Objective: Oxidative stress contributes to secondary damage after traumatic brain injury (TBI). Hypothermia decreases endogenous antioxidant consumption and lipid peroxidation after experimental cerebral injury. Our objective was to determine the effect of therapeutic hypothermia on oxidative damage after severe TBI in infants and children randomized to moderate hypothermia vs. normothermia.
Design: Prospective randomized controlled study.
Setting: Pediatric intensive care unit of Pittsburgh Children’s Hospital.
Patients: The study included 28 patients.
Measurements and Main Results: We compared the effects of hypothermia (32°C–33°C) vs. normothermia in patients treated in a single center involved in a multicentered randomized controlled trial of hypothermia in severe pediatric TBI (Glasgow Coma Scale score ≤8). The patients randomized to hypothermia (n = 13) were cooled to target temperature within ∼6 to 24 hours for 48 hours and then rewarmed. Antioxidant status was assessed by measurements of total antioxidant reserve and glutathione. Protein oxidation and lipid peroxidation were assessed by measurements of protein thiols and F2-isoprostane, respectively, in ventricular cerebrospinal fluid (CSF) samples (n = 76) obtained on day 1–3 after injury. The association between Glasgow Coma Scale score, age, gender, treatment, temperature, time after injury, and CSF antioxidant reserve, glutathione, protein-thiol, F2-isoprostane levels were assessed by bivariate and multiple regression models. Demographic and clinical characteristics were similar between the two treatment groups. Mechanism of injury included both accidental injury and nonaccidental injury. Multiple regression models revealed preservation of CSF antioxidant reserve by hypothermia (p = 0.001). Similarly, a multiple regression model showed that glutathione levels were inversely associated with patient temperature at the time of sampling (p = 0.002). F2-isoprostane levels peaked on day 1 after injury and were progressively decreased thereafter. Although F2-isoprostane levels were approximately three-fold lower in patients randomized to hypothermia vs. normothermia, this difference was not statistically significant.
Conclusion: To our knowledge, this is the first study demonstrating that hypothermia attenuates oxidative stress after severe TBI in infants and children. Our data also support the concept that CSF represents a valuable tool for monitoring treatment effects on oxidative stress after TBI.
From the Safar Center for Resuscitation Research (HB, PMK, KLJ-F); Children’s Hospital of Pittsburgh (HB, PDA, DB, PMK); Center for Free Radical and Antioxidant Health (HB, VEK); Departments of Critical Care Medicine (HB, PMK); Environmental and Occupational Health and Pharmacology (HB, VEK); Neurosurgery (PDA, DB); Epidemiology and Public Health (SRW); University of Pittsburgh, Pittsburgh, PA; Department of Pediatrics (PS), Division of Critical Care Services, University of Texas Southwestern Medical Center, Children’s Medical Center of Dallas, Dallas, TX; and Department of Pediatrics (YCL), Baylor College of Medicine, Division of Critical Care, Houston, TX.
Supported, in part, by grants NS30318, NS38087, NS34884, NS052478, NS061817, HD057587, and T32-HD40686 (to PS and YCL) from NIH, Laerdal Foundation, CDC (University of Pittsburgh Centers for Injury Research and Control [CIRCL]) and 0535365N by American Heart Association.
Dr. Wisniewski has received consulting fees from Cyberonic Inc., ImaRx Therapeutics Inc., Bristol-Myers Squibbs Co., Organon, and Case–Western University. Dr. Kochanek is a patent holder of EPR. The remaining authors have not disclosed any potential conflicts of interest.
For information regarding this article, E-mail: firstname.lastname@example.org
Therapeutic hypothermia preserves antioxidant defenses after severe traumatic brain injury in infants and children: Erratum
In the article on page 689 of the February 2009 issue, there were several corrections that were inadvertantly left out of the final version. On page 689, in the third column, the reference should have been 21 instead of 16. On page 690, in the first column, line 6, a reference number (21) should have been added after children. On page 693, in the third column, in the section entitled Developmental Ramifications, the first sentence should have stated, “Experimental studies in developmental studies of TBI support the notion that immature brain is particularly vulnerable to oxidative stress because of compromised antioxidant status (60).”
This erratum is published in the April 2009 issue of the journal.