Noon Conf: Therapeutic hypothermia

therapeutic hypothermiain survivors of cardiac arrest

Sherry Goldyn, MD, MPHPulmonary/Critical Care

July 13, 2011

Therapeutic hypothermia (TH)

The use of mild induced hypothermia (32-34°C) as a way to protect the brain after anoxic injury from cardiac arrest

overview: Incidence of cardiac arrest Pathophysiology post-arrest Historical context, recent supportive data for

therapeutic hypothermia Physiologic changes during cooling Kaiser’s TH protocol

Incidence

Out-of-hospital cardiac arrest 350,000-450,000 cases in US per year 80% occur at home

death rate ~90% Resuscitation attempted in ~100,000 40,000 survive to hospital admission 10,000-15,000 survive to hospital discharge

Incidence In-hospital cardiac arrest

36,902 cases January 2000-March 2004 Voluntary reporting by 253 hospitals to the

National Registry of Cardiopulmonary Resuscitation (AHA)

ROSC in 44% Survival to discharge ~17%

Good neuro function in 60% of survivors

NEJM 2009;361:605-11

Post cardiac arrest syndrome

Anoxic brain injury Arrest-related myocardial dysfunction

Global hypokinesis, elevated LVEDP Systemic ischemic/reperfusion response

Systemic inflammation, clotting cascade activation, disturbed vasoregulation, infection risk

Persistent underlying pathology ACS PE Cardiomyopathy

Circulation. 2011;123:1428-1435

Post cardiac arrest syndrome

Anoxic brain injury Arrest-related myocardial dysfunction

Global hypokinesis, elevated LVEDP Systemic ischemic/reperfusion response

Systemic inflammation, clotting cascade activation, disturbed vasoregulation, infection risk

Persistent underlying pathology ACS PE Cardiomyopathy

Circulation. 2011;123:1428-1435

Post-cardiac arrest

Neurologic outcome ~80% of post-arrest patients remain comatose

for >1h post-resuscitation <50% of these have “good neurologic

recovery” Clinical Performance Category 1 or 2

CPC 1. Good cerebral performance: conscious, alert, able to work, might have mild neurologic or psychologic deficit

CPC 2. Moderate cerebral disability: conscious, sufficient cerebral function for independent activities of daily life. Able to work in sheltered environmentCPC 3. Severe cerebral disability: conscious, dependent on others for daily support because of impaired brain function. Ranges from ambulatory state to severe dementia or paralysisCPC 4. Coma or vegetative state: any degree of coma without the presence of all brain death criteria. Unawareness, even if appears awake (vegetative state) without interaction with environment; may have spontaneous eye opening and sleep/awake cycles. Cerebral unresponsiveness.CPC 5. Brain death: apnea, areflexia, EEG silence, etc.

Clinical Performance Category

Lancet 1975. 1(7905):480-4

Pathophysiology of anoxic injury

Vasomotor paralysis Initial hyperemia Prolonged hypoperfusion during arrest/CPR After ROSC reperfusion and reoxygenation

injury Stores of O2 in the brain lost in seconds Stores of glucose/ATP lost within 5 minutes Inflammatory response, endothelial activation,

leukocyte infiltration

NEJM 2010. 363;23:1256-1264

Free radical formation, oxidative damage Loss of blood-brain barrier Loss of transmembrane chemical gradients Glutamate releaseincrease intracellular Ca+

+ excitotoxic cell death Further exacerbated by brain edema, loss of

cerebral autoregulation, hypotension, hypoxia

Pathophysiology of anoxic injury

Rationale for cooling Reduces the cerebral metabolic rate for oxygen

(CMRO2) ↓6% for every 1°C reduction in brain temperature >28°

Suppresses chemical reactions associated with reperfusion injury

Inhibits excitatory amino acid release (eg glutamate) Decreases free radical production Limits calcium shifts that cause mitochondrial damage

and apoptosis Decreases intracranial pressure

Historical context

Hypothermia used in various scenarios Described by ancient Greeks and Romans Treatment of tetanus in 4th century BC Treatment of trauma, Hippocrates Treatment of typhoid fever, Osler 19th century

Historical context

Neurosurgeon Temple Fay advocated local and generalized refrigeration in 1930s-1950s

intractable headache pain traumatic brain injury abscess cerebritis, seizures malignancy

Fay T, Early experiences with local and generalized refrigeration of the human brain,

Journal of Neurosurgery, May, 1959, number 3; 16:239-260, 

Historical context

Nazis confiscated Dr. Fay’s data and used hypothermia without anesthesia during medical experiments in Dachau

