Monitoring and evaluation of the surgical Potts shunt physiology using 4-dimensional flow magnetic resonance imaging.

OBJECTIVE: The reversed Potts shunt is an increasingly applied mode of surgical palliation of severe pulmonary hypertension (PH). However, the long-term flow hemodynamic effect of the Potts shunt physiology and desirable long-term hemodynamic end points are not defined. The purpose of this descriptive study was to analyze a series of pediatric patients who underwent surgical Potts shunt as a part of end-stage PH palliation using 4-dimensional (4D)-flow magnetic resonance imaging (MRI) to (1) quantitate the flow through the anastomosis, (2) correlate the shunting pattern with phases of cardiac cycle and PH comorbidities, and (3) describe chronologic changes in shunting pattern. METHODS: This was a 2-center study evaluating 4 patients seen in the Pulmonary Hypertension Clinic at Children's Hospital Colorado who were evaluated and selected to undergo surgical reverse Potts shunt at Washington University School of Medicine and were serially followed using comprehensive imaging including cardiac MRI and 4D-flow MRI. RESULTS: After the procedure, each child underwent 2 4D-flow MRI evaluations. Pulmonary pressure offload was evident in all patients, as demonstrated by positive systolic right-to-left flow across the Potts shunt. All patients experienced some degree of the flow reversal, which occurs primarily in diastole. Interventricular dyssynchrony further contributed to flow reversal across the Potts shunt. Lastly, systemic and pulmonary blood mixing in the descending aorta results in secondary helical flow persisting throughout the diastole. CONCLUSIONS: 4D-flow MRI demonstrates that children who have undergone a Potts shunt for severe PH can experience shunt flow reversal. Cumulatively, this left-to-right pulmonary shunt adds to right ventricular volume overload. We speculate that a valved conduit may decrease the left to right shunting and improve overall cardiac output.

Pulmonary-to-Systemic Arterial Shunt to Treat Children With Severe Pulmonary Hypertension.

BACKGROUND: The placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease. OBJECTIVES: The aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure. METHODS: Retrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States. RESULTS: Seventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001). CONCLUSIONS: A pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure.

Midterm outcomes of the Potts shunt for pediatric pulmonary hypertension, with comparison to lung transplant.

OBJECTIVE: For children with severe pulmonary hypertension, addition of Potts shunt to a comprehensive palliation strategy might improve the outcomes afforded by medications and delay lung transplantation. METHODS: A prospective analysis was conducted of all children undergoing Potts shunt (first performed in 2013) or bilateral lung transplant for pulmonary hypertension from 1995 to present. RESULTS: A total of 23 children underwent Potts shunt (20 surgical, 3 transcatheter), and 31 children underwent lung transplant. All children with Potts shunt had suprasystemic right ventricle pressures despite maximal medical treatment. In the majority of patients, the Potts shunt was performed through a left thoracotomy approach (90%, 18/20), by direct anastomosis (65%, 13/20), and without the use of extracorporeal support (65%, 13/20). Perioperative outcomes after Potts shunt were superior to lung transplant including mechanical ventilation time (1.3 vs 10.2 days, P = .019), median hospital length of stay (9.8 vs 34 days, P = .012), and overall complication rate (35% [7/20] vs 81% [25/31], P = .003). Risk factors for operative mortality after Potts shunt (20%, 4/20; compared with 6%, 2/31 for lung transplant, P = .195) included preoperative extracorporeal membrane oxygenation and significant right ventricle dysfunction. In midterm follow-up (median 1.8, maximum 6.1 years), patients with Potts shunt had durable equalization of right ventricle/left ventricle pressures and improved functional status. There was no significant survival difference in patients with Potts shunt and patients with lung transplant (P = .258). CONCLUSIONS: Potts shunt is an effective palliation for children with suprasystemic pulmonary hypertension that may become part of a strategy to maximize longevity and functional status for these challenging patients.

Rapid development of pulmonary hypertension during treatment of paediatric cancer.

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.

Infants with Atypical Presentations of Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins Who Underwent Bilateral Lung Transplantation.

OBJECTIVE: To describe disease course, histopathology, and outcomes for infants with atypical presentations of alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) who underwent bilateral lung transplantation. STUDY DESIGN: We reviewed clinical history, diagnostic studies, explant histology, genetic sequence results, and post-transplant course for 6 infants with atypical ACDMPV who underwent bilateral lung transplantation at St. Louis Children's Hospital. We compared their histology with infants with classic ACDMPV and compared their outcomes with infants transplanted for other indications. RESULTS: In contrast with neonates with classic ACDPMV who present with severe hypoxemia and refractory pulmonary hypertension within hours of birth, none of the infants with atypical ACDMPV presented with progressive neonatal respiratory failure. Three infants had mild neonatal respiratory distress and received nasal cannula oxygen. Three other infants had no respiratory symptoms at birth and presented with hypoxemia and pulmonary hypertension at 2-3 months of age. Bilateral lung transplantation was performed at 4-20 months of age. Unlike in classic ACDMPV, histopathologic findings were not distributed uniformly and were not diffuse. Three subjects had apparent nonmosaic genetic defects involving FOXF1. Two infants had extrapulmonary anomalies (posterior urethral valves, inguinal hernia). Three transplanted children are alive at 5-16 years of age, similar to outcomes for infants transplanted for other indications. Lung explants from infants with atypical ACDMPV demonstrated diagnostic but nonuniform histopathologic findings. CONCLUSIONS: The 1- and 5-year survival rates for infants with atypical ACDMPV are similar to infants transplanted for other indications. Given the clinical and histopathologic spectra, ACDMPV should be considered in infants with hypoxemia and pulmonary hypertension, even beyond the newborn period.

