Nutritional Considerations for the Neonate with Congenital Heart Disease

Abstract

The importance of nutrition in the management of the critically ill infant 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 six pre-defined areas of clinical care for a target population of infants <6 months with CHD admitted to the intensive care unit 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.

Table of Contents Summary:

Given the high prevalence of malnutrition in infants with congenital heart disease, this review provides standardized, consensus recommendations regarding common inpatient nutritional practices.

INTRODUCTION

This review represents the first set of recommendations from the Neonatal Cardiac Care Collaborative (NeoC3) to describe the best evidence-based practices for the provision of nutritional support in neonates and infants with CHD. The target population for these recommendations are critically ill neonates and infants (0 days – 6 months) with CHD.

Congenital heart defects are among the most common birth defects in the United States.¹ Advances in antenatal, operative and perioperative management have improved mortality and shifted the focus on minimizing morbidities - such as poor growth and neurodevelopment. Neonates and infants with CHD suffer from a high incidence of malnutrition.² The etiology of malnutrition is likely multifactorial and related to inadequate intake, inefficient nutrient absorption and utilization and increased energy requirements. Furthermore, neonates and infants who undergo cardiac surgery with or without cardiopulmonary bypass (CPB) suffer from a predictable inflammatory response.³ This event induces an acute and profound metabolic response characterized by catabolism and insulin resistance.⁴ The adequate provision of nutrition is challenging in critically ill neonates as nutrient requirements fluctuate between the various phases of illness and estimated energy and protein needs are unknown. Estimates of resting energy expenditure (REE) are difficult to obtain with available technology as neonates and infants with CHD are often too small, hemodynamically unstable and may have other technical limitations to indirect calorimetry (IC).⁵ In addition, the provision of enteral nutrition (EN) is precarious given the risk for mesenteric ischemia.⁶

The use of parenteral nutrition (PN) is high in neonates and infants with CHD; however, the risks of use are common including infectious complications, venous thrombosis and PN-associated liver disease (PNALD).⁷ Finally, nutritional status and adequacy have been associated with poor clinical outcomes - such as increased infectious complications, prolonged duration of mechanical ventilation (MV), and increased length of stay (LOS); uncovering a potentially modifiable risk factor to diminish morbidity and mortality in this vulnerable population.^8–11

The Society of Critical Care Medicine (SCCM) and American Society of Parenteral and Enteral Nutrition (ASPEN) produced guidelines in 2017 focused on best practices in nutrition therapy in critically ill children, however they excluded term neonates from their recommendations.¹² In 2020, the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) produced nutrition guidelines that included term neonates, but still did not focus specifically on children with CHD.¹³ Due to the gap in representation in previously published guidelines, lack of high-quality evidence and multidisciplinary expertise, the NeoC3 formed a Nutrition Section to address specific unanswered clinical questions regarding the nutritional support of critically ill neonates and infants with CHD. We assembled a multidisciplinary team of nutritional support specialists trained formally in pediatric cardiac critical care, neonatology, or dietetics to represent the Nutrition section. The section formally met in August 2019 and generated six clinical questions currently debated among clinicians (Table 1). The study population included critically ill full-term neonates (≥ 37 weeks estimated gestational age and ≤ 28 days old) and infants (> 28 days old) up to 6 months of age with CHD (either structural, myopathic or arrhythmic).

TABLE 1.

Guidelines for the Provision and Assessment of Nutritional Support in Infants With Congenital Heart Disease

Questions	Class	LOE	Recommendations
Determination of energy
Q1a. What is the most accurate method to determine REE in infants with CHD?	IIa	C-LD	IC is the preferred and most accurate method for determining REE.
Q1b. If IC is unavailable, what other methods are available to determine REE in infants with CHD?	IIb	C-EO	If IC is not feasible, use of estimating equations to approximate REE is an acceptable alternative. However, cohort studies have suggested estimating equations both under- and overestimate REE in neonates with CHD. Thus, we recommend using estimating equations without the addition of stress factors.
Nutrient requirements
Q2a. What are the recommended energy and protein requirements for infants with CHD?	IIb	C-LD	Energy requirements for neonates with CHD are likely greater than healthy full-term controls (90–120 kcal/kg/d).
Q2b. How do energy requirements in infants with CHD evolve during preoperative, perioperative, and postoperative disease states?	IIb	C-EO	To maintain a positive nitrogen balance, protein requirements for neonates with CHD are at least the same as healthy full-term controls (>2 g/kg/d).
	IIb	C-EO	Energy requirements in unrepaired infants with CHD may be higher than healthy full-term controls, are unpredictable in the perioperative phase and likely normalize to age- matched controls 1 week following surgery.
Enteral nutrition
Q3a. Is EN safe in preoperative infants with CHD?	IIb	C-LD	Preoperative enteral feeding may be reasonable when considering type of cardiac lesion, hemodynamic support, and clinical parameters.
Q3b. Is EN safe in infants with ductal-dependent CHD?	IIb	C-LD	EN may be considered if hemodynamically stable and in a monitored setting.
Q3c. Is EN safe in infants with CHD using vasopressors or inotropes?	IIb	C-EO	EN may be considered in patients on stable or decreasing amount of hemodynamic pharmacologic support.
Q3d. Is EN safe in infants with CHD when umbilical lines are in situ?	IIb	C-EO	The presence of umbilical arterial catheters in isolation should not prevent the initiation of EN.
Q3e. Are fortified feeds safe in infants with CHD?	IIb	C-LD	There is insufficient evidence to conclude that fortified feeds are unsafe or poorly tolerated. In fluid-restricted states, fortified feeds may be beneficial.
Q3f. Is EN safe in infants with CHD on mechanical support (ECMO or VAD)?	IIb	C-EO	Initiating EN is recommended in hemodynamically stable and well-supported patients on mechanical circulatory support.
Feeding practice
Q4a. How do we advance EN in infants with CHD?	IIb	C-LD	Standardized feeding algorithms improve time to feed initiation and energy adequacy but have not demonstrated an effect on improving anthropometric measurements or lowering mortality.
Q4b. Is there an advantage to gastric versus postpyloric enteral feeds in infants with CHD?	IIb	C-LD	Both gastric and postpyloric feeds are safe in infants with CHD. Postpyloric feeds may shorten duration to goal energy intake.
Q4c. Are there any benefits to feeding human milk as opposed to formula in infants with CHD?	IIb	C-LD	Human milk is recommended over formula, when available, in infants with CHD.
Q4d. Are there special nutritional considerations for infants with CHD suffering from chylous effusions?	IIb	B-NR	Use of defatted human milk or MCT-rich formula for 4 to 6 wk is recommended to treat infants with CHD who develop chylous effusions.
Q4e. Is there a subset of infants with CHD at risk for aspiration?	IIb	C-LD	Infants who undergo aortic arch repair are at risk for developing vocal cord dysfunction secondary to injury to the recurrent laryngeal nerve. In addition, infants with CHD suffer from a high incidence of oropharyngeal dysphagia.
Q4f. Are there predictive risk factors in infants with CHD to determine need for surgical feeding tube placement?	IIb	C-LD	Several risk factors have been identified to predict need for surgical feeding tube placement in infants with CHD.
Parenteral nutrition
Q5a. What is the indication for initiation of PN in infants with CHD?	IIb	C-LD	If enteral nutrition is insufficient, PN should be considered in neonates.
Q5b. What is the optimal timing for initiation of PN in infants with CHD?	llb	B-R	A delayed PN strategy may be beneficial if energy adequacy will be achieved during the first week of admission.
Q5c. What formulation of intravenous lipid emulsion should be initially prescribed for infants with CHD?	llb	C-EO	A soy-based lipid emulsion should be prescribed when intravenous nutrition is initiated in patients without known comorbidities. There is insufficient evidence to recommend the use of novel lipid emulsions as an immunomodulator.
Q5d. What are the complications associated with PN utilization? Outcomes	llb	C-LD	PNALD, CLABSIs, and catheter-related venous thromboses are complications associated with PN.
Q6. Does nutritional status impact the clinical outcomes of infants with congenital heart disease?	IIa	C-LD	Efforts to minimize malnutrition in infants with CHD may improve important clinical outcomes.

