Hypoxic-Ischemic Brain Injury

Epidemiology

  • Incidence and Mortality: anoxic brain injury is responsible for 66% of deaths in the post-cardiac arrest period

Etiology

  • Cardiac Arrest (see Cardiac Arrest, [[Cardiac Arrest]])
  • Intoxication
    • Carbon Monoxide Intoxication (see Carbon Monoxide, [[Carbon Monoxide]])
    • Drug Overdose
  • Severe Hypoxemia (see Hypoxemia, [[Hypoxemia]]): resulting in cerebral hypoxia
    • Unsuccessful Intubation
  • Traumatic Brain Injury (TBI) (see Traumatic Brain Injury, [[Traumatic Brain Injury]])
  • Vascular Compromise to Cerebral Blood Supply

Physiology

  • Mechanisms
    • Cell Death Signaling Pathways
    • Cerebral Edema (Limited Extent): increased intracranial pressure is not a prominent feature of post-cardiac arrest syndrome
    • Disrupted Calcium Homeostasis
    • Free Radical Formation
    • Impaired Cerebrovascular Autoregulation: with impaired cerebral microcirculatory blood flow
    • No Reflow
    • Reperfusion Injury
    • Additional Brain Insults: due to pyrexia, hyperglycemia, hyperoxygenation, etc

Diagnosis

Head CT (see Head Computed Tomography, [[Head Computed Tomography]])

  • Indications
    • Exclusion of Intracerebral Hemorrhage/Focal or Multifocal Infarcts
  • Findings
    • Cerebral Edema May Be Noted: however, there is insufficient date to determine the prognostic utility of imaging data [MEDLINE]

Brain MRI (see Brain Magnetic Resonance Imaging, [[Brain Magnetic Resonance Imaging]])

  • Indications
    • Exclusion of Intracerebral Hemorrhage/Focal or Multifocal Infarcts
  • Findings
    • Cerebral Edema May Be Noted: however, there is insufficient date to determine the prognostic utility of MRI DWI and FLAIR [MEDLINE]

Electroencephalogram (EEG) (see Electroencephalogram, [[Electroencephalogram]])

  • Utility of EEG in Predicting Prognosis
    • American Academy of Neurology Practice Parameter (Neurology, 2006) [MEDLINE]: burst suppression or generalized epileptiform discharges predict poor outcome, but with insufficient prognostic accuracy (recommendation level C)

Cerebral Performance Category (CPC)

  • CPC at Hospital Discharge is a Useful Surrogate Measure of Long-Term Survival After Cardiac Arrest (Crit Care Med, 2013) [MEDLINE]

Serum Neuron-Specific Enolase (NSE) and S100 Beta (see Serum Neuron-Specific Enolase, [[Serum Neuron-Specific Enolase]])

  • Rationale: neuron-specific enolase is released into cerebrospinal fluid, cerebral circulation, and systemic circulation after brain injury
    • Elevated levels 72 hrs after cardiac arrest are an indicator of hypoxic brain damage and correlate significantly with neurologic outcome
  • Utility of Neuron-Specific Enolase in Predicting Prognosis
    • American Academy of Neurology Practice Parameter (Neurology, 2006) [MEDLINE]:
      serum neuro-specific enolase level >33 g/L at days 1-3 post-CPR accurately predicts poor outcome (recommendation level B)

Somatosensory Evoked Potentials (SSEP) (see Somatosensory Evoked Potentials, [[Somatosensory Evoked Potentials]])

  • Utility of SSEP in Predicting Prognosis
    • American Academy of Neurology Practice Parameter (Neurology, 2006) [MEDLINE]: the assessment of poor prognosis can be guided by the bilateral absence of cortical SSEPs (N2O response) within 1-3 days (recommendation level B)
    • However, the presence of somatosensory evoked potentials does not necessarily guarantee a good neurological outcome

