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Frequently Asked Questions

What are the treatment options for post-operative shivering?

Introduction
Postoperative shivering is an unpleasant side effect of recovery from anesthesia. It is characterized as involuntary mechanical oscillatory muscle movements that can be clonic in nature.1-3 These tremors can affect one or more groups of skeletal muscles, and their onset may range from 5 to 30 minutes after stopping anesthesia.3-4 It is unclear how many patients experience shivering, but the incidence can vary from 5% to 60% of patients recovering from anesthesia.3 Several risk factors are thought to increase the incidence of postoperative shivering including male gender, young age, length of surgery and anesthesia, perioperative hypothermia, and type of anesthetic used during surgery.1 Halogenated agents and thiopental appear to increase the incidence of shivering postoperatively.

While there may be several causes behind postoperative shivering, it can be effectively categorized into one of two classes: thermoregulatory and non-thermoregulatory shivering.3 Thermoregulatory shivering is a response to a drop in core body temperature, typically caused by perioperative hypothermia. The onset of hypothermia is usually a consequence of thermoregulatory inhibition by anesthetics. The causes of non-thermoregulatory shivering are not completely understood, but postoperative pain may play an important role in its onset. Often, it is the combination of anesthetic-induced hypothermia and exposure to a cold environment (such as the operating room) that results in postoperative shivering.

While discomfort and increased postoperative pain (due to surgical incision stretching) are the main clinical implications of shivering, it has been proposed that oxygen consumption and metabolic demand may also be increased.3 However, the extent of this increase and its effect on clinical status or cardiac morbidity are still unclear. Shivering also increases metabolic heat production up to 600% above baseline.

Treatment of postoperative shivering

There are several non-pharmacological approaches that can address shivering in recovering patients. Shivering caused by hypothermia can be prevented by skin surface re-warming, either by covering the patient with surgical drapes, using a forced-air warmer prior to anesthesia, raising the temperature in the operating room, or warming intravenous solutions when possible.1 Several pharmacological options can be used for preventing or treating postoperative shivering.3 These include opiates (with meperidine showing the most remarkable and consistent results), tramadol, magnesium sulfate, α2-agonists (eg, clonidine and dexmedetomidine), physostigmine, doxapram, methylphenidate, and 5-HT3 antagonists. Of note, nefopam (a centrally-acting nonopioid analgesic) and urapidil (α1-agonist and 5-HT1A agonist) are both agents that may be used in the treatment of postoperative shivering. However, neither are approved for use in the United States.

Literature review

Despite the number of pharmacological options available for postoperative shivering, no "gold-standard" treatment exists. In fact, the mechanism and relative efficacy of these interventions is unclear. A number of trials have evaluated the role of several parenteral medications in postoperative shivering prophylaxis and treatment. The results of these trials are discussed below.

Prophylaxis

A meta-analysis of 27 randomized controlled trials involving over 2200 patients found clonidine to be the most frequently studied drug in the prevention of shivering.5 Other commonly studied medications included meperidine and tramadol. All the studies compared single parenteral doses of the medication to placebo or no treatment. Varying doses were investigated; however, all studies involving these agents showed that pharmacological therapy was more effective than the control intervention at preventing postoperative shivering. Data on the absence of shivering were evaluated based on the relative benefit and the number needed to treat (NNT). The average incidence of shivering in controls was 52%, although the reported range was variable, from 20% or less to over 70%.

The results of this analysis for the most commonly studied interventions are included in Table 1.5 For clonidine, the authors of the meta-analysis also looked at the dose of clonidine and its relative benefit on shivering; the dosage categories were arbitrarily set (see Table 1). For meperidine, the doses tested in the clinical trials were 0.3, 0.4, and 0.5 mg/kg, and 12.5 and 25 mg. The mg/kg doses were converted to a fixed dose, resulting in a dosage range of 12.5 to 35 mg. Based on the results of individual studies, lower doses of meperidine (<24 mg) were no more effective than controls. Tramadol dosing was treated in the same manner-the original dosing regimens were 0.5, 1, 2, and 3 mg/kg. However, individual studies found all dose levels to be more effective than controls. Of note, methylphenidate, midazolam, dolasetron, ondansetron, physostigmine, and flumazenil were all independently studied in a smaller number of trials with a limited number of patients.

