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ANESTHETIC PHARMACOLOGY

Buspirone and Meperidine Synergistically Reduce the Shivering Threshold

Masoud Mokhtarani, MD^*, Adel N. Mahgoub, MD^*, Nobutada Morioka, MD^*, Anthony G. Doufas, MD^*, Michael Dae, MD, Thomas E. Shaughnessy, MD^*, Andrew R. Bjorksten, PhD, and Daniel I. Sessler, MD

Departments of *Anesthesia and Radiology, University of California, San Francisco; Department of Anaesthesia, Royal Melbourne Hospital, Parkville, Australia; Outcomes Research Institute, Department of Anesthesiology, University of Louisville, Kentucky; and the Ludwig Boltzmann Institute, University of Vienna, Austria

Address correspondence and reprint requests to Daniel I. Sessler, University of Louisville, Abell Administration Center, Room 217, 323 E. Chestnut St., Louisville, KY 40202-3866. Address e-mail to sessler{at}louisville.edu

	Abstract

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Mild hypothermia (i.e., 34°C) may prove therapeutic for patients with stroke, but it usually provokes shivering. We tested the hypothesis that the combination of buspirone (a serotonin 1A partial agonist) and meperidine synergistically reduces the shivering threshold (triggering tympanic membrane temperature) to at least 34°C while producing little sedation or respiratory depression. Eight volunteers each participated on four randomly-assigned days: 1) large-dose oral buspirone (60 mg); 2) large-dose IV meperidine (target plasma concentration of 0.8 µg/mL); 3) the combination of buspirone (30 mg) and meperidine (0.4 µg/mL); and 4) a control day without drugs. Core hypothermia was induced by infusion of lactated Ringer’s solution at 4°C. The control shivering threshold was 35.7°C ± 0.2°C. The threshold was 35.0°C ± 0.8°C during large-dose buspirone and 33.4°C ± 0.3°C during large-dose meperidine. The threshold during the combination of the two drugs was 33.4°C ± 0.7°C. There was minimal sedation on the buspirone and combination days and mild sedation on the large-dose meperidine day. End-tidal PCO₂ increased 10 mm Hg with meperidine alone. Buspirone alone slightly reduced the shivering threshold. The combination of small-dose buspirone and small-dose meperidine acted synergistically to reduce the shivering threshold while causing little sedation or respiratory toxicity.

IMPLICATIONS: Mild hypothermia may be an effective treatment for acute stroke, but it usually triggers shivering, which could be harmful. Our results indicate that the combination of small-dose buspirone and small-dose meperidine acts synergistically to reduce the shivering threshold while causing little sedation or respiratory toxicity. This combination may facilitate the induction of therapeutic hypothermia in stroke victims.

	Introduction

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Stroke is the third leading cause of death in the United States and is the most important cause of major adult-onset disability. The annual US cost of strokes has been estimated at US$45 billion. Stroke victims are also substantial users of intensive care resources. Any reduction in stroke-related morbidity would thus benefit an enormous number of people and markedly reduce overall health care costs. Considerable animal data suggest that as little as a 2°C–3°C reduction in temperature provides increased protection against tissue hypoxia and ischemia compared with available drugs, including large-dose isoflurane or barbiturate coma (1).

Only limited human data are currently available, but therapeutic hypothermia clearly reduces intracranial pressure (2) and seems to be relatively safe (3). Hypothermia was reported to be an effective treatment for traumatic brain injury (4), although a subsequent study failed to confirm any benefit (5). Hypothermia also seems to improve recovery from catastrophic strokes resulting from middle cerebral artery occlusion (6). Mild hypothermia thus remains a promising intensive treatment for ischemic brain injury.

Autonomic cold defenses are well maintained in most stroke victims (7). The induction of therapeutic hypothermia in these patients is thus complicated by the need to overcome arterio-venous shunt vasoconstriction and shivering and to do so without provoking extreme thermal discomfort (8) or sympathetic nervous system activation (9), neither of which would be appropriate in these fragile patients. Numerous drugs reduce cold-defense thresholds by 2°C–3°C. However, they are all anesthetics or major sedatives that significantly compromise airway defense and ventilatory competence when given in sufficient doses (10). None would thus be suitable without critical care levels of monitoring and facilities for mechanical ventilation.

Numerous drugs have proved effective for the treatment of shivering, including clonidine, magnesium sulfate, and physostigmine. However, meperidine (11), unlike other opioids, possesses a special antishivering action. Specifically, the drug inhibits shivering twice as much as vasoconstriction (12) without altering the gain of the response (a proportional increase in shivering intensity) (13). The mechanism mediating meperidine’s special antishivering action remains unclear but seems unlikely to be serotonergic. Even with meperidine, though, large plasma concentrations are required to reduce the shivering threshold to 33.5°C (12). At these concentrations, humans no longer reliably breathe spontaneously; meperidine alone will thus be insufficient for the induction of thermoregulatory tolerance except in intensively monitored patients.

Buspirone is a serotonin (5-HT) 1A partial agonist (14). It is a very mild sedative that produces hypothermia in rats (15) but has little effect in humans (16). Application of 5-HT in the hypothalamus activates heat-loss mechanisms in most experiments, whereas application of norepinephrine increases heat conservation and production (17). Because buspirone and meperidine apparently inhibit thermoregulatory control via different mechanisms, these drugs may facilitate the induction of therapeutic hypothermia synergistically rather than additively. We therefore tested the hypothesis that the combination of buspirone and meperi- dine synergistically reduces the shivering threshold in humans.

	Methods

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With approval of the Committee on Human Research at the University of California–San Francisco and informed consent, we studied eight healthy male volunteers. None was obese, taking medication, or had a history of thyroid disease, dysautonomia, or Raynaud’s syndrome.

The volunteers had a light breakfast and refrained from caffeine for at least 8 h before the study. During the studies, the volunteers rested supine on a standard operating room table; they were minimally clothed, and ambient temperature was maintained near 19°C–20°C. The volunteers were studied on four randomly assigned days, separated by at least 48 h: 1) control (no drug), 2) meperidine at a target plasma concentration of 0.8 µg/mL; 3) meperidine at a target concentration of 0.4 µg/mL and buspirone 30 mg; and 4) buspirone 60 mg.

Meperidine was given by target-controlled infusion starting approximately 15 min before active cooling (below). The infusion profile was based on a modification of the method of Kruger-Thiemer (18) and published data (19). The time to peak plasma concentrations after the oral administration of buspirone is 60 min; the mean elimination half-life is 150 min (20). Buspirone was thus given in three equally spaced oral doses, with the first being 90 min before active cooling and the last at the time cooling started. This dosing scheme was intended to rapidly achieve therapeutic concentrations, minimize side effects during the initial phase, and maintain a therapeutic level throughout the study.

A 20-cm-long IV catheter was inserted into the left upper arm for fluid and drug administration; a catheter was also inserted into a vein in the right arm for blood sampling. Throughout the study period, mean skin temperature was maintained at 32°C by adjusting the temperature of circulating water (Cincinnati Sub-Zero, Cincinnati, OH) and forced-air warmers (Augustine Medical, Inc., Eden Prairie, MN). Furthermore, the back, upper body, and lower body were individually maintained at the designated skin temperature.

Lactated Ringer’s solution cooled to 4°C was infused at rates sufficient to decrease the tympanic membrane temperature 2.5°C/h. Fluid was given until the shivering threshold was identified (below) or a total of 70 mL/kg of fluid was given. We have used this model in numerous previous studies; it markedly reduces core temperature and is well tolerated by young, healthy volunteers. Heart rate was measured continuously with an electrocardiogram; blood pressure was determined oscillometrically at 5-min intervals at the left ankle.

Core temperature was recorded from the tympanic membrane by using Mon-a-Therm thermocouples (Mallinckrodt Anesthesiology Products, Inc., St. Louis, MO). The aural probe was inserted by volunteers until they felt the thermocouple touch the tympanic membrane; appropriate placement was confirmed when volunteers easily detected gentle rubbing of the attached wire. The aural canal then was occluded with cotton, the probe securely taped in place, and a gauze bandage positioned over the external ear. The mean skin surface temperature was determined from 15 area-weighted sites (21).

