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BACKGROUND: Multiple listing (ML) is a practice utilized to increase the potential for transplant but is controversial due to concerns that it disproportionately benefits patients with greater access to healthcare resources. RESEARCH QUESTION: Is there disparity in ML practices based on social deprivation in the United States and does ML lead to quicker time to transplant? STUDY DESIGN AND METHODS: A retrospective cohort study of adult (>18 years old) lung transplant candidates listed for transplant (2005-2018) was conducted. Exclusion criteria included heart only or heart and lung transplant and patients relisted during the observation period. Data were obtained from the UNOS Standard Transplant Analysis and Research File. The first exposure of interest was social deprivation index (SDI) with a primary outcome of ML status, to assess disparities between ML and SL participants. The second exposure of interest was ML status with a primary outcome of time to transplant, to assess whether implementation of ML leads to quicker time to transplant. RESULTS: 35,890 subjects were included in the final analysis, of whom 791 (2.2%) were ML and 35,099 (97.8%) were SL. ML participants had lower median level of social deprivation (5 units, more often female (60.0% vs 42.3%), and had lower median LAS (35.3 vs 37.3). ML patients were more likely to be transplanted compared to SL patients (OR=1.42, 95%CI [1.17-1.73]), but there was a significantly quicker time to transplant only for whom ML was early (within 6 months of initial listing) (sHR=1.17, 95%CI [1.04-1.32]). INTERPRETATION: ML is an uncommon practice with disparities existing between ML and SL patients on the basis of several factors including social deprivation. ML patients are more likely to be transplanted, but only if they ML early in their transplant candidacy. With changing allocation guidelines, it is yet to be seen how ML will change with the implementation of continuous distribution.
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BACKGROUND: Children with congenital heart disease (CHD) demonstrate long-term neurodevelopmental impairments. We investigated contrast-enhanced ultrasound (CEUS) cerebral perfusion in a fetal animal model exposed to sub-physiologic oxygen at equivalent levels observed in human fetuses with CHD. METHODS: Fifteen fetal lambs [hypoxic animals (n = 9) and normoxic controls (n = 6)] maintained in an extrauterine environment underwent periodic brain CEUS. Perfusion parameters including microvascular flow velocity (MFV), transit time, and microvascular blood flow (MBF) were extrapolated from a standardized plane; regions of interest (ROI) included whole brain, central/thalami, and peripheral parenchymal analyses. Daily echocardiographic parameters and middle cerebral artery (MCA) pulsatility indices (PIs) were obtained. RESULTS: Hypoxic lambs demonstrated decreased MFV, increased transit time, and decreased MBF (p = 0.026, p = 0.016, and p < 0.001, respectively) by whole brain analyses. MFV and transit time were relatively preserved in the central/thalami (p = 0.11, p = 0.08, p = 0.012, respectively) with differences in the peripheral parenchyma (all p < 0.001). In general, cardiac variables did not correlate with cerebral CEUS perfusion parameters. Hypoxic animals demonstrated decreased MCA PI compared to controls (0.65 vs. 0.78, respectively; p = 0.027). CONCLUSION: Aberrations in CEUS perfusion parameters suggest that in environments of prolonged hypoxia, there are regional microvascular differences incompletely characterized by MCA interrogation offering insights into fetal conditions which may contribute to patient outcomes. IMPACT: This work utilizes CEUS to study cerebral microvascular perfusion in a unique fetal animal model subjected to chronic hypoxic conditions equal to fetuses with congenital heart disease. CEUS demonstrates altered parameters with regional differences that are incompletely characterized by MCA Doppler values. These findings show that routine MCA Doppler interrogation may be inadequate in assessing microvascular perfusion differences. To our knowledge, this study is the first to utilize CEUS to assess microvascular perfusion in this model. The results offer insight into underlying conditions and physiological changes which may contribute to known neurodevelopmental impairments in those with congenital heart disease.
