This guideline discusses nutritional support for neonatal and pediatric patients requiring extracorporeal membrane oxygenation (ECMO) support. Data for nutrient delivery during ECMO support and its impact on outcomes are scarce. Hence, practice may be variable and evidence-based guidelines are limited. Provision of nutrition during ECMO may be impeded by concerns of patient instability, volume restriction, and possible enteral nutrition (EN) intolerance due to splanchnic ischemia. These guidelines include evidence-based, where available, or consensus-based recommendations for best practices on five domains of nutritional delivery in the neonatal and pediatric ECMO patient. A summary table of pertinent literature is included (Table 1).

Table 1. - Selection of Pertinent Articles and Level of Evidence Study Population Summary Level of Evidence Mehta et al. 1 Pediatric critically ill patients Thorough guidelines regarding best practices in nutrition therapy Systematic review using GRADE: Includes studies with level II evidence Farr et al. 2 Neonatal and pediatric ECMO patients Invited review of current evidence and guidelines for the prescription and delivery of nutrition for patients receiving ECMO Review: Includes studies with level II evidence Ong et al. 3 Pediatric ECMO patients Description of nutritional practices and adequacy and association with mortality Retrospective cohort: Level V Greathouse et al. 4 Pediatric ECMO patients Survival rates in patients who received early nutrition and met their nutritional intake goal Retrospective chart review

GRADE, grading of recommendations, assessment, development and evaluations; ECMO, extracorporeal membrane oxygenation.

Neonatal and Pediatric Venovenous and Venoarterial ECMO Nutrition Guideline Domains 1. Performing nutrition screening and assessment 2. Characterizing metabolic needs and nutritional requirements 3. Timing of initiation of enteral or parental nutrition 4. Recognizing feeding intolerance and suggested management strategies 5. Utilizing a consensus-based nutritional delivery algorithm to promote advancement of nutritional support 1. Performing nutrition screening and assessment A nutritional assessment within 24–48 hours of admission is warranted to serve as baseline for monitoring patient outcomes and to aid in identifying the degree of nutritional risk.5 The nutritional state of patients admitted to the pediatric intensive care unit (PICU) is at risk for deterioration, impacting morbidity and mortality. Therefore, periodic nutritional assessments are necessary within this patient population.6–8 A thorough assessment includes comprehensive nutritional history, anthropometric measurements, biochemical data, and conducting a Nutrition Focused Physical Exam (NFPE) taking into account the severity of illness and fluid status of the patient.5 However, not all aspects of this exam are feasible in the ECMO patient. Attention should be paid to admission weight and baseline nutritional status. The American Society for Parenteral and Enteral Nutrition (ASPEN) developed the NFPE to guide healthcare professional’s assessment of malnutrition by examining the extent of muscle and fat depletion, identifying potential signs of micronutrient deficiencies, and evaluating shifts in fluid.7 The NFPE serves as a tool to assist in efficiently identifying possible signs of malnutrition so a nutritional care plan can be tailored to prevent further nutritional deterioration. To conduct an efficient nutritional care plan, an NFPE integrating palpation to assess body composition and fluid shifts is necessary.7 A study aiming to determine the correlation of NFPE findings and malnutrition severity found that use of the NFPE resulted in a reduction of the severity of malnutrition through early identification of fat and muscle loss.9 Although nutritional screening is an important element of critical care nutrition, there is no current gold standard for the nutritional assessment within this patient population that is universally accepted or validated.10 Height, weight, and head circumference (in children less than 36 months of age) are basic, essential elements of assessment. Screening tools that can be performed by any healthcare team member include Screening Tool for Risk on Nutritional status and Growth kids, the Screening Tool for the Assessment of Malnutrition in Pediatrics, or the Subjective Global Analysis tool. However, all ECMO patients should be considered at high nutritional risk, especially those receiving continuous renal replacement therapy, and these tools are not validated in ECMO patients. Future investigation regarding reliable nutritional assessment methods in pediatric ECMO is required.11,12 Consequently, while we recommend nutritional assessment for ECMO patients using the NFPE, we cannot recommend the use of any one specific assessment tool. 2. Characterizing metabolic needs and nutritional requirements a. Energy requirements in neonatal and pediatric patients on ECMO support may be considered equivalent to those of the general pediatric critical care population. Metabolic alterations are