A Randomized, Double-Blind, Placebo-Controlled Trial of the Effects of
Prophylactic Theophylline on Renal Function in Term Neonates
With Perinatal Asphyxia
Alejandro G. Jenik, MD*; José M. Ceriani Cernadas, MD*; Adriana Gorenstein, MD‡;
José A. Ramirez, MD*; Nestor Vain, MD‡; Marcelo Armadans, MD§; and Jorge R. Ferraris, MD*
ABSTRACT. 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 5 24) or
placebo (control group: n 5 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) 5 .45 3 length (cm)/plasma creatinine (mg/100 mL)
during the first 5 days of life. Tubular performance was
assessed as the concentration of b2-microglobulin (b2M)
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
x2 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
From the *Department of Pediatrics of the Hospital Italiano; ‡Sanatorio
Güemes; and §Clı́nica Maternal Lomas, Buenos Aires, Argentina.
Received for publication May 24, 1999; accepted Nov 10, 1999.
Reprint requests to (A.G.J.) Carlos Villate 909, Olivos, 1636, Buenos Aires,
Argentina. E-mail: ajenik@drwebsa.com.ar
PEDIATRICS (ISSN 0031 4005). Copyright © 2000 by the American Academy of Pediatrics.
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 6 7.96 vs 6.42 6 4.16). The GFR (estimated
by Schwartz’s formula) was markedly decreased in the
placebo group. Urinary b2M concentrations were significantly reduced in the theophylline group (5.01 6 2.3
mg/L vs 11.5 6 7.1 mg/L). Moreover, 9 (33%) patients of
the theophylline group versus 20 (63%) infants of the
control group had urinary b2M 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 mg/mL (range: 7.5–18.9 mg/mL) at 36 to 48
hours of live versus traces (an average serum level of .87
mg/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 b2M, 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. Pediatrics
2000;105(4). URL: http://www.pediatrics.org/cgi/content/
full/105/4/e45; perinatal asphyxia, theophylline, renal
function.
ABBREVIATIONS. ARF, acute renal failure; GFR, glomerular filtration rate; FF, filtration fraction; b2M, b2-microglobulin; CNS,
central nervous system.
F
etal and neonatal asphyxia are the primary
causes of transient renal impairment or acute
renal failure (ARF) in neonates.1,2 Circulatory
adaptive responses to perinatal asphyxia may lead to
renal injury as a consequence of decreased perfusion
of the kidney.3,4 Recently, Gunn et al5 reported that
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all the infants with hypoxic-ischemic encephalopathy included in their study developed signs of ARF.
A persistent tubular dysfunction at 1 year old has
been described in infants with a neonatal history of
renal failure associated with asphyxia.6
The study of the protection of renal adverse effects
of hypoxemic and/or ischemic impairments has
been the focus of numerous investigations. Experimental data obtained from animal models suggest
that various pharmacological agents, such as methylxantines,7 calcium entry blockers,8 and atrial natriuretic peptide,9 are effective in the prevention of
renal impairment associated with hypoxemia.
Experiments in rabbits10 and rats11 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 (FF).12 Vasoconstriction produced by adenosine can be inhibited by the
nonspecific adenosine receptor antagonist, theophylline.13
Gouyon and Guignard7 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. To
determine whether theophylline could prevent
and/or ameliorate the renal dysfunction in term infants with severe asphyxia, we designed a randomized, multicenter, double-blind, placebo-controlled
trial.
METHODS
Infants eligible for study admission were of term or postterm
gestation and had severe birth asphyxia manifested by: 1) history
of fetal distress (late decelerations, decreased heart rate variability,
or bradicardia (,100 beats/minute with or without meconium
stained amniotic fluid); 2) 5-minute Apgar score of 6 or lower; 3)
base deficit equal to or greater than 15 mEq/L in cord blood or
admission arterial blood sample; and 4) requirement of immediate
neonatal ventilation with mask or traqueal tube for .2 minutes
after delivery.
Exclusion criteria applied on infants were: 1) any condition that
was abnormal or unrelated to asphyxia; 2) small for gestational
age; 3) congenital abnormalities of kidneys and/or urinary tract;
4) cardiovascular pathology not related to prenatal asphyxia; 5)
prenatal or neonatal exposure to medications that might have
modified renal hemodynamics and renal function; 6) polycythemia; 7) clinical evidence of potential antenatal injury, ie, microcephaly, multiple pregnancy, hypothyroidism, or chromosomal
disorders; and 8) pharmacological depression.14
The study population included infants born at 3 hospitals of
Buenos Aires, Argentina (Hospital Italiano, Sanatorio Güemes,
and Clı́nica Maternal Lomas).
