Nutrition In Pediatric CRRT Michael Zappitelli, MD, MSc Nutrition in AKI AND CRRT McGill University Health Center Montreal, Quebec, Canada

Objectives Discuss the impact of nutrition in acute kidney injury... and vice versa Discuss clearance of nutrition and nutrition adjustment in pediatric CRRT.

No real prevention/treatment Poorer outcome, increased mortality Critical Illness X No real prevention/treatment Acute Kidney Injury X Left with: 1) Modifying the negative effects of AKI 2) Providing adequate nutrition ??? Modify outcome??? Poorer outcome, increased mortality

Critical Illness Acute Kidney Injury hormone changes Acute: increase Later: decrease ↑ cytokines Altered substrate utilization CH2O: ↑hepatic gluconeogenesis (shift away from glycolysis) ↑lipogenesis - Inefficient glucose oxidation - Insulin resistance - Shift in use of amino acids: gluconeogenesis + APR’s MALNUTRITION Impaired nutrient transport Inefficient/inadequate supply Impaired A.a. conversion ↓lipid oxidation Uremia Acidosis Altered Glucose metab. Cytokines Acute Kidney Injury

Critical Illness and Nutrition Adequate nutrition needed for recovery + normal functioning of growing child. Tissue synthesis and immune function. Desire to avoid over- and under-feeding. Underfeeding: increase morbidity, mortality, infection, wound healing, length of ventilation.

Critical Illness and Nutrition Children: high risk of malnutrition. High basal metabolic rates. Limited energy reserves. High (15-30%) baseline poor nutrition.

Malnutrition AND AKI Same difficulties/pathophysiology + Increased difficulty in nutrition provision. Higher rate of baseline malnutrition/ comorbidities Metabolic changes of AKI. Children with AKI – increased risk of malnutrition at PICU discharge. RRT – increases nutritional losses.

Nutrition and AKI Problem: No evidence-based guidelines. Difficulty to show effect on hard outcomes. Recommendations based on Adult studies Known metabolic alterations with AKI Nutrition in critically ill children Measuring nutritional losses by RRT.

Critical Illness – Energy needs Metabolic needs vary according to the injury. RDA versus predictive equations vs direct measurement (indirect calorimetry). No single predictive equation shown to accurately estimate REE. Limitations to indirect calorimetry in critically ill patients.

AKI and energy needs Controversial – AKI per se may not affect energy expenditure. Affected more by coexisting conditions. Almost no data on pediatric AKI and energy needs.

Indirect calorimetry AND CRRT IC: measure resting energy expenditure. Based on: Expired CO2 and O2 (O2 consumption + CO2 production). Potential problem with CRRT May affect IC measurements. IC may not be reliable? HCO3/CO2 fluxes Hemofilter Effluent Dialysis fluid

Critical Illness – Energy needs Controversy: ? RDA ? 25-30% above REE. Mean REE in literature: 35 to 60 kcal/kg/day (0.15-0.27 MJ/kg/day) Adults: 25-35 kcal/kg/day – probably need more in children. Almost no studies in AKI.

Carbohydrates Patients become hyperglycemic. Insulin resistance, ↑hepatic gluconeogenesis. Stress hormones Inflammatory mediators and cytokines Metabolic acidosis Pre-existing hyperparathyroidism

Critical Illness - protein Protein synthesis AND breakdown are increased: breakdown more increased. Manifestation: net negative nitrogen balance, skeletal muscle wasting. Nitrogen balance = Nin – Nout.

Critical Illness & AKI - protein Protein metabolism abnormal: Reduced renal synthesis of amino acids Altered amino acid uptake Factors related to critical illness (elevated stress hormones, increased hepatic gluconeogenesis, relative insulin resistance).