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OBJECTIVES: The primary objectives were to examine utilization of the Hybrid versus the Norwood procedure for patients with hypoplastic left heart syndrome or variants and the impact on hospital mortality. The Hybrid procedure was 1st used at our institution in 2004. METHODS: Review of all subjects undergoing the Norwood or Hybrid procedure between 1 January 1984 and 31 December 2022. The study period was divided into 8 eras: era 1, 1984-1988; era 2, 1989-1993; era 3, 1994-1998; era 4, 1999-2003; era 5, 2004-2008; era 6, 2009-2014; era 7, 2015-2018 and era 8, 2019-2022. The primary outcome was in-hospital mortality. Mortality rates were computed using standard binomial proportions with 95% confidence intervals. Rates across eras were compared using an ordered logistic regression model with and adjusted using the Tukey-Kramer post-hoc procedure for multiple comparisons. In the risk-modelling phase, logistic regression models were specified and tested. RESULTS: The Norwood procedure was performed in 1899 subjects, and the Hybrid procedure in 82 subjects. Use of the Hybrid procedure increased in each subsequent era, reaching 30% of subjects in era 8. After adjustment for multiple risk factors, use of the Hybrid procedure was significantly and positively associated with hospital mortality. CONCLUSIONS: Despite the increasing use of the Hybrid procedure, overall mortality for the entire cohort has plateaued. After adjustment for risk factors, use of the Hybrid procedure was significantly and positively associated with mortality compared to the Norwood procedure.
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Mortalidade Hospitalar , Síndrome do Coração Esquerdo Hipoplásico , Procedimentos de Norwood , Humanos , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Síndrome do Coração Esquerdo Hipoplásico/mortalidade , Recém-Nascido , Procedimentos de Norwood/mortalidade , Procedimentos de Norwood/métodos , Procedimentos de Norwood/estatística & dados numéricos , Mortalidade Hospitalar/tendências , Feminino , Masculino , Estudos RetrospectivosRESUMO
OBJECTIVE: Lung transplant for acute respiratory distress syndrome in patients supported with extracorporeal membrane oxygenation was rare before 2020, but was rapidly adopted to rescue patients with COVID-19 with lung failure. This study aims to compare the outcomes of patients who underwent lung transplant for COVID-associated acute respiratory distress syndrome and non-COVID acute respiratory distress syndrome, and to assess the impact of type and duration of extracorporeal membrane oxygenation support on survival. METHODS: Using the United Network for Organ Sharing database, we identified 311 patients with acute respiratory distress syndrome who underwent lung transplant from 2007 to 2022 and performed a retrospective analysis of the patients who required extracorporeal membrane oxygenation preoperatively, stratified by COVID-associated acute respiratory distress syndrome and non-COVID acute respiratory distress syndrome listing diagnoses. The primary outcome was 1-year survival. Secondary outcomes included the effect of type and duration of extracorporeal membrane oxygenation on survival. RESULTS: During the study period, 236 patients with acute respiratory distress syndrome and preoperative extracorporeal membrane oxygenation underwent lung transplant; 181 patients had a listing diagnosis of COVID-associated acute respiratory distress syndrome (77%), and 55 patients had a listing diagnosis of non-COVID acute respiratory distress syndrome (23%). Patients with COVID-associated acute respiratory distress syndrome were older, were more likely to be female, had higher body mass index, and spent longer on the waitlist (all P < .02) than patients with non-COVID acute respiratory distress syndrome. The 2 groups had similar 1-year survival (85.8% vs 81.1%, P = .2) with no differences in postoperative complications. Patients with COVID-associated acute respiratory distress syndrome required longer times on extracorporeal membrane oxygenation pretransplant (P = .02), but duration of extracorporeal membrane oxygenation support was not a predictor of 1-year survival (P = .2). CONCLUSIONS: Despite prolonged periods of pretransplant extracorporeal membrane oxygenation support, selected patients with acute respiratory distress syndrome can undergo lung transplant safely with acceptable short-term outcomes. Appropriate selection criteria and long-term implications require further analysis.
