Postoperative Cognitive Dysfunction in the Elderly: A Review Comparing the Effects of Desflurane and Sevflurane

ORIGINAL ARTICLE

Postoperative Cognitive Dysfunction in Elderly: A Review Comparing the Effects of Desflurane and Sevflurane Rahmah Alalawi, MSN, RN, Nusrath Yasmeen, MPharm, PhD Purpose: The incidence of postoperative cognitive dysfunction (POCD) remains a relatively common complication in the elderly following surgery. Use of anesthesia for surgery might precipitate certain cognitive alterations. The purpose of this review is to address the impact of two volatile anesthetic agents, desflurane and sevoflurane, on POCD. Design: The focus of this review was on postoperative recovery and complications using two anesthetic agents. Methods: Several databases including PubMed and Cochrane were searched from the date of inception. The search words POCD, elderly, general anesthetics, desflurane, and sevoflurane were used and the search was limited to human, randomized clinical trials, and English. Findings: The findings show no difference in the emergence time between sevoflurane and desflurane and the incidence of POCD. Conclusions: No definitive conclusion can be drawn about the type of anesthetic used and its relation to occurrence of POCD. However, the information presented is crucial, which can help to improve anesthetic usage and patient safety.

Keywords: postoperative cognitive dysfunction, desflurane, sevoflurane, inhaled anesthetics, elderly patients. Ó 2017 by American Society of PeriAnesthesia Nurses

IN RECENT YEARS much research has been conducted regarding the impact of surgery and anesthesia on the elderly. The world population statistics report for the year 2012 states that 16% of the population of developed countries comprised elderly individuals (aged greater than 65 years), which is likely to increase to 21% by 2025.1,2 The advancement in medical techniques including anesthesia and surgery and better medical facilities, attributed to better economic development, are likely to increase the life

expectancy. This results in a major group of elderly patients with multiple comorbidities who eventually undergo complex surgical procedures.

Rahmah Alalawi, MSN, RN, School of Nursing, College of Nursing, King Saud Bin Abdulaziz University for Health Science-National Guard, Jeddah, Saudi Arabia, and School of Nursing, University of Pennsylvania, Philadelphia, PA; and Nusrath Yasmeen, MPharm, PhD, College of Nursing, King Saud Bin Abdulaziz University for Health ScienceNational Guard Health Affairs, Jeddah, Saudi Arabia, and University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Telangana, India.

Conflict of interest: None to report. Address correspondence to Rahmah Alalawi, King Saud Bin Abdulaziz University for Health Science-Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia; e-mail address: [email protected]. Ó 2017 by American Society of PeriAnesthesia Nurses 1089-9472/$36.00 http://dx.doi.org/10.1016/j.jopan.2017.04.009

Journal of PeriAnesthesia Nursing, Vol -, No - (-), 2017: pp 1-9

Differential Diagnosis Concern has been growing over the last decade pertaining to persistent cognitive impairments of varying severity and duration that can develop as an adverse effect of these surgical procedures after administration of anesthesia, a phenomenon that is

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predominantly seen in the elderly.3-5 The most common types of cognitive deterioration are postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), both of which are significantly associated with morbidity and mortality, reinforcing the importance of perioperative assessment. Earlier POD and POCD were considered as manifestations of the same clinical entity, but after much research it became evident that both are different separate entities.6 Delirium is defined by the International Classification of Disease, Tenth Revision, as an ‘‘etiologically nonspecific cerebral syndrome characterized by concurrent disturbances of consciousness and attention, perception, thinking, memory, psychomotor behavior, emotion, and the sleep-wake scheduled. The duration is variable and the degree of severity ranges from mild to very severe.’’7 Delirium can be either emergence delirium or POD. Emergence delirium is benign temporal disorientation that occurs during transition from anesthesia to wakefulness, may resolve within minutes or hours,8 whereas POD is a cognitive syndrome, which may occur during first few postoperative days.9,10 The differences in POCD, POD, and dementia are tabulated in Table 1.

