Feasibility and Safety of Targeting Neutral vs Liberal Fluid Balance in Traumatic Brain Injured Patients- LIMIT-TBI Trial (LIMIT-TBI)
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.
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
Description détaillée
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.
Type d'étude
Inscription (Estimé)
Phase
- Phase 2
Contacts et emplacements
Coordonnées de l'étude
- Nom: Fabio Silvio Taccone, MD, PhD
- Numéro de téléphone: +32 2 555 33 95
- E-mail: fabio.taccone@hubruxelles.be
Lieux d'étude
-
-
-
Brussels, Belgique, 1070
- Recrutement
- Erasme University Hospital
-
Contact:
- Fabio Silvio Taccone, MD,Phd
- Numéro de téléphone: +32 2 555 33 95
- E-mail: fabio.taccone@hubruxelles.be
-
-
-
-
-
Genova, Italie, 16132
- Recrutement
- IRCCS Ospedale Policlinico San Martino
-
Contact:
- Chiara Robba, MD
- Numéro de téléphone: +3910 555 4970
- E-mail: chiara.robba@unige.it
-
Roma, Italie, 00168
- Recrutement
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS
-
Contact:
- Anselmo Caricato, MD
- Numéro de téléphone: +396 3015 4490
- E-mail: anselmo.caricato@unicatt.it
-
-
Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
- Adulte
- Adulte plus âgé
Accepte les volontaires sains
La description
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
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Randomisé
- Modèle interventionnel: Affectation parallèle
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
|---|---|
|
Expérimental: Neutral Fluid Balance Strategy
Participants randomized to the experimental arm will receive a protocolized fluid management strategy targeting a neutral fluid balance (0 ± 500 mL per day) during the first 5 days following ICU admission. All fluid inputs (intravenous fluids, medications, enteral nutrition) and outputs (urine, drains, gastrointestinal losses, etc.) will be strictly monitored and included in the daily balance calculation. Fluid administration will be minimized, and no routine maintenance fluids will be administered unless required to ensure a minimum daily intake of approximately 1 L (including medications and nutrition). If the daily fluid balance exceeds ±500 mL, adjustments will be made in subsequent days by reducing fluid administration and/or introducing diuretics to achieve cumulative neutrality. Hemodynamic targets (mean arterial pressure ≥70 mmHg, systolic arterial pressure ≥100 mmHg, and/or cerebral perfusion pressure ≥60 mmHg) will be maintained using vasopressors (e.g., norepinephrine) |
Protocolized strategy targeting a daily fluid balance of 0 ± 500 mL for 5 days using restricted fluids, diuretics, and vasopressors to maintain hemodynamic and cerebral perfusion targets.
|
|
Aucune intervention: Standard of Care Fluid Management
Participants randomized to the control arm will receive standard fluid management according to local ICU practice and clinician judgment. Intravenous fluids may be administered as maintenance therapy if part of local protocols, and to correct hypovolemia, dehydration, electrolyte imbalances, or ongoing losses. Hemodynamic targets, including cerebral perfusion pressure, will be achieved using fluids and/or vasopressors at the discretion of the treating clinician, without a predefined protocol for fluid balance. Fluid balance will be monitored but no specific target for neutrality will be enforced. |
Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Feasibility of achieving a neutral daily fluid balance
Délai: At 5 days after randomisation
|
Proportion of patients achieving a mean daily fluid balance within 0 ± 500 mL during the 5 days after ICU admission - mean daily fluid balance will be measured at day 5 as the mean of the fluid balances of the 5 previous days
|
At 5 days after randomisation
|
Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Incidence of systemic organ complications
Délai: ICU discharge
|
Incidence of new organ dysfunction or complications during ICU stay.
|
ICU discharge
|
|
Cerebral perfusion pressure (CPP)
Délai: From randomisation to day 5 after randomisation
|
Mean and daily cerebral perfusion pressure during ICU stay.
|
From randomisation to day 5 after randomisation
|
|
Daily fluid balance and fluid input
Délai: From randomisation to day 5 after randomisation
|
Mean daily fluid balance and total fluid input during the first 5 days
|
From randomisation to day 5 after randomisation
|
|
Vasopressor and diuretic use
Délai: ICU discharge
|
Total and daily dose of vasopressors and diuretics during ICU stay.
