ARTICLE IN PRESS

Randomized Trial of Milrinone Versus Placebo for Prevention of Low

Systemic Blood Flow in Very Preterm Infants
MARY PARADISIS, MBBS, MMED, FRACP, NICK EVANS, DM, MRCPCH, MARTIN KLUCKOW, MBBS, PHD, FRACP, AND
DAVID OSBORN, MBBS, MMED, PHD, FRACP

Objective To assess the effectiveness of early prophylactic milrinone versus placebo for prevention of low systemic blood
flow in high-risk preterm infants.
Study design Double-blind randomized placebo controlled trial of milrinone (loading dose 0.75 g/kg/min for 3 hours then
maintenance 0.2 g/kg/min until 18 hours after birth) versus placebo. Infants born <30 weeks gestational age and <6 hours
of age were eligible and were monitored with serial echocardiography, head ultrasound scanning, and continuous invasive
blood pressure. Primary outcome was maintenance of superior vena cava (SVC) flow >45 mL/kg/min through the first 24
hours. The exit criterion was hypotension unresponsive to volume and inotropes.
Results Ninety infants were enrolled, equal proportions maintained SVC flow >45 mL/kg/min after treatment commenced.
No significant difference was observed in SVC flow, right ventricular output, and blood pressure during the first 24 hours; or
grades 3 to 4 periventricular/intraventricular hemorrhage and death. Heart rate was higher and constriction of the ductus was
slower in the infants randomized to milrinone.
Conclusions Milrinone did not prevent low systemic blood flow during the first 24 hours in very preterm infants, and no
adverse effects were attributable to milrinone. Use of a preventative treatment with rescue model allowed comparison of an
inotrope with placebo in this high-risk group of infants. (J Pediatr 2008;xx:xxx)

remature infants born before 30 weeks gestation have improved survival and long-term outcomes.1,2 However, a

P significant proportion of these infants have some degree of neurodevelopmental disability that impacts on their quality
of life. Low cerebral blood flow during the first day after birth in the extremely preterm infant is postulated to be involved
in the pathogenesis of brain injury,3,4 including periventricular/intraventricular hemorrhage (P/IVH). Low cerebral blood flow
and low systemic blood flow (SBF) during the early transitional circulation on the first day birth in the extremely preterm infant
almost always precedes P/IVH.4-6 Early low SBF as measured by superior vena cava
(SVC) flow is common in preterm infants born before 30 weeks gestational age (GA) and
outcomes in up to 50% of infants less than 27 weeks GA.6,7 Low SVC flow occurs in a
predictable time frame with a nadir usually in the first 3 to 12 hours and improvement by
From the Department of Neonatal Medi-
24 hours of age. Risk factors for low SVC flow include higher mean airway pressures,
cine, Royal North Shore Hospital (M.P.,
lower GA, larger patent ductus arteriosus (PDA), higher systemic vascular resistance and M.K.), St Leonards, the Department of
worse myocardial contractility.5,6,8,9 Inability of the immature myocardium to adapt to Newborn Care, Royal Prince Alfred Hospi-
tal (M.P., N.E., D.O.), Camperdown, and
higher ex-utero afterload may contribute to low SBF.9 Low SVC flow is strongly the Faculty of Medicine, University of Syd-
5 5,6,10 10,11
associated with P/IVH, death, and neurodevelopmental disability at 3 years. ney (M.P., N.E., M.K., D.O.), Sydney, New
South Wales, Australia.
The P/IVH is believed to occur after improvement in SBF and cerebral blood flow,
Supported by the North Shore Heart Re-
suggesting a hypoperfusion-reperfusion mechanism. Therapeutic strategies with the com- search Foundation. The authors declare no
monly used inotropes, dopamine, and dobutamine, have been unreliable in improving and potential conflicts of interest, real or per-
maintaining SVC flow in a significant proportion of neonates12 with no difference found ceived.
11 Submitted for publication Mar 11, 2008;
in neonatal or long-term outcomes. last revision received Jun 20, 2008; ac-
cepted Jul 29, 2008.
Reprint requests: Nick Evans, Faculty of
BP Blood pressure Medicine, University of Sydney and Depart-
PDA Patent ductus arteriosus
BW Birth weight P/IVH Periventricular/intraventricular hemorrhage ment of Newborn Care, Royal Prince Al-
GA Gestational age PVL Periventricular leukomalacia fred Hospital, Camperdown, NSW 2050,
HR Heart rate RVO Right ventricular output Australia. E-mail: nevans@med.usyd.edu.au.
HUS Head ultrasound SBF Systemic blood flow 0022-3476/$ - see front matter
MCA Middle cerebral artery SVC Superior vena cava Copyright 2008 Mosby Inc. All rights
NEC Necrotizing enterocolitis UBVR Upper body vascular resistance reserved.
NICU Neonatal Intensive Care Units
10.1016/j.jpeds.2008.07.059

