Refractory Pulmonary Arterial Hypertension Research Articles

Monitoring of the right ventricular responses to pressure overload: prognostic value and usefulness of echocardiography for clinical decision-making.

Regardless of whether pulmonary hypertension (PH) results from increased pulmonary venous pressure in left-sided heart diseases or from vascular remodeling and/or obstructions in pre-capillary pulmonary vessels, overload-induced right ventricular (RV) dysfunction and its final transition into right-sided heart failure is a major cause of death in PH patients. Being particularly suited for non-invasive monitoring of the right-sided heart, echocardiography has become a useful tool for optimizing the therapeutic decision-making and evaluation of therapy results in PH. The review provides an updated overview on the pathophysiological insights of heart-lung interactions in PH of different etiology, as well as on the diagnostic and prognostic value of echocardiography for monitoring RV responses to pressure overload. The article focuses particularly on the usefulness of echocardiography for predicting life-threatening aggravation of RV dysfunction in transplant candidates with precapillary PH, as well as for preoperative prediction of post-operative RV failure in patients with primary end-stage left ventricular (LV) failure necessitating heart transplantation or a LV assist device implantation. In transplant candidates with refractory pulmonary arterial hypertension, a timely prediction of impending RV decompensation can contribute to reduce both the mortality risk on the transplant list and the early post-transplant complications caused by severe RV dysfunction, and also to avoid combined heart-lung transplantation. The review also focuses on the usefulness of echocardiography for monitoring the right-sided heart in patients with acute respiratory distress syndrome, particularly in those with refractory respiratory failure requiring extracorporeal membrane oxygenation support. Given the pathophysiologic particularity of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection to be associated with a high incidence of thrombotic microangiopathy-induced increase in the pulmonary resistance, echocardiography can improve the selection of temporary mechanical cardio-respiratory support strategies and can therefore contribute to the reduction of mortality rates. On the whole, the review aims to provide a theoretical and practical basis for those who are or intend in the future to be engaged in this highly demanding field.

Pulmonary Arterial Hypertension Induced by Immune Checkpoint Inhibitor Combined Therapy in a Patient with Intrahepatic Cholangiocarcinoma: A Case Report.

Immune Checkpoint Inhibitors (ICIs) have dramatically revolutionized the therapeutic approaches by which we treat a series of cancers accompanied by immune-related adverse events (irAEs). Herein, we reported an intrahepatic cholangiocarcinoma male patient with a history of ankylosing spondylitis developing pulmonary arterial hypertension (PAH) under ICI combined therapy with pembrolizumab and lenvatinib. The indirect measurement of cardiac ultrasound showed a pulmonary artery pressure (PAP) of 72mmHg after 21 three-week cycles of ICI combined therapy. The patient partially responded to the treatment of glucocorticoid and mycophenolate mofetil. The PAP decreased to 55mmHg 3 months after the ICI combined therapy was discontinued, but increased to 90mmHg after the ICI combined therapy was rechallenged. We treated him with adalimumab -an antitumor necrosis factor-alpha (ani-TNF-α) antibody- combined with glucocorticoid and immunosuppressants under lenvatinib monotherapy. The patient responded again with PAP decreasing to 67mmHg after 2 two-week cycles of adalimumab. Accordingly, we diagnosed him to have irAE-related PAH. Our findings supported the use of glucocorticoid disease-modifying antirheumatic drugs (DMARDs) as a treatment option in refractory PAH.

Infections Acquired During Venoarterial Extracorporeal Membrane Oxygenation Postcardiac Surgery in Children: A Retrospective Observational Study

