More information is becoming available about therapeutic hypothermia (TH) for patients following a cardiac arrest. Read more about this innovative treatment here. Since the advent of cardiopulmonary resuscitation (CPR) and defibrillation, few discoveries have changed patient outcomes in the way that induction of therapeutic hypothermia for initial survivors has. History Induction of TH following cardiac arrest has many historic roots, but is probably most attributed to Dr. Peter Safar, who in the 1960s argued that the “ABC’s” of resuscitation should include an “H” for application of TH.1-3 However, because of side effects from prolonged moderate hypothermia used at that time and the deficiency in knowledge about optimal TH duration and temperatures, it was abandoned until the 1980s, when animal studies were resumed.2-5 The results from these studies provided the impetus to continue studies in humans.6-10 However, it wasn’t until 2002, when two randomized clinical trials of TH were published side by side in the New England Journal of Medicine, that TH hit the mainstream.11,12 In one of the trials, Bernard and colleagues randomized 77 ventricular fibrillation (VF) cardiac arrest survivors to TH (with a goal temperature of 33ºC for 12 hours) or normo-thermia, and demonstrated an almost doubling in good neurologic outcome from 26% to 49% (p=0.046).11,12 Meanwhile, the Hypothermia After Cardiac Arrest group randomized 136 patients and demonstrated a similar improvement (39% to 55%; p=0.009).11,12 Subsequently, in 2002 the American Heart Association’s Advanced Life Support Task Force of the International Liaison Committee on Resuscitation (ILCOR) recommended that unconscious adult patients with return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA) should be cooled to 32-34ºC for 12-24 hours when the initial rhythm is VF, and that cooling may also be beneficial for other rhythms as well as in-hospital cardiac arrest.13 Many studies since then have demonstrated improved outcomes with TH.14-20 Pathophysiology The full mechanism by which TH works is not entirely clear. However, several studies have shown that TH conserves and increases ATP synthesis,21-23 increases brain PO2,22 and decreases cerebral blood flow, the cerebral metabolic rate for glucose and oxygen22 and intracellular acidosis.22-24 Other studies have demonstrated decreased permeability of cellular membranes,25 the blood-brain barrier,26,27 and blood vessel walls resulting in reduced edema formation with the use of hypothermia. Hypothermia appears to decrease or block the release of glutamate21,28-32 and the influx of intracellular calcium,33,34 and prevent mitochondrial damage and activation of destructive enzymes, which lead to further cell destruction and death.35 Furthermore, TH may improve protein synthesis and delay anoxic depolarization,21 suppress inflammatory responses36 and free radical production,32,37 and provide multiple additional protective effects against damaging cascades that lead to neuronal death.21,38-40 Target Population TH after cardiac arrest is currently recommended as standard treatment for qualified patients after cardiac arrest. According to consensus guidelines, patients who follow verbal commands and those who have severe refractory cardiogenic shock, life-threatening arrhythmias, primary coagulopathy, or who are pregnant should be excluded from treatment, since complications associated with TH may be compounded.13 Many studies have limited inclusion to patients with VF as a primary rhythm; however, TH is likely worth initiating for patients with primary rhythms of pulseless electrical activity and asystole, since many studies on patients in these rhythms have shown a trend toward improved outcomes.7,8,10,16-18,20 Methods and Equipment Optimal target temperature, time to initiation, duration of therapy, and rewarming rate have not been strictly established; however, most studies target temperatures of 32 to 34ºC to be initiated as soon as possible after ROSC6-12,14-19 and maintained for 12 to 24 hours.6,9-12,15-19 Rewarming should generally be done gradually to prevent complications.13 A variety of methods can be used, including external or internal cooling devices and/or infusion or lavage of chilled fluids. Surface cooling with ice packs alone6,11 or combined with other cooling methods including cool air,12,15 cooling mattresses,14 gel pads18 and wet cold cloths15,18,19,41 are safe and effective. The use of cooling caps has also been explored, but reaching and maintaining desired temperatures were difficult.8,42 The time to target temperatures ranges from 1 to 9 hours6,15 with surface methods alone. Along with surface cooling, TH may be safely initiated with a 30ml/kg rapid infusion or gastric or bladder lavage of chilled (4ºC) lactated ringers solution or normal saline,10,16-18,43-45 which can reduce induction time.18,20,43 Chilled fluids should be delivered as rapidly as possible to achieve maximal effect.46 Although the combination of chilled fluids and surface cooling is still inconsistent in achieving target temperatures7,10,12,15,19,47 and may lead to some temperature overshoot,47,48 ease of implementation decreases time to TH initiation,19,20 and staff experience has been shown to facilitate success with these methods.14,15,20 Intravascular cooling devices are closed catheters inserted into a central vein and connected to a controller that monitors temperature and circulates warm or cool saline through the catheter to maintain