Congenital cytomegalovirus and pulmonary hypertension.

Lung involvement in children with congenital cytomegalovirus infection has been scarcely described. We describe three new cases of persistent pulmonary hypertension in children with congenital cytomegalovirus and review the other seven cases reported in the literature since 1988. All children had a symptomatic infection, including severe central nervous system or visceral findings. Morbidity and mortality were high. Persistent pulmonary hypertension may be a rare complication in severely symptomatic congenital cytomegalovirus infants. It is important to screen for congenital cytomegalovirus in cases of idiopathic refractory persistent pulmonary hypertension. Intensive treatment should be undertaken to treat this potentially rare lung involvement in combination with antiviral treatment.

Vasodilators for persistent pulmonary hypertension of the newborn: A network meta-analysis.

OBJECTIVES: To compare the efficacy and safety of different vasodilators in the treatment of persistent pulmonary hypertension of the newborn (PPHN) by a Bayesian network meta-analysis. METHODS: We searched databases (Cochrane, PubMed, Embase, and Web of Science) from January, 1990 up to December, 2023. Randomized controlled trials on the use of vasodilators in the treatment of PPHN. We extracted details of population, intervention, and outcome indicators. R and STATA software were used for data analysis. Sixteen articles were included, encompassing 776 neonates with PPHN. Among them, 12 articles were included in the quantitative analysis. The vasodilators included Sildenafil, Bosentan, Milrinone, Magnesium, Adenosine, and Tadalafil. RESULTS: The Bayesian network meta-analysis results suggested that compared to placebo, Milrinone [OR = 0.125, 95% CI (0.0261, 0.562)], Sildenafil [OR = 0.144, 95% CI (0.0428, 0.420)], and Sildenafil_Milrinone [OR = 0.0575, 95% CI (0.00736, 0.364)] reduced the mortality, but the difference among the three was not significant. There was also no significant difference in the incidence of hypotension, the duration of mechanical ventilation, and the use of extracorporeal membrane oxygenation among the vasodilators. Compared to Bosentan, Adenosine was more effective in reducing the oxygenation index [MD = -12.78, 95% CI (-25.56, -0.03)], and Magnesium was less effective in reducing the oxygenation index than Sildenafil [MD = 5.19, 95% CI (1.23, 9.2)]. CONCLUSIONS: Milrinone, Sildenafil, and Sildenafil_Milrinone reduced the mortality of neonates with PPHN. More clinical trials are needed to verify the efficacy and safety of vasodilators in the treatment of PPHN.

Persistent Pulmonary Hypertension of Newborns Secondary to Labile Hypoxemia Associated With Cyanosis: A Case Series.

Persistent pulmonary hypertension of the newborn (PPHN) is a condition that can be fatal, marked by increased pulmonary vascular resistance that causes blood to shunt from the right to the left. Six infants that present with PPHN due to labile hypoxemia and related cyanosis are examined in this case series. Clinical manifestations, such as premature deliveries, maternal problems, and different reactions to early therapies, are revealed by perinatal and postnatal histories. The newborns' respiratory distress prompted the use of oxygen supplementation and continuous positive airway pressure (CPAP), but intubation was required due to continued hypoxemia. The series aims to establish a way for further study in this crucial area while offering insightful contributions to the clinical subtleties of PPHN and illustrating the importance of specific therapeutic approaches.

Inhaled Nitric Oxide in Neonatal Pulmonary Hypertension.

Pivotal trials investigating the use of inhaled nitric oxide (iNO) in the 1990s led to approval by the Food and Drug Administration in 1999. Inhaled nitric oxide is the only approved pulmonary vasodilator for persistent pulmonary hypertension of the newborn (PPHN). Selective pulmonary vasodilation with iNO in near-term and term neonates with PPHN is safe, and targeted use of iNO in less mature neonates with pulmonary hypertension (PH) can be beneficial. This review addresses a brief history of iNO, clinical features of neonatal PH, and the clinical application of iNO.

Comparison of treprostinil and oral sildenafil for the treatment of persistent pulmonary hypertension of the newborn: a retrospective cohort study.

