Highlight
– A single intravenous dose of paracetamol reduced mean cerebral temperature (CT) by 0.6°C versus placebo over 6 hours in febrile brain‑injured patients (n = 99).
– Paracetamol maintained CT <38.5°C for a median 215 minutes vs. 0 minutes with placebo; however, ~30% of treated patients were nonresponders.
– CT consistently exceeded systemic temperature (ST) by ≈0.3°C, underscoring that peripheral measurements may underestimate cerebral hyperthermia.
Background
Fever and hyperthermia are frequent complications after acute brain injury (traumatic brain injury, subarachnoid hemorrhage, intracerebral hemorrhage, and other insults) and are independently associated with worse outcomes. Elevated temperature increases cerebral metabolic rate, can worsen intracranial hypertension, and may exacerbate secondary injury cascades in the injured brain. Consequently, many neurocritical care protocols emphasize active management of fever and avoidance of hyperthermia, but evidence on the optimal methods and pharmacologic agents to reduce cerebral temperature is limited.
Rationale
Paracetamol (acetaminophen) is the most commonly used antipyretic in critical care because of its availability, ease of administration, and favorable safety profile when used at recommended doses. However, most research has focused on systemic temperature endpoints; whether paracetamol effectively lowers cerebral temperature in brain‑injured patients has not previously been established. Brain temperature can diverge from peripheral body temperature measurements, with injured brain often being warmer. Demonstrating a pharmacodynamic effect of paracetamol on cerebral temperature has important implications for bedside fever management strategies in the neuro‑ICU.
Study design
The NEUROTHERM study is a prospective, randomized, double‑blind, placebo‑controlled pharmacodynamic trial conducted in a neuro‑intensive care setting. Eligible patients had acute brain injury and active fever defined as intracerebral temperature ≥38.5°C for longer than 30 minutes and were already monitored with an intraparenchymal pressure sensor that included a thermal probe.
Interventions and monitoring
Participants were randomized to receive a single intravenous administration of paracetamol (dose unspecified in the abstract) or placebo. Cerebral temperature and systemic temperature were recorded every 10 minutes for 6 hours after the injection. Hemodynamic variables were recorded to capture safety signals.
Primary endpoint
The primary endpoint was the difference in mean cerebral temperature over the 6‑hour post‑treatment period between the paracetamol and placebo groups.
Key findings
The trial enrolled 99 patients (mean age 55 ± 13 years; 24% female): 49 were randomized to paracetamol and 50 to placebo. Main results reported in the abstract are:
Primary outcome
– Mean cerebral temperature over 6 hours was significantly lower in the paracetamol group than in the placebo group: 38.4 ± 0.5°C versus 39.0 ± 0.5°C (p < 0.001). The absolute mean difference was 0.6°C in favor of paracetamol.
Time below threshold
– The median duration with cerebral temperature <38.5°C was 215 minutes (interquartile range 0–290) in the paracetamol group compared with 0 minutes (0–5) in the placebo group (p < 0.001). This indicates that paracetamol produced a clinically appreciable period during which cerebral hyperthermia was mitigated.
Responder analysis
– Approximately 30% of patients in the paracetamol arm were classified as nonresponders. Among responders, paracetamol produced a larger mean CT reduction of about 1.0°C, indicating heterogeneity in treatment effect.
Systemic versus cerebral temperature
– In both groups the cerebral temperature was higher than systemic temperature: average CT 38.7 ± 0.6°C vs. ST 38.4 ± 0.6°C (p < 0.001). The CT–ST gradient was consistently ≈0.3°C, highlighting that peripheral or bladder/core readings underestimate cerebral warmth.
Safety and physiologic effects
– Paracetamol was associated with a modest decrease in systolic arterial pressure and heart rate; no other significant adverse physiologic effects were reported in the abstract. The trial was not designed to evaluate clinical outcomes (e.g., neurological recovery, mortality) or hepatic safety with repeated dosing.
Interpretation
NEUROTHERM provides the first randomized, placebo‑controlled demonstration that a single intravenous dose of paracetamol lowers cerebral temperature in febrile brain‑injured patients. The overall mean reduction of 0.6°C over 6 hours is modest but clinically relevant because even small reductions in brain temperature may reduce cerebral metabolic demand and secondary injury processes. The finding that CT exceeds ST by roughly 0.3°C reinforces the concept that systemic temperature measurements can underrepresent cerebral hyperthermia; clinicians should be cautious when using peripheral sites to infer cerebral temperature status in neurocritical care.
Clinical implications
– Paracetamol is an appropriate first‑line pharmacologic intervention for fever control in brain‑injured patients when the goal is to limit cerebral temperature elevation. A single IV dose provided several hours of control in many patients, which can be helpful as part of a stepwise fever management algorithm.
