Association between high cytokine levels with white matter injury in preterm infants with sepsis

Objective: To examine the association among interleukin-6, interleukin-8, tumor necrosis factor-alpha, interleukin-10, and interleukin-1 beta and white matter injury in very-low-birth-weight infants with clinical sepsis and to help predict infants at risk for development of white matter injury. Design: A prospective cohort study was carried out. Setting: Neonatal intensive care unit. Patients: Very low birth weight infants with clinical early-onset sepsis. Exclusion criteria were death before 14 days, major malformations, and congenital infections. Intervention: Ultrasound brain scans were carried out on the third day and weekly until the sixth week of life or discharge and confirmed by a magnetic resonance image performed in the first year. Plasma was assayed for interleukin-6, interleukin-8, tumor necrosis factor-alpha, interleukin-10, and interleukin-1 beta in the same sample collected for sepsis work-up. Mann-Whitney, chi-square, t tests, multiple regression, and receiver operating characteristic analysis were applied. Measurements and Main Results: From July 2005 to October 2007 we studied 84 very-low-birth-weight infants, 27 (32%) with white matter injury, and 57 (68%) control subjects (with no white matter injury). Proven early-onset sepsis and necrotizing enterocolitis were high risk for white matter injury after adjustment for gestational age and birth weight (relative risk, 3.04; 1.93-4.80 and relative risk, 2.2; 1.31-3.74, respectively). Interleukin-6, interleukin- 8, and tumor necrosis factor-alpha levels were higher in infants with white matter injury than in control subjects (p < .0001). Interleukin-1 beta and interleukin-10 were similar. The areas under the curve for interleukin-6, interleukin-8, and tumor necrosis factor-alpha were 0.96 (0.92-0.99), 0.97 (0.94-1.0), and 0.93 (0.86-0.99), respectively. Interleukin-8 >= 100 pg/mL was the best predictor of white matter injury; the sensitivity and specificity were 96% and 83%, respectively, and negative predictive value was 98%. Conclusions: Very-low-birth-weight infants with proven early-onset sepsis, necrotizing enterocolitis, and high plasma levels of interleukin-6, interleukin-8, and tumor necrosis factor-alpha are at high risk for white matter injury. (Pediatr Crit Care Med 2012; 13:183-187)