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Effectiveness of Magnesium in Preventing Shivering in Surgical Patients: A Systematic Review and Meta-analysis

Kawakami, Hiromasa MD*; Nakajima, Daisuke MD; Mihara, Takahiro MD, PhD‡,§; Sato, Hitoshi MD*; Goto, Takahisa MD, PhD§

doi: 10.1213/ANE.0000000000004024
Anesthetic Clinical Pharmacology
Free
SDC

BACKGROUND: Clinical trials regarding the antishivering effect of perioperative magnesium have produced inconsistent results. We conducted a systematic review and meta-analysis with Trial Sequential Analysis to evaluate the effect of perioperative magnesium on prevention of shivering.

METHODS: We searched PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and 2 registry sites for randomized clinical trials that compared the administration of magnesium to a placebo or no treatment in patients undergoing surgeries. The primary outcome of this meta-analysis was the incidence of shivering. The incidence of shivering was combined as a risk ratio with 95% CI using a random-effect model. The effect of the route of administration was evaluated in a subgroup analysis, and Trial Sequential Analysis with a risk of type 1 error of 5% and power of 90% was performed. The quality of each included trial was evaluated, and the quality of evidence was assessed using the Grading of Recommendation Assessment, Development, and Evaluation approach. We also assessed adverse events.

RESULTS: Sixty-four trials and 4303 patients (2300 and 2003 patients in magnesium and control groups, respectively) were included. The overall incidence of shivering was 9.9% in the magnesium group and 23.0% in the control group (risk ratio, 0.42; 95% CI, 0.33–0.52). Subgroup analysis revealed that the incidence of shivering was lower with IV (risk ratio, 0.29; 95% CI, 0.29–0.54; Grading of Recommendation Assessment, Development, and Evaluation, moderate), epidural (risk ratio, 0.24; 95% CI, 0.13–0.43; Grading of Recommendation Assessment, Development, and Evaluation, low), and intrathecal administration (risk ratio, 0.64; 95% CI, 0.43–0.96; Grading of Recommendation Assessment, Development, and Evaluation, moderate). Only trials with low risk of bias were included for Trial Sequential Analysis. The Z-cumulative curve for IV magnesium crossed the Trial Sequential Analysis monitoring boundary for benefit even though only 34.9% of the target sample size had been reached. The Z-cumulative curve for epidural or intrathecal administration did not cross the Trial Sequential Analysis monitoring boundary for benefit. No increase in adverse events was reported.

CONCLUSIONS: Perioperative IV administration of magnesium effectively reduced shivering and Trial Sequential Analysis suggested that no more trials are required to confirm that IV magnesium effectively reduces shivering.

From the *Department of Anesthesiology

Intensive Care Department, Yokohama City University Medical Center, Yokohama, Japan

Education and Training Department, Yokohama City University Hospital, YCU Center for Novel and Exploratory Clinical Trials, Yokohama, Japan

§Department of Anesthesiology, Yokohama City University, School of Medicine, Yokohama, Japan.

Published ahead of print 12 December 18.

Accepted for publication December 12, 2018.

Funding: This study was supported by funding from the Department of Anesthesiology, Yokohama City University, Yokohama, Japan.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Trial registry number: CRD42018083337 (PROSPERO). URL: www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42018083337.

Reprints will not be available from the authors.

Address correspondence to Hiromasa Kawakami, MD, Department of Anesthesiology, Yokohama City University Medical Center, Urafunecho 4-57 Minamiku Yokohama, Kanagawa 232-0024, Japan. Address e-mail to hiro.k210@gmail.com.

Shivering is common during the perioperative period. It can increase the oxygen demand of the body and may induce myocardial ischemia. Despite rigorous efforts to prevent hypothermia, many patients suffer from perioperative shivering.1 Younger age, endoprosthetic surgery, low core temperature, and longer duration of surgery were considered as risk factors for postoperative shivering in a previous trial.2 Pharmacological intervention may reduce the incidence of shivering. Drugs such as dexmedetomidine,3 5-hydroxytryptamine 3 receptor antagonists,4 and meperidine5 have been demonstrated to have antishivering effects, but their cost is prohibitive, and their safety is questionable.