1
 ARTICLE IN PRESS
Therefore we explored a preventative approach to low SBF
with a view to improving outcomes in very premature infants.
Milrinone is a selective inhibitor of type III cAMP phosphodi-
esterase isoenzyme in cardiac and vascular muscle. It has both
positive inotrope and vasodilator effects.13,14 Milrinone has been
used therapeutically14-17 and prophylactically18 to improve
low cardiac output in infants after heart surgery, and also in
children.19,20 One hypothesis is that milrinone when given
prophylactically from early after birth to at-risk very preterm
infants will reduce low SBF and subsequently reduce the risk
of P/IVH. In an open-label pilot study, we previously estab-
lished a dosage regimen for milrinone in preterm infants and
found some uncontrolled evidence of efficacy.21,22 The aim of
this study was to assess, using a double blind randomized
controlled trial, the effectiveness of early prophylactic milri-
none for prevention of low SVC flow in high-risk preterm
infants.
METHODS
This was a 2-center study performed in the Neonatal
Intensive Care Units (NICU) of Royal Prince Alfred Hospital
and Royal North Shore Hospital, Sydney, Australia. This
study was approved by the Human Research Ethics Commit-
tee and Clinical Trials Committee of both hospitals. Written
informed parental consent was obtained before study entry.
Participants
Infants born before 30 weeks gestation and who were
less than 6 hours of age were eligible. Inclusion criteria were
based on a predictive model for low SVC flow, determined
from previous observational cohorts.6,7 For infants born be-
fore 28 weeks, gestation alone predicted the risk of low flow,
and all babies born in this range were included. Infants born
at 28 to 29 weeks had additional selection criteria on the basis
of predictive respiratory criteria for development of low SVC
flow, mean airway pressure 8 cm H2O and FiO2 0.3 at
time study entry.6 Infants were excluded if they were outborn,
more than 6 hours of age, not expected to survive, had
structural abnormality of the heart or brain, P/IVH grade 3 to
4 on an initial cranial ultrasound scan, perinatal asphyxia (base
excess 16 mmol/L on umbilical arterial gas), no parental
consent, or no continuous invasive arterial blood pressure
(BP) monitoring.
Study Design
In a double-blind randomized placebo-controlled trial,
infants were randomized to milrinone (0.75 g/kg/min for 3
hours then reduced to 0.2 g/kg/min until 18 hours after birth)
or placebo (5% dextrose). The milrinone dosing regimen was
developed from our pilot work.22 Milrinone lactate injection
(Primacor, 1 mg/mL in a 10-mL vial; Sanofi-Synthelabo, Aus-
tralia, North Ryde, Australia) was used and reconstituted by
Baxter Pharmaceuticals (Sydney, NSW, Australia). Syringes
were identical and labeled with a number code supplied by the
clinical trials pharmacist. Syringes were infused at the same rates
2 Paradisis et al
(milliliters/hour) depending on the infants birth weight
(BW). Trial investigators, clinicians, and participants were
blinded to treatment allocation. Random sequencing was gen-
erated with random number tables. Randomization was strat-
ified by hospital and GA (28 weeks or 28-29 weeks). For
each stratum, infants were allocated the next available number
on study entry. The randomization code and allocation list
was kept by the pharmacists and revealed to the investigators
only after all infants were recruited and data collected.
Cointerventions
To ensure adequate intravascular volume, all infants
received 15 mL/kg normal saline solution infused concurrent
with the study drug over the first hour. Indomethacin 0.1
mg/kg was administered if the ductus arteriosus diameter at
first scan was 2 mm. Infants received continuous positive
airway pressure or were intubated and mechanically ventilated
