Left ventricular thrombus in the multisystem inflammatory syndrome in children associated with COVID-19.

A 3-year-old girl presenting with fever, mucocutaneous inflammation, and acute gastrointestinal symptoms met criteria for the multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C). Echocardiography showed severely decreased left ventricular (LV) function with an apical mass. After treatment with intravenous (IV) immunoglobulin, IV steroids, anakinra, milrinone, and systemic anticoagulation, her LV function rapidly improved and the mass became increasingly mobile. Given the risk of systemic embolization, the mass was excised through left ventriculotomy and pathology confirmed a thrombus.

Infliximab versus second intravenous immunoglobulin for treatment of resistant Kawasaki disease in the USA (KIDCARE): a randomised, multicentre comparative effectiveness trial.

BACKGROUND: Although intravenous immunoglobulin (IVIG) is effective therapy for Kawasaki disease, 10-20% of patients have recrudescent fever as a sign of persistent inflammation and require additional treatment. We aimed to compare infliximab with a second infusion of IVIG for treatment of resistant Kawasaki disease. METHODS: In this multicentre comparative effectiveness trial, patients (aged 4 weeks to 17 years) with IVIG resistant Kawasaki disease and fever at least 36 h after completion of their first IVIG infusion were recruited from 30 hospitals across the USA. Patients were randomly assigned (1:1) to second IVIG (2 g/kg over 8-12 h) or intravenous infliximab (10 mg/kg over 2 h without premedication), by using a randomly permuted block randomisation design with block size of two or four. Patients with fever 24 h to 7 days following completion of first study treatment crossed over to receive the other study treatment. The primary outcome measure was resolution of fever at 24 h after initiation of study treatment with no recurrence of fever attributed to Kawasaki disease within 7 days post-discharge. Secondary outcome measures included duration of fever from enrolment, duration of hospitalisation after randomisation, and changes in markers of inflammation and coronary artery Z score. Efficacy was analysed in participants who received treatment and had available outcome values. Safety was analysed in all randomised patients who did not withdraw consent. This clinical trial is registered with ClinicalTrials.gov, NCT03065244. FINDINGS: Between March 1, 2017, and Aug 31, 2020, 105 patients were randomly assigned to treatment and 103 were included in the intention-to-treat population (54 in the infliximab group, 49 in the second IVIG group). Two patients randomised to infliximab did not receive allocated treatment. The primary outcome was met by 40 (77%) of 52 patients in the infliximab group and 25 (51%) of 49 patients in the second IVIG infusion group (odds ratio 0·31, 95% CI 0·13-0·73, p=0·0076). 31 patients with fever beyond 24 h received crossover treatment: nine (17%) in the infliximab group received second IVIG and 22 (45%) in second IVIG group received infliximab (p=0·0024). Three patients randomly assigned to infliximab and two to second IVIG with fever beyond 24h did not receive crossover treatment. Mean fever days from enrolment was 1·5 (SD 1·4) for the infliximab group and 2·5 (2·5) for the second IVIG group (p=0·014). Mean hospital stay was 3·2 days (2·1) for the infliximab group and 4·5 days (2·5) for the second IVIG group (p<0·001). There was no difference between treatment groups for markers of inflammation or coronary artery outcome. 24 (44%) of 54 patients in the infliximab group and 33 (67%) of 49 in the second IVIG group had at least one adverse event. A drop in haemoglobin concentration of at least 2g/dL was seen in 19 (33%) of 58 patients who received IVIG as either their first or second study treatment (three of whom required transfusion) and in three (7%) of 43 who received only infliximab (none required transfusion; p=0·0028). Haemolytic anaemia was the only serious adverse events deemed definitely or probably related to study treatment, and was reported in nine (15%) of 58 patients who received IVIG as either their first or second study treatment and none who received infliximab only. INTERPRETATION: Infliximab is a safe, well tolerated, and effective treatment for patients with IVIG resistant Kawasaki disease, and results in shorter duration of fever, reduced need for additional therapy, less severe anaemia, and shorter hospitalisation compared with second IVIG infusion. FUNDING: Patient Centered Outcomes Research Institute.

Changes in Provider Prescribing Behavior for Infants with Single Ventricle Physiology After Evidence-Based Publications.

