Standardization of the Norwood Procedure Improves Outcomes in a Medium-Sized Volume Center.

The Norwood operation has become common practice to palliate patients with hypoplastic left heart structures. Surgical technique and postoperative care have improved; yet, there remains significant attrition prior to stage II palliation. The objective of this study is to report outcomes before and after standardizing our approach to the Norwood operation. Patients who underwent the Norwood operation at Children's of Alabama were identified, those who underwent hybrid palliation operations were excluded. Pre- (2015-2020) and post- (2020-January 2023) standardization groups were compared and outcomes analyzed. Ninety-one patients were included (pre-standardization 44 (48.3%) and 47 (51.7%) post-standardization). There were no differences in baseline and intraoperative characteristics at Norwood between the pre- and post-standardization groups. Compared with pre-standardization, post-standardization was associated with decreased time to extubation (OR 0.87, 95%CI 0.79-0.96), inotrope duration (OR 0.92, 95%CI 0.86-0.98) and hospital length of stay (OR 0.98, 95%CI 0.96-0.99). There was a trend toward decreased cardiac arrest, reintervention rates, and interstage mortality for the post-standardization group. A standardized approach to complex neonatal cardiac operations such as the Norwood procedure may improve morbidity and decrease hospital resource utilization. We recommend establishing protocols at an institutional level to optimize outcomes in such high-risk patient populations.

Pharmacogenomics of coronary artery response to intravenous gamma globulin in kawasaki disease.

Kawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that can result in acute vasculitis. The mechanism of coronary artery aneurysms (CAA) in KD despite intravenous gamma globulin (IVIG) treatment is not known. We performed a Whole Genome Sequencing (WGS) association analysis in a racially diverse cohort of KD patients treated with IVIG, both using AHA guidelines. We defined coronary aneurysm (CAA) (N = 234) as coronary z ≥ 2.5 and large coronary aneurysm (CAA/L) (N = 92) as z ≥ 5.0. We conducted logistic regression models to examine the association of genetic variants with CAA/L during acute KD and with persistence >6 weeks using an additive model between cases and 238 controls with no CAA. We adjusted for age, gender and three principal components of genetic ancestry. The top significant variants associated with CAA/L were in the intergenic regions (rs62154092 p < 6.32E-08 most significant). Variants in SMAT4, LOC100127, PTPRD, TCAF2 and KLRC2 were the most significant non-intergenic SNPs. Functional mapping and annotation (FUMA) analysis identified 12 genomic risk loci with eQTL or chromatin interactions mapped to 48 genes. Of these NDUFA5 has been implicated in KD CAA and MICU and ZMAT4 has potential functional implications. Genetic risk score using these 12 genomic risk loci yielded an area under the receiver operating characteristic curve (AUC) of 0.86. This pharmacogenomics study provides insights into the pathogenesis of CAA/L in IVIG-treated KD and shows that genomics can help define the cause of CAA/L to guide management and improve risk stratification of KD patients.

Pharmacogenomics of Coronary Artery Response to Intravenous Gamma Globulin in Kawasaki Disease.

Background: Kawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that can result in acute vasculitis. The pathological walls of afflicted coronary arteries show propensity for forming thrombosis and aneurysms. The mechanism of coronary artery aneurysms (CAA) despite intravenous gamma globulin (IVIG) treatment is not known. Methods: We performed a Whole Genome Sequencing (WGS) association analysis in a racially diverse cohort of KD patients treated with IVIG, both using AHA guidelines. We defined coronary aneurysm (CAA) (N = 234) as coronary z>2.5 and large coronary aneurysm (CAA/L) (N = 92) as z>5.0. We conducted logistic regression models to examine the association of genetic variants with CAA/L during acute KD and with persistence >6 weeks using an additive model between cases and 238 controls with no CAA. We adjusted for age, gender and three principal components of genetic ancestry. We performed functional mapping and annotation (FUMA) analysis and further assessed the predictive risk score of genomic risk loci using the area under the receiver operating characteristic curve (AUC). Results: The top significant variants associated with CAA/L were in the intergenic regions (rs62154092 p<6.32E-08 most significant). Variants in SMAT4, LOC100127 , PTPRD, TCAF2 and KLRC2 were the most significant non-intergenic SNPs. FUMA identified 12 genomic risk loci with eQTL or chromatin interactions mapped to 48 genes. Of these NDUFA5 has been implicated in KD CAA and MICU and ZMAT4 has potential functional implications. Genetic risk score using these 12 genomic risk loci yielded an AUC of 0.86. Conclusions: This pharmacogenomics study provides insights into the pathogenesis of CAA/L in IVIG-treated KD patients. We have identified multiple novel SNPs associated with CAA/L and related genes with potential functional implications. The study shows that genomics can help define the cause of CAA/L to guide management and improve risk stratification of KD patients.

