Publication

• Title: Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia
• Acronym: None
• Year: 2002
• Journal published in: The New England Journal of Medicine
• Citation: Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-563.

Context & Rationale

• Background

  • Neurologic injury after return of spontaneous circulation (ROSC) is a dominant cause of death and disability after out-of-hospital cardiac arrest (OHCA).
  • Experimental data and early clinical experience suggested mild hypothermia could attenuate post-ischaemic neuronal injury and improve functional recovery.
  • Prior neuroprotective strategies (e.g., barbiturates, calcium antagonists, glucocorticoids) had not improved clinically meaningful outcomes after cardiac arrest.
  • Key implementation uncertainties included feasibility of rapid cooling in emergency systems and safety concerns (arrhythmias, infection, coagulopathy, electrolyte disturbance).¹
• Research Question/Hypothesis

  • In comatose adult survivors of OHCA due to ventricular fibrillation (VF), does early induced mild hypothermia (target 33°C) compared with active normothermia improve survival to hospital discharge with good neurologic function?
• Why This Matters

  • An intervention that increases neurologically intact survival (rather than survival alone) would meaningfully shift patient-centred outcomes and population burden.
  • Hypothermia is a biologically plausible, potentially low-cost therapy that could be deployed widely if benefit and safety are robust.

Design & Methods

• Research Question: In comatose adult survivors of OHCA with VF, does induced hypothermia to 33°C improve favourable neurologic outcome at hospital discharge compared with active normothermia?
• Study Type: Prospective, multicentre, investigator-initiated, prehospital-to-ICU controlled trial with allocation by calendar day (odd vs even day of admission); conducted across 4 hospitals in Melbourne, Australia; unblinded.
• Population:
  • Adults with OHCA of presumed cardiac cause, VF as initial rhythm at ambulance arrival, ROSC, and persistent coma (not responding to verbal commands) after ROSC.
  • Exclusions included: age <18 years (men) or <50 years (women); cardiogenic shock (systolic blood pressure <90 mm Hg despite epinephrine infusion); suspected cause of coma other than cardiac arrest (drug overdose, head trauma, cerebrovascular accident); lack of an ICU bed at a participating institution.
• Intervention:
  • Induced hypothermia: paramedic-initiated surface cooling (clothes removed, water spray and fanning), then ED/ICU surface cooling (ice packs + cooling blanket) targeting bladder temperature 33°C within 2 hours of ROSC.
  • Maintenance: target 33°C for 12 hours after hospital arrival; sedation and neuromuscular blockade (midazolam and vecuronium as needed) to prevent shivering.
  • Rewarming: active rewarming initiated 18 hours after arrival over ~6 hours using warmed air blanket; sedation and neuromuscular blockade continued.
• Comparison:
  • Active normothermia: standard ICU treatment with sedation and neuromuscular blockade, targeting 37°C; passive rewarming if mild spontaneous hypothermia on admission.
  • Other care (including thrombolysis or angioplasty) applied as clinically indicated; specific use rates not reported.
• Blinding: Unblinded; clinicians were aware of temperature assignment (with potential implications for co-interventions and end-of-life decision-making).
• Statistics: Power calculation: 62 patients required to detect an increase in “good outcome” from 14% to 50% with 80% power at the 5% significance level; analysis performed in the analysed cohort with additional logistic regression adjusting for age, time to ROSC, and bystander cardiopulmonary resuscitation.
• Follow-Up Period: In-hospital follow-up to hospital discharge (no post-discharge follow-up reported).

Key Results

This trial was not stopped early. An interim analysis was performed after 62 eligible patients; enrolment continued to 84 eligible patients, with 77 included in the reported analysis.

• Favourable discharge outcome was higher with induced hypothermia (49% vs 26%) with a wide confidence interval (OR 2.65; 95% CI 1.02 to 6.88).
• Mortality was numerically lower with hypothermia (51% vs 68%), but not statistically significant (P=0.145).
• Hypothermia produced expected physiological effects (lower cardiac index and higher systemic vascular resistance in catheterised patients, and early hyperglycaemia), without quantified excess of major complications reported.