BACKGROUND: The impact of published evidence on clinical practice has been understudied in pediatric cardiology. OBJECTIVE: We sought to assess changes in prescribing behavior for angiotensin-converting enzyme inhibitor (ACEI) and digoxin at discharge after initial palliation of infants with single ventricle (SV) physiology following the publication of two large studies: The Pediatric Heart Network Infant Single Ventricle (PHN-ISV) trial showing no benefit with routine ACEI use and the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) analysis showing an association between digoxin and survival. METHODS: ICD-9-10 codes identified SV infants from the Pediatric Health Information System (1/2004 to 1/2018) and charge codes identified medications at discharge. Generalized estimating equations implementing segmented logistic regressions modeled medication use, before and after (with a 3-month washout period) the relevant publication (ACEI 7/1/2010; digoxin 4/1/2016). A subgroup analysis was performed for hypoplastic left heart syndrome (HLHS). RESULTS: ACEI use (37 centers, n = 4700) at discharge did not change over time during the pre-publication period. After publication of the PHN-ISV trial, ACEI use decreased (OR: 0.61, CI 0.44-0.84, p = 0.003). Digoxin use (43 centers, n = 4778) decreased by 1% monthly before publication. After the NPC-QIC publication, digoxin use increased (OR: 2.07, CI 1.05-4.08, p = 0.04) with an ongoing increase of 9% per month. Results were similar for the HLHS subgroup. CONCLUSIONS: Prescribing behavior changed congruently after the publication of evidence-based studies, with decreased ACEI use and increased digoxin use at discharge following initial palliation of SV infants. Our findings suggest scientific findings were rapidly implemented into clinical practice.

Poor Weight Recovery Between Stage 1 Palliation and Hospital Discharge for Infants with Single Ventricle Physiology: An Analysis of the National Pediatric Cardiology Quality Improvement Collaborative Phase II Dataset.

OBJECTIVE: To investigate change in weight-for-age z-scores (WAZ) and risk factors for impaired weight gain between stage 1 palliation (S1P) for single ventricle physiology and discharge. STUDY DESIGN: This was a secondary analysis of the National Pediatric Cardiology Quality Improvement Collaborative Phase II database. The primary outcome was change in WAZ between S1P and discharge. Risk factors were selected using multivariable mixed effects regression constructed by step-wise model selection, with adjustment for WAZ at S1P and a random effect for center. RESULTS: Of 730 infants who were discharged after S1P, WAZ decreased in 98.6% (-1.5 ± 0.7). WAZ at discharge was <-1 but >-2 (at risk) in 40% and <-2 (failure to thrive) in 35% of participants. Males, higher WAZ at S1P, non-S1P procedures (mostly noncardiac), increased length of stay, necrotizing enterocolitis, and angiotensin-converting enzyme inhibitor use at discharge were associated with a greater decrease in WAZ. Preoperative enteral feeding and respiratory medications were associated with a lesser decrease in the WAZ. CONCLUSIONS: Nearly all infants lose weight after S1P with little recovery by hospital discharge. At discharge, three-quarters of the infants in the cohort were at risk for impaired weight gain or had failure to thrive. Most risk factors associated with change in WAZ were unmodifiable or surrogates of disease severity. Novel interventions are needed to minimize the early catabolic effects and promote anabolic recovery after S1P.

Implications of Left Ventricular Dysfunction at Presentation for Infants with Coarctation of the Aorta.

Infants with aortic coarctation may present with left ventricular (LV) dysfunction which may complicate the postoperative course and lead to increased healthcare costs. We aimed to define the prevalence of moderate to severe left ventricular (LV) systolic dysfunction, evaluate time to recovery, and compare health care costs. Single-center retrospective cohort study at a tertiary care hospital was conducted. Infants < 6 months old at diagnosis with aortic coarctation were identified using surgical codes for coarctation repair between January 2010 and May 2018. Moderate to severe dysfunction was defined as ejection fraction (EF) < 40%. Of 160 infants studied, 18 (11%) had moderate to severe LV dysfunction at presentation. Compared to those with better LV function, infants with moderate to severe LV dysfunction were older at presentation (12 vs. 6 days, p = 0.004), had more postoperative cardiac intensive care unit (ICU) days (5 vs. 3, p < 0.001), and more ventilator days (3.5 vs. 1, p < 0.001). The median time to normal LV EF (≥ 55%) was 6 days postoperatively (range 1-230 days). Infants presenting with moderate to severe LV dysfunction had higher index hospitalization costs ($90,560 vs. $59,968, p = 0.02), but no difference in cost of medical follow-up for the first year following discharge ($3,078 vs. $2,568, p = 0.46). In the current era, > 10% of infants with coarctation present with moderate to severe LV dysfunction that typically recovers. Those with moderate to severe dysfunction had longer duration of mechanical ventilation and postoperative cardiac ICU stays, likely driving higher costs of index hospitalization.

The association between feeding protocol compliance and weight gain following high-risk neonatal cardiac surgery.

