Pentoxifylline for neonatal sepsis.
BACKGROUND
Although the overall incidence of neonatal sepsis has declined over the past decade, mortality remains high in the pre term infant. The high level of mortality and morbidity from sepsis despite the use of potent anti-microbial agents, and the global emergence of antibiotic resistance, have led to the search for new modalities to boost new born host defences. Pentoxifylline, a xanthine derivative and a phosphodiesterase inhibitor, has been shown to possess a broad spectrum of activity modulating inflammation.


OBJECTIVE
The primary objective was 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.


METHODS
The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2002), MEDLINE, EMBASE and CINAHL were searched in October 2002 and again in March 2003. Science Citation Index for articles referencing Lauterbach 1996 and Lauterbach 1999 was searched as well as proceedings of the Pediatric Academic Societies which were published in Pediatric Research from 1980. Doctoral dissertations and theses were searched from 1980. The reference lists of identified RCTs, and personal files were searched. No language restriction was applied.


METHODS
Studies were included if they were randomised or quasi-randomised trials, assessing the efficacy of pentoxifylline compared to placebo or no intervention as an adjunct to antibiotic therapy of suspected or confirmed sepsis in newborn infants less than 28 days old. Eligible trials were required to report treatment effects on at least one of the following outcomes: all cause mortality during initial hospital stay, neurological development at two years of age or later, length of hospital stay, duration of ventilation via endotracheal intubation, chronic lung disease in survivors, periventricular leukomalacia, necrotising enterocolitis, or adverse events.


METHODS
Two reviewers independently abstracted information for the outcomes of interest. Any differences were resolved by mutual discussion. Typical Relative Risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using fixed effects model are reported for dichotomous outcomes. NNT was calculated for outcomes for which there was a statistically significant reduction in RD.


RESULTS
Two RCTs enrolled a total of 140 preterm (< 36 weeks) neonates with suspected late onset (> 7 days) sepsis to evaluate the effect of pentoxifylline on neonatal outcomes. However, the two studies reported outcomes of only the 107 randomised patients with confirmed sepsis. The results showed a reduction in 'all cause mortality during hospital stay' following pentoxifylline treatment [typical RR 0.14 (95% CI 0.03, 0.76), RD -0.16 (95% CI -0.27, - 0.04), NNT 6 (95% CI 4, 25)]. No adverse effects due to pentoxifylline were observed in the two included trials. No other outcomes of interest were reported.


CONCLUSIONS
Current evidence suggests that the use of pentoxifylline as an adjunct to antibiotics in neonatal sepsis reduces mortality without any adverse effects. But the number of neonates studied is small and considerable methodological weaknesses exist in the included trials. Hence these results should be interpreted with caution. Researchers are encouraged to undertake large well-designed trials to confirm or refute the effectiveness of pentoxifylline to reduce mortality and adverse outcomes in neonates with suspected or confirmed neonatal sepsis. Researchers might also compare pentoxifylline with other adjuncts to antibiotics which modulate inflammation (e.g. intravenous immunoglobulins, haematopoetic colony stimulating factors among others) in reducing mortality and morbidity due to neonatal sepsis.
Epsom & St Helier NHS Trust, Division of Neonatology, Department of Child Health, Queen Mary's Hospital for Children, Wrythe Lane, Carshalton, Surrey, UK, SM5 1AA.
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Haque
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Mohan
D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy; D017024:Chemotherapy, Adjuvant; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D010431:Pentoxifylline / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D018805:Sepsis / Q000188:drug therapy*
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D010726:Phosphodiesterase Inhibitors; D010431:Pentoxifylline