Veno-venous extracorporeal membrane oxygenation support of pulmonary insufficiency using Avalon Elite® cannula in pediatric patients.

The "Avalon Elite®" cannula is a double-lumen cannula used to establish veno-venous extracorporeal membrane oxygenation support. The reported advantages are that extracorporeal circulation can be established by cannulating through the right internal jugular vein only, and there is less re-circulation than with a two-cannula technique. It is available in a wide range of cannula sizes and can be used in a variety of patients, from children to adults. We herein report three pediatric cases in which an Avalon Elite® cannula was useful. The first was a case of acute mitral regurgitation due to idiopathic chordal rupture for postoperative severe lung injury and atelectasis due to cardiogenic pulmonary edema. The second was a case of end-stage radiation pneumonitis for safe transfer to facility of lung transplantation. The third was a convalescent case of fulminant myocarditis with severe atelectasis due to cardiogenic pulmonary edema. In each case, veno-venous extracorporeal membrane oxygenation using an Avalon Elite® cannula was established, the expected sufficient support was secured, and a good clinical course was obtained without major complications associated with an Avalon Elite® cannula.

Percutaneous treatment of an iatrogenic femoral arteriovenous fistula from an accessory arterial branch: a case report and review of the literature.

Vascular access-related complications are an important consideration in patients undergoing cardiac catheterisation. Patients with CHD are increasingly undergoing percutaneous treatment for suitable procedures as an alternative, less invasive option to surgical intervention. As such, recognition and treatment of these complications are becoming increasingly important. We present a case of a patient with repaired Tetralogy of Fallot who developed a femoral arteriovenous fistula and femoral artery pseudoaneurysm arising from an accessory arterial branch following percutaneous Harmony valve implantation, both of which were treated endovascularly with placement of a stent.

Lung ultrasound score follows the chronic pulmonary insufficiency of prematurity trajectory in early infancy.

Extremely preterm birth is associated with a high risk of chronic pulmonary insufficiency of prematurity (CPIP). Lung ultrasound score (LUS) proved capable to characterise CPIP progression beyond the acute setting, but still, post-discharge data remain lacking. We hypothesised a priori that LUS in both BPD and no-BPD infants declines with postnatal age from birth through early infancy. This observational retrospective cohort study included preterm infants < 32 gestational weeks, who underwent the follow-up for CPIP. LUS was assessed from birth to 8 months postnatal age, over antero-lateral (LUS) and posterior (pLUS) pulmonary areas, placing the transducer longitudinally over the midclavicular and midaxillary lines and medial to the scapular line respectively. Extended LUS (eLUS) including LUS and pLUS was calculated. The primary outcome was LUS time course. Secondary outcomes included the correlation between LUS and pLUS. Sixty-two infants were included: 22 (35.5%) in the BPD group and 40 (64.5%) in the no-BPD group. BPD group infants were smaller (weight 841 g (± 228) vs 1226 (± 328), p < 0.001) and younger (26.8 weeks (± 2.0) vs 28.9 (± 1.9), p < 0.001). LUS declined over time in the entire population (ß = - 1.75, p < 0.001) and in both no-BPD and BPD groups (ß = - 1.64, p < 0.001 and ß = - 1.93, p < 0.001, respectively). eLUS declined correspondingly (p < 0.001). LUS and likewise eLUS were significantly different between BPD and no-BPD groups over time (p < 0.001).  Conclusion: LUS trajectory progressively decreased from birth to early infancy. BPD cohort tracked higher, implying a worse respiratory status. pLUS had a similar timepoint course, adding no further information to LUS. To the best of our knowledge, this is the first study that describes preterm LUS time course after discharge. LUS may help track the CPIP progression. What is Known: • Extremely preterm birth is associated with high risk of chronic pulmonary insufficiency of prematurity (CPIP). • Several studies investigated the ability of lung ultrasound score (LUS) to characterize CPIP progression beyond the acute setting, still post-discharge data remain lacking. What is New: • LUS trajectory progressively decreases from birth to early infancy; BPD cohort tracks higher, implying a worse respiratory status. pLUS has similar timepoint course, adding no further information to LUS. • The use of LUS may contribute to better characterising and monitoring CPIP in BPD and no-BPD infants.

