Glial fibrillary acidic protein as a brain injury biomarker in children undergoing extracorporeal membrane oxygenation

Abstract

Objective: To determine whether, in children, plasma glial fibrillary acidic protein is associated with brain injury during extracorporeal membrane oxygenation and with mortality.

Design: Prospective, observational study.

Setting: Pediatric intensive care unit in an urban tertiary care academic center.

Patients: Neonatal and pediatric patients on extracorporeal membrane oxygenation (n = 22).

Interventions: Serial blood sampling for glial fibrillary acidic protein measurements.

Measurements and main results: Prospective patients age 1 day to 18 yrs who required extracorporeal membrane oxygenation from April 2008 to August 2009 were studied. Glial fibrillary acidic protein was measured using an electrochemiluminescent immunoassay developed at Johns Hopkins. Control samples were collected from 99 healthy children (0.5-16 yrs) and 59 neonatal intensive care unit infants without neurologic injury. In controls, the median glial fibrillary acidic protein concentration was 0.055 ng/mL (interquartile range, 0-0.092 ng/mL) and the 95th percentile of glial fibrillary acidic protein was 0.436 ng/mL. In patients on extracorporeal membrane oxygenation, plasma glial fibrillary acidic protein was measured at 6, 12, and every 24 hrs after cannulation. We enrolled 22 children who underwent extracorporeal membrane oxygenation. Median age was 7 days (interquartile range, 2 days to 9 yrs), and primary extracorporeal membrane oxygenation indication was: cardiac failure, six of 22 (27.3%); respiratory failure, 12 of 22 (54.5%); extracorporeal cardiopulmonary resuscitation, three of 22 (13.6%); and sepsis, one of 22 (4.6%). Seven of 22 (32%) patients developed acute neurologic injury (intracranial hemorrhage, brain death, or cerebral edema diagnosed by imaging). Fifteen of 22 (68%) survived to hospital discharge. In the extracorporeal membrane oxygenation group, peak glial fibrillary acidic protein levels were higher in children with brain injury than those without (median, 5.9 vs. 0.09 ng/mL, p = .04) and in nonsurvivors compared with survivors to discharge (median, 5.9 vs. 0.09 ng/mL, p = .04). The odds ratio for brain injury for glial fibrillary acidic protein >0.436 ng/mL vs. normal was 11.5 (95% confidence interval, 1.3-98.3) and the odds ratio for mortality was 13.6 (95% confidence interval, 1.7-108.5).

Conclusions: High glial fibrillary acidic protein during extracorporeal membrane oxygenation is significantly associated with acute brain injury and death. Brain injury biomarkers may aid in outcome prediction and neurologic monitoring of patients on extracorporeal membrane oxygenation to improve outcomes and benchmark new therapies.

Figure 1

Peak plasma GFAP concentrations in children on ECMO with and without acute neurologic injury (n=22) GFAP: glial fibrillary acidic protein; ECMO: extracorporeal membrane oxygenation. Please note logarithmic scale on Y axis.

Figure 2

A. Serial plasma GFAP concentrations in children on ECMO with acute neurologic injury (n=7). X represents death in the pediatric intensive care unit; open squares represent the time of diagnosis of acute neurologic injury closest in time (within 24 hours) to the last GFAP measurement; dashed line marks the 95^th percentile of normal controls. Note only 6 open squares – one patient had a diagnostic head ultrasound 48 hours after the only GFAP measurement (GFAP measurement 24 hours prior to diagnosis is missing). Please note different scales in Figures 2A. and 2B. B. Serial plasma GFAP concentrations in children on ECMO without acute neurologic injury (n=15). X represents death in the pediatric intensive care unit; dashed line marks the 95^th percentile of normal controls. Please note different scales in Figures 2A. and 2B.

Figure 2

A. Serial plasma GFAP concentrations in children on ECMO with acute neurologic injury (n=7). X represents death in the pediatric intensive care unit; open squares represent the time of diagnosis of acute neurologic injury closest in time (within 24 hours) to the last GFAP measurement; dashed line marks the 95^th percentile of normal controls. Note only 6 open squares – one patient had a diagnostic head ultrasound 48 hours after the only GFAP measurement (GFAP measurement 24 hours prior to diagnosis is missing). Please note different scales in Figures 2A. and 2B. B. Serial plasma GFAP concentrations in children on ECMO without acute neurologic injury (n=15). X represents death in the pediatric intensive care unit; dashed line marks the 95^th percentile of normal controls. Please note different scales in Figures 2A. and 2B.