Histopathology, mRNA expression profile, and donor-derived cell-free DNA for assessment of rejection in pediatric heart transplantation.

BACKGROUND: The relationship between histopathologic and molecular ("MMDx"®) assessments of endomyocardial biopsy (EMB) and serum donor-derived cell-free DNA (ddcfDNA) in acute rejection (AR) assessment following pediatric heart transplantation (HT) is unknown. METHODS: EMB sent for MMDx and histopathology from November 2021 to September 2022 were reviewed. MMDx and histopathology results were compared. DdcfDNA obtained ≤1 week prior to EMB were compared with histopathology and MMDx results. The discrimination of ddcfDNA for AR was assessed using receiver-operating curves. FINDINGS: In this study, 177 EMBs were obtained for histopathology and MMDx, 101 had time-matched ddcfDNA values. MMDx and Histopathology displayed moderate agreement for T-cell-mediated rejection (TCMR, Kappa = 0.52, p < .001) and antibody-mediated rejection (ABMR, Kappa = 0.41, p < .001). Discordant results occurred in 24% of cases, most often with ABMR. Compared with no AR, ddcfDNA values were elevated in cases of AR diagnosed by both histopathology and MMDx (p < .01 for all). Additionally, ddcfDNA values were elevated in injury patterns on MMDx, even when AR was not present (p = .01). DdcfDNA displayed excellent discrimination (AUC 0.83) for AR by MMDx and/or histopathology. Using a threshold of ≥0.135%, ddcfDNA had a sensitivity of 90%, specificity of 63%, PPV of 52%, and NPV of 94%. CONCLUSIONS: Histopathology and MMDx displayed moderate agreement in diagnosing AR following pediatric HT, with most discrepancies noted in the presence of ABMR. DdcfDNA is elevated with AR, with excellent discrimination and high NPV particularly when utilizing MMDx. A combination of all three tests may be necessary in some cases.

Interventions on residual lesions in patients with heterotaxy syndrome following orthotropic heart transplantation: A single-center experience.

BACKGROUND: Heterotaxy syndrome (HS) is a defect in lateralization which often results in complex intra and extracardiac abnormalities. Orthotropic heart transplantation (OHT) in HS involves intricate and individualized modifications to surgical technique. Post-OHT outcomes are worse in patients with HS, however, the impact of post-OHT residual lesions has not yet been characterized. METHODS: Patients with HS who underwent OHT at Ann & Robert H. Lurie Children's Hospital of Chicago between January 2012 and June 2023 were identified. Patients were excluded if follow-up data was not available due to follow up at a different institution of early mortality. Pre-OHT clinical data, surgical data, and post-OHT surgical and catheterization data were collected. RESULTS: Two early mortalities were excluded from analysis, leaving 15 patients in the study cohort. Median age at OHT was 3.7 years (range: 0.7-15.4). Nine out of 15 patients were diagnosed with residual lesions requiring intervention at a median of 188 days post transplantation. All interventions on residual lesions occurred via catheterization. Overall mortality rate was 27% (4/15) with all deaths occurring in patients with residual lesions (4/9 patients, 44%). 83% (10/12) of lesions were diagnosed via catheterization, and 83% (10/12) of lesions of occurred in the first year after transplant. CONCLUSIONS: Patients with HS are at high risk for residual lesions after OHT, which may contribute to increased mortality. Comprehensive invasive diagnostics were required to diagnose residual lesions, which were all addressed percutaneously.

Echocardiogram-Guided Balloon Valvuloplasty of the Aortic Valve in Neonates and Infants Reduces Contrast Exposure with Maintained Efficacy and Less Aortic Regurgitation.