Transcatheter pulmonary valve implantation in tetralogy of Fallot and Ebstein's anomaly with one and a half ventricular repair.

The coexistence of tetralogy of Fallot and Ebstein's anomaly is extremely rare. There are only a few case reports in the literature, and surgical options for the treatment are controversial. There is insufficient data on long-term follow-up of patients and management of complications. In this case report, we present a 20-year-old adult with operated tetralogy of Fallot, Ebstein's anomaly, and Glenn anastomosis who underwent transcatheter pulmonary valve implantation for severe pulmonary insufficiency.

Changes in left and right ventricular longitudinal function after pulmonary valve replacement in patients with Tetralogy of Fallot.

Timing and indication for pulmonary valve replacement (PVR) in patients with repaired Tetralogy of Fallot (rToF) and pulmonary regurgitation (PR) are uncertain. To improve understanding of pumping mechanics, we investigated atrioventricular coupling before and after surgical PVR. Cardiovascular magnetic resonance was performed in patients (n = 12) with rToF and PR > 35% before and after PVR and in healthy controls (n = 15). Atrioventricular plane displacement (AVPD), global longitudinal peak systolic strain (GLS), atrial and ventricular volumes, and caval blood flows were analyzed. Right ventricular (RV) AVPD and RV free wall GLS were lower in patients before PVR compared with controls (P < 0.0001; P < 0.01) and decreased after PVR (P < 0.0001 for both). Left ventricular AVPD was lower in patients before PVR compared with controls (P < 0.05) and decreased after PVR (P < 0.01). Left ventricular GLS did not differ between patients and controls (P > 0.05). Right atrial reservoir volume and RV stroke volume generated by AVPD correlated in controls (r = 0.93; P < 0.0001) and patients before PVR (r = 0.88; P < 0.001) but not after PVR. In conclusion, there is a clear atrioventricular coupling in patients before PVR that is lost after PVR, possibly because of loss of pericardial integrity. Impaired atrioventricular coupling complicates assessment of ventricular function after surgery using measurements of longitudinal function. Changes in atrioventricular coupling seen in patients with rToF may be energetically unfavorable, and long-term effects of surgery on atrioventricular coupling is therefore of interest. Also, AVPD and GLS cannot be used interchangeably to assess longitudinal function in rToF.NEW & NOTEWORTHY There is a clear atrioventricular coupling in patients with Tetralogy of Fallot (ToF) and pulmonary regurgitation before surgical pulmonary valve replacement (PVR) that is lost after operation, possibly because of loss of pericardial integrity. The impaired atrioventricular coupling complicates assessment of ventricular function after surgery when using measurements of longitudinal function. Left ventricular atrioventricular plane displacement (AVPD) found differences between patients and controls and changes after PVR that longitudinal strain could not detect. This indicates that AVPD and strain cannot be used interchangeably to assess longitudinal function in repaired ToF.

Altered biventricular hemodynamic forces in patients with repaired tetralogy of Fallot and right ventricular volume overload because of pulmonary regurgitation.

