Post-Operative Delirium: Predictors and Prognosis in Elderly Orthopedic Patients Pamela Williams-Russo MDIMPH, Barbara L. Urquhart RN, Nigel E. Sharrock MD, and M a y E. Charlson M D Objective: To compare the effect of post-operative analgesia using epidural versus intravenous infusions on the incidence of delirium after bilateral knee replacement surgery in elderly patients. Additional risk factors and impact on post-operative recovery were also assessed. Design: Prospective randomized controlled trial. Setting: Urban referral hospital specializing in elective orthopedic surgery. Patients: 60 consecutive patients undergoing bilateral knee replacement surgery with epidural anesthesia were approached; 51 patients were eligible and consented. The mean age was 68, 55% were women, and there was a high prevalence of comorbid medical disease. No patient was demented pre-operatively . Intervention: Random allocation to either continuous epidural infusion of bupivicaine and fentanyl or continuous

intravenous infusion of fentanyl. Infusions were initiated at the first complaint of pain and continued through the 36- to 48-hour stay in the recovery room. Main Outcome Measure: Acute post-operative delirium defined using an algorithm based on DSM I11 criteria. Results: The overall incidence of acute delirium was 4196, with no difference between types of post-operative analgesia. Predictors of delirium were age, gender, and pre-operative alcohol use. All cases resolved within 1 week, and length of stay and achievement of physical therapy goals were the same for delirious and non-delirious patients. Conclusions: There is a high incidence of post-operative delirium in elderly non-demented patients following bilateral knee replacement, regardless of whether post-operative analgesia is administered by the epidural or intravenous route. J Am Geriatr SOC90759-767,1992

METHODS here is a growing body of literature on the incidence, course, and early sequelae of delirium Assembly of Population All patients undergoing (acute confusional states) in hospitalized elderly elective bilateral total knee replacement at the Hospital patients. The reported incidence ranges from 2% to for Special Surgery between June 1989 and January 50%, reflecting differences in the diagnostic criteria for 1990 were potential candidates for the study. To be delirium, the populations under study, and the method eligible for entry into the study, patients had to be of post-operative surveillance for Previous scheduled for a bilateral knee replacement, speak Engreports on acute delirium in geriatric patients have lish as a primary language, and have no serious hearing found that patients experiencing delirium had an in- or vision impairment which would preclude cognitive creased risk of other serious complications including testing. The protocol was reviewed and approved by progression to severe permanent cognitive dysfunction the Institutional Human Rights Committee. Informed and death.17-24Multiple potential risk factors for acute consent for participation in testing and randomization delirium have been identified, including anti-cholin- to post-operative analgesia via either continuous epiergic medications, metabolic derangements, and un- dural or continuous intravenous infusion was obtained derlying medical problems such as infection or hy- from all patients. Sixty patients were initially evaluated poxia.2, 11, 25-30 At our institution, acute post-operative for eligibility. Of the 60 patients, four patients did not delirium was noted to occur frequently in patients speak English, one patient underwent only a unilateral undergoing bilateral total knee replacement. This op- replacement, one patient refused to participate and eration is associated with severe post-operative pain, three patients dropped out after initial enrollment. and patients typically require high doses of narcotics Thus, 51 patients completed the study. This represents for pain control. The objective of this study was to 80% of all patients undergoing the procedure during determine the effect of post-operative analgesia via this time period. epidural infusion versus systemic infusion on the inciPre-Operative Evaluation The pre-operative evaldence of acute post-operative delirium in older adults uation was performed on the day prior to surgery at undergoing this elective surgical procedure, to assess the time of admission to the hospital. The baseline other potential risk factors, and to examine the impact evaluation documented the patient's sociodemographic of delirium on the hospital course. status, education, and occupational history. A standardized history and physical exam were performed. Comorbid diseases, medications, alcohol use greater From the Departments of Medicine and Anesthesiology, Hospital for Special than three drinks per week, psychiatric history, and Surgery, Cornell Arthritis and Musculoskeletal Diseases Center, Cornell Uniprevious peri-operative complications were all reversity Medical College, New York, New York. corded. Patients were also introduced to the use of a This study was supported in part by a grant from the National Institute of Aging, No. R 0 1 AG08562, and in part by the Cornell Arthritis and Musculovisual analogue scale (VAS) for pain measurement. skeletal Diseases Center. 31, 32 This consisted of a 10-cm horizontal line labeled Address reprint requests to Dr. Pamela Williams-Russo, Cornell Medical College, 515 East 71st Street, S-919, New York, NY 10021. at the left end "no pain" and at the right end "worst

T

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IACS 40:759-767, 1992 0 1992 by the American Geriatrics Society