and received surfactant (Survanta 4 mL/kg) for respiratory
distress syndrome. Further cardiovascular support was pro-
vided on the basis of hypotension with volume bolus (10
mL/kg) and dopamine. Hypotension was defined as mean BP
24 mm Hg for more than 30 minutes or a drop in mean BP
20% within 2 hours of commencing the infusion. Dopa-
mine was the first-line inotrope because its vasopressor effects
were most appropriate for hypotension from vasodilator ef-
fects of milrinone. Dopamine was begun at 4 g/kg/min and
titrated to achieve a minimally acceptable BP. Hypotension
(rather than low SVC flow) was the criterion for added
cardiovascular support. The rationale being that dopamine for
hypotension is standard treatment in most NICUs with echo-
cardiography not readily available.
Primary Outcome
Maintenance of SVC flow 45 mL/kg/min was mea-
sured by echocardiography throughout the first 24 hours. Low
SBF was defined as SVC 45 mL/kg/min, defined from
previous cohort data from healthy preterm infants.7
Secondary Outcomes
Hemodynamic outcomes were hypotension (defined
above), additional inotrope, tachycardia (160 beats/min),
maintenance of right ventricular output (RVO) 120 mL/
kg/min, upper body vascular resistance (UBVR) calculated as
mean BP at time of scan divided by SVC flow (mm Hg per
mL/kg/min), presence of a PDA treated with indomethacin
or surgery, and middle cerebral artery (MCA) diameter and
velocity. PDA treatment was defined as early if treatment
was given on the basis of diameter of 2 mm at the first
echocardiogram and before commencement of the study drug
and late if treatment was given after the study drug was
commenced and the diameter was 1.6 mm. Clinical out-
comes were necrotizing enterocolitis (NEC) defined clinically
or surgically; chronic lung disease defined as oxygen depen-
dency at 36 weeks postmenstrual age; pulmonary hemorrhage
defined as major if frank blood in endotracheal secretions and
The Journal of Pediatrics Month 2008
 ARTICLE IN PRESS
associated with respiratory deterioration, P/IVH greater than
Papile grade 2,23 periventricular leukomalacia (PVL) and
death before discharge from hospital. P/IVH was defined as
early if present on the initial head ultrasound (HUS) scan
obtained before commencement of study drug; and late if
P/IVH developed on subsequent scans after the infusion.
HUS was also performed on days 7 and 28. All HUS were
reviewed by an independent radiologist. PVL was diagnosed
on the day 28 ultrasound scan. Neurodevelopmental outcomes
at 1 and 3 years will be assessed and reported later. Outcomes
relating to milrinone side effects were hypotension, throm-
bocytopenia defined as platelet count 50 000 mm3 and
tachyarrhythmia.
Exit Criteria
Exit criteria included sustained hypotension 24 mm
Hg for more than 30 minutes and unresponsive to volume and
dopamine at a dose greater than 15 g/kg/min.
Clinical Monitoring
Before each ultrasound scan, hemodynamic and respi-
ratory measures were obtained. These included heart rate
(HR), systolic, diastolic and mean BP, respiratory rate, ven-
tilation type, ventilator settings, oxygen requirement, and
mean airway pressure.
Ultrasound Monitoring
An Acuson (Mountain View, California) Aspen ultra-
sound scanner was used with a 7-MHz vector array transducer
incorporating color-flow and pulsed-wave Doppler scanning.
Echocardiographic monitoring was performed between 3 and
6 hours of age (baseline scan before commencing infusion), 6
and 9 hours after infusion was commenced, at 24 and 48
hours of age. Structural normality was established on the
initial scan. Hemodynamic variables measured were SVC
maximum and minimum diameters, SVC flow, RVO, PDA
color-flow Doppler diameter, and direction of ductal shunt.
Techniques and methods for SVC flow, RVO and Doppler
