Chronic Treatment with Antidepressants Decreases Intraoperative Core Hypothermia

Abstract

We investigated temperature regulation during anesthesia and postoperative shivering in chronically depressed patients given antidepressant drugs. We studied 35 depressed patients and 35 control patients who underwent orthopedic surgery. Tympanic membrane temperatures 60, 75, and 90 min after induction in the depression group were significantly (P < 0.05) higher than those of the control group. There were no significant differences in mean skin temperature between the depression and the control groups. Eight of 35 patients in the depression group and 2 of 35 patients in the control group developed postanesthetic shivering. The incidence of shivering in the depression group was significantly more frequent than that in the control group (P = 0.04). The tympanic membrane temperature of the patients treated with clomipramine tended to be higher than that of the patients treated with maprotiline. In conclusion, intraoperative core hypothermia in chronically depressed patients was decreased. However, the incidence of shivering in depressed patients was significantly more frequent.

In Brief

IMPLICATIONS: Thermoregulation in chronically depressed patients is often altered. The alteration of body temperature is affected by depression itself and by antidepressants. General anesthesia has an influence on thermoregulatory control. However, temperature regulation during anesthesia in chronically depressed patients remains unclear.

Thermoregulation is often altered in affective disorders such as depression. Depressed patients are reported to have high nocturnal temperatures ⁽¹⁾, which are caused by increased thermogenesis and impaired heat-loss mechanisms, such as increased vasoconstriction ⁽²⁾. Defects in the regulation of serotonergic neurotransmission play a key role in the pathophysiology of depression ⁽³⁾. Serotonin (5-HT_1A) neurotransmission mediates body temperature, and a 5-HT_1A agonist decreases it ^(3,4). However, antidepressant drugs are also associated with the regulation of body temperature. Chronic treatment with amitriptyline, a tricyclic antidepressant, impairs hypothermia after the 5-HT_1A agonist ⁽⁵⁾.

General anesthesia disturbs autonomic thermoregulatory control. The core temperature is reduced during the first hour of anesthesia, and hypothermia results from a core-to-peripheral redistribution of body heat induced by vasodilation with anesthetics ⁽⁶⁾ from heat loss exceeding metabolic heat production ⁽⁷⁾. Intraoperative hypothermia increases the incidence of postanesthetic shivering ⁽⁸⁾. The shivering increases oxygen consumption and lactic acidosis and may cause postoperative confusion and myocardial isch-emia during the early postoperative period ⁽⁹⁾. The incidence of postoperative shivering is increased fourfold if anticholinergic premedications are used ⁽¹⁰⁾. Antidepressants have moderate anticholinergic effects. Intraoperative thermoregulation in chronically depressed patients remains unclear. In this study, we investigated temperature regulation and postoperative shivering during anesthesia in depressed patients receiving antidepressant therapy.

Methods

The study was approved by the medical ethics committee of our institution. Informed consent was obtained from all patients. We studied 35 patients (Group D) ranging in age from 35 to 60 yr who were diagnosed as having major depression according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria ⁽¹¹⁾ and 35 patients (Group C) ranging in age from 35 to 60 yr who were selected randomly as controls. All depressed patients had been taking antidepressants (imipramine, clomipramine, maprotiline, or mianserin) for more than a year. Clomipramine is a low anticholinergic antagonist, imipramine is a moderate anticholinergic antagonist, and maprotiline and mianserin are low muscarine antagonists. The mean half-life is 21 h for clomipramine, 15 h for imipramine, 46 h for maprotiline, and 18 h for mianserin. The antidepressants were discontinued on the day of the operation and restarted the next day. The state of depression was estimated quantitatively 2 days before and 4 days after surgery by means of the Hamilton Rating Scale for Depression (HAM-D) ⁽¹²⁾, which is a useful, standardized questionnaire method for measuring the symptoms of depression. The questionnaire consists of 21 items with a cumulative scoring system based on questions about symptoms that are common in depression, such as sleep disturbance, weight change, fatigue factors, sexual dysfunction, and cognitive components of depressive illness.

All patients had orthopedic surgery, including surgical reduction of bone fracture, lumbar spinal surgery, and repair of knee ligaments using general anesthesia at Hakodate Watanabe Hospital and Hirosaki National Hospital. Before surgery, if patients complained of pain, they were treated by a diclofenac sodium 50-mg suppository or pentazocine 15 mg IM. Patients with a history of cardiovascular disease were excluded. Anesthesia was induced with 2 μg/kg of IV fentanyl and 1.5 mg/kg of IV propofol at an infusion rate of 0.75 mg · kg⁻¹ · min⁻¹, and tracheal intubation was then facilitated by vecuronium 0.1 mg/kg IV.

