Efficacy and safety of prophylactic use of ketamine for prevention of postanesthetic shivering: a systematic review and meta analysis

Background Postanesthetic shivering is a common complication of anesthesia, which accounts for much discomfort in postoperative patients and may increase postoperative complications in high-risk patients. Due to the lack of high-quality evidence, it is difficult to draw a conclusion about optimal anti-shivering medication. The main purpose of this meta-analysis was to analyze and evaluate the efficacy and safety of prophylactic use of ketamine for preventing postanesthetic shivering. Methods We searched the following databases: Medline, Embase, and the Cochrane Central Register of Controlled Trails for randomized controlled trials. The primary outcome observed was the difference of the incidence rate of postanesthetic shivering between ketamine group and placebo group. The secondary outcomes were the sedation score and incidence of the side effects caused by ketamine and any other drugs utilized in the studies. Results In this meta-analysis, we analyzed a total of 16 trials including 1485 patients. Ketamine reduced the incidence rate of postanesthetic shivering compared to a placebo (odds ratio [OR]: 0.13, 95% confidence interval [CI]: 0.06 to 0.26, P<0.01). Regarding side effects, there was no evident variability of the incidence of nausea and vomiting. Usage of ketamine was associated with a lower rate of hypotension and bradycardia when compared to a placebo. Hallucinations were more frequently observed in patients who received higher doses of ketamine. No significant difference was found in the incidence of postanesthetic shivering with ketamine versus other pharmacological interventions. Conclusions Ketamine can prevent postanesthetic shivering without severe side effects. However, ketamine shows no advantage over other anti-shivering drugs.


Background
Postanesthetic shivering is a frequent complication of anesthesia, perhaps even aggravating pain. It is characterized by involuntary movement that may affect one or more muscle groups and is a very unpleasant and physiologically stressful experience. Postanesthetic shivering can interfere with electrocardiography (ECG) and oxygen saturation (SpO2) monitoring [1]. More importantly, it can increase oxygen consumption combined with minute ventilation and carbon dioxide production. Moreover, it is believed that postanesthetic shivering can increase mortality in the elderly and patients with coronary artery disease [2].
The aetiology of shivering is not sufficiently understood. Thermoregulatory and non-thermoregulatory factors may contribute to postoperative shivering including exposure to cold weather, inadequate pain control, and opioid withdrawal [3,4]. The gold standard for treatment and prevention has not yet been defined. A variety of pharmacological treatments and methods to reduce postoperative shivering have been used including meperidine, alfentanil, tramadol, magnesium sulfate, ondansetron, dolasetron, and dexmedetomidine [5][6][7][8][9]. Ketamine has also been used as an anti-shivering drug. It is a non-competitive Nmethy-D-aspartate (NMDA) receptor antagonist; it may prevent postanesthetic shivering by decreasing core-toperipheral heat distribution. Although many published literatures have investigated the potential effects of ketamine for prevention of postanesthetic shivering, there is no consensus regarding the appropriateness of this drug. Thus, an evidence-based understanding of the benefits and risks of ketamine would identify its rational and optimal use. We conducted the meta-analysis to assess the efficacy and safety of ketamine for the prevention of shivering in patients undergoing various surgical procedures.

Methods
This meta-analysis was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.

Criteria for considering studies for this review
The selection criteria were pre-established. Inclusion criteria were: (1) controlled clinical trial; (2) prophylactic use of ketamine compared with a placebo or other pharmacological interventions; (3) reported the incidence of postoperative shivering. Trials were not considered for the following reasons: (1) other anti-shivering drugs were also administrated during the anesthetic induction or maintenance period besides ketamine; (2) data from abstracts, letters, or reviews. We included any participants undergoing operative procedures with general or spinal anesthesia. The following outcomes were measured: (1) incidence of postanesthetic shivering; (2) sedation score; (3) incidence of other side effects.

Data collection and analysis
Two review authors (Y.Z., A.M.) independently screened all the titles and abstracts of the studies during the initial search to identify the included studies. After removing the duplicates, potentially relevant studies were retrieved in full-text version for the further assessment. We resolved any disagreement by discussion with another author (G. H. L) of our group.
Data extraction was conducted by two authors (Y.Z., A.M.) independently using the data collection form established previously. The following data were collected from each study: primary author, publication year, anesthetic methods, demographic characteristics of participants, surgery types, comparisons, and other nonpharmacological warming methods. We recorded the number of patients experiencing shivering in each group for dichotomous data.
We used the Review Manager software of the Cochrane Collaboration (RevMan 5.2) to perform the quantitative analysis. The results of dichotomous data are expressed as odds ratio (OR) and 95% confidence intervals (CIs). Heterogeneity testing was performed with Z score and X 2 statistical analysis; P < 0.1 was considered to indicate heterogeneity. The fixed effect model or the random effect model were applied according to the heterogeneity of the study. A fixed effect model was used when I 2 < 50%. We reported the results of included studies when the pooled analysis was not appropriate. Sensitivity and subgroup analysis were performed to explore the reason for the heterogeneity. Subgroup analysis was conducted based on the anesthetic methods, various doses of ketamine used, and the types of surgery. Publication bias was evaluated by Begg's test using Stata 13.1 software (Stata, College Station, TX, USA).

