HM Medical Clinic

Diamondl.ca

Haloperidol prophylaxis decreases delirium incidence in elderly
patients after noncardiac surgery: A randomized controlled trial*
Wei Wang, MD; Hong-Liang Li, MD; Dong-Xin Wang, MD, PhD; Xi Zhu, MD; Shuang-Ling Li, MD;Gai-Qi Yao, MD; Kai-Sheng Chen, MD; Xiu-E Gu, RN, BSN; Sai-Nan Zhu, MS Objectives: To evaluate the efficacy and safety of short-term
23.2% (53/228) in the control group (p ⴝ .031). The mean time
low-dose intravenous haloperidol for delirium prevention in crit-
to onset of delirium and the mean number of delirium-free days
ically ill elderly patients after noncardiac surgery.
were significantly longer (6.2 days [95% confidence interval
Design: Prospective, randomized, double-blind, and placebo-
5.9ⴚ6.4] vs. 5.7 days 关95% confidence interval 5.4ⴚ6.0兴; p ⴝ
controlled trial in two centers.
.021; and 6.8 ⴞ 0.5 days vs. 6.7 ⴞ 0.8 days; p ⴝ .027,
Setting: Intensive care units of two large tertiary teaching
respectively), whereas the median length of intensive care unit
stay was significantly shorter (21.3 hrs 关95% confidence inter-
Patients: Four hundred fifty-seven patients 65 yrs or older who
val 20.3ⴚ22.2兴 vs. 23.0 hrs 关95% confidence interval 20.9 –
were admitted to the intensive care unit after noncardiac surgery.
25.1]; p ⴝ .024) in the haloperidol group than in the control
Intervention: Haloperidol (0.5 mg intravenous bolus injection
group. There was no significant difference with regard to
followed by continuous infusion at a rate of 0.1 mg/h for 12 hrs;
all-cause 28-day mortality between the two groups (0.9%
n ⴝ 229) or placebo (n ⴝ 228) was randomly administered from
[2/229] vs. 2.6% [6/228]; p ⴝ .175). No drug-related side
intensive care unit admission.
effects were documented.
Measures: The primary end point was the incidence of delirium
Conclusions: For elderly patients admitted to intensive care
within the first 7 days after surgery. Secondary end points in-
unit after noncardiac surgery, short-term prophylactic adminis-
cluded time to onset of delirium, number of delirium-free days,
tration of low-dose intravenous haloperidol significantly de-
length of intensive care unit stay, all-cause 28-day mortality, and
creased the incidence of postoperative delirium. The therapy was
adverse events. Delirium was assessed using the confusion as-
well-tolerated. (Crit Care Med 2012; 40:731–739)
sessment method for the intensive care unit.
KEY WORDS: aged; control; delirium; haloperidol; intensive care
Results: The incidence of delirium during the first 7 days
units; postoperative complications; prevention
after surgery was 15.3% (35/229) in the haloperidol group and
acterized by disturbances of 80% in those who required intensive care hibitors, sleep-wake cycle regulators, and (3–5). A review analysis by Dyer et al (6) others) have been assessed for potential cognition, and perception showed that the average incidence of roles in postoperative delirium preven- that develops over a short period and postoperative delirium was 36.8%, and tion (15–21). However, the results from tends to fluctuate throughout a day (1). It the prevalence increased with age.
these studies are inconsistent. In a more is one of the most common central ner- The occurrence of delirium is associ- recent study, Larsen et al (22) found that vous system disorders in elderly patients ated with worse outcomes of patients, i.e., prophylactic olanzapine (an atypical anti- after surgery (2). The reported incidence they had poorer functional recovery, psychotic) reduced the incidence of post- ranged from 15% to 53% in elderly post- more frequent complications, longer hos- operative delirium in elderly joint re- pital stays, higher mortality rates, and placement patients. But, in patients who greater hospital costs (7–11). Further- had delirium develop, delirium lasted *See also p. 982.
more, delirium has negative impacts on longer and was more severe in the olan- From the Departments of Anesthesiology and Sur- patients' long-term outcomes, even zapine group. To date no recommenda- gical Intensive Care (WW, DXW, SLL, KSC, XEG) andBiostatistics (SNZ), Peking University First Hospital, though its symptoms are usually tran- tion can be made for a drug's routine Beijing, China; Department of Critical Care Medicine sient. It has been noticed that patients clinical use to prevent delirium (23, 24).
(HLL, XZ, GQY), Peking University Third Hospital, Bei- with early postoperative delirium tended Haloperidol is a typical antipsychotic jing, China.
to have long-term cognitive impairment and has been used widely to treat the The first two authors, Wei Wang and Hong-Liang Li, contributed equally to this work.
and lowered quality of life (12, 13).
established delirium (25). In a small non- The authors have not disclosed any potential con- Considering the facts that the popula- blinded study, haloperidol prophylaxis (5 flicts of interest.
tion is aging and the number of elderly mg intravenously for 5 consecutive post- For information regarding this article, E-mail: patients undergoing surgery is increasing operative days) was proved effective in Copyright 2012 by the Society of Critical Care (14), finding measures to prevent postop- reducing postoperative delirium in gas- Medicine and Lippincott Williams & Wilkins erative delirium is of utmost importance.
