1. Case Study in RRT in In Born Error of Metabolism Timothy E. Bunchman Pediatric Nephrology & Transplantation VCU School of Medicine tbunchman@mcvh-vcu.edu pcrrt@aol.com www.pcrrt.com

2. In Born Error of Metabolism 2.9 kg infant presents at 48 hours of life with lethargy. Child is afebrile, BP is 75/40, HR of 130 BPM, RR of 50 BPM On exam “floppy” infant with poor neurologic tone

3. In Born Error of Metabolism Normal laboratory data shows of –H/H of 15/45; Cr of 0.9 mg/dl (maternal), K of 4.3 mq/dl, Ca of 9.5 mg/dl, Phos of 6.0 mg/dl (nl) Abnormal laboratory data shows –CO2 of 14 mg/dl and a ammonia of 1533 micromls/l (nl < 40)

4. 30 newborns at OBG: OA 14 pts : 8 PA, 4 MMA, 1 HMG, 1 IVA UCD 16 pts : 3 CPS, 4 OTC, 5 AL, 3 AS,1 HHH Dionisi-Vici et al. J Inher Met Dis 2003

5. INCIDENCE Overall: 1:9160 Organic Acidurias: 1:21422 Urea Cycle Defects: 1:41506 Fatty Acids Oxidation Defects: 1:91599 AGE OF ONSET Neonate: 40% Infant: 30% Child: 20% Adult: 5-10% (?) Dionisi-Vici et al, J Pediatrics, 2002. “SMALL MOLECULES” DISEASES INDUCING CONGENITAL HYPERAMMONEMIA.

6. hyperammonemia is extremely toxic to the brain (per se or through intracellular excess glutamine formation) causing astrocyte swelling, brain edema, coma, death or severe disability, thus: emergency treatment has to be started even before having a precise diagnosis since: prognosis mainly depends on coma duration KEY POINTS FACING TO A HYPERAMMONEMIC NEWBORN

7. PROGNOSIS OF HYPERAMMONEMIC COMA IS DEPENDENT ON COMA DURATION. from Msall M et al, N Eng J Med 1984.

8. TREATMENT of SEVERE NEONATAL HYPERAMMONEMIA ? IMMEDIATE MEDICAL THERAPY NO RESPONSE DIALYSIS MAINTAINANCE MEDICAL THERAPY + REFEEDING IMMEDIATE DIALYSIS + MEDICAL THERAPY MAINTAINANCE MEDICAL THERAPY + REFEEDING

9. Pharmacological treatment before having a diagnosis AIMS  precursors  catabolism  anabolism stop protein caloric intake  100 kcal/kg insulin …and endogenous depuration arginine 250 mg/Kg/2 hrs + 250 - 500 mg/Kg/day carnitine 1g i.v. bolus 250 - 500 mg/Kg/day vitamins (B12 1 mg,biotin 5-15 mg) benzoate 250 mg/Kg/2 hrs + 250 mg/Kg/day or peroral phenylbutyrate (only after UCD diagnosis) Picca et al. Ped Nephrol 2001

10. time urea PD HD CRRT [C] generation rateclearance ammonium?

11. RRT intervention Child was electively intubated for airway protection Foley catheter placed for use for urine collection and accurate I/O Na Pheyacetate, Na Benzoate, Arginine Cl, Carnitine were all begun once urine and plasma amino and organic acids obtained.

12. RRT intervention A 7 Fr 10 cm MedComp “softline” duel lumen vascular access placed HD begun using a blood prime and a Phoenix (Gambro) – BRF of 70 mls/min (~ 22 mls/kg/min) –DFR of 500 mls/min with a physiologic K and Phos bath Ammonia levels collected at 1 hr intervals

13. Ammonia Clearance 0 200 400 600 800 1000 1200 1400 1600 1800 1235711151719 HD Begins Time (hours) Ammonia (micromol/l) HD Ends

14. RRT intervention At 2 hours of HD the ammonia was ~ 200 micromls/l and HD was exchanged for CVVHDF (Gambro Prisma M 60 membrane) using the same vascular access A blood prime bypass maneuver was performed Replacement rate of 2 liters per hour and a dialysate rate of 1 liter per hour (HD clearance was 30 l/hr now decreased to 3 l/hr)

15. Ammonia Clearance 0 200 400 600 800 1000 1200 1400 1600 1800 1235711151719 HD Begins Time (hours) Ammonia (micromol/l) HD Ends HF Begins HF Ends

16. RRT intervention A few practical comments Ammonia is non-osmolar so no risk of dialysate disequilibrium exists In Born Error of metabolism infants appear to be polyuric so keeping them intubated and keeping them “wet” is important

17. TREATMENT of NEONATAL HYPERAMMONEMIA HOSPITALIZATION DIAGNOSIS PHARMACOLOGICAL TREATMENT DIALYSIS NO RESPONSE RESPONSE RE-FEEDING

18. NH4p (percent of initial value) Time (hours) 0510152025 0 20 40 60 80 100 120 140 160 180 PD patients

19. 0102030405060 0 20 40 60 80 100 CAVHD patients 0102030405060 0 20 40 60 80 100 HD patients TIME (hours) 0102030405060 0 20 40 60 80 100 CVVHD patients NH4p (percent of initial value) Picca et al. Ped Nephrol 2001

20. AMMONIUM CLEARANCE AND FILTRATION FRACTION USING DIFFERENT DIALYSIS MODALITIES. Picca et al., 2001

21. DIALYSIS IN NEONATAL HYPERAMMONEMIA. Data of the literature

22. Drug clearance Where as ammonia is a small molecular wt compound Na Phenylacetate and Na Benzoate are also small, non protein bound So will your therapy clear the drug?

23. Solute Clearance in I E M

24. Conclusion Hyperammonemia of the new born is a medical and dialytic emergency Immediate institution of medical therapy is needed and a early decision of RRT institution is needed

25. Conclusion PD has little to offer in this disease HD is the preferred modality and prevention of the rebound can occur by transitioning HD to HF With RRT monitor K and Phos closely to avoid loss of these electrolytes during the RRT