Clinical Manifestations

Neurologic Manifestations

Clinical Patterns

  • Akinetic Mutism
  • Brain Death (see Brain Death, [[Brain Death]])
  • Coma (see Obtundation-Coma, [[Obtundation-Coma]])
  • Dementia (see Dementia, [[Dementia]])
  • Locked-In Syndrome (see Locked-In Syndrome, [[Locked-In Syndrome]])
  • Persistent Vegetative State: term was first used in 1972
  • Minimally Conscious State

BRAIN INJURY

Intracranial Hypertension (see Increased Intracranial Pressure, [[Increased Intracranial Pressure]])

  • Epidemiology: ICP >20 mm Hg has been associated with poor outcome in comatose patients in some studies

Myoclonus (see Myoclonus, [[Myoclonus]])

  • Multifocal Myoclonus
  • Myoclonic Status Epilepticus (MSE)
    • Physiology: post-mortem studies indicate severe ischemic brain/brainstem/spinal cord damage (a pathologic pattern which is distinct from that of status epilepticus) [MEDLINE]
    • Clinical
      • Persistent Bilaterally Synchronous Myoclonus in the Face/Limbs/Axial Musculature, Often with Eye Opening and Upward Deviation of the Eyes: importantly this must be distinguished from status epilepticus (see Seizures, [[Seizures]])
    • Prognosis
      • Myoclonic Status Epilepticus has Been associated with Poor Outcome (Even in Patients with Intact Brainstem Reflexes and Some Motor Response): however, cases with good recovery have been reported where the circulatory arrest was secondary to respiratory failure
      • American Academy of Neurology Practice Parameter (Neurology, 2006) [MEDLINE]: myoclonic status epilepticus within the first day after a primary circulatory arrest carries a poor prognosis (Recommendation Level B)

Seizures (see Seizures, [[Seizures]])

  • Epidemiology: seizures/nonconvulsive status epilepticus/other epileptiform activity occur in 12-22% of comatose patients after cardiac arrest
  • Clinical
    • Nonconvulsive Status Epilepticus: may result in coma (see Obtundation-Coma, [[Obtundation-Coma]])

Treatment-Immediate Care

Specific Management Post-Cardiac Arrest

Pre-Hospital Therapeutic Hypothermia (see Therapeutic Hypothermia, [[Therapeutic Hypothermia]])

  • Clinical Efficacy
    • Pre-Hospital Mild Hypothermia After Cardiac Arrest (JAMA, 2014) [MEDLINE]: pre-hospital cooling reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34°C, but it did not improve survival or neurological outcome
    • Pre-Hospital Mild Hypothermia After Cardiac Arrest (J Am Heart Assoc, 2015) [MEDLINE]: pre-hospital hypothermia did not improve neurological outcome or 1‐year mortality rate
    • Systematic Review of Pre-hospital Versus In-Hospital Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest (Cochrane Database Syst Rev, 2016) [MEDLINE]: no convincing evidence to delineate beneficial or harmful effects of pre-hospital induction of cooling, as compared to in-hospital induction of cooling (based on low quality evidence)
  • Recommendations (2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care) [MEDLINE]
    • Pre-Hospital Hypothermia with Rapid Infusion of Cold Intravenous Fluids is Not Recommended: no evidence that this intervention has clinical benefit

Treatment-First 24 Hours of Hospital Care

Specific Management Post-Cardiac Arrest

Intracranial Pressure Monitoring

  • Clinical Efficacy
    • American Academy of Neurology Practice Parameter (Neurology, 2006) [MEDLINE]: insufficient data to determine the utility of monitoring of brain oxygenation (SjO2) and intracranial pressure monitoring

Myoclonic Status Epilepticus Management

  • Clonazepam (Klonopin, Rivotril, Clonotril) (see Clonazepam, [[Clonazepam]]): may be used
  • Valproic Acid (see Valproic Acid, [[Valproic Acid]]): may be useful
  • Propofol (Diprivan) (see Propofol, [[Propofol]]): limited data suggests utility

Seizure Management (see Seizures, [[Seizures]])