Perioperative magnesium may reduce the need for anesthetic agents,6,7 neuromuscular blocking agents,6 and opioids.8–10 In a previous meta-analysis,5 combined data from 3 trials showed that magnesium reduced the incidence of shivering. Results from other meta-analyses are inconsistent.9–12 This may be because the meta-analyses included only a few trials that evaluated primary outcomes. Many trials in which shivering was evaluated as one of the secondary outcomes or adverse events were not included. The quality of evidence in those trials has not been evaluated. Thus, it was still unclear how effective perioperative magnesium is in preventing shivering. Moreover, magnesium has been administered intravenously, epidurally, or intrathecally, even though neuraxial magnesium is considered off-label and investigational. The difference of antishivering effect of magnesium according to the route of administration has not been evaluated.

In this review, we searched for randomized clinical trials that compared perioperative magnesium administration with a control and included trials that evaluated the incidence of shivering. The primary objective of this study was to evaluate the effectiveness of perioperative magnesium in preventing shivering. A secondary objective was to examine side effects associated with magnesium administration.

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METHODS

This study was a systematic review with meta-analysis and Trial Sequential Analysis. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement13 and the Cochrane Handbook.14 Our study protocol and methods were prespecified and are registered on PROSPERO (CRD42018083337). They can be accessed at www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42018083337.

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Search Strategy

The PubMed, Cochrane Central Register of Controlled Trials, EMBASE, and Web of Science databases were searched from inception to December 8, 2017 without language restrictions. We also searched clinicaltrials.gov and the UMIN Clinical Trials Registry on December 10, 2017. The PubMed search strategy is outlined in Supplemental Digital Content 1, Text 1, http://links.lww.com/AA/C705. Related reviews and reference lists were manually scrutinized for any relevant trials not identified through the strategy described above.

Two out of 3 authors (H.K., D.N., H.S.) independently examined titles and abstracts of reports identified by the search strategies described above to exclude irrelevant articles. The complete article was retrieved if eligibility could not be determined from the title or abstract. Potentially relevant studies, chosen by ≥1 author, were retrieved, and full-text versions were evaluated. Articles that met the inclusion criteria were assessed separately by 2 authors (H.K., D.N.), and discrepancies were resolved through discussion.

We searched for randomized clinical trials that evaluated the incidence of shivering after the administration of magnesium compared with a placebo or no medication in patients expected to be extubated after surgery. We excluded studies in which patients underwent surgeries with cardiopulmonary bypass or in which patients were not expected to be extubated after surgery. We excluded studies that did not report shivering, in which the subjects were not surgical patients, and in which oral magnesium was compared with a placebo. We also excluded data from case reports, observational studies, comments, letters to the editor, reviews, and animal studies.

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Outcomes

The primary outcome was the incidence of postoperative or intraoperative shivering. For patients who underwent general anesthesia, we evaluated only postoperative shivering because intraoperative shivering could be masked with neuromuscular blocking agents or other medications. For patients who did not undergo general anesthesia, we evaluated the overall incidence of shivering during the intraoperative and postoperative periods. If the number of patients with shivering was recorded at multiple time points and the overall incidence of shivering was not reported, we considered shivering at the earliest time point after the surgery as the shivering of the trial. If shivering was reported at multiple time points only intraoperatively, we used the latest time point during the surgery. When scales were used, we considered existence of visible tremor as shivering. We did not limit the timing of observation of shivering because shivering is an important outcome during the whole perioperative period because it is unpleasant to patients and can cause cardiopulmonary problems. Secondary outcomes included serum magnesium concentration before and after surgery, time to extubation after surgery, length of postanesthetic care unit (PACU) stay, length of hospital stay, and adverse events.

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Data Collection

A data collection sheet was created. It included the (1) number of patients in the study, (2) age, (3) American Society of Anesthesiologists physical status, (4) type of anesthesia, (5) anesthetic agents used, (6) type of surgery, (7) route of magnesium administration, (8) bolus dose of magnesium, (9) continuous dose of magnesium, (10) timing of magnesium administration as bolus, (11) estimated duration of continuous infusion, (12) number of cases with shivering, (13) serum magnesium concentration, (14) time to extubation, (15) length of PACU stay, (16) length of hospital stay, and (17) adverse events. Two authors (H.K., D.N.) independently extracted the data from the included studies using a piloted form and cross-checked the data. When the incidence of shivering was not available in the literature even though it was recorded, we attempted to contact the corresponding author.

