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Anesth Analg 2003;97:759-762
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Doxapram Produces a Dose-Dependent Reduction in the Shivering Threshold in Rabbits

Katsumi Okuyama, MD*, Takashi Matsukawa, MD*, Makoto Ozaki, MD{dagger}, Daniel I. Sessler, MD§, Tomoki Nishiyama, MD{ddagger}, Makoto Imamura, MD*, and Teruo Kumazawa, MD*

Departments of Anesthesia, *University of Yamanashi, Faculty of Medicine, Yamanashi; {dagger}Tokyo Women’s Medical University, and {ddagger}Tokyo University School of Medicine, Tokyo, Japan; and §Outcomes ResearchTM Institute and Departments of Anesthesiology, University of Louisville, Louisville, Kentucky

Address correspondence and reprint requests to Dr. Takashi Matsukawa, Department of Anesthesia, University of Yamanashi, Faculty of Medicine, Tamaho, Yamanashi 409-3898, Japan. Address e-mail to takashim{at}res.yamanashi-med.ac.jp


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Dopamine is a thermoregulatory neurotransmitter that provokes hypothermia when injected in or near the hypothalamus. Doxapram stimulates release of dopamine from carotid bodies, but is known to have central effects that are probably, at least in part, similarly mediated. We thus tested the hypothesis that doxapram produces a substantial, dose-dependent reduction in the shivering threshold in rabbits. Twenty-four rabbits, anesthetized with isoflurane, were randomly assigned to 1) saline (control), 2) 0.25 mg · kg-1 · h-1 doxapram, or 3) 0.50 mg · kg-1 · h-1 doxapram. These doses are within the recommended range for humans. Body temperature was reduced at a rate of 2° to 3°C/h by perfusing water at 10°C through a U-shaped thermode positioned in the colon. Core temperatures were recorded from the distal esophagus. A blinded observer evaluated shivering. Core temperature at the onset of shivering defined the threshold. Data were analyzed with a one-way analysis of variance; P < 0.05 was considered statistically significant. Hemodynamic and respiratory responses were comparable in the groups. The control rabbits shivered at 36.3° ± 0.3°C, those given 0.25 mg · kg-1 · h-1 doxapram shivered at 34.8° ± 0.5°C, and those given 0.50 mg · kg-1 · h-1 shivered at 33.7° ± 0.6°C. All the shivering thresholds significantly (P < 0.001) differed from one another. The magnitude of this inhibition, if similar in humans, would be clinically important.

IMPLICATIONS: Doxapram produced a substantial and dose-dependent reduction in the shivering threshold. The magnitude of this inhibition, if similar in humans, would be clinically important. Clinical studies are thus indicated to determine whether the drug might help defeat thermoregulatory defenses during induction of therapeutic hypothermia.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Overwhelming evidence in animals indicates that even mild hypothermia provides substantial protection against cerebral (1,2) and myocardial (3) ischemia. Mild hypothermia improves neurological outcome after cardiac arrest in humans (4,5), and randomized trials are underway to evaluate the potential benefits of mild hypothermia during aneurysm clipping, and after stroke or acute myocardial infarction. Many of these studies target core temperatures between 33° and 34°C.

Induction of hypothermia during surgery is relatively easy because anesthetics profoundly impair thermoregulatory responses (6). However, use of therapeutic hypothermia in patients having acute myocardial infarction or stroke may be compromised because tiny reductions in core temperature trigger aggressive thermoregulatory defenses (7), even in stroke victims (8). The most important autonomic cold defenses in humans are arteriovenous shunt vasoconstriction (9) and shivering (10). Both impede induction of hypothermia via surface cooling, but only shivering is critical when hypothermia is induced by internal heat-exchanging catheters (11). This has led to a search for drugs that impair shivering without causing excessive sedation or respiratory toxicity. Although the combination of buspirone and meperidine seems helpful (12), the optimal drug or drug combination has yet to be identified.

Dopamine is among the most important thermoregulatory neurotransmitters (13), and it is well established that increasing preoptic dopamine concentrations provokes hypothermia in mammals (14,15) and fish (16). Conversely, serotonin and dopamine antagonists are associated with hyperthermia (17) and the neuroleptic malignant syndrome (18).

