- Email: [email protected]
Administration of Olanzapine to Prevent Postoperative Delirium in Elderly Joint-Replacement Patients: A Randomized, Controlled Trial
Administration of Olanzapine to Prevent Postoperative Delirium in Elderly Joint-Replacement Patients: A Randomized, Controlled Trial Kenneth A. Larsen, D.Min., Ph.D., Susan E. Kelly, M.D. Theodore A. Stern, M.D., Robert H. Bode, Jr., M.D. Lori Lyn Price, M.A.S., David J. Hunter, M.D., Ph.D. Diane Gulczynski, R.N., M.S., Benjamin E. Bierbaum, M.D. Gerard A. Sweeney, M.D., Karen A. Hoikala, R.P.H., M.S. James J. Cotter, R.P.H., M.S., Adam W. Potter, B.A. Background: Delirium is a serious postoperative condition for which few pharmacologic prevention trials have been conducted. Objective: The authors tested the efficacy of perioperative olanzapine administration to prevent postoperative delirium in elderly patients after jointreplacement surgery. Method: The authors conducted a randomized, double-blind, placebocontrolled, prophylaxis trial at an orthopedic teaching hospital, enrolling 495 elderly patients age ⱖ65 years, who were undergoing elective knee- or hip-replacement surgery; 400 patients received either 5 mg of orally-disintegrating olanzapine or placebo just before and after surgery. The primary efficacy outcome was the incidence of (DSM-III-R) delirium. Results: The incidence of delirium was significantly lower in the olanzapine group than in the placebo group; this held true for both knee- and hip-replacement surgery. However, delirium lasted longer and was more severe in the olanzapine group. Advanced age, a high level of medical comorbidity, an abnormal albumin level, and having knee-replacement surgery were independent risk factors for postoperative delirium (Clinicaltrials.gov Identifier: NCT000699946). Conclusion: Administration of 10 mg of oral olanzapine perioperatively, versus placebo, was associated with a significantly lower incidence of delirium. These findings suggest that olanzapine prophylaxis of postoperative delirium may be an effective strategy. (Psychosomatics 2010; 51:409 – 418)
D
elirium is an acute neuropsychiatric syndrome that affects higher cortical functioning; its cardinal symptom is disruption of attention, accompanied by disturbances of cognition, perception, thought processes, motor activity, and sleep.1,2 The consequences of delirium are serious and expensive,3,4 costing the United States healthcare system anywhere from $38 billion to $152 billion per year.5 In particular, postoperative delirium is a common problem in hospitalized patients, with a prevalence of 44% in elderly patients after major surgery.6 The incidence is particularly high after orthopedic surgery; it occurs in approximately 41% Psychosomatics 51:5, September-October 2010
of patients after bilateral knee replacement7 and in roughly 28% of patients after hip-replacement surgery.8 –10 Received December 2, 2009; revised January 21, 2010; accepted January 26, 2010. From the Depts. of Medicine, Anesthesiology, Research, Orthopedics, Nursing, Pharmacy, Administration, the New England Baptist Hospital, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; Dept. of Medicine, Tufts Medical Center, Boston, MA; Dept. of Statistical Analysis and Dept. of Psychiatry, Massachusetts General Hospital, Boston, MA. Send correspondence and reprint requests to Susan E. Kelly, M.D., Beth Israel Deaconess Medical Center, Dept. of Gastroenterology, 110 Francis St., 8th Floor, Boston, MA 02215. e-mail: [email protected] © 2010 The Academy of Psychosomatic Medicine
http://psy.psychiatryonline.org
409
Olanzapine and Postoperative Delirium In 2006, more than 1 million hip and knee replacements were performed in the U.S.11 By 2030, the demand for primary total hip arthroplasties will increase 174%, to 572,000 cases per year, and primary total knee arthroplasties will grow by 673%, to 3.48 million cases per year.12 At that time, costs to Medicare will be close to $50 billion.12–14 Delirium will greatly add to that cost.5 Current management involves the identification and correction of the underlying medical conditions as well as the control of symptoms.15 Because of its prevalence, morbidity, and mortality, effective interventions are sorely needed.10,15 First-generation antipsychotics (e.g., haloperidol) and atypical antipsychotics (e.g., olanzapine) have been efficacious for the treatment of delirium.16,17 However, evidence regarding prophylactic pharmacologic treatment to prevent delirium has been derived from only a few trials.18 –24 Our study sought to evaluate the impact of the perioperative administration of olanzapine on the prevention of postoperative delirium in elderly patients undergoing elective joint-replacement surgery. Secondary objectives included the length of stay, medical complications, the severity and duration of delirium, and disposition after hospital discharge.
produce an inactive ODT for marketing purposes) donated an ODT placebo of similar appearance to the olanzapine tablet. The hospital pharmacy prepackaged the study drug and placebo in identical packages, carried out the randomization, and blinded investigators and subjects. An independent data and safety monitoring committee evaluated all potentially serious adverse events. Subjects
METHOD
This study was approved by the NEBH’s Institutional Review Board (IRB). Patients were recruited from 2005 to 2007. Those screened for the trial included all patients age ⱖ65 years and those ⬍ age 65 with a history of postoperative delirium who were scheduled for elective total knee- or total hip-replacement surgery. Inclusion criteria were impending joint-replacement surgery, ability to speak English, and ability to provide informed consent. Exclusion criteria included a diagnosis of dementia (present in ⬍1% of our patient population), active alcohol use (ⱖ10 drinks per week), a history of alcohol dependence or abuse, allergy to olanzapine, and current use of an antipsychotic medication. Patients with dementia were excluded so as to maintain a homogeneous sample of high-functioning patients undergoing elective joint-replacement surgery. On enrollment, all patients provided written informed consent.
Study Design
Procedures
We conducted a single-center, observational, doubleblind, randomized, placebo-controlled study at the New England Baptist Hospital (NEBH) in Boston, MA. Eligible patients were initially stratified into two cohorts according to the complexity of the joint-replacement surgery (i.e., simple or complex). The simple cohort involved first-time, unilateral joint-replacement surgery; the complex cohort involved bilateral joint-replacement or joint-revision surgery. The patients were then randomly assigned to receive either perioperative olanzapine or placebo. The statistician provided the pharmacy with a computer-generated random-number table for participant randomization. We chose olanzapine for its low incidence of extrapyramidal side effects, its readily-available placebo, and its availability in a dissolvable tablet that could be easily administered after surgery. The NEBH supplied the olanzapine (paid for by a grant from the NEBH Research Department) in the form of an orally-disintegrating tablet (ODT). Cardinal Health (originally under contract to Eli Lilly and Company to
Those preparing for elective joint-replacement surgery were evaluated in the preadmission screening unit (PASU). All patients underwent a standard preoperative evaluation and were given an American Society of Anesthesiologists (ASA) classification based on their medical comorbidities.25 On the day of the surgery, patients were admitted to the pre-anesthesia care unit (PACU). PACU nurses not involved in the postoperative care of the study patients administered the study drug (olanzapine 5 mg or placebo) immediately before surgery. Subsequently, intravenous (IV) midazolam (1 mg–2 mg) and fentanyl (50 mcg–100 mcg) were given as preoperative sedation. General anesthesia, induced with 1 mg/kg–2 mg/kg of IV propofol and maintained with isoflurane or desflurane, was used in 90% of patients; the rest received regional anesthesia (spinal or epidural). Maintenance of anesthesia included the administration of 3 mcg/kg– 6 mcg/kg of IV fentanyl; an average of 329 mcg was used in those receiving hip replacements and 386 mcg in those receiving knee replacements.
