This report focuses on cardioprotection and describes the advantages and disadvantages of various methods of inducing therapeutic hypothermia (TH) with regard to neuroprotection and cardioprotection for patients with cardiac arrest and ST-segment elevation myocardial infarction (STEMI). TH is recommended in cardiac arrest guidelines. For patients resuscitated after out-of-hospital cardiac arrest, improvements in survival and neurologic outcomes were observed with relatively slow induction of TH. More rapid induction of TH in patients with cardiac arrest might have a mild to modest incremental impact on neurologic outcomes. TH drastically reduces infarct size in animal models, but achievement of target temperature before reperfusion is essential. Rapid initiation of TH in patients with STEMI is challenging but attainable, and marked infarct size reductions are possible. To induce TH, a variety of devices have recently been developed that require additional study. Of particular interest is transcoronary induction of TH using a catheter or wire lumen, which enables hypothermic reperfusion in the absence of total-body hypothermia. At present, the main methods of inducing and maintaining TH are surface cooling, endovascular heat-exchange catheters, and intravenous infusion of cold fluids. Surface cooling or endovascular catheters may be sufficient for induction of TH in patients resuscitated after out-of-hospital cardiac arrest. For patients with STEMI, intravenous infusion of cold fluids achieves target temperature very rapidly but might worsen left ventricular function. More widespread use of TH would improve survival and quality of life for patients with out-of-hospital cardiac arrest; larger studies with more rapid induction of TH are needed in the STEMI population.
Survival rates for out-of-hospital cardiac arrest (OHCA) are traditionally very low (5% to 8%). Therapeutic hypothermia (TH) has been used clinically for many years to preserve the heart during surgery (e.g., coronary artery bypass) and to preserve organs before transplantation. More recently, the International Liaison Committee on Resuscitation in 2002 and the American Heart Association in 2005 recommended TH for certain patients with OHCA; however, most health care systems have not incorporated TH into treatment protocols. TH has been deployed in experimental animals to protect the heart against acute infarction, with impressive results. The clinical application of TH for ST-segment elevation myocardial infarction (STEMI) is challenging because STEMIs are unpredictable, and cooling the heart rapidly without increasing door-to-balloon time is difficult. Accordingly, studies of TH in humans for acute STEMI have been limited, although several are ongoing. In this review, we describe the importance of the timing of TH for neuroprotection and cardioprotection, with a focus on cardioprotection, and describe various methods of inducing TH, including the advantages and disadvantages related to neuroprotection and cardioprotection.
Therapeutic Hypothermia for Neuroprotection After Cardiac Arrest
The use of TH after cardiac arrest is based on 2 randomized trials that studied resuscitated patients with OHCA with an initial rhythm of ventricular fibrillation who remained comatose on arrival at the emergency department. One trial included 273 patients and showed that TH improved 6-month survival (55% vs 41%, p = 0.02) and favorable neurologic outcomes (55% vs 39%, p = 0.009). The other trial randomized 77 patients and observed the TH group to have more favorable neurologic outcomes (49% vs 26%, p = 0.011). TH is now recommended in the cardiac arrest guidelines. Emergency response systems that instituted TH in their clinical algorithms have shown improved survival rates and improved neurological recovery. A recent analysis of 140 OHCA patients admitted to a TH-capable hospital reported overall survival to hospital discharge of 56%, with 92% of survivors discharged with favorable neurologic outcomes. (Patients with initial rhythms of pulseless electrical activity or asystole were excluded from most, but not all, investigations of TH for OHCA. Initial evidence indicates that patients with initial rhythms of pulseless electrical activity or asystole may also benefit from TH, although outcomes are worse than for an initial rhythm of ventricular fibrillation ).
In 1 of the landmark trials, the median time from return of spontaneous circulation (ROSC) to initiation of TH was 105 minutes, and time to target temperature was 8 hours. Although conventional teaching and experimental evidence dictates that the brain experiences irreversible injury within minutes of acute ischemia, delayed induction of TH conveyed significant neuroprotection. In experimental models, neuroprotection was related to the rapidity of TH. Nonrandomized analyses reported that the time to target temperature was shorter in survivors than nonsurvivors and that earlier achievement of TH correlated with improved outcomes. The superiority of early versus delayed TH, however, has not been demonstrated in randomized trials. Early initiation of TH in the ambulance compared with initiation after hospital admission did not significantly improve outcomes in 234 randomized patients. Similarly, in a randomized trial with 200 patients, no difference was observed in clinical outcomes between TH initiated during resuscitation versus after hospital arrival despite significantly lower tympanic and core temperatures on hospital arrival in the early TH group (this study was not powered to detect differences in clinical outcomes). In conclusion, experimental models and nonrandomized analyses suggest that earlier TH improves outcomes, although the incremental benefits of early versus later TH appear relatively small. The superiority of early versus later TH has not been demonstrated in randomized trials. In patients with ROSC after OHCA, survival and neurologic outcomes were markedly improved with relatively delayed (105 minutes to initiation) and slow (8 hours to target temperature) TH.