Abbreviations: CHD, congenital heart disease; CLABSI, central line-associated bloodstream infection; ECMO, extracorporeal membrane oxygenator; EN, enteral nutrition; IC, indirect calorimetry; LOE, level of evidence; MCT, medium-chain triglycerides; NEC, necrotizing enterocolitis; PN, parenteral nutrition; PNALD, PN-associated liver disease; REE, resting energy expenditure; VAD, ventricular assist device.

The members performed a comprehensive search of the Medline/PubMed database using the Medical Subject Heading folders for peer-reviewed publications relevant to six predefined questions on nutritional provision in critically ill neonates and infants with CHD. Key terms indexed in the Medical Subject Heading folders included “critical care,” “intensive care” and “critical illness” as well as “nutritional support,” “malnutrition,” “energy intake,” and “dietary protein” and were restricted to “infant” and “pediatrics.” Included studies were randomized controlled trials (RCTs), case-control and cohort studies in English since 2000. Additional studies were included based on the section member’s personal knowledge according to their expertise and relevance to the specific clinical question (including publications before 2000). Studies with preterm infants, not in English or publications that were animal studies, case reports/series, editorials, or commentaries were excluded. After retrieval of the full text publications, all section members independently reviewed the studies and suggested whether to include or exclude the study based on the strength of the evidence. A subsequent critical and objective analysis was performed of the evidence using American College of Cardiology/American Heart Association Clinical Practice Guideline Recommendation Classification System methodology highlighted in the NeoC3 Executive Committee introductory paper. In the absence of high-quality trials, consensus-derived recommendations were derived by qualitative methods and expert opinion as quantitative analysis was impractical.

This manuscript is part of a larger series of articles simultaneously published as a Supplement in Pediatrics by the Neonatal Cardiac Care Collaborative (NeoC3). Please refer to the Executive Committee introductory paper for discussion on Class of Recommendations/Level of Evidence (LOE), writing committee organization, and document review and approval.

DETERMINATION OF ENERGY REQUIREMENTS

The assessment of nutrient requirements in critically ill infants with CHD is challenging (Table 2). In addition to known factors that affect the metabolic state of critically ill children - such as MV, pyrexia, and sedation and neuromuscular blockade - infants with CHD make the estimation of energy expenditure even more unpredictable. Variations in anatomic diagnosis, severity of heart failure symptomatology and disease state (i.e. preoperative or postoperative) complicate the assessment of energy requirements in infants with CHD. Unfortunately, currently available estimating equations are poor correlates for energy requirement assessments in infants with CHD, as they have also been shown in critically ill children.^14–16 Thus, IC is the gold standard for measuring REE and guiding the daily provision of nutrition. However, the utilization of IC is problematic in infants with CHD given size limitations (current technical limitations in patients under 5 kilograms), tachypnea often present in patients with heart failure, and the potential presence of a postoperative air leak treated with chest tubes.

TABLE 2.

Determination of Resting Energy Expenditure (REE) in Neonates With Congenital Heart Disease (CHD)

Reference	Study Design, No. of Sites	Study Aim(s)	Population (n), Eligibility	Results/Outcomes	Comments
Ackerman et al96	Prospective, cohort, single center	To compare measured REE by IC and doubly labeled water in patients with VSD versus control	n = 18 Mean age ± SD: VSD: 4.1 mo ± 0.5 Control: 4.1 mo ± 0.6	REE similar between patients with VSD compared with controls TEE higher in patients with VSD compared with controls	Not directly applicable because of infant ages
Avitzur et al20	Prospective, cohort, single center	To compare measured REE with estimating equations	n = 29 Children < 3 y Median age (range): Cyanotic: 3.2 mo (0.2–13) Acyanotic: 12.3 mo (0.1–30)	Measured REE was dissimilar to calculated REE but more similar by Schofield than by WHO	Unclear number of neonates Technical difficulties limited number of patients with measured REE
Floh et al3	Prospective, cohort, single center	To examine relationship between systemic inflammation and measured REE after CPB	n = 111 Mechanically ventilated children Median age (range): 5.3 mo (0.8–10.5)	Measured REE between 40 and 60 kcal/kg/d REE directly associated with CO and inflammation REE inversely associated with anti-inflammatory therapies	Protocolized nutritional assessments were not completed One-third of patients did not complete 72 h REE measurements because of extubation
Leitch et al97	Prospective, cohort, single center	To measure and compare energy intake, REE, and TEE in unrepaired cyanotic CHD at 2 wk and 3 mo	n = 22 Spontaneously breathing children on full enteral nutrition	Higher TEE in cyanotic infants at 3 mo, but not 2 wk No difference in REE between cases and controls
Li et al27	Prospective, cohort, single center	To measure REE before and after the Norwood To compare measured REE to actual caloric and protein intake before and after the Norwood	n = 17 Mean age ± SD: 17 ± 22 d	Neonates were hypermetabolic following the Norwood Energy and protein intake were inadequate to meet energy expenditure in the first 2 d after the Norwood	Measurements accomplished with mass spectrometer; device no longer commercially available
Nydegger et al22	Prospective, cohort, single center	To relate changes in REE to timing of CHD repair To compare estimating equations to measured REE	n = 38 Spontaneously breathing infants > 12 mo admitted for cardiac surgery Median age (range): 16 d (0–352)	Increased REE normalizes within 1 week of corrective surgery Growth failure is more common in infants >10 d who undergo surgery compared with those <10 d Estimating equations do not accurately predict measured REE	Excluded patients with chromosomal abnormalities
Roebuck et al98	Retrospective, cohort study, single center	To assess if allometric scaling can predict REE To compare the accuracy of estimating equations in predicting REE to IC	n = 107 Mechan i cally venti lated children undergoing cardiac surgery Median age (range): 5.2 mo (0.8–10.7)	Allometric scaling was inferior to estimating equations in calculating REE IC remains gold standard to measure REE

Abbreviations: CHD, congenital heart disease; CO, cardiac output; CPB, cardiopulmonary bypass; IC, indirect calorimetry; REE, resting energy expenditure; TEE, total energy expenditure; VSD, ventricular septal defect; WHO, World Health Organization.