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Risk of Bias

We followed the Cochrane Handbook for Systematic Reviews of Interventions.14 We assessed the risk of bias in sequence generation, allocation sequence concealment, the blinding of patients or health care providers, the blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other biases. The risk of bias was classified into 3 categories: low, high, or unclear. Two authors (H.K, D.N.) evaluated the risk of bias in each trial. When there was a difference in the evaluations of bias, the 2 authors discussed their evaluations and reached a consensus. Trials with ≥1 risks of bias classified as unclear or high were considered to be trials with high risk of bias.

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Statistical Analysis

We compare the incidence of shivering and other dichotomous data with the risk ratio. The mean difference was used to combine continuous data. We summarized the risk ratio and mean difference with a 95% CI. In multi-arm trials with different doses of magnesium, the intervention group was combined and included all the patients who received magnesium of any dose from 1 route of administration, and a single pair-wise comparison was made between the combined intervention group and the control group. In multi-arm trials with different routes of magnesium administration, we needed to compare each route of administration with the control group. In these trials, we divided the total number of patients and the number of patients with shivering in the control group evenly by the number of intervention groups and compared each intervention group with the divided control group as described in the Cochrane handbook.14 If the 95% CI included a value of 1 for the risk ratio and 0 for the mean difference, the difference between the magnesium and control groups was not considered statistically significant. We used a random-effect model to assess the treatment effect across studies. Heterogeneity was quantified with the I2 statistic. An I2 value of 30–60 indicated moderate heterogeneity, while a value >60 indicated considerable heterogeneity. Forest plots were used to graphically represent and evaluate the effects of treatment. When the necessary data were available, we conducted a subgroup analysis to evaluate the difference in the effects according to the route of magnesium administration.

Small-study effects were assessed using a funnel plot and Egger’s regression asymmetry test15 when the number of studies was ≥10 and were considered to be positive if P < .1. The funnel plot was used to display the small-study effect, a tendency for the intervention effects estimated in smaller studies to be larger.16 Publication bias is one of the causes of small-study effects. When the funnel plot was asymmetrical, we considered that there was a possibility of publication bias.

Sensitivity analyses were performed for the primary outcome according to the risk of bias (low versus high) to evaluate whether the result was robust.

For our primary outcome, Trial Sequential Analysis was performed to correct for the increased type 1 error associated with repeated meta-analysis testing over time. The risk of type 1 error was maintained at 5% with a power of 90%. A risk ratio of 0.75 for the incidence of shivering was considered clinically significant. If the Trial Sequential Analysis–adjusted CI included a value of 1, the difference was not considered statistically significant, but it may become significant with further studies. When the Z-cumulative curve crossed the Trial Sequential Analysis monitoring boundary for futility on the graph, it was considered that there was enough evidence to conclude that the difference was not greater than the predetermined clinically significant difference, a risk ratio of 0.75 in this study.

The Review Manager (RevMan, version 5.3.5; The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark) was used for meta-analyses, and the R statistical software package (version 3.3.0; R Foundation for Statistical Computing, Vienna, Austria) was used for analysis of the small-study effect. Trial Sequential Analysis was performed using TSA viewer version 0.9.5.10 Beta (Copenhagen Trial Unit, Copenhagen, Denmark; www.ctu.dk/tsa).

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Quality of Evidence

We graded the quality of evidence of the main outcome using the Grading of Recommendations Assessment, Development, and Evaluation approach.17,18 Judgments of the quality of evidence were based on the presence or absence of the following: risk of bias, inconsistency, indirectness, imprecision of the results, and publication bias. The quality of evidence for the main outcome was graded as very low, low, moderate, or high. We formulated a table to summarize the findings using GRADEpro GDT (GRADEpro Guideline Development Tool, McMaster University, 2015, developed by Evidence Prime, Inc, Hamilton, Canada; https://gradepro.org/).

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RESULTS

In the initial search, 3294 publications were identified. Sixty-four trials were included in the meta-analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram detailing the disposition of retrieved publications is shown in Figure 1. Because we could not obtain some articles, we tried to contact the journal offices. However, the full texts of 11 articles19–29 were not available. Because the incidence of shivering and other data could be derived from the abstract of one of these articles, this trial29 was included. Some trials showed that the incidence of shivering was similar in both intervention and control groups, and in other trials, the number of patients with shivering was not reported. Some authors indicated that the incidence of shivering would be reported but then failed to do so or only reported that the incidence was similar. We tried to contact the corresponding authors of these articles to ask for the number of patients with shivering and other relevant information. Two authors responded (R. Farías López, Department of Anesthesiology, Dr Miguel Pérez Carreño Hospital, Caracas, Venezuela, and J. Y. Hwang, Department of Anesthesiology and Pain Medicine, SMG-SNU Boramae Medical Center College of Medicine, Seoul National University, Korea, personal communication, 2018).30,31 Four trials32–35 were excluded, because the authors did not respond. All of the included articles were written in English, with the exception of 6 published in Persian,36–38 Korean,39,40 and Turkish.41

Figure 1.

Figure 1.

The characteristics of the included trials are shown in Supplemental Digital Content 2, Table 1, http://links.lww.com/AA/C706. The evaluated trials included data from 4303 subjects; 2300 of them received magnesium (1114 with IV administration in 35 trials,29–31,36–67 440 with epidural administration in 12 trials,68–79 638 with intrathecal administration in 16 trials,67,80–94 and 108 via other routes in 4 trials59,67,95,96). All trials compared magnesium sulfate with a placebo or no medication. Two trials compared multiple routes of magnesium administration.59,67

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Synthesis of Results

Figure 2.

Figure 2.

Conventional meta-analysis showed a significantly lower incidence of shivering in patients who received magnesium (risk ratio, 0.42; 95% CI, 0.33–0.52; P < .00001; I2 = 43%). As there were a sufficient number of trials, a subgroup analysis was conducted according to the route of administration. The incidence of shivering was significantly reduced in the magnesium group with IV administration (risk ratio, 0.39; 95% CI, 0.29–0.54; I2 = 50%; n = 2124), epidural administration (risk ratio, 0.24; 95% CI, 0.13–0.43; I2 = 21%; n = 880), and intrathecal administration (risk ratio, 0.64; 95% CI, 0.43–0.96; I2 = 14%; n = 1120), but not with intra-articular administration (risk ratio, 1.01; 95% CI, 0.46–2.19; I2 = 0%; n = 81) (Figure 2).

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Risks of Bias

The risks of bias in the included trials are summarized in Figure 2. Twenty-one trials were considered to have low risk of bias; the rest were considered to have high risk of bias.

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Sensitivity Analysis

Sensitivity analysis was conducted according to the risk of bias. When only trials with low risk of bias were included, the incidence of shivering was reduced in the magnesium group with IV administration (risk ratio, 0.22; 95% CI, 0.13–0.38; I2 = 0%), epidural administration (risk ratio, 0.20; 95% CI, 0.08–0.51; I2 = 0%), and intrathecal administration (risk ratio, 0.45; 95% CI, 0.29–0.70; I2 = 0%). Note that I2 was 0% for all 3 routes of administration, and risk ratios were relatively smaller than those of the analysis with all trials included.

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Small-Study Effect

Because there were a sufficient number of studies, the small-study effect was examined in regard to the route of administration. A funnel plot of IV administration showed asymmetrical distribution (Supplemental Digital Content 3, Figure 1A, http://links.lww.com/AA/C707). Egger’s regression asymmetry test was positive with a P value of <.0001. When the analysis was limited to trials with a low risk of bias, the funnel plot appeared asymmetrical even though the asymmetry test was negative with a P value of .12 (Supplemental Digital Content 3, Figure 1B, http://links.lww.com/AA/C707). A funnel plot of epidural administration was also asymmetrical, and the P value was .035 (Supplemental Digital Content 3, Figure 1C, http://links.lww.com/AA/C707). The small-study effect in the intrathecal administration was negative with a P value of .45 (Supplemental Digital Content 3, Figure 1D, http://links.lww.com/AA/C707). A limited analysis of studies with low risk of bias was not conducted for epidural or intrathecal injection because the number of studies with low risk of bias was small. We considered there is a possibility of publication bias in IV and epidural magnesium administration.