trointestinal surgery patients (26). Sub- Various pharmacologic agents (such as sequently, Kalisvaart et al (15) performed Crit Care Med 2012 Vol. 40, No. 3

a randomized controlled trial in 430 el- during or after anesthesia; neurosurgery; in- by bedside nurses to a target sedation level derly hip surgery patients. Haloperidol dividuals unlikely to survive for ⬎24 hrs; and (Richmond Agitation Sedation Scale range, prophylaxis (0.5 mg orally three times prolonged corrected QT (QTc) interval of 460 ⫺2 to ⫹ 1) (31, 32). Daily awakening was used daily) was started preoperatively and con- ms or higher for men and 470 ms or higher for for those who were not extubated in the morn- tinued for up to 3 days after surgery.
women on the baseline electrocardiogram.
ing. No other analgesics or sedatives were al- Their results showed that haloperidol de- Randomization was stratified by center. El- lowed during the study period.
creased the severity and duration, but not igible patients were sequentially randomly as- For all patients, multicomponent ap- the incidence, of postoperative delirium.
signed to either haloperidol group or placebo proaches to reduce risk factors of delirium as Therefore, further study was needed to group according to computer-generated ran- suggested by Inouye et al (33, 34) were in- domization codes. Detailed information in- cluded in routine care. For patients who had determine the efficacy of haloperidol in cluding baseline demographics, preoperative postoperative delirium develop, nonpharma- delirium prevention (27).
medical history, admission diagnosis, severity cologic strategies were applied first (34).
The difference in haloperidol dosage of illness, as well as perioperative variables Open-label haloperidol treatment was only re- used in these two studies perhaps can were obtained at the time of enrollment.
served for those with severe agitation. An ini- explain the inconsistent results. Because tial dose of 0.5 to 1 mg haloperidol was ad- the oral bioavailability of haloperidol is Study Drug Administration and
ministered intravenously, repeated every 20 to only 35% to 60% (28, 29), it is possible 30 mins until agitation was effectively con- that the dosage of haloperidol used in the trolled (35).
study of Kalisvaart et al (15) was too Study drug was prepared by an indepen- small to prevent delirium. Furthermore, dent nurse with either haloperidol (5 mg di- studies showed that postoperative delir- luted with normal saline to a final concentra- ium mainly occurred in the early postop- tion of 0.1 mg/mL) or placebo (normal saline), The primary end point was the incidence of erative period. The number of new delir- and was prepackaged according to the ran- delirium during the first 7 days after surgery.
ium cases was highest on the first domization code. Placebo medication was Secondary end points included safety and tol- postoperative day and then decreased rap- identical in the appearance to the active drug.
erability of haloperidol administration, time to idly over time (8, 30). We therefore hy- Trial medication was started within 1 hr after onset of delirium, daily prevalence of delirium, pothesized that short-term use of low- enrollment and continued for 12 hrs. Study number of delirium-free days, and use of dose intravenous haloperidol might be drug was administrated intravenously by bolus open-label haloperidol. Additional outcomes effective in preventing postoperative de- injection of 5 mL (0.5 mg haloperidol or pla- included time to extubation, length of stay in lirium. The purpose of this study was to cebo), followed by continuous infusion at a ICU, occurrence of other postoperative com- rate of 1 mL/hr (0.1 mg/hr haloperidol or plications, length of stay in hospital after sur- determine the efficacy and safety of short- gery, and all-cause 28-day mortality.
term administration of low-dose intrave- All study personnel, healthcare team mem- Outcome assessments were performed by nous haloperidol in preventing delirium bers, and patients were unaware of treatment research members who were not involved in in critically ill elderly patients after non- group assignment, and blinding was main- clinical care of patients. Before the study, phy- cardiac surgery.
tained throughout the whole study period.
sicians performing assessment (H.L.L. and Code envelopes were stored at the site of in- W.W.) were trained to follow standard proce- MATERIALS AND METHODS
vestigation. In case of emergency, attending dures. They were also trained by a psychiatrist intensivist for patient care could request un- to use the confusion assessment method for Study Design
masking of the treatment allocation. A state- the ICU (36, 37). During the study phase, ment had to be made in the case report for- patients were assessed for delirium once daily This was a prospective, randomized, dou- mulary in that case. Study drug was (from 4:00 PM to 6:00 PM) in either the ICUs or ble-blind, and placebo-controlled two-center discontinued if life-threatening drug-related the general wards (for those who had been clinical trial. The study protocol was approved adverse events (such as torsades de pointes, or discharged from ICU) until the seventh post- by the local Clinical Research Ethics Commit- other ventricular tachycardia requiring treat- operative day.
tees. Written informed consent was obtained ment) occurred. These patients would be in- Delirium assessment was performed in two from each patient or, if the patient could not cluded in the final intention-to-treat analyses.
steps. First, level of sedation (level of arousal) provide informed consent, from the surrogate Postoperative analgesia routinely included was assessed using the Richmond Agitation of the patient. The study was conducted from patient-controlled epidural analgesia (estab- Sedation Scale. If the patient was deeply se- June 2009 to May 2010 in intensive care units lished with 250 mL of 0.12% ropivacaine plus dated or was unarousable (⫺4 or ⫺5 on the (ICUs) of two large tertiary teaching hospitals 0.5 ␮g/mL sufentanil, programmed to deliver Richmond Agitation Sedation Scale), then as- in Beijing, China.
