title: Sulfonylurea Receptor-1: A Novel Biomarker for Cerebral Edema in Severe Traumatic Brain Injury.
abstract: Cerebral edema is a key poor prognosticator in traumatic brain injury. There are no biomarkers identifying patients at-risk, or guiding mechanistically-precise therapies. Sulfonylurea receptor-1-transient receptor potential cation channel M4 is upregulated only after brain injury, causing edema in animal studies. We hypothesized that sulfonylurea receptor-1 is measurable in human cerebrospinal fluid after severe traumatic brain injury and is an informative biomarker of edema and outcome.
  
  
  
  A total of 119 cerebrospinal fluid samples were collected from 28 severe traumatic brain injury patients. Samples were retrieved at 12, 24, 48, 72 hours and before external ventricular drain removal. Fifteen control samples were obtained from patients with normal pressure hydrocephalus. Sulfonylurea receptor- 1 was quantified by enzyme-linked immunosorbent assay. Outcomes included CT edema, intracranial pressure measurements, therapies targeting edema, and 3-month Glasgow Outcome Scale score.
  
  
  
  Sulfonylurea receptor-1 was present in all severe traumatic brain injury patients (mean = 3.54 ± 3.39 ng/mL, peak = 7.13 ± 6.09 ng/mL) but undetectable in all controls (p < 0.001). Mean and peak sulfonylurea receptor-1 was higher in patients with CT edema (4.96 ± 1.13 ng/mL vs 2.10 ± 0.34 ng/mL; p = 0.023). There was a temporal delay between peak sulfonylurea receptor-1 and peak intracranial pressure in 91.7% of patients with intracranial hypertension. There was no association between mean/peak sulfonylurea receptor-1 and mean/peak intracranial pressure, proportion of intracranial pressure greater than 20 mm Hg, use of edema-directed therapies, decompressive craniotomy, or 3-month Glasgow Outcome Scale. However, decreasing sulfonylurea receptor-1 trajectories between 48 and 72 hours were significantly associated with improved cerebral edema and clinical outcome. Area under the multivariate model receiver operating characteristic curve was 0.881.
  
  
  
  This is the first report quantifying human cerebrospinal fluid sulfonylurea receptor-1. Sulfonylurea receptor-1 was detected in severe traumatic brain injury, absent in controls, correlated with CT-edema and preceded peak intracranial pressure. Sulfonylurea receptor-1 trajectories between 48 and 72 hours were associated with outcome. Because a therapy inhibiting sulfonylurea receptor-1 is available, assessing cerebrospinal fluid sulfonylurea receptor-1 in larger studies is warranted to evaluate our exploratory findings regarding its diagnostic, and monitoring utility, as well as its potential to guide targeted therapies in traumatic brain injury and other diseases involving cerebral edema.
authors.affiliation: 1Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA. 2Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA. 3Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA. 4Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA. 5Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, PA. 6Department of Biostatistics, School of Medicine, University of Pittsburgh, Pittsburgh, PA. 7Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA. 8Department of Anesthesiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Ruchira M
authors.initials: RM
authors.lastname: Jha
authors.forename: Ava M
authors.initials: AM
authors.lastname: Puccio
authors.forename: Sherry Hsiang-Yi
authors.initials: SH
authors.lastname: Chou
authors.forename: Chung-Chou H
authors.initials: CH
authors.lastname: Chang
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Wallisch
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Molyneaux
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Zusman
authors.forename: Lori A
authors.initials: LA
authors.lastname: Shutter
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Poloyac
authors.forename: Keri L
authors.initials: KL
authors.lastname: Janesko-Feldman
authors.forename: David O
authors.initials: DO
authors.lastname: Okonkwo
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001929:Brain Edema / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging / Q000209:etiology / Q000628:therapy; D000070642:Brain Injuries, Traumatic / Q000134:cerebrospinal fluid* / Q000150:complications; D016022:Case-Control Studies; D005260:Female; D015600:Glasgow Coma Scale; D023261:Glasgow Outcome Scale; D006801:Humans; D007427:Intracranial Pressure; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012372:ROC Curve; D064233:Sulfonylurea Receptors / Q000378:metabolism*; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D055815:Young Adult
chemical_list: C577507:ABCC8 protein, human; D015415:Biomarkers; D064233:Sulfonylurea Receptors