Use and impact of high intensity treatments in patients with traumatic brain injury across Europe: a CENTER-TBI analysis

Abstract

Purpose: To study variation in, and clinical impact of high Therapy Intensity Level (TIL) treatments for elevated intracranial pressure (ICP) in patients with traumatic brain injury (TBI) across European Intensive Care Units (ICUs).

Methods: We studied high TIL treatments (metabolic suppression, hypothermia (< 35 °C), intensive hyperventilation (PaCO₂ < 4 kPa), and secondary decompressive craniectomy) in patients receiving ICP monitoring in the ICU stratum of the CENTER-TBI study. A random effect logistic regression model was used to determine between-centre variation in their use. A propensity score-matched model was used to study the impact on outcome (6-months Glasgow Outcome Score-extended (GOSE)), whilst adjusting for case-mix severity, signs of brain herniation on imaging, and ICP.

Results: 313 of 758 patients from 52 European centres (41%) received at least one high TIL treatment with significant variation between centres (median odds ratio = 2.26). Patients often transiently received high TIL therapies without escalation from lower tier treatments. 38% of patients with high TIL treatment had favourable outcomes (GOSE ≥ 5). The use of high TIL treatment was not significantly associated with worse outcome (285 matched pairs, OR 1.4, 95% CI [1.0-2.0]). However, a sensitivity analysis excluding high TIL treatments at day 1 or use of metabolic suppression at any day did reveal a statistically significant association with worse outcome.

Conclusion: Substantial between-centre variation in use of high TIL treatments for TBI was found and treatment escalation to higher TIL treatments were often not preceded by more conventional lower TIL treatments. The significant association between high TIL treatments after day 1 and worse outcomes may reflect aggressive use or unmeasured confounders or inappropriate escalation strategies.

Take home message: Substantial variation was found in the use of highly intensive ICP-lowering treatments across European ICUs and a stepwise escalation strategy from lower to higher intensity level therapy is often lacking. Further research is necessary to study the impact of high therapy intensity treatments.

Trial registration: The core study was registered with ClinicalTrials.gov, number NCT02210221, registered 08/06/2014, https://clinicaltrials.gov/ct2/show/NCT02210221?id=NCT02210221&draw=1&rank=1 and with Resource Identification Portal (RRID: SCR_015582).

Keywords: Barbiturates; Decompressive craniectomy; Hyperventilation; Hypothermia; Therapy intensity level; Traumatic brain injury.

Fig. 1

Flowchart: patient inclusion. This flowchart is showing the inclusion of high TIL patients. High TIL patients were defined as patients receiving any treatment during ICU stay representing maximum therapy intensity of the TIL scale: Barbiturates for metabolic suppression, (secondary) decompressive craniectomy, intensive hyperventilation to PaCO2 < 4 kPa, and hypothermia < 35 °C at any point during their ICU stay

Fig. 2

Between-centre variation in high TIL use. This figure shows the between-centre variation in the use of high TIL (Therapy Intensity Level) treatment. The use of high TIL per centre was adjusted for case-mix severity, brain herniation on imaging, maximum ICP value at the day of the start of high TIL treatment and random variation per centre with a random effects logistic regression model. For each centre, the random effect with corresponding 95% CI is plotted (average effect is log odds of zero). The MOR reflects the odds of high TIL treatment between two randomly selected centres for patients with the same case-mix severity (a higher MOR reflects larger between-centre variation) The MOR represents the median odds ratio; the higher the MOR the larger the between-centre variation (a MOR of 1 reflects no variation)

Fig. 3

Definitions of aggressiveness. This figure illustrates the concordance between two definitions to identify aggressiveness of centers. On the x-axis is the definition of aggressiveness according to previous studies: the percentage of patients receiving ICP monitoring according to the BTF guidelines (GCS < 8 and abnormal CT, or normal CT and 2 or more of the following: hypotension, age > 40 years, unilateral or bilateral motor posturing, or systolic blood pressure (BP) < 90 mmHg). This percentage ICP monitoring was calculated in the ICU database (including all patients). On the y-axis is the definition of aggressiveness according to our study: the random effects of high TIL treatment per centers (log odds of receiving high TIL treatment). The upper right quadrant shows the centers that are both identified as aggressive by the previous definition (threshold 50% ICP monitoring) and the definition in our study (threshold random effect of zero).The lower left quadrant shows the centers that are identified as non-aggressive centers by both definitions. The two other quadrants show a discrepancy between the definitions of aggressiveness. Overall, there is no relationship between aggressiveness defined using ICP monitoring rates and actual use of aggressive therapies for ICP control

Fig. 4

Functional outcome at 6 months. This figure shows the functional outcome (GOSE) at 6 months for patients who receive low therapy and high therapy intensity. GOSE 1: death, 2: vegetative state, 3: severe disability lower, 4: severe disability upper, 5: moderate disability lower, 6: moderate disability upper, 7: good recovery lower, 8: good recovery upper. Patients in categories (2) and (3) on the GOSE were combined in a single category. GOSE: Glasgow Outcome Scale Extended, TIL: Therapy Intensity Level were combined in a single category. GOSE: Glasgow Outcome Scale Extended, TIL: Therapy Intensity Level