common in critical illness, and patients present with a variety of metabolic states that cannot be predicted, ranging from hypometabolism to hypermetabolism.1 In a study where energy expenditure in neonates on ECMO was measured using stable isotope tracer techniques, patients were hypermetabolic during ECMO and for 3 weeks post-ECMO support.13 In another study using an intravenous isotope-labeled infusion technique to estimate energy requirements in neonates supported with ECMO, energy needs were not significantly greater than age-matched neonates.14 Indirect calorimetry is the gold standard for the determination of energy expenditure and is based on the spirometric analysis of oxygen consumption (VO2) and carbon dioxide production (VCO2). However, this technique cannot be used during ECMO because the CO2 removed across the extracorporeal membrane lung cannot accurately be identified by the calorimeter.15,16 Multiple cohort studies have demonstrated that most published predictive equations that were developed using data from healthy children are frequently inaccurate in estimating resting energy expenditure (REE) in critically ill children, leading to unintentional overfeeding or underfeeding with potential negative clinical consequences.17–19 Recommendations for the pediatric critically ill population suggest the use of the Schofield or Food Agriculture Organization/World Health Organization (WHO)/United Nations University equations without the addition of stress factors to estimate energy expenditure.1 Until further evidence becomes available, we acknowledge estimating energy requirements in ECMO patients is challenging. Consideration can be given to using the same methods for estimation of needs as for other critically ill pediatric patients. b. Neonatal and pediatric patients on ECMO support have elevated protein requirements and require adequate provision to decrease catabolic losses. Critical illness is a condition in which protein requirements, utilization, and balance change rapidly in proportion to the acute physiologic state. The metabolic stress response to injury is characterized by muscle breakdown and the release of free amino acids that participate in the inflammatory response and tissue repair.17,20 Prolonged protein catabolism during illness may result in a cumulative protein deficit with a net negative protein or nitrogen balance that lead to decrements in weight and lean body mass. Although there is low level of evidence for protein requirements in ECMO patients, data and guidelines from the general PICU population may be extrapolated. Protein intake adequacy was associated with lower mortality in a large multicenter prospective study of mechanically ventilated children. This study evaluated delivery of energy and protein in 1,200 critically ill, mechanically ventilated children admitted to 59 PICUs at academic institutions from 15 countries. Their results demonstrated a significant association between higher enteral protein adequacy and lower 60 day mortality in this cohort, independent of disease severity, and that delivery of more than 60% of the prescribed protein intake was associated with lower odds of mortality in mechanically ventilated children.21 In a systematic review of protein supplementation trials in children, a minimum of 1.5 gm/kg/d of protein delivery was associated with a positive nitrogen balance.22,23 ASPEN guidelines recommend age-based protein delivery goals for critically ill children significantly higher than those recommended for healthy children.1 In neonates, whole-body protein breakdown was found to be 100% higher than in age-matched healthy neonates.13Neonatal and pediatric patients on ECMO have increased protein requirements because of increased catabolism, and provision of adequate protein is essential.13 Whole-body protein breakdown in neonatal ECMO patients was found to be 100% higher than in age-matched healthy neonates.6Neonatal and pediatric patients on ECMO have increased protein requirements because of increased catabolism.13 We agree with nutrition guidelines for neonatal patients on ECMO, which recommend provision of up to 3 gm/kg/d protein to offset catabolic losses.24 Until further evidence becomes available, we recommend protein delivery at minimum of 1.5 gm/kg/d in neonatal and pediatric ECMO patients, with gradual increase as needed to meet protein requirements according to age and degree critical illness. 