Pulmonary Hypertension Of The Newborn Research Articles

Study on the comparison between Bosentan and Macitentan in the treatment of persistent pulmonary hypertension of the newborns, simultaneously on sildenafil: A randomized double-blinded non-inferiority parallel clinical trial

BackgroundPersistent Pulmonary Hypertension of the newborn (PPHN) is characterized by sustained elevated Pulmonary Artery Pressure (PAP). Drug resistance and the adverse effects of current therapeutic agents warrant investigation of other targeted therapies. Bosentan has shown benefits in affected neonates. However, trials reported the association with unwanted effects. Thus, in this study, we assess another agent in the same family, Macitentan. However, its efficacy in the treatment of PPHN is not yet reported. Hence, this study evaluated the effect of Macitentan compared to Bosentan in terms of efficacy and safety in the treatment of PPHN. MethodsThis randomized, double-blinded non-inferiority clinical trial was conducted in Shahid Akbar Abadi hospital, Tehran, Iran. Sixty clinically stable neonates with signs suggestive of PPHN were randomly allocated into two groups (n = 30 in each group) and they received either Bosentan 1 mg/kg/dose BD (twice daily) or Macitentan 1 mg/kg/dose BD simultaneously with sildenafil. The echocardiographic and laboratory indices of efficacy and safety were compared between groups. SPAP (systolic pulmonary artery pressure) was used to assess the non-inferiority of the Macitentan compared to the Bosentan in their respective doses used in the study. ResultsParticipants’ mean (SD) age was 3.53 (1.21) days, and 55% were female. No mortality case occurred. SPAP was reduced in both Bosentan and Macitenan groups with the mean difference in SPAP of 9 (95% CI: 7.34–10.65) in Bosentan and SPAP mean difference of 14 (95% CI: 12.12–15.86) in Macitentan group. Categorical comparison of primary outcome improvement showed that Macitentan was superior to Bosentan with a 10% non-inferiority margin. Similar results were obtained in other echocardiographic indices. Also, no significant alterations were observed in laboratory safety parameters. ConclusionMacitentan 1 mg/kg/dose BD (twice daily) is non-inferior to Bosentan 1 mg/kg/dose BD in improving echo outcomes of PPHN and it was even more effective in improving some of these. Also, it is non-inferior to Bosentan in terms of safety. Trial registry number(IRCT20160120026115N9).

Management of neonatal pulmonary hypertension-a survey of neonatal intensive care units in India

BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is a common neonatal condition associated with significant morbidity and mortality. First-line diagnostic and treatment options such as echocardiography and inhaled nitric oxide (iNO) are not routinely available in resource limited settings and alternative treatment modalities need to be utilized. This study was conducted to assess current diagnostic and management strategies used for PPHN in Indian neonatal intensive care units (NICUs).MethodsA questionnaire in multiple choice question format was sent to practising neonatologists in India via an online survey tool between July to August 2021. Information pertaining to demographic data, diagnostic criteria and management strategies of PPHN was requested. The responses were collated and information processed.ResultsThere were 118 respondent NICUs (response rate 74%). The majority of neonatal units (65%) admitted an average of 1–3 patients of PPHN per month. Targeted neonatal echocardiography (TnECHO) was practised in 80% of the units. Most common management strategies being followed were pulmonary vasodilators (88.1%), inotropes (85.6%), conventional ventilation (68.6%) and high frequency ventilation (59.3%). The most preferred pulmonary vasodilator was sildenafil (79%) and inotropic agent was milrinone (32%). Only 25% of respondents reported use of iNO. None of the participating units used extracorporeal membrane oxygenation.ConclusionWe found wide variability in management practices of PPHN across Indian NICUs. Non-selective pulmonary vasodilators are more widely used than iNO. There is an urgent need for structured TnECHO training programs and evidence based national guidelines for standardized management of PPHN as per availability of resources in India. Additional research on low cost alternative therapies to iNO in Indian settings might be helpful.

