Abstract
Objectives: To compare clonidine with tramadol for shivering control following spinal anesthesia.
Methods: The literature was searched updated to August 2020, and only randomized controlled trials comparing clonidine and tramadol for shivering control following spinal anesthesia were eligible for this study.
Results: Fourteen studies with 960 patients were identified. Clonidine demonstrated a lower effective rate of shivering control (OR: 0.59; 95% CI: 0.40-0.88; p=0.009; I2=36%), but with decreased occurrence of nausea, vomiting, and dizziness. Clonidine increased the occurrence of bradycardia, hypotension, and sedation compared to tramadol.
Conclusion: Tramadol is more effective for shivering control than clonidine, but with increased occurrence of nausea, vomiting, and dizziness.
PROSPERO No: CRD42020207979
Shivering frequently occurs in the perioperative period.1 Various medications have been studied for shivering control, including dexmedetomidine, clonidine, pethidine, tramadol, magnesium sulphate, dexamethasone, and ketamine.2 Despite availability of numerous drugs for shivering control, no single drug has been found to be effective without any side effects.
In recent years, increasing randomized controlled trials (RCTs) comparing clonidine with tramadol for shivering control following spinal anesthesia have been conducted. Hence, we conducted this meta-analysis to compare clonidine with tramadol for shivering control following spinal anesthesia.
Methods
The recommendations of the PRISMA guidelines were followed in this meta-analysis.3 We searched Pubmed, Embase, Cochrane library, and Google Scholar, updated to August 2020 without language restrictions. All databases were searched using the following terms: “shivering,” “clonidine,” “tramadol,” “hypothermia,” “spinal anesthesia,” “intrathecal injection,” or “subarachnoid anesthesia.” The references of all included articles were manually scanned for additional relevant publications.
Inclusion criteria were as follows: i) the study design is an RCT; ii) the participants were adult patients undergoing surgeries under spinal anesthesia; iii) the intervention of the study involved treating shivering following spinal anesthesia with intravenous clonidine or tramadol. The exclusion criteria were as follows: i) the study is not an RCT; ii) animal studies, meeting papers, editorials, correspondence, case reports or review papers; iii) and the intervention of the study includes clonidine or tramadol combined with other medications for shivering treatment.
The quality of the eligible RCTs were independently assessed by NW and HZ. Study quality was assessed with the Jadad score and the Cochrane risk of bias tool.4,5 Disagreement was solved by JW. The data from each eligible RCT was separately extracted by JW and YL. Disagreement was also settled by RW. The following data were obtained from each eligible article: number of patients, publication year, study interventions, effective parameters of shivering control (effective rate of shivering control and recurrence rate), and the related complications. The main outcome was the efficacy of shivering control, and the secondary outcome was the related complications (hypotension, bradycardia, sedation, nausea, vomiting, dizziness, dry mouth).
Statistical analysis
Review Manager 5.3 was used for statistical analysis. The efficacy of shivering control and the related complications were displayed by the odds ratio (OR) with 95% confidence intervals (CI). Heterogeneity was estimated by the value of I2. If I2 was less than 50%, data were analyzed utilizing the fixed-effect model, or the random-effects model. P<0.05 was statistically significant.
Results
Initially, we found 476 studies. After assessment, 22 full texts were included; however, 8 articles were excluded because they involved children or animals, or were non-RCTs or correspondences.
Thus, 14 RCTs involving 960 patients were eligible for the present study.6-19 (Figure 1) Table 1 displays the characteristics of the identified RCTs in details and shows that all included studies in this meta-analysis had moderate to high quality. A risk-of-bias overview is shown in Figure 2.
- Flow chart of selected randomized controlled trials.
- Risk of bias evaluation.
- Characteristics of the included trials.
As shown in Figure 3A, 12 studies including 860 participants recorded the effective rate of shivering control, and clonidine was less effective than tramadol (OR: 0.59; 95% CI: 0.40-0.88; p=0.009; I2=36%). The difference in shivering recurrence rate was not statistically significant between clonidine and tramadol (OR: 0.82; 95% CI: 0.52-1.31; p=0.41; I2=36%). (Figure 3B)
- A) Forest plot for effective rate of shivering control, B) and recurrent rate of shivering.
The most common treatment-related complications were evaluated. Clonidine had higher incidences of hypotension (OR: 5.97; 95% CI: 2.76-12.91; p<0.00001; I2=0%), bradycardia (OR: 3.94; 95% CI: 1.69-9.20; p= 0.002; I2 = 0%), and sedation (OR: 2.67; 95% CI: 1.80–3.94; p<0.00001; I2=46%), and lower incidence of dizziness (OR: 0.02; 95% CI: 0.01-0.09; p<0.00001; I2=0%) compared with tramadol. (Figure 4)
- Forest plot for related complications (hypotension, bradycardia, sedation, nausea, vomiting, dizziness, dry mouth).
Compared with tramadol, clonidine had a lower incidence of nausea and vomiting (OR 0.10; 95% CI: 0.03-0.31; p<0.0001; I2=76%) (Figure 4). Sensitivity analysis was performed by taking out every included RCT sequentially. The result was confirmed, and no source of heterogeneity was identified.
The difference in the incidence of dry mouth was not statistically significant between clonidine and tramadol (OR: 2.35; 95% CI: 0.95-5.77; p=0.06; I2=0%) (Figure 4).
The funnel plot of the effective rate of shivering control was symmetrical, so there were no potential publication biases.
Discussion
The present meta-analysis indicates that tramadol is more effective than clonidine for shivering control following spinal anesthesia. However, the difference is not significant in the shivering recurrence rate between clonidine and tramadol. In terms of complications, tramadol use resulted in higher incidences of nausea, vomiting, and dizziness, while clonidine increased the probability of bradycardia, hypotension, and sedation.
Nausea, vomiting, and dizziness are very distressing for patients and may lead to serious consequences.20 According to the included RCTs, bradycardia and hypotension could be promptly treated by intravenous drugs. If surgeries are performed under spinal anesthesia, sedation caused by clonidine is beneficial for the patients. In addition, no patients were over sedated in the identified studies.
Clonidine has a high lipid solubility; therefore, it can promptly cross the blood-brain barrier.21 Hence, clonidine can activate α2 receptors in the central nervous system to reduce the central thermosensitivity by suppressing the neuronal conductance, consequently reducing the thermoregulatory threshold for shivering.21 The antishivering mechanism of tramadol possibly results from its opioid or serotonergic and noradrenergic function.22
Although the search strategy was designed to be as thorough as possible to identify eligible RCTs, the included RCTs were limited. Tramadol can significantly increase the effective rate of shivering treatment, but in terms of the complications, there is not enough clinical evidence to determine which of the 2, clonidine or tramadol, is better for shivering treatment after spinal anesthesia. Thus, further high-quality evidence from a large sample is needed.
In conclusion, tramadol is more effective than clonidine for shivering treatment, but with increased incidences of nausea, vomiting, and dizziness.
Acknowledgment
The authors gratefully acknowledge Editage (www.editage.cn) for English language editing.
Footnotes
Disclosure. Authors have no conflict of interests, and the work was not supported or funded by any drug company.
- Received October 7, 2020.
- Accepted January 26, 2021.
- Copyright: © Saudi Medical Journal
This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial License (CC BY-NC), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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