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We report a case of ventricular septal defect (VSD) in which we attempted to treat pulmonary arterial hypertension (PAH) with the goal of VSD closure in an adult with suspected Eisenmenger syndrome in childhood. Four years previously (age 41 years), she was referred to our department due to repeated hemoptysis requiring further treatment of PAH. We started combination therapy with several pulmonary vasodilators. Two years later, her pulmonary vascular resistance (PVR) was improved but still not at the level where VSD closure was possible. To control the increased PA flow resulting from intensive PAH treatment and to reduce the risk of hemoptysis, we performed pulmonary artery banding (PAB). As the risk of hemoptysis decreased, a prostacyclin analog was introduced, and the dose was increased. More than 1 year after PAB, active vasoactivity testing became positive, suggesting that the pulmonary vascular lesion was now “reversible”. We performed VSD closure and atrial septal defect creation even though her PVR was still high. After the operation, her exercise capacity was remarkably improved. We suggest that stepwise surgical repair with pulmonary vasodilators is an important treatment option for select patients with VSD with severe PAH.

Persistent pulmonary hypertension of the neonate (PPHN) refractory to inhaled nitric oxide still represents a frequent clinical challenge with negative outcomes in neonatal critical care. Several pulmonary vasodilators have become available thanks to improved understanding of pulmonary hypertension pathobiology. These drugs are commonly used in adults and there are numerous case series and small studies describing their potential usefulness in neonates, as well. New vasodilators act on different pathways, some of them can have additive effects and all have different pharmacology features. This information has never been summarized so far and no comprehensive pathobiology-driven algorithm is available to guide the treatment of refractory PPHN.Conclusion: We offer a rational clinical algorithm to guide the treatment of refractory PPHN based on expert advice and the more recent pathobiology and pharmacology knowledge. What is Known: • Refractory PPHN occurs in 30-40% of iNO-treated neonates and represents a significant clinical problem. Several pulmonary vasodilators have become available thanks to a better understanding of pulmonary hypertension pathobiology. What is New: • Available vasodilators have different pharmacology, mechanisms of action and may provide additive effect. We provide a rational clinical algorithm to guide the treatment of refractory PPHN based on expert advice and the more recent pathobiology and pharmacology knowledge.

Abernethy syndrome is shunting of blood from portal to systemic circulation resulting in pulmonary vasodilation and ventilation perfusion mismatch. On evaluation of a young male with severe pulmonary hypertension no cause was found. On CECT abdomen channel suggestive of Abernethy syndrome was found and patient was sent for surgical correction.

There are multiple management strategies and a wide array of therapeutic options in the management of pulmonary hypertension in children. This survey was designed to assess the current trends in diagnosis and management of pulmonary hypertension including use of inhaled nitric oxide (iNO) and utilization of other pulmonary vasodilators. A 21 question web-based survey was created on a survey design program (Qualtrics®) and distributed to participating pediatric ICUs in the virtual PICU systems network. The survey content and design was reviewed by the institutional review board and approved as exempt research. Survey was distributed to 135 institutions with a 23% response rate (31/135). Of all the respondents, 24 were pediatric intensivists; six described themselves as cardiac intensivists, and one cardiologist. Fifty percent of mixed PICU and CICU units had a protocol for iNO use compared 37% of primary pediatric cardiac ICU. 10/31 (32.2%) respondents used iNO more than 20 times a year. Sildenafil was the main second-line agent with 8/31 (25.8%) reported using sildenafil drip for refractory pulmonary hypertension. 23/31 (74.1%) use inhaled Flolane. Only 12/31 (38.7%) respondents weaned iNO within the first 24 to 48 h, 8/31 (25.8%) did not have a defined timeline of iNO use and based it off of clinical response. 27/31 (87%) primarily used iNO in children less than one year of age. There is need for standardization of iNO usage across institutions to be able to generate evidence of its efficacy and indications, dosage, and weaning strategies.

Pulmonary hypertension (PH), the syndrome of increased pressure in the pulmonary arteries, is associated with significant morbidity and mortality for affected children and is associated with a variety of potential underlying causes. Several pulmonary arterial hypertension-targeted therapies have become available to reduce pulmonary artery pressure and improve outcome, but there is still no cure for most patients. This review provides a description of select causes of PH encountered in pediatrics and an update on the most recent data pertaining to evaluation and management of children with PH. Available evidence for specific classes of PH-targeted therapies in pediatrics is discussed.

Despite progress in pharmacotherapy in pediatric pulmonary hypertension, real-world patterns of directed pulmonary hypertension therapy have not been studied in the current era. A retrospective observational study of children (≤18 years) with pulmonary hypertension was performed using data from the MarketScan® Commercial and Medicaid claims databases. Associations between etiology of pulmonary hypertension and pharmaceutical regimen were evaluated, as were the associations between subject social and geographic characteristics (insurance-type, race, and/or census region) and regimen. Annualized costs of single- and multi-class regimens were calculated. In total, 873 subjects were studied, of which 94% received phosphodiesterase-5 inhibitors, 31% endothelin receptor antagonist, 9% prostacyclin analogs, and 7% calcium channel blockers. Monotherapy was used in 72% of subjects. Phosphodiesterase-5 inhibitors monotherapy was the most common regimen (93%). Subjects with idiopathic pulmonary hypertension, congenital heart disease, and unclassified pulmonary hypertension receive more than one agent and were more likely to receive both endothelin receptor antagonist and prostacyclin analogs than other forms of pulmonary hypertension. Compared to recipients of public insurance, subjects with commercial insurance were more likely to receive more intense therapy ( p = 0.003), which was confirmed in multivariable analysis (OR: 1.4, p = 0.03). Receipt of commercial insurance was also associated with increased annual costs across all subjects ( p

