Yonago Acta medica 1999;42:179–184

Prophylactic Consecutive Administration of Haloperidol Can Reduce
the Occurrence of Postoperative Delirium in Gastrointestinal Surgery
Tetsuya Kaneko, Jianhui Cai, Takanori Ishikura, Makoto Kobayashi, TakujiNaka 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 caninterfere 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 beenused to treat the delirium and agitation, especially in geriatric patients. To assess theeffectiveness and safety of the use of haloperidiol for the reduction of postoperativedelirium, 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 thesame 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 postoperativedelirium safely.
Key words: haloperidol; postoperative delirium

Delirium, defined as an acute disorder ofcognition, wakefulness and attention, has beenrecognized as a relatively common postoperative complication in the elderly for some time,
yet, to date, surprisingly little is known about
effective procedures to reduce its occurrence.
Postoperative delirium can result in increased
morbidity, delayed functional recovery andprolonged hospital stay (Adams et al., 1986).
Therefore, early diagnosis, assessment, prompt
treatment and prevention of postoperative delirium are important objectives for improved
management of elderly surgical patients.
Various hypotheses have been proposed to
explain the pathogenesis of postoperative delirium (Adams et al., 1986). The responsible
causative factors proposed are preoperative
factors (e.g., aging, pathologic status in thebrain, polypharmacy and drug interactions,metabolic problems, depression, dementia andanxiety), intraoperative factors such as type of

surgery and anesthetic drugs and postoperative
factors (e.g., hypoxia, hypocarbia and sepsis).
Although preventative measures against postoperative delirium have been applied at preoperative, intraoperative and postoperative
levels, there is still little definitive information
available on successful prevention of postoperative delirium. The first consideration in
the management of delirium is to find and treat
any underlying organic cause of the presented
state of confusion. When confusion is evident,
prompt treatment is mandatory. The first therapy of choice for such cases is an antipsychotic
drug such as haloperidol, which does not produce hypotension, aggravate diabetes, hepaticdisease or renal disease nor does cause oversedation. The successful use of haloperidol insuch cases makes it an interesting therapeuticcandidate for testing in the prevention of postoperative delirium in surgical patients. So far,there has been no effective prevention of post-

Abbreviation: DSM, Diagnostic and Statistical Manual of Mental Disorders

179

T. Kaneko et al.

Table 1. Demographic data of patients

Number of patients randomized
Postrandomization exclusion
Number of evaluable patients
Male/female ratio
Age* (year)
Ishemic heart disease
Hypertension
Respiratory disease
Diabetes mellitus
Liver disease
Premorbid cognitive impairment
Operation method
Partial gastrectomy
Total gastrectomy
Colectomy*Mean ± SD.
( ), percentage.

Haloperidol group

Saline group

40
2
38
24/14
72.4 ± 8.2
5(13.2)
13(34.2)
6(15.8)
9(23.7)
3( 7.9)
2( 5.3)

40
0
40
26/14
73.1 ± 9.3
8(20.0)
12(30.0)
4(10.0)
12(25.0)
6(15.0)
4(10.0)

20
8
10

23
6
11

(52.6)(21.1)(26.3)

operative delirium with therapy which placesemphasis on medication. We proposed, therefore, that prophylactic administration of haloperidol may have a potential application as apreventative medication for postoperative delirium in surgical patients.
The aim of the current study was to evaluate
the effect and safety of daily postoperative administration of haloperidol as a preventative
measure against the development of postoperative delirium, with special attention being paid
to the sleep-wakefulness rhythm, in patients
undergoing gastrointestinal surgery.

(57.5)(15.0)(27.5)and subjected to routine laboratory testing. Before entering the study, oral consent was required from each patient. The consenting patientswere then randomized into 2 comparative study
treatment groups. The randomization was conducted by way of a closed envelope system. Postoperatively, one group received daily administration of haloperidol intravenously, while theother group was given normal saline. After the
5th day of the postoperative study treatment, the2 treatment groups were compared for the incidence of development of postoperative delirium.

Study drug

Subjects and Methods

Study design and subjects
Ethical comittee approval was obtained before
commencement of this study. Eighty patients
who were scheduled for elective gastrointestinal surgery and admitted to the High and Intensive Care Unit at Tottori University Hospital
1 or 2 weeks before the scheduled surgery,between April 1995 and August 1998, comprised the study population. After admission, thepatients were interviewed, clinically examined

Haloperidol (Serenase, Dainippon Pharmaceutical, Osaka, Japan) at a dose of 5 mg in 1.0 mL
was administered intravenously daily at 21:00
from the 1st through the postoperative day.
This dose of haroperidol was considered adequate for providing comparable sedation for thepatients. An equal volume of normal saline forinjection (0.9% NaCl,Otsuka Pharmaceutical,
Tokushima, Japan) was administered by thesame route and schedule as the comparative
group of patients not receiving haloperidol.

180

Haloperidol for postoperative delirium

Study measurements and evaluation
On the 5th day after surgery, postoperative data
were collected from the patients and their nursing 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 sleepwakefulness rhythm. Psychotic diagnoses werebased on the Diagnostic and Statistical Manualof Mental Disorders (DSM) criteria, DSM-III-R(American Psychiatric Association, 1987).

