therapeutic hypothermia post-resuscitation care david b. seder richard r. riker gilles l. fraser...

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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

How Should She be Treated?

• What are the patient’s relevant medical problems?

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

Key Words and Concepts

• Return of spontaneous circulation (ROSC)

• Downtime

• Hypoxic-ischemic encephalopathy (HIE)

• Cardiocerebral resuscitation

• Surface vs. intravascular cooling

• Core temperature

• Shivering

• Overcooling

• Neuroprognostication

• Myoclonic status epilepticus

• Cerebral performance category (CPC)

• Brain death

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

– Factors influencing outcome:• Early defibrillation • Duration of arrest• Bystander CPR• Quality of CPR • Age• Therapeutic hypothermia

Callans. Effect of early defibrillation on survival after cardiac arrest. N Engl J Med. 2004;351:632.

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.

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.

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!

Triage of the Cardiac Arrest (CA) Survivor

• Cardiac assessment

– Rhythm stabilization

– BP stabilization

– Evaluation and treatment of the underlying cause of the cardiac arrest

– Consideration of urgent coronary angiography and revascularization

• Neurological assessment

– Severity of HIE

– CT head to rule out intracranial bleed

– Institution of therapeutic hypothermia

– EEG monitoring if appropriate

– Maintenance of adequate cerebral blood flow

Seder. Curr Opin Neurol Neurosurg. 2008;8:508-517.

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

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

Wijdicks. AJNR Am J Neuroradiol. 2001;22:1561.

Hyperintense (white) areas on diffusion-weighted imaging (DWI) reflect acute injury

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.

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

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 6- month mortality

HACA Study Group. N Engl J Med. 2002;346:549.


HACA Study Group. N Engl J Med. 2002;346:549.


• 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.

2005 AHA Guidelines

• “Unconscious adult patients with ROSC after out-of-hospital 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 non-VF arrest out of hospital or for in-hospital arrest (Class IIb).”

Circulation 2005;111:IV-84-IV-88

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

Only 10% Patients with OHCA Will Meet RCT Criteria for TH

Risks• Infections

• Bleeding

• Need for sedation Benefits

• Strongly neuroprotective

• Decreased mortality

• Better neurological outcome

• The decision to initiate TH is usually based on clinical judgment of risk and benefit, not on direct proof!

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.

Therapeutic Hypothermia and Cardiac Revascularization

• More bleeding complications

• More infections

• But…a strong trend toward lower mortality

Wolfrum. Crit Care Med. 2008;36:1780-1786.

How to Perform Therapeutic Hypothermia

• Nuts and bolts:

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

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

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

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. 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!

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

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

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.

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.

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)

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

Lemiale. Resuscitation. 2008;76:17.Gueugniaud. Resuscitation. 1990;20:203.Gueugniaud. Resuscitation 1991;17:392.

Intensive Care Med. 1991;17:392-398.

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.

EEG of OHCA survivor with multiple generalized epileptiform discharges discovered after therapeutic hypothermia

Outcome after OHCA

• “Utstein method” of data collection and outcome assessment

• Good outcome typically considered CPC 1 or 2

• Many neurologists prefer the Modified Rankin score

• 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.

Booth. JAMA. 2004;291:870.

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.”

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

Wijdicks. Neurology. 2006;67:203.

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.

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

Case Studies

The following are case studies that can be used for review of this presentation.

Review Cases

End

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

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

Self Assessment

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References

• See SCCM LearnICU webpage for more information on Hypothermia

• See SCCM LearnICU webpage for more information on Hypothermia

therapeutic hypothermia post-resuscitation care david b. seder richard r. riker gilles l. fraser...

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