[Background] Mortality of pulmonary hypertension associated with congenital heart disease (PAH-CHD) in adults remains high., [Objectives] To identify predictors of death and to assess the impact of treatment on outcome., [Methods] Retrospective, multicenter cohort study of 103 adults with PAH-CHD followed-up for 8.6 ± 4.6 years. Patients were grouped according to underlying shunt type into pre-tricuspid, post-tricuspid and complex. Survival rates were analyzed and predictors of death were investigated with Cox regression models., [Results] In the post-tricuspid and complex groups (38 and 37 patients, respectively), the most common clinical PAH-CHD subgroup was Eisenmenger syndrome (76.3% and 59.5%, respectively) whereas, in the pre-tricuspid group (28 patients), 46.5% of patients had small or corrected defects. Overall, 88 patients received vasodilators; 39% required combination-therapy. Overall survival at 10 years was 65%. Mortality was highest in the pre-tricuspid group, FC-III-IV and amongst patients receiving monotherapy (p < 0.050). On multivariate analysis, predictors of poor outcome were pericardial effusion (HR: 4,520 [1,470–13,890]; p = 0,008), oxygen saturation(HR: 0.940 [0,900 - 0,990]; p = 0,018) and genetic syndromes(HR: 3,280 [1,098–9,780]; p = 0,033)., [Conclusions] Patients in advanced stages at initiation of treatment were at high risk of death and strong consideration should be given for more aggressive therapy., This study was supported by Clinical Research Grant 2017 from the Spanish Society of Cardiology. The regional Registry of Adult Congenital Heart Disease in Andalusia (RACCA) is supported by the Spanish Society of Cardiology and was launched through a research grant from Actelion Pharmaceuticals.

Few meta-analyses evaluated the efficacy and safety of pulmonary vasodilators in patients with Eisenmenger syndrome. Recently, some studies have reported conflicting results regarding improvements in exercise capacity. This study evaluated the efficacy and safety of pulmonary vasodilators in patients with Eisenmenger syndrome. Relevant studies were identified by searching major databases. Pooled outcomes were used to assess the efficacy and safety of pulmonary vasodilators. In total, five studies with 508 patients were included. Meta-analysis indicated that the pulmonary vasodilators reduced the mortality (odd risk (OR) = 0.35; 95% CI, 0.13 to 0.95; P = 0.04), slashed the mean pulmonary artery pressure (mean difference (MD) = −4.35 mmHg; 95% CI, −7.19 to −1.50; P = 0.003), decreased pulmonary vascular resistance index (MD = −480.08 dyn · s · cm −5 · m 2 ; 95% CI, −753.51 to −206.64; P = 0.0006), increased the 6-min walk distance (MD = 28.38 m; 95% CI, 2.99 to 53.77; P = 0.03), and elevated the systemic oxygen saturation at rest (MD = 1.00%; 95% CI, 0.12 to 1.88; P = 0.03). Four studies reported side effects, but only two studies reported serious adverse effects which were mostly rare and curable. The present meta-analysis indicated that pulmonary vasodilators decrease mortality and improve hemodynamics and exercise capacity in patients with Eisenmenger syndrome. Overall, pulmonary vasodilators are well tolerated.

Congenital diaphragmatic hernia (CDH) is a rare disease, which affects 1 in 2,500 newborns. Congenital diaphragmatic hernia can interfere with the normal development of the pulmonary parenchyma and vascular bed, and in severe cases, it can lead to the development of severe pulmonary arterial hypertension (PAH) and right ventricular failure. We present a neonate with CDH who developed severe PAH and right ventricular dysfunction and was managed with a unique strategy combining venoarterial extracorporeal membrane oxygenation, prostaglandin E1, and a variety of PAH therapies.

ZusammenfassungDas perioperative Management von Patienten mit pulmonaler Hypertonie erfordert von den behandelnden Anästhesisten fundierte Kenntnisse über die zugrunde liegenden Ursachen, die Pathophysiologie, den Einfluss anästhesiologischer und chirurgischer Maßnahmen wie z. B. die mechanische Beatmung sowie intraoperative Behandlungsoptionen. In der präoperativen Vorbereitung gilt es, alle vorliegenden Befunde zu evaluieren, die Belastbarkeit des Patienten zu erheben und die bestehende Dauermedikation zu kennen. Die Basis für einen sicheren intraoperativen Verlauf stellt die Vermeidung einer pulmonalarteriellen Druckerhöhung und Rechtsherzdysfunktion dar. Hierbei gilt es Hypoxie, Hyperkapnie, Azidose, Hypothermie, Stress und eine koronare Hypoperfusion zu verhindern. Bei einem Anstieg des pulmonalarteriellen Drucks können sowohl inhalative, selektive pulmonale Vasodilatatoren, wie Stickstoffmonoxid oder Prostazykline, als auch intravenös Phosphodiesterase-3-Inhibitoren und Phosphodiesterase-5-Inhibitoren eingesetzt werden. Bei einer rechtsventrikulären Dysfunktion oder Dekompensation sollte mittels inotroper Substanzen und Inodilatoren die Herzfunktion unterstützt werden. Abhängig vom Ausmaß der Operation und dem Schweregrad der pulmonalen Hypertonie erfordert die postoperative Betreuung vor allem Expertise und Strukturen, die ein kontinuierliches Monitoring zulassen.

Paediatric pulmonary hypertension has been described as a secondary complication of multiple diseases and their treatment. Limited information exists about the relationship between pulmonary hypertension and cancer in children. A review of charts was performed in all patients treated for cancer and developed pulmonary hypertension. A total of four patients developed pulmonary hypertension during treatment of cancer. All patients had solid tumors, had echocardiographic evidence of elevated right ventricular pressures, and required intensive care stays. Treatment courses included inhaled and oral pulmonary vasodilators along with systemic steroids. Each had normalisation of echocardiograms and resolution of pulmonary symptoms. Prompt diagnosis of pulmonary hypertension and treatment with pulmonary vasodilators and steroids are considered important measures followed by chemotherapy and radiation regimens.

Adult‐onset Still's disease (AOSD) is a rare inflammatory autoimmune disorder characterized by fever, skin rash, and arthralgia. Pulmonary artery hypertension (PAH) rarely occurs with AOSD and has not been reported in the absence of typical symptoms of AOSD. A 33‐year‐old woman was admitted to our hospital with dyspnoea on exertion. Although she had not had symptoms of AOSD for 18 months before her admission, she presented with gradually progressing PAH. Because she had no typical symptoms of AOSD, she was treated with pulmonary vasodilators. However, her PAH did not improve. At one month after vasodilator treatment, she developed a high fever with elevation of ferritin. We determined that her AOSD had relapsed. Immunosuppressants were started and both her AOSD and PAH quickly improved. PAH may develop in the absence of typical symptoms of AOSD and immunosuppressants may be effective in such a case., We report a patient previously diagnosed with adult‐onset still's disease (AOSD) who presented with pulmonary artery hypertension (PAH) but without typical symptoms of AOSD. Immunosuppressive agents rapidly improved PAH.