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Trial Sequential Analysis

Because there were a number of trials with low risk of bias, Trial Sequential Analysis was conducted according to the route of administration. Only studies with low risk of bias were included. The estimated required information size for IV administration was 1839. Even though the accrued information size reached only 34.9%, the cumulative Z-curve for IV administration crossed the Trial Sequential Analysis monitoring boundary for benefit (Figure 3A), which indicated that there were sufficient data to support the shivering prevention effect of IV magnesium, and that more trials are not necessary to reach a conclusion. The Trial Sequential Analysis–adjusted CI ranged from 0.19 to 0.25. While the required information size for epidural administration of magnesium was 3408, the accrued information size was 410 (12.0%). For intrathecal administration, the required information size was 2428, and the accrued information size was 560 (23.1%). The Z-curve for epidural or intrathecal magnesium did cross the dotted horizontal lines, which represented a Z value of +1.96, but it did not cross the Trial Sequential Analysis monitoring boundary for efficacy or futility. This suggests that though there was statistically significant difference if adjustment was not made for repeated testing, the difference did not remain statistically significant when repeated testing was taken into account. Thus, sufficient data have not been accumulated to determine conclusively whether epidural or intrathecal magnesium prevents shivering in surgical patients (Figure 3B, C). The Trial Sequential Analysis–adjusted CIs ranged from 0.00 to 9.21 for epidural administration and from 0.17 to 1.21 for intrathecal administration.

Figure 3.

Figure 3.

To explore the source of heterogeneity in the use of IV magnesium, a post hoc subgroup analysis was conducted according to the total amount of magnesium. We estimated the duration of continuous magnesium administration and calculated the total amount of administered magnesium in each trial as the sum of the initial bolus and continuous dose, which is continuous rate multiplied by duration of continuous infusion. We used average weight from the trial to convert the unit of amount to mg kg−1 when necessary. The median value of the total amount was 60 mg kg−1. We divided the trials into a low-dose category (<60 mg kg−1) and high-dose category (≥60 mg kg−1).

Compared with the control, the incidence of shivering was reduced both in high-dose (risk ratio, 0.45; 95% CI, 0.28–0.71; I2 = 51%) and low-dose (risk ratio, 0.35; 95% CI, 0.23–0.52; I2 = 43%) categories (Supplemental Digital Content 3, Figure 2, http://links.lww.com/AA/C707). The heterogeneity was moderate in both subgroups, and the difference in treatment effect between the categories was not statistically significant (P = .41).

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Adverse Events

The time to extubation was evaluated in 4 trials,49,54,55,60 but there was no significant difference in time to extubation between the groups in all 4 trials. Owing to heterogeneity, we did not combine the time to extubation.

The length of PACU stay was evaluated in 1 trial,60 and the length of hospital stay was not evaluated in any. The length of PACU stay was shorter in the IV magnesium group than in the placebo group (53 vs 63 minutes; P = .04).60

The serum concentration of magnesium was reported in 9 trials30,39,42,43,48,52,59,64,66 that used IV magnesium. There was no statistically significant difference in preoperative concentrations. Postoperative measurements were taken during the first hour after surgery. One trial66 was excluded from the meta-analysis because the unit for reporting the concentration was not documented and the corresponding author could not be reached. We combined the concentration with the mean difference, after converting the unit to mmol L−1. The concentration was significantly higher in the magnesium group, and there was considerable heterogeneity (mean difference, 0.39; 95% CI, 0.28–0.50; I2 = 100%) (Supplemental Digital Content 3, Figure 3, http://links.lww.com/AA/C707).

Serious adverse events such as permanent neurologic damage or fatal dysrhythmia were not reported in any trials.

Nausea and/or vomiting was reported in 54 trials.30,36,37,39,40,44–58,60,61,63–77,79–88,90–94,96 The incidence was lower in the IV magnesium group than in the control group (risk ratio, 0.83; 95% CI, 0.69–0.99; I2 = 4%), but there was no difference between the groups with epidural (risk ratio, 0.66; 95% CI, 0.44–1.00; I2 = 0%) or intrathecal administration (risk ratio, 0.98; 95% CI, 0.74–1.29; I2 = 0%) (Supplemental Digital Content 3, Figure 4, http://links.lww.com/AA/C707).

