Occurrence Of Spreading Depolarization Research Articles

Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial.

Retrospective clinical data and case studies support a therapeutic effect of ketamine in suppression of spreading depolarization (SD) following brain injury. Preclinical data strongly support efficacy in terms of frequency of SD as well as recovery from electrocorticography (ECoG) depression. The authors present the results of the first prospective controlled clinical trial testing the role of ketamine used for clinical sedation on occurrence of SD. Ten patients with severe traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH) were recruited for this pilot trial. A standard ECoG strip was placed at the time of craniotomy, and the patients were then placed on an alternating every-6-hour schedule of ketamine or other sedation agent. The order of treatment was randomized. The ketamine dose was adjusted to clinical effect or maintained at a subanesthetic basal dose (0.1 mg/kg/hr) if no sedation was required. SD was scored using standard criteria, blinded to ketamine dosing. Occurrence of SD was compared with the hourly dose of ketamine to determine the effect of ketamine on SD occurrence. Successful ECoG recordings were obtained in all 10 patients: 8 with SAH and 2 with TBI. There were a total of 1642 hours of observations with adequate ECoG: 833 hours off ketamine and 809 hours on ketamine. Analysis revealed a strong dose-dependent effect such that hours off ketamine or on doses of less than 1.15 mg/kg/hr were associated with an increased risk of SD compared with hours on doses of 1.15 mg/kg/hr or more (OR 13.838, 95% CI 1.99-1000). This odds ratio decreased with lower doses of 1.0 mg/kg/hr (OR 4.924, 95% CI 1.337-43.516), 0.85 mg/kg/hr (OR 3.323, 95% CI 1.139-16.074), and 0.70 mg/kg/hr (OR 2.725, 95% CI 1.068-9.898) to a threshold of no effect at 0.55 mg/kg/hr (OR 1.043, 95% CI 0.565-2.135). When all ketamine data were pooled (i.e., on ketamine at any dose vs off ketamine), a nonsignificant overall trend toward less SD during hours on ketamine (χ2 = 3.86, p = 0.42) was observed. Ketamine effectively inhibits SD over a wide range of doses commonly used for sedation, even in nonintubated patients. These data also provide the first prospective evidence that the occurrence of SD can be influenced by clinical intervention and does not simply represent an unavoidable epiphenomenon after injury. These data provide the basis for future studies assessing clinical improvement with SD-directed therapy.Clinical trial registration no.: NCT02501941 (clinicaltrials.gov).

Near-infrared diffuse reflectance signals for monitoring spreading depolarizations and progression of the lesion in a male rat focal cerebral ischemia model.

In ischemic stroke research, a better understanding of the pathophysiology and development of neuroprotection methods are crucial, for which in vivo imaging to monitor spreading depolarizations (SDs) and evolution of tissue damage is desired. Since these events are accompanied by cellular morphological changes, light-scattering signals, which are sensitive to cellular and subcellular morphology, can be used for monitoring them. In this study, we performed transcranial imaging of near-infrared (NIR) diffuse reflectance at ∼800 nm, which sensitively reflects light-scattering change, and examined how NIR reflectance is correlated with simultaneously measured cerebral blood flow (CBF) for a rat middle cerebral artery occlusion (MCAO) model. After MCAO, wavelike NIR reflectance changes indicating occurrence of SDs were generated and propagated around the ischemic core for ∼90 min, during which time NIR reflectance increased not only within the ischemic core but also in the peripheral region. The area with increased reflectance expanded with increase in the number of SD occurrences, the correlation coefficient being 0.7686 (n = 5). The area with increased reflectance had become infarcted at 24 hr after MCAO. The infarct region was found to be associated with hypoperfusion or no-flow response to SD, but hyperemia or hypoperfusion followed by hyperemia response to SD was also observed, and the regional heterogeneity seemed to be connected with the rat cerebrovasculature and hence existence/absence of collateral flow. The results suggest that NIR reflectance signals depicted early evolution of tissue damage, which was not seen by CBF changes, and enabled lesion progression monitoring in the present stroke model.

