousness, while also maintaining autonomic stability during the conduct of the surgical or diagnostic procedure. The primary way in which this occurs is through the lowering of the electrical membrane potential (or voltage) of the neuron. In the classical view of neurophysiology, neurons communicate by passing neurotransmitters across a synapse [12]. This release is caused by an electrical stimulation to the neuron, called an action potential. These action potentials occur when the millivolts inside the neuron reach the threshold, resulting in the entry of cations into the neuron and the establishment and propagation of an electric "spark" down the axon of the neuron [12]. Anesthetics lower voltage inside the neuron, so more and more impulses are required to cause the neuron to fire. With enough anesthesia, the neuron can be completely inhibited from firing or it can be inhibited enough to prevent consciousness [12,13,14,15,16,17].

This inhibition of neural function can be accomplished with many combinations of anesthetic agents. This course will focus on two primary classes of anesthetics: intravenous anesthetics and the volatile (inhaled) agents. The mechanism of action of the intravenous agents, particularly propofol and ketamine, is very well known. The inhaled agents, despite more than 100 years of use, are less well understood.

INTRAVENOUS AGENTS: FOCUS ON PROPOFOL AND KETAMINE

Propofol

Propofol is nearly universally used for both the induction and maintenance of general anesthesia [13,17]. Induction is the process whereby an intravenous bolus dose of propofol quickly renders the patient unconscious. A period of less than 30 seconds from injection to unresponsiveness is not uncommon. Propofol acts on a specific binding site on gamma-amino butyric acid proteins (i.e., type A or GABAA) on the surface of neurons in the brain [18]. These proteins act as channels that allow the passage of chloride ions from the plasma into the interior of the neuron. As chloride ions are negatively charged (anions), they lower the membrane potential inside the cell. This makes the cell less likely to generate an action potential, and less likely to send impulses to other brain cells. When enough neuronal transmissions are inhibited, classical brain theory states that unconsciousness occurs [16]. Note that this inhibition occurs along a continuum, where smaller doses of the agent lead not to unconsciousness, but sedation (response to a voice while feeling unconcerned). This continuous spectrum of effects impacts executive function. In small doses, executive function is diminished, but still in effect. For example, a patient may receive a local anesthetic technique resulting in the numbing of an arm or leg. In order to diminish the anxiety associated with such a technique, patients may receive a continuous intravenous infusion of a low dose of propofol [17]. They will still respond to questions, take deep breaths when requested, and move other unblocked extremities in response to a verbal command. Propofol wears off in a fashion that inversely mirrors its onset; patients awaken extremely rapidly when the agent is discontinued [13]. Further, they have no hangover effect, such as that seen with barbiturate agents; indeed, they seem to have a feeling of well-being upon awakening, and some have reported feelings of euphoria [19].

Ketamine

Ketamine is a dissociative anesthetic with a different mechanism of action than propofol. While binding with numerous receptors in the brain, its primary effect derives from binding with and blocking the N-methyl d-aspartate (NMDA) receptor [17]. When activated, these receptors excite the brain by allowing the entry of positive ions (or cations) into neurons, thus moving the resting membrane potential of the neurons closer to threshold, making it easier for the brain to become excited and aroused. Ketamine affects neurons in both the brain and the spinal cord, making both an anesthetic as well as a potent analgesic. Sufficient doses of the agent completely abolish executive function, and even small doses result in altering inhibition and cognitive ability. Indeed, patients receiving ketamine demonstrate markedly reduced executive function, which may continue after emergence from anesthesia. Calvey and Williams have described ketamine's emergence phenomena as such [13]:

During recovery from ketamine anesthesia there is a significant possibility of emergence phenomena, ranging from vivid dreams and visual images to hallucinations and delirium, which occur in about 30% of patients and may continue for 24 hours after administration. These psychotomimetic sequelae may be extremely unpleasant, and it has been suggested that they are related to the misperception or misinterpretation of sensory information, particularly visual or auditory stimuli. Emergence phenomena may be considerably modified by the use of appropriate premedication with opiates or benzodiazepines.

Almost counterintuitively, however, is the use of small doses of ketamine being administered to patients with neuropsychiatric disorders, particularly treatment-resistant depression and post-traumatic stress disorder [20,21]. The degree to which this agent changes executive function places it in an area of interest for those studying POCD. At this time, there is no research that has been done to determine the extent to which ketamine helps or hurts the development of POCD.

INHALED AGENTS: FOCUS ON DESFLURANE, ISOFLURANE, AND SEVOFLURANE

Since the first public reported use of ether in 1846 by Morton, those using inhaled anesthetic vapors have always known that they work. However, they simply have not been able to figure out how they work [22]. Many theories have been put forth, only to find that some agent does not follow the rules, requiring researchers to rethink their postulations. Broadly speaking, inhaled agents lower the resting membrane potential of neurons, in a fashion similar to the intravenous agents. The halogenated anesthetics are delivered as an inhaled vapor, absorbed into the bloodstream from the pulmonary capillaries, and delivered via the vascular system to the brain [13,23]. Being lipid soluble in nature, they cross the blood brain barrier and come into contact with the neurons. It is at this point that their mechanism of action becomes less clear.

Research postulates that these inhaled agents work at one or more of several receptor sites [13,15,17,22,23]. All of the potential mechanisms of action depend on the classical model of neuronal function (i.e., inhibiting a critical mass of neurons results in unconsciousness) [16].

To begin, there is evidence showing the inhaled agents act at the same GABAA and NMDA receptors discussed in relation to intravenous agents. The inhaled agents appear to have binding sites in these receptors that are distinct from those sites used by the intravenous agents, thus accounting for the synergistic effect of the agents when used simultaneously [14]. Other sites have also been identified that show evidence of neuronal inhibition when exposed to the inhaled agents. The channels in the brain showing the most promise for understanding the mechanism of action of inhaled anesthetics include [23,24]:

- TREK-1

- TASK-1

- Sodium channels

- Glycine receptors

A channel is simply a large protein that extends through the cell membrane. Once stimulated, specific ions flow through the channel created in the protein—for example, potassium. There are many types of potassium channels throughout the body. The loss of these cations from the interior of the neuron lowers the cell's resting membrane potential. The inhaled agents act to stimulate the TREK-1 and TASK-1 channels, both of which are critical to the efflux of potassium ions. With these two proteins, anesthetics act as agonists: they activate the protein, causing the channels to open.

