Postoperative cognitive function as an outcome of regional anesthesia and analgesia

Postoperative Cognitive Function as an Outcome of Regional Anesthesia and Analgesia Christopher L. Wu, M.D., Wesley Hsu, B.S., Jeffrey M. Richman, M.D., and Srinivasa N. Raja, M.D. Background and Objectives: It has been suggested that intraoperative neuraxial (spinal, epidural) anesthesia may decrease postoperative cognitive dysfunction when compared with general anesthesia, but the issue remains controversial. We systematically reviewed the data from published studies to determine the effect of intraoperative neuraxial anesthesia versus general anesthesia on postoperative cognitive dysfunction and delirium. Methods: Studies were identified by searching the PubMed database of the National Library of Medicine (1966 to 2003) for terms related to cognitive dysfunction after surgery. Inclusion criteria were a comparison of intraoperative neuraxial anesthesia versus general anesthesia, and the outcome of postoperative cognitive dysfunction. A total of 196 abstracts were identified, and 24 articles were analyzed. Each article was reviewed, and data were extracted from tables or text or extrapolated from figures as needed. Results: Of the 24 trials obtained, 19 were randomized and 4 were observational (nonrandomized) trials (1 trial was a combination of randomized and observational data). The age of patients studied was typically greater than 60 years, and a wide range of neuropsychometric tests were used to evaluate cognitive function. The majority of trials (23/24 of all trials and 18/19 of randomized trials) did not demonstrate a benefit from neuraxial anesthesia in decreasing the incidence of postoperative cognitive dysfunction. Conclusions: The use of intraoperative neuraxial anesthesia does not appear to decrease the incidence of postoperative cognitive dysfunction when compared with general anesthesia. There are methodologic and study-design issues present in many studies, and further elucidation of the pathophysiology of postoperative cognitive dysfunction may provide a direction for future studies. Reg Anesth Pain Med 2004;29:257-268. Key Words:

Regional anesthesia, Cognitive function, Postoperative delirium, Dementia.

P

ostoperative cognitive disorders are marked by deficits in cognition and memory.1 Postoperative cognitive disorders comprise a wide range (and severity) of disorders from neurocognitive or postoperative cognitive dysfunction (impairment in cognitive function) to dementia (impairment in memory) to postoperative delirium (impairment of consciousness). Although mental function typically reaches a nadir in the early postoperative period and recovers to preoperative levels in most patients by 1 week after surgery,2,3 a significant number of patients, especially those undergoing certain types

From the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD. Accepted for publication November 9, 2003. Supported by the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University. Reprint requests: Christopher L. Wu, M.D., Johns Hopkins Hospital, Carnegie 280, 600 North Wolfe Street, Baltimore, MD 21287. E-mail: [email protected] © 2004 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/04/2903-0013$30.00/0 doi:10.1016/j.rapm.2003.11.007

of surgery or with coexisting medical diseases, preexisting cognitive dysfunction, or advanced age,4 are at higher risk for postoperative cognitive disorders and may experience long-term postoperative cognitive disorders.5 Postoperative cognitive disorders, especially postoperative delirium, are associated with poor patient outcomes, increased mortality, and longer lengths of hospital stay.6,7 Use of perioperative regional anesthesia and postoperative analgesia is associated with a decrease in perioperative mortality8 and morbidity, including reduction of thromboembolic events,8,9 pulmonary complications,10,11 and myocardial infarction.12 On the other hand, a large number of randomized trials comparing intraoperative neuraxial anesthesia with general anesthesia have shown that use of perioperative neuraxial anesthesia does not decrease the incidence of postoperative cognitive disorders. We systematically review the available literature examining the effect of perioperative neuraxial anesthesia on cognitive function, provide an overview of the pathophysiology of postoperative cognitive disorders, describe the methodologic issues in assess-

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ing postoperative cognitive function, and examine future directions of research in this arena.