Abstract Introduction Extracorporeal membrane oxygenation (ECMO) is increasingly being used in refractory cardiac and pulmonary dysfunction as a rescue modality. The common indications for establishing venoarterial ECMO (VA-ECMO) support in children postcardiac surgery are failure to wean from cardiopulmonary bypass (CPB), postcardiotomy cardiogenic shock (PCCS), refractory pulmonary arterial hypertension, and as a bridge to recovery or transplant. The survival rate of children on VA-ECMO support is 45%. The most frequently encountered complications during VA-ECMO are bleeding, thrombosis, acute kidney injury, and infections. Among those, infections acquired during VA-ECMO lead to high morbidity and mortality. Hence, this study aimed to determine infection rates, causal microorganisms, and mortality risk factors in children developing an infection during VA-ECMO therapy. Methods This retrospective observational study was conducted on 106 children under 14 years of age who underwent elective or emergent cardiac surgery (between 2016 and 2020) and required VA-ECMO support. Medical records were reviewed to collect the targeted variables and analyzed. Results Out of 106 children, 49 (46.23%) acquired infections representing a prevalence of 46.23% and an infection rate of 186.4 episodes per 1,000 ECMO days. Prevalence and acquired infection rate/1,000 ECMO days were higher in the nonsurvivor group than in the survivor group (26.42 vs.19.81%) and (215.07 vs. 157.49), respectively. The bloodstream infection (BSI) and catheter-associated urinary tract infection (CAUTI) episodes were 53.04 and 68.19 per 1,000 ECMO days, and the ventilator-associated pneumonia (VAP) rate was 44.50 per 1,000 ventilator days. The mean preoperative admission duration, aortic cross-clamping duration, CPB duration (minutes), and vasoactive-inotropic score were higher in the nonsurviving children (p < 0.001). Similarly, prolonged mean ECMO duration was also found in the nonsurvivor group compared with the survivor group (p = 0.03). Conclusion In our study, the prevalence of acquired infection during VA-ECMO was 46.23%. The incidence of BSI, CAUTI, and VAP per 1,000 ECMO days was higher in the nonsurvivor group than in survivors. Acinetobacter baumannii was the most common cultured gram-negative organism in VAP and BSI, with 67.65% Acinetobacter spp. resistant to carbapenems. CAUTI was predominately due to Candida species during VA-ECMO.

Lung Transplantation for Pulmonary Hypertension and Strategies to Bridge to Transplant.

AbstractDespite an expanded armamentarium of medical therapies, pulmonary arterial hypertension (PAH) remains a progressive disease associated with significant morbidity and premature mortality. Lung transplantation (LT) is the last safety net for patients failing medical therapy, providing excellent overall long-term survival and health-related quality-of-life outcomes in line with more common parenchymal lung disease indications. Waitlist mortality remains disproportionally elevated, however, reflecting an inability of the lung allocation score to completely capture PAH disease severity, and a propensity for PAH to deteriorate rapidly without warning, even in patients who appear externally “well.” Early referral to a LT center can mitigate these risks and facilitate rapid listing if necessary. Several bridging therapies are available to support severely unwell patients to LT, such as extracorporeal life support (ECLS) and atrial septostomy. Unique perioperative considerations include higher rates of primary graft dysfunction and dynamic right ventricular outflow obstruction which may, at least in part, reflect rapid afterload reduction in the face of a conditioned right ventricle. Extending ECLS into the perioperative period may ameliorate these risks by allowing more gradual adaptation of both ventricles to their new loading conditions. Chronic lung allograft dysfunction, particularly bronchiolitis obliterans syndrome, remains a major cause of long-term morbidity and mortality, and complications from corticosteroid and immunosuppressive therapy are common. Nevertheless, the morbidity, mortality, and burden of disease management after LT continue to improve and compare favorably to that of refractory PAH in carefully selected patients.

Sorafenib as a potential strategy for refractory pulmonary arterial hypertension

Sorafenib is an inhibitor of multi-kinases including tyrosine and serine/threonine kinases. We investigated the efficacy and safety of sorafenib for the treatment of patients with refractory pulmonary arterial hypertension (PAH). Sorafenib was started in 9 patients (7 with idiopathic PAH, 2 with pulmonary veno-occlusive disease) who had severe PAH and right heart failure, in spite of treatment with vasodilators specific for PAH. Sorafenib was started as an add-on therapy at a dose of 50 or 100 mg/day, and increased to 100–400 mg/day. New York Heart Association functional class improved in 8 patients and did not change in 1. Mean pulmonary arterial pressure improved in 6 patients (14–28% decrease) and did not apparently change in 2 (follow-up catheterization was not performed in 1 patient). The main adverse effects of sorafenib were skin reactions on the hands and feet, which appeared in 5 patients. They were tolerable in 4 patients, but discontinuation of sorafenib was needed in only 1 patient. In conclusion, sorafenib had favorable effects to improve symptoms and objective variables in patients with refractory PAH, with tolerable adverse events. Sorafenib is an alternative strategy for patients with refractory PAH.

Dual phosphodiesterase type 5 inhibitor therapy for refractory pulmonary arterial hypertension: a pilot study.