The sodium channels allow the entry of sodium ions into the cell. Halogenated anesthetics, particularly sevoflurane, inhibit the function of the channel [25]. Because sodium ions cannot enter the cell as easily, the cell has decreased ability to create an action potential, thus decreasing neuronal function. This would lead to sedation and unconsciousness.

Glycine is an inhibitory neurotransmitter and its receptors are found throughout the brain [26]. When stimulated, glycine receptors open channels that admit chloride anions into the neurons, in a fashion similar to GABAA receptors [26]. The increased presence of chloride anions inside the neuron moves the resting membrane potential further from threshold, inhibiting neuronal transmission. Sufficient stimulation of these receptors will result in diminished sensory awareness.

Both intravenous and inhaled agents used for anesthesia provide effects that are inherently reversible. While the intravenous agents tend to undergo hepatic and renal degradation, the inhaled agents tend to be exhaled nearly unchanged. In modern anesthetics, the unchanged portion exhaled exceeds 90%; sevoflurane undergoes just 5% metabolism, isoflurane 0.5%, and desflurane less than 0.1%. Despite this reversibility and lack of significant metabolic by products, patients continue to experience POCD.

4. OVERVIEW OF POSTOPERATIVE COGNITIVE DYSFUNCTION

Discussing POCD can be difficult, if for no other reason than there is no formal diagnostic code or agreed upon set of signs and symptoms forming boundaries around this phenomenon. Despite the plethora of research and review articles on POCD, there is a great deal of variability in the mental models put forth. To better understand the concept, one turns first to some of the broader, more well-agreed upon definitions of POCD. An editorial in the European Journal of Anaesthesia defines it in the following way [27]:

Postoperative cognitive deficits are generally characterized as limitations of attention, cognition, recognition, orientation, memory and learning. While numerous synonyms, such as acute brain syndrome, mental dysfunction, and acute confusional state, exist, it is important to discriminate between an early and mostly short-term postoperative delirium and the longer lasting postoperative cognitive dysfunction.

Inherent in the definition is the P in POCD, namely, patients have had surgery of some kind. Early studies focused primarily on large, involved surgical procedures requiring significant anesthesia interventions, frequently supplemented with the concomitant administration of vasoactive medications. Specifically, the earliest studies focused on patients receiving open heart surgical procedures. Placing the patient on cardiopulmonary bypass was shown to have an intrinsic inflammatory response.

Patients receiving surgery frequently complained of not feeling "right" postoperatively. In the late 1970s and early 1980s, open heart surgery was becoming more common, and a significant number of patients began to complain about a lack of mental acuity after surgery. One of the earliest studies noted the severity of this problem, estimating average rates of 10% (with some researchers finding rates nearing 50%) of some form of neuropsychiatric dysfunction after open-heart surgery [28]. The work of these researchers was exhaustive. They measured 16 physiologic variables related to heart function, provided each patient with a neurologic examination, psychiatric examination, and cardiovascular examination five months before and after surgery, while administering no less than 30 psychologic tests for executive function, depression, intellectual ability, and other states [28]. Regrettably, they enrolled only 69 patients, and lost 9 of these due to death or refusal to participate after surgery. Further, their sample was quite homogenous, including Finnish men and women only, and at only one hospital. Despite these limitations, their study is a model of rigor and concern for the well-being of their patients. Their findings opened debate about how POCD occurred. For example, patients presenting with high preoperative hypochondriasis scores were significantly more likely to experience POCD than those with normal scores [28]. Further, patients who experienced what the authors described as postoperative psychosis or delirium were also more likely to have subsequent POCD [28]. In short, this is a multifactorial problem, and despite all the data obtained, the measurements were of limited utility in determine which patients would develop POCD.

Another early study done 10 years later followed 2,000 patients postoperatively during a 45-month period, all of whom had open heart surgery with requisite cardiopulmonary bypass [29]. The researchers tracked the patients for the development of neurologic abnormalities, which they defined as, "the presence of new sensory, motor, or reflex abnormalities at any time after entry into the intensive care unit, or occurrence of stupor or coma in association with intracranial injury confirmed by a staff neurologist" [29]. They found these pathologies occurred at rates of 0.9% in those younger than 65 years of age, 3.6% in those 65 to 74 years of age, and 8.9% in those 75 years of age and older. Of interest, they did not consider postoperative changes in executive function as a neurologic abnormality: instead, they state that patients diagnosed with postoperative disorders such as "psychosis," "dementia," or confusion were not considered to have neurologic injury unless a focal neurologic deficit was also present [29]. It is important to look at that statement as an early sign that patients could have significant function degradation without the presence of a quantifiable diagnosis (e.g., the presence of a bleed in the brain shown by computed tomography [CT] scan).

These earliest studies searching for causes of POCD inferred that such causes were likely the result of surgical or anesthesia insult that caused actual degradation of the neurons themselves, rather than simply altering their function. This is the essential background of POCD.

POSTOPERATIVE NEUROLOGIC SYNDROMES VERSUS POCD

There are many who work in health care who have little or no experience in the operating room, and even fewer with the responsibility of caring for patients who have undergone general anesthesia. Their experience may be limited to media, which inevitably shows patients having extreme surgical procedures whilst lying blissfully asleep on the operating table. Rendering a patient insensate for anesthesia, under normal circumstances, takes less two minutes, and in an emergency, can be done in less than 60 seconds. The true art, however, of the anesthetist is the timely and stable emergence from anesthesia shortly after the end of the operation. It is the most difficult thing to teach, and variance in patient physiology and response to medications make the learning curve of the signs and symptoms of emergence reactions very steep.

