For secondary outcomes, linear mixed models were used with group effect, time effect and interaction between time effect and group effect. We first investigated the interaction between time effect and group effect. For the values with no significant interaction, the mean difference citation between groups within the study period was provided. For the value with a significant interaction between time effect and group effect, comparisons were performed independently and P values were calculated at each time point. Residual analysis was used to assess the appropriateness of the models (including normality and homoscedasticity). Nonparametric data are expressed as medians and interquartile ranges (IQRs). Categorical data are expressed as numbers and percentages. ��2 test, Fisher’s exact test and Wilcoxon rank-sum test were used as appropriate.

A subgroup analysis considering severe TBI patients was performed a posteriori using the same analytical strategy. Regarding ICP evolution, subgroup analysis considering the 15 patients with ICH was performed. All statistical tests were two-sided. Statistical analyses were performed using SAS 9.1 statistical software (SAS Institute, Cary, NC, USA).ResultsStudy populationOf the 42 patients included, 41 were included in the ITT analysis (one consent withdrawal) and 40 were included in the FAS analysis (exclusion of one patient who received HSS infusion within the first six hours; Figure Figure1).1). Demographic data are provided in Table Table22 (see Additional file, Table S1, for the demographics of the FAS population).

The total volume of fluid infusion was not altered by study group (Table (Table3).3). The total amount of chloride infusion was lower in the balanced group than in the saline group (median 744 mmol (IQR = 572 to 952) and median 918 mmol (IQR = 689 to 1,148), respectively; P = 0.014) (Table (Table3).3). Two patients in the saline group and one patient in the balanced group received one bolus of 500 ml of colloid diluted in a saline solution (Gelofusine; B Braun Medical) out of the study protocol, and data from these patients were kept in the statistical analysis.Figure 1Flowchart of the study. GCS: Glasgow Coma Scale score, FAS: full analysis set; HES: hydroxyethyl starch; HSS: hypertonic saline solution, SAH: subarachnoid haemorrhage, TBI: traumatic brain injury, WFNS: World Federation of Neurological Societies.Table 2Baseline characteristicsaTable 3Fluid administration within the first 48 hoursEfficacy outcomesIn the ITT population, 19 patients (90%) in the saline group and 10 patients (50%) in Batimastat the balanced group had hyperchloraemic acidosis within the first 48 hours (P = 0.004).