3. Timing of initiation of enteral or parental nutrition The delivery of early nutritional support is warranted in critically ill pediatric patients.1,4,25–27 The pathophysiological changes associated with metabolic stress can lead to the depletion of energy reserves and protein-energy malnutrition.25,28 Macronutrient energy reserves of children are minimal when compared with adults. These low macronutrient reserves put children at a high nutritional risk.28 Malnutrition in the critically ill child is associated with an increase in length of stay (LOS), longer periods of ventilation, increased risk of developing a hospital-acquired infection, and mortality.1,21,25,29 In a meta-analysis reviewing early versus late EN among pediatric critically ill patients, a lower mortality rate was associated with the early initiation of EN.25 Meeting nutritional goals within 72 hours has been associated with a shorter LOS in the intensive care unit (ICU) and overall hospital LOS when compared with not achieving goals within 72 hours.27 Rapid loss of lean body mass is common, particularly in neonates on ECMO; therefore, EN should be initiated expeditiously in all pediatric ECMO patients once the patient has clinically stabilized.1,24 ASPEN and Society of Critical Care Medicine’s (SCCM) guidelines for the provision of nutrition support to critically ill pediatric patients have suggested that early provision of protein is ideal to achieve protein delivery goals and attain a positive nitrogen balance.1 The definition of early EN is variable within the literature, ranging between 6 hours and as late as 48 hours after admission to the ICU.1 As patients receiving ECMO support are among the most severely ill patients in an ICU, we recommend initiation of nutritional delivery within 48 hours of ECMO support or as soon as the patient is deemed clinically stable.1 b Initiation of parenteral nutrition (PN) EN is the preferred route for all critically ill patients and is beneficial for gastrointestinal mucosal integrity and motility.1 EN is an appropriate and safe nutrition modality for neonatal and pediatric ECMO patients. One study found that EN adequacy was associated with lower mortality for pediatric ECMO patients.3 An additional study provided a review that suggests the safety of EN for neonates and pediatric patients on both venovenous (VV) and venoarterial (VA) ECMO.30 Further studies examined gastrointestinal outcomes in enteral and nonenteral critically ill pediatric patients receiving vasoactive agents and determined EN is safe.31 Contraindications for EN include hemodynamic instability (e.g., rising lactate, increasing vasoactive requirement), unrepaired congenital diaphragmatic hernia (CDH), significant ileus, or other abdominal pathology.2 In patients in whom the digestive tract cannot be used or is insufficient to meet their requirements, PN should be considered to decrease energy and protein deficits.2,32 Interruptions in EN delivery (i.e., frequent and prolonged nil per os status or perceived intolerance) for all pediatric critical care patients should be minimized to optimize nutritional intake.1,33,34 One study revealed that less than one-third of the pediatric critical care patients achieved optimal EN delivery.34 Initiating EN at a continuous low volume rate (i.e., 10–20 ml/kg/d) and increasing volume slowly (i.e., every 6–12 hours), along with strict monitoring for intolerance, is one approach to consider.2 A reasonable goal is to achieve two-thirds of the EN nutrient goal in the first week of critical illness.1,21 In a prospective cohort study of children receiving mechanical ventilation, EN delivery of more than two-thirds of the energy goal and more than 60% of the protein goal was significantly associated with lower 60 day mortality.21 When EN is unable to be provided or is insufficient, PN should be considered.1,35 Timing of PN initiation remains controversial in all pediatric critical care patients. The current nutritional support guidelines recommend against starting PN in the first 24 hours of admission to the ICU.1 Many studies of nutrition in patients receiving ECMO report significant use of PN as a supplemental or primary source of nutrition within the first week.2–4,32 Farr et al.2 recommend considering PN in neonates and malnourished pediatric patients by days 3–5 and by day 7 for eutrophic pediatric patients. The frequently cited Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit (PEPaNIC) trial—which included ECMO patients—claims superiority in late (after 7 days) PN administration.36 However, this study must be interpreted with caution due to certain limitations.37 There is currently no clear consensus on timing of PN but clear guidance that PN is an appropriate consideration by days 3–7. Lipids can be used as a routine part of PN for pediatric patients on ECMO. In the early years of ECMO, the use of lipids was associated with circuit complications (i.e., circuit clotting, lipid deposition, and oxygenator dysfunction and failure). Since the change of oxygenator membranes from microporous polypropylene membranes to “true” nonporous, polymethylpentene membranes, more recent experience suggests that lipid infusions are not associated with oxygenator failure.38 In summary, we recommend early initiation and slow advancement of EN in neonatal and pediatric patients on ECMO as the method of choice for nutritional support. If nutrient delivery goal cannot be achieved by EN alone, we recommend initiation of PN with lipids within 3–5 days for malnourished children and within 5–7 days for well-nourished children. 