Severe Persistent Pulmonary Hypertension Of The Newborn Research Articles

Prostaglandin-E1 infusion in persistent pulmonary hypertension of the newborn.

Neonates with persistent pulmonary hypertension of the newborn (PPHN) can present with hypoxia and right ventricular dysfunction with resultant inadequate oxygen delivery and end-organ damage. This study describes the use of prostaglandin-E1 (PGE) for ductal patency to preserve right ventricular systolic function and limit afterload in newborns with PPHN. This is a retrospective cohort study that follows the hemodynamics, markers of end-organ perfusion, length of therapeutics, and echocardiographic variables of 57 newborns who used prostglandin-E1 in the setting of PPHN. Tachycardia, lactic acidosis, and supplemental oxygen use improved following PGE initiation. Fractional area change (FAC), to assess right ventricular systolic function, and pulmonary arterial acceleration time indexed to right ventricular ejection time (PAAT/RVET), to assess right ventricular afterload, also improved over three time points relative to PGE use (before, during, and after). Overall, we described the safety and utility of PGE in newborns with severe PPHN for stabilization while allowing natural disease progression.

Use of Vasopressin as Rescue Therapy in Refractory Hypoxia and Refractory Systemic Hypotension in Term Neonates with Severe Persistent Pulmonary Hypertension-A Prospective Observational Study.

Persistent pulmonary hypertension of the newborn (PPHN) is a serious cardiorespiratory problem. PPHN is frequently associated with refractory hypoxia and hypotension, and optimal management has the potential to improve important clinical outcomes including mortality. The primary objective is to evaluate the efficacy and safety of rescue vasopressin (VP) therapy in the management of severe (refractory) hypoxia and refractory systemic hypotension in term neonates with severe PPHN. Neonates with refractory hypoxia and refractory hypotension due to severe PPHN needing VP were prospectively enrolled in the study. Refractory hypoxia was defined as oxygenation index (OI) ≥ 25 for at least 4 hours after the commencement of high-frequency oscillatory ventilation and nitric oxide at 20 ppm. Refractory hypotension was defined as mean blood pressure lesser than mean gestational age lasting for more than 15 minutes in spite of dopamine infusion at 10 µg/kg/min, adrenaline infusion at 0.3 µg/kg/min, and noradrenaline infusion at 0.1 µg/kg/min. Thirty-two neonates with PPHN were recruited. The baseline OI (mean ± standard deviation [SD]) before starting VP was 33.43 ± 16.54 which started decreasing significantly between 1 and 6 hours after the commencement of VP (p < 0.05). The mean blood pressure also increased concomitantly with a significant effect seen by 1 hour (p < 0.05). The vasoactive infusion score before the commencement of VP was mean 46.07 (SD = 25.72) and started decreasing after 12 to 24 hours of commencement of VP (p < 0.05). Lactate levels (mean ± SD) before starting VP were 7.8 ± 8.6 mmol/L and started decreasing between 6 and 12 hours (p < 0.05). Two neonates died due to refractory hypoxia and refractory hypotension (overall mortality 6.2%) CONCLUSION: Rescue VP therapy is a useful adjunct in the management of neonates with severe PPHN with refractory hypoxia and/or refractory hypotension. Improvement in oxygenation and hemodynamics with the use of VP results in reduced mortality. · Rescue vasopressin is a useful adjunct in the management of neonates with severe PPHN.. · Vasopressin helps reduce OI.. · Vasopressin reduces the vasoactive inotrope score..