Arterio-venous shunt vasomotor tone was evaluated with forearm-minus-fingertip and calf-minus-toe skin temperature gradients. There is an excellent correlation between skin temperature gradients and volume plethysmography (22). Vasoconstriction was defined by a forearm skin temperature gradient exceeding 0°C.

All temperatures were recorded by using Mon-a-Therm thermocouples. Temperatures were recorded from thermocouples connected to calibrated Iso-Thermex 16-channel electronic thermometers having an accuracy of 0.1°C and a precision of 0.01°C (Columbus Instruments International Corp., Columbus, OH). Individual and mean skin temperatures were computed by a data acquisition system, displayed at 1-s intervals, and recorded at 1-min intervals.

Oxygen consumption, as measured by a DeltaTrac (SensorMedics Corp., Yorba Linda, CA) metabolic monitor, quantified shivering; the system was used in canopy mode (23). Measurements were averaged over 1-min intervals and recorded every minute. End-tidal PCO₂ was measured from nasal prongs with an Ultima monitor (Datex, Helsinki, Finland); exhaust gas from this monitor was returned to a oxygen consumption monitor.

Blood for meperidine and buspirone concentrations was obtained at the time cooling started and at the shivering threshold (or after 70 mL/kg of fluid had been given). Blood samples were centrifuged at 4°C and then frozen at -170°F (-112°C) until assayed. For meperidine, plasma (1 mL), 0.050 mL bupivacaine 30 mg/L (internal standard), 0.1 mL 2.4 M NaOH, and 6 mL ethyl acetate were combined in a polypropylene tube, capped, and vortexed for 10 s. The mixture was centrifuged at 1000g for 10 min, and the ethyl acetate phase was transferred to a second polypropylene tube containing 0.125 mL 30 mM of o-phosphoric acid. This was vortexed and centrifuged, and the ethyl acetate phase was discarded. The injection volume was 0.080 mL of the o-phosphoric acid phase into the high-performance liquid chromatograph running a mobile phase of 400:100:40 of 20 mM K₂HPO₄ at pH 7.0:acetonitrile:methanol at 1 mL/min through a 15 cm x 3.9 mm Novapak CN column (Waters Inc., Milford, CT). Detection was by ultraviolet absorbance at 205 nm. This method is linear to at least 10 µg/mL, with a limit of quantitation of 20 ng/mL. The within-day coefficient of variation was 4.6% at 500 ng/mL (n = 8) (12).

For buspirone, plasma (1 mL), 1 mL buspirone standard or water (for samples), 0.050 mL sufentanil 10 mg/L (internal standard), 1.5 mL 0.5 M Na₃PO₄, and 6 mL 5% methanol in chlorobutane were combined in a borosilicate glass tube, capped, and vortexed for 10 s. The mixture was centrifuged at 1000g for 10 min. The chlorobutane phase was transferred to a second glass tube and evaporated to dryness at 40°C. The residue was reconstituted in 0.025 mL methanol and the whole sample injected into the gas chromatograph. The chromatograph used a programmable temperature vaporizer, a 30 m x 0.25 mm BPX-50 column (SGE Inc., Melbourne, Australia), and nitrogen-phosphorus detection. This method is linear to at least 1000 ng/mL, with a limit of quantitation of 0.1 ng/mL. The within-day coefficient of variation was 5.4% at 5 ng/mL (n = 8).

Sedation was evaluated with the Bispectral index of the electroencephalogram (BIS). The level of sedation was also evaluated with the Observer’s Assessment of Alertness/Sedation Score (OAA/S). The OAA/S test consists of four components (Table 1); as described by Chernik et al. (24), we summed the component scores. The OAA/S score sum is at least as reliable and valid as the visual analog scale and the digit-symbol substitution test (24). A score was obtained at 0.5°C intervals throughout cooling.

All IV anesthetics and sedatives that have been specifically evaluated in humans have a linear dose dependent effect on thermoregulatory thresholds (25). The dose dependence of opioids, including meperidine, is also linear (12). We therefore assumed that the thermoregulatory effects of buspirone were also likely to be linear. The interaction between buspirone and meperidine was evaluated by comparing the shivering threshold with a full dose of each drug with the combination of a half-dose of each. Specifically, we used linear regression to estimate the shivering threshold that would be expected were the effects of each drug additive. In practice, this consisted of a linear regression between the two full-dose points. The resulting value in each volunteer was then compared with the observed value with a half-dose of each drug by using a two-tailed, paired Student’s t-test. Results are expressed as mean ± SD; differences were considered statistically significant when P < 0.01.