4. Recognizing feeding intolerance and suggested management strategies The most common reason cited for withholding39 or in achieving adequate EN is feeding intolerance.40 Monitoring for signs and symptoms of feeding intolerance is an essential part of care39,41–43 as identification and treatment of the cause may avoid compromising nutritional goals.42 Defining feeding intolerance is difficult as definitions are inconsistent and assessment subjective. Nevertheless, a frequently used vague definition is difficulty in digesting food or the presence of adverse gastrointestinal symptoms. Although high gastric residual volumes (GRVs) are most commonly used to define feeding intolerance, there is insufficient evidence to support this. Signs and symptoms of feeding intolerance are most frequently described as rising lactate, vomiting, altered gastric motility, abdominal distention or constipation. Feeds may be poorly tolerated due to altered hormonal response, side effects of sedation and muscle relaxants, decreased splanchnic perfusion due to positive pressure ventilation, postoperative ileus, the use of catecholamines, and gastric comorbidities. Older children may experience anxiety that can affect their tolerance for feeding.44 One of the most common complications associated with enteral feeding in ECMO patients is delayed gastric emptying.43 Around 50% of critically ill children experience gastric dysmotility as manifested by delayed gastric emptying.44 To support gastric emptying in pediatric (“not” neonatal patients) ECMO patients, the use of prokinetic agents should be considered.45 In a retrospective adult study, 21 out of 33 patients who experienced feeding intolerance met their nutritional goal after being treated with a prokinetic agent.46 There is limited evidence to indicate the ideal prokinetic agent for pediatric patients on ECMO support, therefore, further investigation is required. Studies have found no difference in the ability to tolerate feeds when given either nasogastric tube or nasojejunal tube,1,35,47 nor between intermittent or continuous feeds. However, if a patient experiences intolerance via one route, it is reasonable to change to another. Dietitians may consider increasing protein content while keeping volume low if the child does not tolerate large volumes of feed. Absorption may also increase with hydrolyzed feeds where there is an intolerance to cow’s milk.25 In summary, feeding intolerance is likely to be encountered in the ECMO patient. We recommend close monitoring for feeding intolerance, with suggestions for interventions as per above to prevent delay and promote tolerance and advancement of support. 5. Utilizing a consensus-based nutritional delivery algorithm to promote advancement of nutritional support in neonatal and pediatric ECMO patients. A stepwise nutrition support algorithm is recommended to determine the feasibility of early EN versus the need for PN.1,2,48,49 There is evidence that using an algorithm significantly decreases the duration to achieve energy goals, decreases avoidable interruptions, and improves optimal nutritional intake.30 A published algorithm by Farr et al.2 in Nutrition in Clinical Practice is an example of a pragmatic algorithm that may be utilized/adapted to promote nutritional advancement. This algorithm may be used as a reference point for nutritional delivery in pediatric ECMO patients. Nutritional algorithms should provide guidance regarding timing of EN initiation, advancement, contraindications, and timing of PN initiation (if indicated). Summary of Recommendations We recommend nutritional assessment for ECMO patients using the NFPE. However, we cannot recommend the use of any one specific assessment tool. We recommend using the same methods for estimation of nutritional needs for the ECMO patient as for other critically ill pediatric patients. We recommend protein delivery at minimum of 1.5 gm/kg/d in neonatal and pediatric ECMO patients, with gradual increase to 3 gm/kg/d as needed to meet protein requirements according to age and degree of critical illness. We recommend initiation of nutritional delivery within 48 hours of ECMO support or as soon as the patient is deemed clinically stable. We recommend early initiation and slow advancement of EN as the method of choice for nutritional support. A reasonable goal is to achieve two-thirds of the EN nutrient goal in the first week of critical illness. If nutrient delivery goal cannot be achieved by EN alone, we recommend initiation of peripheral nutrition (PN) with lipids within 3–5 days for malnourished children and within 5–7 days for well-nourished children. We recommend close monitoring for feeding intolerance, with suggestions for intervention as follows: change of route of EN delivery, consideration of volume reduction while maintaining protein goal, consideration of use of hydrolyzed formulas, as well as consideration of a prokinetic agent for the pediatric (“not” neonatal) ECMO patient. We recommend utilizing a stepwise nutrition support algorithm to determine the feasibility of early EN versus the need for PN. Acknowledgment

The authors thank Elaine Cooley, MSN, RN, RRT, Christine Stead, MHSA, Peter Rycus, MPH, and the Board of Directors for help in the overall process.

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