Innovations in treatment
BMJ Case Rep: first published as 10.1136/bcr-2019-232440 on 2 December 2019. Downloaded from http://casereports.bmj.com/ on January 2, 2020 at UniversitaetsSpital Bibliothek.
1
Department of Neonatology,
Royal North Shore Hospital,
Northern Sydney Local Health
District, St Leonards, New South
Wales, Australia
2 protocol for treatment of NLI and limited evidence to guide
The University of Sydney,
Camperdown, New South Wales,
Australia
3
Department of Neonatology,
The Hospital for Sick Children,
Toronto, Ontario, Canada
4
Department of Paediatrics,
University of Toronto, Toronto,
Ontario, Canada
Correspondence to
Dr Stephanie Boyd;
​stephanie.​boyd@h​ ealth.​nsw.​
gov.a​ u
Accepted 13 November 2019
© BMJ Publishing Group
Limited 2019. No commercial
re-­use. See rights and
permissions. Published by BMJ.
To cite: Boyd S, Shah V,
Belik J. BMJ Case Rep
2019;12:e232440.
doi:10.1136/bcr-2019-
232440
Case report
A novel role for milrinone in neonatal acute limb
ischaemia: successful conservative treatment of
thrombotic arterial occlusion without thrombolysis
Stephanie Boyd  ‍ ‍,1,2,3 Vibhuti Shah,3,4 Jaques Belik3,4
SUMMARY
Acute neonatal limb ischaemia (NLI) is most frequently an
iatrogenic complication, however, may also occur in utero
due to thromboembolism. There is no widely accepted
management. Thrombolysis and surgical management
have been attempted, though both are associated with
significant morbidities. Milrinone is a phosphodiesterase-3
inhibitor used for its vasodilatory effects on the systemic
and pulmonary vasculature. There is also emerging
evidence for benefit of milrinone in ameliorating
ischaemia-­reperfusion injury. The authors present a case
report of a term infant with spontaneous perinatal acute
limb ischaemia secondary to near-­completely occlusive
thrombosis of the right subclavian artery. The infant was
successfully managed conservatively with milrinone without
requirement for thrombolysis or surgical intervention.
Milrinone represents a novel treatment option for neonates
with acute limb ischaemia and consideration of a trial
of milrinone prior to higher risk treatment options is
warranted in this patient group.
Background
Acute neonatal limb ischaemia (NLI) occurs most
frequently as an iatrogenic complication. However,
it may also occur spontaneously in utero or peri-
natally due to thromboembolic phenomena.1 The
postulated mechanism is placental in origin, with
passage to the fetal systemic arterial circulation via
the foramen ovale.2 There is no widely accepted
protocol for treatment of NLI and limited evidence
to guide management.1 Thrombolysis and surgical
management have been attempted, though both
strategies are associated with significant morbidi-
ties. The risk of stroke complicating thrombolysis
in the neonatal population is of particular concern.
Milrinone is a phosphodiesterase-3 (PDE3) inhib-
itor increasingly used in neonatology for its vaso-
dilatory effects on the systemic and pulmonary
vasculature.3 There is also emerging translational
evidence for benefit of milrinone in ischaemic
postconditioning, or amelioration of ischaemia-­
reperfusion injury following an ischaemic event.4
Milrinone has not previously been described as a
treatment modality for NLI.
Case presentation
The infant’s mother was a 33-­year-­old primigravida
with no intercurrent medical problems. There was
Boyd S, et al. BMJ Case Rep 2019;12:e232440. doi:10.1136/bcr-2019-232440
no known family history of thrombophilia. Preg-
nancy was unremarkable, with spontaneous onset
of labour at 41 weeks and rupture of membranes
32 hours prior to delivery. There was no history of
maternal fever during labour and her group B Strep-
tococcus status was negative. A live female infant
was delivered via emergency Caesarean section for
failure to progress. The baby was born with Apgar
scores of 9 and 9 at 1 and 5 min, respectively, and
the cord gas showed a pH of 7.17 and base excess
−9.1. The infant’s birth weight was 3570 g (52nd
centile). The newborn remained with her mother
initially for routine postnatal care. At 2 hours of
age, however, medical assessment was sought for
mild tachypnoea. Asymmetry in upper limb perfu-
Protected by copyright.
