1. Nutrient Support in Critically Ill Children with ARF NJ Maxvold MD Pediatric Critical Care Medicine DeVos Childrens Hospital Grand Rapids, MI, USA

2. Nutrition in Pediatric ARF Critical Illness Metabolism: Stress: Inflammatory Cytokines; Gene Expression Modulation NeuroEndocrine Axis Phases Altered Substrate Utilization Metabolic Alterations in ARF catabolism from uremia, acidosis, impaired fluid/solute K AA Profile / Interconversion in ARF Vitamin Derangements Impaired Lipolysis: Lipase Activity; LDL & VLDL, Cholesterol

4. Hyperglycemia of Critical Illness Altered Substrate Utilization in Acute Illness Carbohydrate Utilization: a. Oxidation ( Inefficient) b.Glycogenesis c.Lipogenesis Insulin Resistance

5. CHO Metabolism in Critical Illness Inefficient Glucose Metabolism: Shift of Glycolysis to Pyruvate, then cycling back through the liver for Gluconeogenesis [Cori Cycle] Decrease Pyruvate entry into TCA cycle Therefore net energy produced is significantly diminished, and continues to feed into a hypermetabolic state of partial glucose oxidation then regeneration of Glucose { High Glucose Turnover}

6. [Van den Berghe G, et al. Crit care Med 2003; 31:359-366] Normoglycemic Control [80- 110 mg/dl] Crit Illness Polyneuropathy Bactermia Inflammation Anemia Reduction of Mortality Insulin Dose Preventive Effect on ARF Reduction of Mortality Prolonged Inflammation

7. CHO Metabolism in Critical Illness Glycolysis: Glucose>>> 2 Lactate G°´= - 47.0 kcal/mol TCA Complete Oxidation: Glucose + 6 O2 6 CO2 + 6 H2O G°´= - 686.0 kcal/mol

8. Metabolic Alterations in Critical Illness Lipid Utilization in Acute Illness: Stress Hormones (Catecholamines/Cortisol) Lipolysis: FFA (major fuel in acute illness) a. Oxidation via TCA cycle b. Lipogenesis c. Ketogenesis (Glucagon inhibited during critical illness) d.PDH Inhibition (prevents Glucose TCA Oxidation and increases FFA TCA Oxidation)

9. Protein Metabolism in Acute Illness Catabolism (Skeletal Muscle) a. Gluconeogenesis (Alanine) b. Acute Phase Proteins (Liver Synthesis) Negative Nitrogen Balance

10. Stress Liver synthetic Changes Anabolic : Albumin, antithrombin, protein C High Density Lipoproteins Stress/Acute Phase: Fibrinogen Ferritin, alpha-1antitrypsinogen anitiproteases

11. Altered Cellular Metabolism Diminished Mitochondrial Energy Production: I.Dysfunctional Respiration: Downregulation of genes coding for electron transport chain II.Dysfunctional Glycolytic pathway: Downregulation of gene for PFK (rate limiting enzyme) [Callahan et al, J Appl Physiol 2005;99:1120-1126]

12. Hypermetabolism in Children with Critical Illness AveEnergy Intake REE Coss-Bu ( Am J Clin Nutr 2001) 0.23 MJ/kg/d >25% Verhoeven (Int Care Med 1998) 0.24 MJ/kg/d >14% Joosten (Nutrition 1999) 0.26 MJ/kg/d >20%

13. Substrate Utilization/Nutrient Composition 75%CHO:15% AA: 10% Lipid 15%CHO: 15%AA: 70% Lipid C 13 Glucose, C 13 Acetate Maximum Glu Oxidation 4mg/kg/min Lipogenesis from Excess Glucose Metabolism Gluconeogenesis and Protein Catabolism was not effected [Tappy et al. Crit Care Med 1998;26:860-867]

14. Protein Catabolism in ARF Adult Studies: Protein Catabolic Rate ~ 1.4 - 1.7 g/kg/d [Macias WL, et al. JPEN 1996;20:56-62] [Chima CS, et al. JASN 1993; 3:1516-1521] Pediatric Studies: Urea Nitrogen Appearance ~ 185- 290mg/kg/d [ Kuttnig M, et al. Child Nephrol Urol 1991;11:74-78] [ Maxvold N, et al. Crit Care Med 2000;28:1161-1165]

15. Nitrogen Balance in ARF [Bellomo R, et al. Ren Fail 1997;19:111-120] Protein Intake : Nitrogen Balance 1.2 g/kg/d AA -5.5g N/d 2.5 g/kg/d AA -1.9g N/d * Patients were on CRRT