The use of bosentan and sildenafil as rescue therapy in persistent pulmonary hypertension of the newborn: A single center's experience

BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is a serious condition characterized by elevation of pulmonary vascular resistance. Pulmonary vasodilators are currently used as a rescue therapy or combined with inhaled nitric oxide in patients with PPHN. ObjectiveThis study aimed to determine the effect of bosentan and sildenafil on the oxygenation and short-term adverse events of patients with PPHN. MethodsA retrospective study was conducted in neonates diagnosed with PPHN and received bosentan or sildenafil therapy between 2010 and 2017 at the neonatal intensive care unit of tertiary referral hospital in Thailand. ResultsA total of 31 neonates with PPHN were included in this study. The median (IQR) gestation age and mean ± SD birth weight were 38 (36–40) weeks and 2961 ± 888 g, respectively. Of the 31 neonates, 16 received bosentan and 15 received sildenafil treatment. The initial mean oxygen index (OI) in the bosentan group was 18.7 ± 16.7, which decreased significantly at 24 h after treatment (OI = 8.5 ± 6.3, p < 0.001). In the sildenafil group, the initial mean OI was 47.1 ± 33.2, which decreased dramatically at 24 h after treatment (OI = 23.4 ± 19.5, p < 0.001). Oxygen saturation significantly improved at 96 h of bosentan and 36 h of sildenafil treatment, respectively. Blood pressure before and after treatment were not significantly different changed in both groups. ConclusionsBosentan and sildenafil are effective pulmonary vasodilators that are safe in PPHN treatment. Both drugs can be used as a rescue therapy in patients with PPHN, especially in centers lacking inhalable nitric oxide.

Can sonographic assessment of pulmonary vascular reactivity following maternal hyperoxygenation predict neonatal pulmonary hypertension? (HOTPOT study protocol)

BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is a condition that occurs in 0.5–7 per 1000 live births and can result in significant cardiovascular instability in the newborn. It occurs when there is a failure of the normal circulatory transition in the early newborn period. Recent studies have shown that fetal pulmonary vasculature reacts to maternal hyperoxygenation (MH). The aim of the study is to assess if the in-utero response to MH can predict pulmonary hypertension in the early newborn period. MethodsWe will perform a prospective cohort study. It will evaluate the use of fetal echocardiographic Doppler assessment of the pulmonary vasculature prior to and following MH to predict fetuses that may develop pulmonary hypertension in the neonatal period. The study will be undertaken in the Rotunda Hospital, Dublin, Ireland. A fetal ultrasound and echocardiography will be performed on fetuses in the third trimester. Blood flow velocity waveforms will be recorded during periods of fetal quiescence. Pulsatility index (PI), Resistance index (RI), Peak systolic (PSV) and end diastolic velocity (EDV), time-averaged velocity (TAV), acceleration time (AT), and ejection time (ET) will be measured within the fetal distal pulmonary artery (PA). The acceleration-to-ejection time ratio (AT: ET) will be used to assess pulmonary vascular resistance (PVR). Doppler measurements will be taken at baseline and repeated immediately following MH for 10 min (O2 100% v/v inhalational gas) at a rate of 12L/min via a partial non-rebreather mask. Doppler waveform measurements from the umbilical artery (UAD), middle cerebral artery (MCA) ductus arteriosus (DA), aortic isthmus (AoI) and ductus venosus (DV) will also be obtained. After birth, a comprehensive neonatal functional echocardiogram will be performed within the first 24 hours of life. DiscussionThis study proposes to validate methods described to date in investigating the fetal pulmonary vascular response to MH, with expansion of the study subjects to include fetuses at risk of PPHN. Evaluation of the different at-risk subgroups will be informative in relation to the fetal circulatory adaptation close to term. Prediction of neonatal pulmonary hypertension may help guide the pharmacological and neonatal ICU strategies that optimise postnatal survival.

Milrinone Use in Persistent Pulmonary Hypertension of the Newborn.