Incidence of sedation was reported in 16 trials,37,43,51,54,64,65,68,71,73–75,85,87,90,92,94 and in 11 of them, no patients were sedated in either group. Meta-analysis revealed that there was no significant difference between groups (risk ratio, 1.54; 95% CI, 0.81–2.95; I2 = 0%) (Supplemental Digital Content 3, Figure 5, http://links.lww.com/AA/C707). Eight trials49,52,56,61,79,83,84,89 reported a sedation score for each group. One trial reported that the sedation score was higher in the magnesium group,61 and another reported that it was higher in the control group.79 The remaining 6 trials reported that there was no significant difference.49,52,56,83,84,89

Pruritus was reported in 22 trials.37,42,43,50,67,69,70,72–74,77,79–83,85–87,91,92,94 The incidence was lower in the magnesium group with IV administration (risk ratio, 0.48; 95% CI, 0.30–0.75; I2 = 0%), but there was no difference with epidural (risk ratio, 1.49; 95% CI, 0.46–4.89; I2 = 0%) or intrathecal administration (risk ratio, 1.03; 95% CI, 0.72–1.46; I2 = 0%) (Supplemental Digital Content 3, Figure 6, http://links.lww.com/AA/C707).

Hypotension was reported in 36 trials.30,36,39,41,42,44,46,48,49,56,57,59,60,65,66,68–71,73,74,78–86,88,90,92–95 The overall incidence was similar in all trials (risk ratio, 0.91; 95% CI, 0.79–1.03; I2 = 0%), and no difference was observed in subgroup analysis according to the route of administration (Supplemental Digital Content 3, Figure 7, http://links.lww.com/AA/C707). In 15 trials,40,43,51,52,54,55,58,61,63,64,67,75–77,87,89 hypotension was not reported, but blood pressure was recorded after administration of the study drug. In 10 of the trials, blood pressures were similar between the groups,40,43,51,52,55,58,63,67,75,76 and 5 reported that blood pressures were lower in the magnesium group at some point.54,61,64,77,87

Bradycardia was reported in 32 studies.30,36,39,41,42,46,48,49,51,56,57,59,61,65,68,70,71,73,74,78–80,82–86,88,90,93,95 The overall incidence did not vary (risk ratio, 0.85; 95% CI, 0.66–1.08; I2 = 0%), and no difference was observed in subgroup analysis according to the route of administration (Supplemental Digital Content 3, Figure 8, http://links.lww.com/AA/C707). In 12 trials,40,43,52,54,55,58,63,64,67,75,77,87 bradycardia was not reported, but heart rate (HR) was compared between the groups. In 9 of them, the HR was not significantly different.40,43,52,55,58,63,67,75,87 The remaining 3 reported that the HR was lower in the magnesium group at some point after administration of the study drug.54,64,77

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Grading of Recommendation Assessment, Development, and Evaluation

The quality of evidence was evaluated for each route of administration. The Grading of Recommendation Assessment, Development, and Evaluation for the effect of IV, epidural, and intrathecal magnesium for shivering prevention was moderate, low, and moderate, respectively (Supplemental Digital Content 4, Table 2, http://links.lww.com/AA/C708). The quality of evidence of IV administration was not downgraded by inconsistency because I2 was 0% when the analysis was limited to studies with low risk of bias, even though it was 50% when all IV administration was included. The Grading of Recommendation Assessment, Development, and Evaluation of IV magnesium was downgraded due to publication bias because the funnel plot was asymmetrical. The Grading of Recommendation Assessment, Development, and Evaluation of epidural administration was downgraded due to publication bias demonstrated by a funnel plot and Egger’s asymmetry test. The quality of evidence regarding epidural and intrathecal magnesium was downgraded due to imprecision because the Trial Sequential Analysis–adjusted CI included the value of 1.

The quality of evidence of intra-articular magnesium for shivering prevention was very low due to limitations of the study designs, imprecision, possible publication bias, and inconsistency.

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DISCUSSION

Our meta-analysis demonstrated that IV magnesium effectively reduces the incidence of shivering (Grading of Recommendation Assessment, Development, and Evaluation; moderate). Epidural (Grading of Recommendation Assessment, Development, and Evaluation; low) and intrathecal administration (Grading of Recommendation Assessment, Development, and Evaluation; moderate) were also effective. Perioperative magnesium did not increase the occurrence of adverse events.

