Neuroprotection for ischemic stroke: past, present and future.

The 30-year anniversary of the discovery of 'ischaemic preconditioning' is in 2016. This endogenous phenomenon can paradoxically protect the heart from acute myocardial infarction by subjecting it to one or more brief cycles of ischaemia and reperfusion. Apart from complete reperfusion, this method is the most powerful intervention known for reducing infarct size. The concept of ischaemic preconditioning has evolved into 'ischaemic conditioning', a term that encompasses a number of related endogenous cardioprotective strategies, applied either directly to the heart (ischaemic preconditioning or postconditioning) or from afar, for example a limb (remote ischaemic preconditioning, perconditioning, or postconditioning). Investigations of signalling pathways underlying ischaemic conditioning have identified a number of therapeutic targets for pharmacological manipulation. Over the past 3 decades, a number of ischaemic and pharmacological cardioprotection strategies, discovered in experimental studies, have been examined in the clinical setting of acute myocardial infarction and CABG surgery. The results from many of the studies have been disappointing, and no effective cardioprotective therapy is currently used in clinical practice. Several large, multicentre, randomized, controlled clinical trials on cardioprotection have highlighted the challenges of translating ischaemic conditioning and pharmacological cardioprotection strategies into patient benefit. However, a number of cardioprotective therapies have shown promising results in reducing infarct size and improving clinical outcomes in patients with ischaemic heart disease.

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Ischaemic conditioning and reperfusion injury

The translation from numerous successful animal experiments on cardioprotection beyond that by reperfusion to clinical practice has to date been disappointing. Animal experiments often use reductionist approaches and are mostly performed in young and healthy animals which lack the risk factors, comorbidities, and comedications which are characteristics of patients suffering an acute myocardial infarction or undergoing cardiovascular surgery. Conceptually, it is still unclear by how much the time window for successful reperfusion is extended by preconditioning, and how long the duration of ischemia can be so that adjunct cardioprotection by postconditioning at reperfusion still protects. Experimental studies addressing long-term effects of adjunct cardioprotection beyond infarct size reduction, that is, on repair, remodeling, and mortality, are lacking. Technically, reproducibility and robustness of experimental studies are often limited. Grave faults in design and conduct of clinical trials have also substantially contributed to the failure of translation of cardioprotection to clinical practice. Cardiovascular surgery with ischemic cardioplegic arrest is only a surrogate of acute myocardial infarction and confounded by the choice of anesthesia, hypothermia, cardioplegia, and traumatic myocardial injury. Trials in patients with acute myocardial infarction have been performed on agents/interventions with no or inconsistent previous animal data and in patients who had either some reperfusion already at admission or were reperfused too late to expect any myocardial salvage. Of greatest concern is the lack of adequate phase II dosing and timing studies when rushing from promising proof-of-concept trials with surrogate end points such as infarct size to larger clinical outcome trials. Future trials must focus on interventions/agents with robust preclinical evidence, have solid phase II dosing and timing data, and recruit patients who have truly a chance to benefit from adjunct cardioprotection.

Critical Issues for the Translation of Cardioprotection.

Hypothermia for neuroprotection after cardiac arrest: mechanisms, clinical trials and patient care.

Targeted temperature management is recommended after out-of-hospital cardiac arrest and may be achieved using a variety of cooling devices. This study was conducted to explore the performance and outcomes for intravascular versus surface devices for targeted temperature management after out-of-hospital cardiac arrest. A retrospective analysis of data from the Targeted Temperature Management trial. N = 934. A total of 240 patients (26%) managed with intravascular versus 694 (74%) with surface devices. Devices were assessed for speed and precision during the induction, maintenance and rewarming phases in addition to adverse events. All-cause mortality, as well as a composite of poor neurological function or death, as evaluated by the Cerebral Performance Category and modified Rankin scale were analysed. For patients managed at 33 °C there was no difference between intravascular and surface groups in the median time taken to achieve target temperature (210 [interquartile range (IQR) 180] minutes vs. 240 [IQR 180] minutes, p = 0.58), maximum rate of cooling (1.0 [0.7] vs. 1.0 [0.9] °C/hr, p = 0.44), the number of patients who reached target temperature (within 4 hours (65% vs. 60%, p = 0.30); or ever (100% vs. 97%, p = 0.47), or episodes of overcooling (8% vs. 34%, p = 0.15). In the maintenance phase, cumulative temperature deviation (median 3.2 [IQR 5.0] °C hr vs. 9.3 [IQR 8.0] °C hr, p = <0.001), number of patients ever out of range (57.0% vs. 91.5%, p = 0.006) and median time out of range (1 [IQR 4.0] hours vs. 8.0 [IQR 9.0] hours, p = <0.001) were all significantly greater in the surface group although there was no difference in the occurrence of pyrexia. Adverse events were not different between intravascular and surface groups. There was no statistically significant difference in mortality (intravascular 46.3% vs. surface 50.0%; p = 0.32), Cerebral Performance Category scale 3–5 (49.0% vs. 54.3%; p = 0.18) or modified Rankin scale 4–6 (49.0% vs. 53.0%; p = 0.48). Intravascular and surface cooling was equally effective during induction of mild hypothermia. However, surface cooling was associated with less precision during the maintenance phase. There was no difference in adverse events, mortality or poor neurological outcomes between patients treated with intravascular and surface cooling devices. TTM trial ClinicalTrials.gov number https://clinicaltrials.gov/ct2/show/NCT01020916
 NCT01020916; 25 November 2009

