Stress Ulcer Prophylaxis Versus Placebo-A Blinded Pilot Randomized Controlled Trial to Evaluate the Safety of Two Strategies in Critically Ill Infants With Congenital Heart Disease.

OBJECTIVES: The routine use of stress ulcer prophylaxis (SUP) in infants with congenital heart disease (CHD) in the cardiac ICU (CICU) is controversial. We aimed to conduct a pilot study to explore the feasibility of performing a subsequent larger trial to assess the safety and efficacy of withholding SUP in this population (NCT03667703). DESIGN, SETTING, PATIENTS: Single-center, prospective, double-blinded, parallel group (SUP vs. placebo), pilot randomized controlled pilot trial (RCT) in infants with CHD admitted to the CICU and anticipated to require respiratory support for greater than 24 hours. INTERVENTIONS: Patients were randomized 1:1 (stratified by age and admission type) to receive a histamine-2 receptor antagonist or placebo until respiratory support was discontinued, up to 14 days, or transfer from the CICU, if earlier. MEASUREMENTS AND MAIN RESULTS: Feasibility was defined a priori by thresholds of screening rate, consent rate, timely drug allocation, and protocol adherence. The safety outcome was the rate of clinically significant upper gastrointestinal (UGI) bleeding. We screened 1,426 patients from February 2019 to March 2022; of 132 eligible patients, we gained informed consent in 70 (53%). Two patients did not require CICU admission after obtaining consent, and the remaining 68 patients were randomized to SUP (n = 34) or placebo (n = 34). Ten patients were withdrawn early, because of a change in eligibility (n = 3) or open-label SUP use (n = 7, 10%). Study procedures were completed in 58 patients (89% protocol adherence). All feasibility criteria were met. There were no clinically significant episodes of UGI bleeding during the pilot RCT. The percentage of patients with other nonserious adverse events did not differ between groups. CONCLUSIONS: Withholding of SUP in infants with CHD admitted to the CICU was feasible. A larger multicenter RCT designed to confirm the safety of this intervention and its impact on incidence of UGI bleeding, gastrointestinal microbiome, and other clinical outcomes is warranted.

Risk Factors for Adverse Outcomes in Term Infants with CHD and Definitive Necrotising Enterocolitis.

OBJECTIVES: To define the incidence of definitive necrotising enterocolitis in term infants with CHD and identify risk factors for morbidity/mortality. METHODS: We performed a 20-year (2000-2020) single-institution retrospective cohort study of term infants with CHD admitted to the Boston Children's Hospital cardiac ICU with necrotising enterocolitis (Bell's stage ≥ II). The primary outcome was a composite of in-hospital mortality and post-necrotising enterocolitis morbidity (need for extracorporeal membrane oxygenation, multisystem organ failure based on the paediatric sequential organ failure assessment score, and/or need for acute gastrointestinal intervention). Predictors included patient characteristics, cardiac diagnosis/interventions, feeding regimen, and severity measures. RESULTS: Of 3933 term infants with CHD, 2.1% (n = 82) developed necrotising enterocolitis, with 67% diagnosed post-cardiac intervention. Thirty (37%) met criteria for the primary outcome. In-hospital mortality occurred in 14 infants (17%), of which nine (11%) deaths were attributable to necrotising enterocolitis. Independent predictors of the primary outcome included moderate to severe systolic ventricular dysfunction (odds ratio 13.4,confidence intervals 1.13-159) and central line infections pre-necrotising enterocolitis diagnosis (odds ratio 17.7, confidence intervals 3.21-97.0) and mechanical ventilation post-necrotising enterocolitis diagnosis (odds ratio 13.5, confidence intervals 3.34-54.4). Single ventricle, ductal dependency, and feeding related factors were not independently associated with the primary outcome. CONCLUSIONS: The incidence of necrotising enterocolitis was 2.1% in term infants with CHD. Adverse outcomes occurred in greater than 30% of patients. Presence of systolic dysfunction and central line infections prior to diagnosis and need for mechanical ventilation after diagnosis of necrotising enterocolitis can inform risk triage and prognostic counseling for families.