410
http://psy.psychiatryonline.org
Psychosomatics 51:5, September-October 2010
Larsen et al. After surgery, patients were admitted to the postanesthesia care unit (P-ACU). P-ACU nurses not involved in the ongoing care of the study patients administered the second dose of 5 mg of olanzapine or placebo according to the randomization schedule. Postoperative pain was evaluated by nursing staff via a Visual Analog Scale (VAS) scored from 0 (no pain) to 10 (worst pain imaginable). Postoperative analgesics were initiated in the P-ACU and continued on the surgical units. Postoperative analgesia routinely included IV fentanyl (25 g every 10 min., to a 1-hr. maximum of 150 g) on arrival to the P-ACU. Either IV morphine (2 mg every 5 min., to a maximum of 16 mg in 1 hr.) or hydromorphone (0.2 mg every 5 min., to a maximum of 2 mg in 1 hr.) was used to provide longer periods of analgesia. Approval by an anesthesiologist was required to increase narcotic dosages. Since patients having total knee arthroplasty experience significant pain (as compared with those having hip-replacement surgery), they received a femoral nerve block in the P-ACU (using 30 cc of 0.375% bupivicaine with 1:400,000 epinephrine). Those who had had epidural anesthesia received a continuous infusion of 0.25% bupivicaine for analgesia. Patients were typically transferred to the nursing floor 4 – 6 hours after surgery. As per the NEBH routine, standardized protocols and postoperative medication orders were used to enhance patient safety (appendix available from the authors on request). The majority of patients received patient-controlled analgesia (PCA) as the sole source of pain-control for the first 36 hours postoperatively; this was followed by the use of intramuscular (IM) or oral narcotics. Study patients, attending and consulting staff, nursing staff, research assistants, and investigators remained blinded to study-group assignments throughout the trial. A research assistant interviewed patients and gathered information from the nursing staff about each patient’s mental status and any signs or symptoms of delirium. Nurses trained in the use of the Confusion Assessment Method (CAM) documented observed manifestations of delirium. Research assistants administered the Mini-Mental State Exam (MMSE) and the Delirium Rating Scale-Revised-98 (DRS-R-98) delirium assessment instruments. A blinded co-investigator (clinical psychologist) collected and verified each day’s data; the information was used to determine which patients met diagnostic criteria for delirium, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition–Revised (DSM-III-R). Psychosomatics 51:5, September-October 2010
Diagnostic Instruments Outcome measures were collected daily from Postoperative Days 1– 8, or through discharge (if discharge occurred before Day 8). Test results from daily bedside interviews were entered into a Tablet PC from WiFiMed (Atlanta, GA). Diagnostic scales were sensitive to both hyperactive and hypoactive delirium. DSM-III-R The primary outcome was the incidence of delirium as defined according to DSM-III-R criteria.1,26 The DSM-III-R provides more complete criteria than the DSM-IV.27 These criteria include rapid onset, fluctuation of symptoms, impaired attention, disorganized thinking or incoherent speech, and two of the following symptoms: clouding or disturbed consciousness, perceptual disturbances, disturbance of the sleep–wake cycle, increased or decreased motor activity, disorientation, or memory impairment. MMSE The MMSE28 is an 11-question tool that measures cognitive functioning (e.g., orientation, registration, attention, calculation, recall, and language) on a scale of 0 (profound cognitive impairment) to 30 (intact cognition), with a score of ⬍24 indicating cognitive impairment.29 DRS-R-98 The DRS-R-9826,30 is a 16-item clinicianrated scale with 13 severity items and 3 diagnostic items. The maximum delirium score is 46 points; the maximum severity score is 39. The DRS-R-98 has high interrater reliability and very high internal consistency. It is a valid measure of delirium severity, as well as a useful tool for the diagnosis and daily assessment of patients.26 Patients were rated daily with the DRS-R-98 to determine the duration and severity of delirium. CAM The CAM31 is a validated instrument for monitoring delirium; it is based on the operational application of DSM-III-R criteria.32 The four-item diagnostic algorithm for the identification of delirium is based on the presence of two primary symptoms: 1) acute onset and fluctuating course, and 2) inattention. It also requires at least one secondary feature (disorganized thinking or altered level of consciousness).31 Secondary Outcomes Secondary outcomes were time-to-onset of delirium; duration and severity of delirium; perceived pain; total narcotic use in morphine-equivalents; presence of hypohttp://psy.psychiatryonline.org
411
Olanzapine and Postoperative Delirium tension (i.e., a systolic/diastolic blood pressure ⬍90/60 mmHg); abnormal laboratory results (e.g., electrolyte imbalance); medical complications (e.g., stroke and atrial fibrillation, pulmonary problems, infections, gastrointestinal complaints); clinical consultations (e.g., from a hospitalist or cardiologist); interventions (e.g., use of a sitter or restraints, blood transfusions); type of anesthesia used (e.g., general or spinal); hospital length of stay; and disposition to home or to a rehabilitation facility. Race/ethnicity was included because this was a drug trial, and, in some instances, a variable response to a drug may have a racial/ethnic basis. Statistical Methods For the primary outcome, reduction in postoperative delirium, we assumed that olanzapine would lead to a 30% risk-reduction and a 30% incidence of delirium. To achieve these with a significance level of 0.05 and a power of 80%, we required at least 198 participants in each arm, or a total of 400 patients. The Student’s t-test, Wilcoxon rank sum test, and chi-square test were used as appropriate. Kaplan-Meier curves and the log-rank test were generated to compare the time-to-first day of delirium and the type of surgery in the treatment and control groups. Analyses were limited to the first 4 postoperative days because the vast majority of patients were discharged by Hospital Day 4. All participants who were randomized and entered into the study were analyzed in the group to which they were assigned. Multiple logistic regression was performed to test for associations among risk factors, treatment groups, and the presence or absence of delirium during the first 4 postoperative days. Subjects discharged before the 4th hospital day without developing delirium were assumed to have not developed delirium during the entire 4-day period. The software program R 2.6.1 (Free Software Association; Boston, MA) was used to generate the Kaplan-Meier figures; SAS 9.1 (SAS; Cary, NC) was used for all analyses. Variables with univariate p values ⬍0.10 were included in the multivariate model. A two-sided significance level of ⬍0.05 was used for all analyses. RESULTS Sample Enrollment and Randomization Each of 4,836 patients preparing for elective orthopedic surgery at the NEBH was evaluated per hospital protocol in the PASU and screened for potential enroll412
http://psy.psychiatryonline.org
ment (Figure 1). Because manpower issues dictated that interviewing for the study could not be accomplished throughout an entire day, only 1,032 of the 2,234 patients ⱖage 65 and all 3 of the eligible patients of the 2,602 ⬍age 65 were approached by a research associate to participate in the study. Of these, 495 patients agreed to participate and were enrolled. After stratification by complexity of surgery, 243 were randomly assigned to receive olanzapine, and 252 patients were assigned to receive placebo; 95 patients dropped out before receiving the study drug and before having the surgery (see Figure 1 for reasons for study dropout). Of the 400 patients who completed the study, 333 were in the simple (unilateral) knee- or hip-joint replacement group, and 67 were in the complex (bilateral/revision) jointreplacement group (Figure 1); 110 developed delirium. Attrition occurred from normal discharge from the hospital, with 400 patients remaining in the hospital on Postoperative Day 1 (POD: 1), 398 on POD 2; 318 on POD 3; and 129 on POD 4. Although there were no significant baseline differences between groups in patient demographics and surgical characteristics, there were more women in the placebo group than in the treatment group (Table 1). Incidence and Severity of Delirium The study met its primary objective. MMSE, CAM, and DRS results were used as evidence (for diagnosis and severity) to determine a DSM diagnosis of delirium by a blinded reviewer. The incidence of postoperative delirium was lower in the olanzapine group than in the placebo group for the entire sample (14.3% [N⫽28] versus 40.2% [N⫽82]; 95% confidence interval [CI]: 17.6 –34.2; p⬍0.0001). Subgroup analysis also revealed significant differences for those having knee- (17.7% [N⫽23] versus 47.8% [N⫽54]; 95% CI: 18.8 – 41.4; p⬍0.0001) and hipreplacement surgery (7.6% [N⫽5] versus 30.8% [N⫽28]; 95% CI: 11.8 –34.6; p⫽0.0004; Figure 2). The incidence of delirium was also lower for olanzapine-treated patients in the simple joint-replacement surgery group (12.4% [N⫽21] versus 40.9% [N⫽67]; 95% CI: 18.8 –37.5; p⬍0.0001) and the complex joint-replacement group (25.9% [N⫽7] versus 37.5% [N⫽15]; 95% CI: 10.7– 33.99; p⫽0.32). A Kaplan-Meier survival analysis showed that the time-to-onset of delirium was significantly longer (p⬍0.0001) in the olanzapine group than in the placebo group as a whole (Figure 3). Delirium developed most often within the first 2 Psychosomatics 51:5, September-October 2010
Larsen et al.
FIGURE 1.
Enrollment and Outcomes Patients screened for eligibility (N=4,836)
≥ 65 years
< 65 years
Were screened (N=2,602)
Were screened (N=2,234) Were interviewed
Were eligible and enrolled (N=3)
Declined (N=487) Were excluded (N=53) Were enrolled (N=492)
Were stratified (N=495)
Simple hip replacement (N=168) Simple knee replacement (N=248)
“Complex” hip replacement (N=33) “Complex” knee replacement
Randomized to olanzapine (N=207)
Randomized to placebo (N=209)
Randomized to olanzapine (N=36)
Randomized to placebo (N=43)
Dropouts before surgery Lost to anxiety (N=22) Surgery cancelled (N=7) Family pressure (N=2) Drug not given (N=3) Medical advice (N=2) Clerical error (N=2)
Dropouts before surgery Lost to anxiety (N=16) Surgery cancelled (N=12) Family pressure (N=12) Drug not given (N=3) Medical advice (N=2)
Dropouts before surgery Lost to anxiety (N=3) Surgery cancelled (N=1) Family pressure (N=3) Medical advice (N=1) Clerical error (N=1)
Dropouts before surgery Lost to anxiety (N=1) Surgery cancelled (N=1) Family pressure (N=1)
Included in analysis (N=169)
Included in analysis (N=164)
Included in analysis (N=27)
Included in analysis (N=40)
postoperative days, with only one patient developing delirium after the 4th postoperative day. Delirium lasted longer in the olanzapine group than in the placebo group (2.2 [SD⫽1.3] versus 1.6 [SD⫽0.7] days; p⫽0.02). Within 4 days of onset, cognitive functioning (as assessed by the DRS-R-98) returned to baseline in 22 patients (79% of 28 patients) in the olanzapine-treated group and 80 patients (98% of 82 patients) who received placebo (Figure 2). The severity of delirium (expressed as the maximum DRS-R-98 score on the first day of delirium) was also greater in the olanzapinetreated group than in the placebo group (16.44 [SD: 3.7] versus 14.5 [SD: 2.7]; p⫽0.02; Table 1). Psychosomatics 51:5, September-October 2010
Secondary Outcomes We saw a trend toward use of fewer narcotics in the olanzapine-treated group, but the difference was not significant. More patients in the olanzapine-treated group were discharged to home-with-services (41% versus 30%) than to a rehabilitation facility (59% versus 70%; p⫽0.02; Table 2). Measurement of longer-term outcomes was beyond the scope of this study. Another postoperative difference between groups was the proportion of patients with abnormal calcium and albumin levels; it was lower in the olanzapine-treated group with delirium than in the placebo-treated group with dehttp://psy.psychiatryonline.org
413
Olanzapine and Postoperative Delirium
TABLE 1.
Baseline Characteristics All Patients at Baseline (Nⴝ400)
Patients Who Developed Delirium (Nⴝ110)
Olanzapine (Nⴝ196)
Placebo (Nⴝ204)
Olanzapine (Nⴝ28)
Placebo (Nⴝ82)
73.4 (6.1)
74.0 (6.2)
76.1 (5.2)
75.1 (6.3)
Variable Age, years N (%): ⬍70 70-79 ⱖ80 Female gender, N (%) Race or ethnic group,a N (%) White Non-white Marital status, N (%) Married Widowed Single/divorced ASA Score,b N (%) 1, 2 3 BMIc (kg/m2) Type of anesthesia,d N (%) General Other Orthopedic procedure,e N (%) Simple (knee) Simple (hip) Complex (knee) Complex (hip) All simple joints All complex joints MMSEf (1st day of delirium) DRS-R-98g (1st day of delirium)
64 (32.6) 99 (50.5) 33 (16.8) 94 (48.0)
58 (28.4) 110 (53.9) 36 (17.7) 123 (60.3)
4 (14.3) 19 (67.9) 5 (17.9) 10 (35.7)
17 (20.7) 49 (59.8) 16 (19.5) 50 (61.0)
192 (98.0) 4 (2.0)
201 (98.5) 3 (1.5)
27 (96.4) 1 (3.6)
81 (98.8) 1 (1.2)
127 (64.8) 30 (15.3) 39 (19.9)
117 (57.4) 48 (23.5) 39 (19.1)
18 (64.3) 6 (21.4) 4 (14.3)
45 (54.9) 20 (24.4) 17 (20.7)
118 (60.5) 77 (39.5) 29.4 (5.8)
110 (54.7) 91 (45.3) 29.6 (5.7)
11 (39.3) 17 (60.7) 28.1 (5.4)
35 (43.8) 45 (56.3) 30.5 (6.5)
182 (92.9) 14 (7.1)
191 (93.6) 13 (6.4)
25 (89.3) 3 (10.7)
76 (92.7) 6 (7.3)
117 (59.7) 52 (26.5) 13 (6.6) 14 (7.1) 169 (86.2) 27 (13.8)
85 (41.7) 79 (38.7) 28 (13.7) 12 (5.9) 164 (80.4) 40 (19.6)
18 (64.3) 3 (10.7) 5 (17.9) 2 (7.1) 21 (75.0) 7 (25.0) 19.6 (6.5) 16.4 (3.7)
42 (51.2) 25 (30.5) 12 (14.6) 3 (3.7) 67 (81.7) 15 (18.3) 24.5 (3.5) 14.5 (2.7)
Values are mean (standard deviation), unless otherwise noted. a Race was self-reported. b ASA (morbidity) class: American Society of Anesthesiologists Class 1 was combined with ASA Class 2 because there were very few subjects in ASA Class 1. c BMI: body mass index. d General anesthesia includes general, general plus epidural, or general plus spinal. Other includes epidural, spinal, or a combined spinal-epidural (CSE). e Single: unilateral joint replacement; complex: bilateral joint or revision surgery. f MMSE: Mini-Mental State Exam. g DRS-R-98: Delirium Rating Scale-Revised-98.