proximately 5% of the US Gross Domestic Product).21

General Overview of Postoperative Cognitive Dysfunction

Etiology and Pathophysiology of Postoperative Cognitive Dysfunction

Importance of Postoperative Cognitive Dysfunction and Postoperative Delirium

Etiology

Postoperative cognitive dysfunction (POCD) may occur more frequently than previously thought, especially in high-risk patients (e.g., elderly patients). A large international multicenter trial of approximately 1,200 patients over the age of 60 years noted that POCD was present in 25.8% of patients 1 week after surgery and in 9.9% of patients 3 months after surgery (versus 3.4% at 1 week and 2.8% at 3 months for nonsurgical control subjects).5 Even middle-aged surgical patients had significantly higher levels of POCD at 1 week after surgery than did nonsurgical control subjects (19.2% versus 4.0%).13 Postoperative delirium, a particularly troublesome subset of POCD, may occur in 9% to 11% of elderly patients undergoing elective noncardiac surgery,14,15 but the incidence may be as high as 36.8% in certain subgroups.4 The presence of POCD is an independent predictor of short-term and long-term outcomes, even after adjusting for factors such as age, comorbidities, and functional status.16,17 Postoperative delirium is independently associated with higher mortality, higher rates of major complications, longer lengths of hospital stay, and higher rates of discharge to rehabilitative facilities.7 Acute confusional states, such as postoperative delirium, conservatively cost Medicare alone at least $2 billion annually.18 Other sources estimate that inpatient delirium contributes to at least an additional 17.5 million inpatient days and $4 billion in health-care expenditures annually.16 Early (short-term) POCD is also a significant predictor for long-term cognitive dysfunction.19 Patients who have delirium may experience persistent symptoms for as long as 12 months after hospitalization.16 In addition, a decrease in neurocognitive function is associated with a significant decrease in health-related quality of life and has important social and financial implications for patients and their caregivers.20 Thus, POCD occurs relatively frequently in higher-risk patients and is independently associated with poor short-term and long-term outcomes. POCD may also serve as an indicator of quality of hospital care.16 The problem of POCD will only continue to increase as the percentage of elderly increases to approximately 17% of the total United States population by 2020, with 38% of all health-care dollars spent on this population (ap-

The general etiology of POCD is unclear; however, a multifactorial model appears to be supported by available studies.22,23 A currently popular view is that a perioperative imbalance of neurotransmitter systems (particularly acetylcholine and serotonin) in the presence of a decreased neurophysiologic reserve (as may be seen in the elderly) may contribute to the development of POCD.24-27 Others propose that inflammatory mediators (e.g., cytokines) may play a role in the development of POCD.28 There appears to be no “final common pathway” for the development of POCD, which actually may be the final common symptoms of multiple neurotransmitter abnormalities in predisposed individuals who are at further risk when they undergo a surgical procedure.26 Of the primary neurotransmitters, acetylcholine is particularly important in activities of consciousness. POCD is thought to be the result of a central cholinergic deficiency through either anticholinergic mechanisms or impaired acetylcholine production.29 Although epidemiologic studies indicate that use of anticholinergic medications is not associated with a higher incidence of POCD,23,30 experimental and other studies suggest an association between cholinergic inhibition and delirium, with a possible dose-response relationship between the degree of anticholinergic activity and symptoms of delirium.26,29 Serotonin, which mediates many behaviors (e.g., mood, sleep, and cognition), may also contribute to development of POCD. An excess of serotonin or enhancement in its neurotransmission may result in confusion and restlessness.29 Reduced serotoninergic function may also contribute to development of POCD through a reduced availability of cerebral tryptophan or elevated levels of phenylalanine.26,27 Other neurotransmitters, such as dopamine, gamma-aminobutyric acid (GABA), and glutamate, may also contribute to POCD.26 Inflammatory mediators have been implicated in the development of POCD, particularly postoperative delirium. Cytokines, including interleukins, are released in stressful situations (e.g., surgery, infections, or sepsis) and may influence hormone regulation and neurotransmitter activity.27 Infusions of interleukin 2 have been associated with cognitive dysfunction, delirium, and emotional and behavior disturbances.27,31 Hormonal imbalances resulting from surgical stress may potentially affect POCD.

Postoperative Cognitive Function and Regional Anesthesia Table 1. Risk Factors for Postoperative Cognitive Dysfunction and Delirium Preoperative Age (elderly)4,5,23 Baseline cognitive impairment4,15,23,34 Poor baseline functional status25,35,37-39 Alcohol abuse Abnormalities in serum sodium, potassium, or glucose levels Intraoperative Surgical procedures (coronary artery bypass, aortic aneurysm repair)23,33 Surgical population (hip fracture patients)35,42 Operative duration5,47 Postoperative Psychoactive medications4,23,30,48 Postoperative infections and respiratory complications14 Postoperative pain30,50,51

Elevated levels of cortisol may adversely affect mood, sleep, energy, and cognition (especially in elderly patients), in part through modulation of neurotransmitter activity.26,32 Thus, there are several hypotheses for the development of POCD. Disruption of normal neurotransmitter activity, release of inflammatory mediators, and hormonal imbalances may occur after surgery and contribute to the development of POCD. Risk Factors Because POCD is a multifactorial disease, many factors may contribute to its development (Table 1). There have been several studies investigating the effects of various factors on the development of POCD, and we have divided these factors into preoperative, intraoperative, and postoperative factors. The majority of the studies discussed focus on POCD after noncardiac surgery, as cognitive changes after cardiac surgery with cardiopulmonary bypass have been well recognized and may be the results of different pathophysiology than that seen primarily after noncardiac surgery.33 Preoperative Factors. Elderly patients4,5,23 and patients with poor preoperative cognitive4,15,23,34 or functional status23,35 are generally at higher risk for POCD. The typical decreases in brain blood flow, neuronal loss, and neurotransmitter concentrations associated with aging26 may also place elderly patients at high risk for POCD. In a study of approximately 1,200 patients, investigators found a significant correlation between increasing age and both short-term and long-term POCD (3month examination; odds ratio ⫽ 2.1).5 Examination of more than 1,300 patients undergoing elective noncardiac surgery revealed that patients older than 70 years had a relative risk of 3.4 for postoperative delirium versus the risk for patients younger than 70 years (15% versus 4%).23 The risk factors

