PEDIATRICS Vol. 105 No. 4 April 2000, p. e45
ELECTRONIC ARTICLE:
A Randomized, Double-Blind, Placebo-Controlled Trial of the
Effects of Prophylactic Theophylline on Renal Function in Term
Neonates With Perinatal Asphyxia
Received May 24, 1999; accepted Nov 10, 1999.
,,
From the * Department of Pediatrics of the Hospital Italiano;
Sanatorio Güemes; and § Clínica Maternal Lomas, Buenos
Aires, Argentina.
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 × length (cm)/plasma creatinine (mg/100 mL) during
the first 5 days of life. Tubular performance was assessed as the
concentration of 
2-microglobulin (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 
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 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 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 µg/mL
(range: 7.5-18.9 µg/mL) at 36 to 48 hours of live versus traces (an
average serum level of .87 µg/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 full-term 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 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.
Key words:
perinatal asphyxia,
theophylline,
renal
function.
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