Pulmonary hypertension (PH) is a severe disease that affects people of all ages. It can occur as an idiopathic disorder at birth or as part of a variety of cardiovascular and pulmonary disorders. Inhaled pulmonary vasodilators (IPV) can reduce pulmonary vascular resistance (PVR) and improve RV function with minimal systemic effects. IPV includes inhaled nitric oxide (iNO), inhaled aerosolized prostacyclin, or analogs, including epoprostenol, iloprost, treprostinil, and other vasodilators. In addition to pulmonary vasodilating effects, IPV can also be used to improve oxygenation, reduce inflammation, and protect cell. Off-label use of IPV is common in daily clinical practice. However, evidence supporting the inhalational administration of these medications is limited, inconclusive, and controversial regarding their safety and efficacy. We conducted a search for relevant papers published up to May 2020 in four databases: PubMed, Google Scholar, EMBASE and Web of Science. This review demonstrates that the clinical using and updated evidence of IPV. iNO is widely used in neonates, pediatrics, and adults with different cardiopulmonary diseases. The limitations of iNO include high cost, flat dose-response, risk of significant rebound PH after withdrawal, and the requirement of complex technology for monitoring. The literature suggests that inhaled aerosolized epoprostenol, iloprost, treprostinil and others such as milrinone and levosimendan may be similar to iNO. More research of IPV is needed to determine acceptable inclusion criteria, long-term outcomes, and management strategies including time, dose, and duration.

Background: We performed a meta-analysis to evaluate the efficacy and safety of pulmonary vasodilators in pediatric pulmonary hypertension (PH) patients.Methods: We searched electronic databases including PubMed, EMBASE, and the Cochrane Library up to May 2020, and conducted a subgroup analysis for pulmonary vasodilators or underlying disease.Results: Fifteen studies with 719 pediatric PH patients were included in the meta-analysis. Adverse events did not differ (p = 0.11, I2 = 15%) between the pulmonary vasodilators group and the control group, neither in the subgroups. In total, compared with the control group treatment, pulmonary vasodilators significantly decreased the mortality (p = 0.002), mean pulmonary artery pressure (mPAP, p = 0.02), and mechanical ventilation duration (p = 0.03), also improved the oxygenation index (OI, p = 0.01). In the persistent pulmonary hypertension of the newborn (PPHN) subgroup, phosphodiesterase type 5 inhibitors (PDE5i) significantly reduced mortality (p = 0.03), OI (p = 0.007) and mechanical ventilation duration (p = 0.004). Administration of endothelin receptor antagonists (ERAs) improved OI (p = 0.04) and mechanical ventilation duration (p < 0.00001) in PPHN. We also found that in the pediatric pulmonary arterial hypertension (PPAH) subgroup, mPAP was pronouncedly declined with ERAs (p = 0.006). Systolic pulmonary artery pressure (sPAP, p < 0.0001) and pulmonary arterial/aortic pressure (PA/AO, p < 0.00001) were significantly relieved with PDE5i, partial pressure of arterial oxygen (PaO2) was improved with prostacyclin in postoperative PH (POPH) subgroup (p = 0.001). Compared with the control group, pulmonary vasodilators could significantly decrease PA/AO pressure (p < 0.00001) and OI (p < 0.00001) in the short-term (duration p = 0.03) and PaO2 (p = 0.01) in the mid-term (7–30 days) follow-up subgroup, also decrease mortality, mPAP (p = 0.0001), PA/AO pressure (p = 0.0007), duration of mechanical ventilation (p = 0.004), and ICU stay (p < 0.00001) in the long-term follow subgroup (>30 days).Conclusion: Pulmonary vasodilators decrease the mortality in pediatric PH patients, improve the respiratory and hemodynamic parameters, reduce the mechanical ventilation duration.

Background:Cardiac dysfunction, arrhythmia, and hepatic fibrosis are well-known complications after right heart bypass surgery in patients with single-ventricle physiology. However, little is known about coronary arterial fistulae, and only a few reports have been published. This study aimed to elucidate the clinical characteristics of these rare coronary arterial fistulae that developed as complications in cases of single-ventricle physiology after right heart bypass surgery.Methods:We retrospectively investigated the clinical features and courses of patients who developed acquired and progressive coronary arterial fistulae after right heart bypass surgery in our hospital.Results:We identified three cases of coronary arterial fistulae out of 21 patients who underwent right heart bypass surgery. All three cases underwent cardiac catheterisation for post-operative evaluation and were administered pulmonary vasodilators of phosphodiesterase type V inhibitors, antiplatelet, anticoagulation, and diuretics. Moreover, they had common clinical features such as right-dominant single ventricle and long-term exposure to chronic hypoxia. Serial angiograms revealed acquired and progressive coronary arterial fistulae. In addition, coronary arterial fistulae contributed to their symptoms of heart failure.Conclusion:Patients with chronic hypoxia and dominant right ventricle, who are treated with phosphodiesterase type V inhibitors, should be followed up after right heart bypass surgery to monitor the possible development of coronary arterial fistulae. Moreover, the indication for pulmonary vasodilators in single-ventricle physiology after right heart bypass surgery should be optimised to avoid adverse effects.

BackgroundInhaled nitric oxide (iNO) effectively reduces right ventricular afterload when administered in the immediate phase of acute pulmonary embolism (PE) in preclinical animal models. In a porcine model of intermediate-risk PE, we aimed to investigate whether iNO has pulmonary vasodilator efficacy both in the immediate and prolonged phase of acute PE.MethodsAnesthetized pigs (n = 18) were randomized into three subgroups. An acute PE iNO-group (n = 6) received iNO at 40 ppm at one, three, six, nine and 12 hours after onset of PE. Vehicle animals (n = 6) received PE, but no active treatment. A third group of sham animals (n = 6) received neither PE nor treatment. Animals were evaluated using intravascular pressures, respiratory parameters, biochemistry and intracardiac pressure-volume measurements.ResultsThe administration of PE increased mean pulmonary artery pressure (mPAP) (vehicle vs sham; 33.3 vs 17.7 mmHg, p ConclusionsiNO is a safe and effective pulmonary vasodilator both in the immediate and prolonged phase of acute PE in an in-vivo porcine model of intermediate-risk PE.