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of increasing age and baseline cognitive or functional impairment for development of delirium also reflect the risk in general medical inpatients.6,22,30,36 Alcohol abuse and marked abnormalities in preoperative sodium, potassium, or glucose levels (which may be a reflection of diuretic use and dehydration) have been reported as predictors of POCD.23,37-39 Finally, low educational levels have also predicted POCD,5,34 as subjects with higher levels of education may perform relatively better on tests with a high learned component (e.g., language and secondary memory) than on tests measuring attention, implicit memory, and visual-spatial analysis.34,40 Intraoperative Factors. Certain types of surgical procedures are associated with higher rates of POCD. Patients undergoing cardiac surgery with cardiopulmonary bypass33 or thoracic or aortic aneurysm procedures are at higher risk for POCD.23 In addition, certain subgroups of patients are at higher risk for POCD. For instance, the overall incidence of POCD in elderly orthopedic patients may be as high as 7.5% to 17.5%41; however, patients with hip fractures have a much higher incidence (28% to 50%).35,42 Although intraoperative factors such as hypotension and hypoxia were widely believed to contribute to development of POCD, the overall contribution of intraoperative factors to the development of POCD is unclear.14,43 The presence of deliberate intraoperative hypotension appears not to be a significant factor for the development of POCD.14 A randomized trial of 235 older patients undergoing elective primary hip replacement surgery revealed no differences in cognitive outcome in patients randomized to a mean arterial blood pressure of 45 to 55 mm Hg when compared with patients who had a mean arterial pressure of 55 to 70 mm Hg.44 Cerebral hypoperfusion and abnormalities in intraoperative glucose and hematocrit levels do not appear to correlate with POCD.45,46 On the other hand, the relationship of sustained and profound hypotension, hypoglycemia, anemia, or hypoxia to the development of POCD is not clear. A longer duration of anesthesia is associated with an increase in the incidence of POCD.5,47 Postoperative Factors. The administration of certain drugs has been independently associated with development of POCD, especially postoperative delirium. The use of psychoactive medications, such as anticholinergic drugs,4 meperidine (odds ratio ⫽ 2.7),23 and benzodiazepines (odds ratio ⫽ 3.0)23, is significantly associated with development of POCD.4,23,48 In other studies, opioids other than meperidine and anticholinergic agents have not been associated with delirium.23,30 Although deliberate hypotension per se does not appear to influ-

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ence development of POCD, a postoperative hematocrit less than 30% (odds ratio ⫽ 1.7) was independently associated with a higher incidence of postoperative delirium in patients older than 50 years undergoing major elective noncardiac surgery.14 In addition, the presence of postoperative infections and respiratory complications has been shown to significantly correlate with development of POCD.5 It also appears that postoperative factors such as hypotension and hypoxia43 do not significantly contribute to development of POCD. Although an earlier smaller study (40 patients) suggested that postoperative hypoxemia was associated with decreased mental function,49 a more recent larger trial demonstrated that hypotension (odds ratio ⫽ 1.0) and hypoxia (odds ratio ⫽ 0.8) may not be as important in development of POCD.5 The same study also noted that the presence of pulmonary complications was associated with a significant increase in POCD (odds ratio ⫽ 1.6).5 Inpatients with infections, although not necessarily of respiratory etiology, in general have a significantly higher risk of postoperative delirium (odds ratio ⫽ 2.96).6,30 What has also been shown, however, is that increased levels of postoperative pain are associated with a higher incidence of POCD.30,50,51 An early study noted that poorly controlled pain in medical and surgical inpatients after adjusting for age and gender was associated with an increased risk of postoperative delirium (odds ratio ⫽ 1.89).30 A multivariate analysis of a trial of 60 patients between 50 and 80 years of age who underwent elective total-hip replacement indicated that poor control of pain predicted a decline in mental status as assessed by validated instruments.51 A larger subsequent study in patients older than 50 years undergoing a variety of noncardiac surgical procedures confirmed that higher pain scores at rest were associated with an increased risk of delirium (adjusted odds ratio ⫽ 1.20).50 Although increased pain with movement or maximal pain was not associated with an increased incidence of POCD, the authors hypothesized that pain at rest is experienced by the patient for a longer duration and may adversely affect the sleep-wake cycle,50 which may influence the development of POCD.52 Thus, it seems that the strongest risk factors for POCD may be those that cannot be altered (e.g., age, preexisting cognitive impairment, and severity of coexisting illness).26 It is unclear whether intraoperative factors significantly influence the development of POCD; however, postoperative factors such as poorly controlled pain and presence of postoperative infections (including respiratory complications) may be associated with a higher incidence

of POCD. Despite the association between poorly controlled pain and POCD, there is a paucity of data examining the effect of postoperative regional analgesic techniques on the development of POCD.