a 2-mL bolus with a lockout interval of 20 sessment was stopped and repeated later, and mins and a background infusion of 4 mL/hr) the patient was noted as comatose. If Rich- Patient Recruitment and
or patient-controlled intravenous analgesia mond Agitation Sedation Scale was ⬎⫺4 (⫺3 (established with 100 mL of 0.5 mg/mL mor- through ⫹ 4), then assessment was continued phine, programmed to deliver a 2-mL bolus to the next step. Second, delirium was diag- Patients 65 yrs or older who were admitted with a lockout interval of 6 –10 mins and a nosed using the confusion assessment method to the ICU after noncardiac surgery were background infusion of 1 mL/hr). Supplemen- for the ICU. It detects four features of delir- screened consecutively. The exclusion criteria tal analgesia was administered with fentanyl if ium: acute onset of mental status changes or a included: preoperative history of schizophre- necessary (25 ␮g every 10 mins to a 1-hr fluctuating course; inattention; disorganized nia, epilepsy, parkinsonism, use of cholinest- maximum of 150 ␮g, with or without contin- thinking; and altered level of consciousness.
erase inhibitor, or levodopa treatment; inabil- uous infusion started at 12.5 ␮g/hr). For pa- To have delirium diagnosed, a patient must ity to communicate in the preoperative period tients with endotracheal tubes, intravenous display the first two aforementioned features, (coma, profound dementia, or language bar- sedatives including propofol or midazolam with either the third or fourth aforementioned rier); use of haloperidol or other neuroleptics were administrated continuously and titrated Crit Care Med 2012 Vol. 40, No. 3

Safety and tolerability were assessed by monitoring vital signs, electrocardiogram, 1346 Patients screened and adverse events. Blood pressure and elec-trocardiogram were monitored continuously 738 Patients excluded during ICU stay to check for episodes ofhypotension and arrhythmia. Electrocardio- 311 Non-surgical patients gram was recorded in case of an adverse 299 Less than 65 years event and at the time of study drug discon- 51 Prolonged baseline QTc tinuation for evaluation of QTc interval. Sig- 26 Terminally ill nificant QTc prolongation was defined as prolongation of QTc interval of ⬎60 ms or 18 Visual/hearing impairment QTc interval longer than 500 ms (38, 39).
Patients were clinically assessed hourly forsigns of sedation and extrapyramidal symp- 2 Neuromuscular disease toms. Adverse events were monitored until24 hrs after surgery.
608 Patients eligible Patients were followed-up until 28 days after surgery. Postoperative complicationswere defined as medical events that required 151 Refused to participate therapeutic intervention. All data were col-lected from the standardized patient recordswith a double-check manner.
229 Assigned to haloperidol group 228 Assigned to placebo group 3 Failed to receive study drug 1 Failed to receive study drug Sample Size Determination. The incidence of postoperative delirium in a comparable pop-ulation of a previous study was 44.5% (8). We 229 Included in final ITT analyses 228 Included in final ITT analyses assumed that the incidence of delirium wouldbe 29.7% in the haloperidol group, i.e., a one- Figure 1. Flow diagram of the study. ITT, intention-to-treat; QTc, heart rate-corrected QT interval.
third reduction from the initial incidence. Thecalculated sample size that would provide 80%power to detect this difference based on atwo-tailed significance level of 0.05 was 180 Table 1. Baseline demographics and characteristics of all patients
patients per group. The sample size calcula- tion was performed on STATA 10.0 software Group (n ⫽ 229) Group (n ⫽ 228) (StataCorp, College Station, TX).
Efficacy and Safety Analysis. Intention-to- Age, mean ⫾ SD, yr treat analyses were performed. Continuous variables were analyzed with independent Body mass index, mean ⫾ SD, kg/m2 samples t test or Mann-Whitney U test. Cate- Education, mean ⫾ SD, yr gorical variables were analyzed with chi- Preoperative comorbidity, number (%) square analysis or Fisher exact test. Times to Coronary heart disease onset of delirium, extubation, ICU discharge, Diabetes mellitus and hospital discharge after surgery were cal- culated using Kaplan-Meier survival analyses, with differences between groups assessed by Chronic obstructive pulmonary disease the log-rank test. Patients without onset of delirium were censored at the seventh postop- erative day. Otherwise, they were censored at Chronic smokingd postoperative day 28.
A multivariate logistic regression model History of surgery, number (%) was used to determine whether the association Preoperative American Society of between the intervention and the primary out- Anesthesiologists class, n (%) come was confounded by baseline differences.
Baseline and perioperative variables that dif- fered between the two groups (p ⬍ .10) were Baseline heart-rate corrected QT, entered into the model.
Statistical analyses were performed on SPSS 14.0 software (SPSS, Chicago, IL). No aArrhythmia that required medical or interventional therapy; bserum creatinine ⬎177 ␮mol/L.
interim analysis was planned or performed.
calanine transaminase and/or aspartate transaminase more than five-times the upper limit of normal; Statistical tests were two-sided, and p ⬍ .05 dsmoking half a pack of cigarettes per day for at least 2 yrs; etwo drinks or more daily, or weekly were considered statistically significant.
consumption of the equivalent of 150 mL of alcohol.
Crit Care Med 2012 Vol. 40, No. 3

Table 2. Perioperative variables of all patients
Group (n ⫽ 229) Group (n ⫽ 228) A total of 608 patients met the inclu- sion/exclusion criteria. Among them, 457 Emergency operation, n (%) patients gave written informed consents Type of anesthesia, n (%) and were randomized into the study.
Study drug infusion was failed to initiate in four patients (three in the haloperidol Intraoperative medication, number (%) group and one in the placebo group) be- cause of heavy clinical workload. The re- sults of these four patients were included Duration of anesthesia, mean ⫾ SD, hr in the final intention-to-treat analyses Type of surgery, n (%) Baseline characteristics were similar be- Spinal and extremital tween the two groups (Table 1). Despite double-blind randomization, the durations Duration of surgery, mean ⫾ SD, hr of anesthesia and surgery were significantly Estimated intraoperative bleeding, median longer, and the volume of total intraopera- tive infusion was significantly larger in the Total intraoperative infusionc, median (IQR), mL 2700 (2000–4000) 2550 (1600–3675) Surgery for malignant tumord, number (%) haloperidol group than in the placebo Acute Physiology and Chronic Health Evaluation group. There were no significant differ- II score on ICU admission, mean ⫾ SD, ences with regard to other intraoperative and postoperative variables between the Endotracheal tube on ICU admission, n (%) two groups (Table 2).