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BACKGROUND: Cholestasis characterised by conjugated hyperbilirubinemia is a marker of hepatobiliary dysfunction following neonatal cardiac surgery. We aimed to characterise the incidence of conjugated hyperbilirubinemia following neonatal heart surgery and examine the effect of conjugated hyperbilirubinemia on post-operative morbidity and mortality. METHODS: This was a retrospective study of all neonates who underwent surgery for congenital heart disease (CHD) at our institution between 1/1/2010 and 12/31/2020. Patient- and surgery-specific data were abstracted from local registry data and review of the medical record. Conjugated hyperbilirubinemia was defined as perioperative maximum conjugated bilirubin level > 1 mg/dL. The primary outcome was in-hospital mortality. Survival analysis was conducted using the Kaplan-Meier survival function. RESULTS: Conjugated hyperbilirubinemia occurred in 8.5% of patients during the study period. Neonates with conjugated hyperbilirubinemia were more likely to be of younger gestational age, lower birth weight, and non-Caucasian race (all p < 0.001). Patients with conjugated hyperbilirubinemia were more likely to have chromosomal and non-cardiac anomalies and require ECMO pre-operatively. In-hospital mortality among patients with conjugated hyperbilirubinemia was increased compared to those without (odds ratio 5.4). Post-operative complications including mechanical circulatory support, reoperation, prolonged ventilator dependence, and multi-system organ failure were more common with conjugated hyperbilirubinemia (all p < 0.04). Patients with higher levels of conjugated bilirubin had worst intermediate-term survival, with patients in the highest conjugated bilirubin group (>10 mg/dL) having a 1-year survival of only 6%. CONCLUSIONS: Conjugated hyperbilirubinemia is associated with post-operative complications and worse survival following neonatal heart surgery. Cholestasis is more common in patients with chromosomal abnormalities and non-cardiac anomalies, but the underlying mechanisms have not been delineated.
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BACKGROUND & AIMS: Biliary atresia (BA) is an obstructive cholangiopathy that initially affects the extrahepatic bile ducts (EHBDs) of neonates. The etiology is uncertain, but evidence points to a prenatal cause. Fetal tissues have increased levels of hyaluronic acid (HA), which plays an integral role in fetal wound healing. The objective of this study was to determine whether a program of fetal wound healing is part of the response to fetal EHBD injury. METHODS: Mouse, rat, sheep, and human EHBD samples were studied at different developmental time points. Models included a fetal sheep model of prenatal hypoxia, human BA EHBD remnants and liver samples taken at the time of the Kasai procedure, EHBDs isolated from neonatal rats and mice, and spheroids and other models generated from primary neonatal mouse cholangiocytes. RESULTS: A wide layer of high molecular weight HA encircling the lumen was characteristic of the normal perinatal but not adult EHBD. This layer, which was surrounded by collagen, expanded in injured ducts in parallel with extensive peribiliary gland hyperplasia, increased mucus production and elevated serum bilirubin levels. BA EHBD remnants similarly showed increased HA centered around ductular structures compared with age-appropriate controls. High molecular weight HA typical of the fetal/neonatal ducts caused increased cholangiocyte spheroid growth, whereas low molecular weight HA induced abnormal epithelial morphology; low molecular weight HA caused matrix swelling in a bile duct-on-a-chip device. CONCLUSION: The fetal/neonatal EHBD, including in human EHBD remnants from Kasai surgeries, demonstrated an injury response with prolonged high levels of HA typical of fetal wound healing. The expanded peri-luminal HA layer may swell and lead to elevated bilirubin levels and obstruction of the EHBD. IMPACT AND IMPLICATIONS: Biliary atresia is a pediatric cholangiopathy associated with high morbidity and mortality rates; although multiple etiologies have been proposed, the fetal response to bile duct damage is largely unknown. This study explores the fetal pathogenesis after extrahepatic bile duct damage, thereby opening a completely new avenue to study therapeutic targets in the context of biliary atresia.