Postoperative Cognitive Dysfunction and Regional Anesthesia We performed a PubMed search (May 12, 2003) using the database covering the time period of 1966 through May 2003, which yielded a total of 943 articles, 760 of which were in English and 196 of which were clinical trials. The details of the literature search are available upon request. The abstracts of these 196 articles were reviewed to determine whether the studies investigated postoperative cognitive function between receiving neuraxial regional anesthesia versus general anesthesia. A total of 22 articles met these criteria. The references from all of these articles and several review articles39,53-55 were reviewed to yield an additional 2 articles (total ⫽ 24 articles). A summary of these articles is shown in the Table 2.56-76 Of the 24 trials obtained, 19 were randomized and 4 were observational (nonrandomized) trials. One trial combined both observational and randomized data. There were 9 trials examining orthopedic patients, 6 trials examining urologic patients, 1 trial examining gynecologic patients, 3 trials examining ophthalmologic patients, 2 trials examining patients undergoing vascular surgery, and 3 trials examining patients undergoing a combination of surgical procedures. The age of patients studied was greater than 25 years, with the vast majority older than 60 years. The number of patients in each study ranged from 30 to 9,598, with the median being 64 to 72 patients. Table 3 summarizes all randomized trials examining intraoperative neuraxial anesthesia versus general anesthesia. Of the 19 trials, 18 did not demonstrate a difference in cognitive function between intraoperative general anesthesia versus regional anesthesia. Table 4 summarizes all observational (nonrandomized) trials examining intraoperative neuraxial anesthesia versus general anesthesia. None of the 5 trials (which includes the 1 trial combining both observational and randomized data) demonstrated a difference in cognitive function between intraoperative general versus regional anesthesia.

Methodologic Issues in Assessing Postoperative Cognitive Dysfunction The vast majority of currently available randomized controlled trials do not demonstrate any difference between intraoperative neuraxial anesthesia

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Table 2. Summary of Intraoperative Neuraxial Regional Versus General Anesthesia Trials Surgical Population