Associations With Extubation Failure and Predictive Value of Risk Analytics Algorithms With Extubation Readiness Tests Following Congenital Cardiac Surgery.

OBJECTIVES: Extubation failure is associated with morbidity and mortality in children following cardiac surgery. Current extubation readiness tests (ERT) do not consider the nonrespiratory support provided by mechanical ventilation (MV) for children with congenital heart disease. We aimed to identify factors associated with extubation failure in children following cardiac surgery and assess the performance of two risk analytics algorithms for patients undergoing an ERT. DESIGN: Retrospective cohort study. SETTING: CICU at a tertiary-care children's hospital. PATIENTS: Children receiving MV greater than 48 hours following cardiac surgery between January 1, 2017, and December 31, 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Six hundred fifty encounters were analyzed with 49 occurrences (8%) of reintubation. Extubation failure occurred most frequently within 6 hours of extubation. On multivariable analysis, younger age (per each 3-mo decrease: odds ratio [OR], 1.06; 95% CI, 1.001-1.12), male sex (OR, 2.02; 95% CI, 1.03-3.97), Society of Thoracic Surgery-European Association for Cardiothoracic Surgery category 5 procedure (p equals to 0.005), and preoperative respiratory support (OR, 2.08; 95% CI, 1.09-3.95) were independently associated with unplanned reintubation. Our institutional ERT had low sensitivity to identify patients at risk for reintubation (23.8%; 95% CI, 9.7-47.6%). The addition of the inadequate delivery of oxygen (IDO2) index to the ERT increased the sensitivity by 19.0% (95% CI, -2.5 to 40.7%; p = 0.05), but the sensitivity remained low and the accuracy of the test dropped by 8.9% (95% CI, 4.7-13.1%; p < 0.01). CONCLUSIONS: Preoperative respiratory support, younger age, and more complex operations are associated with postoperative extubation failure. IDO2 and IVCO2 provide unique cardiorespiratory monitoring parameters during ERTs but require further investigation before being used in clinical evaluation for extubation failure.

Fluid Restriction Contributes to Poor Nutritional Adequacy in Patients With Congenital Heart Disease Receiving Renal Replacement Therapy.

OBJECTIVES: Critically ill patients receiving renal replacement therapy (RRT) in the pediatric cardiac intensive care unit (CICU) are at high risk for inadequate nutrition delivery. The objective of this study is to evaluate barriers to adequate energy and protein delivery in critically ill patients with congenital heart disease receiving RRT. METHODS: This is a single-center retrospective cohort study of patients receiving RRT in the CICU from 2011 to 2019. Energy and protein adequacy was recorded over the first 7 days of RRT. Adequacy was defined as delivery of >80% of the energy and protein targets during this time period. Patients who achieved adequacy were compared to those who did not. Multivariable logistic regression models were constructed to determine factors independently associated with energy and protein adequacy while receiving RRT. RESULTS: Sixty patients were included for analysis. Fifty-five patients (92%) achieved energy adequacy and 37 patients (62%) achieved protein adequacy. A higher weight-for-age z-score (WAZ) on admission to the CICU was the only independent predictor of inadequate energy intake (odds ratio 0.07, 95% confidence interval 0.01-0.58, P = .014); median WAZ was -1.17 versus +1.24 for those with adequate versus inadequate energy intake, respectively. Fluid restriction to <80% of maintenance fluid at the time of RRT initiation was more likely in patients with higher WAZ. Fluid restriction was the only independent predictor of inadequate protein intake (odds ratio 0.13, 95% confidence interval 0.02-0.7, P = .018); 5% versus 30% were fluid restricted in those with adequate versus inadequate protein intake, respectively. Azotemia was not associated with inadequate protein intake. Initiation of RRT did not allow for liberalization of fluid intake over the time period evaluated. CONCLUSIONS: Protein delivery was inadequate in 38% of children undergoing RRT in the CICU. Fluid restriction was associated with inadequate protein intake and higher WAZ was associated with inadequate energy intake.