Postoperative analgesia, n (%) Patient-controlled intravenous analgesiae Patient-controlled epidural analgesiaf Other analgesics/sedatives in ICU Use of fentanyl, n (%) The incidence of postoperative delir- Dose of fentanylg, median (IQR), ␮g/kg 0.50 (0.00–6.59) 0.73 (0.00–8.09) ium within the first 7 days after surgery Use of propofol, n (%) was significantly lower in the haloperidol Dose of propofolg, median (IQR), mg/kg 0.89 (0.00–4.90) 0.99 (0.00–5.33) group than in the placebo group (15.3% Use of midazolam, n (%) [35/229] vs. 23.2% [53/228]; p ⫽ .031).
Dose of midazolamg, median (IQR), mg/kg 0.00 (0.00–0.29) 0.00 (0.00–0.32) Use of glucocorticoids in ICU, n (%) Subgroup analysis also revealed a signif-icant difference for those undergoing in- ICU, intensive care unit; IQR, interquartile range.
tra-abdominal surgery (14.5% [25/172] aMainly dexamethasone (10 mg) for prophylaxis of postoperative nausea and vomiting; bmainly vs. 24.7% [41/166]; p ⫽ .018). Daily prev- atropine (1 mg), combined with neostigmine, for reversal of residual neuromuscular blockade; alence of delirium on the first and the cincluding blood products; dconfirmed by final pathologic examination; eestablished with 250 mL of third days after surgery were significantly 0.12% ropivacaine plus 0.5 ␮g/mL sufentanil, programmed to deliver a 2-mL bolus with a lockout lower in the haloperidol group than in interval of 20 mins and a background infusion of 4 mL/hr; festablished with 100 mL of 0.5 mg/mL the placebo group (7.0% [16/229] vs.
morphine, programmed to deliver a 2-mL bolus with a lockout interval of 6 –10 mins and a backgroundinfusion of 1 mL/hr; gcalculated as total dose used during the first 7 postoperative days divided by body 13.2% [30/228]; p ⫽ .028 and 1.7% [4/ 229] vs. 5.3% [12/228]; p ⫽ .041, respec-tively) (Table 3, Figs. 2 and 3).
Variables that differed between the Further analyses revealed that the Furthermore, the incidence of nonde- two groups (p ⬍ .10) in Tables 1 and 2 time to onset of delirium and the number lirium complications within 7 days after were entered into a multivariate logistic of delirium-free days during the first 7 surgery was significantly less, and that regression analysis model, except for the postoperative days was significantly lon- within 28 days after surgery also tended duration of anesthesia, which was ex- ger, whereas the length of ICU stay was to be less in the haloperidol group than in cluded because of collinearity with the significantly shorter in the haloperidol the placebo group (Table 4, Fig. 5B).
duration of surgery (Pearson correlation group than in the placebo group. How- coefficient ⫽ 0.974; p ⬍ .001). The re- ever, the time to hospital discharge was sults showed that after adjustment for the similar between the two groups. There duration of surgery, the estimated intra- were no significant differences with re- operative bleeding, the total intraoper- gard to the incidences of nondelirium No ventricular arrhythmia or other ative infusion volume, and the type of complications occurring within either 7 significant adverse effects occurred dur- surgery for malignant tumor, the odds days or 28 days after surgery (Table 3, ing the period of study drug infusion.
ratio for the occurrence of postopera- Figs. 4 and 5A).
Therefore, no emergent unmasking of tive delirium in the haloperidol group Among patients who had postopera- the treatment allocation was needed in all as compared with the placebo group tive delirium develop, the length of ICU enrolled patients. The Richmond Agita- was 0.574 (95% confidence interval stay was significantly shorter in the hal- tion Sedation Scale results at the end of 0.352– 0.937; p ⫽ .026).
operidol group than in the placebo group.
study drug infusion and the time to ex- Crit Care Med 2012 Vol. 40, No. 3

Table 3. Efficacy outcomes of all patients
lactic administration of low-dose intrave-nous haloperidol significantly decreased the incidence of delirium during the first 7 postoperative days. It also significantlyprolonged the time to onset of delirium, Length of stay in intensive care unita, median 21.3 (20.3–22.2) 23.0 (20.9–25.1) increased the number of delirium-free Time to onset of deliriuma, mean (95% CI), d days, and shortened the length of postop- Occurrence of brain dysfunctionb, n (%) erative ICU stay. No drug-related side ef- fects were documented.
The pathophysiology of delirium after Coma or deliriumc Number of days without brain dysfunctiond, anesthesia and surgery remains obscure and is thought to be multifactorial (34, 41). Extensive evidence supported the role of cholinergic deficiency and/or do- Coma-free and delirium-freec paminergic excess (42, 43). In fact, ace- Occurrence of nondelirium complications, n (%) Within 7 d after surgery tylcholine release is regulated by dopami- Within 28 d after surgery nergic function, i.e., dopamine inhibits Length of stay in hospital after surgerya, median 11.0 (10.1–11.9) 11.0 (10.2–11.8) the release of acetylcholine by acting at dopamine D2 receptor, whereas blockadeof D2 receptor is associated with en- CI, confidence interval.
a hanced release of acetylcholine (44, 45).
