Acta PBdiatr 84: 360-4.

1995

Aminophylline versus caffeine citrate for apnea and bradycardia

prophylaxis in premature neonates
PB Larsen, L Brendstrup, L Skov and H Flachs'
Department of Neonatology and Department of Clinical Chemistry', National University Hospital, Rigshospitalet, Copenhagen, Denmark

Larsen PB, Brendstrup L, Skov L, Flachs H. Aminophylline versus caffeine citrate for apnea and
bradycardia prophylaxis in premature neonates. Acta Paediatr 1995;84:360-4. Stockholm. ISSN
0803-5253
We investigated the efficacy and adverse effects of aminophylline and caffeine citrate in 180 premature
neonates for 10 days and nights. Aminophylline (n = 98) and caffeine citrate (n = 82) were equally
effectivein preventing apnea and bradycardia. The caffeine citrate group had a lower median heart rate
on day 3, fewer neonates with tachycardia and a smaller amount of gastric aspirate on day 7. The need
for mononasal continuous positive airway pressure and respirator therapy was similar in both groups.
We conclude that caffeine citrate is the drug of choice for apnea and bradycardia prophylaxis in
premature neonates with a gestational age 5 3 3 full weeks. Aminophyylline, apnea, bradycardia,
caffeine citrate, neonate, premature
PB Larsen, Skyttevangen 30, D K 3450 Allered, Denmark

The objective of this study was to determine if aminophylline was more effective than caffeine citrate in
preventing apnea and bradycardia in premature neonates and if there were any differences in adverse effects.
At the Department of Neonatology, Rigshospitalet,
aminophylline is used for apnea and bradycardia
prophylaxis in all premature neonates with a gestational age 5 3 3 full weeks. The drug is administered
orally, iv or rectally, with a loading dose of 6.0mg/kg
followed by a maintenance dose of 2.0mg/kg twice a
day. At other neonatal departments, both aminophylline and caffeine (a metabolic product of aminophylline
in premature neonates) are used for apnea and bradycardia prophylaxis in premature neonates. Both treatments are equally accepted, but only a few studies
comparing the two drugs exist, and they do not show
any difference in efficacy in preventing apnea and
bradycardia (1 -4). These studies, with the same statistical conditions as in our study, have a 75% risk of
committing an error of the second type, because of the
small number of patients (18-45 neonates).
Theoretically, caffeine citrate should be a better
drug than aminophylline, as the therapeutic index is
more favorable (5, 6). The literature describes no
adverse effects for caffeine citrate near the upper
limit of the alleged therapeutic interval, whereas a
variety of adverse effects of aminophylline are
reported at just above its alleged therapeutic interval.
These include failure to gain weight, sleeplessness,
irritability, tachycardia, hyperglycemia, dehydration,
hyperreflexia, tremor, seizures, hypertension and
cardiac arrhythmia (5, 6). Tachycardia is the most
frequent side effect of aminophylline. Furthermore, it

is thought that aminophylline may induce necrotizing

enterocolitis (5-7). The main action of methylxanthines (theophylline and caffeine) is mediated
through an apnea and bradycardia preventing effect
by stimulating the central nervous system (CNS) and
the cardiovascular system. The methylxanthines stimulate the CNS on various levels: (1) stimulation of
formatio reticularis with increased alertness; (2) stimulation of the intrinsic activity of the central respiratory
rhythm generator; (3) increased ventilatory drive (not
related to chemoreceptor sensitivity; and (4) increased
chemoreceptor sensitivity to carbon dioxide. Methylxanthines stimulate the cardiovascular system by
increasing the sensitivity to catecholamines, resulting
in increased cardiac output. Other factors that may
facilitate the anti-apneic effects of methylxanthines
include increased blood glucose and improved diaphragmatic and skeletal muscle contraction (5, 6).
The mature liver (age > 52 gestational weeks)
demethylates caffeine by cytochrome P450 mixed function oxidase to the more water-soluble theophylline and
by further oxidation/demethylation to other xanthines,
which are mainly excreted by the kidneys. Theophylline
is mainly N7-methylated to caffeine in the neonatal
immature liver, and due to the high lipophilicity of
caffeine, it may undergo considerable reabsorption in
the renal tubules, thus contributing to a slower elimination than theophylline. Approximately 61 YO of
aminophylline administered to premature neonates is
excreted unchanged by the kidneys. The rest is excreted
as other methylxanthines, among them caffeine. Premature neonates treated with caffeine citrate excrete 86%
of the administered caffeine unchanged in urine (5-8).