Pulmonary veno-occlusive disease (PVOD) is a rare but devastating cause of pulmonary hypertension (PH) characterized by preferential remodeling of the pulmonary venules. Mitomycin-C (MMC) is an alkylating agent commonly used in chemotherapy with documented lung toxicity as well as PVOD adverse effect. The incidence of PVOD in patients with anal cancer is much higher than in those with idiopathic PVOD, especially following treatment with MMC. An accurate diagnosis of PVOD can be made based on noninvasive investigations utilizing oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest. No evidence-based medical therapy exists for PVOD at present and lung transplant remains the preferred definitive therapy for eligible patients. We present a case of autopsy confirmed MMC induced PVOD in a patient with metastatic anal cancer.

Background The Fontan circulation is a palliative procedure for patients born with a single ventricle physiology. The Fontan circulation is associated with significant late morbidity commonly including atrial arrhythmias. Case presentation We report a case of an adult Fontan patient who developed protein losing enteropathy (PLE) following persistent atrial arrhythmias. Treatment with a pulmonary vasodilator, sildenafil, resolved the PLE. Conclusions The importance of a low pulmonary vascular resistance to maintain wellbeing in the Fontan patient is discussed, as is the role of pulmonary vasodilators.

Systemic sclerosis sine scleroderma (ssSSc) is a rare variant of systemic sclerosis, with only one pediatric case reported in the medical literature to date. Pulmonary arterial hypertension as the presenting feature of ssSSc is extremely rare, even in adults, and so far has never been reported in children. We report, for the first time, a case of pediatric ssSSc in a 3-year-old girl, who presented with interstitial lung disease and pulmonary hypertension. The patient was prescribed early aggressive pulmonary vasodilators combined with anti-inflammatory medications. The clinical response was good, and her current condition at 12 years of age is remarkable, considering the high mortality rates reported in adults. We underscore the importance of early aggressive treatment in future cases of similar presentation.

Background: The condition of pulmonary vasculature is a key to determine the outcome of Fontan candidates. The previous reports described no significant growth of pulmonary arteries (PA) after having bi-directional Glenn shunt (BDG), which may influence peri- and post-operative management of Fontan procedure. Aim: We hypothesized the pulmonary vasodilators (PVDs) facilitate to grow small PA even after BDG in Fontan Candidates. Method: The twenty-one cases after BDG, whose PA index (Nakata index) were less than 140 mm 2 /m 2 , were enrolled. The enrolled cases were divided into two group: 15 with PVDs treatment ( PV+) and 6 without (PV-). PVDs used in this study were PDE5 inhibitor, Endothelin-receptor-blocker, oral prostacyclines , and their combination. In addition to measure the hemodynamic parameters ( mean PA pressure(mPAp), indexed pulmonary vascular resistance (Rp), Pulmonary flow (Qp) ), PA index and PA branch index ( a sum of cross-sectional area of first PA branches at both side indexed by body surface area) were measured and compared at the timing of after BDG and at after Fontan completion, respectively. Result: PA index and PA branch index after BDG of (PV+) and (PV-)were 104±33 vs 104±17 mm 2 /m 2 : 151±33 vs 194±45 mm 2 /m 2 . PA index in both groups after Fontan procedure was increased up to 153±42 vs 152±56 mm 2 /m 2 in same fashion, while PA branch index of (PV+) was significantly increased up to 199±60 than that of (PV-) 226±65 mm 2 /m 2 (% increase was 131% vs 116%). Rp and mPAp in both groups were not changed , while Qp in (PV+) was significantly more increased (140%) than that in (PV-)(107%). In conclusion, PVDs facilitates the growth of PA branches by increasing Qp, which brings a favor outcome of Fontan patients.

BACKGROUND: The purpose of this study was to compare the outcomes of infants with giant omphalocele (GO) born in two different epochs over two decades at a single institution. Specifically, it examined whether the utilization of selective pulmonary vasodilators and extracorporeal membrane oxygenator (ECMO) in the management of pulmonary hypertension in the second epoch were associated with improved outcomes. METHODS: The medical records of all patients diagnosed with GO at a large children’s hospital from January 1, 1996 to December 31, 2016 were reviewed and divided into two epochs. Patients were classified as having an isolated GO or GO with minor or major associated anomalies. GO was defined as a defect more than or equal to 5 cm in size and/or liver in the sac. RESULTS: During the study period, 59 infants with GO were identified. The duration of invasive mechanical ventilation was significantly shorter among the survivors from the second epoch (p = 0.03), with none greater than seven days. There were no significant differences in the outcomes of survival to NICU discharge and length of stay (LOS) between infants in the two epochs. CONCLUSIONS: Infants with GO who required invasive mechanical ventilation for more than seven days did not survive in the second epoch. Survival did not improve with uses of selective pulmonary vasodilators and ECMO. This information could be shared with families during prenatal and postnatal counselling to facilitate informed decision making regarding goals of care.

