Evolving Nutritional Support for Pediatric Acute Renal Failure

1
Evolving Nutritional Support for Pediatric Acute
Renal Failure

• NJ Maxvold MD
• Pediatric Critical Care Division
• DeVos Childrens Hospital
• Grand Rapids MI

2
Nutrition in Pediatric ARF

• Overview of Current Knowledge of Altered
  Metabolic Balances During Stress /Acute Illness
• Substrate / Energy Metabolism
• Neuroendocrine Axis
• Specific Metabolic Alterations in ARF

3
TSH Profile in Critical IllnessG. Van den
Berghe. Frontiers in Neuroendocrinology 23
(2002) 370-391
4
GH Profile in Critical IllnessG. Van den Berghe
Frontiers in Neuroendocrinology 23 (2002)
370-391
5
NEA SummaryGreet Van den Berghe. Frontiers in
Neuroendocrinology 23 (2002) 370-391

6
Mortality Outcome PredictorsG. Van den Berghe
Frontiers in Neuroendocrinology 23 (2002)
370-391
7
Van Den Berghe G et al. Intensive Insulin
Therapy in Critically Ill Patients. N Engl J Med
2001 3451359-1367

• N 1548 pts
• Prospectiverandomizedcontrolled Study
• Intensive Insulin Therapy Glu80-110
• Conventional Insulin Therapy Glu180-200
• Diet 20-30 kcalNP/kg/d 0.13-0.26 g N/kg/d
• 20-40 of kcalNP Lipids.

8
Van Den Berghe G et al. Intensive Insulin
Therapy in Critically Ill Patients. N Engl J Med
2001 3451359-1367
9
Van den Berghe G et al. Crit care Med 2003
31359-366

• Glycemic Control 80-110 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
• i Inflammation

10
rGH Therapy in Critical Illness

• Finnish ( N170) and MultiNational (N190)
• Enrolled gt 5 ICU days rGH 5.3/8.0 mg/d
• h Hyperglycemia and Insulin Suppl
• h Sepsis and MOF
• Improved Nitrogen Balance (Finnish)
• rGH Supplementation ghMortality RR 2.4
• Takala J et al. Increased Mortality associated
  with Growth Hormone Treatment in Critically Ill
  Patients. N Engl J Med 1999341785-92

11
Hypothalamic Secretagogues for Pituitary and
Metabolic Improvement

• N14 Prolonged Illnessgt 14 ICU
  days
• GHRP-2 TRH for 5 day therapy crossing
  over to placebo
• 600 am GHRP-2 bolus 1 mcg/kg and TRH
  bolus of 1 mcg/kg then
• continuous infusion of 1mcg/kg/hr
• Restored the pulsatile profile of GH and TSH and
  peripheral responses (IGF-I IGFBP-3
  ALSLeptin Insulin)
• No effect of Cortisol levels
• Improved Urea to creatinine ratio
• Van den Berghe G et al. J Clin
  Endocrinol Metab 84 1311-1323 1999

12
Neuroendocrine Axis Modulation in Acute Illness

• Acker CG et al. A trial of thyroxine in ARF.
  Kidney Int 200057293-298
• Triiodothyronine Suppl (T3)ghMortality
• Bettendorf M et al. Lancet 2000 Aug 12
  356(9229)529-34
• 40 Postop Cardiac Children Randomized Blinded
• 2mcg/kg T3 on Day 1 thereafter 1mcg/kg/d
• Improved Cardiac Index
• 20 (T3) vs 10 (Placebo)

13
Future Nutritional Adaptions

• Potential Endocrine Intervention in ARF
• Ding H et al. J Clin Invest
  1993 912281-7
• IGF-1 Accelerate Regeneration in ARF
• Improved Nitrogen Balance
• Hirschberg R et al. Kidney Int 1999
  552423-32
• IGF-1 No clinical effect in ARF patients

14
Lipid UtilizationCritical Illness

• Fatty Acids
• l m
• l m
• l m
• Oxidation ffffngggg Fat Accrual
• (Acute) ///
  (Prolonged)
• ///
• Leptin

15
NEA Leptin

• Source Adipocyte pulsatile release
• 16 -kDa Protein hormone encoded obgene
• Actions
• Appetite Control (Neuropeptide Y)
• Substrate (Fat) Utilization
• Bone Metabolism

16
Pediatric Nutrition

• Components of Pediatric Nutrition in ARF
• 1. Growth and Development of Child
• 2. Cessation anabolic growth during acute
• illness
• A.Maintenance of Cellular Metabolism
• B. Repair / Healing Process

17
Nutrition in ARF

• Acute Renal Failure Nutritional Effects
• High Protein Catabolic Rate
• Altered Amino Acid Profile
• Altered Substrate Utilization and Elimination
• Altered Renal Solute Clearance and UF
• 5. Altered Renal Synthetic Function

