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Anesth Analg 2002;94:106-111
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Dolasetron for Preventing Postanesthetic Shivering

Swen N. Piper, MD, Kerstin D. Röhm, MD, Wolfgang H. Maleck, Moritz T. Fent, MD, Stefan W. Suttner, MD, and Joachim Boldt, MD

Department of Anesthesiology and Critical Care Medicine, Klinikum Ludwigshafen, Ludwigshafen, Germany

Address correspondence and reprint requests to Dr. Swen N. Piper, Department of Anesthesiology and Critical Care Medicine, Klinikum Ludwigshafen, Bremserstraße 79, D-67063 Ludwigshafen, Germany. Address e-mail to wolfgang_maleck{at}hotmail.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We designed this study to assess the efficacy of dolasetron compared with clonidine and placebo in prophylaxis of postanesthetic shivering. We included 90 patients undergoing elective abdominal or urologic surgery. The patients were randomly assigned to one three groups (each group n = 30) using a double-blinded study protocol: Group A received 12.5 mg dolasetron, Group B 3 µg/kg clonidine, and Group C saline 0.9% as placebo. The medication was given after the induction of anesthesia. Postanesthetic shivering was judged by using a five-point scale. In the Clonidine group, 86.6% showed no shivering, whereas in the Dolasetron and Placebo groups, only 63.3% and 66.6%, respectively, were symptom free. Only clonidine, but not dolasetron, significantly reduced the incidence and the severity of shivering. We conclude that clonidine is effective in preventing shivering when given before surgery, whereas dolasetron, at the dose used, is not effective.

IMPLICATIONS: Shivering, an irregular muscular fasciculation lasting longer than 15 s, is a common complication secondary to general anesthesia. We compared dolasetron with clonidine (an established antishivering drug) in the prevention of postanesthetic shivering. Dolasetron 12.5 mg was not effective.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Along with postoperative nausea and vomiting (PONV), postanesthetic shivering is one of the leading causes of distress of patients recovering from general anesthesia (1,2). Apart from the obvious discomfort, postanesthetic shivering may be associated with the risk of several complications, especially in patients with coronary artery disease, secondary to increased oxygen consumption, cardiac output, catecholamine release, carbon dioxide production, and intraocular pressure (3–8).

Postanesthetic shivering is often preceded by core hypothermia (3), but shivering can occur in patients who are normothermic at the end of surgery (9). Intrahypothalamic serotonin (5-hydroxytryptamine [5-HT]) has an important impact on thermoregulation (10). Ketanserin, a 5-HT2 antagonist like nefopam and tramadol, which both inhibit 5-HT reuptake, reduced postanesthetic shivering (11–13). This therapeutic approach showed that the serotoninergic pathways are involved in the development and the regulation of postanesthetic shivering. An approach to prevent both PONV and shivering with one drug would be an ideal therapy to reduce patient discomfort postoperatively. Recently, the 5-HT3 antagonists, well known anti-PONV drugs, have been thought to contribute to the prevention of postanesthetic shivering (14,15). Powell and Buggy (14) demonstrated that ondansetron (8 mg), a 5-HT3 antagonist, given before induction of anesthesia, reduced postanesthetic shivering compared with placebo. Dolasetron (dolasetron mesylate) is a pseudopelletierine-derived 5-HT3 antagonist that has recently become available for treating and preventing PONV. After systemic administration, it is rapidly converted in vivo to its active metabolite, hydrodolasetron, which seems to be largely responsible for dolasetron’s pharmacologic activity (16). Bock et al. (15) reported that a large dose of dolasetron (1 mg/kg) is effective in preventing postanesthetic shivering. The dose usually used to prevent PONV is 12.5 mg IV (16). Because it has not been established whether "normal" doses of dolasetron have beneficial effects on shivering, we designed the present study to evaluate the efficacy of 12.5 mg of dolasetron to prevent postanesthetic shivering compared with both Placebo (negative control group) and Clonidine (positive control group).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With approval from our ethics committee and written informed consent, we included 90 patients (ASA physical status I, II, or III) scheduled for elective abdominal or urologic surgery. Patients with myocardiac insufficiency (New York Heart Association III or IV), cardiac arrhythmias, muscle diseases, Parkinson disease, fever (temperature >37.5°C), needing vasoconstrictors perioperatively and having received {alpha}2-adrenergic agonists for long-term treatment were excluded from the study. All patients received 7.5 mg of midazolam orally 45–60 min before surgery as premedication. General anesthesia was induced by thiopental (5 mg/kg) and fentanyl (3 µg/kg). Rocuronium (0.5 mg/kg) was given to facilitate orotracheal intubation.