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Ductos Biliares Extra-Hepáticos , Atresia Biliar , Humanos , Animais , Camundongos , Ratos , Criança , Ovinos , Atresia Biliar/patologia , Ductos Biliares Extra-Hepáticos/patologia , Feto/patologia , Cicatrização , BilirrubinaRESUMO
BACKGROUND: There is a significant incidence of pre-Fontan attrition-defined as failure to undergo Fontan completion-after superior cavopulmonary connection. This study investigated the impact of at least moderate ventricular dysfunction (VD) and atrioventricular valve regurgitation (AVVR) on pre-Fontan attrition. METHODS: This single-center retrospective cohort study included all infants who underwent Norwood palliation from 2008 to 2020 and subsequently underwent superior cavopulmonary connection. Pre-Fontan attrition was defined as death, listing for heart transplantation before Fontan completion, or unsuitability for Fontan completion. The study's secondary outcome was transplant-free survival. RESULTS: Pre-Fontan attrition occurred in 34 of 267 patients (12.7%). Isolated VD was not associated with attrition. However, patients with isolated AVVR had 5 times the odds of attrition (odds ratio, 5.4; 95% CI 1.8-16.2), and patients with both VD and AVVR had 20 times the odds of attrition (odds ratio, 20.1; 95% CI 7.7-52.8) compared with patients without VD or AVVR. Only patients with both VD and AVVR had significantly worse transplant-free survival compared with patients without VD or AVVR (hazard ratio, 7.7; 95% CI 2.8-21.6). CONCLUSIONS: The additive effect of VD and AVVR is a powerful contributor to pre-Fontan attrition. Future research investigating therapies that can mitigate the degree of AVVR may help improve Fontan completion rates and long-term outcomes.
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Técnica de Fontan , Cardiopatias Congênitas , Transplante de Coração , Disfunção Ventricular , Lactente , Humanos , Estudos Retrospectivos , Valvas Cardíacas/cirurgia , Resultado do Tratamento , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/cirurgiaRESUMO
PURPOSE OF REVIEW: Primary graft dysfunction (PGD) is a clinical syndrome occurring within the first 72âh after lung transplantation and is characterized clinically by progressive hypoxemia and radiographically by patchy alveolar infiltrates. Resulting from ischemia-reperfusion injury, PGD represents a complex interplay between donor and recipient immunologic factors, as well as acute inflammation leading to alveolar cell damage. In the long term, chronic inflammation invoked by PGD can contribute to the development of chronic lung allograft dysfunction, an important cause of late mortality after lung transplant. RECENT FINDINGS: Recent work has aimed to identify risk factors for PGD, focusing on donor, recipient and technical factors both inherent and potentially modifiable. Although no PGD-specific therapy currently exists, supportive care remains paramount and early initiation of ECMO can improve outcomes in select patients. Initial success with ex-vivo lung perfusion platforms has been observed with respect to decreasing PGD risk and increasing lung transplant volume; however, the impact on survival is not well delineated. SUMMARY: This review will summarize the pathogenesis and clinical features of PGD, as well as highlight treatment strategies and emerging technologies to mitigate PGD risk in patients undergoing lung transplantation.
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Transplante de Pulmão , Disfunção Primária do Enxerto , Traumatismo por Reperfusão , Humanos , Disfunção Primária do Enxerto/etiologia , Transplante de Pulmão/métodos , Pulmão , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle , Fatores de Risco , Inflamação/etiologiaRESUMO
Objective: The molecular pathways underlying hypoxemia-induced alterations in neurodevelopment of infants with congenital heart disease have not been delineated. We used transcriptome analysis to investigate differential gene expression induced by hypoxemia in an ovine artificial-womb model. Methods: Mid-gestation fetal sheep (median [interquartile range] 109 [107-112] days' gestation) were cannulated via the umbilical vessels, attached to a pumpless, low-resistance oxygenator circuit, and incubated in a sterile, fluid environment for 22 [21-23] days. Fetuses were maintained with an oxygen delivery of 20-25 mL/kg/min (normoxemia, n = 3) or 14-16 mL/kg/min (hypoxemia, n = 4). Transcriptional profiling by RNA sequencing was carried out on left frontal brains and hypoxemia-regulated genes were identified by differential gene expression analysis. Results: A total of 228 genes whose expression was up or down regulated by ≥1.5-fold (false discovery rate ≤0.05) were identified. The majority of these genes were induced in hypoxemic animals compared to normoxemic controls, and functional enrichment analysis identified respiratory electron transport as a pathway strongly upregulated in the brain during chronic hypoxemia. Further examination of hypoxemia-induced genes showed robust induction of all 7 subunits of the mitochondrial NADH:ubiquinone oxidoreductase (complex I). Other hypoxemia-induced genes included cytochrome B, a component of complex III, and ATP6, ATP8, both of which are components of complex V. Conclusions: Chronic fetal hypoxemia leads to upregulation of multiple mitochondrial respiratory complex genes critical for energy production and reactive oxygen species generation, including complex I. These data provide valuable insight into potential pathways involved in chronic hypoxemia-induced neuropathology and offers potential therapeutic targets for fetal neuroprotection in fetuses with congenital heart defects.
