Nutrient Support in Critically Ill Children with ARF

NJ Maxvold MD

Pediatric Critical Care Medicine

DeVos Children’s Hospital

Grand Rapids, MI, USA

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

“ 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 [80-110 mg/dl]

Crit Illness Polyneuropathy Bactermia Inflammation AnemiaReduction of Mortality

• Insulin Dose• Preventive Effect on

ARF• Reduction of Mortality• Prolonged

Inflammation

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

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)

• 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-

1antitrypsinogen• anitiproteases

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]

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%

• Substrate Utilization/Nutrient Composition 75%CHO:15% AA: 10% Lipid 15%CHO: 15%AA: 70% Lipid C13 Glucose, C13 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]

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]

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

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: Muscle Free pool GlnMuscle protein

catabolismMuscle 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 : 0.57g/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)

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?

Conditional” Essential Nutrients?

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]

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, Aachen1984, pp231-239.

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

Lipid Metabolism in ARF

• LDL and VLDL

• Cholesterol and HDL-Cholesterol

Impaired Lipolysis

Lipase Activity ~50%

Lipoprotein Lipase

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 total body clearance

Fraction of Lipid Oxidation Improved

Vitamins in Acute Renal Failure

Water Soluble

• Vit B1 Def Altered Energy Metabolism,

Lactic Acid, Tubular damage

• Vit B6 Def Altered Amino acid and lipid

metabolism • Folate Def Anemia • Vit C Def Limit 200 mg/d as precursor to

Oxalic acid

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

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*