AKI and protein Protein synthesis CAN be increased by providing more amino acids. Bellomo et al, Int J of Artif Organs, 2002 Scheinkestel et al, Nutrition, 2003 Still very difficult to achieve positive N balance.

therapy in critically ill children. Zappitelli et al, submitted Amino acid, trace metal and folate clearance by continuous renal replacement therapy in critically ill children. Zappitelli et al, submitted CVVHD clearance of amino acids measured on Day 2 and Day 5 N=15 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 Tau Asp Thr Ser Asn Glu Gln Pro Gly Ala Cit Val Cys Met Ile Leu Tyr Phe Orn Lys His Arg 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 2.1 335.8±483.7, 53.6 3.9±4.1, 3.2 2.6 234.0±349.8, 51.1 5.6±4.4, 2.6 12.0 31.9±25.0, 22.6 15.7±18.5, 9.9 4.1 38.8±25.1, 29.8 11.9±5.9, 12.0 18.9 29.1±25.6, 17.8 8.1±8.6, 5.7 3.6 34.6±27.7, 22.3 6.0±3.3, 5.0 9.2 37.2±32.1, 32.3 7.7±8.1, 4.5 9.8 35.5±19.8, 34.3 5.0±3.4, 5.3 28.6 9.4±10.6, 6.2 2.7±4.0, 1.8 0.6 6.1±5.0, 3.8 1.6±0.7, 1.7 1.0 19.4±20.1, 13.2 47.4±63.7, 23.0 2.2 85.4±152.9, 21.2 44.2±30.7, 34.5 0.7 38.3±32.7, 31.2 24.3±22.2, 17.6 0.2 37.5±21.9, 27.3 19.4±11.2, 20.5 0.8 28.1±25.7, 18.0 16.0±16.1, 7.5 3.9 35.3±30.2, 19.8 12.0±7.1, 14.1 12.9 26.1±24.6, 15.4 23.4±21.2, 13.5 5.2 37.9±38.8, 25.2 20.0±11.5, 24.1 6.9 25.6±24.3, 15.9 2.8±4.5, 1.3 4.1 39.3±50.4, 25.7 1.5±1.1, 1.4 5.7 24.8±22.0, 14.8 16.8±13.4, 12.7 5.2 39.1±37.3, 25.1 14.4±6.9, 13.9 5.5 27.4±54.5, 8.6 0.8±1.2, 0.5 0.5 34.7±29.9, 44.3 1.3±1.1, 1.1 5.2 18.0±19.9, 8.2 5.9±13.5, 12.7 3.6 26.8±31.1, 17.2 2.2±1.8, 2.2 5.1 29.9±29.8, 17.3 6.0±5.7, 4.3 6.9 38.6±34.7, 22.1 5.4±2.7, 4.3 6.6 22.9±20.9, 13.6 11.6±9.2, 7.8 3.9 32.2±28.8, 22.7 10.3±5.2, 10.9 4.4 22.2±23.3, 10.7 9.2±13.5, 4.3 4.4 36.5±41.3, 21.4 5.6±2.7, 5.2 10.5 23.9±20.8, 12.9 18.4±23.1, 7.8 4.5 34.9±29.7, 26.4 11.3±6.2, 10.1 7.0 8.4±8.7, 12.9 3.4±5.0, 1.0 0.3 91.0±249.7, 10.6 2.5±3.4, 1.4 0.7 7.7±9.0, 2.8 10.0±11.1, 4.4 0.3 108.4±299.5, 9.6 8.7±8.9, 5.6 0.9 13.2±15.8, 10.0 8.0±15.9, 2.8 0.7 33.4±66.3, 15.7 4.5±3.8, 5.1 12.1 15.8±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