Abandoned as a therapy for several decades because of uncertain benefit and difficulties with its implementation

Hypothermia introduced as a protective strategy during cardiac surgery in the 1950s

Ann Surg. 1958 September; 148(3): 462–466

Fast forward 45 years…

Hypothermia after Cardiac Arrest Group

European multicenter RCT, blinded assessment of outcome

Inclusion criteria: ROSC after witnessed VF or pulseless VT arrest

Presumed cardiac origin of arrest 18-75 years old 5-15 minute interval to 1st attempt at resuscitation <60 minutes to ROSC

275 patients enrolled 137 hypothermia 138 normothermia

Hypothermia after Cardiac Arrest Group

Goal temperature 32-34°C with external cooling device within 4 hours, started in ICU

Cooled for 24 hours Passively rewarmed over 8 hours Primary endpoint:

cerebral performance category of 1 (good recovery) or 2 (moderate disability)

Secondary endpoints: 6 month mortality Complications within 1st week

The Hypothermia after Cardiac Arrest Study Group. N Engl J Med 2002;346:549-556

The Hypothermia after Cardiac Arrest Study Group. N Engl J Med 2002;346:549-556

Cumulative Survival

The Hypothermia after Cardiac Arrest Study Group. N Engl J Med 2002;346:549-556

Induced hypothermia after out-of-hospital cardiac arrest Australian multicenter, RCT Inclusion criteria:

VF as initial rhythm Successful ROSC Persistent coma after ROSC

Exclusion criteria: Male<18yo or F<50yo Cardiogenic shock (SBP<90 despite epi gtt)

77 included in study 43 hypothermia 34 normothermia

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

Induced hypothermia after out-of-hospital cardiac arrest Randomization in the field

Cooling measures (ice packs) instituted in ambulance Cooled to 33°C, maintained for 12 hours At 18 hours, active rewarming for 6 hours with

heated-air blanket Primary endpoint:

survival to hospital discharge with sufficiently good neuro function to go home or to rehab

Secondary endpoints: hemodynamic, biochemical, hematologic effects

Crit Care Med 2009; 37(7):S223-S226.

Cooling techniques

Ice packs Iced saline infusion Iced nasogastric or bladder lavage Cooling blankets Fans ECMO Cooling devices

Cool Gard with Icy Femoral Catheter

Arctic Sun

Physiologic effects of cooling

Physiologic effects of cooling

3 stages of therapeutic hypothermia Induction phase

Goal <34°C ?as quickly as possible Highest risk of acute instability (electrolytes,

hemodynamics) Maintenance phase

24h tight core temp control Highest risk of long-term complications (infections,

skin breakdown) Rewarming phase

Slow, controlled 0.2-0.5 degree/hour Some acute instability but more easily managed

Physiologic effects of cooling

Cardiovascular Initially: cold vasoconstriction ↑ venous

return reflex tachycardia ↑SVR, ↑BP, ↑CVP

<35 degrees: bradycardia, ↓ CO 25-40% MVO2 ~same (↓ O2 consumption)

Hypovolemia due to “cold diuresis” Vasoconstriction, hyperglycemia, ↓ renal tubular

absorption, increased ADH Lactate levels elevated (but stable)

Physiologic effects of cooling

Cardiovascular HR 40-60 ↑PR, ↑QTc, widened QRS Osborne waves

Physiologic effects of cooling

Cardiovascular Arrhythmias:

Sinus brady AfibVTVF (particularly <28C) Myocardium less sensitive to anti-arrhythmics

Ischemia prevented/mitigated?

Physiologic effects of cooling

Hepatic ↓ drug metabolism

Paralytics Opioids Benzodiazepines AEDs propofol cephalosporins

Physiologic effects of cooling

Metabolic derangements intracellular shift (K+, magnesium) and ↑ renal

excretion Hyperglycemia

↓ insulin sensitivity in tissues ↓ insulin secretion by islet cells

Metabolic acidosis ↑FFA, ketones, lactate Intracellular pH is actually higher

↓ O2 consumption/CO2 production

Physiologic effects of cooling

Hematologic ↑ bleeding time platelet dysfunction, mild thrombocytopenia clotting factor dysfunction activation of fibrinolysis cascade

no significant increase in bleeding risk unless already bleeding (eg trauma)

Physiologic effects of cooling

Study of 31 comatose patients post-cardiac arrest due to AMI treated with hypothermia 2005-2006

Historical matched controls Goal temp 33°C 11 pts received thrombolysis in the field 25 pts underwent PCI and stenting All pts got clopidogrel 600mg load/75mg daily, heparin

gtt 16 PCI pts received IIb/IIIa inhibitor

Int J Cardiology.132;2009:387-391.

