Treatment of Persistent Pulmonary Hypertension of the Newborn: Use of Pulmonary Vasodilators in Term Neonates

AbstractPersistent pulmonary hypertension of the newborn (PPHN) represents a challenging condition associated with significant morbidity. A successful transition from intrauterine to extrauterine life is contingent on adequate pulmonary vasodilation. Several pathophysiologies contribute to the failure of this cascade and may result in life-threatening hypoxia and acidosis in the newborn. Management includes optimal respiratory support, adequate sedation and analgesia, and support of vascular tone and cardiac function. Pulmonary vasodilation has the potential to overcome the cycle of hypoxia and acidosis, improving outcome in these infants. Oxygen and inhaled nitric oxide represent the foundation of therapy. Tertiary pulmonary vasodilators represent a greater challenge, selecting between therapies that include prostanoids, sildenafil, and milrinone. Variable levels of evidence exist for each agent. Thorough review of available data informing efficacy and adverse effects contributes to the development of an informed approach to neonates with refractory PPHN.

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Search for an animal model to investigate selective pulmonary vasodilation

Laboratory Animals ◽

10.1177/0023677216675384 ◽

2016 ◽

Vol 51 (4) ◽

pp. 376-387

Author(s):

Bodil Petersen ◽

Thilo Busch ◽

Katharina Noreikat ◽

Lorenz Homeister ◽

Ralf Regenthal ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Animal Models ◽

Vascular Tone ◽

Acute Hypoxia ◽

Haemodynamic Instability ◽

Time Interval ◽

Systemic Hypotension ◽

Pulmonary Vasodilation ◽

Selective Pulmonary Vasodilation

Pulmonary arterial hypertension is a life-threatening disease with a poor prognosis. Oral treatment with vasodilators is often limited by systemic hypotension. Inhalation of vasodilators offers the opportunity for selective pulmonary vasodilation. Testing selective pulmonary vasodilation by inhaled nitric oxide or alternative substances in animal models requires an increased pulmonary vascular tone. The aim of this study was to identify animal models that are suitable for investigating selective pulmonary vasodilation. To do so, a haemodynamic stable pulmonary hypertension was initiated, with a 30 min duration deemed to be a sufficient time interval before and after a possible intervention. In anaesthetized and mechanically-ventilated Sprague–Dawley rats pulmonary hypertension was induced either by acute hypoxia due to reduction of the inspired oxygen fraction from 0.21 to 0.1 ( n = 6), a fixed infusion rate of the thromboxane analogue U46619 (240 ng/min; n = 6) or a monocrotaline injection (MCT; 60 mg/kg applied 23 days before the investigation; n = 7). The animals were instrumented to measure right ventricular and systemic arterial pressures. Acute hypoxia caused a short, and only transient, increase of pulmonary artery pressure as well as profound systemic hypotension which suggested haemodynamic instability. U46619 infusion induced variable changes in the pulmonary and systemic vascular tone without sufficient stabilization within 30 min. MCT provoked sustained pulmonary hypertension with normal systemic pressure values and inhalation of nitric oxide caused selective pulmonary vasodilation. In conclusion, out of the three examined rat animal models only MCT-induced pulmonary hypertension is a solid and reliable model for investigating selective pulmonary vasodilation.

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The Practical Challenges of Diagnosis and Treatment Options in Persistent Pulmonary Hypertension of the Newborn: A Developing Country's Perspective

American Journal of Perinatology ◽

10.1055/s-0038-1660462 ◽

2018 ◽

Vol 35 (14) ◽

pp. 1366-1375 ◽

Cited By ~ 1

Author(s):

Narongsak Nakwan

Keyword(s):

Pulmonary Hypertension ◽

Low Income ◽

Treatment Options ◽

Limited Resource ◽

High Rate ◽

Persistent Pulmonary Hypertension ◽

Timely Diagnosis ◽

Pulmonary Vasodilators ◽

High Frequency Oscillatory ◽

Made In

AbstractPersistent pulmonary hypertension of the newborn (PPHN) is a complication of several respiratory diseases characterized by an elevation in pulmonary vascular resistance with resultant right-to-left shunting of blood and severe hypoxemia in the neonatal period. PPHN carries a high rate of morbidity and mortality, particularly in limited-resource settings (low-income and/or developing country). Echocardiography remains the gold standard for diagnosis of PPHN. Modern therapies such as inhaled nitric oxide, high-frequency oscillatory ventilation, extracorporeal membrane oxygenation, and/or other pulmonary vasodilators agents can reduce the mortality rate of PPHN. Unfortunately, echocardiography and the use of these modern therapies are often difficult for a medical institution to provide for patients in developing countries, even when a timely diagnosis of PPHN has been made. In this review, the practical challenges of timely diagnosis of PPHN and efficient use of available treatment options faced by pediatricians or neonatologists in limited-resource settings are discussed.