Aminophylline versus caffeine citrate

ACTA PRDIATR 84 (1995)

These are mean values and considerable interindividual

variation exists.
In neonates treated with theophylline, the mean ratio
of caffeine to theophylline in plasma is about 0.3 (5, 6),
which is why it is almost impossible to separate the
actions of the two drugs.

Patients
This investigation included all premature neonates
with a gestational age 533 full weeks admitted to the
neonatal department from April 1, 1990 to June 1,
1992, and for whom parental informed consent was
obtained. The investigation was approved by the local
Ethics Committee and the Danish National Health
Service. As both aminophylline and caffeine citrate
have a well documented effect on apnea and bradycardia in neonates, it was considered unethical to include
a placebo group in the investigation. Neonates were
excluded if they were receiving respirator therapy for
more than 96h. The design of the investigation was
prospective and double-blind, and the neonates were
randomized to receive treatment with either aminophylline or caffeine citrate. All premature neonates
with a gestational age 533 full weeks in the neonatal
department are routinely treated with mononasal
continuous positive airway pressure (NCPAP) for
apnea and bradycardi prophylaxis.
The aminophylline group received an iv loading
dose of 6.2mg/kg followed by a maintenance dose of
3.1 mg/kg iv or by a gastric baby feeding tube twice a
day for 10 days. The caffeine group received an iv
loading dose of caffeine citrate 20.2 mg/kg followed
by a maintenance dose of 2.5mgIkg iv or by a gastric
baby feeding tube twice a day for 10 days. The loading
and maintenance doses used were those recommended
by Roberts (5) (20mg of caffeine citrate is equivalent
to 10 mg of active caffeine base, and 6.2 mg of aminophylline is equivalent to 5mg of active theophylline
base (5)). Treatment efficacy was measured as the need
for NCPAP and ventilator therapy, and by the number
of episodes of apnea and- bradycardia in 24 h for 10
days. Apnea was defined as cessation of breathing for
more than 15s, which might be accompanied by
cyanosis and/or bradycardia (pulse less than 100
beatslmin). The neonates were observed in unstable
phases with a respiratory-cardiac monitor and in
more stable phases with ECG. Adverse effects were

36 1

quantified by median heart rate on day 3, percentage

of full fluid requirements taken orally on day 7 and
total volume of gastric aspirate on day 7. All data were
obtained from observation reports and adverse effects
described in the case records. Three days after enrollment in the study, a blood sample (500~1)was taken
to measure plasma theophylline and caffeine concentrations to ensure that the therapeutic interval was
achieved. The blood samples were taken together
with other blood samples to avoid unnecessary pinpricks. Plasma theophylline and caffeine levels were
quantified by EMIT Syva Kit adapted to the Cobas
Mira Instrument.
Stat ist ics
Non-parametric statistics, Mann-Whitney U-test
(MW) and Fishers exact test (F) of two independent
samples were used. The study was initially designed to
include two groups of 72 patients each, as the following
statistical conditions were required: (1) risk of committing an error of the first type (2a) = risk of committing
an error of the second type (p) = 0.05; (2) an estimated
SD = f 5 episodes of apnea/bradycardia in 24 h; and (3)
a Mlnimal RElevant DIFference (MIREDIF) at 3
episodes of apnealbradycardia in 24 h.
During the investigation it became evident that
approximately one-third of the patients left the study
before the designed 10 days of observation, because
of either respirator therapy >96 h, transfer to other
hospitals or death. Therefore the investigation was
extended by 50%, increasing the number to 108 neonates in each group.

Results
Included in the study were 214 patients out of a possible
total of 359 premature neonates in this period. We
planned to include 216 patients, but two of the
medicine packages were defective and were not used.
Of the remaining 214 neonates, 34 were excluded for
reasons listed in Table 1. Of the remaining 180 neonates,
only 131 completed all 10 days of the study, but all 180
neonates were included in the calculations, while
breathing spontaneously, with as many data as
possible. Patient characteristics for the 180 neonates
are listed in Table 2. No differences were found between
the groups regarding sex, birth weight, gestational age,

Table 1. Survey of different reasons for exclusion from the study.