Calculated using Kaplan-Meier survival analysis, with differences between groups assessed by the As a typical antipsychotic drug, haloper- log-rank test; bindicates the occurrence of brain dysfunction at any time during the first 7 days aftersurgery; cindicates that the patient was deeply sedated or unarousable ( idol exerts its action by blocking dopa- ⫺4 or ⫺5 on the Richmond Agitation Sedation Scale); dnumber of days alive without brain dysfunction during the first 7 days after mine D2 receptor (46) and continues to be the mainstay for the treatment of de-lirium in ICU patients (23–25, 47). There-fore, it is reasonable to postulate that it might also be effective in the prevention of postoperative delirium.
A concern with the use of haloperidol prophylaxis is its potential side effects (hypotension, sedation, extrapyramidalsymptoms, altered cardiac conduction,and others), which are usually dose- dependent. Keeping the total daily dose⬍3 mg may reduce the risk of extrapyra- midal side effects (48). Significant QTcprolongation had been reported in a pa- Incidence of delirium (%)
tient with acute coronary syndrome after2 mg of intravenous haloperidol (49). Forelderly patients, it has been suggested that haloperidol should be administered in the lowest possible doses for the short- Type of surgery
est possible time (35). In our study, hal-operidol was administered intravenously Figure 2. Incidence of postoperative delirium by type of surgery. The incidence of postoperative
delirium was significantly lower in the haloperidol group than in the placebo group in all patients and
by a bolus injection (0.5 mg), followed by in those undergoing intra-abdominal surgery.
a continuous infusion (at a rate of 0.1mg/hr) for 12 hrs. The aim of bolus in-jection was to reach therapeutic blood tubation were similar between the two study drug. Only one patient in the pla- level rapidly once the drug was started, groups (Table 5).
cebo group was found to be prescribed and the bolus dose was chosen according The changes of QTc interval after such medication (moxifloxacin) (40). All- to the suggested starting dose for treat- study drug infusion were similar between cause 28-day mortality was not signifi- ment of delirium in elderly patients (35).
the two groups. Significant QTc prolon- cantly different between treatment Haloperidol is commonly administered gation occurred in nine patients at the groups and no death was considered re- via intermittent intravenous injection in time of study drug discontinuation, lated to study drug (Table 5).
the critical care setting. However, a con- among them four were in the haloperidol tinuous intravenous infusion was used in group and five were in the placebo group our study to achieve a more consistent (p ⫽ .995; Table 5). Detailed history re- serum concentration (50, 51). In contrast views were conducted for these patients The present study demonstrated that to other studies (15, 26), we chose a to find medications that might induce QT in elderly patients admitted to ICU after much shorter prophylactic period. One interval prolongation other than the noncardiac surgery, short-term prophy- reason was that we wanted to limit the Crit Care Med 2012 Vol. 40, No. 3

ICU stay (median, 1.7 hrs shorter in all patients and 21.8 hrs shorter in delirious patients) and lowered incidence of early postoperative complications (in delirious patients) implied that haloperidol mighthave changed the underlying course of delirium 10
delirium. Kalisvaart et al (15) also found that in patients who had delirium de- velop, haloperidol prophylaxis signifi- cantly decreased the severity and dura-tion of delirium and shortened the length of hospital stay. In a retrospective cohort study, Milbrandt et al (52) reported that Daily prevalence of
haloperidol use was associated with de- creased mortality rate in mechanically ventilated patients. The clinical signifi- Date after surgery (day)
cances of a 0.1-day increase of delirium-free time and a 1.7-hr decrease of ICU Figure 3. Daily prevalence of postoperative delirium. The prevalence of postoperative delirium was
significantly lower in the haloperidol group than in the placebo group on the first and the third days
length of stay warrant further study.
after surgery.
It is worth noting that the incidence of postoperative delirium in the controlgroup was lower than our previous result (23.3% vs. 44.5%) (8). One possible rea- son is that the patient populations werenot exactly the same. For example, al- though patients were older (74.2 ⫾ 6.5 yrs vs. 69.1 ⫾ 10.7 yrs), illness was lesssevere (Acute Physiology and Chronic Health Evaluation II score 8.6 ⫾ 2.9 vs.
9.8 ⫾ 4.6) in the present study. This Log-rank p = 0.021 probably resulted in a lower delirium in- Cumulative %
cidence. Another possible reason is thatthe method of delirium assessment wasdifferent. In our previous study, delirium was assessed using the Nursing DeliriumScreening Scale three times daily fromthe day of surgery, which might possibly detect more delirium cases (8, 53, 54).
The third possible reason is that routinepatient care had been improved in the Time to onset of delirium, d
present study. Multicomponent preven- Figure 4. Time to onset of delirium in all patients. The mean time to onset of delirium was
tive measures as suggested by Inouye et significantly longer in the haloperidol group than in the placebo group.
al (33, 34) were implemented after ourprevious study (55) and were included in total dose of haloperidol on the first post- higher than in the study of Kalisvaart et the daily nursing care during the current operative day (1.7 mg) to ⬍2 mg to de- al (1.5 mg/day orally) (15).
study period.
