Reverse Potts for the Treatment of Severe Idiopathic Pulmonary Hypertension in Children.

Idiopathic pulmonary arterial hypertension is a rare and progressive disease with poor prognosis. Many patients progressively worsen even when using combinations of specific drugs for its treatment. Herein, we present our experience in the management of three children with severe pulmonary arterial hypertension refractory to clinical treatment who underwent Potts surgery in addition to clinical treatment.

Early implementation of renal replacement therapy after lung transplantation does not impair long-term kidney function in patients with idiopathic pulmonary arterial hypertension.

OBJECTIVES: In patients with idiopathic pulmonary arterial hypertension, cardiac function can be impaired in the early postoperative phase after lung transplantation because the chronically untrained left ventricle is prone to fail. Thus, restrictive fluid management is pivotal to unload the left heart. In our institution, continuous renal replacement therapy is implemented liberally whenever a patient cannot be balanced negatively. It remains unclear whether such strategy impairs long-term kidney function. METHODS: We retrospectively reviewed our institutional database for patients with idiopathic pulmonary arterial hypertension who underwent transplantation between 2000 and 2018. The impact of postoperative continuous renal replacement therapy on long-term outcomes was investigated using a linear mixed model and multivariable Cox regression. RESULTS: A total of 87 idiopathic pulmonary arterial hypertension lung transplant recipients were included in this analysis. In 38 patients (43%), continuous renal replacement therapy was started in the early postoperative period for a median of 16 days (10-22). In this group, urine production significantly decreased and patients began to acquire a positive fluid balance; however, homeostatic functions of the kidney were still preserved at the time of continuous renal replacement therapy initiation. All patients were successfully weaned from continuous renal replacement therapy and fully recovered their kidney function at the time of hospital discharge. No difference in kidney function was found between continuous renal replacement therapy and noncontinuous renal replacement therapy in patients within 5 years. CONCLUSIONS: Early implementation of continuous renal replacement therapy for perioperative volume management does not impair long-term kidney function in idiopathic pulmonary arterial hypertension lung transplant recipients. Our data suggest that such a strategy leads to excellent long-term outcomes.

BLTx Combined With Cardiac Correction in Treatment of PAH in Puerpera: Is It a Feasible Strategy?

Though pregnancy is not recommended under current guidelines in pulmonary arterial hypertension, some women insist on parturition. The related surgical treatments are controversial, especially to those complicated with Eisenmenger syndrome. In this report, 2 cases of severe pulmonary arterial hypertension complicated with Eisenmenger syndrome were reviewed. Owing to a lifesaving tenet, bilateral lung transplantation combined with surgical atrioventricular defect correction were performed after careful assessments. Both patients were followed up at 1 year and displayed no obvious complication. It showed that the strategy of bilateral lung transplantation combined with a cardiac correction may be feasible and worthy of further investigation.

Lung transplantation as an intervention for pediatric pulmonary hypertension.

Lung transplantation is a treatment option for selected children with end-stage lung disease and pulmonary vascular disorders. Overall, pulmonary hypertension (PH) is the second most frequent indication for infants and children requiring lung transplants. In pediatric PH patients, timing for listing remains a difficult decision due to patient heterogeneity and varying allocation policies across different countries. Furthermore, perioperative management can be challenging, making interdisciplinary collaboration among surgical, anesthesiology, critical care, and lung transplant teams essential. Because pediatric PH patients typically have preserved cardiac index and exercise tolerance even with advanced disease, they should be referred early even if they do not meet the criteria for listing of primarily adults by International Society for Heart and Lung Transplantation (ISHLT) published in 2015: New York Heart Association (NYHA) functional class III or IV without improvement, cardiac index < 2 L/min/m2 , mean right atrial pressure of >15 mmHg. Bridging strategies with extracorporeal support should be determined at the time of listing in anticipation of possible clinical deterioration. Bilateral lung transplantation using cardiopulmonary bypass to provide hemodynamic stability is nowadays the standard surgical approach in pediatric centers. The immediate post-transplant period is characterized by dramatic changes in the right ventricle (RV) and and left ventricle (LV) anatomy and physiology, which can be life-threatening. Induction, immunosuppression, prophylaxis, and surveillance are not different from patients without PH. Overall, outcomes in pediatric lung and heart-lung transplant patients for PH are not different from those children undergoing transplantation for other indications. In fact, long-term survival is superior in children with idiopathic PH compared to other diseases, providing most recipients with improved quality of life.

