Effect of Continuous Infusion of Hypertonic Saline vs Standard Care on 6-Month Neurological Outcomes in Patients With Traumatic Brain Injury: The COBI Randomized Clinical Trial

Abstract

Importance: Fluid therapy is an important component of care for patients with traumatic brain injury, but whether it modulates clinical outcomes remains unclear.

Objective: To determine whether continuous infusion of hypertonic saline solution improves neurological outcome at 6 months in patients with traumatic brain injury.

Design, setting, and participants: Multicenter randomized clinical trial conducted in 9 intensive care units in France, including 370 patients with moderate to severe traumatic brain injury who were recruited from October 2017 to August 2019. Follow-up was completed in February 2020.

Interventions: Adult patients with moderate to severe traumatic brain injury were randomly assigned to receive continuous infusion of 20% hypertonic saline solution plus standard care (n = 185) or standard care alone (controls; n = 185). The 20% hypertonic saline solution was administered for 48 hours or longer if patients remained at risk of intracranial hypertension.

Main outcomes and measures: The primary outcome was Extended Glasgow Outcome Scale (GOS-E) score (range, 1-8, with lower scores indicating worse functional outcome) at 6 months, obtained centrally by blinded assessors and analyzed with ordinal logistic regression adjusted for prespecified prognostic factors (with a common odds ratio [OR] >1.0 favoring intervention). There were 12 secondary outcomes measured at multiple time points, including development of intracranial hypertension and 6-month mortality.

Results: Among 370 patients who were randomized (median age, 44 [interquartile range, 27-59] years; 77 [20.2%] women), 359 (97%) completed the trial. The adjusted common OR for the GOS-E score at 6 months was 1.02 (95% CI, 0.71-1.47; P = .92). Of the 12 secondary outcomes, 10 were not significantly different. Intracranial hypertension developed in 62 (33.7%) patients in the intervention group and 66 (36.3%) patients in the control group (absolute difference, -2.6% [95% CI, -12.3% to 7.2%]; OR, 0.80 [95% CI, 0.51-1.26]). There was no significant difference in 6-month mortality (29 [15.9%] in the intervention group vs 37 [20.8%] in the control group; absolute difference, -4.9% [95% CI, -12.8% to 3.1%]; hazard ratio, 0.79 [95% CI, 0.48-1.28]).

Conclusions and relevance: Among patients with moderate to severe traumatic brain injury, treatment with continuous infusion of 20% hypertonic saline compared with standard care did not result in a significantly better neurological status at 6 months. However, confidence intervals for the findings were wide, and the study may have had limited power to detect a clinically important difference.

Trial registration: ClinicalTrials.gov Identifier: NCT03143751.

Figure 1.. Flow of Participants Through the Continuous Hyperosmolar Therapy for Traumatic Brain-Injured Patients (COBI) Trial

Data for the primary outcome at 6 months were available for 359 patients (97%; 181 in the continuous hyperosmolar therapy group and 178 in the control group). Data at 3 months were available for 175 and 176 patients, respectively.

Figure 2.. Physiological Measurements During the First 7 Days

Box plots show observed data (no imputation if not monitored at the indicated time). A, B, and D, Horizontal lines within boxes indicate medians; box tops and bottoms, IQR; whiskers, the furthest value within 1.5× IQR; and dots, outliers. The mean differences attributed to the treatment effects calculated by linear mixed-effects models taking into account the effects of time and treatment were 13.50 (95% CI, 10.07-16.93) mmol/L for blood osmolarity, 7.38 (95% CI, 6.35-8.41) mmol/L for blood sodium, and −1.3 (95% CI, −2.8 to 0.3) mm Hg for intracranial pressure. C, Patients without invasive intracranial pressure monitoring were considered free of intracranial hypertension. The odds ratio of the treatment effect calculated by logistic mixed-effects models accounting for time and treatment effects was 0.07 (95% CI, 0.02-0.26).

Figure 3.. Outcomes at 6 Months

A, Distribution of Extended Glasgow Outcome Scale (GOS-E) scores at 6 months. Different colors correspond to GOS-E scores. The connecting line between the 2 study groups indicates the GOS-E outcome dichotomization (poor vs favorable). B, Kaplan-Meier estimates of the unadjusted probability of death at 6 months in patients receiving continuous infusion of 20% hypertonic saline solution or standard care. The estimate adjusted probability of death at 6 months is a hazard ratio of 0.79 (95% CI, 0.48-1.28). The median observation time was 180 days (interquartile range, 180-180 days) in both treatment groups. Graphical assessment indicates that the proportionality assumption was met.