|
ICU discharge
|
|
Vasopressor-free days
Délai: From randomisation to day 28 after randomisation
|
Number of days alive and free from vasopressor support.
|
From randomisation to day 28 after randomisation
|
|
Ventilator-free days
Délai: From randomisation to day 28 after randomisation
|
Number of days alive and free from invasive mechanical ventilation.
|
From randomisation to day 28 after randomisation
|
|
Therapy intensity level (TIL)
Délai: At day 5 after randomisation
|
Maximum therapy intensity level during the intervention period.
|
At day 5 after randomisation
|
|
ICU and hospital mortality
Délai: Hospital discharge
|
All-cause mortality during ICU and hospital stay.
|
Hospital discharge
|
|
Neurological outcome (GOSE)
Délai: Hospital discharge
|
Functional neurological outcome assessed by Glasgow Outcome Scale Extended.
|
Hospital discharge
|
|
Long-term mortality
Délai: 180 days after randomization
|
All-cause mortality at follow-up.
|
180 days after randomization
|
|
Long-term neurological outcome (GOSE)
Délai: 180 days after randomization
|
Functional neurological outcome assessed by Glasgow Outcome Scale Extended.
Scale 1 to 8, 1= dead; 8=good recovery no social and mental deficits
|
180 days after randomization
|
Collaborateurs et enquêteurs
Parrainer
Collaborateurs
Publications et liens utiles
Publications générales
- Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J, Wright DW, Ghajar J. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017 Jan 1;80(1):6-15. doi: 10.1227/NEU.0000000000001432.
- Majdan M, Plancikova D, Brazinova A, Rusnak M, Nieboer D, Feigin V, Maas A. Epidemiology of traumatic brain injuries in Europe: a cross-sectional analysis. Lancet Public Health. 2016 Dec;1(2):e76-e83. doi: 10.1016/S2468-2667(16)30017-2. Epub 2016 Nov 29.
- Wiegers EJA, Lingsma HF, Huijben JA, Cooper DJ, Citerio G, Frisvold S, Helbok R, Maas AIR, Menon DK, Moore EM, Stocchetti N, Dippel DW, Steyerberg EW, van der Jagt M; CENTER-TBI; OzENTER-TBI Collaboration Groups. Fluid balance and outcome in critically ill patients with traumatic brain injury (CENTER-TBI and OzENTER-TBI): a prospective, multicentre, comparative effectiveness study. Lancet Neurol. 2021 Aug;20(8):627-638. doi: 10.1016/S1474-4422(21)00162-9.
- Oddo M, Poole D, Helbok R, Meyfroidt G, Stocchetti N, Bouzat P, Cecconi M, Geeraerts T, Martin-Loeches I, Quintard H, Taccone FS, Geocadin RG, Hemphill C, Ichai C, Menon D, Payen JF, Perner A, Smith M, Suarez J, Videtta W, Zanier ER, Citerio G. Fluid therapy in neurointensive care patients: ESICM consensus and clinical practice recommendations. Intensive Care Med. 2018 Apr;44(4):449-463. doi: 10.1007/s00134-018-5086-z. Epub 2018 Mar 2.
- Messina A, Bakker J, Chew M, De Backer D, Hamzaoui O, Hernandez G, Myatra SN, Monnet X, Ostermann M, Pinsky M, Teboul JL, Cecconi M. Pathophysiology of fluid administration in critically ill patients. Intensive Care Med Exp. 2022 Nov 4;10(1):46. doi: 10.1186/s40635-022-00473-4.
- Clifton GL, Miller ER, Choi SC, Levin HS. Fluid thresholds and outcome from severe brain injury. Crit Care Med. 2002 Apr;30(4):739-45. doi: 10.1097/00003246-200204000-00003.
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude (Réel)
Achèvement primaire (Estimé)
Achèvement de l'étude (Estimé)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Réel)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Mots clés
Termes MeSH pertinents supplémentaires
Autres numéros d'identification d'étude
- SRB2023231
Plan pour les données individuelles des participants (IPD)
Prévoyez-vous de partager les données individuelles des participants (DPI) ?
Informations sur les médicaments et les dispositifs, documents d'étude
Étudie un produit pharmaceutique réglementé par la FDA américaine
Étudie un produit d'appareil réglementé par la FDA américaine
Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .