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PCRRT for Metabolic Disease Timothy E. Bunchman Professor Pediatrics Signs and Symptoms of Hyperammonemia Initially healthy appearing neonate with decompensation after several days Often seen after institution of protein feedings Lethargy Poor feeding Vomiting Hypotonia bunchman Signs and Symptoms of Hyperammonemia Respiratory distress, tachypnea, apnea Irritability Seizure activity Neurologic deterioration leading to coma Death bunchman Long Term Effects of Neonatal Ammonemia Demonstrated correlation between prolonged neonatal hyperammonemic coma and brain damage with impaired intellectual functioning Did not demonstrate correlation between peak ammonia level and level of intellectual impairment [Msall et al. NEJM, 1984] bunchman Major Causes of Hyperammonemia Urea cycle defects Organic acidemias Transient hyperammonemia of the newborn Severe asphyxia - increased protein breakdown during hypoxic stress plus liver damage due to ischemia Liver failure - due to multiple causes bunchman particularly infection Flow Diagram to Evaluate Hyperammonemia acidosis Increased ammonia Lactate/pyruvate No acidosis bunchman Urine for organic acids Plasma amino acids Flow Diagram to Evaluate Hyperammonemia Sig incr Plasma amino acids citrulline citrullinemia Nl. Nl. Or sl. increased ASA Incr. low urine Orotic acid bunchman THN Low or absent Incr. ASA CPS OTC Treatment of Ammonemia Prior to Further Diagnosis Prevent further catabolism by providing adequate calories, fluids and electrolytes Minimize protein intake Provide alternate pathways for ammonia removal May require exchange transfusion, peritoneal dialysis or hemodialysis for ammonia removal bunchman Alternate Pathways for Removal of Ammonia Sodium benzoate SODIUM BENZOATE HIPPURATE + GLYCINE Cleared by the kidney at 5X the GFR Each mole of benzoate removes one mole of ammonia as glycine bunchman Alternate Pathways for Removal of Ammonia Sodium phenylacetate PHENYL- + GLUTAMINE ACETATE PHENYlAC ETYLGLUTAMIN E Easily excreted in the urine One mole of phenylacetate removes 2 moles of ammonia as glutamine bunchman Alternate Pathways for Removal of Ammonia Arginine supplementation provides the urea cycle with ornithine and nacetylglutamate Abbreviated version of the urea cycle continues not recommended for use in arginase deficiency or organic acidemias bunchman But what do I do when the drugs don’t work? bunchman You call your friendly dialysis folks bunchman Mode of RRT PD nope Hemodialysis looks like a good place to start Hemofiltration a great way to go home at night bunchman micromoles/l NH4 HD Rx of ammonemia (Gregory et al, Vol. 5,abst. 55P,1994: ) 2000 1800 1600 1400 1200 1000 800 600 400 200 0 NH4 rebound with reinstitution of HD 0 bunchman 1 2 3 4 5 6 10 11 12 13 17 18 19 20 Time (Hrs) HD to CRRT (prevention of the rebound) 1200 micromoles/L NH4 1000 800 Transition from HD to CVVHD 600 400 200 0 0 bunchman 1 2 3 4 5 Time (Hrs) 10 11 17 Local experience (McBryde et al, JASN 2000) 18 children underwent 20 therapies of RRT due to in-born error of metabolism mean age 56 + 7.9 mos mean weight 15 + 3.7 kg (smallest 1.2 kg) mean duration of therapy 6.1 + 1.3 days bunchman Local experience (McBryde et al, JASN 2000) Modalities used HD only-9 time on HD 2.2 + 0.9 days HF only-3 time on HF 6.3 + 2.9 days HD followed by HF-8 time on HD + HF 10.25 + 1.8 days bunchman Local experience (McBryde et al, JASN 2000) Outcome 12/18 patients survived 2/12 continued to be medication and RRT dependent bunchman But what do I do when the drugs and RRT doesn’t work? bunchman You call your friendly liver transplant folks bunchman CVVHD for NH4 Bridge to Hepatic Transplantation 800 700 micromoles/L NH4 600 Successful Liver Transplantation 500 400 300 200 100 0 1 bunchman 2 4 6 8 Time (days) 10 12 14 16 Considerations of PCRRT for metabolic disease Dialysis Bath “metabolic cocktail” clearance nutritional needs with the balance of restricted protein intake and amino acid loss via HF bunchman Hemodialysis Bath Considerations Electrolyte Na (meq/l) Cl (meq/l) Glucose (mg/dl) Ca (mg/dl) MG (meq/l) HCO3 (meq/l) K (meq/l) Phos (mg/dl) bunchman ARF 140 96 200 3.5 1 40 0-3 0 Metabolic 140 96 200 3.5 1 40 4-5 4-5 (add to B jug) Metabolic Cocktail drug clearance Drug clearance related small molecular weight minimal protein binding volume of distribution Phenylacetate, Benzoate, Arginine all will be cleared ? Re bolus? bunchman Comparison of Total Amino Acid losses: CVVH vs CVVHD (Maxvold et al, Crit Care Med April 2000) Amino Acid Losses (g/day/1.73 m2) 16 14 12 10 8 6 4 2 0 CVVH bunchman CVVHD Conclusion Hyperammonemia is a medical emergency When medical management does not work consider RRT early HD should be used initially with HF in tandem Liver transplant should be considered if medical and RRT management is not successful bunchman