Prognostic Value of Spreading Depolarizations in Patients With Severe Traumatic Brain Injury

Abstract

Importance: Advances in treatment of traumatic brain injury are hindered by the inability to monitor pathological mechanisms in individual patients for targeted neuroprotective treatment. Spreading depolarizations, a mechanism of lesion development in animal models, are a novel candidate for clinical monitoring in patients with brain trauma who need surgery.

Objective: To test the null hypothesis that spreading depolarizations are not associated with worse neurologic outcomes.

Design, setting, and participants: This prospective, observational, multicenter cohort study was conducted from February 2009 to August 2013 in 5 level 1 trauma centers. Consecutive patients who required neurological surgery for treatment of acute brain trauma and for whom research consent could be obtained were enrolled; participants were excluded because of technical problems in data quality, patient withdrawal, or loss to follow-up. Primary statistical analysis took place from April to December 2018. Evaluators of outcome assessments were blinded to other measures.

Interventions: A 6-contact electrode strip was placed on the brain surface during surgery for continuous electrocorticography during intensive care.

Main outcomes and measures: Electrocorticography was scored for depolarizations, following international consensus procedures. Six-month outcomes were assessed by the Glasgow Outcome Scale-Extended score.

Results: A total of 157 patients were initially enrolled; 19 were subsequently excluded. The 138 remaining patients (104 men [75%]; median [interquartile range] age, 45 [29-64] years) underwent a median (interquartile range) of 75.5 (42.2-117.1) hours of electrocorticography. A total of 2837 spreading depolarizations occurred in 83 of 138 patients (60.1% incidence) who, compared with patients who did not have spreading depolarizations, had lower prehospital systolic blood pressure levels (mean [SD], 133 [31] mm Hg vs 146 [33] mm Hg; P = .03), more traumatic subarachnoid hemorrhage (depolarization incidences of 17 of 37 [46%], 18 of 32 [56%], 22 of 33 [67%], and 23 of 30 patients [77%] for Morris-Marshall Grades 0, 1, 2, and 3/4, respectively; P = .047), and worse radiographic pathology (in 38 of 73 patients [52%] and 42 of 60 patients [70%] for Rotterdam Scores 2-4 vs 5-6, respectively; P = .04). Of patients with depolarizations, 32 of 83 (39%) had only sporadic events that induced cortical spreading depression of spontaneous electrical activity, whereas 51 of 83 patients (61%) exhibited temporal clusters of depolarizations (≥3 in a 2-hour span). Nearly half of those with clusters (23 of 51 [45%]) also had depolarizations in an electrically silent area of the cortex (isoelectric spreading depolarization). Patients with clusters did not improve in motor neurologic examinations from presurgery to postelectrocorticography, while other patients did improve. In multivariate ordinal regression adjusting for baseline prognostic variables, the occurrence of depolarization clusters had an odds ratio of 2.29 (95% CI, 1.13-4.65; P = .02) for worse outcomes.

Conclusions and relevance: In this cohort study of patients with acute brain trauma, spreading depolarizations were predominant but heterogeneous and independently associated with poor neurologic recovery. Monitoring the occurrence of spreading depolarizations may identify patients most likely to benefit from targeted management strategies.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Shutter reported grants from the National Institutes of Health and the US Department of Defense during the conduct of the study. Dr Strong reported grants from the US Army Congressionally Directed Medical Research Program during the conduct of the study. Dr Foreman reported grants from the National Institutes of Health (grant K23NS101123), US Department of Defense (grants DOD X81XWH-18-DMRDP-PTCRA, DOD W81XWH-16-2-0020, and DOD FA8650-15-2-6B39), and National Science Foundation (grant NSF 1014552) and personal fees from UCB Pharma and Minnetronix outside the submitted work. Dr Okonkwo reported grants from the US Department of Defense during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Scoring, Classification, and Timing of Spreading Depolarizations After Acute Brain Trauma

