These two studies are both issues that I am involved with, Theresa Ochoa’s study I was aware of, and was waiting for the full publication, the other, from Egypt, I didn’t know about but should have done, but it confirms the need for a large RCT.
This study enrolled just under 200 babies and randomized them to lactoferrin or placebo in three NICUs in Lima, Peru. It showed that routine lactoferrin prophylaxis reduced clinically diagnosed sepsis episodes in low birth weight infants, a reduction which was not quite significant on the primary statistical analysis, but if you are only interested in culture positive, “definite” sepsis, then there was no difference. The authors note that in low and middle income countries lab facilities may be limited, so a clear definition of clinical sepsis, might be the best that can be done. The study included babies up to 2.5 kg, and used a body weight adjusted dose of lactoferrin. In my pilot study (accepted for publication in the Journal of Perinatology), we also did not show a difference in sepsis, but our study was even smaller than this one (with 79 infants enrolled) so we knew we were underpowered for sepsis, but we did work out many of the mechanics of performing a masked RCT of lactoferrin.
Which means that we need other, larger, better powered studies. Hello ELFIN and LIFT, and hopefully soon LIFT-CAN!
Shabaan AE, et al. Pentoxifylline Therapy for Late-Onset Sepsis in Preterm Infants: A Randomized Controlled Trial. Pediatric Infectious Disease Journal. 2015;34(6):e143-e8. Pentoxifylline has many different actions, in particular it inhibits transcription of tumour necrosis factor-alpha, which might be a good thing in sepsis; also, according to the authors of this study, it
preserves microvascular blood flow, prevents circulatory failure and intestinal vasoconstriction and has beneficial effects on endothelial cell function and coagulation in sepsis.
This study randomized 120 newborn preterm babies with clinical signs of sepsis to get either pentoxifylline or placebo, starting with the first dose of antibiotics, and continuing for 6 days. The babies in the pentoxifylline group had inotropic support less frequently, and less intravascular coagulation and thrombocytopenia. There was a minor benefit in mortality with the treatment (10% vs 17%), and other differences between groups favoured the pentoxifylline babies.
The latest version of the Cochrane review of pentoxifylline notes that the data are currently inadequate to be sure that this is a good thing to do, but they are all, so far, positive. It concludes
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.
The NHMRC in Australia has just funded such a trial! I am privileged to be one of the investigators, for an international trial of 900 very preterm babies with sepsis or NEC who will get either pentoxifylline or placebo. Pentoxifylline is already licensed in many countries, for other indications, and is actually fairly cheap. So if this works in a well-performed trial then there is a real chance of doing good things for preterms around the world.