lirium (53.6% versus 19.5%; p ⬍0.0005; 25% versus 11%, p⫽0.07, respectively; Table 3). There were no significant differences in any other secondary endpoints (e.g., blood pressure, arrhythmia [Table 4]). Our study showed that the use of olanzapine reduced the incidence of delirium, but not its severity or duration (Table 5). Univariate analysis (Table 6 [Part A]) comparing patients with and without delirium in the entire study sample, showed that patients’ age, having knee-replacement surgery, abnormal albumin level, and high ASA score (indicating severity of medical comorbidities) were each significantly associated with the development of postoperative delirium; use of olanzapine was associated 414
http://psy.psychiatryonline.org
with a lower incidence of delirium. All factors were entered into multiple logistic-regression analysis. It showed that advanced age, a high ASA class, an abnormal albumin level, and knee-replacement surgery were independent risk factors for postoperative delirium (Table 6 [Part B]). No serious adverse events (SAEs; e.g., stroke, infection, or atrial fibrillation) were attributed to use of the study drug. DISCUSSION Our results show that 10 mg of perioperatively-administered oral olanzapine (given as 5 mg just before and again immediately after joint-replacement surgery) was associPsychosomatics 51:5, September-October 2010
Larsen et al.
FIGURE 2.
TABLE 3.
Incidence of Postoperative Delirium by Type of Surgery
Secondary Outcomes: Abnormal Laboratory Values Among Patients With and Without Delirium, Day of Surgery Through Postoperative Day 4
Incidence of Delirium 60
Percent
50
Placebo Olanzapine
p<0.0001
40
Patients With Delirium
p<0.0001
Variable, N (%) Olanzapine (Nⴝ28) Placebo (Nⴝ82) Sodiuma Albuminb Calciumc
p<0.0004
30
1 (3.6) 7 (25.0) 15 (53.6)
p NS 0.07 ⬍0.001
Absence of Delirium
20
Variable, N (%)
Olanzapine (Nⴝ168)
Placebo (Nⴝ122)
p
10 (6.0) 10 (6.0) 25 (14.9)
6 (4.9) 6 (4.9) 20 (16.4)
NS NS NS
a
Sodium Albuminb Calciumc
10 0
All
FIGURE 3.
Hip Intervention Type
Knee
Abnormal serum sodium is defined as ⬍ 135 mmol/L. Abnormal serum albumin defined as ⬍ 3.5 g/dl. c Abnormal serum calcium is defined as ⬍ 8.4 mg/dl. a
b
Time-to-First Day of Delirium, by Study Group TABLE 4.
1.0 Proportion Delirium-Free
8 (9.8) 9 (11.0) 16 (19.5)
Secondary Outcomes: Medical Complications, Consultations, and Clinical Interventions—Day of Surgery Through Postoperative Day 4
0.8 Variable, N (%) 0.6 Olanzapine
0.4
Placebo p<0.0001
0.2 0.0
TABLE 2.
0
1 2 3 Days Post-Surgery
4
Secondary Outcomes: Disposition of Patients at Discharge
Variable, N (%)
Olanzapine (Nⴝ196)
Placebo (Nⴝ204)
Home with services Rehabilitation facility
80 (40.8) 116 (59.2)
61 (29.9) 143 (70.1)
p
Placebo (Nⴝ204)
p
6 (3.1) 2 (1.0) 1 (0.5) 5 (1.0) 3 (1.5) 1 (0.5)
3 (1.5) 1 (0.5) 1 (0.5) 1 (0.5) 0 (0.0) 4 (2.0)
NS NS NS NS NS NS
44 (22.5) 6 (3.1) 14 (7.1) 1 (0.5) 36 (18.4) 6 (3.1)
37 (18.1) 3 (1.5) 9 (4.4) 1 (0.5) 35 (17.2) 6 (2.9)
NS NS NS NS NS NS
9 (4.6) 5 (2.6) 11 (5.6)
4 (2.0) 0.0 7 (3.4)
NS 0.03 NS
0.02
Rehabilitation facility was defined as providing skilled nursing or acute (hospital-level) care.
ated with a lower incidence of delirium (14.3%; number needed to treat [NNT]⫽4) than placebo (40.2%). Although olanzapine has been reported as an effective and well-tolerated agent in the off-label treatment of delirium,16,33–36 its use as a prophylactic agent may be even more appealing. According to Leslie and associates,5 costs Psychosomatics 51:5, September-October 2010
Medical complications Atrial fibrillation Arrhythmia Congestive heart failure Alcohol withdrawal Pneumonia Urinary tract infection Medical consultations Cardiology Pulmonary Endocrinology/diabetes Neurology Behavioral medicine Gastroenterology Clinical interventions Sitter Restraints Bed alarm
Olanzapine (Nⴝ196)
per day incurred among patients with delirium are more than 2.5 times that of patients without delirium. Several studies have shown that antipsychotic agents can prevent delirium. In a placebo-controlled, randomized, non-blinded study on the effect of haloperidol on postoperative delirium in gastrointestinal surgery, Kaneko and colleagues37 found a lower incidence of delirium among haloperidol- than among placebotreated patients (10.5% versus 32.5%). More recently, Prakanrattana and Prapaitrakool15 reported that 1 mg of http://psy.psychiatryonline.org
415
Olanzapine and Postoperative Delirium
TABLE 5.
Secondary Outcomes
TABLE 6.
Duration of Delirium Days of Delirium, N (%)
Olanzapine (Nⴝ28)
Placebo (Nⴝ82)
1 2 3 ⱖ4
10 (35.7) 4 (14.3) 5 (17.9) 9 (32.0)
39 (47.6) 28 (34.2) 7 (8.5) 8 (10.0)
Severity of Delirium (DRS-R-98 Scores) Olanzapine (Nⴝ28)
POD POD POD POD
1 2 3 4
Placebo (Nⴝ82)
Mean (SD)
N (%)
Mean (SD)
N (%)
17.2 (3.9) 15.0 (2.4) 14.0 (1.4) 13.0a
20 (71.4) 5 (17.9) 2 (7.1) 1 (3.6)
14.6 (3.1) 14.1 (1.4) 15.0 (2.7) 13.0a
54 (66.0) 23 (28.0) 4 (5.0) 1 (1.0)
Association of Risk Factors With Presence of Postoperative Delirium
[A]: Univariate Relationship of Risk Factors to Postoperative Delirium Independent variable Olanzapine treatment Advanced age ASA Class 3 Abnormal albumin levela Knee-replacement surgery Joint-revision surgery Abnormal sodium level Being married Female gender
sublingual risperidone given immediately after cardiac surgery significantly decreased the incidence of delirium, from 31% to 11%. Studies by Kalisvaart and colleagues22 and Schraeder and associates38 have found that low-dose haloperidol prophylaxis can significantly reduce the severity and duration of delirium (but not the incidence) as well as hospital length of stay. Our study showed that use of olanzapine reduced the incidence of delirium, but not its severity or duration. According to Breitbart and colleagues,34 factors that predicted reduced response to olanzapine for the treatment of delirium among hospitalized cancer patients included an age ⬎ 70 years, hypoactive delirium, and delirium of severe intensity. Outcomes in our study may have been influenced by the anticholinergic potency of olanzapine as well as the patients who developed unanticipated postoperative alcohol withdrawal during the study. Preoperative misrepresentation of alcohol intake (⬎10 drinks/week met exclusion criteria) resulted in acute alcohol withdrawal in 5 of the 28 patients (17.9%) who developed delirium in the olanzapine-treated group and 1 of the 82 (1.2%) who developed it in the placebo-treated group. Symptoms of alcohol withdrawal were included in our assessments for delirium. Also, exploratory analysis revealed that a high incidence of abnormally low albumin levels (⬍3.5 gm) 416
http://psy.psychiatryonline.org
0.3 1.1 2.3 2.9 1.7 1.4 1.5 0.8 1.0
(0.2–0.4) (1.0–1.1) (1.5–3.6) (1.4–6.1) (1.1–2.8) (0.8–2.4) (0.7–3.6) (0.5–1.3) (0.7–1.6)
p ⬍0.001 0.009 0.003 0.004 0.02 NS NS NS NS
[B]: Multivariable Relationship of Risk Factors to Postoperative Delirium Independent variable
SD: standard deviation. Days of delirium: the duration in days as defined by the DRS-R-98 (Delirium Rating Scale, Revised–98), using a cutoff score of 13 (p⫽0.004). POD: Postoperative Day. Severity of delirium is defined as DRSR-98 score on the first day of delirium. Scores are for the total number of patients who developed delirium on each postoperative day. a Given that only one subject developed delirium on POD 4, no SD was calculated.