Failure of the normal transition from in utero to ex utero physiology leads to "persistent" pulmonary hypertension of the newborn (PPHN). PPHN is frequently associated with low systemic blood pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction. The general management of newborns with PPHN is geared toward maintenance of normothermia, normal serum electrolytes, normal intravascular volume, correction of acidosis, adequate sedation/analgesia, adequate ventilation and oxygenation with optimal lung recruitment, and avoidance of hyperoxia. Inotropic and vasoactive agents are commonly initiated early to increase cardiac output, maintain adequate systemic blood pressure, and enhance oxygen delivery to the tissue. Unfortunately, there is not much evidence on the choice, timing of initiation, dosing, monitoring, and titrating of vasoactive agents in this patient population. In this review, we will discuss the pathophysiology of PPHN and review the use of inotropic, lusitropic, and vasoactive agents in the management of PPHN, with particular attention to milrinone.

Frequent mutation of hypoxia-related genes in persistent pulmonary hypertension of the newborn

AimsPersistent pulmonary hypertension of the newborn (PPHN) is characterized by sustained high levels of pulmonary vascular resistance after birth with etiology unclear; Arterial blood oxygen saturation of Tibetan newborns at high latitudes is higher than that of Han newborns at low latitudes, suggesting that genetic adaptation may allow sufficient oxygen to confer Tibetan populations with resistance to pulmonary hypertension; We have previously identified genetic factors related to PPHN through candidate gene sequencing; In this study, we first performed whole exome sequencing in PPHN patients to screen for genetic-related factors.Methods and resultsIn this two-phase genetic study, we first sequenced the whole exome of 20 Tibetan PPHN patients and compared it with the published genome sequences of 50 healthy high-altitude Tibetanshypoxia-related genes, a total of 166 PPHN-related variants were found, of which 49% were from 43 hypoxia-related genes; considering many studies have shown that the differences in the genetic background between Tibet and Han are characterized by hypoxia-related genetic polymorphisms, so it is necessary to further verify whether the association between hypoxia-related variants and PPHN is independent of high-altitude life. During the validation phase, 237 hypoxia-related genes were sequenced in another 80 Han PPHN patients living in low altitude areas, including genes at the discovery stage and known hypoxia tolerance, of which 413 variants from 127 of these genes were shown to be significantly associated with PPHN.hypoxia-related genes.ConclusionsOur results indicates that the association of hypoxia-related genes with PPHN does not depend on high-altitude life, at the same time, 21 rare mutations associated with PPHN were also found, including three rare variants of the tubulin tyrosine ligase-like family member 3 gene (TTLL3:p.E317K, TTLL3:p.P777S) and the integrin subunit alpha M gene (ITGAM:p.E1071D). These novel findings provide important information on the genetic basis of PPHN.

Bronchoalveolar Lavage to Treat Neonatal Meconium Aspiration Syndrome Under Monitoring of Lung Ultrasound Based on a Prospective Case Series Study

Objectives: This study investigated the efficacy and safety of bronchoalveolar lavage (BAL) under lung ultrasound (LUS) monitoring for the treatment of meconium aspiration syndrome (MAS). Methods: A total of 120 patients were randomly divided into 2 groups: a BAL group (70 patients) and a control group (50 patients). Patients in the BAL group received an injection of lavage fluid through an endotracheal tube. After each lavage, LUS was performed to assess lung pathological changes. The control group underwent the traditional treatment. The rate of invasive and/or noninvasive ventilator use, time of ventilator use, incidence of pulmonary hypertension of the newborn (PPHN) and/or incidence of pneumothorax, duration of hospitalization of pediatric patients, hospitalization expenses and mortality were compared between the 2 groups. Results: Compared with the control group, MAS patients in the BAL group had (1) a significantly lower rate of invasive ventilator use (reduced by 57.7%, P < 0.001), (2) a significantly shortened duration of invasive ventilator treatment (reduced by 84.6%, P < 0.001), (3) a significantly reduced incidence of PPHN and/or pneumothorax (reduced by 84.6%, P < 0.001), (4) a reduced rate of mortality (from 2% to 0%), (5) a significantly shortened duration of hospitalization (reduced by 30.1%, P < 0.001), (6) significantly reduced hospitalization expenses (reduced by 42.6%, P < 0.001), and (7) stable vital signs during lavage among all patients, with no adverse effects. Conclusions: Treatment of MAS using BAL under LUS monitoring showed remarkable efficacy without adverse effects.