In clinical practice, TH has been reserved for use after ROSC. In animal models of cardiac arrest, instituting TH during cardiac arrest improved rates of ROSC, neurologic outcomes, and survival. Major obstacles would need to be addressed before introducing TH into practice for use during cardiac arrest. First, a reliable, safe, rapid method of inducing TH would need to be established. All emergency responders would need training in instituting TH in addition to their current responsibilities. Additionally, the ethical considerations of patient selection would need addressing, because patients in cardiac arrest are by definition dead.
Therapeutic Hypothermia for Cardioprotection
Timing
In animal models of coronary artery occlusion and reperfusion (experimental myocardial infarction), TH has reliably and markedly reduced myocardial infarct size (IS) when initiated during myocardial ischemia but before reperfusion. TH’s beneficial effects on IS have been consistent in a variety of models with numerous methods of inducing TH and in different species. In addition, TH attenuates ischemia-reperfusion injury and improves coronary blood flow after occlusion. By limiting ischemia-reperfusion injury, TH attenuated adverse left ventricular remodeling and preserved the ejection fraction and cardiac output 8 weeks after infarction. TH also reduced the incidence of ventricular arrhythmias and improved defibrillation rates in pigs.
IS reduction is closely related to the temperature and the timing of TH in experimental models. A large reduction in IS of 49% to 65% was observed when TH was initiated before coronary artery occlusion, ensuring that target temperature was reached during occlusion and before reperfusion. Initiation of TH during occlusion resulted in varying degrees of IS reduction and was loosely correlated with the timing of TH (large reductions when initiated early during occlusion and small or nonsignificant reductions when initiated later ). Induction of TH at the time of reperfusion generally failed to reduce IS. Single experiments that initiated TH at various time points showed progressively larger IS reductions with progressively earlier initiation of TH.
Left atrial temperature at reperfusion correlated more closely with IS than temperature at any other time point. The temperature of the reperfusing blood may be more important than myocardial temperature. Support for this hypothesis comes from 2 very similar experiments in which rabbits were subjected to 30 minutes of coronary occlusion followed by 3 hours of reperfusion with initiation of TH 5 minutes before reperfusion. IS was not reduced by placing an ice bag on the surface of the heart (hypothermic myocardium reperfused by warm blood), whereas total-body TH (hypothermic myocardium reperfused by hypothermic blood) reduced IS. In addition, only 1 study has reported a reduction in IS when TH was initiated at the time of reperfusion. In this study, cold (4°C) saline was infused through an infusion balloon catheter during the first 30 minutes of reperfusion (warm myocardium reperfused by hypothermic blood).
Translation of these studies to conscious patients with STEMI is not clear, because STEMI is managed optimally with timely reperfusion therapy. Two similar studies, Intravascular Cooling Adjunctive to Percutaneous Coronary Intervention for Acute Myocardial Infarction (ICE-IT; n = 228) and Cooling as an Adjunctive Therapy to Percutaneous Intervention in Patients With Acute Myocardial Infarction (COOL-MI; n = 357), included patients with STEMIs with anterior or large inferior infarcts and onset of symptoms within 6 hours. Patients were randomized to standard therapy or standard therapy plus TH induced using an endovascular cooling device. IS was not significantly reduced by TH in either study. However, only approximately 1 of 3 patients randomized to TH achieved a temperature <35°C before reperfusion. The subgroups of patients with anterior infarctions who reached temperatures <35°C before reperfusion had significantly smaller IS (ICE-IT: 13% vs 23%, p = 0.09; COOL-MI: 9% vs 18%, p = 0.05). A reanalysis of the Hypothermia After Cardiac Arrest (HACA) trial trial reached a similar conclusion: IS was decreased in the subset of patients who achieved target temperature within 8 hours compared with beyond 8 hours.