Brain temperature but not core temperature increases during spreading depolarizations in patients with spontaneous intracerebral hemorrhage

Spreading depolarizations (SDs) are highly active metabolic events, commonly occur in patients with intracerebral hemorrhage (ICH) and may be triggered by fever. We investigated the dynamics of brain-temperature (Tbrain) and core-temperature (Tcore) relative to the occurrence of SDs. Twenty consecutive comatose ICH patients with multimodal electrocorticograpy (ECoG) and Tbrain monitoring of the perihematomal area were prospectively enrolled. Clusters of SDs were defined as ≥2 SDs/h. Generalized estimating equations were used for statistical calculations. Data are presented as median and interquartile range. During 3097 h (173 h [81–223]/patient) of ECoG monitoring, 342 SDs were analyzed of which 51 (15%) occurred in clusters. Baseline Tcore and Tbrain was 37.3℃ (36.9–37.8) and 37.4℃ (36.7–37.9), respectively. Tbrain but not Tcore significantly increased 25 min preceding the onset of SDs by 0.2℃ (0.1–0.2; p < 0.001) and returned to baseline 35 min following SDs. During clusters, Tbrain increased to a higher level (+0.4℃ [0.1–0.4]; p = 0.006) when compared to single SDs. A higher probability (OR = 36.9; CI = 36.8–37.1; p < 0.001) of developing SDs was observed during episodes of Tbrain ≥ 38.0℃ (23% probability), than during Tbrain ≤ 36.6℃ (9% probability). Spreading depolarizations – and in particular clusters of SDs – may increase brain temperature following ICH.

Simulation of spreading depolarization trajectories in cerebral cortex: Correlation of velocity and susceptibility in patients with aneurysmal subarachnoid hemorrhage.

In many cerebral grey matter structures including the neocortex, spreading depolarization (SD) is the principal mechanism of the near-complete breakdown of the transcellular ion gradients with abrupt water influx into neurons. Accordingly, SDs are abundantly recorded in patients with traumatic brain injury, spontaneous intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage (aSAH) and malignant hemispheric stroke using subdural electrode strips. SD is observed as a large slow potential change, spreading in the cortex at velocities between 2 and 9 mm/min. Velocity and SD susceptibility typically correlate positively in various animal models. In patients monitored in neurocritical care, the Co-Operative Studies on Brain Injury Depolarizations (COSBID) recommends several variables to quantify SD occurrence and susceptibility, although accurate measures of SD velocity have not been possible. Therefore, we developed an algorithm to estimate SD velocities based on reconstructing SD trajectories of the wave-front's curvature center from magnetic resonance imaging scans and time-of-SD-arrival-differences between subdural electrode pairs. We then correlated variables indicating SD susceptibility with algorithm-estimated SD velocities in twelve aSAH patients. Highly significant correlations supported the algorithm's validity. The trajectory search failed significantly more often for SDs recorded directly over emerging focal brain lesions suggesting in humans similar to animals that the complexity of SD propagation paths increase in tissue undergoing injury.

Contribution of prostanoid signaling to the evolution of spreading depolarization and the associated cerebral blood flow response.

The significance of prostanoid signaling in neurovascular coupling during somatosensory stimulation is increasingly more appreciated, yet its involvement in mediating the cerebral blood flow (CBF) response to spreading depolarization (SD) has remained inconclusive. Selective cyclooxygenase (COX) enzyme inhibitors (NS-398, SC-560) or an antagonist (L161,982) of the EP4 type prostaglandin E2 receptor were applied topically to a cranial window over the parietal cortex of isoflurane-anesthetized Sprague-Dawley rats (n = 60). Global forebrain ischemia was induced by occlusion of both common carotid arteries in half of the animals. SDs were triggered by the topical application of 1M KCl. SD occurrence was confirmed by the acquisition of DC potential, and CBF variations were recorded by laser-Doppler flowmetry. EP4 receptor antagonism significantly decreased peak hyperemia and augmented post-SD oligemia in the intact but not in the ischemic cortex. COX-1 inhibition and EP4 receptor blockade markedly delayed repolarization after SD in the ischemic but not in the intact brain. COX-2 inhibition achieved no significant effect on any of the end points taken. The data suggest, that activation of EP4 receptors initiates vasodilation in response to SD in the intact brain, and – together with COX-1 derived prostanoids – shortens SD duration in the acute phase of ischemia.

