Eur J Pediatr (2005) 164: 626–629
`DOI 10.1007/s00431-005-1724-x
`
`O R I G I N A L P A P E R
`
`Amadu E. Juliana Æ Filomena C. B. Abbad
`Severe persistent pulmonary hypertension of the newborn
`in a setting where limited resources exclude the use of inhaled
`nitric oxide: successful treatment with sildenafil
`
`Received: 7 February 2004 / Accepted: 17 May 2005 / Published online: 13 July 2005
`Ó Springer-Verlag 2005
`
`Abstract We present the case of a full term neonate with
`severe persistent pulmonary hypertension of the new-
`born (PPHN) after birth asphyxia cared for at the
`St. Elizabeth Hospital in Curacao, Netherlands Antilles.
`Although the child was ventilated with high pressures
`and was given high doses of cardiovascular pressors, the
`arterial oxygen levels remained low with an alveolar-
`arterial O2 gradient of 651 mmHg. As a last resort, sil-
`denafil (1.5 mg/kg) was given via a nasogastric tube.
`This resulted in an immediate and sustained elevation of
`arterial oxygenation and subsequent complete recovery.
`After administration of sildenafil there was a transient
`hypotension which was corrected by a single bolus of
`saline. Conclusion: We discuss the current treatment
`modalities of persistent pulmonary hypertension of the
`newborn and the potential use of phosphodiesterase 5
`inhibitors such as sildenafil
`in a situation where the
`standard of practice with inhaled nitric oxide and
`extracorporeal membrane oxygenation is not available.
`
`Keywords Persistent pulmonary hypertension of the
`newborn Æ Sildenafil
`
`Abbreviations ECMO: extracorporeal membrane
`oxygenation Æ iNO: inhaled nitric oxide Æ PDE:
`phosphodiesterase Æ PPHN: persistent pulmonary
`hypertension of the newborn
`
`Introduction
`
`the newborn
`Persistant pulmonary hypertension of
`(PPHN) is a serious disorder with high mortality. The
`
`A. E. Juliana (&)
`Delfzicht Ziekenhuis, Jachtlaan 50,
`9934 JD Delfzijl, The Netherlands
`E-mail: amadu@gmx.net
`
`F. C. B. Abbad
`St. Elizabeth Hospital, Willemstad,
`Curacao, Netherlands Antilles
`
`introduction of inhaled nitric oxide (iNO) has greatly
`improved survival and reduced morbidity; however, in
`many countries this form of treatment is not readily
`available. Here we describe our experience of using sil-
`denafil in a neonate with severe PPHN.
`
`Case report
`
`The patient was the 3215 g product of a 38 week ges-
`tation pregnancy born to a 22-year-old G1P0 female.
`Pregnancy was complicated by oligohydramnios, which
`was detected 5 days before delivery. Leakage of amniotic
`fluid could not be detected, therefore the mother was
`admitted for fetal monitoring. The mother denied any
`use of drugs/medications during pregnancy. Labour was
`induced due to oligohydramnios. The mother received
`two doses of pethidine (100 mg/dose)7 h and 5 h before
`birth. Due to fetal heart beat decelerations with slow
`recovery, vacuum extraction was performed. There was
`a tight nuchal cord but no meconium staining of the
`amniotic fluid.
`The birth weight was 3215 g (50th percentile), length
`47 cm (10th percentile), and head circumference 36 cm
`(50th percentile). There were no dysmorphic signs. There
`was central cyanosis, and no spontaneous respiratory
`movements. The heart rate was approximately 40 per
`minute, with normal heart sounds and no murmurs
`during auscultation. The abdomen was flat with no
`apparent organomegaly on palpation. There were two
`umbilical arteries and one vein. In both elbows and both
`knees there was a mildly decreased passive extension.
`The infant was hypotonic, and showed no spontaneous
`movements. Laboratory findings 30 min after birth re-
`vealed: Hb 16 g/dl, WBC 25·109/l, platelets 347·109/l,
`arterial blood gases: pH 6,88, pCO2 96 mmHg, pO2
`53 mmHg, HCO3 17.4 mmol/l, and BE 16 mmol/l. A
`
`chest X-ray film showed decreased pulmonary vascular
`markings.
`After mask and bag ventilation, the infant was intu-
`bated and mechanical positive pressure ventilation
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`
`started. The Apgar scores were 3, 5 and 7 after 1, 5 and
`10 min. Initially high pressures (PIP 26 cm H2O), (PEEP
`5 cm H2O, frequency 60/min)) and 100% oxygen were
`needed to achieve and maintain adequate oxygenation.