Respirator therapy
>96 h
~

Aminophylline group
Caffeine group

I
15

Parental
request

Death

Treatment
failure

Medication
error

Insufficient
case record

362

P B Larsen et al.

ACTA PRDIATR 84 (1995)

Table 2. Demographic data and total needs for respiratory support

Median
(2.5%-97.5%)

Sex
(MF)

Birth weight

Gestation age
(weeks)

NCPAP
(days)

Intubdted
(days)

Aminophylline group

98

59/39

82

0.3702
F
43/39

180

102178

1300
(619-2378)
0.6152
MW
1275
(670-2450)
1290
(653-2450)

29
(26-33)
0.7475
MW
29
(25- 33)
29
(26-33)

7
(0- 10)
0.9751
MW
6.5
(0- 10)
7

0
(0-4)
0.6653
MW
0
(0-4)
0
(0-4)

P=
Test type
Caffeine group
Both groups

(0-10)
~~

F = Fishers exact test, MW = Mann-Whitneys U-test. NCPAP = Mononasal continuous positive airway pressure.

numbers of days with NCPAP or numbers of days of scaled baby syndrome and one neonate was intubated
intubated. No differences were found between the two because of hydrops fetalis.
groups regarding the number of neonates who needed
The 22 neonates who were excluded because of
respirator therapy (28 in the aminophylline group and respirator therapy for more than 96h did not differ
34 in the caffeine group F; p = 0.3533). No differences from the group of patients who completed the investiwere found in the number of episodes of apnea or gation regarding birth weight (MW: p = 0.1 163) or
bradycardia between the two groups (Table 3).
umbilical cord pH (MW: p = 0.9494). But they were
The caffeine citrate group proved to have a lower pretreated with Celestone less often (F: p = 0.0420),
median heart rate on day 3 and a smaller amount of were born 1 week earlier (median 28 versus 29 gestagastric aspirate on day 7 (Table 4). Furthermore, the tional weeks (MW: p = 0.0020)) and had a lower
caffeine citrate group had fewer premature neonates median Apgar score (4.5 at 1 min and 8.5 at 5min
with tachycardia (heart rate >160 beats/min) than the versus 8 at 1 min and 10 at 5min (MW: p = 0.0001))
aminophylline group (38 of 92 neonates versus 12 of 67 than those neonates who were not excluded.
neonates; p = 0.003).
In both the aminophylline and caffeine citrate groups,
Among the 62 neonates who were intubated and the central 95% of all neonates had a plasma theophylventilated, 22 neonates had to be excluded because of line or plasma caffeine concentration within the alleged
respirator therapy for more than 96h (7 from the therapeutic interval (Table 5). There were no differences
aminophylline group and 15 from the caffeine group) in the frequency of RDS (F: p = 0.1155) or necrotizing
(F: 2a = p = 0.0938, /3 = 0.4259). Seventeen of these enterocolitis (F: p = 0.7469) between the two groups.
neonates were intubated because of severe respiratory
All the above calculations were made on the basis of
distress syndrome (RDS) with chest X-ray anomalies data from all 180 neonates in the study. Using the data
and a median arterial/alveolar (a/A)-P02 ratio (9, 10) from the 131 neonates who completed all 10 days of the
of 0.16 and an interquartile range of 0.11-0.18 (a/A study yielded similar results.
) (PaC02/0.8))).
PO2-ratio = Pa02/((Fi02 ~ 0 . 9 5 Of the 17 neonates with RDS, 4 neonates were transferred intubated to the department. Of the remaining
five excluded neonates, two neonates were intubated Discussion
because of septicemia, one neonate was intubated in One of the more serious clinical problems in the neothe delivery room, one neonate was intubated because natal intensive care unit is apnea and bradycardia in the
Table 3. Observations of apnea and bradycardia.
Median
(2.5Yo-97.5 Yo)

Aminophylline group

98

P=
Test type
Caffeine group
Both groups

82
180

Apnea in 10 days
(no.)

Apnea/24 h
(mean no.)

BC in 10 days
(no.)

BC/24 h
(mean no.)

