5/29/2015 Therapeutic Hypothermia: Where Do We Stand? Melina Aguinaga-Meza, MD Assistant Professor of Medicine Gill Heart Institute University of Kentucky Disclosure Information Melina Aguinaga-Meza, MD “Therapeutic Hypothermia: Where Do We Stand?” • FINANCIAL DISCLOSURE: – No relevant financial relationship exists • UNLABELED/UNAPPROVED USES DISCLOSURE: – No relevant relationship exists 1 5/29/2015 The Clinical Problem • Out-of-hospital cardiac arrest (OHCA) is a leading cause of death among adults in the US • Approx. 300,000 OHCA events occur each year in the US • Resuscitation is attempted in 100,000 of these arrests • Less than 40 000 survive to hospital admission MMWR / July 29, 2011 / Vol. 60 / No. 8 2 5/29/2015 Consequences From Cardiac Arrest Myocardial Brain injury dysfunction Post-Cardiac Arrest Syndrome Systemic ischemia Disorder that + reperfusion caused the cardiac responses arrest • The effects of this syndrome are severe and pervasive MMWR / July 29, 2011 / Vol. 60 / No. 8 Survival and Neurological Outcomes after OHCA • Only one third of patients admitted to the hospital survive to hospital discharge • Approx. one out of ten people who experience OHCA survive to hospital discharge • Only 2 out of 3 of them have a good/moderate neurologic recovery MMWR / July 29, 2011 / Vol. 60 / No. 8: CARES 3 5/29/2015 “Chain of Survival” • Actions needed to improve chances of survival from out-of-hospital cardiac arrest Circulation 2010; 122:S676-84 • Try to identify and treat the precipitating causes of the arrest and prevent recurrent arrest. • Identify and treat acute coronary syndromes (ACS) • Optimize mechanical ventilation to minimize lung injury • Reduce the risk of multiorgan injury and support organ function if required • Control body temperature to optimize survival and neurological recovery 4 5/29/2015 Historical Development History • 1803 “Russian Method of Resuscitation” consisted of burying the victim of a cardiac arrest in snow hoping for ROSC Resuscitation 80 (2009) 1335 5 5/29/2015 History • In 1930s-1940s, hypothermia in cancer patients • In 1950s, induced TH was widely used during head/ spinal cord injuries and cardiac surgery • In 1959, Benson et al., case series of 19 patient post cardiac arrest Induced Hypothermia Normothermia (30-32 oC) Survived 6 (50%) 1(14%) Died 6 6 Total 12 7 CHEST 2008; 133:1267–1274 History • 1950 -1960s , Deep Hypothermia (<30°C) – Cardiac irritability and ventricular fibrillation – Infections – Coagulopathy • 1960 -1990s, the use of TH decreased • 1990s, animal experiments – Neurological outcome could be improved by using mild to moderate hypothermia (31°C–35°C) rather than deep hypothermia (<30°C) – Fewer and less severe side effects CHEST 2008; 133:1267–1274 6 5/29/2015 Pathophysiology and Effect of Therapy Ischemia-Reperfusion Brain Injury • Cascade of destructive events and processes • Begins in minutes and continues for hours/days • Retriggered by new episodes of ischemia All of these processes are temperature dependent Crit Care Med 2009; 37[Suppl.]:S186 –S202 7 5/29/2015 Maintains Neuronal Integrity • Inhibit the “Neuroexcitatory cascade” (Ca++ influx, accumulation of glutamate, and release of glycine) • Blocks Astroglial activation Front Neuro 2011; 2:1-8 Crit Care Med 2009; 37[Suppl.]:S186 – S202 Avoids Apoptosis Front Neuro 2011; 2:1-8 Crit Care Med 2009; 37[Suppl.]:S186 – S202 8 5/29/2015 Decreases Brain Metabolism and Oxidative Stress • Decrease in Cerebral Metabolism, oxygen consumption and glucose • Lowers lactate levels from anaerobic metabolism decreasing cellular acidosis • Blocks release of free radicals • Decreases the concentrations of thromboxane A2 Front Neuro 2011; 2:1-8 Crit Care Med 2009; 37[Suppl.]:S186 – S202 Other Mechanisms of Action • Decreases Inflammation: – Decreases inflammatory cytokines, leukotrienes, and inflammatory cells function (macrophages) • Decreases cytotoxic edema • Reduces disruption of the blood–brain barrier • Decreases the damage of the endothelial vasculature • Suppresses epileptogenic electrical activity Front Neuro 2011; 2:1-8 Crit Care Med 2009; 37[Suppl.]:S186 – S202 9 5/29/2015 Clinical Evidence Fever 10 5/29/2015 Hypothermia-40% Hyperthermia-26% Fever Worse survival Stroke . 