Doxapram stimulates release of dopamine from carotid bodies (19), but is known to have central effects (20) that are probably, at least in part, similarly mediated. As might thus be expected, doxapram is a useful treatment for postanesthetic shivering (21,22). However, even drugs that reduce the shivering threshold (triggering core temperature) only a fraction of a degree (23) are often effective in postoperative patients (24). An important question is whether clinically relevant doses of doxapram reduce the shivering threshold from its normal value near 35.5 (25) to approximately 34°C, which is likely to provide protection against cerebral or myocardial ischemia. We thus used an established rabbit model (26) to test the hypothesis that doxapram produces a substantial, dose-dependent reduction in the shivering threshold.


   Methods
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 Abstract
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 Methods
Results
 Discussion
 References
 
With approval from the Committee on Animal Research at University of Yamanashi, Faculty of Medicine, we studied 24 male Japanese white rabbits, weighing 2.7–4.0 kg (mean 3.4 kg). Daytime core temperatures in these rabbits is usually near 39°C. Ambient temperature was maintained near 24°C throughout the study.

The animals were anesthetized by inhaled isoflurane (1.0%–2.5% end-tidal concentration) and nitrous oxide (67% in oxygen) (NORMAC AA-102; Datex, Andover, MA). A femoral venous catheter was inserted, and 2–3 mL · kg-1 · h-1 lactated Ringer’s solution was infused throughout the protocol. Each rabbit had a 3-mm endotracheal tube inserted and was allowed to breathe spontaneously under 0.2 minimum alveolar anesthetic concentration (MAC) isoflurane in 100% oxygen. The animals were loosely restrained in an experimental chamber during the study. Core temperature was cooled at a rate of 2° to 3°C/h by perfusing water at 10°C through a U-shaped plastic tube (thermode) positioned in the colon. We have previously described this methodology in detail (26–28). Twenty-four rabbits were assigned randomly to one of three infusion regimens: 1) saline (control), 2) 0.25 mg · kg-1 · h-1 doxapram hydrochloride (A. H. Robins, Inc., Saint Davids, PA), or 3) 0.50 mg · kg-1 · h-1 doxapram. Drug or saline infusion was started at the same time as core cooling.

Core temperatures were recorded from the distal esophagus (MGA 3-219; Nihon Kohden, Tokyo, Japan) at 1-min intervals with a laboratory computer. Shivering was evaluated by inspection by an observer blinded to treatment. Sustained, vigorous shivering was considered physiologically significant. The core temperature triggering significant shivering identified the thermoregulatory threshold for this response. Arterial blood was sampled for gas analysis at the shivering threshold in each rabbit. All studies were started near 10:00; shivering generally started between 14:00 to 15:00.

Morphometric characteristics, hemodynamic and respiratory responses at the time of shivering, arterial oxygen partial pressures, and the shivering thresholds were compared with one-way analysis of variance and Student-Newman-Keuls tests. Data were expressed as means ± SD; P < 0.05 identified statistically significant differences.


   Results
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 Abstract
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 Methods
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Discussion
 References
 
Weights did not differ significantly among the three groups. Hemodynamic and respiratory responses at the time of shivering were also comparable (Table 1).


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  		Table 1. Weight, and Hemodynamic and Respiratory Responses at the Time of Shivering
 
The rabbits with saline infusion shivered at 36.3° ± 0.3°C. In contrast, 0.25 mg · kg-1 · h-1 doxapram infusion reduced the shivering threshold to 34.8° ± 0.5°C. The larger dose of 0.50 mg · kg-1 · h-1 doxapram reduced it even further to 33.7° ± 0.6°C (Fig. 1).



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  		Figure 1. The shivering thresholds during 0 (saline), 0.25, and 0.50 mg · kg-1 · h-1 doxapram infusion. Doxapram reduced the threshold in a dose-dependent manner. The shivering thresholds in each of the 3 groups differed significantly (P < 0.001). Data are presented as mean ± SD.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Therapeutic hypothermia improves the outcome from cardiac arrest (4,5), although it seems unhelpful for traumatic brain injury (29). Whether hypothermia will prove helpful for stroke and acute myocardial infarction remains to be determined. However, it is already evident that few patients tolerate induction of hypothermia without pharmacologic intervention to blunt thermoregulatory defenses that otherwise trigger intense vasoconstriction and vigorous shivering (8). These responses are themselves associated with hypertension, tachycardia, and sympathetic nervous system activation (30–34)—all of which are likely to be detrimental in patients with stroke or acute myocardial infarction.