`Blood pressures were 75/54 mmHg initially. Blood cul-
`tures were obtained and ampicillin and gentamycin were
`started for a possible perinatal
`infection. Umbilical
`catheters were inserted. After an initial mild recovery
`with normal blood gases and lowering of the ventilation
`pressures and oxygen requirement (FiO2 0.3), the baby
`deteriorated with a decrease in oxygen saturation to
`80%. The post-ductal saturation was 10% points lower
`than the preductal measurement, raising the suspicion of
`PPHN with right-to-left shunting at the ductus arterio-
`sus. A cardiac ultrasound scan excluded any anatomical
`cardiac
`abnormalities,
`and
`confirmed
`increased
`pulmonary arterial pressure at the systemic level and
`right-to-left shunt through the open arterial duct. The
`mechanical ventilation was intensified with maximum
`pressures of 35 cm H2O PIP and 6 cm H2O PEEP.
`Ventilation was not the problem as very low PCO2 levels
`between 15 and 20 mmHg were achieved; however,
`every attempt to lower frequency or ventilation pressure
`in order to elevate the PCO2 resulted in decreased oxy-
`gen saturation. Due to arterial hypotension (lowest 45/
`32 mmHg) and the need for optimal systemic pressures,
`the patient received numerous normal saline boluses
`with a total of 150 ml/kg in 24 h. After every bolus there
`was a short-lived increase in oxygen saturation. Dopa-
`mine and dobutamine were titrated to high doses with a
`maximum of 25 lg/kg per min each. Noradrenalin was
`also added for a few hours with no beneficial effect.
`Adequate sedation was achieved with morphine (20 lg/
`kg/h) and midazolam (max 200 lg/kg/h). When entering
`the 3rd day of life, the prognosis looked bleak with
`ongoing low oxygen saturations around 80%, and fre-
`
`quent dips to 70% (PaO2  40 mmHg, alveolar-arterial
`O2 gradient 651 mmHg). In our setting,
`iNO and
`extracorporeal membrane oxygenation (ECMO) were
`lacking due to the high costs of such treatments. As a
`last resort, one dose of sildenafil
`(1.5 mg/kg) was
`administered through a nasogastric tube (suspension
`made out of a 50 mg tablet). Ten minutes after admin-
`istration of sildenafil the oxygen saturation rose rapidly
`to 99% and the PaO2 to 287 mmHg (alveolar-arterial O2
`gradient 406 mmHg). With this there was an associated
`flushing of the face and abdomen accompanied by a
`drop in systemic pressure (from 76/55 to 50/32 mmHg).
`After a bolus of 20 ml/kg normal saline, the pressure
`recovered within 7 min and remained adequate
`thereafter. Subsequently, the ventilation pressure and
`frequency could be lowered significantly (20/5 cm H2O,
`frequency 30/min, FiO2 0,6), and extubation followed 2
`days later (6th day of life). Dopamine and dobutamine
`could be tapered of over a 2-day period.
`Eight days postpartum, he developed a sepsis-men-
`ingitis for which he received meropenem for 3 weeks.
`Blood and cerebrospinal fluid cultures were positive for
`Acinetobacter baumannii. On discharge 1 month after
`
`627
`
`admission, he was still slightly irritable but otherwise
`had a normal physical examination. At 4 months of age
`the brainstem electric response audiometry was normal
`and he had achieved appropriate developmental mile-
`stones. There was still a slight hypertonicity of the
`extremities.
`
`Discussion
`
`We present a case of severe PPHN refractory to the
`initiated supportive therapy, which in the absence
`of
`iNO and ECMO, was successfully treated with
`sildenafil.
`According to data from the United States, the prev-
`alence of PPHN of the newborn is widely variable and is
`estimated to be 1.9 per 1000 live births [18]. On the is-
`land of Curacao (approximately140,000 inhabitants) the
`annual incidence is 4 per year (unpublished data) and
`occurs mainly in term or near term infants. Under
`normal circumstances, a progressive fall in the pulmo-
`nary vascular resistance is accompanied by a rise in
`systemic vascular resistance within the first hours after
`birth. This leads to a steady increase in pulmonary blood
`flow. Factors that interfere with these events can cause
`the transitional circulation to persist.
`In a major observational study (by the National
`Institute of Child Health and Human Development
`Neonatal Research Network)
`in the United States,
`clinical features were described of 385 infants with
`PPHN in 12 level III neonatal intensive care units [18].
