Pediatric Drugs

, Volume 12, Issue 5, pp 301–311 | Cite as

Pentoxifylline in Preterm Neonates

A Systematic Review
  • Emma Harris
  • Sven M. Schulzke
  • Sanjay K. PatoleEmail author
Review Article


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.


Chronic Lung Disease Pentoxifylline Intraventricular Hemorrhage Preterm Neonate Theobromine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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.


  1. 1.
    Stoll BJ, Hansen N, Fanaroff AA, et al. Late onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002; 110(2): 285–91PubMedCrossRefGoogle Scholar
  2. 2.
    Wheater M, Rennie JM. Perinatal infection is an important risk factor for cerebral palsy in very low birth weight neonates. Dev Child Neurol 2000; 42: 364–67CrossRefGoogle Scholar
  3. 3.
    Schulzke SM, Deshpande GC, Patole SK. Neurodevelopmental outcomes of very low-birth-weight neonates with necrotizing enterocolitis: a systematic review of observational studies. Arch Pediatr Adolesc Med 2007; 161: 583–90PubMedCrossRefGoogle Scholar
  4. 4.
    Pinsky MR, Vincent JL, Deviere J, et al. Serum cytokine levels in human septic shock: relation to multiple-system organ failure and mortality. Chest 1993; 103(2): 565–75PubMedCrossRefGoogle Scholar
  5. 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. 6.
    Ohlsson A, Lacy LB. Intravenous immunoglobulin for proven infection in neonates. Cochrane Database Syst Rev 2004; (1): CD001239Google Scholar
  7. 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
  8. 8.
    Llanos AD, Moss ME, Pinzon MC, et al. Epidemiology of neonatal necrotising enterocolitis: a population-based study. Pediatr Perinat Epidemiol 2002; 16: 342–9CrossRefGoogle Scholar
  9. 9.
    Kleigman RM, Fanaroff AA. Necrotising enterocolitis. N Engl J Med 1984; 31: 1093–103CrossRefGoogle Scholar
  10. 10.
    Hsueh W, Caplan MS, QU XW, et al. Neonatal necrotising enterocolitis: clinical consideration and pathogenetic concepts. Paediatr Dev Pathol 2003; 6: 6–23CrossRefGoogle Scholar
  11. 11.
    Caplan MS, Sun XM, Hsueh W, et al. Role of platelet activating factor and TNF-α in neonatal necrotising enterocolitis. J Pediatr 1990; 116: 960–4PubMedCrossRefGoogle Scholar
  12. 12.
    Lemons JA, Bauer CR, Oh W, et al. Very low weight birth outcomes of the National Child Health and Human Development Neonatal Network, January 1995 through December 1996. Pediatrics 2001; 107(1): E1PubMedCrossRefGoogle Scholar
  13. 13.
    Speer CP. Inflammation and bronchopulmonary dysplasia. Semin Neonatol 2003; 8: 29–38PubMedCrossRefGoogle Scholar
  14. 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. 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. 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
  17. 17.
    American Academy of Pediatrics, Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm neonates. Pediatrics 2002; 109: 330–8CrossRefGoogle Scholar
  18. 18.
    Schmidt B, Roberts RS, Davis P et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006; 354(20): 2112–21PubMedCrossRefGoogle Scholar
  19. 19.
    Schmidt B, Roberts RS, Davis P et al. Long term effects of caffeine for apnea of prematurity. N Engl J Med 2007; 357(19): 1893–902PubMedCrossRefGoogle Scholar
  20. 20.
    Ostrea EM, Villeanueva-Uy ET, Natarajan G, et al. Persistent pulmonary hypertension of the newborn: pathogenesis, etiology and management. Pediatric Drugs 2006; 8(3): 179–88PubMedCrossRefGoogle Scholar
  21. 21.
    Ely H. Is pentoxifylline the drug of the decade? J Am Acad Dermatol 1994; 30: 639–42PubMedCrossRefGoogle Scholar
  22. 22.
    Stauback KH, Schroder J, Stuber F, et al. Effect of pentoxifylline in severe sepsis: results of a randomised, double blind, placebo controlled study. Arch Surgery 1998; 133: 94–100CrossRefGoogle Scholar
