Association of mortality and neurological outcomes with hypocapnia in adult patients with acute brain injury: an updated meta-analysis.

Abstract

Carbon dioxide is a key determinant of cerebral blood flow and is needed to prevent secondary damage in neurocritical care; however, optimal targets across the heterogeneous spectrum of acute brain injury (ABI) remain to be elucidated. The aim of this study was to evaluate the association between arterial hypocapnia and mortality and neurological outcomes in adult patients with ABI. Six electronic databases were systematically searched from inception to January 2025. Observational and randomized controlled trials comparing exposure to hypocapnia, defined as an arterial partial pressure of carbon dioxide (PaCO₂) lower than 35 mmHg, and no-hypocapnia in adult patients with ABI-related conditions (including traumatic brain injury, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, central nervous system infections, brain tumors, and post-cardiac arrest encephalopathy) were included. Random-effects meta-analyses were conducted using the restricted maximum likelihood (REML) method to pool unadjusted odds ratios (ORs). The primary outcome was all-cause mortality, and the secondary outcome was the occurrence of poor neurological outcomes defined using validated scales. Prespecified subgroup analyses and meta-regression were conducted to explore sources of heterogeneity. A total of 8,637 records were identified after duplicate removal, of which 37 studies met inclusion criteria for the systematic review. Twenty-seven studies (51,373 patients) were included for mortality outcomes, and thirteen studies (3,814 patients) were included for neurological outcomes. Hypocapnia was associated with higher odds of mortality in adult patients with ABI (OR 1.29, 95% CI 1.05-1.59). Subgroup analyses demonstrated variability across ABI types, with stronger associations observed in subarachnoid hemorrhage and ischemic stroke populations. Hypocapnia was also associated with increased odds of poor neurological outcomes (OR 2.09, 95% CI 1.24-3.54), particularly in the traumatic brain injury population. Subgroup analyses suggested that the association with neurological outcomes was more consistent in studies defining exposure as severe hypocapnia (PaCO₂<32 mmHg). Arterial hypocapnia was associated with increased mortality and poor neurological outcomes in adults with acute brain injury, although the evidence is predominantly observational and limited randomized data are available. These findings underscore the need for cautious, individualized PaCO₂ management and further high-quality prospective research.