OR (95% CI)
Olanzapine treatment Knee-replacement surgery Abnormal albumin levela ASA Class 3 Advanced age
OR (95% CI) 0.2 2.3 3.1 2.0 1.1
(0.1–0.4) (1.3–3.8) (1.4–6.8) (1.2–3.2) (1.0–1.1)
p ⬍0.001 0.002 0.006 0.007 0.01
OR: odds ratio; CI: confidence interval. a Abnormal serum albumin level defined as ⬍3.5 g/dl.
occurred in olanzapine-treated delirium patients. Since olanzapine is highly protein-bound, those with hypoalbuminemia may have been more likely to develop more severe delirium due to higher available levels of the active drug. Further studies are needed to explore and confirm these possibilities. Other secondary outcomes showed that olanzapinetreated patients used less narcotic medication than those who received placebo; perhaps use of olanzapine reduced the need for pain medications. In our study, there were slightly more postoperative cardiac complications (although not significant statistically) in the olanzapine-treated patients than in those who received placebo. Furthermore, the overall incidence was similar to that observed in a study of cardiovascular complications after joint-replacement surgery at the same institution by Basilico and colleagues39 (4.6% versus 3.9% of 5,367 patients undergoing total joint replacement). Although our study confirmed advanced age and knee-replacement surgery as risk factors for delirium after orthopedic surgery, we identified a new high-risk group: patients with a high ASA class and abnormal albumin levels as independent risk factors for postoperative delirium. Our study design has several limitations, including a Psychosomatics 51:5, September-October 2010
Larsen et al. lack of intention-to-treat analysis, and an absence of longterm follow-up. Other limitations include a lack of preoperative assessment of cognition (e.g., with a baseline MMSE), no assessment of smoking or use of sleeping aids, and use of a socioeconomically homogeneous population. Although unidentified impaired cognition might have existed preoperatively, we believe that the risk was low among our patients preparing for elective joint-replacement surgery. Strengths of our study include our randomized, placebo-controlled, double-blinded design with stratification; our baseline measure of comorbidities by use of ASA classification; our use of standard protocols and pathways; our daily assessment of patients with validated instruments; our large sample size; our blinding of the study assessor; and our clear descriptions of usual care and confounders. Our study was designed to test the efficacy (but not the treatment) of a short-acting drug for the prevention of delirium. Hip- and knee-replacement surgeries are two of the most commonly performed and effective operations in the United States.14,40,41 By 2030, the total number of primary and revision replacements will be nearly 4.5 million,12 up from 750,000, performed in 2005.14 As the number of replacement procedures continues to grow, the focus on strategies and policies to manage growing costs will continue to increase.42 This large-scale, randomized, double-blind, controlled trial showed that perioperative prophylactic administration of olanzapine led to a reduced incidence of postoperative delirium after elective hip- or knee-replacement surgery. Although our results should be replicated, clinical interventions to prevent delirium should be initiated on a wider scale.
Kenneth A. Larsen, D.Min., Ph.D., Susan E. Kelly, M.D., and Theodore A. Stern, M.D., are all first-authors of this article. The authors thank Marie Nolan for administrative assistance; Noreen Howie, R.N., Casey Flynn, P.T., Brian Johnson, N.P., and Jennifer Silva, P.T., for patient recruitment and medical record review work; Bryan Ciccarelli, Glen Mortimer, and Emily McCaffrey, P.T., for assistance in postoperative patient assessment; Roberto Cruz-Gervis, M.D., and his hospitalist staff for the medical care of study patients; Joyce Welsh, R.N., and the dedicated nursing staff of the pre- and post- anesthesia care units for nursing care supervision; Olga Lyczmanenko for librarian services; Meredith Cameron for the assistance of the Department of Medical Records; and Rita Buckley for research and editorial services provided in the development of the manuscript. This study was made possible by a grant from the New England Baptist Hospital Research Department. The sponsor supplied the olanzapine and retained the study data; however, it had no other role in the study design; in the collection, analysis, and interpretation of the study; in the writing of the report; or in the decision to submit the paper for publication. Theodore A. Stern, M.D., has been a consultant to and is on the speaker’s bureau of Eli Lilly and Company, and has been a consultant to and shareholder of WiFiMed, the company that designed the Tablet PC data-management software. No other authors reported conflicts of interest.
References 1. American Psychiatric Association: Arlington, VA (accessed Sept. 2009); available from http://www.psych.org 2. Overshott R, Karim S, Burns A: Cholinesterase inhibitors for delirium. Cochrane Database Syst Rev 2008; Jan 23:CD005317 3. Redelmeier DA, Thiruchelvam D, Daneman N: Delirium after elective surgery among elderly patients taking statins. CMAJ 2008; 179:645– 652 4. Bellelli G, Bianchetti A, Trabucchi M: Delirium and costs of informal home care. Arch Intern Med 2008; 168:1717 5. Leslie DL, Marcantonio ER, Zhang Y, et al: One-year healthcare costs associated with delirium in the elderly population. Arch Intern Med 2008; 168:27–32 6. Robinson TN, Raeburn CD, Tran ZV, et al: Postoperative delirium in the elderly: risk factors and outcomes. Ann Surg 2009; 249:173–178 7. Williams-Russo P, Urquhart BL, Sharrock NE, et al: Post-operative delirium: predictors and prognosis in elderly orthopedic patients. J Am Geriatr Soc 1992; 40:759 –767
Psychosomatics 51:5, September-October 2010
8. Rogers MP, Liang MH, Daltroy LH, et al: Delirium after elective orthopedic surgery: risk factors and natural history. Int J Psychiatry Med 1989; 19:109 –121 9. Sampson EL, Raven PR, Ndhlovu PN, et al: A randomized, double-blind, placebo-controlled trial of donepezil hydrochloride (Aricept®) for reducing the incidence of postoperative delirium after elective total hip replacement. Int J Geriatr Psychiatry 2007; 22:343–349 10. Inouye SK: Delirium in older persons. N Engl J Med 2006; 354:1157–1165 11. American Academy of Orthopaedic Surgeons: Patient demographics. Rosemont, IL (accessed Sept 13, 2009); available from: http://www.aaos.org/research/stats/patientstats.asp 12. Kurtz S, Ong K, Lau E, et al: Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am 2007; 89:780 –785 13. Centers for Medicare and Medicaid Services: 100 Percent MEDPAR Inpatient Hospital National Data for Fiscal Year 2006,
http://psy.psychiatryonline.org
417
Olanzapine and Postoperative Delirium Short-Stay Inpatient Diagnosis-Related Groups. (accessed Sept. 12, 2009); available from http://www.cms.hhs.gov/MedicareFeeforSvcPartsAB/Downloads/DRG06.pdf 14. Wilson NA, Schneller ES, Montgomery K, et al: Hip and knee implants: current trends and policy considerations. Health Aff (Millwood) 2008; 27:1587–1598 15. Prakanrattana U, Prapaitrakool S: Efficacy of risperidone for prevention of postoperative delirium in cardiac surgery. Anaesth Intensive Care 2007; 35:714 –719 16. Ozbolt LB, Paniagua MA, Kaiser RM: Atypical antipsychotics for the treatment of delirious elders. J Am Med Dir Assoc 2008; 9:18 –28 17. Lonergan E, Britton AM, Luxenberg J, et al: Antipsychotics for delirium. Cochrane Database Syst Rev 2007; April 18: CD005594 18. Siddiqi N, Stockdale R, Britton AM, et al: Interventions for preventing delirium in hospitalised patients. Cochrane Database Syst Rev 2007; April 18:CD005563 19. Aizawa K, Kanai T, Saikawa Y, et al: A novel approach to the prevention of postoperative delirium in the elderly after gastrointestinal surgery. Surg Today 2002; 32:310 –314 20. 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 21. Dı´az V, Rodrı´guez J, Barrientos P, et al: Use of procholinergics in the prevention of postoperative delirium in hip fracture surgery in the elderly: a randomized, controlled trial. Rev Neurol 2001; 33:716 –719 22. Kalisvaart KJ, de Jonghe JF, Bogaards MJ, et al: Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized, placebo-controlled study. J Am Geriatr Soc 2005; 53:1658 –1666 23. Liptzin B, Laki A, Garb JL, et al: Donepezil in the prevention and treatment of post-surgical delirium. Am J Geriatr Psychiatry 2005; 13:1100 –1106 24. Marcantonio ER, Flacker JM, Wright RJ, et al: Reducing delirium after hip fracture: a randomized trial. J Am Geriatr Soc 2001; 49:516 –522 25. American Society of Anesthesiologists (accessed Sept 13, 2009); available from http://www.asahq.org/index.htm 26. Trzepacz PT, Mittal D, Torres R, et al: Validation of the Delirium Rating Scale, Revised–98: comparison with the Delirium Rating Scale and the Cognitive Test for Delirium. J Neuropsychiatry Clin Neurosci 2001; 13:229 –242 27. Laurila JV, Pitkala KH, Strandberg TE, et al: The impact of different diagnostic criteria on prevalence rates for delirium. Dement Geriatr Cogn Disord 2003; 16:156 –162 28. Folstein MF, Robins LN, Helzer JE: The Mini-Mental State Exam. Arch Gen Psychiatry 1983; 40:812
418
http://psy.psychiatryonline.org
29. Inouye SK, Bogardus ST Jr., Charpentier PA, et al: A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340:669 – 676 30. Wei LA, Fearing MA, Sternberg EJ, et al: The Confusion Assessment Method: a systematic review of current usage. J Am Geriatr Soc 2008; 56:823– 830 31. Inouye SK, van Dyck CH, Alessi CA, et al: Clarifying confusion: the Confusion Assessment Method: a new method for detection of delirium. Ann Intern Med 1990; 113:941–948 32. Gonza´lez M, Martı´nez G, Caldero´n J, et al: Impact of delirium on short-term mortality in elderly inpatients: a prospective cohort study. Psychosomatics 2009; 50:234 –238 33. Skrobik YK, Bergeron N, Dumont M, et al: Olanzapine vs. haloperidol: treating delirium in a critical-care setting. Intens Care Med 2004; 30:444 – 449 34. Breitbart W, Tremblay A, Gibson C: An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics 2002; 43:175–182 35. Kim KS, Pae CU, Chae JH, et al: An open pilot trial of olanzapine for delirium in the Korean population. Psychiatry Clin Neurosci 2001; 55:515–519 36. Sipahimalani A, Masand PS: Olanzapine in the treatment of delirium. Psychosomatics 1998; 39:422– 430 37. Kaneko T, Jianhui C, Ishikura T, et al: Prophylactic consecutive administration of haloperidol can reduce the occurrence of postoperative delirium in gastrointestinal surgery. Yonaga Acta Medica 1999; 42:179 –184 38. Schrader SL, Wellik KE, Demaerschalk BM, et al: Adjunctive haloperidol prophylaxis reduces postoperative delirium severity and duration in at-risk elderly patients. Neurologist 2008; 14: 134 –137 39. Basilico FC, Sweeney G, Losina E, et al: Risk factors for cardiovascular complications following total joint-replacement surgery. Arthritis Rheum 2008; 58:1915–1920 40. Henry J. Kaiser Family Foundation: Range of Medicare Payments (Low-25th Percentile/High-75th Percentile) for Top Five Elective Inpatient Hospital Procedures, FY 2006. (accessed Sept 12, 2009); available from http://www.statehealthfacts.org/ comparetable.jsp?cat⫽6&ind⫽289 41. Centers for Medicare and Medicaid Services: Medicare ShortStay Hospital DRGs Ranked by Discharges, Fiscal Year 2006 (accessed Sept. 2009); available from http://www.cms.hhs.gov/ datacompendium/17_2007_data_compendium.asp 42. Agency for Healthcare Research and Quality: Hospital Stays Involving Musculoskeletal Problems, 1997–2005. HCUP Statistical Brief # 34 (accessed Sept. 2009); available from www.hcupus.ahrq.gov/reports/statbriefs/sb34.pdf