Statistical methods
The chi-square test and unpaired student t-test
were used for the statistical analyses of theresults, which are presented as mean ± SD. A P
value of less than 0.05 was regarded as statistically significant.

Results
During the study, 80 patients scheduled forgastrointestinal surgery were selected for random placing into the 2 treatment groups, 40 into
the haloperidol treatment group and 40 into thesaline control group. Two patients who hadentered the Intensive Care Unit had to be excluded before randomization into the study.
The 2 groups were comparable with respect tobaseline criteria (e.g., age, sex, preexisting dis-

Table 2. The incidence of postoperative delirium in patients with haloperidol treatment
and saline treatment
Delirious

Non-delirious

Haloperidol
4*34
Saline
13
27
Total
17
61
*P < 0.05 compared to the saline treament patients.

eases, preoperative medications, duration of operation and anesthesia, conditions during anesthesia as event of hypotension and hypoxemia,
and intraoperative blood loss). The demographic data of the 78 evaluable patients arelisted in Table 1, and there were no statisticallysignificant demographic differences between
the 2 groups.
Postoperative delirium developed in 17 of
78 patients (21.8%). Postoperative delirium
began 2 to 4 days after surgery. Four of the 38
patients (10.5%) were clinically diagnosed ashaving postoperative delirium in the study
group. On the other hand, there were only 13
out of 40 (32.5%) in the control group (Table2). Intensity and duration of postoperativedelirial symptoms in the control group weresevere and longer respectively than those in the
study group. Several other factors (e.g., drugs
and method for postoperative pain control,
hypoxia and infection) were examined and not
found to be associated with the occurrence of(min)Day sleep time

500

Night sleep time

Time

400
300
200
100
0

SalineHaloperidol

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.

181

T. Kaneko et al.

(min)

*

*

Day sleep time

500

Time

Night sleep time
400
300
200
100
0

Delirious
patients

Non-delirious
patients

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 statisticallysignificant differences in day and night sleeping times between the delirious and non-delirious group (P <0.05).

postoperative delirium. The patients who developed postoperative delirium in the control
group were administered haloperidol immediately until the delirial symptoms disappeared.
Furthermore, the patients who developed postoperative delirium in the haloperidol group also
were administered more haloperidol and flunitrazepam to control sleep-wakefulness rhythm.
Extrapyramidal side effects have not developed during the use of this protocol; however, onepatient who was administered haloperidol
developed transient tachycardia, but this did not
substantially interfere with clinical management. No other complications or side effects ofhaloperidol use occurred with this protocol.
Between the 2 groups, there was no considerable variability in the duration of sleep time inthe day or night. As a result, the difference inthe average and total time of sleep between the
2 groups was not statistically significant (Fig.
1). The ratio of sleep time during the day andnight was lower during the use of haloperidol.
In contrast, special attention was paid to the patients who had developed postoperative delirium, and there was close correlation between thedevelopment of postoperative delirium and deprivation of sleep rhythm, that is, a short sleep
period during the night and a long sleep period
during the day (Fig. 2).

Discussion
Postoperative delirium and other organic mental syndromes have been frequent and problematic complications, often requiring aggressive
medical management. Notably cardiotomy andorgan transplantation have appeared to involve
several additive risk factors for the occurrenceof postoperative mental disorders. Postoperative delirium has also been a common problem
in the field of gastrointestinal surgery. Unfamiliar surroundings and a sense of alienation
appear to be factors which make patients more
likely to develop postoperative delirium. We
recently reported that sleep deficiency is likely
to predispose elderly patients to postoperativedelirium and so techniques designed to prevent
sleep deprivation may be of considerable value
in reducing the incidence of postoperative delirium (Kaneko et al., 1997).
Haloperidol, a high-potency antipsychotic
agent, is considered to be the drug of choice for
rapid control of delirium in the critically ill patient. Unlike other neuroleptic agents, haloperidol has minimal adverse effects on hemodynamic and respiratory function and does notaggravate other functions (Fish, 1991). For thisreason and because the number of elderly pa-

