Eurotherm3235: Hypothermia for Intracranial Hypertension after TBI (2015)

“In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury, therapeutic hypothermia led to a worse outcome, as measured by the Extended Glasgow Outcome Scale, than standard care.”

  • The Eurotherm3235 Trial Investigators

1. Publication Details

  • Trial Title: Hypothermia for Intracranial Hypertension after Traumatic Brain Injury
  • Citation: Andrews PJD, Sinclair HL, Rodriguez A, et al. Hypothermia for Intracranial Hypertension after Traumatic Brain Injury. N Engl J Med. 2015;373(25):2403-2412. DOI: 10.1056/NEJMoa1507581
  • Published: December 17, 2015, in The New England Journal of Medicine
  • Author: Peter J. D. Andrews, M.D.
  • Funding: The European Union Seventh Framework Programme.

2. Keywords

  • Traumatic Brain Injury (TBI), Therapeutic Hypothermia, Intracranial Hypertension, Neurocritical Care, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with traumatic brain injury (TBI) and refractory intracranial hypertension (ICP > 20 mm Hg) (Population), does a strategy of therapeutic hypothermia (Intervention) compared to standard care with normothermia (Comparison) improve favorable functional outcomes at 6 months (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Refractory intracranial hypertension after TBI is a life-threatening condition with high mortality. Therapeutic hypothermia was known to effectively lower ICP and was thought to be a promising neuroprotective strategy, based on its use in cardiac arrest and on smaller, inconclusive studies in TBI.
  • Knowledge Gap: Despite its use in some centers, there was no high-quality evidence from a large, multicenter randomized trial to determine if therapeutic hypothermia improved patient-centered outcomes in this population, or if it was simply effective at treating a number (the ICP) without helping the patient.
  • Proposed Hypothesis: The authors hypothesized that therapeutic hypothermia would be superior to standard care in improving the rate of favorable functional outcomes at 6 months.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 47 intensive care units (ICUs) in 18 countries.
  • Trial Period: Enrollment ran from December 2009 to October 2014.
  • Population:
    • Inclusion Criteria: Adult patients (16-65 years) with a primary closed TBI who had an ICP of >20 mm Hg for more than 5 minutes that was refractory to initial standard therapies.
    • Exclusion Criteria: Included patients who were unsalvageable, had bilateral fixed and dilated pupils, or had contraindications to hypothermia.
  • Intervention: Patients were cooled to a target temperature of 32°C to 35°C for at least 48 hours, followed by gradual rewarming.
  • Control: Patients received standard medical care with a goal of normothermia (37°C).
  • Management Common to Both Groups: All patients were managed with a tiered approach to ICP control based on Brain Trauma Foundation guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 600 patients would provide 80% power to detect a 10% absolute difference in the rate of favorable outcomes. (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: Functional outcome at 6 months, as assessed by the Extended Glasgow Outcome Scale (GOSE). A favorable outcome was defined as a GOSE score of 5-8 (lower moderate disability to good recovery).
    • Secondary Outcomes: Included mortality at 6 months and the distribution of GOSE scores.

6. Key Results

  • Enrollment and Baseline: 387 patients were randomized (202 to hypothermia and 185 to standard care). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early for futility by the data and safety monitoring committee after enrolling 387 of the planned 600 patients.
  • Primary Outcome: There was no significant difference in the primary outcome. A favorable neurologic outcome at 6 months occurred in 52 of 196 patients (26%) in the hypothermia group and in 49 of 177 patients (28%) in the standard-care group (p=0.77).
  • Secondary Outcomes: Mortality at 6 months was significantly higher in the hypothermia group (35% vs. 22%; p=0.009).
  • Adverse Events: The incidence of adverse events was not systematically reported in the primary publication, but the increased mortality is a major adverse finding.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using an ordinal logistic regression model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the distribution of GOSE scores between the two groups.
  • Key Statistic(s) Reported: Odds Ratio (OR) for a favorable outcome (GOSE 5-8): 0.89 (95% CI, 0.55 to 1.45; P-value: 0.65).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of Favorable Outcome in Intervention Group) / (Odds of Favorable Outcome in Control Group).
      • Calculation: The paper reports the result as 0.89.
      • Clinical Meaning: An OR of 0.89 suggests a non-significant 11% lower odds of a favorable outcome in the hypothermia group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.55 to 1.45.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 45% harm to a 45% benefit.
    • P-value: The p-value of 0.65 for the primary outcome is much higher than the 0.05 threshold, indicating the result is not statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for the outcome of mortality):
    • Absolute Risk Increase (ARI):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 35% – 22% = 13%.
      • Clinical Meaning: For every 100 patients with TBI and high ICP treated with hypothermia, about 13 additional deaths occurred.
    • Number Needed to Harm (NNH):
      • Formula: NNH = 1 / ARI
      • Calculation: NNH = 1 / 0.13 = 7.7, which is rounded up to 8.
      • Clinical Meaning: You would only need to treat 8 patients with therapeutic hypothermia to cause one additional death.
  • 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 47 diverse centers across 18 countries increases the external validity of the findings.
  • Patient-Centered Outcomes: The primary outcome of 6-month functional status is a robust and highly relevant 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 study population was a specific group of TBI patients with refractory intracranial hypertension.
  • Other: The trial was stopped early for futility and slow recruitment, meaning it was underpowered to definitively rule out a smaller treatment effect. However, the clear signal of harm (increased mortality) is a powerful finding.

10. Conclusion of the Authors

  • The authors concluded that in patients with TBI and refractory intracranial hypertension, the use of therapeutic hypothermia did not improve functional outcomes at 6 months and was associated with an increased risk of death.

11. To Summarize

  • Impact on Current Practice: This was a landmark “negative” trial that provided strong evidence to argue against the routine use of therapeutic hypothermia for the management of intracranial hypertension in TBI.
  • Specific Recommendations:
    • Patient Selection: For adult patients with TBI and refractory elevated ICP.
    • Actionable Intervention: Do not routinely use therapeutic hypothermia (32-35°C) to control intracranial pressure.
    • Expected Benefit: Avoiding this therapy prevents one additional death for every 8 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that temperature control is not important in TBI. Aggressively treating fever (maintaining normothermia) remains a cornerstone of neurocritical care.
  • Implementation Caveats: The findings of this trial support the de-adoption of a complex and harmful intervention.

12. Context and Related Studies

  • Building on Previous Evidence: The Eurotherm3235 trial (2015) was designed to provide a definitive answer to a question that had been debated for years, based on promising but inconclusive smaller studies.
  • Influence on Subsequent Research: The definitive finding of harm in this trial has been highly influential in shaping international guidelines, which now recommend against the use of prophylactic or therapeutic hypothermia for TBI.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear signal of harm.
  • Future Directions: The failure of yet another promising neuroprotective agent has shifted the focus of TBI research towards other areas, such as advanced neuromonitoring, personalized physiological targets, and surgical interventions like decompressive craniectomy.

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 devastating condition.
  • Methods: The multicenter RCT design was appropriate. The main methodological weaknesses are the open-label design and the early termination for futility, which underpowered the study for its primary outcome.
  • Results: The study reported a neutral finding for its primary outcome but a statistically significant and clinically profound increase in harm (mortality) as a secondary outcome.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The trial is a classic example of how a therapy that improves a physiological number (ICP) can worsen patient-centered outcomes. Its findings are broadly applicable and provide strong evidence to avoid this harmful intervention.

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.
Scroll to Top