Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury

Abstract

Spreading depolarizations are waves of mass neuronal and glial depolarization that propagate across the injured human cortex. They can occur with depression of neuronal activity as spreading depressions or isoelectric spreading depolarizations on a background of absent or minimal electroencephalogram activity. Spreading depolarizations are characterized by the loss of neuronal ion homeostasis and are believed to damage functional neurons, leading to neuronal necrosis or neurological degeneration and poor outcome. Analgesics and sedatives influence activity-dependent neuronal ion homeostasis and therefore represent potential modulators of spreading depolarizations. In this exploratory retrospective international multicentre analysis, we investigated the influence of midazolam, propofol, fentanyl, sufentanil, ketamine and morphine on the occurrence of spreading depolarizations in 115 brain-injured patients. A surface electrode strip was placed on the cortex, and continuous electrocorticographical recordings were obtained. We used multivariable binary logistic regression to quantify associations between the investigated drugs and the hours of electrocorticographical recordings with and without spreading depolarizations or clusters of spreading depolarizations. We found that administration of ketamine was associated with a reduction of spreading depolarizations and spreading depolarization clusters (P < 0.05). Midazolam anaesthesia, in contrast, was associated with an increased number of spreading depolarization clusters (P < 0.05). By using a univariate odds ratio analysis, we also found a significant association between ketamine administration and reduced occurrence of isoelectric spreading depolarizations in patients suffering from traumatic brain injury, subarachnoid haemorrhage and malignant hemispheric stroke (P < 0.05). Our findings suggest that ketamine-or another N-methyl-d-aspartate receptor antagonist-may represent a viable treatment for patients at risk for spreading depolarizations. This hypothesis will be tested in a prospective study.

Long-Term Consequences of Traumatic Brain Injury: Current Status of Potential Mechanisms of Injury and Neurological Outcomes

“…Episodes of CSD have been shown to be sensitive to selective pharmacological treatments, including NMDA receptor and calcium antagonists. [151][152][153] Also, previous data have indicated that CSD episodes are sensitive to brain temperature. 154,155 Additional experimental and clinical data are therefore required to determine the incidence of CSD in various TBI patient populations and the testing of novel treatment strategies targeting episodes of PTE and CSD in patients who could benefit in terms of long-term outcomes.…”

Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature

“…SD-induced peak hyperemia (component II) is often smaller, and the initial hypoperfusion (component I) is more prominent, when resting CBF and vessel calibers are elevated (e.g., acetazolamide, inhalational anesthesia, dimethyl sulfoxide) than when they are reduced (e.g., barbiturate or propofol anesthesia, indomethacin, hypocapnia, or post-SD oligemia after a preceding SD) (71,95,257,394,460). Although anesthetics can alter SD susceptibility (74,191,200,240,241,375,404,443,466), they do not appear to have a consistent direct effect on the hemodynamic response (443); both absent and potent peak hyperemic responses have been reported in unanesthetized animals in different studies (95,424,443). Nevertheless, anesthesia can indirectly influence the hemodynamic response by changing resting CBF (128) or systemic blood pressure (see below).…”

Remote Limb Ischemic Preconditioning: A Neuroprotective Technique in Rodents

“…Ketamine, an NMDA antagonist, has a multitude of protective effects in vivo 38 , including the potential to prevent excitotoxicity to neurons, activate the mTOR pathway and release BDNF into the serum [39][40][41] . Ketamine has been reported to enhance neuronal survival following brain trauma in humans and reduce light injury in rodent photoreceptors 42,43 . Investigations into the mechanism of remote ischemic conditioning with awake blood pressure cuffing will avoid anesthetic confounds.…”