Cortical Spreading Depression Phenomena Are Frequent in Ischemic and Traumatic Penumbra: A Prospective Study in Patients With Traumatic Brain Injury and Large Hemispheric Ischemic Stroke.

PURPOSE: Spreading depolarization (SD) phenomena are waves of neuronal depolarization, which propagate slowly at a velocity of 1 to 5 mm/minute and can occur in patients with ischemic or hemorrhagic stroke, traumatic brain injury, and migraine with aura. They form part of secondary injury, occurring after spreading ischemia. The purposes of this study were to describe the frequency and characteristics of SD phenomena and to define whether a correlation existed between SD and outcome in a group of patients with TBI and large hemispheric ischemic stroke. METHODS: This was a prospective observational study of 39 adult patients, 17 with malignant middle cerebral artery infarction and 22 with moderate or severe traumatic brain injury, who underwent decompressive craniectomy and multimodal neuromonitoring including electrocorticography. Identification, classification, and interpretation of SDs were performed using the published recommendations from the Cooperative Study on Brain Injury Depolarization group. The outcomes assessed were functional disability at 6 and 12 months after injury, according to the extended Glasgow outcome scale, Barthel index, and modified Rankin scale. RESULTS: Four hundred eighty-three SDs were detected, in 58.9% of the patients. Spreading depolarizations were more common, particularly the isoelectric SD type, in patients with malignant middle cerebral artery infarction (P < 0.04). In 65.21% of patients with SDs on electrocorticography, the "peak" day of depolarization was day 0 (the first 24 hours of recording). Spreading depolarization convulsions were present in 26.08% of patients with SDs. Patients with more SDs and higher depolarization indices scored worse on extended Glasgow outcome scale (6 months) and Barthel index (6 and 12 months) (P < 0.05). CONCLUSIONS: Evidence on SD phenomena is important to ensure continued progress in understanding their pathophysiology, in the search for therapeutic targets to avoid additional damage from these secondary injuries.

Is Spreading Depolarization a Risk Factor for Late Epilepsy? A Prospective Study in Patients with Traumatic Brain Injury and Malignant Ischemic Stroke Undergoing Decompressive Craniectomy.

OBJECTIVE: Spreading depolarizations (SDs) have been described in patients with ischemic and haemorrhagic stroke, traumatic brain injury, and migraine with aura, among other conditions. The exact pathophysiological mechanism of SDs is not yet fully established. Our aim in this study was to evaluate the relationship between the electrocorticography (ECoG) findings of SDs and/or epileptiform activity and subsequent epilepsy and electroclinical outcome. METHODS: This was a prospective observational study of 39 adults, 17 with malignant middle cerebral artery infarction (MMCAI) and 22 with traumatic brain injury, who underwent decompressive craniectomy and multimodal neuromonitoring including ECoG in penumbral tissue. Serial electroencephalography (EEG) recordings were obtained for all surviving patients. Functional disability at 6 and 12 months after injury were assessed using the Barthel, modified Rankin (mRS), and Extended Glasgow Outcome (GOS-E) scales. RESULTS: SDs were recorded in 58.9% of patients, being more common-particularly those of isoelectric type-in patients with MMCAI (p < 0.04). At follow-up, 74.7% of patients had epileptiform abnormalities on EEG and/or seizures. A significant correlation was observed between the degree of preserved brain activity on EEG and disability severity (R [mRS]: + 0.7, R [GOS-E, Barthel]: - 0.6, p < 0.001), and between the presence of multifocal epileptiform abnormalities on EEG and more severe disability on the GOS-E at 6 months (R: - 0.3, p = 0.03) and 12 months (R: - 0.3, p = 0.05). Patients with more SDs and higher depression ratios scored worse on the GOS-E (R: - 0.4 at 6 and 12 months) and Barthel (R: - 0.4 at 6 and 12 months) disability scales (p < 0.05). The number of SDs (p = 0.064) and the depression ratio (p = 0.1) on ECoG did not show a statistically significant correlation with late epilepsy. CONCLUSIONS: SDs are common in the cortex of ischemic or traumatic penumbra. Our study suggests an association between the presence of SDs in the acute phase and worse long-term outcome, although no association with subsequent epilepsy was found. More comprehensive studies, involving ECoG and EEG could help determine their association with epileptogenesis.

Does Normobaric Hyperoxia Cause Oxidative Stress in the Injured Brain? A Microdialysis Study Using 8-Iso-Prostaglandin F2α as a Biomarker.

Significant controversy exists regarding the potential clinical benefit of normobaric hyperoxia (NBO) in patients with traumatic brain injury (TBI). This study consisted of two aims: 1) to assess whether NBO improves brain oxygenation and metabolism and 2) to determine whether this therapy may increase the risk of oxidative stress (OxS), using 8-iso-Prostaglandin F2α (PGF2α) as a biomarker. Thirty-one patients with a median admission Glasgow Coma Scale score of 4 (min: 3, max: 12) were monitored with cerebral microdialysis and brain tissue oxygen sensors and treated with fraction of inspired oxygen (FiO2) of 1.0 for 4 h. Patients were divided into two groups according to the area monitored by the probes: normal injured brain and traumatic penumbra/traumatic core. NBO maintained for 4 h did not induce OxS in patients without preOxS at baseline, except in one case. However, for patients in whom OxS was detected at baseline, NBO induced a significant increase in 8-iso-PGF2α. The results of our study showed that NBO did not change energy metabolism in the whole group of patients. In the five patients with brain lactate concentration ([Lac]brain) > 3.5 mmol/L at baseline, NBO induced a marked reduction in both [Lac]brain and lactate-to-pyruvate ratio. Although these differences were not statistically significant, together with the results of our previous study, they suggest that TBI patients would benefit from receiving NBO when they show indications of disturbed brain metabolism. These findings, in combination with increasing evidence that TBI metabolic crises are common without brain ischemia, open new possibilities for the use of this accessible therapeutic strategy in TBI patients.

