Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates

Mortality and morbidity due to neonatal sepsis and necrotizing enterocolitis (NEC) is high despite the use of potent antimicrobial agents. Agents that modulate inflammation may improve outcomes. Pentoxifylline, a phosphodiesterase inhibitor, is one such agent.

The primary objectives were to assess the effect on mortality and the safety of intravenous pentoxifylline as an adjunct to antibiotic therapy in neonates with suspected or confirmed sepsis and NEC.

The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2011), MEDLINE, EMBASE and CINAHL, Science Citation Index for articles referencing Lauterbach 1996, proceedings of the Pediatric Academic Societies (1990 to 2011), BIOSIS (1992 to 2011), conference proceedings (1992 to 2011), ongoing trials and reference lists of identified RCTs were searched in July 2011.

Randomised or quasi-randomised trials assessing the efficacy of pentoxifylline as an adjunct to antibiotics for treatment of suspected or confirmed sepsis or NEC in neonates were eligible.

Two review authors independently abstracted information for the outcomes of interest. Typical relative risk (RR) and risk difference (RD) with 95% confidence intervals (CI) using fixed effects model are reported for dichotomous outcomes and mean differences for continuous outcomes. NNT was calculated for outcomes for which there was a statistically significant reduction in RD.

In four randomised controlled trials, 227 neonates with suspected or confirmed sepsis were randomised to pentoxifylline or placebo. Pentoxifylline therapy significantly decreased "all cause mortality during hospital stay" in the overall population of infants with sepsis [typical RR 0.40 (95%CI 0.20 to 0.77); typical RD -0.15 (95%CI -0.26 to -0.05); NNT 7 (95%CI 4 to 20)]. Subgroup analyses revealed significant reduction in mortality in preterm infants, infants with confirmed sepsis and gram-negative sepsis. Pentoxifylline treatment significantly decreased length of hospital stay [mean difference -11.20 [95%CI -22.09 to -0.31] but not development of NEC in neonates with sepsis [typical RR 0.29 (95%CI 0.07 to 1.24); typical RD -0.20 (95%CI -0.41 to 0.01)]. No adverse effects due to pentoxifylline were noted. No completed trial of treatment with pentoxifylline for treatment of NEC was identified.

Current evidence from four small studies suggests that the use of pentoxifylline as an adjunct to antibiotics in neonatal sepsis decreases mortality without any adverse effects. Researchers are encouraged to undertake large well-designed multicenter trials to confirm or refute the effectiveness of pentoxifylline in reducing mortality and adverse outcomes in neonates with suspected or confirmed neonatal sepsis and NEC.