2.0
(0-67)
0.2762
MW
2.5
(0-70)
2.0
(0-66)

0.2
(0-7)
0.2396
MW
0.3
(0-8)
0.3
(0-7)

4.5
(0-78)
0.1481
MW
5.0
(0-72)
5.0
(0-73)

0.6
(0-9)
0.1 143
MW
0.8
(0-10)
0.7
(0-9)
-

MW = Mann-Whitneys U-test, BC = bradycardia. Numbers apnea/BC in 10 days = total amount in 10 days and nights. Mean apnea/24 h
or BC/24 h is based on numbers of valid days each neonate contributed to the investigation while breathing spontaneously.

Arninophylline versus caffeine cilrate

ACTA PEDIATR 84 (1995)

363

Table 4. Median heart rate on day 3 and gastrointestinal function on day 7.

Day 7
~~

Median
(2 5%-97 5%)
Aminophylline group

P=
Test type
Caffeine group
Both groups

Per 0s
total amount
(mu

Per 0s
(YOof 100%
fluid req )

Aspirate
(total amount
in ml)

Aspirate
(YOof by mouth
admin )

(YOof 100%

158
(1 33- 176)
<0.00005
MW
149
(123- 168)
155
(127-174)

83
(0-316)
0.5095
MW
114
(0-323)
88
(0-3 18)

35
(0-87)
0.4039
MW
49
(0--91)
41
(0-87)

2.0
(0-33)
0.0074
MW
0.0
(0-1 1)

2.0
(0-117)
0.0137
MW
0.0
(0-79)
0.7
(0-92)

0.7
(0-9)
0.0087
MW
0.0
(0-6)
0.4
(0-8)

MW = Mann-Whitneys U-test, Req = requirement at 24 h, Admin.

premature neonate. Prevention of apnea and bradycardia in neonates is brought about by treating
concurrent disorders such as infection, hypoxemia,
hypoglycemia and hypothermia, and avoiding apnea
and bradycardia provoking stimulations. In addition,
the incidence and severity of neonatal apnea and
bradycardia can be decreased by treatment with
methylxanthines.
The frequency of apnea and bradycardia was
registered by monitoring the neonates with a respiratory-cardiac monitor, ECG and an apnea mattress,
and the nursing staffs clinical observations. Some
episodes of apnea or bradycardia may have been
overlooked, but this source of error may be assumed
to be identical in both groups. This investigation
revealed that aminophylline and caffeine citrate
decrease the incidence of neonatal apnea and bradycardia to the same extent. With regard to adverse
effects, we exposed a significant difference between
the two drugs. The caffeine group had a lower heart
rate on day 3 and less gastric aspirate on day 7 than
the aminophylline group.
Other studies have shown that aminophylline reduces
cerebral blood flow (CBF) in stable preterm neonates,
without affecting the visual evoked potential (1 l),
whereas caffeine injection was not associated with significant changes in CBF (12). In a parallel study we have
demonstrated that aminophylline reduces CBF, without
any associated changes in cardiac output, whereas
Table 5. Measured plasma (P) theophylline and caffeine concentrations on day 3.

Median
(2.5%-97.5%)

Aspirate

Heart rate
Day 3
(beatsimin)

Therapeutic
interval

Aminophylline
group

Caffeine
group

P theophylline (mg/l)

5-15

P caffeine (mg/l)

5-25

10.3
(4.8-16.8)
4.0
(1.4-6.2)

0.5
(0.0-3.0)
16.0
(9.6-23.8)

To convert from mg/l to pmol/l theophylline, multiply by 5.55. To

convert from mg/l to pmol/l caffeine, multiply by 5.20.

(0-20)

fluid req )

