OBJECTIVES: The nutritional management of critically ill term neonates and preterm infants varies widely, and controversies exist in regard to when to initiate nutrition, mode of feeding, energy requirements, and composition of enteral and parenteral feeds. Recommendations for nutritional support in critical illness are needed. METHODS: The ESPGHAN Committee on Nutrition (ESPGHAN-CoN) conducted a systematic literature search on nutritional support in critically ill neonates, including studies on basic metabolism. The Medline database and the Cochrane Library were used in the search for relevant publications. The quality of evidence was reviewed and discussed before voting on recommendations, and a consensus of 90% or more was required for the final approval. Important research gaps were also identified. RESULTS: This position paper provides clinical recommendations on nutritional support during different phases of critical illness in preterm and term neonates based on available literature and expert opinion. CONCLUSION: Basic research along with adequately powered trials are urgently needed to resolve key uncertainties on metabolism and nutrient requirements in this heterogeneous patient population.

Department of Clinical Sciences Paediatrics Umeå University Umeå Sweden

Department of Health Sciences University of Milan; Department of Paediatrics Ospedale dei Bambini Vittore Buzzi Milan Italy

Department of Medical and Surgical Sciences University of Foggia Italy

Department of Neonatal Intensive Care Oslo University Hospital Norway

Department of paediatric Gastroenterology Great Ormond Street Hospital for Children NHS Foundation Trust London UK

Department of Paediatrics University Hospital Motol Prague Czech Republic

Human Nutrition School of Medicine Dentistry and Nursing University of Glasgow New Lister Building Glasgow Royal Infirmary Glasgow UK

Newcastle Neonatal Service Newcastle Hospitals NHS Trust and Newcastle University Newcastle upon Tyne UK

Paediatreic Hepatology Gastroenterology and Transplantation ASST Papa Giovanni XXIIII Bergamo Italy

Paediatric Gastroenterology Erasmus MC Sophia Children's Hospital Rotterdam The Netherlands

Paris University APHP Necker Enfants Malades hospital Paris France and CNRC Baylor College of Medicine Houston TX

Zobrazit více v PubMed

Cuthbertson DP. Second annual Jonathan E. Rhoads lecture. The metabolic response to injury and its nutritional implications: retrospect and prospect. JPEN J Parenter Enteral Nutr 1979; 3:108–129.

Gillis C, Carli F. Promoting perioperative metabolic and nutritional care. Anesthesiology 2015; 123:1455–1472.

Kulkarni OP, Lichtnekert J, Anders H-J, et al. The immune system in tissue environments regaining homeostasis after injury: is “inflammation” always inflammation? Mediators Inflamm 2016; 2016: 2856213.

Bestati N, Leteurtre S, Duhamel A, et al. Differences in organ dysfunctions between neonates and older children: a prospective, observational, multicenter study. Crit Care 2010; 14:R202doi: 10.1186/cc9323. DOI

Pomerantz, Wendy J and Weiss, Scott L. Systemic inflammatory response syndrome (SIRS) and sepsis in children: definitions, epidemiology, clinical manifestations, and diagnosis. UpToDate, 2020. Available at: https://www.uptodate.com/contents/systemic-inflammatory-response-syndrome-sirs-and-sepsis-in-children .

Parry G, Tucker J, Tarnow-Mordi W. CRIB II: an update of the clinical risk index for babies score. Lancet 2003; 361:1789–1791.

Lee SM, Lee MH, Chang YS. The clinical risk index for babies II for prediction of time-dependent mortality and short-term morbidities in very low birth weight infants. Neonatology 2019; 116:244–251.

Patrick SW, Schumacher RE, Davis MM. Methods of mortality risk adjustment in the NICU: a 20-year review. Pediatrics 2013; 131: (Suppl 1): S68–S74.

Leteurtre S, Martinot A, Duhamel A, et al. Validation of the paediatric logistic organ dysfunction (PELOD) score: prospective, observational, multicentre study. Lancet 2003; 362:192–197.

Graciano AL, Balko JA, Rahn DS, et al. The Pediatric Multiple Organ Dysfunction Score (P-MODS): development and validation of an objective scale to measure the severity of multiple organ dysfunction in critically ill children. Crit Care Med 2005; 33:1484–1491.

Janota J, Stranák Z, Statecná B, et al. Characterization of multiple organ dysfunction syndrome in very low birthweight infants: a new sequential scoring system. Shock 2001; 15:348–352.

Pollack MM, Holubkov R, Funai T, et al. The Pediatric Risk of Mortality Score: Update 2015. Pediatric critical care medicine: a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2016; 17:2–9.

Ezz-Eldin ZM, Hamid TA, Youssef MR, et al. Clinical Risk Index for Babies (CRIB II) scoring system in prediction of mortality in premature babies. J Clin Diagnost Res: JCDR 2015; 9:Sc08–Sc11.

Dammann O, Shah B, Naples M, et al. Interinstitutional variation in prediction of death by SNAP-II and SNAPPE-II among extremely preterm infants. Pediatrics 2009; 124:e1001–e1006.

Sharma K, Mogensen KM, Robinson MK. Pathophysiology of critical illness and role of nutrition. Nutr Clin Pract 2019; 34:12–22.

Taylor AF, Lally KP, Chwals WJ, et al. Hormonal response of the premature primate to operative stress. J Pediatr Surg 1993; 28:844–846.

Anand KJ, Brown MJ, Bloom SR, et al. Studies on the hormonal regulation of fuel metabolism in the human newborn infant undergoing anaesthesia and surgery. Horm Res 1985; 22:115–128.