Table 1. Comparison of parenteral IV agents in prevention of postoperative shivering.5
Drug and dosage Total number of patients enrolled Relative benefit (95% CI) vs control NNT
Clonidine 65 to 300 mcg 978 (14 trials) 1.58 (1.43-1.74) 3.7
Clonidine 65 to 110 mcg 230 (3 trials) 1.32 (1.16-1.51)
Clonidine 140 to 150 mcg 440 (5 trials) 1.83 (1.47-2.27)
Clonidine 220 to 330 mcg 308 (6 trials) 1.61 (1.38-1.87)
Meperidine 12.5 to 35 mg 250 (5 trials) 1.67 (1.37-2.03) 3
Tramadol 35 to 220 mg 250 (4 trials) 1.93 (1.56-2.39) 2.2

CI=confidence interval; IV=intravenous; NNT=number needed to treat.

The authors noted that all 3 agents were associated with a low NNT to avoid one episode of postoperative shivering. However, the particularly high incidence of shivering in the control groups suggests that the study populations were at a higher baseline risk for shivering, potentially limiting the generalizability of these findings and inflating the efficacy of these agents compared with controls. Regardless, several experts have conflicting opinions about the role of pharmacological prevention in clinical practice. It is argued that the best first-line prevention of postoperative shivering is through non-pharmacological methods, such as direct skin re-warming or covering the patients with surgical drapes. Furthermore, parenteral agents should be reserved for patients who shiver despite non-pharmacological methods.6

Treatment
Several interventions including opioids, centrally-acting analgesics, sodium-channel blockers, α2-agonists, methylphenidate, doxapram, magnesium, and ketanserin, were evaluated in a meta-analysis of 20 randomized, placebo-controlled studies published between 1984 and 2000.2 The most frequently studied agents were meperidine, clonidine, doxapram, alfentanil, and ketanserin (an antihypertensive agent not available in the United States). Data on the absence of shivering after treatment were evaluated by calculating the relative risk and the NNT and stratified according to time of observation after drug administration. Meperidine, clonidine, ketanserin, and doxapram were found to have the most evidence in favor of their efficacy when evaluated at 5 minutes. Significance remained in favor of meperidine, clonidine, and alfentanil when shivering was assessed at 10 minutes after administration. There was not enough data about other agents to draw conclusions about their role in postoperative shivering. Some of the efficacy data regarding meperidine, clonidine, and doxapram are presented in Table 2.

Table 2. Comparison of parenteral agents in treatment of postoperative shivering.2
Drug/Dose Percent not shivering after
(RR [95% CI]):
(versus control)
Relative Risk (95% CI)a NNT (95% CI)a
1 minute 5 minutes 10 minutes
Meperidine 25 mg 43% vs 6% 87% vs 9% 91% vs 23% 9.55 (5.72-15.9) 1.3 (1.2-1.4)
Clonidine 150 mcg NA 87% vs 12% 77% vs 26% 6.82 (3.28-14.2) 1.3 (1.1-1.6)
Doxapram 100 mg 33% vs 8% 78% vs 20% NA 3.97 (2.42-6.53) 1.7 (1.4-2.3)
Alfentanil 250 mcg 23% vs 4% 50% vs 9% 54% vs 22% 5.56 (2.04-15.1) 2.4 (1.7-4.0)

a At 5 minutes after treatment. CI=confidence interval; NA=not available: NNT=number needed to treat.

These data suggest that approximately 2 shivering patients need to be treated with meperidine, clonidine, or doxapram to stop shivering in one patient within 5 minutes. Also, these data suggest that meperidine, clonidine, and doxapram may have comparable efficacy at treating postoperative shivering in postsurgical patients. Although significant from the control group, the rates of patients without shivering were lowest with alfentanil. However, it is important to note that the meta-analysis relied on indirect comparisons of the agents.

