Efficacy spectrum of antishivering medications: meta-analysis of randomized controlled trials

Shivering after anesthesia or in the critical care setting is frequent, can be prolonged, and has the potential for serious adverse events and worsening outcomes. Furthermore, there are conflicting published data and clinical protocols on how to best treat shivering. In this study, we aimed to critically analyze the published evidence of antishivering medications.

We systematically reviewed, categorized, and analyzed all literature on antishivering medications published in English. Target key words and study types were determined and major scientific databases (PubMed, EMBASE, the Cochrane Controlled Trials Register, Ovid-Medline, and JAMA Evidence) and individual target journals were systematically searched up to August 1, 2011.

Publications were categorized by the pharmacological intervention used, regardless of whether the subjects were ventilated, underwent surgery, received anesthesia, or received additional medications. Randomized, double-blinded, placebo-controlled trials investigating antishivering treatment were extracted and evaluated for clinical and statistical homogeneity and, if suitable, included in a subsequent meta-analysis using linear comparisons calculating shivering risk-reduction ratios.

A total of 41 individual and eight combination antishivering medications were tested in 124 publications containing 208 substudies and recruiting a total of 9,668 subjects. Among those, 80 publications containing 119 substudies were identified as randomized, double-blinded, placebo-controlled of which 94 substudies were subjected to linear comparison analysis.

Study drug frequencies, calculated pooled risk benefits, and pooled numbers needed to treat of the five most frequently studied and efficacious medications were clonidine (22 studies; risk ratio: 1.6, numbers needed to treat: 4), meperidine (16; 2.2, 2), tramadol (8; 2.2, 2), nefopam (7; 2.1, 2), and ketamine (7; 1.8, 3).

There is significant heterogeneity in the literature with respect to study methods and efficacy testing of antishivering treatments. Clonidine, meperidine, tramadol, nefopam, and ketamine were the most frequently reported pharmacological interventions and showed a variable degree of efficacy in randomized, double-blinded, placebo-controlled trials.