Anand KJ, Aynsley-Green A. Measuring the severity of surgical stress in newborn infants. J Pediatr Surg 1988; 23:297–305.

Chwals WJ. Overfeeding the critically ill child: fact or fantasy? New Horiz 1994; 2:147–155.

Jones MO, Pierro A, Hashim IA, et al. Postoperative changes in resting energy expenditure and interleukin 6 level in infants. Br J Surg 1994; 81:536–538.

Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987; 1:62–66.

Anand KJ, Hansen DD, Hickey PR. Hormonal-metabolic stress responses in neonates undergoing cardiac surgery. Anesthesiology 1990; 73:661–670.

Srinivasan V. Stress hyperglycemia in pediatric critical illness: the intensive care unit adds to the stress!. J Diabetes Sci Technol 2012; 6:37–47.

Coss-Bu JA, Hamilton-Reeves J, Patel JJ, et al. Protein requirements of the critically ill pediatric patient. Nutr Clin Pract 2017; 32:128s–141s.

Joosten KF, Kerklaan D, Verbruggen SC. Nutritional support and the role of the stress response in critically ill children. Curr Opin Clin Nutr Metab Care 2016; 19:226–233.

Mesotten D, Joosten K, van Kempen A, et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: carbohydrates. Clin Nutr 2018; 37:2337–2343.

Joosten K, Embleton N, Yan W, et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: energy. Clin Nutr 2018; 37:2309–2314.

Lambell KJ, Tatucu-Babet OA, Chapple LA, et al. Nutrition therapy in critical illness: a review of the literature for clinicians. Crit Care 2020; 24:35doi: 10.1186/s13054-020-2739-4. DOI

Oshima T, Heidegger CP, Pichard C. Supplemental parenteral nutrition is the key to prevent energy deficits in critically ill patients. Nutr Clin Pract 2016; 31:432–437.

Tian T, Coons J, Chang H, et al. Overfeeding-associated hyperglycemia and injury-response homeostasis in critically ill neonates. J Pediatr Surg 2018; 53:1688–1691.

McClintock R, Lifson N. Determination of the total carbon dioxide outputs of rats by the D2O18 method. Am J Physiol 1958; 192:76–78.

Wong WW, Roberts SB, Racette SB, et al. The doubly labeled water method produces highly reproducible longitudinal results in nutrition studies. J Nutr 2014; 144:777–783.

Tissot S, Delafosse B, Bertrand O, et al. Clinical validation of the Deltatrac monitoring system in mechanically ventilated patients. Intensive Care Med 1995; 21:149–153.

Westerterp KR, Lafeber HN, Sulkers EJ, et al. Comparison of short term indirect calorimetry and doubly labeled water method for the assessment of energy expenditure in preterm infants. Biol Neonate 1991; 60:75–82.

Bendavid I, Lobo DN, Barazzoni R, et al. The centenary of the Harris-Benedict equations: how to assess energy requirements best? Recommendations from the ESPEN expert group. Clin Nutr 2020; Nov 20;S0261-5614(20)30616-6.

Rehal MS, Fiskaare E, Tjader I, et al. Measuring energy expenditure in the intensive care unit: a comparison of indirect calorimetry by E-sCOVX and Quark RMR with Deltatrac II in mechanically ventilated critically ill patients. Crit Care 2016; 20:54doi: 10.1186/s13054-016-1232-6. DOI

Carpenter A, Pencharz P, Mouzaki M. Accurate estimation of energy requirements of young patients. J Pediatr Gastroenterol Nutr 2015; 60:4–10.

Kerklaan D, Fivez T, Mehta NM, et al. Worldwide survey of nutritional practices in PICUs. Pediatr Crit Care Med 2016; 17:10–18.

Kerklaan D, Hulst JM, Verhoeven JJ, et al. Use of indirect calorimetry to detect overfeeding in critically ill children: finding the appropriate definition. J Pediatr Gastroenterol Nutr 2016; 63:445–450.

Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics 2001; 107:270–273.

Ehrenkranz RA, Dusick AM, Vohr BR, et al. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics 2006; 117:1253–1261.

Valentine CJ, Fernandez S, Rogers LK, et al. Early amino-acid administration improves preterm infant weight. J Perinatol 2009; 29:428–432.

Dinerstein A, Nieto RM, Solana CL, et al. Early and aggressive nutritional strategy (parenteral and enteral) decreases postnatal growth failure in very low birth weight infants. J Perinatol 2006; 26:436–442.

Martin CR, Brown YF, Ehrenkranz RA, et al. Nutritional practices and growth velocity in the first month of life in extremely premature infants. Pediatrics 2009; 124:649–657.

Stoltz SE, Ohlund I, Ahlsson F, et al. Nutrient intakes independently affect growth in extremely preterm infants: results from a population-based study. Acta Paediatr 2013; 102:1067–1074.

Stephens BE, Walden RV, Gargus RA, et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics 2009; 123:1337–1343.

Brandt I, Sticker EJ, Lentze MJ. Catch-up growth of head circumference of very low birth weight, small for gestational age preterm infants and mental development to adulthood. J Pediatr 2003; 142:463–468.

Ehrenkranz RA, Das A, Wrage LA, et al. Early nutrition mediates the influence of severity of illness on extremely LBW infants. Pediatr Res 2011; 69:522–529.

Hulst JM, van Goudoever JB, Zimmermann LJ, et al. The effect of cumulative energy and protein deficiency on anthropometric parameters in a pediatric ICU population. Clin Nutr 2004; 23:1381–1389.

