What’s New in Nutrition? NJ Maxvold MD Associate Professor of Pediatrics Pediatric Critical Care Medicine DeVos Children’s Hospital.

What’s New in Nutrition?

NJ Maxvold MD

Associate Professor of Pediatrics

Pediatric Critical Care Medicine

DeVos Children’s Hospital

Nutrition and PCRRT

Is there anything New?

Current General Knowledge:

Stress Response elicits change in Utilization of Fuel/Substrates:

1. Cellular (End Organ) Insulin Resistance, therefore hyperglycemia and altered cellular energetics

2. Fatty Acids increased utilization as Glucose Utilization becomes Inefficient

3. Protein metabolism shift from anabolism to catabolism

4. Phasic changes in metabolism during acute Illness

Nutrition and PCRRT

Carbohydrate Utilization• Limit of oxidation of Carbohydrate

~ 5 mg/kg/min of Glucose

• Hyperglycemia Insulin Resistance

Gluconeogenesis

Nutrition and PCRRT

Lipid Metabolism Fatty Acid Utilization (major myocardial oxidation fuel)

Mitochondrial adaptation to acute stress (Carnitine dependent enzymes) Calvani et al Basic Res Cardiol 2000Mitochondrial control of FFA oxidation and CHO oxidation AcetylCoA/ CoA ratio on PDH Complex

Nutrition and PCRRT

High Protein Catabolism• Muscle Efflux of Amino Acids to fuel

Gluconeogenesis

• Protein metabolism shift from anabolic to Acute phase proteins

(Hepatic Inflammatory Response)

Net Negative Nitrogen Balance

Critical Illness

hormone changes-Acute: increase-Later: decrease

↑ cytokines Altered substrate utilizationCHO: ↑hepatic gluconeogenesis (shift away from liver glycolysis)Hyperglycemia- Inefficient glucose oxidation- Insulin resistance- Shift in use of amino acids: gluconeogenesis + APR’s

MALNUTRITION

Acute Kidney Injury

UremiaAcidosisAltered Glucose metab.

Cytokines

Impaired nutrient transportInefficient/inadequate supplyImpaired A.a. conversion↓lipid oxidation

Nutrition and PCRRT

Impaired Nutrient Support: Diminished Cellular Energy

• Inefficiency of normal cellular transport activities:

• Disturbances in the Na/K ATPase pump (energy dependent function)

• Intracellular mitochondrial adaptations (Dysfunctional electron transport respiration)

Muscle wasting & Malnutrition Mortality

Nutrition and PCRRT Adequate Calories: REE or Indirect Calorimetry ??Should we add 10-15 % or More??

REE in Children : 35-60 kcal/kg/d Briassoulis et al Crit Care Med 2000

MEE in Crit Ill Children: 30-35 kcal/kg/d ?? How soon?? Heyland D et al JPEN 2003 24-48 Hrs

Indirect calorimetry AND CRRT

• IC: measure resting energy expenditure.• Based on: Expired CO2 and O2 (O2 consumption +

CO2 production).

Potential problem with CRRT

Hemofilter

Dialysis fluidEffluent

HCO3/CO2 fluxes May affect ICmeasurements.

IC may not be reliable?

Nutrition and PCRRT

• Protein Support for Nitrogen Balance:

• Nitrogen Intake = Nitrogen Output

Protein Catabolic Rate in AKI: Macias et al JPEN 1996

~ 1.4 -1.7 g/kg/day

Maxvold et al Crit Care Med 2000

~ 1.2 - 1.8 g/kg/day

Nutrition and PCRRT

Can Nitrogen Balance be Achieved in AKI patients on CRRT? Conflicting Studies Bellomo et al Ren Fail 1997

Protein Intake : Nitrogen Balance 1.2 g/kg/d AA -5.5 g N /d 2.5 g/kg/d AA -1.9 g N /d

Does Increasing Protein Intake Help?