24 Persistent pulmonary hypertension and short-term neurological outcomes in infants with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia

Abstract Background Neonatal hypoxic ischemic encephalopathy (HIE) after perinatal asphyxia is a serious clinical condition that may result in permanent neurologic deficits or death. There is an increased incidence of persistent pulmonary hypertension of the newborn (PPHN) in asphyxiated infants. Due to the high disease burden of HIE, studying its altered cardiopulmonary hemodynamics might identify those patients at highest risk for adverse outcome early on. Objectives To investigate the relationship between severity of PPHN and the extent of short-term brain injury in infants with moderate to severe HIE who received therapeutic hypothermia (TH). Design/Methods Retrospective cohort study of 230 TH-treated HIE infants. PPHN was defined and graded clinically and based on echocardiography findings. The primary outcome was the presence of HIE changes on brain MRI and/or death within the first month of life according to the diagnosis and severity of PPHN. Secondary outcomes were the pattern of HIE on brain MRI; abnormal electroencephalogram (EEG) background, clinical, or electrographic seizures, or need for anti-ictal treatment; clinical and laboratory differences between HIE babies with and without PPHN. A logistic regression model was performed to identify PPHN severity as risk factor for moderate-to-severe brain injury or death. Results Brain injury was not found to be different between the two groups according to presence of PPHN whether clinically or based on echocardiography. However, the combined outcome of severe brain injury or death was higher in the clinical PPHN group vs non-PPHN (32.6 vs 22.8%, p=0.014), and early exit from TH due to severe PPHN was associated with the highest mortality (71.4%). Death was found to have a relationship with the severity of PPHN based on echocardiography, with the highest incidence in severe PPHN (36.0 vs 7.7% and 10.0% in the severe, moderate, and mild PPHN groups, respectively, p=0.002). Infants with clinical PPHN were sicker with higher ventilation needs and worse laboratory values compared to those without PPHN. None of the other outcomes were different among the two groups. Conclusion In infants with HIE treated with TH, PPHN was not associated with increased risk of brain injury as evident on MRI, nor clinical or electrographic seizure burden. However, mortality was higher in the most severe PPHN categories.

Efficacy of sildenafil in persistent pulmonary hypertension of the newborn.

Objective: To find out efficacy of sildenafil for the treatment of persistent pulmonary hypertension of the newborn (PPHN). Study Design: Observational study. Setting: Department of Neonatology, Sughra Shafi Medical Complex, Sahara Medical College, Narowal. Period: May 2020 to April 2021. Material &amp; Methods: A total of 22 neonates of both genders with diagnosis of PPHN were enrolled during the study period. Demographic characteristic along with information about perinatal and postnatal characteristics were recorded among all neonates at the time of admission. X-ray chest were asked. Oral sildenafil was administered as 2mg/kg per dose thrice a day to all study cases and continued till extubation. Outcome was recorded on the basis of difference in FiO2 need after initiating sildenafil, time required to get ventilator off or mortality. Results: Out of a total of 22 neonates, 13 (59.1%) were male. Majority of the neonates, 15 (68.2%) were term newborns. Mode of delivery was lower segment cesarean section in 17 (77.3%) cases. APGAR score at 5 minutes was between 7 to 10 in 13 (59.1%) newborns. There were 13 (59.1%) newborns who required immediate resuscitation following birth. Meconium aspiration syndrome was the commonest associated condition found among 8 (36.4%) neonates. As per echocardiographic findings, 13 (59.1%) neonates had severe PPHN, 5 (22.7%) moderate and 4 (18.2%) mild. Mean oxygenation index at the time of admission was noted to be 46+14. Inotropic support was administered to 19 (86.4%) cases. Mean length of neonatal intensive care unit was 15+5 days. Mortality was reported among 10 (45.4%) neonates. Conclusion: Oral sildenafil was found to be a promising option for the treatment of neonates having PPHN. Oral sildenafil was found to successfully improve oxygenation among neonates having PPHN.

Experience of cases with inhaled nitric oxide and therapeutic hypothermia.