Recommendations

1a. Indirect calorimetry (IC) to measure resting energy expenditure (REE) can be useful in critically ill children keeping in mind technical limitations of weight and presence of postoperative air leak. (Class IIa, Level of Evidence C-LD)

1b. If IC is not feasible, use of estimating equations, specifically the Schofield equation, to calculate REE may be an acceptable alternative. However, cohort studies have suggested estimating equations both under- and over-estimate REE in neonates with congenital heart disease (CHD). Therefore. if IC is technically unfeasible, it may be reasonable to estimate REE with the Schofield equation and without the addition of stress factors to avoid the untoward clinical outcomes associated with overfeeding. (Class IIb, Level of Evidence C-EO)

NUTRIENT REQUIREMENTS

Basal energy and protein requirements

The energy requirement for healthy full-term neonates is between 90 to 120 kcal/kg/day.^{17, 18} The energy requirement for infants with CHD may be higher than healthy age-matched controls based on a meta-analysis of cohort studies. Recommended protein requirements for term neonates and infants are between 2 to 3 g/kg/d (Table 3).¹²

TABLE 3.

Energy and Protein Requirements for Neonates With Congenital Heart Disease

Reference	Study Design, No. of Sites	Study Aim(s)	Population (n), Eligibility	Results/Outcomes	Comments
Ackerman et al96	Prospective, case-control, single center	To determine the effect on REE, TEE, and energy intake in infants with unrepaired VSDs compared with age-matched healthy infants (control)	n = 18 Mean age ± SD: VSD: 4.1 mo ± 0.5 Control: 4.1 mo ± 0.6	REE and energy intake are similar in infants with VSDs compared with controls	Percent total body water was significantly higher and percent fat mass was significantly lower in infants with VSDs compared with controls
Avitzur et al20	Prospective, cohort, single center	To measure REE by IC between cyanotic and acyanotic patients with CHD 1 d before and 5 d after CPB	n = 29 Children <3 y Median age (IQR): Cyanotic: 3.2 mo (0.2–13) Acyanotic: 12.3 mo (0.1–30)	The measured REE was similar in cyanotic and acyanotic CHD before and after CPB	Unclear number of neonates Technical difficulties limited number of patients with measured REE
Botran et al29	Prospective, RCT, single center	To compare a standard diet and a protein- enriched diet in critically ill children	n = 51 (73% postoperative CHD) Children 1 mo-16 y (75% <1 y) Median age (IQR): 7 mo (3–13 mo)	Protein-enriched diet trends toward a positive nitrogen balance compared with standard protein diet by postoperative day 5	Intervention was not blinded
De Wit et al21	Prospective, cohort, single center	To determine pre- and postoperative predictors of REE in children with CHD and to compare measured REE with IC to current predictive equations	n = 21 Mean age ± SD: 7.3 mo ± 10.3	Poor nutritional status preoperatively was associated with greater postoperative energy expenditure None of the current predictive equations predicted energy requirements
Geukers et al30	Prospective, RCT, single center	To quantify the effect on protein kinetics with a short-term high-protein diet (5 g/kg/d) versus standard diet (2 g/kg/d)	n = 2 COMedian age (IQR): High protein: 7 mo (3–14) Normal protein: 12 mo (3–15)	Surplus protein may increase oxidation and ureagenesis and may be harmful for children following cardiac surgery	Study was underpowered because of high dropout rates
van der Kuip et al19	Prospective, cohort, single center	To assess energy requirements and body composition in preoperative children with CHD using doubly labeled water and compared with historic, healthy controls	n = 11 Mean age ± SD: CHD: 4.6 mo ± 1.9 Control: 4.3 mo ± 2.5	TEE was significantly higher in infants with CHD compared with controls	Percent total body water was significantly higher in infants with CHD compared with controls

Abbreviations: CHD, congenital heart disease; CPB, cardiopulmonary bypass; IC, indirect calorimetry; IQR, interquartile range; RCT, randomized controlled trial; REE, resting energy expenditure; TEE, total energy expenditure; VSD, ventricular septal defect.

Energy and protein requirements during preoperative, perioperative and postoperative disease states

The total energy expenditure (TEE) for infants with CHD has been shown to be up to 35% greater when compared with age-matched controls (90 to 120 kcal/kg/day) in a meta-analysis of cohort studies.^17–19 The REE in infants with cyanotic versus acyanotic CHD has been shown to be no different.²⁰ The effect of CPB on REE is unknown, as studies demonstrate both a significant difference and no difference between disease states.^{20, 21} Preoperative infants with unrepaired CHD have higher energy requirements when compared to age-matched controls.^{19, 22} Meanwhile, studies in postoperative infants with CHD have demonstrated both a hypo- and hypermetabolic state.^23–27 The unpredictable nature and duration of the postoperative phase supports the use of IC for assessing REE. There are limited longitudinal studies examining the effects of disease state on infants with CHD, however they support the notion that energy requirements may normalize one week after cardiac surgery.²²

Critically ill infants and children are frequently affected by protein deficiency and muscle wasting.²⁸ The additive effect of CPB on protein synthesis and catabolism in critically ill infants with CHD is unknown. Although protein requirements are unknown, the following studies support the ASPEN and SCCM current protein intake guidelines for critically ill infants to be between 2 to 3 gm/kg/day.¹² A RCT examined the effect of protein intake on the nitrogen balance of postoperative infants with CHD and found infants exposed to a protein-enriched diet (2.6 gm/kg/day) were more likely to achieve a positive nitrogen balance by the fifth postoperative day when compared to infants administered a standard diet (1.5 gm/kg/day).²⁹ However, when postoperative infants with CHD were exposed to a high (5 gm/kg/day) versus standard (2 gm/kg/day) protein intake, ureagenesis and azotemia developed.³⁰

Recommendations

2a. Energy requirements vary throughout the phases of disease. Based on limited observational data, energy requirements may be higher in infants with unrepaired CHD, are unpredictable during the postoperative phase and likely normalize to similar age-matched controls one week following surgery. Adjustments in energy intake in infants with CHD may be considered on an individual basis. (Class IIb, LOE C-EO)

2b. Based on observational studies, use of high-protein supplementation in infants with CHD is not well supported and protein surplus may be harmful. (Class III, Level of Evidence C-LD) (Protein: Class III, Level of Evidence C-LD)

ENTERAL NUTRITION

The benefits of EN are well documented in preterm neonates and many have been translated to the clinical care of infants with CHD (Table 4). These benefits include decreased rates of NEC, infectious complications, chronic lung disease, and improved neurodevelopmental outcomes.^31–34 However, the details as to how EN is provided for infants with CHD remains controversial due to concerns regarding feeding intolerance, frequent interruptions and the development of NEC. ^{35, 36} Mesenteric hypoperfusion in the setting of diastolic steal from an open patent ductus arteriosus is thought to be an important mechanism in which NEC develops in infants with CHD (excluding isolated patent ductus arteriosus).^37–40

TABLE 4.

