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.

Is it Really PPHN? Think Before Starting Sildenafil!.

The use of sildenafil has become a common practice in neonatal intensive care unit on clinical ground, because opinion by Pediatric Cardiologist is usually not available especially in peripheral centers. We consider it essential to share our experience that severe pulmonary arterial hypertension can be due to some unusual hemodynamics or extremely rare structural causes which do not require pulmonary vasodilator therapy.

Emerging Role of Sildenafil in Neonatology.

Over the last few years, sildenafil is increasingly being used in the neonatal ICU for a variety of indications. The use is even more so in the developing world due to the limited availability of nitric oxide and extracorporeal membrane oxygenation (ECMO). There are still no clear cut guidelines for its use. At present the drug appears relatively safe and effective when other treatment options have been optimized. However, the use of sildenafil must be monitored and reported. Due to its easy availability and ease of administration we must guard against its inappropriate use.

eNOS Gene Polymorphisms in Perinatal Hypoxic-Ischemic Encephalopathy

BACKGROUND: In perinatal hypoxic-ischemic encephalopathy (HIE), cerebral blood flow is impaired and the activity of nitric oxide systhase (NOS) is markedly increased. For the association with the development of a stroke, the endothelial NOS (eNOS) polymorphisms are well-known. METHODS: Three clinically relevant polymorphisms of the eNOS gene were determined in 37 term/near-term infants with perinatal HIE (HIE group) and 54 normal term newborn infants without any perinatal problems (control group) using a polymerase chain reaction with or without restriction fragment enzyme digestion. The differences in the genotype, allele, and haplotype frequencies were evaluated between the groups. RESULTS: The analysis of the allele frequencies showed that the G allele of Glu298Asp was more frequent in the HIE group than in the controls. The comparisons between the controls and each subgroups with complications that occurred with HIE showed that the TC genotype and C allele of T(-786)C were more common in patients with persistent pulmonary hypertension of the newborn (PPHN) than in the controls. The frequency of the A b T haplotype was lower in the HIE patients than in the controls. CONCLUSIONS: The G allele of Glu298Asp was associated with perinatal HIE, while the TC genotype and C allele of T(-786)C were associated with PPHN.

Persistent Pulmonary Hypertension of the Newborn

Persistent pulmonary hypertension of the newborn (PPHN) is defined as a failure of normal pulmonary vascular relaxation at or shortly after birth, resulting in impedance to pulmonary blood flow which exceeds systemic vascular resistance, such that unoxygenated blood is shunted to the systemic circulation. Perinatal stressors including hypoxia, hypoglycemia, cold stress, sepsis, and direct lung injury alter the course of transition. The initial clinical picture of PPHN is one of dynamic pulmonary vasospasm, with labile flow through the pulmonary circuit and right-to-left shunting of blood across the ductus arteriosus and foramen ovale. The normal postnatal decline in pulmonary vascular tone is absent following exposure to chronic hypoxia. The pathophysiology of neonatal pulmonary hypertension can involve multiple pathways of injury, from altered circulating agonist balance, to endothelial dysfunction, to smooth muscle dysfunction and phenotypic change. The treatment for PPHN has evolved over the past 10 to 15 years but reported mortality remains at 10% to 20% in newborns with PPHN. Extracorporeal membrane oxygenation (ECMO) has been proven of value for this condition, and several "alternative" therapies such as high-frequency ventilation (HFV), surfactant, and inhaled NO (iNO) have been used in a rescue mode.

Persistent Pulmonary Hypertension of the Newborn

Persistent pulmonary hypertension of the newborn (PPHN) is defined as a failure of normal pulmonary vascular relaxation at or shortly after birth, resulting in impedance to pulmonary blood flow which exceeds systemic vascular resistance, such that unoxygenated blood is shunted to the systemic circulation. Perinatal stressors including hypoxia, hypoglycemia, cold stress, sepsis, and direct lung injury alter the course of transition. The initial clinical picture of PPHN is one of dynamic pulmonary vasospasm, with labile flow through the pulmonary circuit and right-to-left shunting of blood across the ductus arteriosus and foramen ovale. The normal postnatal decline in pulmonary vascular tone is absent following exposure to chronic hypoxia. The pathophysiology of neonatal pulmonary hypertension can involve multiple pathways of injury, from altered circulating agonist balance, to endothelial dysfunction, to smooth muscle dysfunction and phenotypic change. The treatment for PPHN has evolved over the past 10 to 15 years but reported mortality remains at 10% to 20% in newborns with PPHN. Extracorporeal membrane oxygenation (ECMO) has been proven of value for this condition, and several "alternative" therapies such as high-frequency ventilation (HFV), surfactant, and inhaled NO (iNO) have been used in a rescue mode.