Combined results of clearance of essential amino acids by CRRT. Zappitelli et al (submitted) and Maxvold et al, Critical Care, 2000 (n=6). Grey bars represent amino acid clearance achieved by continuous veno-venous hemofiltration [4] and black bars from continuous veno-venous hemodialysis [45]. K, clearance; Thr, threonine; Glu, glutamic acid; Gln, glutamine; Pro, Proline; Gly, Glycine; Ala, Alanine; Val, Valine; Met, Methionine; Phe, Phenylalanine; Lys, Lysine; His, Histidine; Arg, Arginine. This graph was derived using data from: Crit Care Med 2000 28:1161-1165 and J Am Soc Nephrol 2006 17:767A. Several studies, adult and child: ~ 10-20% intake “lost” through hemofilter. Both studies: Highest losses with Glutamine/Glutamic acid

therapy in critically ill children. Zappitelli et al, submitted Amino acid, trace metal and folate clearance by continuous renal replacement therapy in critically ill children. Zappitelli et al, submitted Amino Acid serum levels measured on Days 1, 2 and 5 Amino Acid2 CVVHD initiation % low/normal/high3 Day 2 % low/high/normal Day 5 % low/normal/high Tau Asp Thr Ser Asn Glu Gln Pro Gly Ala Cit Val Cys Met Ile Leu Tyr Phe Orn Lys His Arg 43±96, 16 0/ 93.3/6.7 40±102, 14 6.7/ 86.7/ 6.7 18±14, 13 11.1/ 88.9/ 0 4±3, 3 0/ 100.0/ 0 5±5, 3 6.7/ 93.3/ 0 13±16, 8 11.1/ 66.7/ 22.2 100±81, 66 20.0/60.0/20.0 99±54, 109 13.3/ 80.0/ 6.7 105±67, 95 0/ 88.9/ 11.1 53±26, 51 60.0/ 40.0/ 0 65±30, 56 53.3/ 46.7/ 0 66±34, 58 44.4/ 55.6/ 0 37±21, 30 0/ 100.0/ 0 42±23, 43 0/ 93.3/ 6.7 42±27, 41 11.1/ 77.8/ 11.1 57±89, 23 0/ 86.7/ 13.3 55±55, 37 0/ 80.0/ 20.0 119±146, 82 11.1/ 44.4/ 44.4 315±146, 295 46.7/ 53.3/ 0 372±167, 364 0/ 33.3/ 66.7 382±261, 336 33.3/ 55.6/ 11.1 124±66, 111 6.7/ 93.3/ 0 142±69, 127 0/ 100.0/ 0 182±113, 132 0/ 88.9/ 11.1 200±135, 167 26.7/ 66.7/ 6.7 186±89, 177 20.0/ 66.7/ 13.3 190±100, 165 11.1/ 77.8/ 11.1 195±133, 157 13.3/ 80.0/ 6.7 259±149, 210 13.3/ 80.0/ 6.7 283±192, 236 11.1/ 77.8/ 11.1 12±7, 10 13.3/ 86.7/ 0 12±8, 11 20.0/ 80.0/ 0 12±7, 12 22.2/ 77.8/ 0 148±58, 151 20.0/ 80.0/ 0 144±43, 142 6.7/ 93.3/ 0 140±57, 148 11.1/ 88.9/ 0 27±25, 21 20.0/ 60.0/ 20.0 17±24, 10 33.3/ 60.0/ 6.7 24±35, 12 33.3/ 55.6/ 11.1 32±52, 16 6.7/ 80.0/ 13.3 37±39, 25 6.7/ 53.3/ 40.0 25±16, 26 0/ 88.9/ 11.1 31±19, 24 13.3/ 86.7/ 0 43±22, 42 6.7/ 93.3/ 0 45±23, 41 0/ 88.9/ 11.1 78±34, 70 0/ 93.3/ 6.7 97±28, 95 0/ 100.0/ 0 101±41, 100 11.1/ 77.8/ 11.1 57±38, 42 6.7/ 73.3/ 20.0 51±27, 45 6.7/ 86.7/ 6.7 46±27, 45 22.2/ 77.8/ 0 92±59, 71 0/ 73.3/ 26.7 98±63, 79 0/ 46.7/ 53.3 83±45, 87 0/ 44.4/ 55.6 47±37, 38 0/ 86.7/ 13.3 56±41, 51 0/ 86.7/ 13.3 67±84, 52 11.1/ 77.8/ 11.1 152±65, 136 0/ 86.7/ 13.3 173±84, 153 0/ 66.7/ 33.3 153±90, 127 11.1/ 66.7/ 22.2 76±32, 71 6.7/ 80.0/ 13.3 75±38, 65 6.7/ 80.0/ 13.3 65±36, 57 11.1/ 77.8/ 11.1 43±26, 39 20.0/ 80.0/ 0 74±56, 55 0/ 93.3/ 6.7 56±31, 50 11.1/ 88.9/ 0