0002-8614/92/$3.50

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WILLIAMS-RUSSO ET AL

pain in my life." They were asked to mark on the line their level of pain at the time of the pre-operative interview, and the interviewer then asked for a verbal description of that level of pain to verify that the patient understood the use of the scale. Laboratory data included a complete blood count, biochemistry profile, sedimentation rate, electrocardiogram, chest Xray, and perfusion lung scan, which are all routinely performed as pre-operative testing. The pre-operative cognitive battery included the Mattis Dementia Rating Scale (DRS) and the Geriatric Depression Scale (GDS).The Mattis DRS is a brief; 36item scale which measures higher cortical function in adults. It consists of five subscales which measure attention, initiation/perseveration, construction, conceptualization, and memory.33,34 The Mattis DRS is a more sensitive and specific discriminator of cortical impairment then are the commonly used dementia screening measures such as the Mini-Mental State Exam, the Mental Status Questionnaire, or the Short Portable Mental Status Examination which can discriminate only gross cognitive i m ~ a i r m e n t . ~ ~ The -~* DRS requires an average of 5 minutes to complete. Previous neuropsychological studies have established norms for the DRS, with a mean of approximately 137 k 6.9 (SD) for health1 people between 65-81 who are not institutionalized. 9, 40 Studies of performance on the DRS by patients with senile dementia of the Alzheimer's Type, patients with depression, and patients with other psychological disorders led to the use of a total score of less than 123 as a cutoff for dementia. 41* 4 2 The GDS is a 30-item self-rating scale developed as a brief screening test for depression in older adults. 43, 44 The GDS specifically excludes items that relate to somatic symptoms of depression, which are less discriminatory in older adults and in patients with chronic medical illness.45,46 The reliability and validity of the A, score of 11 or GDS have been d e m ~ n s t r a t e d .44~ ~ greater on the GDS indicates possible depression, with an 84% sensitivity rate and 95% specificity rate.47 Intra-Operative Management Pre-operative sedation was not employed routinely. Intra-operatively, all patients received epidural anesthesia at level L2-3 or L3-4 with bupivicaine 0.75%. Intraoperative sedatives included midazolam and fentanyl. All patients were continuously monitored with radial artery and pulmonary artery pressure catheters, pulse oximetry, and electrocardiographic leads. Post-Operative Management Post-operatively, all patients were closely monitored in the recovery room for 36 to 48 hours with continuous radial artery and pulmonary artery pressure, pulse oximetry, and electrocardiographic monitoring of cardiac rhythm and rate. Additional surveillance in the recovery room included daily arterial blood gases, electrocardiograms, blood tests and measurements of cardiac index. Post-Operative Analgesia Patients were allocated to receive either continuous epidural bupivicaine (4 mg/mL) and fentanyl (10 mcg/mL) or continuous intravenous fentantyl (10 mcg/mL) infusion by random number table assignment. Post-operative analgesia was initiated as soon as patients complained of pain in the

JAGS-AUGUST 1992-VOL. 40, NO. 8

recovery room and was continued throughout their 36to 48-hour stay in the recovery room. The dosing of post-operative analgesic was left to the discretion of the treating anesthesiologists, with the clinical goal of maximizing pain relief without causing respiratory sedation. After discharge from the recovery room to the floor, intramuscular and oral narcotics were used for analgesia on a prn basis. Post-Operative Surveillance Study patients received care from their usual physicians and nurses, who were not aware of the purpose of the study. Study personnel were not involved in patient care or treatment decisions. All patients were examined at least once daily by study personnel in the recovery room and through the seventh post-operative day in the hospital. A directed physical examination was performed, emphasizing cardiopulmonary and neurologc status. Patients were asked each day about symptoms of confusion, delirium, hallucinations, nightmares, or abnormal behavior. Their family members were also specifically questioned about the patient's mental status and behavior. After resolution of delirium, patients were asked about their recall of the events during the delirious period. The Mattis DRS was readministered daily. At the time of the cognitive assessment, oxygen saturation was measured using a pulse oximeter. Patients were also asked to rate their current pain level on the VAS pain scale on each post-operative day. Nurses were asked to rate the patients as not confused, slightly confused, or very confused during their shift. All chart notes were reviewed for any mention of symptoms or interventions related to post-operative confusion. When staff had noted possible signs of delirium, they were interviewed by the study investigators to provide additional information. All medications administered to patients through post-operative day 7 were recorded. Special note was taken of medications used to treat symptoms of disorientation or delirium. Definition of Delirium Specific criteria had to be satisfied for a patient to be diagnosed as delirious. Our operational definition of post-operative delirium was based on the criteria described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R)48 and used only the data from study investigator examinations and documented physician and nurse reports. For a patient to be classified as delirious (1) cognitive impairment had to be of acute onset and demonstrate a fluctuating course and (2) there had to be evidence of significantly impaired attention. In addition to these two basic conditions, at least two of the following signs of delirium had to occur: disorientation, disorganized thought, altered level of consciousness, hyperactive or hypoactive psychomotor activity, perceptual disturbances such as hallucinations, or memory impairment. Altered level of consciousness alone, (ie, somnolence) was not a sufficient condition, as it was not uncommon for patients to be sedated and drowsy after receiving narcotics. Nor was it uncommon for patients to have a disturbed sleep-wake cycle with no other symptoms or signs during the first few days post-operatively, and these patients were not classed as delirious. Our defi-

PREDICTORS & PROGNOSIS OF POST-OP DELIRIUM

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nition is thus a stringent definition for post-operative delirium. The subset of delirious patients whose delirium was recognized and treated by the physicians and nurses caring for the patients was noted. Clinical interventions included physical restraints, medications for delirium such as haloperidol or other tranquilizers, or diagnostic investigation including neurology consult, MRI, or head CT scan. Data for this group were assessed separately to determine if there were any differences between this subset of delirious patients and those whose delirium was not noted or treated by the staff. Analysis To test for an association between method of post-operative analgesia and delirium, Chisquare with continuity correction was used. The association between total amount of fentanyl received during the period of continuous analgesia infusion and delirium was evaluated using student’s t test. Other potential risk factors for delirium were also evaluated by comparing baseline clinical variables between delirious and non-delirious patients using student’s t test and Chi-square with continuity correction. Type of analgesia and covariates that were significant in univariate analysis were entered into logistic regression models. Potential second-order interactions between main effects remaining in the model were then tested.

