Optimal cerebrovascular reactivity thresholds for the determination of individualized intracranial pressure thresholds in traumatic brain injury: a CAHR-TBI cohort study

Critical Care volume 29, Article number: 420 (2025) Published: 06 October 2025

Abstract

It has been demonstrated that patient-specific intracranial pressure (ICP) thresholds are possible to derive using the function intersectionality between ICP and cerebrovascular reactivity (CVR). Such individualized ICP (iICP) thresholds represent a potential personalized medicine approach to neurocritical care management. However, it is currently unknown how various CVR thresholds compare in regard to deriving iICP. Here we attempt to identify the CVR thresholds that are best suited for iICP derivation. Leveraging 365 patient data sets from the CAnadian High-Resolution TBI (CAHR-TBI) Research Collaborative, iICP was derived using three ICP-based CVR indices: the pressure reactivity index (PRx); the pulse amplitude index (PAx); and the RAC index, and thresholds ranging from − 1 to + 1, in 0.05 increments. Patients were dichotomized based on 6-month outcome scores into Alive vs. Dead and Favorable vs. Unfavorable outcome. 2 × 2 tables were created for each threshold, grouping patients by outcome and whether their mean ICP was greater or less than their calculated iICP. Chi-squares were calculated for each table and subsequently plotted. The thresholds that produced the largest Chi-square values were identified as those able to derive the iICP with the greatest ability to predict outcomes. Next, Spearman rank correlation testing was used to evaluate associations between iICP, for each threshold, and measures of cerebral physiologic insult burden. With consideration of yield data, ability to predict outcome, and association with cerebral physiologic insult burden, a threshold of + 0.05 was identified for PRx. No optimal threshold could be identified for PAx or RAC.

 

Brain tissue oxygen monitoring in traumatic brain injury: part I—To what extent does PbtO2 reflect global cerebral physiology?

 

by Teodor Svedung Wettervik, Erta Beqiri, Stefan Yu Bögli, Michal Placek, Mathew R. Guilfoyle, Adel Helmy, Andrea Lavinio, Ronan O’Leary, Peter J. Hutchinson and Peter Smielewski 

 

Critical Care volume 27, Article number: 339 (2023)

 

Background

The primary aim was to explore the association of global cerebral physiological variables including intracranial pressure (ICP), cerebrovascular reactivity (PRx), cerebral perfusion pressure (CPP), and deviation from the PRx-based optimal CPP value (∆CPPopt; actual CPP-CPPopt) in relation to brain tissue oxygenation (pbtO2) in traumatic brain injury (TBI).

Methods

A total of 425 TBI patients with ICP- and pbtO2 monitoring for at least 12 h, who had been treated at the neurocritical care unit, Addenbrooke’s Hospital, Cambridge, UK, between 2002 and 2022 were included. Generalized additive models (GAMs) and linear mixed effect models were used to explore the association of ICP, PRx, CPP, and CPPopt in relation to pbtO2. PbtO2 < 20 mmHg, ICP > 20 mmHg, PRx > 0.30, CPP < 60 mmHg, and ∆CPPopt < − 5 mmHg were considered as cerebral insults.

Results

PbtO2 < 20 mmHg occurred in median during 17% of the monitoring time and in less than 5% in combination with ICP > 20 mmHg, PRx > 0.30, CPP < 60 mmHg, or ∆CPPopt < − 5 mmHg. In GAM analyses, pbtO2 remained around 25 mmHg over a large range of ICP ([0;50] mmHg) and PRx [− 1;1], but deteriorated below 20 mmHg for extremely low CPP below 30 mmHg and ∆CPPopt below − 30 mmHg. In linear mixed effect models, ICP, CPP, PRx, and ∆CPPopt were significantly associated with pbtO2, but the fixed effects could only explain a very small extent of the pbtO2 variation.