Physiologic effects of delayed sternal closure following stage 1 palliation.

BACKGROUND: Following stage 1 palliation, delayed sternal closure may be used as a technique to enhance thoracic compliance but may also prolong the length of stay and increase the risk of infection. METHODS: We reviewed all neonates undergoing stage 1 palliation at our institution between 2010 and 2017 to describe the effects of delayed sternal closure. RESULTS: During the study period, 193 patients underwent stage 1 palliation, of whom 12 died before an attempt at sternal closure. Among the 25 patients who underwent primary sternal closure, 4 (16%) had sternal reopening within 24 hours. Among the 156 infants who underwent delayed sternal closure at 4 [3,6] days post-operatively, 11 (7.1%) had one or more failed attempts at sternal closure. Patients undergoing primary sternal closure had a shorter duration of mechanical ventilation and intensive care unit length of stay. Patients who failed delayed sternal closure had a longer aortic cross-clamp time (123±42 versus 99±35 minutes, p=0.029) and circulatory arrest time (39±28 versus 19±17 minutes, p=0.0009) than those who did not fail. Failure of delayed sternal closure was also closely associated with Technical Performance Score: 1.3% of patients with a score of 1 failed sternal closure compared with 18.9% of patients with a score of 3 (p=0.0028). Among the haemodynamic and ventilatory parameters studied, only superior caval vein saturation following sternal closure was different between patients who did and did not fail sternal closure (30±7 versus 42±10%, p=0.002). All patients who failed sternal closure did so within 24 hours owing to hypoxaemia, hypercarbia, or haemodynamic impairment. CONCLUSION: When performed according to our current clinical practice, sternal closure causes transient and mild changes in haemodynamic and ventilatory parameters. Monitoring of SvO2 following sternal closure may permit early identification of patients at risk for failure.

Is Endomyocardial Biopsy a Safe and Useful Procedure in Children with Suspected Cardiomyopathy?

Endomyocardial biopsy (EMB) is a common procedure used to aid in the diagnosis, prognosis and treatment of suspected pediatric cardiomyopathy. In suspected cardiomyopathy, no multicenter experience has previously reported on the safety and utility of EMBs. Retrospectively, adverse event (AE) and patient and procedural characteristics were obtained at seven institutions participating in the Congenital Cardiac Catheterization Outcomes Project for both a cardiomyopathy (n = 158) and a post-transplant surveillance (n = 2665) cohort. Descriptive information regarding biopsy indication, pathology and clinical management based on EMB findings were retrospectively obtained. High-severity AEs were more common in the cardiomyopathy cohort when compared to the post-transplant surveillance cohort. The cardiomyopathy cohort was younger, more hemodynamically vulnerable and required more cardiorespiratory support during the procedure. The eight high-severity AEs in the cardiomyopathy group included one myocardial perforation, two ECMO cannulations and three deaths following the EMB. Factors associated with high-severity AEs included performing another catheter-based intervention during the EMB and longer fluoroscopy time. Notably, an increased number of biopsy attempts did not increase the risk of an AE. Suspected myocarditis was the most common indication. Diagnostic EMB pathology and thus alteration to clinical management based on pathology occurred more frequently in patients with suspected myocarditis. In conclusion, there is an increased incidence of high-severity AEs in patients undergoing EMB for suspected cardiomyopathy. EMB may be more clinically useful in the management of suspected myocarditis. The increased risk of high-severity AEs when additional interventions are performed highlights the hemodynamic vulnerability in patients with suspected cardiomyopathy.

Duplication of 20p12.3 associated with familial Wolff-Parkinson-White syndrome.