Intracardiac hemodynamic forces have been proposed to influence remodeling and be a marker of ventricular dysfunction. We aimed to quantify the hemodynamic forces in patients with repaired tetralogy of Fallot (rToF) to further understand the pathophysiological mechanisms as this could be a potential marker for pulmonary valve replacement (PVR) in these patients. Patients with rToF and pulmonary regurgitation (PR) > 20% ( n = 18) and healthy control subjects ( n = 15) underwent MRI, including four-dimensional flow. A subset of patients ( n = 8) underwent PVR and MRI after surgery. Time-resolved hemodynamic forces were quantified using 4D-flow data and indexed to ventricular volume. Patients had higher systolic and diastolic left ventricular (LV) hemodynamic forces compared with control subjects in the lateral-septal/LV outflow tract ( P = 0.011 and P = 0.0031) and inferior-anterior ( P < 0.0001 and P < 0.0001) directions, which are forces not aligned with blood flow. Forces did not change after PVR. Patients had higher RV diastolic forces compared with control subjects in the diaphragm-right ventricular (RV) outflow tract (RVOT; P < 0.001) and apical-basal ( P = 0.0017) directions. After PVR, RV systolic forces in the diaphragm-RVOT direction decreased ( P = 0.039) to lower levels than in control subjects ( P = 0.0064). RV diastolic forces decreased in all directions ( P = 0.0078, P = 0.0078, and P = 0.039) but were still higher than in control subjects in the diaphragm-RVOT direction ( P = 0.046). In conclusion, patients with rToF and PR had LV hemodynamic forces less aligned with intraventricular blood flow compared with control subjects and higher diastolic RV forces along the regurgitant flow direction in the RVOT and that of tricuspid inflow. Remaining force differences in the LV and RV after PVR suggest that biventricular pumping does not normalize after surgery. NEW & NOTEWORTHY Biventricular hemodynamic forces in patients with repaired tetralogy of Fallot and pulmonary regurgitation were quantified for the first time. Left ventricular hemodynamic forces were less aligned to the main blood flow direction in patients compared with control subjects. Higher right ventricular forces were seen along the pulmonary regurgitant and tricuspid inflow directions. Differences in forces versus control subjects remain after pulmonary valve replacement, suggesting that altered biventricular pumping does not normalize after surgery.

Perioperative Factors Influence the Long-Term Outcomes of Children and Adolescents with Repaired Tetralogy of Fallot.

Tetralogy of Fallot (TOF) often carries long-term seqüelae following surgical intervention. We hypothesized that early perioperative factors are associated with long-term adverse right ventricular (RV) remodeling, diminished exercise capacity, and increased morbidity. We conducted a retrospective cohort study of patients operated for TOF that underwent cardiac magnetic resonance imaging study (CMR), exercise stress test (EST), and detailed review of past medical history. Outcome variables included measures of RV size, and function, maximal work rate, and oxygen consumption, and interim hospitalizations, surgeries, and catheterizations. Thirty-nine subjects were included. Age at surgical repair was 0.3 ± 0.3 years and age at testing was 9.7 ± 1.4 years. On CMR, there was borderline RV dilation with moderate pulmonary insufficiency (PI) [RF 32% (8; 43)] and normal RV ejection fraction [60% (55; 67)]. On EST, there was low percent-predicted maximal oxygen consumption (77 ± 20%), and percent-predicted maximal work rate (84 ± 23%). On multivariable analysis, mechanical ventilation and Blalock-Taussig (BT) shunt prior to complete surgical repair were associated with the number of future hospitalizations. Duration of cardiopulmonary bypass and prior BT shunt were associated with future catheterizations. Prior BT shunt was a predictor of worse RVEF, while duration of mechanical ventilation and use of transannular patch were predictors of worse PI. Longer duration of mechanical ventilation (or LOS) was associated with worse maximal work rate. Surgical and perioperative factors may portend long-term RV remodeling and outcome in TOF. Further studies are warranted to explore these associations and potential underlying mechanisms.

Total Joint Arthroplasty in Patients With Schizophrenia: How Much Does It Increase the Risk of Complications?

