Hypothermic forHypothermic for Cardiac ArrestCardiac ArrestThe Evidence BaseStephan A. Mayer, MDDirector Neuro-ICUDirector, Neuro ICUColumbia UniversityNew York, NY

DisclosuresDisclosures

• Columbia University– Clinical Trials Pilot Award

• Radiant Medical, Inc.– Scientific Advisory Boardy– Stock Options

• Medivance, Inc.– Research Grant– Research Grant– Stock Options

• Seacoast TechnologiesS i tifi Ad i B d– Scientific Advisory Board

PETER SAFAR1924-2003

“Father of CPR”

Pioneered Intensive Care Units

Conceptualized fHypothermia for

“Suspended Animation”

HYPOTHERMIA: Mechanisms of I h i N t tiIschemic Neuroprotection

• Profound reduction of active and basal cellular i tenergy requirements

• Reduced excitotoxic neurotransmitter release• Reduced oxygen free radical productionReduced oxygen free radical production• Improved BBB stability• Decreased “ischemic depolarizations” in the

bpenumbra• Protection against cytoskeletal proteolysis• Decreased neutrophil infiltrationDecreased neutrophil infiltration• Decreased cytokine and leukotriene production

The ChallengeThe Challenge

• Intensivists manipulate physiologyIntensivists manipulate physiology• We now have improved tools to

precisely control body (and brain)precisely control body (and brain) temperature

• As intensivists, we are obliged toAs intensivists, we are obliged to identify and maintain an optimal temperature in patients with acute p pbrain injury

Out-of-hospital cardiac arrest is common

350,000+ per year in US, p y One out of 5 out-of hospital deaths occurs as a

sudden cardiac arrest Overall survival in US / Western Europe is 5-

8% B ti t d l i By some estimates, good neurologic recovery

occurs in only 3% of out-of-hospital arrests “Best” EMS systems: Seattle 1998-2001 Best EMS systems: Seattle 1998-2001

• Overall survival to hospital discharge 17.5%• VF/VT: 34% survived (vs. 6% with other rhythms)

NEJM 2004; 351 (7): 632

Out-of-hospital cardiac arrestOut of hospital cardiac arrest• Factors (likely) influencing outcome:( y) g

– Duration of non-perfusing rhythm– Bystander CPR– AEDs / early defibrillation– Quality of CPR (adequate cardiac

t t)output)– Age

Th ti h th i– Therapeutic hypothermia

NEJM 2004; 351 (7): 632

Out-of-hospital cardiac arrestOut of hospital cardiac arrest• Factors (likely) influencing outcome:( y) g

– Duration of non-perfusing rhythm– Bystander CPR– AEDs / early defibrillation– Quality of CPR (adequate cardiac

t t)output)– Age

Th ti h th i– Therapeutic hypothermia

NEJM 2004; 351 (7): 632

Effect of early time to defibrillationEffect of early time to defibrillation

NEJM 2004; 351 (7): 632

Improving OOHCA OutcomesImproving OOHCA Outcomes

FDNY Medics 2002 2003 2004 2005 2006 2007# of arrests 1537 1636 1555 1688 1801

% VF 12.88% 13.99% 13.69% 12.26% 12.66%

ROSC - overall 15.81% 17.60% 15.31% 15.40% 16.49%

ROSC – nonVF 14.04% 16.13% 13.71% 14.04% 15.44%

ROSC – VF/VT 27.78% 26.64% 25.35% 25.12% 23.25%

Sustained ROSC 11.13% 12.78% 10.03% 11.32% 11.94%

Improving OOHCA OutcomesImproving OOHCA Outcomes

FDNY Medics 2002 2003 2004 2005 2006 2007# of arrests 1537 1636 1555 1688 1801 1735

% VF 12.88% 13.99% 13.69% 12.26% 12.66% 14.72%**

ROSC - overall 15.81% 17.60% 15.31% 15.40% 16.49% 23.69%**

ROSC – nonVF 14.04% 16.13% 13.71% 14.04% 15.44% 18.32%**

ROSC – VF/VT 27.78% 26.64% 25.35% 25.12% 23.25% 54.88%**

Sustained ROSC 11.13% 12.78% 10.03% 11.32% 11.94% n/a

NYC Project HypothermiaNYC Project Hypothermia

Phase #1: Beginning July 1 2008 allPhase #1: Beginning July 1, 2008, all OOHCA patients achieving ROSC in New York City will only beNew York City will only be transported to facilities actively employing therapeutic hypothermiaemploying therapeutic hypothermia.