The best method of preventing shivering (short of anesthesia or muscle relaxants) is the combination of buspirone and meperidine (12). However, meperidine can cause respiratory toxicity and is associated with seizures when given in large doses for prolonged periods. The value of buspirone is also limited because the drug is only available orally. Our results are thus intriguing because they suggest that doxapram may be equally effective. But doxapram, unlike buspirone, can be given IV and reaches peak activity within a minute or two. It is also a relatively nontoxic drug with its major side effect being a transient pressor action. Although doxapram may have more serious side effects including hypertension, pulmonary hypertension, muscle hyperactivity, muscle spasticity, clonus, and convulsion, these side effects are rare.

The pharmacology of doxapram remains poorly understood. Its action is at least partially attributed to release of dopamine from the carotid body (just as hypoxia does) (19). Ventilatory stimulation occurs in or below the pons as its action is unaffected by brainstem transection in fetal lambs (35). It is also associated with electroencephalographic evidence of arousal in dogs (36). Unlike caffeine, however, doxapram does not increase regional cerebral glucose use (37). Doxapram has central effects (20), and it is likely that tolerance for hypothermia in our rabbits resulted from increases in hypothalamic dopamine concentration, which provokes hypothermia in mammals (14,15) and fish (16).

Whether hypothermia proves an effective treatment for stroke or acute myocardial infarctions has yet to be established, and the optimal temperature certainly remains unknown. Nonetheless, core temperatures between 33° and 34°C are being targeted in most current trials. The shivering threshold in our rabbits was 33.7° ± 0.6°C (a reduction of 2.6°C) when they were given an infusion of doxapram at a rate of 0.50 mg · kg-1 · h-1. The observed hypothermia was thus of a clinically relevant magnitude.

The primary indication for doxapram is central respiratory depression. The recommended dose ranges up to 2 mg/kg, repeated at 5-min intervals, followed by an infusion of 180 mg/h to a maximal daily dose of 3 g. The doses used in our study are thus well within the suggested human dose range. Furthermore, animals are typically less sensitive to drugs. For example, even the larger dose of doxapram had little effect on arterial PCO2. It thus seems likely that routine doses of doxapram will produce similar or even larger reduction of the shivering threshold than observed in our rabbits. Naturally, this speculation will need to be confirmed clinically.

A limitation of our protocol is that the rabbits were given background isoflurane anesthesia. However, the concentration was restricted to 0.2 MAC during the study period. Isoflurane and other volatile anesthetics (38–40) differ from IV anesthetics and sedatives (41,42) in producing a highly nonlinear inhibition of thermoregulation, with a disproportionate effect at larger concentrations. In humans, 0.4 MAC of isoflurane reduces the shivering threshold only 0.5°C, suggesting that 0.2 MAC background isoflurane is unlikely to have much influenced even the absolute magnitude of the shivering threshold. But in any case, the background anesthetic is unlikely to substantially alter the observed 2.6°C reduction in the shivering threshold during doxapram administration.

In summary, the control rabbits shivered at 36.3° ± 0.3°C. Those given 0.25 mg · kg-1 · h-1 doxapram shivered at 34.8° ± 0.5°C, and those given 0.50 mg · kg-1 · -1 infusion shivered at 33.7° ± 0.6°C. Doxapram thus produced a substantial, dose-dependent reduction in the shivering threshold. The magnitude of this inhibition, if similar in humans, would be clinically important. Clinical studies are therefore indicated to determine whether the drug might help defeat thermoregulatory defenses during induction of therapeutic hypothermia.


   Acknowledgments
 
Supported by National Institutes of Health Grant GM 58273 and the Commonwealth of Kentucky Research Challenge Trust Fund.

The authors thank Mr. Masanobu Koshimizu, BS, for his technical assistance.


   Footnotes
 
Mallinckrodt Anesthesiology Products, Inc. (St. Louis, MO) donated the thermocouples used.

DIS has a personal financial interest in Radiant Medical, Inc. (Redwood City, CA).


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 16, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press