182

Haloperidol for postoperative delirium

tients in the operative population who are at risk
in developing postoperative delirium has been
increasing, we felt that haloperidol would be asuitable candidate medication to test for prevention of postoperative delirium.
Several authors have proposed dosage
guidelines for haloperidol use in the treatmentof acute delirium. The initial intravenous doseof haloperidol prescribed for acute delirium
varies with the degree of delirium from only
0.5–2 mg for mild agitation, to 2–5 mg for moderate agitation, to 10–20 mg for severe agitation(Fish, 1991). On the other hand, Levenson (1995)
reported a case of delirium following lungtransplantation that required 2,842 mg of
haloperidol intravenously over 4 days. Though
the maximally tolerated total daily dosage of
haloperidol has not been fully established, it has
been reported to range from 100 mg to over 530
mg (Korp et al., 1985; Levenson, 1995; Kaneko
et al., 1997) and to be as high as 975 mg(Levenson, 1995). One case has been reported
in which the intravenous administration of 7.5
mg of haloperidol appeared to cause cardiac
arrest (Menza et al., 1987). Thus, for the current study, it was important to design a protocolof haloperidol dose and schedule that not only
was potentially therapeutically effective, butalso safe for use in our patient population. Ourconsideration on the safety of our haloperidol
administration protocol depended on several
factors, which included its limitations of use in
an intensive care setting, frequent reassessmentof the patients mental state and careful monitoring for side effects.
As haloperidol is rapidly absorbed after
both oral and intramuscular administration,
rapid control of acute delirium with extreme
agitation is best accomplished with intravenous
delivery. Moulaert (1989) recommended intravenous administration of haloperidol because
the absorption may be erratic when the drug is
given by the intramuscular route. Moreover,the pain of intramuscular injection may be added to the patient’s confusion. Menza and colleagues (1987) also recommended intravenous
administration of haloperidol in the immunosuppressed patient due to the lower frequencyof extrapyramidal side effects when it was de-livered by the intravenous route. The reason forthis route of administration-related difference
in toxicity is not clear.
The use of haloperidol in physically compromised patients with delirium is not entirely
without complications. As a high-potency
neuroleptic agent, haloperidol has increased
potential to cause extrapyramidal side effectsymptoms. These effects are not dose-related
and are sudden in onset. Extrapyramidal symptoms are seldom observed with the use of haloperidol administered by the intravenous route.
Craven (1990) first reported on the prophylactic intravenous administration of a small
dose of haloperidol 4 times daily, and demonstrated its effectiveness and safety in the
management of postoperative delirium in lungtransplant recipients. Although further systematic investigation is required to determine thefull potential of clinical effectiveness for haloperidol administration in the prevention of postoperative delirium, we have not found any increased frequency of postoperative delirium.
These preliminary findings suggest that thisstudy protocol of daily postoperative intravenous haloperidol administration may be bothan effective and a safe means of preventing theoccurrence of postoperative delirium in patients
undergoing gastrointestinal surgery, particularly in elderly patients who are at a higher riskof development of postoperative delirium.
This prospective study is the first systematic
evaluation of the use of prophylactic administration of intravenous haloperidol to reduce theoccurrence of postoperative delirium. The
mechanism by which haloperidol reduces theoccurrence of postoperative delirium is notclear. Some studies suggest that actions otherthan the blockade of central dopamine receptors
may be responsible for haloperidol’s calming
effect in patients with delirium (Korp et al.,
1985; Tesar and Stern, 1988). It is also not
clearly understood why prophylactic administration of haloperidol reduced the incidence of
postoperative deliriums after gastrointestinal
surgery; we intend to perform further investigation of the optimization of dosage and timingof haloperidol administration.

183

T. Kaneko et al.

References
1 Adams F, Fernandez F, Anderson B. Emergency
pharmacotherapy of delirium in the critically illcancer patient. Psychosomatics 1986;27 (Suppl):
33–37.
2 American Psychiatric Association. Diagnostic
and statistical manual of mental disorders. 3rd
rev. ed. Washington, DC: American Psychiatric
Association; 1987. p. 100–104.
3 Craven JL. Postoperative organic mental syndromes in lung transplant recipients. Tront Lung
Transplantation Group. J Heart Transplant
1990;9:129–132.
4 Fish DN. Treatment of delirium in the criticallyill patient. Clin Pharm 1991;10:456–466.
5 Huyse F, strack van Schijndel R. Haloperidol
and cardiac arrest. Lancet 1988;2:568–569.
6 Kaneko T, Takahashi S, Naka T, Hirooka Y,
Inoue Y, Kaibara N. Postoperative delirium following gastrointestinal surgery in elderly patients. Surg Today 1997;27:107–111.
7 Korp ER, Costakos DT,Wyatt RJ. Interconversions of haloperidol and reduced haloperidol

in guinea pig and rat liver microsomes. Biochem
Pharmacol 1985;34:2923–2927.
8 Levenson JL. High-dose intravenous
haloperidol for agitated delirium following lungtransplantation. Psychosomatics 1995;36:66–68.
9 Menza MA, Murray GB, Holmes VF, and Rafuls
WA. Decreased extrapyramidal symptoms withthe use of intravenous haloperidol. J Clin Psychiatr 1987;48:278–280.
10 Moulaert P. Treatment of acute nonspecificdelirium with i.v. haloperidol in surgical intensive care patients. Acta Anaesthesiol Belg 1989;
40:183–186.
11 Parikh SS, Chung F. Postopertave delirium inthe elderly. Anesth Analg 1995;1223–1232.
12 Stern TA. The management of depression andanxiety following myocardial infarction. Mt
Sinai J Med 1985;52:623–633.
13 Tesar GE, Murray GB, Cassem NH. Use ofhigh-dose intravenous haloperidol in thetreatment of agitated cardiac patients. J Clin
Psychopharmacol 1985;5:344–347.
14 Tesar GE, Stern TA. Rapid tranquilization of theagitated intensive care unit patient. J Intensive
Care Med 1988;3:195–201.

(Received June 28, Accepted August 11, 1999)

184