THERAPEUTIC hypothermia has generated significant interest as a modality to treat neurologic injury. Unfortunately, even mild hypothermia is associated with several adverse effects, one of which is shivering. α-2 Adrenergic agonists can be used to reduce the shivering threshold, allowing the body to be cooled significantly before shivering is induced. Two articles in this issue of Anesthesiology report the efficacy of α-2 agonists in combination with other drugs to reduce the shivering threshold in humans.1,2One drug combination (dexmedetomidine/buspirone) had additive effects on shivering threshold, whereas the other drug combination (clonidine/nefopam), unexpectedly, did not.

Clonidine and dexmedetomidine are subtype-nonselective α-2 adrenoceptor agonists. They are used clinically for their hemodynamic and sedative effects. In addition they have numerous other effects, such as, analgesia, sympatholysis, and reduction of thermoregulatory thresholds. α-2 agonists are some of the most potent nonanesthetic drugs to decrease the shivering threshold and are effective in treating postoperative shivering.

Clinical studies that are evaluating the effectiveness of mild therapeutic hypothermia to treat neurologic injury are targeting core temperatures of 33–34°C. Thus, up to a 3.5°C reduction in shivering threshold (normal is around 36.5°C) would be needed to prevent shivering during these studies. In healthy volunteers, dexmedetomidine reduces shivering threshold by 2.4°C per ng/ml (plasma concentration) and clonidine by 0.19°C per μg/kg (PO dose).3,4Inferring from these data, for dexmedetomidine and clonidine to reduce the shivering threshold by 3.5°C, dexmedetomidine plasma level of 1.5 ng/ml should be targeted, or 18 μg/kg of clonidine should be administered PO. However, at these drug concentrations, several other physiologic effects (hemodynamic and excessive sedation) would make the use of clonidine and possibly also dexmedetomidine unfeasible as single therapeutic agents to prevent shivering.

In this issue of Anesthesiology, there are two studies in which an α-2 agonist was administered in combination with another drug in attempt to increase the reduction of shivering threshold while minimizing drug-induced side effects.1,2Dexmedetomidine administered together with buspirone had an additive effect on shivering threshold, whereas clonidine administered with nefopam did not. What are the clinical implications of these two very different findings?

Patients receive many drugs during their hospitalization. Some drugs are used for several different purposes, creating a variety of possible drug interactions. For most drug combinations, these interactions have not been studied and are not known. This issue becomes even more complex with drugs such as clonidine and dexmedetomidine that have multiple physiologic effects. For example, we know that dexmedetomidine and meperidine have additive effects on shivering threshold. We also know that both dexmedetomidine and meperidine have sedative and analgesic effects. Just because dexmedetomidine and meperidine have an additive interaction for one physiologic effect (shivering threshold) does not allow us to assume that they have additive effects also for other physiologic effects. Both clonidine and nefopam have analgesic and antishivering effects. Before the studies in this issue of Anesthesiology, we most likely would have falsely assumed that this drug combination would have significantly greater analgesic and antishivering effects than either drug alone. The studies in this issue of Anesthesiology point out the importance of being aware of unsuspected drug interactions.

The lack of additive effect of clonidine and nefopam on shivering threshold was unexpected because most drugs that reduce shivering threshold have additive or synergistic effects when used in combination. Fortunately, these findings may shine some light into the mechanism of action of these drugs. Clonidine is an α-2 agonist, and it reduces norepinephrine turnover. Nefopam does not have affinity for the α-2 adrenoceptors, but it does inhibit synaptic uptake of norepinephrine. Thus, clonidine and nefopam have opposing effects of synaptic norepinephrine concentrations, providing one possible pharmacologic explanation for the lack of an additive effect of this drug combination on shivering threshold.

There are several reasons why it is difficult to infer the clinical significance of these data from healthy volunteers for use of α-2 agonists during therapeutic hypothermia in critically ill patients. First, numerous α-2 agonist–induced physiologic effects, other than reduction in shivering threshold, may have implications to patients receiving therapeutic hypothermia. For example, α-2 agonists do not increase intracranial pressure, but they do decrease mean arterial pressure, thus, reducing cerebral perfusion pressure. This may not be ideal for some patients with a stroke or head trauma. Also, α-2 agonists may exasperate hypothermia-induced reduction in cardiac output and increase in systemic vascular resistance. These events may not be ideal for some patients after cardiac arrest. When choosing a therapeutic agent, all physiologic effects of the drug must be understood and considered.