Scheinkestel et al Nutrition 2003

• 11 critically ill adults on CRRT, protein intake 2.5 g/kg/day a) normal amino acid levels b) positive nitrogen balance.

• 50 critically ill adults on CRRT: 1.5 vs 2.0 vs 2.5 g/kg/day. NB related to protein intake. NB related to hospital stay Protein intake 2.5 g/kg/d: improved survival!

Protein and calorie prescription for children and young adults receiving CRRT: a report from the Prospective Pediatric Continuous Renal Replacement Therapy Registry group. Zappitelli et al, submitted.

0

1

2

3

4

5

1 2 3 4 5 6 7 8 9 10excludes outside values

Protein intake(g/kg/day)

Day of CRRT

Daily change in protein prescription during treatment with CRRT.

Protein and calorie prescription for children and young adults receiving CRRT: a report from the Prospective Pediatric Continuous Renal Replacement Therapy Registry group. Zappitelli et al, submitted.

Characteristics (N) Protein intake (g/kg/day) Initial Maximal

Gender Males (111) Females (84) p-value1

Age Group≤ 1 year (35)1 to ≤13 years (95)>13 years (65)p-value

MODS (155)No MODS (40)p-valueSurvival Survivors (117) Non-survivors (78) p-valueCRRT indication Electrolytes (31) Fluid overload (66) Electrolytes and fluid overload (98) p-value

1.4, 1.0[1.4] 2.0, 1.6[1.6]1.3, 1.0[1.2] 1.9, 1.8[1.5] 0.7 0.9

1.5, 1.8[1.5] 2.5, 2.4[2.3] 1.3, 1.0[1.2] 2.0, 1.9[1.5] 1.4, 1.0[1.0] 1.6, 1.3[1.1] 0.09 0.009*

1.3, 1.0[1.2] 1.9, 1.8[1.5]1.5, 1.0[0.8] 2.0, 1.3[1.7] 0.1 0.2

1.4, 1.0[1.2] 2.0, 1.6[1.5]1.3, 1.0[1.3] 1.8, 1.8[1.7] 0.6 0.9

1.2, 1.0[0.9] 1.6, 1.4[1.1]1.6, 1.2[1.2] 2.1, 1.8[1.8]1.2, 1.0[1.3] 2.0, 1.8[1.6] 0.07 0.2

All groups:-Maximal protein>initial

Multivariate predictors ofmaximal protein intake

- Younger age- Higher initial protein Rx- #CRRT days

Protein Rx >2g/kg/day in 40%

Amino acid, trace metal and folate clearance by continuous renal replacement therapy in critically ill children. Zappitelli et al, submitted

CVVHD initiation (N=15) Day 2 (N=15) Day 5 (N=9)Mean±SD, Median Mean±SD, Median Mean±SD, Median

Protein intake (g/kg/d)N balance (g/kg/d)Caloric intake (kcal/kg/d)Caloric balance (kcal/kg/day)

1.98±1.24, 1.75 2.04±1.02, 2.09 1.85±0.60, 2.08

NA -0.88±1.60, -0.22 -0.23±0.19, -0.24

32.6±27.6, 23.8 40.3±22.3, 33.6 43.2±18.4, 42.7

-0.4±25.4, -8.0 +7.7±21.7, +1.5 +10.6±17.7, +10.8

Protein and energy intake and output at CVVHD1 initiation, Day 2 and Day 5.

Maxvold et al, Crit Care Med, 2000

Protein intake was 1.5 g/kg/day – Negative nitrogen balance

It’s not easy to achieve a positive nitrogen balance.