Hypothermia: Techniques

LIFE RECOVERY SYSTEMS

Intravascular heat exchange catheter d i d f i ti i th j l

Heat exchange

designed for insertion in the jugular vein and combined centralvenous capabilities (multiple infusion g

3 infusion lumens

ports)

Inflow Outflow

COOINNERCOOL

MEDIVANCE ARCTIC ARCTIC

SUN

Polderman et al. Induction of hypothermia in patients with various types of neurologic injury with use of large volumes ofvarious types of neurologic injury with use of large volumes of ice-cold intravenous fluid. Crit Care Med 2005;33:2744

• 134 brain injured• 134 brain- injured patients

• In addition to surface cooling 30 ml/kg 36

37 Temp (�

cooling 30 ml/kg (mean 2.3 liters) of cold normal saline over 50 minutes 34

35

over 50 minutes• MAP increased 15

mm Hg• No CHF

32

33

• No CHF

30

31

Baseline 1 Hour 2 Hours

METHODS: Mild/Moderate H th i P t l (33° C)Hypothermia Protocol (33° C)

• Endotracheal intubation• Sedation:

– Meperidine 25-100 mg IVP q 2-4 HD d t idi 0 3 0 7 /k /h– Dexmedetomidine 0.3 – 0.7 µg/kg/hr

• Paralysis: Vecuronium 0.1 mg/kg PRN• Thermistors: bladder, rectal, esophagealThermistors: bladder, rectal, esophageal• Radial artery and internal jugular lines• Intraparenchymal ICP & temperature monitor• Insulin drip for BS >180 mg/dl• Hypokalemia <3.4 mEq/l replaced

11

Hemodynamic Support afterHemodynamic Support after Cardiac Arrest

Norepinephrine

708090

100Dobutamine

708090

100Volume Expansion

708090

100% pts% pts

010203040506070

010203040506070

010203040506070

00-6 hrs 6-24 hrs 24-48 hrs 0-6 hrs 6-24 hrs 24-48 hrs

00-6 hrs 6-24 hrs 24-48 hrs

HypothermiaNormothermiaNormothermia

Oddo M, Crit Care Med, 2006;34(7):1865

METHODS: Mild/Moderate H th i P t lHypothermia Protocol

• ABGs at room temp (alpha-stat) • Vasopressors to keep CPP >70 mm Hg• ICP >20 mm Hg treated per protocol• Feedings held x 48 hoursFeedings held x 48 hours• Cultures/antibiotics for work of device heat transfer (indicating

thermogenesis)• Passive controlled rewarming (0 25 to 0 3 °C / hr)• Passive controlled rewarming (0.25 to 0.3 C / hr)• Active cooling is maintained at 36.5°C thereafter for 24 hrs to

avoid “overshoot”

2

Volume 346:549-556 February 21 2002 Number 8Volume 346:549-556 February 21, 2002 Number 8

Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest

The Hypothermia after Cardiac Arrest Study Group

Volume 346:557-563 February 21, 2002 Number 8

Treatment of Comatose Survivors of Cardiac ArrestTreatment of Comatose Survivors of Cardiac Arrest with Induced Hypothermia

Stephen A. Bernard, MB, BS,.and others

European HACA TrialEuropean HACA Trial

• SUBJECTS: 273 patients with out-of-hospital p pVT/VF arrest– Ages 18-75– Initiation of CPR within 15 minutes– Interval from collapse to ROSC <60 mins

• INTERVENTION: 32 34°C for 24 hours• INTERVENTION: 32-34°C for 24 hours– Mean 8 hours from initiation of cooling to

temperature <34°Cp

HACA Study Group, NEJM, 2002

Kinetic Concepts Air Cooling Devicep g

• Cool air blanket initiated ~2 hours after ROSCCool air blanket initiated 2 hours after ROSC

