Prophylactic Consecutive Administration of Haloperidol Can Reduce
the Occurrence of Postoperative Delirium in Gastrointestinal Surgery

Tetsuya Kaneko, Jianhui Cai, Takanori Ishikura, Makoto Kobayashi, Takuji
Naka and Nobuaki Kaibara

First Department of Surgery, Faculty of Medicine, Tottori University, Yonago 683-0826, Japan Postoperative delirium has in recent years been a common complication which can
interfere with the recovery of patients after surgery. Unfortunately there is still no
medical procedure available which can completely prevent the occurrence of
postoperative delirium. Haloperidol is a psychopharmacological agent that has been
used to treat the delirium and agitation, especially in geriatric patients. To assess the
effectiveness and safety of the use of haloperidiol for the reduction of postoperative
delirium, we performed a randomized, comparative clinical study in which 78 patients
who underwent gastrointestinal surgery received either 5 mg of haloperidol
intravenously postoperatively at 21:00 for 5 consecutive days, or normal saline with the
same schedule. Postsurgical evaluation revealed the incidence of postoperative delirium
to be only 10.5% (4 of 38 patients) in the group receiving haloperidol treatment,
compared to 32.5% (13 of 40 patients) in the saline treatment group. No significant
neuroleptic side effects were seen in any of the patients. These results suggest that daily
postoperative administration of haloperidol can reduce the occurrence of postoperative
delirium safely.

Key words: haloperidol; postoperative delirium
Delirium, defined as an acute disorder of surgery and anesthetic drugs and postoperative cognition, wakefulness and attention, has been factors (e.g., hypoxia, hypocarbia and sepsis).
recognized as a relatively common postopera- Although preventative measures against post- tive complication in the elderly for some time, operative delirium have been applied at pre- yet, to date, surprisingly little is known about operative, intraoperative and postoperative effective procedures to reduce its occurrence.
levels, there is still little definitive information Postoperative delirium can result in increased available on successful prevention of post- morbidity, delayed functional recovery and operative delirium. The first consideration in prolonged hospital stay (Adams et al., 1986).
the management of delirium is to find and treat Therefore, early diagnosis, assessment, prompt any underlying organic cause of the presented treatment and prevention of postoperative de- state of confusion. When confusion is evident, lirium are important objectives for improved prompt treatment is mandatory. The first ther- management of elderly surgical patients.
apy of choice for such cases is an antipsychotic drug such as haloperidol, which does not pro- explain the pathogenesis of postoperative de- duce hypotension, aggravate diabetes, hepatic lirium (Adams et al., 1986). The responsible disease or renal disease nor does cause over- causative factors proposed are preoperative sedation. The successful use of haloperidol in factors (e.g., aging, pathologic status in the such cases makes it an interesting therapeutic brain, polypharmacy and drug interactions, candidate for testing in the prevention of post- metabolic problems, depression, dementia and operative delirium in surgical patients. So far, anxiety), intraoperative factors such as type of there has been no effective prevention of post- Abbreviation: DSM, Diagnostic and Statistical Manual of Mental Disorders Table 1. Demographic data of patients
operative delirium with therapy which places and subjected to routine laboratory testing. Be- emphasis on medication. We proposed, there- fore entering the study, oral consent was requir- fore, that prophylactic administration of halo- ed from each patient. The consenting patients peridol may have a potential application as a were then randomized into 2 comparative study preventative medication for postoperative delir- treatment groups. The randomization was con- ducted by way of a closed envelope system. Post- The aim of the current study was to evaluate operatively, one group received daily adminis- the effect and safety of daily postoperative ad- tration of haloperidol intravenously, while the ministration of haloperidol as a preventative other group was given normal saline. After the measure against the development of postopera- 5th day of the postoperative study treatment, the tive delirium, with special attention being paid 2 treatment groups were compared for the inci- to the sleep-wakefulness rhythm, in patients dence of development of postoperative delir- undergoing gastrointestinal surgery.
Study drug
Subjects and Methods
Haloperidol (Serenase, Dainippon Pharmaceu-tical, Osaka, Japan) at a dose of 5 mg in 1.0 mL Study design and subjects
was administered intravenously daily at 21:00 Ethical comittee approval was obtained before from the 1st through the postoperative day.
commencement of this study. Eighty patients This dose of haroperidol was considered ade- who were scheduled for elective gastrointes- quate for providing comparable sedation for the tinal surgery and admitted to the High and In- patients. An equal volume of normal saline for tensive Care Unit at Tottori University Hospital injection (0.9% NaCl,Otsuka Pharmaceutical, 1 or 2 weeks before the scheduled surgery, Tokushima, Japan) was administered by the between April 1995 and August 1998, compris- same route and schedule as the comparative ed the study population. After admission, the group of patients not receiving haloperidol.
patients were interviewed, clinically examined Table 2. The incidence of postoperative de-
Study measurements and evaluation
lirium in patients with haloperidol treatment
and saline treatment

