Therapeutic hypothermia after cardiac arrest

May 6,2010Damascus

Ashraf Altarifi,MD,FCCPConsultant Intensivist and Pulmonologist

King Faisal Specialist Hospital and Research Center

Riyadh, Saudi Arabia

Case presentation

65 year old male patient with hx of DM,HTN was found unresponsive at home

Patient taken to ER, found to be in asystole.

Patient intubated, CPR done for 25 minutes with return of pulse and blood pressure. Pt in sinus rhythm but requiring inotropes.

Neuro exam

Pt unresponsive, pupils non reactive. No spontaneous movements in arms

or legs. 2 hours later ,Pt develops myoclonic

jerks.EEG negative for seizures. Patient started on sedation

Common Scenario! Three weeks later patient remained

comatosed in a persistent vegetative state.GCS 4/15.Tracheostomy done.

Patient develops ventilator associated pneumonia.

Patient develops respiratory failure, septic shock, and renal failure.

Patient dies 27 days after the initial cardiac arrest.

Cardiopulmonary resuscitation on TV

97 episodes of ER, Chicago Hope and Rescue 911 reviewed

60 incidents of Cardiac arrest observed Etiology of cardiac arrest 55% trauma,28%

cardiac 75% of patients survived the immediate arrest 68% survived to hospital discharge 10 cases had miraculous recovery when

physicians gave up hope. Almost all patients surviving had normal

neurolgic and functional outcome.

NEJM 1996 :334 (1578-82)

Real life outcome of cardiac arrests

Survival usually defined as survival to hospital discharge.

Varies greatly between different EMS systems.

Varies according to downtime prior to resuscitation.

Varies according to initial rhythm.

Outcome of in-hospital cardiac arrest National Registry of Cardiopulmonary Resuscitation (NRCPR)

of 14720 in-hospital arrests with 17% hospital discharge.

– 16% of patients had V Fib as initial rhythm with 34% hospital discharge

105 patients with in-hospital arrests reviewed.44% survived the arrest and 22% survived to discharge

Better prognosis

– Cardiac etiology

– V Tach or V Fib The only predictor of hospital survival was absence for need

of endotracheal intubations 76% of patients had good neurologic outcome (CPC 1)

Internal Medicine Journal 34 ; 398  - July 2004

Cardiac arrest in the ICU

Causes of arrest– Metabolic

disturbances 29%– Shock 26%– Hypoxemia 23%– Cardiac ischemia

11%– Brain death 7%– PE 2%

Initial rhythms– Asystole 47%– Brdycardia

followed by asystole 29%

– PEA 18%– V Fib/V Tach 6%

Hospital survival is 11%Critical care, 2001

Critical care medicine 1999

Survival according to initial rhythm

Mode of death after admission to ICU post cardiac arrest

Intensive care medicine, 2004

0

10

20

30

40

50

60

70

80

MOFNeurologic complications

shock

VF/VT PEA/asyst

Cerebral performance categories after cardiac arrest

CPC 1 Good awake alert, May have mild psycho-cognitive dysfunction

CPC 2 Moderate awake, alert. May have weakness or dysarthria but able to do ADL.

CPC 3 Severe conscious, dependent on others. May have dementia or minimal communication

CPC 4 Coma Unconscious, Persistent Vegetative State

CPC 5 Brain death

Critical Care Medicine: Volume 24(2S) Supplement February 1996 pp 69S-80S

Overall performance after cardiac arrest

OPC 1 Good CPC 1,capable of normal life, no other organ disability

OPC 2 Moderate CPC 2 or disability from another organ dysfunction.Can work under special conditions.

OPC 3 Severe CPC 3 or severe disability from another organ. Dependent on others.

OPC 4 Vegetative Persistent Vegetative State OPC 5 Death

Critical Care Medicine: Volume 24(2S) Supplement February 1996 pp 69S-80S

Can the outcome of cardiac arrest be improved?

Benson et al,Anesth Analg 1959; 38: 423-8.

Comatose survivors Asystole or VF 31-32°C Cooling until

neurologic recovery(3 hours to 8 days)

Water-filled blanket

0

10

20

30

40

50

60

Favorable neurologicrecovery

%

Hypothermia (n=12)

Normothermia (n=7)

The Use of Hypothermia After Cardiac Arrest

Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest (HACA)

Patients with witnessed cardiac arrest from VF or pulseless VT, 18-75 years of age, estimated 5-15 minutes to attempted resuscitation, and less than 60 minutes from collapse to restoration of spontaneous circulation (ROSC).

275 patients of 3,551 cardiac arrests screened were eligible for the study (8%)

137 patients randomized to receive hypothermia (32-34°c) for 24 hours

Dr. Fritz Sterz, Vienna, Austria, and The Hypothermia After Cardiac Arrest Study Group, N Engl J Med 2002; 346:549-556

HACA Study Group

Randomized trial 2002 -Hypothermia vs Normothermia

Methods– Inclusion - OOHCA due to VF

– Exclusion – cardiogenic shock

Hypothermia group– 32°C - 34°C

– Cooled for 24 hrs

– Rewarming over 8 hrs

Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556.