Heart-lung transplantation for idiopathic pulmonary arterial hypertension and giant pulmonary artery aneurysm - case report.

BACKGOUND: Idiopathic pulmonary arterial hypertension (IPAH) is a rare condition that requires lung transplantation in patients' refractory to medical therapy. Pulmonary artery aneurysm (PAA) is a documented complication of IPAH however, optimal management and timing of intervention for this rare entity is not well understood. CASE REPORT: We report a case of a 51-year-old female who underwent heart-lung transplantation for IPAH and giant PAA. The extreme size of the PAA and underlying pathology encountered in this case precluded both lung transplantation and conventional aneurysm repair. CONCLUSION: This case demonstrates that heart-lung transplantation is a good surgical option for IPAH complicated by giant sized PAA and right heart failure.

Pediatric lung transplantation in the largest lung transplantation center of China: embarking on a long road.

Lung transplantation (LT) has been an effective treatment for carefully selected children with end-stage lung diseases. The aim of this retrospective study is to introduce our experience at the largest LT center in Wuxi, China and to compare the outcomes of pediatric LT between children with idiopathic pulmonary arterial hypertension (IPAH) and other end-stage lung diseases. Ten pediatric patients undergoing LT from 2007 to 2019 were included. Sequential bilateral lung transplantation (BLT) with bilateral anterior thoracotomies was performed in all patients, seven of whom also underwent reduced size LT. Eight children survived until the end of our follow-up period on July 31st, 2019, with the longest survival of 11 years. Extracorporeal membrane oxygenation (ECMO) was intraoperatively used in all IPAH children and one non-IPAH child. Left heart function of IPAH children, though initially compromised, recovered after surgery. Statistically significant differences in operation time and post-operative mechanical ventilation between IPAH group and non-IPAH group were observed without discernible impact on post-LT survival. Pediatric LT appears to be a safe treatment for IPAH children to improve longevity and quality of life and ECMO may help reduce the risk of surgery and the postoperative complications.

Single Lung Transplant vs Double Lung Transplant: A Single-Center Experience With Particular Consideration for Idiopathic Pulmonary Arterial Hypertension.

BACKGROUND: Lung transplant remains the only viable treatment for certain patients with end-stage lung diseases. Such patients can become either single or double lung recipients. The 2 procedures are associated with specific risks and benefits. The aim of the study was to assess the survival of patients after lung transplant in a single center. METHODS: The retrospective study consists of 128 lung transplant recipients. Patients underwent transplant between 2004 and 2017 because of following diseases: chronic obstructive pulmonary disease (28.2%), cystic fibrosis (26.5%), and primary pulmonary hypertension (12.3%), including idiopathic pulmonary arterial hypertension and interstitial lung diseases (33%). Patients with idiopathic pulmonary arterial hypertension were not treated with postoperative extracorporeal membrane oxygenation as left heart conditioning. RESULTS: Regardless of underlying disease, 75% of DLT recipients and 51% of SLT recipients reached 5-year survival (P = .0066). A total of 87% of lung transplant recipients with cystic fibrosis reached 1-year survival. Among lung recipients with primary pulmonary hypertension who underwent DLT and SLT, 5-year survival was reached by 84% and 51%, respectively (P = .025). Among patients with chronic obstructive pulmonary disease, 82% of DLT recipients and 62% of SLT recipients reached 1-year survival (P = .22). Patients who received transplants because of primary pulmonary hypertension presented the worst short-term survival among all SLT recipients. CONCLUSIONS: Patients with CF have the best overall survival among all lung transplant recipients. Double lung transplant provides statistically significantly better outcomes than single lung transplant. This observation is also present among recipients who underwent transplant because of primary pulmonary hypertension, as single lung transplant is not recommended among such patients in particular.

The Impact of Airway Complications on Survival Among Lung Transplant Recipients.