Hybrid Thrombectomy and Central Extracorporeal Membrane Oxygenation for Massive Pulmonary Embolism in a Child.

We describe a hybrid thrombectomy and central extracorporeal membrane oxygenation for a child in cardiogenic shock due to a massive pulmonary embolism.

Central Extracorporeal Membrane Oxygenation Support Following Calcium Channel Blocker Overdose in Children.

Refractory vasodilatory shock (RVS) following massive calcium channel blocker (CCB) overdose remains a challenging clinical entity. Peripheral venoarterial extracorporeal membrane oxygenation (ECMO) has proven useful in several cases of CCB intoxication, however, its use in the pediatric population poses unique challenges given the generally small size of pediatric peripheral vasculature in comparison to the high flow rates necessary for adequate mechanical circulatory support. As a result of these challenges, our group has adopted a "primary" central ECMO cannulation approach to the treatment of children and adolescents admitted to our center with profound RVS after CCB ingestion. We present four cases within the last year using this approach. All patients were successfully discharged from the hospital with no late morbidity at most recent follow-up. Central ECMO support in cases of massive vasodilatory shock following CCB overdose is safe and effective and should be considered early in the clinical course of these critically ill patients.

Seasonality and geographical distribution of Kawasaki disease among Black children in the Southeast United States.

Introduction: Kawasaki Disease (KD) is a leading cause of pediatric acquired heart disease in the United States, affecting up to 7,000 children annually. Seasonal variation, an epidemiological characteristic of KD, has previously been reported predominantly among Asian children; however, little is known about the epidemiology and seasonality of KD of Black children within the U.S. Methods: Electronic medical records were abstracted from 529 hospitalized KD patients admitted to a single tertiary center in Alabama between 2005 and 2019. Medical charts were reviewed to confirm KD diagnosis following American Heart Association criteria. Cases were stratified by the month of diagnosis date to assess seasonality, and statewide distribution of incidence is reported at county level using geographical spatial analysis. Comparisons were performed between Black patients and White patients with KD. Results: The average number of KD cases per year was 35. Approximately, 60% were males and 44% were White children (N = 234), 45% were Black children (N = 240) and 11% were other races (N = 55). Black children were younger than White children at KD admission (median age 32 vs. 41 months respectively, p = 0.02). Overall, the highest rates of cases occurred between January and April. When stratifying by race, cases started to rise in December among White children with the highest rates between February and April with a peak in March. Among Black children cases were high during the winter season (January-April) with a peak in April. Similarly high rates also occurred in June, July and November. There were no differences in geographical distribution of cases by race. Conclusion: KD incidence among White children in Alabama follows a seasonal cycle similar to other regions in the U.S. However, sustained incidence and additional peaks outside of the usual KD seasonality were seen among Black children with KD. Further studies are needed to investigate differential triggers between races.

Hybrid Norwood for Hypoplastic Left Heart Syndrome With Rare Aortic Arch Anatomy.

We describe the hybrid Norwood as first-stage palliation for a patient with hypoplastic left heart syndrome, right aortic arch, right descending aorta, bilateral ductus arteriosus, and left innominate artery arising from the left ductus.

