Efficacy And Safety Of Nefopam For The Prevention Of Shivering Following General Anaesthesia

Backgrounds and ObjectivePostoperative shivering is the most frequent complication after anaesthesia and surgery. The incidence of postanaesthetic shivering among previous studies is inconsistent, with an incidence up to 60%. Shivering may act as a response to hypothermia during the perioperative period. The mechanism of shivering differs from general anaesthesia to neuraxial anaesthesia. General anaesthesia could impair the central thermoregulation, while neuraxial anaesthesia impairs both central and peripheral thermoregulation, by enlarging interthreshold range via raising the sweating threshold and decreasing the vasoconstriction and shivering thresholds. This type of shivering may be associated with volatile anaesthetics, postoperative pain, prolonged duration of surgery, blood transfusion et al. As previous study reported, young age, core hypothermia, endoscopic surgery are important risk factors of perioperative shivering following anaesthesia. The volume of surgical irrigation is significant associated with the incidence of perioperative shivering.In a survey on 33 clinical problems, anesthesiologists ranked postoperative shivering 8th when its frequency was considered and 21st when asked about the importance of preventing this complication. This suggests that most anesthesiologists did not consider shivering to be a true medical problem.Postanaesthetic shivering is not only cause of uncomfortable but also interferes with monitoring. Shivering never caused patients direct death and became chronic response.However, shivering increased oxygen consumption(100%-300%), increased carbon dioxide and lactic acidosis. These responses will threaten some special patiens, especially in patients with pre-existing cardiorespiratory diseases. A greater incidence of cardiovascular complications has been found in patients unergoing abdominal, thoracic and vascular surgery with mild hypothermia and shivering. Therefore, it is essential to prevent or treat perioperative shivering. In most circumstances, shivering may act as physiological response as core hypothermia. Body core temperature influences vasoconstriction and shivering thresholds, triggering vasoconstriction and shivering. Therefore, it is very important to maintain the patients normothermia. Several measures could be used to diminish perioperative hypothermia:warming blankets; warmed intravenous solutions; heated, humidified inspired gases; and increasing ambient air temperature. However, keeping the patients normothermia is not always available. Moreover, sometimes we intentionally keep the patients hypothermia to reduce the effects of hypoxia and ischemia on brain tissue. Besides, normothermic patients also developed shivering. Thus, besides adequate body warming, it is very necessary to prevent or treat shivering by using pharmacological therapies. According to previous studies, many pharcological agents were effective for the prevention and treatment of postanaesthetic shivering, such as α-2 receptor agonists (clonidine, dexmedetomidine), opioids(meperidine, tramadol, fentanyl), nefopam et al. However, the side effects of these regimens confined their clinical appliance, such as inhibition of hemodynamics or excessive sedation of α-2 receptor agonist, nausea and vomiting and respiratory depression of opioids. Thus, there is still no ideal pharmacological drug for the prevention and treatment of shivering to date. Unlike other antishivering agents, nefopam may possess special antishivering mechanism. Nefopam may decrease shivering threshold to some extent without influencing vascular effects. That modulations of vasoconstriction and shivering can be separated is of considerable clinical and physiologic interest.Nefopam is a cyclized analogue of diphenhydramine. Plasma half life is 3-5 hours; plasma peak concentrations are 15-20 minutes after i.v. injection and 30 minutes after continuous infusion. Owing to a first-pass metabolism, oral bioavailability is only 40%.Nefopam undergoes extensive hepatic biotransformation. The major route of elimination(87%) is renal whereas a small part is excreted in the faeces(8%). Nefopam, neither an opioidal and nor a steroidal, is a centrally acting analgesic which is widely used for the relief of moderate and severe pain in western countries. However, nefopam is not approved by Food and Drug Administration (FDA). It is suggested by many studies that nefopam is effective for the prevention and treatment of postanaesthetic shivering. The mechanisms of antishivering and thermoregulation are not completely clear. It may act as interaction with a-2 adrenergic receptor. Nefopam inhibits uptake of dopamine, norepinephrine and 5-HT. According to previoius studies, clonidine and tramadol were the most frequently reported drugs for the prevention and treatment of shivering. Nefopam is as effective as other antishivering agents. Besides, nefopam