Marked Gender Effect on Lipid Peroxidation after Severe Traumatic Brain Injury in Adult Patients

Striking gender differences have been reported in the pathophysiology and outcome of acute neurological injury. Greater neuroprotection in females versus males may be due, in part, to direct and indirect sex hormone-mediated antioxidant mechanisms. Progesterone administration decreases brain levels of F2-isoprostane, a marker of lipid peroxidation, after experimental traumatic brain injury (TBI) in male rats, and estrogen is neuroprotective in experimental neurological injury. In this study, we evaluated the effect of gender on lipid peroxidation, as assessed by cerebrospinal fluid (CSF) levels of F2-isoprostane, after severe TBI in humans. Lipid peroxidation was assessed in CSF from 68 adults enrolled in two randomized controlled trials evaluating the effect of therapeutic hypothermia after severe TBI (Glasgow coma scale [GCS] score ≤ 8). Patients treated with hypothermia (n = 41, 12 females, 29 males) were cooled to 32-33°C (within ~6 h) for either 24 or 48 h and then re-warmed. F2-isoprostane levels were assessed by ELISA in ventricular CSF samples (n = 199) on day 1, 2, and 3. The association between age, GCS score, time, gender, treatment, duration of treatment, core temperature at the time of CSF sampling, secondary hypoxemia, and CSF F2-isoprostane level was assessed by multivariate and dichotomous analyses. F2-isoprostane was ~2-fold higher in males than females (145.8 ± 39.6 versus 75.4 ± 16.6 pg/mL, day 1 p = 0.018). An effect of time after injury (p = 0.007) was reflected by a marked early peak in F2-isoprostane (day 1). CSF F2-isoprostane was also associated with hypoxemia (p = 0.04). Hypothermia tended to decrease F2-isoprostane levels only in males on d1 after TBI. To our knowledge, this is the first study showing gender differences in lipid peroxidation after clinical TBI. Lipid peroxidation occurs early after severe TBI in adults and is more prominent in males vs females. These results established that gender is an important consideration in clinical trial design, particularly in the case of antioxidant strategies.