Safety of Enteral Nutrition in Infants With Congenital Heart Disease

Reference	Study design, No. of sites	Study Aim(s)	Population (n), Eligibility	Results/Outcomes	Comments
Becker et al46	Retrospective cohort study, multicenter	To evaluate incidence of NEC and its association with feeding in infants with ductal- dependent CHD	n = 6710 Median EGA (IQR): 38 wk (37–39)	EN was not associated with an increased risk for NEC development Risk factor associated with NEC development included singleventricle heart disease Inotropic/vasoactive support was not associated with NEC development	Diagnosis of NEC defined based on documentation by treating neonatologist and did not include Bell staging All cases of “suspected” and “presumed” NEC were excluded
Cognata et al82	Retrospective, cohort, single center	To evaluate the risk of developing preoperative NEC in infants with CHD who are fed large volumes (>100 mL/ kg/d) of cow’s milk formula	n = 546 Infants of all gestational ages with complex CHD requiring intervention 3.3% of patients developed NEC preoperatively	Exclusive human milk diet was associated with lower risk of preoperative NEC Feeding volumes >100 mL/kg/d associated with greater risk for preoperative NEC	Ductal-dependent pulmonary blood flow lesions were associated with higher risk for preoperative NEC
Day et al47	Retrospective, cohort, single center	To describe the incidence of NEC with EN in neonates with ductal- dependent CHD	n = 177 Neonates with ductal- dependent CHD requiring PGE1 infusion 10% of patients diagnosed with suspected/confirmed NEC	No association between the diagnosis of NEC and EN in neonates with CHD on PGE1 infusion
del Castillo et al48	Retrospective, case-control, single center	To examine the impact of standardized feeding protocol on incidence of NEC and postoperative GI morbidity	n = 98 Neonates with HLHS admitted to the CICU after stage 1 palliation	The incidence of NEC decreased with institution of standardized feeding protocol
lannucci et al43	Retrospective, case-control, single center	To determine the incidence of NEC in neonates with CHD and explore the relationship between EN and the development of NEC	n = 1551 Neonates >36 wk EGA with CHD	45 (3%) neonates developed NEC No differences in EN patterns in patients who developed NEC compared with controls	Most NEC cases (68%) developed in infants with single-ventricle physiology High mortality rate (24%) for neonates who developed NEC
lliopoulos et al44	Retrospective, cohort, single center	To determine preoperative factors associated with prolonged LOS after ASO	n = 57 Short stay (n = 25) <7 d Long stay (n = 32) >14 d	Short stay patients have higher incidence of preoperative feeding compared with long stay patients
Kataria-Hale et al49	Meta-analysis of 5 retrospective cohort studies	To summarize current evidence for preoperative feeding in neonates with ductal-dependent CHD and its association with important clinical outcomes	n = 6807 (NEC) n = 57 (hospital LOS) n = 56 (feeding intolerance) Infants of all EGA with ductal-dependent CHD requiring surgery	No significant difference in NEC, hospital LOS or feeding intolerance when exposed to preoperative EN in neonates with ductal- dependent CHD
McElhinney et al99	Retrospective, case-control, single center	To determine risk factors for NEC in neonates with CHD	n = 643 21 (3%) neonates developed NEC and were compared with 70 matched controls	The diagnosis of HLHS, truncus arteriosus or aortopulmonary window were associated with NEC Earlier EGA and low cardiac output were associated with NEC Preoperative feeding was not associated with NEC High doses of PGE1 (>0.05 mcg/kg/min) were associated with NEC, but not the presence of PGE1 infusions alone	Inotropic/vasoactive use was not associated with NEC The presence of an indwelling umbilical arterial catheter was not associated with NEC
Natarajan et al50	Retrospective, cohort, single center	To determine the incidence of feeding- related morbidities and evaluate success of EN in infants with CHD on PGE1	n = 67 Neonates >32 wk EGA with CHD who underwent surgical repair at <1 mo	Nearly all of the infants had EN initiated preoperatively (93%) and only 1 patient with HLHS developed medical NEC at 6 d while on PGE1 and receiving 100 mL/kg/d of EN	Inotropic/vasoactive medications were used in 7 (10.4%) patients and umbilical arterial catheters were in 14 patients (21%), but there was no independent analysis of associated morbidity
Scahill et al45	Retrospective, cohort, single center	To determine if preoperative feeding is associated with NEC in neonates with CHD	n = 130 Neonates (≤31 d of age at admission) admitted to the CICU who required cardiac surgery Mean age ± SD: NEC: 8 d ± 13 No NEC: 10 d ± 13	12 (9%) infants developed NEC No difference in the incidence of NEC between neonates who fed preoperatively versus neonates who were NPO Higher volume feeds (>20 mL/kg/d) were not associated with NEC Preoperative NPO status was not associated with growth failure or longer LOS	No difference in the incidence of NEC in the preoperative presence of an umbilical arterial catheter or inotropic/ vasoactive support
Tabbutt et al100	Secondary analysis of a prospective RCT, multicenter	To identify risk factors for mortality and morbidity during stage 1 palliation	n = 549 Neonates with HLHS or single right ventricle anomalies prospectively enrolled from 15 centers during stage 1 palliation	14 (3%) infants developed NEC at a median of 23 d (IQR 2–66 d) after the Norwood procedure No significant risk factors for NEC were identi fi ed
Toms et al51	Retrospective, cohort, single center	To determine if preoperative trophic feeds can improve outcomes after Stage 1 palliation	n = 50 Full-term neonates with HLHS	Preoperative trophic feeds were associated with less fluid administration in the OR, a more negative 48-h postoperative fluid balance, and shorter duration of mechanical ventilation No development of NEC in either group	Patients kept NPO preoperatively may inherently be less well and thus confound data
Willis et al52	Retrospective, cohort, single center	To assess feeding tolerance in neonates with CHD on PGE1	n = 34 Infants >35 wk EGA and <28 d with ductal- dependent CHD	33/34 neonates tolerated EN while receiving PGE, infusion	9 (27%) patients had an umbilical artery catheter and 2 (6%) patients were on vasopressor medications while concurrently on a PGE1 infusion
Zyblewski et al101	Prospective, RCT, single center	To evaluate intestinal barrier function in neonates undergoing cardiac surgery and determine correlations with early human milk feeding	n = 27 Term (>37 wk EGA) neonates with CHD requiring cardiac surgery with CPB randomized to NPO (n = 13) versus trophic (n = 14) human milk feeds	Intestinal barrier function was markedly abnormal following CPB, but no different between neonates who received preoperative trophic EN compared with neonates who remained NPO No difference in GI morbidity between groups	The study was not powered for clinical outcomes

Abbreviations: ASO, arterial switch operation; CHD, congenital heart disease; CICU, cardiac ICU; EGA, estimated gestational age; EN, enteral nutrition; GI, gastrointestinal; HLHS, hypoplastic left heart syndrome; IQR, interquartile range; LOS, length of stay; NEC, necrotizing enterocolitis; NPO, nil per os; OR, operating room; PGE1, prostaglandin.