18
Nutrition in ARF

• Protein Support in Acute Renal Failure
• Additive Losses by RRT
• Nitrogen Balance Can it Occur in ARF
• Special AA formulations
• Additional Cellular Agonists/Antagonists of
  Muscle Protein turnover

19
Critical Care Nutrition

• Nutritional Components of Critical Illness
• Daily Energy Needs/Expenditure
• Energy Formulation
• Substrate Utilization
• Stage of Critical Illness- Neuroendocrine Axis
• 5. Euglycemic Control

20
Nutrition in Pediatric ARF

• Age ( m2) BMR(kcal/m2/hr) REE (kcal/d)
• 0-1 (.34-.45) 53
  320-500
• 2-6 (.58-.8) 52-47
  740-950
• 7-10 (1.0) 47-42 1130
  
• 11-14(m/1.4) 43-42 1440
  
• 11-14(f/1.4) 42-39 1310
  
• 15-18(m/1.7) 41-40 1760
  
• 15-18(f/1.6) 37-35 1370
  
• BMR from Fleisch table of
  basal met standards

21
Developmental/Age Effect on Energy and Protein
Needs (RDA)

• Age Wt BMR REE RDA Protein NCalorie
• Infant 9 53 500 972
  2 1337
• Child 30 43 1130 2400
  1.2 1416
• Adoles 70 40 1760 2700
  0.8 1301
• Healthy Nitrogen to Calories
  1350
• Critical Illness Nitrogen to Calories
  1150

22
Estimation of Energy Needs

• Harris Benedict Equation
• Males BEE 66 (13.7 x W(kg)) (5 x H(cm))
  (6.8 x A (yr))
• Females BEE 655 (9.6 x W(kg)) (1.7 x
• H(cm)) (4.7 x A (yr))

23
Energy Requirements in Illness

• Stress Factors Relative Contribution on
  Hypermetabolic Needs
• Burns 1.2 2.0 x BEE
• Neoplasm 1.1-1.3 x BEE
• Multiple Trauma 1.2-1.4 x BEE
• Severe Infection/Sepsis 1.2-1.4 x BEE

24
Measurement of REE

• Indirect Calorimetry
• REE (kcal/d) VO2 (L/min) x 4.3(kcal/L)
• VCO2 (L/min) x 1.1 (kcal/L) x 1440
• Steady state of activity FiO2 60 or less
• minimal leak (Vti Vte)

25
RQ Measurements

• Respiratory Quotient (R) VCO2/VO2
• Substrate R
• Carbohydrate 1.0
• Protein 0.8
• Fat 0.7
• Synthesis of fat gt1.0

26
RQ Measurements

• Potential Errors in RQ
• Lack of Steady state Acidosis
• Hyperventilation g hCO2
• CRRT using as anticoagulation Citrate
• 1 Citrate 2 CO2

27
Estimated vs Measured Energy

• Coss-Bu JA et al.Am J Clin Nutr 2001
  Nov74(5)664-9
• Hypermetabolic as Metabolic Index (REE/EEE)
  gt 1.1
• REE(ave) 0.23 /- 0.10 MJ/kg/d
• EEE (ave) 0.19 /- 0.04 MJ/kg/d
• Metabolic Index (ave)
  1.2
• EEE was predicted from Talbot tables
  of BMR in children

28
Estimated vs Measured Energy

• Correlation of REE(pred) to MEE
• Briassoulis G et al Crit Care Med 2000 Vol
  28(4)p1166-1172
• MEE 1000kcal/m2/d
• (1019166) without MOSF
• 860 kcal/m2/d
• (862 241) with MOSF
• MEE did not differ significantly between
  disease groups (Sepsis Brain injury Resp
  Failure Transplant Cardiac Surg)

29
Briassoulis G et al Energy expenditure in
critically ill children. Crit Care Med
2000281166-1172
30
Briassoulis G et al Energy expenditure in
critically ill children. Crit Care Med
2000281166-1172
31
Briassoulis G et al Energy expenditure in
critically ill children. Crit Care Med
2000281166-1172
32
Glucose Metabolism in Critical Illness

• Inefficient Glucose Oxidation iMitochondrial
  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

33
Glucose Inefficiency in Acute Ilnness

• Glycolysis
• Glucosegtgtgt 2 Lactate
• DG - 47.0 kcal/mol
• TCA Complete Oxidation
• Glucose 6 O2 a 6 CO2 6 H2O
• DG - 686.0 kcal/mol