Wolff-Parkinson-White (WPW) syndrome is caused by preexcitation of the ventricular myocardium via an accessory pathway which increases the risk for paroxysmal supraventricular tachycardia. The condition is often sporadic and of unknown etiology in the majority of cases. Autosomal dominant inheritance and association with congenital heart defects or ventricular hypertrophy were described. Microdeletions of 20p12.3 have been associated with WPW syndrome with either cognitive dysfunction or Alagille syndrome. Here, we describe the association of 20p12.3 duplication with WPW syndrome in a patient who presented with non-immune hydrops. Her paternal uncle carries the duplication and has attention-deficit hyperactivity disorder and electrocardiographic findings consistent with WPW. The 769 kb duplication was detected by the Affymetrix Whole Genome-Human SNP Array 6.0 and encompasses two genes and the first two exons of a third gene. We discuss the potential role of the genes in the duplicated region in the pathogenesis of WPW and possible neurobehavioral abnormalities. Our data provide additional support for a significant role of 20p12.3 chromosomal rearrangements in the etiology of WPW syndrome.

Nutrition for critically ill children with congenital heart disease.

Children with congenital heart disease often require admission to the cardiac intensive care unit at some point in their lives, either after elective surgical or catheter-based procedures or during times of acute critical illness. Meeting both the macronutrient and micronutrient needs of children in the cardiac intensive care unit requires complex decision-making when considering gastrointestinal perfusion, vasoactive support, and fluid balance goals. Although nutrition guidelines exist for critically ill children, these cannot always be extrapolated to children with congenital heart disease. Children with congenital heart disease may also suffer unique circumstances, such as chylothoraces, heart failure, and the need for mechanical circulatory support, which greatly impact nutrition delivery. Guidelines for neonates and children with heart disease continue to be developed. We provide a synthesized narrative review of current literature and considerations for nutrition evaluation and management of critically ill children with congenital heart disease.

Cardiovascular intensive care unit variables inform need for feeding tube utilization in infants with hypoplastic left heart syndrome.

OBJECTIVE: Feeding strategies in infants with hypoplastic left heart syndrome (HLHS) following stage 1 palliation (S1P) include feeding tube utilization (FTU). Timely identification of infants who will fail oral feeding could mitigate morbidity in this vulnerable population. We aimed to develop a novel clinical risk prediction score for FTU. METHODS: This was a retrospective study of infants with HLHS admitted to the Boston Children's Hospital cardiovascular intensive care unit for S1P from 2009 to 2019. Infants discharged with feeding tubes were compared with those on full oral feeds. Variables from early (birth to surgery), mid (postsurgery to cardiovascular intensive care unit transfer), and late (inpatient transfer to discharge) hospitalization were analyzed in univariate and multivariable models. RESULTS: Of 180 infants, 66 (36.7%) discharged with a feeding tube. In univariate analyses, presence of a genetic disorder (early variable, odds ratio, 3.25; P = .014) and nearly all mid and late variables were associated with FTU. In the mid multivariable model, abnormal head imaging, ventilation duration, and vocal cord dysfunction were independent predictors of FTU (c-statistic 0.87). Addition of late variables minimally improved the model (c-statistic 0.91). A risk score (the HV2 score) for FTU was developed based on the mid multivariable model with high specificity (93%). CONCLUSIONS: Abnormal head imaging, duration of ventilation, and presence of vocal cord dysfunction were associated with FTU in infants with HLHS following S1P. The predictive HV2 risk score supports routine perioperative head imaging and vocal cord evaluation. Future application of the HV2 score may improve nutritional morbidity and hospital length of stay in this population.

Nutritional Considerations for the Neonate With Congenital Heart Disease.

