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

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)

OA UCD

Lethargy/coma 100% 100%

Axial hypotonia 100% 100%

Abnormal movements 78% 81%

Feeding difficulties/vomiting 78% 68%

Dyspnea/tachipnea 57% 56%

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 ONSETNeonate: 40%Infant: 30%Child: 20%Adult: 5-10% (?) Dionisi-Vici et al, J Pediatrics, 2002.

“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 COMAIS DEPENDENT ON COMA DURATION.

from Msall M et al, N Eng J Med 1984.

TREATMENT of SEVERE NEONATAL HYPERAMMONEMIA

? IMMEDIATE MEDICAL THERAPY

NO RESPONSE RESPONSE

DIALYSIS

MAINTAINANCE MEDICAL THERAPY + REFEEDING

IMMEDIATE DIALYSIS+ MEDICAL THERAPY

MAINTAINANCE MEDICAL THERAPY

+REFEEDING

Pharmacological treatmentbefore having a diagnosis

AIMSprecursors 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

time

urea

PD

HD

CRRT

[C]generation rate clearance

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

0

200

400

600

800

1000

1200

1400

1600

1800

1 2 3 5 7 11 15 17 19

HD Begins

Time (hours)

Am

mon

ia (

mic

rom

ol/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

0

200

400

600

800

1000

1200

1400

1600

1800

1 2 3 5 7 11 15 17 19

HD Begins

Time (hours)

Am

mon

ia (

mic

rom

ol/l

)

HD Ends HF BeginsHF 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

DIAGNOSISPHARMACOLOGICAL

TREATMENT

DIALYSIS

NO RESPONSE RESPONSE

RE-FEEDING

NH

4p (

per

cen

t o

f in

itia

l val

ue)

Time (hours)0 5 10 15 20 25

0

20

40

60

80

100

120

140

160

180 PD patients

0 10 20 30 40 50 60

0

20

40

60

80

100 CAVHD patients

0 10 20 30 40 50 600

20

40

60

80

100 HD patients

TIME (hours)

0 10 20 30 40 50 60

0

20

40

60

80

100 CVVHD patients

NH

4p (

per

cen

t o

f in

itia

l val

ue)

Picca et al. Ped Nephrol 2001

AMMONIUM CLEARANCE AND FILTRATION FRACTION USING DIFFERENT DIALYSIS MODALITIES.

Patient

(n)

Type of

Dialysis

Qb

(ml/min)

Qd

(ml/min)

Ammonium Clearance (ml/min/kg

BW)

Ammonium Filtration Fraction

(%)

3

CAVHD

10-20

8.3 (0.5 l/h)

0.87-0.97

12.5-14.3

3

CVVHD

20-40

33.3-83.3 (2-5 l/h)

2.65-6.80

53.0-58.0

2

HD

10-15

500

3.95-5.37

95.0-96.0

Picca et al., 2001

DIALYSIS IN NEONATAL HYPERAMMONEMIA.Data of the literature

Type of dialysis (No of pts.)

NH4 in vivo clearance (ml/min/kg

BW)

Survivors Pts. with

neurological improvement

Hypotensive pts. (%)

Peritoneal dialysis (n=16)

0.71 0SD

9 (56%)

3 (18%) 0-16%

Hemodialysis (n=17) 6.4 3SD 12 (70%) 10 (62%) 0-63%

Continuous hemofiltration

(n=6) 1.2 0.1SD

4 (67%)

3 (50%)

0-25%

Continuous hemodialysis

(n=16) 4.4 1SD

13 (81%)

10 (62%)

0-19%

From : Siegel 73, Wiegand 80, Ring 92, Rutledge 90, Sperl 90, Thompson 91, Falk 94,

Gregory 94, Sadowsky 96, Picca 97, Schaefer 99, Picca 01, Chan 02, Rajpoot 04, McBryde 04.

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

0

200

400

600

800

1000

1200

1400

PrefilterHD

Postfilter HD

PrefilterHF

Postfilter HF

AmmoniaNaPhenyNaBenz

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