There is wide variation in preoperative feeding management strategies given concerns regarding the safety and tolerance of EN.⁴¹ An international survey described the decision to feed preoperatively to be based partly on the direction of ductal flow, presence of umbilical catheters, and/or the concurrent use of prostaglandins and hemodynamic pharmacologic agents.⁴² Variation in practice and associated complications with EN intolerance has impaired well-designed, multicenter studies from being conducted.

However, multiple retrospective studies have evaluated the effect of EN on important perioperative outcomes, including NEC in infants with complex CHD.^43–52 The consensus among available publications is that there is insufficient evidence to conclude EN adversely affects important clinical outcomes such as NEC, LOS and feeding tolerance. However, these studies have many limitations and biases owing to study design and the propensity to feed “healthier” patients, thereby naturally eliminating infants with high-risk lesions. The decision to initiate EN is ultimately at the discretion of the provider given the lack of standardization.

There is no available evidence describing the risks or benefits of EN initiation in infants with CHD supported on hemodynamic pharmacologic agents – either in the pre-, peri- or postoperative state. However, cohort studies in critically ill children without CHD have demonstrated that EN can be administered without any significant adverse events.^{53, 54} Thus, based on expert opinion and data extrapolated from critically ill children without CHD, EN may be considered in infants with CHD with signs of adequate cardiac output supported on vasoactive or inotropic agents. Infants who are on escalating doses of vasoactive or inotropic agents or suffer from inadequate cardiac output should not have EN initiated. Similarly, the provision of EN in infants with CHD with umbilical arterial catheters in place may be safe based on neonatology studies; however, there is no evidence specific to infants with CHD available.^55–57

Additionally, the use of fortified feeds in infants with CHD is commonplace, but there is limited evidence guiding the risks and benefits of this practice. Two RCTs have demonstrated no increased incidence of feeding intolerance or NEC and an increase in adequacy of both energy and protein.^{58, 59} Both studies had a small sample size and thus clinical outcome measures were no different between the two treatment groups.

Finally, studies in term neonates without CHD on ECMO or VAD have demonstrated tolerance to EN without an increase in gastrointestinal complications. ^60–62 Based on expert opinion and these retrospective studies, the initiation of EN in hemodynamically stable infants with CHD on ECMO or VAD is encouraged.

Recommendations

3a. In neonates with critical CHD, there is insufficient evidence to conclude that preoperative feeding adversely affects important perioperative outcomes, such as necrotizing enterocolitis (NEC), length of stay (LOS), and tolerance of feeds. Based on retrospective studies, however, preoperative enteral nutrition (EN) may be reasonable when considering type of cardiac lesion, hemodynamic support and clinical parameters. This includes infants with ductal dependent lesions provided, hemodynamic variables are stable and the infant is in a closely monitored setting. (Class IIb, LOE C-LD)

3b. There is insufficient evidence to conclude that EN in infants with CHD on vasopressor or inotropic medications is beneficial or harmful. EN in this population may be considered in patients on stable or decreasing amounts of hemodynamic pharmacologic support. (Class IIb, LOE C-EO)

3c. The initiation of EN in infants with CHD in the presence of umbilical arterial catheters may be reasonable but efforts to limit catheter days are important. (Class IIb, LOE C-EO)

3d. Infants with CHD may benefit from protein or energy-enriched formulas to achieve their nutritional requirements in fluid-restricted states. There is insufficient evidence to conclude that protein or energy-enriched formulas are unsafe or poorly tolerated in infants with CHD. (Class IIb, LOE C-LD)

3e. Initiating EN may be considered in infants with CHD who are hemodynamically stable and well supported on ECMO OR VAD. However, there is insufficient evidence to conclude that EN is beneficial. (Class IIb, LOE C-EO)

FEEDING PRACTICE

Advancing EN in infants with CHD

Feeding protocols are associated with improved outcomes including shortened duration of MV, fewer infectious complications, decreased LOS, and reduced mortality in critically ill patients with CHD (Table 5).^63–65 A survey done by the National Pediatric Cardiology Quality Improvement Collaboration (NPC-QIC) examined feeding algorithms in single ventricle patients and found that 48% of centers do not use a standard feeding protocol.⁶⁶ However, standardized feeding practices in postoperative patients with hypoplastic left heart syndrome (HLHS) have shown a significant reduction not only in the rate but also in the severity of NEC.⁴⁸ An independent study looking at the timing of initiation of feedings and trial of early feedings showed a reduction in PN use, duration of MV and infectious complications.⁶⁷ Early trophic EN may help with restoration of the gut microbiome and reduction of bacterial translocation.⁶⁷ Furthermore, oral feeding algorithms detailing timing and initiation are beneficial in reducing LOS and increasing oral feeding rates.⁶⁵ Prospective multicenter trials are lacking to determine optimal standardized feeding, feeding modality, type and schedule but overall improved outcomes are seen with protocolized feeding practices at individual institutions.

TABLE 5.

Feeding Advancement Algorithms in Infants With Congenital Heart Disease

Reference	Study Design, No. of Sites	Study Aim(s)	Population (n), Eligibility	Results/Outcomes	Comments
Braudis et al64	Prospective, case-control, single center	To test the safety and efficacy of an EN algorithm in infants with HLHS following stage 1 palliation	n = 36 Patients ≥35 wk EGA and weight ≥2 kg with HLHS admitted to CICU	Implementation of EN algorithm resulted in shorter time to goal energy intake and decreased duration of PN utilization EN algorithm did not result in increased episodes of NEC	EN protocol: 1. Start with gastric feeds unless history of feeding intolerance 2. Start with clear liquidfeedings at 1mL/kg/h 3. Transition to human- milk/formula at 1 mL/kg/d for 4 h 4. Increase by 1 mL/kg/d every 4 h to goal
del Castillo et al48	Retrospective, case- control, single center	To examine the impact of a standardized EN protocol on the incidence of NEC and postoperative GI morbidity	n = 98 (52 preprotocol, 46 postprotocol) Neonates with HLHS admitted to the CICU after Stage 1 palliation	Incidence of NEC decreased with implementation of EN protocol	EN protocol: 1. Start with NG feeds 2. Start clear liquid feedings at 3 mL/h x 6 h 3. Advance to human milk or Pregestimil at 3 mL/h x 6h 4. Advance by 3 mL every 6 h to goal volume 5. Fortify to 24 kcal/oz after 12 h of goal vol feeds 6. Consider bolus feeds after 24 h of full- fortified feeds
Kalra et al67	Prospective, RCT, single center	To assess the feasibility of initiating EN within the first 24 h after CHD repair and its impact on outcomes	n = 15 Cyanotic CHD with increased pulmonary blood flow, weighing <5 kg and undergoing CHD repair Diagnosis of single ventricle, ECMO utilization, open sternum, palliative procedure, or contraindication to feed excluded	Neonates and infants tolerate feeds immediately following CHD repair Feeds associated with decreased duration of mechanical ventilation and ICU LOS	EN Protocol: Feed group receiving 10–20 mL/kg/d starting 4–6 h after surgery compared with NPO group who did not have feeds initiated until 48 h after surgery
Simsic et al65	Retrospective, cohort, single center	To develop experience- based CICU newborn feeding guidelines for the initiation and advancement of EN	n = 129 (36 preguidelines, 93 postguidelines) Newborns (>35 wk EGA) admitted to CICU for cardiac surgery	Implementation of guidelines reduced practice variation and hospital LOS No difference in the percentage of full oral feeding at discharge with implementation of guidelines No difference in mesenteric ischemia after guidelines implementation	EN protocol:  If extubated:   1. One day following extubation, PO ad lib human milk or formula x 24 h   2. If inadequate intake on day #2, start gavage feeds at 3 mL/kg/feed every 3 h   3. Advance by 3 mL/kg/feed every 24 h to goal of 1 18 mL/kg/feed every 3 h
					If intubated:    1. Place NG/NJ   2. Start 1 mL/kg/h for 24 h   3. Advance by 1mL/kg/h every 24 h to 70 mL/ kg/h   4. Fortify if tolerated goal volume for 24 h