– Expect variability: roughly one‑third of patients did not respond to a single dose. Nonresponsiveness suggests the need for multimodal strategies (repeat dosing per safe schedules, physical cooling, or invasive cooling devices) in refractory cases.
– Because CT often exceeds ST, clinicians should not assume adequate cerebral temperature control based on peripheral temperature alone. Where feasible, targeted intracerebral monitoring provides more precise physiologic targets, although it is invasive and limited to selected patients.
– The modest hemodynamic effects observed underscore the need to monitor blood pressure and heart rate after paracetamol in unstable patients, particularly those with tenuous cerebral perfusion pressure.
Mechanistic considerations
Paracetamol acts centrally to reduce the hypothalamic setpoint via inhibition of prostaglandin E2 synthesis (likely through central COX‑dependent and COX‑independent pathways) and possibly via serotonergic and endocannabinoid mechanisms (Graham and Scott, 2005). In the setting of brain injury, blood‑brain barrier disruption may alter central drug penetration, potentially affecting pharmacodynamics. The observed heterogeneity in response could reflect differences in injury type, blood‑brain barrier integrity, baseline metabolic rate, or concurrent sedative and vasoactive treatments.
Limitations
– The trial evaluated a single intravenous dose of paracetamol and followed patients for 6 hours; it does not inform the effects of repeated dosing, scheduled antipyresis, or combined modalities over days when fever recurs.
– Participants were a selected population already undergoing intracerebral monitoring, which may limit generalizability to all brain‑injured patients.
– The study was pharmacodynamic and not powered or designed to assess clinical outcomes such as neurological recovery, ICU length of stay, or mortality. Therefore, the relationship between the observed reductions in CT and patient‑centered outcomes remains unknown.
– The paracetamol dose and specific responder criteria are not detailed in the abstract; full protocol details from the published manuscript should be consulted for implementation considerations.
Expert commentary and guideline context
Current practice guidelines for severe traumatic brain injury and general neurocritical care emphasize avoidance of fever, although specific recommendations about antipyretic choice are pragmatic rather than evidence‑based. The Brain Trauma Foundation guidelines (Carney et al., 2017) recommend control of fever but do not endorse a single pharmacologic agent as superior. NEUROTHERM supplies randomized pharmacodynamic evidence supporting paracetamol’s role as an initial antipyretic in monitored neuro‑ICU patients, while also signaling that paracetamol alone may be insufficient for a substantial subset of patients.
Future directions
Key unanswered questions include whether repeated or scheduled paracetamol dosing achieves sustained cerebral temperature control, whether combining paracetamol with surface or intravascular cooling improves effectiveness or outcomes, and whether cerebral temperature reductions translate into improved neurologic outcomes. Future randomized trials should: (1) evaluate repeated dosing strategies and safety (including hepatic endpoints), (2) compare paracetamol versus or in combination with physical cooling modalities, and (3) be powered to test effects on clinically meaningful outcomes such as functional recovery and mortality.
Conclusion
The NEUROTHERM randomized pharmacodynamic trial demonstrates that a single intravenous dose of paracetamol produces a modest but statistically significant reduction in cerebral temperature in febrile brain‑injured patients and maintains CT below 38.5°C for a median of approximately 3.6 hours compared with placebo. Cerebral temperature was consistently higher than systemic temperature, emphasizing the limits of peripheral monitoring for detecting cerebral hyperthermia. Paracetamol is a reasonable first‑line antipyretic in the neuro‑ICU, but clinicians should anticipate incomplete response in a sizeable minority and be prepared to escalate to combination or physical cooling strategies when needed. Larger trials that assess repeated dosing, multimodal approaches, and patient‑centered outcomes are warranted.
Funding and trial registration
Funding sources and trial registration were not provided in the abstract supplied here. Readers should consult the full published manuscript (de Mesmay et al., Crit Care Med. 2025) for detailed funding and registration information.
References
1. de Mesmay M, Geral L, Gregoire C, Roy M, Welschbillig S, Le Cossec C, Engrand N. Effect of Paracetamol on Cerebral Temperature in Febrile Brain‑Injured Patients. The NEUROTHERM Study: A Randomized Controlled Pharmacodynamic Trial. Crit Care Med. 2025 Nov 11. doi: 10.1097/CCM.0000000000006951. PMID: 41217349.
2. Carney N, Totten AM, O’Reilly C, et al.; Brain Trauma Foundation. Guidelines for the Management of Severe Traumatic Brain Injury, 4th Edition. Neurosurgery. 2017;80(1):6–15. doi:10.1227/NEU.0000000000001432.
3. Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther. 2005;12(1):46–55. doi:10.1097/01.mjt.0000152988.07666.ef.
