1. Publication
- Title: Effect of Paracetamol on Cerebral Temperature in Febrile Brain-Injured Patients. The NEUROTHERM Study: A Randomized Controlled Pharmacodynamic Trial
- Acronym: NEUROTHERM
- Year & Journal: Critical Care Medicine, epublished November 11, 2025 (print: 2026;54(1):108-118)
- Citation: de Mesmay M, Geral L, Gregoire C, et al. Effect of Paracetamol on Cerebral Temperature in Febrile Brain-Injured Patients. The NEUROTHERM Study: A Randomized Controlled Pharmacodynamic Trial. Crit Care Med. 2026;54(1):108-118. doi:10.1097/CCM.0000000000006951
2. Context & Rationale
Background: Hyperthermia is common in brain-injured patients and considered a systemic secondary brain injury. Paracetamol is the most common first-line antipyretic, but its efficacy in controlling cerebral (as opposed to peripheral/systemic) temperature had never been directly evaluated — a genuine, previously unaddressed physiological question given that brain and systemic temperatures can differ.
Research Question/Hypothesis: In febrile brain-injured patients monitored with an intracerebral thermal probe, does IV paracetamol reduce cerebral temperature (CT) compared with placebo?
Why This Matters: Directly tests whether a nearly universal first-line fever treatment actually achieves its presumed target-organ effect (lowering brain temperature specifically), a question with direct bedside relevance given hyperthermia's association with secondary brain injury.
3. Design & Methods
- Study Type: Pharmacodynamic, prospective, randomized, double-blind, placebo-controlled trial
- Setting & Centers: Single-center, Neuro-ICU, Rothschild Foundation Hospital, Paris, France
- Population:
- Inclusion: Brain-injured patients, febrile (cerebral temperature ≥38.5°C for >30 min), monitored with an intracerebral pressure sensor including a thermal probe
- Exclusions: Not detailed in available trial text
- Intervention: Single IV paracetamol administration (n=49)
- Comparator: Placebo, single IV administration (n=50)
- Randomization: 1:1, 99 patients (mean age 55±13y, 24% female)
- Blinding: Double-blind
- Statistical Power & Follow-Up: Primary outcome: cerebral temperature (CT) during 6-hour follow-up, measured via intracerebral thermal probe. Secondary: gradient between cerebral temperature (CT) and systemic/skin temperature (ST), duration maintaining CT <38.5°C.
4. Key Results
99 patients randomized (49 paracetamol, 50 placebo).
Outcome | Paracetamol | Placebo | Effect Size | Notes |
Mean cerebral temperature during 6h follow-up (primary) | 38.4 ± 0.5°C | 39.0 ± 0.5°C | Mean reduction 0.6°C | Statistically significant reduction |
Duration maintaining CT <38.5°C | Median 3.6h | — | — | Effect was time-limited, not sustained indefinitely |
CT-ST gradient | ~0.3°C consistently | ~0.3°C consistently | — | Gradient between cerebral and systemic temperature remained stable regardless of treatment |
5. Internal Validity Assessment
- Randomization & Allocation: 1:1 randomization; specific concealment mechanics not detailed in available trial text.
- Protocol Adherence & Separation: Direct, objective, continuous intracerebral thermal-probe measurement (rather than indirect/surrogate temperature assessment) is a major methodological strength — this is a genuinely novel, direct pharmacodynamic measurement not previously available in this specific context.
- Blinding & Detection Bias: Full double-blind design with an objective, device-measured primary outcome — minimal risk of either performance or detection bias.
- Missing Data & Sensitivity Analyses: Not detailed in available trial text.
- Overall Internal Validity Conclusion: Strong — double-blind design with a directly measured, objective, continuous physiological primary outcome (intracerebral thermal probe) provides high confidence in this precise pharmacodynamic finding, though the single-center design and modest sample size (99 patients) limit broader inference.
6. External Validity Assessment
- Population Representativeness: Febrile, brain-injured Neuro-ICU patients requiring intracerebral pressure/thermal monitoring — a specific, monitored subpopulation (not all febrile brain-injured patients have this invasive monitoring).
- Practice Context: Requires intracerebral thermal-probe monitoring capability, available only in specialized neurocritical care units — limiting the population in whom the measurement (though not necessarily the paracetamol treatment itself) could be directly replicated.
- Overall External Validity Conclusion: Moderate — the pharmacodynamic finding (paracetamol reduces cerebral temperature by ~0.6°C for a median of 3.6h) is directly measured and likely generalizes to the broader febrile brain-injured population even without invasive monitoring, though this specific trial's population was restricted to those already undergoing intracerebral monitoring.
7. Strengths & Limitations
Strengths:
- First trial to directly measure paracetamol's effect on cerebral (not just systemic) temperature, using a novel, objective intracerebral thermal-probe methodology
- Double-blind, placebo-controlled design
- Fills a genuine, previously unaddressed physiological evidence gap for a nearly universal first-line fever treatment
Limitations:
- Single-center design
- Modest sample size (99 patients)
- Pharmacodynamic (physiological) trial, not designed or powered to assess clinical/patient-centered outcomes
- Single-dose administration; effect was time-limited (median 3.6h maintaining target), raising questions about optimal dosing frequency for sustained control
8. Interpretation & Practice Impact
- Clinical Implications: Confirms that IV paracetamol does meaningfully reduce cerebral (not just systemic) temperature in febrile brain-injured patients, supporting its continued use as first-line antipyretic therapy in this population — but the time-limited effect (median 3.6h) suggests single dosing may be insufficient for sustained temperature control, an important dosing-frequency consideration.
- Mechanistic Coherence: The consistent ~0.3°C CT-ST gradient regardless of treatment provides useful physiological reference data for clinicians relying on peripheral/systemic temperature as a proxy for cerebral temperature.
- Systems-Level Takeaway: Supports paracetamol's continued first-line role, while highlighting that redosing schedules (rather than single-dose assumptions) should be considered to maintain fever control given the demonstrated ~3.6-hour effect duration.
9. Controversies & Subsequent Evidence
- Editorial Commentary/Debates: Not detailed in available trial text; a related contemporaneous JAMA piece ("Fever Prevention in Acute Vascular Brain Injury," Okazaki, 2025) addresses the broader fever-management context in which this trial's findings are situated.
- Guideline Integration: Provides novel, direct physiological evidence supporting existing practice patterns (paracetamol as first-line antipyretic in neurocritical care) rather than challenging them, while refining understanding of effect duration for dosing-interval decisions.
10. Summary & Executive Takeaway
Summary: NEUROTHERM, a single-center, double-blind RCT, randomized 99 febrile brain-injured patients with intracerebral thermal monitoring to IV paracetamol or placebo. Paracetamol significantly reduced mean cerebral temperature during 6-hour follow-up (38.4±0.5°C vs 39.0±0.5°C, mean reduction 0.6°C), maintaining CT <38.5°C for a median of 3.6 hours.
Overall Takeaway: This is the first trial to directly confirm that paracetamol meaningfully reduces cerebral (not just systemic) temperature in febrile brain-injured patients, using a novel intracerebral thermal-probe methodology — supporting its continued first-line antipyretic role while suggesting redosing intervals shorter than previously assumed may be needed to maintain sustained cerebral temperature control.
11. Bibliography
- Okazaki T. Fever Prevention in Acute Vascular Brain Injury [commentary]. JAMA. 2025;333(7):635.
- Kitagawa R, Cook R, Zima L. Fever in the Neurocritically Ill Patient. Neurosurg Clin N Am. 2025;36(3):365-373.