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Therapeutic Hypothermia
Post-Resuscitation Care
David B. Seder
Richard R. Riker
Gilles L. Fraser
Maine Medical Center
Portland, Maine
Clinical Case
• A previously healthy 44-year-old woman collapses at work after
complaining of chest tightness
– 3 minutes: bystander CPR initiated
– 7 minutes: defibrillation provided by bystanders using an
automated external defibrillator (AED)
– 9 minutes: EMS arrives, intubation performed
• Pulse present
• Generalized seizure activity noted
• Lorazepam 2 mg administered
– In the ED
•
•
•
•
Does not open eyes or follow commands
Extensor motor response to pain
Pupils minimally reactive at 3 mm
Corneal and weak gag reflexes present
Slide 3
How Should She be Treated?
• What are the patient’s relevant medical problems?
Slide 4
Learning Objectives
• Epidemiology of cardiac arrest
• Triage of the cardiac arrest survivor
• Role of therapeutic hypothermia as a neuroprotective
therapy after cardiac arrest
• Performing therapeutic hypothermia
– How to cool
– Managing the complications of therapy
• Outcome and prognosis
Slide 5
Key Words and Concepts
• Return of spontaneous
circulation (ROSC)
• Shivering
• Downtime
• Neuroprognostication
• Hypoxic-ischemic
encephalopathy (HIE)
• Myoclonic status epilepticus
• Overcooling
• Cardiocerebral resuscitation
• Cerebral performance category
(CPC)
• Surface vs. intravascular
cooling
• Brain death
• Core temperature
Slide 6
Epidemiology of Out-of-Hospital
Cardiac Arrest (OHCA)
•
Cardiac arrest is common
– 350,000+ per year in US
– Overall survival 5%-8%
– Best EMS systems: i.e.,
Seattle 1998-2001
• 17.5% survival to hospital
discharge
• 34% VT/VF subgroup
Callans. Effect of early defibrillation on survival
after cardiac arrest. N Engl J Med. 2004;351:632.
– Factors influencing outcome:
•
•
•
•
•
•
Early defibrillation
Duration of arrest
Bystander CPR
Quality of CPR
Age
Therapeutic hypothermia
Slide 7
Valenzuela. Effect of early bystander CPR
added to a “time-to-defibrillation” model on
survival after cardiac arrest. Circulation.
1997;96:3308-3313.
Acute MI is Common in Patients
Presenting after Cardiac Arrest…
• Etiology of OHCA
– 84 consecutive OHCA
survivors underwent urgent
cardiac cath after OHCA
– 48% had acute coronary
occlusion
– Chest pain and ST
elevation were poor
predictors of coronary
occlusion
– Successful angioplasty an
independent predictor of
survival
Spaulding. N Engl J Med. 1997;336:1629.
Slide 8
Neurological Injury is the Primary
Driver of Mortality
•
Rapid initiation of neuroprotective
therapy is the most important
intervention
•
But…the brain cannot survive
without adequate blood flow!
Seder. Cause of death in patients surviving out of hospital
cardiac arrest but dying during hospitalization. Proceedings of
the American Thoracic Society 2007; 4:A792.
Slide 9
Oddo. Effect of the implementation of a therapeutic
hypothermia protocol on neurological outcome after
out-of-hospital VF/VT arrest. Crit Care Med.
2006;34:1865.
The Critical Hours after ROSC!
• Support the heart:
– If there is suspicion of acute coronary thrombosis
• Coronary angiography and percutaneous revascularization
– If circulatory shock develops
• Revascularization
• Aortic counterpulsation device
• Vasopressor support
• Protect the brain:
– Secondary neurological injury can be suppressed and halted by
therapeutic hypothermia
– Adequate cerebral perfusion during this time is critical to
neurological recovery!
Slide 10
Triage of the Cardiac Arrest (CA)
Survivor
• Cardiac assessment
• Neurological assessment
– Rhythm stabilization
– Severity of HIE
– BP stabilization
– CT head to rule out
intracranial bleed
– Evaluation and treatment of
the underlying cause of the
cardiac arrest
– Consideration of urgent
coronary angiography and
revascularization
– Institution of therapeutic
hypothermia
– EEG monitoring if
appropriate
– Maintenance of adequate
cerebral blood flow
Slide 11
Seder. Curr Opin Neurol
Neurosurg. 2008;8:508-517.
Slide 12
Mechanisms of Brain Injury in
Circulatory Arrest
• “Energy failure” due to absence of ATP
– Loss of transcellular electrolyte gradients
• Ca, Na, Cl enter cell
• K exits cell
• Cells swell as water follows Na into cell
– Membrane injury due to lipid peroxidases
– Excitotoxicity due to neurotransmitter release
– Activation of apoptotic pathways
– Microvascular thrombosis
– Reperfusion injury
Slide 13
Rincon. Semin Neurol.
