Towards causal relationships of intracranial pressure, cerebrovascular reactivity, interventions and outcome in severe traumatic brain injury – a CENTER-TBI high-resolution sub-study

Abstract

Background: Most available evidence for treatment and outcome prediction in traumatic brain injuries (TBI) is derived from observational studies. Such association studies provide limited evidence for the causality of relationships. Whilst randomized controlled trials are appropriately regarded as the gold-standard for causal inference, there are many domains where such experimental approaches are not feasible. During the last decades however, mathematical methods have been developed to infer causal relationships from observational data. This study aims to investigate causal relations of systemic and cerebral physiological parameters, ICP lowering interventions and outcome in patients with severe TBI. Methods: Patients with severe TBI enrolled in the prospective observational Collaborative European neurotrauma effectiveness research in TBI (CENTER-TBI) high resolution sub-study group were included (n=201). We applied a causal inference algorithm to determine causal relations between the first week post injury mean of values of intracranial pressure (ICP), cerebrovascular reactivity (PRx), cerebral perfusion pressure (CPP), heart rate, oxygen saturation, arterial partial pressure of carbon dioxide, ICP lowering therapies (represented by the therapy intensity level (TIL) score) and 6-month outcome represented by Glasgow outcome scale extended (GOSE). Results: The median age was 51.5 years (interquartile range (IQR) 31-64), 158 were men (77.5%) and median GOSE at 6 months was 3 (IQR 3-5). PRx and TIL score were the only features identified as directly related to outcome in this analysis (r=-0.19 (p=0.003), and r=-0.20 (p=0.002), respectively). Significant correlations between ICP and CPP (r=-0.62, p<0.0001), ICP and PRx (r=0.31, p<0.001), PRx and heart rate (r=0.17, p=0.007), and PaCO2 and TIL score (r=-0.19, p=0.004) were identified after conditioning on triples of the other features.