Logic: bigger filter, higher Qd or Quf = increased clearance

Amino acid, trace metal and folate clearance by continuous renal replacement therapy in critically ill children. Zappitelli et al, submitted

Amino Acid

Day 2 (n=15) Day 5 (n=9)K1 CVVHD CVVHD Losses K Renal (n=2) K CVVHD CVVHD Losses K Renal (n=3)(ml/min/1.73m2) (mcg/kg/d) (ml/min/1.73m2) (ml/min/1.73m2) (mcg/kg/d) (ml/min/1.73m2) Mean±SD, Median Mean±SD, Median Mean Mean±SD, Median Mean±SD, Median Mean

TauAspThrSerAsnGluGlnProGlyAlaCitValCysMetIleLeuTyrPheOrnLysHisArg

104.5±179.0, 32.9 8.4±11.1, 4.8 1.0 77.8±111.2, 24.2 4.5±5.4, 1.8 2.1335.8±483.7, 53.6 3.9±4.1, 3.2 2.6 234.0±349.8, 51.1 5.6±4.4, 2.6 12.031.9±25.0, 22.6 15.7±18.5, 9.9 4.1 38.8±25.1, 29.8 11.9±5.9, 12.0 18.929.1±25.6, 17.8 8.1±8.6, 5.7 3.6 34.6±27.7, 22.3 6.0±3.3, 5.0 9.237.2±32.1, 32.3 7.7±8.1, 4.5 9.8 35.5±19.8, 34.3 5.0±3.4, 5.3 28.69.4±10.6, 6.2 2.7±4.0, 1.8 0.6 6.1±5.0, 3.8 1.6±0.7, 1.7 1.019.4±20.1, 13.2 47.4±63.7, 23.0 2.2 85.4±152.9, 21.2 44.2±30.7, 34.5 0.738.3±32.7, 31.2 24.3±22.2, 17.6 0.2 37.5±21.9, 27.3 19.4±11.2, 20.5 0.828.1±25.7, 18.0 16.0±16.1, 7.5 3.9 35.3±30.2, 19.8 12.0±7.1, 14.1 12.926.1±24.6, 15.4 23.4±21.2, 13.5 5.2 37.9±38.8, 25.2 20.0±11.5, 24.1 6.925.6±24.3, 15.9 2.8±4.5, 1.3 4.1 39.3±50.4, 25.7 1.5±1.1, 1.4 5.724.8±22.0, 14.8 16.8±13.4, 12.7 5.2 39.1±37.3, 25.1 14.4±6.9, 13.9 5.527.4±54.5, 8.6 0.8±1.2, 0.5 0.5 34.7±29.9, 44.3 1.3±1.1, 1.1 5.218.0±19.9, 8.2 5.9±13.5, 12.7 3.6 26.8±31.1, 17.2 2.2±1.8, 2.2 5.129.9±29.8, 17.3 6.0±5.7, 4.3 6.9 38.6±34.7, 22.1 5.4±2.7, 4.3 6.622.9±20.9, 13.6 11.6±9.2, 7.8 3.9 32.2±28.8, 22.7 10.3±5.2, 10.9 4.422.2±23.3, 10.7 9.2±13.5, 4.3 4.4 36.5±41.3, 21.4 5.6±2.7, 5.2 10.523.9±20.8, 12.9 18.4±23.1, 7.8 4.5 34.9±29.7, 26.4 11.3±6.2, 10.1 7.08.4±8.7, 12.9 3.4±5.0, 1.0 0.3 91.0±249.7, 10.6 2.5±3.4, 1.4 0.77.7±9.0, 2.8 10.0±11.1, 4.4 0.3 108.4±299.5, 9.6 8.7±8.9, 5.6 0.913.2±15.8, 10.0 8.0±15.9, 2.8 0.7 33.4±66.3, 15.7 4.5±3.8, 5.1 12.115.8±17.1, 8.0 11.4±23.4, 3.5 1.8 45.8±68.6, 8.6 6.0±4.8, 4.1 6.2

CVVHD clearance of amino acids measured on Day 2 and Day 5 N=15

0

10

20

30

40

50

60

K

ml/min/1.73m 2

Thr Glu Gln Pro Gly Ala Val Met Phe Lys His Arg

Amino Acids

Combined results of clearance of essential amino acids by CRRT. Zappitelli et al (submitted) and Maxvold et al, Critical Care, 2000 (n=6).