The objective of this study is to evaluate mortality, causes and risk factors of death in adults with congenital heart disease (ACHD) and PHT on Pulmonary vasodilator therapy (PVT). Methods 170 cases with PHT were identified in RACCA (Left heart disease were excluded (n=20)). We examined mortality, causes of death and complications during a mean follow-up (FU) of 7.9+4.6 years. For each patient demographic data, shunt location, clinical PHT group and functional class (FC) were collected. In an unselected sample of 103 patients, O2Sat, NT-proBNP, right ventricle function (RV) and 6-minute-test (6min) were retrospectively reviewed at 2 data collection time points: evaluation at baseline and the most recent data preceding death or at last clinical visit. Survival was assessed with Kaplan-Meier curves and differences between groups using the log-rank test. To look for predictors of death, Cox regression analysis was performed. Results Patients with PHT were predominantly women (61%), aged 45 years (IQR 33–58.5). The distribution of PHT group by underlying defects were 58 Eisenmenger (ES) (Complex 50%) and 45 non-ES (pretricuspid 46.7% (p=0,0002). PHT-pretricuspid defects occurred more in women with unrepaired simple defects and at older ages. In the sample, 85% were commenced on therapy with PVT (5% on initial dual therapy). The treated patients presented worse functional situation, more desaturation of O2 and worse TAPSE. In the group of treatment, 53% required treatment escalation during the FU. Initially, 82% were in sinus rhythm, in FC I-II 53% and in FC III-IV 39%. 10% had moderate-severe RV dysfunction. At the last visit, 38% were on monotherapy, 40% on dual therapy and 22% on triple therapy. FC improved from III-IV to I-II in 35% and 79% remained in FC-I-II without clinical deterioration. The Δ6min was +53±72 mts in those patients alive at the end of FU, and −126±26 mts in exitus cases (p=0,003), but O2 saturation did not change significantly. Over the FU, 29 patients died. The main cause of death was heart failure, followed by sudden death. The event-free survival was 84% at 5 years. Survival was significantly worst for patients presenting with arrhythmias and more advanced FC at initiation of PVT and for those who developed RV dysfunction over FU. At multivariate analysis, syndromic forms, pretricuspid shunt, non-ES physiology, PVT and monotherapy at baseline, FC III-IV and desaturation were independent predictors for death. Conclusions Although a positive clinical response was observed, mortality of PHT in CHD under advanced PVT remains high at mid-term FU. Heart failure is the leading cause of death. In terms of mortality, non ES patients and pretricuspid shunts were less responsive to treatment than patients with ES. Our results may suggest that patients with more advanced disease at the initiation of therapies do not respond properly and support the need for early treatment and initial dual therapy. Funding Acknowledgement Type of funding source: None

Background: Inhaled pulmonary vasodilators are used as adjunctive therapies for the treatment of refractory hypoxemia. Available evidence suggest they improve oxygenation in a subset of patients without changing long-term trajectory. Given the differences in respiratory failure due to COVID-19 and “traditional” ARDS, we sought to identify their physiologic impact. Methods: This is a retrospective observational study of patients mechanically ventilated for COVID-19, from the ICUs of 2 tertiary care centers, who received inhaled epoprostenol (iEpo) for the management of hypoxemia. The primary outcome is change in PaO2/FiO2. Additionally, we measured several patient level features to predict iEpo responsiveness (or lack thereof). Results: Eighty patients with laboratory confirmed SARS-CoV2 received iEpo while mechanically ventilated and had PaO2/FiO2 measured before and after. The median PaO2/FiO2 prior to receiving iEpo was 92 mmHg and interquartile range (74 – 122). The median change in PaO2/FiO2 was 9 mmHg (-9 – 37) corresponding to a 10% improvement (-8 – 41). Fifty-percent (40 / 80) met our a priori definition of a clinically significant improvement in PaO2/FiO2 (increase in 10% from the baseline value). Prone position and lower PaO2/FiO2 when iEpo was started predicted a more robust response, which held after multivariate adjustment. For proned individuals, improvement in PaO2/FiO2 was 14 mmHg (-6 to 45) vs. 3 mmHg (-11 – 20), p = 0.04 for supine individuals; for those with severe ARDS (PaO2/FiO2 < 100, n = 49) the median improvement was 16 mmHg (-2 – 46). Conclusion: Fifty percent of patients have a clinically significant improvement in PaO2/FiO2 after the initiation of iEpo. This suggests it is worth trying as a rescue therapy; although generally the benefit was modest with a wide variability. Those who were prone and had lower PaO2/FiO2 were more likely to respond.

Inhaled pulmonary vasodilators are a powerful tool in the arsenal of therapies designed to treat pulmonary hypertension in pediatrics. Yet only 1 inhaled vasodilator, inhaled nitric oxide (INO), has been approved by the Food and Drug Administration for use in neonates > 34 weeks gestational age with persistent pulmonary hypertension of the newborn. Off-label use of inhaled vasodilators is common in the neonatal and pediatric population despite a lack of evidence. Growing focus on providing evidence-based therapies combined with the increasing cost of INO has led to the exploration of other inhaled pulmonary vasoactive agents. Advancements in technology have led to the creation of nitric oxide generation devices that do not require tanks. This review evaluates the current evidence regarding the use of inhaled vasodilators and INO delivery devices in the neonatal and pediatric intensive care population.

Background The physiological functions of the paranasal sinuses are as yet unclear, and it is often assumed that these empty air-filled spaces have no vital function in our body. Recently, nitric oxide has been reported to be synthetized in high concentration by the paranasal sinuses which seems to be the main function of these air-filled empty spaces. Body of abstract The functional role of the paranasal sinuses is still ambiguous despite the several hypotheses that have been put forward to justify their existence. Although it has been recently demonstrated that the paranasal sinuses produce large amounts of nitric oxide (NO), otolaryngologists overwhelmed by attempting to unravel the enigmatic etiology underlying chronic rhinosinusitis have interpreted the high NO output in this context. Nevertheless, NO prime function is vasodilation and has long been recognized to be produced by the endothelial cells. In this review, evidence in the literature is piled and pieces of the puzzle are put together to show that NO synthesized in the paranasal sinuses functions as an airborne messenger that induces pulmonary vasodilation and thereby decreases the workload on the heart. Recognition that the paranasal sinuses are in fact an organ with known function is likely to foster further research and has an impact on our current surgical philosophy. Conclusion The paranasal sinuses seem to play a vital physiological role in our body rather than being evolutionary remnants as initially thought. They are likely responsible for regulating the pulmonary blood pressure thereby preventing pulmonary hypertension.

Right ventricular (RV) dysfunction may occur after cardiac surgery and it is not rare after corrective repair of tetralogy of Fallot (TOF). If traditional treatments with volume management, infusion of inotropic agents, and use of pulmonary vasodilators cannot stabilize the patient, extracorporeal membrane oxygenation (ECMO) or a ventricular assist device (VAD) will be considered as the last resort. Here, we report a young infant patient with RV failure after corrective repair of TOF and without closure of an atrial septal defect (ASD), who was rescued by veno-venous (VV) -ECMO.