Normal Emergence

At (or close to) the end of the surgical procedure, the anesthesia provider turns off the device administering the anesthetic (a pump for intravenous infusions, or the vaporizer for the inhaled agents). It is important to ensure the patient has adequate analgesia, as the inhibition of painful stimuli by the inhaled or IV agents will soon stop. As patient begins to recover, depth and regularity of respirations increases, and the patient may begin to move his or her extremities. In each case, patients pass through what is referred to as stage 2 (or the "delirium stage") of anesthesia, first defined in a paper by Arthur Guedel in 1936 [30]. During stage 2, patients may experience a transient delirium during which they will not obey instructions or respond to verbal stimuli and may thrash about the operating bed. Inadequate analgesia makes this much worse, while the use of benzodiazepines and analgesics may ameliorate it. Usually, this is a very transient period, lasting two to four minutes, after which the patient has recovered sufficiently to be transported safely to the postanesthesia care unit. Theoretically, this is attributed to the late offset of anesthetics to inhibitory neurons, as is reflected by irregular respiratory status, dilated pupils, and divergent gaze. This is normal if the patient spontaneously and quickly passes through this stage. Some patients, particularly those in whom surgery is less complex and/or who have received opioids, seem to effortlessly pass through this stage and awaken with minimal disruption. In other cases, the term stormy emergence seems inadequate to describe the several minutes of complete disinhibition that can occur as the patient passes through this stage. Although risk factors for stormy emergence have not been clearly identified, there have been studies linking hypochondriasis to POCD [28]. A long-standing truism in anesthesia is: "Go to sleep scared, wake up scared." This is not a new discovery, having been first reported in the literature in the 1960s [31]. Indeed, it is incumbent upon the anesthetist to reassure the patient during the preoperative evaluation and to administer antianxiety agents when indicated. This is done to decrease the likelihood (or at least the severity) of going to sleep "scared." In either case, smooth emergence or stormy emergence, the normal course shows an increasing degree of executive function from the time the anesthetic is discontinued until the patient is discharged from the facility.

Agitation Associated with Emergence

Delirium is a state in which the patient's mental functions are profoundly degraded and executive function nearly completely absent. One of the earliest studies of postoperative delirium characterized the condition as, "an acute brain syndrome characterized by impairment of orientation, memory, intellectual function, and judgment with lability of affect" [31]. This study matched 57 patients not experiencing delirium with 60 who had. The researchers found the principle pathologic states associated with delirium included metabolic imbalance, excessive surgical stress, cardiac failure, infection, intoxication, pre-existing brain disease, and anemia [31]. In the more than 50 years that followed, knowledge about delirium has grown, though not as exponentially as might be imagined.

The types of hyperactive behavior the average clinician would associate with delirium actually account for only 20% of cases [32]. Most delirium is hypoactive in nature, which is far more difficult to observe in the patient recovering from anesthesia; the signs include disorientation, memory problems, and disorganized thought, which can be mimicked by the sedated postsurgical patients [32]. Delirium may occur in 5% to 10% of postoperative patients [33]. Delirium may develop from the preoperative self-administration of drugs or alcohol and thus may be seen after emergency surgery in patients who have used these substances. Other causes of delirium include tumor, psychiatric disturbance, or other pre-existing neuropathology [33,34]. Delirium is thus differentiated from POCD by the presence of either an inherent disease process or extrinsic substance abuse. Ordinarily, in the case of those with substance use disorder, as the drug effects wear off, so does the delirium. Some have linked delirium to hypoxia or perioperative anemia, though this remains under investigation. There is also an age component involved in patients developing delirium, as will be discussed in more detail later in this course [32].

It is important not to confuse dementia, a diagnosable and named disorder, with POCD. In extremes, patients with POCD may experience dementia, but for the purposes of this course, dementia refers to an organic condition of cognitive impairment the patient brings to the operating room before any planned or emergent procedure is performed. Age-related cognitive decline is an expected aspect of the aging process. The likelihood of surgery increases with age, and one study reported that 55% of all surgeries in the United States are performed on patients 65 years of age or older [35]. Delirium rates also increase in a stepwise fashion as patients age [35]. Patients presenting with pre-existing diagnoses, such as Alzheimer disease, organic brain syndromes, or senility, are at significantly increased risk for poor postoperative cognitive outcomes [36]. In one study of older adult patients being screened for elective surgery, 44% showed a preoperative baseline measurement consistent with impaired cognition [36]. Patients with cognitive deficits also developed delirium at higher rates, and their hazard for death was 2.77 times that for patients who had impaired cognition but did not develop delirium [36]. Numerous studies have reported that patients presenting with some form of cognitive impairment preoperatively are far more likely to experience postoperative cognitive effects that are both more severe and longer lasting than those without pre-existing impairment [29,34,35,36,37]. The clinician should, therefore, be observant of patients' existing cognitive status during preoperative evaluation and seek input from family members who also may be present to determine the degree of preoperative dysfunction.

Neurologic insults may occur during anesthesia and surgery. While their incidence grows smaller each year as advances in both anesthetic agent safety and monitoring modalities occur, patients may rarely experience some form of pathologic condition during the conduct of anesthesia. Such insults include stroke, central nervous system hemorrhage, and/or embolism to the vasculature of the brain. Stroke during surgery is quite rare, with rate of occurrence ranging from 0.08% to 0.7% [38,39]. Stroke incidence also varies by the type of surgery involved. The rates vary quite widely, and operations concerning any aspect of the vascular tree, as may be expected, have far higher rates. It is important to note that the incidence of perioperative stroke increases, on average and across types of surgery, approximately 0.15% for each decade of life over the age of 65 [40]. It is extremely difficult to determine the presence of brain ischemia during general anesthesia, as the paralyzed, anesthetized and intubated patient has nearly all the signs and symptoms of stroke effectively hidden from view. In some cases, types of electroencephalography are used to monitor brain function, but this is quite rare. Ordinarily diagnosis of ischemic stroke is made in the post anesthesia recovery room, further adding to the long list of postoperative central nervous system dysfunctions which may occur.

POCD RISK BY TYPE OF SURGERY

As part of the normal preoperative workups, both in surgery and in anesthesia, patients are advised of the perioperatively and postoperatively risks of surgery. It is rare, however, to find the idea of POCD being addressed. For example, what happens when the patient is a 75-year-old knowledge worker who presents for an elective total hip replacement [41]? What can you, as the clinician, tell this patient about the likelihood he will endure some form of POCD? As discussed, a major drawback of this conversation is a lack of ability to pin down the mechanisms or causes of POCD with any degree of certainty. What we do know is that some types of surgery and some anesthetic agents have higher incidences of POCD than others.