Study

Design

Type of Anesthesia

Population Age

Asbjorn, 198958

GU

RCT

GA, EA

60-80

Berggren, 1987

ORTH

RCT

GA, EA

⬎64

Bigler, 198557 ORTH Campbell, 199358 OPHTH

RCT RCT

GA, SA GA, LA

⬎60 65-98

Chung, 198759

GU

RCT

GA, SA

⬎60

Chung, 198960 Cook, 198661

GU Vascular

RCT RCT

GA, SA GA, SA

⬎60 mean ⫽ 67

GU

RCT

GA, SA

65-85

GU

RCT

GA, SA

⬎60

Ghoneim, 198864 GYN, GU, RCT ORTH

GA, RA

25-86

Haan, 199165

GU

RCT, OBS

GA, SA

63-86

Hole, 198066 Hughes, 198867 Jhaveri, 198968 Jones, 199069

ORTH ORTH OPHTH ORTH

RCT RCT OBS RCT

GA, GA, GA, GA,

56-84 50-80 ⬎60 ⬎60

Karhunen, 198270 OPHTH

RCT

GA, LA

⬎65

Marcantonio, 199814

Noncardiac OBS

⬎50

Nielson, 199071

ORTH

RCT

GA, EA, SA, GA⫹EA GA, RA

60-86

O’Hara, 200072 Rasmussen, 200373

ORTH OBS Noncardiac RCT

GA, RA GA, RA

⬎60 61-84

Riis, 19832

ORTH

RCT

GA, EA, GA⫹EA

⬎60

OBS

GA, EA

Not defined

Somprakit, 200275

GYN, GU, RCT ORTH

GA, RA

Williams-Russo, 199576

ORTH

GA, EA

48

Crul, 199262 Fredman, 1998

63

Ryhanen, 197874 Vascular

RCT

EA SA RA RA

50% of patients ⬍60 ⬎40

n

Cognitive Assessments

40 Digit span, paired-associate learning, free recall, story recall, visual memory (LM,A) 57 Organic brain syndrome scale (LA,PO,EF,LM,PF,A,EM) 40 Roth-Hopkins test (abbreviated) (LA,LM) 169 RBMT (recall subset), digit copying, FPUQ, Holbrook Activity Index, digit span, FOMT (PO,EF,LM,PF,A) 44 MMSE, GEMS, anxiety visual analog scale (LA,PO,EF,LM,PF,A,EM) 44 MMSE, GEMS (LA,PO,EF,LM,PF,A,EM) 101 Subjective clinical assessment for postoperative confusion 60 Standardized subjective examination of observable behaviors 100 Digit symbol, visual analog scale for coordination/ anxiety (EF,PF,A,EM) 105 SIP, SCL-90-R, metamemory questionnaire, mental status questionnaire, reaction time, tapping, symbol cancellation, sorting test, digit span, immediate/ delayed free recall, delayed recognition, pairedassociate learning, addition, SCWIT, digit symbol (LA,PO,EF,LM,PF,A,EM) 53 MMSE, object assembly, digit symbol, word learning (LA,PO,EF,LM,PF,A) 60 Nonstandardized interview 30 Standardized short-term recall and recognition (LM) 83 RBMT, unprepared simple reaction time (LM,PF) 129 NART, choice reaction time, critical flicker fusion threshold, object learning, digit copying, functional life scale, cognitive difficulties scale (LA,PO,EF,LM,PF,A) 60 WMS subsets (orientation, memory, digit span, associate learning), Luria test, finger tapping, State Anxiety Inventory (EF,LM,PF,A,EM) 1,341 Confusion assessment method, chart/nursing intensity criteria for evaluation of delirium (PO,EF,LM,PF,A) 64 WAIS-Rev, WMS-Rev, trail making A and B, COWA, finger oscillation, two-point discrimination, hand preference questionnaire, SIP (LA,PO,EF,LM,PF,A,EM) 9,425 Mental status change 428 Visual verbal learning test, concept shifting test, SCWIT, letter digit coding test, depression scale, subjective cognitive functioning questionnaire, instrument for activities of daily living (PO,EF,LM,PF,A,EM) 30 Trail making A and B, digit symbol, digit span, story recall, verbal selective reminding, visual gestalts, picture recognition, block design, sorting (KasaninHanfmann) (PO,EF,LM,PF,A) 72 Hamilton Anxiety Rating scale, digit span. GrahamKendall test for design memory, nonsense word series learning. Bourdon-Wiersma test, James test for visualization, color test for brain injury, symmetry-drawing, Rorschach, MMPI, Wartegg’s test (PO,LM,PF,A,EM) 120 Thal Mental Status examination (LA,PO,EF,LM,PF,A) 262 Boston Naming test, COWA, digit symbol, trail making A and B, digit span, Benton Visual Retention/Recognition, Mattis-Kovner Verbal Recall/Recognition, evaluation for delirium (LA,PO,EF,LM,PF,A)

Abbreviations: GU, genitourinary; GYN, gynecology; OPHTH, ophthalmology; ORTH, orthopedics; RCT, randomized controlled trial; OBS, observational; EA, epidural; GA, general; LA, local; RA, regional; SA, spinal; COWA, controlled oral word association; FPUQ, Felix Post Unit questionnaire; FOMT, Fuld Object Memory test; GEMS, geriatric mental status exam; MMPI, Minnesota Multiphasic Personality Inventory; MMSE, Mini-Mental Status exam; NART, National Adult Reading test; RBMT, Rivermead Behavioural Memory test; SIP, sickness impact profile; SCWIT, Stroop Color-Word Interference task; WAIS, Wechsler Adult Intelligence scale; WMS, Wechsler Memory scale; LA, language; PO, perceptual organization; EF, executive function; LM, learning/memory; PF, psychomotor function; A, attention and concentration; EM, emotionality.

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Regional Anesthesia and Pain Medicine Vol. 29 No. 3 May–June 2004 Table 3. Results of Intraoperative Neuraxial Regional Versus General Anesthesia Randomized Trials Type of Anesthesia

Asbjorn, 198956

GU

GA, EA

LM,A

Preop/day 4; wk 3

Berggren, 198748 Bigler, 198557 Campbell, 199358 Chung, 198759

ORTH ORTH OPHTH GU

GA, GA, GA, GA,

EA SA LA SA

LA,PO,EF,LM,PF,A,EM LA,LM PO,EF,LM,PF,A LA,PO,EF,LM,PF,A,EM

Preop/6, 12 mo Preop/wk 1,12 Preop/day 1; wk 2; 3 mo Preop/6 h; day 1,3,5; 1 mo

Chung, 198960 Cook, 198661 Crul, 199262 Fredman, 199863

GU Vascular GU GU

GA, GA, GA, GA,

SA SA SA SA

LA,PO,EF,LM,PF,A,EM N/A N/A EF,PF,A,EM

Ghoneim, 198864

GA, RA

LA,PO,EF,LM,PF,A,EM

Haan, 199165 Hole, 198066 Hughes, 198867

GYN, GU, ORTH GU ORTH ORTH

Preop/6 h; day 1,3,5; 1 mo Before discharge Preop/day 3; wk 4 Preop/0, 15, 30, 60, 90, 120 min Preop/day 4; 3 mo