Neonates with hypoxic-ischemic encephalopathy (HIE) on therapeutic hypothermia (TH) therapy may show persistent pulmonary hypertension of the newborn (PPHN). In Japan, the reported mortality rate is lower than in the US, possibly due to treatment differences of newborns with moderate to severe HIE and PPHN. This study aimed to determine the feasibility and long-term outcomes of inhaled nitric oxide (iNO) and TH therapy in newborns with moderate to severe HIE and PPHN. This was a retrospective review of neonates with moderate to severe HIE that were treated with TH from 2008 to 2017 at a large medical center in Japan. We documented their long-term neurological prognosis, measuring their developmental and Gross Motor Function Classification System level at 18 months old. A total of 37 neonates with moderate to severe HIE underwent TH therapy and six of them were started with iNO therapy for PPHN. iNO with TH was safely administered to all six newborns with moderate to severe HIE with PPHN. In two neonates TH was discontinued because of intraventricular hemorrhage (IVH) and severe hypotension. Neurological outcomes were similar in newborns who were treated with iNO and TH and those who were treated with TH alone. These initial findings suggest that monitoring hematological and cardiovascular status is important with iNO for severe asphyxia in infants with PPHN. Safer and more feasible protocols are needed for when iNO and TH therapy are administered together.

Comparison of Efficacy between Sildenafil Alone and Sildenafil with Milrinone for Treatment of Persistent Pulmonary Hypertension of the Newborn

Introduction: In persistent pulmonary hypertension of the newborn (PPHN), some neonates do not response to single pulmonary vasodilator drug, so recently combination therapy is being tried to decrease pulmonary artery systolic pressure (PASP). The aim of the study was to compare the efficacy of oral sildenafil alone with combination of oral sildenafil and milrinone in neonates suffering from PPHN. Methods: This RCT study was conducted in Dhaka Shishu (Children) Hospital, from July 2018 to June 2020. Sixty eight (68) term and near term neonates aged &lt;10 days (34 cases in each group) with moderate to severe PPHN were taken. Monotherapy with oral sildenafil was given in group-A and combined therapy with oral sildenafil and i/v milrinone in Group-B. Serial echocardiography was done at before starting the therapy, at 3 days and at 5 days of treatment. Data regarding baseline characteristics, clinical features, PASP, PO2, Spo2, hospital stay, mortality and others investigations were recorded and analyzed with SPSS version-26. Results: Post treatment PASP was significantly reduced in group A (sildenafil) and group-B (sildenafil plus milrinone) (p&lt;0.05). But in combination group PASP was more reduced than monotherapy group (p&lt;0.05). Within the group, the oxygen saturation and PO2 significantly improved in both groups (p&lt;0.05) but no significant difference was found in between two groups (p&gt;0.05). Adrenaline infusion, hypotension and less hospital stay were significantly seen (P&lt;0.05) in combination group. Conclusion: Combined therapy with oral sildenafil and milrinone are more effective than monotherapy with oral sildenafil in reduction of PASP. Both therapies are effective in improvement of oxygenation.

Persistent pulmonary hypertension of the newborn.

Persistent pulmonary hypertension of the newborn (PPHN) is a significant clinical problem characterized by refractory and severe hypoxemia secondary to elevated pulmonary vascular resistance resulting in right-to-left extrapulmonary shunting of deoxygenated blood. PPHN is associated with diverse cardiopulmonary disorders and a high early mortality rate for infants with severe PPHN. Surviving infants with PPHN have an increased risk of long-term morbidities. PPHN physiology can be categorized by (1) maladaptation: pulmonary vessels have normal structure and number but have abnormal vasoreactivity; (2) excessive muscularization: increased smooth muscle cell thickness and increased distal extension of muscle to vessels that are usually not muscularized; and (3) underdevelopment: lung hypoplasia associated with decreased pulmonary artery number. Treatment involves adequate lung recruitment, optimization of cardiac output and left ventricular function, and pulmonary vasodilators such as inhaled nitric oxide. Infants who fail to respond to conventional therapy should be evaluated for lethal lung disorders including alveolar-capillary dysplasia, T-box transcription factor 4 gene, thyroid transcription factor-1, ATP-binding cassette A3 gene, and surfactant protein diseases.

