Hypothermia for AMI

ST elevation myocardial infarction (STEMI) is the most serious type of heart attack (AMI), wherein the damage to the heart can frequently lead to structural changes (ventricular remodeling) and even heart failure. For STEMI patients, early and successful reperfusion therapy is widely accepted as the most effective interventional strategy for reducing infarct size. However, the process of reperfusion itself can also cause substantial injury to the myocardium.1,2 Studies in animal models suggest that lethal reperfusion injury can account for a sizable percentage of the final infarct size (i.e. the initial reintroduction of oxygenated blood, while on the whole beneficial, has a negative side effect of causing some myocardial tissue death).1 A number of studies have confirmed the presence of significant reperfusion injury despite the administration of pharmacological and immunological cardioprotective intervention at the onset of reperfusion therapy.1

The effect of therapeutic hypothermia in reducing infarct size has shown great promise in animal models. Based on these models, a 10% reduction in myocardial infarct size can be expected for every 1°C decrease in body temperature.3 One group of investigators performed a study in swine using FDA-cleared endovascular temperature modulation technology and cold saline infusion to better evaluate early hypothermia intervention in a clinically relevant model.4 They found significant reductions in infarct size and microvascular obstruction in this swine model, but only when hypothermia was induced prior to reperfusion therapy; pre-reperfusion hypothermia reduced infarct size (area) at risk by 43% (46 ± 8%) compared to post-reperfusion hypothermia (80 ± 6%, p < 0.05) and by 39% compared to normothermia (75 ± 5%, p < 0.05).

The need to cool prior to reperfusion was recently confirmed by Kanemoto, et al. who sought to assess the time course over which subtle levels of hypothermia need to be applied to significantly improve myocardial salvage in an animal model.5 Compared to normothermic controls, cooling for as little as five minutes prior to reperfusion significantly improved infarct size whereas cooling at the onset of reperfusion did not show a significant effect.5 As hypothermia was achieved closer to the start of ischemia, infarct size continued to improve; when cooled at the start of ischemia, infarct sizes were significantly improved over both normothermic control rats and rats cooled at the onset of reperfusion.5 The benefit gained from inducing hypothermia at an early stage supports the theory that more rapid intervention with mild hypothermia may lead to improved efficacy.

Therapeutic hypothermia clinical trials performed in the STEMI population have used both external and endovascular means of cooling patients and while they have been found to be safe, most have not shown significant decreases in infarct size.6-12 As discussed above, the lack of efficacy is likely the result of hypothermia induced late in the intervention. Evidence for this comes from post-hoc subgroup analyses performed in both the COOL-MI and ICE-IT endovascular hypothermia trials. In the COOL-MI trial, patients presenting with an anterior infarct who achieved hypothermia (< 35°C) prior to reperfusion had significantly smaller infarct sizes as compared to the control (9.3% vs. 18.2%, p = 0.05).8 The ICE-IT trial found similar results with a 43% relative reduction in infarct size (12.9% vs. 22.7% p = 0.09) in same cohort of patients.12 In contrast, when patients did not achieve hypothermia prior to reperfusion, myocardial infarct sizes were larger as compared to the control group in the COOLMI trial (21.9% vs. 18.2%) and were slightly smaller than the control group in the ICE-IT trial (17.6% vs. 22.7%). These subgroup analyses provide strong support for what Kanemoto, et al. previously described – hypothermia is cardioprotective only if achieved prior to reperfusion.

In 2010 data supporting the use of hypothermia for acute MI patients with STEMI was published by Götberg, et al from Lund, Sweden.13 In the RAPID MI-ICE trial 20 patients with acute myocardial infarction scheduled to undergo primary PCI were randomized to either hypothermia (administered by cold IV saline plus an endovascular cooling catheter) or no hypothermia. Patients in the hypothermia cohort were hypothermic prior to reperfusion of the occluded vessel and infarct area. The trial showed a significant relative reduction in infarct size normalized to myocardium at risk (as measured by T2 MRI) of 38% versus the control group (p=0.041, n=8+8). This data was supported by a significant decrease in both peak and cumulative release of Troponin T in the hypothermia group (p=0.01 and 0.03, respectively, n=9+9). It is important to note that reperfusion was not delayed by the use of hypothermia; door-to-balloon times between the treatment and control groups had no significant difference (43 ± 7 minutes vs. 40 ± 6 minutes, p=0.12, n=9+9).

The importance of rapidly cooling the patient to therapeutic temperatures was further emphasized in a pooled analysis of the ICE-IT and RAPID MI-ICE data, by Erlinge, et al. Erlinge states “The results indicate that reaching a temperature of less than 35°C before reperfusion is of paramount importance to reduce infarct size in the treatment of STEMI patients” and “… this needs to be performed without significant delay in the “door-to-balloon-time” interval for patients treated with hypothermia.” 14

The International Liaison Committee on Resuscitation (ILCOR) stated in their 2010 treatment recommendations “Limited available evidence suggests that PCI during therapeutic hypothermia is feasible and safe and may be associated with improved outcome.” 15 Additionally, ILCOR stated “Five studies indicated that the combination of therapeutic hypothermia and PCI is feasible and safe after cardiac arrest caused by acute myocardial infarction” (three studies with retrospective controls and two without a control group).16-20 Similarly, the American Heart Association 2010 Guidelines state “Concurrent PCI and hypothermia are safe, with good outcomes reported for some comatose patients who undergo PCI.” 21

References

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