  • Recommendations (2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care) [MEDLINE]
    • EEG Should Be Performed in Comatose Patients After Cardiac Arrest to Detect Seizure Activity
    • If Present, Seizures Should Be Treated By Standard Therapies
    • Impact of Continuous EEG During Therapeutic Hypothermia Following Cardiac Arrest (Neurology, 2013) [MEDLINE]: grades 1 and 3 EEG severity grading scale during therapeutic hypothermia and normothermia correlated with outcome -> however, treatment of seizures did not improve outcome

Therapeutic Hypothermia (see Therapeutic Hypothermia, [[Therapeutic Hypothermia]])

  • Rationale
    • Combination Hypothermia and Coronary Intervention: may be more efficacious than each therapy alone
  • Technique: most are easily managed in the intensive care unit
    • Arctic Sun Device
    • Surface Cooling with Cooling Blankets/Ice Packs
    • Endovascular Cooling Catheters: more accurate and reliable at maintaining target temperature than other methods
    • Gaymar Medi-Therm II
    • Transnasal Evaporation: novel method which may be used during cardiac arrest
  • Physiologic Effects of Therapeutic Hypothermia
    • Cardiovascular
      • Decreased Heart Rate
      • Decreased Infarct Size with Cardiac Arrest or Acute Myocardial Infarction
      • Increased Myocardial Salvage: with use of therapeutic hypothermia before revascularization in STEMI
      • Increased Systemic Vascular Resistance (SVR)
    • Neurologic
      • Decreased Cerebral Oxygen Demand
      • Decreased Formation of Reactive Oxygen Species in Brain
      • Direct Cellular Effects on Brain
  • Adverse Effects
    • Therapeutic Hypothermia May Impair the Prognostic Utility of Somatosensory Evoked Potentials and Serum Neuron-Specific Enolase (NSE) (see Somatosensory Evoked Potentials, [[Somatosensory Evoked Potentials]] and Serum Neuron-Specific Enolase, [[Serum Neuron-Specific Enolase]]) [MEDLINE] [MEDLINE]: for this reason, caution must be exercised with regard to determining prognosis in the setting of therapeutic hypothermia
  • Clinical Efficacy
    • Hypothermia After Cardiac Arrest Study Group (HACA) Trial (NEJM, 2002) [MEDLINE]: therapeutic hypothermia (32-34 degrees C) improved neurologic outcome after cardiac arrest due to ventricular fibrillation
    • Trial of Therapeutic Hypothermia in Comatose Survivors of Out-of-Hospital Cardiac Arrest (NEJM, 2002) [MEDLINE]: therapeutic hypothermia (33 degrees C) improved neurologic outcome after cardiac arrest
      • Hypothermia was associated with a lower cardiac index, higher systemic vascular resistance, and hyperglycemia
    • TTM Trial: Therapeutic Hypothermia (33°C versus 36°C) After Cardiac Arrest (NEJM, 2013) [MEDLINE]: hypothermia to 33°C did not confer a benefit as compared with hypothermia to 36°C
    • Pre-Hospital Mild Hypothermia After Cardiac Arrest (JAMA, 2014) [MEDLINE]: pre-hospital cooling reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34°C, but it did not improve survival or neurological outcome
    • Pre-Hospital Mild Hypothermia After Cardiac Arrest (J Am Heart Assoc, 2015) [MEDLINE]: pre-hospital hypothermia did not improve neurological outcome or 1‐year mortality rate
    • Systematic Review of Pre-hospital Versus In-Hospital Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest (Cochrane Database Syst Rev, 2016) [MEDLINE]: no convincing evidence to delineate beneficial or harmful effects of pre-hospital induction of cooling, as compared to in-hospital induction of cooling (based on low quality data)
    • Systematic Review of Therapeutic Hypothermia After Cardiac Arrest (Cochrane Database Syst Rev, 2016) [MEDLINE]: therapeutic hypothermia improves neurologic outcome after cardiac arrest (based on moderate quality evidence)
      • Insufficient evidence to show the effects of therapeutic hypothermia with in-hospital cardiac arrest, asystole, non-cardiac causes of arrest
  • Recommendations (2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care) [MEDLINE]
    • Therapeutic Hypothermia is Recommended (Between 32-36 Degrees) for At Least 24 hrs for Comatose Adult Patients with Return of Spontaneous Circulation After Cardiac Arrest (Including In-Hospital Cardiac Arrest)
      • The temperature sensitivity of the brain after cardiac arrest may persist as long as the brain dysfunction (coma) is present: consequently, the upper limit time duration for temperature management is unknown
      • Similar recommendation was provided from the 2015 Recommendations from the International Liaison Committee on Resuscitation (ILCOR)
    • Pre-Hospital Hypothermia with Rapid Infusion of Cold Intravenous Fluids is Not Recommended: no evidence that this intervention has clinical benefit