Infants were managed according to an identical special protocol
approved by the local ethics committees of each hospital.
After parental consent was obtained, infants were randomized
by sequential computer-generated numbers to receive intravenously a single dose of either theophylline (8 mg/kg; 1.6 mL/kg)
or an equal volume of placebo (5% dextrose in water). The loading
infusion was administrated as soon as possible after admission to
the neonatal intensive care unit over a 5-minute period within the
first hour after birth. Investigators and caregivers were blinded to
the assignment of the patient. Preparation of both treatment and
placebo drugs were provided by Phoenix Pharmaceutical (Buenos
Aires, Argentina) in vials with the same external appearance and
placed in consecutive numbered sealed opaque envelops based on
a randomized table with predetermined group allocation.
The theophylline dose selected for this trial was based on
studies by Kelly and Shannon15 that used a 7.5-mg/kg dose in
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term newborns with apnea without finding adverse side effects,
except for vomiting in 2 patients.
The Score of Portman et al16 was used to determine the severity
of the asphyxia and to assess whether patients belonging to both
groups had potentially the same multiorganic risk predictability.
The score (range: 0 –9) was based on fetal heart rate, 5-minute
Apgar score, and base deficit in the first hour of life. According to
Portman et al,16 the score for severe asphyxia was defined as .6
and for moderate asphyxia as ,5.
The indication for treatment of hypotension was a systemic
mean arterial blood pressure ,45 mm Hg.17
Infants initially received an intravenous infusion of D10W at a
rate of 60 mL/kg/day. Fluid and electrolyte intake was subsequently adjusted as indicated by the clinical status of each patient.
After a poor response of a reduced urine output with a fluid
challenge, a 2-mg/kg dose of furosemide was given. Fluid restriction was instituted in the infants with oliguric renal failure.
The 24-hour fluid intake and the urine volumes formed were
recorded during the first 5 days of life. Hourly urinary output was
carefully collected by attaching a urine bag to the perineum or was
measured via a urine catheter. The spilled urine was measured by
weighing the diapers. All fluid volume infusions, transfusions,
and medications administered were recorded. Daily volume balances (water output/input ratio and weights) were determined.
Body weight was measured on admission to the unit and then
every 24 hours for the first week of life.
To assess renal function, we determined daily serum creatinine
levels (Yaffe method, Astra, Beckman) and electrolytes in the first
week of life; 12-hour urine collections were obtained between the
second and third days of life to evaluate urine creatinine levels
and electrolytes.
The GFR was estimated during the second to third days of life
by endogenous creatinine clearance (mL/minute/1.73 m2) and
also using Schwartz’s formula18: GFR (mL/minute/1.73 m2) 5
.45 3 length (cm)/plasma creatinine (mg/100 mL) during the first
5 days of life.
Criteria for post asphyxia severe renal dysfunction were: a
serum creatinine elevated above 1.50 mg/dL, for at least 2 consecutive days after a fluid challenge consisting of a total of 20
mL/kg of normal saline, or rising levels of serum creatinine (.3
mg/dL/day). These values are according to literature data1,17 and
also correspond to 12 standard deviation over mean normal
standard value that we obtained from 55 healthy neonates born at
a gestational age of .37 weeks (unpublished data). Oliguria was
defined as a urine output of ,1 mL/kg per hour for at least 24
hours, based on our experience and literature data.19
Hematuria was assessed using standard dipstick reagent strips
(Multistix, Bayer Diagnostics, Buenos Aires, Argentina).
Tubular performance was assessed as the concentration of b2microglobulin (b2M) determined by enzyme immunoassay (Enzygnost (R) 2 b2M), on the first voided urine 12 hours after
theophylline administration. All urine samples were collected before the administration of the first dose of aminoglycoside antibiotics. Suprapubic compression was performed at the beginning of
each urine collection to ensure that the urine preserved in the
bladder had not been formed before the inutero asphyxia event.
Urine samples were frozen promptly and stored at 220°C until
determinations were performed. Our data from healthy infants
showed that the 95% confidence limit (mean 1 2 standard deviation) for urinary b2M concentration was 3.8 mg/L.20 We used this
value as the upper limit of normal. Our data were consistent with
those reported by Tack et al21 who found that the 95% confidence
limit for b2M concentrations in healthy infants was 4.00 mg/L on
the first voided specimens.
Serum theophylline levels were determined at 36 to 48 hours of
life.