`The diagnoses associated with PPHN were meconium
`aspiration syndrome (41%), pneumonia (14%), RDS
`(13%), pneumonia and/or RDS (14%), congenital dia-
`phragmatic hernia (10%), pulmonary hypoplasia (4%),
`and idiopathic (17%). In the infant described, perinatal
`depression due to hypoxia probably led to development
`of PPHN; however, oligohydramnios was detected at the
`very end of this pregnancy which might have led to
`pulmonary hypoplasia thereby also contributing to
`PPHN. It is rather unlikely that it played a significant
`role as the infant responded rapidly to sildenafil.
`The treatment of PPHN is largely supportive and
`widely variable. Before the introduction of iNO ther-
`apy, the most commonly used modalities (often in
`combination) were hyperventilation (66%), continuous
`alkali infusion (75%), inotropic agents (84%), vasodi-
`lators
`including tolazoline (39%),
`sedation (94%),
`paralysis (73%), high frequency ventilation (39%) and
`ECMO (34%) [18]. It is important to note that most of
`these therapies (except for ECMO) were not evaluated
`by randomised controlled trials before implementation.
`The effects of iNO in PPHN, however, have been
`studied extensively. Since its introduction, iNO is cur-
`rently regarded as the gold standard, and ECMO may
`be used as an escape therapy; however, in large parts of
`the world the last two treatments are often not avail-
`able due to the high costs and lack of required infra-
`structure.
`
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`
`628
`
`the
`reduces
`Inhaled NO improves oxygenation,
`need for ECMO in term and near term infants with
`severe PPHN and does not appear to have significant
`toxicity [1, 3, 4, 5, 6, 7, 10,13]. NO activates guanyl
`cyclase leading to production of c-GMP. This activates
`c-GMP dependent protein kinase, which increases the
`opening of calcium-sensitive potassium channels,
`in
`turn causing membrane hyperpolarisation, and inhibits
`calcium influx through the L-type calcium channel.
`This leads to relaxation of the vascular smooth muscle
`cell [2].
`C-GMP is deactivated by phosphodiesterase (PDE).
`Recently interest has focused on PDE inhibitors because
`of their potent vasodilatation properties. There are ten
`families of PDE isoenzymes. PDE 5 is particularly pre-
`valent in vascular smooth muscle, and PDE 5 inhibitors
`are widely known as a treatment for erectile dysfunction
`[12]. Studies in animal models with pulmonary hyper-
`tension have shown that PDE 5 inhibitors such as
`zaprinast and sildenafil are potent pulmonary vasodila-
`tors and augment the vasodilatation effect of iNO [8, 9,
`17,19]; however, there is also a significant drop in sys-
`temic blood pressure with higher doses of both agents
`[14, 17,19]. Five minutes after a dose of 1.5 mg/kg
`administered through a gastric tube, our patient had a
`drop in systemic pressure which lasted for only 5–7 min
`and was not accompanied by significant tachycardia. In
`sepsis and septic shock, inflammatory mediators result
`in the production of increased concentrations of NO
`which are responsible for changes in vasomotor tone,
`decreased vasopressor responsiveness, and decreased
`myocardial function [15]. In the case of PPHN due to
`sepsis, the use of sildenafil may theoretically worsen the
`circulatory status. Another potential risk is the use of
`sildenafil
`in parynchymal
`lung disease (such as in
`meconium aspiration syndrome) where it might induce
`or worsen ventilation perfusion mismatch, resulting in a
`lower PaO2. Administration in an aerosolised form
`lowers the potential systemic side-effects and might also
`prevent this ventilation perfusion mismatch [8,9]. In a
`recent review, the current clinical experience with silde-
`nafil has been summarised [16]. In all the PPHN cases
`mentioned, sildenafil was used as an adjunct to iNO. We
`believe our case is novel due to the fact that sildenafil
`was used primarily and not in combination with iNO or
`other vasodilators. We chose the dosage based on liter-
`ature data available at that moment [11, 14,19]. Al-
`though we do not advocate it as a standard therapy, we
`used sildenafil to successfully treat a case of severe
`PPHN. Further research is needed to determine opti-
`mum dose, safety, and route of administration. If found
`effective in randomised controlled trials, PDE 5 inhibi-
`tors could contribute greatly to the treatment of PPHN
`in countries with limited resources.
`
`Acknowledgements We wish to thank Prof. R. M. F. Berger (Be-
`atrix Children’s Hospital/University Hospital, Groningen, The
`Netherlands) and Prof. Rashmin C. Savani (Children’s Hospital of
`Philadelphia, USA) for their advice and critical review of the
`article.
`
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