Prognosis

Neurologic Prognosis Related to the Duration of Cardiopulmonary Resuscitation (CPR)

  • Study of Survival After CPR for Out-of-Hospital Cardiac Arrest (Eur Neurol, 1997( [MEDLINE]: no patient who required >15 min of CP survived >6 wks
    • Initial Survival: 44% of patients
    • Survival at 24 hrs: 30% of patients
    • Survival at 1 mo: 13% of patients
    • Survival at 6 mo: 6% of patients

Neurologic Prognosis Related to Clinical Findings (JAMA, 2004) [MEDLINE]

  • Clinical Parameters Associated with Poor Prognosis
    • Duration of Anoxia: >8-10 min
    • Duration of CPR: >30 min
    • Pupillary Light Response: absent on day 3
    • Motor Response to Pain: absent on day 3
    • Brainstem Reflexes: absent
    • Blood Glucose on Admission: >300 mg/dL
    • Glasgow Coma Scale: <5 on day 3
    • Glasgow-Pittsburgh Coma Score (GPCS): <22 on day 3
  • Patients with Virtually No Chance of Regaining Independence
    • Initial Exam: no pupillary light reflex
    • Day 1 Exam: motor response no better than flexor and spontaneous eye movements neither orienting nor roving conjugate
    • Day 3 Exam: motor response no better than flexor, no spontaneous eye opening
    • Day 7 Exam: motor response not obeying commands and spontaneous eye movements neither orienting nor roving conjugate
    • Day 14 Exam: oculocephalic response not normal, not obeying commands, no spontaneous eye opening, eye opening not improved at least 2 grades from initial examination
  • Patients with Best Chance of Regaining Independence
    • Initial Exam: pupillary light reflexes present and motor response flexor or extensor; spontaneous eye movements roving conjugate or orienting
    • Day 1 Exam: motor response withdrawal or better and eye opening improved at least 2 grades
    • Day 3 Exam: motor response withdrawal or better and spontaneous eye movements normal
    • Day 7 Exam: motor response obeying commands
    • Day 14 Exam: normal oculocephalic response
  • Clinical Findings Which Predict Poor Prognosis (American Academy of Neurology Practice Parameter; Neurology, 2006) [MEDLINE]: with 100% specificity
    • Within First Day After Primary Circulatory Arrest: presence of myoclonic status epilepticus (recommendation level B)
    • Day 3 Exam: absent or extensor motor responses (recommendation level A)
    • Day 3 Exam: absent pupillary or corneal reflexes (recommendation level A)

Neurologic Prognostication Guidelines (2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care) [MEDLINE]