Advancing age and ischemia elevate the electric threshold to elicit spreading depolarization in the cerebral cortex of young adult rats

Spreading depolarizations of long cumulative duration have been implicated in lesion development and progression in patients with stroke and traumatic brain injury. Spreading depolarizations evolve less likely in the aged brain, but it remains to be determined at what age the susceptibility to spreading depolarizations starts to decline, especially in ischemia. Spreading depolarizations were triggered by epidural electric stimulation prior and after ischemia induction in the cortex of 7–30 weeks old anesthetized rats (n = 38). Cerebral ischemia was achieved by occlusion of both common carotid arteries. Spreading depolarization occurrence was confirmed by the acquisition of DC potential and electrocorticogram. Cerebral blood flow variations were recorded by laser-Doppler flowmetry. Dendritic spine density in the cortex was determined in Golgi-COX stained sections. Spreading depolarization initiation required increasingly greater electric charge with older age, a potential outcome of consolidation of cortical connections, indicated by altered dendritic spine distribution. The threshold of spreading depolarization elicitation increased with ischemia in all age groups, which may be caused by tissue acidosis and increased K+ conductance, among other factors. In conclusion, the brain appears to be the most susceptible to spreading depolarizations at adolescent age; therefore, spreading depolarizations may occur in young patients of ischemic or traumatic brain injury at the highest probability.

Changes in electrocorticographic beta frequency components precede spreading depolarization in patients with acute brain injury.

Spreading depolarization (SD) occurs after traumatic brain injury, subarachnoid hemorrhage, malignant hemispheric stroke and intracranial hemorrhage. SD has been associated with secondary brain injury, which can be reduced by ketamine. In this present study frequency bands of electrocorticographic (ECoG) recordings were investigated with regards to SDs. A total of 43 patients after acute brain injury were included in this retrospective and explorative study. Relative delta 0.5-4Hz, theta 4-8Hz, alpha 8-13Hz and beta 13-40Hz bands were analyzed with regards to SD occurrence and analgesic and sedative administration. Higher frequencies, including gamma 40-70Hz, fast gamma 70-100Hz and high frequency oscillations 100-200Hz were analyzed in a subset of patients with a sampling rate of up to 400Hz. A close association of relative beta frequency and SD was found. Relative beta frequency was suppressed up to two hours prior to SD when compared to hours with no SD. This finding was partially explained by administration of ketamine. Even after removal of all patient data during administration of ketamine, SDs occurred predominantly during times with low relative beta frequency in a patient-independent analysis. Suppression of beta frequency by ketamine or without ketamine is associated with low SD counts. Alteration of beta frequency might help to predict occurrence of SDs in acutely brain injured patients.

Pharmacological modulation of spreading depolarizations.

Spreading depolarization (SD) is a wave of almost complete depolarization of the neuronal and glial cells. Nowadays there is sufficient evidence demonstrating its pathophysiological effect in migraine with aura, transient global amnesia, stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and traumatic brain injury. In these cases, occurrence of SD has been associated with functional neuronal damage, neuronal necrosis, neurological degeneration, and poor clinical outcome. Animal models show that SD can be modulated by drugs that interfere with its initiation and propagation. There are many pharmacological targets that may help to suppress SD occurrence, such as Na⁺, K⁺, Cl⁻, and Ca²⁺ channels; Na⁺/K⁺ -ATPase; gap junctions; and ligand-based receptors, for example, adrenergic, serotonin, sigma-1, calcitonin gene-related peptide, GABAA, and glutamate receptors. In this regard, N-methyl-d-aspartate (NMDA) receptor blockers, in particular, ketamine, have shown promising results. Therefore, theoretically pharmacologic modulation of SD could help diminish its pathological effects.

The effect of ketamine on optical and electrical characteristics of spreading depolarizations in gyrencephalic swine cortex

Spreading depolarization (SD) is a wave of mass neuronal and glial depolarization that propagates across the cerebral cortex and has been implicated in the pathophysiology of brain injury states and migraine with aura. Analgesics and sedatives seem to have a significant effect on SD modulation. Studies have shown that ketamine, an NMDA receptor blocker, has the capacity to influence SD occurrence. The aim of this study was to analyze the dose-dependent effect of ketamine on SD susceptibility through electrocorticography (ECoG) and intrinsic optical signal (IOS) imaging in a gyrencephalic brain. Ketamine in a low-dose infusion (2 mg/kg/h) decreases SD spread and had an effect on the amplitude of SD deflections, as well as on duration, and speed. Moreover, during ketamine infusion at this dose, there was a sustained decrease in the hyperemic response following SD. However, a high-dose infusion (4 mg/kg/h) of ketamine inhibited SD induction and expansion. Furthermore, a high-dose bolus (4 mg/kg), 1 min after stimulation, blocked SD propagation abruptly within 1–2 min, and hindered SD induction and expansion for the following 15–30 min. The results suggest that ketamine may be therapeutically beneficial in preventing SDs. Nonetheless, an adequate dosage and way of administration should be considered and established for human use.

