Editorial 

September 25, 2024

Feasibility of Fever Prevention in Vascular Brain Injury

Teresa May, Lori Shutter

JAMA. Published online September 25, 2024. doi:10.1001/jama.2024.16415

How to manage fever in the neurocritical care unit in patients with acute stroke was clearly a question in need of an answer. The association of fever burden with poor outcome for diverse conditions in the neurocritical care unit has been well described.^1-3 However, distinguishing association from causation has been difficult, with prior randomized trials of hypothermia in various neurologic injuries showing neither clear benefit nor harm.^4-6 Additionally, while it might seem nuanced to those unfamiliar with this field, fever control requires an entirely different approach from interventions to achieve hypothermia. Guidelines are available to support the logistics of providing this therapy⁷ and the neurocritical care community who manage these patients have gained expertise in temperature control over the past 20 years, while testing targeted temperature management in a wide variety of neurologic injuries, including cardiac arrest, traumatic brain injury, severe stroke, and spinal cord injury.

So it was with notable enthusiasm that the neurocritical care community greeted the news of the funding and launch of the Impact of Fever Prevention in Brain Injured Patients (INTREPID) Study on a cool afternoon in Waikoloa, Hawaiʻi, in October 2017. INTREPID was a pragmatic trial with an elegant simplicity to the trial design: test the same concept in a broad population of neurocritical care patients with vascular brain injury and efficiently answer the same question once and for all for patients with ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The trial design included reasonable approaches to the nuances of controlling shivering induced by cooling, how different subtypes of patients might respond to the intervention, and how soon treatment should be started.

In this issue of JAMA, Greer et al⁸ report the results of the INTREPID study that randomized critically ill patients with stroke in 43 different intensive care units to fever prevention (targeting 37.0 °C) vs standard tiered fever treatment on occurrence of fever greater than 38 °C. INTREPID did indeed show that centers were able to maintain temperature at a more normal range in the fever prevention group. The primary outcome of mean daily fever burden was significantly lower in the actively treated group, despite increased shivering that appears to have been well tolerated. The temperature graphs visually show modest separation of groups for the first 5 days, although separation diminished after day 6 and the fever prevention group appears to have had a higher fever burden in days 6 to 9.⁸ Despite this, the interim analysis performed of 686 patients of a planned enrollment of 1176 patients showed futility for the secondary functional neurologic outcome at 3 months for all stroke subtypes. Consolation regarding this neutral result for functional clinical outcome is that the trial is currently the largest temperature modulation study of critically ill patients with stroke to date. The data reported in the article and supplement are robust, and these data can be used to gain additional insights regarding investigations into temperature control in the neurocritical care unit. There is clearly much more to be learned from both the investigators and data they have curated during this study.

The INTREPID team should also be commended for supporting their clinical trial through the COVID-19 pandemic. All clinical trialists who had their scientific endeavors upended by unexpected and widespread clinical emergencies share a special camaraderie. It is no easy task to start enrolling in a large clinical trial only to have to try to keep it afloat in the chaos of a global pandemic,⁹ and many studies started in 2019 and 2020 struggled and collapsed. Maintaining momentum (and funding) for INTREPID is a testament to the research team’s desire to answer this important question. We acknowledge with special appreciation the coordinating study team, the patients and their families who agreed to participate during this time, and the centers who endured continuing to enroll despite all the obstacles that needed to be overcome.

Since the time of the trial design, advances in clinical trials and clinical evidence generation have occurred. This is the era of big data, machine learning, phenotyping, and precision medicine. Causal inference investigation can now be a powerful tool both to address clinical questions directly or to complement clinical trial design.^10,11 Due to the heterogeneous nature of cerebrovascular disease and variability in management options, it is rare for any single intervention to achieve a 10% change in functional outcome. After decades of nonpositive pragmatic clinical trials in broad populations, focus needs to shift to studies determining which more granular patient types would benefit most from the treatment approaches and incorporating adaptive designs in clinical research. INTREPID taught us that we can prevent fever effectively and safely in a wide variety of patient populations, which was an unknown at the time the trial was designed. Given that there is now understanding that fever prevention does not benefit everyone, there is still the open question of whether it will benefit anyone. If a subcategory stroke type that benefits from temperature modulation is found in the future, it will have been because of the groundwork laid by the INTREPID trial.

Aside from the primary findings of the trial, INTREPID offers nuanced and detailed approaches to temperature modulation that is worth evaluating.¹² Clearly developed by experts in the field, not only the actively managed intervention but also the control standardized tiered approach to temperature management are sensible and would be available to most centers. Although additional treatments are likely to be incorporated in future trials, this will clearly be a starting point for both future studies and for centers looking to refine their current temperature management protocols.

So, where do we go from here? We have a clear association between fever and poor outcome but INTREPID has shown that there is no clear benefit to maintaining normothermia in all patients. Is fever simply a biomarker rather than cause of injury? Should the intervention for fever prevention be enhanced with prophylactic infection control or more effective shivering management? Can it be predicted who will experience a fever and thus focus attention on individual patients? With the pendulum swinging toward precision medicine, the next iteration of fever management in neurocritical care patients has an opportunity to refine its methods from lessons learned here.