  • Timing of Assessment
    • The Earliest Time That Neurologic Prognostication Can Usually Be Made by Clinical Exam is 72 hrs After Cardiac Arrest or After Return to Normothermia: this time period may be even longer if sedatives/paralytics are involved
    • In Patients Treated/Not Treated with Therapeutic Hypothermia, the Absence of Pupillary Response to Light at 72 hrs or More After Cardiac Arrest is a Reasonable Exam Finding Which Predicts Poor Neurologic Outcome
  • Motor Findings/Myoclonus
    • Absent Motor Movements or Extensor Posturing Should Not Be Used Alone to Predict Neurologic Outcome
    • Mycoclonus Should Not Be Used Alone to Predict Neurologic Outcome
    • Status Myoclonus (In Combination with Other Diagnostic Testing) at 72-120 hrs After Cardiac Arrest is a Reasonable Finding to Predict Poor Neurologic Outcome
  • Seizures/Electroencephalogram Findings
    • In Comatose Post–Cardiac Arrest Patients Who are Treated with Therapeutic Hypothermia, Persistent Absence of EEG Reactivity to External Stimuli at 72 hrs After Cardiac Arrest and Persistent Burst Suppression After Rewarming Predict a Poor Neurologic Outcome
    • Intractable and Persistent (>72 hrs) Status Epilepticus in the Absence of EEG Reactivity to External Stimuli Predicts a Poor Neurologic Outcome
    • In Comatose Post–Cardiac Arrest Patients Who are Not treated with Therapeutic Hypothermia, Burst Suppression on EEG at 72 hrs or More After Cardiac Arrest (In Combination with Other Diagnostic Testing) Predicts a Poor Neurologic Outcome
  • Brain Imaging
    • In Patients Who are Comatose After Resuscitation from Cardiac Arrest and Not Treated with Therapeutic Hypothermia, it May be Reasonable to Use the Presence of a Marked Reduction of the Gray/White Ratio on Head CT Obtained Within 2 hrs After Cardiac Arrest to Predict Poor Outcome
    • It May Be Reasonable to Consider Extensive Restriction of Diffusion on Brain MRI at 2-6 days After Cardiac Arrest in Combination with Other Established Predictors to Predict a Poor Neurologic Outcome
  • Serum Neuron-Specific Enolase (NSE)
    • Given the Possibility of High False-Positives, Blood Levels of NSE and S-100B Should Not Be Used Alone to Predict a Poor Neurologic Outcome
  • Somatosensory Evoked Potentials
    • In Comatose Post–Cardiac Arrest Patients Regardless of Treatment with Therapeutic Hypothermia, Bilateral Absence of the N20 Somatosensory Evoked Potential Wave 24-72 hrs After Cardiac Arrest or After Rewarming Predicts a Poor Neurologic Outcome

Neurologic Prognosis in Post-Anoxic Vegetative State in Subacute Setting

  • Study of Coma Recovery Scale-Revised (CRS-R) (Neurology, 2013) [MEDLINE]
    • CRS-R >6 at 1 mo Post-Injury: predicts subsequent recovery of responsiveness within the next 24 mo