Abbreviations: CHD, congenital heart disease; CICU, cardiac ICU; ECMO, extracorporeal membrane oxygenator; EGA, estimated gestational age; EN, enteral nutrition; GI, gastrointestinal; HLHS, hypoplastic left heart syndrome; LOS, length of stay; NEC, necrotizing enterocolitis; NG, nasogastric; NJ, nasojejunal; NPO, nil per os; PN, parenteral utilization; PO, per os; RCT, randomized controlled trial.

Gastric versus post-pyloric (PP) enteral feeds in infants with CHD

Traditionally, postoperative feedings, both gastric and PP, in complex CHD patients have been shown to be safe (Table 6).^68–71 In addition, certain studies have demonstrated a decrease in time to goal energy intake when PP feeds are initiated as nil per os (NPO) times may not need to be adhered to surrounding procedures such as extubation.^{69, 70} However, PP feeds have not been shown to prevent tracheal aspiration of gastric fluids.⁶⁹ Though prospective trials looking at the benefits of PP feedings over gastric feedings in long-term successes are lacking, both are superior to PN when EN is feasible.

TABLE 6.

Gastric Versus Postpyloric Feeding in Neonates With Congenital Heart Disease

Reference	Study Design, No. of Sites	Study Aim(s)	Population (n), Eligibility	Results/Outcomes
Lyons et al70	Prospective, RCT, single center	To examine the safety and efficacy of continuous compared with interrupted post-pyloric feeds at the time of extubation	n = 59 All critically ill children, including postcardiac surgery Mean age (± SD): Continuous (n = 29): 23 mo ± 10 Interrupted (n = 30): 10.8 mo ± 3	Continuous postpyloric feeding during extubation is safe and results in improved energy adequacy
Meert et al72	Prospective, RCT, single center	To determine the effect of feeding tube position on adequacy of nutrient delivery and feeding complications	n = 74 Critically ill children <18 y requiring MV, including postcardiac surgery Mean age (± SD): Gastric (n = 32): y ± 5.8 Small bowel (n = 30): y ± 5.8	Small bowel feeds allow for increased energy adequacy; however, they do not prevent aspiration of gastric contents
Sanchez et al71	Prospective, cohort, single center	To assess the utility of postpyloric EN in children post-CHD surgery	n = 212 Mean age (± SD): 15 mo ± 29	Postpyloric feeds can be delivered safely to children with CHD in the postoperative period Postpyloric feeds allow for high calorie delivery in the postoperative period

Abbreviations: CHD, congenital heart disease; EN, enteral nutrition; MV, mechanical ventilation; RCT, randomized controlled trial.

Human milk versus formula in infants with CHD

Human milk is the preferred feeding for all preterm and term infants.⁷⁰ However, there is a paucity of high-quality studies specific to infants with CHD. Retrospective data suggest a protective effect of an unfortified human milk diet against the development of NEC.⁷¹ One of the largest challenges with human milk feeding in infants with CHD is meeting the high-energy requirements of some of those infants with congestive heart failure. Infants with CHD can have improved growth on human milk versus formula but strong lactation support is an essential component of human milk provision.^{72, 73}

Special nutritional considerations for infants with CHD and chylous effusions

Chylothorax occurs in 1.3 to 4.7% of patients following cardiac surgery, with even higher rates and greater variation described in neonates and infants.⁷⁴ Chylothoraces are associated with increased morbidity and mortality.⁷⁵ Prolonged chylous drainage results in the loss of nutrients and immune cells increasing the risk for malnutrition. Adherence to standard management protocols have shown to be beneficial in reduction of total chest tube (CT) days, days of fat restriction and elimination of practice variation.⁷⁶

Providing DHM is a viable, safe way to continue to provide human milk in this vulnerable population as human milk provides immunologic as well as nutritional benefits to infants.^77–80 Upon the diagnosis of chylothorax, initiation of DHM or MCT-based formulas should be initiated if output is low. Low output is often defined as <10 ml/kg/day.⁷⁶ If CT output remains high, ranging from 10–20 ml/kg/day, the patient is often made NPO and placed on PN for 5–14 days.⁷⁹ Recent studies suggest that earlier NPO status based on output alone can decrease total NPO days and thus LOS.⁸¹ DHM or MCT-based formula diets have varied across institutions ranging between 4 to 6 weeks from initiation to time of CT removal.^{76, 81}A small percentage of long chain triglycerides are found both in MCT-based formulas as well as DHM fortification to prevent essential fatty acid deficiency in this population during chylothorax treatment.⁸² DHM and /or MCT-based formulas may be supplemented by octreotide as a safe treatment to decrease postoperative chylothorax. ⁸³

Infants with CHD at risk for aspiration

In infants with CHD, cyanotic lesions are associated with significant delays in feeding readiness, successful gastric feeding, oral motor readiness and successful oral motor skills.⁸⁴ Factors that have been identified in delaying feeding milestones include the duration of respiratory support, use of CPB and aortic arch repair.⁸⁶ Infants who undergo aortic arch repair are at increased risk for aspiration due to the development of vocal cord dysfunction from damage to the recurrent laryngeal nerve.

Predictive risk factors in infants with CHD to determine need for surgical feeding tube placement

Many infants with CHD do not develop the skills to exclusively orally feed and require surgical feeding tube placement. A diagnosis of HLHS, lower gestational age, longer duration of MV and number of postoperative days NPO have been associated with failure to attain full oral feeds by hospital discharge.^87–89 The presence of gastroesophageal reflux disease has also been a poor predictor for all oral feedings.^{85, 86} Specifically in infants following the Norwood procedure, vocal cord dysfunction and longer duration of infusions had a direct association with requirement for a gastrostomy tube post hospitalization.⁸⁷

Recommendations

4a. The use of standardized feeding algorithms may be reasonable as they have improved time to feed initiation and energy adequacy, but they have not demonstrated an effect on improving anthropometric measurements or lowering mortality (Class IIb, LOE C-LD).

4b. Both gastric and postpyloric feeds are safe in infants with CHD. Neither method is superior, but postpyloric feeds may shorten duration to goal energy intake (Class IIb, LOE C-LD)

4c. There is strong support for the use of human milk over formula in preterm and healthy term infants based on the myriad of benefits attributed to the bioactive and immunologic properties of human milk, including the reduction of necrotizing enterocolitis (NEC). Despite limited data specific to infants with CHD, human milk feeding is still recommended for this population (Class I, LOE C-LD).

