Anesth Analg 2004;98:111-115
© 2004 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Chronic Treatment with Antipsychotics Enhances Intraoperative Core Hypothermia
Akira Kudoh, MD,
Hajime Takase, MD, and
Tomoko Takazawa, MD
Department of Anesthesiology, Hirosaki National Hospital, Hirosaki, Japan
Address correspondence and reprint requests to Akira Kudoh, MD, Department of Anesthesiology, Hirosaki National Hospital, 1 Tominocho, Hirosaki 036-8545, Aomori, Japan.
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Abstract
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Antipsychotics can induce hypothermia, but intraoperative temperature regulation in schizophrenic patients taking antipsychotics remains unclear. We investigated intraoperative temperature regulation and postoperative shivering in chronic schizophrenic patients receiving antipsychotics. We studied 30 schizophrenic patients and 30 control patients who underwent orthopedic surgery. Tympanic membrane temperatures (35.7°C ± 0.5°C, 35.6°C ± 0.5°C, 35.6°C ± 0.4°C, 35.5°C ± 0.4°C, 35.4°C ± 0.5°C, and 35.4°C ± 0.3°C) 15, 30, 45, 60, 75, and 90 min, respectively, after induction in schizophrenic patients were significantly (P < 0.001) lower than those (36.5°C ± 0.5°C, 36.4°C ± 0.5°C, 36.3°C ± 0.4°C, 36.2°C ± 0.5°C, 36.2°C ± 0.4°C, and 36.1°C ± 0.4°C) in control patients. Mean skin temperatures (31.1°C ± 0.4°C [P = 0.008], 31.1°C ± 0.3°C [P = 0.007], and 31.1°C ± 0.2°C [P = 0.006]) 60, 75, and 90 min, respectively, after induction in schizophrenic patients were significantly lower than those (31.5°C ± 0.3°C, 31.5°C ± 0.3°C, and 31.5°C ± 0.3°C) in control patients. Four of 30 schizophrenic patients and 7 of 30 control patients developed postanesthesia shivering. There were no significant differences within 1 h after tracheal extubation in tympanic membrane temperatures between patients who shivered and those who did not shiver. In conclusion, chronic schizophrenic patients were more hypothermic during anesthesia. The incidence of postanesthesia shivering was not significantly increased.
IMPLICATIONS: Antipsychotics inhibit autonomic thermoregulation. This is caused by decreased heat production, increased heat loss, and impaired central action at the hypothalamus. Thus, schizophrenic patients receiving antipsychotics may have impaired intraoperative temperature regulation.
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Introduction
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Thermoregulatory control is impaired in schizophrenic patients receiving antipsychotics. Antipsychotics induce hypothermia through at least three mechanisms: central inhibition of shivering, which decreases heat production; peripheral vasodilation, which results in increased heat loss; and a central action at the hypothalamus (1). Antipsychotics used in the treatment of schizophrenia have actions of dopamine antagonism. Central dopamine has been implicated in the process of thermoregulation (2). The risk of hypothermia by antipsychotics is increased by the direct effect on hypothalamic thermoregulation caused by dopamine blockade with antipsychotics (3). Chronic treatment with haloperidol, an antipsychotic, potentiated apomorphine- and ethanol-induced decreases in core temperature. The potentiation may have been related to dopamine supersensitivity (4). Thus, intraoperative core hypothermia in schizophrenic patients taking antipsychotics may change.
Intraoperative core hypothermia results initially from a redistribution of body heat and, subsequently, from heat loss exceeding metabolic heat production (5) and is suppressed by vasoconstriction (6). Hypothermia increases the incidence of morbid myocardial outcome (7), reduces resistance to surgical wound infection (8), and prolongs both postoperative recovery and hospitalization (9). Hypothermia in schizophrenic patients is a possible link between antipsychotics and sudden unexplained death (1). In this study, we investigated temperature regulation during anesthesia in schizophrenic patients receiving antipsychotic medication.