References

General

  • The significance of myoclonic status epilepticus in postanoxic coma. Neurology. 1990;40(12):1843 [MEDLINE]
  • The prognostication of cerebral hypoxia after out-of-hospital cardiac arrest in adults. Eur Neurol. 1997;37(3):135 [MEDLINE]
  • Systematic review of early prediction of poor outcome in anoxic-ischaemic coma. Lancet. 1998;352(9143):1808 [MEDLINE]
  • Time course of serum neuron-specific enolase: A predictor of neurological outcome in patients resuscitated from cardiac arrest.  Stroke  1999; 30:1598-1603 [MEDLINE]
  • The prognostic value of evoked responses from primary somatosensory and auditory cortex in comatose patients.  Clin Neurophysiol 2003; 114:1615-1627 [MEDLINE]
  • Serum neuron-specific enolase predicts outcome in post-anoxic coma: A prospective cohort study.  Intensive Care Med  2003; 29:189-195 [MEDLINE]
  • Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest. JAMA. 2004;291(7):870 [MEDLINE]
  • Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;67(2):203 [MEDLINE]
  • Passive oxygen insufflation is superior to bag-valve-mask ventilation for witnessed ventricular fibrillation out-of-hospital cardiac arrest. Ann Emerg Med. 2009;54:656–660 [MEDLINE]
  • Improved patient survival using a modified resuscitation protocol for out-of-hospital cardiac arrest. Circulation. 2009;119:2597–2605 [MEDLINE]
  • 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: Adult advanced cardiovascular life support. Circulation 2010; 122(18 Suppl 3):S729-S767
  • Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):S829-861 [MEDLINE]
  • The natural history of chronic disorders of consciousness. Neurology. 2010;75(3):206 [MEDLINE]
  • Long-term cognitive outcomes following out-of-hospital cardiac arrest: a population-based study. Neurology. 2011;77(15):1438 [MEDLINE]
  • Prognostication after cardiac arrest and hypothermia: a prospective study. Ann Neurol. 2010;67(3):301 [MEDLINE]
  • Poor prognosis despite successful treatment of postanoxic generalized myoclonus.  Neurology  2010; 74:1392-1394 [MEDLINE]
  • Timing of neuroprognostication in postcardiac arrest therapeutic hypothermia. Crit Care Med. 2012 Mar;40(3):719-24 [MEDLINE]
  • Alternative approach to improving survival of patients with out-of-hospital primary cardiac arrest. J Am Coll Cardiol 2013;61:113-118 [MEDLINE]
  • Cerebral Performance Category and long-term prognosis following out-of-hospital cardiac arrest. Crit Care Med. 2013 May;41(5):1252-7. doi: 10.1097/CCM.0b013e31827ca975 [MEDLINE]
  • Predictors of recovery of responsiveness in prolonged anoxic vegetative state. Neurology. 2013 Jan;80(5):464-70. Epub 2013 Jan 9 [MEDLINE]
  • Part 8: Post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015 Nov 3;132(18 Suppl 2):S465-82. doi: 10.1161/CIR.0000000000000262 [MEDLINE]
  • Cardiocerebral Resuscitation: An Approach to Improving Survival of Patients With Primary Cardiac Arrest. J Intensive Care Med. 2016 Jan;31(1):24-33. doi: 10.1177/0885066614544450. Epub 2014 Jul 30 [MEDLINE]

Seizure Management

  • Continuous EEG in therapeutic hypothermia after cardiac arrest: prognostic and clinical value. Neurology. 2013 Jan;80(4):339-44. Epub 2013 Jan 2 [MEDLINE]

Therapeutic Hypothermia

  • Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–63 [MEDLINE]
  • Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346: 549–56 [MEDLINE]
  • Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. Hypothermia after Cardiac Arrest Study Group. N Engl J Med. 2002;346(8):549 [MEDLINE]
  • Therapeutic hypothermia after cardiac arrest. N Engl J Med 2002;346:612 [MEDLINE]
  • From evidence to clinical practice: Effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest. Crit Care Med 2006;34:1865 [MEDLINE]
  • Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest. Resuscitation. 2009;80:418-424 [MEDLINE]
  • Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013 Dec 5;369(23):2197-206. doi: 10.1056/NEJMoa1310519. Epub 2013 Nov 17 [MEDLINE]
  • Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA. 2014 Jan 1;311(1):45-52. doi: 10.1001/jama.2013.282173 [MEDLINE]
  • Effect of prehospital induction of mild hypothermia on 3-month neurological status and 1-year survival among adults with cardiac arrest: long-term follow-up of a randomized, clinical trial. J Am Heart Assoc. 2015 Mar 11;4(3):e001693. doi: 10.1161/JAHA.114.001693 [MEDLINE]
  • Cardiac arrest and therapeutic hypothermia. Trends Cardiovasc Med. 2015 Oct 22. pii: S1050-1738(15)00240-6. doi: 10.1016/j.tcm.2015.10.002 [MEDLINE]
  • Pre-hospital versus in-hospital initiation of cooling for survival and neuroprotection after out-of-hospital cardiac arrest. Cochrane Database Syst Rev. 2016 Mar 15;3:CD010570 [MEDLINE]
  • Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev. 2016 Feb 15;2:CD004128. doi: 10.1002/14651858.CD004128.pub4 [MEDLINE]