Background: This study aims to evaluate the effectiveness of treprostinil and oral sildenafil in managing persistent pulmonary hypertension of newborns (PPHN). Methods: We conducted a retrospective cohort study of 42 neonates with PPHN treated with continuous intravenous treprostinil or oral sildenafil from January 2020 to October 2022 in China. Outcomes assessed included echocardiographic pulmonary artery systolic pressure (PASP), shunt direction, and arterial blood gas measures. Results: Treprostinil lowered PASP and improved oxygenation significantly better than sildenafil on days 1, 2, and 3 of treatment (P < 0.05). Treprostinil also corrected shunt direction faster than sildenafil (P < 0.05). The duration of mechanical ventilation, length of NICU stay, and overall hospital stay did not significantly differ between the two groups (P > 0.05). Conclusions: Treprostinil effectively lowers pulmonary artery pressure and improves oxygenation in neonates with PPHN, without being associated with severe complications. It may serve as a beneficial adjunct therapy for neonates with PPHN.

Successful Weaning From Veno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO) After Initiation of Inhaled Epoprostenol in a Neonate With Refractory Persistent Pulmonary Hypertension of the Newborn (PPHN).

Despite improvements in the medical management of persistent pulmonary hypertension of the newborn (PPHN), a significant number of patients persist with inadequate gas exchange and are treated with extracorporeal membrane oxygenation (ECMO). Prolonged time to weaning ECMO can increase mortality risk. Therefore, multiple therapies are utilized for pulmonary hypertension treatment, including pharmacotherapy with pulmonary vasodilators, to improve the prognosis of these critical patients. We report a case of a 37 2/7-week neonate with severe PPHN refractory to triple pulmonary vasodilator therapy (inhaled nitric oxide (iNO), sildenafil, and milrinone) and required veno-venous (VV)-ECMO support to improve oxygenation. Our patient was successfully weaned from ECMO after the addition of inhaled epoprostenol (iEPO) therapy. This report indicates that inhaled prostacyclin therapy effectively helps refractory PPHN patients off extracorporeal life support (ECLS) and should be considered a valuable treatment.

Diastolic ventricular function in persistent pulmonary hypertension of the newborn.

Background: Persistent pulmonary hypertension of the newborn (PPHN) is usually considered a consequence of impaired pulmonary circulation. However, little is known regarding the role of cardiac dysfunction in PPHN. In this study, we hypothesized that the tolerance for pulmonary hypertension in newborn infants depends on the biventricular function. The aim of this study is to evaluate biventricular cardiac performance by using Tissue Doppler Imaging (TDI) in an healthy newborn infants with asymptomatic pulmonary hypertension and in newborn infants with PPHN. Methods: Right and left cardiac function were investigated using conventional imaging and TDI in 10 newborn infants with PPHN ("PPHN") and 10 asymptomatic healthy newborn infants ("asymptomatic PH"). Results: Systolic pulmonary artery pressure (PAP) as assessed by TDI and the mean systolic velocity of the right ventricular (RV) free wall were similar in both groups. The isovolumic relaxation time of the right ventricle at the tricuspid annulus was significantly longer in the "PPHN" than in the "asymptomatic PH" group (53 ± 14 ms vs. 14 ± 4 ms, respectively; p < 0.05). Left ventricular (LV) function was normal in both groups with a systolic velocity (S'LV) at the LV free wall groups (6 ± 0.5 cm/s vs. 8.3 ± 5.7 cm/s, p > 0.05). Conclusion: The present results suggest that high PAP with or without respiratory failure is not associated with altered right systolic ventricular function and does not affect LV function in newborn infants. PPHN is characterized by a marked right diastolic ventricular dysfunction. These data suggest that the hypoxic respiratory failure in PPHN results, at least in part, from diastolic RV dysfunction and right to left shunting across the foramen ovale. We propose that the severity of the respiratory failure is more related to the RV diastolic dysfunction than the pulmonary artery pressure.

Short-time mortality and severe complications of very premature infants-a multicenter retrospective cohort study from Jiangsu Province during 2019-2021.