Identification of genetic factors underlying persistent pulmonary hypertension of newborns in a cohort of Chinese neonates

BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is a severe clinical problem among neonatal intensive care unit (NICU) patients. The genetic pathogenesis of PPHN is unclear. Only a few genetic polymorphisms have been identified in infants with PPHN. Our study aimed to investigate the potential genetic etiology of PPHN.MethodsThis study recruited PPHN patients admitted to the NICU of the Children’s Hospital of Fudan University from Jan 2016 to Dec 2017. Exome sequencing was performed for all patients. Variants in reported PPHN/pulmonary arterial hypertension (PAH)-related genes were assessed. Single nucleotide polymorphism (SNP) association and gene-level analyses were carried out in 74 PPHN cases and 115 non-PPHN controls with matched baseline characteristics.ResultsAmong the patient cohort, 74 (64.3%) patients were late preterm and term infants (≥ 34 weeks gestation) and 41 (35.7%) were preterm infants (< 34 weeks gestation). Preterm infants with PPHN exhibited low birth weight and a high frequency of bronchopulmonary dysplasia, respiratory distress syndrome (RDS) and mortality. Nine patients (only one preterm infant) were identified as harboring genetic variants, including three with pathogenic/likely pathogenic variants in TBX4 and BMPR2 and six with variants of unknown significance in BMPR2, SMAD9, TGFB1, KCNA5 and TRPC6. Three SNPs (rs192759073, rs1047883 and rs2229589) in CPS1 and one SNP (rs1044008) in NOTCH3 were significantly associated with PPHN (p < 0.05). CPS1 and SMAD9 were identified as risk genes for PPHN (p < 0.05).ConclusionsIn this study, we identified genetic variants in PPHN patients, and we reported CPS1, NOTCH3 and SMAD9 as risk genes for late preterm and term PPHN in a single-center Chinese cohort. Our findings provide additional genetic evidence of the pathogenesis of PPHN and new insight into potential strategies for disease treatment.

An Asian multicenter retrospective study on persistent pulmonary hypertension of the newborn: incidence, etiology, diagnosis, treatment and outcome

Objectives: To explore the incidence, etiologies, diagnostic methods, treatment options and outcomes in neonates with persistent pulmonary hypertension of the newborn (PPHN) and to identify mortality risk factors in a study from six Asian countries.Methods: A retrospective chart review of patients with documented PPHN from seven centers in six Asian countries (Japan, Kuwait, India, Pakistan, Singapore, and Thailand) between 1 January, 2014 and 31 December, 2016, was performed.Results: A total of 369 PPHN infants were identified. The incidence of PPHN ranged from 1.2 to 4.6 per 1000 live births. The all-cause mortality rate was 20.6% (76 of 369). Meconium aspiration syndrome was the primary cause of PPHN (24.1%). In most cases (84.8%) echocardiography was used to establish the diagnosis of PPHN. Sildenafil was the most commonly used pulmonary vasodilator (51.2%). Multivariate multiple regression analysis indicated gestational age <34 weeks (adjusted odds ratio (OR) = 3.27; 95% CI 1.56–6.74), congenital diaphragmatic hernia (CDH)/lung hypoplasia (LH) (adjusted OR = 6.13 (95% CI 2.28–16.42)), treatment with high frequency oscillation ventilation (HFOV) with or without inhaled nitric oxide (iNO) (adjusted OR = 3.11 (95% CI 1.52–6.34)), and inotropic agents (adjusted OR = 9.43 (95% CI 2.71–32.83)) were independently associated with increased risk of death.Conclusions: The incidence of PPHN in the current study was higher than in western settings. Birth weight, gestational age, CDH/LH, HFOV/iNO, and inotropic agents were significant mortality risk factors.