Conclusions

PbtO2 below 20 mmHg was relatively frequent and often occurred in the absence of disturbances in ICP, PRx, CPP, and ∆CPPopt. There were significant, but weak associations between the global cerebral physiological variables and pbtO2, suggesting that hypoxic pbtO2 is often a complex and independent pathophysiological event. Thus, other variables may be more crucial to explain pbtO2 and, likewise, pbtO2 may not be a suitable outcome measure to determine whether global cerebral blood flow optimization such as CPPopt therapy is successful.

 

Acute traumatic coma awakening by right median nerve electrical stimulation: a randomised controlled trial

Intensive Care Medicine (2023) Published: 13 May 2023

 

Purpose

Severe traumatic brain injury (TBI) leads to acute coma and may result in prolonged disorder of consciousness (pDOC). We aimed to determine whether right median nerve electrical stimulation is a safe and effective treatment for accelerating emergence from coma after TBI.

Methods

This randomised controlled trial was performed in 22 centres in China. Participants with acute coma at 7–14 days after TBI were randomly assigned (1:1) to either routine therapy and right median nerve electrical stimulation (RMNS group) or routine treatment (control group). The RMNS group received 20 mA, 300 μs, 40 Hz stimulation pulses, lasting 20 s per minutes, 8 h per day, for 2 weeks. The primary outcome was the proportion of patients who regained consciousness 6 months post-injury. The secondary endpoints were Glasgow Coma Scale (GCS), Full Outline of Unresponsiveness scale (FOUR), Coma Recovery Scale-Revised (CRS-R), Disability Rating Scale (DRS) and Glasgow Outcome Scale Extended (GOSE) scores reported as medians on day 28, 3 months and 6 months after injury, and GCS and FOUR scores on day 1 and day 7 during stimulation. Primary analyses were based on the intention-to-treat set.

Results

Between March 26, 2016, and October 18, 2020, 329 participants were recruited, of whom 167 were randomised to the RMNS group and 162 to the control group. At 6 months post-injury, a higher proportion of patients in the RMNS group regained consciousness compared with the control group (72.5%, n = 121, 95% confidence interval (CI) 65.2–78.7% vs. 56.8%, n = 92, 95% CI 49.1–64.2%, p = 0.004). GOSE at 3 months and 6 months (5 [interquartile range (IQR) 3–7] vs. 4 [IQR 2–6], p = 0.002; 6 [IQR 3–7] vs. 4 [IQR 2–7], p = 0.0005) and FOUR at 28 days (15 [IQR 13–16] vs. 13 [interquartile range (IQR) 11–16], p = 0.002) were significantly increased in the RMNS group compared with the control group. Trajectory analysis showed that significantly more patients in the RMNS group had faster GCS, CRS-R and DRS improvement (p = 0.01, 0.004 and 0.04, respectively). Adverse events were similar in both groups. No serious adverse events were associated with the stimulation device.

Conclusion

Right median nerve electrical stimulation is a possible effective treatment for patients with acute traumatic coma, that will require validation in a confirmatory trial.

 

“THE MANTLE” bundle for minimizing cerebral hypoxia in severe traumatic brain injury

by Daniel Agustin Godoy, Francisco Murillo-Cabezas, Jose Ignacio Suarez, Rafael Badenes, Paolo Pelosi and Chiara Robba 

Critical Care volume 27, Article number: 13 Published: 12 January 2023

Abstract

To ensure neuronal survival after severe traumatic brain injury, oxygen supply is essential. Cerebral tissue oxygenation represents the balance between oxygen supply and consumption, largely reflecting the adequacy of cerebral perfusion. Multiple physiological parameters determine the oxygen delivered to the brain, including blood pressure, hemoglobin level, systemic oxygenation, microcirculation and many factors are involved in the delivery of oxygen to its final recipient, through the respiratory chain. Brain tissue hypoxia occurs when the supply of oxygen is not adequate or when for some reasons it cannot be used at the cellular level. The causes of hypoxia are variable and can be analyzed pathophysiologically following “the oxygen route.” The current trend is precision medicine, individualized and therapeutically directed to the pathophysiology of specific brain damage; however, this requires the availability of multimodal monitoring. For this purpose, we developed the acronym “THE MANTLE,” a bundle of therapeutical interventions, which covers and protects the brain, optimizing the components of the oxygen transport system from ambient air to the mitochondria.

