doi:10.1111/j.1440-1754.2007.01211.

ORIGINAL ARTICLE

Effect of single loading dose of intravenous caffeine infusion on

superior mesenteric artery blood flow velocities in preterm infants
Amuchou S Soraisham,1 Davis Elliott2 and Harish Amin1
Departments of 1Paediatrics and 2Diagnostic Imaging, University of Calgary, Alberta, Canada

Aim: To evaluate the effects of a single loading dose of caffeine base (10 mg/kg) on superior mesenteric artery (SMA) blood flow velocities
(BFV).
Methods: Eighteen preterm infants of gestational age ≤32 weeks gestation were investigated prospectively. SMA BFV before infusion, 1 h,
2 h and 6 h after a single loading dose of caffeine were measured using Doppler ultrasonography.
Results: The peak systolic velocity in SMA decreased by 18% from baseline at 1 h after caffeine infusion and improved towards the baseline
by 6 h after the infusion. The reduction in velocity after caffeine infusion was not statistically significant. No significant changes were observed
in heart rate, blood pressure and incidence of necrotising enterocolitis.
Conclusion: A single 10 mg/kg intravenous loading dose of caffeine does not cause a significant reduction in SMA BFV and therefore does
not place the preterm intestine at increased risk of ischemic injury.

Key words: blood flow velocity; caffeine; premature infant.

The methylxanthines, caffeine and aminophylline are used
commonly to treat and prevent apnea of prematurity1,2 and to
assist weaning of preterm infants from assisted ventilation.3
Caffeine and theophylline stimulate the respiratory center in
the medulla of brain. This is associated with a regular breathing
pattern, increased alveolar ventilation and decreased episodes
of apnea. Caffeine has several advantages over theophylline
such as a more reliable enteral absorption and longer half-life,
thus requiring a less frequent dosing schedule with fewer side
effects.4 Hence, caffeine is preferred over theophylline for the
treatment of apnea in preterm infants.
Erenberg et al.5 have shown that a loading dose of 10 mg/kg
of caffeine base followed by 2.5 mg/kg/day is safe and effective
for treating apnea of prematurity. A single high loading dose of
caffeine base 25 mg/kg has been reported to reduce the cerebral
Key Points
1 A standard single loading dose of caffeine base (10 mg/kg) did
not significantly reduce the blood flow velocities in the superior
mesenteric artery.
2 A single high dose (25 mg/kg) of caffeine reduces intestinal and
cerebral blood flow velocity.
3 No changes in heart rate and blood pressure were observed
after a single loading dose of caffeine.
Correspondence: Dr Amuchou S Soraisham, Department of Paediatrics,
Foothills Medical Centre, C 211, 1403, 29th Street, NW, Calgary, Alberta,
Canada, T2N 2T9. Fax: +1 403 944 4892; email: amuchou.soraisham@
calgaryhealthregion.ca
Accepted for publication 13 May 2007.
and intestinal blood flow velocities (BFV).6,7 A divided high
loading dose of 25 mg/kg caffeine base given four hours apart
was shown to decrease BFV in cerebral arteries after the second
dose, whereas BFV in intestinal arteries was not affected.8
Uncontrolled, retrospective studies have shown that oral theo-
phylline increases the risk of necrotising enterocolitis whereas
intravenous theophylline did not.9,10
Despite the extensive use of methylxanthines in neonatal
units, no study has evaluated the effects of a caffeine infusion
given at a loading dose of 10 mg/kg on intestinal blood flow in
preterm infants. A recent multicenter study showed that there
is no increase in the incidence of necrotising enterocolitis with
caffeine use.11 The impact of caffeine on superior mesenteric
artery (SMA) BFV would help understand the degree to which
blood flow in mesenteric arteries is altered, and if so the time
taken for recovery to occur. This study was designed to inves-
tigate the effects of caffeine base given at a loading dose of
10 mg/kg intravenously over 30 min on SMA BFV in preterm
infants.
Methods
This study was conducted at the Foothills Medical Centre,
a regional tertiary neonatal intensive care unit in Calgary,
Canada. Preterm infants with birthweight <1500 g and/or ges-
tation ≤32 weeks with apnea of prematurity or being weaned
from assisted ventilation towards extubation for whom caffeine
is indicated, at discretion of the attending physician were
included.
Infants with the following conditions were excluded from the
study: perinatal asphyxia (because BFV parameters show a sig-
nificant reduction, directly correlated to severity of asphyxia12),