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Methods
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The study was approved by the medical ethics committee of our institution. Informed consent was obtained orally and by a document from all patients or their families. We studied 30 patients (18 men and 12 women) (group S) ranging in age from 40 to 55 yr who were diagnosed with schizophrenia by psychiatrists according to Diagnostic and Statistical Manual of Mental Disorders criteria (10). The schizophrenic patients had been treated by chlorpromazine or perphenazine of phenothiazine derivatives and haloperidol or bromperidol of butyrophenone derivatives for at least 7 yr. Thirty patients (17 men and 13 women) ranging in age from 40 to 55 yr were studied as the control (group C). The control patients were selected from ASA physical status I–II patients undergoing elective orthopedic surgery. Patients with preoperative fever (>38°C), severe cardiovascular and respiratory disease, or autonomic dysfunction; obese patients; and those with thyroid disease or autonomic dysfunction were excluded from the study. All patients underwent elective orthopedic surgery, including surgical reduction of a bone fracture, lumbar spinal surgery, or repair of a knee ligament, under general anesthesia at Hakodate Watanabe Hospital and Hirosaki National Hospital. Regarding the subtypes of schizophrenia, 13 paranoid types, 7 catatonic types, 6 disorganized types, and 4 undifferentiated types were involved. Schizophrenic patients took antipsychotics on the day of operation. Anesthesia was induced with IV fentanyl 2 µg/kg and IV propofol 1.5 mg/kg at an infusion rate of 0.75 mg · kg-1 · min-1. Tracheal intubation was then facilitated by IV vecuronium 0.1 mg/kg. Anesthesia was maintained with 1.2%–2.0% sevoflurane according to clinical symptoms such as increases of heart rate and arterial blood pressure. All patients received fentanyl 6 µg/kg before skin incision, and fentanyl was further administered depending on vital sign responses such as systolic blood pressure and heart rate, which were controlled to within 20% of preoperative values. Systolic and diastolic blood pressure and heart rate were measured every 2 min for the first 30 min after the start of the induction of anesthesia and then every 5 min. The concentrations of sevoflurane were monitored throughout the anesthesia period by using a 5250 RGM Analyzer (Ohmeda, Madison, WI). The temperature of the operating room was maintained at 26°C. A heat-moisture exchanger was attached to the tracheal tube. A lactated or acetated Ringer’s solution was infused at a rate of 5 mL · kg-1 · h-1 to all patients, and the IV fluids were warmed to 38°C. Intraoperative surface heating was not provided. The lungs were mechanically ventilated to maintain ETCO2 at 35–40 mm Hg. After surgery, all patients were treated with nonsteroidal analgesics (diclofenac 50-mg suppository) every 6 h for incisional pain. If they complained of pain, patients were treated with IV pentazocine.
The tympanic membrane was monitored with an infrared tympanic membrane thermometer (Quick-Termo MC-500; Omron, Tokyo, Japan). Skin temperature probes (PD-K161; Terumo, Tokyo, Japan) were attached to the chest, upper arm, and lateral unoperated midthigh and midcalf; mean skin temperature (MST) was calculated according to the formula given by Ramanathan (11):
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Postoperative shivering lasting longer than 5 min was recorded and was defined as any involuntary movements resembling those normally seen in thermoregulatory shivering. The postoperative shivering was evaluated by operating room nurses for 90 min after tracheal extubation. Pain scores and confusion were evaluated by nurses every 8 h for the first 24 h after the end of operation and then every 24 h. Pain was estimated by using a 100-mm visual analog scale (with 0 mm representing no pain and 100 mm representing the worst imaginable pain). Postoperative confusion was assessed by using the confusion assessment method, which has been shown to be a sensitive and reliable method for assessment of confusion (12). It is composed of four key features: 1) acute change in mental status with a fluctuating course, 2) inattention, 3) disorganized thinking, and 4) altered level of consciousness. Diagnosis of confusion requires both of the first two features. The patients were examined at least once daily with confusion assessment method until the seventh day after operation. The nurses were not aware of the purpose of the study.