Hypertrophic pyloric stenosis following persistent pulmonary hypertension of the newborn: a case report and literature review

BackgroundAlthough persistent pulmonary hypertension of the newborn (PPHN) and infantile hypertrophic pyloric stenosis (HPS) are both well-known diseases that occur in early infancy, PPHN complicated by HPS is rare. As nitric oxide (NO) is an important mediator of biological functions, on both the vascular endothelium and smooth muscle cells, the decreased production of NO might play a role in the pathogenesis of both PPHN and HPS. We present the case of a neonate who developed HPS following PPHN, including a detailed review on research published to date, and we discuss the pathogenesis of PPHN and HPS.Case presentationA female neonate born at 38 weeks of gestation, weighing 3140 g, developed PPHN due to meconium aspiration syndrome. Intensive treatment with high frequency oscillations and inhaled NO were initiated, and sildenafil and bosentan were added. She gradually recovered. At 15 days of age, the patient developed recurrent vomiting after feeding and the diagnosis of HPS was made. Intravenous atropine therapy was started at 20 days of age, but the efficacy was clinically unsatisfactory. The coadministration with transdermal nitroglycerin improved the symptoms, and oral feeding was successfully re-introduced.ConclusionsOur patient recovered from both PPHN and HPS using NO-related medications. A decrease in NO synthesis is likely to be a common pathway for PPHN and HPS.

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

Persistent 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.

A Term Neonate with a Malpositioned Umbilical Artery Catheter Tip

A term neonate with respiratory distress receiving endotracheal mechanical ventilation undergoes placement of umbilical venous and arterial catheters. ### Prenatal and Birth Histories ### Presentation The infant was admitted to the community hospital NICU. Endotracheal intubation was performed at 2 hours of age for increasing oxygen requirements and respiratory failure. Conventional mechanical ventilation was initiated with a fraction of inspired oxygen of 1.0. Chest radiography suggested meconium aspiration syndrome. Exogenous surfactant was administered and umbilical vein catheter (UVC) was placed. On radiography, the UVC tip was visualized in the liver and the catheter readjusted to a low-lying position and secured at 5 cm. The umbilical artery catheter (UAC) placement was unsuccessful. Blood culture specimen was obtained and treatment with ampicillin and gentamicin initiated. Persistent pulmonary hypertension of the newborn was suspected based on a 10% difference in pre- and postductal oxygen saturation; at 3 hours of age, inhaled nitric oxide (iNO) of 20 parts per million (ppm) was initiated for an oxygen index of 18 determined on a radial arterial blood gas. The infant was transferred to a level IV NICU for further evaluation and consideration of extracorporeal membrane oxygenation. Upon arrival at the level IV NICU, the neonate was placed on high-frequency oscillatory ventilation …

The Fetus Can Teach Us: Oxygen and the Pulmonary Vasculature.

Neonates suffering from pulmonary hypertension of the newborn (PPHN) continue to represent an important proportion of patients requiring intensive neonatal care, and have an increased risk of morbidity and mortality. The human fetus has evolved to maintain a high pulmonary vascular resistance (PVR) in utero to allow the majority of the fetal circulation to bypass the lungs, which do not participate in gas exchange, towards the low resistance placenta. At birth, oxygen plays a major role in decreasing PVR to enhance pulmonary blood flow and establish the lungs as the organ of gas exchange. The failure of PVR to fall following birth results in PPHN, and oxygen remains the mainstay therapeutic intervention in the management of PPHN. Knowledge gaps on what constitutes the optimal oxygenation target leads to a wide variation in practices, and often leads to excessive oxygen use. Owing to the risk of oxygen toxicity, avoiding hyperoxemia is as important as avoiding hypoxemia in the management of PPHN. Current evidence supports maintaining arterial oxygen tension in the range of 50–80 mm Hg, and oxygen saturation between 90–97% in term infants with hypoxemic respiratory failure. Clinical studies evaluating the optimal oxygenation in the treatment of PPHN will be enthusiastically awaited.

Fatal vernix caseosa aspiration associated with persistent pulmonary hypertension of the newborn

Fatal vernix caseosa aspiration associated with persistent pulmonary hypertension of the newborn

Melatonin reduces oxidative stress and improves vascular function in pulmonary hypertensive newborn sheep.