Experience of Milrinone Treatment for Persistent Pulmonary Hypertension of the Newborn

PURPOSE:Persistent pulmonary hypertension of the newborn (PPHN) is life threatening neonatal disease. Nitric oxide (NO) has been proven to improve oxygenation, however its usage is limited and 30% of patients with PPHN are NO nonresponders. Milrinone decreases right ventricular afterload and has selective pulmonary vasodilator effect. We studied the effects of milrinone on neonates with respiratory failure originated in PPHN. METHODS:Six neonates, who had oxygen index above 20 and responded poorly to other management, were treated with intravenous milrinone after confirming pulmonary hypertension with echocardiography. We reviewed their medical records retrospectively. Intravenous milrinone was started at a dose of 0.375 microgram/kg/min. Respiratory indices (Oxygenation index [OI], ventilation settings, and arterial blood gas) and cardiovascular stability (mean arterial pressure and heart rate) were documented just before; and at 6, 12, 24, 36, 48, and 72 hours after commencement of milrinone therapy. The primary outcome was the effect of milrinone on oxygenation, which was 40% reduction in OI. RESULTS:Primary cause of PPHN was meconium aspiration syndrome in three infants, respiratory distress syndrome (RDS) in the other three. Milrinone was commenced at a median age of 22.3+/-6.1 hours with a dose of 0.375 microgram/kg/min except one infant (0.5 microgram/kg/min) and infants were treated for median 58.3+/-16.7 hours. OI of all infants showed 40% reduction within 24 hours. There were no mortality, and no infants with hypotension, and intraventricular hemorrhage. CONCLUSION:Milrinone proved to be effective for PPHN by improving oxygenation. It did not cause any complications in clinical trials for newborns. It is suggested that Milrinone can replace NO or can be used as adjunct to NO in the treatment of PPHN.

Pathophysiology of Persistent Pulmonary Hypertension of the Newborn / 소아과

Persistent pulmonary hypertension of the newborn(PPHN) is a disorder characterized by persistence of the pattern of fetal circulation after birth due to a sustained elevation of pulmonary vascular resistance. The two primary events in the pathophysiology of neonatal pulmonary hypertension are hypoxic pulmonary vasoconstriction(HPV) and hypoxic pulmonary vascular remodeling(HPR). Chronic hypoxemia may cause increased muscularity of the pulmonary arteries and extension of the muscularity to more distal arteries. The mechanisms underlying neonatal hypoxic pulmonary vascular remodeling are complex and multifactorial, requiring the involvement of endothelial, vascular smooth muscle, and adventitial cells. Endothelin-1(ET-1) has strong vasoactive properties, and acts via two different receptors, ETA and ETB. In pulmonary artery, ETA receptors mediate vasoconstriction and are found on vascular smooth muscle cells, while ETB receptors that are mostly located on endothelial cells mediate vasodilation by NO and prostacyclin release. eNOS derived NO is an important mediator of pulmonary vascular response to chronic hypoxia. Atrial natriuretic peptides(ANP) plays an important role in the regulation of pulmonary arterial pressure. Vascular endothelial growth factor (VEGF) release is increased in hypoxic pulmonary arterial smooth muscle cells, and hence may be involved in hypoxic pulmonary artery remodeling and edema. Retinol is essential for fetal lung morphogenesis and subsequent normal neonatal lung growth and maturation. ATP-sensitive potassium channels may be involved in the later stage of hypoxia. Activation of these channels may counteract the vasoconstrictive effect of hypoxia.