Psychosomatics 51:5, September-October 2010
D
elirium is an acute neuropsychiatric syndrome that affects higher cortical functioning; its cardinal symptom is disruption of attention, accompanied by disturbances of cognition, perception, thought processes, motor activity, and sleep.1,2 The consequences of delirium are serious and expensive,3,4 costing the United States healthcare system anywhere from $38 billion to $152 billion per year.5 In particular, postoperative delirium is a common problem in hospitalized patients, with a prevalence of 44% in elderly patients after major surgery.6 The incidence is particularly high after orthopedic surgery; it occurs in approximately 41% Psychosomatics 51:5, September-October 2010
of patients after bilateral knee replacement7 and in roughly 28% of patients after hip-replacement surgery.8 –10 Received December 2, 2009; revised January 21, 2010; accepted January 26, 2010. From the Depts. of Medicine, Anesthesiology, Research, Orthopedics, Nursing, Pharmacy, Administration, the New England Baptist Hospital, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; Dept. of Medicine, Tufts Medical Center, Boston, MA; Dept. of Statistical Analysis and Dept. of Psychiatry, Massachusetts General Hospital, Boston, MA. Send correspondence and reprint requests to Susan E. Kelly, M.D., Beth Israel Deaconess Medical Center, Dept. of Gastroenterology, 110 Francis St., 8th Floor, Boston, MA 02215. e-mail: [email protected] © 2010 The Academy of Psychosomatic Medicine
http://psy.psychiatryonline.org
409
Olanzapine and Postoperative Delirium In 2006, more than 1 million hip and knee replacements were performed in the U.S.11 By 2030, the demand for primary total hip arthroplasties will increase 174%, to 572,000 cases per year, and primary total knee arthroplasties will grow by 673%, to 3.48 million cases per year.12 At that time, costs to Medicare will be close to $50 billion.12–14 Delirium will greatly add to that cost.5 Current management involves the identification and correction of the underlying medical conditions as well as the control of symptoms.15 Because of its prevalence, morbidity, and mortality, effective interventions are sorely needed.10,15 First-generation antipsychotics (e.g., haloperidol) and atypical antipsychotics (e.g., olanzapine) have been efficacious for the treatment of delirium.16,17 However, evidence regarding prophylactic pharmacologic treatment to prevent delirium has been derived from only a few trials.18 –24 Our study sought to evaluate the impact of the perioperative administration of olanzapine on the prevention of postoperative delirium in elderly patients undergoing elective joint-replacement surgery. Secondary objectives included the length of stay, medical complications, the severity and duration of delirium, and disposition after hospital discharge.
produce an inactive ODT for marketing purposes) donated an ODT placebo of similar appearance to the olanzapine tablet. The hospital pharmacy prepackaged the study drug and placebo in identical packages, carried out the randomization, and blinded investigators and subjects. An independent data and safety monitoring committee evaluated all potentially serious adverse events. Subjects
METHOD
This study was approved by the NEBH’s Institutional Review Board (IRB). Patients were recruited from 2005 to 2007. Those screened for the trial included all patients age ⱖ65 years and those ⬍ age 65 with a history of postoperative delirium who were scheduled for elective total knee- or total hip-replacement surgery. Inclusion criteria were impending joint-replacement surgery, ability to speak English, and ability to provide informed consent. Exclusion criteria included a diagnosis of dementia (present in ⬍1% of our patient population), active alcohol use (ⱖ10 drinks per week), a history of alcohol dependence or abuse, allergy to olanzapine, and current use of an antipsychotic medication. Patients with dementia were excluded so as to maintain a homogeneous sample of high-functioning patients undergoing elective joint-replacement surgery. On enrollment, all patients provided written informed consent.
Study Design
Procedures
We conducted a single-center, observational, doubleblind, randomized, placebo-controlled study at the New England Baptist Hospital (NEBH) in Boston, MA. Eligible patients were initially stratified into two cohorts according to the complexity of the joint-replacement surgery (i.e., simple or complex). The simple cohort involved first-time, unilateral joint-replacement surgery; the complex cohort involved bilateral joint-replacement or joint-revision surgery. The patients were then randomly assigned to receive either perioperative olanzapine or placebo. The statistician provided the pharmacy with a computer-generated random-number table for participant randomization. We chose olanzapine for its low incidence of extrapyramidal side effects, its readily-available placebo, and its availability in a dissolvable tablet that could be easily administered after surgery. The NEBH supplied the olanzapine (paid for by a grant from the NEBH Research Department) in the form of an orally-disintegrating tablet (ODT). Cardinal Health (originally under contract to Eli Lilly and Company to
Those preparing for elective joint-replacement surgery were evaluated in the preadmission screening unit (PASU). All patients underwent a standard preoperative evaluation and were given an American Society of Anesthesiologists (ASA) classification based on their medical comorbidities.25 On the day of the surgery, patients were admitted to the pre-anesthesia care unit (PACU). PACU nurses not involved in the postoperative care of the study patients administered the study drug (olanzapine 5 mg or placebo) immediately before surgery. Subsequently, intravenous (IV) midazolam (1 mg–2 mg) and fentanyl (50 mcg–100 mcg) were given as preoperative sedation. General anesthesia, induced with 1 mg/kg–2 mg/kg of IV propofol and maintained with isoflurane or desflurane, was used in 90% of patients; the rest received regional anesthesia (spinal or epidural). Maintenance of anesthesia included the administration of 3 mcg/kg– 6 mcg/kg of IV fentanyl; an average of 329 mcg was used in those receiving hip replacements and 386 mcg in those receiving knee replacements.
410
http://psy.psychiatryonline.org
Psychosomatics 51:5, September-October 2010
Larsen et al. After surgery, patients were admitted to the postanesthesia care unit (P-ACU). P-ACU nurses not involved in the ongoing care of the study patients administered the second dose of 5 mg of olanzapine or placebo according to the randomization schedule. Postoperative pain was evaluated by nursing staff via a Visual Analog Scale (VAS) scored from 0 (no pain) to 10 (worst pain imaginable). Postoperative analgesics were initiated in the P-ACU and continued on the surgical units. Postoperative analgesia routinely included IV fentanyl (25 g every 10 min., to a 1-hr. maximum of 150 g) on arrival to the P-ACU. Either IV morphine (2 mg every 5 min., to a maximum of 16 mg in 1 hr.) or hydromorphone (0.2 mg every 5 min., to a maximum of 2 mg in 1 hr.) was used to provide longer periods of analgesia. Approval by an anesthesiologist was required to increase narcotic dosages. Since patients having total knee arthroplasty experience significant pain (as compared with those having hip-replacement surgery), they received a femoral nerve block in the P-ACU (using 30 cc of 0.375% bupivicaine with 1:400,000 epinephrine). Those who had had epidural anesthesia received a continuous infusion of 0.25% bupivicaine for analgesia. Patients were typically transferred to the nursing floor 4 – 6 hours after surgery. As per the NEBH routine, standardized protocols and postoperative medication orders were used to enhance patient safety (appendix available from the authors on request). The majority of patients received patient-controlled analgesia (PCA) as the sole source of pain-control for the first 36 hours postoperatively; this was followed by the use of intramuscular (IM) or oral narcotics. Study patients, attending and consulting staff, nursing staff, research assistants, and investigators remained blinded to study-group assignments throughout the trial. A research assistant interviewed patients and gathered information from the nursing staff about each patient’s mental status and any signs or symptoms of delirium. Nurses trained in the use of the Confusion Assessment Method (CAM) documented observed manifestations of delirium. Research assistants administered the Mini-Mental State Exam (MMSE) and the Delirium Rating Scale-Revised-98 (DRS-R-98) delirium assessment instruments. A blinded co-investigator (clinical psychologist) collected and verified each day’s data; the information was used to determine which patients met diagnostic criteria for delirium, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition–Revised (DSM-III-R). Psychosomatics 51:5, September-October 2010
Diagnostic Instruments Outcome measures were collected daily from Postoperative Days 1– 8, or through discharge (if discharge occurred before Day 8). Test results from daily bedside interviews were entered into a Tablet PC from WiFiMed (Atlanta, GA). Diagnostic scales were sensitive to both hyperactive and hypoactive delirium. DSM-III-R The primary outcome was the incidence of delirium as defined according to DSM-III-R criteria.1,26 The DSM-III-R provides more complete criteria than the DSM-IV.27 These criteria include rapid onset, fluctuation of symptoms, impaired attention, disorganized thinking or incoherent speech, and two of the following symptoms: clouding or disturbed consciousness, perceptual disturbances, disturbance of the sleep–wake cycle, increased or decreased motor activity, disorientation, or memory impairment. MMSE The MMSE28 is an 11-question tool that measures cognitive functioning (e.g., orientation, registration, attention, calculation, recall, and language) on a scale of 0 (profound cognitive impairment) to 30 (intact cognition), with a score of ⬍24 indicating cognitive impairment.29 DRS-R-98 The DRS-R-9826,30 is a 16-item clinicianrated scale with 13 severity items and 3 diagnostic items. The maximum delirium score is 46 points; the maximum severity score is 39. The DRS-R-98 has high interrater reliability and very high internal consistency. It is a valid measure of delirium severity, as well as a useful tool for the diagnosis and daily assessment of patients.26 Patients were rated daily with the DRS-R-98 to determine the duration and severity of delirium. CAM The CAM31 is a validated instrument for monitoring delirium; it is based on the operational application of DSM-III-R criteria.32 The four-item diagnostic algorithm for the identification of delirium is based on the presence of two primary symptoms: 1) acute onset and fluctuating course, and 2) inattention. It also requires at least one secondary feature (disorganized thinking or altered level of consciousness).31 Secondary Outcomes Secondary outcomes were time-to-onset of delirium; duration and severity of delirium; perceived pain; total narcotic use in morphine-equivalents; presence of hypohttp://psy.psychiatryonline.org