Anesthesia was maintained with 1.2%–2.0% sevoflurane in nitrous oxide 2 L/min and oxygen 2 L/min according to clinical symptoms, such as an increase of heart rate and arterial blood pressure. Fentanyl 6 μg/kg was given for all patients until skin incision, and this was followed by further increments according to vital signs such as systolic blood pressure and heart rate, which were controlled within 20% of preoperative values. Electrocardiogram, arterial blood pressure, inspiratory oxygen, ETco₂, and transcutaneous oxygen saturation were monitored throughout the anesthesia period by using a 5250 RGM analyzer. The temperature of the operating theater was maintained at 26°C. A heat-moisture exchanger was attached to the tracheal tube. 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. The lungs were mechanically ventilated to maintain ETco₂ at 35–40 mm Hg. After surgery, all patients were treated with a nonsteroidal analgesic (diclofenac sodium, 50-mg suppository) every 6 h for incisional pain. If they complained of pain, they were treated with pentazocine, which has less of an effect on temperature.

Tympanic membrane temperature 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, lateral unoperated midthigh, and midcalf; mean skin temperature (MST) was calculated according to the formula given by Ramanathan ⁽¹³⁾:equation

Postoperative shivering lasting longer than 5 min was recorded. Shivering was defined as any involuntary movements resembling those seen normally in thermoregulatory shivering and was graded as shown in Table 1.

Table 1: Grading of Postoperative Shivering

The pain score was evaluated by nurses 1 h after the end of anesthesia and then every 8 h for the first 24 h after the end of operation and every 24 h after that. Pain was estimated with a 100-mm visual analog scale (with 0 mm representing no pain and 100 mm representing the worst imaginable pain). The pain score was not evaluated if postoperative delirium or confusion occurred. The pain scores were evaluated 5 h after haloperidol treatment. Haloperidol alone has less of an effect on body temperature. The nurses were not aware of the purpose of the study.

Data were expressed as mean ± sd. Comparisons between groups in visual analog scale pain score, blood pressure, heart rate, mean duration of anesthesia and surgery, and mean volume of blood loss were analyzed by repeated-measures analysis of variance followed by Bonferroni’s correction. Comparison in tympanic or skin temperature before and after the operation was analyzed by analysis of variance followed by Dunnett’s test. The incidence of postoperative shivering was analyzed by χ² testing. P values <0.05 were considered significant.

Results

There were no significant differences in age, average weight, mean duration of anesthesia and surgery, mean volume of blood loss, or total fentanyl consumption between groups (Table 2). Mean blood pressure and heart rate were similar in the two groups (Table 3). In this study, no patient had severe complications throughout the postoperative course. There were no clinically significant differences in the postoperative pain score between the groups 3 days after the operation. The mean HAM-D score was 14.1 ± 5.2 for Group D and 4.7 ± 1.7 for Group C before surgery and was 13.4 ± 6.6 for Group D and 4.8 ± 1.5 for Group C 4 days after surgery. Confusion in the first three postoperative days occurred in five (14%) patients in Group D and in no patients in Group C.

Table 2: Profile of Patients and Clinical Data During Anesthesia in This Study

Table 3: Hemodynamic Data and Visual Analog Scale Score

Tympanic membrane temperature before induction was 37.1°C ± 0.4°C in Group D and 36.9°C ± 0.4°C in Group C. Tympanic membrane temperatures 60, 75, and 90 min after induction in Group D were significantly (P < 0.05) higher than in Group C (Fig. 1). There were no correlations between tympanic membrane temperatures and HAM-D scores. There were no significant differences in MST between Group D and C (Fig. 2).

Figure 1: Time course of tympanic membrane temperatures. Values are mean ± sd. *P < 0.05 between groups.

Figure 2: Time course of mean skin temperature. Values are mean ± sd.

Eight of 35 patients in Group D and 2 of 35 patients in Group C developed postanesthetic shivering (grade >0). The incidence of shivering in Group D was significantly (P = 0.04) more frequent than that in Group C. Postanesthetic shivering occurred in five patients (42%) taking imipramine, two patients (40%) taking clomipramine, and one patient (10%) taking maprotiline. However, there was no significant difference in the incidence of shivering among patients receiving imipramine, clomipramine, maprotiline, and mianserin.

We compared intraoperative temperature in depressed patients receiving imipramine, clomipramine, maprotiline, and mianserin. The tympanic membrane temperature of the patients treated by clomipramine tended to be warmer than that of the patients treated by maprotiline (Fig. 3).

Figure 3: Tympanic membrane temperatures of the patients treated with clomipramine (n = 8) and of the patients treated with maprotiline (n = 10). Values are mean ± sd. *P < 0.05 between groups.