IV magnesium was effective in preventing shivering, and the Grading of Recommendation Assessment, Development, and Evaluation was moderate. Funnel plots of trials with low risk of bias and of all trials appeared asymmetrical, and the quality was downgraded by publication bias. When analysis was limited to studies with low risk of bias, the Z-cumulative curve crossed the Trial Sequential Analysis boundary of benefit, and I2 was 0%, which indicates that there was little heterogeneity. The Grading of Recommendation Assessment, Development, and Evaluation was not downgraded by limitation of study design, precision, or heterogeneity. More trials are not required to prove IV magnesium effectively reduces shivering. In previous meta-analyses on the topic, only a few studies were included, and, to our knowledge, the quality of evidence has not been assessed.

Neuraxial magnesium was also effective in reducing the incidence of shivering, but the quality of evidence was lower. It was downgraded due to imprecision; the Z-cumulative curve did not cross the Trial Sequential Analysis monitoring boundary for benefit even though it crossed the conventional test boundary.

This meta-analysis could be considered as an update to the previous systematic review by Park et al,5 but some aspects were different between the studies. First, the word “shivering” was used for the literature search in their analysis, while we examined all the randomized control trials comparing magnesium and control. In addition, our search was without language restriction, while they limited the publications to those written in English. Therefore, our search not only covered the latest publications, but it was broader in scope. Moreover, in their meta-analysis, the antishivering effect was summarized using “risk-benefit.” We reconstructed their analysis from our result and found that risk-benefit is the risk ratio of not-shivering, and a risk-benefit of 2 indicates that patients receiving shivering treatment are not half times as likely to shiver, as they described, but 2 times as likely not to shiver. Thus, it is impossible for the risk-benefit to be >2.0 when nonshivering patients in the control group is >50%, no matter how effective the treatment might be. Because the incidence of nonshivering in the control groups varied substantially among the medications, it is practically meaningless to compare the antishivering effect of each medication using risk-benefit or number needed to treat in their analysis.

The cost of magnesium administration is low, and our meta-analysis showed that IV magnesium was not associated with an increased incidence of adverse outcomes. Thus, administering magnesium to patients who are at high risk of shivering, such as those who are young or undergoing long surgery, should be considered to prevent unpleasant shivering. In addition, patients who have limited cardiac reserve and would suffer from cardiac compromise due to shivering would benefit from active warming and pharmacological prevention of shivering. Even though there was no difference in the incidence of hypotension with magnesium administration in the included trials, close monitoring would be important when magnesium is administered to those who have limited cardiac reserve because even small vasodilatation might cause significant hemodynamic change in those patients.

The mechanism by which magnesium exerts its antishivering effect is unclear. During general or neuraxial anesthesia, body temperature tends to drop due to vasodilation.97–99 Vasoconstriction and shivering are autonomic thermoregulatory mechanisms for the prevention of hypothermia. Shivering increases oxygen consumption and carbon dioxide production,100 but it requires peripheral muscular oxygenation and it causes vasodilatation which counteracts vasoconstriction.99 It may not be so effective in preventing hypothermia, but it can still be deleterious to patients with limited cardiac reserve. General anesthesia97,98 and neuraxial anesthesia101 have been reported to decrease the shivering threshold, the temperature below which patients shiver. While in some trials intrathecal89 and IV51,57 magnesium administration was associated with lower body temperature by 1–2°C at some point after spinal anesthesia, which is thought to be due to vasodilatory effect of magnesium, the incidence of shivering was reduced with magnesium administration. This may be because, as demonstrated in healthy volunteers, magnesium reduces the shivering threshold.102 Shivering could be protective against hypothermia, but Faiz et al89 demonstrated that patients who did not receive intrathecal magnesium were associated with postoperative hyperthermia, with a core temperature of around 39°C, while patients who received intrathecal magnesium remained normothermic. Shivering is uncomfortable and can occur in normothermic surgical patients.57 Hypothermia should be treated or prevented with warming devices.