TH has been initiated safely in patients with STEMIs without delaying primary percutaneous coronary intervention (PCI), but target temperature was not reached by the time of angioplasty. In a recent trial, patients with STEMIs were randomly assigned to standard therapy or standard therapy with TH, induced rapidly with intravenous infusion of refrigerated saline and then maintained with an endovascular cooling device. All 9 patients in the TH group reached temperatures <35°C before reperfusion without a significant or clinically meaningful delay in door-to-balloon time (43 vs 40 minutes, p = 0.12). IS was reduced in the TH group by 38% (30% vs 48%, p = 0.041). This study showed that rapid induction of TH is feasible in patients with STEMIs without delaying reperfusion therapy and markedly reduces IS.
Several barriers need to be overcome regarding the use of TH for STEMI. TH must be achieved rapidly, before reperfusion, and must not significantly delay reperfusion. Methods of rapidly inducing TH are under development. Patients who are awake and oriented may be fearful or resistant to undergoing TH. Moreover, TH often causes discomfort and shivering which require additional medications. Shivering has been successfully controlled with neuromuscular blockade (the optimal method in sedated patients), skin warming (which cannot be used with surface cooling devices), and meperidine with or without buspirone (the optimal method in conscious patients).
Temperature and mechanism
Larger IS reduction was observed with TH of 32°C compared to 35°C. In a pig model of coronary occlusion (1 hour) and reperfusion (3 hours), temperature was maintained at a constant level throughout the experiment in 5 groups, at 39.5°C, 38.5°C, 37.5°C, 36.5°C, and 35.5°C, resulting in IS (as a percentage of area at risk) of 72%, 63%, 49%, 39%, and 22%, respectively. A >10% reduction in IS was observed for every 1°C reduction in temperature. The risk for arrhythmias increases significantly at <30°C. Temperatures <30°C cause primarily atrial fibrillation, however ventricular fibrillation can also occur, especially at <28°C. Thus, most of the TH studies used mild TH. Within the range of mild hypothermia (32°C to 36°C), lower temperatures convey more cardioprotection.
The earlier TH is initiated during coronary occlusion, the larger the reduction in IS, which suggests that TH attenuates or halts ischemic injury to myocardial cells. TH also prevents the no-reflow phenomenon, suggesting that TH attenuates reperfusion injury. The mechanisms by which TH protects tissues from ischemia-reperfusion injury have been only partially described and are probably multifactorial. As opposed to pharmacologic therapy that targets 1 specific pathway, the effectiveness of TH is probably related to the fact that it affects multiple pathways simultaneously. TH decreases the rate-pressure product, but IS is also reduced in paced hearts (with the same rate-pressure product as controls), so TH induces additional mechanisms of cardioprotection. Cardioprotection may be conveyed through energy preservation. TH slows the metabolic rate and oxygen demand and preserves adenosine triphosphate and glycogen stores. An alternative, and perhaps complementary hypothesis, is that TH alters signal transduction pathways, similar to ischemic conditioning, and may ultimately prevent opening of the mitochondrial permeability transition pore.
Therapeutic Hypothermia for Cardioprotection
Timing
In animal models of coronary artery occlusion and reperfusion (experimental myocardial infarction), TH has reliably and markedly reduced myocardial infarct size (IS) when initiated during myocardial ischemia but before reperfusion. TH’s beneficial effects on IS have been consistent in a variety of models with numerous methods of inducing TH and in different species. In addition, TH attenuates ischemia-reperfusion injury and improves coronary blood flow after occlusion. By limiting ischemia-reperfusion injury, TH attenuated adverse left ventricular remodeling and preserved the ejection fraction and cardiac output 8 weeks after infarction. TH also reduced the incidence of ventricular arrhythmias and improved defibrillation rates in pigs.
IS reduction is closely related to the temperature and the timing of TH in experimental models. A large reduction in IS of 49% to 65% was observed when TH was initiated before coronary artery occlusion, ensuring that target temperature was reached during occlusion and before reperfusion. Initiation of TH during occlusion resulted in varying degrees of IS reduction and was loosely correlated with the timing of TH (large reductions when initiated early during occlusion and small or nonsignificant reductions when initiated later ). Induction of TH at the time of reperfusion generally failed to reduce IS. Single experiments that initiated TH at various time points showed progressively larger IS reductions with progressively earlier initiation of TH.
Left atrial temperature at reperfusion correlated more closely with IS than temperature at any other time point. The temperature of the reperfusing blood may be more important than myocardial temperature. Support for this hypothesis comes from 2 very similar experiments in which rabbits were subjected to 30 minutes of coronary occlusion followed by 3 hours of reperfusion with initiation of TH 5 minutes before reperfusion. IS was not reduced by placing an ice bag on the surface of the heart (hypothermic myocardium reperfused by warm blood), whereas total-body TH (hypothermic myocardium reperfused by hypothermic blood) reduced IS. In addition, only 1 study has reported a reduction in IS when TH was initiated at the time of reperfusion. In this study, cold (4°C) saline was infused through an infusion balloon catheter during the first 30 minutes of reperfusion (warm myocardium reperfused by hypothermic blood).