Discussion

This study showed that core hypothermia during anesthesia was attenuated in chronically depressed patients. Depressed patients are reported to have reduced amplitude of the circadian temperature rhythm and high nocturnal temperatures ⁽¹⁾. The high nocturnal temperature observed in depressed patients is caused by increased thermogenesis and impaired heat-loss mechanisms ⁽²⁾. Thus, decreased intraoperative core hypothermia in depressed patients appeared to result partly from increased heat production, because environmental heat loss may have been similar for both groups. However, there were no significant differences in MST between depressed patients and control patients. Skin-temperature gradients are relatively specific measures of arteriovenous shunt vasomotor status. In addition, impaired core hypothermia in chronically depressed patients was greater during the second phase of hypothermia, which is a slower, linear decrease in core temperature, apparently resulting when heat loss exceeds metabolic heat production. This result indicated that decreased intraoperative core hypothermia in depressed patients would not be affected by arteriovenous shunt flow and thermoregulatory redistribution. Thus, decreased core hypothermia in depressed patients may be associated with alterations in central thermoregulation.

Lesch et al. ⁽¹⁴⁾ reported that the hypothermic responses to 5-HT_1A agonists were attenuated in depressed patients as compared with normal volunteers. They suggested that the impaired hypothermia after 5-HT_1A agonists in depressed patients resulted from decreased serotonergic activity. In addition, chronic treatment with amitriptyline, a tricyclic antidepressant, further impairs hypothermia after a 5-HT_1A agonist. As attenuation of pre- and postsynaptic 5-HT_1A receptor after long-term treatment with tricyclic antidepressants has been demonstrated ^(3,15), the downregulation of the 5-HT_1A receptor by long-term treatment with antidepressants results in an impairment of 5-HT_1A agonist-induced hypothermia. Thus, downregulation of serotonergic receptors by long-term treatment with tricyclic antidepressants also appears to be associated with decreased intraoperative core hypothermia in chronically depressed patients. In this study, the intraoperative core hypothermia was greater with maprotiline than with clomipramine. Clomipramine is a moderate 5-HT_1A antagonist, and maprotiline does not block 5-HT_1A receptors. Our results also suggest that the degree of serotonergic receptor downregulation affects intraoperative core hypothermia.

Abnormal sympathetic nervous systems are associated with depressive illness. The plasma norepinephrine (NE) concentration of patients with depression is increased ⁽¹⁶⁾. We previously reported that plasma NE concentrations during surgery in chronically depressed patients were larger ⁽¹⁷⁾. These increased concentrations of plasma NE are caused both by depression itself ⁽¹⁶⁾ and by antidepressants ⁽¹⁸⁾. The plasma NE increase by antidepressants is caused by inhibition of NE reuptake and the depressed negative feedback mechanism because of inhibited α-adrenergic receptors ⁽¹⁸⁾. Thus, the impaired autonomic nervous system in chronically depressed patients might result in decreased core hypothermia during anesthesia.

In this study, the incidence of postoperative shivering in chronically depressed patients was significantly more frequent than in control patients. Postanesthetic shivering is a thermoregulatory phenomenon caused by core hypothermia sustained during anesthesia. The incidence of postanesthetic shivering is inversely related to core temperature ⁽⁸⁾. Because core hypothermia during anesthesia is attenuated in chronically depressed patients, postoperative shivering in these patients appears to be associated with mechanisms other than core hypothermia. Cholinergic systems contribute to the genesis and control of postoperative shivering. Anticholinergic premedication is reported to increase the incidence of postoperative shivering ⁽¹⁹⁾. Postoperative shivering is prevented by the application of central cholinergic agonists in mice ⁽²⁰⁾. Antidepressants have anticholinergic effects. In addition, shivering is also associated with activation of noradrenaline ⁽²¹⁾ and 5-HT_1A⁽²²⁾ receptors. Maprotiline and mianserin are high noradrenaline antagonists and low muscarine antagonists. Whereas clomipramine is a very low noradrenaline antagonist and a low muscarine antagonist, imipramine is a low noradrenaline antagonist and a moderate muscarine antagonist. In this study, the incidence of shivering in depressed patients treated with clomipramine and imipramine tended to be more frequent. Thus, the anticholinergic effects and downregulation of serotonergic receptors by long-term treatment with antidepressants appears to increase postoperative shivering in chronically depressed patients.

Postoperative pain is involved in the development of postoperative shivering. However, there was no difference in postoperative pain scores between the groups. In this study, antidepressants were continued until the day of the operation because discontinuation of antidepressants is associated with an increased incidence of postoperative confusion and depressive symptoms ⁽²³⁾. The continuation of antidepressants might affect intraoperative body temperature in chronically depressed patients. This study may be criticized for use of subgroups to compare intraoperative temperature in depressed patients receiving imipramine, clomipramine, maprotiline, and mianserin. The small sample size in each subgroup may be inadequate to detect a difference in the intraoperative temperature of depressed patients receiving each antidepressant.

In conclusion, the intraoperative core temperature was higher and the incidence of shivering was significantly more frequent in chronically depressed patients receiving antidepressants than in control patients.