All these interventions were statistically significantly more effective than placebo at all time points, except for ketanserin 10 mg after 30 min. Meperidine 25 mg was most often tested and performed consistently best at 1, 5, 10, and 15 min. After one min, the NNT to prevent any further shivering with meperidine 25 mg compared with placebo was approximately 3, suggesting that it acted faster than alfentanil 250 μg or doxapram 100 mg. After 5, 10, and 15 min, the NNTs for meperidine 25 mg were less than 2. Some of the other interventions came close to this; clonidine 150 μg and doxapram 100 mg, for instance, had NNTs less than 2 at 5 min but not thereafter.
Shivering, as nausea or vomiting, never becomes chronic and it is unlikely to kill a patient. However, in shivering postoperative patients, left ventricular systolic work index and oxygen consumption index may be increased (54). It is, therefore, encouraging that some simple and inexpensive interventions are effective in the treatment of this adverse effect of anesthesia and surgery. Two shivering patients need to be treated with meperidine 25 mg, clonidine 150 μg, or doxapram 100 mg for one to stop shivering within five minutes who would have continued to shiver had they all received a placebo. This degree of efficacy relates to the “average” shivering adult patient in the postoperative period. Most often, shivering was diagnosed clinically; the role of body temperature remained unclear. As these trials used randomized treatment allocation, differences in body temperature (core or peripheral) were unlikely to have an effect on the overall efficacy. In none of the trials, a stratified (factorial) design with efficacy evaluation in normothermic versus hypothermic patients was applied. Average body temperatures were comparable across the studies, and no profound hypothermia was reported. We do not know, if these antishivering interventions are more (or less) effective in specific subgroups of patients, for instance in those who are hypothermic.
There were several methodological problems with this analysis. First, we had to rely on indirect comparisons (i.e., comparisons from placebo-controlled trials). This was necessary because, for shivering, as for many other clinical settings, a “gold standard” treatment is unknown. As a consequence, trialists do not know what standard comparator they should choose to test the efficacy of a new, experimental intervention. We retrieved many potentially valid randomized trials that compared an experimental intervention with a randomly chosen comparator. Combining these heterogeneous data was impossible. Active comparisons, however, may be used to test the validity of the league table of relative antishivering efficacy (Fig. 4). For instance, in a recent direct comparison, there was equivalence between meperidine 25 mg and clonidine 150 μg (55), and the league table suggested the same.
Third, when analyzing the control event rates (i.e., the incidence of shivering in placebo patients) it became obvious that the length of the observation period was a factor (Fig. 3). In such circumstances it was invalid to combine efficacy data that originated from different observation times. The relative efficacy of the different experimental interventions was, therefore, compared within similar observation periods only, and indeed the data within these periods were statistically homogenous. Because observation times were inconsistently reported and because many interventions were tested in no more than 1 trial each, only 5 regimens could be compared: meperidine 25 mg, doxapram 100 mg, clonidine 150 μg, ketanserin 10 mg, and alfentanil 250 μg after 5 minutes. One drug only was tested up to 30 minutes; this was ketanserin 10 mg, and it was not significantly different from placebo. Thus, the information on the relative efficacy of these drugs remains limited.
Reporting of adverse drug reactions was sparse. The problem then is that we do not know if adverse drug reactions did not occur, or if they were not reported. Typically opioid-related side effects, such as nausea, vomiting or respiratory depression, seemed to be rare with relatively small and single doses of morphine, fentanyl, alfentanil, meperidine, nalbuphine, or pentazocine. The absence of bradycardia and hypotension with clonidine up to 150 μg is less obvious; it may be cautious to titrate the clonidine.
The fact that simple regimens such as meperidine 25 mg are very effective in treating shivering patients begs the question as to whether more trials to investigate the efficacy of yet other drugs that may have some antishivering efficacy are actually needed. However, there were some weaknesses in almost all these trials; this may justify the definition of a research agenda. For instance, there was a lack of data on long-term outcome. Many trials stopped observations after only 5 or 10 minutes. Such short observation periods may not be long enough to identify the true efficacy of these interventions and their long-term effect on patients. Also, data on the efficacy of these drugs in children are lacking. Finally, because the time course plays a crucial role in this setting, it seems reasonable to report the time to the first treatment application to allow for meaningful comparisons between studies.
We thank Daniel Haake from the Medical libraries of the Center Medical Universitaire, Geneva University, Geneva, for his help in searching electronic databases. We are grateful to Keinosuke Nara, MD, PhD, Alexander Stetsenko, MD, and Greta Poglia, MD, who translated Japanese, Russian, and Italian papers.
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