TL;DR: ⚪ Physiology succeeded, function didn't — automated fever prevention significantly reduced fever burden in critically ill stroke patients but did NOT improve 90-day functional outcomes.
1. Publication
- Title: Fever Prevention in Patients With Acute Vascular Brain Injury: The INTREPID Randomized Clinical Trial
- Acronym: INTREPID
- Year & Journal: JAMA, published September 25, 2024 (332(18):1525-1534)
- Citation: Greer DM, Helbok R, Badjatia N, et al; INTREPID Study Group. JAMA. 2024;332(18):1525-1534. doi:10.1001/jama.2024.14745
2. Context & Rationale
Background: Fever is associated with poor outcomes in vascular brain injury (doubling short-term mortality odds in ischemic stroke per meta-analysis), but no conclusive trial had shown fever prevention (rather than treatment after fever starts) improves outcomes.
Research Question/Hypothesis: In critically ill stroke patients, does an automated surface temperature management device targeting normothermia (37.0°C) prevent fever and improve functional outcomes compared with standard tiered fever treatment?
3. Design & Methods
- Study Type: Open-label RCT with blinded outcome assessment
- Setting & Centers: 43 ICUs, 7 countries; March 2017–April 2020
- Population: Critically ill stroke patients (ischemic or hemorrhagic)
- Intervention: Automated surface temperature management (ArcticSun System), target 37.0°C for 14 days or ICU discharge
- Comparator: Standard care — tiered fever treatment only if temperature ≥38°C (n=338)
- Blinding: Open-label treatment, blinded outcome assessment
- Statistical Power & Follow-Up: Primary: daily mean fever burden (AUC above 37.9°C, scaled to 24h). Also assessed functional outcomes at 90 days.
4. Key Results
Outcome | Fever Prevention Device | Standard Care | Notes |
Daily mean fever burden (primary) | Significantly reduced | — | Device effectively reduced fever burden |
Functional outcomes at 90 days | Not improved | — | No significant difference despite reduced fever burden |
5. Internal Validity Assessment
Large (described as "the largest study of critically ill cerebrovascular patients in a temperature-modulation RCT"), multicenter, blinded-outcome-assessment RCT. Overall: Strong — the device clearly achieved its physiological target (reduced fever burden), isolating the question of whether fever prevention itself (not just reduced fever) changes function — a genuinely important dissociation.
6. External Validity Assessment
43-center, 7-country stroke ICU population — excellent generalizability given scale and international scope.
7. Strengths & Limitations
Strengths: Largest trial of its kind; confirmed device efficacy on the physiological target (fever burden); blinded outcome assessment.
Limitations: Open-label treatment delivery (inherent to a device intervention); the dissociation between physiological success and functional outcome null result mirrors patterns seen elsewhere in this handbook (e.g., FASTEST, BICARICU-2) where correcting a physiological marker doesn't always translate to better function.
8. Interpretation & Practice Impact
Does not support routine automated fever-prevention devices for improving functional outcomes in critically ill stroke patients, despite effectively reducing fever burden — an important dissociation between physiological surrogate and patient-centered outcome.
9. Controversies & Subsequent Evidence
An accompanying JAMA editorial ("Feasibility of fever prevention in vascular brain injury," May, Shutter) addresses the practical and interpretive implications of this dissociation. Independent commentary (Neurology Today) titled this "Fever Prevention Does Not Improve Outcomes in Patients With Stroke" — a clear, direct framing of the trial's practical message despite its physiological success.
10. Summary & Executive Takeaway
Summary: INTREPID, the largest trial of its kind, randomized critically ill stroke patients across 43 ICUs in 7 countries to automated fever-prevention (target 37.0°C) or standard tiered fever treatment. The device significantly reduced fever burden but did not improve 90-day functional outcomes.
Overall Takeaway: Fever prevention in critically ill stroke patients successfully achieves its physiological target but does not translate into better functional recovery — an important cautionary finding against assuming that correcting an observational risk marker (fever) will necessarily improve patient-centered outcomes.
11. Bibliography
- May T, Shutter L. Feasibility of fever prevention in vascular brain injury [editorial]. JAMA. 2024.
- Greer DM, Funk SE, Reaven NL, et al. Impact of fever on outcome in stroke and neurologic injury: meta-analysis. Stroke. 2008.