Background: Pulmonary vasodilators as add-on to current treatment strategies in acute pulmonary embolism may improve right ventricular unloading and hence improve patient outcome. We aimed to investigate whether stimulation of the nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) pathway with riociguat, sildenafil or inhaled NO causes pulmonary vasodilation and improves right ventricular function in a porcine model of acute intermediate risk pulmonary embolism. Methods: Two large autologous blood clots were administered to the pulmonary circulation of 28 pigs (60 kg). Animals were randomized to four increasing, clinically equivalent doses of riociguat ( n=6), sildenafil ( n=6), inhaled NO ( n=6) or vehicle ( n=6). Sham animals ( n=4) did not receive pulmonary embolism or treatment. Haemodynamic responses were evaluated at baseline, after pulmonary embolism and after each dose using invasive pressure measurements, transoesophageal echocardiography, respiratory parameters and blood analysis. Results: Pulmonary embolism caused a three-fold increase in pulmonary vascular resistance compared with baseline (pulmonary embolism: 352±29 vs. baseline: 107±6 dynes, pConclusion: Stimulation of the NO–sGC–cGMP pathway by riociguat, sildenafil and inhaled NO reduces pulmonary vascular resistance in a porcine model of acute pulmonary embolism without lowering systemic blood pressure.

The aim of this retrospective study was to investigate the clinical characteristics and therapeutic outcomes of pulmonary arterial hypertension (PAH) secondary to congenital portosystemic shunts (CPSS). Thirty-three pediatric patients diagnosed in our institution with CPSS between 2012 and 2019 were enrolled in this study. The patients were divided into PAH and non-PAH groups. The PAH group included 15 patients who presented with unexplained PAH when CPSS was diagnosed. Two patients with microangiopathic hemolytic anemia died of right heart failure shortly after diagnosis. One patient received a liver transplant at the age of 4.3 years and showed a mild decrease in pulmonary artery pressure (PAP) 4 years after the operation. Seven patients underwent one-stage shunt closure at a median age of 2.8 years (1.4-13 years). Follow-up examinations, from 1.6 to 4.1 years after intervention, showed marked reduction of PAP in one patient and stabilization of PAH in six others. However, in one patient who underwent two-stage shunt closure, a marked increase in PAP was noted after partial ligation of the shunt. The remaining four patients received only pulmonary vasodilator therapy, and one of them died of right heart failure 12 years after the PAH diagnosis. The non-PAH group included 18 patients without evidence of PAH upon CPSS diagnosis. Shunt closure was carried out in eight of these patients, but one patient subsequently developed PAH after the resolution of hepatopulmonary syndrome.Conclusion: CPSS may be a more likely cause of unexplained PAH in pediatric patients than previously thought. Shunt closure or liver transplantation may prevent the progression of PAH, or even improve it for the majority of CPSS patients.

Pulmonary arterial hypertension is a multifactorial nosological entity that increases neonatal mortality as a result of heart failure. Pulmonary vasodilators are the cornerstone of treatment, of which sildenafil is the most commonly used drug. Therefore, the results of a recently updated Cochrane systematic review are summarized, in which the efficacy and safety of sildenafil for the treatment of pulmonary hypertension in neonates was evaluated.

The development of pulmonary hypertension (PH) in patients with heart failure is associated with increased morbidity and mortality. In this article, the authors examine recent changes to the definition of PH in the setting of left heart disease (PH-LHD), and discuss its epidemiology, pathophysiology and prognosis. They also explore the complexities of diagnosing PH-LHD and the current evidence for the use of medical therapies, promising clinical trials and the role of left ventricular assist device and transplantation.

Premature neonates 30-55mm Hg promotes pulmonary vasodilation. Targeting saturations of 80-85% by 5min, 85-95% by 10min during resuscitation and 90-95% during the postnatal course are appropriate targets for routine management of preterm infants. Among preterm infants with PHT, avoiding hypoxia/hyperoxia by titrating supplemental oxygen to maintain saturations in low to mid 90s with alarm limits at 90 and 97% seems to be a reasonable approach pending further studies. Further high-quality evidence generated from randomized trials is required to guide oxygen therapy in preterm PHT.

Right ventricular function critically affects the prognosis of patients with pulmonary arterial hypertension. We aimed to analyze the prognostic value of right ventricular indices calculated using magnetic resonance imaging and right heart catheterization metrics in pulmonary arterial hypertension. We retrospectively collected data from 57 Japanese patients with pulmonary arterial hypertension and 18 controls and calculated six indices of right ventricular function: two indices of contractility (end-systolic elastance calculated with right ventricular maximum pressure and with magnetic resonance imaging metrics); two indices of right ventricular-pulmonary arterial coupling (end-systolic elastance/arterial elastance calculated with the pressure method (end-systolic elastance/arterial elastance (P)) and with the volume method (end-systolic elastance/arterial elastance (V)); and two indices of right ventricular diastolic function (stiffness (beta) and end-diastolic elastance). We compared the indices between controls and patients with pulmonary arterial hypertension and examined their prognostic role. In patients with pulmonary arterial hypertension, end-systolic elastance (right ventricular maximum pressure) was higher (pulmonary arterial hypertension 0.94 (median) vs control 0.42 (mmHg/mL),p < 0.001), end-systolic elastance/arterial elastance (V) was lower (pulmonary arterial hypertension 0.72 vs control 1.69,p < 0.001), and beta and end-diastolic elastance were significantly higher than those in the controls. According to the log-rank test, end-systolic elastance/arterial elastance (P) and end-diastolic elastance were significantly associated with the composite event rate. According to the multivariate Cox regression analysis, decreased end-systolic elastance/arterial elastance (P) was associated with a higher composite event rate (hazard ratio 11.510, 95% confidence interval: 1.954-67.808). In conclusion, an increased right ventricular contractility, diastolic dysfunction, and a trend of impaired right ventricular-pulmonary arterial coupling were observed in our pulmonary arterial hypertension cohort. According to the multivariate outcome analysis, a decreased end-systolic elastance/arterial elastance (P), suggestive of impaired right ventricular-pulmonary arterial coupling, best predicted the pulmonary arterial hypertension-related event.