The importance of nutrition in managing critically ill infants with congenital heart disease (CHD) is foundational to optimizing short- and long-term health outcomes. Growth failure and malnutrition are common in infants with CHD. The etiology of growth failure in this population is often multifactorial and may be related to altered metabolic demands, compromised blood flow to the intestine leading to nutrient malabsorption, cellular hypoxia, inadequate energy intake, and poor oral-motor skills. A dearth of high-quality studies and gaps in previously published guidelines have led to wide variability in nutrition practices that are locally driven. This review provides recommendations from the nutrition subgroup of the Neonatal Cardiac Care Collaborative for best evidence-based practices in the provision of nutritional support in infants with CHD. The review of evidence and recommendations focused on 6 predefined areas of clinical care for a target population of infants <6 months with CHD admitted to the ICU or inpatient ward. These areas include energy needs, nutrient requirements, enteral nutrition, feeding practice, parenteral nutrition, and outcomes. Future progress will be directed at quality improvement efforts to optimize perioperative nutrition management with an increasing emphasis on individualized care based on nutritional status, cardiorespiratory physiology, state of illness, and other vulnerabilities.

Extracorporeal Membrane Oxygenation in Infants Undergoing Truncus Arteriosus Repair.

BACKGROUND: Infants undergoing truncus arteriosus (TA) repair suffer one of the highest mortality rates of all congenital heart defects. Extracorporeal membrane oxygenation (ECMO) can support patients undergoing TA repair, but little is known about factors contributing to mortality in this cohort. The objective of this study was to identify risk factors for mortality in infants with TA requiring perioperative ECMO. METHODS: Data from the Extracorporeal Life Support Organization from 2002 to 2017 for infants less than 60 days old undergoing TA repair were analyzed. Demographics, clinical characteristics, and ECMO characteristics and complications were compared between survivors and nonsurvivors. Multivariable logistic regression was used to evaluate independent risk factors for mortality. RESULTS: Of 245 patients analyzed, 92 (37.6%) survived to discharge. Nonsurvivors had a lower weight and a longer ECMO duration. A higher proportion of nonsurvivors suffered complications on ECMO, including mechanical complications, circuit thrombus, bleeding, and need for renal replacement therapy. In multivariable analysis lower weight (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.33-0.95), duration of ECMO (OR, 1.1; 95% CI, 1.02-1.18), need for renal replacement therapy (OR, 3.23; 95% CI, 1.68-6.2), cardiopulmonary resuscitation on ECMO (OR, 11.52; 95% CI, 1.3-102.33), and infection on ECMO (OR, 4.47; 95% CI, 1.2-16.64) were independently associated with mortality. CONCLUSIONS: Many factors associated with mortality for infants requiring perioperative ECMO with TA repair are related to complications suffered on ECMO. Thoughtful patient selection and meticulous ECMO management to prevent complications are essential in improving outcomes for these infants.

Stress ulcer prophylaxis versus placebo-a blinded randomized control trial to evaluate the safety of two strategies in critically ill infants with congenital heart disease (SUPPRESS-CHD).

BACKGROUND: Critically ill infants with congenital heart disease (CHD) are often prescribed stress ulcer prophylaxis (SUP) to prevent upper gastrointestinal bleeding, despite the low incidence of stress ulcers and limited data on the safety and efficacy of SUP in infants. Recently, SUP has been associated with an increased incidence of hospital-acquired infections, community-acquired pneumonia, and necrotizing enterocolitis. The objective of this pilot study is to investigate the feasibility of performing a randomized controlled trial to assess the safety and efficacy of withholding SUP in infants with congenital heart disease admitted to the cardiac intensive care unit. METHODS: A single center, prospective, double-blinded, randomized placebo-controlled pilot feasibility trial will be performed in infants with CHD admitted to the cardiac intensive care unit and anticipated to require respiratory support for > 24 h. Patients will be randomized to receive a histamine-2 receptor antagonist (H2RA) or placebo until they are discontinued from respiratory support. Randomization will be performed within 2 strata defined by admission type (medical or surgical) and age (neonate, age < 30 days, or infant, 1 month to 1 year). Allocation will be a 1:1 ratio using permuted blocks to ensure balanced allocations across the two treatment groups within each stratum. The primary outcomes include feasibility of screening, consent, timely allocation of study drug, and protocol adherence. The primary safety outcome is the rate of clinically significant upper gastrointestinal bleeding. The secondary outcomes are the difference in the relative and absolute abundance of the gut microbiota and functional microbial profiles between the two study groups. We plan to enroll 100 patients in this pilot study. DISCUSSION: Routine use of SUP to prevent upper gastrointestinal bleeding in infants is controversial due to a low incidence of bleeding events and concern for adverse effects. The role of SUP in infants with CHD has not been examined, and there is equipoise on the risks and benefits of withholding this therapy. In addition, this therapy has been discontinued in other neonatal populations due to the concern for hospital-acquired infections and necrotizing enterocolitis. Furthermore, exploring changes to the microbiome after exposure to SUP may highlight the mechanisms by which SUP impacts potential microbial dysbiosis of the gut and its association with hospital-acquired infections. Assessment of the feasibility of a trial of withholding SUP in critically ill infants with CHD will facilitate planning of a larger multicenter trial of safety and efficacy of SUP in this vulnerable population. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03667703. Registered 12 September 2018, https://clinicaltrials.gov/ct2/show/NCT03667703?term=SUPPRESS+CHD&draw=2&rank=1 . All WHO Trial Registration Data Set Criteria are met in this manuscript.