Background: The short-term and long-term severe complications of preterm infants have brought serious psychological and economic burdens to the society and family. Therefore, our study aimed to investigate the risk factors for the mortality and serious complications in very premature infants less than 32 weeks of gestational age (GA), so as to guide the antenatal and postnatal care of very premature. Methods: The very premature infants from 1 January 2019 to 31 December 2021 from 15 member hospitals of the Neonatal Intensive Care Unit (NICU) Multi-center Clinical Research Collaboration Group in Jiangsu Province were recruited. In accordance with the plan of the intensive care unit for unified management, recruitment of premature infants is carried out on the day of admission, and discharge or death is the outcome indicator in 1-2 months by telephone follow-up. The research content mainly includes three aspects: clinical information of mother and infant, outcomes and complications. According to the final outcomes, very premature infants were divided into two categories: survival without severe complications, survival with severe complications and death. Then, univariate and multivariate logistic regression model and receiver operating characteristic (ROC) analyses were used to analyze the independent risk factors. Results: A total of 3,200 very premature infants with GA less than 32 weeks were recruited. The median GA is 30.00 (28.57, 31.14) weeks, the average birth weight is 1,350 (1,110, 1,590) g, among whom 375 premature infants survived with severe complications, and 2,391 premature infants survived without severe complications. Then, it was found that GA at birth was a protective factor for death and severe complications, whereas severe neonatal asphyxia and persistent pulmonary hypertension of the newborn (PPHN) were independent risk factors for death and severe complications in very premature infants born at less than 32 weeks of gestation. Conclusions: The prognosis of very premature infants in NICU treatment depends not only on GA, but also on various perinatal factors and their clinical management, such as preterm asphyxia and PPHN occurrence, so the next step is necessary for multicenter continuous quality improvement to improve outcomes in very preterm infants.

Genome-wide association study identifies WWC2 as a possible locus associated with persistent pulmonary hypertension of the newborn in the Thai population.

Background: There is known to be significant genetic involvement in persistent pulmonary hypertension of the newborn (PPHN), but to date there is not a clear understanding of this situation, and clarifying that involvement would be of considerable assistance in devising effective treatments for the disease. This case-control study was undertaken to search for genetic variants associated with PPHN in the Thai population using a genome-wide association study (GWAS). Methods: A 659,184 single nucleotide polymorphisms from 387 participants (54 PPHN cases and 333 healthy participants) were genotyped across the human genome using an Illumina Asian Screening Array-24 v1.0 BeadChip Array. After quality control, we obtained 443,063 autosomal SNPs for the GWAS analysis. The FaST-LMM and R packages were used for all statistical analyses. Results: For the case-control analysis, the genomic inflation factor (λ) was 1.016, rs149768622 T>C in the first intron of WWC2 gene showed the strongest association with a P value of 3.76E-08 and odds ratio (OR) of 13.24 (95% CI: 3.91-44.78). The variants at the LOC102723906/LOC105377599, CADM4, GPM6A, CIT, RIMBP2, LOC105374510, LOC105375193, PTPRN2, CDK14, and LCORL loci showed suggestive evidence of associations with PPHN (P<1E-05). Conclusions: This GWAS found that rs149768622 T>C in the WWC2 gene was possibly associated with PPHN. However, replication and functional studies are needed to validate this association and further explore the role(s) of the WWC2 gene in PPHN.

Clinical characteristics and outcomes in neonates with perinatal acute respiratory distress syndrome in China: A national, multicentre, cross-sectional study.

Background: Neonatal acute respiratory distress syndrome (NARDS) was defined in 2017 and the epidemiological data remain unknown. Our objective was to explore aetiological factors, clinical characteristics and outcomes in patients with perinatal NARDS. Methods: A multicentre, prospective, cross-sectional study was performed in 58 tertiary neonatal intensive care units in China from Jan 1, 2018 to June 30, 2019. Neonates diagnosed with NARDS were included. Primary outcomes were aetiological factors, clinical characteristics and outcomes. Binary logistic regression and multivariate cox proportional regression were performed to identify independent predictors for bronchopulmonary dysplasia (BPD) and/or death or single death. This study was registered with ClinicalTrials.Gov, NCT03311165. Findings: Among 70,013 admitted neonates, the incidence of NARDS was 1.44% (1005). The cumulative incidences were 65.6%, 86.7%, 94.1% within one, two and three days after birth. The median gestational age and birth weight were 36.4 weeks and 2700 g. Three main aetiological triggers included pneumonia (58.1%), asphyxia (24.3%) and early-onset sepsis (EOS) (21.3%). BPD and/or death was observed in 213 (21.2%) infants, consisting 104 (10.3%) BPD and 126 (12.6%) deaths. The numbers of mild, moderate and severe NARDS were 537 (53.4%), 286 (28.4%) and 182 (18.2%). Two or more doses of surfactant was associated with increased mortality as compared with one or less doses of surfactant (odds ratio [OR] 1.93, 95% confidence interval [CI] 1.20-3.10, P = 0.006). Similarity also appeared in the comparison between EOS and non-EOS triggers (OR 1.57, 95% CI 1.06-2.33, P = 0.023). Interpretation: NARDS incidence was 1.44% and the three main aetiologies were pneumonia, asphyxia and EOS. The cumulative incidences were 65.6%, 86.7%, and 94.1% within one, two and three days after birth. Our results suggested that two or more doses of surfactant increased mortality compared with one or less doses of surfactant. Funding: The National Clinical Research Center of China and Clinical Medical Study Program of Children's Hospital of Chongqing Medical University (NCRC-2019-GP-13) and Natural Science Foundation of Chongqing (cstc2020jcyj-msxmX0197).