Translation of these studies to conscious patients with STEMI is not clear, because STEMI is managed optimally with timely reperfusion therapy. Two similar studies, Intravascular Cooling Adjunctive to Percutaneous Coronary Intervention for Acute Myocardial Infarction (ICE-IT; n = 228) and Cooling as an Adjunctive Therapy to Percutaneous Intervention in Patients With Acute Myocardial Infarction (COOL-MI; n = 357), included patients with STEMIs with anterior or large inferior infarcts and onset of symptoms within 6 hours. Patients were randomized to standard therapy or standard therapy plus TH induced using an endovascular cooling device. IS was not significantly reduced by TH in either study. However, only approximately 1 of 3 patients randomized to TH achieved a temperature <35°C before reperfusion. The subgroups of patients with anterior infarctions who reached temperatures <35°C before reperfusion had significantly smaller IS (ICE-IT: 13% vs 23%, p = 0.09; COOL-MI: 9% vs 18%, p = 0.05). A reanalysis of the Hypothermia After Cardiac Arrest (HACA) trial trial reached a similar conclusion: IS was decreased in the subset of patients who achieved target temperature within 8 hours compared with beyond 8 hours.
TH has been initiated safely in patients with STEMIs without delaying primary percutaneous coronary intervention (PCI), but target temperature was not reached by the time of angioplasty. In a recent trial, patients with STEMIs were randomly assigned to standard therapy or standard therapy with TH, induced rapidly with intravenous infusion of refrigerated saline and then maintained with an endovascular cooling device. All 9 patients in the TH group reached temperatures <35°C before reperfusion without a significant or clinically meaningful delay in door-to-balloon time (43 vs 40 minutes, p = 0.12). IS was reduced in the TH group by 38% (30% vs 48%, p = 0.041). This study showed that rapid induction of TH is feasible in patients with STEMIs without delaying reperfusion therapy and markedly reduces IS.
Several barriers need to be overcome regarding the use of TH for STEMI. TH must be achieved rapidly, before reperfusion, and must not significantly delay reperfusion. Methods of rapidly inducing TH are under development. Patients who are awake and oriented may be fearful or resistant to undergoing TH. Moreover, TH often causes discomfort and shivering which require additional medications. Shivering has been successfully controlled with neuromuscular blockade (the optimal method in sedated patients), skin warming (which cannot be used with surface cooling devices), and meperidine with or without buspirone (the optimal method in conscious patients).
Temperature and mechanism
Larger IS reduction was observed with TH of 32°C compared to 35°C. In a pig model of coronary occlusion (1 hour) and reperfusion (3 hours), temperature was maintained at a constant level throughout the experiment in 5 groups, at 39.5°C, 38.5°C, 37.5°C, 36.5°C, and 35.5°C, resulting in IS (as a percentage of area at risk) of 72%, 63%, 49%, 39%, and 22%, respectively. A >10% reduction in IS was observed for every 1°C reduction in temperature. The risk for arrhythmias increases significantly at <30°C. Temperatures <30°C cause primarily atrial fibrillation, however ventricular fibrillation can also occur, especially at <28°C. Thus, most of the TH studies used mild TH. Within the range of mild hypothermia (32°C to 36°C), lower temperatures convey more cardioprotection.
The earlier TH is initiated during coronary occlusion, the larger the reduction in IS, which suggests that TH attenuates or halts ischemic injury to myocardial cells. TH also prevents the no-reflow phenomenon, suggesting that TH attenuates reperfusion injury. The mechanisms by which TH protects tissues from ischemia-reperfusion injury have been only partially described and are probably multifactorial. As opposed to pharmacologic therapy that targets 1 specific pathway, the effectiveness of TH is probably related to the fact that it affects multiple pathways simultaneously. TH decreases the rate-pressure product, but IS is also reduced in paced hearts (with the same rate-pressure product as controls), so TH induces additional mechanisms of cardioprotection. Cardioprotection may be conveyed through energy preservation. TH slows the metabolic rate and oxygen demand and preserves adenosine triphosphate and glycogen stores. An alternative, and perhaps complementary hypothesis, is that TH alters signal transduction pathways, similar to ischemic conditioning, and may ultimately prevent opening of the mitochondrial permeability transition pore.
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