Balloon aortic valvuloplasty (BAV) is performed in children with significant aortic stenosis (AS). Traditionally, contrast angiography measures the annulus and assesses aortic regurgitation (AR) after each dilation. Echocardiographic guidance is hypothesized to reduce contrast and radiation exposure, without compromising efficacy or safety. Patients < 10 kg undergoing BAV from 2013 to 2022 were retrospectively investigated. Agreement between echocardiographic and angiographic annulus measurements was assessed. Echocardiogram-guided (eBAV) and traditional angiogram-guided (tBAV) outcomes were compared controlling for weight, critical AS, and other congenital heart disease (CHD). Twelve eBAV and 19 tBAV procedures were performed. The median age was 33 days, median weight was 4.3 kg, 7 patients (23%) had critical AS, and 9 patients (29%) had other CHD. Annulus measurements by intraprocedural echocardiography and angiography displayed excellent correlation (ICC 0.95, p < 0.001). eBAV patients received less contrast (0.5 vs 3.5 ml/kg, p < 0.01). Five recent eBAV procedures were performed contrast free. Radiation exposure was not statistically different between the eBAV and tBAV groups (155 vs 313 µGy·M2, p = 0.12). One eBAV patient (8%) and 3 tBAV patients (16%, p = 0.62) experienced serious adverse events. Technical success (gradient < 35 mmHg and increase in AR by ≤ 1 grade) occurred in 11 eBAV patients (92%) and 16 tBAV patients (84%, p = 0.22). AR increased in 2 eBAV patients (17%) and 8 tBAV patients (44%, p = 0.02). eBAV was associated with similar efficacy and significantly lower contrast exposure and risk of aortic regurgitation. There was strong agreement between aortic valve annulus measurements by intraprocedural echocardiography and angiography, ultimately permitting contrast free BAV.

Left Atrial Hypertension and Respiratory Failure Requiring Venoarterial ECMO After Transcatheter Pulmonary Valve Replacement.

A 33-year-old woman with aortic valve stenosis status-post Ross at age 6 years developed symptomatic right heart failure from right ventricle to pulmonary artery conduit stenosis. Conduit rehabilitation and transcatheter pulmonary valve replacement resulted in acute left atrial hypertension and respiratory failure requiring venoarterial extracorporeal membrane oxygenation and atrial septal defect creation as a bridge to recovery.

Differences in outcomes between surgical pericardial window and pericardiocentesis in children with postpericardiotomy syndrome.

Children with postpericardiotomy syndrome may develop hemodynamically significant pericardial effusions warranting drainage by surgical pericardial window or pericardiocentesis. The optimal approach is unknown. We performed a retrospective observational study at two pediatric cardiac centers. We included 42 children aged <18 years who developed postpericardiotomy syndrome following cardiac surgery between 2014 and 2021. Thirty-two patients underwent pericardial window and 10 underwent pericardiocentesis. Patients in the pericardial window group presented with postpericardiotomy syndrome sooner than those who underwent pericardiocentesis (median 7.5 days vs. 14.5 days, P = 0.03) and tended to undergo earlier intervention (median 8 days vs. 16 days, P = 0.16). No patient required subsequent drainage. There were no differences between groups in days of pericardial tube duration (median 4 days), complications, and subsequent days of intensive care or hospitalization. For children with postpericardiotomy syndrome with a pericardial effusion warranting drainage, these data suggest that pericardial window and pericardiocentesis have similar efficacy, safety, and resource utilization.

A Volume Challenge Reveals the Diagnosis of Pediatric Restrictive Cardiomyopathy.

A healthy 11-year-old girl presented with exercise intolerance of unclear etiology, and her physical exam was notable for a 3/6 systolic ejection murmur at the left upper sternal border with radiation to the back. Extensive noninvasive workup consisted of ECG, transthoracic echocardiogram, and cardiac MRI/MRA, which were all nondiagnostic. She was ultimately referred for cardiac catheterization. Baseline invasive hemodynamics demonstrated a normal cardiac index and pulmonary vascular resistance but was notable for mildly elevated right and left end-diastolic pressures. A diagnosis remained elusive, so a 500 mL volume challenge was performed, which unmasked right and left ventricular waveform transformations to reveal the pathognomonic "square root sign" of restrictive cardiomyopathy with concordant RV/LV respirophasic variation. These findings and her clinical history allowed for the rare pediatric diagnosis of restrictive cardiomyopathy early in her clinical course, prior to the development of overt signs of pathologic myocardial remodeling, such as pulmonary hypertension and biatrial enlargement.