Ng DVY, Unger S, Asbury M, et al. Neonatal morbidity count is associated with a reduced likelihood of achieving recommendations for protein, lipid, and energy in very low birth weight infants: a prospective cohort study. JPEN J Parenter Enteral Nutr 2018; 42:623–632.

Mara J, Gentles E, Alfheeaid HA, et al. An evaluation of enteral nutrition practices and nutritional provision in children during the entire length of stay in critical care. BMC Pediatr 2014; 14:186doi: 10.1186/1471-2431-14-186. DOI

Lapillonne A, Kermorvant-Duchemin E. A systematic review of practice surveys on parenteral nutrition for preterm infants. J Nutr 2013; 143:2061s–2065s.

Iacobelli S, Viaud M, Lapillonne A, et al. Nutrition practice, compliance to guidelines and postnatal growth in moderately premature babies: the NUTRIQUAL French survey. BMC Pediatr 2015; 15:110doi: 10.1186/s12887-015-0426-4. DOI

Mason DG, Puntis JW, McCormick K, et al. Parenteral nutrition for neonates and children: a mixed bag. Arch Dis Child 2011; 96:209–210.

Lapillonne A, Carnielli VP, Embleton ND, et al. Quality of newborn care: adherence to guidelines for parenteral nutrition in preterm infants in four European countries. BMJ Open 2013; 3:e003478doi: 10.1136/bmjopen-2013-003478. DOI

Lapillonne A, Fellous L, Mokthari M, et al. Parenteral nutrition objectives for very low birth weight infants: results of a national survey. J Pediatr Gastroenterol Nutr 2009; 48:618–626.

Bechard LJ, Parrott JS, Mehta NM. Systematic review of the influence of energy and protein intake on protein balance in critically ill children. J Pediatr 2012; 161:333.e1–339.e1.

Westin V, Stoltz Sjostrom E, Ahlsson F, et al. Perioperative nutrition in extremely preterm infants undergoing surgical treatment for patent ductus arteriosus is suboptimal. Acta Paediatr 2014; 103:282–288.

Westin V, Klevebro S, Domellof M, et al. Improved nutrition for extremely preterm infants—a population based observational study. Clin Nutr ESPEN 2018; 23:245–251.

Rochow N, Fusch G, Muhlinghaus A, et al. A nutritional program to improve outcome of very low birth weight infants. Clin Nutr 2012; 31:124–131.

Ziegler EE, Thureen PJ, Carlson SJ. Aggressive nutrition of the very low birthweight infant. Clin Perinatol 2002; 29:225–244.

Miller M, Donda K, Bhutada A, et al. Transitioning preterm infants from parenteral nutrition: a comparison of 2 protocols. JPEN J Parenter Enteral Nutr 2017; 41:1371–1379.

Brennan AM, Fenton S, Murphy BP, et al. Transition phase nutrition recommendations: a missing link in the nutrition management of preterm infants. JPEN J Parenter Enteral Nutr 2018; 42:343–351.

Brennan AM, Kiely ME, Fenton S, et al. Standardized parenteral nutrition for the transition phase in preterm infants: a bag that fits. Nutrients 2018; 10:170doi: 10.3390/nu10020170. DOI

Gentles E, Mara J, Diamantidi K, et al. Delivery of enteral nutrition after the introduction of practice guidelines and participation of dietitians in pediatric critical care clinical teams. J Acad Nutr Diet 2014; 114:1974.e3–1980.e3.

dit Trolli SE, Kermorvant-Duchemin E, Huon C, et al. Early lipid supply and neurological development at one year in very low birth weight (VLBW) preterm infants. Early Hum Dev 2012; 88: (Suppl 1): S25–S29.

Leenders E, de Waard M, van Goudoever JB. Low- versus high-dose and early versus late parenteral amino-acid administration in very-low-birth-weight infants: a systematic review and meta-analysis. Neonatology 2018; 113:187–205.

Osborn DA, Schindler T, Jones LJ, et al. Higher versus lower amino acid intake in parenteral nutrition for newborn infants. Cochrane Database Syst Rev 2018; 3:Cd005949doi: 10.1002/14651858.cd005949.pub2. DOI

Patel JJ, Martindale RG, McClave SA. Controversies surrounding critical care nutrition: an appraisal of permissive underfeeding, protein, and outcomes. JPEN J Parenter Enteral Nutr 2018; 42:508–515.

Moonen H, Van Zanten ARH. Mitochondrial dysfunction in critical illness during acute metabolic stress and convalescence: consequences for nutrition therapy. Curr Opin Crit Care 2020; 26:346–354.

Fivez T, Kerklaan D, Mesotten D, et al. Early versus late parenteral nutrition in critically ill children. N Engl J Med 2016; 374:1111–1122.

van Puffelen E, Vanhorebeek I, Joosten KFM, et al. Early versus late parenteral nutrition in critically ill, term neonates: a preplanned secondary subgroup analysis of the PEPaNIC multicentre, randomised controlled trial. Lancet Child Adolesc Health 2018; 2:505–515.

van Puffelen E, Jacobs A, Verdoorn CJM, et al. International survey of de-implementation of initiating parenteral nutrition early in paediatric intensive care units. BMC Health Serv Res 2019; 19:379doi: 10.1186/s12913-019-4223-x. DOI

Mehta NM, Skillman HE, Irving SY, et al. Guidelines for the provision and assessment of nutrition support therapy in the pediatric critically ill patient: society of critical care medicine and American Society for Parenteral and Enteral Nutrition. Pediatr Crit Care Med 2017; 18:675–715.