GA, SA GA, EA GA, SA

LA,PO,EF,LM,PF,A N/A LM

Preop/day 1-7; wk 12 Preop/before discharge Preop/day 1, 2, 7

Jones, 199068

ORTH

GA, RA

LA,PO,EF,LM,PF,A

Preop/3 mo

Karhunen, 198270 Nielson, 199071 Rasmussen, 200373

OPHTH ORTH Noncardiac

GA, LA GA, RA GA, RA

EF,LM,PF,A,EM LA,PO,EF,LM,PF,A,EM PO,EF,LM,PF,A,EM

Preop/wk 1 Preop/3 mo Preop/wk 1, 12

Riis, 19832

ORTH

PO,EF,LM,PF,A

Preop/day 2, 4, 7: wk 12

Somprakit, 200275

GYN,GU, ORTH ORTH

GA, EA, GA⫹EA GA, RA

No Yes Recognition: SA significantly worse postoperative day 1 only Choice reaction time: GA group significantly better No No Intention to treat : 19.7% GA versus 12.5% RA show cognitive dysfunction (P ⫽ .06) at 1 wk. [Per protocol: 21.2% GA versus 12.7% RA (P ⫽ .04)] No

LA,PO,EF,LM,PF,A

Preop/day 1, 3

No

GA, EA

LA,PO,EF,LM,PF,A

Preop/1 wk; 6 mo

No

Study

Williams-Russo, 199576

Cognitive Assessments

Significant Difference Between/Among Anesthesia Groups

Surgical Population

Frequency of Assessment

Visual memory : EA group significantly worse on day 4 only No No No MMSE: Significant difference at 6 h only No No No No No

Abbreviations: GU, genitourinary; GYN, gynecology; OPHTH, ophthalmology; ORTH, orthopedics; EA, epidural; GA, general; LA, local; RA, regional; SA, spinal; A, attention and concentration; EF, executive function; EM, emotionality; LA, language; LM, learning memory; PF, psychomotor function; PO, perceptual organization.

and general anesthesia in preserving postoperative cognitive function, although it might seem intuitive to some anesthesiologists that intraoperative neuraxial anesthesia would be superior to general anesthesia in decreasing POCD. However, it is possible that a relatively brief unimodal intervention

such as intraoperative neuraxial anesthesia might only have a small impact on a complex perioperative complication such as POCD, which has a multifactorial etiology. Unlike the beneficial effects seen with other organ systems (e.g., facilitating return of gastrointestinal function or preserving postopera-

Table 4. Results of Intraoperative Neuraxial Regional Versus General Anesthesia Observational Studies Study Jhaveri, 198968 Marcantonio, 199814 O’Hara, 200072 Ryhanen, 197874

Surgical Population

Type of Anesthesia

Cognitive Assessments

Frequency of Assessment

OPHTH Noncardiac

GA, RA GA, EA, SA, GA⫹EA GA, RA GA, EA

LM,PF PO,EF,LM,PF,A

Preop/day 4, wk 4 Preop/day 1-5

No No

N/A PO,LM,PF,A,EM

Postop/day 1-7 Preop/day 1-7

No No

ORTH Vascular

Significant Difference Between/ Among Anesthesia Groups

Abbreviations: OPHTH, ophthalmology; ORTH, orthopedics; EA, epidural; GA, general; LA, local; RA, regional; SA, spinal; A, attention and concentration; EF, executive function; EM, emotionality; LA, language; LM, learning memory; PF, psychomotor function; PO, perceptual organization; N/A, not available.