Surgical Experience With Nine Cases of Obstructed Right Aortic Arch.

BACKGROUND: Right-sided aortic arch obstruction is an extremely rare congenital anomaly. A variety of surgical approaches have been described. This study reviews our institutional experience over the last 30 years. METHODS: Our surgical database at the University of Alabama at Birmingham and Children's Hospital of Alabama from 1992 to 2022 was reviewed to include all patients who underwent surgical repair for right-sided aortic arch obstruction. RESULTS: A total of nine patients underwent surgical repair for right-sided aortic arch obstruction. Surgical approach was via thoracotomy (n = 2, 22%), sternotomy (n = 5, 56%), or combined (n = 2, 22%). Primary extended end-to-end anastomosis was utilized for patients with discrete coarctation (n = 1, 11%), reverse subclavian flap for coarctation with associated distal arch hypoplasia (n = 2, 22%), GORE-TEX® tube graft for circumflex aorta (n = 1, 11%), and aortic arch advancement (n = 5, 56%) with or without patch augmentation for those with an interrupted or severely hypoplastic aortic arch. Reintervention was required in one patient (11%) for recoarctation. All patients were discharged in good condition. There was no hospital mortality and at 10.5 years (mean) follow-up there was one late death. CONCLUSION: Right aortic arch obstruction is a rare entity. Surgical approach should be tailored to the anatomy and associated intracardiac defects. Preoperative imaging with a CT angiogram is useful for operative planning. Sternotomy with single-stage primary repair is safe, effective, and our preferred surgical approach for patients with right aortic arch obstruction and associated intracardiac pathology.

Association Between Venous Homografts and Allosensitization After Norwood Procedure.

BACKGROUND: Right ventricle (RV) to pulmonary artery (PA) shunts have become the shunt of choice at many centers for use during the Norwood procedure for single ventricle palliation. Some centers have begun to use cryopreserved femoral or saphenous venous homografts as an alternative to polytetrafluoroethylene (PTFE) for shunt construction. The immunogenicity of these homografts is unknown, and potential allosensitization could have significant implications on transplant candidacy. METHODS: All patients undergoing Glenn procedure at our center between 2013 and 2020 were screened. Patients who initially underwent Norwood procedure with either PTFE or venous homograft RV-PA shunt and had available pre-Glenn serum were included in the study. The primary outcome of interest was panel reactive antibody (PRA) level at the time of Glenn surgery. RESULTS: Thirty-six patients met inclusion criteria (N = 28 PTFE, N = 8 homograft). Patients in the homograft group had significantly higher median PRA levels at the time of Glenn surgery (0% [IQR 0-18] PTFE vs 94% [IQR 74-100] homograft, P = .003). There were no other differences between the two groups. CONCLUSIONS: Despite potential improvements in PA architecture, the use of venous homografts for RV-PA shunt construction at the time of Norwood procedure is associated with significantly elevated PRA level at the time of Glenn surgery. Centers should carefully consider the use of currently available venous homografts given the high percentage of these patients who may require future transplantation.

A Multidisciplinary Surgical Approach to Mediastinal Masses in Children.

The aim of this study is to demonstrate the safety and advantages of a multidisciplinary approach to surgical resection of mediastinal masses in children. Eight patients underwent resection of a mediastinal mass by a team involving both a pediatric general surgeon and pediatric cardiothoracic surgeon. One patient required rapid initiation of cardiopulmonary bypass to complete the tumor resection and repair an aortic injury that occurred when removing adherent tumor from the structure. Perioperative outcomes were excellent for all patients. This series shows that a multidisciplinary surgical approach can be potentially life saving.

Health-Related Quality of Life After Single Ventricle Palliation or Tetralogy of Fallot Repair.