Recommendations for utilization of the paracorporeal lung assist device in neonates and young children with pulmonary hypertension.

The management of decompensating critically ill children with severe PH is extremely challenging and requires a multidisciplinary approach. Unfortunately, even with optimal care, these children might continue to deteriorate and develop inadequate systemic perfusion and at times cardiac arrest secondary to a pulmonary hypertensive crisis. Tools to support these children are limited, and at times, the team should proceed with offering extracorporeal support, especially in newly diagnosed patients who have not benefitted from medical therapy prior to their acute deterioration, in patients with severe pulmonary venous disease and in patients with alveolar capillary dysplasia. Currently, the only approved mode for extracorporeal support in pediatric patients with PH eligible for lung transplantation is ECMO. To decrease the risks associated with ECMO, and offer potential for increased duration of support, extubation, and rehabilitation, we transitioned four small children with refractory PH from ECMO to a device comprising an oxygenator interposed between the PA and LA. This work describes in great detail our experience with this mode of support with emphasis on exclusion criteria, the implantation procedure, and the post-implantation management.

Potts Shunt and Pediatric Pulmonary Hypertension: What We Have Learned.

BACKGROUND: A Potts shunt has been proposed as effective palliative therapy in children with severe pulmonary hypertension (PH) who have suprasystemic right ventricular pressures. METHODS: A retrospective single-center study was performed to assess outcomes in 5 children who underwent a Potts shunt for severe PH. RESULTS: All 5 children were in World Health Organization functional class IV. Only 3 children were classified as having idiopathic pulmonary arterial PH. Preoperatively, 4 children were receiving intravenous prostacyclins, and 3 were placed on intravenous inotropes for acute right-side heart failure. Three children were potential lung transplant candidates. All but 1 child had evidence for suprasystemic right heart pressures immediately before their operation. All 5 children survived the procedure without significant complications. Four of the 5 children were successfully discharged from the hospital and have had sustained clinical improvement with follow-up ranging from approximately 5 to 16 months. The child who did not have suprasystemic right-side heart pressures before the operation did not benefit from the Potts shunt. CONCLUSIONS: The Potts shunt can be an effective palliation for children with severe PH. Our results further suggest that (1) a Potts shunt should be considered early in a child's clinical course, before right ventricular deterioration develops; (2) a Potts shunt should be considered in any child with severe, intractable PH regardless of etiology; (3) one might consider a Potts shunt in lieu of intravenous prostacyclins; and (4) a Potts shunt should be considered before lung transplantation and does not preclude future transplantation candidacy.

Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins.

Position effects due to disruption of distant cis-regulatory regions have been reported for over 40 human gene loci; however, the underlying mechanisms of long-range gene regulation remain largely unknown. We report on two patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) caused by overlapping genomic deletions that included a distant FOXF1 transcriptional enhancer mapping 0.3 Mb upstream to FOXF1 on 16q24.1. In one patient with atypical late-onset ACDMPV, a ∼1.5 Mb deletion removed the proximal 43% of this enhancer, leaving the lung-specific long non-coding RNA (lncRNA) gene LINC01081 intact. In the second patient with severe neonatal-onset ACDMPV, an overlapping ∼194 kb deletion disrupted LINC01081. Both deletions arose de novo on maternal copy of the chromosome 16, supporting the notion that FOXF1 is paternally imprinted in the human lungs. RNAi-mediated knock-down of LINC01081 in normal fetal lung fibroblasts showed that this lncRNA positively regulates FOXF1 transcript level, further indicating that decrease in LINC01081 expression can contribute to development of ACDMPV.

Paracorporeal lung assist devices as a bridge to recovery or lung transplantation in neonates and young children.