BACKGROUND: Mental illness is an often overlooked comorbidity in the total joint arthroplasty (TJA) population. The purpose of this study was to evaluate the risk of schizophrenia on the outcomes of TJA. METHODS: The nationwide inpatient sample was used to identify a cohort of 505,840 patients having total hip arthroplasty between 2009 and 2012, of which 953 patients (0.2%) had been diagnosed with schizophrenia. Multivariate logistic regression was used to identify the impact of schizophrenia on short-term medical and surgical complications. Differences in length of stay and discharge disposition were also compared. RESULTS: Schizophrenic patients are 15 times more likely to have pulmonary insufficiency after surgery (odds ratio [OR] 15.1, P = .0133). Patients were 11 times more likely to have mental status changes (OR 11.1, P = .0002), 3 times more likely to have a mechanical complication of the implant (OR 3.2, P = .0031), and 2 times more likely to require a transfusion (OR 2.4, P < .0001). All-cause medical (OR 2.2, P < .0001) and surgical (OR 1.5, P < .0001) complications were higher in schizophrenic patients. Patients stayed 0.63 days longer in the hospital (P < .0001), and were 3 times more likely to discharge to a facility (OR 2.7, P < .0001). CONCLUSIONS: TJA in patients with schizophrenia had markedly increased complications. Particularly, pulmonary complications, mechanical complications of the implant, mental status changes, and transfusion rates were higher. Future risk adjustment models should include schizophrenia as a major contributor to increased complications.

Scoping review shows wide variation in the definitions of bronchopulmonary dysplasia in preterm infants and calls for a consensus.

The use of different definitions for bronchopulmonary dysplasia (BPD) has been an ongoing challenge. We searched papers published in English from 2010 and 2015 reporting BPD as an outcome, together with studies that compared BPD definitions between 1978 and 2015. We found that the incidence of BPD ranged from 6% to 57%, depending on the definition chosen, and that studies that investigated correlations with long-term pulmonary and/or neurosensory outcomes reported moderate-to-low predictive values regardless of the BPD criteria. CONCLUSION: A comprehensive and evidence-based definition for BPD needs to be developed for benchmarking and prognostic use.

Longitudinal Validation of the Diastolic to Systolic Time-Velocity Integral Ratio as a Doppler-Derived Measure of Pulmonary Regurgitation in Patients with Repaired Tetralogy of Fallot.

Pulmonary regurgitation (PR) is a common residual lesion and major determinant of outcome following surgical repair for tetralogy of Fallot. We sought to longitudinally study a previously described echocardiographic index as a correlate of PR measured by cardiac magnetic resonance imaging (CMR). We conducted a retrospective longitudinal study of patients with baseline and follow-up echocardiogram and CMR. The baseline studies were obtained as part of a research protocol, while the follow-up studies were performed for clinical purposes. On echocardiogram, the ratio of diastolic and systolic time-velocity integrals (DSTVI) in the main pulmonary artery was calculated. The Wilcoxon matched-pairs signed-rank test was used to test for individual changes in PR on echocardiogram and CMR. A linear regression of pulmonary valve regurgitant fraction (RF) was fit on DSTVI to identify clinically meaningful cut points of DSTVI. Thirty-five subjects were included, age at follow-up 18.3 ± 3.5 years. The follow-up between consecutive CMRs was a median time of 60 months (interquartile range 46-73). There was a moderate correlation between DSTVI and PR measured as RF by CMR (r = 0.62, p = 0.0001). A CMR RF of 20 and 40 % (the boundaries between mild/moderate and moderate/severe PR) corresponded with DSTVI of 0.52 and 0.79 (95 % CI 0.39; 0.66, and 0.69; 89), respectively. There was no significant change in either DSTVI (p = 0.61) or PR (p = 0.89) from baseline to follow-up. This study lends further credence to the DSTVI as an accurate reflection of PR. This index might become helpful in the routine echocardiographic assessment of PR. Further studies are needed to determine whether changes in RF by CMR result in changes in DSTVI.

Repaired Tetralogy of Fallot: Have We Understood the Right Timing of PVR?

Despite many advances in surgical repair during the past few decades, the majority of tetralogy of Fallot patients continue to experience residual hemodynamic and electrophysiological abnormalities. The actual issue, which has yet to be solved, is understanding how this disease evolves in each individual patient and, as a result, who is truly at risk of sudden death, as well as the proper timing of pulmonary valve replacement (PVR). Our responsibility should be to select the most appropriate time for each patient, going above and beyond imaging criteria used up to now to make such a clinically crucial decision. Despite several studies on timing, indications, procedures, and outcomes of PVR, there is still much uncertainty about whether PVR reduces arrhythmia burden or improves survival in these patients and how to appropriately manage this population. This review summarizes the most recent research on the evolution of repaired tetralogy of Fallot (from adolescence onwards) and risk factor variables that may favor or delay PVR.