Predictors of Clinical Outcome in the Newborns of Persistent Pulmonary Hypertension Treated with Inhaled Nitric Oxide

PURPOSE: Inhaled nitric oxide (iNO) has been known to improve oxygenation in newborns with persistent pulmonary hypertension (PPHN). This study was performed to evaluate the predictors of clinical outcome in the newborn infants with PPHN treated with iNO. METHODS: Between September 1998 and August 2002, 23 newborn infants with PPHN treated with iNO were enrolled in this study. Reduction of oxygenation index (OI) and AaDO2 to 30% or more were defined as clinical response. Accoding to the response time within or after 12 hours, the clinical response was sub-categorized as early or delayed response, respectively. RESULTS: The mean gestational age and birth weight of 23 newborn infants were 36.7+/-4.4 weeks and 2,644+/-907 g. The mean baseline OI and AaDO2 were 22.20+/-13.63 and 477.16+/-127.96. There were ten non-responsders, eight early responsders and five delayed responders. Eleven neonates showed sustained response for 24 hours. The mean AaDO2, and PaO2 were decreased after 12 hours (P<0.05), while there was no difference in oxygenation index, arteral pH and PaCO2. The mortality rates of non-responders or not- sustained responders were higher than those of responders or sustained responders (P< 0.05). The birth weight of death group was lower than that of survival group and AaDO2, and OI at 12 hours after iNO therapy in survival group were lower than those in death group. CONCLUSION: Predictors of the clinical outcome of iNO therapy were clinical response patterns after iNO therapy, time taken until clinical response, duration of response and change of oxygenation at 12 hours after iNO therapy.

Predictors of Clinical Outcome in the Newborns of Persistent Pulmonary Hypertension Treated with Inhaled Nitric Oxide

PURPOSE: Inhaled nitric oxide (iNO) has been known to improve oxygenation in newborns with persistent pulmonary hypertension (PPHN). This study was performed to evaluate the predictors of clinical outcome in the newborn infants with PPHN treated with iNO. METHODS: Between September 1998 and August 2002, 23 newborn infants with PPHN treated with iNO were enrolled in this study. Reduction of oxygenation index (OI) and AaDO2 to 30% or more were defined as clinical response. Accoding to the response time within or after 12 hours, the clinical response was sub-categorized as early or delayed response, respectively. RESULTS: The mean gestational age and birth weight of 23 newborn infants were 36.7+/-4.4 weeks and 2,644+/-907 g. The mean baseline OI and AaDO2 were 22.20+/-13.63 and 477.16+/-127.96. There were ten non-responsders, eight early responsders and five delayed responders. Eleven neonates showed sustained response for 24 hours. The mean AaDO2, and PaO2 were decreased after 12 hours (P<0.05), while there was no difference in oxygenation index, arteral pH and PaCO2. The mortality rates of non-responders or not- sustained responders were higher than those of responders or sustained responders (P< 0.05). The birth weight of death group was lower than that of survival group and AaDO2, and OI at 12 hours after iNO therapy in survival group were lower than those in death group. CONCLUSION: Predictors of the clinical outcome of iNO therapy were clinical response patterns after iNO therapy, time taken until clinical response, duration of response and change of oxygenation at 12 hours after iNO therapy.

Treatment of Persistent Pulmonary Hypertension of the Newborn with Magnesium Sulphate

PURPOSE: MgSO4 was used to evaluate the clinical effects in the treatment of severe persistent pulmonary hypertension of the newborn(PPHN). METHODS: Seven newborn infants with severe PPHN, and a persistent elevation of AaDO2(Alveolar-arterial oxygen tension difference) above 610 mmHg for more than 8 hours despite the aggressive conventional therapy were included. A loading dose of 200 mg/kg MgSO4 was given intravenously over 20-30 minutes, followed by continuous infusion of 20-50 mg/kg/hour. Vital signs, arterial blood gases, serum electrolytes, calcium and magnesium, and ventilatory setting were measured and recorded before MgSO4 was given and periodically thereafter. Severity of impairment of gas exchange was evaluated by AaDO2 and oxygenation index(OI). RESULTS: Mean gestational age and birth weight of seven infants were 38+5 weeks and 2,949844 grams, and one of them was a premature infant with gestational age of 27 weeks, and birth weight of 1,096 grams. There were six males and one female. Four infants were outborn. Four infants were presented with meconium aspiration syndrome, one with birth asphyxia, one with respiratory distress syndrome, and one with subdural hemorrhage. Before the start of the MgSO4 treatment, the mean AaDO2 and OI of seven infants were 638.8+/-10.8 mmHg and 43.811.2, respectively. During the treatment AaDO2 and OI significantly decreased to 538.4+/-114.5 mmHg and 13.4+/-9.4 within 24 hours(P< 0.05). Hypermagnesemia was noted in 7 infants, hypocalcemia in three, bradycardia in five, and hypotension in two. Only one infant was discharged against medical advice, and remaining six survived. CONCLUSION: MgSO4 may be considered as an alternative treatment of severe PPHN when other conventional treatments fail, are contraindicated, or not available.