Parenteral Nutrition in Critically Ill Children

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Parenteral Nutrition in Critically Ill Children Nilesh M. Mehta, M.D. Adequate nutrient delivery may help to offset the catabolic burden imposed by critical illness, preventing nutritional deterioration and improving outcomes. However, questions regarding the most appropriate dose of macronutrients, the route of delivery, and particularly the timing of supplemental parenteral nutrition in critically ill children remain unanswered (Table 1). Enteral nutrition is preferable in patients with a functioning gut but may not always be feasible. Intestinal failure was incompatible with life until the 1960s, when the development of stable intravenous amino acid solutions and lipid emulsions allowed the administration of life-sustaining nourishment through the parenteral route.1 Parenteral nutrition was subsequently extended to critically ill patients when enteral nutrition was insufficient or contraindicated. As awareness of the unintended side effects of parenteral nutrition has increased, patient selection and the tim-

ing of administration are being investigated and the optimization of enteral nutrition emphasized.2 The benefits of early parenteral nutrition during critical illness in children have been questioned, given the results of studies in adults.3,4 When enteral nutrient intake is insufficient in critically ill children, two distinct strategies are now considered: some medical centers initiate early parenteral nutrition to prevent macronutrient deficits, while others, concerned about side effects, delay supplementary parenteral nutrition for a week while providing enteral nutrition.5 Fivez et al. now address this area of uncertainty in the Journal by reporting the results of a threecenter trial, Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit (PEPaNIC).6 In the trial, 1440 patients with insufficient enteral nutrition were randomly assigned to a control group in which parenteral nutrition was administered within 24 hours after admission

Table 1. Areas of Consensus and Controversy in Critical Care Nutrition for Children. Area

Consensus

Controversy or Gaps in Knowledge

Energy requirement

Estimates from equations are often unreliable

Role of hypocaloric diet in nonobese children

Protein requirement

Requirement is increased owing to catabolic response during critical illness; delivery may be inadequate in most patients

Role of specific amino acids

Route of nutrient delivery

Enteral route is preferred if gut is functional; supplemental parenteral nutrition should be delayed and enteral nutrition optimized

Effects of postpyloric feeding and antacids in delivery of enteral nutrition

Enteral intolerance

Intolerance impedes delivery of enteral nutrition; stepwise approach aids delivery of enteral nutrition

Use of gastric residual volume as marker of intolerance

Immunonutrition

Supplementation with a combination of micronutrients and glutamine is not beneficial

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or to an intervention group in which parenteral nutrition was withheld until day 8. All patients received early enteral nutrition followed by stepwise, standardized advancement to the prescribed goal. The sites used different methods to determine energy requirements, parenteral nutrition strategies, and targets for glycemic control. An absolute reduction in the risk of new infections (7.8 percentage points) and a reduced time to “readiness for discharge” from the intensive care unit (ICU) were recorded in the group receiving late parenteral nutrition as compared with that receiving early parenteral nutrition. The duration of mechanical ventilation and the odds of renal replacement were also lower in the lateparenteral-nutrition group. The internal validity of the study was high in terms of sample size, randomization, concealed allocation, adherence to the protocol, standardization of the intervention, and statistical analysis. To determine the external validity of the study, some design elements must be discussed — the population selected, the generalizability of the protocol, and the relevance of the outcomes. More than 55% of the patients in the control group were discharged by day 4. These patients would not be considered candidates for parenteral nutrition within 24 hours after admission in most medical centers. More than 77% of patients in the group receiving late parenteral nutrition were discharged by day 8 without having received any parenteral nutrition. The equations used to determine energy requirements are unreliable.7 The true adequacy of energy delivered, and the potential caloric underfeeding and overfeeding, cannot be determined in the absence of the measurement of energy expenditure. The dose of enteral nutrient delivery beyond which the risks of supplemental parenteral nutrition offset its benefits is unknown. A threshold enteral delivery of less than 80% of the nutrient target triggered supplementation with parenteral nutrition in this trial, whereas enteral delivery of 66% of the nutrient target has been associated with improved outcomes in children receiving mechanical ventilation.8 The poor outcomes in the group receiving early parenteral nutrition may represent the risks associated with the parenteral route of delivery or the effects of caloric overfeeding. The device investigators used to calculate the risk of malnutrition, the Screening Tool