Association between gestational age and persistent pulmonary hypertension of the newborn (PPHN) severity in preterm babies at Sidoarjo Regional Hospital

AbstractPersistent pulmonary hypertension of the newborn (PPHN) is a condition that occurs due to increased resistance to blood vessels in the lungs that occur persistently after the baby is born. This can be attributed to congenital heart disease such as right-to-left shunts through foramen ovale (PFO) or patent ductus arteriosus (PDA) due to an error transition fetal blood circulation to the neonate. Although PPHN is always associated with births in post-term babies, PPHN cases are often found in preterm babies. Chances of babies born with PPHN are quite large, at 1.9% per 1000 live births. PPHN can be fatal, causing mortality rates ranging from 4 to 33%. The incidence of preterm births in Indonesia is estimated at 7-14%, around 459,200 - 900,000 babies per year. This study aimed to prove the relationship between premature babies and persistent pulmonary hypertension of the newborn (pphn) in Sidoarjo Regional Hospital and to know the characteristics and analyze these variables. This research used crossed sectional studied design; the population was all preterm babies in the NICU at Sidoarjo regional hospital. All samples are from medical records in January-December 2018. There is a significant difference between preterm babies and PPHN (p &lt; 0.05); besides, the results from Spearman's correlation analysis obtained a correlation coefficient (ρ) = 0.485. In the cross-tabulation analysis, the result of the proportion with the highest correlation was Late Preterm babies with severe PPHN of 46.7%. It can be concluded that there is a relationship between premature babies and PPHN in Sidoarjo regional hospital..Keywords : Persistent pulmonary hypertension of the newborn, PPHN, Preterm BabiesCorrespondence : aisyahhelmadevithalib@gmail.com

Caracteristics, Diagnosis, Management and Output of Persistent Pulmonary Hypertension of the Newborn at Dr. Soetomo Hospital

Background Persistent pulmonary hypertension of the new-born (PPHN) is a failure of lung circulation innew-born. However the data related the characteristics of clinical profile, diagnostic, management and theoutcome was still limited.Objective To investigated the characteristics, diagnostics, management and outcome from PPHN.MethodsRetrospective observational study. Neonates with PPHN from January 2015 to December 2019 wereidentified from medical record. After the data was excluded, the characteristics, diagnostic, management andthe outcome was collected. The statistical analysis to known the frequency and the chi-square test used toanalyse the association between the treatment and the outcomes (P < 0.05).Results 37 medical records enrolled the study, with the characteristics; 62.2% babies was boy, 70.3% withterm infant, 70.3% with normal birth weight, 24.3% with maternal history of eclampsia. 62.2% babiesborn by C-section, 21.9% with history of asphyxia and MAS. 78.4% with differences between pre- andpost-ductal saturation. From echocardiography result, 13.5% diagnosed as mild PPHN, 54.1% as moderatePPHN and 32.4% severe PPHN. From the management consisted of 5.4% with O2 nasal, 32.4% O2 CPAPand 62.2% O2 ventilator, 24.3% with sildenafil, 5.4% with combination sildenafil and illoprost, 5.4% withcombination sildenafil, illoprost, and surfactant, 2.7% with combination sildenafil, illoprost, surfactant,and inotropic, 24.3% with combination sildenafil, illoprost, and inotropic, and 37.8% with combinationsildenafil and inotropic. The outcomes was obtained 35.1% babies was died and 64.9% babies was cured,with oxygenation supplementation had significantly affecting the outcomes (P=0.02)Conclusion The characteristics of PPHN was dominated by baby boy, term infant and good birth weight,history of asphyxia and MAS, maternal history of eclampsia, C-section delivery and the differences betweenpre- and post-ductal saturation. The diagnosis commonly with moderate PPHN. The management with O2ventilator and combination sildenafil-inotropic. The outcome mostly the babies was cured.

Postnatal causes and severity of persistent pulmonary Hypertension of Newborn.