The dose–response relationship of magnesium for the prevention of shivering is unclear. Our post hoc subgroup analysis conducted according to the IV dose indicated that >60 mg kg−1 of magnesium sulfate will not further reduce the incidence of shivering, but we could not determine the optimal dose from our results. The lowest dose intravenously administered among the included trials was 2.48 mmol (300 mg of magnesium sulfate), and, though there was no statistical difference, the incidence of shivering was lower in the magnesium group. Of note, only 12 among the included studies comparing IV magnesium demonstrated a significant reduction in the incidence of shivering. We cannot conclude that IV magnesium sulfate as low as 300 mg was not effective in reducing the incidence of shivering. Further trials evaluating the minimal effective dose would be interesting.

The incidence of adverse events did not increase with magnesium administration. Magnesium reportedly has a sedative effect, but perioperative administration of magnesium did not result in sedation in our review. Though magnesium has been shown to prolong the effect of neuromuscular blocking drugs,103,104 the time to extubation was not significantly prolonged in patients administered magnesium in the included trials. Magnesium has been associated with nausea and/or vomiting in some patient populations,105,106 but this association was not observed in the perioperative period. This may be related to the opioid-sparing effect of magnesium.10

Some of the trials reported that blood pressure or HR was significantly lower after administration of magnesium.54,77 Some demonstrated that an increase in HR or blood pressure was blunted,64 but the incidence of hypotension or bradycardia was not significantly reduced in the magnesium group in our analysis. IV magnesium was associated with decreased incidence of pruritus, which contradicts a previous meta-analysis.11 Neither the previous meta-analysis nor ours included all the trials that evaluated the preventive effect for pruritus. This may be worth investigating in the future.

The strengths of this systematic review and meta-analysis included the following: first, we conducted a broad literature search without language restriction to find eligible trials. Second, we did not limit our search to trials in which the incidence of shivering was the primary outcome, but instead collected all randomized clinical trials that compared magnesium with a control and then selected those that reported the incidence of shivering. In many randomized clinical trials, the incidence of shivering was not the primary outcome but one of several adverse events. We read many full texts to decide whether each trial could be included in our review because the incidence of shivering was often not reported in the abstract, even when it was evaluated in the trial. As a result, we included more trials than previous meta-analyses.5,9–12,107 Due to the large number of studies, we were able to demonstrate that the Z-cumulative curve for IV administration of magnesium crossed the Trial Sequential Analysis boundary for benefit and that the Grading of Recommendation Assessment, Development, and Evaluation was moderate.

There were several limitations to our review. First, while all trials comparing perioperative magnesium with a control should be included for the proper analysis of adverse events, we analyzed only the studies that reported the incidence of shivering. This led to the exclusion of many trials that did not evaluate shivering. Second, the optimal dose for prevention of shivering could not be determined. Third, shivering was rarely defined in the trials. The incidence and risk ratio may change significantly depending on the definition. Fourth, we did not compare the antishivering effect of magnesium with that of other medications. Last, medications with antishivering effect may have been given to patients as part of a protocol in some of the included trials. We could not differentiate the synergistic or additive antishivering effect of magnesium.

In conclusion, our meta-analysis and Trial Sequential Analysis have demonstrated that IV administration of magnesium significantly reduces the incidence of shivering in surgical patients. Trial Sequential Analysis failed to demonstrate that epidural or intrathecal magnesium is effective in reducing shivering, and studies with a low risk of bias that assess the antishivering effect of epidural and intrathecal magnesium are necessary to establish a conclusion, but more studies are not required to confirm that IV magnesium effectively reduces shivering. Further study is needed, however, to estimate the optimal dose.

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ACKNOWLEDGMENTS

We are grateful to Dr Hyun Ah Lee for her interpretation of Korean literature. We would like to thank Editage (www.editage.jp) for English language editing.

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DISCLOSURES

Name: Hiromasa Kawakami, MD.

Contribution: This author helped design the study, perform the literature search, extract and analyze the data, assess the articles, and prepare the manuscript.

Name: Daisuke Nakajima, MD.

Contribution: This author helped perform the data extraction, assess the articles, and prepare the manuscript.

Name: Takahiro Mihara, MD, PhD.

Contribution: This author helped design and conduct the study, analyze the data, and prepare the manuscript.

Name: Hitoshi Sato, MD.

Contribution: This author helped design the study, search the literature, and prepare the manuscript.

Name: Takahisa Goto, MD, PhD.

Contribution: This author helped search the literature and prepare the manuscript.

This manuscript was handled by: Ken B. Johnson, MD.

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