diameter of PDA shunt have been described previously.7,24,25
HUS was performed concurrent with the echocardiograms.
P/IVH was graded according to Papile classification23; MCA
diameter and velocity were calculated as described previously.25
Most scans (more than 90%) were conducted by 1 investigator
(M.P.), interobserver variability for measurement of SVC has
been assessed previously and is 14%.7
Sample Size and Statistical Analysis
Ninety infants (45 in each arm) were needed to show a
reduction in incidence of low flow from 50% to 20% of infants
with 80% power. Data analyses were performed according to
intention to treat. Categorical data were analyzed with 2 test
or Fisher exact test where there were small expected frequen-
cies. For continuous data, the means SD are presented if
the assumptions of normality were met. Differences between
the treatment groups were assessed with the Student t test for
Randomized Trial of Milrinone Versus Placebo for Prevention of Low Systemic Blood Flow in Very Preterm Infants
normally distributed data or Mann Whitney U test for non-
parametric data. Statistical significance was set at a P value
.05. Statistical analyses were done with the Statistical Pack-
age for Social Sciences (SPSS/PC version 15). Safety analysis
was conducted at study midpoint. Only the data monitoring
statistician, who was independent from the trial, was un-
blinded to the data.
RESULTS
Ninety infants with a mean GA of 26 weeks and mean
BW of 899 g were enrolled from November 2003 to Novem-
ber 2006, 53 from RPAH and 37 from RNSH. Mean BW
and GA were similar for infants who were and were not
included (data not shown). Of the 90 randomized infants, 42
were allocated to milrinone and 48 to placebo (Figure). In-
fants in the 2 groups did not differ in their baseline charac-
teristics at study entry (Table I). In the placebo group, 1
infant met exit criteria, however, continued to have data
collected and was analyzed by intention to treat. Most babies
were born 28 weeks, with 6 infants born 28 to 29 weeks
gestation of whom 4 were randomized to placebo and 2 to
milrinone.
Hemodynamic Outcomes
The primary outcome was maintenance of SVC flow
45 mL/kg/min, 83% in the milrinone group and 81% in the
placebo group maintained SVC flow after treatment was
commenced. Secondary outcomes are compared in Tables II
and III. No significant differences were observed between the
2 groups in median SVC flow; RVO or UBVR at 3, 7, 10, and
24 hours.
Infants randomized to milrinone had significantly
higher HR and lower mean BP after commencing the infu-
sion. No significant difference seen in incidence of hypoten-
sion in infants randomized to milrinone (50% vs 38% for
placebo). Significantly more infants randomized to milrinone
had tachycardia (67% vs 22%) during study drug infusion
(P .0001). No significant differences were seen in the
number treated with additional inotropes (45% vs 35%), time
to starting inotrope (8 hours milrinone versus 11 hours pla-
cebo), or the mean dose of inotrope. Infants randomized to
milrinone had significantly larger PDA diameters after com-
mencing the infusion. The overall rate of PDA treated with
indomethacin was 81% for milrinone and 69% for placebo
group, not statistically significant. Of these, 44% of milrinone
and 33% of the placebo group required late treatment with
indomethacin after the study drug was commenced. The
median time for this was 9 hours, range 5 to 72 hours for
milrinone and 3 to 72 hours for placebo. Surgical ligation was
performed in 4 infants from the milrinone group and 2 in the
placebo group. No significant differences were seen in MCA
velocities and resistance index. Pulsatility index was signifi-
cantly higher in the milrinone group after commencement of
the study drug, but this difference did not persist at 24 hours
of age.
3
 ARTICLE IN PRESS