Background & Objective:Persistent pulmonary hypertension of the newborn (PPHN) is described as severe respiratory failure along with hypoxaemia. PPHN is known to be linked with high morbidity and mortality around the world. This study was planned to determine the postnatal causes and assess the severity of persistent pulmonary hypertension of newborn in babies presenting to the Children’s Hospital, Multan.Methods:This observational study was conducted at the Department of Paediatric Cardiology, The Children Hospital &Institute of Child Health, Multan, Pakistan from July to December 2019. A total of 122 confirmed cases of PPHN admitted having gestational age above 34 weeks were enrolled. Demographic data of the newborns was recorded along with maternal medical history, pregnancy status and postnatal causes of PPHN. Severity of PPHN was also recorded.Results:Out of a total of 122 cases of PPHN, 81 (66.3%) were male. Majority, 78 (64.0%) had gestational age above 37 weeks. Mode of delivery as cesarean section was noted in 70 (57.4%). Meconium aspiration syndrome 52 (42.6%), birth asphyxia 48 (39.3%), respiratory distress syndrome 23 (18.8%) and sepsis 33 (27.0%) were found to be the commonest causes of PPHN. Severe PPHN was found to be the most frequent, noted among 63 (51.6%) while Moderate PPHN was observed in 40 (32.8%) and Mild PPHN in 19 (15.6%). Morality was noted among 26 (21.3%) of cases.Conclusion:Meconium aspiration syndrome, birth asphyxia and respiratory distress syndrome were the commonest postnatal causes of PPHN. Severe PPHN was found to be the most frequent form of PPHN.

Risk Factors and Outcomes of Acute Kidney Injury in Neonates with Persistent Pulmonary Hypertension of the Newborn.

ObjectiveTo identify the incidence of and risk factors for acute kidney injury (AKI) in neonates with persistent pulmonary hypertension of the newborn (PPHN) and to evaluate its association with neonatal outcomes.MethodA total of 78 newborns with confirmed PPHN admitted to the neonatal intensive care unit of a university hospital between 2016 and 2020 were retrospectively analyzed. AKI was defined according to the modified neonatal Kidney Disease: Improving Global Outcomes criteria.ResultsOf 78 PPHN infants, AKI was found in 29.5% (23/78). Multivariate analysis indicated that male sex (OR 3.43 95% CI 1.03-11.48, p=0.04) and severe PPHN (OR 5.67 95% CI 1.55-20.68, p<0.01) were independently associated with increased risk for AKI. Infants with AKI had significantly higher mortality rate than infants without AKI (43.5% vs. 9.1%, p<0.01). Mortality rates in stage 1, stage 2 and stage 3 AKI were similar (36.4%, 57.1%, and 40%, respectively, p=0.68). Among survivors, AKI infants had significantly longer mechanical ventilation and lenght of stay than infants without AKI.ConclusionIn infants with PPHN, AKI is a common complication and is associated with increased mortality, and longer mechanical ventilation and lenght of stay. Careful monitoring of kidney function in infants with PPHN, especially in males and those who had severe PPHN can help to improve patient outcomes.

Cost-Utility of Sildenafil for Persistent Pulmonary Hypertension of the Newborn.

While advanced therapies for severe persistent pulmonary hypertension of the newborn (PPHN) such as inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO) are standard treatments in high-income countries, these therapies are often unavailable in resource-limited settings such as middle-income countries. However, there are small clinical trials illustrating the efficacy of sildenafil at reducing mortality in PPHN. This analysis sought to determine the cost-utility of enteral sildenafil for the treatment of severe PPHN. A Markov-state transition model was constructed for the two clinical approaches to compare costs, clinical outcomes, and quality of life: (1) "conventional," (2) "sildenafil." The impact of sildenafil was modeled as a relative risk modifier of the conventional strategy's mortality risk. Transitional probabilities, costs, and utility metrics were extracted from the literature. Sensitivity analyses for each model input as well as 100-patient Monte Carlo simulations were used to test the durability of the model conclusion. The sildenafil strategy was cost-effective for upper but not lower middle-income countries with an incremental cost-effectiveness ratio of $2,339 per quality-adjusted life year. This conclusion was durable across a wide-range of model assumptions; the sildenafil strategy only failed to meet criteria for cost-effectiveness when sildenafil therapy had a mortality relative risk efficacy of >0.89, if life expectancy in that country is <40 years, or if the lifetime forecasted costs of a survivor's life was quite high. Enteral sildenafil is a cost-effective intervention for severe PPHN for upper middle-income countries where ECMO and iNO are not available. · PPHN is a common life-threatening condition in newborns.. · Sildenafil improves survival of PPHN.. · Sildenafil is cost-effective for upper-middle income countries..