Definition POCD is a well-known phenomenon considered as the most common type of cognitive impairments, which usually occur in the postoperative patient.11-14 POCD is neither listed in the International Classification of Disease, Tenth Revision, nor as a diagnosis in the Diagnostic and Statistical Manual IV. However, a general description of patients who complain of impairment in memory and thought process in the postoperative period is used by clinicians.15,16 According to the 1995 consensus statement, POCD may be defined as ‘‘spectrum of postoperative central nervous system dysfunction both acute and persistent including stroke, cerebral death, elusive neurologic signs with neuropsychological illness.’’17,18 POCD can occur in the immediate postoperative phase and might last for hours (early phase), but this is not always recognized as it requires elaborate neuropsychological tests.19 POCD that is lasting generally resolves within a few days or weeks (intermediate). In certain cases it can be quite severe and remain for months or years

(late follow up) after anesthesia and surgery, leading to a permanent disorder.20 This late POCD can have a negative impact on quality of life, overall functional capacity, and mortality and may lead to limiting the ability of patients and increasing their dependency on society.21 As POCD is discrete in nature it is often recognized by the patient or his family after surgery, usually when resuming daily activities. It is distressful for patients, their loved ones, and the health systems, as it occurs at a vulnerable age, where a change in cognitive function can result in a withdrawal from work because of loss of independence and an anticipated increase in perioperative care needs and expenses. It is quite possible that these complications exist and are overlooked.22 The fact that POCD can sometimes lead to permanent deterioration of a patient’s cognitive ability is still elusive and needs more research.23 Approximately 30% to 70% of elderly patients undergoing emergency or major surgery experience POD and nearly 10% of elderly patients after elective procedures are susceptible to develop POCD.6,24,25

Incidence POCD has been associated with cardiac surgery and is well described in this setting, but little is known about the prevalence or scope of this problem in connection with noncardiac surgery. The International Study of Post-operative Cognitive Dysfunction 1 compared cognitive outcome with age using a control group in 1,218 patients undergoing major noncardiac surgery and aged greater than 60 years. The incidence of POCD was 26% at 1 week and 10% at 3 months. Other studies reported an incidence of POCD after cardiac surgery of between 20% and 60% several months postoperatively.20,26,27 There is a great variation in the actual incidence of POCD depending on the way the condition is defined and which neuropsychological tools are used in measuring cognitive function. The incidence rate of POCD is at least twice as high in the elderly aged greater than 60 years than in the middle aged or younger age groups. The average POCD incidence reported was 53% at discharge time, 30% to 80% a few weeks postoperatively, 10% to 60% 3 to 6 months postoperatively, and 30% 1 to 2 years after surgery.6 The incidence of POCD increases with an increase in the population of older surgical patients, which is evident from Figure 1.

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Table 1. The Differences Between Postoperative Neurologic Disturbances (POCD, POD, and Dementia) Manifestations

Diagnostic Methods

Timing

Prognosis

Arises immediately after Reversible in days to Preoperative and New cognitive deficits months surgery, may last up to postoperative that appear 6 months psychometric testing postoperatively (impairment of memory, ability to combine tasks, psychomotor dexterity, and so forth) Reversible if the Various delirium scales, Days to weeks, POD Cognitive deficits, underlying condition is eg, Nu-DESC, Cam-ICU depending on cause hallucinations, treatable (eg, withdrawal fluctuating state of phenomenon, consciousness, and complicating other manifestations infection) Develops progressively Poor prognosis, no cure Various dementia tests, Dementia Impaired memory, over months to years available eg, Mini–Mental Status impairment of abstract Examination, Short thinking and Syndrome Test, judgment, central Dementia Detection impairment of tool Test manipulation (aphasia, apraxia, agnosia, and/ or executive dysfunction), personality changes

POCD

Cam-ICU, Confusion Assessment Method for intensive care patients; Nu-DESC, Nursing Delirium Screening Scale; POCD, postoperative cognitive dysfunction; POD, postoperative delirium.