Cardiovascular Procedures

As noted, cardiovascular procedures have been extensively studied for their relationship to POCD. A significant percentage of patients undergoing cardiovascular or extensive vascular procedures manifest POCD, as has been observed almost since the genesis of open-heart surgery. As early as 1972, altered states of postoperative consciousness ranging from mild impairment to major delusional and hallucinatory activity after open heart surgery were being reported [42]. In a 1972 study, 43 of 86 patients (52%) experienced some form of cognitive impairment in the intensive care unit following open-heart surgery [42]. Studies such as this provided the impetus for further research. The road to finding out the nature of POCD after cardiac surgery has not, however, been an easy one. In one systematic review of 420 studies related solely to POCD after cardiac surgery, the researchers found little consensus on the incidence, severity, and time course of symptoms [43]. This is primarily because no one neuropsychologic test covers all areas of executive function, and the sheer volume and time of testing that would be required is quite daunting.

In a systematic review of 62 studies, researchers analyzed POCD prevalence among a broad spectrum of surgical patients [44]. The presence of POCD was measured at various time periods postoperatively. Researchers found a median incidence rate of 48% in the first 21 postoperative days, 24% from day 22 to 5 months, 24% from 6 months to 1 year, and 42% after 1 year [44]. They cautioned that this failed to account for atherosclerotic or other organic postoperative changes, but the rates of POCD remain significant. Another systematic review supported these findings. Patel and associates found the percentage of patients experiencing some degree of cognitive dysfunction after cardiac surgery to be high, but with a wide degree of variability [43]. Significantly, 10% to 20% of patients studied were still experiencing dysfunction after one year, and after five years, the incidence increased to approximately 30% [43]. There should be some care taken with the longer-term data, as the evidence for diminished executive function due solely to age is quite robust, and the changes may unrelated to surgery or anesthesia.

While systematic reviews are helpful to our understanding, prospective studies are also of value. One such study of 101 patients 45 to 75 years of age assessed the extent to which preoperative comorbidities and perioperative management might decrease the rate of POCD [45]. The research team administered the Wechsler Memory Test (WMT) preoperatively, three to five days postoperatively, and then once more five months postoperatively. While not the broadside of tests required for complete executive function analysis, the researchers nonetheless used their postoperative WMT score as a proxy measure for POCD. The findings provided some information about why people develop POCD. First, the researchers found a significant correlation between the preoperative WMT score and the postoperative score; in other words, 59% of the memory test score variation could be attributed to the memory ability patients demonstrated prior to surgery [45]. Patients who had pre-existing cognitive issues were likely to continue to display impairment after surgery. Another noncardiac contributing factor identified was the presence of chronic obstructive pulmonary disease (COPD), which correlated negatively with WMT scores (i.e., those who had COPD before surgery experienced diminished cognitive ability after surgery) [45]. There are numerous theories about the mechanisms of action leading to POCD, and this study supports the concept that existing hypoxia (or perhaps hypercarbia) may result in decreased cognitive functioning, as will be discussed in greater detail later in this course. In terms of actual relationship of cardiovascular surgery and POCD, the only factor this research team found to be statistically significant was a correlation with aortic cross-clamp time and postoperative WMT score. As cross-clamp time increased, memory ability after surgery decreased; the correlation was statistically significant, but weak [45].

Another team of researchers tested the hypothesis that cerebral regional oxygen saturation (rSO_2) deficits (i.e., hypoxia in the brain) resulted in POCD [46]. They tested 57 patients by performing complete neurocognitive test batteries on the day before surgery, and four to seven days after (dysfunctions in this group were described as early POCD), as well as one month after surgery (dysfunctions in this group were described as late POCD). Of importance in this study is that the researchers set a high bar for POCD; patients had to experience a score decline of one standard deviation below their preoperative test score in two or more of the cognitive tests administered postoperatively [46]. Finally, in an effort to determine the extent to which placing the patient on a cardiac bypass pump created dysfunction, the patients were analyzed as two groups: one whose surgery was conducted with the patient "on-pump" and the other whose surgery was conducted with the heart still beating "off pump." In this study, researchers found that 80.7% of the patients overall experienced early POCD, while 38% experienced late POCD [46]. When the researchers looked at rSO_2 values, they found that a value of 50% or lower was predictive for the development of early POCD. In patients who had this level, approximately 40% experienced early POCD, while 8% did not. Also, they found patients were more likely to have POCD if placed on bypass pump [46].

Unfortunately, the preponderance of evidence related to POCD after cardiac surgery is still evolving. Two studies show the divergence of opinion on both the cause and the extent of POCD. In the first study. researchers sought to determine the extent to which cerebral hypoxia resulted in POCD [47]. These authors found that cerebral oxygen levels were not predictive of POCD, and their reported rate of POCD was 23%. In a second study, researchers looked at 1,156 patients who had open heart surgery and compared the rates of POCD between the two groups [48]. This was a large, multisite study, in which participants received an extensive neurocognitive evaluation after open heart surgery. In this sample, 581 of the participants had surgery using cardiopulmonary bypass pump, while 575 had off-pump surgery. The neurocognitive scores were measured approximately two days before surgery (baseline) and one year after surgery. In this large sample, the only predictors of POCD were lower baseline cognitive score, older age, lower level of education, and non-White ethnicity [48]. Use of the bypass pump had no effect on score differences. Further, the researchers reported that at one year, the rate of POCD was less than 14% in both sub-samples [48]. This is markedly different from some studies showing levels higher than 30%.

In one final study, researchers followed 326 patients for 7.5 years after their cardiac surgery to determine the extent to which POCD progressed into dementia [49]. In contradistinction to the previously described study, these researchers found a POCD rate of 32.8% and dementia rate of 30.8% in the patients they followed [49]. In the patients they followed, pre-existing cognitive impairment was present in 32.2% of those with POCD or dementia. They also found that pre-existing peripheral vascular disease was a significant predictor for POCD. As will be discussed later in this course, atherosclerotic vascular disease is associated with increased levels of systemic inflammation, which may be significant. Finally, the presence of POCD at 3 months and 12 months was associated with increased mortality [49].

While cardiovascular surgery may have initiated the interest in POCD, the predictive indicators are far from settled. Considering only cardiovascular procedures, it is safe for the clinician to infer that:

- People who have existing cognitive decline may develop worsened POCD.

- Age and fragility correlate positively with the development of POCD.

- The presence of periods of hypoxia, while undesired during the surgical procedure, cannot be directly linked to the development of POCD.

- The use of cardiopulmonary bypass pump cannot be clearly linked to the formation of POCD.