Single ventricle (SV) cardiac lesions and tetralogy of Fallot (TOF) are both common forms of cyanotic congenital heart disease. With advances in perioperative care and longitudinal follow-up, survival of these patients has dramatically improved and the majority survive to adulthood. This study compares health-related quality of life (HRQoL) of adult SV and TOF patients to each other and the general population. HRQoL of all surviving, non-transplanted SV and TOF patients 21 years of age and older at our institution was assessed with the SF-36 questionnaire via phone. Additional data including demographic parameters and information related to comorbidities and healthcare utilization were also analyzed. Among 81 eligible SV patients and 207 TOF patients, 33 (41%) and 75 (36%) completed the SF-36 phone survey, respectively. The mean age of SV patients was 32 vs. 38 years in the TOF group (p=0.01). SV patients reported more hepatic, pulmonary, and renal comorbidities. TOF patients were more likely to complete advanced degrees and more likely to have children (p=0.03). SV physical functioning scores were worse compared to TOF. In other domains of the SF-36 questionnaire, SV and TOF scores were similar. Compared to the general population, both groups reported worse bodily pain and mental health, but other aspects of psychosocial and general health were comparable. Overall HRQoL is good for both SV and TOF patients through early and mid-adulthood. Some QoL metrics were modestly worse in the SV patients. While these patients may have some physical limitations, psychosocial wellbeing appears preserved.

Pharmacogenomics of intravenous immunoglobulin response in Kawasaki disease.

Introduction: Kawasaki disease (KD) is a diffuse vasculitis in children. Response to high dose intravenous gamma globulin (IVIG), the primary treatment, varies according to genetic background. We sought to identify genetic loci, which associate with treatment response using whole genome sequencing (WGS). Method: We performed WGS in 472 KD patients with 305 IVIG responders and 167 non-responders defined by AHA clinical criteria. We conducted logistic regression models to test additive genetic effect in the entire cohort and in four subgroups defined by ancestry information markers (Whites, African Americans, Asians, and Hispanics). We performed functional mapping and annotation using FUMA to examine genetic variants that are potentially involved IVIG non-response. Further, we conducted SNP-set [Sequence] Kernel Association Test (SKAT) for all rare and common variants. Results: Of the 43,288,336 SNPs (23,660,970 in intergenic regions, 16,764,594 in introns and 556,814 in the exons) identified, the top ten hits associated with IVIG non-response were in FANK1, MAP2K3:KCNJ12, CA10, FRG1DP, CWH43 regions. When analyzed separately in ancestry-based racial subgroups, SNPs in several novel genes were associated. A total of 23 possible causal genes were pinpointed by positional and chromatin mapping. SKAT analysis demonstrated association in the entire MANIA2, EDN1, SFMBT2, and PPP2R5E genes and segments of CSMD2, LINC01317, HIVEPI, HSP90AB1, and TTLL11 genes. Conclusions: This WGS study identified multiple predominantly novel understudied genes associated with IVIG response. These data can serve to inform regarding pathogenesis of KD, as well as lay ground work for developing treatment response predictors.

Racial and socioeconomic disparities in pediatric heart transplant outcomes in the era of anti-thymocyte globulin induction.

BACKGROUND: Black race is associated with worse outcomes across solid organ transplantation. Augmenting immunosuppression through antithymocyte globulin (ATG) induction may mitigate organ rejection and graft loss. We investigated whether racial and socioeconomic outcome disparities persist in children receiving ATG induction. METHODS: Using the Pediatric Heart Transplant Society registry, we compared outcomes in Black and White children who underwent heart transplant with ATG induction between 2000 and 2020. The primary outcomes of treated rejection, rejection with hemodynamic compromise (HC), and graft loss (death or re-transplant). We explored the association of these outcomes with race and socioeconomic disparity, assessed using a neighborhood deprivation index [NDI] score at 1-year post-transplant (high NDI score implies more socioeconomic disadvantage). RESULTS: The study cohort included 1,719 ATG-induced pediatric heart transplant recipients (22% Black, 78% White). There was no difference in first year treated rejection (Black 24.5%, White 28.1%, p = 0.2). During 10 year follow up, the risk of treated rejection was similar; however, Black recipients were at higher risk of HC rejection (p = 0.009) and graft loss (p = 0.02). Black recipients had a higher mean NDI score (p < 0.001). Graft loss conditional on 1-year survival was associated with high NDI score in both White and Black recipients (p < 0.0001). In a multivariable Cox model, both high NDI score (HR 1.97, 95% CI 1.23-3.17) and Black race (HR 2.22, 95% CI 1.40-3.53) were associated with graft loss. CONCLUSION: Black race and socioeconomic disadvantage remain associated with late HC rejection and graft loss in children with ATG induction. These disparities represent important opportunities to improve long term transplant outcomes.