After induction of anesthesia, the patients were randomly assigned to receive IV 12.5 mg of dolasetron, 3 µg/kg clonidine (Positive Control group) or 0.9% saline as placebo (Negative Control group). All drugs were given as a 10-mL injection in a double-blinded manner. Randomization was performed with closed envelopes containing the study assignment opened after inclusion in the study.

Intraoperatively, a mixture of isoflurane 0.6%–1.5% (end-tidal), nitrous oxide 60%, and oxygen 40%, was used to maintain anesthesia. Mechanical ventilation was used in all patients with positive end-expiratory pressure of 5 mbar, a standard procedure in our institution to prevent atelectasis. Ventilation was mechanically controlled to maintain end-tidal carbon dioxide tension pressure at 30–36 mm Hg. The fresh gas flow was 2 L/min. Intraoperatively, patients were not actively warmed, but covered with sheets as far as possible. After surgery and extubation, patients were transferred to the postanesthesia recovery unit (PACU).

The postoperative inquiry of patients and the evaluation of patients’ shivering score were assessed by an anesthesiologist in the PACU, who did not know the patients’ grouping or the tympanic temperature. The severity of postanesthetic shivering was classified in five grades by using a scale similar to that validated by Wrench et al. (17) and previously used by our group (18): 0 = no shivering; 1 = one or more of the following: piloerection, peripheral vasoconstriction, peripheral cyanosis without other cause, but without visible muscular activity; 2 = visible muscular activity confined to one muscle group; 3 = visible muscular activity in more than one muscle group; and 4 = gross muscular activity involving the entire body. If 2 score points or more were reached, 10 mg of nefopam, an established drug in preventing and treating postanesthetic shivering (12,18), was given IV. Mean arterial blood pressure (MAP) and heart rate (HR) were measured after induction of anesthesia before surgery, 5, 15, 30, and 60 min after extubation. The tympanic temperature was measured before surgery, at the end of surgery, and after 15 and 60 min postoperatively by means of an infrared thermometer (First Temp Genius; Sherwood-Davis & Geck, Gosport, UK) according to the manufacturer’s instructions (19). The time from the end of application of isoflurane and nitrous oxide until extubation (extubation time) was documented. Postanesthetic recovery was scored by using the Aldrete score (20) on arrival at the PACU and on discharge. Pain was treated by IV doses of the opioid piritramide (increments of 3.75 mg) or diclofenac (50 or 100 mg) given rectally.

Demographic data, duration of surgery and anesthesia, recovery time between end of anesthesia and extubation, and the effects of treatment on all studied variables (tympanic temperature, MAP, HR) were analyzed with Student’s t-test. The incidence of shivering (i.e., shivering grade >1) was analyzed with Fisher’s exact test. The ranked sum test of Raatz (21) was used to analyze the shivering and Aldrete scores, and the postoperative piritramide and nefopam consumption. The Raatz test is a modified rank order test with corrections for multiple ties to be used for values that fall into classes (e.g., school notes or scores). Before the study, the number of patients required in each group was determined after a power calculation according to data obtained from a previous investigation in our institution on the incidence of postanesthetic shivering secondary to abdominal and orthopedic surgery (22). We expected an incidence of shivering in the Placebo group of at least 50% and a reduction of the incidence to approximately 15% with an effective medication such as clonidine. Consequently, the present study was powered to detect such a reduction from 50% to 15% incidence with an {alpha} error of 0.05 (two-sided) and a ß error was set at 0.2. Based on that assumption, a minimum of 27 patients per group was required and 30 patients were included per group to have a reserve for dropouts. All values were expressed as mean (SD) or as median (range). P values < 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
All groups were similar with regard to demographics, duration of anesthesia and surgery (Table 1), tympanic temperature at all data points (Table 2), and postoperative consumption of analgetics (Table 3).