Case Report: Stüve-Wiedemann syndrome-a rare cause of persistent pulmonary hypertension of the newborn.

Introduction: Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening condition characterized by hypoxemia due to elevated pulmonary vascular resistance. PPHN commonly arises secondary to various underlying conditions, including infection, meconium aspiration, and respiratory distress syndrome. Management includes pulmonary vasodilators, mechanical ventilation, oxygen supplementation, vasopressors, and volume replacement. Stüve-Wiedemann syndrome (SWS), a rare genetic disorder characterized by bone dysplasia, respiratory distress, hyperthermia, and swallowing difficulties, may present with pulmonary hypertension, indicating a poor prognosis. Case description: A term female neonate presented with secondary respiratory failure and severe PPHN of unknown etiology on the second day of life, necessitating intubation. Clinical findings included facial dysmorphia, camptodactyly, skeletal anomalies, and generalized muscular hypotonia. High-frequency oscillation ventilation and surfactant administration yielded marginal improvement. On the third day of life, a severe pulmonary hypertensive crisis necessitated inhaled and systemic pulmonary vasodilators along with volume and catecholamine therapy. Whole exome sequencing revealed a homozygous mutation in the leukemia inhibitory factor receptor (LIFR) gene, consistent with Stüve-Wiedemann syndrome. Discussion/conclusion: The case underscores the importance of considering and prompting evaluation of rare genetic causes in the differential diagnosis of PPHN, especially when other abnormalities are present and conventional therapies prove inadequate. Therapeutic strategies must account for the different pathophysiology of primary PPHN including vascular remodeling, as seen in SWS, which may not respond to pulmonary vasodilators typically employed in secondary PPHN due to vasoconstriction. In this case, the patient responded well to treatment for primary PPHN, but the use of high-frequency oscillation ventilation and surfactant was not helpful.

Possible association between a polymorphism of EPAS1 gene and persistent pulmonary hypertension of the newborn: a case-control study

Abstract Objective: To explore possible genes related to the development of persistent pulmonary hypertension of the newborn (PPHN). Methods: The authors identified 285 single nucleotide polymorphisms (SNPs) of 11 candidate genes (BMPR2, EPAS1, PDE3A, VEGFA, ENG, NOTCH3, SOD3, CPS1, ABCA3, ACVRL1, and SMAD9), using an Illumina Asian Screening Array-24 v1.0 BeadChip Array. The FastLmmC and R package was used for statistical analyses. The chi-square test and Cochrane-Armitage trend test were used to compare the allele and genotype frequencies between the groups and to test the genetic models, respectively. Results: A total of 45 PPHN infants and 294 control subjects were analyzed. The most common cause of PPHN was meconium aspiration syndrome. Among the 285 SNPs, 17 SNPs from 6 candidate genes (BMPR2, EPAS1, PDE3A, VEGFA, ENG, and NOTCH3) were significantly associated with PPHN (P < 0.05). After using the Bonferroni correction (P < 0.00018), only the rs17034984 SNP located in intron 1 of the EPAS1 gene remained significantly different between the PPHN and control subjects (P = 0.00014). The frequency of the TC/TT genotype of rs17034984 in the gene with the dominant model was significant in the patients with PPHN (OR = 5.38, 95% CI: 2.15-13.49). The T allele frequency of rs17034984 in the gene showed a significant difference compared with the control subjects (OR = 4.89, 95% CI: 2.03-11.82). Conclusions: The present study suggests that the rs17034984 variant of EPAS1 gene is associated with PPHN.

