Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates

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

Our primary objectives were :1.To assess the effect of intravenous pentoxifylline as an adjunct to antibiotic therapy on mortality and morbidity in neonates with suspected or confirmed sepsis.2.To assess the effect of intravenous pentoxifylline as an adjunct to antibiotic therapy on mortality and morbidity in neonates with NEC.

We searched the Cochrane Neonatal Review Group Specialized Register, CENTRAL (The Cochrane Library Issue 2, 2014), EMBASE (January 1980 to May 2014), PubMed (January 1966 to May 2014), CINAHL (January 1982 to May 2014), Science Citation Index (January 1990 to May 2014), and BIOSIS (January 1992 May 2014) in May 2014. We checked references and cross-references from identified studies. We handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings (from January 1990 to May 2014). We placed no restrictions on language.

We included 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.

We reported typical risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI) using fixed-effect model for dichotomous outcomes and mean difference (MD) for continuous outcomes. We calculated the number needed to treat for an additional beneficial outcome (NNTB) if there was a statistically significant reduction in RD.

Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis decreased all-cause mortality during hospital stay (typical RR 0.57, 95% CI 0.35 to 0.93; typical RD -0.08, 95% CI -0.14 to -0.01; NNTB 13, 95% CI 7 to 100; 6 studies, 416 participants, low-quality evidence). Subgroup analyses revealed decrease in mortality in preterm infants, infants with confirmed sepsis, and infants with gram-negative sepsis (low-quality evidence, four studies). Pentoxifylline decreased length of hospital stay (MD -7.59 days, 95% CI -11.65 to -3.52; 2 studies, 148 participants, low-quality evidence). Pentoxifylline did not change the risk of development of NEC, chronic lung disease, severe intraventricular haemorrhage, retinopathy of prematurity, or periventricular leukomalacia in neonates with sepsis (one to two studies, very low-quality evidence). Pentoxifylline therapy compared to pentoxifylline and immunoglobulin M-enriched intravenous immunoglobulin or immunoglobulin M-enriched intravenous immunoglobulin alone did not change mortality or development of NEC in neonates with sepsis (one study, very low-quality evidence). We noted no adverse effects due to pentoxifylline. We identified no trials evaluating pentoxifylline treatment for NEC.

Low-quality evidence from six small studies suggests that pentoxifylline therapy as an adjunct to antibiotics in neonatal sepsis decreases mortality without any adverse effects. We encourage researchers to undertake large, well-designed multicentre trials to confirm or refute the effectiveness of pentoxifylline in reducing mortality and morbidity in neonates with sepsis or NEC.