INTRODUCTION: Long-term outcomes of airway complications (AC) after lung transplantation are unknown. The incidence of AC varies from 1.6% to 32% with the related mortality rate of 2% to 4%. The management of most AC is based on endobronchial methods, including balloon bronchoplasty, endobronchial stent placement, and ablative techniques. The aim of the study was to assess the connection between airway complications treated by bronchial intervention (BI) and the survival of lung transplant recipients. MATERIALS AND METHODS: The single-center retrospective study reviewed the cases of 165 patients (63 women [38.18%], 103 men [61, 82%]; median age at referral for lung transplantations (LTx), 41 years [range, 15-68 years]). The cohort was stratified into 2 groups comprising those whose procedures were complicated by ACs and those without. The primary outcome measured was mortality, with survival endpoints calculated at 6 months. RESULTS: The comparison of the survival of recipients regarding underlying disease (cystic fibrosis [CF], chronic obstructive pulmonary disease [COPD], idiopathic pulmonary artery hypertension [IPAH], and others) with the use of the Kaplan-Meier estimator indicated that the only statistically significant (P = .0194) differences between patients who underwent BI and patients without BI performed were observed in CF patients (Fig 1). In any other diagnosis, the results were not statistically significant (P > .05). CONCLUSIONS: Bronchoscopic intervention because of airway complications after lung transplantation are often-used procedures, but they have no impact on the survival of patients with cystic fibrosis.

Nocturnal hypercapnia with daytime normocapnia in patients with advanced pulmonary arterial hypertension awaiting lung transplantation.

BACKGROUND: Pulmonary arterial hypertension (PAH) is frequently complicated by sleep disordered breathing (SDB), and previous studies have largely focused on hypoxemic SDB. Even though nocturnal hypercapnia was shown to exacerbate pulmonary hypertension, the clinical significance of nocturnal hypercapnia among PAH patients has been scarcely investigated. METHOD: Seventeen patients with PAH were identified from 246 consecutive patients referred to Kyoto University Hospital for the evaluation of lung transplant registration from January 2010 to December 2017. Included in this study were 13 patients whose nocturnal transcutaneous carbon dioxide partial pressure (PtcCO2) monitoring data were available. Nocturnal hypercapnia was diagnosed according to the guidelines of the American Academy of Sleep Medicine. Associations of nocturnal PtcCO2 measurements with clinical features, the findings of right heart catheterization and pulmonary function parameters were evaluated. RESULTS: Nocturnal hypercapnia was diagnosed in six patients (46.2%), while no patient had daytime hypercapnia. Of note, nocturnal hypercapnia was found for 5 out of 6 patients with idiopathic PAH (83.3%). Mean nocturnal PtcCO2 levels correlated negatively with the percentage of predicted total lung capacity (TLC), and positively with cardiac output and cardiac index. CONCLUSION: Nocturnal hypercapnia was prevalent among advanced PAH patients who were waiting for lung transplantation, and associated with %TLC. Nocturnal hypercapnia was associated with the increase in cardiac output, which might potentially worsen pulmonary hypertension especially during sleep. Further studies are needed to investigate hemodynamics during sleep and to clarify whether nocturnal hypercapnia can be a therapeutic target for PAH patients.

Extracorporeal Membrane Oxygenation as a Postoperative Left Ventricle Conditioning Tool After Lung Transplantation in Patients With Primary Pulmonary Artery Hypertension: First Polish Experience.

BACKGROUND: Primary pulmonary hypertension can lead to hypertrophy of the right ventricle and ultimately to its insufficiency. Lung transplantation remains the only viable treatment for patients with certain forms of this disease. Usage of extracorporeal membrane oxygenation in veno-arterial form (VA-ECMO) after transplantation is both protective for left ventricle (enables adaptation to increased blood flow) and right ventricle (provides time to return to appropriate dimensions and in some cases to correct tricuspid regurgitaion). CASE PRESENTATION: The case study describes 4 patients who were treated with VA-ECMO as a perioperative support. Three patients were diagnosed with idiopathic form of precapillary primary pulmonary hypertension. A fourth patient was a 49-year old woman diagnosed with hypoplastic pulmonary veins representing the postcapillary form of pulmonary hypertension. In all of the cases, VA-ECMO was introduced during the surgery (femoral vein/internal jugular vein and femoral artery) and maintained for several days after the transplantation. Regular echocardiographic and biochemical assessment in postoperative course revealed that cardiac function improved during and after such treatment among all patients. They were successfully weaned off ECMO and finally surgically explanted without any local complications. One patient was treated with awake ECMO protocol. CONCLUSIONS: VA-ECMO was proved to be a useful tool during the transplantation and postoperative period. It helps to restore proper cardiac function, as well as prevent adverse effects of aforementioned pathologic changes of a heart.