  23. 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
  24. 24.
    Furukawa S, Matsubara T, Umezaa Y, et al. Pentoxifylline and intravenous gamma globulin combination for acute Kawasaki disease. Eur J Pediatr 1994; 153(9): 663–37PubMedCrossRefGoogle Scholar
  25. 25.
    Schroer R. Antithrombotic potential of pentoxifylline, a hemorrheologically active drug. Angiology 1985; 36: 387–98PubMedCrossRefGoogle Scholar
  26. 26.
    Schonhartig M, Musikic P, Muller R. The hemorrheologic and antithrombotic potential of pentoxifylline (Trental): a review. Pharmatherapeutica 1988; 5: 159–69Google Scholar
  27. 27.
    Krause PJ, Kristie J, Wang WP, et al. Pentoxifylline enhancement of defective neutrophil function and host dense in neonatal mice. Am J Pathol 1987; 129: 217–22PubMedGoogle Scholar
  28. 28.
    Wang P, Wood TJ, Ba ZF, et al. Pentoxifylline maintains vascular endothelial cell function during hyperdynamic sepsis. Surgery 1996; 130: 367–73CrossRefGoogle Scholar
  29. 29.
    Boldt J, Muller M, Heyn S, et al. Influence of long term continuous administration of pentoxifylline infusion on endothelial related coagulation in critically ill patients. Crit Care Med 1996; 24: 940–6PubMedCrossRefGoogle Scholar
  30. 30.
    Betticher DC, Keller H, Malvy FE, et al. The effect of endotoxin and tumor necrosis factor on erythrocyte and leukocyte deformability in vitro.Br J Haematol 1993; 83: 130–7PubMedCrossRefGoogle Scholar
  31. 31.
    Costantini TW, Deree J, Loomis W, et al. Phosphodiesterase inhibition attenuates alterations to the tight junction proteins occluding and ZO-1 in im-munostimulated Caco-2 intestinal monolayers. Life Sci 2009; 84(1–2): 18–22PubMedCrossRefGoogle Scholar
  32. 32.
    Costantini TW, Loomis WH, Putman JG, et al. Pentoxifylline modulates intestinal tight junction signalling after burn injury. J Trauma 2009; 66(1): 17–24PubMedCrossRefGoogle Scholar
  33. 33.
    Aviado DM, Dettelbach HR. Pharmacology of pentoxifylline, a hemorheo-logic agent for the treatment of intermittent claudication. Angiology 1984; 35(7): 407–17PubMedCrossRefGoogle Scholar
  34. 34.
    Magnusson M, Gunnarsson M, Berntorp E. Effects of pentoxifylline and its metabolites on platelet aggregation in whole blood from healthy humans. Eur J Pharmacol 2008; 581(3): 290–5PubMedCrossRefGoogle Scholar
  35. 35.
    Fantin M, Quintieri L, Kusz E, et al. Pentoxifylline and its major oxidative metabolites exhibit different pharmacological properties. Eur J Pharmacol 2006; 535(1–3): 301–9PubMedCrossRefGoogle Scholar
  36. 36.
    Ward A, Clissold S. Pentoxifylline: a review of its pharmodynamic and phar-mokinetic properties, and its therapeutic efficacy. Drugs 1987; 34: 50–97PubMedCrossRefGoogle Scholar
  37. 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
  38. 38.
    Lauterbach R, Pawlik D, Tomaszcyk B, et al. Pentoxifylline treatment of sepsis of premature neonates: preliminary clinical observations. Eur J Pediatr 1994; 153: 672–4PubMedCrossRefGoogle Scholar
  39. 39.
    Hinshaw LB. Sepsis/septic shock: participation of the microcirculation an abbreviated review. Crit Care Med 1996; 24: 1072–8PubMedCrossRefGoogle Scholar
  40. 40.
    Lauterbach R, Szymura-Oleksiak J. Nebulized pentoxifylline in successful treatment of five premature neonates with bronchopulmonary dysplasia. Eur J Pediatr 1999; 158: 607–10PubMedCrossRefGoogle Scholar
  41. 41.
    Lauterbach R, Zembala M. Pentoxifylline reduces plasma tumour necrosis factor-alpha concentration in premature neonates with sepsis. Eur J Pediatr 1996; 155: 404–9PubMedCrossRefGoogle Scholar
  42. 42.
    Lauterbach R, Pawlik D, Kowalczyk D, et al. Effect of the immunomodulating agent, pentoxifylline, in the treatment of sepsis in prematurely delivered neonates: a placebo-controlled, double-blind trial. Crit Care Med 1999; 27(4): 807–14PubMedCrossRefGoogle Scholar