Continuous variables with normal distribution were analyzed
by Student’s t test. The x2 test was used for analysis of discrete
data. Differences were considered significant at P , .05. The
results are reported as mean 6 standard deviation.
RESULTS
General Features
During a 74-month study, 60 consecutive patients
met the entry criteria of severe birth asphyxia. Nine
of these infants were excluded: 4 because of congen-
EFFECTS OF THEOPHYLLINE
ON
RENAL FUNCTION INbyASPHYXIATED
TERM NEONATES
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TABLE 1.
Clinical Characteristics on the First Day of Life in the Two Groups of Asphyxiated Neonates*
Birth weight (g)
Gestation age (wk)
Cesarean section (%)
Meconium staining of amniotic fluid (%)
Initial arterial blood gases values
pH
Base excess (mEq/L)
Asphyxia score .6 (%)
Age of starting loading infusion of theophylline or placebo (m)
Inotropic agents infused (%)
Mean blood pressure (mm Hg; 12 h of life)
Theophylline Group
n 5 24
Placebo Group
n 5 27
P
Value
3.256 6 309
39.3 6 1.6
14 (58)
17 (70)
3.387 6 376
39.4 6 1.4
13 (48)
18 (67)
.99†
.81†
.46‡
.98‡
7.04 6 .13
218.32 6 2.45
18 (75)
45 6 7
14 (58)
51 6 8
7.02 6 .17
219.15 6 4.07
21 (77)
38 6 5.0
17 (63)
49 6 6
.64†
.38†
.92‡
.24†
.96‡
.31†
* Values are expressed as mean 6 standard deviation.
† Student’s t test.
‡ Values calculated from x2 analysis (Yate’s correction).
ital malformations, 2 because of pharmacological depression, 1 because of maternal heroin addiction, 1
because the mother died just after delivery, and 1
because the mother had renal failure with a serum
creatinine value of 2.1 mg/dL. Fifty-one asphyxiated
term infants were enrolled in the study. Twenty-four
infants randomized were assigned to the theophylline group, and 27 to the placebo group.
Intubation was performed in 41 patients; biochemical resuscitation in 28.
There were no significant differences in birth
weight, gestational age, sex, cesarean rate, presence
of meconium-stained amniotic fluid, individual components of the asphyxia morbidity score (fetal heart
rate, 5-minute Apgar score, and base excess), arterial
blood pH, and blood pressure. No infants were
breech or small for gestational age (,10th percentile). Each group received either theophylline or an
equal volume of placebo at similar chronological
ages (45 6 7 vs 38 6 5.0 minutes; Table 1).
Four of these critically ill infants died. One patient
belonging to the theophylline group died from persistent pulmonary hypertension. There were 3 neonatal deaths in the placebo group: 2 of them attributable to multisystemic organ failure, and 1 caused
by overwhelming sepsis.
All asphyxiated infants required respiratory support; none hyperventilated. Involvement of 1 or
more organs occurred in 75% of the infants. Central
nervous system (CNS) involvement (seizures, transient cerebral irritability, and feeding problems) occurred in 38 (74%) of the infants. Clinical seizures
required treatment with anticonvulsants in 13 control infants and 9 infants receiving theophylline. Pulmonary involvement (meconium aspiration, persistent pulmonary hypertension, and mild respiratory
distress syndrome) was evidenced in 18 (35%) infants. Seven infants had abnormal echocardiographic
findings (tricuspid or mitral regurgitation and/or
myocardial dyskinesia not affecting ventricular output). Gastrointestinal involvement (bloody stools,
necrotizing enterocolitis, and bilious residuals) occurred in 11 (21%) infants. We found no significant
differences in frequency and severity of CNS, pulmonary, heart, and gastrointestinal involvement between the 2 groups. However, severe renal dysfunction was present in 4 (17%) infants of the
theophylline group and in 15 (55%) of the control
group (relative risk: .30; 95% confidence interval:
.12-.78; P , .001; Fig 1).
Renal Evaluation
Table 2 summarizes the balances during the first 5
days of life in the 2 groups of asphyxiated neonates.
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 theophylline. Over the next days, the change in fluid
Fig 1. The frequency of organ involvement for the
2 groups of asphyxiated neonates.
* p 5 .001
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TABLE 2.