Koletzko B, Goulet O, Hunt J, et al. 1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr 2005; 41: (Suppl 2): S1–S87.

Agostoni C, Buonocore G, Carnielli VP, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010; 50:85–91.

Reichman BL, Chessex P, Putet G, et al. Partition of energy metabolism and energy cost of growth in the very low-birth-weight infant. Pediatrics 1982; 69:446–451.

Kleinman R. Pediatric Nutrition Handbook. American Academy of Pediatrics, 6th edItasca, IL (illinois), USA: 2009.

Cai W, Yu L, Lu C, et al. Normal value of resting energy expenditure in healthy neonates. Nutrition 2003; 19:133–136.

Bauer J, Werner C, Gerss J. Metabolic rate analysis of healthy preterm and full-term infants during the first weeks of life. Am J Clin Nutr 2009; 90:1517–1524.

Abranches AD, Soares FVM, Villela LD, et al. Energy expenditure, growth, and nutritional therapy in appropriate and small for gestational age preterm infants. J Pediatr 2018; 94:652–657.

Bell EF, Johnson KJ, Dove EL. Effect of body position on energy expenditure of preterm infants as determined by simultaneous direct and indirect calorimetry. Am J Perinatol 2017; 34:493–498.

Roberts SB, Young VR. Energy costs of fat and protein deposition in the human infant. Am J Clin Nutr 1988; 48:951–955.

Pierro A, Carnielli V, Filler RM, et al. Partition of energy metabolism in the surgical newborn. J Pediatr Surg 1991; 26:581–586.

Jones MO, Pierro A, Hammond P, et al. The metabolic response to operative stress in infants. J Pediatr Surg 1993; 28:1258–1262. discussion 62–63.

Feferbaum R, Leone C, Siqueira AA, et al. Rest energy expenditure is decreased during the acute as compared to the recovery phase of sepsis in newborns. Nutr Metab (Lond) 2010; 7:63doi: 10.1186/1743-7075-7-63. DOI

Howell HB, Farkouh-Karoleski C, Weindler M, et al. Resting energy expenditure in infants with congenital diaphragmatic hernia without respiratory support at time of neonatal hospital discharge. J Pediatr Surg 2018; 53:2100–2104.

Haliburton B, Chiang M, Marcon M, et al. Nutritional intake, energy expenditure, and growth of infants following congenital diaphragmatic hernia repair. J Pediatr Gastroenterol Nutr 2016; 62:474–478.

Shanbhogue RL, Lloyd DA. Absence of hypermetabolism after operation in the newborn infant. JPEN J Parenter Enteral Nutr 1992; 16:333–336.

Bauer J, Hentschel R, Linderkamp O. Effect of sepsis syndrome on neonatal oxygen consumption and energy expenditure. Pediatrics 2002; 110:e69doi: 10.1542/peds.110.6.e69. DOI

Chwals WJ, Letton RW, Jamie A, et al. Stratification of injury severity using energy expenditure response in surgical infants. J Pediatr Surg 1995; 30:1161–1164.

Chwals WJ, Lally KP, Woolley MM, et al. Measured energy expenditure in critically ill infants and young children. J Surg Res 1988; 44:467–472.

Powis MR, Smith K, Rennie M, et al. Effect of major abdominal operations on energy and protein metabolism in infants and children. J Pediatr Surg 1998; 33:49–53.

Bouwmeester NJ, Anand KJ, van Dijk M, et al. Hormonal and metabolic stress responses after major surgery in children aged 0–3 years: a double-blind, randomized trial comparing the effects of continuous versus intermittent morphine. Br J Anaesth 2001; 87:390–399.

Tueting JL, Byerley LO, Chwals WJ. Anabolic recovery relative to degree of prematurity after acute injury in neonates. J Pediatr Surg 1999; 34:13–17.

Briassoulis G, Venkataraman S, Thompson A. Cytokines and metabolic patterns in pediatric patients with critical illness. Clin Dev Immunol 2010; 2010:354047doi: 10.1155/2010/354047. DOI

Hulst JM, van Goudoever JB, Zimmermann LJ, et al. Adequate feeding and the usefulness of the respiratory quotient in critically ill children. Nutrition 2005; 21:192–198.

Mtaweh H, Garros C, Ashkin A, et al. An exploratory retrospective study of factors affecting energy expenditure in critically ill children. JPEN J Parenter Enteral Nutr 2020; 44:507–515.

Pierro A, Jones MO, Hammond P, et al. A new equation to predict the resting energy expenditure of surgical infants. J Pediatr Surg 1994; 29:1103–1108.

Pierro A. Metabolism and nutritional support in the surgical neonate. J Pediatr Surg 2002; 37:811–822.

Jones MO, Pierro A, Hammond P, et al. Glucose utilization in the surgical newborn infant receiving total parenteral nutrition. J Pediatr Surg 1993; 28:1121–1125.

Basu R, Muller DP, Eaton S, et al. Lipid peroxidation can be reduced in infants on total parenteral nutrition by promoting fat utilisation. J Pediatr Surg 1999; 34:255–259.

Denne SC, Kalhan SC. Glucose carbon recycling and oxidation in human newborns. Am J Physiol 1986; 251:E71–E77.

Tappy L, Schwarz JM, Schneiter P, et al. Effects of isoenergetic glucose-based or lipid-based parenteral nutrition on glucose metabolism, de novo lipogenesis, and respiratory gas exchanges in critically ill patients. Crit Care Med 1998; 26:860–867.