761

Logistic regression was performed using PROC LOGIST, available in the Statistical Analysis System (SAS In~titute).~~

RESULTS Baseline Characteristics Seventy-five percent of the study patients were age 65 or older, with a mean age of 68 ( f 7 . 3 ) and a maximum age of 84 (Table 1). Fifty-five percent were women. As expected in an elderly population, there was a high prevalence of comorbid medical conditions. Forty-three percent of patients had a history of hypertension, 14% myocardial infarction or angina, 14% chronic pulmonary disease, and 2% cerebrovascular accident. Twenty-seven percent of patients reported drinking at least three alcoholic beverages per week. Two patients were on medications for psychiatric illness, one for manic-depressive illness, and one for depression. An additional two patients had scores on the Geriatric Depression Scale suggesting probable depression. Using the Comorbidity Index,5037 patients had a comorbidity score of zero, 13 a score of one, and one a score of two. The patients enrolled in this study represent a very distinct group from the populations described in most prior reports of delirium in hospitalized elderly. All patients lived independently in the community at the

TABLE 1. PRE-OPERATIVE CHARACTERISTICS AND OUTCOME OF DELIRIUM Not Delirious n (%) Delirious (%) P Value** Number of subjects Age range Mean age Gender Women Men Comorbidity Score 0 1 2 Hypertension Yes No Coronary artery disease Yes No COPD Yes No Psychiatric disease and/or GDS > 11* Yes No Alcohol use > 3 drinkslweek Yes No Working full- or part-time Yes No Early post-operative analgesia Epidural Intravenous

51

21 58-84 71.6

30 48-80 65.6

-003

28 23

7 (25) 14 (61)

21 (75) 9 (39)

.010

37 13 1

15 (41) 6 (46) 0 (0)

22 (59) 7 (54) l(lO0)

.657

22 29

6 (27) 15 (52)

16 (73) 14 (48)

.078

7 44

5 (71) 16 (36)

2 (29) 28 (64)

.09

7 44

3 (43) 18 (40)

4 (57) 26 (59)

.616

4 47

2 (50) 19 (40)

2 (50) 28 (60)

.549

14 37

9 (64) 12 (32)

5 (36) 25 (68)

.039

19 32

6 (32) 15 (47)

13 (68) 17 (53)

.283

26 25

10 (38) 11 (44)

16 (62) 14 (56)

.68Y

‘ A Geriatric Depression Score (GDS)greater than 1 2 .

** P values based on student’s t test for age; Fisher exact test for coronary artery disease, COPD, and psychiatric disease; Chi square for all other comparisons.

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WILLIAMS-RUSSO ET AL

time of admission. None was considered to be demented pre-operatively by their orthopedic or medical physicians or by family members. Thirty-seven percent of patients were still actively employed despite their age and arthritis. The patients’ pre-operative DRS scores ranged from 116 to 144, with a mean of 135. Using the previously described cutoff of 123, two of the 51 patients in the study would have been classified as mildly demented pre-operatively. Intervention-Analgesic Groups Twenty-six patients received continuous epidural infusions and 25 patients received continuous intravenous infusions. There were no significant differences between the two treatment groups in age, sex, ASA classification, comorbid conditions, occupational or educational status, or baseline DRS, GDS, or VAS pain scores. As expected, the patients randomized to receive epidural fentanyl and bupivicaine infusions received significantly lower doses of fentanyl as a group than patients randomized to receive intravenous fentanyl infusions. For example, the mean dose during the recovery room continuous infusion period of 36 to 48 hours was 1108 f 370 mcg fentanyl in the epidural group and 4892 f 2530 mcg fentanyl in the intravenous group. Over the 24-hour period of post-operative day 1 (POD #l), the mean dose in the epidural group was 722 f 248 mcg fentanyl versus 3312 f 1662 mcg fentanyl in the intravenous group. Converted to the more clinically familiar mean hourly infusion rate, the epidural infusion group received a mean dose of 30 mcg/hr fentanyl versus 138 mcg/hour in the intravethere nous group on POD # 1. As reported el~ewhere,~’ was no differencein the efficacy of pain relief between the two analgesic groups as measured by daily VAS pain scores. Outcome Twenty-one patients (41%) developed acute post-operative delirium. This included eleven patients (22% of total, 52% of delirious) whose postoperative delirium was recognized and treated by their physicians and nurses. Four of the 11 recognized cases manifested their delirium as an acute agitated organic psychosis in the recovery room; for example, these patients were pulling out catheters, attempting to get out of bed, and accusing the staff of persecution. Other patients had more subtle signs and symptoms. Their post-operative central nervous system dysfunction was manifested by disorientation, confusion, and hallucinations without marked agitation. Many of these patients, for example, attempted to get out of bed and walk by themselves, oblivious to their newly placed knee prosthesis. Eighty-five percent of patients were first noted to be delirious within 48 hours of surgery. Two additional patients were diagnosed as delirious on POD #3. One patient did not develop signs of delirium until POD #4, and was the only patient found to be hypoxic when delirious. Risk Factors for Delirium Delirium occurred slightly more often in patients who received postoperative analgesia with intravenous fentanyl (11/25, 44%) than in those who received analgesia with epidural fentanyl (10/26, 38%). This difference was not significant (x2 = .16, P = .688, RR of delirium with