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OBJECTIVES: The objective of this study was to investigate changes in serum biomarkers of acute brain injury, including white matter and astrocyte injury during chronic foetal hypoxaemia. We have previously shown histopathological changes in myelination and neuronal density in fetuses with chronic foetal hypoxaemia at a level consistent with CHD. METHODS: Mid-gestation foetal sheep (110 ± 3 days gestation) were cannulated and attached to a pumpless, low-resistance oxygenator circuit, and incubated in a sterile fluid environment mimicking the intrauterine environment. Fetuses were maintained with an oxygen delivery of 20-25 ml/kg/min (normoxemia) or 14-16 ml/kg/min (hypoxaemia). Myelin Basic Protein and Glial Fibrillary Acidic Protein serum levels in the two groups were assessed by ELISA at baseline and at 7, 14, and 21 days of support. RESULTS: Based on overlapping 95% confidence intervals, there were no statistically significant differences in either Myelin Basic Protein or Glial Fibrillary Acidic Protein serum levels between the normoxemic and hypoxemic groups, at any time point. No statistically significant correlations were observed between oxygen delivery and levels of Myelin Basic Protein and Glial Fibrillary Acidic Protein. CONCLUSION: Chronic foetal hypoxaemia during mid-gestation is not associated with elevated serum levels of acute white matter (Myelin Basic Protein) or astrocyte injury (Glial Fibrillary Acidic Protein), in this model. In conjunction with our previously reported findings, our data support the hypothesis that the brain dysmaturity with impaired myelination found in fetuses with chronic hypoxaemia is caused by disruption of normal developmental pathways rather than by direct cellular injury.
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Lesões Encefálicas , Proteína Básica da Mielina , Animais , Biomarcadores , Lesões Encefálicas/complicações , Feminino , Feto , Proteína Glial Fibrilar Ácida , Humanos , Hipóxia , Proteína Básica da Mielina/análise , Proteína Básica da Mielina/metabolismo , Oxigênio/metabolismo , Gravidez , OvinosRESUMO
OBJECTIVE: We investigated the incidence and predictors of failure to undergo the Fontan in children with hypoplastic left heart syndrome who survived superior cavopulmonary connection. METHODS: The cohort consists of all patients with hypoplastic left heart syndrome who survived to hospital discharge after superior cavopulmonary connection between 1988 and 2017. The primary outcome was attrition, which was defined as death, nonsuitability for the Fontan, or cardiac transplantation before the Fontan. Subjects were excluded if they were awaiting the Fontan, were lost to follow-up, or underwent biventricular repair. The study period was divided into 4 eras based on changes in operative or medical management. Attrition was estimated with 95% confidence intervals, and predictors were identified using adjusted, logistic regression models. RESULTS: Of the 856 hospital survivors after superior cavopulmonary connection, 52 died, 7 were deemed unsuitable for Fontan, and 12 underwent or were awaiting heart transplant. Overall attrition was 8.3% (71/856). Attrition rate did not change significantly across eras. A best-fitting multiple logistic regression model was used, adjusting for superior cavopulmonary connection year and other influential covariates: right ventricle to pulmonary artery shunt at Norwood (P < .01), total support time at superior cavopulmonary connection (P < .01), atrioventricular valve reconstruction at superior cavopulmonary connection (P = .02), performance of other procedures at superior cavopulmonary connection (P = .01), and length of stay after superior cavopulmonary connection (P < .01). CONCLUSIONS: In this study spanning more than 3 decades, 8.3% of children with hypoplastic left heart syndrome failed to undergo the Fontan after superior cavopulmonary connection. This attrition rate has not decreased over 30 years. Use of a right ventricle to pulmonary artery shunt at the Norwood procedure was associated with increased attrition.