On the 5th day after surgery, postoperative datawere collected from the patients and their nurs- ing charts regarding i) cognition, with particularattention to signs and symptoms of delirium, ii) use of pain medication and iii) sleep pattern, with special attention being paid to the sleep- wakefulness rhythm. Psychotic diagnoses were *P < 0.05 compared to the saline treament patients.
based on the Diagnostic and Statistical Manualof Mental Disorders (DSM) criteria, DSM-III-R(American Psychiatric Association, 1987).
eases, preoperative medications, duration of op-eration and anesthesia, conditions during anes-thesia as event of hypotension and hypoxemia, Statistical methods
and intraoperative blood loss). The demo- The chi-square test and unpaired student t-test graphic data of the 78 evaluable patients are were used for the statistical analyses of the listed in Table 1, and there were no statistically results, which are presented as mean ± SD. A P significant demographic differences between value of less than 0.05 was regarded as statis- Postoperative delirium developed in 17 of 78 patients (21.8%). Postoperative deliriumbegan 2 to 4 days after surgery. Four of the 38 patients (10.5%) were clinically diagnosed ashaving postoperative delirium in the study During the study, 80 patients scheduled for group. On the other hand, there were only 13 gastrointestinal surgery were selected for ran- out of 40 (32.5%) in the control group (Table dom placing into the 2 treatment groups, 40 into 2). Intensity and duration of postoperative the haloperidol treatment group and 40 into the delirial symptoms in the control group were saline control group. Two patients who had severe and longer respectively than those in the entered the Intensive Care Unit had to be ex- study group. Several other factors (e.g., drugs cluded before randomization into the study.
and method for postoperative pain control, The 2 groups were comparable with respect to hypoxia and infection) were examined and not baseline criteria (e.g., age, sex, preexisting dis- found to be associated with the occurrence of Fig. 1. Comparison of postoperative sleeping times for saline treatment patients and haloperidol treatment
patients during the day and night during the first 5 postoperative days. Values are expressed as mean ± SD.
Fig. 2. Comparison of postoperative sleeping times for delirious and non-delirious patients during the day
and night during the first 5 postoperative days. Values are expressed as mean ± SD. There are statistically
significant differences in day and night sleeping times between the delirious and non-delirious group (P <
postoperative delirium. The patients who dev-eloped postoperative delirium in the control Discussion
group were administered haloperidol immedi-ately until the delirial symptoms disappeared.
Postoperative delirium and other organic men- Furthermore, the patients who developed post- tal syndromes have been frequent and problem- operative delirium in the haloperidol group also atic complications, often requiring aggressive were administered more haloperidol and flunitra- medical management. Notably cardiotomy and zepam to control sleep-wakefulness rhythm.
organ transplantation have appeared to involve Extrapyramidal side effects have not develop- several additive risk factors for the occurrence ed during the use of this protocol; however, one of postoperative mental disorders. Postopera- tive delirium has also been a common problem developed transient tachycardia, but this did not in the field of gastrointestinal surgery. Un- substantially interfere with clinical manage- familiar surroundings and a sense of alienation ment. No other complications or side effects of appear to be factors which make patients more haloperidol use occurred with this protocol.
likely to develop postoperative delirium. We Between the 2 groups, there was no consider- recently reported that sleep deficiency is likely able variability in the duration of sleep time in to predispose elderly patients to postoperative the day or night. As a result, the difference in delirium and so techniques designed to prevent the average and total time of sleep between the sleep deprivation may be of considerable value 2 groups was not statistically significant (Fig.
in reducing the incidence of postoperative de- 1). The ratio of sleep time during the day and night was lower during the use of haloperidol.
Haloperidol, a high-potency antipsychotic In contrast, special attention was paid to the pa- agent, is considered to be the drug of choice for tients who had developed postoperative deliri- rapid control of delirium in the critically ill pa- um, and there was close correlation between the tient. Unlike other neuroleptic agents, haloperi- development of postoperative delirium and de- privation of sleep rhythm, that is, a short sleep dynamic and respiratory function and does not period during the night and a long sleep period aggravate other functions (Fish, 1991). For this reason and because the number of elderly pa- tients in the operative population who are at risk livered by the intravenous route. The reason for in developing postoperative delirium has been this route of administration-related difference increasing, we felt that haloperidol would be a suitable candidate medication to test for preven- The use of haloperidol in physically com- promised patients with delirium is not entirely guidelines for haloperidol use in the treatment neuroleptic agent, haloperidol has increased of acute delirium. The initial intravenous dose potential to cause extrapyramidal side effect of haloperidol prescribed for acute delirium symptoms. These effects are not dose-related varies with the degree of delirium from only and are sudden in onset. Extrapyramidal symp- 0.5–2 mg for mild agitation, to 2–5 mg for mod- toms are seldom observed with the use of halo- erate agitation, to 10–20 mg for severe agitation peridol administered by the intravenous route.
