A 2015 meta-analysis evaluated the effectiveness of prophylactic nefopam administration for the prevention of perioperative shivering by aggregating data from nine randomized controlled trials encompassing 925 adult surgical participants. The included trials enrolled patients undergoing general, neuraxial, or conscious sedation anesthesia, with nefopam administered intravenously at various time points, either preoperatively or at the end of surgery. Only one study (Rosa et al.) was referenced which evaluated the use of nefopam in populations who experienced perioperative shivering related to amphotericin use. This meta-analysis demonstrated a robust and statistically significant reduction in the risk of perioperative shivering with nefopam compared to placebo, with a pooled relative risk (RR) of 0.08 (95% confidence interval [CI] 0.05 to 0.13) and no significant heterogeneity across trials (I² = 0%). Subgroup findings revealed consistent efficacy in both general anesthesia (RR 0.10 95% CI 0.06 to 0.16) and neuraxial anesthesia settings (RR 0.05 95% CI 0.01 to 0.18). A further analysis of three trials directly comparing nefopam to clonidine (n = 407) indicated that nefopam was more effective in reducing shivering (RR 0.34 95% CI 0.17 to 0.70). Additionally, pooled extubation time data from four trials showed no significant difference between nefopam and placebo groups (weighted mean difference [WMD] 0.92 minutes; 95% CI −0.15 to 1.99), underscoring the agent’s neutrality in recovery duration. Across the included trials, nefopam did not demonstrate an increased risk of major adverse effects, highlighting its favorable safety profile relative to alpha-2 agonists or opioids commonly used for shivering prophylaxis. However, the generalizability of findings to patient populations experiencing shivering and rigors due to amphotericin is limited due to the lack of adequate representation. [1]
In a dated randomized trial, a total of 45 patients with cancer and systemic fungal infections received either nefopam IV 0.3 mg/kg, meperidine IV 0.7 mg/kg, or saline for a total of 15 minutes prior to amphotericin B infusion cessation, in an effort to reduce post-operative shivering. If saline patients were still shivering following administration, nefopam IV 0.3 mg/kg or meperidine IV 0.7 mg/kg were administered. Shivering was significantly less pronounced in nefopam patients (6.6%) and meperidine patients (40%) compared to saline, with nefopam terminating shivering more quickly compared to meperidine (29.1 ± 4.8 vs 200.0 ± 30.2 seconds). Adverse reactions observed from nefopam use was primarily nausea, while meperidine use observed more sedation; both adverse reactions were minute. Though nefopam appears to be more efficacious than meperidine in prevention of post-operative shivering associated with amphotericin, the agent is not currently available on the US market. [2]
A 2022 systematic review and meta-analysis sought to evaluate efficacy of pharmacological agents administered intra-operatively to manage shivering in patients undergoing elective surgery under regional anesthesia. A total of 10 randomized trials were included, which utilized tramadol, dexmedetomidine, clonidine, meperidine, nalbuphine, magnesium sulfate, nefopam, and butorphanol; tramadol and dexmedetomidine were the most commonly utilized medications. Control of shivering was reported in seven trials, though reporting method was heterogeneous (e.g., success rate, response rate). The most effective drug appears to be IV dexemedetomidine 0.5 mcg/kg when given immediately after appearance of shivering. Clonidine has been used similarly, with some adverse events. Tramadol, pethidine, and butorphanol were considered effective opioid interventions in the management of shivering. Comparisons of the agents to meperidine were not provided, however, evidence is not specific to cases of amphotericin-induced shivering and data in general are limited. [3]
A 2004 systematic review assessed the relative efficacy of pharmacological interventions in preventing postoperative shivering. Although not related to intraoperative amphotericin-use, the review included randomized comparisons of prophylactic, parenteral, single-dose antishivering interventions against inactive controls (placebo or no treatment). A total of 27 trials (N= 1248) were analyzed, and the average incidence of shivering in the control group was 52%. Clonidine (65-300 mcg), meperidine (12.5-35 mg), tramadol (35-220 mg), and nefopam (6.5-11 mg) were tested in at least three trials each. All were found to be more effective than control. Clonidine, meperidine, and nefopam showed weak evidence of dose responsiveness. For small-dose clonidine (65-110 mcg), the relative risk (RR) was 1.32 (95% CI 1.16 to 1.51), while medium-dose clonidine (140-150 mcg) had an RR of 1.83 (95% CI 1.47 to 2.27), and large-dose clonidine (220-300 mcg) had an RR of 1.52 (95% CI 1.30 to 1.78). The overall RR for clonidine was 1.58 (95% CI 1.43 to 1.74), with a number needed to treat (NNT) of 3.7. For all meperidine regimens combined, the RR was 1.67 (95% CI 1.37 to 2.03), with an NNT of 3. Tramadol had an RR of 1.93 (95% CI 1.56 to 2.39), with an NNT of 2.2, while nefopam had an RR of 2.62 (95% CI 2.02 to 3.40), with an NNT of 1.7. Other interventions, such as methylphenidate, midazolam, dolasetron, ondansetron, physostigmine, urapidil, and flumazenil, were tested in fewer trials with limited patient numbers. Overall, the authors found that using simple pharmacological treatments to prevent postoperative shivering is effective, especially in patients with a high risk of developing this complication. [4]