Electrical Stimulation-Guided Approach to Pulmonary Artery Catheter Ablation in Patients with Idiopathic Pulmonary Arterial Hypertension: A Pilot Feasibility Study with a 12-Month Follow-Up.

BACKGROUND: Recently, transcatheter pulmonary artery (PA) ablation aiming at sympathetic denervation has been proposed in pulmonary arterial hypertension (PAH). This pilot feasibility study aimed to assess the feasibility of selective radiofrequency PA ablation based on response to high-frequency stimulation mapping. METHODS: The study comprised 3 female patients with idiopathic PAH (IPAH). The following reactions to PA stimulation were noted and marked by color points on the three-dimensional map: sinus bradycardia (heart rate decrease ≥15%), tachycardia (heart rate increase ≥15%), phrenic nerve capture, and cough. Since the most appropriate ablation strategy was unknown, two approaches were suggested, according to stimulation results: ablation at points with any heart rate response (either bradycardia or tachycardia)-this approach was applied in patient #1 (IPAH long-term responder to calcium channel blockers); segmental ablation at points with no response and with tachycardia response (one IPAH long-term responder to calcium channel blockers patient and one-IPAH with negative vasoreactive testing). Hemodynamic measurements were performed before and after denervation. Follow-up visits were scheduled at 6 and 12 months. RESULTS: Six-months follow-up was uneventful for patients #1 and 3; patient #2 had one syncope and reduced 6-minute walk test distance and peak VO2 consumption. At 12 months, there was a normalization of mean PA pressure and pulmonary vascular resistance (PVR) in patient #1. Patient #2 had no change in PA pressure and PVR at 12 months. Patient #3 remained in II functional class; however, there was an increase in mean PA pressure and loss of vasoreactivity. CONCLUSIONS: Electrical high-frequency stimulation of the PA identifies several types of evoked reactions: heart rate slowing, acceleration, phrenic nerve capture, and cough. The improvement in clinical and hemodynamic parameters following targeted PA ablation in the IPAH patient with positive vasoreactive testing should be confirmed in larger studies.

Right ventricular systolic to diastolic duration ratio: A novel predictor of outcome in adult idiopathic pulmonary arterial hypertension.

BACKGROUND: The systolic to diastolic (SD) duration ratio reflects global RV performance in pulmonary arterial hypertension (PAH) yet limited data exists on its application to adult non-congenital PAH. We measured SD ratios on echocardiogram in idiopathic PAH (IPAH) to establish its response to pulmonary vasodilator therapy and prognostic value at diagnosis and follow up. METHODS: Incident patients with IPAH undergoing echocardiogram, haemodynamic and exercise assessments were identified within our centre between 2005 and 2018. SD ratios were adjusted for heart rate at diagnosis and follow up. RESULTS: In 98 patients at diagnosis, the mean SD ratio was 1.03 ±â€¯0.37 decreasing to 0.85 ±â€¯0.25, p < 0.001 at follow-up echocardiogram performed at a median interval of 9.0 months. The SD ratio at diagnosis correlated weakly with RV basal diameter (r = 0.24, p = 0.04) and 6MWD (r = 0.23, p = 0.04). At follow up, the mean SD ratio was lower in those receiving combination vs monotherapy pulmonary vasodilator treatment (71 ±â€¯25 vs 92 ±â€¯22% baseline respectively, p < 0.001). After a median follow-up of 4.8 years, 3 patients were transplanted and 23 patients died. The SD ratio at diagnosis and follow up predicted an increased risk of death/transplantation (HR 2.41 (1.09-5.29), p = 0.03; HR 5.02 (1.27-19.77), p = 0.02 respectively), retaining its predictive value at diagnosis in bivariate models with 6MWD (HR 2.18 (1.06-4.08)), WHO Functional Class (HR 2.33 (1.04-5.21)) and TAPSE (HR 2.36 (1.07-5.19)), all p < 0.05. CONCLUSIONS: The SD ratio carries prognostic value at diagnosis and follow up in IPAH. Its further evaluation alongside current PAH risk stratification parameters should be considered.