Internal Validity

• Randomisation and Allocation:
  • Allocation was by odd vs even day of admission (not concealed), increasing risk of selection bias.
• Drop out or exclusions:
  • 84 eligible patients; 7 excluded from the reported analysis (5 transfers to non-participating centres; 2 refusal of consent for data collection), leaving 77 analysed.
• Performance/Detection Bias:
  • Unblinded temperature management could influence co-interventions, neuroprognostication, and withdrawal-of-care decisions.
  • Withdrawal of life-sustaining therapy required agreement of two physicians not directly involved in patient care, but could still be influenced by awareness of assignment.
• Protocol Adherence:
  • 72/77 were treated according to the correct assignment.
  • Hypothermia arm: 4/43 did not undergo cooling.
  • Normothermia arm: 1/34 became moderately hypothermic during emergency angioplasty.
• Baseline Characteristics:
  • Time from collapse to ROSC was similar (26.5 ± 12.9 min vs 25.0 ± 8.9 min; P=0.54).
  • Bystander cardiopulmonary resuscitation differed (21/43 [49%] vs 24/34 [71%]; P=0.05).
  • Sex distribution differed (25/43 [58%] male vs 27/34 [79%] male; P=0.05).
• Heterogeneity:
  • Clinical heterogeneity was reduced by narrow eligibility (VF only, presumed cardiac aetiology, shock excluded), but this also narrows inference.
  • Small sample and four-centre design increases vulnerability to chance imbalance and centre-level effects.
• Timing:
  • Cooling was initiated prehospital and the target 33°C was achieved within 2 hours of ROSC.
• Dose:
  • Target 33°C for 12 hours (shorter exposure than later 24-hour protocols).
  • Rewarming led to similar temperatures by 24 hours (37.4 ± 0.98°C vs 37.3 ± 0.63°C; P=0.60).
• Separation of the Variable of Interest:
  • ICU admission temperature: 33.3 ± 0.98°C vs 36.0 ± 0.76°C; P<0.001.
  • 6-hour temperature: 32.7 ± 1.19°C vs 37.1 ± 0.75°C; P<0.001.
  • 12-hour temperature: 33.1 ± 0.95°C vs 37.2 ± 0.93°C; P<0.001.
• Key Delivery Aspects:
  • Surface cooling and rewarming were protocolised and achieved rapid separation, supporting delivery fidelity of the temperature component.
  • Co-interventions (e.g., reperfusion strategies) were not protocolised; treatment rates were not reported.
• Outcome Assessment:
  • Primary endpoint was a functional/disposition composite at discharge (home or rehabilitation), clinically meaningful but susceptible to discharge practice variation.
  • No long-term neurologic or quality-of-life follow-up was reported.
• Statistical Rigor:
  • Power calculation assumed a very large effect (14% to 50%), increasing risk of imprecision if the true effect is smaller.
  • Adjusted modelling produced a larger point estimate than unadjusted analysis (adjusted OR 5.25 vs unadjusted OR 2.65), with risk of overfitting given the limited number of events.

Conclusion on Internal Validity: Moderate internal validity: the intervention achieved clear physiological separation and the endpoint is clinically meaningful, but allocation by calendar day, lack of blinding, exclusions from analysis, and protocol deviations introduce bias risk and widen uncertainty around the effect estimate.

External Validity

• Population Representativeness:
  • Restricted to OHCA with VF and presumed cardiac cause; patients in cardiogenic shock were excluded.
  • Women under 50 years were excluded (pregnancy possibility), limiting applicability to younger women.
  • Patients were excluded if an ICU bed was unavailable, selecting for systems with ICU capacity.
• Applicability:
  • Cooling method (prehospital surface cooling plus ED/ICU ice packs and cooling blanket) is broadly feasible, but requires structured sedation, shivering control, monitoring, and controlled rewarming.
  • Contemporary post-arrest care (coronary angiography pathways, sedation strategies, neuroprognostication and withdrawal practices) has evolved since 1996–1999, which may modify absolute benefits and harms.
  • Generalisation to non-shockable rhythms and in-hospital cardiac arrest is uncertain.

Conclusion on External Validity: Generalisability is moderate for comatose survivors of VF OHCA managed in similarly resourced EMS/ICU systems, but limited for other arrest rhythms, patients with shock, and healthcare systems with different post-arrest pathways.