Balloon pulmonary valvuloplasty: A systematic review.

There is conclusive evidence for relief of pulmonary valve obstruction immediately after balloon pulmonary valvuloplasty (BPV) and at follow-up. Development of infundibular obstruction is seen in more severe PS cases and in older subjects. Reappearance of PS was observed in approximately 10 % of patients following BPV. The reasons for recurrence were found to be balloon/annulus ratio less than 1.2 and immediate post-BPV pulmonary valve peak gradients greater than 30 mmHg. Recurrent stenosis is successfully addressed by repeating BPV with lager balloons than used initially. Long-term results revealed continue relief of obstruction, but with development of pulmonary insufficiency, some patients requiring replacement of the pulmonary valve. It was concluded that BPV is the treatment of choice in the management valvar PS and that balloon/annuls ratio used for BPV should be lowered to 1.2 to 1.25. It was also suggested that strategies should be developed to prevent/reduce pulmonary insufficiency at long-term follow-up.

Prognostic value of the early lung ultrasound B-line score for postoperative pulmonary insufficiency in patients undergoing thoracic surgery: an observational study.

BACKGROUND: Postoperative pulmonary insufficiency (PPI) is an important contributor to morbidity and mortality after thoracic surgery. Lung ultrasound is a reliable tool for assessing respiratory function. We sought to determine the clinical value of the early lung ultrasound B-line score for predicting changes in pulmonary function after thoracic surgery. METHODS: Eighty-nine patients undergoing elective lung surgery were included in this study. The B-line score was determined 30 min after removal of the endotracheal tube, and the PaO2/FiO2 ratio was recorded 30 min after extubation and on the third postoperative day. Patients were divided into normal (PaO2/FiO2 ≥ 300) and PPI (PaO2/FiO2 < 300) groups according to their PaO2/FiO2 ratios. A multivariate logistic regression model was used to identify independent predictors of postoperative pulmonary insufficiency. Receiver operating characteristic (ROC) analysis was performed for significantly correlated variables. RESULTS: Eighty-nine patients undergoing elective lung surgery were included in this study. We evaluated 69 patients in the normal group and 20 in the PPI group. Patients conforming to NYHA class 3 at administration were significantly more represented in the PPI group (5.8 and 55%; p < 0.001). B-line scores were significantly higher in the PPI group than in the normal group (16; IQR 13-21 vs. 7; IQR 5-10; p < 0.001). The B-line score was an independent risk factor (OR = 1.349 95% CI 1.154-1.578; p < 0.001), and its best cutoff value for predicting PPI was 12 (sensitivity: 77.5%; specificity: 66.7%). CONCLUSIONS: Lung ultrasound B-line scores 30 min after extubation are effective in predicting early PPI in patients undergoing thoracic surgery. Trial registration This study was registered with the Chinese Clinical Trials Registry (ChiCTR2000040374).

Right ventricular longitudinal function is linked to left ventricular filling pressure in patients with repaired tetralogy of fallot.

Experimental data on pulmonary regurgitation has linked right ventricular longitudinal function to left ventricular filling pressure in animals with induced and treated pulmonary regurgitation but this relationship has not been investigated in patients with repaired Tetralogy of Fallot (rToF). The aim of this study was to determine if right ventricular longitudinal function assessed using cardiovascular magnetic resonance (CMR) is associated with left ventricular filling pressure in patients with rToF. A second objective of this study was to determine if direction of septal movement is related to right ventricular pressure load in rToF. Eighteen patients with rToF undergoing CMR and heart catheterization prior to pulmonary valve replacement were retrospectively included and catheter-based pressure measurements were compared with CMR-derived RV regional function. Left ventricular filling pressure was measured as precapillary wedge pressure (PCWP). Longitudinal contribution to RV stroke volume correlated with PCWP (r = 0.48; p = 0.046) but not with RV EF or pulmonary regurgitation. Neither RV longitudinal strain nor TAPSE showed correlation with PCWP. Longitudinal contribution to stroke volume was lower for the RV compared to the LV (49 vs 54%; p = 0.039). Direction of septal movement did not show a correlation with RV end-systolic pressure. Right ventricular longitudinal pumping is associated with left ventricular filling pressure in rToF-patients and this inter-ventricular coupling may explain LV underfilling in patients with pulmonary regurgitation and rToF and may be of value to determine right ventricular dysfunction. RV systolic pressure, however, cannot be assessed from the direction of septal movement, in these patients.

