Premedication with Famotidine Augments Core Hypothermia during General Anesthesia

Methods: In a randomized, placebo-controlled study, 30 ASA physical status 1 or 2 patients, scheduled for open abdominal surgery, were given either placebo or 40 mg oral famotidine 3 h before induction of anesthesia. Epidural buprenorphine (4 micro gram/kg) was injected, and anesthesia was maintained with 0.4–0.6% isoflurane and 66% nitrous oxide in oxygen. The tympanic membrane temperature was measured to assess core temperature, and forearm-fingertip and calf-toe skin-surface temperature gradients were used to assess peripheral vasoconstriction. Tympanic membrane temperature triggering initial vasoconstriction (a skin temperature gradient of 0 degree Celsius) identified the vasoconstriction threshold.

Results: Tympanic membrane temperature during surgery in the patients premedicated with famotidine was significantly less than those in the patients without famotidine. Famotidine significantly reduced the thermoregulatory threshold for vasoconstriction in the leg (35.0 plus/minus 0.5 degree Celsius, P < 0.05), compared to that in the placebo group (36.4 plus/minus 0.6 degree Celsius) Once triggered, thermoregulatory vasoconstriction produced a core-temperature plateau and no further hypothermia was observed for the duration of the study. Neither mean arterial pressure nor heart rate were significantly different between the two groups.

Conclusions: Premedication with famotidine augments intraoperative hypothermia. The mechanism appears to be inhibition of centrally mediated thermoregulatory control. (Key words: Histamine, antagonists: famotidine. Temperature: regulation. Thermoregulation: vasoconstriction.)

HISTAMINE is widely distributed within the mammalian central nervous system. Strong evidence supports the concept that histamine has a role as a neurotransmitter or neuromodulator, and that it is a neurotransmitter in the central thermoregulatory pathways. Thermoregulatory responses have been observed when histamine is injected into the cerebral ventricles in rats, mice, and cats. .

Intravenous anesthetics, opioids, and muscle relaxants are known to induce histamine release from human skin, lung, and heart mast cells. Intraperitoneal injection of pentobarbital increases the whole brain concentration of histamine in mice, although the effects of this drug on brain mast cells have not been well investigated. Sessler and colleagues demonstrated that hypothermia immediately after induction of general anesthesia results from a core-to-peripheral redistribution of body heat. Vasodilatory response to histamine may play a partial role in vasodilation during general anesthesia. In addition to a vasodilatory response caused by an increase in the histamine concentration in the peripheral tissues, an increase in the histamine concentration in the central nervous system may affect thermoregulatory response during general anesthesia.

Premedication with a histamine Hydrogen²receptor antagonist is used to reduce the risk of acid aspiration before general anesthesia. The Hydrogen²receptors involved in the central thermoregulatory pathways are reportedly located close to the walls of the third ventricle. However, it is unclear whether systemic administration of an Hydrogen²-antagonist, which poorly penetrates the blood-brain barrier, influences thermoregulation.

The vasodilation induced by premedication with nifedipine is reported to affect the internal redistribution of body heat and to induce change in thermoregulation during general anesthesia. To investigate the effect of Hydrogen²-antagonists on the central thermoregulatory pathways, the effect of vasodilation caused by the Hydrogen²-antagonist must be avoided. Hydrogen²-antagonists do not inhibit the hemodynamic change induced by peripheral histamine release, but a combination of Hydrogen¹- and Hydrogen²-antagonists does. Cimetidine by itself is reported to decrease arterial pressure secondary to peripheral vasodilation in contrast to ranitidine and famotidine, which have no hemodynamic effect. To avoid the effect of vasodilation on thermoregulation, we therefore selected famotidine to investigate the central thermoregulatory effects of premedication with Hydrogen²-antagonists.

A total of 30 patients (ASA Physical Status 1 or 2), aged 22–60 years scheduled for open abdominal surgery were enrolled in this study. None of them had any cardiopulmonary or autonomic disorders, or was taking any medications that affect cardiovascular function. The patients were randomly allocated to either of the two groups: orally administered placebo (control group, n = 15) or famotidine (famotidine group, n = 15). The study was approved by the Ethics Committee of our institution, and all patients gave their written informed consent before participating in the study.

The patients received either the placebo or famotidine (40 mg) 3 h before induction of anesthesia. After transfer of the patient into the operating room, an intravenous catheter was inserted for administration of fluid (8 ml *symbol* kg sup -1 *symbol* h sup -1 lactated Ringer's solution). In all patients, an epidural catheter was placed via the T12-L1 or the L1-L2 vertebral interspaces while the patient was in the lateral position. A 3-ml test dose of 1% lidocaine with epinephrine (5 micro gram/ml) was then administered. Before induction of anesthesia, each patient received epidural 4 micro gram/kg buprenorphine in 5 ml saline. Anesthesia was induced with 5 mg/kg thiopental and was maintained with 0.4–0.6% isoflurane and 66% nitrous oxide in oxygen.

Vecuronium bromide (0.1 mg/kg) was used to facilitate tracheal intubation and also for muscle relaxation during surgery. All patients remained in the horizontal position during surgery. The ambient temperature in the operating room was maintained between 24 and 25 degrees Celsius whenever possible, but the patients were not actively warmed during the study. We did not use local epidural anesthetics during the study. Postoperative epidural analgesia was instituted with continuous infusion at 0.7 ml/h 0.25% bupivacaine containing buprenorphine (12 micro gram/ml) using a disposable balloon-operated infuser (Sure-fuser SFA-0503D, Nipro, Japan) for 3 days.