Morbidity of Persistent Pulmonary Hypertension of the Newborn in the First Year of Life

To assess postdischarge mortality and morbidity in infants diagnosed with different etiologies and severities of persistent pulmonary hypertension of the newborn (PPHN), and to identify risk factors for these adverse clinical outcomes. This was a population-based study using an administrative dataset linking birth and death certificates, hospital discharge and readmissions records from 2005 to 2012 in California. Cases were infants ≥34weeks' gestational age with International Classification of Diseases,9th edition, codes consistent with PPHN. The primary outcome was defined as postdischarge mortality or hospital readmission during the first year of life. Crude and adjusted risk ratio (aRR) with 95% CIs were calculated to quantify the risk for the primary outcome and to identify risk factors. Infants with PPHN (n=7847) had an aRR of 3.5 (95% CI, 3.3-3.7) for the primary outcome compared with infants without PPHN (n=3 974 536), and infants with only mild PPHN (n=2477) had an aRR of 2.2 (95% CI, 2.0-2.5). Infants with congenital diaphragmatic hernia as the etiology for PPHN had an aRR of 8.2 (95% CI, 6.7-10.2) and infants with meconium aspiration syndrome had an aRR of 4.2 (95% CI, 3.7-4.6) compared with infants without PPHN. Hispanic ethnicity, small for gestational age, severe PPHN, and etiology of PPHN were risk factors for the primary outcome. The postdischarge morbidity burden of infants with PPHN is large. These findings extend to infants with mild PPHN and etiologies with pulmonary vascular changes that are thought to be short term and recoverable. These data could inform counseling of parents.

Hydrocortisone Improves Oxygenation Index and Systolic Blood Pressure in Term Infants With Persistent Pulmonary Hypertension.

Persistent pulmonary hypertension of the newborn (PPHN) is an essential cause for hypoxic respiratory failure with significant morbidity and mortality in term and near-term neonates. Hydrocortisone has been shown to decrease oxygen dependency and pulmonary hypertension in neonates with meconium aspiration syndrome and animal studies, respectively. We hypothesize that hydrocortisone will improve oxygenation in term and near-term infants with pulmonary hypertension. We performed a retrospective chart review of all infant with PPHN who received intravenous hydrocortisone therapy as a rescue for severe PPHN. Clinical response was objectively measured using, oxygenation index (OI), PaO2/FiO2 ratio, and inotrope score before, during, and after the hydrocortisone course. We found that hydrocortisone administration resulted in significant improvement of systolic blood pressure, OI, and PaO2/FiO2. In conclusion, hydrocortisone increased systolic blood pressure and improved oxygenation in term and near-term infants with persistent pulmonary hypertension. Prospective randomized trials are required to evaluate these findings further.