Journal of Paediatrics and Child Health 44 (2008) 119–121 119

© 2007 The Authors
Journal compilation © 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Caffeine and SMA blood flow velocities AS Soraisham et al.

symptomatic patent ductus arteriosus13,14 and major congenital Results

malformations.
Caffeine is used in our neonatal intensive care unit for: (i)
spontaneously breathing infants with recurrent apnea/brady-
cardia requiring stimulation or positive pressure ventilation;
and (ii) mechanically ventilated infants with gestational age
below 30 weeks at 4 to 6 h prior to planned extubation.
A loading dose of 10 mg/kg caffeine base was given as an
intravenous infusion over 30 min. To exclude the possible influ-
ence of postprandial changes on intestinal blood supply,15,16 all
infants were studied at least 2 h after a feed, if they were
receiving oral feeds. No enteral feeds were provided during the
6-h study period. Oral feeds were resumed after the last BFV
measurement.
Superior mesenteric artery peak systolic and end diastolic
velocities were measured using Doppler ultrasound (Acuson
Sequoia 512 model). The first measurements were taken
15 min before caffeine administration. These measurements
were repeated at 60, 120 and 300 min after caffeine adminis-
tration. At the same time, heart rate and blood pressure were
recorded. The Doppler scan was performed by the same sonog-
raphy technician. BFV in SMA were measured using a longitu-
dinal abdominal approach with a HC 8.5 MHz transducer.
Doppler tracings were assessed visually, audibly and stored on
a stereo videotape. This recorded videotape was subsequently
analysed by a radiologist, who was blinded to the time of Dop-
pler scans. Vital signs in all infants were monitored during the
study period. All infants were also observed for signs of necro-
tising enterocolitis for at least 72 h after completion of SMA BFV
measurement. This study was approved by the Conjoint Health
Research Ethics Board of the Faculty of Medicine at the
University of Calgary.
A total of 18 preterm infants were enrolled in the study. The
mean gestational age (SD) was 28(2) weeks (range: 24–
32 weeks) and mean birthweight was 1143 (228) g (range:
680–1550 g). The mean age at the time of study was 7.6 days
(range: 2–32 days).
Table 1 shows the effects of a standard loading dose of caffeine
on SMA BFV. After a 10 mg/kg loading dose of caffeine infusion,
the peak systolic BFV in SMA decreased by 18% at 1 h when
compared with baseline. However, this difference was not
statistically significant (Fig. 1). The peak systolic BFV increased
gradually towards baseline value by 6 h after caffeine adminis-
tration. There was no significant difference in the end diastolic
BFV before and after caffeine administration (Fig. 2).
We did not find significant differences in the heart rate and
blood pressure before and after caffeine administration. None
of the study infants developed necrotising enterocolitis (NEC)
during their hospital stay.
Discussion
Caffeine inhibits adenosine induced vasodilatation.17 Endothe-
lium dependent and independent vasoconstrictions have also
been reported following caffeine infusion in canine SMA.18 This
may be responsible for reduction in BFV following caffeine
administration. Oxygen consumption is increased by about 20%
following 48 h of caffeine treatment in preterm infants.19 It
is unclear whether oxygen consumption is already increased
during the first hour of caffeine treatment. A rise in oxygen
1

Sample size and statistical analysis 0.8

A sample size was calculated based on the primary objectives.