JAGS-AUGUST 1992-VOL. 40, NO.8

epidural versus fentanyl = .87, Taylor series 95% confidence limits .45-1.69). Given the finding of no difference between the groups, the power of the study was calculated. The observed rates of delirium were .38 and .44, and the observed difference in rates was thus .06. Setting alpha at .05, and using the observed rates of delirium of .38 and .44, the power of the study is 81% to detect a true difference in rates of 0.20. However, the power of the study to detect a difference of 0.15 and 0.10 in rates is only 70% and 56%, respectively. No significant association between fentanyl dose and the occurrence of delirium was observed, although the delirious patients did receive a higher mean dose as a group than the non-delirious patients. This association was tested in several ways: (1)the total dose of fentanyl received in the recovery room period, (2) the total dose of fentanyl received in the initial RR period on the day of surgery, (3) the total dose of fentanyl received in the 24 hours of POD #1, and (4) the total dose of fentanyl received on POD #2 before discharge to the floor. For example, during the 24-hour time period of POD #l, the delirious patients received a mean total dose of 2158 f 2073 mcg of fentanyl, versus the non-delirious patients with a mean total dose of 1875 +- 1513 mcg fentanyl. High narcotic dose was not a necessary or sufficient condition for the occurrence of delirium as a patient who received a total fentanyl dose on POD #1 of only 445 mcg developed delirium, while another patient who received 5540 mcg did not develop delirium. Variables found to be associated with an increased risk of delirium on univariate analysis were age (P = 0.003), male sex ( P = 0.009), and history of alcohol use (P = 0.039) (Table 1). The mean age of those who became delirious was 71.6 years versus 65.6 in those who did not become delirious. In the logistic regression model, age, sex, and alcohol use were again the only significant predictors of delirium. Age was the most important predictor of post-operative delirium, based upon comparisons of the -2 Log likelihood Chi-square for the effects of the covariates in the models that included age and sex, age and alcohol, and sex and alcohol. No significant interactions among these three variables were observed. The pen-operative use of either anticholinergic drugs (including antidepressants, neuroleptics, anti-incontinence, and sleeping medications) or benzodiazepines did not show an association with post-operative delirium. None of the patients in the study received cimetidine or metoclopramide. Pre-operative cognitive status as measured by DRS score, history of psychiatric illness, comorbidity score, and specific comorbid medical conditions (hypertension, coronary artery disease, chronic obstructive pulmonary disease, cerebrovascular disease) also showed no association with occurrence of post-operative delirium. In the subset of 11 patients whose delirium was recognized by their physicians and nurses, the only predictor was age (P = 0.001). The mean age of these patients was 75.6 years. No other factor was associated with an increased risk of clinically recognized postoperative delirium.

PREDICTORS & PROGNOSIS OF POST-OP DELIRIUM

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763

Post-Operative Delirium and Other Post-Opera- Manifestations of fat embolism syndrome include acute tive Complications Early post-operative complica- mental status changes such as acute delirium, hypoxtions were frequent in this elderly surgical population, emia and tachypnea, fever, and thromb~cytopenia.~’ but none of these showed a significant association with To determine whether the high incidence of postthe development of post-operative delirium (Table 2). operative delirium in the bilateral knee replacement For example, C 0 2 retention greater than 45 mmHg population might be due to fat embolism syndrome, during the first 48 hours post-operatively was observed we tested for an association between post-operative in 29% (6/21) of delirious patients, but also in 40% delirium, thrombocytopenia, and respiratory signs. (12/30) of non-delirious patients. Eleven patients de- Early post-operative fever would not be a useful indiveloped post-operative hyponatremia, defined as a so- cator in the total knee replacement population, as the dium less than 134, but only two of these 11 patients vast majority of patients are febrile in the first 48 to 72 became delirious. Atrial arrhythmias in the recovery hours after operation. Thrombocytopenia, defined as a room occurred in 22% (11/51) of patients; five of the platelet count less than 120,000, was seen in 39% (20/ 11 patients became delirious. Urinary tract infections 51) of patients, half of whom were delirious. No patient were the only infectious complication noted in this complained of respiratory symptoms or was noted to population, occurring in only 6% of patients (3/51), be wheezing or tachypneic. Hypoxemia was noted in and were not associated with post-operative delirium. only three of the 21 delirious patients, and in two of Thus, multiple clinically significant post-operative the 30 non-delirious patients. Although the diagnosis complications occurred within the first 48 hours after of fat embolism syndrome is difficult to make with surgery, but no single complication showed an associ- certainty, it does not appear that fat embolism was the ation with the occurrence of post-operative delirium. major cause of the high incidence of post-operative There was also no difference in the rate of other post- delirium in this population. The majority of patients recovered within 24 to 48 operative complications between the two analgesic hours of their initial symptoms, although one patient treatment groups. With regard to other major post-operative compli- did not regain his normal mental status until the sixth cations, the only patient who suffered a post-operative postoperative day. Patients who became overtly conmyocardial infarction (non-Q-wave) also developed fused post-operatively did not experience slower redelirium. No patient experienced symptomatic pulmo- habilitation or prolonged hospital stays. The mean length of stay was 16 days for both groups of patients. nary emboli or pulmonary edema. Fat embolism syndrome is a potential cause of delir- Both groups also achieved major physical therapy goals ium in orthopedic patients who have either fractures at the same rate post-operatively. or surgery involving reaming of bone m a r r ~ w . ~ ’ - ~ ~Change in daily performance on the Mattis Dementia Rating Scale accurately reflected the clinical course of acute delirium and recovery. When the delirious paTABLE 2. EARLY POST-OPERATIVE tients’ mental status permitted completion of the Mattis COMPLICATIONS DRS, their scores showed a decline from their preopNot Deerative performance. (Figure 1) Deterioration was not P Delirious lirious (95) Value* n (%I -0- Non-delirious Deliriow C 0 2 Retention > 45 mmHg

-

Yes No Atrial arrhythmias Yes No Elevated P.A.D.** Yes

No Sodium < 134 meq/L Yes No PO2 Saturation < 95% Yes

No

Platelet count < 120,000 Yes No Abdominal ileus Yes No * P values based on Chi square

18 6 (67) 33 15 (45)

12 (33) 18(55)

.400

11 6 (55) 40 15 (38)

5 (45) 25 (62)

.309

15 9 (60) 36 12 (33)

6 (40) 24 (67)

.077

11 2(18) 40 19 (47)

9 (82) 21 (53)

.077

5 3 (60) 46 18 (39)

2 (40) 28 (61)

.337

20 10 (50) 31 11 (35)

10 (50) 20 (65)

.304

8 l(12) 43 20 (47)

7 (88) 23 (53)

.076

for C 0 2 retention, atrial arrhythmias, elevated PAD, and thrombocytopenia. P values based on Fisher exact tesf for other comparisons. ** Elevated PAD is defined as a pulmonary artery diastolic pressure greater than 20 mmHg during the first 48 hours post-operatively.