Risk Factors The etiology leading to POCD is unclear and poorly understood; however, several putative risk factors have been identified. Despite controversies many researchers agree that POCD is a multifactorial disorder led by many precipitating risk factors, which can be classified as patient-related, surgical, and anesthetic. Among them the only strong preoperative risk factor associated with POCD is the older age probably because of gradual degeneration of various organ functions and multiple comorbidities or ailments related to aging.28 The possible risk factors for POCD are summarized and presented in Table 2.

flammation have always been associated with impaired neurocognition.30 Suggested possible causes of POCD are summarized in Table 3.

Pathophysiology Despite the broad agreement that POCD is a multifactorial diagnosis, the underlying mechanism responsible for POCD induced by anesthesia and 50 40 30

% Populaon above 65

20 % populaon above 65 receiving anesthesia

10 0

Etiology of POCD After numerous investigations that were carried out to identify the causes of POCD some have been proposed. Postoperative stress, immunomodulation, and systemic changes causing neuroin-

2000 2005

2010 2015

2020 2025

2030 2050

Figure 1. Predicted increase in the prevalence of usage of anesthetics in the elderly aged greater than 65 years for the world. This figure is available in color online at www.jopan.org.

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Table 2. Risk Factors of POCD Old age, low level of education,12,28 presence of preoperative cognitive impairment, the chronic use of narcotics and/or benzodiazepines preoperatively, the number of comorbid conditions, the cerebrovascular occurrence of POD,13 role of genetic predisposition, high alcohol intake, high ASA status, history of CVA Surgery-related factors Cardiac surgery, noncardiac surgery, use of cardiopulmonary bypass, reoperation, infections, postoperative pulmonary complications, major and invasive surgeries, long duration surgery29 Anesthesia-related factors Type of anesthesia, intraoperative cerebral desaturation, postoperative neurotoxic effects of anesthesia Patient-related factors

ASA, American Society of Anesthesiology; CVA, cerebrovascular accident; POCD, postoperative cognitive dysfunction; POD, postoperative delirium.

surgery or both in the elderly remains elusive, but could reflect altered drug responses, loss of functional reserve, or the cumulative effects on chronic disease over time. Aging results in the decline of total number of neurons by decreasing rates of neurogenesis and synaptogenesis causing accumulation of potentially toxic metabolites. These processes lead to a gradual loss of reserve, increasing the vulnerability of the brain to insults. Current theories that could explain anesthetic contributions to POCD include direct toxic effects of anesthetic agents used, alterations in calcium homeostasis,40 systemic inflammatory effects because of the surgical insult,41 suppression of neuronal stem cell function led by aging,42,43 increased activity of endogenous neurodegenerative processes.44,45

POCD and Anesthetic Agents Numerous investigations have been performed to establish the role of anesthesia and surgery in generating POCD, yet it is extremely difficult to discriminate which effects between anesthesia and surgery are responsible. Table 3. Causes of POCD Neurotoxicity of volatile anesthetic agents31 Disturbed cortisol secretion and early POCD32 Anticholinergic activity in elderly/preoperative intake of anticholinergic drugs33,34 Low intraoperative cerebral oxygenation35,36 Cerebral microemboli37 still matter of debate Systemic inflammatory markers CRP and IL-6 in relation to POCD after cardiac surgery38 Neuroinflammation with enhanced production of Alzheimer’s-related biomarkers (b-amyloid and t proteins)39 CRP, C-reactive protein; POCD, postoperative cognitive dysfunction; IL-6, interleukin 6.