• Target temp attained ~8 hours later

HACA: Rate of CoolingHACA: Rate of Cooling

HACA: Rate of CoolingHACA: Rate of Cooling

European HACA TrialEuropean HACA Trial

• OUTCOME MEASURE: SurvivalOUTCOME MEASURE: Survival with minimal or moderate disability at 6 monthsy– 55% hypothermic – 39% normothermic39% normothermic

• Risk ratio for good outcome 1.40(1 08-1 81)(1.08-1.81)

• Number needed to treat = 6HACA Study Group, NEJM, 2002

Absolute mortality ydifference of 14%

Relative mortality d ti f 26%reduction of 26%

AUSTRALIAN Hypothermia i lTrial

• SUBJECTS: 77 patients with out-of-hospital p pVT/VF arrest– No upper age limit

Comatose– Comatose– Refractory shock (MAP <90) excluded– Randomization according to date (odd-even)

• INTERVENTION: 32-34°C for 12 hours– Cooling started in the field using ice bags

within 2 hours of collapsewithin 2 hours of collapse– Cooling period 12 hours– Rewarming over 6 hours

Bernard et al, NEJM, 2002

35% 21%

International Task ForceInternational Task Force

• 2003 ILCOR meeting on hypothermia drecommends:

“Unconscious patients with spontaneous circulation after out of hospital arrest should be cooled to 32-34°C for 12-24 hours when the initial rhythm is ventricular fibrillation.”

AND“Such cooling may also be beneficial for other rhythms or in-hospital arrest.”

Nolan, JP, Resuscitation, 2003

Post Resuscitation CarePost Resuscitation Care

The “Second” T l tiTranslationFROM SCIENCE FROM SCIENCE TO DAILY TO DAILY PRACTICE

Therapeutic hypothermia utilization among physicians after cardiac arrest Raina M Merchant et al Crit Care Med 2006 34 1935cardiac arrest Raina M. Merchant, et al, Crit Care Med 2006;34;1935.

• Web-based survey of 2,248 physicians• USA: 74% have never cooled

• EU: 64% have never cooled

Have you ever? If not why not?

Out-of-hospital cooling by Emergency Physician (Markus Födisch, Bonn)y ( )

• Can “evidence-based • Swiss retrospective study: 14 medicine” be implemented outside of the multicenter RCT

bed MICU in “university hospital” medical center

• June 1999 – May 2002: the multicenter RCT environment?

• Does TH work in smaller

– 54 patients with OHCA• June 2002-December 2004:

– 55 patients with OHCA medical centers?

ptreated with TH

CCM 2006:34:1865

Improved OutcomesImproved Outcomes

Time from collapse to ROSC

Probability ofProbability of good

outcome

Duration of cardiac arrest predicts outcome (OR of good outcome for each additional 5 min: 0 53 95% CI: (OR of good outcome for each additional 5 min: 0.53, 95% CI:

0.37-0.72, p<0.001)Oddo et al, CCM 2007

Results VUMC

Preliminary evidence in patients with asystole/PEA…

Polderman KH et al. Induced hypothermia improves neurological outcome in asystolic patients with out-of hospital cardiac arrest. Circulation 2003; 108: IV-581 [abstract 2646]

Northern H th i N t kHypothermia Network www.scctg.orgwww.hypothermianetwork.com

• Six scandanavian countries

• >500 patients

• 64% VT/VF

• 28% PEA

• 8% Asystole

HypothermicHypothermic

Polderman KH. Lancet 2008; 371:1955-1969

City Pushes Cooling Therapy for Cardiac A tArrest

December 4 2008December 4, 2008

Chain of SurvivalChain of Survival

• VF / pulseless VT (AHA level 2A)– Pulseless electrical activity / asystole (HA level 2B)y y ( )

• Comatose• Absence of refractory post-resuscitation shock

D ti f di t 5 30 i t• Duration of cardiac arrest 5-30 minutes• Age ≤75 years

Getting Serious about Hypothermia for CA:Keys to ImplementationKeys to Implementation

Education and Knowledgeg

Champion

Team Building

Administration and Nursing

P t lProtocols

The New ParadigmThe New Paradigm

CPR CCRCPR CCR

Cardio-Pulmonary Resuscitation

Cardio-Cerebral ResuscitationResuscitation Resuscitation