BackgroundRecent vasodilating drugs have improved prognosis of Pulmonary arterial hypertension (PAH). Some reports describe the merits of combination therapies for PAH, and this study evaluated the efficacy and safety of phosphodiesterase type 5 inhibitors (PDE5i) combination therapy, using sildenafil and tadalafil, for multi-drug-resistant PAH.MethodsWe retrospectively analyzed 7 consecutive refractory patients with PAH administered either sildenafil 60 mg or tadalafil 40 mg as well as both ERA and prostanoid as combination therapies. All were started on the dual PDE5i (sildenafil and tadalafil at maximum dose).ResultsTreatment was generally well tolerated without severe adverse events. On completion of the study, the seven patients received right heart catheterization and the 6-minute walk test (6WMT) 9.6 ± 1.4 months after initiation of the dual PDE5i therapy, showing significant improvements in hemodynamic parameters and exercise tolerance. Mean pulmonary arterial pressure and pulmonary vascular resistance decreased from 47.9 ± 9.7 to 41.7 ± 9.2 mmHg (P = 0.004) and 9.3 ± 2.7 to 6.7 ± 2.9 mmHg (P = 0.018), respectively. Cardiac index and 6MWT also increased from 2.8 ± 0.9 to 3.1 ± 0.8 L/min/m2 (P = 0.026) and 353 ± 60 to 382 ± 62 m (P = 0.014), respectively.ConclusionThe findings support dual PDE5i therapy as a new treatment option for refractory PAH.

Atrial septostomy in a patient with severe pulmonary hypertension and hypoxia: A therapeutic dilemma

Atrial septostomy may be considered in individuals with severe pulmonary arterial hypertension and right heart failure, despite maximal medical therapy, as a palliative procedure or bridge to transplant. Low oxygen saturation is a relative contraindication to atrial septostomy. However, the majority of the patients with severe refractory pulmonary arterial hypertension for whom atrial septostomy may be indicated have a certain degree of hypoxia. We describe a case of an adult patient with severe pulmonary hypertension and hypoxia, who presented with syncope from reduced left ventricular filling. She subsequently underwent successful atrial septostomy. We extensively discuss the role of atrial septostomy and the management conundrum in such patients.

Potts Shunt in a Child With End-Stage Pulmonary Hypertension After Late Repair of Ventricular Septal Defect

We report on a 10-year-old boy with medically refractory pulmonary arterial hypertension (PAH) and end-stage right heart failure after closure of a ventricular septal defect. The boy was a candidate for lung transplantation (LTX), but an alternative option was to create an Eisenmenger physiology with right-to-left shunting. The shunt could be created either as an intracardiac or as an extracardiac shunt. We decided to create a Potts shunt, a direct anastomosis between the left pulmonary artery and the descending aorta. The Potts shunt functioned as a right-to-left shunt, thus reducing the afterload on the right ventricle. The boy's clinical condition improved markedly, so he was discharged two weeks after the procedure. The ultimate therapeutic option for medically refractory PAH is LTX or heart-lung transplantation, but because of the short life span after LTX, time was bought by postponing the time of transplantation.

Circulating Endothelial Cells in Refractory Pulmonary Hypertension in Children: Markers of Treatment Efficacy and Clinical Worsening

BackgroundPulmonary vasodilators in general and prostacyclin analogues in particular have improved the outcome of patients with pulmonary arterial hypertension (PAH). Endothelial dysfunction is a key feature of PAH and we previously described that circulating endothelial cell (CEC) level could be used as a biomarker of endothelial dysfunction in PAH. We now hypothesized that an efficient PAH-specific vasodilator therapy might decrease CEC level.Methods/ResultsCECs were prospectively quantified by immunomagnetic separation with mAb CD146-coated beads in peripheral blood from children with idiopathic PAH (iPAH, n = 30) or PAH secondary to congenital heart disease (PAH-CHD, n = 30): before, after treatment and during follow up. Controls were 23 children with reversible PAH. Oral treatment with endothelin receptor antagonists (ERA) and/or phosphodiesterase 5 inhibitors (PDE5) significantly reduced CEC counts in children. In 10 children with refractory PAH despite oral combination therapy, subcutaneous (SC) treprostinil was added and we observed a significant decrease in CEC counts during the first month of such treatment. CECs were quantified during a 6 to 36 month-follow-up after initiation of SC treprostinil and we found that CEC counts changed over time, with rising counts always preceding clinical deterioration.ConclusionCECs might be useful as a biomarker during follow-up of pediatric iPAH and PAH-CHD to assess response to treatment and to anticipate clinical worsening.