OBJECTIVE: To evaluate paracorporeal lung assist devices to treat neonates and children with decompensated respiratory failure as a bridge to recovery or lung transplantation. METHODS: One neonate (23 days old) and 3 young children (aged 2, 9, and 23 months) presented with primary lung disease with pulmonary hypertension, including alveolar capillary dysplasia in 2 and right pulmonary hypoplasia and primary pulmonary hypertension in 1. The patients were listed for lung transplantation but decompensated and required extracorporeal membrane oxygenation (ECMO). The patients were transitioned from ECMO to a pumpless paracorporeal lung assist device (Maquet Quadrox-iD oxygenator in 3, Novalung in 1) with inflow from the pulmonary artery and return to the left atrium. RESULTS: The patients were weaned from ECMO and supported by the device for 44 ± 29 days (range, 5-74). Three patients were extubated while supported by the device (after 9, 15, and 72 days). One patient was bridged to lung transplant (9 months old, with alveolar capillary dysplasia, supported 5 days). One patient was bridged to recovery with maximal medical therapy (23 months old, with primary pulmonary hypertension, supported 23 days). Two patients died while awaiting a suitable lung donor after a support time of 54 and 72 days. CONCLUSIONS: Pediatric patients bridged from ECMO to lung transplantation have poor results. An alternative method for longer term respiratory support was necessary as a bridge for these patients. The use of a paracorporeal lung assist device successfully supported 4 patients to recovery, lung transplantation, or past the average wait time for pediatric donor lungs (27 days). This therapy has the potential to bridge children with decompensated respiratory failure to lung transplantation.

Neonatal paracorporeal lung assist device for respiratory failure.

Neonates who experience respiratory failure despite maximal ventilatory support have only extracorporeal membrane oxygenation as a rescue therapy, but it has very poor outcomes as a bridge to transplantation. A pumpless lung-assist device has been used in adults as a bridge to lung transplantation. An alternative membrane oxygenator, the Quadrox iD, is a suitable size for neonatal blood flow. Here we report the use of the Quadrox iD membrane oxygenator with central cannulation as a paracorporeal respiratory support therapy for a neonate with alveolar capillary dysplasia awaiting lung transplantation.

Lung transplantation in children with idiopathic pulmonary arterial hypertension: an 18-year experience.

BACKGROUND: The natural history of idiopathic pulmonary arterial hypertension (IPAH) in patients of all ages is one of relentless progression. For those who fail medical therapy, lung transplantation remains the ultimate palliation. In the USA, IPAH is the second leading indication for lung transplantation in children and first for children 1 to 5 years of age. In this study, we report our 18-year experience with lung transplantation in children with IPAH. METHODS: We performed a retrospective chart review of children with IPAH listed for lung transplant at our center between 1991 and 2009. Our data reflect a total of 26 children ranging in age from 1.6 to 18.9 years. Nineteen were transplanted and 7 died while waiting (27%). The impact of a number of pre-transplant variables on survival was evaluated. RESULTS: Median survival for those transplanted was 5.8 years, with 1- and 5-year survival rates of 95% and 61%, respectively. Survival was independent of pre-transplant considerations such as age, weight, need for intravenous (IV) inotropes, use of IV pulmonary vasodilators, year of transplant and severity of right-sided cardiac pressures. There was 1 hospital death. Compared with the transplanted group, children who died waiting had a significantly higher incidence of supra-systemic right heart pressures (p = 0.02) and hemoptysis (p = 0.01). CONCLUSIONS: Our study is the largest to date to look at outcomes for lung transplantation in children with IPAH. Their median survival compares favorably with that of all pediatric lung transplant recipients, 5.8 years vs 4.5 years, respectively. We did not identify any pre-transplant variables that presaged a poorer outcome. Thus, survival seemed more related to factors that influence long-term outcomes in all transplant recipients such as rejection and infection. Lung transplantation remains a viable option for children with IPAH, especially for those with supra-systemic right heart pressures despite maximal medical therapy.

Dismal lung transplant outcomes in children with tetralogy of Fallot with pulmonary atresia compared to Eisenmenger syndrome or pulmonary vein stenosis.

BACKGROUND: Certain congenital heart lesions in children can lead to irreversible lung disease thus making lung transplantation a therapeutic option. We retrospectively analyzed our experience with lung transplantation in 32 children with three distinct underlying congenital heart defects: (1) Eisenmenger syndrome (EIS); (2) tetralogy of Fallot with pulmonary atresia (PA); and (3) pulmonary vein stenosis (PVS). METHODS: Pediatric patients <18 years of age with either EIS (n = 7), PA (n = 8) or PVS (n = 17), who underwent lung or heart-lung transplantation, were analyzed. We compared survival rates between the three groups. Pre- and peri-operative variables were also assessed for their effect on outcome. RESULTS: Compared with EIS and PA patients, PVS patients were younger and sicker at the time of transplantation. All EIS and PA patients required either additional intracardiac repairs or a heart transplant at the time of lung transplantation. PA patients had the highest rate of major post-operative complications and in-hospital deaths. Median survival was comparable between EIS (6.1 years) and PVS (6.5 years) patients. Outcomes for PA patients were dramatically worse, with a median survival of only 0.12 year ( approximately 47 days). Needing additional intracardiac surgery or a heart transplant at the time of lung transplantation did not impact survival. The diagnosis of PA itself correlated with a worse outcome. CONCLUSIONS: Outcomes in EIS and PVS patients undergoing lung transplantation compare favorably to that of all pediatric lung transplant recipients (median survival 4.3 years). For PA patients, their underlying pathology appears to make them high-risk candidates for lung transplantation. For the younger and acutely sicker PVS patients, lung transplantation is a viable therapeutic alternative.