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  		Table 1. Demographic Characteristics and Perioperative Data
 

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  		Table 2. MAP, HR, and TT
 

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  		Table 3. Aldrete Score (20) and Postoperative Consumption of Piritramide, Diclofenac, and Nefopam
 
At all postoperative data points, MAP was significantly lower in the Clonidine group compared with the Dolasetron- and Placebo-Treated patients (Table 2). HR decreased significantly in the Clonidine group compared with patients who had received placebo at T3 and T4 and with Dolasetron patients at T4 (Table 2). However, there were no instances of hemodynamic effects requiring therapeutic interventions in any of the groups.

We found no significant influence of the study medication on the extubation time (Table 1). Postanesthetic recovery assessed by the Aldrete score showed no significant differences among the groups (Table 3).

Twenty-six patients (86.6%) of the Clonidine group showed no symptoms of shivering, 3 (10%) had signs of piloerection, peripheral vasoconstriction, or peripheral cyanosis (shivering score grade 1), and 1 patient shivered (3.3%). Nineteen patients who had received dolasetron showed no symptoms of shivering (63.3%), 3 patients had a shivering score of 1 (10%), and 8 patients had shivering with muscular activity (26.6%). In the untreated Control group, 20 patients (66.6%) had no shivering, 2 patients (6.6%) reached shivering grade 1, and 8 patients (26.6%) showed signs of muscular activity. Using the Fisher’s exact test we found a significant reduction in the incidence of shivering in the Clonidine group compared to the other groups (Fig. 1). Analyzing the shivering score, we found that clonidine reduced the score significantly compared with the other two groups (Fig. 2).



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  		Figure 1. Incidence of shivering (defined as shivering grade >1). *P < 0.05 different versus other two groups.

 


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  		Figure 2. Severity of shivering, using the scale of Wrench et al. (17). *P < 0.05 different versus other two groups.

 
We found no significant difference between the Dolasetron and Placebo groups concerning incidence and severity of shivering. It must be noted, however, that the incidence in the Placebo group was only 30%, not 50% as expected, so that the ex post power of the study was lower than what was calculated beforehand.

The postoperative consumption of piritramide and diclofenac did not differ significantly among the groups (Table 3).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Postanesthetic shivering is a potential complication for any surgical patient. It is defined as readily detectable fasciculation of the face, jaw, head, trunk, or extremities lasting longer than 15 seconds (3) and occurs in 5%–60% of patients recovering from general anesthesia (1,14,18). In the present study, the incidence of postanesthetic shivering was 26.6% in patients treated with both 12.5 mg dolasetron and placebo, but only 3.3% after the administration of 3 µg/kg clonidine. The effectiveness of clonidine is not surprising because many other studies have shown that clonidine reduced both shivering and vasoconstriction, and that it was effective in the treatment of shivering (11,23) and for its prevention (18,22,24,25).

The starting point of shivering is adjacent to the center in the posterior hypothalamus on which the impulses from the cold receptors impinge. It is normally inhibited by impulses from the preoptic anterior hypothalamic area, but if the cold impulses exceed the rate at which the former impulses may be received, the starting point for shivering becomes activated and sends impulses bilaterally into the anterior motor neurons of the spinal cord (3).