Balances: Comparison of Weight and Water Output/Input Ratio During the First Five Days of Life in the Two Groups of
Asphyxiated Neonates
Days of Life
1
2
3
4
5
Water Output/Input Ratio
Theophylline Group
Placebo Group
.23 6 .18
1.45 6 .11
1.6 6 .55
1.38 6 .6
NE
.71 6 .3
.36 6 .8
.92 6 .6
1.7 6 .54
NE
P
Value
,.001
,.001
,.001
.05
Weight
Theophylline Group
Placebo Group
3.190 6 301
3.126 6 293
3.050 6 289
2935 6 106
3019 6 284
3.481 6 383
3.421 6 368
3.319 6 364
3097 6 389
3107 6 401
P
Value*
.004
.003
.005
.047
.375
NE indicates not evaluated in all the patients.
* Student’s t test.
balance favored the theophylline group. The diuretic
response was significantly greater in the theophylline group (Fig 2). On the first day of life, plasma
creatinine values were similar in the 2 groups, but
significantly higher mean plasma creatinine values
were recorded in the placebo group from the second
to the fifth days of life (Table 3). During the second to
the third days of life, mean endogenous creatinine
clearance (mL/minute/1.73 m2) of the theophylline
group was significantly increased compared with the
creatinine clearance in infants receiving placebo
(21.84 6 7.96 vs 8.42 6 4.16; P , .001). The GFR
(estimated by Schwartz’s formula) were markedly
decreased in the placebo group (Table 3). No difference was found in sodium excretion obtained from
12-hour urine collections between the second and
third days of life in the theophylline group with
respect to the control group (45 6 55 mEq/L vs 57 6
49 mEq/L; P 5 .24). Urinary b2M concentrations
were significantly reduced in the theophylline group
(5.01 6 2.3 mg/L vs 11.5 6 7.1 mg/L; P 5 .005).
Moreover, 9 (33%) patients of the theophylline group
versus 20 (63%) infants of the control group had
urinary b2M above the normal limit (P , .018).
Dipstick testing for hematuria over the first 3 days
of life demonstrated large blood on at least one occasion in 15 of 24 in the theophylline group and 19 of
27 in the control group (P 5 .766).
Serum Theophylline Levels
The theophylline group achieved an average serum level of 12.7 mg/mL (range: 7.5–18.9 mg/mL) at
36 to 48 hours of life versus traces (an average serum
level of .87 mg/mg) in the placebo group.
DISCUSSION
Our findings indicate that treatment with 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
creatinine and urinary b2M, together with a significant increase in the creatinine clearance. In addition,
the present study shows that using theophylline in
neonatal asphyxia helps to reduce the severe renal
dysfunction. All infants reported in this study were
critically ill according to their immediate postpartum
conditions and exhibited numerous signs of multisystemic dysfunction.
The kidney is the most damaged organ in asphyxiated full-term infants.2,22 Acute hypoxemia is associated with an increase in renal vascular resistance
and a decrease in GFR and FF.23 During oxygen
deficit, when adenosine triphosphate hydrolysis prevails over adenosine triphosphate synthesis, adenosine (a direct degradative product of 59adenosine
monophosphate) increases and activates its receptors
resulting in an increment of the renal vascular resistance (preglomerular vasoconstriction and postglomerular vasodilatation) thus decreasing GFR and
FF.24
Hemodynamic renal changes produced by adenosine were observed during ischemic or hypoxemic
experimental studies.25 Moreover, adenosine admin-
Fig 2. Diuretic expressed as rate of
urine formation in mL/kg/hour
(mean 6 standard deviation). Theophyline group (filled boxes) and placebo group (filled triangles).
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EFFECTS OF THEOPHYLLINE
ON RENAL FUNCTION IN ASPHYXIATED TERM NEONATES
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TABLE 3.
Renal Evaluation: The GFR (Estimated by Schwartz’s Formula) and Plasma Creatinine in the First Five Days of Life in the
Two Groups of Asphyxiated Neonates*
Days of Life
1
2
3
4
5
Glomerular Filtration Rate
Theophylline Group
Placebo Group
23.17 6 10.3
24.01 6 8.6
25.94 6 11.2
27.29 6 9.1
32.41 6 7.4
22.07 6 9
14.9 6 6.8
11.36 6 5.1
32.41 6 7.4
18.0 6 9.8
P Value
.68
,.001
,.001
,.03
,.001
Plasma Creatinine (mg/dL)
Theophylline Group
Placebo Group
1.0 6 .3
.97 6 .17
1.02 6 .69
.89 6 .7
.71 6 .2
1.05 6 .4
1.51 6 .41
1.94 6 1.1
1.59 6 .7
1.36 6 .9
P Value†
.62
,.001
,.001
,.001
,.001
* Values are expressed as mean 6 standard deviation.
† Student’s test.
istrated into the renal artery led to decreased GFR26
in humans.