Postoperative Cognitive Function and Regional Anesthesia

tive pulmonary function), intraoperative neuraxial anesthesia does not confer any apparent direct physiologic benefit on cognitive function and, because of its limited duration of action, may be unable to provide adequate postoperative pain control, which has been shown to be a factor in the development of POCD.50 The issue of whether perioperative neuraxial anesthetic techniques can attenuate the decline in POCD may not be as clear because of the presence of some conceptual, methodologic, and studydesign issues in most studies. In general, these issues revolve around the definition of cognitive dysfunction, properties of the specific neuropsychological tests used to assess cognitive function, statistical considerations when analyzing the results of such tests, and possible confounding factors. Although an in-depth analysis of methodologic concerns in the study of cognitive decline is beyond the scope of this article, there are several excellent reviews on this topic.77-79 Definition and Measurement of Cognitive Dysfunction Cognitive function is an abstract concept that may be divided into several components, including memory, attention, language, visuospatial ability, abstraction, and psychomotor performance.78 Ideally, tests used to assess the presence of POCD should address all or focus on those components of cognitive function most likely to be affected; however, not all trials have done so. The criteria for the presence of a postoperative “cognitive deficit” has not yet been standardized and may be arbitrarily chosen on the basis of a change in test performance (e.g., 1 standard deviation).77 In addition, assessment of “cognitive function” may be limited to only 1 or 2 of the domains that constitute cognitive function; that is, verbal comprehension, perceptual organization (e.g., visuospatial abilities), executive function (e.g., abstraction, problem solving, and cognitive flexibility), learning and memory, attention and concentration, and processing or psychomotor speed.80 Thus, a “cognitive deficit” may be based on just the presence of a change in 1 or 2 domains. Furthermore, when a large number of tests are being used to assess POCD, the chance of the investigator finding a “cognitive deficit” increases substantially.77 Using a large number of tests increases the chance of drop-out/withdrawal and patient fatigue, which in itself may affect test results. Thus, the wide range in incidence of POCD may in part be caused by the definition and criteria of “cognitive deficit” chosen by the investigator.

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Properties of Available Instruments There are a variety of neuropsychological tests available for assessing “cognitive function”; however, many tests only assess a specific component of cognitive function (e.g., attention, language, memory, orientation, psychomotor, abstraction, or psychomotor function) (Table 5). A number of factors may influence the results of these tests and must be considered when assessing postoperative cognitive function, including the intrinsic variability in performance, practice effects, sensitivity of the test, “floor” (minimum score) and “ceiling” (maximum score) effects, influence of external elements (e.g., testing environment), and patient characteristics (e.g., education, age, and presence of depression). There is normally considerable interpatient and intrapatient variability in neuropsychological test performance,77 which in certain instances may be incorrectly interpreted as presence of a cognitive deficit. Neuropsychological tests have primarily been designed to evaluate longer-term cognitive performance in broader population-based studies or in subjects with dementing illnesses (e.g., Alzheimer’s disease) and not devised to assess cognitive function after medical or surgical interventions.79,81 Tests chosen to assess POCD should be sensitive and responsive enough to detect subtle and incremental changes in cognitive deterioration postoperatively.77 Ideally, neuropsychological tests should not have a “floor” or “ceiling,” which may result in a higher probability in detecting “cognitive deficits.”77 Factors such as depression, anxiety, lower educational attainment, and increasing age may have a “floor” or “ceiling” effect that may lead to misleading conclusions of cognitive function postoperatively.77,79 Otherwise, improper interpretation of the results of such tests may lead to improper conclusions when comparing the effect of interventions (e.g., neuraxial anesthesia versus general anesthesia) on POCD. Statistical Considerations Many of the statistical considerations and properties of neuropsychologic tests in the assessment of postoperative cognitive function have been described in detail by Rasmussen and colleagues, who have also provided a series of recommendations for the use and analysis of neuropsychological tests in the evaluation of postoperative cognitive function.77 One of the most common problems in the statistical analysis of POCD is the issue of patient drop-out, or missing data points, which typically ranges from approximately 10% to 30% but may be as high as 50%.77 Although there are several meth-

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Anxiety visual analogue scale59 Benton visual retention/recognition76 Block design (WAIS)2 Boston naming test76 Bourdon-Wiersma74 Choice reaction time69 Cognitive difficulties scale69 Color test for brain injury74 Concept shifting test73 Confusion assessment method14 Controlled oral word association71,76 Coordination visual analogue scale63 Critical flicker fusion threshold69 Delayed recognition64 Digit copying58,69 Digit span (WAIS)56,58,64,74,76 Digit symbol (WAIS)2,63-65,76 Felix post unit questionnaire58 Finger oscillation71 Finger tapping70 Free recall56,64 Fuld object memory test58 Functional life scale69 Geriatric mental status exam59,60 Geriatric depression scale73 Graham-Kendall design memory74 Hamilton anxiety rating scale74 James visualization test74 Letter digit coding test73 Luria test70 Mattis-Kovner verbal recall/recognition76 Metamemory questionnaire64 Minnesota multiphasic personality inventory74 Mini-mental status exam59,60,65 National Adult Reading test69 Object assembly (WAIS)65 Organic brain syndrome scale48 Paired-associate learning56,64 Picture recognition2 Reaction time64 Rivermead behavioral memory test58,68 Rorschach74 Roth-Hopkins (abbreviated)57 SCL-90-R64 Sickness impact profile64,71 Sorting test2,64 State anxiety inventory70 Story recall2,56 Stroop color-word interference task64,73 Symbol cancellation64 Symmetry drawing74 Tapping64 Thai mental state examination75 Trail making A & B2,71,76 Two-point discrimination71 Unprepared simple reaction time68 Verbal selective reminding2 Visual gestalts2 Visual memory58 Visual verbal learning test73 WAIS-Rev71 Wartegg’s test74 WMS-Rev70,71 NOTE. Data from studies listed in Table 2.