Strengths & Limitations

• Strengths:
  • Pragmatic and early (prehospital) initiation of cooling with simple, scalable technology.
  • Clear separation of core temperature between groups at clinically relevant timepoints.
  • Functional endpoint at discharge prioritising neurologically intact survival.
  • Multicentre delivery with protocolised cooling and rewarming.
• Limitations:
  • Allocation by calendar day without concealment; unblinded design.
  • Small sample size and wide confidence intervals; powered for a very large effect.
  • Exclusions from analysis and protocol deviations (4 not cooled; 1 crossover).
  • Outcome potentially influenced by discharge practices and end-of-life decisions; no standardised long-term neurologic follow-up.
  • Highly selected population (VF only, shock excluded, younger women excluded).

Interpretation & Why It Matters

• Landmark finding

  Induced hypothermia to 33°C for 12 hours increased favourable discharge outcome in comatose survivors of VF OHCA (49% vs 26%), providing early controlled clinical evidence that temperature manipulation could modify neurologic outcome.
• Practical implementation

  The trial demonstrated feasibility of rapid cooling across prehospital and hospital settings with simple surface techniques, catalysing broad clinical adoption of targeted temperature management programmes.
• Modern practice context

  Subsequent trials and evidence synthesis have shifted emphasis toward active temperature control and fever prevention rather than routine mandatory hypothermia for all patients after cardiac arrest.

Controversies & Subsequent Evidence

• Methodological controversies (trial design and inference):
  • Allocation by calendar day and absence of blinding increase susceptibility to selection and performance bias; early editorial commentary highlighted the need for replication and rigorous control of prognostication and withdrawal-of-care processes.¹
  • Correspondence questioned whether baseline coma severity and the timing/structure of neurologic examination were adequately reported; published correspondence included early neurologic exam data suggesting comparable or more severe coma in the hypothermia arm (e.g., no motor response to pain 39/43 [91%] vs 26/34 [76%]).²
• Safety concerns raised in editorial/correspondence:
  • Electrolyte disturbance, diuresis/fluid shifts, infection, arrhythmias, and coagulopathy were emphasised as clinically relevant risks requiring protocolised monitoring and replacement strategies when cooling is used.¹²
• Subsequent randomised evidence (direction of travel):
  • HACA trial (published contemporaneously) also reported improved neurologic outcome with 32–34°C hypothermia, supporting early guideline endorsement of temperature management after cardiac arrest.³
  • TTM (33°C vs 36°C) found no difference in mortality or neurologic outcome, raising the possibility that avoiding fever (rather than deeper hypothermia) accounted for benefit in earlier trials.⁴
  • HYPERION (non-shockable rhythms) reported higher favourable neurologic outcome with 33°C vs 37°C, but the absolute effect was modest and vulnerability to bias and fragility remained a focus of debate.⁵
  • TTM2 (33°C vs active normothermia with fever prevention) found no benefit of hypothermia and higher arrhythmia risk, accelerating a shift toward fever prevention as the central therapeutic target.⁶
• Evidence synthesis (meta-analytic conclusions):
  • Network meta-analysis and updated systematic review evidence incorporating later trials show no consistent survival or neurologically favourable advantage of routine 32–34°C hypothermia compared with controlled normothermia/fever prevention.⁷⁸
• Guideline evolution:
  • Modern guidance emphasises active temperature control with fever avoidance rather than routine mandatory hypothermia for all patients, reflecting the post-TTM/TTM2 evidence base.⁹

Summary

• In comatose survivors of VF OHCA, induced hypothermia to 33°C for 12 hours increased favourable discharge outcome (21/43 [49%] vs 9/34 [26%]; OR 2.65; 95% CI 1.02 to 6.88; P=0.046).
• All-cause in-hospital mortality was numerically lower but not statistically significant (22/43 [51%] vs 23/34 [68%]; P=0.145).
• Core temperature separation was large and sustained early (ICU admission 33.3 ± 0.98°C vs 36.0 ± 0.76°C; P<0.001).
• Cooling produced expected physiological changes (lower cardiac index and higher systemic vascular resistance in catheterised patients; early hyperglycaemia), without quantified excess of major complications reported.
• Despite landmark impact, internal validity is constrained by quasi-random allocation and lack of blinding; later large trials suggest benefit is more closely related to fever prevention than to routine deep hypothermia for all patients.