BACKGROUND: Children with congenital heart disease are at high risk for malnutrition. Standardisation of feeding protocols has shown promise in decreasing some of this risk. With little standardisation between institutions' feeding protocols and no understanding of protocol adherence, it is important to analyse the efficacy of individual aspects of the protocols. METHODS: Adherence to and deviation from a feeding protocol in high-risk congenital heart disease patients between December 2015 and March 2017 were analysed. Associations between adherence to and deviation from the protocol and clinical outcomes were also assessed. The primary outcome was change in weight-for-age z score between time intervals. RESULTS: Increased adherence to and decreased deviation from individual instructions of a feeding protocol improves patients change in weight-for-age z score between birth and hospital discharge (p = 0.031). Secondary outcomes such as markers of clinical severity and nutritional delivery were not statistically different between groups with high or low adherence or deviation rates. CONCLUSIONS: High-risk feeding protocol adherence and fewer deviations are associated with weight gain independent of their influence on nutritional delivery and caloric intake. Future studies assessing the efficacy of feeding protocols should include the measures of adherence and deviations that are not merely limited to caloric delivery and illness severity.

Digoxin Use in Infants with Single Ventricle Physiology: Secondary Analysis of the Pediatric Heart Network Infant Single Ventricle Trial Public Use Dataset.

Digoxin has been associated with reduced interstage mortality after Norwood procedure. We sought to determine its association with survival and change in weight-for-age Z-score (WAZ) before the superior cavopulmonary connection (SCPC) surgery and at 14 months in a heterogeneous group of single ventricle infants. We performed a post-hoc analysis of the Pediatric Heart Network Infant Single Ventricle public use dataset to determine associations between digoxin and survival, transplant-free survival, and change in WAZ pre-SCPC and at 14 months. Sub-analyses of survival and transplant-free survival were performed for subjects who underwent Damus-Kaye-Stansel (DKS)/Norwood. Propensity score weighting was used in Cox hazard-proportion models. Of 229 subjects, 82 (36%) received digoxin and 147 (64%) received no digoxin. Pre-SCPC and 14-month survival and transplant-free survival were not significantly different between the digoxin and no digoxin groups for the main cohort and DKS/Norwood sub-group. However, in DKS/Norwood subjects there was a trend towards improved interstage transplant-free survival in the digoxin group (95.7 vs. 89.6%, p = 0.08). Digoxin was associated with a greater decrease in WAZ from birth to pre-SCPC (- 1.96 ± 0.19 vs. - 1.31 ± 0.18, p < 0.001) and birth to 14 months (- 0.64 ± 0.15 vs. - 0.19 ± 0.15, p = 0.03). Digoxin was not associated with improved survival during the interstage or at 14 months in a mixed single ventricle cohort, but there was a trend towards improved interstage transplant-free survival in post-Norwood infants. As digoxin was associated with poorer weight gain, further research is needed to identify the risks/benefits for anatomic subtypes of infants with single ventricles.

Tricuspid Valve Adaptation during the First Interstage Period in Hypoplastic Left Heart Syndrome.

BACKGROUND: Tricuspid regurgitation (TR) is an important risk factor for morbidity and mortality in hypoplastic left heart syndrome (HLHS), yet the evolution of tricuspid valve (TV) dysfunction in HLHS is poorly understood. This study sought to examine changes in TV function in HLHS between the first two stages of surgical palliation and to determine the mechanism of TR at the time of stage two surgery-bidirectional cavopulmonary anastomosis (BCPA). METHODS: We prospectively investigated 44 infants at two time points-prior to Norwood-Sano (T1 - median age 5.4 days) and prior to BCPA (T2 - median age 4.7 months) using two-dimensional (2DE) and three-dimensional echocardiography (3DE). Right ventricular (RV) size, function and shape was assessed with 2DE. Extracted spatial coordinates from 3DE were used to calculate TV leaflet and annular area, tethering and prolapse volumes, bending angle, and coaptation index. TR was graded qualitatively, and 2D and 3D vena contracta (VC) were measured. RESULTS: The cohort from T1 to T2 had increased indexed leaflet and annular area (P < .0001) and tethering volume (P < .0001), with no change in coaptation. Significant TR was present in 14 infants (32%) at T2 and was associated with greater leaflet (P = .02) and annular areas (P = .002) and greater prolapse volume (P = .008), but not tethering volume or reduced coaptation. At latest follow-up (median 23 months), 13 patients died or required transplantation. Only 3DE VC at T2 was associated with death or transplantation. CONCLUSIONS: The TV in HLHS adapts to interstage stressors (increased preload and afterload) by increasing leaflet size to maintain adequate leaflet coaptation. Significant TR at T2 was associated with greater leaflet size and prolapse. This may represent TV maladaptation from an excessive response in leaflet expansion to stressors.

Platelet Inhibition in Shunted Infants on Aspirin at Short and Midterm Follow-Up.