Several studies, adult and child: ~ 10-20% intake “lost” through hemofilter.

Both studies: Highest losses with Glutamine/Glutamic acid

Critical Illness – trace metals

• Deficiencies linked to:

- Lymphocyte dysfunction

- Cardiovascular dysfunction

- Platelet activity

- Antioxidant function

- Wound healing

Amino acid, trace metal and folate clearance by continuous renal replacement therapy in critically ill children. Zappitelli et al, submitted

K1 Day 2 K Day 5 Serum concentrations _____________________ (ml/min/1.73m2) (ml/min/1.73m2) Initiation Day 2 Day 5 Reference range2

SeleniumCopperChromiumZincManganeseFolate

10.1±7.2, 9.5 8.6±3.9, 7.2 55±19, 49 61±24, 59 64±23, 63 23 to 190 (µg/l) 0.4±0.3, 0.3 0.54±0.46, 0.44 88±21, 87 L3 110±27, 106 104±27, 103 90 to 190 (µg/dl)24.0±10.6, 25.4 24.7±7.1, 26.0 2±1, 2 2±1, 2 2±0.4, 2 0 to 2.1 (µg/l)4.2±4.1, 3.2 4.0±2.4, 2.9 66±44, 53 L 68±28, 61 76±38, 68 60 to 120 (µg/dl)9.0±12.9, 4.6 38.2±121.4, 5.1 9±16, 4 H3 8±15, 3 H 8±15, 3 H 0 to 2 (µg/l)29.4±54.9, 16.2 15.6±3.2, 16.3 16±12, 12 10±4, 9 8±2, 7 5.4 to 40 (ng/l)

Churchwell et al, NDT, 2007

Critically ill adults receiving CVVHD and CVVHDFTransmembrane clearancesMuch lower clearance of selenium and chromiumOverall, trace metal clearance negligible.

CRRT-Vitamins

02468

10121416

Serum folate level (ng/ml)

Pre CRRT Day 2 Day 5

Day of CRRT

Amino acid, trace metal and folate clearance by continuous renal replacement therapy in critically ill children. Zappitelli et al, submitted

**

Nutrition and PCRRT

Berger et al AM J Clin Nutr 2004

24º Balance Studies Intake (Replacement Fluid) = Output (Effluent)

[SeRF] = [SeEff] -0.97 µmol (2 x RI)

[CuRF] = [CuEff] -0.54 µmol (0.3 x RI)

[Vit B1RF] = [Vit B1Eff] -4.12 mg (1.5 x RI)

[ZnRF] = [ZnEff] 20.7 µmol (1.5 x RI) Negative Balance for Se, Cu, VitB1 and Se and VitB1 Losses > 1.5 x the Recommended Intake

Critical Illness - Vitamins

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 acidPotential for losses during CRRT.

Critical Illness - Vitamins

Fat Soluble

• Vit D Def Hypocalcemia

• Vit A Excess renal catabolism of

retinol binding protein

• Vit E Def >50% plasma and

RBC

Critical Illness & AKI - Lipids

LDL and VLDL

• Cholesterol and HDL-Cholesterol

Impaired Lipolysis

Lipase Activity ~50%

Lipoprotein Lipase

Hepatic Triglyceride Lipase

Nutrition and PCRRT

Initial Nutritional Prescription for Kids with AKI on CRRT:

• Early Nutrition : 24-48 hrs of PICU admission • Enteral feeding + Parenteral feeding (often require partial Parenteral Nutrition early in acute illness) • REE for age (without additional kcal % allowance) ( REE is already >33% Above mean MEE )

• MEE if available

Initial Nutritional PrescriptionPediatric AKI on CRRT

Component Prescription:

CHO

Fat

Protein

Vitamins

Trace elements

Monitoring

Consider

4-5 mg/kg/min Glucose support [5.8-7.2 g/kg/d] (Insulin as needed for Hyperglycemia)

0.5-1g/kg/d

2 to 3 g/kg/day with AKI (Increase intake if on High flow CRRT (by 20%)

Daily recommended intake (± replacement ) Monitor serum folate, water soluble vitamin levels

Daily Recommended Intake

MEE, Nitrogen Balance, Electrolytes, Vitamins, Trace elements

-Pharmaconutrients: Glutamine, Ala, Se, Omega 3 FA, L-Carnitine, etc

Nutrition and PCRRT

Future Development

PharmacoNutrients:

• Gln

• Omega 3 Fatty Acids

• Arginine

• L-Carnitine

• Growth Factors

PharmacoNutrients

Singer et al Intensive Care Med 2008

• Omega-3 FA: Augment immune defense through inhibition of NF-kappaß

Luiking st al Crit Care Med 2007 Kalil et al Crit Care Med 2006

• Arginine: + Effect - Improved microcircuation, gut function, Plt and WBC Adherence,Endothelial function

- Effect -Hemodynamic Instability, Oxidative Stress

Prevot et al Pediatr Nephrol 2009

• Growth Factors (IGF-1, GH, Insulin)

Glutamine: Conditionally Essential Nutrient

• Substrate for Rapidly dividing cells(Kidney tubular cells, Enterocytes, Immune cells)

• Precursor for Glutathione• Substrate for Gluconeogenesis• Substrate for Ammoniagenesis• Osmotic regulator, • Precursor of purine/pyridimine

Potential Beneficial Effects of Glutamine

Fuel forFuel forEnterocytesEnterocytes

Fuel forFuel forLymphocytesLymphocytes

Nuclotide Nuclotide SynthesisSynthesis

Maintenance ofMaintenance ofIntestinalIntestinalMucosal BarrierMucosal Barrier

Maintenance ofMaintenance ofLymphocyteLymphocyteFunctionFunction

Preservation Preservation of TCA Functionof TCA Function

Decreased FreeRadical availability (Anti-inflammatory action)

GlutathioneGlutathioneSynthesisSynthesis

GLNGLNpoolpool

GlutamineTherapy

Enhanced HeatEnhanced Heat Shock ProteinShock Protein

Anti-cataboliceffect

Preservation of Muscle mass

Reduced Reduced TranslocationTranslocationEnteric BacteriaEnteric Bacteriaor Endotoxinsor Endotoxins

Reduction ofReduction ofInfectious Infectious complicationscomplications

Inflammatory Cytokine Inflammatory Cytokine AttenuationAttenuation

Preserved CellularEnergetics- ATP content

GLNGLNPoolPool

Critical IllnessCritical Illness

Enhanced insulin sensitivity

• CRISIS Trial: Multicenter Pediatric Trial ofEnteral Se, Zn, Gln, IV Metoclopramide

1º Outcome: Time between PICU [DOA] and Infection [nosocomial or clinical]

• REDOXS Study: Multicenter Adult Trial 4 Treatment Arms: Gln; Gln and AntiOxidants; Antioxidants; Placebo Remember!

Gln Loss on CRRT:15-20% of Total AA Clearance

Glutamine Studies

Nutrition and PCRRT

Carnitine Studies

• Conditionally Essential Supplement• Improved Mitochondrial Cellular

Energetics

Nutrition in PCRRT

Carnitine Role in Cell Energetics:• Facilitates Long Chain AcylCoA

[transformed FattyAcids within cytosol]

• Diminishes Acetyl CoA/CoA Ratio -

Improves the PDH Complex Activity• Increases Pyruvate Oxidation and

decreases Lactate Production

Nutrition in PCRRT

That’s Enough for Now!

Many Thanks and Gratitude :Dr. Bunchman Dr. Zappitelli

My Associates in Michigan, especially the PICU nurses!