Anesthesia is an indispensable part of surgery, which is considered safe and effective. However, anesthetics administered may alter the cognitive ability of patients, especially the elderly because the residual effects can alter the activity of the central nervous system. Inhalational anesthetic agents have been the most widely administered drugs in general anesthesia. The volatile anesthetics generally used show rapid elimination, low blood partition coefficients, and minimal metabolic breakdown. Such agents can reduce the risk of POCD by facilitating faster recovery in elderly surgical patients. Two such agents are sevoflurane and desflurane with low blood gas partition coefficients (0.69 and 0.42, respectively).46,47 Although there have been several studies suggesting the rapid emergence of sevoflurane48 and desflurane49,50 compared with isoflurane, to date, no studies have compared sevoflurane directly with desflurane in a randomized, controlled trial manner. This review will focus on the relationship between POCD and the volatile anesthetics commonly used (eg, isoflurane, desflurane, and sevoflurane) especially concentrating on desflurane and sevoflurane. The purpose of this review was to address the effects of two volatile anesthetic agents, desflurane and sevoflurane, and their effects on POCD. A randomized controlled trial is designed to test the hypothesis that there is no difference in time to specific recovery of events between desflurane and sevoflurane when used as part of a balanced anesthetic technique specifically in elderly patients.

Methods A thorough and sensitive literature search was performed using PubMed, Cochrane, Embase,

POSTOPERATIVE COGNITIVE DYSFUNCTION IN THE ELDERLY

Scopus, and Ovid Medline databases from the date of inception till date. The terms used in search strategy included index terms, text words, word variations such as postoperative cognitive dysfunction, elderly, general anesthetics, desflurane, and sevoflurane. The search was limited to human, randomized clinical trials (RCTs), and English language. The abstracts were reviewed and studies were excluded if there were no interventions or appropriate outcomes. Relevant references from the articles identified from the literature search were also retrieved for further analysis. One of the risk factors of POCD is age; several articles were excluded after taking age as criterion. Finally three RCTs, which compared the results of POCD incidence between sevoflurane and desflurane in elderly population, were selected (Figure 2). Anesthetic agents may cause temporary depression of cerebral functions. The symptoms of which can vary from drowsiness, slurred speech to impaired memory, these symptoms can resolve quickly or can stay long after recovery from anesthesia. Hence, there lies a possibility that hypnotic or anesthetic agents amplify the effects of the insults associated with surgery leading to permanent structural changes in the brain or long-term cognitive deficits.

Analysis Three RCTs comparing the effects of desflurane and sevoflurane on the incidence of POCD are described here. In the first study, Chen et al51 studied the recovery of cognitive function in 70 patients aged greater than 65 years, and with the American Society of Anesthesiology (ASA) physical status I-III, undergoing total knee or hip replacement after anesthesia with desflurane and sevoflurane. The ASA uses a scoring system that assesses the overall patient health and classifies into five classes. A patient who is in complete health and fit will be given a score of I, a patient with mild systemic disease a score of II, and a score of III for patients with severe systemic disease that is not debilitating.51 In a second study, R€ ortgen et al52 investigated the effects of desflurane and sevoflurane anesthesia on cognitive function and recovery in 80 patients. The patients in this RCT were aged 65 to 75 years, ASA I-III, and underwent elective surgery in traumatology, ear, nose, and throat surgery, gynecology, urology, or neurosurgery (limited to spine surgeries).52 The third RCT used in this review is the study by Deepak et al53 who studied the incidence of POCD after sevoflurane and desflurane in 60 south

Records identified through database searching(n=600)

Records excluded after scrutiny(n=400)

Records after duplicates removed(n=35)

Full-text articles for f further assessment (n=35)

Articles excluded after checking relevance to Desflurane or sevoflurane (n=7)

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Full text articles using randomized clinical trials(n=10)

Articles included in this review(n=3)

Figure 2. Flow chart showing the selection procedure of the published Research for this review. Articles used for comparing the incidence of postoperative cognitive dysfunction with desflurane and sevoflurane in elderly patients (aged greater than 65 years). This figure is available in color online at www.jopan.org.