Data were expressed as mean ± SD. Comparisons between groups in tympanic or skin temperature, visual analog scale pain score, blood pressure, heart rate, mean duration of anesthesia and surgery, and mean volume of blood loss were analyzed by two-tailed unpaired Student’s t-tests. The incidence of postoperative shivering was analyzed by 
2 testing.
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Results
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The sex, age, weight, and height of the patients did not differ significantly between groups. The operating room temperature, fluid-replacement volume, and total fentanyl consumption also did not differ significantly between groups (Table 1). The mean systolic blood pressure 2 min after induction was 83 ± 12 mm Hg in group S, which was significantly (P = 0.02) lower than that (94 ± 14 mm Hg) in group C. Seven (23%) of 30 patients in group S and 2 (7%) of 30 patients in group C had episodes of hypotension <70 mm Hg in systolic blood pressure 2 min after the induction (P = 0.07). Postoperative confusion during 72 h after the end of operation occurred in 7 (23%) of 30 schizophrenic patients and in 2 (7%) of 30 control patients (P = 0.07). The average duration of antipsychotic use was 17 ± 6 yr (range, 7–34 yr). Postoperative pain scores at the first, second, and third day after the end of anesthesia were 19.6 ± 9.2, 14.7 ± 7.0, and 11.3 ± 4.5 for group S and 21.3 ± 10.4, 16.0 ± 8.7, and 12.9 ± 6.6 for group C. There were no significant differences in postoperatively pain scores between groups S and C through 3 days after the operation.
The tympanic membrane temperature before induction was 36.6°C ± 0.4°C in group S and 36.9°C ± 0.4°C in group C (P = 0.06). Tympanic membrane temperatures (35.7°C ± 0.5°C, 35.6°C ± 0.5°C, 35.6°C ± 0.4°C, 35.5°C ± 0.4°C, 35.4°C ± 0.5°C, and 35.4°C ± 0.3°C) 15, 30, 45, 60, 75, and 90 min, respectively, after induction in group S were significantly (P < 0.001) lower than those (36.5°C ± 0.5°C, 36.4°C ± 0.5°C, 36.3°C ± 0.4°C, 36.2°C ± 0.5°C, 36.2°C ± 0.4°C, and 36.1°C ± 0.4°C) in group C (Fig. 1). The lowest intraoperative core temperature in group S was 35.5°C ± 0.5°C, which was significantly (P < 0.001) lower than that (36.2°C ± 0.5°C) in group C. MSTs ( 31.1°C ± 0.4°C [P = 0.008], 31.1°C ± 0.3°C [P = 0.007], and 31.1°C ± 0.2°C [P = 0.006]) 60, 75, and 90 min, respectively, after induction in group S were significantly lower than those (31.5°C ± 0.3°C, 31.5°C ± 0.3°C, and 31.5°C ± 0.3°C) in group C.
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Figure 1. Time course of tympanic membrane temperatures. Values are mean ± SD. *P < 0.001 between groups.
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Four of 30 patients in group S and 7 of 30 patients in group C developed postanesthetic shivering. There was no significant (P = 0.051) difference in the incidence of shivering between the groups. Schizophrenic patients shivered at a core temperature of 35.9°C ± 0.4°C, whereas control patients shivered at a core temperature of 35.9°C ± 0.2°C (P = 0.80). The incidence of shivering in group S was not significantly more frequent in patients with a tympanic membrane temperature of <36°C. All patients who had postanesthetic shivering in group S developed postoperative confusion, and two of seven patients who had postanesthetic shivering in group C developed postoperative confusion. The incidence of postoperative confusion in patients who had postanesthetic shivering was significantly (P = 0.02) more frequent in group S than in group C. Three of 26 patients who did not have postanesthetic shivering in group S developed postoperative confusion. There were no postoperatively confused patients in the 23 patients who did not have postanesthetic shivering in group C. There was no significant (P = 0.09) difference in the incidence of postoperative confusion in patients who did not have postanesthetic shivering between groups S and C.