2002;33:1759-1762 • Japan, 1980-1990 • Fever Worse neurological outcomes • Hyperthermia is an early indicator of brain damage after resuscitation Intensive Care Med (1991) 17:419-420 11 5/29/2015 • Austria, observational, prospective, 1992-1995 • Witness cardiac arrest with ROSC • Fever Unfavorable neurologic recovery Arch Intern Med 2001;161:2007 • Fever is a common complication in patients with various types of neurological injury • Fever is independently associated with an increased risk of adverse outcome 12 5/29/2015 Therapeutic Hypothermia in OHCA with Shockable Rhythm • Melbourne, Australia • September 1996 and June 1999 • Randomized controlled trial • Patients: – Ventricular Fibrillation – ROSC with persistent coma • Exclusion criteria: – Cardiogenic shock (SBP < 90 mm Hg despite epinephrine infusion) – Other possible causes of coma (drug overdose, head trauma, or cerebrovascular accident) N Engl J Med 2002;346:557-63 13 5/29/2015 Methods Hypothermia Normothermia (n=43) (n=34) • At discharge, outcomes: • Favorable neurologic outcome • Mortality N Engl J Med 2002;346:557-63 Hypothermia Protocol • Cold packs (ambulance) + ice packs (ED/ICU) • Midazolam + Vecuronium PRN for shivering • Optimal ventilator and hemodynamic support • Thrombolytic for AMI/Heparin for ACS • Lidocaine to prevent recurrent ventricular arrhythmias • Target temperature of 33°C for 12h • Passive rewarming over 8h ROSC ICU Rewarmed Target temp -2h 0h 33C 12h 18h 24h N Engl J Med 2002;346:557-63 14 5/29/2015 Characteristics of the Patients N Engl J Med 2002;346:557-63 Outcomes Outcome Hypothermia Normothermia p (n=43) (n=34) Good 21 (49%) 9(26%) 0.046 (Neuro) Death 22 (51%) 23(68%) 0.145 • Hypothermia group – OR 5.25 (95% 1.47-18.76; P=0.011) for good outcome N Engl J Med 2002;346:557-63 15 5/29/2015 Hemodynamics and Adverse Effects • No significant differences between the two groups with respect to the frequency of adverse events N Engl J Med 2002;346:557-63 • Europe, March 1996 - January 2001 • Multicenter (9 centers in 5 countries) , randomized, controlled trial • Patients: – Witnessed cardiac arrest – Ventricular Fibrillation or ventricular tachycardia – Collapse - CPR by EMS < 15min. – Collapse - ROSC, < 60 min • Excluded: – Temp < 30 OC, comatose before the cardiac arrest (drugs), response to verbal commands after ROSC, MAP < 60mmHg , persistent hypoxemia, coagulopathy N Engl J Med 2002;346:549-56 16 5/29/2015 Methods Hypothermia Normothermia (n=137) (n=138) • Outcomes at 6 months: – Favorable neurologic outcomes – Overall Mortality – Rate of complications N Engl J Med 2002;346:549-56 Hypothermia Protocol • External cooling device (TheraKool) • Sedation with Midazolam and Fentanyl • Pancuronium to prevent shivering • Target temperature of 32°C to 34°C for 24h • Passive rewarming over 8h Initiation ROSC of cooling Rewarmed Target temp 32-34°C 0h <2h 8h 28h 36h N Engl J Med 2002;346:549-56 17 5/29/2015 Temperature Curves • ROSC-initiation of cooling : 105 min. • ROSC- target temp 8h N Engl J Med 2002;346:549-56 Characteristics of the Patients N Engl J Med 2002;346:549-56 18 5/29/2015 Neurologic Outcomes Cerebral Performance Category V CPC 1 (good recovery) V CPC 2 (moderate disability) • Therapeutic Mild Hypothermia Favorable Neurologic Outcome N Engl J Med 2002;346:549-56 Survival 59% 45% P=0.02 • Therapeutic Mild Hypothermia Improved Survival N Engl J Med 2002;346:549-56 19 5/29/2015 Complications • Complication rate did not differ significantly between the two groups N Engl J Med 2002;346:549-56 Therapeutic Hypothermia in OHCA with Non-shockable Rhythm 20 5/29/2015 • Brussels, Belgium • Randomized controlled trial • Asystole or pulseless electrical activity (PEA) • Remained unconscious after ROSC • Target temp 34°C for 4h • Helmet device Resuscitation 51 (2001) 275–281 Outcome Hypothermia Normothermia (n=16) (n=14) Death 13 (81%) 13(92%) • Lactate and O2 extraction ratio were significantly lower in the hypothermia group Resuscitation 51 (2001) 275–281 21 5/29/2015 • 19 sites (Europe), 2003-2005, observational, registry • Lower mortality in the hypothermia group in patients with PEA/asystole as first rhythm Circulation . 2011;123:877-886 • Paris, France, 2000-2009, prospective cohort • No difference in outcomes in patients with PEA/asystole as first rhythm Circulation . 2011;123:877-886 22 5/29/2015 Therapeutic Hypothermia after In-hospital Cardiac Arrest • 19 sites (Europe), 2003-2005, observational, registry • No difference in outcomes for patients with in-hospital arrest Circulation . 2011;123:877-886 23 5/29/2015 Guidelines Circulation. 2003;108:118-121 Resuscitation 57 (2003) 231/235 24 5/29/2015 2005 Circulation. 2005;000:IV-84-IV-88 Circulation. 2010;122[suppl]:S768 –S786 25 5/29/2015 Circulation. 2010;122[suppl]:S768 –S786 Clinical Use 26 5/29/2015 Phases of Hypothermia Treatment Induction Maintenance Re-warming Normothermia Crit Care Med 2009; 37[Suppl.]:S186 –S202 Physiological Aspects of Cooling “Cold diuresis” “Hypovolemia” “Electrolyte disorders” “Hyperglycemia” “Shivering” “Prevention of infections” “Continuous EEG: Seizures” “Hypoglycemia” “Electrolyte disorders: Hyperkalemia” “Maintain Normothermia” Crit Care Med 2009; 37[Suppl.]:S186 –S202 J Am Coll Cardiol 2012;59:197–210 27 5/29/2015 Physiologic Effects and Complications • Shivering • Cardiovascular