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Asian elderly patients. The patients were aged greater than 65 years and were undergoing elective surgeries under general anesthesia.53 In all the three RCT studies patients were excluded with clinically significant cardiovascular, hepatic, renal, neurologic, psychiatric, or metabolic diseases. This included any prior history of renal failure, liver impairment, diabetes mellitus, disabling neuropsychiatric conditions, history of stroke or myocardial infraction, cardiopulmonary resuscitation, or brain trauma in the last 12 months, intracranial pressure, anesthesia anaphylactic reaction, emergency surgeries, or congestive heart failure were used. Patients with a history of alcohol or drug abuse, or undergone general anesthesia within 7 days were excluded in all the three studies.51-53 Patients with more than 50% increase in their ideal body weight were excluded in study done by Chen et al,51 whereas Deepak et al53 excluded patients with body mass index greater than 30. To ensure ability to complete cognitive function tests, patients who did not speak English or did not have at least an elementary school education were excluded from the study. Patients who scored less than 23 on the Mini–Mental State Examination (MMSE) preoperatively were excluded from the Deepak et al.53 study. The maximum score in the MMSE is 30 points with 23 or less indicating cognitive impairment. Uncooperative or legally incapacitated patients were excluded. All of the three studies were double-blinded randomized controlled studies. After informed consent, patients were assigned randomly and equally to one of the two anesthetics, sevoflurane or desflurane, by computerized random sequence generator. Only the anesthesia provider was aware of the groups with all others involved in the study blinded to the group assignment.

Patient Management Patients were asked to complete a visual analog scale using 100-mm scale (0 5 none, 100 5 maximum) for fatigue, discomfort, pain, and nausea, in addition to the MMSE in preoperative holding to assess the patient’s cognitive functions. Patients fasted for 8 hours and abstained from water for 4 hours preoperatively. Arterial

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blood pressure, heart rates, an electrocardiogram, peripheral blood oxygen saturation, bispectral index, end tidal CO2, and internal jugular central venous pressures were monitored in the operating room and recorded every 5 minutes. After 3 minutes of preoxygenation (with 100% O2), anesthesia was induced by means of a single slow intravenous (IV) injection of midazolam 1 mg to all patients. Fentanyl and propofol IV were used for anesthesia induction, whereas desflurane 2% to 6% or sevoflurane 1.0% to 1.5% in combination with nitric oxide (N2O) 66% in oxygen were given for anesthesia maintenance. Anesthesia duration (from the start of induction to discontinuation of N2O) and surgery duration (from surgical opening to skin closing) were documented. To evaluate the quality of recovery patients were asked to repeat the visual analog scale and MMSE at 1, 3, 6, and 24 hours after the end of the anesthesia. As POCD affects the neurologic functions, detection is quite complicated and requires a repeated testing of neurologic function that can be accomplished by a series of comprehensive neurophysiological tests. There are several neurophysiological tests to evaluate the cognitive function, primarily the test for attentional performance (TAP) with its subtests of alertness, divided attention, visual scanning, working memory, and reaction change, and also Paper-Pencil Test with its subtests DigitSymbol-Substitution Test, Recall of Digit Span, and the Trial making tests A and B. The TAP and Paper-Pencil test baseline measurements were conducted anytime between 12 and 24 hours preoperatively in quiet setting, free from distraction, and all electronic devices such as telephone and television turned off. Repeated TAP and PaperPencil tests were assessed in the same way for each patient at 6 to 8 and 66 to 27 hours postoperatively. Patients were screened for cognitive impairment using the MMSE before and after anesthesia. This test is reported as a very useful screening tool for POCD patients and is capable of identifying patients at greater risk of delirium after cardiac surgery. This screening test is easy and reliable and assesses cognitive impairment on a scale from 0 to 30. A decrease in MMSE greater than 2 points is clinically significant as lower scores indicate

DES, desflurane; MMSE, Mini–Mental State Examination; PPT, Paper-Pencil test; RCT, randomized clinical trial; SEV, sevoflurane; TAP, test for attentional performance.