sion was observed, with distinct pallor and bluish
discolouration of the right upper limb from the
elbow distally (figure 1). Brachial and radial pulses
in the right upper limb were impalpable and neither
oximetry (SpO2) or non-­ invasive blood pressure
readings could be obtained. Fetal Doppler appa-
ratus were also unable to obtain a signal over the
right brachial or radial arteries. Both limbs were
warmed using warm compresses for 15 min to try
to improve regional blood flow with no appre-
ciable improvement. The infant’s vital signs were
stable and included a heart rate=140 beats/min,
respiratory rate=64 breaths/min, blood pressure
(left upper limb) 69/40 (mean 50) mm Hg, SpO2
(left upper limb) 96% in room air and tempera-
ture 36.7°C. There was no evidence of respiratory
distress and on auscultation the chest was clear and
there was no cardiac murmur. There was no estab-
lished necrosis and neuromuscular function of the
limb was intact.
Investigations
Initial blood tests demonstrated: haemo-
globin=173 g/L, haematocrit=0.51, platelet
count=159×109/L, white blood cell
count=14.2×109/L, international normalised
ratio=2.2, partial thromboplastin time=42  s,
fibrinogen level=1.5 g/L and C reactive protein
level 12.4 mg/L. No blood culture was collected
and no antibiotics were given due to low clinical
suspicion for sepsis. A Doppler ultrasound was
performed at 6 hours of age, which demonstrated
a near-­occlusive thrombus in the mid-­ subclavian
artery on the right side, extending into the prox-
imal axillary artery (figure 2), and minimal flow in
1
 Innovations in treatment
Figure 1  Appearance of poorly perfused right upper limb at 2 hours
of age.
the brachial artery. The internal jugular, subclavian, axillary and
brachial veins were patent.
Treatment
A decision was made to manage the infant conservatively in view
of the significant risks of thrombolysis. She was commenced on
a therapeutic heparin infusion at 28 units/kg/hour. Throughout
the next 16 hours, there was persistence of impalpable brachial,
radial and ulnar pulses and pallor affecting the right upper limb.
The limb was pale and cool, with a skin temperature differ-
ence between the upper limbs (using a standard neonatal skin
temperature sensor probe) of 2.5°C. Further imaging demon-
strated a normal cranial ultrasound and patent right internal
carotid artery. Echocardiography showed a structurally normal
heart and no evidence of intracardiac thrombus. Ongoing assess-
ment revealed no evidence of compartment syndrome. A partial
thrombophilia screen (including factor V Leiden, homocysteine
and activated protein C levels) was normal, with an equivocal
antiphospholipid screen. No further thrombophilia investiga-
tions were ordered in the context of acute thrombosis and chal-
lenges in interpretation during the neonatal period.
In view of the ongoing concern about the vascular status of the
right upper limb, a decision was made to escalate conservative
management. The infant’s total fluids were increased from 60
to 90 mL/kg/day and a milrinone infusion was commenced at
0.33 µg/kg/min. A total of 20 mL/kg of normal saline for volume
expansion was given for mild hypotension during the first 3 hours
Figure 2  2D ultrasound image of right subclavian artery, illustrating
near-o­ cclusive thrombus.
2 Boyd S, et al. BMJ Case Rep 2019;12:e232440. doi:10.1136/bcr-2019-232440
BMJ Case Rep: first published as 10.1136/bcr-2019-232440 on 2 December 2019. Downloaded from http://casereports.bmj.com/ on January 2, 2020 at UniversitaetsSpital Bibliothek.
of milrinone infusion (blood pressure nadir 58/20 mm Hg, mean
33 mm Hg) and the blood pressure subsequently remained stable.
Bedside cardiac telemetry monitoring was continued throughout
milrinone treatment. There was a total of two episodes of hypo-
glycaemia (blood glucose nadir=2.2 mmol/L) requiring two
boluses of 10% dextrose and in increased dextrose concentra-
tion of intravenous fluids. Within 24 hours, the perfusion of
the limb had improved, weak pulses were palpable and the skin
temperature difference between both upper limbs had improved
to 0.7°C. An ultrasound showed no appreciable change in the
subclavian/axillary artery thrombus, suggesting dynamic changes
to the vasculature resulting in improved perfusion, rather than a
reduction in size of the thrombus. A therapeutic standard heparin
assay level after 24 hours of treatment with heparin was 0.54
(range 0.35–0.75), with sustained therapeutic levels recorded
after a further 24 hours. Milrinone was ceased after a total of
48 hours of treatment due to ongoing clinical improvement.