Decreased Cortical Spreading Depolarizations In Neurosurgical Patients Being Given Ketamine

Evaluation of: Hertle DN, Dreier JP, Woitzik J et al.; Cooperative Study of Brain Injury Depolarizations (COSBID). Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. Brain 135(Pt 8), 2390–2398 (2012). This retrospective review by the Cooperative Study of Brain Injury Depolarizations group of 115 patients correlates the occurrence of cortical spreading depolarization (SD), measured with cortical electrodes, with the type of sedation used during monitoring in the intensive care unit. SD has recently been implicated in the progression of acute brain injury, and this study represents the first systematic approach to attempt to understand whether the deleterious effects of SD can be impacted with drug therapy. A significantly decreased probability of SD occurrence was documented with ketamine, but none of the five other drugs that were studied. This effect was seen across all days of monitoring and seemed to have a dose-dependent effect. In evaluating clusters of SD (which most likely contribute to injury progression), ketamine remained significantly associated with decreased likelihood of clusters, along with a weaker effect with propofol and a surprising positive association with midazolam. Owing to the retrospective nature of the study, no causal association can be concluded, although the suppressive effect of NMDA receptor antagonists is consistent with prior animal data. This work will provide critical clinical groundwork for carefully designed clinical trials focused on SD suppression and outcome.

Clusters of Spreading Depolarizations Are Associated With Disturbed Cerebral Metabolism in Patients With Aneurysmal Subarachnoid Hemorrhage

We studied the dynamics of extracellular brain tissue concentrations of glucose, lactate, pyruvate, and glutamate during the occurrence of spreading depolarizations (SDs) in patients with aneurysmal subarachnoid hemorrhage. In this prospective observational study, patients with aneurysmal subarachnoid hemorrhage received multimodal cerebral monitoring, including intracranial pressure, cerebral microdialysis, and subdural electrocorticography. Seven of the 17 recruited patients had intracerebral hemorrhage, acute ischemia and severe brain oedema leading to acute ischemic neurological deficits associated with early disturbance of metabolism at the recording site. They displayed a total of 130 SDs. The remaining 10 patients without acute ischemic neurological deficits exhibited 138 single SDs and 68 SDs in clusters. In patients without acute ischemic neurological deficits, clustered SDs were associated with a significant transient decrease in glucose and increase in lactate compared with baseline during the first 140 minutes after SDs. Moreover, the number of clustered SDs correlated with the outcome (R=-0.659; P<0.01). SDs can propagate in nonischemic human brain tissue. Clusters of SDs are related to metabolic changes suggestive of ongoing secondary damage in primarily nonischemic brain tissue.

The relationship between sudden severe hypoxia and ischemia-associated spreading depolarization in adult rat brainstem in vivo

Severe ischemia can induce spreading depolarization (SD) in the cerebral cortex, which is thought to contribute significantly to cerebral dysfunction. Whether the mature brainstem shows SD upon reduced oxygen supply has not been investigated although SDs may significantly influence brainstem functions. In anesthetized adult rats, we induced severe short-lasting hypoxia (SSH) by stopping artificial respiration for about 1 min or by ventilation with pure nitrogen for 1, 2 or 3 min, and milder hypoxia by ventilation with 6% O 2 in N 2 for 10 min. We measured DC potentials in the brainstem and cerebral cortex, systemic arterial blood pressure, heart rate and local blood flow at the brainstem or cerebral cortex surface. SSH lasting up to 1 min did not induce DC shifts in native brainstem but reduced heart rate, systemic blood pressure and blood flow in cortex and brainstem. Longer lasting SSH protocols both reduced systemic blood pressure and induced SD in the brainstem, but the magnitude of the cardiovascular response was not influenced by the simultaneous occurrence of SD. When neuronal excitability in the brainstem was artificially enhanced, SSH of 1 min evoked SD but again the magnitude of cardiovascular changes during SSH was not increased. SSH lasting 3 min evoked non-reversible sustained depolarization. SSH did not render the brainstem more excitable for classical SD evoked by local KCl application. Thus, sudden severe hypoxia/ischemia evokes SDs in the brainstem, but the occurrence of the so-elicited SD does not influence the immediate cardiovascular response to SSH.