	Results

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Morphometric characteristics of volunteers were the following: age, 34 ± 5 yr; height, 172 ± 5 cm; and weight, 73 ± 14 kg. Ambient temperature and relative humidity were comparable on all study days. The mean skin temperature was maintained near 32°C. All the volunteers were vasoconstricted before infusion of cold fluid started.

Drug concentrations before cooling and at the shivering threshold did not differ significantly. Individual drug concentrations were stable over time, although there was considerable interindividual variability. Except on the large-dose meperidine day, volunteers were minimally sedated, as determined by individual average OAA/S scores uniformly equal to 20 and BIS values from 97 to 98. BIS scores remained similar during large-dose meperidine, but OAA/S was from 18 to 20, indicating moderate sedation. Two volunteers experienced respiratory difficulty and needed verbal reminders to breathe during the study, both during large-dose meperidine. End-tidal PCO₂ was 5–12 mm Hg more on the large-dose meperidine day than during the other study conditions. Heart rate, mean arterial blood pressure, and oxygen saturation were comparable on each study day (Table 2).

Buspirone reduced the shivering threshold nearly 1°C, from 35.7°C ± 0.2°C to 35.0°C ± 0.8°C. In contrast, large-dose meperidine reduced the shivering threshold more than 2°C, to 33.4°C ± 0.3°C. However, the combination of small-dose buspirone and small-dose meperidine similarly reduced the shivering threshold to 33.4°C ± 0.7°C (Table 2, Fig. 1). The actual threshold during the small-dose combination was significantly less than predicted for an additive response (P = 0.006). The combination of buspirone and meperidine thus synergistically reduced the shivering threshold.

View larger version (12K): [in this window] [in a new window]   Figure 1. The shivering threshold (triggering core temperature) without drugs (Control), with 60 mg of buspirone (Buspirone), with meperidine at a target plasma concentration of 0.8 µg/mL (Meperidine), and a combination of buspirone 30 mg and meperidine at a target plasma concentration of 0.4 µg/mL (Combination). Data are shown as mean ± SD. The shivering threshold with a combination of small-dose meperidine and small-dose buspirone was similar to that with a full dose of meperidine. Furthermore, the combination threshold was significantly less than expected from the regression between the thresholds observed with the large doses of each drug alone (i.e., if the effects of each drug were additive) (P = 0.006). This figure thus indicates that the combination synergistically reduces the shivering threshold. See Table 2 for additional statistical analysis.

	Discussion

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Large-dose buspirone produced slight thermoregulatory inhibition. But as expected from previous studies (12), large-dose meperidine reduced the shivering threshold to 33.5°C—more than 2°C below normal. This is a clinically relevant reduction, because numerous studies indicate that comparable hypothermia provides marked protection against ischemic tissue injury. However, large-dose meperidine was associated with substantial sedation and respiratory depression. Our key result is thus that the combination of small-dose meperidine and small-dose buspirone produced comparable thermoregulatory tolerance without concomitant sedation or respiratory toxicity.

Why the combination of buspirone and meperidine should be synergistic rather than additive remains unknown. Buspirone produces hypothermia in rats (30) because it is a 5-HT_1A partial agonist (14). 5-HT produces hyperthermia in cats (31) but produces hypothermia in numerous other species (32). 5-HT₃ receptors may also reduce the shivering threshold in humans (33). The mechanism behind meperidine’s special antishivering action remains unknown, although activation of -opioid receptors, anticholinergic action, and N-methyl-D-aspartate antagonism have all been proposed. However, there is no expectation that the special antishivering action of meperidine is mediated by 5-HT receptors. The two drugs thus apparently inhibit thermoregulatory control via different mechanisms. We can only speculate that these pathways interact to amplify their respective antishivering actions.

