Endothelin-1 Is Increased in Cerebrospinal Fluid and Associated with Unfavorable Outcomes in Children after Severe Traumatic Brain Injury

Abstract

Severe pediatric traumatic brain injury (TBI) is associated with unfavorable outcomes secondary to injury from activation of the inflammatory cascade, the release of excitotoxic neurotransmitters, and changes in the reactivity of cerebral vessels, causing ischemia. Hypoperfusion of injured brain tissues after TBI is also associated with unfavorable outcomes. Therapeutic hypothermia is an investigational treatment strategy for use in patients with severe TBI that has shown differential effects on various cerebrospinal fluid (CSF) mediators in pediatric patients. Endothelin-1 (ET-1) is a powerful vasoconstrictor that exerts its effects on the cerebrovascular endothelium for sustained periods after TBI. The purpose of this study was to determine if CSF concentrations of ET-1 are increased after severe TBI in children, and if they are associated with demographics and outcomes that are affected by therapeutic hypothermia. This was an ancillary study to a prospective, randomized-controlled trial of early hypothermia in a tertiary care pediatric intensive care unit. Children (n = 34, age 3 months-15 years) suffering from severe TBI were randomized to hypothermia (n = 19) and normothermia (n = 15) as part of the efficacy study. Children undergoing diagnostic lumbar puncture (n = 11) to rule out infection were used as controls. Patients received either mild to moderate hypothermia (32-33°C) or normothermia as part of their treatment protocol. CSF was serially collected during the first 5 days after TBI. ET-1 concentrations were quantitated in patient and control CSF samples by a validated ELISA in duplicate with a limit of quantification of 0.195 pg/mL. CSF ET-1 concentrations were increased by two- to threefold in children after TBI compared to controls, and the increase was sustained for up to 5 days post-TBI. This relationship was not affected by hypothermia, and there were no differences in ET-1 response between children with inflicted and accidental TBI. Group-based trajectory analysis revealed two distinct groups with similar ET-1 levels over time. Univariate analysis showed a significant association between ET-1 levels and Glasgow Outcome Scale (GOS) scores, for which higher ET-1 levels over time were associated with unfavorable outcomes. ET-1 is increased in children with severe TBI and is associated with unfavorable outcomes. This increase in ET-1 may mediate the hypoperfusion or cerebrovascular dysfunction accompanying severe TBI in children. Importantly, hypothermia does not affect the brain's ET-1 response as measured in the CSF.

Fresh Frozen Plasma Resuscitation Provides Neuroprotection Compared to Normal Saline in a Large Animal Model of Traumatic Brain Injury and Polytrauma

“…20 High CSF levels of ET-1 have thus been shown to predict adverse outcome after TBI. 21 Counteracting this vasoconstrictor effect are factors such as eNOS, an endothelial-derived enzyme generating nitric oxide (NO) and thus an important aspect of maintaining vasodilation and cerebral perfusion. Several converging lines of evidence have thus collectively identified an important role of eNOS and NO in regulation of cerebral blood flow after TBI.…”

Pediatric Neurocritical Care

“…These may have potential to act as markers of injury severity or predict outcome in patients with TBI [28][29][30]. In addition, biomarkers have been studied as a means to differentiate inflicted trauma from accidental trauma, to elucidate differences in the pathophsyiology of these injury types, and to serve as a screening tool for the diagnosis of iTBI [30][31][32][33][34][35]. These studies provide further evidence that the biochemical response to inflicted TBI may be different from noninflicted injury.…”

Endothelin-1-mediated vasoconstriction alters cerebral gene expression in iron homeostasis and eicosanoid metabolism

“…Furthermore, endothelin receptor antagonists have recently been shown to significantly reduce vasospasmrelated morbidity in post-SAH patients (Macdonald et al, 2012). Similarly, ET-1 levels are elevated in the CSF and plasma of TBI patients potentially contributing to secondary ischemia and vasogenic edema (Chatfield et al, 2011;Salonia et al, 2010). In Alzheimer's disease, ET-1 mRNA and protein levels are elevated in the neurons and cerebral blood vessels of the temporal cortex, possibly in response to oligomeric amyloid-beta (Palmer et al, 2012).…”