2006;26:387.
MRI in HIE
• Different susceptibility of
metabolically active neurons to
hypoxic-ischemic injury
• Growing interest in MRI for HIE
– Prognostication
– Study pathophysiology
Hyperintense (white) areas on diffusionweighted imaging (DWI) reflect acute
injury
Wijdicks. AJNR Am J Neuroradiol. 2001;22:1561.
Slide 14
Hypothermic Neuroprotection
• Decreased systemic metabolic demand
• Decreased cerebral oxygen consumption
• Decreased release of glutamate and other toxic
excitatory neurotransmitters
• Suppression of systemic inflammation and inflammatory
mediators
• Stabilization of neuronal cell membranes
• Decrease in the destructive activity of lipases, proteases,
and nucleases and the related inflammatory response.
Rincon. Semin Neurol. 2006;26:387.
Slide 15
Rationale for Temperature
Modulation after Brain Injury
• Hypothermia drives
fatally injured cells away
from lysis and toward
apoptosis
• Hypothermia drives
marginally injured cells
away apoptosis and
toward recovery
• Fever causes worsening
of brain injury
Slide 16
Clinical Evidence for TH after CA
• Largest RCT of TH in OHCA
survivors
– 275 patients randomized to
TH or routine care
– Europe 1996-2001
• Absolute 16% increase in
chance of a good neurological
outcome
• Absolute 14% decrease in 6month mortality
HACA Study Group. N Engl J Med. 2002;346:549.
Slide 17
Clinical Evidence for TH after CA
HACA Study Group. N Engl J Med. 2002;346:549.
Slide 18
Clinical Evidence for TH after CA
• Australian randomized clinical
trial conducted 1996-1999
• Randomized on alternating
days to TH or routine care
• TH: good outcome 49%,
routine care good outcome:
26% (p=0.046)
Bernard. N Engl J Med. 2002; 346:557.
Slide 19
2005 AHA Guidelines
• “Unconscious adult patients with ROSC after out-ofhospital cardiac arrest should be cooled to 32°C to 34°C
(89.6°F to 93.2°F) for 12 to 24 hours when the initial
rhythm was VF (Class IIa).”
• “Similar therapy may be beneficial for patients with nonVF arrest out of hospital or for in-hospital arrest (Class
IIb).”
Circulation 2005;111:IV84-IV-88
Slide 20
Which Patients Should be Treated
with TH?
• Out-of-hospital VT/VF arrest
– AHA Level 2a recommendation
– Considered level 1 recommendation in much of
Europe
• Other rhythms
– Level 2b recommendation
• In-hospital arrest
– Level 2b recommendation
Slide 21
Only 10% Patients with OHCA Will
Meet RCT Criteria for TH
• The decision to
initiate TH is
usually based on
clinical judgment
of risk and
benefit, not on
direct proof!
Risks
•
Infections
•
Bleeding
•
Need for
sedation
Benefits
Slide 22
•
Strongly neuroprotective
•
Decreased mortality
•
Better neurological
outcome
TH after Cardiac Arrest
• Clinical criteria for therapeutic hypothermia
– No more than 8 hours have elapsed since the return
of spontaneous circulation.
– Encephalopathy is present, typically defined as the
patient being unable to follow verbal commands.
– There is no life-threatening infection or bleeding.
– Aggressive care is warranted and desired by the
patient or the patient’s surrogate decision-maker.
Slide 23
Therapeutic Hypothermia and
Cardiac Revascularization
• More bleeding
complications
• More infections
• But…a strong trend
toward lower mortality
Slide 24
Wolfrum. Crit Care Med. 2008;36:1780-1786.
