PCRRT for Metabolic Disease

Timothy E. Bunchman Professor Pediatrics

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Signs and Symptoms of HyperammonemiaInitially healthy appearing neonate with

decompensation after several daysOften seen after institution of protein

feedingsLethargyPoor feedingVomitingHypotonia

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Signs and Symptoms of HyperammonemiaRespiratory distress, tachypnea,

apneaIrritabilitySeizure activityNeurologic deterioration leading to

comaDeath

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Long Term Effects of Neonatal AmmonemiaDemonstrated 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]

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Major Causes of HyperammonemiaUrea cycle defectsOrganic acidemiasTransient hyperammonemia of the newbornSevere asphyxia - increased protein

breakdown during hypoxic stress plus liver damage due to ischemia

Liver failure - due to multiple causes particularly infection

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Flow Diagram to Evaluate Hyperammonemia

Increased ammonia

acidosis

No acidosis

Urine for organic acids

Plasma amino acids

Lactate/pyruvate

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Flow Diagram to Evaluate Hyperammonemia

Plasma amino acids citrulline

citrullinemia

Nl. Or sl. increased

ASA

Nl.

Incr.

Sig incr

ASA

THN

low

Orotic acid

Low or absent CPS

Incr. OTC

urine

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Treatment of Ammonemia Prior to Further DiagnosisPrevent further catabolism by providing

adequate calories, fluids and electrolytesMinimize protein intakeProvide alternate pathways for ammonia

removalMay require exchange transfusion,

peritoneal dialysis or hemodialysis for ammonia removal

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Alternate Pathways for Removal of AmmoniaSodium benzoate

Cleared by the kidney at 5X the GFR

Each mole of benzoate removes one mole of ammonia as glycine

SODIUM BENZOATE SODIUM BENZOATE HIPPURATEHIPPURATE

+ GLYCINE+ GLYCINE

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Alternate Pathways for Removal of AmmoniaSodium phenylacetate

Easily excreted in the urineOne mole of phenylacetate removes 2

moles of ammonia as glutamine

PHENYlACETYLPHENYlACETYLGLUTAMINEGLUTAMINE

PHENYL-PHENYL-ACETATEACETATE

GLUTAMINEGLUTAMINE++

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Alternate Pathways for Removal of AmmoniaArginine supplementation provides

the urea cycle with ornithine and n-acetylglutamate

Abbreviated version of the urea cycle continues

not recommended for use in arginase deficiency or organic acidemias

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But what do I do when the drugs don’t work?

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You call your friendly dialysis folks

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Mode of RRTPD

nopeHemodialysis

looks like a good place to startHemofiltration

a great way to go home at night

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HD Rx of ammonemia(Gregory et al, Vol. 5,abst. 55P,1994: )

0200400600800100012001400160018002000

0 1 2 3 4 5 6 10 11 12 13 17 18 19 20

N

H4

mic

rom

oles

/l

Time(Hrs)

NH4 rebound with reinstitution of HD

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HD to CRRT(prevention of the rebound)

0

200

400

600

800

1000

1200

0 1 2 3 4 5 10 11 17

Time (Hrs)

N

H4

mic

rom

oles

/L Transition from HD to CVVHD

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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 mosmean weight 15 + 3.7 kg (smallest 1.2

kg)mean duration of therapy 6.1 + 1.3

days

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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

Local experience(McBryde et al, JASN 2000)

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Outcome 12/18 patients survived 2/12 continued to be medication and

RRT dependent

Local experience(McBryde et al, JASN 2000)

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But what do I do when the drugs and RRT doesn’t work?

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You call your friendly liver transplant folks

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CVVHD for NH4 Bridge to Hepatic Transplantation

0100200300400500600700800

1 2 4 6 8 10 12 14 16

NH

4m

icro

mol

es/L

Time(days)

Successful Liver Transplantation

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Considerations of PCRRT for metabolic diseaseDialysis Bath“metabolic cocktail” clearancenutritional needs with the balance of

restricted protein intake and amino acid loss via HF

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Hemodialysis Bath Considerations

Electrolyte ARF MetabolicNa (meq/l) 140 140Cl (meq/l) 96 96Glucose (mg/dl) 200 200Ca (mg/dl) 3.5 3.5MG (meq/l) 1 1HCO3 (meq/l) 40 40K (meq/l) 0-3 4-5Phos (mg/dl) 0 4-5 (add to B jug)

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Metabolic Cocktail drug clearanceDrug clearance related

small molecular weight minimal protein binding volume of distribution

Phenylacetate, Benzoate, Arginine all will be cleared ? Re bolus?

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Comparison of Total Amino Acid losses: CVVH vs CVVHD(Maxvold et al, Crit Care Med April 2000)

02

46

810

12

1416

CVVH CVVHD

Am

ino

Aci

d Lo

sses

(g

/day

/1.7

3 m

2)

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ConclusionHyperammonemia is a medical emergencyWhen medical management does not work

consider RRT earlyHD should be used initially with HF in

tandemLiver transplant should be considered if

medical and RRT management is not successful