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Effect of the immunomodulating agent, pentoxifylline, in the treatment of sepsis in prematurely delivered infants: A placebo-controlled, double-blind trial

Lauterbach, Ryszard MD, PhD; Pawlik, Dorota MD; Kowalczyk, Danuta MD, PhD; Ksycinski, Wieslaw MD; Helwich, Ewa MD, PhD; Zembala, Marek MD, PhD

Pediatric Critical Care

Objective To evaluate the influence of the methylxanthine derivative, pentoxifylline, on plasma levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6 in prematurely delivered infants with generalized bacterial infections and to assess the effect of this immunomodulating drug on the clinical outcome in newborns with sepsis.

Design A prospective, randomized, double-blind trial.

Setting The neonatal intensive therapy units in university teaching hospitals.

Patients One hundred patients with sepsis admitted during a 1.5-yr period.

Interventions Patients were randomly assigned to receive pentoxifylline (pentoxifylline group) in a dose of 5 mg/kg/hr for 6 hrs on 6 successive days or an identically presented placebo (placebo group).

Measurements and Main Results Only infants with sepsis confirmed by positive blood culture were recruited into the study. There were no significant differences at randomization between the pentoxifylline and placebo groups with regard to the birth weight, gestational age, gender, Apgar score, hypotension, neutropenia, thrombocytopenia, metabolic acidosis, plasma levels of cytokines, and occurrence of shock. Plasma levels of TNF, IL-1, and IL-6 were evaluated before and after the drug or placebo administration on the first, third, and sixth days of therapy. Cytokines were determined by immunoenzymetric test EASIA (TNF) and Endogen Interleukin-Elisa (IL-1, IL-6). The frequency of Gram-negative sepsis was similar in both groups (37.5% and 36.8%). Pentoxifylline significantly diminished plasma TNF levels (p = .009) but had no effect on plasma IL-1 levels. Mean plasma IL-6 levels, which were measured in the pentoxifylline group on the 6th day of the study, were significantly lower compared with respective data obtained in the placebo group. Only 1 of 40 infants with sepsis in the pentoxifylline group died, whereas 6 of 38 infants in the placebo group did not survive (p = .046). An increased incidence of disordered peripheral circulation and metabolic acidosis (p = .048), anuria or oliguria (p = .03), disseminated intravascular coagulation (p = .043), and the occurrence of clinical symptoms of necrotizing enterocolitis (p = .025) was observed in the course of sepsis in infants in the placebo group.

Conclusion Pentoxifylline significantly affects the synthesis of TNF and IL-6 as well as reduces the mortality rate in premature infants with sepsis. The dosage and schedule of drug administration in this study attenuated the severity of the clinical course of sepsis in this group of patients. (Crit Care Med 1999; 27:807-814)

From the Departments of Neonatology (Drs. Lauterbach, Pawlik) and Clinical Immunology (Drs. Kowalczyk, Zembala), Jagiellonian University Medical College, Cracow; and the Department of Neonatology (Drs. Ksycinski, Helwich), Mother-Children Hospital, Lodz, Poland.

Supported by the Polish State Committee for Research Grant 4 P05E03408.

Address requests for reprints to: Ryszard Lauterbach, MD, PhD, Department of Neonatology, Jagiellonian University Medical College, P-31-501 Cracow, Kopernika 23 Poland.

© 1999 Lippincott Williams & Wilkins, Inc.