Magnetic Resonance Imaging in Pediatric Myocarditis: Trends and Associations With Cost and Outcome.

BACKGROUND: Cardiac magnetic resonance (CMR) provides tissue characterization and structural and functional data. CMR has high sensitivity and specificity for myocarditis in adults and children. The relationship between pediatric CMR use, cost, and clinical outcome has not been studied. OBJECTIVES: This work aims to describe temporal trends in CMR imaging for pediatric myocarditis and examine associations between CMR use, hospital cost, and outcomes. METHODS: A retrospective cohort study of all inpatients <21 years of age with a diagnosis of myocarditis reported to the Pediatric Health Information System (2004-2019) was performed. Trends in CMR use were examined. A propensity-matched subcohort using center and patient level variables was used to assess whether outcomes differed by CMR use. RESULTS: A total of 4,195 children with myocarditis from 47 hospitals were identified. The median age was 11.5 years (IQR: 1.5-16.0 years) and 2,617 (62%) were male. CMR was used in 23% and mortality occurred in 6%. CMR use during hospitalization increased from 2% in 2004 to 37% in 2019 (odds ratio [OR]: 1.19 [95% CI: 1.17-1.21]). After propensity score matching, CMR use was associated with higher median cost (+$5,340 [95% CI: +$1,739 to +$9,936]) and similar median length of stay (0 days [95% CI: -1 to +1 days]). Using quantile regression, CMR was associated with lower 90th percentile cost (-$77,200 [95% CI: -$127,373 to -$31,339]). More children receiving CMR were discharged alive in the first 30 days after admission (OR: 1.89 days [95% CI: 1.28-2.29]). Within the propensity matched cohort, <10 of 790 CMR recipients died compared to 42 of 790 in the non-CMR group. CONCLUSIONS: CMR use in children with myocarditis has increased over the past 15 years. CMR use is associated with higher cost of hospitalization and similar length of stay for most children but lower cost among the sickest children. CMR use in specific patients may improve clinical outcomes at a lower cost.

Perspective on Cerebral Autoregulation Monitoring in Neonatal Cardiac Surgery Requiring Cardiopulmonary Bypass.

The autoregulation of cerebral blood flow protects against brain injury from transient fluctuations in arterial blood pressure. Impaired autoregulation may contribute to hypoperfusion injury in neonates and infants. Monitoring cerebral autoregulation in neonatal cardiac surgery as a guide for arterial blood pressure management may reduce neurodevelopmental morbidity. Cerebral autoregulation monitoring has been validated in animal models and in an adult trial autoregulation monitoring during bypass improved postoperative delirium scores. The nuances of pediatric cardiac disease and congenital heart surgery make simply applying adult trial findings to this unique population inappropriate. Therefore, dedicated pediatric clinical trials of cerebral autoregulation monitoring are indicated.

Deployed Dimensions of the GORE® CARDIOFORM ASD Occluder as Function of Defect Size.