411
Olanzapine and Postoperative Delirium tension (i.e., a systolic/diastolic blood pressure ⬍90/60 mmHg); abnormal laboratory results (e.g., electrolyte imbalance); medical complications (e.g., stroke and atrial fibrillation, pulmonary problems, infections, gastrointestinal complaints); clinical consultations (e.g., from a hospitalist or cardiologist); interventions (e.g., use of a sitter or restraints, blood transfusions); type of anesthesia used (e.g., general or spinal); hospital length of stay; and disposition to home or to a rehabilitation facility. Race/ethnicity was included because this was a drug trial, and, in some instances, a variable response to a drug may have a racial/ethnic basis. Statistical Methods For the primary outcome, reduction in postoperative delirium, we assumed that olanzapine would lead to a 30% risk-reduction and a 30% incidence of delirium. To achieve these with a significance level of 0.05 and a power of 80%, we required at least 198 participants in each arm, or a total of 400 patients. The Student’s t-test, Wilcoxon rank sum test, and chi-square test were used as appropriate. Kaplan-Meier curves and the log-rank test were generated to compare the time-to-first day of delirium and the type of surgery in the treatment and control groups. Analyses were limited to the first 4 postoperative days because the vast majority of patients were discharged by Hospital Day 4. All participants who were randomized and entered into the study were analyzed in the group to which they were assigned. Multiple logistic regression was performed to test for associations among risk factors, treatment groups, and the presence or absence of delirium during the first 4 postoperative days. Subjects discharged before the 4th hospital day without developing delirium were assumed to have not developed delirium during the entire 4-day period. The software program R 2.6.1 (Free Software Association; Boston, MA) was used to generate the Kaplan-Meier figures; SAS 9.1 (SAS; Cary, NC) was used for all analyses. Variables with univariate p values ⬍0.10 were included in the multivariate model. A two-sided significance level of ⬍0.05 was used for all analyses. RESULTS Sample Enrollment and Randomization Each of 4,836 patients preparing for elective orthopedic surgery at the NEBH was evaluated per hospital protocol in the PASU and screened for potential enroll412
http://psy.psychiatryonline.org
ment (Figure 1). Because manpower issues dictated that interviewing for the study could not be accomplished throughout an entire day, only 1,032 of the 2,234 patients ⱖage 65 and all 3 of the eligible patients of the 2,602 ⬍age 65 were approached by a research associate to participate in the study. Of these, 495 patients agreed to participate and were enrolled. After stratification by complexity of surgery, 243 were randomly assigned to receive olanzapine, and 252 patients were assigned to receive placebo; 95 patients dropped out before receiving the study drug and before having the surgery (see Figure 1 for reasons for study dropout). Of the 400 patients who completed the study, 333 were in the simple (unilateral) knee- or hip-joint replacement group, and 67 were in the complex (bilateral/revision) jointreplacement group (Figure 1); 110 developed delirium. Attrition occurred from normal discharge from the hospital, with 400 patients remaining in the hospital on Postoperative Day 1 (POD: 1), 398 on POD 2; 318 on POD 3; and 129 on POD 4. Although there were no significant baseline differences between groups in patient demographics and surgical characteristics, there were more women in the placebo group than in the treatment group (Table 1). Incidence and Severity of Delirium The study met its primary objective. MMSE, CAM, and DRS results were used as evidence (for diagnosis and severity) to determine a DSM diagnosis of delirium by a blinded reviewer. The incidence of postoperative delirium was lower in the olanzapine group than in the placebo group for the entire sample (14.3% [N⫽28] versus 40.2% [N⫽82]; 95% confidence interval [CI]: 17.6 –34.2; p⬍0.0001). Subgroup analysis also revealed significant differences for those having knee- (17.7% [N⫽23] versus 47.8% [N⫽54]; 95% CI: 18.8 – 41.4; p⬍0.0001) and hipreplacement surgery (7.6% [N⫽5] versus 30.8% [N⫽28]; 95% CI: 11.8 –34.6; p⫽0.0004; Figure 2). The incidence of delirium was also lower for olanzapine-treated patients in the simple joint-replacement surgery group (12.4% [N⫽21] versus 40.9% [N⫽67]; 95% CI: 18.8 –37.5; p⬍0.0001) and the complex joint-replacement group (25.9% [N⫽7] versus 37.5% [N⫽15]; 95% CI: 10.7– 33.99; p⫽0.32). A Kaplan-Meier survival analysis showed that the time-to-onset of delirium was significantly longer (p⬍0.0001) in the olanzapine group than in the placebo group as a whole (Figure 3). Delirium developed most often within the first 2 Psychosomatics 51:5, September-October 2010
Larsen et al.
FIGURE 1.
Enrollment and Outcomes Patients screened for eligibility (N=4,836)
≥ 65 years
< 65 years
Were screened (N=2,602)
Were screened (N=2,234) Were interviewed
Were eligible and enrolled (N=3)
Declined (N=487) Were excluded (N=53) Were enrolled (N=492)
Were stratified (N=495)
Simple hip replacement (N=168) Simple knee replacement (N=248)
“Complex” hip replacement (N=33) “Complex” knee replacement
Randomized to olanzapine (N=207)
Randomized to placebo (N=209)
Randomized to olanzapine (N=36)
Randomized to placebo (N=43)
Dropouts before surgery Lost to anxiety (N=22) Surgery cancelled (N=7) Family pressure (N=2) Drug not given (N=3) Medical advice (N=2) Clerical error (N=2)
Dropouts before surgery Lost to anxiety (N=16) Surgery cancelled (N=12) Family pressure (N=12) Drug not given (N=3) Medical advice (N=2)
Dropouts before surgery Lost to anxiety (N=3) Surgery cancelled (N=1) Family pressure (N=3) Medical advice (N=1) Clerical error (N=1)
Dropouts before surgery Lost to anxiety (N=1) Surgery cancelled (N=1) Family pressure (N=1)
Included in analysis (N=169)
Included in analysis (N=164)
Included in analysis (N=27)
Included in analysis (N=40)
postoperative days, with only one patient developing delirium after the 4th postoperative day. Delirium lasted longer in the olanzapine group than in the placebo group (2.2 [SD⫽1.3] versus 1.6 [SD⫽0.7] days; p⫽0.02). Within 4 days of onset, cognitive functioning (as assessed by the DRS-R-98) returned to baseline in 22 patients (79% of 28 patients) in the olanzapine-treated group and 80 patients (98% of 82 patients) who received placebo (Figure 2). The severity of delirium (expressed as the maximum DRS-R-98 score on the first day of delirium) was also greater in the olanzapinetreated group than in the placebo group (16.44 [SD: 3.7] versus 14.5 [SD: 2.7]; p⫽0.02; Table 1). Psychosomatics 51:5, September-October 2010
Secondary Outcomes We saw a trend toward use of fewer narcotics in the olanzapine-treated group, but the difference was not significant. More patients in the olanzapine-treated group were discharged to home-with-services (41% versus 30%) than to a rehabilitation facility (59% versus 70%; p⫽0.02; Table 2). Measurement of longer-term outcomes was beyond the scope of this study. Another postoperative difference between groups was the proportion of patients with abnormal calcium and albumin levels; it was lower in the olanzapine-treated group with delirium than in the placebo-treated group with dehttp://psy.psychiatryonline.org
413
Olanzapine and Postoperative Delirium
TABLE 1.
Baseline Characteristics All Patients at Baseline (Nⴝ400)
Patients Who Developed Delirium (Nⴝ110)
Olanzapine (Nⴝ196)
Placebo (Nⴝ204)
Olanzapine (Nⴝ28)
Placebo (Nⴝ82)
73.4 (6.1)
74.0 (6.2)
76.1 (5.2)
75.1 (6.3)
Variable Age, years N (%): ⬍70 70-79 ⱖ80 Female gender, N (%) Race or ethnic group,a N (%) White Non-white Marital status, N (%) Married Widowed Single/divorced ASA Score,b N (%) 1, 2 3 BMIc (kg/m2) Type of anesthesia,d N (%) General Other Orthopedic procedure,e N (%) Simple (knee) Simple (hip) Complex (knee) Complex (hip) All simple joints All complex joints MMSEf (1st day of delirium) DRS-R-98g (1st day of delirium)
64 (32.6) 99 (50.5) 33 (16.8) 94 (48.0)
58 (28.4) 110 (53.9) 36 (17.7) 123 (60.3)
4 (14.3) 19 (67.9) 5 (17.9) 10 (35.7)
17 (20.7) 49 (59.8) 16 (19.5) 50 (61.0)
192 (98.0) 4 (2.0)
201 (98.5) 3 (1.5)
27 (96.4) 1 (3.6)
81 (98.8) 1 (1.2)
127 (64.8) 30 (15.3) 39 (19.9)
117 (57.4) 48 (23.5) 39 (19.1)
18 (64.3) 6 (21.4) 4 (14.3)
45 (54.9) 20 (24.4) 17 (20.7)
118 (60.5) 77 (39.5) 29.4 (5.8)
110 (54.7) 91 (45.3) 29.6 (5.7)
11 (39.3) 17 (60.7) 28.1 (5.4)
35 (43.8) 45 (56.3) 30.5 (6.5)
182 (92.9) 14 (7.1)
191 (93.6) 13 (6.4)
25 (89.3) 3 (10.7)
76 (92.7) 6 (7.3)
117 (59.7) 52 (26.5) 13 (6.6) 14 (7.1) 169 (86.2) 27 (13.8)
85 (41.7) 79 (38.7) 28 (13.7) 12 (5.9) 164 (80.4) 40 (19.6)
18 (64.3) 3 (10.7) 5 (17.9) 2 (7.1) 21 (75.0) 7 (25.0) 19.6 (6.5) 16.4 (3.7)
42 (51.2) 25 (30.5) 12 (14.6) 3 (3.7) 67 (81.7) 15 (18.3) 24.5 (3.5) 14.5 (2.7)
Values are mean (standard deviation), unless otherwise noted. a Race was self-reported. b ASA (morbidity) class: American Society of Anesthesiologists Class 1 was combined with ASA Class 2 because there were very few subjects in ASA Class 1. c BMI: body mass index. d General anesthesia includes general, general plus epidural, or general plus spinal. Other includes epidural, spinal, or a combined spinal-epidural (CSE). e Single: unilateral joint replacement; complex: bilateral joint or revision surgery. f MMSE: Mini-Mental State Exam. g DRS-R-98: Delirium Rating Scale-Revised-98.
lirium (53.6% versus 19.5%; p ⬍0.0005; 25% versus 11%, p⫽0.07, respectively; Table 3). There were no significant differences in any other secondary endpoints (e.g., blood pressure, arrhythmia [Table 4]). Our study showed that the use of olanzapine reduced the incidence of delirium, but not its severity or duration (Table 5). Univariate analysis (Table 6 [Part A]) comparing patients with and without delirium in the entire study sample, showed that patients’ age, having knee-replacement surgery, abnormal albumin level, and high ASA score (indicating severity of medical comorbidities) were each significantly associated with the development of postoperative delirium; use of olanzapine was associated 414
http://psy.psychiatryonline.org
with a lower incidence of delirium. All factors were entered into multiple logistic-regression analysis. It showed that advanced age, a high ASA class, an abnormal albumin level, and knee-replacement surgery were independent risk factors for postoperative delirium (Table 6 [Part B]). No serious adverse events (SAEs; e.g., stroke, infection, or atrial fibrillation) were attributed to use of the study drug. DISCUSSION Our results show that 10 mg of perioperatively-administered oral olanzapine (given as 5 mg just before and again immediately after joint-replacement surgery) was associPsychosomatics 51:5, September-October 2010
Larsen et al.