The attitudes of religious group leaders towards xenotransplantation: A focus group study.

Clinical trials of xenotransplantation (XTx) may start in coming years. Religious views have been mentioned as possible barriers to XTx acceptance. While there have been reports on perspectives of theologians in regard to XTx, no report has studied the perspectives of community religious leaders. A focus group was conducted with a sample of members of the following faith groups: Islam, Catholicism, and Protestantism. Qualitative content analysis was performed to identify interpretive themes. Four themes emerged. Participants were receptive to the idea of XTx and expressed no religious barriers to accepting a pig xenograft as a lifesaving therapy but did express certain concerns. Religious leaders accept the idea of XTx and do not see it as contradictory to their beliefs. However, some concerns were raised. Future studies addressing these concerns and exploring the potential role of religious leaders in educating the community on XTx are needed.

Will previous palliative surgery for congenital heart disease be detrimental to subsequent pig heart xenotransplantation?

INTRODUCTION: Pig heart xenotransplantation might act as a bridge in infants with complex congenital heart disease (CHD) until a deceased human donor heart becomes available. Infants develop antibodies to wild-type (WT, i.e., genetically-unmodified) pig cells, but rarely to cells in which expression of the 3 known carbohydrate xenoantigens has been deleted by genetic engineering (triple-knockout [TKO] pigs). Our objective was to test sera from children who had undergone palliative surgery for complex CHD (and who potentially might need a pig heart transplant) to determine whether they had serum cytotoxic antibodies against TKO pig cells. METHODS: Sera were obtained from children with CHD undergoing Glenn or Fontan operation (n = 14) and healthy adults (n = 8, as controls). All of the children had complex CHD and had undergone some form of cardiac surgery. Seven had received human blood transfusions and 3 bovine pericardial patch grafts. IgM and IgG binding to WT and TKO pig red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) were measured by flow cytometry, and killing of PBMCs by a complement-dependent cytotoxicity assay. RESULTS: Almost all children and adults demonstrated relatively high IgM/IgG binding to WT RBCs, but minimal binding to TKO RBCs (p < 0.0001 vs WT), although IgG binding was greater in children than adults (p < 0.01). All sera showed IgM/IgG binding to WT PBMCs, but this was much lower to TKO PBMCs (p < 0.0001 vs WT) and was greater in children than in adults (p < 0.05). Binding to both WT and TKO PBMCs was greater than to RBCs. Mean serum cytotoxicity to WT PBMCs was 90% in both children and adults, whereas to TKO PBMCs it was only 20% and < 5%, respectively. The sera from 6/14 (43%) children were cytotoxic to TKO PBMCs, but no adult sera were cytotoxic. CONCLUSIONS: Although no children had high levels of antibodies to TKO RBCs, 13/14 demonstrated antibodies to TKO PBMCs, in 6 of these showed mild cytotoxicity. As no adults had cytotoxic antibodies to TKO PBMCs, the higher incidence in children may possibly be associated with their exposure to previous cardiac surgery and biological products. However, the numbers were too small to determine the influence of such past exposures. Before considering pig heart xenotransplantation for children with CHD, testing for antibody binding may be warranted.

Cardiac and Pulmonary Histopathology in Baboons Following Genetically-Engineered Pig Orthotopic Heart Transplantation.