Prediction score for prolonged hospital stay in meconium aspiration syndrome: A multicentric collaborative cohort of south India.

BACKGROUND AND OBJECTIVE: With improved survival in neonates with meconium aspiration syndrome (MAS), the focus is currently on mitigating the morbidities. The objective of this study was to predict factors determining prolonged hospital stay in neonates with MAS. MATERIALS AND METHODS: It was a retrospective cohort from five centers of south India between 2018 and 2020. Neonates ≥35 weeks of gestation admitted to neonatal intensive care unit with the diagnosis of MAS and requiring oxygen beyond 24 h of life were included in the study. The morbidities in the neonates with stay ≤7 days (short stay) were compared with >7 days (prolonged stay). Logistic regression by the backward stepwise method was used for predictive score creation. RESULTS: Out of 347 neonates with MAS discharged home, 103 (29%) had a short stay and 244 (71%) had prolonged stay. The primary support beyond O2 (continuous positive airway pressure/mechanical ventilation) (42% vs. 83%, p < 0.001), fractional inspired oxygen (FiO2 ) at 1 h >30% (45% vs. 87%, p < 0.001), hypoxic ischemic encephalopathy (HIE) stage 2 or 3 (1% vs. 27%, p < 0.001), moderate-severe persistent pulmonary artery hypertension (PPHN) (3% vs. 31%, p < 0.001) were independent factors associated with prolonged stay on logistic regression. A prediction model was devised using weighted scores of these four associated morbidities. The clinical score thus developed had 83% sensitivity, 68% specificity for the prediction of prolonged stay (area under curve: 82%, 95% confidence interval [78-87], p < 0.001). CONCLUSION: More than two-thirds of neonates with MAS had prolonged stay. The primary support beyond oxygen, FiO2 requirement >30%, Moderate to severe PPHN, HIE stage 2 or 3 were predictive of prolonged stay in neonates with MAS.

Factors to Consider to Study Preductal Oxygen Saturation Targets in Neonatal Pulmonary Hypertension.

There are potential benefits and risks to the infant with higher and lower oxygen saturation (SpO2) targets, and the ideal range for infants with pulmonary hypertension (PH) remains unknown. Targeting high SpO2 can promote pulmonary vasodilation but cause oxygen toxicity. Targeting lower SpO2 may increase pulmonary vascular resistance, especially in the presence of acidosis and hypothermia. We will conduct a randomized pilot trial to compare two ranges of target preductal SpO2 in late-preterm and term infants with hypoxic respiratory failure (HRF) and acute pulmonary hypertension (aPH) of the newborn. We will assess the reliability of a newly created HRF/PH score that could be used in larger trials. We will assess trial feasibility and obtain preliminary estimates of outcomes. Our primary hypothesis is that in neonates with PH and HRF, targeting preductal SpO2 of 95-99% (intervention) will result in lower pulmonary vascular resistance and pulmonary arterial pressures, and lower the need for pulmonary vasodilators (inhaled nitric oxide-iNO, milrinone and sildenafil) compared to targeting SpO2 at 91-95% (standard). We also speculate that a higher SpO2 target can potentially induce oxidative stress and decrease response to iNO (oxygenation and pulmonary vasodilation) for those patients that still require iNO in this range. We present considerations in planning this trial as well as some of the details of the protocol design (Clinicaltrials.gov (NCT04938167)).

Possible association between a polymorphism of EPAS1 gene and persistent pulmonary hypertension of the newborn: a case-control study.

OBJECTIVE: To explore possible genes related to the development of persistent pulmonary hypertension of the newborn (PPHN). METHODS: The authors identified 285 single nucleotide polymorphisms (SNPs) of 11 candidate genes (BMPR2, EPAS1, PDE3A, VEGFA, ENG, NOTCH3, SOD3, CPS1, ABCA3, ACVRL1, and SMAD9), using an Illumina Asian Screening Array-24 v1.0 BeadChip Array. The FastLmmC and R package was used for statistical analyses. The chi-square test and Cochrane-Armitage trend test were used to compare the allele and genotype frequencies between the groups and to test the genetic models, respectively. RESULTS: A total of 45 PPHN infants and 294 control subjects were analyzed. The most common cause of PPHN was meconium aspiration syndrome. Among the 285 SNPs, 17 SNPs from 6 candidate genes (BMPR2, EPAS1, PDE3A, VEGFA, ENG, and NOTCH3) were significantly associated with PPHN (P < 0.05). After using the Bonferroni correction (P < 0.00018), only the rs17034984 SNP located in intron 1 of the EPAS1 gene remained significantly different between the PPHN and control subjects (P = 0.00014). The frequency of the TC/TT genotype of rs17034984 in the gene with the dominant model was significant in the patients with PPHN (OR = 5.38, 95% CI: 2.15-13.49). The T allele frequency of rs17034984 in the gene showed a significant difference compared with the control subjects (OR = 4.89, 95% CI: 2.03-11.82). CONCLUSIONS: The present study suggests that the rs17034984 variant of EPAS1 gene is associated with PPHN.

