A randomized, double-blind, placebo-controlled trial of the effects of prophylactic theophylline on renal function in term neonates with perinatal asphyxia

Background. The kidney is the most damaged organ in asphyxiated full-term infants. Experiments in rabbits and rats have shown that renal adenosine acts as a vasoconstrictive metabolite in the kidney after hypoxemia and/or ischemia, contributing to the fall in glomerular filtration rate (GFR) and filtration fraction. Vasoconstriction produced by adenosine can be inhibited by the nonspecific adenosine receptor antagonist, theophylline. Gouyon and Guignard performed studies in newborn and adult rabbits subjected to normocapnic hypoxemia. Their results clearly showed that the hypoxemia-induced drop in GFR could be avoided by the administration of low doses of theophylline. Objective. This study was designed to determine whether theophylline could prevent and/or ameliorate renal dysfunction in term neonates with perinatal asphyxia. Setting. Buenos Aires, Argentina. Study Design. We randomized 51 severe asphyxiated term infants to receive intravenously a single dose of either theophylline (8 mg/kg; study group: n = 24) or placebo (control group: n = 27) during the first 60 minutes of life. The 24-hour fluid intake and the urine volumes formed were recorded during the first 5 days of life. Daily volume balances (water output/input ratio and weights) were determined. Severe renal dysfunction was defined as serum creatinine elevated above 1.50 mg/dL, for at least 2 consecutive days after a fluid challenge, or rising levels of serum creatinine (.3 mg/dL/day). The GFR was estimated during the second to third days of life by endogenous creatinine clearance (mL/minute/1.73 m2) and using Schwartz's formula: GFR (mL/minute/1.73 m2) =.45 x length (cm)/plasma creatinine (mg/100 mt) during the first 5 days of life. Tubular performance was assessed as the concentration of beta 2-microglobulin (beta 2M) determined by enzyme immunoassay, on the first voided urine 12 hours after theophylline administration. The statistical analysis for the evaluation of the differences between the groups was performed with Student's t and chi(2) tests as appropriate. Results. During the first day of life, the 24-hour fluid balance was significantly more positive in the infants receiving placebo compared with the infants receiving theophyline. Over the next few days, the change in fluid balance favored the theophyline group. Significantly higher mean plasma values were recorded in the placebo group from the second to the fifth days of life. Severe renal dysfunction was present in 4 of 24 (17%) infants of the theophylline group and in 15 of 27 (55%) infants of the control group (relative risk: .30; 95% confidence interval: .12-.78). Mean endogenous creatinine clearance of the theophylline group was significantly increased compared with the creatinine clearance in infants receiving placebo (21.84 +/- 7.96 vs 6.42 +/- 4.16). The GFR (estimated by Schwartz's formula) was markedly decreased in the placebo group. Urinary beta 2M concentrations were significantly reduced in the theophylline group (5.01 +/- 2.3 mg/L vs 11.5 +/- 7.1 mg/L). Moreover, 9 (33%) patients of the theophylline group versus 20 (63%) infants of the control group had urinary beta 2M above the normal limit (<.018). There was no difference in the severity of the asphyxia between infants belonging to the theophylline and control groups in regards of Portman's score. Except for renal involvement, a similar frequency of multiorganic dysfunction, including neurologic impairment, was observed in both groups. The theophylline group achieved an average serum level of 12.7 mu g/mL (range: 7.5-18.9 mu g/mL) at 36 to 48 hours of live versus traces tan average serum level of .87 mu g/mg) in the placebo group. Conclusions. Our data suggest that prophylactic theophylline, given early after birth, has beneficial effects on reducing the renal dysfunction in asphyxiated fullterm infants. A single dose of 8 mg/kg of theophylline within the first postnatal hour in term neonates with severe perinatal asphyxia results in a significant decrease in serum creatine and urinary beta 2M, together with a significant increase in the creatine clearance. The potential clinical relevance of the data would be the avoidance of the contributory role of hypoxemia in the development of acute renal failure. Additional studies will be necessary before the use of theophylline in asphyxiated newborns can be considered for clinical practice.