-15‘

0

I

I

I

1

2

3

4

5

6

I

I

7

8

P O ~ 1 - O C s r 8 t ~day v~

FIGURE 1. Change in daily DRS Score compared with pre-operative score.

764

WILLIAMS-RUSSO ET AL

greater on any particular subscale, such as the subscale measuring attention, but affected performance on all subscales. After the clinical signs of delirium had resolved, DRS performance gradually improved, generally reaching the pre-operative level by post-operative day 7. Conversely, in the patients who did not develop post-operative delirium, their serial scores were characteristic of a practice effect, showing daily incremental improvement approaching the maximum possible score. DISCUSSION Incidence and Detection The reported incidence of acute delirium in elderly patients hospitalized for medical problems ranges from 25% to 50%.’, 3* 56 This variability reflects differences in study populations including age, comorbid conditions, and pre-admission mental status, different study designs (for example, retrospective vs prospective), and differences in the criteria for the diagnosis of delirium. Numerous studies have reported that delirium in hospitalized elderly patients often goes unrecognized by the patients’ health care providers57; thus, the method of surveillance for delirium significantly affects the reported rate.4’56 In designing this prospective study, we utilized strict criteria for the diagnosis of delirium and performed intensive surveillance for this primary outcome. We observed a 41 % rate of acute delirium post-operatively, in comparison to the 22% rate of ”overt”delirium noted and treated or investigated by the physicians and nurses caring for the patients. The presentation of acute delirium in the elderly is easily noted when it takes the form of combative psychotic behavior but not when the manifestations are quieter forms of perceptual disturbances, disorganized throught, disorientation, or memory impairment. The 19% of patients with acute delirium not noted by treating staff were often, nonetheless, greatly distressed by the experience or had family members who were distressed. Post-operative delirium may have different characteristics than delirium in medical patients. In the hipfracture population, the reported incidence rate varies from 23-44%.5-8In contrast, the incidence rate of acute delirium in elderly patients undergoing surgery for other than hip fracture re air a ears to be lower, ranging from 2% to 26%9-16 EKrly patients with disorientation, confusion, and neurologic disease are predisposed to falling and hip fracture.7.58 The higher rate of post-operative delirium in hip fracture patients may be partially a function of a high rate of preoperative organic brain syndrome^.^ Therefore, patients undergoing surgery for hip fracture represent a different population than elderly patients undergoing elective s~rgery.”,~’ The high cognitive functional level of this study’s geriatric patient population is partially the result of selection bias by the orthopedic surgeons. Obvious dementia, which would compromise a patient’s ability to comply with the post-operative rehabilitation therapy, is generally considered a contraindication to knee replacement surgery. Predictors/Risk Factors Many different potential

IAGS-AUGUST 1992-VOL. 40, NO. 8

etiologic factors have been described for acute delirium, and it is likely that the pathogenesis of post-operative delirium is often multifactorial. Peri-operative medications, in particular anti-cholinergics, narcotics, and sedative-hypnotics have been implicated in immediate post-operative cognitive dysfunction.’, 6, 25, 26, 28-30 Withdrawal from pre-operative alcohol and benzodiazepine use may also result in delirium.60 Residual effects of inhaled anesthetic agents have been demonstrated to impair cognitive function in the first 48 to 72 hours post-operatively, due to their high solubility and slow post-operative eliminati~n.~l-~’ Early postoperative hypoxemia and other medical complications may also affect central nervous system function in this period.’, 28r The endocrine response to surgery leads to significant fluctuations in metabolic state, for example changes in oxygen consumption and electrolyte balan~e.~’ Post-operative metabolic disturbances can result in delirium, particularly in the elderly.”, ’’, 70 Sleep deprivation and the stimuli of unfamiliar environments such as post-operative recovery units may also increase vulnerability to delirium. Many of these factors may play a role in the high incidence of post-operative delirium in the elderly hip fracture population. These patients tend to have a greater burden of comorbid diseases (ie, increased rates of coronary artery disease, arrhythmias, pulmonary disease, dementia, and other neurologic disease), frequently use either psychotropic or anticholinergic medications, and frequently experience pre-operative hypoxemia.6, 58, 71-77 Each of these factors may increase the likelihood of delirium occurring in the hip fracture population; however, the occurrence of delirium in our study of elective surgery was not strongly associated with any one of these factors. This study focused on patients undergoing elective bilateral total knee replacement, as an anecdotally high incidence of acute post-operative delirium had been noted in these patients. Restricting the study to one single surgical procedure was done to allow better delineation of patient and peri-operative management variables associated with the development of postoperative delirium. Also, all patients in the study received regional anesthesia, thus bypassing the issue of residual inhalational anesthetics possibly contributing to early post-operative central nervous system dysfunction. Bilateral knee replacement surgery also offered a chance to compare two different techniques of early post-operative analgesia, continuous epidural infusion versus continuous intravenous infusion of narcotic. Both of these forms of analgesia have previously been shown to be effective for pain control,78*79 and research in post-operative and chronic pain analgesia has suggested that continuous administration of narcotics is superior to intermittent (prn) administration for relief of pain.80* Although patients receiving epidural infusions of narcotics show evidence of systemic effects of narcotics and have had documented serum levels of narcotics, the total doses of narcotics needed for pain control are less, especially when combined with the use of an anesthetic agent in the epidural infusion. This provides an opportunity to assess the effect of narcotics on the development of acute post-

