Feasibility and Safety of Targeting Neutral vs Liberal Fluid Balance in Traumatic Brain Injured Patients- LIMIT-TBI Trial

Feasibility and Safety of Targeting Neutral vs Liberal Fluid Balance in Traumatic Brain Injured Patients: a Phase II Randomized Controlled Trial - LIMIT-TBI Trial

The LIMIT-TBI trial is a multicenter, international, randomized, phase II clinical trial designed to evaluate the feasibility and safety of targeting a neutral fluid balance compared to standard care in critically ill adult patients with traumatic brain injury (TBI).

Fluid therapy is a cornerstone of TBI management, but optimal fluid balance remains uncertain, with both fluid overload and restriction potentially leading to adverse outcomes. This study aims to determine whether maintaining a daily fluid balance close to zero (±500 mL) during the first 5 days of ICU admission is achievable and safe.

Participants will be randomized within 48 hours of ICU admission to either a protocolized neutral fluid balance strategy or standard care. Outcomes include feasibility of achieving the target balance, organ complications, hemodynamic parameters, ICU resource utilization, and mortality and neurological outcomes up to 6 months.

Severe traumatic brain injury (TBI) is a major cause of mortality and long-term disability worldwide and frequently requires intensive care management. In these patients, preventing secondary brain injury is essential and involves optimizing cerebral perfusion pressure (CPP), systemic hemodynamics, and organ function. Fluid therapy plays a central role in achieving these goals.

However, the optimal fluid management strategy in TBI remains unclear. Excessive fluid administration may lead to complications such as pulmonary edema and worsening cerebral edema, while restrictive strategies may increase the risk of hypovolemia and impaired cerebral perfusion. Current guidelines provide limited or no specific recommendations due to the lack of high-quality randomized evidence. Observational data suggest that a more positive fluid balance is associated with worse outcomes, but causality has not been established.

The LIMIT-TBI trial is a pragmatic, international, multicenter, randomized, unblinded, parallel-group phase II study designed to address this evidence gap. Adult patients with TBI admitted to the ICU will be randomized within 48 hours in a 1:1 ratio to either:

A neutral fluid balance strategy, targeting a daily balance of 0 mL (±500 mL) and cumulative neutrality over the first 5 days, using a protocolized approach combining fluid restriction, vasopressors, and diuretics when needed; A standard of care strategy, in which fluid administration is guided by local practice and clinician judgment.

In the intervention group, all fluid inputs (intravenous fluids, medications, and enteral nutrition) and outputs are strictly monitored. Maintenance fluids are minimized, and adjustments are made daily to achieve neutrality while maintaining adequate mean arterial pressure and cerebral perfusion pressure targets.

The primary objective is to assess the feasibility and safety of achieving a neutral fluid balance, defined as maintaining a daily balance within ±500 mL. Secondary outcomes include systemic complications, hemodynamic parameters (including CPP), fluid administration metrics, vasopressor and diuretic use, organ support-free days, and ICU/hospital mortality. Long-term outcomes include 6-month mortality and neurological status assessed using the Glasgow Outcome Scale Extended (GOSE).

A total of 88 patients will be enrolled to provide adequate power to detect differences in fluid balance between groups. Statistical analyses will include linear mixed models for repeated measures and appropriate comparative tests for secondary outcomes, with multiple imputation for missing primary endpoint data.

This trial will provide important preliminary randomized evidence on fluid management in TBI and inform the design of future large-scale trials aimed at improving outcomes in this high-risk population.

Inclusion Criteria:

• Adult patients with traumatic brain injury (isolated or associated with extracranial injuries), with or without intracranial pressure monitoring
• Admission to the intensive care unit
• Age >18 years
• Enrollment within 48 hours after ICU admission

Exclusion Criteria:

• Enrollment in another clinical trial not approved for co-enrollment
• Pregnancy or suspected pregnancy
• Concomitant hemorrhagic shock expected to require surgical treatment within 24 hours from inclusion or requiring massive transfusion protocol
• Hemodynamic instability at ICU admission, defined as heart rate >120 beats/min and systolic arterial pressure <100 mmHg despite at least 1 L of fluid resuscitation, or requirement for high-dose norepinephrine (>0.5 mcg/kg/min) or any inotropic support
• Need for continuous venovenous hemodiafiltration (CVVHDF) at admission
• Expected survival <48 hours