Balloon Dilatation in the Management of Congenital Obstructive Lesions of the Heart: Review of Author's Experiences and Observations-Part I.

Balloon dilatation techniques became available to treat congenital obstructive lesions of the heart in the early/mid-1980s. The purpose of this review is to present the author's experiences and observations on the techniques and outcomes of balloon dilatation of pulmonary stenosis (PS), aortic stenosis (AS) and aortic coarctation (AC), both native and postsurgical re-coarctations. Balloon dilatation resulted in a reduction of peak pressure gradient across the obstructive lesion at the time of the procedure as well as at short-term and long-term follow-ups. Complications such as recurrence of stenosis, valvar insufficiency (for PS and AS cases) and aneurysm formation (for AC cases) have been reported, but infrequently. It was recommended that strategies be developed to prevent the reported complications.

Surgical Treatment Outcomes of Tetralogy of Fallot: Experience of the Cardiovascular Department of the Mohammed VI University Hospital in Marrakech.

Background Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. The surgical approach to TOF continues to evolve, with many centers now favoring early repair for TOF. This study aimed to determine the prevalence of postsurgical complications such as pulmonary insufficiency, residual pulmonary stenosis, and interventricular communication. Methodology We conducted a cross-sectional, observational study with a descriptive and analytic focus involving 61 patients who were operated on for TOF. Results In total, 39 (63.9%) patients had a regular TOF and 22 (36.1%) had an irregular TOF. In our study, 32 (56.14%) patients had a pulmonary insufficiency, of whom 20 had a minimal pulmonary insufficiency (62.5% of pulmonary insufficiency cases), and 79.4% of patients with right ventricular outflow tract enlargement had pulmonary insufficiency (p < 0.005). Among patients who did not have a right ventricular outflow tract enlargement, three cases of pulmonary insufficiency were identified with a prevalence of 16.6%. Six (10.52%) patients had residual pulmonary stenosis. In addition, two (3.2%) cases of minimal residual ventricular septal defects were identified in this study. Conclusions Postoperative complications of TOF treatment are frequent and require medical care throughout the lifetime of patients.

Surgical repair of tetralogy of Fallot using autologous right atrial appendages: short- to mid-term results.

OBJECTIVES: The prevention of pulmonary insufficiency (PI) is a crucial part of the tetralogy of Fallot repair. Many techniques have been introduced to construct valves from different materials for the right ventricular outflow tract, including the most commonly constructed monocusp valves. We are introducing a new bicuspid valve made intraoperatively using the autologous right atrial appendage (RAA) to prevent PI in these patients. METHODS: The RAA valve was constructed and used in 21 patients with tetralogy of Fallot. The effective preservation of the native valve was impossible in all patients because of either a severe valve deformity or a small annulus. The RAA valve was created after ventricular septal defect closure and right ventricular outflow tract myectomy and was covered with a bovine transannular pericardial patch. The perioperative data were evaluated, and the echocardiography results were assessed immediately after operations and in follow-up with a median of 10.5 months. The data were retrospectively compared with 10 other patients with similar demographic data but with only transannular patches. RESULTS: The mean age of the patients was 13.3 months. No mortality or related morbidity occurred after repair using the RAA valve. The PI severity early after the operation was trivial or no PI in 18 patients, and mild PI was observed in 3 patients, which progressed to moderate PI in one of them in the mean 12-month follow-up period. Fifteen patients had mild or no pulmonary stenosis, while moderate pulmonary stenosis was observed in 6 others. Compared with the other 10 patients with only transannular patches, the RAA valve patients had prolonged operative and clamping times, but no difference in postoperative course and shorter hospital stays. The degree of PI was, of course, significantly less in the RAA valve patients, but pulmonary stenosis was the same. CONCLUSIONS: The RAA valve construction is a safe and effective technique to prevent PI after the tetralogy of Fallot repair, at least in terms of short- and mid-term results. A longer follow-up period is needed to confirm if this new valve can eliminate or significantly delay the need for pulmonary valve replacement in these patients.

