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7/12/11
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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?