crease the unwanted side effects. Another Apart from decreased incidence of The results of our study showed that reason was that the incidence of delirium postoperative delirium, it was found that no drug-related side effects were docu- was highest on the first postoperative day the time to onset of delirium was signif- mented. No ventricular arrhythmia or ep- and haloperidol has a relatively long half- icantly prolonged (mean, 0.5 day longer) isode of extrapyramidal symptoms oc- life time (18 –54 hrs) (8, 30, 47). There- and the number of delirium-free days was curred. No additive sedative effects were fore, even after cessation of haloperidol significantly increased (mean, 0.1 day present. Furthermore, changes in QTc in- infusion, its effects would continue and more) by haloperidol prophylaxis. Be- terval and occurrence of significant QTc side effects might also occur. Because cause haloperidol can relieve certain prolongation after study drug infusion more than half of our patients stayed in symptoms of delirium (agitation or hy- were similar between two groups. There- the ICU for ⬍24 hrs, we needed to ob- peractive symptoms), it is possible that fore, the dose regimen of haloperidol serve the possible side effects for a time patients receiving haloperidol might tem- used in our study was safe and effective, interval before they were moved to a gen- porarily have their delirious symptoms and it could be administered in critically eral ward. Considering the low bioavail- masked during and immediately after the ill elderly patients after noncardiac ability after oral administration, the dos- period of drug infusion, thus increasing age of haloperidol used on the first the measure of delirium-free time. How- The strengths of our study include postoperative day in our study was much ever, significantly shortened length of randomization, inclusion of a placebo Crit Care Med 2012 Vol. 40, No. 3

Log-rank p = 0.006 Log-rank p = 0.024 Cumulative %
Cumulative %
Time to ICU discharge, d
Time to ICU discharge, d
Figure 5. A, Time to intensive care unit (ICU) discharge in all patients. The median length of ICU stay was significantly shorter in the haloperidol group
than in the placebo group. B, Time to ICU discharge in patients who had postoperative delirium develop. The median length of ICU stay was significantly
shorter in the haloperidol group than in the placebo group.
Table 4. Outcomes of patients who had development of postoperative delirium
group, and blinding of research andhealthcare personnel as well as patients to treatment allocation. However, there were several limitations of this study.
Time to extubationa, median (95% CI), hr First, we did not perform baseline psychi- Length of stay in intensive care unita, median 19.6 (16.3–22.9) 41.4 (39.3–43.5) atric and cognitive screening tests. Pre- operative mental disorders (such as de- Time to onset of deliriuma, mean (95% CI), d pression, cognitive impairment, and Number of delirium-free daysb, mean ⫾ SD, d Open-label haloperidol use, n (%) dementia) may influence the occurrence Occurrence of nondelirium complications, n (%) of postoperative delirium (56, 57). How- Within 7 d after surgery ever, because this was a randomized con- Within 28 d after surgery Length of stay in hospital after surgerya, median 14.0 (10.6–17.4) 12.0 (10.4–13.6) trolled study, the confounding variables such as these should have been expected All-cause 28-d mortality, number (%) to present equally in the two groups. Sec-ond, intraoperative parameters were not CI, confidence interval.
aCalculated using Kaplan-Meier survival analysis, with differences between groups assessed by the similar. Although patients were randomly log-rank test; bnumber of days alive without delirium during the first 7 days after surgery.
divided into two groups, the durations ofanesthesia and surgery were significantlylonger, and the volume of total intraop- Table 5. Safety outcomes of all patients
erative infusion was significantly largerin the haloperidol group than in the con- trol group. However, according to litera- ture, these differences indicated that pa- Arrhythmia during study drug infusiona, n (%) tients in the haloperidol group were Change of heart rate-corrected QT interval after probably at higher risk for development study drug infusion, mean ⫾ SD, ms of delirium (30, 58, 59). After adjustment Significant heart rate-corrected QT interval for these parameters, the odds ratio for prolongation after study drug infusionb, n (%) Episode of extrapyramidal symptoms, n (%) the occurrence of postoperative delirium Other possible adverse effects of study drug was still significantly lower in the halo- therapyc, n (%) peridol group than in the placebo group.
Richmond Agitation Sedation Scale at the end of Third, the incidence of postoperative de- study drug infusion, median (interquartile range) Time to extubationd, median lirium in the control group was lower (95% confidence interval), hr than the anticipated results. The unex- All-cause 28-d mortality, n (%) pected low incidence of delirium in the control group increased the risk of type 2 Nonpatient manifested ventricular arrhythmia; bindicate prolongation of heart rate-corrected QT error. However, we did find differences interval of ⬎60 ms or heart rate-corrected QT interval ⬎500 ms; cthese patients reported dry month duringstudy drug infusion. However, these symptoms were judged to be possibly unrelated to the study drug; between the two groups in the present dcalculated using Kaplan-Meier survival analysis, with differences between groups assessed by the log-rank test.