Numerous and consistent data indicate that mild hypothermia markedly reduces infarct size in a variety of stroke models in numerous animal species. However, it remains to be established whether hypothermia is comparably helpful in humans. A major reason is that therapeutic hypothermia has generally been restricted to surgical patients and those in critical care settings because drugs that sufficiently inhibit thermoregulation produce substantial respiratory toxicity. Our combination of small-dose buspirone and meperidine removes this restriction by inducing thermoregulatory tolerance without toxicity. We thus expect this drug combination to facilitate studies evaluating the putative benefits of therapeutic hypothermia.

The internal cooling method we used, infusion of cold fluid, is unlikely to be safe in stroke victims. However, it is an excellent model for a new generation of internal heat-exchanging catheters that induce core hypothermia without any net exchange of fluid. Stroke victims are typically elderly. Although the risks of hypothermia may be increased in the elderly, it is easy to induce hypothermia in this population because advanced age per se impairs thermoregulatory responses (34). It should thus be possible to induce comparable hypothermia in the elderly with even smaller drug doses or to induce greater hypothermia with similar drug doses.

In preliminary studies, we maintained the mean skin temperature near 34°C. However, we were then unable to reduce the core temperature to the shivering threshold in many volunteers without giving excessive fluid. One reason is that considerable surface heating was required to maintain 34°C. The other reason is that skin temperature contributes 20% to thermoregulatory control (35); high skin temperatures thus reduce the shivering threshold. We therefore decreased the skin temperature to 32°C in these volunteers. A consequence of this reduction is that they were already vasoconstricted before core cooling started; it was thus impossible to evaluate the vasoconstriction threshold.

Although we were unable to evaluate the vasoconstriction threshold in these volunteers, we have simultaneously determined the shivering and vasoconstriction thresholds in numerous previous studies (36). With the sole exception of meperidine (12), the shivering threshold has always been 1°C less than the vasoconstriction threshold. We therefore assume that the vasoconstriction threshold in our volunteers would have been at least 1°C more than the shivering threshold.

The vasoconstriction threshold is of considerable interest because vasoconstriction is an effective thermoregulatory response. Vasoconstriction is the primary autonomic defense against cool environments, and—once triggered—prevents further hypothermia even in surgical patients (37). It might thus be difficult to reduce core temperature below the vasoconstriction threshold with surface cooling. Internal cooling, such as we used, has no such limitation because heat is removed directly from the core thermal compartment. A further advantage of internal cooling is that patient comfort, which largely depends on skin temperature (38), can be improved by simultaneous cutaneous heating.

In summary, large-dose buspirone produced minimal thermoregulatory inhibition, whereas large-dose meperidine reduced the shivering threshold more than 2°C, to 33.5°C. Large-dose meperidine was associated with significant respiratory toxicity and hypercarbia. However, the combination of small-dose meperidine and small-dose buspirone produced comparable thermoregulatory tolerance without sedation or respiratory toxicity. We expect this synergistic combination to facilitate studies evaluating the putative benefits of therapeutic hypothermia.

	Acknowledgments

 
Supported by NIH Grant GM 58273, the Joseph Drown Foundation (Los Angeles, CA), the Commonwealth of Kentucky Research Challenge Trust Fund, and Radiant Medical (Redwood City, CA). Mallinckrodt Anesthesiology Products, Inc. (St. Louis, MO) donated the thermocouples we used. Drs. Dae and Sessler are paid consultants for Radiant Medical, Inc.

	References

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				A. G. Doufas, C.-M. Lin, M.-I. Suleman, E. B. Liem, R. Lenhardt, N. Morioka, O. Akca, Y. M. Shah, A. R. Bjorksten, and D. I. Sessler Dexmedetomidine and Meperidine Additively Reduce the Shivering Threshold in Humans Stroke, May 1, 2003; 34(5): 1218 - 1223. [Abstract] [Full Text] [PDF]

				S. R. Dixon, R. J. Whitbourn, M. W. Dae, E. Grube, W. Sherman, G. L. Schaer, J. S. Jenkins, D. S. Baim, R. J. Gibbons, R. E. Kuntz, et al. Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction J. Am. Coll. Cardiol., December 4, 2002; 40(11): 1928 - 1934. [Abstract] [Full Text] [PDF]

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