Reply to Yang and to Xie and Wang

From the Authors:

We thank Dr. Yang and Drs. Xie and Wang for their interest in our study (1), and we appreciate the opportunity to address their comments and concerns. Regarding baseline characteristics, in patients with traumatic brain injury, the most robust predictor of outcome is the Glasgow Coma scale, just as in patients with subarachnoid hemorrhage it is the Fisher scale and in ischemic stroke it is the NIH Stroke Scale; all three scores were recorded and compared at baseline, showing no difference between the two groups. Besides, because in the present trial patients with severe brain injury with different etiologies were included, we also calculated the Acute Physiology and Chronic Health Evaluation score, which was similar at admission.

Regarding interventions in the lung-protective ventilation group, the protective ventilatory strategy implemented in our study consisted of Vt equal to 6 ml/kg predicted body weight and positive end-expiratory pressure (PEEP) equal to 8 cm H₂O, but no other measures were included, such as recruiting maneuvers. We ensured that the control group represented the standard of care, although it is true that the small differences in Vt between groups may have diluted the effect of the intervention. We acknowledge that future studies should more clearly differentiate the intervention strategies to better isolate their effects.

Regarding fixed PEEP application, we agree with the observation regarding the use of a fixed PEEP in the lung protection group. Current best practices indeed recommend individualized PEEP titration, which can optimize oxygenation and lung function on a case-by-case basis. The decision to use a fixed PEEP in our trial was based on protocol standardization, but we recognize that this may not fully reflect contemporary practices. Moving forward, future research in this area should explore the impact of titrated PEEP.

We completely agree with Dr. Xie that early termination of the trial because of funding constraints represents a limitation. We acknowledge that the statistical power of the study was reduced, and this could indeed limit the strength of our conclusions. As rightly pointed out, a larger, more adequately powered trial is necessary to fully confirm our preliminary results and to minimize the risk of a type II error. We hope that our study serves as a foundation for future research, which can address these limitations and further explore the effects of lung-protective ventilation strategies in this patient population.

Regarding the second point raised by Dr. Xie, we also recognize that the heterogeneity of brain injury etiologies may be a challenge in interpreting the results. Stratification or adjusting for the etiology of brain injury could indeed provide a more focused analysis. Future studies might benefit from performing subgroup analyses to better understand the effect of ventilation strategies on specific types of brain injuries. We share the view on the need to account for additional confounding variables such as cerebral edema and the use of osmotic therapies; indeed, in this prospective study, we recorded Glasgow Coma Scale and Acute Physiology and Chronic Health Evaluation scores at admission and the therapeutic intensity level during the ICU stay, which were all similar in both groups. With regard to the comments on long-term outcomes, we fully agree that longer-term follow-up is crucial in understanding the true impact on neurologic function and quality of life, although our 1-year follow-up period provides some insight.

Last, we appreciate the emphasis on the need for individualized care in patients with severe brain injury. As critical care physicians, we understand the delicate balance required in managing these patients, particularly the potential trade-offs between lung protection and the risk of exacerbating intracranial pressure. As highlighted, a multidisciplinary approach, involving intensivists, neurologists, neurosurgeons, and rehabilitation specialists, will be key to optimizing outcomes for these patients.