Orthopedic Procedures

Orthopedic procedures have been linked to systemic postoperative problems, ordinarily linked to the development of thrombi, often described as bone marrow or fatty embolisms. These are usually linked to long-bone procedures (e.g., repairs of the femur or humerus, especially those involving the insertion of hardware into the damaged area). Therefore, it is not surprising that the interest in POCD after orthopedic procedures has developed. Further, orthopedic implantations (e.g., total hip placements, total knee replacements) may be held in place by an exogenous bone cement (e.g., polymethyl methacrylate), which is associated with transient hypotension in patients.

Total joint arthroplasty (replacement) of hips and knees has become commonplace, particularly in older adult patients. These procedures are associated with low mortality rates (around 0.2%) and provide patients with an improved quality of life [50]. However, they are associated with significant rates of POCD. As early as 1998, research indicated that 26% of patients were experiencing POCD one week after orthopedic surgery, and despite decades of progress in surgery and anesthesia techniques, the rate remains 18.9% [51].

Clinicians have sought approaches to decrease these rates or risk factors that would be helpful in predicting the occurrence of POCD. Orthopedic surgery may entail significant loss of blood, necessitating transfusion. This is especially pronounced in older adult patients, who tolerate hemorrhagic anemia poorly. One group of researchers looked for an association between the administration of blood (and its concomitant release of inflammatory mediators) and the presence of POCD [52]. In this study of 313 patients older than 65 years of age, all of whom received total hip replacements, the research team measured neurocognitive function preoperatively, and seven days postoperatively, using the MMSE [53]. The researchers found a statistically significant decline in MMSE scores, which they used to identify POCD. This POCD group was 1.5 times more likely to have received three or more units of transfused blood than the non-POCD group [52].

Another study sought to determine the relationship, if any, between the stress hormone cortisol and the presence of POCD in patients after hip fracture surgery [54]. In addition to viewing POCD as being linked to inflammation, this group hypothesized that cognitive dysfunction would occur after a stressful event, and that cortisol, as a stress biomarker, might be important in finding a link between orthopedic surgery and POCD. They looked at 175 patients who presented for hip fracture surgery, all of whom were older than 65 years of age. All patients received spinal anesthesia rather than general anesthesia. The research team reported that POCD occurred in 29% of their patients when measured at postoperative day seven [54]. Plasma cortisol was inversely correlated with MMSE score—as the stress biomarker increased, the neurocognitive scores went down [54].

Other researchers sought to determine the extent to which the administration of a general anesthetic would lead to the development of POCD when compared to regional anesthesia [55]. A problem with studies like this is that patients receiving regional anesthesia frequently are moderately to heavily sedated; this study ameliorated that confounding variable by not administering any sedatives before or after the application of the regional anesthetic or during hip replacement surgery. Researchers found that patients receiving general anesthesia had significantly lower MMSE scores on postoperative day one than both the scores on their own baseline, as well as when compared to the scores of the regional anesthesia group [55]. By the fifth postoperative day, neither of the groups had neurocognitive scores that differed significantly from their preoperative scores. However, the researchers also ran a univariate regression on amyloid beta proteins (Ab), which have been found to be biomarkers for Alzheimer disease [55,56]. They found a strong inverse correlation between the presence of Ab and MMSE score. In short, 74% of the variance in neurocognitive scores was predicted by Ab levels in the blood [55]. This is interesting evidence that POCD may have the same pathogenic model as Alzheimer disease.

Another orthopedic study sought to further use these data to predict POCD by measuring Ab and levels of the Tau protein on patients undergoing total knee replacement and total hip replacement [56]. As background, Tau protein helps to construct the microtubules for neurons and helps neurons maintain their structural integrity. This group of researchers enrolled 80 patients having knee replacements or hip replacements and a matched sample of 80 patients not having surgery into their study. They tested neurocognitive function before surgery and then seven days, one month, and three months after surgery. In an effort to decrease the confounding variables associated with general anesthesia, all of the patients were anesthetized using a regional technique (combined spinal and epidural) [56]. Their measurements showed that 40% of patients experienced POCD at day 7, 25% at the end of one month, and 15% at the end of three months. When they performed a ratio of the concentration of Ab protein to tau protein, patients with POCD had significantly lower ratios than those not experiencing POCD. The authors found this ratio to serve as a potential biomarker for the development of POCD [56].

Other Procedures

Other cases with high postoperative rates of POCD have also been reported. It is important that such cases are studied, as other procedures may be more frequently performed than cardiovascular surgeries. One consideration is that the complexity and invasiveness of the surgery may not be correlated to the development of POCD. One of the first attempts to describe the incidence of POCD in patients after minor surgery enrolled 372 patients older than 60 years of age, of whom 199 remained in the hospital for one night and 173 were discharged home after surgery [57]. Neurocognitive tests were performed preoperatively and then repeated seven days and three months after surgery. Of this group, researchers noticed a significant difference between those recovering at home compared with those recovering in the hospital. The one-week POCD rate for those recovering in the hospital was 9.8%, while those recovering at home had a rate of 3.5%, a significant difference [57]. When the cognitive tests were repeated at the three-month mark, there was no statistically significant difference between inpatients (8.8%) and out-patients (4.5%) [57]. The authors did believe that the decreased stress of home recovery probably accounted for the one-week difference in scores, which mirrors the previously discussed studies using cortisol and other stress biomarkers. The lack of difference after three months was not explained, though the incidence was lower than that found in other studies of more complex surgeries.

Another study followed 1,064 adult patients (older than 18 years of age), testing their neurocognitive status preoperatively, one week after surgery (or at discharge if hospitalized less than one week), and once again three months postoperatively [58]. One of the major strengths of this study was a comparison of POCD effects across ages of participants as well as across time. Major surgery was defined as procedures requiring postoperative hospitalization for a minimum of two days. A complete battery of neuropsychiatric tests was administered to all the patients in the study, evaluating all areas of executive function. The participants were divided into three age groups: younger (18 to 39 years of age), middle-aged (40 to 59 years of age), and elderly (60 years of age and older) [58]. At discharge (or one week postoperative), the POCD rates were 36.6% among younger patients, 30.4% for middle-aged patients, and 41.4% for elderly patients. At three months post-discharge, POCD rates fell to 5.7% for young patients, 5.6% for middle-aged patients, and 12.7% for elderly patients [58]. The authors also followed up on mortality rates one year after discharge. Of concern was the finding that for those who had no POCD, the one-year mortality rate was 4%, compared with a mortality rate of 10.6% for those who did have POCD [58]. In this case, POCD was clearly prognostic for increased mortality.