A 2002 systematic review and quantitative meta-analysis investigated the pharmacological treatment of postoperative shivering. The review analyzed 20 randomized controlled trials published between 1984 and 2000, involving a total of 944 adult patients receiving an active drug treatment and 413 controls. Shivering is a common complication following surgery that can increase oxygen consumption and cardiovascular strain. Various drugs are used off-label to treat postoperative shivering; however, their relative efficacy is unclear. The meta-analysis found that meperidine 25 mg, clonidine 150 mcg, ketanserin 10 mg, and doxapram 100 mg showed efficacy in reducing shivering in at least three randomized trials each after five minutes. Meperidine 25 mg had the lowest NNT of 1.3 after five minutes, suggesting it had a shorter onset than the other drugs tested. However, clonidine 150 mcg and doxapram 100 mg also had NNT <2 at five minutes, indicating they could reduce shivering in two out of three patients within five minutes compared to placebo. Ketanserin efficacy declined over time and was not significantly better than placebo after 30 minutes. Long-term efficacy data and information on adverse effects were generally lacking for most drugs. In conclusion, the limited data suggests clonidine and doxapram were found to be effective short-term treatments for postoperative shivering along with meperidine. However, there is insufficient data on patients that may experience amphotericin-related rigors or shivering. [5]
A recent meta-analysis assessed the prophylactic use of IV acetaminophen for preventing postoperative shivering. A total of nine trials involving 856 patients were included in the analysis. The findings indicated that acetaminophen significantly reduced the incidence of postoperative shivering compared to placebo (RR 0.43; 95% CI 0.35 to 0.52). Additionally, subgroup analysis revealed that both a single-dose bolus of IV acetaminophen 1000 mg (RR 0.22; 95% CI 0.10 to 0.45) and IV acetaminophen 15 mg/kg (RR 0.43; 95% CI 0.33 to 0.62) were effective in reducing the incidence of postoperative shivering. Based on these findings, it was suggested that prophylactic infusion of IV acetaminophen may potentially offer advantages in reducing perioperative shivering. [6]
A 2023 meta-analysis evaluated the perioperative administration of dexamethasone to prevent postoperative shivering. The review included 12 randomized controlled trials (N= 1276 patients), all of which assessed the overall incidence of postoperative shivering. The trials included a variety of surgeries, such as orthopedic, urological, and general procedures, performed under both general and spinal anesthesia. The results indicated that patients in the dexamethasone group experienced a significantly lower incidence of postoperative shivering (RR 0.39; 95% CI 0.23 to 0.63; p<0.00001) compared to the control group. Additionally, dexamethasone reduced the grade of shivering, which was classified into five grades (0-4) based on clinical manifestations. Specifically, the reduction was significant for grade 2 (RR 0.48; 95% CI 0.33 to 0.69; p<0.0001), grade 3 (RR 0.14; 95% CI 0.06 to 0.37; p<0.0001), and grade 4 (RR 0.13; 95% CI 0.04 to 0.38; p= 0.0002); however, it was not significant for grade 1 (RR 0.94; 95% CI 0.60 to 1.48). Overall, the authors concluded that the administration of dexamethasone is associated with a lower incidence of postoperative shivering; however, further studies are warranted. [7]
A 2016 abstract describes a randomized, double-blind clinical trial that involved 160 healthy patients (ASA I-II) undergoing surgeries lasting over an hour under general anesthesia. They were divided into four groups: Group A received dexmedetomidine (1 µg/kg), Group B received meperidine (0.4 mg/kg), Group C received ketamine (0.5 mg/kg), and Group D (placebo) received saline. The drugs were given intravenously 20 minutes before skin closure, with standardized anesthesia and postoperative monitoring to ensure consistency. Results showed the highest shivering incidence in the placebo group (47%), particularly for severe shivering (levels 3 and 4: 22% and 18%). Notably, the meperidine group had no cases of severe shivering, and the placebo group required the most additional shivering treatment (38%). The study concluded that a single 0.4 mg/kg dose of intravenous meperidine is highly effective in preventing postoperative shivering. [8]
A 1986 case series described the prophylactic and therapeutic use of intravenous dantrolene sodium in managing amphotericin B–induced rigors in three patients undergoing antifungal therapy for serious systemic infections. Each patient had experienced violent chills and febrile responses during amphotericin B infusions, which were refractory to standard prophylactic interventions such as acetaminophen, antihistamines, corticosteroids, and opioids, including meperidine. Rigors typically developed within 30 to 90 minutes of starting the infusion, despite adequate premedication with conventional agents. Following the administration of dantrolene sodium—either as a prophylactic dose of 50 mg IV given prior to amphotericin B or as an interventional dose ranging from 10 to 20 mg IV upon onset of rigors—all three patients exhibited prompt resolution or significant improvement of symptoms. One patient who received dantrolene preemptively in subsequent doses of amphotericin B remained free of rigors for the remainder of therapy. In another case, rigors subsided within ten minutes of IV dantrolene administration following onset, allowing continuation of antifungal therapy. A third patient experienced partial relief after an initial 20 mg IV dose and complete resolution after an additional 10 mg IV dose; however, due to underlying hyperbilirubinemia, further dantrolene use was avoided, and meperidine was resumed. Notably, no adverse effects attributable to dantrolene were reported in any of the patients treated. The pharmacologic rationale was supported by dantrolene’s mechanism of action as a skeletal muscle relaxant that inhibits calcium release from the sarcoplasmic reticulum, thereby disrupting muscle excitation. These findings suggest that dantrolene may serve as a viable adjunct or alternative to conventional agents in the management of amphotericin B–induced rigors, particularly in cases unresponsive to opioid treatment. [9]