Pulmonary hypertension of the newborn (PHN) constitutes a critical condition with severe cardiovascular and neurological consequences. One of its main causes is hypoxia during gestation, and thus, it is a public health concern in populations living above 2500 m. Although some mechanisms are recognized, the pathophysiological facts that lead to PHN are not fully understood, which explains the lack of an effective treatment. Oxidative stress is one of the proposed mechanisms inducing pulmonary vascular dysfunction and PHN. Therefore, we assessed whether melatonin, a potent antioxidant, improves pulmonary vascular function. Twelve newborn sheep were gestated, born, and raised at 3600 meters. At 3 days old, lambs were catheterized and daily cardiovascular measurements were recorded. Lambs were divided into two groups, one received daily vehicle as control and another received daily melatonin (1 mg/kg/d), for 8 days. At 11 days old, lung tissue and small pulmonary arteries (SPA) were collected. Melatonin decreased pulmonary pressure and resistance for the first 3 days of treatment. Further, melatonin significantly improved the vasodilator function of SPA, enhancing the endothelial- and muscular-dependent pathways. This was associated with an enhanced nitric oxide-dependent and nitric oxide independent vasodilator components and with increased nitric oxide bioavailability in lung tissue. Further, melatonin reduced the pulmonary oxidative stress markers and increased enzymatic and nonenzymatic antioxidant capacity. Finally, these effects were associated with an increase of lumen diameter and a mild decrease in the wall of the pulmonary arteries. These outcomes support the use of melatonin as an adjuvant in the treatment for PHN.

Impaired cerebral angiogenesis in the fetal lamb model of persistent pulmonary hypertension

BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is associated with increased risk of neuro-developmental impairments. Whether relative fetal hypoxia during evolution of PPHN renders the fetal brain vulnerable to perinatal brain injury remains unclear. We hypothesized that in utero ductal constriction, which induces PPHN also impairs cerebral angiogenesis. MethodsFetal lambs with PPHN induced by prenatal ligation of the ductus arteriosus were compared to gestation matched twin controls. Freshly collected or fixed brain specimens were analyzed by immunohistochemistry, Western blot analysis, and RT-PCR. ResultsCortical capillary density was decreased in PPHN lambs compared to controls (Glut-1, isolectin B-4 and factor VIII, n=6, p<0.05). Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels were decreased in cortical cell lysates of PPHN lambs. PPHN increased angiopoetin-1 (Ang-1) and tyrosine-protein kinase receptor (Tie-2) protein expression while angiopoetin-2 (Ang-2) protein levels were decreased (n=6, p<0.05). PPHN did not change mRNA levels of these proteins significantly (n=6). ConclusionsPPHN decreased cortical capillary density in fetal lamb brain. PPHN decreased the expression of proteins involved in angiogenesis. These findings suggest that PPHN is associated with impaired cortical angiogenesis.

Legal Briefs: Iatrogenesis: Prolapsed Umbilical Cord After Artificial Rupture of the Membranes and Unskilled Stabilization

* Abbreviations: AROM, : artificial rupture of the membrane ETT, : endotracheal tube FP, : family practitioner HR, : heart rate PPHN, : pulmonary hypertension of the newborn PPV, : positive pressure ventilation A 3,530-g term infant was delivered to a 22-year-old G1P0 mother who had an unremarkable prenatal course. She smoked during pregnancy and had a placenta previa that resolved by mid-gestation. A family practitioner (FP) was the treating physician during pregnancy. He decided at 39 1/2 weeks’ gestation to induce because of “uterine irritability.” When asked during the deposition why he induced labor, he said that the mother complained of abdominal discomfort, and she was at high risk because of her smoking. The plaintiff obstetrician was critical of the decision to induce because a valid reason was lacking, in his opinion. The defense obstetrician countered by saying 39 weeks is an acceptable gestation to induce. The plaintiff obstetrician said it was very unlikely that a successful induction would occur because the mother was a prima gravida, the fetus was large, and the cervix was unfavorable. Induction was by dinoprostone, followed by oxytocin (Pitocin®, JHP Pharmaceuticals, LLC, Rochester, MI) augmentation. When the cervix was 70% effaced and 2 cm dilated, and the fetus was at a −2 station, the FP decided to rupture the membranes. A few minutes after artificial rupture of the membranes (AROMs), multiple severe variable decelerations occurred, and 8 minutes after AROMs a prolapsed cord was discovered; the fetal heart rate (HR) became 50 beats per minute. The plaintiff obstetrician was critical of the decision to rupture the membranes because the fetal head was not engaged. The FP defendant said that the head was “well applied” to the cervix. The defense obstetrician said that because the FP said the head was well applied to the cervix, it was within standard of care to perform AROM even if the head was not technically engaged. All agreed that engagement of the head meant that in cephalic presentations …

Prenatal programming of pulmonary hypertension induced by chronic hypoxia or ductal ligation in sheep.