Targeting cyclin-dependent kinases for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease with poor prognosis and limited therapeutic options. We screened for pathways that may be responsible for the abnormal phenotype of pulmonary arterial smooth muscle cells (PASMCs), a major contributor of PAH pathobiology, and identified cyclin-dependent kinases (CDKs) as overactivated kinases in specimens derived from patients with idiopathic PAH. This increased CDK activity is confirmed at the level of mRNA and protein expression in human and experimental PAH, respectively. Specific CDK inhibition by dinaciclib and palbociclib decreases PASMC proliferation via cell cycle arrest and interference with the downstream CDK-Rb (retinoblastoma protein)-E2F signaling pathway. In two experimental models of PAH (i.e., monocrotaline and Su5416/hypoxia treated rats) palbociclib reverses the elevated right ventricular systolic pressure, reduces right heart hypertrophy, restores the cardiac index, and reduces pulmonary vascular remodeling. These results demonstrate that inhibition of CDKs by palbociclib may be a therapeutic strategy in PAH.

Reverse Remodeling of Pulmonary Arterioles After Pulmonary Artery Banding in Patients ≥ 2 Years Old with Severe Pulmonary Arterial Hypertension and Congenital Heart Disease.

The purpose of this study was to evaluate the pathological changes of the pulmonary arterioles in patients ≥ 2 years of age who first underwent a pulmonary artery banding (PAB) procedure, followed by bidirectional Glenn or Fontan according to their specific conditions. This was a prospective study of 15 children diagnosed and treated with PAB at the Department of Cardiothoracic Surgery of Anzhen Hospital between January 2009 and December 2012. The percentage of media area (%MS) of pulmonary arteriole, the percentage of media thickness (%MT), and pulmonary arterial density (APSC) were calculated from lung tissue sections. Pulmonary artery pressure decreased significantly after PAB surgery (P < 0.01). Postoperative mean pulmonary artery pressure declined significantly (P < 0.01), the cardiothoracic ratio was reduced (P < 0.05), and percutaneous oxygen saturation (inhaled air) decreased to 80-85% (P < 0.01). %MT (from 35.1 ± 5.6% to 26.9 ± 4.3%, P < 0.01), %MS (from 51.4 ± 6.7% to 32.2 ± 7.4%, P < 0.01), and APSC (from 108.3 ± 38.5 to 83.6 ± 19.6, P < 0.01) were decreased significantly after PAB. Five patients underwent the bidirectional Glenn procedure and four underwent Fontan. In conclusion, the results suggest that PAB can reduce pulmonary artery pressure and that pulmonary arterial lesions can be reversed after PAB.

Risk Analysis of Perioperative Death in Lung Transplant Patients With Severe Idiopathic Pulmonary Hypertension.

OBJECTIVE: To investigate the risk factors for perioperative mortality in patients with severe idiopathic pulmonary hypertension (IPAH) undergoing lung transplantation (LTx). METHODS: Twenty-two IPAH patients were included in the study and were divided 2 groups: a case group with early death post LTx (n = 5, 22.7%) and the remaining 17 recipients (87.3%), who did not die at perioperative time (the control group). All the preoperative clinical data and surgical procedures were analyzed using an independent t-test and Fisher's exact probability test. RESULTS: All the patients had over class III heart function rated by World Health Organization classification. Both groups had significantly reduced capacity of 6-min walking distance (6 MWD), decreased oxygen saturation, increased N-terminal probrain natriuretic peptide (NT-proBNP), certain frequent syncope, hemoptysis, and lower extremity edema. In addition, cardiac catheterization examination demonstrated that all patients had elevated pulmonary artery systolic pressure, mean pulmonary artery systolic pressure, and right atrial pressure. Furthermore, reduced mixed venous oxygen saturation and partial pressure of oxygen were seen in oxygen inhalation in a dose of 5 L/min in both groups. Cardiovascular morphological changes in both groups by cardiac ultrasonography included dilated diameter of the right ventricle and the main pulmonary artery. However, the right ventricular ejection fraction and stroke volume were notedly dropped. Distended inferior vena cava and enhanced frequency of hypertensive tricuspid regurgitation velocity response to stress were seen, and pericardial effusion was developed in both groups of patients. Nevertheless, a paired t-test (n = 5 vs n = 17) showed no significance between groups (P > .05), while there was a significant difference in frequencies of brief loss of consciousness (P < .01). Serum sodium concentration, cardiac index (CI), inner diameter of the left ventricle at end diastolic phase, and inner diameter ratio of RV/LV were 116.80 ± 5.76 mmol/L vs 29.88 ± 7.28 mmol/L (P = .002), 1.30 ± 0.07 L/min/m2 vs 1.58 ± 0.26 L/min/m2 (P = .030), 28.80 ± 3.70 mm vs 34.76 ± 5.43 mm (P = .033) and 1.81 ± 0.28 mmol/L vs 1.43 ± 0.26 (P = .011) between case and control group, respectively. CONCLUSIONS: All patients with IPAH waiting for lung transplantation were in critical condition. The highest death risks at perioperative time in IPAH patients were high frequencies of syncope, hyponatremia, lower CI, inner diameter of the left ventricle, and upward RV/LV ratio.