Second, patients who may benefit from therapeutic hypothermia (cardiac arrest, head trauma, stroke) will receive numerous other medications, some of which may interact with α-2 agonists. Of concern would be drugs that have sedative effects, because most sedatives, hypnotics, and anesthetics have additive or synergistic effects when administered together with α-2 agonists. These interactions may limit the dose of α-2 agonists that can be administered to prevent shivering without causing excessive sedation. On the other hand, there may be yet unknown, potentially beneficial drug interactions. For example, only 1.1 μg/kg of PO clonidine prevented (ED50) shivering postoperatively in neurosurgical patients whose core temperature was 35°C, a dose that is significantly lower than one would predict on the basis of data from healthy volunteers.5Clinicians must stay vigilant for possible, often unknown, drug interactions.

Third, shivering is only one of many side effects associated with therapeutic hypothermia.6Although uncomfortable, shivering has not been associated with frequent poor outcomes, and it is much less prevalent in elderly patients than young healthy volunteers. Effects of α-2 agonists on hypothermia induced side effects (morbid myocardial outcomes, coagulopathy, infections, prolonged recovery and hospitalization, and patient discomfort) should be evaluated to determine if α-2 agonists alone or in combination with other drugs would be beneficial to treat or to prevent therapeutic hypothermia-induced shivering.

Is there a clinical need for use of combinations of therapies to prevent shivering? Because several studies have shown that perioperative hypothermia is associated with poor outcome, and a recent large multicenter study found no evidence of improved outcome when hypothermia was used during intracranial aneurysm surgery, perioperative thermal management (normothermia) may become a pay-for-performance measure, reducing the need to treat perioperative shivering. On the other hand, hypothermia has been shown to improve outcome in patients with cardiac arrest, and it has been investigated as potential therapy in stroke and head trauma patients. Many of these patients are intubated and sedated for medical reasons, and previous trials have used propofol sedation and muscle relaxation to prevent shivering without significant side effects. It is not known whether there is a significant benefit for patients to be awake during therapeutic hypothermia, and it is unclear whether there is a current need for multidrug therapy to prevent shivering.

Articles like the ones in this issue of Anesthesiology are important in helping to define mechanisms of action of antishivering drugs. Although the results may not be directly applicable to complex, critically ill patients, they serve as a platform for clinical study design where therapeutic hypothermia is used. Future studies will determine for which patient populations it is hot to be cool and which patients may benefit from the use of antishivering therapies.

Lenhardt R, Orhan-Sungur M, Komatsu R, Govinda R, Kasuya Y, Sessler DI, Wadhwa A: Suppression of shivering during hypothermia using a novel drug combination in healthy volunteers. Anesthesiology 2009; 111:110–5
Alfonsi P, Passard A, Gaude-Joindreau V, Guignard B, Sessler DI, Chauvin M: Nefopam and alfentanil additively reduce the shivering threshold in humans whereas nefopam and clonidine do not. Anesthesiology 2009; 111:102–9
Talke P, Tayefeh F, Sessler DI, Jeffrey R, Noursalehi M, Richardson C: Dexmedetomidine does not alter the sweating threshold, but comparably and linearly decreases the vasoconstriction and shivering thresholds. Anesthesiology 1997; 87:835–41
Nicolaou G, Chen AA, Johnston CE, Kenny GP, Bristow GK, Giesbrecht GG: Clonidine decreases vasoconstriction and shivering thresholds, without affecting the sweating threshold. Can J Anaesth 1997; 44:636–42
Stapelfeldt C, Lobo EP, Brown R, Talke PO: Intraoperative clonidine administration to neurosurgical patients. Anesth Analg 2005; 100:226–32
Sessler DI: Complications and treatment of mild hypothermia. Anesthesiology 2001; 95:531–43