Chacko SK, Ordonez J, Sauer PJ, et al. Gluconeogenesis is not regulated by either glucose or insulin in extremely low birth weight infants receiving total parenteral nutrition. J Pediatr 2011; 158:891–896.

Rozance PJ. Glucose metabolism in the preterm infant. J Pediatr 2011; 158:874–875.

Dreyfus L, Fischer Fumeaux CJ, Remontet L, et al. Low phosphatemia in extremely low birth weight neonates: a risk factor for hyperglycemia? Clin Nutr 2016; 35:1059–1065.

Ichikawa G, Watabe Y, Suzumura H, et al. Hypophosphatemia in small for gestational age extremely low birth weight infants receiving parenteral nutrition in the first week after birth. J Pediatr Endocrinol Metab 2012; 25:317–321.

Moltu SJ, Strommen K, Blakstad EW, et al. Enhanced feeding in very-low-birth-weight infants may cause electrolyte disturbances and septicemia—a randomized, controlled trial. Clin Nutr 2013; 32:207–212.

Bonsante F, Iacobelli S, Latorre G, et al. Initial amino acid intake influences phosphorus and calcium homeostasis in preterm infants—it is time to change the composition of the early parenteral nutrition. PLoS One 2013; 8:e72880doi: 10.1371/journal.pone.0072880. DOI

El Shazly AN, Soliman DR, Assar EH, et al. Phosphate disturbance in critically ill children: Incidence, associated risk factors and clinical outcomes. Ann Med Surg 2017; 21:118–123.

Cormack BE, Jiang Y, Harding JE, et al. Neonatal refeeding syndrome and clinical outcome in extremely low-birth-weight babies: secondary cohort analysis from the ProVIDe trial. JPEN J Parenter Enteral Nutr 2020; 45:65–78.

Stensvold HJ, Strommen K, Lang AM, et al. Early enhanced parenteral nutrition, hyperglycemia, and death among extremely low-birth-weight Infants. JAMA Pediatr 2015; 169:1003–1010.

Zamir I, Tornevi A, Abrahamsson T, et al. Hyperglycemia in extremely preterm infants-insulin treatment, mortality and nutrient intakes. J Pediatr 2018; 200:104.e1–110.e1.

Farrag HM, Cowett RM. Glucose homeostasis in the micropremie. Clin Perinatol 2000; 27:1–22. v.

Meynaar IA, Eslami S, Abu-Hanna A, et al. Blood glucose amplitude variability as predictor for mortality in surgical and medical intensive care unit patients: a multicenter cohort study. J Crit Care 2012; 27:119–124.

Brunner R, Adelsmayr G, Herkner H, et al. Glycemic variability and glucose complexity in critically ill patients: a retrospective analysis of continuous glucose monitoring data. Crit Care 2012; 16:R175doi: 10.1186/cc11657. DOI

Freire Jorge P, Wieringa N, de Felice E, et al. The association of early combined lactate and glucose levels with subsequent renal and liver dysfunction and hospital mortality in critically ill patients. Crit Care 2017; 21:218doi: 10.1186/s13054-017-1785-z. DOI

Weiss SL, Peters MJ, Alhazzani W, et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Intensive Care Med 2020; 46:10–67.

Bottino M, Cowett RM, Sinclair JC. Interventions for treatment of neonatal hyperglycemia in very low birth weight infants. Cochrane Database Syst Rev 2011; Cd007453doi: 10.1002/14651858.cd007453.pub3. DOI

Sinclair JC, Bottino M, Cowett RM. Interventions for prevention of neonatal hyperglycemia in very low birth weight infants. Cochrane Database Syst Rev 2011; Cd007615doi: 10.1002/14651858.cd007615.pub3. DOI

Van den Berghe G, Wilmer A, Milants I, et al. Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm. Diabetes 2006; 55:3151–3159.

Yamada T, Shojima N, Noma H, et al. Glycemic control, mortality, and hypoglycemia in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials. Intensive Care Med 2017; 43:1–15.

Chen L, Li T, Fang F, et al. Tight glycemic control in critically ill pediatric patients: a systematic review and meta-analysis. Crit Care 2018; 22:57.

Alsweiler JM, Harding JE, Bloomfield FH. Tight glycemic control with insulin in hyperglycemic preterm babies: a randomized controlled trial. Pediatrics 2012; 129:639–647.

Tottman AC, Alsweiler JM, Bloomfield FH, et al. Long-term outcomes of hyperglycemic preterm infants randomized to tight glycemic control. J Pediatr 2018; 193:68.e1–75.e1.

Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Early insulin therapy in very-low-birth-weight infants. N Engl J Med 2008; 359:1873–1884.

Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580–637.

van Goudoever JB, Carnielli V, Darmaun D, et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: amino acids. Clin Nutr 2018; 37:2315–2323.

van Goudoever JB, Vlaardingerbroek H, van den Akker CH, et al. Amino acids and proteins. World Rev Nutr Diet 2014; 110:49–63.

Embleton ND, van den Akker CHP. Protein intakes to optimize outcomes for preterm infants. Semin Perinatol 2019; 43:151154doi: 10.1053/j.semperi.2019.06.002. DOI

Verbruggen S, Sy J, Arrivillaga A, et al. Parenteral amino acid intakes in critically ill children: a matter of convenience. JPEN J Parenter Enteral Nutr 2010; 34:329–340.