There are few data to guide aspirin therapy to prevent shunt thrombosis in infants. We aimed to determine if aspirin administered at conventional dosing in shunted infants resulted in ≥50% arachidonic acid (AA) inhibition in short and midterm follow-up using thromboelastography with platelet mapping (TEG-PM) and to describe bleeding and thrombotic events during follow-up. We performed a prospective observational study of infants on aspirin following Norwood procedure, aortopulmonary shunt alone, or cavopulmonary shunt surgery. We obtained TEG-PM preoperatively, after the third dose of aspirin, at the first postoperative clinic visit, and 2-8 months after surgery. The primary outcome was the proportion of subjects with ≥50% AA inhibition on aspirin. All bleeding and thrombotic events were collected. Of 24 infants analyzed, 13% had ≥50% AA inhibition at all designated time points after aspirin initiation; 38% had ≥50% AA inhibition after the third aspirin dose of aspirin, 60% at the first postoperative clinic visit, and 26% 2-8 months after surgery. Bleeding events occurred in eight subjects, and two had a thrombotic event. Bleeding events were associated with greater AA inhibition just prior to starting aspirin (p = 0.02) and after the third dose of aspirin (p = 0.04), and greater ADP inhibition before surgery (p = 0.03). The majority of infants failed to consistently have ≥50% AA inhibition when checked longitudinally postoperatively. Preoperative TEG-PM may be useful in identifying infants at higher risk of bleeding events on aspirin in the early postoperative period. Further research is needed to guide antiplatelet therapy in this population.

Tricuspid regurgitation in hypoplastic left heart syndrome: mechanistic insights from 3-dimensional echocardiography and relationship with outcomes.

BACKGROUND: Our purpose was to test the following hypotheses: (1) patients with hypoplastic left heart syndrome who develop significant tricuspid regurgitation (TR) or require tricuspid valve (TV) surgery in the medium term have detectable TV abnormalities by 3-dimensional echocardiography (3DE) prestage 1 palliation and (2) TR is associated with reduced survival and increased TV intervention. METHODS AND RESULTS: Infants were prospectively studied with 3DE and 2DE prestage 1 and followed up for the end points of TR, TV surgery, transplantation, or death. From prestage 1 3DE, spatial coordinates of TV annulus and leaflets were extracted; annulus size, leaflet area, prolapse volume, tethering volume, bending angle, and papillary muscle angle were measured. TR was assessed prestage 1 and at latest follow-up. Of 70 patients, 62 (88.6%) had mild or less TR and 8 (11.4%) had moderate or greater TR prestage 1. Prestage 1 tethering volume correlated to leaflet area (r=0.736; P<0.001), annulus area (r=0.651; P<0.001), right ventricular end-diastolic area (r=0.347; P=0.003), fractional area change (r=-0.387; P<0.001), and TR grade (r=0.447; P<0.001). At follow-up, 46 (65.7%) had mild or less TR (group A) and 24 (34.3%) had moderate or greater TR (group B). Prestage 1 3DE showed greater TV tethering volume and flatter annulus in group B. Survival was better in group A. CONCLUSIONS: Increased TV tethering volume and flatter bending angle prestage 1 palliation is associated with TV failure at medium-term follow-up. Increased prestage 1 tethering is related to having larger TV annulus, larger leaflet area, larger right ventricular size, and reduced systolic function. TR progression results in increased TV intervention and decreased survival.

Factors associated with recoarctation after surgical repair of coarctation of the aorta by way of thoracotomy in young infants.

Echocardiography is the mainstay of preoperative arch imaging in infants with coarctation of the aorta. In simple coarctation, repair by way of sternotomy or thoracotomy is often determined by echocardiographic transverse arch measurements. The degree of arch hypoplasia that is prohibitive to repair by way of thoracotomy is unknown. Clinical predictors of recoarctation are also unknown. Demographic, echocardiographic (transverse arch and aortic measurements), operative, and postoperative data of infants <90 days old with simple coarctation repaired by way of thoracotomy between February 2005 and November 2011 were evaluated. Recoarctation was defined as surgical or catheter reintervention after hospital discharge. Eighty-four infants underwent coarctation repair at median age of 12 (range 1-85) days with median follow-up of 12.3 (range 0.5-71.9) months. The seven (8 %) infants with recoarctation underwent balloon angioplasty. In multivariable analysis, only greater postoperative Doppler peak velocity [1.13, confidence interval (CI) 1.04-1.23] and greater sinotubular junction z-score (hazard ratio 4.19, CI 1.47-11.95) independently predicted coarctation. Doppler peak velocity >2.12 m/s had sensitivity of 63 % and specificity of 83 % of predicting recoarctation, and ST junction z-score >-0.93 had sensitivity of 100 % and specificity of 58 %. No transverse arch dimensions were independently associated with recoarctation. Infants with transverse arch z-score as low as -2.8 underwent successful repair by way of thoracotomy. No clinical predictors were significant.