16. Conditional Essential Nutrients? Glutamine – Nitrogen Trafficking Precursor of purine / pyridimine Substrate for Rapidly dividing Cells (Kidney tubular cells, enterocytes, immune cells) Precursor for Glutathione Substrate for Gluconeogenesis Intracellular Osmotic Regulator Primary Substrate for Ammoniagenesis (in Kidney and gut)

17. Glutamine Metabolism Glutamine Release: Muscle Free pool Gln Muscle protein catabolism Muscle synthesis of Gln Glutamine Uptake: Gut [Supply Dependent] Liver, Spleen, Immune System [Active, Independent]

18. Glutamine Metabolism Rested State: Gln [pl] ~500-600 micromol/L Gln [Ms] ~15-20 mmol/L Catabolic State: Rapid Fall in Gln [pl] >30- 50% Muscle Gln Loss Reduced Muscle Resting Membrane Potential [Defect Na + electrochemical Gradient]

19. Glutamine Supplementation [Ziegler et al, Ann Intern Med 1992;116:821] 45 BMT patients with Parenteral Glutamine (L-Gln) Supplemention : 0.57g/kg/d Gln &2.07g/kg/d AA Intake Improved Nitrogen Balance: -1.4g/d vs -4.2g/d Clinical infections: 3/24 vs 9/21 Hospital stay: 29 days vs 36 days [ Schloerb et al; JPEN 1993; 17:407-413] Hospital stay: 26 days vs 32 days Total Body Water: -1.2 L vs 2.2 L (Bioimpedance)

20. Biotin Regulatory Effect on genes of Intermediary Metabolism a. Stimulates genes for Insulin, Insulin Receptor, Glucokinase (pancreatic and Hepatic) b. Decreases gene expression of hepatic Phosphoenolpyruvate Carbosykinase (*Gluconeogenic Enzyme in the liver) Conditional Essential Nutrients?

21. Biotin Dose 15 mg/day Hypertriglyceridemia in Type II Diabetics. [Baez-Saldana et al. Am J Clin Nutr 2004;78:238-43] Glucose Concentration and Insulin Concentrations in Type II Diabetics. [ Fernandez-Mejia et al. Diabetes 2003;52:A459]

22. Nutrition in Pediatric ARF Amino Acids Alterations in ARF: Impaired Conversion : Phenylalanine to Tyrosine* Citrulline to Arginine* Homocysteine to Methionine Methionine to Cystine/Taurine Glycine to Serine

23. Mitch WE, Chesney RW. Amino acid metabolism by the kidney. Mineral Electrolyte Metab 9:190-202 (1982)

24. Druml W. Amino Acid Metabolism and Amino Acid Supply in Acute Renal Failure. Continuous Arteriovenous Hemofiltration (CAVH). Int Conf on CAVH, Aachen1984, pp231-239.

25. Amino Acid Effects in ARF Heyman SN, etal. Kidney Int 1991;40:273-9 Gly, Ala Tubular protectant [ischemic or nephrotoxic injury] Wakabayashi Y, et al. Am J Physiol 1996;270:F784-9 Arg Preserves renal perfusion Singer P, et al. Clin Nutr 1990;9(S):23A Badalamenti S, et al. Hepatology 1990;11:379-386 AA Supplementation- renal perfusion and GFR and diuresis

26. Lipid Metabolism in ARF LDL and VLDL Cholesterol and HDL-Cholesterol Impaired Lipolysis Lipase Activity ~50% Lipoprotein Lipase Hepatic Triglyceride Lipase

27. Cholesterol: Conditional Essential Nutrient in ARF? [Druml et al, Wien Klin Worchenschr 2003;115/21- 22:767-774] Suppl free Cholesterol [4 g/l] added to 20% Lipid emulsions Results: Reduced Plasma Triglycerides with reduced plasma ½ life and total body clearance Fraction of Lipid Oxidation Improved

28. Vitamins in Acute Renal Failure Water Soluble Vit B 1 Def Altered Energy Metabolism, Lactic Acid, Tubular damage Vit B 6 Def Altered Amino acid and lipid metabolism Folate Def Anemia Vit C Def Limit 200 mg/d as precursor to Oxalic acid

29. Vitamins in Acute Renal Failure Fat Soluble Vit D Def Hypocalcemia Vit A Excess renal catabolism of retinol binding protein Vit E Def >50% plasma and RBC

30. Nutrient Prescription in Pediatric ARF? Energy/Caloric Requirements: 0.25 MJ/kg/d Formulation: 20-25% Carbohydrate (Insulin as needed to keep [Glu]= 100-140) Protein/AA : 2-3 g/kg/d with Glutamine comprising 25-35% Biotin Suppl of 10-15 mg/day Cholesterol ? 4 g/l/1.7m2/day Monitor: REE, Nitrogen Balance, Vitamins and Trace Elements *Early Enteral Feeding*