Therapeutic hypothermia preserves antioxidant defenses after severe traumatic brain injury in infants and children*

Abstract

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 ICU of Pittsburgh Children's Hospital Patients-The study included 28 patientsMeasurements and main results-We compared the effects of hypothermia (32-33°C) vs normothermia in patients treated in a single center involved in a multi-center randomized controlled trial of hypothermia in severe pediatric TBI (GCS score ≤ 8). The patients randomized to hypothermia (n=13) were cooled to target temperature within ∼6h-24h for 48h and then re-warmed. Antioxidant status was assessed by measurements of total antioxidant reserve [AOR] and glutathione. Protein oxidation and lipid peroxidation were assessed by measurements of protein-thiols and F 2 -isoprostane, respectively in ventricular CSF samples (n=76) obtained on day1-3 after injury. The association between GCS score, age, gender, treatment, temperature, time after injury, and CSF AOR, glutathione, protein-thiol, F2-isoprostane levels were assessed by bivariate and multiple regression models. Corresponding 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 ∼3-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.

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

“…81 Multiple studies have shown that brain injuries increase the levels of F2-isoprostane both in the CSF and the serum of TBI patients. [82][83][84] For example, Varma et al 85 demonstrated that in children who had severe TBI, the level of F2-isoprostane was elevated by 6-fold compared with that observed in uninjured controls. This marker was found to correlate well with the appearance of NSE, further supporting its use as an indicator of brain damage.…”

Use of Magnesium in Traumatic Brain Injury

“…85,86 In infants and children, hypothermia treatment has shown preservation of oxidative defenses in the CSF after TBI. 87 A meta-analysis of the clinical trials has shown that hypothermia reduced mortality and improved neurological outcome, although this was offset with an increased risk of pneumonia. 88 No combination effects of magnesium and hypothermia have been reported in humans with TBI.…”

Traumatic brain injury in pediatric patients: evidence for the effectiveness of decompressive surgery

“…34 Current medical treatments to reduce ICP include hyperosmolar therapy (such as mannitol or hypertonic saline), 53 hyperventilation, 15,47 sedation and paralytics, and head of bed elevation. In addition, barbiturate-induced coma 2 and hypothermia 7 have been shown to reduce cerebral metabolic rate and oxygen demands, offering a protective role. 2 If medical treatment is ineffective in normalizing ICP, several types of surgical intervention are possible.…”