3351assessed

3246 ineligible

30Not included

275 enrolled

137hypothermia

138 normothermia

HACA Study Group

Neurologic outcome Pittsburgh cerebral performance category scale

Cerebral Performance Category (CPC)

CPC 1 Good cerebral performance

CPC 2 Moderate cerebral disability

CPC 3 Severe cerebral disability

CPC 4 Coma or vegetative state

CPC 5 Brain death

Positive Outcomes

Negative Outcomes

HACA study: results

Bladder Temperature in the Normothermia and Hypothermia Groups.

Hypothermia for Coma After Cardiac Arrest

Hypothermia

Normothermia

P 0.02

Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556.

Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest (HACA)

Mortality at 6 months was 41% in the hypothermia group and 55% in the normothermia group

55% of hypothermia group and 39% of normothermia group had a favorable neurologic outcome (good recovery or moderate disability) p value 0.009

Complication rate did not differ significantly between the two groups

Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556.

Treatment of Comatose Survivors of OOH Cardiac Arrest with Induced Hypothermia 77 patients with cardiac arrest due to VF,

with ROSC but coma, randomized to hypothermia or normothermia

Patients excluded if the age of men was less than 18, and women less than 50, or cardiogenic shock

Hypothermia to 33 degrees begun within two hours and continued for 12 hours with cold packs.

Bernard et al,N Engl J Med 2002; 346:557-563

Treatment of Comatose Survivors of OOH Cardiac Arrest with Induced Hypothermia

Survival was 21/43 of the hypothermia group (49%) vs. 9/34 treated with normothermia (25%) p = 0.01

Good outcome (normal or with minimal or moderate disability) was 49% in hypothermia group and 26% in the normothermia p = 0.046

Bernard et al. (Australia), N Engl J Med 2002; 346:557-563

Favorable Neuro Outcome :All three studies combined

Benson 1959– 50% with Hypo (12)– 15% with Normo (7)

HACA 2002– 55% with Hypo (137)– 39% with Normo (138)

Bernard 2002– 49% with Hypo (43)– 25% with Normo (34)

Total patients:Hypo = 192Normo = 179

Combined Data (3 studies)

Favorable Neuro– Hypothermia = 53%

(102/192)– Normothermia = 35% (63/116)

Chi Square Testing:

p < 0.0005

ILCOR Advisory Statement

Unconscious adult patients with ROSC after out-of-hospital VF cardiac arrest should be cooled to 32°C - 34°C for 12 - 24 hours

Possible benefit for other rhythms or in-hospital cardiac arrest

2005 AHA guidelines for ACLS and post CPR care

In a select subset of patients who were initially comatose but hemodynamicaly stable after a witnessed VF arrest of presumed cardiac etiology, active induction of hypothermia was beneficial. Thus, unconscious adult patients with ROSC after out-of-hospital cardiac arrest should be cooled to 32°C to 34°C for 12 to 24 hours when the initial rhythm was VF (Class IIa). Similar therapy may be beneficial for patients with non-VF arrest out of hospital or for in-hospital arrest (Class IIb).

2005 AHA guidelines, Circulation, 2005

Possible mechanisms for clinical benefit

Interruption of Cerebral Blood Flow

Hypoxia-Ischemia

Resuscitation

Reperfusion Injury

Pathogenesis of Hypoxic-Ischemic Cerebral Injury

Mechanismsischemia

glutamate release

oxygen-free radicals

calcium shifts

mitochondrial dysfunction

reperfusion

excitotoxicity

inflam. cascades

Cell Death

blood brain barrier disruption & cerebral edema

hypothermia

lower metabolic rate

less oxygen consumption

Geocadin RG, Koenig MA, Jia X et al. Management of brain injury after resuscitation from cardiac arrest. Neurol Clin. 2008;22:487-506.

Effects of Hypoxia-Ischemia on Carbohydrate and Energy Metabolism-Anaerobic Glycolysis

Brain Glycogen Lactate production Phosphocreatine Brain Glucose ATP Tissue acidosis

HYPOTHERMIA: Mechanisms of Ischemic Neuroprotection

Profound reduction of active and basal cellular energy requirements

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

penumbra Protection against cytoskeletal proteolysis Decreased neutrophil infiltration Decreased cytokine and leukotriene production

It is not that complicated!!