Continuous Electroencephalography After Moderate to Severe Traumatic Brain Injury

Continuous Electroencephalography After Moderate to Severe Traumatic Brain Injury

 by Lee, Hyunjo; Mizrahi, Moshe A.; Hartings, Jed A.; Sharma, Sameer; Pahren, Laura; Ngwenya, Laura B.; Moseley, Brian D.; Privitera, Michael; Tortella, Frank C.; Foreman, Brandon  

Critical Care Medicine: April 2019 - Volume 47 - Issue 4 - p 574–582

Objectives: After traumatic brain injury, continuous electroencephalography is widely used to detect electrographic seizures. With the development of standardized continuous electroencephalography terminology, we aimed to describe the prevalence and burden of ictal-interictal patterns, including electrographic seizures after moderate-to-severe traumatic brain injury and to correlate continuous electroencephalography features with functional outcome.

Design: Post hoc analysis of the prospective, randomized controlled phase 2 multicenter INTREPID2566 study (ClinicalTrials.gov: NCT00805818). Continuous electroencephalography was initiated upon admission to the ICU. The primary outcome was the 3-month Glasgow Outcome Scale-Extended. Consensus electroencephalography reviews were performed by raters certified in standardized continuous electroencephalography terminology blinded to clinical data. Rhythmic, periodic, or ictal patterns were referred to as “ictal-interictal continuum”; severe ictal-interictal continuum was defined as greater than or equal to 1.5 Hz lateralized rhythmic delta activity or generalized periodic discharges and any lateralized periodic discharges or electrographic seizures. Setting: Twenty U.S. level I trauma centers.

Patients: Patients with nonpenetrating traumatic brain injury and postresuscitation Glasgow Coma Scale score of 4–12 were included.

Interventions: None.

Measurements and Main Results: Among 152 patients with continuous electroencephalography (age 34 ± 14 yr; 88% male), 22 (14%) had severe ictal-interictal continuum including electrographic seizures in four (2.6%). Severe ictal-interictal continuum burden correlated with initial prognostic scores, including the International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (r = 0.51; p = 0.01) and Injury Severity Score (r = 0.49; p = 0.01), but not with functional outcome. After controlling clinical covariates, unfavorable outcome was independently associated with absence of posterior dominant rhythm (common odds ratio, 3.38; 95% CI, 1.30–9.09), absence of N2 sleep transients (3.69; 1.69–8.20), predominant delta activity (2.82; 1.32–6.10), and discontinuous background (5.33; 2.28–12.96) within the first 72 hours of monitoring.

Conclusions: Severe ictal-interictal continuum patterns, including electrographic seizures, were associated with clinical markers of injury severity but not functional outcome in this prospective cohort of patients with moderate-to-severe traumatic brain injury. Importantly, continuous electroencephalography background features were independently associated with functional outcome and improved the area under the curve of existing, validated predictive models.

Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II: A Phase II Randomized Trial

Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II: A Phase II Randomized Trial

Okonkwo, D et al

Critical Care Medicine: November 2017 - Volume 45 - Issue 11 - p 1907–1914

Objectives: A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study. Design: Randomized prospective clinical trial. Setting: Ten ICUs in the United States. Patients: One hundred nineteen severe traumatic brain injury patients. Interventions: Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure –only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale–Extended. 