Effectiveness of oral sildenafil for neonates with persistent pulmonary hypertension of newborn (PPHN): a prospective study in a tertiary care hospital.

INTRODUCTION: The prevalence of persistent pulmonary hypertension of newborn (PPHN) has been estimated 1.9/1000 live births. Although the efficacy of inhaled nitric oxide and extracorporeal membrane oxygenation in PPHN is well established but it is difficult to administer and monitor in resource limited countries. Owing to this, other treatment options need to be evaluated. METHOD: This is a prospective observational study conducted in the Pediatric Cardiology Department, NICVD, Karachi, from February 2020 to October 2020 after the approval from the Institutional Ethical Review Committee. All the neonates referred to our Unit were screened by echocardiography (echo) and those who fulfilled the inclusion criteria were included. Echo were done before starting sildenafil and after 72 h to assess the pressure gradient across tricuspid valve and right to left or bidirectional shunt across patent ductus arteriosus , patent foramen ovale , or both. Sildenafil was started with a dose of 1 mg/kg/dose thrice a day and increased to 2 mg/kg/dose after 48 h if partial pressure of oxygen (PO1] did not increase. In neonates who did not respond to increased dose of Sildenafil were added on oral Bosentan 1 mg/kg/dose twice a day. RESULTS: Total 82 newborns were enrolled. Fifty-two patients improved after 48 h so were continued on same treatment. Sildenafil dose was increased in 30 (37.9%) patients whose PO2 did not increase to at least 10% from baseline after 48 h of starting treatment. Three patients expired within 48-72 h. Out of 27 remaining patients, only four responded whereas 23 patients did not show any improvement. In these patients, Bosentan was supplemented along with sildenafil. CONCLUSION: The results of our study show effectiveness of oral Sildenafil in treating PPHN. The overall improvement observed in the patients was overwhelming. Combination of Sildenafil with Bosentan is beneficial in patients who did not respond on Sildenafil alone.

Case Report: Persistent Pulmonary Hypertension of the Newborn and Narrowing of the Ductus Arteriosus After Topical Use of Non-Steroidal Anti-Inflammatory During Pregnancy.

Background: The use of non-steroidal anti-inflammatory drugs (NSAIDs) during the third trimester of pregnancy can cause premature constriction of the ductus arteriosus. This report describes a case of in utero narrowing of the ductus arteriosus (DA) diagnosed postnatally in a baby with Persistent Pulmonary Hypertension of the Newborn (PPHN), after maternal use of Diclofenac-Epolamine 140 mg patch during the second and third trimester. Case Presentation: A fetal ultrasounds revealed an enlarged hypertrophic right ventricle at 32 weeks of gestation. Detailed questioning of the mother highlighted that topical Diclofenac (FLECTOR®) had been used at 26 and at 31 weeks of gestation. An echocardiography performed 8 h postnatally showed supra-systemic pulmonary hypertension, a restrictive ductus arteriosus and a dilated right ventricle. The newborn was treated by inhaled nitric oxide and oral Sildenafil and was discharged from hospital on day 24. He had a complete normalization of his pulmonary vascular resistance on day 48. Conclusion: This case illustrates the potential fetal and neonatal complications associated with maternal topical Diclofenac medication during pregnancy resulting in antenatal closure of the DA.

Pathophysiology and Management of Persistent Pulmonary Hypertension of the Newborn.