  43. 43.
    Lauterbach R, Szymura-Oleksiak J, Pawlik D, et al. Nebulised pentoxifylline for prevention of bronchopulmonary dysplasia in very low birth weight neonates: a pilot clinical study. J Matern Fetal Neonatal Med 2006; 19(7): 433–8PubMedCrossRefGoogle Scholar
  44. 44.
    Lauterbach R, Pawlik D, Zembala M, et al. Pentoxifylline in the prevention and treatment of chronic lung disease. Acta Paediatr Suppl 2004; 444: 20–2CrossRefGoogle Scholar
  45. 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
  46. 46.
    Selim K, Huseyin C, Ibrahim KH, et al. Effect of pentoxifylline on tumour necrosis factor-alpha and interleukin-6 levels in neonatal sepsis. Med J Malaysia 2004; 59(3): 391–4PubMedGoogle Scholar
  47. 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. 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. 49.
    Haque K, Mohan P. Pentoxifylline for neonatal sepsis. Cochrane Database Syst Rev 2003; (2): CD0044205Google Scholar
  50. 50.
    Erdman AR. Hemorrheologic agents. In: Dart RC, editor. Medical toxicology. 3rd ed. Philadelphia (PA): Lippincott, Williams and Wilkins, 2004: 641–4Google Scholar
  51. 51.
    Travadi J, Patole S, Charles A, et al. Pentoxifylline reduces the incidence and severity of necrotizing enterocolitis in a neonatal rat model. Pediatr Res 2006; 60(2): 185–9PubMedCrossRefGoogle Scholar
  52. 52.
    Erdener D, Bakirtas F, Alkanat M, et al. Pentoxifylline does not prevent hypoxia/reoxygenation-induced necrotizing enterocolitis. Biol Neonate 2004; 86: 29–33PubMedCrossRefGoogle Scholar
  53. 53.
    Lauterbach R. Pentoxifylline treatment of persistent pulmonary hypertension of the newborn. Eur J Pediatr 1993; 152(5): 460PubMedCrossRefGoogle Scholar
  54. 54.
    Crowell RE, Chick TW, Reed WP. Pentoxifylline relaxes isolated pulmonary arteries after preconstruction with norepinephrine. Respiration 1990; 57: 45–50PubMedCrossRefGoogle Scholar
  55. 55.
    Korhonen K, Kiuru A, Svedstrom E, et al. Pentoxifylline reduced regional inflammatory and ventilatory disturbance in meconium-exposed piglet lungs. Pediatr Res 2004 Dec; 56(6): 901–6PubMedCrossRefGoogle Scholar
  56. 56.
    Schulzke SM, Rao S, Patole SK. A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy: are we there yet? BMC Pediatr 2007 Sep 5; 7: 30PubMedCrossRefGoogle Scholar
  57. 57.
    Sahores M, Mendoza-Naranjo A. Gap junctions in brain injury following hypoxia-ischemia. Recent Pat CNS Drug Discov 2008; 3(3): 209–15PubMedCrossRefGoogle Scholar
  58. 58.
    Laptook A, Tyson J, Shankaran S, et al. Elevated temperature after hypoxic-ischemic encephalopathy: risk factors for adverse outcomes. Pediatrics 2008; 122(3): 491–9PubMedCrossRefGoogle Scholar
  59. 59.
    Sheldon RA, Christen S, Ferriero DM. Genetric and pharmacologic manipulation of oxidative stress after neonatal hypoxia-ischemia. Int J DevNeurosci 2008; 26(1): 87–92CrossRefGoogle Scholar
  60. 60.
    Bruno RD, Marques TF, Batista TM, et al. Pentoxifylline treatment improves neurological and neurochemical deficits in rats subjected to transient brain ischemia. Brain Res 2009; 1260: 55–64CrossRefGoogle Scholar
  61. 61.
    Volpe JJ. Perinatal brain injury: from pathogenesis to neuroprotection. Mental Retard Dev Disabil Res Rev 2001; 7: 56–64CrossRefGoogle Scholar
  62. 62.
    Van Bel F, Groenendaal F. Long-term pharmacological neuroprotection after birth asphyxia: where do we stand? Neonatology 2008; 94(3): 203–10PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Emma Harris
    • 1
  • Sven M. Schulzke
    • 1
    • 2
  • Sanjay K. Patole
    • 1
    • 2
    Email author
  1. 1.King Edward Memorial HospitalPerthAustralia
  2. 2.School of Women’s and Infant’s HealthThe University of Western AustraliaCrawleyAustralia

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