A Review of Systemic Vasodilators in Low Cardiac Output Syndrome Following Pediatric Cardiac Surgery.

Following surgery for congenital heart disease, patients develop a predictable and progressive decline in cardiac output known as low cardiac output syndrome. During low cardiac output states, a compensatory response to increase systemic perfusion occurs both innately and as part of the postoperative pharmacologic support strategies intended to increase or sustain adequate oxygen delivery. The result typically involves a rise in systemic vascular resistance and heart rate. These and other responses may actually limit the ability of the recently operated heart to provide sufficient cardiac output to meet the oxygen demands of the body. In order to improve systemic oxygen delivery, clinicians have increasingly employed systemic vasodilator therapy to reduce afterload and improve ventriculoarterial coupling. This review will summarize currently utilized pharmacologic agents that promote systemic vasodilation and improve cardiac output through afterload reduction. This article addresses the fourth of eight topics comprising the special issue entitled "Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery".

Phosphodiesterase Inhibitor-Based Vasodilation Improves Oxygen Delivery and Clinical Outcomes Following Stage 1 Palliation.

BACKGROUND: Systemic vasodilation using α-receptor blockade has been shown to decrease the incidence of postoperative cardiac arrest following stage 1 palliation (S1P), primarily when utilizing the modified Blalock-Taussig shunt. We studied the effects of a protocol in which milrinone was primarily used to lower systemic vascular resistance (SVR) following S1P using the right ventricular to pulmonary artery shunt, measuring its effects on oxygen delivery (DO2) profiles and clinical outcomes. We also correlated Fick-based assessments of DO2 with commonly used surrogate measures. METHODS AND RESULTS: Neonates undergoing S1P were treated according to best clinical judgment prior to (n=32) and following (n=24) implementation of a protocol that guided operative, anesthetic, and postoperative management, particularly as it related to SVR. A majority of the subjects (n=51) received a modified right ventricular to pulmonary artery shunt. In a subset of these patients (n=21), oxygen consumption (VO2) was measured and used to calculate SVR, DO2, and oxygen debt. Neonates treated with the protocol had significantly lower SVR (P=0.02), serum lactate (P<0.001), and Sa-vO2 difference (P<0.001) and a lower incidence of CPR requiring extracorporeal membrane oxygenation (E-CPR, P=0.02) within the first 72 postoperative hours. DO2 was closely associated with SVR (r2=0.78) but correlated poorly with arterial (SaO2) and venous (SvO2) oxyhemoglobin concentrations, the Sa-vO2 difference, and blood pressure. CONCLUSIONS: A vasodilator protocol utilizing milrinone following S1P effectively decreased SVR, improved serum lactate, and decreased postoperative cardiac arrest. DO2 correlated more closely with SVR than with Sa-vO2 difference, highlighting the importance of measuring VO2 in this population. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02184169.