Case Study in RRT in In Born Error of Metabolism Timothy E. Bunchman Pediatric Nephrology & Transplantation VCU School of Medicine

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

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)

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

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, “SMALL MOLECULES” DISEASES INDUCING CONGENITAL HYPERAMMONEMIA.

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

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

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

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 mg/Kg/day carnitine 1g i.v. bolus mg/Kg/day vitamins (B12 1 mg,biotin 5-15 mg) benzoate 250 mg/Kg/2 hrs mg/Kg/day or peroral phenylbutyrate (only after UCD diagnosis) Picca et al. Ped Nephrol 2001

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

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.

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

Ammonia Clearance HD Begins Time (hours) Ammonia (micromol/l) HD Ends

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)

Ammonia Clearance HD Begins Time (hours) Ammonia (micromol/l) HD Ends HF Begins HF Ends

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

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

NH4p (percent of initial value) Time (hours) PD patients

CAVHD patients HD patients TIME (hours) CVVHD patients NH4p (percent of initial value) Picca et al. Ped Nephrol 2001

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

DIALYSIS IN NEONATAL HYPERAMMONEMIA. Data of the literature

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?

Solute Clearance in I E M

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

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