is not associated with any serious side effect. Nefopam is generally considered to be safe and well tolerated. Reported adverse effects are mostly minor and include drowsiness, nausea and vomiting, and sweating. As previous studies reported, pain at injection was observed in patients treated with nefopam for the prevention of shivering after neuraxial anaesthesia. Besides, pain at injection was related to the rapid infusion of nefopam. The incidence of pain at injection was up to 15%. Potentially more serious adverse effects are confusion and tachycardia. Unlike non-steroidal anti-inflammatory drugs, nefopam has no effect on platelet function, and, in contrast to opioids. This drug does not seem to increase the risk of respiratory depression. Therefore, nefopam may be the most promising pharmacological agent for the prevention and treatment of shivering.The aim of this study is to investigate the efficacy of nefopam for prophylaxis of postanaesthetic shivering. The secondary aim of this study is to compare the efficacy of nefopam with that of other pharmacological therapies and to explore the spectrum of side effects of nefopam.Efficacy and safety of nefopam and meperidine for the prevention of shivering following general anaesthesia: a randomised controlled trialObjective1、To compare the efficacy and safety of nefopam with that of meperidine or placebo for prophylaxis of shivering following general anaesthesia.2、To investigate the impact of nefopam and meperidine on the core temperature during the perioperative period.Methods1、This is a single-center, randomised, double-blinded, parallel groups, placebo-controlled trial.2、Adult patients (18-65 years) underwent abdominal or orthopaedic surgery under general anaesthesia will be potentially eligible for inclusion in this trial.3、Within the inclusion criteria, patients will be randomised to receive nefopam(N) or meperidine(M) or placebo(P) group.4、The primary outcome is the influence of shivering. Secondary outcomes are the incidence of postoperative nausea and vomiting (PONV), extubation time and time spent in postanaesthetic care unit (PACU).Results1、A total of 123 participants were approached in this study and 119 of the patients fulfilled the trial.2、The overall incidence of shivering following general anaesthesia was significantly lower in the nefopam and meperidine groups than that in the placebo group. The severity of postanaesthetic shivering of group M and N was also significantly lower than that of group P.3、The risk of PONV in group M was significantly higher than that in group N. However, there was no significantly statistical difference between group P and N.4、The extubation time in group M was significantly longer than that in group P.Conclusion1、Nefopam, as well as meperidine, was effective for the prevention of shivering following general anaesthesia.2、Meperidine prolonged the extubation time and increased the risk of PONV.Efficacy and safety of nefopam for the prevention of perioperative shivering:systematic review of randomised controlled trialsObjective1、To investigate the efficacy of nefopam for prophylaxis of postanaesthetic shivering.2、To compare the the effectiveness of nefopam with other antishivering agents for the prevention of postanaesthetic shivering.3、To explore the spectrum of side effects of nefopam.Methods1、We systematically searched the electronic databases (Pubmed, Embase, Cochrane Central Register of Control Trials) for randomised controlled studies of nefopam for the prevention of postanaesthetic shivering.2、Two authors independently assessed the risk of bias of included studies using the Cochrane Collaboration’s protocol and extracted the data. If there was a discrepancy, the assessment of risk of bias was reached consensus by a third author.3、Dichotomous outcomes were abstracted and analysed by using relative risk(RR) with relevant 95% confidence interval(CI).4、According to presence of heterogeneity or not, statistical analyses were carried out by using random effect model or fixed effect model.Result1、Compared with placebo, prophylactic administration of nefopam significantly reduced the risk of perioperative shivering not only in the patients under general anaesthesia but also neuraxial anaesthesia(RR 0.08; 95%CI 0.05-0.13).2、As compared with clonidine, nefopam was more efficacious in the prevention of perioperative shivering(RR 0.34; 95%CI 0.17-0.70).3、Nefopam has no influence on the extubation time(WMD 0.92; 95% CI-0.15-1.99).4、There was no significant difference between nefopam and placebo group with regard to the risk of the postoperative nausea and vomiting (PONV) (RR 0.07; 95% CI-0.14-0.27).ConclusionOur analysis has demonstrated that nefopam is effective for the prevention of perioperative shivering. The risk of perioperative shivering also appeared to be lowered by using nefopam compared with clonidine. Besides, nefopam is not associated with the increasing of the risk of PONV and prolonged extubation time.