(Fish, 1991). On the other hand, Levenson (1995) Craven (1990) first reported on the prophy- reported a case of delirium following lung lactic intravenous administration of a small transplantation that required 2,842 mg of dose of haloperidol 4 times daily, and demon- haloperidol intravenously over 4 days. Though strated its effectiveness and safety in the the maximally tolerated total daily dosage of management of postoperative delirium in lung haloperidol has not been fully established, it has transplant recipients. Although further system- been reported to range from 100 mg to over 530 atic investigation is required to determine the mg (Korp et al., 1985; Levenson, 1995; Kaneko full potential of clinical effectiveness for halo- et al., 1997) and to be as high as 975 mg peridol administration in the prevention of pos- (Levenson, 1995). One case has been reported toperative delirium, we have not found any in- in which the intravenous administration of 7.5 creased frequency of postoperative delirium.
mg of haloperidol appeared to cause cardiac These preliminary findings suggest that this arrest (Menza et al., 1987). Thus, for the cur- study protocol of daily postoperative intra- rent study, it was important to design a protocol venous haloperidol administration may be both of haloperidol dose and schedule that not only an effective and a safe means of preventing the was potentially therapeutically effective, but occurrence of postoperative delirium in patients also safe for use in our patient population. Our undergoing gastrointestinal surgery, partic- consideration on the safety of our haloperidol ularly in elderly patients who are at a higher risk administration protocol depended on several of development of postoperative delirium.
factors, which included its limitations of use in This prospective study is the first systematic an intensive care setting, frequent reassessment evaluation of the use of prophylactic adminis- of the patients mental state and careful monitor- tration of intravenous haloperidol to reduce the occurrence of postoperative delirium. The mechanism by which haloperidol reduces the both oral and intramuscular administration, occurrence of postoperative delirium is not rapid control of acute delirium with extreme clear. Some studies suggest that actions other agitation is best accomplished with intravenous than the blockade of central dopamine receptors delivery. Moulaert (1989) recommended intra- may be responsible for haloperidol’s calming venous administration of haloperidol because effect in patients with delirium (Korp et al., the absorption may be erratic when the drug is 1985; Tesar and Stern, 1988). It is also not given by the intramuscular route. Moreover, clearly understood why prophylactic adminis- the pain of intramuscular injection may be add- tration of haloperidol reduced the incidence of ed to the patient’s confusion. Menza and col- postoperative deliriums after gastrointestinal leagues (1987) also recommended intravenous surgery; we intend to perform further investi- administration of haloperidol in the immuno- gation of the optimization of dosage and timing suppressed patient due to the lower frequency of extrapyramidal side effects when it was de- in guinea pig and rat liver microsomes. Biochem References
8 L e v e n s o n J L . H i g h - d o s e i n t r a v e n o u s 1 Adams F, Fernandez F, Anderson B. Emergency haloperidol for agitated delirium following lung pharmacotherapy of delirium in the critically ill transplantation. Psychosomatics 1995;36:66–68.
cancer patient. Psychosomatics 1986;27 (Suppl): 9 Menza MA, Murray GB, Holmes VF, and Rafuls WA. Decreased extrapyramidal symptoms with 2 American Psychiatric Association. Diagnostic the use of intravenous haloperidol. J Clin Psy- and statistical manual of mental disorders. 3rd rev. ed. Washington, DC: American Psychiatric 10 Moulaert P. Treatment of acute nonspecific delirium with i.v. haloperidol in surgical inten- 3 Craven JL. Postoperative organic mental syn- sive care patients. Acta Anaesthesiol Belg 1989; dromes in lung transplant recipients. Tront Lung Transplantation Group. J Heart Transplant 11 Parikh SS, Chung F. Postopertave delirium in the elderly. Anesth Analg 1995;1223–1232.
4 Fish DN. Treatment of delirium in the critically 12 Stern TA. The management of depression and ill patient. Clin Pharm 1991;10:456–466.
anxiety following myocardial infarction. Mt 5 Huyse F, strack van Schijndel R. Haloperidol and cardiac arrest. Lancet 1988;2:568–569.
13 Tesar GE, Murray GB, Cassem NH. Use of 6 Kaneko T, Takahashi S, Naka T, Hirooka Y, Inoue Y, Kaibara N. Postoperative delirium fol- treatment of agitated cardiac patients. J Clin lowing gastrointestinal surgery in elderly pa- tients. Surg Today 1997;27:107–111.
14 Tesar GE, Stern TA. Rapid tranquilization of the 7 Korp ER, Costakos DT,Wyatt RJ. Intercon- agitated intensive care unit patient. J Intensive versions of haloperidol and reduced haloperidol (Received June 28, Accepted August 11, 1999)

Source: http://lib.med.tottori-u.ac.jp/yam/bef_41/yam42-3/42_179-184.pdf

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