Assessment of the risk of bias in the included studies
Two authors (Y.Z., A.M.) independently assessed the following domains using the Cochrane 'Risk of bias' tool:

Sequence generation
Allocation concealment Blinding of participants, personnel Blinding of outcome assessment Incomplete outcome data Selective outcome reporting Other bias We completed 'Risk of bias' figures for each included study (Fig. 2). See more details in Appendix.

Publication bias
Begg's test showed that there was no publication bias for the primary outcome (p = 0.055).

Primary outcome Ketamine vs placebo
The incidence of postanesthetic shivering was compared between ketamine and a placebo in 13 trials including 1166 patients (Fig. 3). Ketamine has been shown to significantly decrease the incidence of shivering (pooled OR = 0.13; 95% CI: 0.06 to 0.26, P < 0.00001). There was significant and prominent heterogeneity for this outcome (I 2 = 74%). Begg's test showed that there was no risk of publication bias (P = 0.06). A subgroup analysis was performed to explore the evidence-based reason. In subgroup analysis of anesthetic methods, the heterogeneity was 67% in the GA (general anesthesia) group (Fig. 4). Sensitivity analysis was performed; a trial [22] was removed which utilized an air forced warmer intraoperatively, which showed a similar result favoring ketamine (pooled OR = 0.18; 95% CI: 0.09 to 0.37) and decreased heterogeneity (I 2 from 67 to 21%). Ketamine reduced the incidence of postanesthetic shivering in general anesthesia (pooled OR = 0.13; 95% CI: 0.06 to 0.26) and in spinal anesthesia (pooled OR = 0.08; 95% CI: 0.03 to 0.18). (Fig. 5) shows the subgroup analysis based on the dose of ketamine used in the included trials. Ketamine reduced the incidence of postanesthetic shivering at the dose of 0.25 mg/kg (pooled OR = 0.12; 95% CI: 0.03 to 0.52) and at the dose of 0.5 mg/kg (pooled OR = 0. 14; 95% CI: 0.07 to 0.28). We performed a subgroup analysis based on the type of surgery, as this may influence the incidence of postanesthetic shivering (Fig. 6). Ketamine significantly lowered the incidence of postanesthetic shivering in patients after orthopedic surgery (pooled OR = 0.32; 95% CI: 0.13 to 0.77). Among patients undergoing abdominal, cesarean section, urological, ENT or endoscopic surgery, ketamine also reduced the incidence of postanesthetic shivering.
Ketamine vs other pharmacological interventions A total of four studies [12,13,23,24] investigated the effect of ketamine on the prevention of shivering compared with pethidine. The pooled analysis showed a definite difference in favor of pethidine (pooled OR = 4.38; 95% CI: 1.76 to 10.92). No significant difference in postanesthetic shivering was found between ketamine and other pharmacological interventions (Fig. 7).

Secondary outcomes
Ketamine vs placebo Except for the other side effects (hypotension, bradycardia, hallucination), there was no significant difference in the incidence of postoperative nausea and vomiting (PONV) between ketamine and the placebo (pooled RR = 0.72; 95% CI: 0.48 to 1.08) ( Table 2). Ketamine reduced the incidence of hypotension and bradycardia compared with the placebo (pooled RR = 0.28; 95% CI: 0.17 to 0.47; pooled RR = 0.18; 95% CI: 0.05 to 0.65). The incidence of hallucination was more significant and prevalent in the patients who received 0.5 mg/kg ketamine (Table 3); there was only one episode of hallucination in patients receiving 0.25 mg/kg. A pooled analysis was not performed because of the lack of uniform sedation score scales in the trials. All of these studies showed that the patients in the ketamine group were more sedated compared to the placebo group. Five trials [14,16,17,19,23] reported a significant decrease in core temperature in both the ketamine and placebo groups compared to the baseline temperature of participants. However, it was not significant between groups, at any time point. Three trials [20][21][22] reported a significant difference in core temperature between ketamine and the placebo; a greater decrease in temperature was found in the placebo group. Ketamine vs other pharmacological interventions No significant difference was found in the incidence of PONV between ketamine and pethidine (pooled OR = 0.88; 95% CI: 0.38 to 2.07). Compared to tramadol, the difference in the incidence of PONV and hypotension is not significant (OR = 0.57; 95% CI: 0.18 to 178; OR = 0.90; 95% CI: 0.36 to 2.24). The incidence of PONV was higher in the ketamine group than the ondansetron group (OR = 4.49; 95% CI: 1.24 to 16.21). However, ketamine showed a lower incidence of hypotension compared to ondansetron (OR = 0.09; 95% CI: 0.00 to 3.23). Core temperature changes were reported graphically; there was no significant difference between ketamine and other pharmacological interventions.   Table 4.

