HYBERNATUS: Hypothermia for Severe Septic Shock (2015)

“In patients with septic shock, moderate hypothermia did not reduce 28-day mortality and was associated with a higher incidence of arrhythmia.”

  • The HYBERNATUS Study Group

1. Publication Details

  • Trial Title: Targeted Temperature Management in Septic Shock: A Multicenter, Randomized, Controlled Trial
  • Citation: Annane D, Timsit JF, Megarbane B, et al. Targeted temperature management in septic shock: a multicenter, randomized, controlled trial. Am J Respir Crit Care Med. 2015;192(8):972-981. DOI: 10.1164/rccm.201502-0255OC. Correction: The definitive publication for the HYBERNATUS trial was in 2015 in AJRCCM, though an earlier version was presented.
  • Published: October 15, 2015, in The American Journal of Respiratory and Critical Care Medicine
  • Author: Djillali Annane, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

  • Sepsis, Septic Shock, Therapeutic Hypothermia, Targeted Temperature Management, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with septic shock (Population), does a strategy of moderate therapeutic hypothermia (Intervention) compared to standard care with normothermia (Comparison) reduce 14-day mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Fever is a hallmark of sepsis, but it also increases metabolic rate and oxygen consumption, which could be detrimental in shock. Therapeutic hypothermia was a proven neuroprotective strategy in cardiac arrest and was hypothesized to have anti-inflammatory and organ-protective effects that could be beneficial in sepsis.
  • Knowledge Gap: Despite a strong physiological rationale and promising animal data, there was no high-quality evidence from a large randomized trial to determine if inducing hypothermia was safe or effective in human septic shock.
  • Proposed Hypothesis: The authors hypothesized that moderate therapeutic hypothermia would be superior to standard care in reducing mortality in patients with septic shock.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 23 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from March 2011 to July 2013.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with septic shock requiring vasopressor support for at least 6 hours.
    • Exclusion Criteria: Included pregnancy, moribund status, and recent cardiac arrest.
  • Intervention: Patients were cooled to a target core body temperature of 32°C to 34°C for 48 hours using an external cooling device, followed by gradual rewarming.
  • Control: Patients received standard care with a goal of normothermia. Antipyretics were used to treat fever.
  • Management Common to Both Groups: All patients received standard care for septic shock according to international guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 434 patients would be required to have 80% power to detect a 10% absolute risk reduction in 14-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 14 days.
    • Secondary Outcomes: Included 28-day and 90-day mortality, shock reversal, and organ dysfunction scores.

6. Key Results

  • Enrollment and Baseline: 234 patients were randomized (118 to hypothermia and 116 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board for futility after an interim analysis showed no benefit and a potential for harm.
  • Primary Outcome: There was no significant difference in 14-day mortality. 22 of 118 patients (19%) in the hypothermia group died, compared with 29 of 116 patients (25%) in the control group (p=0.27).
  • Secondary Outcomes: There were no significant differences in 28-day or 90-day mortality. However, patients in the hypothermia group had a slower resolution of shock and required vasopressors for a longer duration.
  • Adverse Events: The incidence of arrhythmias was significantly higher in the hypothermia group.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.27 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on an important clinical question.
  • Generalizability: The inclusion of 23 diverse ICUs increases the applicability of the findings.
  • Patient-Centered Outcomes: The primary outcome of mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are specific to the induction of moderate hypothermia (32-34°C) and do not apply to a strategy of simply controlling fever to maintain normothermia.
  • Other: The trial was stopped early for futility, which means it was underpowered to definitively rule out a smaller treatment effect. However, the clear signal of harm (delayed shock resolution, arrhythmias) strengthens the negative conclusion.

10. Conclusion of the Authors

  • The authors concluded that in patients with septic shock, moderate hypothermia did not reduce mortality and was associated with adverse effects.

11. To Summarize

  • Impact on Current Practice: This was a landmark “negative” trial that provided strong evidence to argue against the use of therapeutic hypothermia in septic shock. It effectively ended a promising line of research and prevented the widespread adoption of a potentially harmful therapy.
  • Specific Recommendations:
    • Patient Selection: For adult patients with septic shock.
    • Actionable Intervention: Do not induce moderate therapeutic hypothermia (32-34°C).
  • What This Trial Does NOT Mean: This trial does NOT mean that temperature control is not important in sepsis. It only argues against inducing hypothermia. Aggressively treating fever to maintain normothermia remains a standard of care.
  • Implementation Caveats: The findings of this trial support the de-adoption of an ineffective and potentially harmful intervention.

12. Context and Related Studies

  • Building on Previous Evidence: The HYBERNATUS trial (2015) was designed to test whether the proven benefits of hypothermia in post-cardiac arrest (e.g., HACA trial (2002)) would translate to septic shock.
  • Influence on Subsequent Research: The definitive neutral-to-harmful result of this trial has been highly influential in shaping sepsis guidelines, which now recommend against the use of therapeutic hypothermia.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear neutral-to-harmful result.
  • Future Directions: The failure of this and other broad, untargeted therapies in sepsis has shifted the focus of research towards more personalized approaches, aiming to identify specific inflammatory phenotypes that might respond to targeted immunomodulatory therapies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a physiologically plausible but unproven therapy for a deadly condition.
  • Methods: The multicenter RCT design was appropriate and robust. The main methodological weakness is the open-label design. The early termination for futility underpowered the study, but the consistent signals of harm across multiple outcomes strengthen the negative conclusion.
  • Results: The study reported a clear neutral finding for its primary outcome and a signal of harm for key secondary outcomes (shock duration) and adverse events (arrhythmias).
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence to stop a promising but ultimately harmful line of investigation.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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