Pathophysiological characterization of traumatic brain injury using novel analytical methods

Severity of traumatic brain injury is usually classified by Glasgow coma scale (GCS) as “mild”, "moderate" or "severe’, which does not capture the heterogeneity of the disease. According to current guidelines, intracranial pressure (ICP) should not exceed 22 mmHg, with no further recommendations concerning individualization or tolerable duration of intracranial hypertension. The aims of this thesis were to identify subgroups of patients beyond characterization using GCS, and to investigate the impact of duration and magnitude of intracranial hypertension on outcome, using data from the observational prospective study Collaborative European neurotrauma effectiveness research in TBI (CENTER-TBI).

To investigate the temporal aspect of tolerable ICP elevations, we examined the correlation between dose of ICP and outcome represented by 6-month Glasgow outcome scale extended (GOSE). ICP dose was represented both by the number of events above thresholds for ICP magnitude and duration and by area under the ICP curve (i.e., “pressure time dose” (PTD)). A variation in tolerable ICP thresholds of 18 mmHg +/- 4 mmHg (2 standard deviations (SD)) for events with duration longer than five minutes was identified using a bootstrapping technique. PTD was correlated to both mortality and unfavorable outcome.

A cerebrovascular autoregulation (CA) dependent ICP tolerability was identified. If CA was impaired, no tolerable ICP magnitude and duration thresholds were identified, while if CA was intact, both 19 mmHg for 5 minutes or longer and 15 mmHg for 50 minutes or longer were correlated to worse outcome. While no significant difference in PTD was seen between favorable and unfavorable outcome if CA was intact, there was a significant difference if CA was impaired. In a multivariable analysis, PTD did not remain a significant predictor of outcome when adjusting for other known predictors in TBI. In a causal inference analysis, both cerebrovascular autoregulation status and ICP-lowering therapies represented by the therapy intensity level (TIL) have a directional relationship with outcome. However, no direct causal relationship of ICP towards outcome was found.

By applying an unsupervised clustering method, we identified six distinct admission clusters defined by GCS, lactate, oxygen saturation (SpO2), creatinine, glucose, base excess, pH, PaCO2, and body temperature. These clusters can be summarized in clinical presentation and metabolic profile. When clustering longitudinal features during the first week in the intensive care unit (ICU), no optimal number of clusters could be seen. However, glucose variation, a panel of brain biomarkers, and creatinine consistently described trajectories. Although no information on outcome was included in the models, both admission clusters and trajectories showed clear outcome differences, with mortality from 7 to 40% in the admission clusters and 4 to 85% in the trajectories. Adding cluster or trajectory labels to the established outcome prediction IMPACT model significantly improved outcome predictions.

The results in this thesis support the importance of cerebrovascular autoregulation status as it was found that CA status was more informative towards outcome than ICP magnitude and duration. There was a variation in tolerable ICP intensity and duration dependent on whether CA was intact. Distinct clusters defined by GCS and metabolic profiles related to outcome suggest the importance of an extracranial evaluation in addition to GCS in TBI patients. Longitudinal trajectories of TBI patients in the ICU are highly characterized by glucose variation, brain biomarkers and creatinine.

List of scientific papers

I. Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study. Åkerlund CA, Donnelly J, Zeiler FA, Helbok R, Holst A, Cabeleira M, Güiza F, Meyfroidt G, Czosnyka M, Smielewski P, Stocchetti N, Ercole A, Nelson DW. PLoS ONE. 2020;15(12 December):1-20.
https://doi.org/10.1371/journal.pone.0243427

II. Clustering Identifies Endotypes of Traumatic Brain Injury in an Intensive Care Cohort: A CENTER-TBI Study. Åkerlund, Cecilia A I, Anders Holst, Nino Stocchetti, Ewout Steyerberg, David K Menon, Ari Ercole, David W Nelson, and CENTER-TBI Participants and investigators. Critical Care. 26, no. 228 (07 2022): 1–15.
https://doi.org/10.1186/s13054-022-04079-w

III. Clinical trajectory subphenotypes of severe traumatic brain injury: The importance of protein biomarkers and glucose variation – a CENTERTBI study. Åkerlund CAI, Holst A, Bhattacharyay S, Stocchetti N, Steyerberg EW, Smielewski P, Menon DK, Ercole A, Nelson DW. [Submitted]

IV. Causal relationships of intracranial pressure, cerebrovascular reactivity, interventions, and outcome in severe traumatic brain injury – a CENTERTBI high-resolution sub-study. Åkerlund CAI, Holst A, Beqiri E, Placek M, Smielewski P, Ercole A, Nelson DW. [Manuscript]