Discussion
In the present study, we compared different randomized controlled trials to identify the beneficial aspects of ketamine. We compared the usage of ketamine and its relevance in anaesthetic shivering. In total, 16 studies including 1485 patients were analysed.
Ketamine was first synthesized in the early 1960s as a safe alternative to phencyclidine [26]. It is a noncompetitive -NMDA receptor antagonist with an effect of thermoregulation. Other than being a competitive NMDA receptor antagonist, ketamine also acts as an opioid agonist [27]. Further, it can cause blockage of amine uptake in the descending inhibitory monoaminergic pain pathways, having a local anaesthetic action and interacting with the muscarinic receptors [28]. In contrast, even at sub-anaesthetic doses, ketamine might cause a dissociative state, characterised by a sense of detachment from one's physical body and the external world (depersonalization and derealization). Ketamine probably controls shivering by acting on non-shivering thermogenesis [29]. Ketamine is predominantly utilized as an anaesthetic agent that induces analgesia but for a long time it has been criticized for some of its side effects which include the induction of a psychedelic state causing agitation and hallucinations [30].
The key findings of our analysis are as follows. Ketamine exposure was relatively better in reducing the occurrence of postanaesthetic shivering compared to placebo. Compared with tramadol and ondansetron, ketamine slightly lowered the incidence of postanaesthetic shivering although not significantly. The effect of ketamine on postanaesthetic shivering remained equally beneficial for both spinal and general types of anaesthesia. A dose of 0.5 mg/kg had an advance effect compared to 0.25 mg/kg on the postanaesthetic shivering rate. The effect remained constant for all types of surgical procedures including orthopaedic surgery, laparotomy, caesarean section, urological, ENT, and endoscopic surgeries. Compared to ketamine, pethidine showed a quicker responsive rate. However, sufficient data was not available in other studies to show any advantage of other pharmacological interventions.
Furthermore, we evaluated the side effects of the anaesthetic drugs and the role of ketamine in preventing or overcoming the effects. Moreover, the efficacy of ketamine was compared with a placebo. The side effects observed in the trials were nausea, vomiting, hypotension, bradycardia, and hallucinations. Ketamine showed a favourable outcome in reducing the incidence rate of hypotension and bradycardia as ketamine causes dose dependent direct stimulation of the CNS which leads to increased sympathetic nervous system stimulation followed by increased systemic blood pressure and heart rate.
However, there was no effect of ketamine in decreasing the incidence rate of nausea and vomiting as compared to placebo. As ketamine is known to have a hallucinogenic effect, it is considered to have a potential role in glutamatergic signalling in psychosis; therefore, the usage of ketamine is suggested to be associated with auditory and verbal hallucinations. In our comparative study, we also found that the rate of occurrence of hallucination episodes was much higher in patients receiving a ketamine dose of 0.5 mg/kg compared to a lower dose of 0.25 mg/kg. The hallucinogenic effect of ketamine was evident when compared with the placebo drugs, for which there was no incidence of hallucinations reported in any of the trials. Ketamine can cause sedation in postoperative patients and deep sedation is considered to be a severe adverse event. However, for those experiencing shivering, mild sedation may prevent them from hurting themselves. In our study, we paid special attention to the sedation score of patients, although pooled analysis was not conducted because of various sedation scales. We found that mild to moderate sedation was more commonly seen in patients receiving different doses of ketamine.
Besides various pharmacological interventions above, we noticed that active warming for elective caesarean delivery reduced the incidence of postoperative shivering and provided more stable perioperative temperature change [31] . Accumulating evidence has shown that the active warming method including electric heating, water-circulating garments, forced-air, and radiant heating is effective in preventing post-anaesthetic shivering. The current American Society of Anesthesiologists Task Force on Postanesthetic Care guidelines recommend forced-air warming as a common method to reduce shivering in the perioperative setting [32] . Future research should focus on combinations of pharmacological interventions with non-pharmacological methods to better solve this problem. The major limitation of our study is that we could not study the hemodynamical changes related to ketamine usage as there were no standard criteria being followed by the trials causing irrelevancy and uneven data for comparing and evaluating precise outcomes in this regard. Second, the sample size of included trials was relatively small which may decrease generalisability of our conclusions. Third, the evidence level for our outcomes was low or very low. However, we believe that our study is of value because it provided clear evidence of the benefit of prophylactic ketamine intervention for preventing post-anaesthetic shivering which may be helpful in clinical practice.

Conclusion
In this meta-analysis, we assessed various aspects of ketamine usage in controlling post-anaesthetic shivering. We found that ketamine reduced the incidence rate of shivering compared to the placebo. Although it is beneficial, it did not show any superiority over other pharmacological interventions. Ketamine is of clinical value, but further studies should be performed on a wider scale to determine more emphasized results. Furthermore, larger clinical trials investigating the combination of different anti-shivering regimens are warranted.    The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) CI Confidence interval; OR Odds ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: We are very uncertain about the estimate