Crit Care Med 2012 Vol. 40, No. 3

after hip fracture. Clin Orthop Relat Res hospitalized adults–a systematic evidence re- 2004; 422:195–200 view. J Gen Intern Med 2009; 24:848 – 853 Our study demonstrated that for el- 11. Franco K, Litaker D, Locala J, et al: The cost 26. Kaneko T, Cai J, Ishikura T, et al: Prophylac- derly patients admitted to ICU after non- of delirium in the surgical patient. Psycho- tic consecutive administration of haloperidol cardiac surgery, short-term prophylactic somatics 2001; 42:68 –73 can reduce the occurrence of postoperative administration of low-dose intravenous 12. Rothenha¨usler HB, Grieser B, Nollert G, et delirium in gastrointestinal surgery. Yonago haloperidol significantly decreased the al: Psychiatric and psychosocial outcome of Acta Med 1999; 42:179 –184 incidence of delirium during the first 7 cardiac surgery with cardiopulmonary by- 27. Schrader SL, Wellik KE, Demaerschalk BM, postoperative days. It also significantly pass: A prospective 12-month follow-up et al: Adjunctive haloperidol prophylaxis re- study. Gen Hosp Psychiatry 2005; 27:18 –28 duces postoperative delirium severity and delayed the onset of postoperative delir- 13. Loponen P, Luther M, Wistbacka JO, et al: duration in at-risk elderly patients. Neurolo- ium. The clinical implications of a slight Postoperative delirium and health related gist 2008; 14:134 –137 increase in delirium-free days and a slight quality of life after coronary artery bypass 28. Cheng YF, Paalzow LK, Bondesson U, et al: decrease in ICU length of stay warrant grafting. Scand Cardiovasc J 2008; 42: Pharmacokinetics of haloperidol in psychotic patients. Psychopharmacology (Berl) 1987; 14. Etzioni DA, Liu JH, Maggard MA, et al: The aging population and its impact on the sur- 29. Chang WH, Lam YW, Jann MW, et al: Phar- gery workforce. Ann Surg 2003; 238: macokinetics of haloperidol and reduced hal- We gratefully acknowledge Dr. Xin-Yu operidol in Chinese schizophrenic patients Sun (Professor, Department of Psychiat- 15. Kalisvaart KJ, de Jonghe JF, Bogaards MJ, et after intravenous and oral administration of rics, Peking University Sixth Hospital, al: Haloperidol prophylaxis for elderly hip- haloperidol. Psychopharmacology (Berl) Beijing, China) for her help in psychiatric surgery patients at risk for delirium: A ran- 1992; 106:517–522 domized placebo-controlled study. J Am 30. Mu DL, Wang DX, Li LH, et al: High serum consultation, and Dr. Daqing Ma (Associ- Geriatr Soc 2005; 53:1658 –1666 cortisol level is associated with increased risk ate Professor, Department of Anaesthet- 16. Prakanrattana U, Prapaitrakool S: Efficacy of of delirium after coronary artery bypass graft ics, Pain Medicine, and Intensive Care, risperidone for prevention of postoperative surgery: A prospective cohort study. Crit Imperial College London, London, UK) delirium in cardiac surgery. Anaesth Inten- Care 2010; 14:R238 for his critical comments during the sive Care 2007; 35:714 –719 31. Sessler CN, Gosnell MS, Grap MJ, et al: The manuscript preparation stage.
17. Gamberini M, Bolliger D, Lurati Buse GA, et Richmond Agitation-Sedation Scale: validity al: Rivastigmine for the prevention of post- and reliability in adult intensive care unit operative delirium in elderly patients under- patients. Am J Respir Crit Care Med 2002; going elective cardiac surgery—A random- 1. American Psychiatric Association: Diagnostic ized controlled trial. Crit Care Med 2009; 32. Ely EW, Truman B, Shintani A, et al: Moni- and Statistical Manual of Mental Disorders.
toring sedation status over time in ICU pa- Fourth Edition. Text Revision (DSM-IV-TR).
18. Liptzin B, Laki A, Garb JL, et al: Donepezil in tients: Reliability and validity of the Rich- Washington, DC, American Psychiatric Asso- the prevention and treatment of post- mond Agitation-Sedation Scale (RASS).
surgical delirium. Am J Geriatr Psychiatry JAMA 2003; 289:2983–2991 2. Silverstein JH, Timberger M, Reich DL, et al: 2005; 13:1100 –1106 33. Inouye SK, Bogardus ST Jr, Charpentier PA, Central nervous system dysfunction after 19. Sampson EL, Raven PR, Ndhlovu PN, et al: A et al: A multicomponent intervention to pre- noncardiac surgery and anesthesia in the el- randomized, double-blind, placebo-con- vent delirium in hospitalized older patients.
derly. Anesthesiology 2007; 106:622– 628 trolled trial of donepezil hydrochloride (Ari- N Engl J Med 1999; 340:669 – 676 3. Demeure MJ, Fain MJ: The elderly surgical cept) for reducing the incidence of postoper- 34. Inouye SK: Delirium in older persons.
patient and postoperative delirium. J Am Coll ative delirium after elective total hip N Engl J Med 2006; 354:1157–1165 Surg 2006; 203:752–757 replacement. Int J Geriatr Psychiatry 2007; 35. Cole MG: Delirium in elderly patients. Am J 4. Robinson TN, Eiseman B: Postoperative de- Geriatr Psychiatry 2004; 12:7–21 lirium in the elderly: Diagnosis and manage- 20. Aizawa K, Kanai T, Saikawa Y, et al: A novel 36. Ely EW, Margolin R, Francis J, et al: Evalu- ment. Clin Interv Aging 2008; 3:351–355 approach to the prevention of postoperative ation of delirium in critically ill patients: 5. Pisani MA, McNicoll L, Inouye SK: Cognitive delirium in the elderly after gastrointestinal Validation of the Confusion Assessment impairment in the intensive care unit. Clin surgery. Surg Today 2002; 32:310 –314 Method for the Intensive Care Unit (CAM- Chest Med 2003; 24:727–737 21. Leung JM, Sands LP, Rico M, et al: Pilot ICU). Crit Care Med 2001; 29:1370 –1379 6. Dyer CB, Ashton CM, Teasdale TA: Postoper- clinical trial of gabapentin to decrease post- 37. Ely EW, Inouye SK, Bernard GR, et al: De- ative delirium. A review of 80 primary data- operative delirium in older patients. Neurol- lirium in mechanically ventilated patients: collection studies. Arch Intern Med 1995; ogy 2006; 67:1251–1253 Validity and reliability of the confusion as- 22. Larsen KA, Kelly SE, Stern TA, et al: Admin- sessment method for the intensive care unit 7. Zakriya K, Sieber FE, Christmas C, et al: istration of olanzapine to prevent postopera- (CAM-ICU). JAMA 2001; 286:2703–2710 Brief postoperative delirium in hip fracture tive delirium in elderly joint-replacement pa- 38. European Agency for the Evaluation of Me- patients affects functional outcome at three tients: A randomized, controlled trial.