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Presumed prenatal closure of foramen ovale and persistent pulmonary hypertension of the newborn

Cardiology in the Young ◽

10.1017/s1047951119003044 ◽

2019 ◽

Vol 30 (2) ◽

pp. 281-283

Author(s):

Katharina Stock ◽

Miriam Michel ◽

Elisabeth Schermer ◽

Elisabeth Ralser ◽

Ursula Kiechl-Kohlendorfer ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Management Strategies ◽

Left Ventricular ◽

Left Ventricular Failure ◽

Persistent Pulmonary Hypertension ◽

Foramen Ovale ◽

Severe Pulmonary Hypertension ◽

Ventricular Failure ◽

Life Threatening ◽

Echocardiographic Findings

AbstractPrenatal closure of foramen ovale without CHD is a rarely reported entity. Therefore, clinical and echocardiographic findings are poorly defined in these patients. We report a patient with prenatal closure of foramen ovale that presented with severe pulmonary hypertension of the newborn and left ventricular failure. Judicious management strategies were utilised to successfully treat both life-threatening conditions.

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Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00425.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. H1812-H1820 ◽

Cited By ~ 88

Author(s):

Girija G. Konduri ◽

Ivane Bakhutashvili ◽

Annie Eis ◽

Kirkwood Pritchard

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Nitric Oxide Synthase ◽

Pulmonary Artery ◽

Ductus Arteriosus ◽

Oxidant Stress ◽

Pulmonary Arteries ◽

Persistent Pulmonary Hypertension ◽

Pulmonary Vasodilation ◽

Oxide Synthase

Persistent pulmonary hypertension of newborn (PPHN) is associated with decreased NO release and impaired pulmonary vasodilation. We investigated the hypothesis that increased superoxide (O2•−) release by an uncoupled endothelial nitric oxide synthase (eNOS) contributes to impaired pulmonary vasodilation in PPHN. We investigated the response of isolated pulmonary arteries to the NOS agonist ATP and the NO donor S-nitroso- N-acetylpenicillamine (SNAP) in fetal lambs with PPHN induced by prenatal ligation of ductus arteriosus and in sham-ligated controls in the presence or absence of the NOS antagonist nitro-l-arginine methyl ester (l-NAME) or the O2•− scavenger 4,5-dihydroxy-1,3-benzenedisulfonate (Tiron). ATP caused dose-dependent relaxation of pulmonary artery rings in control lambs but induced constriction of the rings in PPHN lambs. l-NAME, the NO precursor l-arginine, and Tiron restored the relaxation response of pulmonary artery rings to ATP in PPHN. Relaxation to NO was attenuated in arteries from PPHN lambs, and the response was improved by l-NAME and by Tiron. We also investigated the alteration in heat shock protein (HSP)90-eNOS interactions and release of NO and O2•− in response to ATP in the pulmonary artery endothelial cells (PAEC) from these lambs. Cultured PAEC and endothelium of freshly isolated pulmonary arteries from PPHN lambs released O2•− in response to ATP, and this was attenuated by the NOS antagonist l-NAME and superoxide dismutase (SOD). ATP stimulated HSP90-eNOS interactions in PAEC from control but not PPHN lambs. HSP90 immunoprecipitated from PPHN pulmonary arteries had increased nitrotyrosine signal. Oxidant stress from uncoupled eNOS contributes to impaired pulmonary vasodilation in PPHN induced by ductal ligation in fetal lambs.

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Congenital Cytomegalovirus Infection Manifesting as Neonatal Persistent Pulmonary Hypertension: Report of Two Cases

Pulmonary Medicine ◽

10.1155/2011/293285 ◽

2011 ◽

Vol 2011 ◽

pp. 1-4 ◽

Cited By ~ 7

Author(s):

Elizabeth Walter-Nicolet ◽

Magali Leblanc ◽

Marianne Leruez-Ville ◽

Philippe Hubert ◽

Delphine Mitanchez

Keyword(s):

Pulmonary Hypertension ◽

Persistent Pulmonary Hypertension ◽

High Frequency Ventilation ◽

Cmv Infection ◽

Congenital Cmv Infection ◽

Threatening Condition ◽

Frequency Ventilation ◽

Refractory Hypoxemia ◽

Life Threatening ◽

Congenital Cmv

Various neonatal symptoms can lead to a diagnosis of congenital CMV infection. We report two cases of persistent pulmonary hypertension in relation with congenital CMV infection following maternal primary infection and reinfection, respectively. Both infants had severe refractory hypoxemia, requiring high-frequency ventilation, inhaled nitric oxide and inotropic support. One of them required extracorporeal membrane oxygenation for five days. Ganciclovir therapy was attempted in the two cases on day 12 postnatal. One of the infant died on day 15 postnatal. The other survived and is developing uneventfully at 15 months of age.Conclusion: Neonatal persistent pulmonary hypertension can be the consequence of congenital CMV infection. Intensive respiratory support and IV ganciclovir are indicated in case of life-threatening condition.