Further Reading

Other Trials

• 2002Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-556.
• 2013Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206.
• 2017Kirkegaard H, Søreide E, de Haas I, Pettilä V, Taccone FS, Arus U, et al. Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital cardiac arrest: a randomised clinical trial. JAMA. 2017;318(4):341-350.
• 2019Lascarrou JB, Merdji H, Le Gouge A, Colin G, Grillet G, Girardie P, et al. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med. 2019;381(24):2327-2337.
• 2021Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Levin H, Ullén S, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021;384(24):2283-2294.

Systematic Review & Meta Analysis

• 2021Fernando SM, et al. Targeted temperature management after cardiac arrest: a systematic review and network meta-analysis. Intensive Care Med. 2021;47:1078-1088.
• 2022Holgersson J, et al. Hypothermic versus normothermic temperature control after cardiac arrest. N Engl J Med Evid. 2022;1:EVIDoa2200137.
• 2023Granfeldt A, et al. Temperature control in adult patients after cardiac arrest: a systematic review. Resuscitation. 2023;191:109928.
• 2016Arrich J, Holzer M, Havel C, Müllner M, Herkner H. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev. 2016;CD004128.

Observational Studies

• 2016Chan PS, Berg RA, Tang Y, Curtis LH, Spertus JA. Association between therapeutic hypothermia and survival after in-hospital cardiac arrest. JAMA. 2016;316(13):1375-1382.
• 2020Johnsson J, et al. Temperature management and outcome after out-of-hospital cardiac arrest. Resuscitation. 2020.
• 2024Leadbeater A, et al. Fever prevention after out-of-hospital cardiac arrest: before-and-after study. Resuscitation Plus. 2024;18:100514.
• 2022Luedke MW, et al. Association of time-temperature curves with outcome in out-of-hospital cardiac arrest. Neurology Open. 2022;4(1):e000273.

Guidelines

• 2022Nolan JP, et al. ERC-ESICM guidelines on temperature control after adult cardiac arrest. Intensive Care Med. 2022;48:261-269.
• 2024International Liaison Committee on Resuscitation. International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (CoSTR). Circulation. 2024.
• 2025American Heart Association. 2025 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: Part 11: Post–Cardiac Arrest Care. Circulation. 2025.
• 2025Nolan JP, et al. European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2025: post-resuscitation care. Resuscitation. 2025;110809.

Notes

• Primary endpoint was assessed at hospital discharge; longer-term neurological and quality-of-life outcomes were not reported.
• Key physiological endpoints (cardiac index and systemic vascular resistance) were reported in a pulmonary artery catheter subset (32 vs 22 patients).

Overall Takeaway

This early controlled trial suggested induced hypothermia after VF OHCA can improve neurologically favourable survival and demonstrated that rapid, pragmatic cooling is feasible across prehospital and ICU settings. Although later trials and meta-analyses have not confirmed a universal advantage of 33°C over controlled normothermia with fever prevention, Bernard et al. remains landmark for establishing temperature control as a core post–cardiac arrest therapeutic domain and for catalysing decades of subsequent clinical trials and guideline evolution.

Bibliography

• 1.Safar P, Kochanek PM. Therapeutic hypothermia after cardiac arrest. N Engl J Med. 2002;346:612-613.
• 2.Darby JM, Padosch SA, Kern KB, Böttiger BW, Polderman KH, Girbes ARJ, et al. Therapeutic hypothermia after cardiac arrest. N Engl J Med. 2002;347(1):63-65.
• 3.Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-556.
• 4.Nielsen N, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206.
• 5.Lascarrou JB, et al. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med. 2019;381(24):2327-2337.
• 6.Dankiewicz J, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021;384(24):2283-2294.
• 7.Fernando SM, et al. Targeted temperature management after cardiac arrest: a systematic review and network meta-analysis. Intensive Care Med. 2021;47:1078-1088.
• 8.Granfeldt A, et al. Temperature control in adult patients after cardiac arrest: a systematic review. Resuscitation. 2023;191:109928.
• 9.Nolan JP, et al. ERC-ESICM guidelines on temperature control after adult cardiac arrest. Intensive Care Med. 2022;48:261-269.