Secondary to general anesthesia, an increase in warm-response thresholds and a decrease in cold-response thresholds occurs, such that the normal interthreshold range, between which no effector response occurs, is increased from 0.4° to 4.0°C (26). All currently used volatile anesthetic drugs, including isoflurane, decrease the vasoconstriction and the shivering thresholds (3,27,28). The result of general anesthesia decreasing the thermoregulatory threshold would be tolerance to core hypothermia without initiation of thermoregulatory responses.

Recovery from general anesthesia has two phases: First, thermoregulatory responses are still suppressed by residual anesthesia, followed by a phase in which further decline of anesthetic concentration and concomitant recovery of the thermoregulatory centers occurs. If the temperature is below the thermoregulatory threshold, postanesthetic shivering is triggered (29). It was shown that drugs acting on the serotonergic system, such as ketanserin, tramadol, nefopam, ondansetron, and urapidil, are effective in the treatment and prophylaxis of postanesthetic shivering (11–14,18,30,31). The mechanism has not been clarified but could be related in part to the inhibition of the 5-HT reuptake, which is supposed to encourage the inhibitory effects of serotonin on the preoptic anterior hypothalamic region (10,32).

Bock et al. (15) reported that a dose of dolasetron that was eightfold larger than the dose usually used in prevention of PONV, decreased the incidence of postanesthetic shivering when compared with placebo. The limitation of this placebo-controlled study was the lack of a group with an established drug in the treatment of shivering (e.g., meperidine, clonidine, and nefopam). Moreover, the study was not published as a full-size article, but only as an abstract. In our study, using 12.5 mg of dolasetron IV, the incidence of postanesthetic shivering was similar to placebo, but significantly more frequent than in the patients treated with clonidine. Furthermore, the severity of shivering was not beneficially influenced by 12.5 mg of dolasetron but rather by 3 µg/kg clonidine.

As mentioned in Results, the ex post power of this study was lower than what was assumed for the ex ante power analysis. However, because the incidence of shivering in the Dolasetron and Placebo groups was equal and the severity comparable, it is unlikely that dolasetron in the dose used would have a clinically useful effect on shivering. Even if it had, this study has shown that it is significantly inferior to clonidine.

The limitations of this study include a lack of a formal dose-response study for dolasetron to establish which doses could suppress shivering. However, the dose we used is the dose approved for prophylaxis and treatment of PONV. The eightfold dose used by Bock et al. (15) is—at least in Germany—approved only in oncologic patients undergoing chemotherapy. Performing a formal dose-response study would require especially careful monitoring of adverse effects. In addition, dolasetron is more costly than standard antishivering drugs such as clonidine, meperidine, or nefopam even in the dose we used, but this expense could be justified by its proven effect on PONV. A larger dose would be economically justified only if its side-effect profile were significantly superior to that of established drugs. Nevertheless, the performance of such a dose-response study would be scientifically important.

Clonidine showed some hemodynamic effects. MAP and HR decreased significantly in the Clonidine group compared with the two other groups. These findings are in accordance with various other studies describing the same hemodynamic effects (11,18,22,24). The administration of dolasetron showed no influence on hemodynamics compared with placebo. Although clonidine has vasoconstricting properties via {alpha}-1-agonism, sympatholytic effects on the central nervous system via {alpha}-2-agonism predominate. As a result, the sympathetic outflow from medullary pressor centers is decreased, causing hypotension. Clonidine also exhibits sedative and anxiolytic properties (33). Prolonged recovery time after clonidine administration at the end of surgery has been reported (18). In the present study, clonidine was given after the induction of anesthesia and before surgery was started. We found no significant difference among the three groups concerning the recovery times or the Aldrete scores.

In conclusion, we found that the incidence and severity of postanesthetic shivering was similar with dolasetron 12.5 mg IV and placebo, whereas the incidence and severity were significantly reduced by clonidine 3 µg/kg IV.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 5, 2001.




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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 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press