Combination therapy in the management of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease without a cure, which can lead to right heart failure and death. Over the past decades, several therapeutic advances have been developed for the management of PAH. Although these agents have demonstrated clinical safety and efficacy, some patients may require additional drug therapy due to a lack of response or disease progression. The purpose of this review was to evaluate the safety and efficacy of various combination PAH therapies. A systematic search was conducted using the MEDLINE database (1966 and June 2012) for relevant clinical studies. Searches were limited to English, human and clinical trial using the terms sildenafil, tadalafil, vardenafil, phosphodiesterase inhibitor, prostacyclin, prostaglandin, epoprostenol, treprostinil, iloprost, beraprost, endothelin receptor antagonist, bosentan, ambrisentan, sitaxsentan and pulmonary hypertension. Overall, 22 studies met inclusion criteria. Overall, the majority of trials demonstrated clinical efficacy in improving functional class, reducing pulmonary pressure, or increasing exercise capacity. Most trials were uncontrolled with small sample sizes investigating the acute effects of combination therapy and lacking long-term clinical outcomes. Adjunctive therapy was well tolerated by most patients. Overall, combination therapy is relatively safe and well tolerated. Published guidelines provide evidence-based recommendations for monotherapy. However, suggestions for combination therapy in refractory PAH patients are lacking. Several studies evaluating several combination therapies have been published. The preferred combination treatment among several PAH drug therapies remain controversial. Therefore, clinicians should consider ease of administration, cost, and tolerability when choosing specific combination therapies. Combination therapy appears promising for patients who are refractory to treatment or whose disease progression is not well controlled with monotherapy. An optimal combination drug therapy regimen remains debatable and should be customized for individual PAH patients. Further studies are needed to determine the optimal combination therapy in PAH based upon efficacy, safety and cost.

Transcatheter Potts shunt creation in patients with severe pulmonary arterial hypertension: Initial clinical experience

Patients with severe pulmonary arterial hypertension (PAH) face significant morbidity and death as a consequence of progressive right heart failure. Surgical shunt placement between the left PA and descending aorta (Potts shunt) appears promising for PAH palliation in children; however, surgical mortality is likely to be unacceptably high in adults with PAH. We describe a technique for transcatheter Potts shunt (TPS) creation by fluoroscopically guided retrograde needle perforation of the descending aorta at the site of apposition to the left PA to create a tract for deployment of a covered stent between these vessels. This covered stent-anchored by the vessel walls and surrounding tissue-serves as the shunt. TPS creation was considered in 7 patients and performed in 4. The procedure was technically successful in 3 patients; 1 patient died during the procedure as a result of uncontrolled hemothorax. One acute survivor, critically ill at the time of TPS creation, later died of comorbidities. The 2 mid-term survivors (follow-up of 10 and 4 months) are well at home, with symptomatic improvement and no late complications. The 3 candidate patients in whom the procedure was not performed died within 1 month of consideration, underscoring the tenuous nature of this population. TPS creation is feasible and may offer symptomatic relief to select patients with refractory PAH. Further study of this innovative approach is warranted.

Percutaneous Atrial Septostomy with Modified Butterfly Stent and Intracardiac Echocardiographic Guidance in a Patient with Syncope and Refractory Pulmonary Arterial Hypertension

Syncope is associated with poor prognosis in patients with pulmonary hypertension. Atrial septostomy improves cardiac index and functional class in appropriately selected patients with pulmonary hypertension, and has been shown to improve syncope. One of the major challenges to its effectiveness is maintaining septostomy patency. We report the case of percutaneous deployment of a modified peripheral stent to create an atrial septostomy in a man with severe pulmonary hypertension and syncope, initially intolerant of medical therapy. Percutaneous butterfly stent deployment across the interatrial septum using intracardiac echocardiography and fluoroscopy. The patient improved in all clinical parameters (BNP, six-minute walk test, dyspnoea score), and was subsequently able to tolerate targeted pulmonary hypertension therapies. Atrial septostomy using butterfly stents to maintain patency may play a role in the treatment of patients with advanced pulmonary hypertension who do not respond to targeted therapy.