’’,

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PREDICTORS & PROGNOSIS OF POST-OP DELIRIUM

operative delirium. As expected,-we observed significantly higher doses of narcotics in the intravenous infusion group, but we did not observe any difference in the incidence of delirium by either type of analgesic regimen or total dose of narcotics. Due to the sample size of 51 patients, however, our finding of no difference in the incidence of delirium by type of analgesia is subject to type I1 error. The risk factor most strongly associated with postoperative delirium was absolute age, even within the narrowed age range of the study population. There are multiple potential risk factors for delirium which would be expected to correlate with increasing age. For example, impaired vision and hearing are more likely in older patients, and may contribute to both sensory deprivation and vulnerability to misinterpretation of sensory stimuli, thus increasing the risk of delirium. The increased prevalence and duration of comorbid medical conditions in older adults may result in increased structural cerebrovascular disease and decreased cardiac, pulmonary, or renal reserve, which may increase vulnerability to delirium. A history of alcohol use greater than three drinks per week was also associated with an increased risk of post-operative delirium. Twenty-seven percent of this geriatric population reported drinking more than three drinks per week, higher than expected by the physicians caring for these patients. In this study population, men were more likely than women to develop post-operative delirium, and this association with gender was not the result of an interaction between gender and age or gender and alcohol use. The incidence of post-operative delirium in bilateral total knee replacement patients is markedly higher than the 14% incidence in similar atients undergoing unilateral total knee replacement!’ Possible hypotheses to explain the increased incidence after the bilateral procedure include the longer duration and the overall increased “surgical stress” of the bilateral procedure. In addition, the bilateral knee replacement patients in our institution are monitored for 36 to 48 hours in the recovery room, as compared to only 6 to 24 hours after unilateral knee replacement patients. The recovery room environment is similar to that of an intensive care unit, and this may have been an additional factor contributing to the high incidence and early onset of delirium after bilateral knee replacement. Bilateral total knee replacement patients are also exposed to a greater load of abnormal metabolites such as bone marrow fat emboli in the course of the operative procedure. Fatembolism syndrome may present with neurologic changes including acute d e l i r i ~ m . ~However, ’-~~ we did not observe an association between other markers of fat-embolism syndrome such as hypoxemia and thrombocytopenia and occurrence of acute delirium in this patient population. PROGNOSIS The occurrence of acute delirium has been repeatedly found to be associated with an increased rate of other morbidity and mortality. Delirium occurring in patients hospitalized for medical conditions reportedly predicts

765

17-20* 23r 24 a 15%-30% risk of in-hospital m~rtality.~, Acute delirium in medical patients is also associated with higher rates of other acute complications, prolonged hospital stay, permanent cognitive dysfunction, and an inability to return to independent living.’, 3f 21 While previous reports of hospitalized elderly patients with acute delirium have described a 15%-30% incidence of progression to stupor, coma, and death, none of these complications occurred in any patient in this study. Post-operative delirium may have a different prognosis than acute delirium occurring in elderly patients hospitalized for medical problems, although some studies have reported increased morbidity and mortality,’, ” as well as increased length of stay and delayed rehabilitation,” among patients with post-operative delirium. The reports of poor prognosis associated with post-operative confusion in the hip-fracture population may be related to their increased prevalence of prefracture cognitive and medical morbidity. Relatively little information is available on the prognosis of patients with post-operative delirium undergoing other than hip fracture repair. One previous study of elderly patients undergoing elective total hip or knee replacement found increased rates of other complications and an increased length of stay in patients who experienced acute post-operative delirium.” Another study of total hip replacement patients found that 55% of patients developing acute post-operative delirium had persistent cognitive impairment several months after operation, although the criteria for cognitive impairment were imprecise.’ Our study, in elderly patients undergoing elective bilateral knee replacement, found that despite a high incidence of acute post-operative delirium, there was no apparent increased risk for additional post-operative complications, prolonged length of stay, or early mortality. None of the patients progressed to severe postoperative cognitive dysfunction during hospitalization. Nonetheless, post-operative delirium in the post-total joint replacement population is potentially catastrophic, as a disoriented patient attempting to climb over the bedrails and walk to the bathroom runs a high risk of falling with subsequent fracture or prosthesis dislocation. It is important to note that the experience of delirium was a source of much distress to patients and family members as a sign of frailty and impending dementia. This question, ie, does post-operative delirium mark patients at risk for earlier onset of the symptoms and signs of chronic organic brain syndrome, remains to be answered.

REFERENCES 1. Lipowski ZJ. Delirium (acute confusional states). JAMA. 1987;258:17891792. 2. Lipowski ZJ. Delirium in the elderly patient. N Engl J Med 1989;320:578582. 3. Rockwood K. Acute confusion in elderly medical patients. J Am Geriatr SOC1989;37:150-154. 4. lnouye SK, van Dyck CH, Alessi CA et al. Clarifying confusion. The Confusion assessment method. Ann Intern Med 1990;113:941-948. 5. Williams MA, Holloway JR, Winn MC et al. Nursing activities and acute confusional states in elderly hip-fractured patients. Nurs Res 1979;26:2535.