Blanco CL, Falck A, Green BK, et al. Metabolic responses to early and high protein supplementation in a randomized trial evaluating the prevention of hyperkalemia in extremely low birth weight infants. J Pediatr 2008; 153:535–540.

Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999; 340:448–454.

Streat SJ, Beddoe AH, Hill GL. Aggressive nutritional support does not prevent protein loss despite fat gain in septic intensive care patients. J Trauma 1987; 27:262–266.

Jotterand Chaparro C, Laure Depeyre J, Longchamp D, et al. How much protein and energy are needed to equilibrate nitrogen and energy balances in ventilated critically ill children? Clin Nutr 2016; 35:460–467.

Embleton ND. Optimal protein and energy intakes in preterm infants. Early Hum Dev 2007; 83:831–837.

Reynolds RM, Bass KD, Thureen PJ. Achieving positive protein balance in the immediate postoperative period in neonates undergoing abdominal surgery. J Pediatr 2008; 152:63–67.

Wesselink E, Koekkoek WAC, Grefte S, et al. Feeding mitochondria: potential role of nutritional components to improve critical illness convalescence. Clin Nutr 2019; 38:982–995.

Chwals WJ, Fernandez ME, Jamie AC, et al. Relationship of metabolic indexes to postoperative mortality in surgical infants. J Pediatr Surg 1993; 28:819–822.

Pons Leite H, Gilberto Henriques Vieira J, Brunow De Carvalho W, et al. The role of insulin-like growth factor I, growth hormone, and plasma proteins in surgical outcome of children with congenital heart disease. Pediatr Crit Care Med 2001; 2:29–35.

Alaedeen DI, Queen AL, Leung E, et al. C-Reactive protein-determined injury severity: length of stay predictor in surgical infants. J Pediatr Surg 2004; 39:1832–1834.

Burattini I, Bellagamba MP, Spagnoli C, et al. Targeting 2.5 versus 4 g/kg/day of amino acids for extremely low birth weight infants: a randomized clinical trial. J Pediatr 2013; 163:1278–1282.

Vlaardingerbroek H, Vermeulen MJ, Rook D, et al. Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants. J Pediatr 2013; 163:638–644.

Bonsante F, Gouyon JB, Robillard PY, et al. Early optimal parenteral nutrition and metabolic acidosis in very preterm infants. PLoS One 2017; 12:e0186936doi: 10.1371/journal.pone.0186936. DOI

Calder PC, Adolph M, Deutz NE, et al. Lipids in the intensive care unit: recommendations from the ESPEN Expert Group. Clin Nutr 2018; 37:1–18.

Letton RW, Chwals WJ, Jamie A, et al. Neonatal lipid utilization increases with injury severity: recombinant human growth hormone versus placebo. J Pediatr Surg 1996; 31:1068–1074.

Gebara BM, Gelmini M, Sarnaik A. Oxygen consumption, energy expenditure, and substrate utilization after cardiac surgery in children. Crit Care Med 1992; 20:1550–1554.

Lapillonne A, Fidler Mis N, Goulet O, et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: lipids. Clin Nutr 2018; 37:2324–2336.

Piedboeuf B, Chessex P, Hazan J, et al. Total parenteral nutrition in the newborn infant: energy substrates and respiratory gas exchange. J Pediatr 1991; 118:97–102.

Hasselmann M, Reimund J-M. Lipids in the nutritional support of the critically ill patients. Curr Opin Crit Care 2004; 10:449–455.

Waitzberg DL, Torrinhas RS. Fish oil lipid emulsions and immune response: what clinicians need to know. Nutr Clin Pract 2009; 24:487–499.

Gura KM, Lee S, Valim C, et al. Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease. Pediatrics 2008; 121:e678–e686.

Wanten GJ, Calder PC. Immune modulation by parenteral lipid emulsions. Am J Clin Nutr 2007; 85:1171–1184.

Kapoor V, Malviya MN, Soll R. Lipid emulsions for parenterally fed term and late preterm infants. Cochrane Database Systematic Rev 2019.

Kapoor V, Malviya MN, Soll R. Lipid emulsions for parenterally fed preterm infants. Cochrane Database Systematic Rev 2019.

Hojsak I, Colomb V, Braegger C, et al. ESPGHAN Committee on Nutrition Position Paper. Intravenous lipid emulsions and risk of hepatotoxicity in infants and children: a systematic review and meta-analysis. J Pediatr Gastroenterol Nutr 2016; 62:776–792.

Chessex P, Laborie S, Nasef N, et al. Shielding parenteral nutrition from light improves survival rate in premature infants. JPEN J Parenteral Enteral Nutr 2017; 41:378–383.

Eveleens RD, Joosten KFM, de Koning BAE, et al. Definitions, predictors and outcomes of feeding intolerance in critically ill children: a systematic review. Clin Nutr 2020; 39:685–693.

Tume LN, Valla FV, Joosten K, et al. Nutritional support for children during critical illness: European Society of Pediatric and Neonatal Intensive Care (ESPNIC) metabolism, endocrine and nutrition section position statement and clinical recommendations. Intensive Care Med 2020; 46:411–425.

Puntis J, Hojsak I, Ksiazyk J. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Organisational aspects. Clin Nutr 2018; 37:2392–2400.

McClure RJ. Trophic feeding of the preterm infant. Acta Paediatr Suppl 2001; 90:19–21.

Oddie SJ, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2017; 8:Cd001241doi: 10.1002/14651858.cd001241.pub7. DOI

Tyson JE, Kennedy KA. Trophic feedings for parenterally fed infants. Cochrane Database Syst Rev 2005; Cd000504doi: 10.1002/14651858.cd000504.pub2. DOI

Lucas A, Bloom SR, Aynsley-Green A. Gut hormones and ’minimal enteral feeding’. Acta Paediatr Scand 1986; 75:719–723.