Laparoscopic cholecystectomy (excision of the gall bladder via a small incision and the use of an endoscopic device) is a common surgical procedure. Its sheer volume reflects the importance of a study concerning the development of POCD in this group of 120 elderly patients. The study also compared the utility of the alpha-2 agonist dexmedetomidine anesthetic regimen compared to a control group receiving a placebo [59]. The utility of dexmedetomidine will be discussed later in this paper, of concern at this point is the rate of POCD for cholecystectomy. The incidence of patients who experienced "mild" POCD impairment was 38% in the control group, and 18% in the dexmedetomidine group, while those experiencing "moderate" impairment was 4% in the control group and 2% in the dexmedetomidine group [59]. The presence of POCD remains consistent, despite the intensity of surgery performed.

POSSIBLE MECHANISMS UNDERLYING POCD

The Cholinergic System in the Brain and Possible Links to POCD

Acetylcholine (ACh) is one of the key neurotransmitters in the brain. The primary receptor responsible for this neurotransmission is the nicotinic acetylcholine receptor (nAChR), which is expressed ubiquitously in numerous subtypes throughout the body [60]. Anticholinergic drug use has been related to both POC and post-operative delirium [61]. The normal role of ACh in the brain is primarily one of exciting neurons and causing their discharge. The neurons most affected by ACh are ones that send projections throughout the cortex and striatum, areas responsible for wakefulness, learning, attention, and motivation [62]. Degradation of these neurons, or interruptions in their discharge, would lead to signs and symptoms associated with POCD [63]. Inhaled and intravenous anesthetic agents inhibit the nAChR [64]. This in turn blocks the entry of sodium ions into the cell as well as the entry of calcium ions. The former moves the electric potential within the cell closer to threshold, while the latter functions as a second messenger for numerous intracellular effects. One of the other effects of anesthetics is the desensitization of these receptors, such that even if ACh can bind, the receptor will not respond [64]. This desensitization may last after the anesthetic is no longer in the vicinity of the receptor and may account for prolonged POCD effects.

Inflammation and Stress

The one area in which there was common agreement was that of inflammation after surgery. In one study, the authors found POCD in patients three-months post-procedure in such disparate surgical interventions as open heart surgery (16%), total hip replacement (16%) and coronary angiography (21%), despite the fact that the last procedure was minimally invasive [65]. After nearly any procedure or injury, the natural inflammatory response of the body is activated, and numerous mediators are released into the bloodstream. When inflammation occurs, the blood brain barrier undergoes a breakdown, allowing these circulating mediators to enter the brain [66]. Numerous mediators may result in neuronal damage (Table 1).

Table 1: COMMONLY RELEASED MEDIATORS, CYTOKINES, AND BIOMARKERS DURING INFLAMMATION

Mediator, Cytokine or Biomarker

Abbreviation

Function

C-reactive Protein

CRP

Activate the complement system to destroy damaged or dead cells

Interleukins

Il-1, Il-6, Il-8

Second messengers that activate numerous aspects of the immune system

Tumor necrosis factor-a

TNF-a

Increase the secretion of corticotropin releasing hormone

Beta amyloids

Aβ

Help create brain plaques, associated with Alzheimer disease

Tau proteins

Tau

Protein essential to form microtubules and structure in neurons

Neuron-specific enolase

NSE

Biomarker indicating the presence of neuronal damage

Cortisol

Cortisol

Glucocorticoid secreted during times of stress, including inflammatory processes

Source: [5,56,67]

The presence of brain inflammation appears to satisfy all the requirements needed to explain POCD. Most patients who have surgery share the commonalities of a heightened stress condition preoperatively (whether from a physical condition causing pain, or the psychic stress from the knowledge of impending surgery) and a normal inflammatory response to surgical intervention postoperatively. The release of inflammatory cytokines during this normal response has been associated with numerous neural and behavioral outcomes. One review, which was primarily concerned with psychiatric illness, discussed in depth the effect of cytokines on what was described as sickness behaviors [5]. Using an animal model, physiologic changes in the brain were described, which resulted in diminished social interactions, coupled with cognitive and affective dysfunction, the latter characterized by disturbed operant performance and anhedonia [5]. If this is compared to descriptions of patients experiencing POCD, the similarities are striking. In animals, these behaviors are viewed as adaptive; they create an environment in which the animal can engage in rest and recuperative behaviors. This latter finding has not been assigned to humans, in whom POCD is viewed as maladaptive in nature. The author also reported that the presence of cytokines in the brain may result in motor impairment, a finding in neurocognitive tests of patients manifesting POCD. The elevated presence of mediators such as Il-6, Il-8, and Il-10 was found in postoperative hip replacement patients four weeks after surgery [5]. In the animal model, the presence of the inflammatory mediators TNF-α and Il-1β was found to negatively impact the ability of the hippocampus to create long-term potentiation in the brain, the mechanism by which memories are stored.

Other studies have shown that activation of glucocorticoid and mineralocorticoid receptors during stress and inflammation, while enhancing memory in younger patients, degrades memory in older patients [9]. This would help account for the difference in the incidences of POCD across the lifespan. These steroid receptors are found prominently in the hippocampus, and there is good evidence showing that anesthetics also influence other receptors here, thus resulting in the inability to form memories [68]. A 2013 study found that older patients having hip surgery had an inverse correlation between MMSE scores and plasma cortisol levels [54]. In another study of 94 patients, all of whom were older than 60 years of age and undergoing major noncardiac surgery, salivary cortisol ratios were tested to assess for a link between endogenous steroid activation and POCD [67]. All patients received neurocognitive testing preoperatively, and then had their saliva sampled for cortisol in the morning (between 6:00 a.m. and 7:30 a.m.) and in the evening (between 9:30 p.m. and 11:00 p.m.) on the day before surgery. It is well-established that glucocorticoid levels are diurnal in nature, thus the sampling enabled researchers to obtain the widest range of values. The research team then set up a ratio of morning cortisol value to evening cortisol value [67]. Neurocognitive tests were administered one week after surgery and the results evaluated against the cortisol ratios obtained. The preoperative morning:evening cortisol ratio was nearly twice as high in patients with POCD as in the those without POCD [67]. The researchers suggested that this finding could be used as a simple screen to preoperatively identify those at risk for the development of POCD. Additionally, it lends credence to the theory that the development of POCD is related to stress and inflammation.