Lactate and the lactate-to-pyruvate molar ratio cannot be used as independent biomarkers for monitoring brain energetic metabolism: a microdialysis study in patients with traumatic brain injuries.

BACKGROUND: For decades, lactate has been considered an excellent biomarker for oxygen limitation and therefore of organ ischemia. The aim of the present study was to evaluate the frequency of increased brain lactate levels and the LP ratio (LPR) in a cohort of patients with severe or moderate traumatic brain injury (TBI) subjected to brain microdialysis monitoring to analyze the agreement between these two biomarkers and to indicate brain energy metabolism dysfunction. METHODS: Forty-six patients with an admission Glasgow coma scale score of ≤13 after resuscitation admitted to a dedicated 10-bed Neurotraumatology Intensive Care Unit were included, and 5305 verified samples of good microdialysis data were analyzed. RESULTS: Lactate levels were above 2.5 mmol/L in 56.9% of the samples. The relationships between lactate and the LPR could not be adequately modeled by any linear or non-linear model. Neither Cohen's kappa nor Gwet's statistic showed an acceptable agreement between both biomarkers to classify the samples in regard to normal or abnormal metabolism. The dataset was divided into four patterns defined by the lactate concentrations and the LPR. A potential interpretation for these patterns is suggested and discussed. Pattern 4 (low pyruvate levels) was found in 10.7% of the samples and was characterized by a significantly low concentration of brain glucose compared with the other groups. CONCLUSIONS: Our study shows that metabolic abnormalities are frequent in the macroscopically normal brain in patients with traumatic brain injuries and a very poor agreement between lactate and the LPR when classifying metabolism. The concentration of lactate in the dialysates must be interpreted while taking into consideration the LPR to distinguish between anaerobic metabolism and aerobic hyperglycolysis.

Monitoring intracranial pressure in patients with malignant middle cerebral artery infarction: is it useful?

OBJECT: Intracranial pressure (ICP) monitoring is increasingly used in the treatment of patients with malignant middle cerebral artery (MCA) infarction. However, neurological deterioration may exist independent from intracranial hypertension. This study aimed to present the findings of continuous ICP monitoring in a cohort of patients with malignant MCA infarction and to correlate these findings with clinical and radiological features. METHODS: The authors studied a prospective cohort of 25 patients with malignant MCA infarction consecutively admitted to the neurotrauma intensive care unit of the Vall d'Hebron University Hospital between March 2002 and September 2006. The patients were treated using a combined protocol of initial moderate hypothermia and hemicraniectomy. The latter was performed when patients showed a midline shift (MLS) > or = 5 mm or ICP > 20 mm Hg. Six patients had an MLS > or = 5 mm on the first CT scan and underwent surgery without prior ICP monitoring. This study focuses on the subgroup of 19 patients who underwent intraparenchymatous ICP monitoring before surgery. RESULTS: Intracranial pressure readings were evaluated and correlated with pupillary abnormalities, MLS, and ischemic tissue volume. In 12 of the 19 patients, ICP values were always < or = 20 mm Hg, despite a mean (+/- SD) MLS of 6.7 +/- 2 mm and a mean ischemic tissue volume of 241.3 +/- 83 cm(3). In 2 patients with anisocoria, ICP values were also normal. CONCLUSIONS: In patients with a malignant MCA infarction, pupillary abnormalities and severe brainstem compression may be present despite normal ICP values. Therefore, continuous ICP monitoring cannot substitute for close clinical and radiological follow-up in the management of these patients.

Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases.

OBJECTIVE: Recent experimental evidence suggests that matrix metalloproteinases (MMPs) are implicated in the pathophysiology of traumatic brain injury (TBI) by increasing blood-brain barrier permeability and exacerbating posttraumatic edema. We examined the acute profile of MMP-2 and MMP-9 in the plasma of patients with moderate or severe TBI and in the brain extracellular fluid (ECF). DESIGN: Prospective observational study. SETTING: Neurotraumatology intensive care unit of a tertiary university hospital. PATIENTS: Twenty patients with moderate or severe TBI were included and three groups were used as controls: 20 patients with a mild head injury and normal CT scan, 15 moderate polytrauma patients without TBI, and 20 healthy volunteers. INTERVENTIONS: Plasma samples were collected within the first 12[Symbol: see text]h and at 24[Symbol: see text]h post-injury. Simultaneous brain microdialysate and plasma samples were obtained in four moderate-severe TBI patients at additional timepoints: 48, 72, and 96[Symbol: see text]h post-TBI. MEASUREMENTS AND MAIN RESULTS: Gelatinases (MMP-2 and MMP-9) were measured by gelatin zymography. A significant increase in plasma gelatinases was observed at baseline when compared with healthy volunteers in the study group. This early increase was followed by a significant decrease at 24[Symbol: see text]h post-injury. Brain microdialysis samples presented a similar time profile as plasma samples for both gelatinases. CONCLUSIONS: High levels of gelatinases were found in plasma and brain ECF in the early phase of TBI, indicating that both local and systemic trauma-induced upregulation of gelatinases in the acute phase might play an important role in the pathophysiology of TBI and could be a future therapeutic target.