FIGURE 2.
TABLE 3.
Incidence of Postoperative Delirium by Type of Surgery
Secondary Outcomes: Abnormal Laboratory Values Among Patients With and Without Delirium, Day of Surgery Through Postoperative Day 4
Incidence of Delirium 60
Percent
50
Placebo Olanzapine
p<0.0001
40
Patients With Delirium
p<0.0001
Variable, N (%) Olanzapine (Nⴝ28) Placebo (Nⴝ82) Sodiuma Albuminb Calciumc
p<0.0004
30
1 (3.6) 7 (25.0) 15 (53.6)
p NS 0.07 ⬍0.001
Absence of Delirium
20
Variable, N (%)
Olanzapine (Nⴝ168)
Placebo (Nⴝ122)
p
10 (6.0) 10 (6.0) 25 (14.9)
6 (4.9) 6 (4.9) 20 (16.4)
NS NS NS
a
Sodium Albuminb Calciumc
10 0
All
FIGURE 3.
Hip Intervention Type
Knee
Abnormal serum sodium is defined as ⬍ 135 mmol/L. Abnormal serum albumin defined as ⬍ 3.5 g/dl. c Abnormal serum calcium is defined as ⬍ 8.4 mg/dl. a
b
Time-to-First Day of Delirium, by Study Group TABLE 4.
1.0 Proportion Delirium-Free
8 (9.8) 9 (11.0) 16 (19.5)
Secondary Outcomes: Medical Complications, Consultations, and Clinical Interventions—Day of Surgery Through Postoperative Day 4
0.8 Variable, N (%) 0.6 Olanzapine
0.4
Placebo p<0.0001
0.2 0.0
TABLE 2.
0
1 2 3 Days Post-Surgery
4
Secondary Outcomes: Disposition of Patients at Discharge
Variable, N (%)
Olanzapine (Nⴝ196)
Placebo (Nⴝ204)
Home with services Rehabilitation facility
80 (40.8) 116 (59.2)
61 (29.9) 143 (70.1)
p
Placebo (Nⴝ204)
p
6 (3.1) 2 (1.0) 1 (0.5) 5 (1.0) 3 (1.5) 1 (0.5)
3 (1.5) 1 (0.5) 1 (0.5) 1 (0.5) 0 (0.0) 4 (2.0)
NS NS NS NS NS NS
44 (22.5) 6 (3.1) 14 (7.1) 1 (0.5) 36 (18.4) 6 (3.1)
37 (18.1) 3 (1.5) 9 (4.4) 1 (0.5) 35 (17.2) 6 (2.9)
NS NS NS NS NS NS
9 (4.6) 5 (2.6) 11 (5.6)
4 (2.0) 0.0 7 (3.4)
NS 0.03 NS
0.02
Rehabilitation facility was defined as providing skilled nursing or acute (hospital-level) care.
ated with a lower incidence of delirium (14.3%; number needed to treat [NNT]⫽4) than placebo (40.2%). Although olanzapine has been reported as an effective and well-tolerated agent in the off-label treatment of delirium,16,33–36 its use as a prophylactic agent may be even more appealing. According to Leslie and associates,5 costs Psychosomatics 51:5, September-October 2010
Medical complications Atrial fibrillation Arrhythmia Congestive heart failure Alcohol withdrawal Pneumonia Urinary tract infection Medical consultations Cardiology Pulmonary Endocrinology/diabetes Neurology Behavioral medicine Gastroenterology Clinical interventions Sitter Restraints Bed alarm
Olanzapine (Nⴝ196)
per day incurred among patients with delirium are more than 2.5 times that of patients without delirium. Several studies have shown that antipsychotic agents can prevent delirium. In a placebo-controlled, randomized, non-blinded study on the effect of haloperidol on postoperative delirium in gastrointestinal surgery, Kaneko and colleagues37 found a lower incidence of delirium among haloperidol- than among placebotreated patients (10.5% versus 32.5%). More recently, Prakanrattana and Prapaitrakool15 reported that 1 mg of http://psy.psychiatryonline.org
415
Olanzapine and Postoperative Delirium
TABLE 5.
Secondary Outcomes
TABLE 6.
Duration of Delirium Days of Delirium, N (%)
Olanzapine (Nⴝ28)
Placebo (Nⴝ82)
1 2 3 ⱖ4
10 (35.7) 4 (14.3) 5 (17.9) 9 (32.0)
39 (47.6) 28 (34.2) 7 (8.5) 8 (10.0)
Severity of Delirium (DRS-R-98 Scores) Olanzapine (Nⴝ28)
POD POD POD POD
1 2 3 4
Placebo (Nⴝ82)
Mean (SD)
N (%)
Mean (SD)
N (%)
17.2 (3.9) 15.0 (2.4) 14.0 (1.4) 13.0a
20 (71.4) 5 (17.9) 2 (7.1) 1 (3.6)
14.6 (3.1) 14.1 (1.4) 15.0 (2.7) 13.0a
54 (66.0) 23 (28.0) 4 (5.0) 1 (1.0)
Association of Risk Factors With Presence of Postoperative Delirium
[A]: Univariate Relationship of Risk Factors to Postoperative Delirium Independent variable Olanzapine treatment Advanced age ASA Class 3 Abnormal albumin levela Knee-replacement surgery Joint-revision surgery Abnormal sodium level Being married Female gender
sublingual risperidone given immediately after cardiac surgery significantly decreased the incidence of delirium, from 31% to 11%. Studies by Kalisvaart and colleagues22 and Schraeder and associates38 have found that low-dose haloperidol prophylaxis can significantly reduce the severity and duration of delirium (but not the incidence) as well as hospital length of stay. Our study showed that use of olanzapine reduced the incidence of delirium, but not its severity or duration. According to Breitbart and colleagues,34 factors that predicted reduced response to olanzapine for the treatment of delirium among hospitalized cancer patients included an age ⬎ 70 years, hypoactive delirium, and delirium of severe intensity. Outcomes in our study may have been influenced by the anticholinergic potency of olanzapine as well as the patients who developed unanticipated postoperative alcohol withdrawal during the study. Preoperative misrepresentation of alcohol intake (⬎10 drinks/week met exclusion criteria) resulted in acute alcohol withdrawal in 5 of the 28 patients (17.9%) who developed delirium in the olanzapine-treated group and 1 of the 82 (1.2%) who developed it in the placebo-treated group. Symptoms of alcohol withdrawal were included in our assessments for delirium. Also, exploratory analysis revealed that a high incidence of abnormally low albumin levels (⬍3.5 gm) 416
http://psy.psychiatryonline.org
0.3 1.1 2.3 2.9 1.7 1.4 1.5 0.8 1.0
(0.2–0.4) (1.0–1.1) (1.5–3.6) (1.4–6.1) (1.1–2.8) (0.8–2.4) (0.7–3.6) (0.5–1.3) (0.7–1.6)
p ⬍0.001 0.009 0.003 0.004 0.02 NS NS NS NS
[B]: Multivariable Relationship of Risk Factors to Postoperative Delirium Independent variable
SD: standard deviation. Days of delirium: the duration in days as defined by the DRS-R-98 (Delirium Rating Scale, Revised–98), using a cutoff score of 13 (p⫽0.004). POD: Postoperative Day. Severity of delirium is defined as DRSR-98 score on the first day of delirium. Scores are for the total number of patients who developed delirium on each postoperative day. a Given that only one subject developed delirium on POD 4, no SD was calculated.
OR (95% CI)
Olanzapine treatment Knee-replacement surgery Abnormal albumin levela ASA Class 3 Advanced age
OR (95% CI) 0.2 2.3 3.1 2.0 1.1
(0.1–0.4) (1.3–3.8) (1.4–6.8) (1.2–3.2) (1.0–1.1)
p ⬍0.001 0.002 0.006 0.007 0.01
OR: odds ratio; CI: confidence interval. a Abnormal serum albumin level defined as ⬍3.5 g/dl.
occurred in olanzapine-treated delirium patients. Since olanzapine is highly protein-bound, those with hypoalbuminemia may have been more likely to develop more severe delirium due to higher available levels of the active drug. Further studies are needed to explore and confirm these possibilities. Other secondary outcomes showed that olanzapinetreated patients used less narcotic medication than those who received placebo; perhaps use of olanzapine reduced the need for pain medications. In our study, there were slightly more postoperative cardiac complications (although not significant statistically) in the olanzapine-treated patients than in those who received placebo. Furthermore, the overall incidence was similar to that observed in a study of cardiovascular complications after joint-replacement surgery at the same institution by Basilico and colleagues39 (4.6% versus 3.9% of 5,367 patients undergoing total joint replacement). Although our study confirmed advanced age and knee-replacement surgery as risk factors for delirium after orthopedic surgery, we identified a new high-risk group: patients with a high ASA class and abnormal albumin levels as independent risk factors for postoperative delirium. Our study design has several limitations, including a Psychosomatics 51:5, September-October 2010
Larsen et al. lack of intention-to-treat analysis, and an absence of longterm follow-up. Other limitations include a lack of preoperative assessment of cognition (e.g., with a baseline MMSE), no assessment of smoking or use of sleeping aids, and use of a socioeconomically homogeneous population. Although unidentified impaired cognition might have existed preoperatively, we believe that the risk was low among our patients preparing for elective joint-replacement surgery. Strengths of our study include our randomized, placebo-controlled, double-blinded design with stratification; our baseline measure of comorbidities by use of ASA classification; our use of standard protocols and pathways; our daily assessment of patients with validated instruments; our large sample size; our blinding of the study assessor; and our clear descriptions of usual care and confounders. Our study was designed to test the efficacy (but not the treatment) of a short-acting drug for the prevention of delirium. Hip- and knee-replacement surgeries are two of the most commonly performed and effective operations in the United States.14,40,41 By 2030, the total number of primary and revision replacements will be nearly 4.5 million,12 up from 750,000, performed in 2005.14 As the number of replacement procedures continues to grow, the focus on strategies and policies to manage growing costs will continue to increase.42 This large-scale, randomized, double-blind, controlled trial showed that perioperative prophylactic administration of olanzapine led to a reduced incidence of postoperative delirium after elective hip- or knee-replacement surgery. Although our results should be replicated, clinical interventions to prevent delirium should be initiated on a wider scale.