Persistent Pulmonary Hypertension of the Newborn in Twin-Twin Transfusion Syndrome: A Case-Control Study

Background: Persistent pulmonary hypertension of the newborn (PPHN) is associated with severe morbidity and mortality. Twin-twin transfusion syndrome (TTTS) is suggested to increase the risk of PPHN. Objectives: To describe the incidence of PPHN in TTTS twins and to identify risk factors in TTTS twins for the development of severe PPHN. Methods: Cases with severe PPHN were extracted from our monochorionic twin database (2002-2016). Severe PPHN was defined as severe hypoxaemia requiring mechanical ventilation and inhaled nitric oxide (iNO) treatment, confirmed by strict echocardiographic criteria. A case-control comparison within TTTS survivors was conducted to identify risk factors for PPHN. Results: The incidence of PPHN in TTTS twins was 4% (24/598, 95% confidence interval [CI] 2.7-5.9%) and 0.4% (2/493, 95% CI 0.1-1.5%) in uncomplicated monochorionic twins (odds ratio [OR] 10.3, 95% CI 2.4-43.9; p = 0.002). Two risk factors were independently associated with PPHN: severe prematurity (OR 3.3, 95% CI 1.0-11.4) and recipient status (OR 3.9, 95% CI 1.4-11.0). In TTTS recipients, another risk factor for PPHN is anaemia at birth (OR 7.2, 95% CI 1.8-29.6). Conclusion: Clinicians caring for neonates with TTTS should be aware of the 10-fold increased risk of PPHN compared to uncomplicated monochorionic twins. PPHN occurs more often in case of premature delivery and in recipient twins, particularly in the presence of anaemia at birth. As the development of severe PPHN is difficult to predict, we advise that all TTTS twins should be delivered in a tertiary care centre with iNO treatment options.

Recommendations for the Use of Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension

Recommendations for the Use of Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension

Persistent pulmonary hypertension of the newborn.

Persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance resulting in right-to-left shunting of blood and hypoxemia. PPHN is often secondary to parenchymal lung disease (such as meconium aspiration syndrome, pneumonia or respiratory distress syndrome) or lung hypoplasia (with congenital diaphragmatic hernia or oligohydramnios) but can also be idiopathic. The diagnosis of PPHN is based on clinical evidence of labile hypoxemia often associated with differential cyanosis. The diagnosis is confirmed by the echocardiographic demonstration of – (a) right-to-left or bidirectional shunt at the ductus or foramen ovale and/or, (b) flattening or leftward deviation of the interventricular septum and/or, (c) tricuspid regurgitation, and finally (d) absence of structural heart disease. Management strategies include optimal oxygenation, avoiding respiratory and metabolic acidosis, blood pressure stabilization, sedation and pulmonary vasodilator therapy. Failure of these measures would lead to consideration of extracorporeal membrane oxygenation (ECMO); however decreased need for this rescue therapy has been documented with advances in medical management. While trends also note improved survival, long-term neurodevelopmental disabilities such as deafness and learning disabilities remain a concern in many infants with severe PPHN.Funded by: 1R01HD072929-0 (SL)

Effectiveness and safety of intravenous iloprost for severe persistent pulmonary hypertension of the newborn

The aims of this study were to determine the effectiveness (oxygenation), safety (hemodynamic status) and short term outcomes of intravenous iloprost (IVI) administration as a rescue therapy in severe persistent pulmonary hypertension of the newborn (PPHN). Retrospective medical records review. Tertiary neonatal intensive care unit at Songklanagarind Hospital, Songkhla Province, Hat Yai, Thailand. Newborns who received IVI as an adjunctive therapy for treatment of severe PPHN, as defined by an oxygen index (OI) of >20 and without response to conventional therapies. The change of OI and alveolar-arterial oxygen difference before and after commencement of IVI. 33 neonates with severe PPHN at a median gestation of 39 weeks and a baseline OI of 40 (range, 21-101) received IVI. The median OI and alveolar-arterial oxygen difference had a statistically significant decrease after 2 hours of treatment and continued to decline thereafter (P<0.05). All infants received one or more inotropic medications and volume expanders to provide blood pressure support with no statistically significant difference of blood pressure and heart rate before and after IVI treatment. The mortality rate was 15.2%, all of them had initially severe hypoxemia with a median OI of 53.6. Triglyceride and non-high-density lipoprotein cholesterol are better than low-density lipoprotein cholesterol as predictors of cardiovascular disease risk factors in Chinese Han children and adolescents.