Persistent pulmonary hypertension of the newborn (PPHN) is a disorder of circulatory transition resulting in high pulmonary vascular resistance with extrapulmonary right-to-left shunts causing hypoxemia. There has been substantial gain in understanding of pathophysiology of PPHN over the past 2 decades, and biochemical pathways responsible for abnormal vasoconstriction of pulmonary vasculature are now better understood. Easy availability of bedside echocardiography helps in establishing early definitive diagnosis, understanding the pathophysiology and hemodynamic abnormalities, monitoring the disease process, and response to therapeutic intervention. There also has been significant advancement in specific management of PPHN targeted at deranged biochemical pathways and hemodynamic instability.

Efficacy and Safety of IV Sildenafil in the Treatment of Newborn Infants with, or at Risk of, Persistent Pulmonary Hypertension of the Newborn (PPHN): A Multicenter, Randomized, Placebo-Controlled Trial.

OBJECTIVE: To investigate the efficacy and safety of sildenafil added to inhaled nitric oxide (iNO) for newborn infants with persistent pulmonary hypertension of newborn (PPHN) or hypoxic respiratory failure (HRF) at risk of PPHN. STUDY DESIGN: Part A of a multinational, randomized, double-blind, placebo-controlled trial. Infants ≤96 hours' old, >34 weeks of gestation, receiving iNO (10-20 ppm on ≥50% FiO2) for PPHN or HRF at risk of PPHN, and oxygen index >15 to <60, were randomized (1:1) to intravenous (IV) sildenafil (loading: 0.1 mg/kg, over 30 minutes; maintenance: 0.03 mg/kg/h) or placebo, for up to 14 days. Coprimary end points were treatment failure rate (day 14/discharge) and time on iNO without treatment failure. Secondary end points included time on ventilation and oxygenation measures. RESULTS: Of 87 infants screened, 29 were randomized to IV sildenafil and 30 to placebo; 13 discontinued treatment (sildenafil, n = 6; placebo: n = 7), including 3 deaths (sildenafil: n = 2; placebo: n = 1). Treatment failure rates did not differ with sildenafil (27.6%) vs placebo (20.0%; P = .4935). Mean time on iNO was not different with sildenafil (4.1 days) vs placebo (4.1 days; P = .9850). No differences were noted in secondary end points. Most common adverse events (AEs) with sildenafil (≥10% infants) were hypotension (n = 8/29), hypokalemia (n = 7/29), anemia, drug withdrawal syndrome (n = 4/29, each), and bradycardia (n = 3/29). One serious AE (hypotension) was considered treatment-related. CONCLUSIONS: IV sildenafil added to iNO was not superior to placebo in infants with PPHN or HRF at risk of PPHN. A review of AEs did not identify any pattern of events indicative of a safety concern with IV sildenafil. Infants will have developmental follow-up (Part B). TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT01720524.

Nebulized Magnesium Sulfate for Treatment of Persistent Pulmonary Hypertension of Newborn: A Pilot Randomized Controlled Trial.

OBJECTIVES: To investigate the effectiveness of nebulized magnesium sulfate in treating persistent pulmonary hypertension of newborn (PPHN). METHODS: Twenty-eight mechanically ventilated term neonates with severe PPHN were randomized into two groups: NebMag group (n = 14), who receiving nebulized isotonic magnesium (1024 mg/h), and IVMag group (n = 14), who received intravenous magnesium (200 mg/kg over 30 min, followed by 50 mg/kg/h). The study time frame was 24 h. Outcome measures were the changes in oxygenation index (OI), mean arterial blood pressure (MABP), vasoactive inotropic score (VIS), and serum magnesium level. RESULTS: Baseline demographic, ventilatory, and hemodynamic characteristics were comparable between the two groups. At the end of the study, the OI decreased by 44.3% in the NebMag group compared with 35.3% in the IVMag group (mean difference -3.14; 95%CI -5.08, -1.19; p 0.003). The NebMag group had a higher MABP (mean difference 2.29 mmHg; 95% CI 1.80, 2.77; p 0.000) and lower VIS (mean difference -14.64; 95% CI -16.52, -12.77; p 0.000) at the 24-h study time point. The increase in serum magnesium level, measured at 12-h study time point, was lower in the NebMag group (mean difference -2.26 mmol/L; 95% CI -2.58, -1.96; p 0.000). CONCLUSION: Nebulized magnesium sulfate may be an effective therapeutic modality for neonates with severe PPHN on mechanical ventilation, but this should be confirmed by larger studies. Retrospectively registered at www.clinicaltrials.gov (identifier: NCT04328636).