a steady temperature. These devices have been shown to achieve target temperature more quickly49 while reducing overshoot.44,48,49 However, they are associated with increased costs44 and prolonged time to TH initiation20 because of the time required to insert the catheter. No matter the method of induction, TH is most often accompanied by intubation, with analgesia and sedation administered for comfort. Neuromuscular blockade may also be used if necessary to prevent shivering. Once achieved, target temperatures should be carefully maintained with little or no fluctuation for 12 to 24 hours.13 Temperatures below 32ºC lead to increased side effects.13,23 Tympanic temperatures are often monitored until continuous bladder, esophageal, or pulmonary artery temperatures can be obtained. Since temperature maintenance can be difficult with external cooling methods,10,15,19 external or internal cooling devices with automatic temperature control modules or feedback devices capable of self-adjusting to keep temperatures at a steady state are recommended.50 Rewarming should be performed slowly in a controlled manner to prevent complications, with consensus dictating a rate of between 0.25-0.5ºC/hour.17,18,20 Rewarming is most often done passively and may take between 6 to 12 hours to complete.6,8-12,14,15,19 After rewarming, temperatures should be maintained below 37ºC to help preserve neurological function.51,52 Side Effects Side effects of cooling most often occur during the induction and rewarming phases and can be minimized by rapid induction and slow, controlled rewarming. Complications increase as temperatures drop below 32ºC,23,53 making tight temperature control essential during the maintenance phase of TH. Shivering occurs at temperatures of 30-35ºC, and should be managed with analgesia, sedation and neuromuscular blockade, if needed, to prevent heat generation and increases in metabolic rate and oxygen consumption.23 Hyperglycemia often occurs during the induction phase as a result of insulin resistance.23,53 Current data are mixed regarding the benefits of tight glycemic control during TH.7,11,14,16,18,19,23,50 In addition, drug clearance may be altered with enhanced or diminished effects, and drug levels and outcomes should be measured whenever possible.23,54 Fluid and electrolyte disturbances have also been identified. Diuresis may occur,9,10,14,18,55 necessitating fluid and/or electrolyte replacement. Electrolyte and acid-base fluctuation has been reported to be self-correcting and not clinically significant in trials with mild TH.6,8-11,19,53 However, levels should be monitored closely. Serum potassium levels may decrease during cooling and increase during rewarming without actually being lost from the body.53,56 Replacement of only measured losses has been recommended.56 Some investigators advocate replacement for potassium levels below 4.0 mmol/L.6,9,11,14 Hypophosphatemia and hypomagnesemia may occur, and should be replaced to within normal ranges.55 Decreases in PH have been noted,6,8,9,11 but none have been reported as statistically or clinically significant with mild TH. Respiratory infections have been reported,7,10,12,14,17 but were statistically insignificant in all but one study,7 in which cooling extended beyond 24 hours. Patients should be watched closely for signs of infection, with prophylactic antibiotics administered as necessary. Coagulation disturbances have also been noted; however, no significant bleeding complications have been identified.57,58 Tachycardia has been reported during induction, followed by bradycardia, which is the most common arrhythmia encountered during TH.6,16,18,23,55 Physiologically, this pattern is expected,23 and no treatment has been indicated in any of the major studies. Future Directions TH is a major breakthrough in post-resuscitation care. However, questions remain regarding optimal target temperatures and duration of therapy as well as when TH is best initiated. Animal models have shown intra-arrest TH induction prior to reperfusion to improve neurological outcomes.59-61 Other studies have found induction of deeper levels of hypothermia after prolonged cardiac arrest prior to resuscitation efforts and reperfusion to be beneficial in maintaining neurological viability.62-64 Still, others are evaluating various methods of suspended animation.65,66 Human trials initiating TH in the pre-hospital setting, both immediately after ROSC67,68 as well as intra-arrest69 have demonstrated safety and efficacy. Larger studies encompassing both in-hospital and out-of-hospital cardiac arrest are needed to evaluate neurological outcomes after intra-arrest TH. Rapid achievement of target temperatures remains problematic. Ongoing studies focused on faster, more efficient cooling methods involving new external69-71 and internal methods62-64,72-78 as well as selective brain cooling79-84 are experimental and have not been tested in humans. Combination therapies involving conventional TH methods along with other treatments are also being explored.85-89 Conclusions TH is a promising therapy, with 1 of every 6 patients realizing improved neurological outcomes with minimal complications. Methods of implementation range from simple and inexpensive to complex and costly. More research is needed on optimal temperatures and duration for TH as well as more effective methods to reach and maintain desired temperatures. Expanded use of TH may be realized with education and establishment of standardized protocols.