The GORE® CARDIOFORM ASD occluder (ASDO) is approved for closure of ASDs up to 35 mm diameter. With an adaptable central waist, each device size is suitable over a range of defect diameters. Understanding deployed dimensions across various defect sizes will assist operators. Therefore, this study investigates the deployed dimensions of the ASDO as a function of defect size. A 2-mm-thick ASD model with circular defects ranging from 5 to 35 mm was 3D printed. Diameter, width, and left-right disc diameter were measured by fluoroscopy after ASDO devices were deployed in applicable defects. Linear regression evaluated relationships between device size, defect size, and deployed dimensions. Six ASDOs of each size (27, 32, 37, 44, and 48 mm) were deployed in all applicable defects. There was significant ASDO size-defect size interaction in determining deployed ASDO diameter. Diameter was positively associated with defect size for 48-mm (B = 0.13, p < 0.001) and 44-mm (B = 0.11, p < 0.001) ASDOs, while no association was seen for 27-mm, 32-mm, or 37-mm ASDOs. No such interaction existed for deployed width or left-right disc difference. Controlling for ASDO size, width (B = - 0.12, p < 0.001) and left-right disc difference (B = - 0.06, p < 0.001) were negatively associated with defect size. In smaller defects, the 44-mm and 48-mm ASDOs display progressive diameter foreshortening, and all devices display progressive increase in width and left-right disc asymmetry. Anticipating the degree of diameter foreshortening may be critical when attempting closure of fenestrated lesions and/or in patients with limited total atrial septal length.

Mortality and Factors Associated With Hemorrhage During Pediatric Extracorporeal Membrane Oxygenation.

OBJECTIVES: To quantify and identify factors associated with bleeding events during pediatric extracorporeal membrane oxygenation. DESIGN: Retrospective cohort study with primary outcome of bleeding days on extracorporeal membrane oxygenation. SETTING: Single tertiary care children's hospital. SUBJECTS: One-hundred twenty-two children supported with extracorporeal membrane oxygenation for greater than 12 hours during January 2015 through December 2016. INTERVENTIONS: Bleeding days were identified if mediastinal or cannula site exploration, activated factor VII administration, gastrointestinal, pulmonary, or intracranial hemorrhages occurred. Logistic regression was used to assess factors associated with bleeding days. MEASUREMENTS AND MAIN RESULTS: Study population was identified from institutional extracorporeal membrane oxygenation database. Clinical, laboratory, and survival data were obtained from medical records. Only data from patients' first extracorporeal membrane oxygenation run were used. One-hundred twenty-two patients with median age of 17 weeks (interquartile range, 1-148 wk) were analyzed. Congenital heart disease (n = 56, 46%) was the most common diagnosis. Bleeding days comprised 179 (16%) of the 1,121 observed extracorporeal membrane oxygenation-patient-days. By extracorporeal membrane oxygenation day 4, 50% of users had experienced a bleeding day. Central rather than peripheral cannulation (odds ratio, 2.58; 95% CI, 1.47-4.52; p < 0.001), older age (odds ratio, 1.31 per increased week; 95% CI, 1.14-1.52; p < 0.001), higher lactate (odds ratio, 1.08 per 1 mmol/L increase; 95% CI, 1.05-1.12; p < 0.001), and lower platelets (odds ratio, 0.87 per 25,000 cell/µL increase; 95% CI, 0.77-0.99; p = 0.005) were associated with bleeding days. Patients who experienced more frequent bleeding (> 75th percentile) had fewer ventilator-free and hospital-free days in the 60 days after cannulation (0 vs 31; p = 0.002 and 0 vs 0; p = 0.008) and higher in-hospital mortality (68 vs 34%; p < 0.001). CONCLUSIONS: Central cannulation, older age, low platelets, and high lactate are associated with bleeding days during pediatric extracorporeal membrane oxygenation. Patients who bleed more frequently during extracorporeal membrane oxygenation have higher in-hospital mortality, longer technological dependence, and reduced hospital-free days.

Outcomes of Infants Supported With Extracorporeal Membrane Oxygenation Using Centrifugal Versus Roller Pumps: An Analysis From the Extracorporeal Life Support Organization Registry.