Factors with Disproven Association

Since the 1950s, researchers have been looking for the pathologic nature of postanesthesia cognitive dysfunction. Most research followed the pathway that leads to neuronal damage, meaning that something in the anesthetic or surgical intervention was responsible for causing damage to neurons, resulting in visible behavioral changes in the patient's ability to deal with day-to-day activities. Slowly, studies emerged that provided a list of things that probably were not responsible. This is not to say that any of these, in excess, could not result in neurologic damage to a given patient, but rather that minor changes in these variables were probably not the primary cause of POCD.

Lower oxygen concentrations did not prove to be predictive of POCD, nor did hypercarbia or hypotension. This makes sense based on the brain's ability to maintain constant cerebral blood flow over a wide range of mean arterial pressures (60–160 mm Hg) [66]. This is not to say that such conditions could not damage the brain, but unless found in extreme conditions, these situations were not predictive for POCD. Studies in all of these areas produced varied and inconclusive results.

Next, it was assumed that the action of anesthetics themselves could be linked to POCD. In one study that extensively discussed the problems of neurotoxicity associated with inhaled anesthetics, the researchers concluded that there is limited clinical data directly linking anesthetic agent exposure to cognitive dysfunction in the aging population [23]. POCD exists in varying rates, regardless of the anesthetic used. Further, as evidenced in some of the studies discussed, a number of patients who received regional anesthesia without any form of sedation still developed POCD [54].

5. PROGNOSIS AND TREATMENT FOR THE PATIENT WITH POCD

While we continue to search for a reliable biomarker with a high predictive rate for POCD, we do know that some patients are more likely to develop this disorder than others. Common traits in patients with POCD include [36,49,50,57,58,63,69]:

- Pre-existing neurocognitive dysfunction

- Multiple comorbidities

- Lower level of education

- Increased level of inflammation

- Sleep deprivation

- Advanced age

Even as the safety of anesthesia increases, and even as surgery becomes less invasive, a significant number of postoperative and postprocedural patients continue to experience significant periods of POCD. Identifying those at risk does little good if there is no way to mitigate that risk or treat POCD if it occurs. Research is now turning in these two directions.

ANESTHESIA AND SURGICAL TECHNIQUES TO DECREASE RISK OR EFFECTS OF POCD

Dexmedetomidine

Dexmedetomidine, an alpha-2 agonist, is used as an adjunct agent for anesthesia as well as a sedative in the intensive care unit [70]. Alpha-2 agonists bind on presynaptic neurons and act to diminish neurotransmitter release, with an overall effect of diminishing the output of the sympathetic nervous system. As the sympathetic nervous system is integrated into the inflammatory response, the administration of dexmedetomidine suppresses inflammatory cytokines after surgery [59]. In one study, researchers sought to determine if the use of dexmedetomidine as part of an anesthetic regimen resulted in a lower incidence of POCD when compared with a placebo group. They found significantly less mild cognitive impairment 24 hours after surgery (18% in the dexmedetomidine group vs. 38% in the placebo group); however, there was no difference in MMSE scores two days after surgery [59]. The authors did not follow the patients beyond 72 hours, so they were unable to assess if there was a prolonged effect from the dexmedetomidine. The study does add to the preponderance of evidence that POCD is inflammation related.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Evidence Based Practice Recommendation

The American Society of Anesthesiologists (ASA) Perioperative Brain Health Initiative recommends that prevention of perioperative neurocognitive disorders should involve optimized postoperative pain control, preferably with minimally sedating multimodal pain management.

https://www.bjanaesthesia.org/article/S0007-0912(20)30925-9/fulltext

Last Accessed: February 28, 2026

Level of Evidence: Expert Opinion/Consensus Statement

Another study compared the administration of the nonsteroidal anti-inflammatory drugs (NSAIDs) to that of traditional opioid administration in a large sample of 1,062 patients presenting for noncardiac surgery [71]. These researchers investigated numerous postoperative sequalae that they defined as clinically meaningful events. Some of these clinically meaningful events included outcomes commonly linked to POCD, including fatigue, inability to concentrate, and confusion [71]. These were self-reported by the patients and not based on any rigorous neurocognitive tests, but the results still bear review. When compared with the patients controlling pain solely with opioids and placebo (rather than NSAIDs), patients reported fewer symptoms, and the NSAID group showed better patient-described neurocognitive function [71]. As NSAIDs work primarily by interrupting inflammatory pathways, the increasing use of perioperative NSAIDs may hold out some hope in decreasing POCD.

Lidocaine

Another study tested the degree to which the perioperative infusion of the local amide anesthetic lidocaine would decrease POCD [72]. The authors theorized that lidocaine would act in a neuroprotective fashion and sought to determine if the mechanism of action of this neuroprotection had to do with its effects on levels of circulating inflammatory cytokines and mediators, including IL-6, TNF-α, S100β, neuron-specific enolase, and malondialdehyde. A 2019 study found malondialdehyde levels to be elevated in patients with POCD [73]. Returning to the lidocaine research, Chen and colleagues studied two groups of 40 patients presenting for spinal surgery, one group receiving lidocaine 1 mg/kg over five minutes after the induction of general anesthesia followed by a continuous infusion of 1.5 mg/kg/hour until the completion of surgery, while the second group received an equal fluid volume of normal saline [72]. The team measured blood levels before surgery, at the end of surgery, and three days after surgery. They administered the cognitive tests preoperatively and three days postoperatively. Blood cytokine tests showed significantly higher levels of IL-6, S100β, and neuron-specific enolase in the placebo group at both postoperative time points, indicating that the lidocaine infusion did effectively decrease circulating cytokines [72]. Serum malondialdehyde was significantly lower in the lidocaine group only on the third postoperative day. In terms of MMSE scores, the lidocaine group had a significantly higher mean score than the control group on the third postoperative day, and the postop scores of the lidocaine group did not differ from their preoperative scores. In contrast, the placebo group postoperative scores were significantly lower than their preoperative scores. Further, their postoperative scores were lower than the postoperative scores of the lidocaine group [72]. Lidocaine is a well-known and inexpensive agent and supplements general anesthesia, thus its use in patients who have known risk factors for POCD may be warranted.