Figure. Diagram of participant flow.

Three of 6 infants in the milrinone group had at least 1

Table I. Baseline characteristics of infants at trial
entry measure of low SVC flow. In the placebo group, 2 had
episodes of low SVC flow within the first 24 hours. All babies
Milrinone Placebo who had episodes of low SVC flow in the first 24 hours had
(n 42) (n 48)
late P/IVH after the SVC flow had improved. Seven infants
Antenatal steroids had early P/IVH on the initial scan, but none progressed. No
Any 41 (98%) 45 (94%) survivor had documented PVL. There was no significant
Complete (24 h) 23 (52%) 29 (60%) difference in major pulmonary hemorrhage (7% milrinone vs
Vaginal delivery 20 (48%) 18 (38%) 6% placebo), NEC (5% milrinone vs 17% placebo), or chronic
Gestational age (weeks) 26 1.1 26 1.3
lung disease in survivors at 36 weeks postmenstrual age (33%
Birth weight (g) 959 185 853 249
Sex: Male 28 (67%) 23 (48%)
vs 29%). No evidence of thrombocytopenia or tachyarrhyth-
Apgar score mia was seen in any infant during the first 24 hours of life.
At 1 min 42 52 There was no significant difference between the groups in
At 5 min 71 72 mortality rate before discharge from hospital (n 7 [17%]
Umbilical arterial pH 7.25 1.1 7.29 1.1 milrinone vs 10 [21%] placebo). Causes of death in the
Umbilical arterial base excess 6 3.6 4 4.1 milrinone arm included sepsis/septic shock in 2; grade 3 to 4
Age at first ultrasound (h) 3.4 1.1 3.4 1 P/IVH in 4, and NEC in 1. Three of the infants with P/IVH
Age at commencement of 4.4 1.1 4.3 1.1 also had overwhelming sepsis. In the placebo arm, causes of
study drug (h)
death included sepsis/septic shock in 3; grade 3 to 4 P/IVH in
PDA 2 mm at first scan 19 (45%) 22 (46%)
(before indomethacin) 3; NEC in 2, and respiratory failure in 2.
(Data presented as mean SD unless otherwise stated).
DISCUSSION
Clinical Outcomes This is the first double-blind randomized trial with
There was no significant difference between the groups milrinone used in preterm infants; indeed, this is one of the
in the rate of development of late P/IVH, 8 (19%) milrinone first neonatal trials where an inotrope has been compared with
versus 7 (15%) placebo. Six in the milrinone group and 5 in a placebo. This study showed no evidence of a preventive
the placebo group had development of grade 2 to 4 P/IVH. effect of milrinone on the occurrence of low SVC flow in very