Perfusion and pulses were completely normal within 72 hours
and heparin was ceased after a total of 4 days of treatment. The
platelet count on day 5 after cessation of milrinone and heparin
treatment was 159×109/L.
Outcome and follow-up
An MRI scan of the brain performed at 3 days of age demon-
strated two small foci of diffusion restriction in the right frontal
lobe white matter and left cortical parietal lobe, one possibly
with some minimal microhaemorrhage. These changes were
thought to represent embolic phenomena. Magnetic resonance
Protected by copyright.
arteriogram and venogram were normal. Neurological examina-
tion was normal throughout admission. At the time of discharge
on day 5, examination of the upper limbs was unremarkable,
with normal pulses and perfusion of the right upper limb. The
family were advised to maintain adequate breast feeding to avoid
dehydration and minimise the risk of thrombus extension. A
follow-­up ultrasound as an outpatient at 3 weeks of age demon-
strated improvement of the right upper limb axillary/subclavian
artery thrombus, which was smaller, non-­occlusive and calcified.
Discussion
NLI is uncommon, and there remains a lack of both consensus5
and substantive evidence comparing treatment modalities.1
Although most commonly occurring as a complication of arte-
rial access procedures,6 NLI may also a result from intrauterine
factors.5 Perinatal, or congenital NLI, may be precipitated by
thromboembolic phenomena1 and/or compression ischaemia.2
Prematurity, perinatal asphyxia, maternal diabetes, respiratory
distress, twin–twin transfusion, congenital heart disease and
sepsis are additional risk factors.2 Thromboembolism of placental
origin, the most likely aetiology in this patient in the absence of
other risk factors, enters the fetal systemic arterial circulation
via the foramen ovale,2 most commonly lodging in the brachial
artery.2 The predilection for involvement of upper limb vessels is
thought to be related to preferential flow of blood towards the
head and upper extremities across the foramen ovale in the fetal
circulation.7
Early recognition and prompt treatment of perinatal NLI
is essential to the preservation of limb function.8 9 Systemic
anticoagulation,8 thrombolysis with tissue plasminogen acti-
vator, either systemic or catheter-­directed,1 2 8 peripheral nerve
blockade,10 caudal blockade10 and surgical thrombectomy1 have
all been proposed as suitable management options. Low rates
of revascularisation and significant perioperative mortality have
been reported in infants undergoing surgical management,11

which is technically challenging due to neonates’ small, friable
vessels. Surgery is thus generally reserved for infants where
there is a high risk of imminent limb loss,11 gangrenous skin
changes, paralysis or compartment syndrome warranting urgent
surgical exploration. Failure of improvement after 48 hours of
thrombolytic therapy is also cited as an indication for surgery,12
although later limb length discrepancies are accepted to occur
frequently with the delayed surgical approach. With respect
to thrombolysis, there is a narrow safety margin13 and risks of
10%–40% for major bleeding have been observed in the paedi-
atric population.13
Conservative treatment modalities with a more favourable
side-­effect profile than thrombolytic agents are desirable, and
supportive care alongside systemic anticoagulation with heparin
is an accepted optimal management strategy for the majority of
infants. Unfortunately, in the presence of complete obstruction
by thrombus,13 heparinisation does not result in sufficiently rapid
restoration of limb perfusion to prevent considerable damage
occurring. Heparin acts to prevent thrombus propagation by
inhibiting generation of further thrombin and augmenting the
body’s ability to dissolve thrombus over time.13 Adjunctive
supportive treatment during the initial period of limb ischaemia
is therefore potentially advantageous, particularly if the risks of
thrombolysis are able to be avoided. Success has been reported
with a number of modalities utilising vasodilatation as a means
of re-­establishing blood flow in NLI, including nerve blockade10
and topical nitroglycerin.14 Systemic vasodilatation with milri-
none, however, represents a novel treatment option for NLI that
has not previously been described.