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6. Berggren D, Gustafson Y, Eriksson B et al. Postoperative confusion after anesthesia in elderly patients with femoral neck fractures. Anesth Analg 1987;66:497-504. 7. Billig N, Ahmed SW, Kenmore P et al. Assessment of depression and cognitive impairment after hip fracture. J Am Geriatr SOC1986;34:499503. 8. Bigler D, Adelhoj B, Petring OU et al. Mental function and morbidity after acute hip surgery during spinal and general anesthesia. Anesthesia 1985;40:672-676. 9. Hole A, Terjesen T, Breivik H. Epidural versus general anesthesia for total hip arthroplasty in elderly patients. Acta Anesth Scand 1980;21:279-287. 10. Millar HR. Psychiatric morbidity in elderly surgical patients. Br J Psychiatry 1981;138:17-20. 11. Eaton HM, Liang MH, Daltroy LH et al. Postoperative delirium following total joint surgery. APHA abstract, Annual American Rheumatology Association National Scientific Meeting, June 1987. 12. Seymour G. Medical assessment of the elderly surgical patient. Rockville, MD: Aspen Systems, 1986. 13. Johnson A, Bengtsson M, Merits H, Lofstrom JB. Anesthesia for major hip surgery. Reg Anesth 1986;11:83-88. 14. Blundell EA. A psychological study on the effects of surgery on eight-six elderly patients. Br J SOCClin Psycho1 1967;6:297. 15. Titchener JL, Zwerling 1, Gottschalk I et al. Psychosis in surgical patients. Surg Gynecol Obstet 1956;102:59-65. 16. Rogers M, Reich P. Psychological Intervention with Surgical Patients: Evaluation outcome, Psychological Aspects of Surgery. Guggenheim FG, Base1 S, Karger, AG, eds. 1986, pp 51-68. 17. Bruera R, Chadwick S, Weinlick A, MacDonald N. Delirium and severe sedation in patients with terminal cancer. Cancer Treat Rep 1987;71:787788. 18. Guze SB, Cantwell DP. The prognosis in organic brain syndromes. Am J Psychiatry 1964;120:878. 19. Fields SD, MacKenzie CR, Charlson ME, Perry SW. Reversibility of cognitive impairment in medical inpatients. Arch Intern Med 1986;146:15931596. 20. Beresin EV. Delirium in the elderly. J Geriatr Psychiatry Neurol 1988;1:127-143. 21. Erkinjuntti T, Wikstrom J, Palo J, Autio L. Dementia among medical inpatients. Arch Intern Med 1986;146:1923-1926. 22. Magaziner J, Simonsick EM, Kashner TM et al. Survival experience of aged hip fracture patients. Am J Public Health 1989;79:274-278. 23. Rabins PV, Folstein MF. Delirium and dementia: Diagnostic criteria and fatality rates. Br J Psychiatry 1982;140:149-153. 24. Guze SB, GaengsurisriS. Organic brain syndromes: Prognostic significance in general medical patients. Arch Gen Psychiatry 1967;17:363. 25. Larson EB, Kukull WA, Buchner D, Reifler BV. Adverse drug reactions associated with global cognitive impairment in elderly persons. Ann Intern Med 1987;107:169-173. 26. Gengo FM, Fagan SC, de Padova A et al. The effect of beta blockers on mental performance in older hypertensive patients. Arch Intern Med 1988;148:779-784. 27 Berggren D, Gustafson Y, Eriksson B et al. Postoperative confusion after anesthesia in elderly patients with femoral neck fractures. Anesth Analg 1987;66497-504. 28 Karhunen U,John G. A comparison of memory function following local and general anesthesia for extraction of senile cataract. Acta Anesth Scand 1982;26291-296. 29. Tune LE, Holland A, Folstein MF et al. Association of postoperative delirium with raised serum levels of anticholinergic drugs. Lancet 1981;26:651-652. 30. Golinger RC, Peet T, Tune LE. Association of elevated plasma anticholinergic activity with delirium in surgical patients. Am J Psychiatry 1987;144:1218-1220. 31. Gracely RH. Methods of testing pain mechanisms in normal man. In: Wall PD, Melzack R, eds. Textbook of Pain, Second Ed. New York: Churchill Livingstone, 1989, pp 257-268. 32. Jensen MD, Koroly P, Braver S. The measurement of clinical pain intensity: A comparison of six methods. Pain 1986;27117-126. 33. Mattis S. Mental status examination for organic mental syndromes in the elderly patient. In: Bellak L, Karasu T, Eds. Geriatric Psychiatry. New York: Grune and Stratton, 1976. 34. Coblentz JM, Mattis S, Zingesser H et al. Presentile dementia. Arch Neurol 1973;140:495-496. 35. Ritchie K. The screening of cognitive impairment in the elderly. J Clin Epidemiol 1988;41:635-643. 36. Folstein MF, Folstein SE, McHugh PR. 'Mini-Mental State": A practical guide for grading the cognitive state of patients for the clinician.J Psychiatr Res 1975;12189-198. 37. Rubins SM, Glasser ML, Werckle MA. The examination of physicians' awareness of dementing disorders. J Am Geriatr SOC1987;35:1051-1058. 38. Naugle RI, Kawczak K. Limitations of the Mini-Mental State Examination. Clevel Clin J Med 1989;56277-281. 39. Montgomery KM, Costa L. Neuropsychological test performance of a normal elderly sample. Paper presented at the International Neuropsychological Society Meeting, Mexico City, 1983.