therapy in critically ill children. Zappitelli et al, submitted Amino acid, trace metal and folate clearance by continuous renal replacement therapy in critically ill children. Zappitelli et al, submitted Protein and energy intake and output at CVVHD1 initiation, Day 2 and Day 5. 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 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

Does increasing protein intake help? Scheinkestel et al. 1. Nutrition, 2003 In 11 critically ill adults on CRRT, protein intake 2.5 g/kg/day led to a) normal amino acid levels and b) positive nitrogen balance. 2. Nutrition, 2003 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!

What are we doing? 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. Age (years) CRRT duration (days) Diagnostic category Sepsis/Infection Renal Respiratory Cardiac Hematology Oncology Gastrointestinal/Hepatic Other CRRT indication Electrolyte imbalance Fluid overload only Fluid overload and electrolytes CRRT modality CVVHD CVVH CVVHDF 8.8 ± 6.8 (8.1, 12.8) 10.2±10.7 (7.0, 11.0) days N (%) 74 (38.1) 29 (15.0) 12 (6.2) 21 (10.8) 35 (18.0) 15 (7.7) 9 (4.6) 31 (15.9) 66 (33.9) 98 (50.3) 94 (48.2) 52 (26.7) 49 (25.1)

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. Daily change in protein prescription during treatment with CRRT. Protein intake (g/kg/day) Day of CRRT

Daily change in caloric 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. Daily change in caloric prescription during treatment with CRRT. Caloric Intake (kcal/kg/day) Day of CRRT

Registry group. Zappitelli et al, submitted. 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) Survival Survivors (117) Non-survivors (78) CRRT indication Electrolytes (31) Fluid overload (66) Electrolytes and fluid overload (98) 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 of maximal protein intake Younger age Higher initial protein Rx #CRRT days Protein Rx >2g/kg/day in 40%

Critical Illness & AKI - Lipids h LDL and VLDL iCholesterol and HDL-Cholesterol Impaired Lipolysis Lipase Activity ~50% i Lipoprotein Lipase i Hepatic Triglyceride Lipase

Critical Illness - Vitamins Water Soluble Vit B1 Def Altered Energy Metabolism, h 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 Potential for losses during CRRT.

Critical Illness - Vitamins Fat Soluble Vit D Def Hypocalcemia Vit A Excess i renal catabolism of retinol binding protein Vit E Def i >50% plasma and RBC

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

Critical Illness – trace metals Deficiencies linked to: Lymphocyte dysfunction Cardiovascular dysfunction Platelet activity Antioxidant function Wound healing

therapy in critically ill children. Zappitelli et al, submitted 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 Selenium Copper Chromium Zinc Manganese Folate 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 CVVHDF Transmembrane clearances Much lower clearance of selenium and chromium Overall, trace metal clearance negligible.

Synthesis Nutritional parameter Nutrition modality Energy Protein Vitamins Trace elements Monitoring Consider - Early enteral feeding, will often require parenteral nutrition - Approximately 25% above basal metabolic needs as measured by metabolic cart or estimated with equations. 20 to 25% as carbohydrates (insulin as needed) 30 to 40% lipid formulations (20% lipid emulsions) 40 to 50% protein - 2 to 3 g/kg/day with AKI - Increase intake if on CRRT (by 20%) - Daily recommended intake Monitor serum folate, water soluble vitamin levels ± replacement Resting energy expenditure, nitrogen balance, electrolytes, vitamins, trace elements Glutamine

Acknolwedgements Timothy E. Bunchman Norma J. Maxvold Stuart L. Goldstein