Milrinone is a PDE3 inhibitor, which induces pulmonary
and systemic arterial vasodilatation and is increasingly used
in neonatology.3 Administration post-­cardiac surgery, and for
haemodynamic support of persistent pulmonary hyperten-
sion of the newborn, congenital diaphragmatic hernia and
patent ductus arteriosus ligation postoperatively have all been
described.3 Reported side-­effects of milrinone include hypoten-
sion, dysrhythmias and thrombocytopaenia, as well as concern
regarding delayed renal clearance in the context of hypoplastic
left heart syndrome surgery or hypoxic-­ischaemic encephalop-
athy.3 There are also animal data to suggest a role of PDE3 inhib-
itors such as milrinone in promoting insulin secretion,15 which
is a potential explanation for the hypoglycaemia observed in
our patient. Animal studies have revealed a role for milrinone
in ameliorating ischaemia-­reperfusion injury in multiple organs,
including the kidney16 and liver.4 Cycles of controlled ischaemia
and reperfusion prior to an ischaemia-­reperfusion event (precon-
ditioning), or following an ischaemic event (postconditioning),
are recognised methods to reduce organ injury secondary to
ischaemia-­ reperfusion. Beneficial effects of milrinone as an
adjunct to preconditioning and postconditioning have both
been described.4 Effects during preconditioning are mediated
by activation of intracellular cyclic adenosine monophosphate
(c-­AMP) and c-­AMP-­dependent protein kinase A (PKA).4 16 A
similar mechanism during postconditioning is postulated via a
PKA-­ activated pathway-­ dependent Akt, which has antiapop-
totic effects.4 An inhibitory effect on platelet aggregation and
anti-­inflammatory properties may be additional benefits of PDE
inhibition in this setting in reducing the extent of thrombus.4 16
Although there is no current evidence to support a beneficial
effect of milrinone in attenuating ischaemia-­reperfusion injury
in an extremity via a c-­ AMP-­mediated mechanism, there is
biological plausibility based on effects observed in other organs.
More importantly, an independent therapeutic advantage may
be attained by vasodilatation alone, which is a well-­established
Boyd S, et al. BMJ Case Rep 2019;12:e232440. doi:10.1136/bcr-2019-232440
Innovations in treatment
BMJ Case Rep: first published as 10.1136/bcr-2019-232440 on 2 December 2019. Downloaded from http://casereports.bmj.com/ on January 2, 2020 at UniversitaetsSpital Bibliothek.
action of milrinone. There is safety and pharmacokinetic data
for use of milrinone in neonates3 and use in the neonatal popu-
lation is widely reported.3
Patient’s perspective
We were able to observe signs of improvement in our infant’s
condition very quickly. We noticed dramatic improvements in
the colour of the arm, hand and nail beds within hours. We
are grateful to the medical team who detected the issue and
developed the treatment plan so quickly. We are also grateful
that it was resolved so quickly without using invasive measures.
We hope this case study will help other families who face a
similar situation.
Learning points
►► Milrinone, a phosphodiesterase-3 inhibitor increasingly used
in neonatology, represents a novel treatment option for
neonates with acute limb ischaemia.
►► The medication was used successfully as a key component
of a conservative management strategy for a neonate with
perinatal acute limb ischaemia.
►► The infant made a full recovery without requirement for
more invasive treatment such as thrombolysis or surgery. In
the absence of an appreciable change in dimensions of the
thrombus on serial vascular ultrasound, the infant’s clinical
Protected by copyright.
improvement was attributed to an effect (or effects) of
milrinone.
►► Documented improvement in temperature discordance
between affected and unaffected limbs during treatment
represents an additional, objective means of monitoring
progress in this condition.
►► In conjunction with anticoagulation, consideration of a trial of
milrinone prior to higher risk treatment options is warranted
in cases of acute limb ischaemia caused by thrombotic
arterial occlusion in neonates.
►► Early recognition and prompt treatment of perinatal neonatal
limb ischaemia is essential for the preservation of limb
function.
Acknowledgements  Dr Bonny Jasani, Fellow in Neonatal-­Perinatal Medicine,
Mount Sinai Hospital, Toronto, Canada, for his prompt recognition of limb ischaemia
and timely initiation of the patient’s transfer.
Contributors  All authors contributed to the design of the case report. SB prepared
the draft manuscript. SB, VS and JB reviewed and approved the final manuscript.
Funding  The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests  None declared.
Patient consent for publication  Parental/guardian consent obtained.
Provenance and peer review  Not commissioned; externally peer reviewed.
ORCID iD
Stephanie Boyd http://​orcid.​org/​0000-​0001-​7766-​1817
References
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inhaled nitric oxide. Pediatr Crit Care Med 2013;14:74–84.
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 Innovations in treatment

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4 Boyd S, et al. BMJ Case Rep 2019;12:e232440. doi:10.1136/bcr-2019-232440