4 Paradisis et al The Journal of Pediatrics Month 2008

 ARTICLE IN PRESS
Table II. Hemodynamic variables compared at 3, 7, 10, and 24 hours of age
Age (h) Milrinone (n 42) Placebo (n 48)* P value
SVC (mL/kg/min) 3 78 (51, 107) 86 (67, 107) .2
7 70 (48, 92) 75 (51, 94) .8
10 67 (53, 87) 81 (50, 100) .5
24 88 (73, 101) 93 (72, 121) .4
RVO (mL/kg/min) 3 182 (140, 240) 189 (133, 271) .9
7 177 (147, 258) 187 (140, 240) .9
10 189 (146, 258) 187 (133, 243) .4
24 242 (194, 301) 250 (207, 306) .7
BP (mm Hg) 3 31 6 30 3 .4
7 28 5 32 6 .001
10 29 4 32 5 .004
24 34 5 36 6 .2
HR (beats/min) 3 149 16 151 17 .6
7 158 15 145 10 .001
10 157 13 141 12 .001
24 153 13 144 14 .003
Ductal diameter (mm) 3 2 0.9 1.9 0.6 .5
7 1.9 0.7 1.5 0.6 .001
10 1.9 0.6 1.4 0.6 .001
24 1.7 0.8 0.9 0.7 .001
Calculated UBVR (mm Hg per mL/kg/min) 3 0.5 0.6 0.4 0.2 .2
7 0.5 0.3 0.5 0.4 .6
10 0.5 0.3 0.5 0.3 .6
24 0.5 0.4 0.4 0.2 .4
MCA velocity (m/s) 3 0.27 0.1 0.24 0.1 .4
7 0.27 0.1 0.21 0.1 .6
10 0.29 0.2 0.20 0.1 .2
24 0.36 0.1 0.24 0.1 .2
MCA resistance index 3 0.77 0.2 0.82 0.1 .1
7 0.80 0.1 0.82 0.1 .8
10 0.81 0.2 0.74 0.1 .08
24* 0.74 0.4 0.76 0.1 .5
MCA pulsatility index 3 1.76 0.5 2.0 1.5 .4
7 1.86 0.7 1.57 0.7 .07
10 1.71 0.5 1.38 0.4 .001
24 1.49 0.4 1.47 0.4 .8
Data expressed as mean SD unless stated.
*At 24 hours, n 47 for the placebo group.
Presented as median, 25th to 75th interquartile range.
At 3 hours, these are baseline measures, before commencing study drug.

preterm infants at the dosage used. This is despite consistent
evidence of effects on cardiac outputs in older popula-
tions14-18 and in our open-labeled pilot study in very preterm
infants21 that found no episode of low SVC flow in a group
of infants predicted to have 50% incidence of low flow. The
contrast of this study with our pilot observations highlights
the importance of a placebo control group in therapeutic drug
trials.
Why did milrinone not produce any hemodynamic ben-
efit in this group of very preterm babies? Potential factors
include the use of a preceding volume load in all infants,
myocardial maturity issues, starting time, dosage, and the
effect on the constriction of the ductus arteriosus.
Studies in both newborn and fetal animal (which may
be extrapolated to the very preterm human infant) suggest
milrinone and other phosphodiesterase inhibitors have de-
creased effectiveness for the immature myocardium by way of
diminished inotropic effect.26,27 The cyclic adenosine mono-
phosphate phosphodiesterase activity is low in the newborn
myocardium. Despite milrinone having a positive inotropic
effect in the immature myocardium, it is quantitatively weaker
than in older populations.27
The mean start time of the infusion was 4 hours in both
groups, but was this too late? The nadir of SVC flow is
between 3 to 12 hours of age with improvement by 24
hours.5-7 To prevent this, it is possible that starting earlier
after birth would have been more effective. Delays were
mainly due to the unavoidable problems of obtaining consent
and the need to stabilize the baby before starting the inter-
vention, issues common to early intervention trials.