Pulmonary hypertension of the newborn is caused by a spectrum of functional and structural abnormalities of the cardiopulmonary circuit. The existence of multiple etiologies and an incomplete understanding of the mechanisms of disease progression have hindered the development of effective therapies. Animal models offer a means of gaining a better understanding of the fundamental basis of the disease. To that effect, a number of experimental animal models are being used to generate pulmonary hypertension in the fetus and newborn. In this review, we compare the mechanisms associated with pulmonary hypertension caused by two such models: in utero ligation of the ductus arteriosus and chronic perinatal hypoxia in sheep fetuses and newborns. In this manner, we make direct comparisons between ductal ligation and chronic hypoxia with respect to the associated mechanisms of disease, since multiple studies have been performed with both models in a single species. We present evidence that the mechanisms associated with pulmonary hypertension are dependent on the type of stress to which the fetus is subjected. Such an analysis allows for a more thorough evaluation of the disease etiology, which can help focus clinical treatments. The final part of the review provides a clinical appraisal of current treatment strategies and lays the foundation for developing individualized therapies that depend on the causative factors.

Platelet-activating factor synthesis and receptor-mediated signaling are downregulated in ovine newborn lungs: relevance in postnatal pulmonary adaptation and persistent pulmonary hypertension of the newborn.

Platelet-activating factor (PAF) is a phospholipid with a wide range of biological activities. We studied PAF metabolism and PAF receptor (PAFR) signaling in perinatal ovine lungs to understand PAF's role in transition of the perinatal pulmonary hemodynamics and pathophysiology of persistent pulmonary hypertension of the newborn. We hypothesized that downregulation of PAF synthesis with upregulation of PAF catabolism by acetylhydrolase (PAF-Ah) in the newborn lung is needed for fetus-to-newborn pulmonary adaptation. Studies were conducted on fetal and newborn lamb pulmonary arteries (PA), veins (PV) and smooth muscle cells (SMC). PAF metabolism, PAFR binding and cell proliferation were studied by cell culture; gene expression was studied by qPCR. Fetal lungs synthesized 60% more PAF than newborn lungs. Compared with the fetal PVs and SMCs, PAF-Ah activity in newborn was 40-60% greater. PAF-Ah mRNA expression in newborn vessels was different from the expression by fetal PA. PAF-Ah gene clone activity confirmed deletion of hypoxia-sensitive site. PAFR mRNA expression by the PVs and SMC-PV of the fetus and newborn was greater than by corresponding PAs and SMC-PA. Q-PCR study of PAFR expression by the SMC-PV of both groups was greater than SMC-PA. Fetal SMCs bound more PAF than the newborn SMCs. PAFR antagonist, CV-3988, inhibited PAFR binding and DNA synthesis by the fetal SMCs, but augmented binding and DNA synthesis by newborn cells. We show different PAF-PAFR mediated effects in perinatal lungs, suggesting both transcriptional and translational regulation of PAF-Ah and PAFR expression in the perinatal lamb lungs. These indicate that the downregulation of PAF-mediated effects postnatally protects against persistent pulmonary hypertension of the newborn.

An unusual cause of refractory persistent pulmonary hypertension of the newborn: anomalous origin of one pulmonary artery

Persistent pulmonary hypertension of the newborn is a source of considerable mortality and morbidity. Anomalous origin of one pulmonary artery, an uncommon congenital cardiac malformation, is a rare cause of persistent pulmonary hypertension. Here, we report the case of a patient with an anomalous origin of one pulmonary artery from the innominate artery who presented with persistent pulmonary hypertension refractory to treatment.