Dorling J, Abbott J, Berrington J, et al. Controlled trial of two incremental milk-feeding rates in preterm infants. N Engl J Med 2019; 381:1434–1443.

Moltu SJ, Blakstad EW, Strommen K, et al. Enhanced feeding and diminished postnatal growth failure in very-low-birth-weight infants. J Pediatr Gastroenterol Nutr 2014; 58:344–351.

Maas C, Franz AR, von Krogh S, et al. Growth and morbidity of extremely preterm infants after early full enteral nutrition. Arch Dis Child Fetal Neonatal Ed 2018; 103:F79–f81.

Eveleens RD, Hulst JM, de Koning BAE, et al. Achieving enteral nutrition during the acute phase in critically ill children: associations with patient characteristics and clinical outcome. Clin Nutr 2020; Jul 14:S0261-5614(20)30346-0. doi: 10.1016/j.clnu.2020.07.004. Epub ahead of print. DOI

Thyagarajan B, Tillqvist E, Baral V, et al. Minimal enteral nutrition during neonatal hypothermia treatment for perinatal hypoxic-ischaemic encephalopathy is safe and feasible. Acta Paediatr 2015; 104:146–151.

Chang LL, Wynn JL, Pacella MJ, et al. Enteral feeding as an adjunct to hypothermia in neonates with hypoxic-ischemic encephalopathy. Neonatology 2018; 113:347–352.

Hazeldine B, Thyagarajan B, Grant M, et al. Survey of nutritional practices during therapeutic hypothermia for hypoxic-ischaemic encephalopathy. BMJ Paediatr Open 2017; 1:e000022. doi: 10.1136/bmjpo-2017-000022. DOI

Battersby C, Longford N, Patel M, et al. Study protocol: optimising newborn nutrition during and after neonatal therapeutic hypothermia in the United Kingdom: observational study of routinely collected data using propensity matching. BMJ Open 2018; 8:e026739doi: 10.1136/bmjopen-2018-026739. DOI

Elke G, van Zanten ARH, Lemieux M, et al. Enteral versus parenteral nutrition in critically ill patients: an updated systematic review and meta-analysis of randomized controlled trials. Crit Care 2016; 20:117doi: 10.1186/s13054-016-1298-1. DOI

Reignier J, Boisramé-Helms J, Brisard L, et al. Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2). Lancet 2018; 391:133–143.

Harvey SE, Parrott F, Harrison DA, et al. Trial of the route of early nutritional support in critically ill adults. N Engl J Med 2014; 371:1673–1684.

Davies DP. The first feed of low birthweight infants. Changing attitudes in the twentieth century. Arch Dis Child 1978; 53:187–192.

Widdowson EM, McCance RA. The effect of finite periods of undernutrition at different ages on the composition and subsequent development of the rat. Proc R Soc Lond B Biol Sci 1963; 158:329–342.

Tan M, Abernethy L, Cooke R. Improving head growth in preterm infants—a randomised controlled trial II: MRI and developmental outcomes in the first year. Arch Dis Child Fetal Neonatal Ed 2008; 93:F342–F346.

Tan MJ, Cooke RW. Improving head growth in very preterm infants—a randomised controlled trial I: neonatal outcomes. Arch Dis Child Fetal Neonatal Ed 2008; 93:F337–F341.

Thureen PJ, Melara D, Fennessey PV, et al. Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res 2003; 53:24–32.

Ibrahim HM, Jeroudi MA, Baier RJ, et al. Aggressive early total parental nutrition in low-birth-weight infants. J Perinatol 2004; 24:482–486.

te Braake FW, van den Akker CH, Wattimena DJ, et al. Amino acid administration to premature infants directly after birth. J Pediatr 2005; 147:457–461.

Poindexter BB, Langer JC, Dusick AM, et al. Early provision of parenteral amino acids in extremely low birth weight infants: relation to growth and neurodevelopmental outcome. J Pediatr 2006; 148:300–305.

Drenckpohl D, McConnell C, Gaffney S, et al. Randomized trial of very low birth weight infants receiving higher rates of infusion of intravenous fat emulsions during the first week of life. Pediatrics 2008; 122:743–751.

Bulbul A, Okan F, Bulbul L, et al. Effect of low versus high early parenteral nutrition on plasma amino acid profiles in very low birth-weight infants. J Matern Fetal Neonatal Med 2012; 25:770–776.

Clark RH, Chace DH, Spitzer AR. Effects of two different doses of amino acid supplementation on growth and blood amino acid levels in premature neonates admitted to the neonatal intensive care unit: a randomized, controlled trial. Pediatrics 2007; 120:1286–1296.

Blanco CL, Baillargeon JG, Morrison RL, et al. Hyperglycemia in extremely low birth weight infants in a predominantly Hispanic population and related morbidities. J Perinatol 2006; 26:737–741.

Blanco CL, Gong AK, Green BK, et al. Early changes in plasma amino acid concentrations during aggressive nutritional therapy in extremely low birth weight infants. J Pediatr 2011; 158:543–548.

Balasubramanian H, Nanavati RN, Kabra NS. Effect of two different doses of parenteral amino acid supplementation on postnatal growth of very low birth weight neonates, a randomized controlled trial. Indian Pediatr 2013; 50:1131–1136.