Severe Cardiopulmonary Disease in a Parturient With Noonan Syndrome.

Noonan syndrome is a relatively common genetic disorder and the second most common cause of congenital heart disease after trisomy 21. The spectrum of cardiac anomalies in Noonan syndrome typically involves pulmonary valve stenosis occasionally in conjunction with hypertrophic cardiomyopathy. Mitral valve involvement is a rare finding in Noonan syndrome and is most commonly associated with either mitral valve prolapse or abnormal valvular insertion causing left ventricular outflow tract obstruction. Patients with Noonan syndrome typically have preserved fertility and, given the success of cardiac surgery and medical management of heart failure in this population, are beginning to present more commonly as parturients in adulthood. Maternal physiologic changes during pregnancy introduce an added complexity to hemodynamic management and anesthetic considerations during labor and delivery. In this article, we present a case of a patient with Noonan syndrome with severe mitral stenosis, pulmonary valve insufficiency, and severe restrictive and obstructive pulmonary disease who presented preterm for delivery due to increased dyspnea at rest. Here we review the pathophysiology behind Noonan syndrome and peripartum management strategies in a patient with severe combined cardiac and pulmonary disease.

Advancing Therapeutic Development for Pulmonary Morbidities Associated with Preterm Birth.

Chronic pulmonary and respiratory conditions associated with preterm birth are incompletely characterized, complicating long-term treatment and development of more effective therapies. Stakeholders face challenges in the development of validated, clinically meaningful endpoints that adequately measure morbidities and predict or represent health outcomes for preterm neonates. We propose in this paper a research agenda, informed by the input of experts from a 2018 workshop we convened on this topic, to advance endpoint and treatment development. We discuss the necessity of further evaluation of existing endpoints and the improved characterization of disease endotypes. We also discuss key steps to the development of optimized short- and long-term endpoints that can be linked to meaningful health outcomes. Finally, we discuss the importance of limiting variability in data collection and the application of new clinical trial endpoints as well as the critical nature of multi-stakeholder collaboration to advancing therapeutic development for this vulnerable patient population.

Preterm birth and sustained inflammation: consequences for the neonate.

Almost half of all preterm births are caused or triggered by an inflammatory process at the feto-maternal interface resulting in preterm labor or rupture of membranes with or without chorioamnionitis ("first inflammatory hit"). Preterm babies have highly vulnerable body surfaces and immature organ systems. They are postnatally confronted with a drastically altered antigen exposure including hospital-specific microbes, artificial devices, drugs, nutritional antigens, and hypoxia or hyperoxia ("second inflammatory hit"). This is of particular importance to extremely preterm infants born before 28 weeks, as they have not experienced important "third-trimester" adaptation processes to tolerate maternal and self-antigens. Instead of a balanced adaptation to extrauterine life, the delicate co-regulation between immune defense mechanisms and immunosuppression (tolerance) to allow microbiome establishment is therefore often disturbed. Hence, preterm infants are predisposed to sepsis but also to several injurious conditions that can contribute to the onset or perpetuation of sustained inflammation (SI). This is a continuing challenge to clinicians involved in the care of preterm infants, as SI is regarded as a crucial mediator for mortality and the development of morbidities in preterm infants. This review will outline the (i) role of inflammation for short-term consequences of preterm birth and (ii) the effect of SI on organ development and long-term outcome.