= administered

caffeine citrate did not reduce CBF (13). According to

the literature, the effect of aminophylline on pulmonary
surface tension, production of pulmonary surfactant
and lung maturation in fetal rabbits is contradictory
( 14- 16).
Plasma theophylline and caffeine concentrations were
measured on day 3 when steady state concentrations
were probably not achieved because of the long elimination half-lives of the compounds (theophylline
TlI2 M 19-32h caffeine T1/2M 31-132h (5). In order
to overcome this problem, an iv loading dose was
administered according to the literature (5) with the
purpose of saturating the volume of distribution. The
measured plasma concentrations did not differ by a
great extent from steady state concentrations resulting
from these loading doses.
The neonates converted aminophylline to caffeine
to such a degree that an apnea and bradycardia preventing effect from caffeine cannot be disregarded in
aminophylline-treated neonates (Table 5). It could be
inferred that the therapeutic effect of aminophylline in
premature neonates is provided by its metabolic
product, caffeine.
In conclusion, we found aminophylline and caffeine
citrate equally effective in preventing apnea and bradycardia in premature neonates, with a 5% risk of committing an error of the first and second type and a
discrimination power of three episodes of apnealbradycardia in 24 h. Based on the result of this study, as well as
the more favorable therapeutic index of caffeine citrate,
the possibility of once a day administration, the lack of
influence on CBF and the lack of adverse effects,
caffeine citrate seems to be the drug of choice for
apnea and bradycardia prophylaxis in premature
neonates with a gestational age 533 full weeks.

References
1. Sims ME, Rangasamy R, Lee S , Chung H, Cohen J, Walther FJ.
Comparative evaluation of caffeine and theophylline for weaning
premature infants from the ventilator. Am J Perinatol 1989;6:
72-5.

364

PB Larsen et al.

2. Fuglsang G, Nielsen K, Nielsen LK, Sennels F, Jakobsen P,

Thelle T. The effect of caffeine compared with theophylline in
the treatment of iodiopathic apnea in premature infants. Acta
Pzdiatr Scand 1989;78:786-8
3. Brouard C, Moriette G, Murat I, et al. Comparative efficacy of
theophylline and caffeine in the treatment of idiopathic apnea in
,premature infants. Am J Dis Child 1985;139:698-700
4. Bairam A, Boutroy M-J, Badonnel Y, Vert P. Theophylline versus
caffeine: Comparative effects in treatment of iodiopathic apnea in
the preterm infant. J Pediatr 1987;110:636-9
5. Roberts RJ. Methyl xanthine therapy (caffeine and theophylline).
In: Drug therapy in infants. Philadelphia: WB Saunders
Company, 1984:119-37
6. Aranda JV, Grondin D, Sasyniuk B. Pharmacologic considerations in the therapy of neonatal apnea. Pediatr Clin North Am
1981;28: 113-33
7. Haley TJ. Metabolism and pharmacokinetics of theophylline in
human neonates, children, and adults. Drug Metab Rev
1983;14:295-335
8. Bory C, Baltassat P, Porthault M, Bethenod M, Frederich A,
Aranda JV. Metabolism of theophylline to caffeine in premature
newborn infants. J Pediatr 1979;94:988-93
9. Gilbert R, Keighley JF. The arterial/alveolar oxygen tension
ratio. An index of gas exchange applicable to varying inspired
oxygen concentrations. Am Rev Respir Dis 197q109:142-5

ACTA PEDIATR 84 (1995)

10. Enhorning G, Shennan A, Possmayer F, Dunn M, Chen CP,

Milligan J. Prevention of neonatal respiratory distress syndrome
by tracheal instillation of surfactant: a randomized clinical trial.
Pediatrics 1985;76:145-53
11. Pryds 0, Schneider S. Aminophylline reduces cerebral blood flow
in stable, preterm infants without affecting the visual evoked
potential. Eur J Pediatr 1991;150:366-9
12. Saliba E, Autret E, Gold F, Bloc D, Pourcelot L, Laugier J. Effect
of caffeine on cerebral blood flow velocity in preterm infants. Biol
Neonate 1989;56:198-203
13. Lundstrsm KE, Larsen PB, Brendstrup L, Skov L, Greisen G,
Cerebral blood flow and left ventricular output in spontaneously
breathing, newborn preterm infants treated with caffeine or
aminophylline. Acta Pzdiatr. In press
14. Corbet AJ, Flax P, Alston C, Rudolph AJ. Effect of aminophylline and dexamethasone on secretion of pulmonary surfactant in
fetal rabbits. Pediatr Res 1978;12:797-9
15. Cosmi EV, Di Renzo GC. Prevention and treatment of fetal lung
immaturity. Fetal Ther 1989;4 Suppl 1:52-62
16. Cosmi EV, Saitto C, Barbati A, et al. Effect of aminophylline on
lung maturation in preterm rabbit fetuses. Am J Obstet Gynecol
1986;154436-9
Received April 25, 1994. Accepted Nov. 2, 1994