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Inhaled pulmonary vasodilators for persistent pulmonary hypertension of the newborn: safety issues relating to drug administration and delivery devices

Medical Devices Evidence and Research ◽

10.2147/mder.s99601 ◽

2016 ◽

pp. 45 ◽

Cited By ~ 6

Author(s):

Nathan Cosa ◽

Edward Costa

Keyword(s):

Pulmonary Hypertension ◽

Drug Administration ◽

Persistent Pulmonary Hypertension ◽

Safety Issues ◽

Pulmonary Vasodilators

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Increased incidence of Persistent Pulmonary Hypertension of the Newborn following third trimester maternal COVID-19 infection

European Heart Journal ◽

10.1093/eurheartj/ehab724.1843 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

A Ishqeir ◽

A Nir ◽

I Aptowitzer ◽

M Godfrey ◽

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Ventricular Hypertrophy ◽

Right Ventricular Hypertrophy ◽

Persistent Pulmonary Hypertension ◽

Third Trimester ◽

Term Neonates ◽

Live Births ◽

Pulmonary Vasodilator ◽

Near Term

Abstract Background Novel coronavirus (COVID-19) has been a world concern since December 2019. The knowledge about vertical transmission and fetal morbidity and mortality from maternal COVID-19 infection is limited. We detected an increase in the number of cases of term and near-term neonates with persistent pulmonary hypertension (PPHN) during the COVID-19 pandemic in 2020. Methods and results We collected data on all newborns with PPHN born between 2018 and 2020. We excluded premature infants (<34+0 weeks) and infants with other significant pathology or genetic syndromes. Compared to 5 cases of PPHN of 22930 live births in 2018, and 6 cases of PPHN of 22270 live births in 2019 (2-year average 0.02%, 95% CI 0.013%-0.043%), there were 16 PPHN cases from 22323 live births in 2020 (0.07%, 95% CI 0.044%-0.12%), a 3 fold increase (p<0.01). We report 5 cases of term and near-term neonates born to mothers who had highly suspected (2) and PCR proven (3) COVID-19 infection during the third trimester of pregnancy, who presented with PPHN during COVID-19 pandemic in 2020. All had otherwise unexplained pulmonary hypertension, right ventricular hypertrophy (RVH) and dilatation. Two patients needed endotracheal intubation, one was supported by nasal continuous positive airway pressure (CPAP) without intubation, two needed O2 support by nasal cannula only ant two newborns (one of them was intubated) needed Nitric oxide (NO) as pulmonary vasodilator therapy. No patient required Extracorporeal membrane oxygenation (ECMO) or died, and no prolonged residual cardiovascular or pulmonary morbidity was recorded during a median follow up of 4.8 months (range 4–6 months). Conclusions The increase in the incidence of PPHN during the COVID-19 pandemic, and the cases presented, suggest an intrauterine effect of maternal COVID-19 infection on the fetal pulmonary circulation. It is possible that the maternal infection affected the fetal pulmonary vascular resistance, or altered the normal decline in the resistance after birth. The right ventricular hypertrophy and dilatation with reduced function may be secondary to this hypothetical increased afterload or a direct effect of the infection. Further studies are warranted to elucidate the pathogenesis and clinical implications of this phenomenon. FUNDunding Acknowledgement Type of funding sources: None.

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Shunts in Patients With Respiratory Distress Syndrome

PEDIATRICS ◽

10.1542/peds.92.5.738 ◽

1993 ◽

Vol 92 (5) ◽

pp. 738-738

Author(s):

FRANS J. WALTHER ◽

JOHN O. LEIGHTON

Keyword(s):

Pulmonary Hypertension ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Distress Syndrome ◽

Full Term ◽

Persistent Pulmonary Hypertension ◽

Term Neonates ◽

Premature Neonates ◽

Group 4 ◽

Study Population

In Reply.— We agree with Dr Evans that bidirectional ductal shunting is more common than net right-to-left ductal shunting in premature neonates with severe RDS and persistent pulmonary hypertension. Our conclusion that large right-to-left shunts via the ductus are common findings in these cases was not intended to exclude the presence of concomitant left-to-right shunting. In our study population the incidence of right-to-left ductal shunting at 12 and 24 hours of age was 86% and 94% in premature neonates with fatal RDS, 39% and 34% in the severe RDS group, 4% and 0% in the no/mild RDS group, and 6% and 0% in the full-term neonates without RDS.

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