Clinical Effects of Syncope on Disease Severity and Adverse Outcomes in Children with Idiopathic and Heritable Pulmonary Arterial Hypertension.

Syncope is more common in children with idiopathic pulmonary arterial hypertension (PAH) than in adults with PAH. Although syncope is associated with a poor prognosis in adult PAH, the clinical effects of syncopal events on disease severity and outcome in children have not been carefully investigated. This study assessed the prevalence of syncope in pediatric PAH and examined its clinical, hemodynamic, and prognostic importance. This retrospective study assessed clinical data, including syncope status, from 78 children (37 girls) with idiopathic and heritable PAH (median age at diagnosis, 11 years). Patients were classified as syncopal or non-syncopal, and clinical data from the two groups were compared. The primary outcome was a composite of lung transplantation and cardiac mortality. Overall, 31 (38%) children had a history of syncope at presentation. Median age at diagnosis, sex ratio, brain natriuretic peptide level, and 6-min walk distance at diagnosis did not differ between groups. The hemodynamic parameters of initial right heart catheterization were similar between the syncope and non-syncope group (mean pulmonary artery pressure, 67 versus 71 mm Hg; cardiac index, 2.9 versus 2.9 l/min/m2, respectively). There was not significantly difference in event-free survival rate between two groups. Although syncopal events are common in children with PAH, our findings suggest that syncope may not be correlated with disease severity or outcome in pediatric PAH.

Idiopathic pulmonary arterial hypertension - a unrecognized cause of high-shear high-flow haemostatic defects (otherwise referred to as acquired von Willebrand syndrome) in children.

Acquired von Willebrand syndrome (AVWS) is reported in high-flow high-shear congenital cardiac disorders. We hypothesized that the narrowed pulmonary vasculature in idiopathic pulmonary arterial hypertension (IPAH) may induce AVWS. We conducted a cross-sectional evaluation of children with IPAH. Patients with bleeding symptoms and/or laboratory abnormalities (thrombocytopenia, anomalies in coagulation screening tests) were tested in-depth for haemostatic defects. Fourteen children were followed with IPAH of which 8 were eligible. Four children exhibited abnormal bleeding scores (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool: 3-5). All 8 patients showed very prolonged platelet function analyser (PFA)-100 closure times. Six children demonstrated either mild thrombocytopenia or low-normal von Willebrand factor (VWF) antigen (VWF:Ag) or VWF activity [mean (range), in iu/dl: VWF:Ag: 70 (61-91); VWF activity: 57 (34-70)]. Average VWF collagen binding capacity (VWF:CB) was 64 iu/dl (range: 53-123 iu/dl), with low-normal VWF activity/VWF:Ag or VWF:CB/VWF:Ag ratios occurring in five patients. All children had normal multimers distribution patterns. One patient underwent a lung transplantation, with normalization of haemostatic abnormalities post-surgery. Overall, 8 out of 14 children with IPAH had mild to moderate bleeding symptoms and/or laboratory abnormalities in keeping with AVWS. Normalization of the haemostatic defects following lung transplantation and lack of family history of bleeding attests to the acquired nature of their defects.