Pentoxifylline in Preterm Neonates
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Sepsis, necrotizing enterocolitis (NEC), and chronic lung disease (CLD) in preterm neonates are associated with significant mortality and morbidity, including long-term neurodevelopmental impairment and socioeconomic burden. Safe and effective drugs for the prevention and treatment of these conditions are urgently needed.
Pentoxifylline, a synthetic theobromine derivative, is a non-steroidal immunomodulating agent with unique hemorrheologic effects which has been used in a range of infectious, vascular, and inflammatory conditions in adults and children. The unique properties of pentoxifylline explain its potential benefits in preterm neonates with sepsis, NEC, and CLD, conditions characterized by activation of the inflammatory cytokine cascade, free radical toxicity, and impaired microcirculation. Pentoxifylline has anti-inflammatory properties resulting from inhibition of erythrocyte phosphodiesterase. It lowers blood viscosity and improves microcirculation and tissue perfusion. As a phosphodiesterase inhibitor, pentoxifylline down-regulates pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interferon-γ. Methylxanthines, including caffeine, theophylline, and theobromine are relatively non-toxic drugs; of these, theobromine is the least toxic. Pentoxifylline-related significant adverse events are thus very rare. Unlike other methylxanthines, pentoxifylline does not have significant cardiac and bronchodilating effects at therapeutic doses. Although it is contraindicated in adults with recent cerebral hemorrhage due to its effect on platelets, red blood cells, and plasma fibrinogen levels, no significant adverse effects including thrombocytopenia and bleeding have been reported in critically ill preterm neonates with sepsis or NEC after treatment with pentoxifylline.
Based on data from pilot randomized trials and observational studies, our systematic review suggests that pentoxifylline may reduce mortality and/or morbidity in preterm neonates with sepsis, NEC, and CLD. Results of experimental studies also indicate that pentoxifylline may potentially be beneficial in meconium aspiration syndrome and hypoxic ischemic encephalopathy.
Given the substantial burden of sepsis, NEC, and CLD in high-risk preterm neonates, and the findings of this systematic review, pentoxifylline needs to be evaluated urgently as a preventative and therapeutic agent for these conditions in randomized controlled trials that can detect minimal clinically significant effect sizes. Further clinical and experimental studies are also necessary to evaluate whether pentoxifylline is safe and effective in meconium aspiration syndrome and hypoxic ischemic encephalopathy.
We thank Dr Paula Lister for provision of poster presentations on the use of pentoxifylline in preterm neonates with necrotizing enterocolitis. All authors declare that there are no real or perceived conflicts of interest related to this review. The design and preparation of this review was not supported by external funding.
- 5.Ohlsson A, Lacy LB. Intravenous immunoglobulin for preventing infection in preterm and/or LBW neonates. Cochrane Database Syst Rev 2004; (1): CD000361Google Scholar
- 6.Ohlsson A, Lacy LB. Intravenous immunoglobulin for proven infection in neonates. Cochrane Database Syst Rev 2004; (1): CD001239Google Scholar
- 7.Carr R, Modi N, Dore C. G-CSF or GM-CSF for treating and preventing neonatal infection. Cochrane Database Syst Rev 2003; (1): CD003066Google Scholar
- 14.Halliday HL, Ehrenkranz RA. Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm neonates. Cochrane Database Syst Rev 2000; (1): CD001144Google Scholar
- 15.Halliday HL, Ehrenkranz RA. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease of preterm neonates. Cochrane Database Syst Rev 2000; (2): CD001969Google Scholar
- 16.Halliday HL, Ehrenkranz RA. Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm neonates. Cochrane Database Syst Rev 2001; (1): CD001145Google Scholar
- 23.Hoffman H, Markewitx A, Kreuzer E, et al. Pentoxifylline decreases the incidence of multiple organ failure in patients after major cardio-thoracic surgery. Shock 1998; 19: 234–40Google Scholar
- 26.Schonhartig M, Musikic P, Muller R. The hemorrheologic and antithrombotic potential of pentoxifylline (Trental): a review. Pharmatherapeutica 1988; 5: 159–69Google Scholar
- 37.Szymura-Oleksiak J, Bury H, Lauterbach R, et al. Serum concentrations of pentoxifylline and its metabolites in premature neonates with sepsis when administered by continuous intravenous infusion. Pharm Sci 1997; 3: 367–71Google Scholar
- 45.Ali W, Ahmed P, Bhat M, et al. Pentoxifylline in treatment of sepsis of pre mature neonates. JK Pract 2006; 13(4): 204–7Google Scholar
- 47.Rossouw B, Keily E, Lister P. (a) Safety of pentoxifylline in infants with severe necrotising enterocolitis [P6.1.694]. (b) Pentoxifylline as an adjunct therapy in infants with severe necrotizing enterocolitis [P6.1.703]. Proceedings of the 5th World Congress of Pediatric Critical Care; 2007 Jun 24–28; GenevaGoogle Scholar
- 48.Serafin WE. Drugs used in the treatment of asthma. In: Hardman JG, Limbird L, Gilman AG, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill, 1996: 676Google Scholar
- 49.Haque K, Mohan P. Pentoxifylline for neonatal sepsis. Cochrane Database Syst Rev 2003; (2): CD0044205Google Scholar
- 50.Erdman AR. Hemorrheologic agents. In: Dart RC, editor. Medical toxicology. 3rd ed. Philadelphia (PA): Lippincott, Williams and Wilkins, 2004: 641–4Google Scholar