How to Perform Therapeutic Hypothermia
• Nuts and bolts:
Slide 25
Basics of Therapeutic Hypothermia
• There are 3 phases of treatment:
– Induction
• Rapidly bring the temperature to 32° -34°C
• Sedate with propofol or midazolam during TH
• Paralyze to suppress heat production
– Maintenance
• Maintain the goal temperature at 33°C
• Standard 12-24 hours (optimal duration is unknown)
• Suppress shivering
– De-cooling (rewarming)
• Most dangerous period: hypotension, brain swelling,
• Goal is to reach normal body temperature over 12-24 hours
• Stop all sedation when normal body temperature is achieved
Slide 26
Induction: How to Cool
• Monitor core temperature
– Bladder, esophagus, or central venous/pulmonary arterial
• Cold fluid
– 30 cc/kg LR or 0.9% NS over 30 minutes
• 2.0°-2.5°C temperature reduction
– No adverse cardiovascular results
– Rare to cause pulmonary edema
• Ice packs and cooling mats
– Effective, but difficult to control rate of temperature change
– Overcooling is dangerous
Slide 27
Induction: How to Cool
• Commercial cooling devices
– Feedback 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 metallic heat-exchange catheter
Slide 28
Comparison of Cooling Methods
•
•
•
Traditional cooling
– Inexpensive and available
– Effective
– Very high incidence of overcooling
Noninvasive cooling devices
– Safe – no insertion, lots of clinical
experience
– Effective, unless patients very
heavy
– Expensive
Invasive cooling devices
– Most effective at tight temperature
control
– Better for heavy patients
– Insertion dangers: thrombosis,
infection, placement-related injury
– Expensive
Hoedemaekers. Crit Care.
Slide 29
2007;11:R91.
INDUCTION
MAINTENANCE
Maintenance Phase
• Maintain physiological homeostasis
– Adequate blood pressure and cerebral perfusion
– Normal glucose level (100-140)
– Normal electrolytes
– Recognize and treat seizures
– Suppress shivering
– Adequate sedation
– Adequate oxygenation
– Optimal volume status and cardiac output
• Diagnose and treat the cause
of the arrest!
Slide 30
De-Cooling Phase
• Vasodilation causes hypotension
– May require several liters IVF replacement
• More shivering during this phase
• Inflammation increases at higher temperature
– “Post-resuscitation” syndrome
• Increased ICP and decreased CPP
– Maintain adequate MAP!
• Watch for hyperkalemia
– Can be problematic in patients with renal failure
Slide 31
Side Effects of Hypothermia
•
Infection
– High incidence of pneumonia
• Treat infections early
•
Coagulopathy
– Mild platelet dysfunction and prolonged PT, aPTT
•
Hypokalemia
– K+ may drop as much as 1 mg/dL during induction
•
Arrhythmia
– Almost all patients have asymptomatic bradycardia
– VT/VF: no significant increase with therapeutic hypothermia
• If VT/VF, verify no overcooling or hypokalemia
•
Decreased drug metabolism
– At least a 7-8% decrease per degree below 36°C
•
Shivering
Slide 32
Infection
• Incidence of pneumonia 30%-50%
• Neutrophil oxidative killing, T-cell function impaired at
low temperature
• Fever and inflammation exacerbate brain injury
• When pneumonia or aspiration is suspected, consider:
– Cefuroxime 1500 mg x 2 doses, or
– Ampicillin/sulbactam x 3 days
Sirvent. Am J Respir Crit Care Med. 1997;155:1729.
Aquarolo. Intensive Care Med. 2005;31:510.
Slide 33
Shivering
• Drives up systemic metabolic rate
– Increased CO2 production
– Increased O2 consumption
– Cardiac stressor
• Drives up cerebral oxygen
consumption
– Favors ischemia
• Uncomfortable
Badjatia. Metabolic impact of shivering during
therapeutic temperature modulation: the
Bedside Shivering Assessment Scale . Stroke,
2008, In Press.
Slide 34
Management of Shivering
• Neuromuscular blockade
– Vecuronium bolus 0.1mg/kg prn BSAS >2
– Cisatracurium in renal failure
• Propofol
• Alpha-agonists
– Dexmedetomidine infusion or clonidine
• Scheduled acetaminophen, buspirone
• Meperidine
• Focal counterwarming
• Magnesium infusion (to serum
level 3-4mg/dL)
Slide 35
Neuromonitoring Options During TH
•
•
•
•
EEG
– Nonconvulsive seizure activity is common
– Continuous EEG preferred
– Sedation with propofol/midazolam will suppress
Bispectral index
– Verify no awareness during hypothermia
Systemic oxygen utilization
– Maintain SvO2 > 60%
Brain oxygen extraction
– Jugular venous oximetry is a measure of cerebral blood flow and metabolism
•
•
•
maintain SjvO2 > 55%
Intracranial pressure
– Elevated ICP in 25% survivors, CPP< 50 in 56%
Intracranial metabolism
– Possible role for PbrO2, brain glucose, or cerebral lactate/pyruvate ratio
Intensive Care Med. 1991;17:392-398.
Lemiale. Resuscitation. 2008;76:17.
Gueugniaud. Resuscitation. 1990;20:203.
Gueugniaud. Resuscitation 1991;17:392.