Randomized Trial of Milrinone Versus Placebo for Prevention of Low Systemic Blood Flow in Very Preterm Infants 5
 ARTICLE IN PRESS
ment with lower pressure ventilation (higher MAP is associ-
Table III. Hemodynamic outcomes
ated with low SVC flow),6 earlier use of natural surfactants,
Milrinone Placebo and earlier extubation to continuous positive airway pressure.
(n 42) (n 48) P value The possible effects of these changes are speculative.
SVC 45 mL/kg/min 7 (17%) 9 (19%) .8 The cointerventions may also have impacted on main-
RVO 120 mL/kg/min 6 (14%) 11 (23%) .3 taining the SVC flow. Osborn et al12 found a 42% mean
BP 24 mm Hg 21 (50%) 18 (38%) .2 short-term increase in SVC flow after volume was adminis-
HR 160/min 28 (67%) 11 (22%) .0001 tered to infants with low SVC flow. All infants in our RCT
Need for inotrope 19 (45%) 17 (35%) .3 were given normal saline solution 15 mL/kg at commence-
Age at starting 8.6 4.3 11.4 8.4 .3 ment of the study drug; this may have prevented development
inotrope (h)*
of low SVC flow in some infants. However, there is also
Maximum dose of 8.2 3.8 7 2.6 .3
evidence that routine early volume expansion does not im-
inotrope (g/kg/
min)* prove preterm outcomes.12,32 A large PDA is a known risk factor
Indomethacin (overall) 34 (81%) 33 (69%) .2 for low SVC flow, and it is possible that the cointervention of
Indomethacin (Late) 15/34 (44%) 11/33 (33%) .2 targeted early closure of the ductus arteriosus may have im-
PDA ligated 4 (9%) 2 (4%) .7 pacted on the incidence of low SVC flow.5,6,24 To date there
Data expressed as number (%) unless otherwise specified.
is no evidence that closing the PDA with indomethacin
*Mean SD. improves SVC flow,29 and the effects of echocardiographi-
cally targeted early ductal closure on neonatal outcomes are
yet to be studied. Our group is commencing a placebo con-
Was the correct dosage used? We performed dosage trolled trial of early echocardiographically targeted treatment
escalation studies with pharmacokinetic analysis aimed at and management of the ductus arteriosus (DETECT trial) to
optimizing blood levels,22 with a therapeutic target between assess this question.
180 to 300 ng/mL, on the basis of data in other populations, The main adverse effect of milrinone is hypotension.14,19
which reported pharmacodynamic effects.15,17,18,20 It is pos- The rate of hypotension in the infants randomized to milrinone
sible that this therapeutic target is inadequate in the extremely was comparable to other preterm populations.33 Tachycardia is
premature infant. Hoffman et al28 showed milrinone had another side effect of milrinone. Reports of change in HR are
more effect at higher dose in neonates. We may not have used variable; some studies showed an increase,14,28 and others did not
a high enough dose despite achieving targeted milrinone show any change.16,19 We can speculate the increase in HR may
serum levels in the pilot study. However, we found evidence be related to a direct myocardial effect, produced by an increase
of other hemodynamic effects with higher HR and lower BP in cyclic adenosine monophosphate, leading to increased myo-
in babies randomized to milrinone. What is not clear is why cardial contractility.16
systemic UBVR was not significantly reduced by milrinone, The results of this RCT do not support the use of
because the UBVR is a product of flow and BP. There may milrinone in preventing the development of low SVC in the
have been some effect but not enough to alter the measurable early transitional circulation of the preterm infant. In the
vascular resistance. RCT in very preterm infants, an inotrope was compared
Milrinone appeared to slow the closure of the ductus. against a placebo. A major strength of this study is that we
Larger-diameter ducts are significantly related to low SBF.5,24,29
have designed a preventative trial for a therapy on the basis of
It is possible that any beneficial effects on SBF were balanced known physiology and natural history, as well as determining
by increased left-to-right shunting through the ductus from
pharmacokinetics and safety profile of this therapy in the very
the systemic into the pulmonary circulation. Physiological preterm population, not just extrapolating from pediatric or
dilators of the ductus muscle include prostaglandin E and adult dosing regimens. The advantage of the preventative
nitric oxide, and both are augmented by inhibition of phos- treatment with rescue model used in this trial is that it allows
phodiesterase enzymes.30,31 This effect was predictable and comparison with a placebo. This model could be used to
part of the rationale for use of early indomethacin in babies evaluate preventative approaches for other common circula-
with poor postnatal ductus constriction. tory support interventions. Such studies should include effects
What was striking about these results was that the on SBF, as well as BP and report important clinical and
incidence of low SVC flow in both arms was much lower than long-term neonatal outcomes.
expected from previous cohorts, 17% milrinone versus 19%
placebo. An incidence of low SVC flow of 50% (infants born
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