Kenneth A. Larsen, D.Min., Ph.D., Susan E. Kelly, M.D., and Theodore A. Stern, M.D., are all first-authors of this article. The authors thank Marie Nolan for administrative assistance; Noreen Howie, R.N., Casey Flynn, P.T., Brian Johnson, N.P., and Jennifer Silva, P.T., for patient recruitment and medical record review work; Bryan Ciccarelli, Glen Mortimer, and Emily McCaffrey, P.T., for assistance in postoperative patient assessment; Roberto Cruz-Gervis, M.D., and his hospitalist staff for the medical care of study patients; Joyce Welsh, R.N., and the dedicated nursing staff of the pre- and post- anesthesia care units for nursing care supervision; Olga Lyczmanenko for librarian services; Meredith Cameron for the assistance of the Department of Medical Records; and Rita Buckley for research and editorial services provided in the development of the manuscript. This study was made possible by a grant from the New England Baptist Hospital Research Department. The sponsor supplied the olanzapine and retained the study data; however, it had no other role in the study design; in the collection, analysis, and interpretation of the study; in the writing of the report; or in the decision to submit the paper for publication. Theodore A. Stern, M.D., has been a consultant to and is on the speaker’s bureau of Eli Lilly and Company, and has been a consultant to and shareholder of WiFiMed, the company that designed the Tablet PC data-management software. No other authors reported conflicts of interest.
References 1. American Psychiatric Association: Arlington, VA (accessed Sept. 2009); available from http://www.psych.org 2. Overshott R, Karim S, Burns A: Cholinesterase inhibitors for delirium. Cochrane Database Syst Rev 2008; Jan 23:CD005317 3. Redelmeier DA, Thiruchelvam D, Daneman N: Delirium after elective surgery among elderly patients taking statins. CMAJ 2008; 179:645– 652 4. Bellelli G, Bianchetti A, Trabucchi M: Delirium and costs of informal home care. Arch Intern Med 2008; 168:1717 5. Leslie DL, Marcantonio ER, Zhang Y, et al: One-year healthcare costs associated with delirium in the elderly population. Arch Intern Med 2008; 168:27–32 6. Robinson TN, Raeburn CD, Tran ZV, et al: Postoperative delirium in the elderly: risk factors and outcomes. Ann Surg 2009; 249:173–178 7. Williams-Russo P, Urquhart BL, Sharrock NE, et al: Post-operative delirium: predictors and prognosis in elderly orthopedic patients. J Am Geriatr Soc 1992; 40:759 –767
Psychosomatics 51:5, September-October 2010
8. Rogers MP, Liang MH, Daltroy LH, et al: Delirium after elective orthopedic surgery: risk factors and natural history. Int J Psychiatry Med 1989; 19:109 –121 9. Sampson EL, Raven PR, Ndhlovu PN, et al: A randomized, double-blind, placebo-controlled trial of donepezil hydrochloride (Aricept®) for reducing the incidence of postoperative delirium after elective total hip replacement. Int J Geriatr Psychiatry 2007; 22:343–349 10. Inouye SK: Delirium in older persons. N Engl J Med 2006; 354:1157–1165 11. American Academy of Orthopaedic Surgeons: Patient demographics. Rosemont, IL (accessed Sept 13, 2009); available from: http://www.aaos.org/research/stats/patientstats.asp 12. Kurtz S, Ong K, Lau E, et al: Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am 2007; 89:780 –785 13. Centers for Medicare and Medicaid Services: 100 Percent MEDPAR Inpatient Hospital National Data for Fiscal Year 2006,
http://psy.psychiatryonline.org
417
Olanzapine and Postoperative Delirium Short-Stay Inpatient Diagnosis-Related Groups. (accessed Sept. 12, 2009); available from http://www.cms.hhs.gov/MedicareFeeforSvcPartsAB/Downloads/DRG06.pdf 14. Wilson NA, Schneller ES, Montgomery K, et al: Hip and knee implants: current trends and policy considerations. Health Aff (Millwood) 2008; 27:1587–1598 15. Prakanrattana U, Prapaitrakool S: Efficacy of risperidone for prevention of postoperative delirium in cardiac surgery. Anaesth Intensive Care 2007; 35:714 –719 16. Ozbolt LB, Paniagua MA, Kaiser RM: Atypical antipsychotics for the treatment of delirious elders. J Am Med Dir Assoc 2008; 9:18 –28 17. Lonergan E, Britton AM, Luxenberg J, et al: Antipsychotics for delirium. Cochrane Database Syst Rev 2007; April 18: CD005594 18. Siddiqi N, Stockdale R, Britton AM, et al: Interventions for preventing delirium in hospitalised patients. Cochrane Database Syst Rev 2007; April 18:CD005563 19. Aizawa K, Kanai T, Saikawa Y, et al: A novel approach to the prevention of postoperative delirium in the elderly after gastrointestinal surgery. Surg Today 2002; 32:310 –314 20. 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 21. Dı´az V, Rodrı´guez J, Barrientos P, et al: Use of procholinergics in the prevention of postoperative delirium in hip fracture surgery in the elderly: a randomized, controlled trial. Rev Neurol 2001; 33:716 –719 22. Kalisvaart KJ, de Jonghe JF, Bogaards MJ, et al: Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized, placebo-controlled study. J Am Geriatr Soc 2005; 53:1658 –1666 23. Liptzin B, Laki A, Garb JL, et al: Donepezil in the prevention and treatment of post-surgical delirium. Am J Geriatr Psychiatry 2005; 13:1100 –1106 24. Marcantonio ER, Flacker JM, Wright RJ, et al: Reducing delirium after hip fracture: a randomized trial. J Am Geriatr Soc 2001; 49:516 –522 25. American Society of Anesthesiologists (accessed Sept 13, 2009); available from http://www.asahq.org/index.htm 26. Trzepacz PT, Mittal D, Torres R, et al: Validation of the Delirium Rating Scale, Revised–98: comparison with the Delirium Rating Scale and the Cognitive Test for Delirium. J Neuropsychiatry Clin Neurosci 2001; 13:229 –242 27. Laurila JV, Pitkala KH, Strandberg TE, et al: The impact of different diagnostic criteria on prevalence rates for delirium. Dement Geriatr Cogn Disord 2003; 16:156 –162 28. Folstein MF, Robins LN, Helzer JE: The Mini-Mental State Exam. Arch Gen Psychiatry 1983; 40:812
418
http://psy.psychiatryonline.org
29. Inouye SK, Bogardus ST Jr., Charpentier PA, et al: A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340:669 – 676 30. Wei LA, Fearing MA, Sternberg EJ, et al: The Confusion Assessment Method: a systematic review of current usage. J Am Geriatr Soc 2008; 56:823– 830 31. Inouye SK, van Dyck CH, Alessi CA, et al: Clarifying confusion: the Confusion Assessment Method: a new method for detection of delirium. Ann Intern Med 1990; 113:941–948 32. Gonza´lez M, Martı´nez G, Caldero´n J, et al: Impact of delirium on short-term mortality in elderly inpatients: a prospective cohort study. Psychosomatics 2009; 50:234 –238 33. Skrobik YK, Bergeron N, Dumont M, et al: Olanzapine vs. haloperidol: treating delirium in a critical-care setting. Intens Care Med 2004; 30:444 – 449 34. Breitbart W, Tremblay A, Gibson C: An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics 2002; 43:175–182 35. Kim KS, Pae CU, Chae JH, et al: An open pilot trial of olanzapine for delirium in the Korean population. Psychiatry Clin Neurosci 2001; 55:515–519 36. Sipahimalani A, Masand PS: Olanzapine in the treatment of delirium. Psychosomatics 1998; 39:422– 430 37. Kaneko T, Jianhui C, Ishikura T, et al: Prophylactic consecutive administration of haloperidol can reduce the occurrence of postoperative delirium in gastrointestinal surgery. Yonaga Acta Medica 1999; 42:179 –184 38. Schrader SL, Wellik KE, Demaerschalk BM, et al: Adjunctive haloperidol prophylaxis reduces postoperative delirium severity and duration in at-risk elderly patients. Neurologist 2008; 14: 134 –137 39. Basilico FC, Sweeney G, Losina E, et al: Risk factors for cardiovascular complications following total joint-replacement surgery. Arthritis Rheum 2008; 58:1915–1920 40. Henry J. Kaiser Family Foundation: Range of Medicare Payments (Low-25th Percentile/High-75th Percentile) for Top Five Elective Inpatient Hospital Procedures, FY 2006. (accessed Sept 12, 2009); available from http://www.statehealthfacts.org/ comparetable.jsp?cat⫽6&ind⫽289 41. Centers for Medicare and Medicaid Services: Medicare ShortStay Hospital DRGs Ranked by Discharges, Fiscal Year 2006 (accessed Sept. 2009); available from http://www.cms.hhs.gov/ datacompendium/17_2007_data_compendium.asp 42. Agency for Healthcare Research and Quality: Hospital Stays Involving Musculoskeletal Problems, 1997–2005. HCUP Statistical Brief # 34 (accessed Sept. 2009); available from www.hcupus.ahrq.gov/reports/statbriefs/sb34.pdf
Psychosomatics 51:5, September-October 2010