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Técnica de Fontan , Derivação Cardíaca Direita , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Fatores Etários , Feminino , Técnica de Fontan/efeitos adversos , Técnica de Fontan/mortalidade , Derivação Cardíaca Direita/efeitos adversos , Derivação Cardíaca Direita/mortalidade , Transplante de Coração , Humanos , Síndrome do Coração Esquerdo Hipoplásico/diagnóstico por imagem , Síndrome do Coração Esquerdo Hipoplásico/mortalidade , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Lactente , Masculino , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Background The superior cavo-pulmonary connection was introduced at our institution in 1988 for infants undergoing surgery for hypoplastic left heart syndrome. Patients with hypoplastic left heart syndrome remain at high risk for mortality in the time period between the Norwood procedure and the superior cavo-pulmonary connection. The primary objectives of this study were to compare interstage mortality across 4 eras and analyze factors that may impact interstage mortality. Methods and Results Patients with hypoplastic left heart syndrome who underwent the Norwood procedure, were discharged from the hospital, and were eligible for superior cavo-pulmonary connection between January 1, 1988, and December 31, 2017, were included. The study period was divided into 4 eras based on changes in operative or medical management. Mortality rates were estimated with 95% CIs. Adjusted and unadjusted logistic regression models were used to identify risk factors for mortality. There were 1111 patients who met the inclusion criteria. Overall, interstage mortality was 120/1111 (10.8%). Interstage mortality was significantly lower in era 4 relative to era 1 (4.6% versus 13.4%; P=0.02) during the time that age at the superior cavo-pulmonary connection was the lowest (135 days; P<0.01) and the interstage monitoring program was introduced. In addition, use of the right ventricle to pulmonary artery shunt was associated with decreased interstage mortality (P=0.02) and was more routinely practiced in era 4. Conclusions During this 30-year experience, the risk of interstage mortality decreased significantly in the most recent era. Factors that coincide with this finding include younger age at superior cavo-pulmonary connection, introduction of an interstage monitoring program, and increased use of the right ventricle to pulmonary artery shunt.
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Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Procedimentos de Norwood/mortalidade , Fatores Etários , Peso ao Nascer , Criança , Pré-Escolar , Feminino , Idade Gestacional , Humanos , Síndrome do Coração Esquerdo Hipoplásico/mortalidade , Lactente , Tempo de Internação , Modelos Logísticos , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVES: The objective of this study was to estimate hospital mortality and length of stay (LOS) for children with hypoplastic left heart syndrome undergoing superior cavopulmonary connection (SCPC). METHODS: All hypoplastic left heart syndrome interstage survivors who underwent SCPC between 1 January 1988 and 31 December 2017 were included. The study period was divided into 4 eras based on changes in operative or medical management. Mortality rates were estimated using standard binomial proportions. Adjusted and unadjusted logistic regression models were used to identify risk factors for mortality and LOS. RESULTS: The most common procedures for the cohort (n = 958) were Hemi-Fontan (57.3%) or Bidrectional Glenn shunt (35.7%). The mortality was 4.1% overall and decreased in all 3 later eras compared to era 1. Factors associated with mortality in a multiple covariate model included longer total support time, earlier gestational age, longer LOS at the Norwood Procedure and need for additional procedures. Overall, the median LOS was 7.0 days with a decrease from eras 1 to 2 and plateaued in eras 3 and 4. Predictors of longer LOS included genetic anomaly, longer Norwood LOS, additional procedures, lower weight at surgery and longer total support time. The type of SCPC was not associated with mortality or LOS. CONCLUSIONS: In this large cohort of patients with hypoplastic left heart syndrome undergoing SCPC, hospital mortality has decreased significantly. LOS initially declined but plateaued in recent eras. The risk factors for mortality and longer LOS are related to patient and procedural complexity, especially the need for additional procedures at the time of SCPC.