Slide 36
Seizures
• Up to 50% patients with HIE have
abnormal movements
– Myoclonus
• Marker of severe brain injury & poor
prognosis
– Seizures
• Convulsive seizures
• Nonconvulsive seizures
– 20% (small series) in HIE
– You won’t know unless you have
continuous EEG in place
– Status epilepticus
• Excitotoxicity
• Midazolam or propofol sedation will help
suppress seizures during hypothermia
Hovland. Resuscitation. 2006;68:143.
Claassen. Neurology. 2004;62:1743.
Slide 37
EEG of OHCA survivor with multiple generalized
epileptiform discharges discovered after
therapeutic hypothermia
Outcome after OHCA
•
Glasgow-Pittsburgh Cerebral Performance Categories*
•
1. Good Cerebral Performance
Conscious: Alert, able to work and lead a normal life. May have minor
psychological or neurological deficits (mild dysphasia, nonincapacitating
hemiparesis, or minor cranial nerve abnormalities).
•
2. Moderate Cerebral Disability
Conscious. Sufficient cerebral function for part-time work in sheltered environment
or independent activities of daily life (dressing, traveling by public transportation,
and preparing food). May have hemiplegia, seizures, ataxia, dsysarthria,
dysphasia, or permanent memory or mental changes.
•
3. Severe Cerebral Disability
Conscious. Dependent on others for daily support because of impaired brain
function (in an institution or at home with exceptional family effort). At least limited
cognition. Includes a wide range of cerebral abnormalities from ambulatory with
severe memory disturbance or dementia precluding independent existence to
paralytic and able to communicate only with eyes, as in the locked-in syndrome.
•
4. Coma, Vegetative State
Not conscious. Unaware of surroundings, no cognition. No verbal or psychological
interactions with environment.
•
5. Death
Certified brain dead or dead by traditional criteria.
•
*Adapted with permission from Cummings et al.
• “Utstein method” of data
collection and outcome
assessment
• Good outcome typically
considered CPC 1 or 2
• Many neurologists prefer the
Modified Rankin score
Booth. JAMA. 2004;291:870.
Slide 38
AAN Guidelines
• “Prognosis cannot be based on the
circumstances of CPR”
– “Anoxia time, duration of CPR, and cause
of cardiac arrest are related to poor
outcome after CPR”
– “None of these variables can discriminate
accurately between patients with poor and
those with favorable outcomes”
• “Current indicators of prognosis…are
derived from patients not treated with
hypothermia…these indicators may need
revision.”
Wijdicks. Neurology. 2006;67:203.
Slide 39
Prognostic Tools
•
Neuro exam
24 h, 72 h, 7 day
•
Serum markers
Neuron-specific enolase
S100B protein
•
EEG
•
Somatosensory evoked
potentials (SSEPs)
•
Myoclonic status epilepticus
•
MRI
OHCA Prognosis Paradigm
• Drugs that build
up during
hypothermia may
confound
prognosis!
• Verify that
sedation,
analgesia, and
paralytics are no
longer present!
Wijdicks. Neurology. 2006;67:208.
Slide 40
End-of-Life Issues
• Even when outcome for the patient after cardiac arrest is poor, some
good can often be achieved
• Open, regular communication between family members and
caregivers
• Define the level and limits of care
• Clarify and carefully document DNR if appropriate
– Grieving
• Facilitate the grieving process, take advantage of resources for
families
– Organ donation is an opportunity
• Be aware of local protocols and procedures
• Delicate discussions should be supervised by experienced team
members
Slide 41
Case Studies
The following are case studies that can be used for review
of this presentation.
Review Cases
End
Slide 42
Case Study
• A previously healthy 44-year-old woman collapses at work after
complaining of chest tightness
– 3 minutes: bystander CPR initiated
– 7 minutes: defibrillation provided by bystanders using an
automated external defibrillator (AED)
– 9 minutes: EMS arrives, intubation performed.
• Pulse present
• Generalized seizure activity noted
• Lorazepam 2 mg administered
– In the ED
•
•
•
•
Does not open eyes or follow commands
Extensor motor response to pain
Pupils minimally reactive at 3 mm
Corneal and weak gag reflexes present
Slide 43
Case Study
• Therapeutic hypothermia urgently initiated
– Sedated with propofol, paralyzed with vecuronium
– Cooled to 33°C over 4 hr using cold mat and ice packs
– Rewarmed after 18 hr
• No further seizure activity
• Coronary angiography revealed spontaneous LAD dissection
– Conservative management with antiplatelet therapy
• Discharged with short-term memory deficits and emotional lability
• Cognitively normal at 6 months after ROSC
Slide 44
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References
• See SCCM LearnICU webpage for more information on
Hypothermia
Slide 47