Mortality Risk Stratification After Traumatic Brain Injury and Hazard of Death With Titrated Hypothermia in the Eurotherm3235Trial

Mortality Risk Stratification After Traumatic Brain Injury and Hazard of Death With Titrated Hypothermia in the Eurotherm3235Trial

Andrews, P J et al

Critical Care Medicine: May 2017 - Volume 45 - Issue 5 - p 883–890

Objectives: Hypothermia reduces intracranial hypertension in patients with traumatic brain injury but was associated with harm in the Eurotherm3235Trial. We stratified trial patients by International Mission for Prognosis and Analysis of Clinical Trials in [Traumatic Brain Injury] (IMPACT) extended model sum scores to determine where the balance of risks lay with the intervention. 
Design: The Eurotherm3235Trial was a randomized controlled trial, with standardized and blinded outcome assessment. Patients in the trial were split into risk tertiles by IMPACT extended model sum scores. A proportional hazard analysis for death between randomization and 6 months was performed by intervention and IMPACT extended model sum scores tertiles in both the intention-to-treat and the per-protocol populations of the Eurotherm3235Trial. 
Setting: Forty-seven neurologic critical care units in 18 countries. Patients: Adult traumatic brain injury patients admitted to intensive care who had suffered a primary, closed traumatic brain injury; increased intracranial pressure; an initial head injury less than 10 days earlier; a core temperature at least 36°C; and an abnormal brain CT. 
Intervention: Titrated Hypothermia in the range 32-35°C as the primary intervention to reduce raised intracranial pressure. 
Measurements and Main Results: Three hundred eighty-six patients were available for analysis in the intention-to-treat and 257 in the per-protocol population. The proportional hazard analysis (intention-to-treat and per-protocol populations) showed that the treatment effect behaves similarly across all risk stratums. However, there is a trend that indicates that patients in the low-risk group could be at greater risk of suffering harm due to hypothermia. 
Conclusions: Hypothermia as a first line measure to reduce intracranial pressure to less than 20 mm Hg is harmful in patients with a lower severity of injury and no clear benefit exists in patients with more severe injuries.

Meta-Analysis of Therapeutic Hypothermia for Traumatic Brain Injury in Adult and Pediatric Patients

Meta-Analysis of Therapeutic Hypothermia for Traumatic Brain Injury in Adult and Pediatric Patients
Crompton, E et al
Critical Care Medicine: April 2017 - Volume 45 - Issue 4 - p 575–583

Objective: Therapeutic hypothermia has been used to attenuate the effects of traumatic brain injuries. However, the required degree of hypothermia, length of its use, and its timing are uncertain. We undertook a comprehensive meta-analysis to quantify benefits of hypothermia therapy for traumatic brain injuries in adults and children by analyzing mortality rates, neurologic outcomes, and adverse effects. Data Sources: Electronic databases PubMed, Google Scholar, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov and manual searches of studies were conducted for relevant publications up until February 2016. 
Study Selection: Forty-one studies in adults (n = 3,109; age range, 18–81 yr) and eight studies in children (n = 454; age range, 3 mo to 18 yr) met eligibility criteria. Data Extraction: Baseline patient characteristics, enrollment time, methodology of cooling, target temperature, duration of hypothermia, and rewarming protocols were extracted. Data Synthesis: Risk ratios with 95% CIs were calculated. Compared with adults who were kept normothermic, those who underwent therapeutic hypothermia were associated with 18% reduction in mortality (risk ratio, 0.82; 95% CI, 0.70–0.96; p = 0.01) and a 35% improvement in neurologic outcome (risk ratio, 1.35; 95% CI, 1.18–1.54; p < 0.00001). The optimal management strategy for adult patients included cooling patients to a minimum of 33°C for 72 hours, followed by spontaneous, natural rewarming. In contrast, adverse outcomes were observed in children who underwent hypothermic treatment with a 66% increase in mortality (risk ratio, 1.66; 95% CI, 1.06–2.59; p = 0.03) and a marginal deterioration of neurologic outcome (risk ratio, 0.90; 95% CI, 0.80–1.01; p = 0.06). 
Conclusions: Therapeutic hypothermia is likely a beneficial treatment following traumatic brain injuries in adults but cannot be recommended in children.