Adenosine receptor antagonists like theophylline
can inhibit renal vasoconstriction in response to exogenous and endogenous adenosine and have been
successfully used to improve renal function after
experimental ARF induced by glycerol,27 endotoxin,28 and radiocontrast administration in several animal models.29 It has been observed in rats that theophylline attenuates the extent of GFR reduction
when it is administrated during maintenance phase
of post-ischemic ARF.30 Kemper31 demonstrated in
anesthetized rats that administration of theophylline
(8mg/kg), before adenosine infusion, prevents a
sharp fall in glomerular filtration in comparison to
adenosine alone. Gouyon and Guignard7 demonstrated in newborn and adult animals that the fall in
glomerular filtration induced by hypoxemia can be
prevented by theophylline in low doses. These authors used rabbits as a animal model that showed, in
hypoxemia episodes, renal changes similar to those
observed in human hypoxemic newborns. Used
commonly for apnea of prematurity, theophylline
has also been shown to prevent both the reduction of
GFR after contrast media application in humans and
the renal insufficiency induced by hypoxemia in
newborns with respiratory distress syndrome.32,33
In our study, the incidence of glomerular dysfunction and proximal tubular damage, evidenced by
elevated serum creatinine concentrations and high
urinary levels of b2M, respectively, were considerably lower in the group receiving theophylline. The
mechanism by which the administration of theophylline results in lower serum creatinine and better
diuresis could be attributable, at least in part, to an
increase in GFR explained by the adenosine blockade.36 Moreover, daily fluid balance was significantly
more negative in the theophylline group. The GFR
was estimated by endogenous creatinine clearance
and using Schwartz’s formula. With both methods,
we obtained significantly increased values in the theophylline group. Zacchello et al35 concluded that
Schwartz’s formula provides an adequate estimation
of neonatal creatinine clearance as a marker for GFR
in neonatal asphyxia. Although the levels of urine
sodium showed no difference between the 2 groups,
these results need to be interpreted with caution
because it is known that theophylline causes natriuresis.34 Theophylline levels were within the therapeutic range in patients of the theophylline group
and no side effects were observed.
In newborn asphyxiated piglets, a supply of 8
mg/kg of theophylline attenuates in a nonsignificant
way the increase in brain circulation that normally
takes place in hypoxia episode.36 It has been reported
that pretreatment of rats with aminophylline in experimental cerebral ischemia reduced the mortality
rate from 56% to 10%.37 Bona et al38 showed that
acute treatment with adenosine A1 antagonist before
hypoxic-ischemic reduces brain damage in rat pups.
Significant cerebroprotection was reported in newborn rats by potentiation of endogenous extracellular
adenosine levels with either the adenosine deaminase inhibitor deoxycoformycin or the adenosine
transport inhibitor propentofylline.39 However, we
found no significant differences in the incidence of
CNS involvement and seizures between the 2 groups
of asphyxiated neonates.
CONCLUSION
Our data suggest that prophylactic theophylline
treatment, given early after birth, has beneficial effects reducing the renal involvement in asphyxiated
full-term infants, with no significant changes in CNS
involvement. The potential clinical relevance of these
data would be the avoidance of the contributory role
of hipoxemia in the development of ARF. Additional
and larger studies will be necessary before the use of
theophylline in asphyxiated newborns can be considered for clinical practice.
ACKNOWLEDGMENTS
This study was supported by a grant from the National Academy of Medicine of Argentina.
We thank Dr S. Silberstein for assistance with the manuscript.
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EFFECTS OF THEOPHYLLINE
ON
RENAL FUNCTION INbyASPHYXIATED
TERM NEONATES
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A Randomized, Double-Blind, Placebo-Controlled Trial of the Effects of
Prophylactic Theophylline on Renal Function in Term Neonates With Perinatal
Asphyxia
Alejandro G. Jenik, José M. Ceriani Cernadas, Adriana Gorenstein, José A. Ramirez,
Nestor Vain, Marcelo Armadans and Jorge R. Ferraris
Pediatrics 2000;105;e45
DOI: 10.1542/peds.105.4.e45
Updated Information &
Services
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A Randomized, Double-Blind, Placebo-Controlled Trial of the Effects of
Prophylactic Theophylline on Renal Function in Term Neonates With Perinatal
Asphyxia
Alejandro G. Jenik, José M. Ceriani Cernadas, Adriana Gorenstein, José A. Ramirez,
Nestor Vain, Marcelo Armadans and Jorge R. Ferraris
Pediatrics 2000;105;e45
DOI: 10.1542/peds.105.4.e45
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/105/4/e45
Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
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