Physiologic effects of cooling

Study of 31 comatose patients post-cardiac arrest due to AMI treated with hypothermia 2005-2006

Favorable neuro outcome in TH (19/31 had CPC 1 or 2 vs control 6/31)

No difference in ICU mortality (10/31 in both groups)

No difference in incidence of clinically overt blood loss (6/31 in both groups)

Trend towards increase in # units transfused in TH

Int J Cardiology.132;2009:387-391.

Physiologic effects of cooling Immunologic

Inhibits leukocyte migration, function Inhibits secretion of inflammatory cytokines Increased risk of wound infection

Related to vasoconstriction to skin, hyperglycemia Already at-risk population (higher rates of aspiration,

more ventilator days, higher rates of VAP, sepsis in post-cardiac arrest patients)

Resuscitation 2004;60:65-69.Intensive Care Med 2005;31:621-626

Retrospective review of prospective ICU database from single center in France

421 post-arrest patients 2004-2008 67% of patients had 373 infectious

complications Pneumonia, bloodstream infections GNR 64%

?related to gut hypoperfusion? Staph, e coli, h flu, strept pneumo

Crit Care Med 2011;39(6):1359-1364

Use of and duration of TH associated with ↑ infection, ↑ ventilator days, ↑ ICU LOS

No difference in ICU mortality or neurologic outcome

Challenge of recognizing infection Wbc count, temperature not reliable indicators This group suggests surveillance cultures during

hypothermia phaseCrit Care Med 2011;39(6):1359-1364

Limits: Single institution, retrospective review without

historical comparison No control for premorbid factors Excluded deaths within 1st 24 hrs

Crit Care Med 2011;39(6):1359-1364

Physiologic effects of cooling

Counter-regulatory response to hypothermia <36.5°C vasoconstriction of skin <35.5°C shivering

Increases heat production Increases O2 consumption up to 40%

Avoidance of shivering Medications (narcotics, benzos, paralytics,

magnesium, acetaminophen) Skin counterwarming?

Kaiser NCAL Therapeutic Hypothermia protocol

Kaiser NCAL hypothermia protocol Inclusion Criteria

Age>18 Negative pregnancy test Witnessed cardiac arrest

or known down time <15 min to initiation of ACLS

ROSC within 30 min of cardiac arrest

VF, pulseless VT, PEA, asystole

Unresponsive post-resuscitation (GCS<8)

No eye opening to pain SBP>90 (IVF, 1 pressor ok) Intubated with set RR

Exclusion Criteria Pregnant AMS due to other etiology Major surgery within 14d Pre-existing sepsis or

systemic infection Resuscitation efforts >30m

before ROSC (relative) GCS>/=8 Pre-existing coagulopathy

or bleeding diathesis (INR>2, PTT>40, plt<50)

Relative, eg if on warfarin T<30°C post-resuscitation Known terminal illness or

DNR

Maintenance cooling

Re-warming phase

Post-warming

Prolonged coma Delayed and unpredictable clearance of

opiates, benzos, propofol and paralytics Seizure incidence up to 50% post-cardiac

arrest, increased risk with TH Poor prognostic sign if no neurologic recovery

within 72 hours of normothermia

From the 8th New York Symposium on Neurocritical Care, 2011

Current recommendations“Comatose adult patients (not responding in a

meaningful way to verbal commands) with spontaneous circulation after out-of-hospital VF cardiac arrest should be cooled to 32 to 34°C for 12 to 24 hours. Induced hypothermia might also benefit comatose adult patients with spontaneous circulation after out-of-hospital cardiac arrest from a nonshockable rhythm, or cardiac arrest in hospital.”

American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science,

2010

Current recommendations

Do not delay TH for CT scan, cardiac catheterization, central line placement

Initiate cooling en route? Faster time to cooling may not matter Initiate within 10 hours of ROSC “Bundle” therapy to be used along with other

ICU bundles Continue all other usual supportive measures

Further research

What about other rhythms besides VT/VF? Theoretical benefit is the same Benefit>risk? Registry study of >1000 European

survivors of cardiac arrest at 6 months 56% VT/VF had good neurologic outcome 23% PEA 21% asystole

Acta Anaesthesiol Scand. 2009;53:926–934.

Further research

Continuous eeg monitoring? Prophylactic anti-seizure medication?

Up to 40% seizure incidence post-ROSC Prophylactic antibiotics? Optimal duration of cooling? Optimal temperature goal?