IAGS-AUGUST 1992-VOL. 40, NO. 8 40. Vitaliano PI', Breen AR, Albert MS et al. Memory, attention, and functional status in community-residing Alzheimer Type dementia patients and optimally healthy aged individuals. J Gerontol 1984;39(1):58-64. 41. Vitaliano PP, Breen AR, Russo J et al. The clinical utility of the Dementia Rating Scale for assessing Alzheimer patients. J Chron Disabilities. 1984;37743-753. 42. Montgomery KM, Costa L. Concurrent validity of the Mattis Dementia Rating Scale. Paper presented at the International Neuropsychological Society Meeting, Lisbon, Portugal, 1983. 43. Yesavage JA, Brink TL, Rose TL et al. Development and validation of a geriatric depression screening scale: A preliminary report. J Psychiatr Res 1983;1737-49. 44. Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): Recent evidence and development of a shorter version. In: Clinical Gerontology. TL Brink, Ed. New York: Haworth Press, 1986. 45. Coleman RM, Miles LE, Guilleminault C et al. Sleep-wake disorders in the elderly. J Am Geriatr SOC1981;29:289-296. 46. Salzman C, Shader RI. Depression in the elderly: Relationship between depression, psychologic defense mechanisms, and physical illness. J Am Geriatr SOC1978;26:253-259. 47. Brink TA, Yesavage JA, Lum 0 et al. Screening tests for geriatric depression. Clin Gerontol 1:37-44. 48. American Psychiatric Association Committee on Nomenclature and Statistics. Diagnosticand Statistical Manual of Mental Disorders, 3rd Ed, Revised (DSM-IIIR). Washington, DC: American Psychiatric Association, 1987. 49. Harrell F. PROC LOGIST Supplemental User's Guide. SAS Institute, Cary, NC, 1983, pp 180-202. 50. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 1987;40:373-383. 51. Sharrock NE, Urquhart B, Williams-Russo PG. Failure to demonstrate improved outcomes when using epidural analgesia following bilateral total knee arthroplasty. Presentation, European Society for Regional Anesthesia, Bern, Switzerland, 1990. 52. Dorr LD, Merkel C, Mellman MF, Klein I. Fat emboli in bilateral total knee arthroplasty: Predictive factors for neurologic manifestations. Clinical Orthopaedics 1989;248:112-118. 53. Eddy AC, Rice CL, Carrico CJ. Fat embolism syndrome: Monitoring and management. J Crit Illness 1987;2(6):24-37. 54. Jacobson DM, Terrence CF, Reinmuth OM. The neurologic manifestations of fat embolism. Neurology 1986;36(6):847-851. 55. Gossling HR, Donohue TA. The fat embolism Syndrome. JAMA 1979; 241;25:2740-2742. 56. Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderlv. JAMA 1990;263: 1097-1 101. 57. Mcearney JR, Palmateer LM. Assessment of cognitive deficits in geriatric patients: A study of physician behavior. J Am Geriatr Soc 1985;33:467471. 58. Covert C. Anesthesia for hip surgery in the elderly. Can J Anaesth 1989;36(3):311-319. 59. Ions GK, Stevens J. Prediction of survival in patients with femoral neck fractures. J Bone Joint Surg [Br]. 1987;69:384-387, 60. Madi S, Langonnet F. Postoperative agitation: A new cause. Cah Anesthesiol 1988;36509-5 12. 61. Bruce DL, Bach MJ. Effects of trace anesthetic gases on behavioural performance of volunteers. Br J Anaesth 1976;48:871-876. 62. Davison LA, Steinhelber JC, Eger EI, Stevens WC. Psychological effects of halothane and isoflurane anesthesia. Anesthesiology 1975;43:313-324. 63. Herbert M, Healy TEJ, Bourke JB et al. Profile of recovery after general anaesthesia. Br Med J 1983;286:1539-1542. 64. Manner R, Kanto J, Salonen M. Use of simple tests to determine the residual effects of the analgesic component of balanced anesthesia. Br J Anaesth 1987;59:978-982. 65. Korttila K, Tammisto T, Ertama P et al. Recovery, psychomotor skills, and simulated driving after brief inhalational anesthesia. Anesthesiology 1977;46:20-27. 66. Townes BD, Dikmen SS, Bledsoe SW et al. Neuropsychological changes in a young, healthy population after controUed hypotensive anesthesia. Anesth Analg 1986;65:955-999. 67. Reitan JA, Porter W, Braunstein M. Comparison of psychomotor skills and amnesia after induction of anesthesia with midazolam or thiopental. Anesth Analg 1986;65:933-937. 68. Calabrese JR, Skwerer R, Gulledge AD et al. Incidence of postoperative delirium following myocardial revascularization. Clevel Clin J Med 1987;54:29-32. 69. Riis J, Lomholt 8, Haxholdt 0 et al. Immediate and long-term mental recovery from general versus epidural anesthesia in elderly patients. Acta Anaesthesiol Scand 1983;27:44-49. 70. Moses H, Kaden I. Neurologic consultations in a general hospital. Am J Med 1986;81:955-988. 71. Davis FM, Woolner DF, Frampton C et al. Prospective, multi-centre trial of mortality following general or spinal anesthesia for hip fracture surgery in the elderly. Br J Anaesth 1987;59:1080-1088. 72. Abdon NJ, Nilsson BE. Episodic cardiac arrhythmia and femoral neck fracture. Acta Med Scand 1980;208:73-76.

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73. Ceder L, Elmqvist D, Svensson S. Cardiovascular and neurological function in elderly patients sustaining a fracture of the neck of the femur. J Bone Joint Surg 1981;638:560-566. 74. Rashiq S, Logan RF. Role of drugs in fractures of the femoral neck. Br Med J 1986292861-863. 75. Ray WA, Griffin MR, Schaffner W et al. Psychotropic drug use and the risk of hip fracture. N Engl J Med 1987;316:363-369. 76. Martin VC. Hypoxemia in elderly patients suffering from fractured neck of femur. Anaesthesia 1977;32:852-867. 77. McKenzie PJ, Wishart HY, Dewar KMS et al. Comparison of the effects of spinal anaesthesia and general anaesthesia on postoperative oxygenation and perioperative mortality. Br J Anaesth 1980;52:49-53. 78. Raj PP, Knarr DC, Vigdorth E et al. Comparison of continuous epidural infusion of a local anesthetic and administration of systemic narcotics in

79. 80. 81.

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the management of pain after total knee replacement suqery. Anesth Analg 1987;66:401-406. Loper KA, Ready LB, Downey M et al. Epidural and intravenous fentanyl infusions are clinically equivalent after knee surgery. Anesth Analg 1990;70:72-75. Rutter PC, Murphy F, Dudley HAF. Morphine: Controlled trial of different methods of administration for postoperative pain relief. Br Med J 1980;280:12-13. Portenoy RK, Moulin DE, Rogers A et al. IV infusion of opiods for cancer pain: Clinical review and guidelines for use. Cancer Treat Rep 1986;70:575-581. Williams-Russo PG, Klein S, Sharrock NE, Charlson ME. Delirium After Unilateral Total Knee Replacement. Gerontological Society of America Meeting, November 1991.