4d. Use of defatted human milk (DHM) or medium chain triglycerides (MCT)-rich formula for 4 to 6 weeks may be reasonable in infants who develop chylous effusions (Class IIb, LOE B-NR).

4e. Due to the increased risk for aspiration and feeding issues secondary to oropharyngeal dysphagia, infants who undergo aortic arch repair may benefit from routine postoperative vocal cord assessment. (Class IIb, LOE C-LD).

4f. Infants with CHD are at increased risk for feeding issues secondary to multiple factors that may be considered to help predict risk for aspiration, oropharyngeal dysfunction and the need for surgical feeding tube placement (Class IIb, LOE C-LD)

PARENTERAL NUTRITION

Indication for PN in infants with CHD

PN is indicated when EN is not feasible or enteral energy adequacy is insufficient in critically ill infants with CHD (Table 7). Based on a single multicenter RCT, a delayed PN strategy (initiation on day 8) results in decreased infectious complications, shorter duration of MV and shorter intensive care unit LOS in critically ill children.⁷ Nearly forty percent of the patients enrolled in the “Early versus Late Parenteral Nutrition in Critically Ill Children” (PEPaNIC) study had cardiac diagnoses, affording extrapolation of these findings to our population of interest. Furthermore, a sub-analysis of the term infants in the PEPaNIC trial revealed similar improved clinical outcomes in those treated with a delayed PN strategy.⁸⁸ Generalizing the findings of the PEPaNIC study to infants with CHD requires caution. There were several important limitations relevant to our population of interest including less than a quarter of the subjects were exposed to the intervention arm (delayed PN), energy intake goals were based on estimating equations, and the baseline nutritional status of the subjects (based on Body Mass Index z-scores) indicated well-nourished children.

TABLE 7.

Utilization of Parenteral Nutrition in Infants With Congenital Heart Disease

Reference	Study Design, No. of Sites	Study Aim(s)	Population (n), Eligibility	Results/Outcomes	Comments
Fivez et al7	Prospective, RCT, multicenter	To investigate if a delayed PN strategy (starting on day 8) is superior to an early PN strategy (starting within 24 h) in regard to clinical outcomes	n = 1440 (~40% CHD) Term neonate: 17 y expected to be in ICU for >24 h and STRONGKids Nutrition score >2	A delayed PN strategy results in fewer NIs, shorter duration of MV, and shorter ICU and hospital LOS A delayed PN strategy also resulted in more frequent episodes of hypoglycemia during the first week of illness
Larsen et al88	Prospective, RCT, single center	To investigate the effects of two different lipid emulsions (Lipoplus versus soybean oil) on systemic inflammation after CPB	n = 32 Mean EGA (± SD): 40 wk ± 2.3 Infants with CHD undergoing surgery utilizing CPB were randomized to receive lipid formulation for 1-4 d preoperatively and up to 10 d postoperatively	Provision of fish oil- based lipid emulsion provides a more beneficial inflammatory profile when compared with a soybean oil-based lipid emulsion in postoperative infants with CHD	Underpowered to detect clinical outcome difference
Netto et al102	Prospective, cohort, single center	To assess the epidemiology and associated risk factors of NIs in a CICU	n = 1106 Mean age (± SD): 1 NI 5 3.9 yo ± 6.7 No NI 5 3.1 yo ± 6.6 84 (7.5) NIs	PN use was the most significant predictor for NI in children in the CICU
van Puffelen et al103	Subanalysis, prospective, RCT, multicenter	To evaluate the effect of withholding PN for 1 wk in critically ill, term neonates	n = 145 (~40% CHD) Critically ill neonates <4 wk expected to be in ICU for >24 h and STRONGKids Nutrition score >2	Withholding PN for 1 wk resulted in earlier live discharge from ICU and decreased rate of NIs A delayed PN strategy increased the risk for hypoglycemia, which requires further long-term follow-up
Wylie et al104	Retrospective, case-control, single center	To identify risk factors for CLABSIs in critically ill children	n = 203 (48% CICU) Controls had CVC without CLABSI and were matched within 7 d of admission to cases (+CLABSI with CVC) Median age (IQR): Case = 0.7 y (0–37.5) Control = 3 y (0–54)	PN utilization was a risk factor for CLABSI complications in critically ill children with CVC

Abbreviations: CHD, congenital heart disease; CICU, cardiac ICU; CLABSI, central line-associated bloodstream infection; CPB, cardiopulmonary bypass; CVC, central venous catheter; EGA, estimated gestational age; IQR, interquartile range; LOS, length of stay; MV, mechanical ventilation; NI, nosocomial infection; PN, parenteral nutrition; RCT, randomized controlled trial; STRONGKids, Screening Tool for Risk on Nutritional status and Growth.

Formulation of intravenous lipid emulsion recommended for infants with CHD

Lipid emulsions are a vital source of calories and essential fatty acids for patients receiving PN. Over the last decade, several alternative lipid emulsions utilizing alternative sources of fatty acids have become commercially available. These newer lipid emulsions are used for the treatment of PNALD, but investigators have questioned whether their prophylactic administration can serve as an anti-inflammatory agent in the critically ill. A small RCT in postoperative infants with CHD demonstrated an improvement in the inflammatory cascade of infants prescribed a fish oil-based (Omegaven^™) when compared to a soy-based lipid emulsion, but these findings did not translate to improved clinical outcomes likely secondary to the small sample size.⁸⁹ Given limited evidence, our expert consensus is to prescribe soy-based lipid emulsions in conjunction with PN in infants with CHD. Finally, common complications associated with PN in the neonatal population are likely similar to infants with CHD prescribed PN. These complications include PNALD, CLABSIs and catheter-associated venous thromboses.^{90, 91}There are no available studies comparing the incidence of complications associated with PN in critically ill infants with CHD to infants in either the neonatal or pediatric intensive care unit.

Recommendations

5a. If enteral intake is insufficient, parenteral nutrition (PN) should be considered in infants with CHD. Common scenarios in which enteral nutrition (EN) is insufficient include hemodynamic instability, concerns for gastrointestinal ischemia, or prolonged periods of nil per os (NPO) surrounding procedures while admitted. (Class IIb, LOE C-LD)

5b. Based on a multicenter randomized controlled trial (RCT), critically ill infants with CHD may benefit from a delayed PN strategy (initiation on day 8) if they do not achieve enteral energy adequacy during the first week of hospital admission. However, we caution application of this strategy in infants with malnutrition or those at risk for nutritional deterioration. (Class IIb, LOE B-R)

5c. A soy-based lipid emulsion is reasonable when intravenous nutrition is initiated in infants with CHD without known co-morbidities. There is insufficient evidence to recommend the utilization of fish-oil containing lipid emulsions as an immunomodulator (Class IIa, LOE C-EO).

5d. Parenteral nutrition associated liver disease (PNALD), central line-associated bloodstream infections (CLABSIs) and catheter-related venous thromboses are complications associated with PN in critically ill infants. Early EN may minimize these complications (Class IIb, LOE C-LD).