The use of Sildenafil in the Treatment of Persistent Pulmonary Hypertension of the Newborn: A Review of the Literature

Persistent pulmonary hypertension of the newborn (PPHN) is a serious and potentially fatal condition, characterized by hypoxemia due to increased pulmonary vascular resistance (PVR) with resultant shunting of pulmonary blood to the systemic circulation. Inhaled nitric oxide (iNO) has been considered a revolutionary treatment of PPHN. Data show that the use of iNO has reduced the need of ECMO in neonates with severe PPHN, while in moderate PPHN, iNO administration has been associated with a significant decrease in ventilatory support and prevented progression to severe PPHN. Not all neonates respond to iNO therapy though, and phosphodiesterase (PDE) inhibitors with their potent vasodilator properties have evolved as an alternative therapy or as an adjunct to the treatment of PPHN with iNO. There are ten families of PDE isoenzymes. PDE 5 is particularly prevalent in vascular smooth muscle (VSM) and PDE 5 inhibitors, such as sildenafil, have been used in clinical practice. This review provides a comprehensive account of existing data in the literature, from animal and clinical studies, on the use of sildenafil for the treatment of PPHN. Sildenafil may also have a role as a single mode of therapy, since in resource-limited settings the cost of iNO is a serious concern.

Impaired NO-cGMP signaling in the pathogenesis of neonatal pulmonary hypertension and therapeutic implications

Background Postnatal survival is dependent upon successful transition of the pulmonary circulation at birth. Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that is characterized by the failure to achieve or sustain a marked reduction of pulmonary vascular resistance (PVR) after delivery. High PVR causes extra-pulmonary right-to-left shunt, leading to profound hypoxemia, asphyxia and significant morbidity and mortality. Past studies have shown that NO-cGMP signaling contributes significantly to the normal fall in PVR at birth, and that decreased NO production or activity contributes to PPHN. Multicenter studies have shown that inhaled NO is effective in the treatment of clinical PPHN, but nearly 40% of newborns with PPHN fail to respond to iNO therapy. These findings suggest that additional therapies are essential for enhancing NO-cGMP signaling and improving outcomes of neonates with severe PPHN. Since recent studies demonstrated increased oxidative stress in experimental PPHN, we hypothesized that impaired NO responsiveness in PPHN may be due to decreased soluble guanylate cyclase (sGC) activity due to oxidation. Cinaciguat (BAY 58-2667) is a novel sGC activator that causes vasodilation even in the presence of oxidized heme, but its hemodynamic effects in the perinatal lung are unknown. Therefore, we performed a series of physiologic studies in chronically-prepared, late gestation fetal lambs. Additional in vitro studies were performed with isolated pulmonary artery smooth muscle cells (SMC) from normal and PPHN lambs. Results We found that in the normal fetus, cinaciguat (0.1 to 100 mcg over 10 min) caused dose-related increases in pulmonary blood flow greater than 4-fold above baseline values and reduced PVR by 80%. Treatment with ODQ, an sGC oxidizing inhibitor, enhanced cinaciguat-induced pulmonary vasodilation by over 150%. The pulmonary vasodilator effect of cinaciguat was prolonged, decreasing PVR for more than 1.5 hours after brief intrapulmonary infusion. In vitro stimulation of fetal pulmonary artery SMC with cinaciguat after ODQ treatment demonstrated a 14-fold increase in cGMP in comparison without ODQ. We further studied the pulmonary vascular effects of cinaciguat in fetal sheep with chronic pulmonary hypertension after partial ligation of the ductus arteriosus (PPHN). We found that in contrast with the loss of acetylcholineinduced pulmonary vasodilation 5 days after surgery, the cinaciguat response persisted and was enhanced in PPHN lambs. After cesarean-section delivery and mechanical ventilation, neonatal lambs with PPHN demonstrated markedly impaired vasodiliation to inhaled NO (20 and 40 ppm). In contrast, brief infusion of cinaciguat caused marked and prolonged pulmonary vasodilation.