280: Circulating endothelial cell levels decrease after vasodilator therapy and are a biomarker of deterioration in pediatric pulmonary hypertension

Pulmonary vasodilators in general and prostacyclin therapy in particular have markedly improved the outcome of patients with pulmonary arterial hypertension (PAH). Endothelial dysfunction is a key feature of PAH and we previously described that circulating endothelial cells (CECs) could be used as a biomarker of endothelial dysfunction in PAH. We now hypothesized that PAH-specific vasodilator therapy might decrease CEC numbers. We quantified CECs in peripheral blood from children with idiopathic PAH (iPAH, n =30) or PAH secondary to congenital heart disease (PAH-CHD, n =30), before and after treatment and during follow up. CEC were enumerated by immunomagnetic separation with mAb CD146-coated beads. CEC counts were significantly decreased in children after treatment with oral endothelin antagonists and/or PDE5 inhibitors. In 10 children with refractory PAH despite combination oral therapies, SC treprostinil was added and we found a further significant decrease in CEC count during the first month of treatment in every patient. We quantified CEC during 6 to 36 months follow-up after initiation of SC treprostinil and found that CEC count is modified according to clinical status. CEC counts fall with vasodilatator therapy in PAH and could also be used as biomarker of deterioration in refractory pediatric pulmonary hypertension treated with SC treprostinil.

Add-On Therapy with Subcutaneous Treprostinil for Refractory Pediatric Pulmonary Hypertension

To evaluate the efficacy and tolerability of subcutaneous (SC) treprostinil, a prostacyclin analogue, in young children with refractory pulmonary arterial hypertension. Eight children (median age, 4 years) received SC treprostinil therapy after failure of combined oral treatment (n = 7) or because of severe complications with intravenous epoprostenol (n = 1). Treprostinil was delivered through an SC catheter at gradually increasing doses to an average of 40 ng/kg/min, depending on the presence of adverse effects. Seven patients demonstrated early significant improvement (in functional class, hemodynamics, and/or 6-minute walk distance; P <.05), and 6 had a sustained good response. Site pain could be effectively managed in all but one child. Treprostinil may be a potentially valuable rescue therapy in children with refractory pulmonary arterial hypertension, but further study in a larger number of patients is needed.

Interleukin-6 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension

Interleukin-6 (IL-6) is a pleiotropic cytokine with a wide range of biologic activities in immune regulation, hematopoiesis, inflammation, and oncogenesis. Recent accumulating evidence indicates a pathologic role for IL-6 in promoting proliferation of both smooth muscle and endothelial cells in the pulmonary arterioles, resulting in development of pulmonary arterial hypertension (PAH). Here, we describe a patient with mixed connective tissue disease and severe, refractory PAH. Her functional activity and hemodynamic parameters dramatically responded to tocilizumab, a humanized monoclonal antibody to human IL-6 receptor, which was aimed at treating multicentric Castleman's disease. It appears that IL-6 blockade may hold promise as an adjunct drug in treatment of PAH in idiopathic form as well as in association with connective tissue disease.

Treatment of Refractory Pulmonary Arterial Hypertension with Inhaled Epoprostenol in an Infant with Congenital Heart Disease

Epoprostenol is a potent arterial vasodilator, and its administration by inhalation localizes its effects to the pulmonary circulation. In this case report, we describe a 3-month-old male patient with significant refractory pulmonary hypertension after pulmonary artery banding and placement of a Blalock-Taussig shunt. This patient continued to have significant hypoxic episodes despite maximal therapy with sedation, alkalinization, sildenafil, and inhaled nitric oxide. After the addition of inhaled epoprostenol, improvements in both clinical response and echocardiography-based hemodynamics were observed. The case supports a synergistic role among the agents in the treatment of pulmonary arterial hypertension from congenital heart disease.

Use of Amplatzer Fenestrated Atrial Septal Defect Device in a Child with Familial Pulmonary Hypertension

In a 4.5-year-old child with refractory pulmonary arterial hypertension, we performed atrial septostomy with the application of an Amplatzer fenestrated device designed to maintain patency. Continuous intravenous epoprostenol infusion was started concomitantly. Forty-two months after the procedure, the patient had no recurrent syncope and remained in New York Heart Association functional class II. Fenestration of the atrial septum is feasible in children with pulmonary artery hypertension. No conclusion regarding the patient's need for an atrial septal defect can be drawn since concomitant prostanoid therapy was administered. The long-term patency of the atrial communication needs further confirmation and the optimal timing for its application has to be determined.