Cerebrospinal Fluid Sulfonylurea Receptor-1 is Associated with Intracranial Pressure and Outcome after Pediatric TBI: An Exploratory Analysis of the Cool Kids Trial

Abstract

Sulfonylurea receptor-1 (SUR1) is recognized increasingly as a key contributor to cerebral edema, hemorrhage progression, and possibly neuronal death in multiple forms of acute brain injury. SUR1 inhibition may be protective and is actively undergoing evaluation in Phase-2/3 trials of traumatic brain injury (TBI) and stroke. In adult TBI, SUR1 expression is associated with intracranial hypertension and contusion expansion; its role in pediatric TBI remains unexplored. We tested 61 cerebrospinal fluid (CSF) samples from 16 pediatric patients with severe TBI enrolled in the multicenter Phase-3 randomized controlled "Cool Kids" trial and seven non-brain injured pediatric controls for SUR1 expression by enzyme-linked immunosorbent assay. Linear mixed models evaluated associations between mean SUR1 and intracranial pressure (ICP) over the first seven days and pediatric Glasgow Outcome Scale-Extended (GOS-E Peds) over the initial year after injury. SUR1 was undetectable in control CSF and increased versus control in nine of 16 patients with TBI. Mean SUR1 was not associated with age, sex, or therapeutic hypothermia. Each 1-point increase in initial Glasgow Coma Score was associated with a 1.68 ng/mL decrease in CSF SUR1. The CSF SUR1 was associated with increased ICP over seven days (b = 0.73, p = 0.004) and worse (higher) GOS-E Peds score (b = 0.24, p = 0.004). In this exploratory pediatric study, CSF SUR1 was undetectable in controls and variably elevated in severe TBI. Mean CSF SUR1 concentration was associated with ICP and outcome. These findings are distinct from our previous report in adults with severe TBI, where SUR1 was detected universally. SUR1 may be a viable therapeutic target in a subset of pediatric TBI, and further study is warranted.

Keywords: brain edema; cerebrospinal fluid; pediatrics; traumatic brain injury.

FIG. 1.

Association between detectable sulfonylurea receptor 1 (SUR1) and outcome. (A) Detectable cerebrospinal fluid (CSF) SUR1 was associated with a trend toward increased intracranial pressure (ICP) over the first seven days after injury (p = 0.084). This becomes significantly associated with increased ICP after the early post-injury period (24 h, shown by the vertical dashed line in the figure) during purported SUR1 up-regulation (p = 0.034). Error bars represent 95% confidence intervals. (B) Detectable CSF SUR1 was associated with worse functional outcome on the Glasgow Outcome Scale-Extended Pediatrics (GOS-E Peds) over 12 months (p = 0.045). Shaded areas represent 95% confidence intervals.