We compared intraoperative temperature in schizophrenic patients receiving chlorpromazine (n = 5), perphenazine (n = 12), haloperidol (n = 11), or bromperidol (n = 2). The tympanic membrane temperature of the patients treated with chlorpromazine tends to be lower than that of those treated with haloperidol (Fig. 2).
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Figure 2. Tympanic membrane temperatures of the patients treated with chlorpromazine (n = 5) and of the patients treated with haloperidol (n = 11). Values are mean ± SD.
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Discussion
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This study showed that the intraoperative core temperature in schizophrenic patients treated with antipsychotics was significantly lower than that in control patients. Because patients taking chronic vasodilators have less of a core-peripheral gradient, the enhanced hypothermia in schizophrenic patients treated with antipsychotics appears to be caused by central inhibition of thermoregulation. Chlorpromazine enhances the cooling rate during hypothermic therapy, and the increased cooling rate is caused by a central action at the hypothalamus rather than by vasodilation with chlorpromazine (1). The antipsychotic-induced hypothermia is mediated by dopamine receptors (2). With chronic administration of antipsychotics, the presynaptic autoreceptors develop tolerance, whereupon they become more sensitive to increased synaptic dopamine levels (4,13). Inhaled anesthetics enhance dopamine turnover in the brain synaptosomes (14). Mereu et al. (13) demonstrated that the combination of chronic administration of psychotics and general anesthetics resulted in an increased excitability of dopamine neurons. Dopamine neurons in the hypothalamus play an important role in reducing body temperature via postsynaptic dopamine receptors (15). Thus, alteration of brain dopamine may be partly associated with a decrease in core temperature during anesthesia in chronic schizophrenic patients. The skin temperature gradients measure arteriovenous shunt vasomotor status (16). In this study, the arteriovenous shunts were dilated during anesthesia in both groups; however, the skin temperature gradients demonstrated a similar change in both groups. Low-potency antipsychotics such as chlorpromazine have a higher affinity for the 
1- adrenergic receptors and can increase the risk of hypotension. However, high-potency antipsychotics such as haloperidol have less affinity for the 1-adrenergic receptors (17). The 1- adrenergic receptors mediate antipsychotic-induced hypothermia (18). This study showed that the tympanic membrane temperature of the patients treated with chlorpromazine tended to be lower than that of the patients treated with haloperidol. The results indicate that 1-adrenergic receptors may be partly associated with enhanced intraoperative core hypothermia in schizophrenic patients treated with antipsychotics. However, because the numbers of patients treated by chlorpromazine and haloperidol were small, we could not find a significant difference.
The incidence of shivering in schizophrenic patients treated with antipsychotics was not significantly different compared with that in control patients. This appears to be associated with a central inhibition of shivering by antipsychotics (1). However, in this study, all schizophrenic patients who had shivering developed postoperative confusion. Therefore, special attention is required to maintain normothermia for these patients.
A limitation of this study is that the schizophrenic patients were treated with four kinds of antipsychotics. Therefore, the effect of each antipsychotic on body temperature during anesthesia may have been different. In this study, ambient temperature was maintained near 26°C, which is higher than that in most other studies. Higher ambient temperature would keep skin temperatures relatively higher. Intraoperative hypothermia is inversely related to the percentage of body fat and the ratio of weight to surface area (19). In this study, there was no significant difference in weight between groups.
In conclusion, the intraoperative core temperature in chronic schizophrenic patients treated with antipsychotics was significantly lower than that in control patients. The incidence of shivering in the schizophrenic patients was not significantly different when compared with that in control patients.
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Accepted for publication August 13, 2003.
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Abstract
Introduction