0.6
PSV (m/s)

Hoecker et al.’s study6 showed that there was a significant reduc-

tion in SMA BFV of 30% at 1 h following an oral loading dose
of caffeine. We calculated our study sample size on the basis of 0.4
this study. To demonstrate a difference of 30% in the peak
systolic BFV from baseline (α of 0.05 and a power of 80%), a 0.2
sample size of 18 infants was required. Results are presented as
mean ± standard deviation (SD). A t-test for paired observations
0
was used to test for changes in the measured variables. All Pre 60 min 120 min 300 min
comparisons are with the values before the caffeine infusion.
Analysis was performed by using the SPSS version 10. (SPSS Inc, Fig. 1 Peak systolic velocity (PSV) (m/s) in superior mesenteric artery
Chicago, IL, USA) and a difference was considered statistically before and at 60, 120 and 300 min after the caffeine infusion. All values are
significant at a level of P < 0.05. expressed as mean ± SD.

Table 1 Effect of caffeine on SMA blood flow velocities before and after caffeine infusion

SMA velocity Before caffeine 1h 2h 6h

Peak systolic (m/s)† 0.81 ± 0.10 0.68 ± 0.07 0.73 ± 0.10 0.75 ± 0.12
End diastolic (m/s) 0.17 ± 0.04 0.14 ± 0.03 0.14 ± 0.02 0.17 ± 0.03
Resistive index 0.79 ± 0.03 0.78 ± 0.02 0.78 ± 0.02 0.73 ± 0.05

†Mean ± SEM. SMA, superior mesenteric artery.

120 Journal of Paediatrics and Child Health 44 (2008) 119–121

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AS Soraisham et al.
0.24
0.2
0.16
EDV (m/s)
0.12
0.08
0.04
0
Pre 60 min 120 min
Fig. 2 End diastolic velocity (EDV) (m/s) in superior mesenteric artery
before and at 60, 120 and 300 min after the caffeine infusion. All values are
expressed as mean ± SD.
consumption could seriously jeopardise oxygen supply to vital
tissues, particularly to those with reduced blood flow. Lane
et al.5 observed that the BFV in the intestinal arteries rapidly
falls by about 30% during a 30-min intravenous infusion of
25 mg/kg of caffeine base with minimum values at approxi-
mately 120 min. A decrease in BFV may lead to ischemic injury
to the gastrointestinal tract.
Oral administration of a high loading dose (25 mg/kg) of
caffeine has been shown to markedly reduce intestinal and
cerebral BFV, without changing left ventricular output, heart
rate and blood pressure.6 Hoecker et al.8 showed that a divided
high oral loading dose of 25 mg/kg caffeine in two equal doses
of 12.5 mg/kg administered 4 h apart did not significantly
reduce BFV in the celiac artery and SMA, a finding similar to
ours. These observations suggest that the effect of caffeine on
intestinal BFV may be dose-dependent.
A randomised trial has shown that a high-dose caffeine has
been effective in reducing extubation failure in preterm
infants.20 In this trial, there was no significant difference in
the incidence of feeding intolerance or the need for intrave-
nous parenteral nutrition between a high dose (20 mg/kg)
and a low dose (5 mg/kg) of caffeine. None of the infants in
this study developed necrotising enterocolitis. Similarly, there
is no increase in the incidence of necrotising enterocolitis in
infants treated with standard dose of caffeine for apnea of
prematurity.11
In conclusion, a single 10 mg/kg loading dose of caffeine does
not cause a significant reduction in SMA BFV and therefore
does not place the preterm intestine at increased risk of ischemic
injury.
Acknowledgements
We would like to thank the staff of the NICU at Foothills
Medical Centre, Ultrasound technician and parents of babies
who participated in the study.
Journal of Paediatrics and Child Health 44 (2008) 119–121
© 2007 The Authors
Journal compilation © 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Caffeine and SMA blood flow velocities
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