Indirect blood pressure (Pulsemate BX-5, Colin, Japan), heart rate, oxygen saturation, end-tidal carbon dioxide tension, and end-tidal isoflurane concentration (5250 RGM, Ohmeda, Louisville, CO) were monitored. Normocapnia (35–40 mmHg) was maintained during surgery. Blood loss was evaluated by weighing the surgical sponges and by measuring the blood volume in the suction containers. Blood lost was replaced with three times the volume of additional lactated Ringer's solution.

Skin temperature probes (PD-K161, Terumo, Japan) were attached onto the radial aspect of the forearm halfway between the elbow and the wrist, at the anterior mid-calf, and on opposite sites of the nail bed on the index finger and the big toe. Core temperature was measured using an infrared tympanic membrane thermometer (Quick-Thermo MC-500, Omron, Japan). We averaged the tympanic membrane temperature measured three times to reduce error. Peripheral vasoconstriction was quantified using skin-surface temperature gradients : the upper extremity temperature gradients were monitored using the forearm minus finger skin-surface temperature gradients, and the lower extremity gradients using the calf minus toe skin-surface temperature gradients. The vasoconstriction thresholds was defined as the tympanic membrane temperature at which the gradient equaled zero and 4 degrees Celsius.

The tympanic membrane temperature, skin-surface temperature gradients, ambient temperature, end-tidal isoflurane concentration, mean arterial pressure, and heart rate were recorded before induction and every 15 min after skin incision until the end of the operation.

The Kruskal-Wallis test for unpaired data was used to compare patient demographic data or thermoregulatory thresholds in the two groups. Between-group evaluation of each variable was conducted using one-way analysis of variance. Thereafter, Fisher's least significant difference test was used to identify significant differences in various pairs of comparisons. The null hypothesis was rejected when P < 0.05. All values are reported as means plus/minus SD.

There were no significant differences between the two groups in age, body weight, height, or duration of surgery. The blood loss and fluid replacement volumes as of 60 min after the skin incision also did not differ significantly in the two groups (Table 1). The two groups did not differ significantly in end-tidal isoflurane concentration or ambient operating room temperature (Table 2). We confirmed that no patient complained about awareness during the surgery.

The tympanic membrane temperature in the famotidine group was significantly less than that in the control group during the surgery (Figure 1). Table 3shows the vasoconstriction threshold and the number of patients whose forearm-fingertip and calf-toe temperature gradients equaled zero and 4 degrees Celsius. Vasoconstriction thresholds (the gradient = zero) with famotidine were 35.2 plus/minus 0.9 degrees Celsius for the forearm-fingertip gradient and 35.6 plus/minus 0.5 degree Celsius for the calf-toe gradient, which were significantly less than those without famotidine of 36.2 plus/minus 0.7 and 36.4 plus/minus 0.6 degree Celsius, respectively (P < 0.05) Mean arterial pressure and heart rate were virtually identical in the two groups.

Premedication with famotidine augmented core hypothermia and reduced vasoconstriction threshold during open abdominal surgery under isoflurane anesthesia. The two groups with and without famotidine premedication did not differ in mean arterial pressure or heart rate. Famotidine is likely to decrease core temperature through central thermoregulation, not through a hemodynamic effect.

Injection of histamine into the cerebral ventricles or the hypothalamus reportedly induces dose-dependent hypothermia in unanesthetized rats and mice. Hypothermia, induced by intraventricular injection of Hydrogen²-agonist, was antagonized by intraventricular injection of cimetidine. Conversely, intraventricular injection of histamine in anesthetized rats induces hyperthermia, which is antagonized by cimetidine administered either intraventricularly or intraperitoneally. Intraventricular injection of histamine in cats causes hypothermia followed by hyperthermia. This hypothermic response is prevented by Hydrogen¹-antagonists, and the hyperthermic response is prevented by metiamide, an Hydrogen²-antagonist. The results of the current study agree with those in anesthetized rats and awake cats, but not with those in awake rats.

Hydrogen²receptors located close to the third ventricle play an important role in central thermoregulation. Famotidine is likely to affect the histaminergic central thermoregulatory pathways, which might be activated by histamine released from brain mast cells induced by thiopental or buprenorphine, through the circumventricular organ near the third ventricle, which lacks the blood-brain barrier.

Recent advances in the study of intraoperative thermoregulation have provided an understanding of the mechanism of anesthesia-induced core hypothermia. However, the role of the histaminergic central thermoregulatory pathways has not been evaluated. The current study revealed that premedication with famotidine augmented core hypothermia during general anesthesia.

We selected 0.4–0.6% isoflurane with epidural buprenorphine to maintain anesthesia. The isoflurane-induced decrease in the vasoconstriction threshold is dose-dependent and thus the two groups should have been equally affected. Premedication with larger doses of famotidine may induce a further decrease in the vasoconstriction threshold and therefore more hypothermia. However, we did not evaluate the dose-dependence of thermoregulatory inhibition induced by famotidine. The peak plasma concentration of famotidine, is attained within 1–2 h and, likely gradually decreased during the study. Thus premedication less than 3 h before induction of anesthesia may be associated with more hypothermia than that seen in our patients.

In summary, famotidine premedication decreased the vasoconstriction threshold approximately 1 degree Celsius. Consequently, patients receiving famotidine had significantly more hypothermia than those who did not. These data confirm the clinical importance of the core-temperature plateau and suggest that famotidine produces a centrally mediated inhibition of a thermoregulatory control.