Abstract
Severe traumatic brain injury (TBI) activates a robust systemic response that involves inflammatory and other factors, including estradiol (E2), associated with increased deaths. Tumor necrosis factor-alpha (TNFα) is a significant mediator of systemic shock, and it is an extra-gonadal transcription factor for E2 production. The study objectives were to test the hypotheses: (1) a positive feedback relationship exists between acute serum TNFα and E2; and (2) acute concentrations of E2 and TNFα are prognostic indicators of death after severe TBI. This prospective cohort study included N = 157 adults with severe TBI. Serum samples were collected for the first five days post-injury. The TNFα and E2 levels were averaged into two time epochs: first 72 h (T1) and second 72 h post-injury (T2). A cross-lag panel analysis conducted between T1 and T2 TNFα and E2 levels showed significant cross-lag effects: T1 TNFα and T1 E2 were related to T2 E2 and T2 TNFα, respectively. Cox proportional hazards multi variable regression models determined that increases in T1 E2 (hazard ratio [HR] = 1.79, 95% confidence interval [CI]: 1.15, 2.81), but not T2 E2 (HR = 0.91, 95% CI: 0.56, 1.47), were associated with increased risk of death. Increased T2 TNFα (HR = 2.47, 95% CI: 1.35, 4.53), and T1 TNFα (HR = 1.47, 95% CI: 0.99, 2.19), to a lesser degree, were associated with increased risk of death. Relationships of death with T2 TNFα and T1 E2 were mediated partially by cardiovascular, hepatic, and renal dysfunction. Both E2 and TNFα are systemic, reciprocally related biomarkers that may be indicative of systemic compromise and increased risk of death after severe TBI.