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Intravascular versus surface cooling for targeted temperature management after out-of-hospital cardiac arrest – an analysis of the TTM trial data

In the randomized rapid intravascular cooling in myocardial infarction as adjunctive to percutaneous coronary intervention (RAPID MI-ICE) and rapid endovascular catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction CHILL-MI studies, hypothermia was rapidly induced in conscious patients with ST-elevation myocardial infarction (STEMI) by a combination of cold saline and endovascular cooling. Twenty patients in RAPID MI-ICE and 120 in CHILL-MI with large STEMIs, scheduled for primary percutaneous coronary intervention (PCI) within 30% of the left ventricle) exhibited significantly reduced IS/MaR in the hypothermia group (40.5, 27.0-57.6 vs. 55.1, 41.1-64.4, median, IQR; hypothermia n=42 vs. control n=37, p=0.03), while patients with MaR<30% did not show effect of hypothermia (35.8, 28.3-57.5 vs. 38.4, 27.4-59.7, median, IQR; hypothermia n=15 vs. control n=19, p=0.50). The prespecified pooled analysis of RAPID MI-ICE and CHILL-MI indicates a reduction of myocardial IS and reduction in heart failure by 1-3 hours with endovascular cooling in association with primary PCI of acute STEMI predominantly in patients with large area of myocardium at risk. (ClinicalTrials.gov id NCT00417638 and NCT01379261).

Therapeutic Hypothermia for the Treatment of Acute Myocardial Infarction - Combined analysis of the RAPID MI- ICE and the CHILL-MI trials

Mild hypothermia has been shown to provide protective effects in patients with ischemia (e.g. acute stroke and heart attack), but traditional methods for inducing, maintaining, and reversing hypothermia are slow, difficult to administer and control, and uncomfortable for patients. An innovative method produces mild, wholebody hypothermia (32 degrees C to 34 degrees C) by use of an endovascular heat exchanger placed into the inferior vena cava. A closed-loop system accurately changes core body temperature with average cool-down rates of 4.8 degrees C per hour, tight-target temperature control of +/- 0.1 degree C, and average rewarm rates of 1.9 degrees C per hour. By enhancing the mixing of blood in the vicinity of the heat exchanger, the disposable, small-diameter catheter efficiently exchanges heat between the closed-loop circulating fluid and the blood stream in response to body temperature. A control algorithm adapts to body physiology and thermal mass to mitigate temperature excursions. Flexible, bellow-shaped segments along the length of the catheter allow precise maneuvering within blood vessels. Heparin, covalently bonded to the catheter, helps control thrombogenicity. This novel design has potential clinical applications in cerebrovascular surgery, acute stroke, acute myocardial infarction, cardiac arrest, and fever control.

A novel system for mild hypothermia.

Mild hypothermia has been shown to provide protective effects in patients with ischemia (e.g. acute stroke and heart attack), but traditional methods for inducing, maintaining, and reversing hypothermia are slow, diffi- cult to administer and control, and uncomfortable for patients. An innovative method produces mild, whole- body hypothermia (32°C to 34°C) by use of an endovas- cular heat exchanger placed into the inferior vena cava. A closed-loop system accurately changes core body tempera- ture with average cool-down rates of 4.8°C per hour, tight-target temperature control of +/-0.1°C, and aver- age rewarm rates of 1.9°C per hour. By enhancing the mixing of blood in the vicinity of the heat exchanger, the disposable, small-diameter catheter efficiently exchanges heat between the closed-loop circulating fluid and the blood stream in response to body temperature. A control algorithm adapts to body physiology and thermal mass to mitigate temperature excursions. Flexible, bellow-shaped segments along the length of the catheter allow precise maneuvering within blood vessels. Heparin, covalently bonded to the catheter, helps control thrombogenicity. This novel design has potential clinical applications in cere- brovascular surgery, acute stroke, acute myocardial infarction, cardiac arrest, and fever control.

Brad Klos

Papers

Therapeutic Hypothermia for the Treatment of Acute Myocardial Infarction - Combined analysis of the RAPID MI- ICE and the CHILL-MI trials

A novel system for mild hypothermia.

A Novel System for Mild