Scattolin S, Gaio P, Betto M, et al. Parenteral amino acid intakes: possible influences of higher intakes on growth and bone status in preterm infants. J Perinatol 2013; 33:33–39.

Morgan C, McGowan P, Herwitker S, et al. Postnatal head growth in preterm infants: a randomized controlled parenteral nutrition study. Pediatrics 2014; 133:e120–e128.

Bellagamba MP, Carmenati E, D’Ascenzo R, et al. One extra gram of protein to preterm infants from birth to 1800g: a single-blinded randomized clinical trial. J Pediatr Gastroenterol Nutr 2016; 62:879–884.

Uthaya S, Liu X, Babalis D, et al. Nutritional evaluation and optimisation in neonates: a randomized, double-blind controlled trial of amino acid regimen and intravenous lipid composition in preterm parenteral nutrition. Am J Clin Nutr 2016; 103:1443–1452.

Balakrishnan M, Jennings A, Przystac L, et al. Growth and neurodevelopmental outcomes of early, high-dose parenteral amino acid intake in very low birth weight infants: a randomized controlled trial. JPEN J Parenter Enteral Nutr 2018; 42:597–606.

Vlaardingerbroek H, Veldhorst MA, Spronk S, et al. Parenteral lipid administration to very-low-birth-weight infants—early introduction of lipids and use of new lipid emulsions: a systematic review and meta-analysis. Am J Clin Nutr 2012; 96:255–268.

Joffe A, Anton N, Lequier L, et al. Nutritional support for critically ill children. Cochrane Database Syst Rev 2016; Cd005144.

Moon K, Athalye-Jape GK, Rao U, et al. Early versus late parenteral nutrition for critically ill term and late preterm infants. Cochrane Database Syst Rev 2020; 4:Cd013141.

Gottschlich MM, Jenkins ME, Mayes T, et al. The 2002 Clinical Research Award. An evaluation of the safety of early vs delayed enteral support and effects on clinical, nutritional, and endocrine outcomes after severe burns. J Burn Care Rehabil 2002; 23:401–415.

Meinert E, Bell MJ, Buttram S, et al. Initiating nutritional support before 72 hours is associated with favorable outcome after severe traumatic brain injury in children: a secondary analysis of a randomized, controlled trial of therapeutic hypothermia. Pediatr Crit Care Med 2018; 19:345–352.

Vanhorebeek I, Verbruggen S, Casaer MP, et al. Effect of early supplemental parenteral nutrition in the paediatric ICU: a preplanned observational study of post-randomisation treatments in the PEPaNIC trial. Lancet Respir Med 2017; 5:475–483.

van Puffelen E, Hulst JM, Vanhorebeek I, et al. Outcomes of delaying parenteral nutrition for 1 week vs initiation within 24 hours among undernourished children in pediatric intensive care: a subanalysis of the PEPaNIC randomized clinical trial. JAMA Netw Open 2018; 1:e182668.

Casaer MP, Wilmer A, Hermans G, et al. Role of disease and macronutrient dose in the randomized controlled EPaNIC trial: a post hoc analysis. Am J Respir Crit Care Med 2013; 187:247–255.

De Bruyn A, Gunst J, Goossens C, et al. Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit. Crit Care 2020; 24:536doi: 10.1186/s13054-020-03256-z. DOI

Verstraete S, Verbruggen SC, Hordijk JA, et al. Long-term developmental effects of withholding parenteral nutrition for 1 week in the paediatric intensive care unit: a 2-year follow-up of the PEPaNIC international, randomised, controlled trial. Lancet Respir Med 2019; 7:141–153.

Jacobs A, Dulfer K, Eveleens RD, et al. Long-term developmental effect of withholding parenteral nutrition in paediatric intensive care units: a 4-year follow-up of the PEPaNIC randomised controlled trial. Lancet Child Adolesc Health 2020; 4:503–514.

Verlinden I, Dulfer K, Vanhorebeek I, et al. Role of age of critically ill children at time of exposure to early or late parenteral nutrition in determining the impact hereof on long-term neurocognitive development: a secondary analysis of the PEPaNIC-RCT. Clin Nutr 2020; doi:10.1016/j.clnu.2020.07.004.[Epub ahead of print]. DOI

Mehta NM. Parenteral nutrition in critically ill children. N Engl J Med 2016; 374:1190–1192.

Koletzko B, Goulet O, Jochum F, et al. Use of parenteral nutrition in the pediatric ICU: should we panic because of PEPaNIC? Curr Opin Clin Nutr Metab Care 2017; 20:201–203.

Groenendaal F. Early versus late parenteral nutrition in critically ill children. N Engl J Med 2016; 375:384doi: 10.1056/nejmc1605395. DOI

Chwals WJ. Evaluating the impact of delaying parenteral nutrition in critically ill children. Pediatr Crit Care Med 2018; 19:1169–1172.

Balaguer M, Jordan I. Time of parenteral nutrition in paediatric critical care patients, prior nutritional status probably makes the difference? J Thorac Dis 2016; 8:1869–1871.

Mehta NM, Compher C. A.S.P.E.N. clinical guidelines: nutrition support of the critically ill child. JPEN J Parenter Enteral Nutr 2009; 33:260–276.

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; 40:2204–2211.

Wong JJ-M, Han WM, Sultana R, et al. Nutrition delivery affects outcomes in pediatric acute respiratory distress syndrome. JPEN J Parenteral Enteral Nutr 2017; 41:1007–1013.

High protein intake can lead to serious hypophosphatemia and hypokalemia in growth restricted preterm newborns