OUTCOMES

Based on observational studies, malnutrition and energy inadequacy have been associated with poor clinical outcomes including increased morbidities (i.e. increased infectious complications, longer duration of MV, and longer LOS) and mortality (Table 8).^{8,10 92–95} As postoperative survival improves in infants with CHD, the focus has shifted on outcome optimization. Identifying malnutrition as a modifiable risk factor could allow for the early identification and intervention in at-risk infants with CHD - potentially improving important clinical outcomes. However, no studies to date have demonstrated an improvement in morbidity and mortality rates with the diagnosis and treatment of malnutrition. The formal development of a risk assessment tool in infants with CHD to identify those who are malnourished or suffer from nutritional deterioration, in conjunction with standard anthropometric measurements, may raise awareness of the benefits of nutritional support. However, no formal malnutrition screening tool exists to date specifically for children with CHD.

TABLE 8.

The Impact of Nutritional Status on Clinical Outcomes in Infants With Congenital Heart Disease

Reference	Study design, No. of sites	Study Aim(s)	Population (n), Eligibility	Results/Outcomes
Alsoufi et al8	Retrospective, cohort, single center	To examine the effect of weight at the time of cardiac surgery on hospital outcomes and to analyze the risk factors for mortality	n = 2051 Median age (IQR): 7 d (4–32)	Lower weight associated with longer duration of MV, longer LOS, and increased mortality Lower weight was not associated with an increase in unplanned reoperations or ECMO Weight <2.5 kg associated with poor late survival
Anderson et al94	Retrospective, case series, single center	To assess the effect of nutritional status on short-term outcomes during the BDG	n = 100 Median age (IQR): 5.1 mo (2.4–10)	Lower WAZ associated with longer hospital stay Suboptimal interstage wt gain noted
Costello et al95	Prospective, cohort, 2 centers	To determine the prevalence of growth restriction and investigate the relationship to clinical outcomes	n = 78 Median age (IQR): 4 mo (0–33)	23% of patients had WAZ <−2 Increased LOS associated with poor growth at admission
Eskedal et al93	Retrospective, case-control, single center	To describe the effects long-term growth has on late mortality and to study the relationship of postoperative weight gain and survival	n = 74 Mean WAZ Admit WAZ: 0.12 Operative WAZ —1.31 Final MAZ: —2.09	Decrease in WAZ postoperatively corresponds to poor long-term survival
Evans et al92	Retrospective, longitudinal, multicenter	To investigate if weight gain after stage 1 palliation is associated with transplant- free interstage survival	n = 1501 Transplant-free interstage survival was 90%	Interstage weight gain is significantly associated with transplant-free survival
Medoff-Cooper et al10	Prospective, cohort, single center	To assess the association between early anthropometric measurements, device assisted feeding and early neurodevelopmental outcomes	n = 72 Single ventricle: 34 (47) Biventricle: 38 (53)	Infants with lower anthropometric measurements at 3 mo are at risk for neurodevelopmental delay at 6 and 12 mo
Ross et al105	Retrospective, cohort, single center	To evaluate the impact preoperative malnutrition has on outcomes after pediatric cardiac surgery	n = 2088 Median age (IQR): 4.5 mo (0.7–10)	Each unit decrease in WAZ, increases the risk for cardiac arrest, infectious complications, duration of MV and ICU LOS

Abbreviations: BDG, bidirectional Glenn; ECMO, extracorporeal membrane oxygenator; IQR, interquartile range; LOS, length of stay; MV, mechanical ventilation; WAZ, weight-for-age z-score.

Recommendation

6. Infants with CHD and malnutrition are at increased risk for poor clinical outcomes, however there is no evidence demonstrating improved clinical outcomes with improved nutritional state. It is unclear whether efforts to minimize malnutrition in infants with CHD may improve important clinical outcomes (Class IIb, LOE C-LD).

CONCLUSION

Critically ill neonates and infants with CHD can suffer from a variety of conditions that may compromise nutrition. These include hypermetabolic states, hemodynamic instability requiring inotropic/vasoactive agents, strict fluid intake, heightened risk for gastrointestinal ischemia, associated genetic anomalies, and a predictable metabolic and inflammatory stress response following CPB. These concerns served as the basis for the development of our clinical guideline questions. Our clinical recommendations are the first publication to provide guidance for the optimal nutritional evaluation and management of critically ill neonates and infants with CHD. Several of our considerations are consistent with the ASPEN and ESPNIC guidelines, but neonates and infants with CHD represent unique nutritional challenges necessitating the formulation of distinct guidelines. ^{12, 13}

We acknowledge several limitations in this review and in our recommendations. Most of the studies span several age groups and thus conclusions are not focused solely on infants. In addition, a few of the studies include preterm neonates. The lack of large RCTs did not permit meta-analyses and most of the recommendations were based on expert consensus or low levels of evidence. Finally, in situations where data was unavailable in infants with CHD, we extrapolated data from either critically ill neonates, children or adults who likely suffer from different physiologic and metabolic alterations.

In this article, we have provided guidance for optimal nutrition practices in critically ill infants with CHD. We acknowledge that the six selected questions are not exhaustive and the paucity of high-quality data led a majority of our recommendations to be derived by consensus or low-level evidence. Our review of the evidence and proposed recommendations are intended to pave the way for future quality improvement efforts to address decisional management gaps in supporting the nutritional needs of the sick cardiac infant.

With few high-quality randomized controlled trials in neonates and infants with CHD, wide variation in clinical practice exists as evidenced by our guidelines. To aid in the nutritional management of infants with CHD, future multicenter quality improvement efforts would address these issues. These efforts should include:

• Determining the optimal prescription of energy and protein

• Investigation into the timing of supplemental PN in infants with CHD

• Further study of novel lipid emulsions as potential immunomodulators

• Formalizing guidelines surrounding safe preoperative feeding advancement and practices

• Assessment of the risks and benefits of fortified feeds at different levels

• Development of risk assessment tools to identify at-risk infants with CHD to improve important clinical outcomes

Abbreviations:

CHD

Congenital Heart Disease

NEOC3

Neonatal Cardiac Care Collaborative

CPB

Cardiopulmonary Bypass

REE

Resting Energy Expenditure

IC

Indirect Calorimetry

EN

Enteral Nutrition

PN

Parenteral Nutrition

PNALD

PN associated liver disease

MV

Mechanical Ventilation

LOS

Length of stays

SCCM

Society of Critical Care Medicine

ASPEN

American Society of Parenteral and Enteral Nutrition

ESPNIC

European Society of Pediatric and Neonatal Intensive Care

RCTs

randomized controlled trials

TEE

total energy expenditure

NEC

Necrotizing Enterocolitis

ECMO

extracorporeal membrane oxygenation

VAD

ventricular assist device

NPC QIC

National Pediatric Cardiology Quality Improvement Collaborative

HLHS

Hypoplastic Lefts Heart Syndrome

PP

post pyloric

DHM

defatted human milk

MCT

medium chain triglycerides

NPO

nil per os

CT

chest tube

CLABSI

central line-associated bloodstream infection

PEPaNIC

Early versus Late Parenteral Nutrition in Critically Ill Children