A, Illustration of a 6-contact electrode strip, placed on the brain surface after a decompressive hemicraniectomy. The strip was placed in the frontal lobe in 97 of 133 patients (72.9%), temporal lobe in 27 of 133 (20.3%), and parietal lobe in 11 of 133 (8.3%). B, Flowchart showing patient classifications based on spreading depolarization (SD) types and patterns. Three classification steps yield 4 patient categories. C, Methods to measure and classify SDs are illustrated by recordings from 3 bipolar channels. Each channel is filtered separately to display slow potentials (top traces; 0.01-0.10 Hz) and spontaneous activity (middle traces; 0.5-50 Hz). The power integral of the spontaneous activity aids in scoring of depression periods, as shown for channel 2 (red boxes). Six SDs were observed in this period, and all met the criteria of clustered events. Designations as cortical spreading depression (CSD) or isoelectric SD (ISD) subtypes are shown. Intracranial and arterial pressures were in normal ranges. Scale bars for channel 3 (right) apply to all channels. Total duration of displayed traces was 3 hours and 20 minutes. D, Raster plots show electrocorticography data from individual patients, grouped according to the categories in panel B. Gray bars show periods of high-quality recordings, during which SDs could be evaluated. Black ticks show the times of individual CSDs and red ticks show isoelectric SDs. Blue bars highlight clusters. Patients with clustered CSDs had an initial pattern of sporadic events before cluster development in 18 of 28 cases (64%). By contrast, patients with isoelectric SDs had an initial pattern of sporadic events in only 6 of 23 cases (26%) and were more likely to show clustering from the start (P = .01 by Fisher exact test). In these patients, isoelectric SDs were usually preceded by an initial pattern of CSDs (21 of 23 [91%]). The final isoelectric SDs were sporadic events in 18 of 23 patients (78%), and recordings ended during an isoelectric SD cluster in the remaining 5 cases. In 23 of 23 patients, the final events recorded were isoelectric SDs rather than CSDs, demonstrating that spontaneous electrical activity did not recover within the period of monitoring.

Figure 2.. Risk Factors and Outcomes

A, Bar graphs show the proportion of depolarizations that occurred when variables were in normal (light blue) and abnormal (dark blue) ranges. The number of depolarizations evaluated for each variable is shown at left. Mean values of continuously recorded variables were measured from 60-second epochs within 5 minutes prior to each depolarization onset. Regional cerebral blood flow was monitored in 25 patients with thermal diffusion probes (Hemedex Inc) placed alongside the subdural electrode strip. Intracranial pressure was monitored in 109 patients and brain tissue oxygen in 60 patients. B, Proportions of patients with and without depolarizations according to ranges of prehospital systolic blood pressures. In contrast to prehospital values, systolic blood pressure levels at hospital admission did not differ between patients with and without depolarizations (mean [SD], 143.6 [32.4] mm Hg vs 145.4 [27.6] mm Hg; P = .73). C, Distribution of patients across depolarization categories according to the Morris-Marshall Grade scoring of traumatic subarachnoid hemorrhage (SAH) on presurgical computed tomography head studies. Morris-Marshall Grades are no subarachnoid hemorrhage (0); subarachnoid hemorrhage in only 1 location (1); subarachnoid hemorrhage fills structure at 1 location or any 2 sites, filling neither (2); subarachnoid hemorrhage at 2 sites, including a filled tentorium (3); and subarachnoid hemorrhage at 3 or more sites in any quantity (4). D, Distribution of patients across depolarization categories according to the Rotterdam Computed Tomography (CT) Sum Score, based on assessment of basal cisterns, midline shift, epidural mass, and intraventricular or subarachnoid blood; higher numbers represent more severe pathology. E and F, Distribution of Glasgow Coma Scale (GCS) motor scores, according to depolarization category. Motor scores obtained in presurgical examinations (E) are compared with those obtained several days later, at the end of electrocorticography (F). A score of 4 (withdrawal to painful stimuli) is often used as a threshold to indicate the need for invasive neuromonitoring, whereas those able to localize pain (score 5) or follow commands (score 6) are generally not monitored. F, Status at the end of electrocorticography (ECoG) monitoring. G, Distribution of Glasgow Outcome Scale–Extended scores at 6 months, according to depolarization category. Raw patient numbers are shown for each category in panels B, C, and D. CSD indicates cortical spreading depression; ICP, intracranial pressure; ISD, isoelectric spreading depolarization; MAP, mean arterial pressure; PbtO2, partial pressure of brain tissue oxygen; PVS, persistent vegetative state; rCBF, regional cerebral blood flow; SD, spreading depolarization.