Physiologic Insults and Individualized Treatments in Traumatic Brain Injury*

The concept of "physiologic insults" complicating moderate and severe TBI (msTBI) is widely recognized, as is the notion that they are modifiable (1): treatment strategies targeting intracranial pressure (ICP) and cerebral perfusion pressure (CPP) have been a cornerstone of msTBI resuscitation for decades. Yet therapies focused on meeting or exceeding singular ICP and CPP thresholds may oversimplify the problem. Patients classified as msTBI are exceptionally heterogeneous and have unique physiologic profiles that evolve dynamically over time (2). There is a convergent interest in achieving greater precision in msTBI treatment, but how is this to be achieved? What might a personalized physiologic management strategy look like? One solution might reside in a consideration of cerebral pressure autoregulation. Pressure reactivity index (PRx), a moving correlation coefficient of ICP and arterial blood pressure, is commonly regarded as a pragmatic index of cerebral autoregulation (3). The relationship between PRx and systemic blood pressure is nonlinear: plotted as a function of CPP, the PRx curve describes a parabola with a minimum value that corresponds to the CPP at which autoregulation is putatively most effective, designated optimal CPP (CPPopt). PRx and CPPopt can be computed at the bedside using simple algorithms, and they have emerged as treatment targets in their own right (4). Increases in PRx and positive or negative excursions from the CPPopt, denoted as ΔCPPopt, represent deviations from optimal autoregulation and are consistently associated with secondary neurologic insults and adverse clinical outcomes (5). Studies have underscored the prognostic significance of both the magnitude and duration of elevations in PRx and ΔCPPopt with regard to outcome following msTBI (6,7). Furthermore, the distributions of PRx and CPPopt values indicate considerable variability within msTBI populations, suggesting an opportunity to individualize treatment based on patient-specific targets. Such was the primary hypothesis of a recent phase II randomized controlled trial, which found that an individualized management protocol guided by repeated assessments of CPPopt was both feasible and safe (8). Planned larger RCTs will evaluate the efficacy of this approach. In this issue of Critical Care Medicine, Svedung Wettervik et al (9) expand the exploration of how intensity and duration of physiologic insults additively and cumulatively influence TBI outcomes. Specifically, they investigate the association between four physiologic measures (ICP, CPP, PRx, and CPPopt) and six-month functional outcomes assessed with the Glasgow Outcome Scale (GOS) following msTBI. The data are displayed as color-coded heatmaps cross-referencing insult intensity and duration against GOS. Key findings are first, a confirmation of the previously reported associations between unfavorable outcome and higher intensities and durations of positive PRx and negative ΔCPPopt. Second, results indicate that positive values of PRx are additive with abnormal ICP, CPP, and CPPopt in mediating unfavorable outcomes. In a multivariable model adjusting for age and admission Glasgow Coma Scale, ICP, PRx, and ΔCPPopt below (but not ΔCPPopt above) threshold were independently associated with unfavorable GOS. This research consolidates prior studies that found that CPP below CPPopt was associated with poor outcomes (10). It is a meaningful addition to a body of research that has developed the concept of physiologic insult "dose" in msTBI (6,7). It identifies a continuum of patients with different degrees of autoregulation impairment in whom insults may be particularly deleterious. While they have previously demonstrated the heatmap visualization (11), the present study illustrates particularly well several transition points toward poor outcomes for higher insult intensities and for longer periods of positive PRx and negative ΔCPPopt. Limitations in the work are worth noting. Although the analysis is conducted on a large msTBI sample with rich neurophysiologic annotation, the cohort is from a single center and was accrued over 2 decades (2002–2022) during which significant changes in msTBI management are likely to have occurred, including a shift in some cases toward PRx- and CPPopt-guided management. Additionally, it remains unclear how such multiparameter visualizations might be deployed in real-world ICU workflows, and how their impact could be determined and measured. Although the heatmaps are conceptually appealing, the value they might bring in terms of improved decision-making remains to be determined. Studies are thus needed to understand how such tools generalize to other centers, and how they might be operationalized by clinicians. Conceivably the multi-parameter heatmap could become a component of a patient-specific "TBI dashboard" which would inform therapeutic decision-making based on individualized optimization of ICP, CPP, and PRx. The visualizations may be relevant to other physiologic data sources used in assessing cerebral autoregulation such as cerebral blood flow velocity via transcranial Doppler or cerebral oximetry via near-infrared spectroscopy (12); they might be used with other autoregulation-based indices such as the lower limit of reactivity (13), and in the evaluation of patients with other types of acute brain injury, most notably aneurysmal subarachnoid hemorrhage (14). Overall, the capacity to detect physiologic insults and map their severities against outcome probabilities is certainly of interest, yet a different approach in which physiologic insults are predicted ahead of time and, in due course, prevented, is likely to be even more impactful. In this paradigm, instances of physiologically "susceptible" patients might be viewed as latent "endotypes" whose characterization is advancing rapidly with the help of computational methods applied to high-resolution clinical and physiologic time series data (2,15).