Systemic sclerosis is an auto-immune disease characterized by skin involvement that often affects multiple organ systems. Pulmonary hypertension is a common finding that can significantly impact prognosis. Molecular pathophysiological mechanisms underlying pulmonary hypertension in systemic sclerosis can be extremely heterogeneous, leading to distinct clinical phenotypes. In addition, different causes of pulmonary hypertension may overlap within the same patient. Since pulmonary hypertension treatment is very different for each phenotype, it is fundamental to perform an adequate diagnostic work-up to properly and promptly identify the prevalent mechanism underlying pulmonary hypertension in order to start the right therapies. When pulmonary hypertension is caused by a primary vasculopathy of the small pulmonary arteries, treatment with pulmonary vasodilators, often in an initial double-combination regimen, is indicated, aimed at reducing the mortality risk profile. In this review, we describe the different clinical phenotypes of pulmonary hypertension in the scleroderma population and discuss the utility of clinical tools to identify the presence of pulmonary vascular disease. Furthermore, we focus on systemic sclerosis-associated pulmonary arterial hypertension, highlighting the advances in the knowledge of right ventricular dysfunction in this setting and the latest updates in terms of treatment with pulmonary vasodilator drugs.

Background: Significant pulmonary hypertension [PH] is often considered a contraindication for closure of atrial septal defects [ASD]. Treatment of pulmonary arterial hypertension [PAH] with selective pulmonary vasodilators can allow for surgical repair of ASD otherwise considered prohibitive. We describe our experience in the assessment and treatment of adults with ASD and PAH with pulmonary vasodilator therapy who underwent successful surgical repair. Methods: Retrospective case series of patients with atrial level shunts and significant PAH who met clinical criteria for repair. Clinical and demographic data were collected through review of the electronic medical records. Echocardiographic data were analyzed by a single cardiologist. Results: Four patients with ASD and PAH were identified. All four patients experienced a decrease in pulmonary vascular resistance and increase in shunt fraction with institution of PH-directed therapy. Each underwent successful surgical repair with improvements in six-minute walk distance, right ventricular systolic function, and natriuretic peptide levels. All patients remained improved and stable on PH medications at last follow-up. Conclusion: With appropriate selection and application of therapy, patients with atrial level shunts and severe PAH can successfully undergo surgical closure following medical treatment of their pulmonary arterial hypertension.

Acute respiratory distress syndrome (ARDS) is associated with high rates of mortality. Inhaled nitric oxide and inhaled epoprostenol (iEPO) are inhaled pulmonary vasodilators used for adjunctive management in patients with severe ARDS. This article describes the safe and effective use of iE

Numerous conditions give rise to pulmonary arterial hypertension (PAH), with most of them being idiopathic. Signs and symptoms are generally difficult to recognize initially because they present as nonspecific and typically are mistaken for age-related physiological processes or alternate medical conditions. Many advances have been made toward PAH-specific therapies that have led to advanced clinical management of the disease. The present investigation describes new pulmonary vasodilator agents that are currently available or under development that could impact perioperative management. The 6-min walk test is the gold standard in assessing the efficacy of any pulmonary hypertension treatment, and the only drug to show any mortality benefit in pulmonary hypertension is epoprostenol. The present investigation also describes the latest evidence on using these medications in the perioperative period, including clinical trials and practice guidelines. Future direction for research and clinical management of pulmonary hypertension is described.

Restrictive cardiomyopathy (RCM) is a rare form of cardiomyopathy that is characterized by restrictive ventricular filling. Elevated filling pressure leads to pulmonary hypertension (PH), which often progresses to combined post- and pre-capillary PH (Cpc-PH) with increased diastolic pulmonary vascular pressure gradient (DPG) and pulmonary vascular resistance (PVR) caused by longstanding backward hemodynamic consequences of left heart disease (LHD) leading to morphological changes in the pulmonary vasculature. Patients with high PVR undergoing left ventricular assist device (LVAD) implantation are at increased risk of postoperative right-sided heart failure requiring concomitant implantation of a right ventricular assist device (RVAD). We report a case of RCM with severe Cpc-PH due to extremely elevated DPG and PVR. The patient presented recurrent syncope caused by severe PH. Right heart catheterization (RHC) revealed highly elevated DPG 30 mmHg and PVR 25.3 Wood units (WU) and subsequent significant reduction of right ventricular afterload during vasoreactivity testing with inhaled nitric oxide (NO) to DPG 5 mmHg and PVR 10.5 WU. During the administration of pulmonary vasodilators, pulmonary congestion worsened. Second RHC revealed elevated pulmonary arterial wedge pressure (PAWP) and modest decrease of pulmonary arterial pressure (PAP) 87 mmHg and PVR 9.6 WU. Therefore, an inotropic agent and systemic vasodilator were added for the treatment of left-sided heart failure. Targeting elevated filling pressures with both PAH-specific and heart failure treatment, a further decrease of right ventricular afterload with DPG of 5 mmHg and PVR of 3.8 WU was achieved. In a next step, LVAD was successfully implanted, without need for RVAD, as a bridge to transplantation. This is the first reported case of Cpc-PH that revealed the potential reversibility of extremely elevated DPG and PVR, and suggests the importance of preoperative RHC-guided optimized medical PAH-specific and heart failure treatment before LVAD implantation.

Aim and Background Congenital heart diseases constitute a major category of disorders associated with pulmonary hypertension in atrial septal defect there is tendency to repair essentially all large defect except some of those with severe obstructive pulmonary vascular diseases. in this study the isoproterenol is used for assessment of patients with atrial septal defect, with elevated pulmonary / systemic vascular resistance ratio. Methods and Results 100 cases with atrial septal defect, with pulmonary hypertension received isoproterenol infusion. Haemodynamic findings found among all patients with atrial septal defect before and after isoproterenol infusion. There is a significant in pulmonary blood flow after isoproterenol infusion (from 5.34455 + 0.730 to 6.3300 + 0.870 liter/minute P < 0.001). Conclusion Isoproterenol is a successful and reliable pulmonary vasodilator that can be used to predict the reversible element of pulmonary hypertension in patient with left to right shunts (ASD) patients.

