INTREPID

Clinical Context

Fever is a common complication after acute vascular brain injuries such as ischemic stroke, intracerebral hemorrhage (ICH), and aneurysmal subarachnoid hemorrhage (aSAH). Observational studies have consistently linked fever in these patients to secondary brain injury, increased physiological stress, and worse neurological outcomes, including increased mortality and greater long-term disability. The proposed mechanisms include exacerbation of ischemic injury, increased intracranial pressure, and promotion of inflammatory cascades.

While treating established fever is standard practice, the strategy of proactively preventing fever (maintaining normothermia) to potentially mitigate these detrimental effects has been an area of active investigation. The INTREPID (Impact of Fever Prevention in Brain Injured Patients) Study aimed to determine if a strategy of active fever prevention using an automated surface temperature management device could improve functional recovery in critically ill patients with acute stroke admitted to the intensive care unit.

Patient Population

The INTREPID trial was a multicenter study that enrolled 677 critically ill adult patients (≥18 years) admitted to the ICU with a primary diagnosis of acute vascular brain injury. This included patients with:

• Acute ischemic stroke
• Spontaneous intracerebral hemorrhage
• Aneurysmal subarachnoid hemorrhage

Patients were eligible if they were expected to require an ICU stay of at least 72 hours and did not have a significant fever (defined as ≥38.0°C for more than 1 hour, or more than one instance) prior to enrollment. Exclusions comprised conditions that would confound neurological or functional assessment, a very poor premorbid prognosis, or contraindications to the cooling device or continuous core temperature monitoring.

The mean age of the participants was around 60-65 years, with a mix of stroke subtypes.

Study Design

INTREPID was a multicenter, randomized, open-label trial with blinded outcome assessment (PROBE-like design).

Protocol Details

Eligible patients were randomized 1:1 to:

• Fever Prevention Group: These patients were targeted to a core body temperature of 37.0°C for a duration of 14 days or until ICU discharge, whichever occurred first. Temperature was managed using an automated surface temperature management device (e.g., Arctic Sun). Continuous core temperature monitoring (via bladder or esophageal probe) was mandatory.
• Standard Care Group: These patients received standardized, tiered fever treatment only if their core body temperature reached 38.0°C or greater. Standard fever treatment could include pharmacological antipyretics and conventional surface cooling methods as per local ICU protocols.

Outcome Assessment

The primary outcome focused on the effectiveness of the intervention in controlling temperature. Functional outcomes were assessed at 3 months (90 days) by trained personnel blinded to the treatment allocation.

Power Analysis & Statistical Approach

The primary outcome was the daily mean fever burden. Secondary outcomes included the ordinal analysis of the modified Rankin Scale (mRS) score at 3 months. The trial was powered to detect a difference in fever burden and to assess for differences in functional outcomes.

Risk of Bias Analysis

(Content for this section needs to be added. Considerations: Open-label nature of the intervention (unavoidable), but outcome assessment was blinded. Use of automated devices, adherence to protocol, standardized fever definition.)

Results

A total of 677 patients were randomized (339 to fever prevention, 338 to standard care). Baseline characteristics were generally well-balanced.

Primary Outcome: Daily Mean Fever Burden

The strategy of active fever prevention was effective in reducing temperature:

• Fever Prevention Group: Daily mean fever burden was 0.37 (°C-hour).
• Standard Care Group: Daily mean fever burden was 0.73 (°C-hour).
  This difference was statistically significant (difference, –0.35 [95% CI, –0.51 to –0.20]; p < .001), indicating that the intervention successfully reduced the overall exposure to fever.

Secondary Outcome: Functional Outcome (mRS distribution) at 3 Months

Despite the successful reduction in fever burden, there was no significant difference in functional outcomes at 3 months between the two groups, as assessed by the ordinal analysis of the mRS score distribution:

• Adjusted common odds ratio (acOR) for improvement in the fever prevention group: 0.90 (95% CI, 0.69 to 1.17; p=0.43).

Other Secondary Outcomes

• Favorable Outcome (mRS 0-3) at 3 months: No significant difference (Fever prevention: 34.8%; Standard care: 34.0%).
• Mortality at 3 months: No significant difference (Fever prevention: 26.0%; Standard care: 28.1%).
• ICU and hospital length of stay were similar.

Safety Outcomes

Major adverse events occurred in 82.2% of participants in the fever prevention group versus 75.9% in the standard care group. Specific adverse event categories like infections, cardiac disorders, and respiratory disorders were reported and generally similar, though the overall rate was numerically higher in the intervention group.

Final Thoughts & Critical Appraisal

The INTREPID trial rigorously tested a strategy of proactive fever prevention against standard reactive fever treatment in a mixed population of critically ill patients with acute vascular brain injury. While the intervention effectively reduced fever burden, this did not translate into improved functional outcomes at 3 months.

Key takeaways:

• Fever Prevention is Achievable: Automated surface cooling devices can effectively maintain normothermia and reduce overall fever burden in neurocritical care patients.
• No Improvement in Functional Outcome: Despite reducing fever, the strategy of proactive fever prevention did not lead to better mRS scores or a higher rate of favorable outcomes at 3 months compared to standard reactive fever treatment.
• Fever as a Marker vs. Mediator: These results might suggest that while fever is strongly associated with worse outcomes (acting as a marker of injury severity or systemic inflammation), simply suppressing the fever itself may not be sufficient to alter the underlying trajectory of brain injury and recovery in this broad population. The detrimental effects associated with fever might be established very early or driven by processes not solely modifiable by temperature control alone.
• Safety: While major adverse events were broadly similar, the numerically higher overall rate in the intervention group warrants consideration, although no specific category stood out as dramatically different.
• Implications for Practice: The findings of INTREPID do not support the routine adoption of aggressive, device-based prophylactic normothermia for all critically ill stroke patients with the expectation of improving functional recovery. Standard care, including prompt treatment of fever when it occurs, remains the appropriate approach based on this evidence.

The INTREPID trial is an important contribution, demonstrating that even if a physiological target (like fever burden) is successfully modified, this doesn’t always lead to improved patient-centered outcomes. It underscores the complexity of secondary brain injury and the challenges in finding effective neuroprotective strategies.

How do we reconcile the results with other studies?

(Content for this section needs to be added, discussing INTREPID in the context of other temperature management trials in neurocritical care, the TTM trials in cardiac arrest, and the broader understanding of fever’s role in acute brain injury.)

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