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for Risk on Nutritional Status and Growth (STRONGkids), is based on a simple questionnaire without anthropometric variables.9 The use of STRONGkids has not been validated in critically ill children and may not be a reliable indicator of severe malnutrition.10 According to z scores for body-mass index, only a small fraction of patients in this trial had moderate or severe malnutrition. Standard outcomes related to infection, such as ventilator-associated pneumonia and catheter-associated bloodstream infections, were not recorded. The intensive care team determining the pragmatic “readiness for discharge” outcome was not masked to patient randomization, which introduces the potential for bias. Despite the above limitations, the results of this landmark trial will change practice in centers that supplement insufficient enteral nutrition with parenteral nutrition on day 1 and will provide data that support the strategy of delayed parenteral nutrition practiced in other centers. Further examination is required to determine the best possible timing for the introduction of supplemental parenteral nutrition in severely malnourished children in the pediatric ICU. Ideally, nutrition therapy for critically ill children must be individualized. The presupposition that a uniform approach would apply to all is too simplistic. On the basis of the results of the PEPaNIC trial, delaying parenteral nutrition, along with early initiation and stepwise advancement of enteral nutrition, seems prudent in patients who are not severely malnourished. Patience and substantial resources will be required to systematically address unresolved questions through randomized, controlled trials. As the tapestry of evidence is gradually woven, we must be circumspect in our interpretation of study results, invest in mechanistic and hypothesis-generating studies, and explore relevant long-term outcomes. The PEPaNIC trial represents an important step forward, and its results will help to recalibrate the safe application of parenteral nutrition in critically ill children. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From Harvard Medical School and the Division of Critical Care Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital — both in Boston. This article was published on March 15, 2016, and updated on March 15, 2016, at NEJM.org.



Editorial

1. Wilmore DW, Dudrick SJ. Growth and development of an infant receiving all nutrients exclusively by vein. JAMA 1968;203: 860-4. 2. Mehta NM, Compher C. A.S.P.E.N. clinical guidelines: nutrition support of the critically ill child. JPEN J Parenter Enteral Nutr 2009;33:260-76. 3. Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011; 365:506-17. 4. Doig GS, Simpson F, Sweetman EA, et al. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA 2013;309:2130-8. 5. Hamilton S, McAleer DM, Ariagno K, et al. A stepwise enteral nutrition algorithm for critically ill children helps achieve nutrient delivery goals. Pediatr Crit Care Med 2014;15:583-9. 6. Fivez T, Kerklaan D, Mesotten D, et al. Early versus late par-

enteral nutrition in critically ill children. N Engl J Med. 10.1056/ NEJMoa1514762. 7. Hunter DC, Jaksic T, Lewis D, Benotti PN, Blackburn GL, Bistrian BR. Resting energy expenditure in the critically ill: estimations versus measurement. Br J Surg 1988;75:875-8. 8. Mehta NM, Bechard LJ, Cahill N, et al. Nutritional practices and their relationship to clinical outcomes in critically ill children — an international multicenter cohort study. Crit Care Med 2012;40:2204-11. 9. Hulst JM, Zwart H, Hop WC, Joosten KF. Dutch national survey to test the STRONGkids nutritional risk screening tool in hospitalized children. Clin Nutr 2010;29:106-11. 10. Spagnuolo MI, Liguoro I, Chiatto F, Mambretti D, Guarino A. Application of a score system to evaluate the risk of malnutrition in a multiple hospital setting. Ital J Pediatr 2013;39:81. DOI: 10.1056/NEJMe1601140 Copyright © 2016 Massachusetts Medical Society.



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