Review question/objective The objective of this systematic review is to synthesize the best available evidence on the effectiveness of intraoperative administration of low-dose intravenous ketamine on prevention of post-anesthetic shivering in adult patients undergoing general or regional anesthesia. Background Post-anesthetic shivering (PAS) is a common complication following general and regional anesthesia.7 Various studies report the incidence of shivering to be between 5% and 65% in patients recovering from general anesthesia and 40 and 60% in patients recovering from regional anesthesia.7,8,9 PAS can be distressing to the patient and has been cited as one of the primary causes of discomfort during the postoperative period.1 Many physiological consequences are also associated with PAS. Among the most significant of these consequences is an increase in oxygen consumption by up to six times, which can cause rapid oxygen depletion, potentially leading to tissue death.1,7,10 Additionally, PAS can result in tachycardia, lactic acidosis, increased intracranial and intraocular pressures, and increased carbon dioxide and stress hormone production.7,8,9,11 These complications can lead to cardiovascular and neurological deficits, as well as organ damage. PAS can also interfere with electrocardiogram, blood pressure, and pulse oximetry monitoring, which may pose patient safety issues.7,9 Adequate monitoring is essential for the provision of safe and effective post-anesthetic care. PAS is a common problem that may detrimentally impact patient outcomes, prolong recovery, and lengthen the period of hospitalization, therefore identification of safe, effective methods for prevention of PAS may improve anesthesia care. Research has identified several factors that are associated with an increased risk of PAS, including hypothermia, young age, increased duration of surgery, and orthopedic surgery.12 The etiology of PAS is multi-factorial and not entirely understood. Patients undergoing general or regional anesthesia are predisposed to developing hypothermia due to exposure to cold operating room environments, vasodilation resulting in core to peripheral heat loss, and impairment of normal thermoregulatory mechanisms by anesthetic agents.11,12,13 Core body temperature can decrease as much as 0.5 to 1.5° during the first hour of anesthesia.10 Though it is generally accepted that PAS is a normal thermoregulatory response to hypothermia, shivering can also occur in patients who are normothermic.10,12,14 This suggests that mechanisms other than heat loss may play a role in the development of PAS, including pain, inflammation, and the anesthetic agents themselves.1,10 Anesthetic agents alter the body's predetermined target temperature; consequently, patients undergoing anesthesia will reach lower core temperatures before thermoregulatory mechanisms attempt to restore normothermia.4 While maintenance of normothermia during surgery plays an important role in preventing PAS, it may not prevent shivering in all patients.14 Furthermore, adequate warming is not always possible.14 Therefore, the use of preventative measures beyond those targeted at the restoration of normothermia may be warranted. Various pharmacological agents have been evaluated for their efficacy in preventing and treating PAS, however, a “gold standard” drug treatment has not been defined.10 Studies have shown that several agents may be efficacious in treatment of PAS, including meperidine, clonidine, ondansetron, granisetron, midazolam, sufentanil, alfentanil, tramadol, physostigmine, and nalbuphine.7,9,11,13,15 Among these, meperidine (also called pethidine) is the most widely used. However, the varied actions of these drugs can result in wide-ranging and unpredictable side effects, including respiratory depression, hypotension, sedation, itching, nausea, and vomiting.11 Respiratory depression and hypotension can lead to decreased oxygen delivery to body tissues which may result in organ damage. Itching, nausea, and vomiting can cause patient discomfort and distress. Thus, use of these agents may be unfavorable or detrimental in certain patient populations. In recent years, several studies have evaluated the efficacy of ketamine for prevention of PAS. Ketamine is an inexpensive, widely available general anesthetic agent that produces analgesia and amnesia, with or without loss of consciousness, by antagonizing the N-methyl-D-aspartate (NMDA) receptor in the brain.16 The NMDA receptor is also thought to play a role in the transmission of thermal signals to the brain and spinal cord.17 Ketamine differs from other anesthetic agents as it produces a significant analgesic effect whilst rarely causing cardiovascular or respiratory depression.18 The dose of ketamine for induction and maintenance of general anesthesia is 1-2 mg/kg.18 However, at these doses, ketamine has been associated with adverse effects including cardiovascular stimulation, increased intracranial and intraocular pressures, delirium, and other psychological effects, which may preclude its use in certain patient populations.18 Nevertheless, recent studies have shown that ketamine may prevent PAS at doses of 0.75mg/kg or less, which decreases the likelihood of adverse effects.18 Though ketamine's role in preventing shivering is not fully understood, it appears that it is likely to affect thermoregulation through multiple mechanisms.11,15 First, it is well documented that ketamine decreases core-to-peripheral redistribution of heat by preventing the vasodilation that occurs with other anesthetic agents.19 In addition, it is hypothesized that ketamine may prevent shivering by interfering with thermoregulatory control mechanisms in the brain.9,11 Due to its unique properties, low cost, and wide availability, ketamine should be evaluated for its efficacy in preventing PAS. An initial search of Cochrane Library of Systematic Reviews, JBI Library of Systematic Reviews, DARE database, and MEDLINE was performed in order to locate any systematic reviews published between 1980 and 2013 on the proposed topic. A MEDLINE search yielded a systematic review published in 2002 that compared the efficacy of multiple pharmacological treatments for PAS but did not evaluate any preventative measures for PAS.10 The MEDLINE search also located a systematic review published in 2004 that evaluated the efficacy of multiple pharmacological interventions for prevention of PAS.14 This review concluded that prevention of PAS is effective and beneficial for patient populations at high risk for development of postoperative shivering.14 Neither of these systematic reviews included the use of ketamine and no systematic review of the proposed topic was located. A systematic review synthesizing the best available evidence on this topic may aid anesthesia providers in selecting a patient-appropriate drug for prevention of PAS. The following definitions will be used for the purpose of this review: • Post-anesthetic shivering (PAS) is defined as a symptom of involuntary muscular activity in one or more muscle groups following the administration of anesthesia.1 Post anesthetic shivering is measured by direct observation of involuntary muscular activity.• General anesthesia is a drug-induced state of unconsciousness during which patients are unresponsive to external stimulation, including painful stimulation.2 Ventilatory and cardiovascular functioning may be impaired during general anesthesia.2 • Regional anesthesia is a type of anesthesia in which a region of the body is rendered insensible to pain.3 Regional anesthesia is accomplished by injecting local anesthetic near a nerve or group of nerves. Types of regional anesthesia include epidural and spinal (also called subarachnoid or intrathecal) anesthesia. • Normothermia refers to the narrow range of core temperatures that the body seeks to maintain.4 Normothermia is defined as 36.5-37.5°.4 • Thermoregulation describes the body's physiological processes for maintaining normothermia.4 Even small alterations in body temperature can trigger thermoregulatory mechanisms, which include vasoconstriction, shivering- and non-shivering thermogenesis (heat production), vasodilatation, and sweating.5 • Hypothermia is defined as a core body temperature less than 36°.6