Purpose Patients with heterotaxy syndrome have a high rate of congenital heart disease, often requiring surgical interventions, including palliative procedures to augment or restrict pulmonary blood flow. Pulmonary hypertension in this setting complicates surgical interventions and overall management. Pulmonary vasodilators may be used to treat pulmonary hypertension and facilitate surgical interventions. We describe the use of pulmonary vasodilators in patients with heterotaxy syndrome. Methods Single-center retrospective chart review of patients with heterotaxy syndrome who underwent at least one cardiac operation from Jan 1 2008 to Oct 31 2019. The diagnosis of heterotaxy syndrome was established from imaging studies performed prior to intervention. Surgical interventions were reviewed from operative reports. Pulmonary vasodilator use was assessed from progress notes and medication reconciliation at all inpatient and outpatient encounters. Results Thirty-four patients with heterotaxy syndrome were treated at our center during the study period, with follow up ranging from 18 to 3385 days. Palliative surgical interventions included restriction of pulmonary blood flow in 8 patients and augmentation of pulmonary blood flow in 11 patients. Pulmonary vasodilators were used in 16 patients (47%): 7 (20%) received inhaled nitric oxide while admitted, 3 (9%) received supplemental oxygen as outpatients, 12 (35%) received sildenafil as outpatients, 5 (14%) received multiple agents. Treatment was initiated in the inpatient setting in all patients. All patients on supplemental oxygen and the majority of patients on sildenafil continued on treatment at most recent follow up (10 patients, 83% of patients ever prescribed). There was no difference in pulmonary vasodilator use when stratified by surgical palliation strategy, and no differences in survival between patients with and without pulmonary vasodilator use. Conclusion Pulmonary vasodilator use is common in patients with heterotaxy syndrome undergoing surgical interventions for congenital heart disease. It is typically initiated in the inpatient setting but well-tolerated on a long-term basis, and may facilitate treatment in this challenging population.

Bronchopulmonary dysplasia (BPD) is the leading cause of long-term respiratory morbidity in newborns who require respiratory support at birth. BPD is a multifactorial disorder, and infants are frequently subjected to treatment with multiple pharmacologic agents of dubious efficacy and questionable safety, including diuretics, bronchodilators, corticosteroids, anti-reflux medications, and pulmonary vasodilators. These agents, with narrow therapeutic indices, are widely used despite the lack of an evidence base, and some may do more harm than good. It is incumbent on the clinician to establish a risk:benefit ratio and to avoid drugs that have little efficacy and a high rate of toxicity.

Inhaled nitric oxide (INO) is only FDA-cleared for neonates (> 34 weeks gestation) with hypoxic respiratory failure-associated pulmonary hypertension. Off-label use of INO is common in the pediatric population despite a lack of evidence regarding survival benefit, questioning whether the therapy should be considered outside the neonatal period. A lack of definitive evidence combined with increasing health-care costs has led to the use of less costly inhaled prostacyclin as an alternative to INO, presenting unique patient safety concerns. We evaluate the current evidence and patient safety considerations regarding inhaled pulmonary vasodilators in the pediatric population.

Therapeutic advance by pulmonary vasodilators has provided huge impacts on prognosis in patients with pulmonary arterial hypertension (PAH), but outcomes of systemic sclerosis (SSc)-associated PAH still remain unsatisfactory. One of the major reasons is a series of potential unfavorable effects triggered by pulmonary vasodilators, which result from the complex pathophysiology of SSc-PAH. We herein present and discuss five representative conditions potentially induced by pulmonary vasodilators, including (i) emergence of latent pulmonary veno-occlusive disease, (ii) emergence of latent left-heart disease, (iii) worsening of pulmonary gas change in the presence of interstitial lung disease, (iv) ischemic limb gangrene by stealing of blood flow, and (v) uncontrolled hemorrhage from gastrointestinal telangiectasia. The former three conditions are common causes for worsening of dyspnea or oxygenation during treatment with pulmonary vasodilators, whereas the latter two are rare, but have significant negative impacts on patients’ quality of life and survival. These unfavorable conditions are pitfalls in clinical practice, and interfere with optimizing therapies in patients with SSc-PAH. Therefore, pre-assessment of pathophysiology of pulmonary hypertension and cautious monitoring during the treatment are necessary to achieve better outcomes in patients with SSc-PAH.

Pregnancy with pulmonary arterial hypertension (PAH) has a significantly high risk of maternal death and women with PAH are basically advised to avoid pregnancy. Recently, several reports have described pregnant women with PAH who were treated with pulmonary vasodilators during pregnancy and delivered safely. However, the efficacy of this treatment during pregnancy is still not clear. Here we report on the short-term outcomes of three primiparous women with PAH who were prescribed pulmonary vasodilator therapy during their pregnancies. All women delivered preterm due to cardiac and/or obstetric reasons and were discharged without any complication. Pulmonary vasodilator therapy can be used safely during the pregnancies of PAH patients and may contribute to improved maternal and fetal prognoses.

Suprarenal aortic cross clamping (SRACC) and reperfusion may cause acute pulmonary hypertension and multiple organ failure.The organic mononitrites of 1,2-propanediol (PDNO), an nitric oxide donor with a very short half-life, are a more efficient pulmonary vasodilator and attenuator of end-organ damage and inflammation without significant side effects compared with nitroglycerin and inorganic nitrite in a porcine SRACC model.Anesthetized and instrumented domestic pigs were randomized to either of four IV infusions until the end of the experiment (n = 10 per group): saline (control), PDNO (45 nmol kg min), nitroglycerin (44 nmol kg min), or inorganic nitrite (a dose corresponding to PDNO). Thereafter, all animals were subjected to 90 min of SRACC and 10 h of reperfusion and protocolized resuscitation. Hemodynamic and respiratory variables as well as blood samples were collected and analysed.During reperfusion, mean pulmonary arterial pressure and pulmonary vascular resistance were significantly lower, and stroke volume was significantly higher in the PDNO group compared with the control, nitroglycerin, and inorganic nitrite groups. In parallel, mean arterial pressure, arterial oxygenation, and fraction of methaemoglobin were similar in all groups. The serum concentration of creatinine and tumor necrosis factor alpha were lower in the PDNO group compared with the control group during reperfusion.PDNO was an effective pulmonary vasodilator and appeared superior to nitroglycerin and inorganic nitrite, without causing significant systemic hypotension, impaired arterial oxygenation, or methaemoglobin formation in an animal model of SRACC and reperfusion. Also, PDNO may have kidney-protective effects and anti-inflammatory properties.