Perceptual Executive Learning/ Psychomotor Attention and Language Organization Function Memory Function Concentration Emotionality

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Postoperative Cognitive Function and Regional Anesthesia

ods to address this issue, what is probably more important are the reasons for patient drop-out, as the true incidence of POCD may be underreported if a large number of subjects withdrew from the trial as a result of severe POCD. Inadequate sample sizes may result in an underpowered study, particularly when neuropsychologic tests of low sensitivity are used, large variabilities in test results exist, or there is a failure to account for practice effects (leading to an erroneous perception of cognitive improvement).77 Finally, the accurate interpretation of large numbers of neuropsychologic tests is difficult at best, with errors increasing at a rate possibly greater than the number of neuropsychologic tests used.80

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Thus, there are many methodologic and studydesign issues in the assessment of POCD, including questions surrounding the actual and arbitrary definitions of a “cognitive deficit,” properties of the specific neuropsychological tests used, and statistical considerations of the analysis of these tests. In addition, there are issues with the use of only a single measurement to assess the presence of POCD (versus measuring changes in cognition over time) or of multiple cognitive tests, the results of which may be combined to increase the probability of finding a “cognitive deficit.”77,78 Finally, the clinical implications or correlates of a statistically significant difference in some neuropsychological tests are unclear.

Study-Design Issues Additional study-design concerns may further contribute to ambiguity in the interpretation of currently available studies. Almost all of the trials investigating the effect of intraoperative neuraxial anesthesia compared with general anesthesia have allowed the routine use of benzodiazepines in the perioperative period, which, as previously mentioned, is significantly associated with development of POCD.23 In an observational study, use of intraoperative spinal anesthesia without any premedication or sedation, such as benzodiazepines or opioids, yielded a 0% incidence of delirium in elderly patients undergoing repair of femoral neck fractures, which typically is associated with a delirium rate of at least 25%.36,82 However, other data did not demonstrate a correlation between serum benzodiazepine concentration and postoperative cognitive dysfunction 1 week after surgery.83 Another area of potential concern is the general lack of control of postoperative analgesia in currently available trials. The effect of postoperative analgesia on mental function has not been rigorously investigated, and it is recognized that higher levels of postoperative pain are associated with a higher incidence of POCD (especially delirium).50,51 Thus, control of postoperative pain may theoretically influence the incidence of POCD, which typically peaks within the first 3 postoperative days.4 Furthermore, different analgesic regimens may potentially result in different effects on postoperative cognitive function, as certain types of analgesic regimens (e.g., epidural analgesia with a local anesthetic-based solution) not only provide superior pain control versus systemic opioids84 but also minimize the systemic effects of opioids, which may be associated with development of POCD.23 Finally, like almost all “regional versus general” anesthesia trials, none of the randomized controlled trials were blinded, leading to the possibility of bias.85

Future Directions and Conclusions We are just beginning to understand the complex pathophysiology of POCD. Although unable to provide a causal relationship, epidemiologic studies have been useful in identifying predictive risk factors for POCD. Although many of the strongest risk factors for POCD may be those that cannot be altered (e.g., increasing age, preexisting cognitive impairment, and severity of coexisting illness),88 it does appear that other factors, such as poorly controlled pain and presence of respiratory complications, may be associated with a higher incidence of POCD. Thus, critically examining possible therapeutic options in the postoperative period (especially in light of the fact that postoperative delirium peaks in the second or third postoperative day) may be as important, if not more important, as studying those in the intraoperative period. One possible therapeutic option might be the use of perioperative epidural analgesia (with a local anestheticbased regimen) in a multimodal approach, as this type of intervention may attenuate known risk factors for POCD, such as decreasing the incidence of respiratory complications,10,11 providing superior postoperative pain control,84 and improving patient-oriented outcomes (e.g., sleep)85,87 that may contribute to POCD or postoperative delirium.52 Our systematic review suggests that intraoperative neuraxial anesthesia does not decrease the incidence of POCD when compared with general anesthesia. However, there are many methodologic and study-design issues that may affect interpretation of some of these studies. There are many concerns with regard to the assessment of cognitive function in general, and there are limitations to the wide variety of tests used to evaluate cognitive function. Until some of these issues are resolved and a consensus is reached, the routine use of neuropsychological tests in the typical clinical setting

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may only be of limited usefulness. Future work in this area will allow correlation of the degree of cognitive impairment (as assessed by appropriate neuropsychological testing) to a clinically relevant decrease in cognitive or physical function.

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