BACKGROUND Although improving, survival after pig orthotopic heart transplantation (OHTx) in baboons has been mixed and largely poor. The causes for the high incidence of early failure remain uncertain. MATERIAL AND METHODS We have carried out pig OHTx in 4 baboons. Two died or were euthanized within hours, and 2 survived for 3 and 8 months, respectively. There was evidence of a significant 'cytokine storm' in the immediate post-OHTx period with the elevations in IL-6 correlating closely with the final outcome. RESULTS All 4 baboons demonstrated features suggestive of respiratory dysfunction, including increased airway resistance, hypoxia, and tachypnea. Histopathological observations of pulmonary infiltration by neutrophils and, notably, eosinophils within vessels and in the perivascular and peribronchiolar space, with minimal cardiac pathology, suggested a role for early lung acute inflammation. In one, features suggestive of transfusion-related acute lung injury were present. The 2 longer-term survivors died of (i) a cardiac dysrhythmia with cellular infiltration around the conducting tissue (at 3 months), and (ii) mixed cellular and antibody-mediated rejection (at 8 months). CONCLUSIONS These initial findings indicate a potential role of acute lung injury early after OHTx. If this response can be prevented, increased survival may result, providing an opportunity to evaluate the factors affecting long-term survival.

Informed Consent for Potential Recipients of Pig Kidney Xenotransplantation in the United States.

Clinical trials of kidney xenotransplantation are being considered in the United States. Before this novel procedure can take place, investigators will have to obtain approval from the institutional review board. The consent form that will be used for such a trial and that will receive approval from the institutional review board will be complex. Informed consent-the process by which a research participant provides his/her permission to participate in a clinical trial-is a staple of the research process and most commonly is in the form of a physical document. In the case of a novel procedure with uncertain benefits and risks and a participant population in acute need of a transplant, the consent process is crucial. These complexities may raise several ethical considerations for the initial pig kidney xenotransplantation recipients in the United States that will require adaptations of the required elements of the informed consent process by the US Department of Human and Health Services. The ethical issues include (1) a subject's ability to withdraw from the trial, (2) restrictions on their reproductive rights, and (3) the possibility of the need for quarantine if there is a perceived risk of xenozoonosis. This article aims to discuss ethical considerations that may challenge the general required elements of the informed consent form stipulated by the 45 Code of Federal Regulations 46 of the US Department of Health and Human Services and to suggest recommendations for deliberation.

Hemodilution in high-risk cardiac surgery: Laboratory values, physiological parameters, and outcomes.

BACKGROUND: Acute normovolemic hemodilution (ANH) is a blood conservation strategy in cardiac surgery, predominantly used in coronary artery bypass graft (CABG) and/or valve procedures. Although higher complexity cardiac procedures may benefit from ANH, concerns for hemodynamic instability, and organ injury during hemodilution hinder its wider acceptance. Laboratory and physiological parameters during hemodilution in complex cardiac surgeries have not been described. STUDY DESIGN AND METHODS: This observational cohort (2019-2021) study included 169 patients who underwent thoracic aortic repair, multiple valve procedure, concomitant CABG with the aforementioned procedure, and/or redo sternotomies. Patients who received allogeneic blood were excluded. Statistical comparisons were performed between ANH (N = 66) and non-ANH controls (N = 103). ANH consisted of removal of blood at the beginning of surgery and its return after cardiopulmonary bypass. RESULTS: Intraoperatively, the ANH group received more albumin (p = .04) and vasopressor medications (p = .01), while urine output was no different between ANH and controls. Bilateral cerebral oximetry (rSO2 ) values were similar before and after hemodilution. During bypass, rSO2 were discretely lower in the ANH versus control group (right rSO2 p = .03, left rSO2 p = .05). No differences in lactic acid values were detected across the procedural continuum. Postoperatively, no differences in extubation times, intensive care unit length of stay, kidney injury, stroke, or infection were demonstrated. DISCUSSION: This study suggests hemodilution to be a safe and comparable blood conservation technique, even without accounting for potential benefits of reduced allogenic blood administration. The study may contribute to better understanding and wider acceptance of ANH protocols in high-risk cardiac surgeries.