How to apply hypothermia

Four Modes of Heat Transfer

Conduction– Cold water immersion

Radiation– Cold room

Convection– Fans (do not use for infection control

purposes) Evaporation

– Sweating

Basics of Therapeutic Hypothermia: Three phases of treatment

– Induction• Rapidly bring the temperature to 32-34C• Sedate with propofol or midazolam during TH• Paralyze to suppress heat production

– Maintenance• maintain the goal temperature at 33C• Standard 12-24 hours (optimal duration is unknown)• Suppress shivering

– Rewarming• Most dangerous period: hypotension, brain swelling, • Goal is to reach normal body temperature over 12-

24h• Stop all sedation when normal body temperature is

achieved

Induction: how to cool

Commercial cooling devices– Servo mechanism varies temperature of

circulating water or air (prevents overcooling)– External (surface cooling) systems

• Hydrogel heat exchange pads• Cold water circulating through plastic “suit”• Cold water immersion – awaiting safety data

– Invasive (catheter based) systems• Heat exchange catheter in SVC or IVC• Plastic or metalic heat-exchange catheter

Devices

Medivance ARCTIC SUN

Cold IV Fluids

Polderman 2005– 110 patients, 2-3L over

50 min– 36.9°C to 34.6°C, MAP

increased by 15mmHg, no pulmonary edema

Bernard 2003- 22 patients 30cc/kg LR at 4°C over 30 min: 35.5°C to 33.8°CImprovements in MAP, renal function, no pulmonary edema

Polderman. Crit Care Med 2005;33:2744Bernard. Resuscitation 2003;56:9

Maintainance: how to cool

Monitor core temperature– Bladder, esophagus, or central

venous/pulmonary arterial Ice packs and cooling mats

– Effective, but difficult to control rate of temperature change

– Overcooling is dangerous Endovascular cooling allows for gradual

reduction in temp, maintainence at desired temp and prevents over cooling

Management of shivering

Neuromuscular blockade– Vecuronium bolus 0.1mg/kg prn BSAS>2– Cisatricurium in renal failure

Propofol Alpha blockade

– Dexmedetomidine infusion or clonidine Scheduled acetaminophen, buproprion Meperidine or fentanyl Focal counterwarming Magnesium infusion (serum level 3mg/dl)

Re-warming

If using surface cooling: Use passive re-warming Remove Ice packs Stop cold Iv fluids

If using endovascular cooling: set temperature rise at 0.3-0.5 degrees per hour

Avoid rapid re-warming

Re-warming

Vasodilation causes hypotension– May require several liters IVF

More shivering during this phase Inflammation increases at higher temperature

– “post-resuscitation” syndrome Increased ICP Watch for hyperkalemia

– Primarily problematic in renal failure

Side Effects of hypothermia Toxicity increases with increased duration &

intensity of cooling Four categories of toxicity:

– Cardiovascular• Arrhythmia

– Hematologic• Platelet dysfunction, coagulopathy

– Immunologic• Impaired neutrophil function leading to increased infection

– Metabolic• Hypokalemia, hyperglycemia, ileus, pancreatitis• Re-warming: SIRS physiology?

Hypothermia Questions

How quickly?– ASAP, but at least within 6 hours of event– Longer the delay, the longer hypothermia must be

continued to provide protection

How cold?– At least 35oC core temperature but not lower than 32oC– Temp < 30 degrees leads to more complications

How to cool? Use NSAID? – Blanket cooling not effective in adults; intravascular

cooling with bolus of iced RL or NS is effective– Selective head cooling may benefit neonates

Hypothermia Questions

How long to cool?– At least 12 hours; 24 hours probably better

How to rewarm?– Worse outcome if rewarm rapidly – Management of shivering/stress response

Which patients should be cooled?– Only comatose adults after ROSC who are

“hemodynamically stable” – Should cooling start in the field or at the referring

hospital?

Hypothermia Questions

How to monitor cooling?– Bladder, rectal or blood temperature? Brain

temperature? How should we manage shivering?

– If use NMB, need to monitor EEG– Sub-clinical seizures may be more common than

clinically recognized – should we load with anticonvulsants?

How to adjust medications in the hypothermic patient

Are there useful biomarkers?

Use of Therapeutic Hypothermia survey

Yes 13%

No 87%

Critical Care

(n=33)

Cardiology

(n=64)

Emergency

Medicine

(n=109)

All respondents

(n=263)

Yes No

5% 95%

11% 89%

29% 71%

13% 87%

Use of Therapeutic Hypothermia by Clinical Specialty

Not enough data

Haven’t considered it

Not in ACLS guidelines

Too technically difficult

Current methods cool too slow

Unsatisfactory initial attempts

0% 10% 20% 30% 40% 50%

Reason for nonuse- Percentage of respondents

49%

32%

32%

19%

9%

4%

Reasons Against Use of Hypothermia as a Therapeutic Tool

Cooling Technique

Cooling blankets

Ice / cold liquid packing

Ice / cold liquid gastric lavage

IV cooling catheter

Cooling mist

Other method

0% 10% 20% 30% 40% 50%

Cooling technique Percentage of respondents

50%

15%

13%

2%

2%

17%

KFSH Hypothermia protocol

Different ScenarioNew patient April 18

55 year old male s/p gastric bypass surgery with hx of pyloric stenosis

Massive aspiration leading to respiratory then cardiac arrest.

CPR done for 20 minutes Pt admitted to ICU. Hypothermia protocol applied Within 48 hours, pt fully awake, follows

commands Extubated day 5.

Take home messages

Strong evidence that mild hypothermia is neuro-protective after return of spontaneous circulation.

Fever is detrimental post resuscitation (and for any neuro patient)

Hypothermia is underutilized so far but should be included in post resuscitaion care of cardiac arrest victims

CHAIN OF SURVIVAL

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