Nutrient Support in Critically Ill Children with ARF

Nutrient Support in Critically Ill Children with ARF NJ Maxvold MD Pediatric Critical Care Medicine De. Vos Children’s Hospital Grand Rapids, MI, USA

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

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

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}

[Van den Berghe G, et al. Crit care Med 2003; 31: 359 -366] Normoglycemic Control [80110 mg/dl] i Crit Illness i Polyneuropathy i Bactermia i Inflammation i Anemia Reduction of Mortality • Insulin Dose • Preventive Effect on ARF • Reduction of Mortality • Prolonged Inflammation

CHO Metabolism in Critical Illness • Glycolysis: Glucose>>> 2 Lactate DG°´= - 47. 0 kcal/mol TCA Complete Oxidation: Glucose + 6 O 2 a 6 CO 2 + 6 H 2 O DG°´= - 686. 0 kcal/mol

Metabolic Alterations in Critical Illness • Lipid Utilization in Acute Illness: Stress Hormones (Catecholamines/Cortisol) h 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)

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

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

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

Hypermetabolism in Children with Critical Illness Ave. Energy Intake REE 0. 23 MJ/kg/d >25% Coss-Bu( Am J Clin Nutr 2001) Verhoeven(Int Care Med 1998) 0. 24 MJ/kg/d >14% Joosten (Nutrition 1999) 0. 26 MJ/kg/d >20%

• 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 4 mg/kg/min Lipogenesis from Excess Glucose Metabolism Gluconeogenesis and Protein Catabolism was not effected [Tappy et al. Crit Care Med 1998; 26: 860 -867]

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 - 290 mg/kg/d [ Kuttnig M, et al. Child Nephrol Urol 1991; 11: 74 -78] [ Maxvold N, et al. Crit Care Med 2000; 28: 1161 -1165]

Nitrogen Balance in ARF [Bellomo R, et al. Ren Fail 1997; 19: 111 -120] Protein Intake • 1. 2 g/kg/d AA • 2. 5 g/kg/d AA : Nitrogen Balance -5. 5 g N/d -1. 9 g N/d * Patients were on CRRT

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)

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

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]

Glutamine Supplementation [Ziegler et al, Ann Intern Med 1992; 116: 821] 45 BMT patients with Parenteral Glutamine (L-Gln) Supplemention : 0. 57 g/kg/d Gln &2. 07 g/kg/d AA Intake Improved Nitrogen Balance: -1. 4 g/d vs i Clinical infections: 3/24 vs 9/21 i Hospital stay: 29 days vs 36 days -4. 2 g/d [ Schloerb et al; JPEN 1993; 17: 407 -413] i Hospital stay: 26 days vs 32 days i Total Body Water: -1. 2 L vs 2. 2 L (Bioimpedance)

Conditional” Essential Nutrients? 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? Biotin Dose 15 mg/day i Hypertriglyceridemia in Type II Diabetics. [Baez-Saldana et al. Am J Clin Nutr 2004; 78: 238 -43] i Glucose Concentration and Insulin Concentrations in Type II Diabetics. [ Fernandez-Mejia et al. Diabetes 2003; 52: A 459]

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

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

Druml W. Amino Acid Metabolism and Amino Acid Supply in Acute Renal Failure. Continuous Arteriovenous Hemofiltration (CAVH). Int Conf on CAVH, Aachen 1984, pp 231 -239.

Amino Acid Effects in ARF • Heyman SN, etal. Kidney Int 1991; 40: 273 -9 • Gly, Ala • • Wakabayashi Y, et al. Am J Physiol 1996; 270: F 784 -9 • Arg • • Tubular protectant [ischemic or nephrotoxic injury] Preserves renal perfusion Singer P, et al. Clin Nutr 1990; 9(S): 23 A Badalamenti S, et al. Hepatology 1990; 11: 379 -386 AA Supplementation- h renal perfusion and GFR and diuresis

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

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 h total body clearance Fraction of Lipid Oxidation Improved

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

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

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. 7 m 2/day Monitor: REE, Nitrogen Balance, Vitamins and Trace Elements *Early Enteral Feeding*