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Severe traumatic brain injury in children elevates glial fibrillary acidic protein in cerebrospinal fluid and serum*

Fraser, Douglas D. MD, PhD; Close, Taylor E. MSc; Rose, Keeley L. MSc, PhD; Ward, Roxanne RN; Mehl, Martin PhD; Farrell, Catherine MD; Lacroix, Jacques MD; Creery, David MD, MSc; Kesselman, Murray MD; Stanimirovic, Danica MD, PhD; Hutchison, James S. MD; for the Canadian Critical Care Translational Biology Group

Pediatric Critical Care Medicine:
doi: 10.1097/PCC.0b013e3181e8b32d
Neurocritical Care
Abstract

Objectives: 1) To determine the levels of glial fibrillary acidic protein (GFAP) in both cerebrospinal fluid and serum; 2) to determine whether serum GFAP levels correlate with functional outcome; and 3) to determine whether therapeutic hypothermia, as compared with normothermia, alters serum GFAP levels in children with severe traumatic brain injury (TBI).

Design: Laboratory-based analyses; postrandomized, controlled trial.

Setting: Four Canadian pediatric intensive care units and a university-affiliated laboratory.

Patients: Twenty-seven children, aged 2–17 yrs, with severe TBI (Glasgow Coma Scale score of ≤8).

Interventions: Hypothermia therapy (32.5°C) for 24 hrs with cooling started within 8 hrs of injury and rewarming at a rate of 0.5°C every 2 hrs or normothermia (37.0°C).

Measurements and Main Results: GFAP was measured in cerebrospinal fluid and serum, using enzyme-linked immunosorbent assay. Levels of GFAP were maximal on day 1 post-TBI, with cerebrospinal fluid GFAP (15.5 ± 6.1 ng/mL) 25-fold higher than serum GFAP (0.6 ± 0.2 ng/mL). Cerebrospinal fluid GFAP normalized by day 7, whereas serum GFAP decreased gradually to reach a steady state by day 10. Serum GFAP measured on day 1 correlated with Pediatric Cerebral Performance Category scores determined at 6 months post-TBI (ρ = 0.527; p = .008) but failed to correlate with the injury scoring on admission, physiologic variables, or indices of injury measured on computerized tomography imaging. The areas under the receiver operating characteristic curves for pediatric intensive care unit day 1 serum GFAP in determining good outcome were 0.80 (pediatric cerebral performance category, 1–2; normal-mild disability) and 0.91 (pediatric cerebral performance category, 1–3; normal-moderate disability). For a serum GFAP cutoff level of 0.6 ng/mL, sensitivity and specificity were 88% to 90% and 43% to 71%, respectively. Serum GFAP levels were similar among children randomized to either therapeutic hypothermia or normothermia.

Conclusions: GFAP was markedly elevated in cerebrospinal fluid and serum in children after severe TBI and serum GFAP measured on pediatric intensive care unit day 1 correlated with functional outcome at 6 months. Hypothermia therapy did not alter serum GFAP levels compared with normothermia after severe TBI in children. Serum GFAP concentration, together with other biomarkers, may have prognostic value after TBI in children.

Author Information

From the Division of Critical Care Medicine (DDF), Department of Pediatrics, Departments of Physiology and Pharmacology (DDF, TEL, KLR), Department of Clinical Neurological Sciences (DDF), University of Western Ontario, London, ON, Canada; Children's Health Research Institute (DDF, TEC, KLR), London, ON, Canada; Centre for Critical Illness Research (DDF), London, ON, Canada; Children's Hospital of Eastern Ontario Research Institute (RW), Ottawa, ON, Canada; R-Biopharm AG (MM), Darmstadt, Germany; Division of Intensive Care (CF, JL), Department of Pediatrics, Sainte-Justine's Hospital, Montreal, QC, Canada; Division of Intensive Care (DC), Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada; Division of Intensive Care (MK), Department of Pediatrics, Children's Hospital of Winnipeg, Winnipeg, MB, Canada; Institute for Biological Sciences (DS), National Research Council, Ottawa, ON, Canada; Departments of Critical Care Medicine and Pediatrics (JSH), Hospital for Sick Children, Toronto, ON, Canada; Neuroscience and Mental Health Research Program (JSH), Hospital for Sick Children Research Institute, Toronto, ON, Canada; and Institute of Medical Science (JSH), University of Toronto, Toronto, ON, Canada.

Douglas D. Fraser was supported, in part, by the Children's Health Research Institute and the Centre for Critical Illness Research. He is a Canadian Institutes of Health Research Strategic Training Fellow in the Canadian Child Health Clinician Scientist Program. Taylor E. Close was supported, in part, by a Canadian Institutes of Health Research Doctoral Scholarship. Keeley L. Rose was supported, in part, by a Canadian Diabetic Association Doctoral Scholarship. The remaining authors have not disclosed any potential conflicts of interest. The biomarker research program within HyP-HIT was supported, in part, by a National Research Council of Canada Genomics and Health Initiative funding (D.S.).

The Hypothermia Pediatric Head Injury Trial (HyP-HIT) was supported by grant MCT50398 from the Canadian Institutes of Health Research (Canadian Neurotrauma Research Program), grants ONBO-00009 and ONRO-41 from the Ontario Neurotrauma Foundation, grant XG 99-057 from the Rick Hansen Institute, the Hospital for Sick Children Foundation, grant 98-62 from Physicians Services Incorporated, grant 004095-104 from Fonds de la Recherche en Santé du Québec, and grant 98/16S[E] from Children's Hospital of Eastern Ontario Research Institute.

For information regarding this article, E-mail: douglas.fraser@lhsc.on.ca

©2011The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies