Therapeutic Hypothermia: Where Do We Stand?

5/29/2015

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

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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

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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

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“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

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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

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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

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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

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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

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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

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Clinical Evidence

Fever

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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

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• 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

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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

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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

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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

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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

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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

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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

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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

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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

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• 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

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• 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

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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

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Guidelines

Circulation. 2003;108:118-121 Resuscitation 57 (2003) 231/235

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2005

Circulation. 2005;000:IV-84-IV-88

Circulation. 2010;122[suppl]:S768 –S786

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Circulation. 2010;122[suppl]:S768 –S786

Clinical Use

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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

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Physiologic Effects and Complications

• Shivering • Cardiovascular manifestations • Hyperglycemia • Electrolyte disorders • Bleeding • Alterations in drug metabolism • Risk of Infections

Crit Care Med 2009; 37[Suppl.]:S186 –S202 J Am Coll Cardiol 2012;59:197–210

Cooling Techniques

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Conventional Cooling Systems

• Cold saline, crushed ice or ice bags • Easiest and effective way to induce hypothermia • Not so effective in maintaining target temperature

Resuscitation (2007) 73 , 46—53

Surface Cooling Systems • Circulating cold fluid or cold air through blankets/pads wrapped around the patient • Easy to apply and rapid initiation of treatment • Maintenance of temperature may be difficult • Shivering is more common • Complication: Skin burns/irritation

Critical Care (2015) 19:103

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Intravascular Cooling Systems • Percutaneously placed central venous catheters • Circulating cool or warm saline in a closed loop through the catheter’s balloon • Less shivering compared to surface devices • Complication: Thrombosis

Critical Care (2015) 19:103

• No difference in outcomes between the groups

Resuscitation 81 (2010) 1117–1122

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• Endovascular cooling – Longer time within the target temperature range – Less temperature fluctuation – Better control during rewarming – Less overcooling – Less failure to reach the target temperature

Resuscitation 81 (2010) 1117–1122

Implementation

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• Paris, France, 2000-2009 • Prospective cohort

Circulation . 2011;123:877-886

• 243 ICUs in UK • 2002–2009

Anaesthesia, 2010, 65, pages 260–265

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National Trends in the Use of Postcardiac Arrest Therapeutic Hypothermia and Hospital Factors Influencing Its Use • Across 2007–2010, in United States

25% 20% 15% 10% 5% 0% 2007 2010 Hospitals using TH 4.60% 22.16% Patients received 0.34% 2.49% TH

Ther Hypothermia Temp Manag. 2015 Mar;5(1):48-54. Epub 2015 Jan

National Trends in the Use of Postcardiac Arrest Therapeutic Hypothermia and Hospital Factors Influencing Its Use

Significant hospital factors associated with TH utilization were: • Large hospitals • Urban location, northeast or west regions • Teaching hospitals • Non-safety net hospitals • Increasing year • Hospitals with higher annual cardiac arrest volume

Ther Hypothermia Temp Manag. 2015 Mar;5(1):48-54. Epub 2015 Jan

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Survival During The Last Decade

Survival following OHCA

• In Denmark , Danish Cardiac Arrest Registry • Patients with OHCA , 2001 - 2010

JAMA . 2013;310(13):1377-1384

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Survival following OHCA

J Intern Med 2013; 273: 572–583.

• Get with the Guidelines Resuscitation Registry • 374 hospitals in the US, 2000 - 2009

N Engl J Med 2012;367:1912-20

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Interventions In Resuscitation Over The Last Decade

• Bystander CPR • Increased use of AED • High quality compressions: compression-only • Good chest compressions and minimal “hands-off time” • Early revascularization (PCI) • Improved post-resuscitation care • Use of ‘track and trigger systems’ to detect patients deterioration (Rapid Response Team) • Mild Therapeutic Hypothermia

N Engl J Med 2012;367:1912-20.

Targeted Temperature Management Post Cardiac Arrest

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