OBJECTIVES: To determine whether mortality differs between roller and centrifugal pumps used during extracorporeal membrane oxygenation in infants weighing less than 10 kg. DESIGN: Retrospective propensity-matched cohort study. SETTING: All extracorporeal membrane oxygenation centers reporting to the Extracorporeal Life Support Organization. PATIENTS: All patients less than 10 kg supported on extracorporeal membrane oxygenation during 2011-2016 within Extracorporeal Life Support Organization Registry. INTERVENTIONS: Centrifugal and roller pump recipients were propensity matched (1:1) based on predicted probability of receiving a centrifugal pump using demographic variables, indication for extracorporeal membrane oxygenation, central versus peripheral cannulation, and pre-extracorporeal membrane oxygenation patient management. MEASUREMENTS AND MAIN RESULTS: A total of 12,890 patients less than 10 kg were supported with extracorporeal membrane oxygenation within the Extracorporeal Life Support Organization registry during 2011-2016. Patients were propensity matched into a cohort of 8,366. Venoarterial and venovenous extracorporeal membrane oxygenation runs were propensity matched separately. The propensity-matched cohorts were similar except earlier year of extracorporeal membrane oxygenation (standardized mean difference, 0.49) in the roller pump group. Within the propensity-matched cohort, survival to discharge was lower in the centrifugal pump group (57% vs 59%; odds ratio, 0.91; 95% CI, 0.83-0.99; p = 0.04). Hemolytic, infectious, limb injury, mechanical, metabolic, neurologic, pulmonary, and renal complications were more frequent in the centrifugal pump group. Hemorrhagic complications were similar between groups. Hemolysis mediated the relationship between centrifugal pumps and mortality (indirect effect, 0.023; p < 0.001). CONCLUSIONS: In this propensity score-matched cohort study of 8,366 extracorporeal membrane oxygenation recipients weighing less than 10 kg, those supported with centrifugal pumps had increased mortality and extracorporeal membrane oxygenation complications. Hemolysis was evaluated as a potential mediator of the relationship between centrifugal pump use and mortality and met criteria for full mediation.

RBC Exposure in Pediatric Extracorporeal Membrane Oxygenation: Epidemiology and Factors Associated With Large Blood Transfusion Volume.

OBJECTIVES: To quantify and identify factors associated with large RBC exposure in children supported with extracorporeal membrane oxygenation. DESIGN: Retrospective cohort study. SETTING: Single tertiary care children's hospital. PATIENTS: One-hundred twenty-two children supported with extracorporeal membrane oxygenation for greater than 12 hours during January 1, 2015, to December 31, 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical, laboratory, and survival data were obtained from medical records. Only data from patients' first extracorporeal membrane oxygenation run were used. The primary outcome was RBC volume exposure during extracorporeal membrane oxygenation (mL/kg/d). Patients with RBC exposure volume greater than 75th percentile were categorized as "high RBC use" patients. A "bleeding day" was identified if mediastinum or cannula sites were explored and/or Factor VIIa administration, gastrointestinal, pulmonary, or intracranial hemorrhages occurred. Median age was 0.3 years (interquartile range, 0-3 yr). Congenital heart disease (n = 56; 46%) was the most common diagnosis. Median RBC volume transfused during extracorporeal membrane oxygenation was 39 mL/kg/d (interquartile range, 21-66 mL/kg/d). High RBC use patients were more likely be supported by venoarterial extracorporeal membrane oxygenation (100 vs 76%; p = 0.006), have congenital heart disease (68 vs 39%; p = 0.02), and experience bleeding (33 vs 11% d; p < 0.001). High RBC use patients showed a trend toward higher in-hospital mortality (58 vs 37%; p = 0.07). In the multivariable analysis, younger age (-9% per year; 95% CI, -10% to -7%; p < 0.001), more blood draws per day (+8%; 95% CI, 6-11%; p < 0.001), and higher proportion of bleeding days (+22% per 10% increase; 95% CI, 16-29%; p < 0.001) were associated with larger RBC exposure (model R = 0.66). CONCLUSIONS: Bleeding during extracorporeal membrane oxygenation, frequent laboratory draws, and younger age were associated with increased RBC exposure during extracorporeal membrane oxygenation. Higher transfusion volume was associated with increased mortality.