APPROACHES TO TREATMENT

Postoperative treatment of patients with POCD remains problematic. This is not surprising given that there is no criterion standard for POCD diagnosis; the diagnosis is merely a description of behaviors (dysfunctional) and an event (surgery) [56,66]. Also, the degree to which POCD is organic (like senility or Alzheimer disease) versus a temporary inflammatory and/or stress event is unclear. Finally, there is clear difficulty in determining both the likelihood POCD will occur in a given patient and its degree of severity. Regardless, some approaches to management of POCD have been explored.

The clinician seeking to treat the patient with POCD may experience frustration in trying to find the criterion standard for care. Compounding this, research is much less promising for patients with POCD who are experiencing cognitive dysfunction symptoms. An extensive review of the literature reveals little current research being directed toward treatment. This may be due to many potential factors, including [32,59,61,63,69,71,74,75,76,77]:

- A relatively small number of patients experience this phenomenon for prolonged periods. Most cases of POCD are self-limiting and resolve within months of the surgical procedure.

- Because there is no formal diagnosis, it is often difficult to determine the extent to which cognitive degradation is related to surgery or the onset of the normal aging process.

- The multifactorial nature of the disorder makes finding treatment options difficult.

- POCD may be confused with the side effects of analgesics (particularly opioids) or sedatives prescribed to help ease the patient's postoperative discomfort.

Postoperative treatment options are generally focused on treating the patient symptomatically and offering them behavior-based assistance (e.g., write things down, use mnemonic assists). Patients should be advised to use their assistive devices (e.g., hearing aids), adhere to a scheduled routine, rely on family members for help, and follow postoperative instructions. These instructions are not markedly different than those given to any patient experiencing executive function impairment for any reason.

Statins

One idea for decreasing the incidence of POCD and treating possible postoperative effects is the administration of statin drugs prior to surgery [78]. In addition to their cholesterol-lowering effects, statins reduce inflammation throughout the body, including in the brain. Note that the inflammatory cytokines produced by surgery are nearly all impacted by the administration of statins, and there is research supporting their possible usefulness in treating delirium (rather than POCD). A 2009 study showed that the administration of statin drugs to a group of more than 1,000 patients reduced their incidence of postoperative delirium by 46% [79]. Further, studies are showing some cautious optimism in the use of statins as adjuncts to treat neuropsychiatric disorders, including depression [80]. Because these symptoms are similar to those experienced by patients with POCD, and because these agents are useful for conditions that are based on inflammatory processes, it seems reasonable to assume the same positive effects would occur in POCD.

Ketamine

The dissociative anesthetic ketamine has recently been introduced as a potential option for treatment-resistant major depressive disorder and post-traumatic stress disorder [20,21]. Further, at least one study has shown that the use of perioperative ketamine decreased the likelihood of POCD [81]. Some researchers have advocated its use to decrease the incidence of POCD, but so far, its use in treating existing cases of POCD in postsurgical patients has not been reported [23].

Electroacupuncture

A 2017 animal study showed that rats responded well to electroacupuncture [82]. This research team took four groups of 20 rats and operated on three of the groups (partial hepatectomy), retaining one group as a control. In the three surgical groups, the rats received either surgery only, surgery and the anti-inflammatory drug minocycline, or surgery and acupuncture in the post-surgery period. They found the rats receiving electroacupuncture had their memory improved compared with rats in the other two surgery groups and that all rats had memory declines after surgery compared with the control group [82]. No human studies have used this technique to date.

Cognitive-Behavioral Therapy (CBT)

Cognitive-behavioral therapy (CBT) has been touted as the criterion standard for the treatment of a number of neuropsychiatric and neurocognitive disorders [83,84]. Its basis is on engaging patients to reflect on how their thoughts and emotions are interlinked and to use the cognitive skills they have to influence how they think about given circumstances [84]. One might be excused for thinking that in a patient with POCD with impaired cognitive abilities this technique might be of limited utility. In fact, this type of therapy has been used in others with cognitive dysfunction, including those with major depressive disorder, attention deficit hyperactivity disorder, obsessive compulsive disorder, and others [83]. As many of the symptoms of these disorders result in degradation of executive function, it may be possible in the future that such a technique might be attempted to ameliorate POCD degradation. For now, there is no evidence supporting use of CBT for the treatment of POCD.

Photobiomodulation

One of the more interesting studies concerned the use of photobiomodulation to mitigate POCD symptoms. This technique is not well-known, but in its most basic form, photobiomodulation is the effect of red light in very specific wavelengths that is shined on the head and thought to affect neurotransmitters and initiators of protein construction in DNA [85]. It is reported that one of the effects is to decrease NFK-b, a cytokine that diminishes neurocognitive function [85]. The use of photobiomodulation has been suggested both in preconditioning patients to resist the effects of anesthesia and surgery on neurons as well as postoperatively to treat the adverse effects of POCD [86]. To date, no studies have been published regarding the use of this technique in humans with POCD.

6. CONCLUSION

While it is possible to assess for biomarkers that indicate that POCD has occurred, there are no routinely used preoperative predictors that are both sensitive and specific. Further, finding a biomarker still does not help mitigate the effects of POCD, and there is still much work to be done to establish best practices for the prevention and treatment of POCD. The presence of POCD in subsets of postoperative patients is significant and, in some cases, devastating. Some POCD risk factors are modifiable, but others are not.

Adverse neurocognitive effects may last for short periods (hours to days) or for long periods (months to years); the likelihood of experiencing these symptoms and signs is inversely proportional to the duration of time they are experienced. In short, most patients are highly unlikely to have long periods of executive function degradation. On the other hand, for those who do experience prolonged cognitive dysfunction, the impact can be significant. Loss of productivity, interference with activities of daily living, problems with social interactions, and increased morbidity and mortality are all associated with prolonged POCD. Therapeutic interventions are in the most rudimentary stages, and there is no criterion standard of pharmacotherapeutic or neurocognitive treatment for these patients. As in all patients experiencing cognitive decline, a supportive environment that minimizes hazards is crucial. Most patients will recover a great deal of executive function as time passes.

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Evidence-Based Practice Recommendations Citations

1. Peden CJ, Miller TR, Deiner SG, Eckenhoff RG, Fleisher LA; Members of the Perioperative Brain Health Expert Panel. Improving perioperative brain health: an expert consensus review of key actions for the perioperative care team. Br J Anaesth. 2021;126(2):423-432. Available at https://www.bjanaesthesia.org/article/S0007-0912(20)30925-9/fulltext. Last accessed February 28, 2026.