Since the publication of the previous meta-analysis, several trials have been conducted comparing the efficacy of different agents in the treatment of postoperative shivering. A recent randomized, prospective, controlled trial evaluated the efficacy of intravenous doxapram 1.5 mg/kg, meperidine 0.35 mg/kg, and saline placebo in 30 postoperative adult patients.4 The study found no statistical difference between doxapram and meperidine nor between doxapram and placebo. However, meperidine was better than placebo at stopping postoperative shivering. Meperidine stopped shivering in 80% of patients, while saline placebo stopped shivering in 20% of patients (p < 0.05). Due to the small sample size, it is difficult to make a meaningful conclusion regarding the efficacy of meperidine. This study also raises the question about the clinical significance of treatment, given that 20% of patients in the placebo group stopped shivering within minutes of administration. Whether this is related to a placebo effect or if it relates to the fact that shivering is often self-resolving is not known.

Another prospective, randomized, double-blind study compared the efficacy of meperidine, clonidine, and urapidil in the treatment of postanesthetic shivering.6 The trial included 149 postoperative patients. Sixty patients developed shivering after their procedure and were randomized to treatment with intravenous meperidine 25 mg, clonidine 0.15 mg, or urapidil 25 mg. Patients received a second dose after 5 minutes if the shivering did not stop (except for clonidine, which was replaced by saline). A 25-mg dose of meperidine was used as rescue therapy if the second dose of the randomized treatment was not effective after another 5 minutes. The trial found that meperidine and clonidine were both more effective than urapidil (p<0.01). Clonidine was effective in stopping shivering in 16 of 20 patients. The 4 remaining patients required longer than 5 minutes for the shivering to resolve. Shivering ceased within 5 minutes in 18 of 20 patients treated with meperidine. A second dose of meperidine was sufficient to stop shivering in the remaining 2 patients. Only 6 of 20 patients in the urapidil group stopped shivering after the first dose, and 6 more had stopped shivering after the second dose. The treatment was not effective in 8 patients.

Conclusion

Postoperative shivering can sometimes be a disturbing side effect for patients recovering from surgery and may result in increased incision pain and metabolic demand. Non-pharmacological methods of preventing shivering include covering the patient with surgical drapes during the procedure, warming intravenous fluids, and raising the temperature in the operating room (>23°C) when possible. Nonetheless, postoperative shivering may still occur, and pharmacological agents have been used for the prevention and treatment of shivering. A wide variety of agents with different mechanisms of action are available for use. Unfortunately, there is no "gold-standard" drug for the treatment of postoperative shivering. Numerous trials have studied the efficacy of several agents, either in comparison to placebo or to each other, and even more trials have been conducted studying the efficacy of such agents in the prevention of postoperative shivering. Clonidine, meperidine, and tramadol all appear to be effective agents in postoperative shivering prophylaxis. However, non-pharmacologic methods such as skin re-warming may be more appropriate options for prevention of shivering.

It appears that clonidine and meperidine have the most data to support their efficacy in treatment. While most studies, including the results from a meta-analysis, show similar efficacy of both agents in stopping shivering in postoperative patients, the choice depends on the patient's clinical status and the drug's side effect profile. Those medications also have additional properties that may determine their usefulness in certain patient populations. For example, meperidine has analgesic effects, while clonidine is an antihypertensive that can be used to lower blood pressure. If pharmacological treatment is to be used in a shivering postoperative patient, the clinical status (including hemodynamic stability) of the patient should be considered along with the medication's mechanism and potential side effects.

References

1. Alfonsi P. Postanaesthetic shivering. Drugs. 2001; 61(15): 2193-2205.

2. Kranke P, Eberhart LH, Roewer N, Tramer MR. Pharmacological treatment of postoperative shivering: a quantitative systematic review of randomized controlled trials. Anesth Analg. 2002;949(2):453-460.

3. Witte J, Sessler DI. Perioperative shivering. Anesthesiology. 2002;96(2):467-484.

4. Shrestha AB. Comparative study on effectiveness of doxapram and pethidine for postanaesthetic shivering. J Nepal Med Assoc. 2009;48(174):116-120.

5. Kranke P, Eberhart LH, Roewer N, Tramer MR. Single-dose parenteral pharmacological interventions for the prevention of postoperative shivering: a quantitative systematic review of randomized controlled trials. Anesth Analg. 2004; 99(3):718-727.

6. Schwarzkopf KRG, Hoff H, Hartmann M, Fritz HG. A comparison between meperidine, clonidine, and urapidil in the treatment of postanesthetic shivering. Anesth Analg. 2001;92(1):257-260.