34
Glucose Metabolism
35
Glucose Utilization

• Studies on Glucose Utilization
• Coss-Bu JA et al. Am J Clin Nutr
  2001 74664-9
• Lipogenesis Glucose Intake 8.5mg/kg/min
• No Lipogenesis Glucose 6.1mg/kg/min
• Sheridan RL et al. JPEN 1998 22212-6
• Maximal Glu Oxidation at 5mg/kg/min
• Wolfe R et al. Metabolism 1979281031-9
• Maximal Glu Oxidation 4mg/kg/min

36
Lipid Metabolism in Critical Illness

• Main Oxidative Fuel in Acute Illness
• Neuroendocrine Axis stimulates Lipolysis
• h FFA ggg Oxidative fuel
• h Glycerol ggg Gluconeogenesis
• Wiener M et al. Fat metabolism in injury and
  stress. Crit Care Clin 1987 325-56.

37
Protein Metabolism in Critical Illness

• h Muscle Protein Catabolism
• Neuroendocrine/ Cytokine Mediators
• iMuscle Protein Synthesis Insulin
  ResistanceNa Electrochemical Pump
• Turnover of Free Amino Acid Pool Main substrate
  for Gluconeogenesis Synthesis APP by Liver

38
Stress Liver Synthetic Changes

• Anabolic
• Albumin antithrombin
• protein C
• High Density Lipoproteins

• Stress/Acute Phase
• Fibrinogen
• Ferritin
• alpha-1antitrypsinogen
• antiproteases

39
McCann UGFinck CM Meguid MM.Metabolic response
in injury and critical Illness. In
DeitchVincentWindsor (Eds) Sepsis and Multiple
Organ Dysfunction. London WB Saunders2002
40
Nutrition in ARF

• Altered Metabolic Functions in ARF
• I. Loss of Normal Renal Excretion
• 1. Daily Body Water Balance
• 2. Solute Clearance Electrolytes
  Vitamins mineral and trace elements
• 3. Substrate Elimination- Amino
  acidspeptides (including Insulin) lipids

41
Fluid Balance in ARF

• Ultrafiltrate/water loss is primarily related to
  solute excretion ( Na K urea) and preservation
  of Osmolalitypl (275-290)
• Free Water Excretion is dependent upon
• 1. Ascending Loop of Henle reabsorbtion of
• NaCl without water
• 2. Collecting tubules Impermeability to water
• (absent ADH)

42
Altered Metabolic Functions in ARF

• Solute Clearance in ARF
• Impaired GFR leads to ielimination as well as
  catabolism increasing many of the electrolytes
  (K PO4Ca) requiring provisional adjustments.
• Vitamin Clearance
• Water Soluble- Low when RRT is used
• Lipid Soluble-Vit ADE

43
Vitamins in Acute Renal Failure

• Water Soluble
• Vit B1 Def Altered Energy Metabolism
• h Lactic Acid Tubular damage
• Vit B6 Def Altered Amino acid and lipid
• metabolism i
  function of T
• lymphocytes
• Folate Def Anemia i DNA synthesis
  
• Vit C Def Limit 200 mg/d as precursor to
• Oxalic acid
  

44
Vitamins in Acute Renal Failure

• Fat Soluble
• Vit D Def Hypocalcemia
• Vit A Excess i renal catabolism of
• retinol binding
  protein
• Vit E Def i gt50 plasma and RBC

45
Metabolic Alterations in ARF

• Lipid Elimination in ARF
• Lipid Alterations Impaired Lipolysis
  prolonging the elimination of lipid infusions
• Elimination half-life is doubled thereby
• i Clearance by gt 50
• Druml W et al. Lipid metabolism in acute renal
  failure. Kidney Int 198324(S 16)139-142

46
Lipid Metabolism in ARF

• h LDL and VLDL
• iCholesterol and HDL-Cholesterol
• Impaired Lipolysis
• Lipase Activity 50
• i Lipoprotein Lipase
• i Hepatic Triglyceride Lipase
• Druml W et al. Post-heparin lipolytic activity
  in acute renal failure. Clin Nephrol
  198523289-293

47
Metabolic Alterations in ARF

• Amino Acids and Peptide Elimination
• Clearance of Amino Acids and Peptides by the
  Kidney is reduced but due to the Increased
  hepatic utilization of Amino acids for
  Gluconeogenesis and APPs
• Increased overall Amino Acids Clearance
• Druml w et al. Elimination of Amino acids in
  renal failure. Am J Clin Nutr 1994 60418-423

48
Druml W. Amino Acid Metabolism and Amino Acid
Supply in Acute Renal Failure. Continuous
Arteriovenous Hemofiltration (CAVH). Int Conf on
CAVH Aachen1984 pp231-239.
49
Mitch WE Chesney RW. Amino acid metabolism by
the kidney. Mineral Electrolyte Metab 9190-202
(1982)
50
Nutrition in Pediatric ARF