dicinal Products HMEU, Committee for Pro- months. Anesth Analg 2004; 98:1798 –1802 Psychosomatics 2010; 51:409 – 418 prietary Medicinal Products (CPMP): Points 8. Shi CM, Wang DX, Chen KS, et al: Incidence 23. Tabet N, Howard R: Pharmacological treat- to consider: The assessment of the potential and risk factors of delirium in critically ill ment for the prevention of delirium: Review for QT interval prolongation by non-cardio- patients after non-cardiac surgery. Chin Med of current evidence. Int J Geriatr Psychiatry vascular medicinal products. London, UK, J 2010; 123:993–999 2009; 24:1037–1044 9. Robinson TN, Raeburn CD, Tran ZV, et al: 24. Flinn DR, Diehl KM, Seyfried LS, et al: Pre- 39. Moss AJ: Drugs that prolong the QT interval: Postoperative delirium in the elderly: Risk vention, diagnosis, and management of post- Regulatory and QT measurement issues from factors and outcomes. Ann Surg 2009; 249: operative delirium in older adults. J Am Coll the United States and European perspectives.
Surg 2009; 209:261–268; quiz 294 Ann Noninvasive Electrocardiol 1999; 10. Edelstein DM, Aharonoff GB, Karp A, et al: 25. Campbell N, Boustani MA, Ayub A, et al: Effect of postoperative delirium on outcome Pharmacological management of delirium in 40. Roden DM: Drug-induced prolongation of Crit Care Med 2012 Vol. 40, No. 3 the QT interval. N Engl J Med 2004; 350: ical practice guidelines for the sustained use delirium screening scale. J Pain Symptom of sedatives and analgesics in the critically ill Manage 2005; 29:368 –375 41. Gunther ML, Morandi A, Ely EW: Pathophys- adult. Crit Care Med 2002; 30:119 –141 54. Luetz A, Heymann A, Radtke FM, et al: Dif- iology of delirium in the intensive care unit.
48. Hassan E, Fontaine DK, Nearman HS: Ther- ferent assessment tools for intensive care Crit Care Clin 2008; 24:45– 65, viii apeutic considerations in the management of unit delirium: Which score to use? Crit Care 42. Hshieh TT, Fong TG, Marcantonio ER, et al: agitated or delirious critically ill patients.
Med 2010; 38:409 – 418 Cholinergic deficiency hypothesis in delir- Pharmacotherapy 1998; 18:113–129 55. Zhang T, Hu MH, Gu XE: Caring for the ium: A synthesis of current evidence.
49. Douglas PH, Block PC: Corrected QT interval elderly patients with delirium in the SICU.
J Gerontol A Biol Sci Med Sci 2008; 63: prolongation associated with intravenous Zhong Hua Xian Dai Hu Li Za Zhi 2009; haloperidol in acute coronary syndromes.
43. Trzepacz P, van der Mast R: The neuropatho- Catheter Cardiovasc Interv 2000; 50: 56. Rudolph JL, Jones RN, Levkoff SE, et al: physiology of delirium. In: Lindesay J, Rock- Derivation and validation of a preoperative wood K, Macdonald A (Eds). Delirium in old 50. Riker RR, Fraser GL, Cox PM: Continuous prediction rule for delirium after cardiac sur- age. Oxford, England, Oxford University infusion of haloperidol controls agitation in gery. Circulation 2009; 119:229 –236 Press, 2002, pp 51–90 critically ill patients. Crit Care Med 1994; 57. Kazmierski J, Kowman M, Banach M, et al: 44. MacKenzie RG, Stachowiak MK, Zigmond Incidence and predictors of delirium after MJ: Dopaminergic inhibition of striatal ace- 51. Seneff MG, Mathews RA: Use of haloperidol cardiac surgery: Results from The IPDACS tylcholine release after 6-hydroxydopamine.
infusions to control delirium in critically ill Study. J Psychosom Res 2010; 69:179 – Eur J Pharmacol 1989; 168:43–52 adults. Ann Pharmacother 1995; 29: 45. Ikarashi Y, Takahashi A, Ishimaru H, et al: 58. Schneider F, Bo¨hner H, Habel U, et al: Risk Regulation of dopamine D1 and D2 receptors 52. Milbrandt EB, Kersten A, Kong L, et al: Hal- factors for postoperative delirium in vascular on striatal acetylcholine release in rats.
operidol use is associated with lower hospital surgery. Gen Hosp Psychiatry 2002; 24: Brain Res Bull 1997; 43:107–115 mortality in mechanically ventilated pa- 46. Seeman P: Atypical antipsychotics: mecha- tients. Crit Care Med 2005; 33:226 –229 59. Redelmeier DA, Thiruchelvam D, Daneman nism of action. Can J Psychiatry 2002; 47: 53. Gaudreau JD, Gagnon P, Harel F, et al: Fast, N: Delirium after elective surgery among el- systematic, and continuous delirium assess- derly patients taking statins. CMAJ 2008; 47. Jacobi J, Fraser GL, Coursin DB, et al: Clin- ment in hospitalized patients: The nursing Crit Care Med 2012 Vol. 40, No. 3

Source: http://www.diamondl.ca/wrha/cme/file.php?id=000280