therapeutic hypothermia: where do we stand?wcm/@gra/documents/... · 5/29/2015 1 therapeutic...

5/29/2015

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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

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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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• The effects of this syndrome are severe and pervasive

MMWR / July 29, 2011 / Vol. 60 / No. 8

Consequences From Cardiac Arrest

Brain injury Myocardial dysfunction

Systemic ischemia + reperfusion

responses

Disorder that caused the cardiac

arrest

Post-Cardiac Arrest

Syndrome

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

CHEST 2008; 133:1267–1274

Induced

Hypothermia

(30-32oC)

Normothermia

Survived 6 (50%) 1(14%)

Died 6 6

Total 12 7

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

Crit Care Med 2009; 37[Suppl.]:S186 –S202

All of these processes are temperature dependent

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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



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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

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



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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

N Engl J Med 2002;346:557-63

• 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)

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Methods

Hypothermia (n=43)

Normothermia

(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

N Engl J Med 2002;346:557-63

ICU

Target temp 33C

Rewarmed

24h18h12h0h-2h

ROSC

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Characteristics of the Patients

N Engl J Med 2002;346:557-63

Outcomes

N Engl J Med 2002;346:557-63

Outcome Hypothermia

(n=43)

Normothermia

(n=34)

p

Good

(Neuro)

21 (49%) 9(26%) 0.046

Death 22 (51%) 23(68%) 0.145

• Hypothermia group

– OR 5.25 (95% 1.47-18.76; P=0.011) for good outcome

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Hemodynamics and Adverse Effects

N Engl J Med 2002;346:557-63

• No significant differences between the two groups with

respect to the frequency of adverse events

• 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 < 30OC, 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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• Outcomes at 6 months:

– Favorable neurologic outcomes

– Overall Mortality

– Rate of complications

N Engl J Med 2002;346:549-56

Hypothermia (n=137)

Normothermia

(n=138)

Methods

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 of cooling

Target temp 32-34°C

Rewarmed

36h28h8h<2h0h

ROSC

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

N Engl J Med 2002;346:549-56


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Neurologic Outcomes

• Therapeutic Mild Hypothermia � Favorable Neurologic Outcome

N Engl J Med 2002;346:549-56

Cerebral Performance Category

� CPC 1 (good recovery)

� CPC 2 (moderate disability)

Survival

59%

45%P=0.02

N Engl J Med 2002;346:549-56

• Therapeutic Mild Hypothermia � Improved Survival

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Complications

N Engl J Med 2002;346:549-56

• Complication rate did not differ significantly between the

two groups

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

• Lactate and O2 extraction

ratio were significantly lower

in the hypothermia group


Outcome Hypothermia

(n=16)

Normothermia

(n=14)

Death 13 (81%) 13(92%)

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Circulation. 2011;123:877-886

• 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

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Therapeutic Hypothermia after

In-hospital Cardiac Arrest

Circulation. 2011;123:877-886

• 19 sites (Europe), 2003-2005, observational, registry

• No difference in outcomes for patients with in-hospital

arrest

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Guidelines

Circulation. 2003;108:118-121

Resuscitation 57 (2003) 231/235

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20052005

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

Physiological Aspects of Cooling

“Cold diuresis”“Hypovolemia”“Electrolyte disorders”“Hyperglycemia”“Shivering”

“Prevention of infections”“Continuous EEG: Seizures”

“Hypoglycemia”“Electrolyte disorders: Hyperkalemia”

“Maintain Normothermia”


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


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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Circulation. 2011;123:877-886

• Paris, France, 2000-2009

• Prospective cohort

• 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

Ther Hypothermia Temp Manag.

2015 Mar;5(1):48-54. Epub 2015 Jan

2007 2010

Hospitals using TH 4.60% 22.16%

Patients received

TH0.34% 2.49%

0%

5%

10%

15%

20%

25%

• Across 2007–2010, in United States

National Trends in the Use of Postcardiac Arrest

Therapeutic Hypothermia and Hospital Factors

Influencing Its Use

Ther Hypothermia Temp Manag.

2015 Mar;5(1):48-54. Epub 2015 Jan

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

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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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N Engl J Med 2013;369:2197-206

• Randomized trial, Nov 2010 - Jan 2013

• 36 ICUs in Europe and Australia

• Patients:

– OHCA, unconscious at presentation to the hospital

• Exclusion:

– ROSC to screening > 240 minutes(4h)

– Unwitnessed arrest with asystole as the initial rhythm

– Suspected or known acute intracranial hemorrhage or

stroke

– Body temperature of less than 30°C

N Engl J Med 2013;369:2197-206

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• Outcomes at 6 months:

– Neurologic outcomes

– Overall Mortality

33°C

(n=473)

36°C

(n=466)

Methods

N Engl J Med 2013;369:2197-206

TTM Protocol• Method of cooling:

– Intravascular cooling catheter (24%)

– Surface cooling system (76%)

• 33°C vs 36°C for a total of 28h

• After 28h gradual rewarming to 37°C (0.5°C/hour)

• Maintain < 37.5°C until 72 h after the cardiac arrest

N Engl J Med 2013;369:2197-206

0h

Randomization

28h

Rewarming

36h

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Temperature Curves

• P<0.001 for separation of curves

N Engl J Med 2013;369:2197-206


N Engl J Med 2013;369:2197-206

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N Engl J Med 2013;369:2197-206

Outcomes

• No outcome difference between the two groups

N Engl J Med 2013;369:2197-206

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Hazard Ratio of Death, According to

Subgroups

The effect of the

intervention was

consistent across

predefined

subgroups

N Engl J Med 2013;369:2197-206

Adverse Events

• Hypokalemia was

more frequent in the

33°C group

• No difference in other

adverse event

N Engl J Med 2013;369:2197-206

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• Comatose patients after OHCA with initial NSR continue to

have a poor prognosis

• No effect of TTM at 33 ◦C compared to 36 ◦C in these patients


Conclusions

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Normothermia vs. TTM

Normothermia

(HACA)

Mortality in Landmark Trials

HACA

(2002)

Bernard

(2002)

TTM

(2013)

Normothermia

(37-38°C)55% 68%

32-34°C 41% 51% 50%

36°C 48%

• Fever is independently associated with an

increased risk of adverse outcome

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• In comatose post cardiac arrest patients:

– FEVER correlates with worse outcomes and should be avoided

– Hypothermia significantly mitigates/prevents destructive processes following ischemia/reperfusion brain injury

– Targeted temperature management of 36°C for 28h seems to offer equal benefits as a targeted temperature of 33°C

– This intervention should be started within 4h from ROSC

Take home messages …..

• Patients who mostly benefit from this

intervention:

– Witnessed cardiac arrest

– Bystander performed CPR (< 5 min)

– Shockable rhythm

– ACLS started < 15 min

– ROSC < 40 min

Take home messages …..

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Thanks

Gill Heart Institute

therapeutic hypothermia: where do we stand?wcm/@gra/documents/... · 5/29/2015 1 therapeutic...

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