• Hypercatabolism of Acute Renal Failure
• Accelerated Muscle Protein Breakdown
• Defective Muscle AA /Protein Synthesis
• Hepatic Gluconeogenesis from A Acids
• Glucocorticoid dependent Pathway

51
Nutrition in Pediatric ARF

• Muscle Protein Catabolism
• Insulin Resistance
• Acidosis
• Catabolic Hormones/Mediators
  GlucocorticoidsCatecholamines
• TNF-a Interleukins Proteases

52
Protein Catabolism in ARF

• Adult Studies
• Protein Catabolic Rate 1.4 - 1.7 g/kg/d
• Macias WL et al. JPEN
  19962056-62
• Chima CS et al. JASN 1993
  31516-1521
• Pediatric Studies
• Urea Nitrogen Appearance 185- 290mg/kg/d
• Kuttnig M et al. Child Nephrol Urol
  19911174-78
• Maxvold N et al. Crit Care Med
  2000281161-1165

53
Protein Catabolic Rate

• Urea Nitrogen Appearance (UNA)
• UNA (UUN x VU) (UFUN VUF)
• ( BUN2 BUN1) x 0.006 x BW (BW2 BW1) x
  BUN2/100
• BUN2 BUN final BW2 BW final
• BUN1 BUN initial BW1 BW initial

54
Nutrition in Pediatric ARF

• Nitrogen Balance in Acute Renal Failure
• Kierdorf H et al. Nephrol Dial Transplant
  1986172
• Protein Intake Nitrogen Balance
• 0.7 g/kg/d AA -8.1g N/d
• 1.5 g/kg/d AA -3.4g N/d
• 1.7g/kg/d AA -3.2g N/d

55
Nitrogen Balance in ARF

• Bellomo R et al. Ren Fail 199719111-120
• 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

56
CRRT Nutritional Effects

• Protein/AA Losses on CRRT
• Davenport A Roberts N. Crit Care Med
  1989171010
• Prescrip Polyamide HF Qbld 140ml/minQUF
  1L/hr
• Nitrogen Loss of 11 the Intake
• Davies S et al. Crit Care Med 1991191510
• Prescrip AN-69 HF Qbld 77 ml/min QD 1L/hr
  or 2L/hr
• Protein Loss of 9-12 of the daily Intake
• Wide Variance in AAINDIntake Loss
• Gln Tyr Loss gt100 the Intake

57
Glutamine Nitrogen Trafficking

• Primary Nitrogen Transporter
• Signals Muscle Catabolism vs Anabolism
• Precursor of purine / pyridimine
• Substrate for Rapidly dividing Cells (Kidney
  tubular cells enterocytes immune cells)

58
Nutrition in Pediatric ARF

• Glutamine
• Precursor for Glutathione
• Substrate for Gluconeogenesis
• Intracellular Osmotic Regulator
• Primary Substrate for Ammoniagenesis
• in Kidney and gut

59
Glutamine Metabolism

• Rested State
• Gln pl 500-600 micromol/L
• Gln Ms 15-20 mmol/L

• Catabolic State
• Rapid Fall in Gln pl
• gt30- 50 Muscle Gln Loss
• Reduced Muscle Resting Membrane Potential Defect
  Na electrochemical Gradient

60
Amino Acid Effects in ARF

• Heyman SN etal. Kidney Int
  199140273-9
• Gly Ala Tubular protectant ischemic or
• nephrotoxic injury
• Wakabayashi Y et al. Am J Physiol
  1996270F784-9
• Arg Preserves renal perfusion
• Singer P et al. Clin Nutr
  19909(S)23A
• Badalamenti S et al. Hepatology
  199011379-386
• AA Supplementation- h renal perfusion and GFR and
  diuresis

61
ARF Nutritional Summary

• Nutritional Energy Requirement for children with
  Acute Renal Failure is determined by the
  underlying critical illness
• Recent studies support use of MEE when possible
  or using the BMR with no to minimal Acuity Factor
  (1-1.2)
• Early implementation of Insulin support to
  facilitate euglycemia and lipid utilization

62
ARF Nutritional Summary

• Carbohydrate load when possible to be lt7mg/kg/min
  to minimize lipogenesis and further hTrigly
• Protein to provide ratio of Nitrogenkcal
• 1 100-150 plus additional adjustments
  for dietary loss of the RRT
• Amino Acid formulation to include NEAAs
• ( Gln Tyr Arg) in addition to EAA

63
ARF Nutritional Summary

• Nutritional Monitoring to include in the care of
  Critically Ill Children with ARF
• MEE PCR Nitrogen Balance at the start of the
  RRT and 1-2 week intervals thereafter or if
  indicated by clinical change in patient