No significant differences No significant differences No significant differences DES vs SEV DES vs SEV DES vs SEV Total knee replacement Mixed surgery Mixed surgery .70 .65 .65

Study

51

Chen et al R€ ortgen et al52 Deepak et al53

2001 2010 2013

70 80 60

RCT RCT RCT

MMSE TAP.PPT MMSE

Findings Measures of Cognitive Data Collection Type of Anesthetics Type of Study Type of Surgery Age of Patients Number of Patients Used Year of Publication

Table 4. Studies Comparing Cognitive Function Before and After Desflurane or Sevoflurane in Elderly Patients

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worse impairment. All three selected studies were carried out similarly with a few variations, such as the sample size, the variety of neuropsychological tests used, and the timing of measurement (Table 4).

Discussion This is a systematic review of observational studies linking the association between exposure to anesthesia and incidence of POCD in elderly. The three studies selected compared the recovery after maintenance with either desflurane or sevflurane (Table 4). Chen et al51 compared the cognitive function in patients aged greater than 65 years between desflurane and sevoflurane using MiniMental test. They reported no statistical significant difference between the groups with respect to Mini-Mental test values preoperatively and postoperatively at 1, 3, 6, and 24 hours. This indicated that the recovery of cognitive functions in the elderly was similar with both anesthetic agents used. The study by R€ ortgen et al52 compared early cognitive function in the elderly after desflurane or sevoflurane anesthesia. There were no significant differences in the TAP (alertness, divided attention, visual scanning, working memory, and reaction change) results between the desflurane and the sevoflurane groups at the 6 to 8 and 66 to 72 hours of assessment. Compared with the baseline, the incidence of POCD was high in both groups (desflurane 39% and sevoflurane 36% at the 6 to 8 hours of assessment and desflurane 41% and sevoflurane 47% at 66 to 72 hours of assessment). Although emergence times, that is, ‘‘time to open eyes’’ and ‘‘time to extubation’’ in the elderly with desflurane were faster than those with sevoflurane. Anesthesia in the elderly with desflurane or sevoflurane seems to be similar regarding recovery.52 Deepak et al53 compared the speed of recovery in elderly patients undergoing general anesthesia with sevoflurane or desflurane and the incidence and duration of cognitive impairment. The end of emergence times, that is, time to open eyes and time to extubation in the elderly were significantly shorter in the desflurane versus sevoflurane group (P , .001). Anesthesia in the elderly with desflurane or sevoflurane seems to be

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similar regarding recovery proved by MMSE that was tested preoperatively and postoperatively at 1, 3, and 6 hours. In all three studies the data were trending but is inconclusive because of lack of statistical significance. The findings of this review are consistent with previously published reports that show no difference in the emergence time between sevoflurane and desflurane and therefore the incidence of POCD.

they are the causative factors for cognitive decline. The prevalence of POCD is of problematic precision. Deepak et al,53 Chen et al,51 and R€ ortgen et al52 also did not find a significant difference between desflurane and sevoflurane groups with respect to incidence of POCD. Desflurane had a faster initial recovery compared with sevoflurane but there were no significant differences found between the two volatile anesthetics in the later recovery period. Hence, they cannot be categorized as the causative factors leading to POCD without in-depth research.

Conclusions POCD will continue to become more of a concern in the elderly patients because of an increase in the life expectancy of the patients. POCD can persist for a longer time in patients more than 65 years old and is typically associated with the length or procedure or anesthetic type. The ideal anesthetic used in surgeries must not affect cognitive functions of the patients for long periods of time. The use of volatile agents with a lower solubility and rapid elimination, for example, desflurane and sevoflurane, can be implicated as to whether

The present review summarizes that the studies carried out until now are primarily observational in nature and fail to provide substantial data or guidance on mechanisms and causation of POCD after using desflurane or sevoflurane. This review may serve to enlighten the researchers and raise novel concerns regarding the use of these two agents in individuals who are susceptible to the development of cognitive function decline. These concerns warrant further research, which may be helpful to develop strategies for preventing, temporizing, and treating POCD.

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