Reliability of radiographic measures in infants with clubfoot treated with the Ponseti method.

PURPOSE: The aim of this study was two-fold: (1) to determine if radiographic measures can be reliably made in infants being treated with the Ponseti method and (2) to document radiographic changes before and after Achilles tenotomy. METHODS: A retrospective radiographic and chart review was performed on children with clubfoot treated by the Ponseti method at a single institution over a 10-year period. Five independent reviewers measured a series of angles from a lateral forced dorsiflexion radiograph taken prior to and following Achilles tenotomy. These measures were taken in triplicate to determine the intra- and inter-reader reliability of dorsiflexion, tibio-calcaneal, talo-calcaneal, and talo-first metatarsal angles. RESULTS: Thirty-six subjects (56 feet) were treated with the Ponseti method and met the inclusion criteria. The median (range) age of patients at the time of tenotomy was 52 (34-147) days. The intra-reader reliability [intra-rater correlation coefficient (ICC)] for each of the measured angles pre- and post-tenotomy ranged from 0.933 to 0.995 and 0.864 to 0.995, respectively. Similarly, the inter-reader reliabilities (ICC) ranged from 0.727 for the pre-tenotomy (talo-calcaneal) to 0.950 for the post-tenotomy (talo-first metatarsal) angles. The mean differences between pre- and post-tenotomy radiographs were: dorsiflexion increase of 17°, tibio-calcaneal angle increase of 19°, talo-calcaneal angle increase of 9°, and talo-first metatarsal angle increase of 10° (p-value ≤0.001 for all measurements except the talo-first metatarsal angle, with a p-value of 0.001). CONCLUSIONS: Reliable radiographic measures can be made from lateral dorsiflexion radiographs of clubfeet treated with the Ponseti method before and after Achilles tenotomy.

Can Radiographs Predict Outcome in Patients With Idiopathic Clubfeet Treated With the Ponseti Method?

BACKGROUND: The aim of this study was to determine if radiographic measurements, taken before tenotomy, can predict outcome in children with idiopathic clubfoot treated by the Ponseti method. METHODS: A retrospective chart and radiographic review was performed on children with idiopathic clubfoot treated with the Ponseti method over a 10-year period with minimum 2-year follow-up that had a forced dorsiflexion lateral foot radiograph before tenotomy. All angles were measured in duplicate on the pretenotomy radiographs, including: foot dorsiflexion (defined as the 90 minus the angle between the tibial shaft and a plastic plate used to dorsiflex the foot), tibio-calcaneal, talo-calcaneal, and talo-first metatarsal angles. Clinical review of patient records identified different patient outcomes: no additional treatment required, relapse (additional casting and/or surgery required), recurrence (any additional surgery required), or reconstruction (surgery not including repeat tenotomy). RESULTS: Forty-five patients (71 feet) were included in the study. The median age at follow-up was 4.6 years. The intrareader reliability was acceptable for all measures. Thirteen of the 71 (18%) feet required additional surgery, occurring at a median age of 3.6 years. Of the 4 radiographic measures, only pretenotomy foot dorsiflexion predicted recurrence (hazard ratio=0.96, P=0.03). Youden's method identified 16.6 degrees of dorsiflexion as the optimal cutoff. Feet with at least that amount of dorsiflexion pretenotomy (n=21) experienced no recurrences; feet with less than that amount of dorsiflexion (n=50) experienced 13 recurrences (P=0.007). CONCLUSIONS: Reduced foot dorsiflexion on lateral forced dorsiflexion pretenotomy radiograph was associated with an increased risk of recurrence. Radiographic dorsiflexion to 15 degrees past neutral before tenotomy appears to predict successful treatment via the Ponseti method.