Case Study in RRT in In Born Error of Metabolism

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 Dis2003

5. “SMALL MOLECULES” DISEASES INDUCING CONGENITAL HYPERAMMONEMIA. • 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.

6. KEY POINTS FACING TO A HYPERAMMONEMIC NEWBORN • 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

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 RESPONSERESPONSE 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. urea PD CRRT HD time ammonium? generation rate clearance [C]

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 HD Begins 1800 HD Ends 1600 1400 1200 Ammonia (micromol/l) 1000 800 600 400 200 0 1 2 3 5 7 11 15 17 19 Time (hours)

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 HD Begins HF Ends 1800 HD Ends 1600 HF Begins 1400 1200 Ammonia (micromol/l) 1000 800 600 400 200 0 1 2 3 5 7 11 15 17 19 Time (hours)

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

18. PD patients 180 160 140 120 100 NH4p (percent of initial value) 80 60 40 20 0 0 5 10 15 20 25 Time (hours)

19. CAVHD patients 100 80 60 40 20 0 0 10 20 30 40 50 60 100 CVVHD patients 80 NH4p (percent of initial value) 60 40 20 0 0 10 20 30 40 50 60 HD patients 100 80 60 40 20 0 0 10 20 30 40 50 60 Picca et al. Ped Nephrol 2001 TIME (hours)

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