CRRT for Metabolic Diseases in the Newborn and Child.

Stefano Picca, MD.Division of Nephrology, Dialysis

and Renal Transplantation.

“Bambino Gesù” Pediatric Research Hospital.

ROMA, Italy.

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.

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

• 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

Bambino Gesù Hospital, Rome 23/30 newborns treated according to our protocol

8 pharmacological therapy

15 pharmacological therapy + dialysis

2 citrullinemia3 ASAuria1 PA1 MMA1 CACT

3 CPS 2 citrullinemia1 ASAuria7 PA2 MMA

• 5 CVVHD • 4 CAVHD• 3 HD• 3 PD

0 4 8 12 16 20 24

0

250

500

750

1000

200040006000

pN

H4 (

m

ol/l

)

HOURS

0-4 HOURS MEDICAL TREATMENT IN NEONATAL

HYPERAMMONEMIA

0 4 8 12 16 20 24

0

250

500

750

1000

200040006000

pN

H4 (

m

ol/l

)

HOURS

non-responders(dialysis)

responders(med. treatment

alone)

0-4 HOURS MEDICAL TREATMENT IN NEONATAL

HYPERAMMONEMIA

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

GOOD OUTCOME

POOR OUTCOME

PHARMACOLOGICAL THERAPY (n=8)

7 1

DIALYSIS (n=15) 7 8(6 died)

TOTAL (n=23)

14 9(6 died)

Follow-up <2 yrs in 23 patients

GOOD OUTCOME

POOR OUTCOME

p

BEFORE DIALYSIS

1413-36

4840-56

AFTER DIALYSIS 34

2-85

5032-213

TOTAL 47.518-99

10272-266

0.048

0.002

NS

Coma duration (hours , median and range)& outcome in 15 dialyzed patients

GOOD OUTCOME

POOR OUTCOME

p

BEFORE TREATMENT

231-36

5340-79

AFTER TREATMENT 33

2-92

6532-213

TOTAL 4718-169

11372-266

0.009

0.004

NS

Coma duration (hours, median and range) & outcome in 22 patients

0 5 10 15 20 25 30 35 40 45 50 55 600

500

1000

1500

2000

2500

3000

3500

4000

4500

6000

7000

hours

pea

k p

NH

4 (

mo

l/l)

n=14good outcome

bad outcome

DIALYZED PATIENTS: NH4 LEVELS AND COMA DURATION BEFORE DIALYSIS

0 5 10152025303540455055606570758085

0500

10001500200025003000350040004500

6000

7000p

eak

pN

H4

( m

ol/l

)

hours

ALL PATIENTS: NH4 LEVELS AND COMA DURATION BEFORE ANY TREATMENT

good outcome

bad outcomen=21

PROGNOSTIC INDICATORS (at 2-yr follow-up)

non-informative• ammonia peak• need of ventilatory support• dialysis mode • type of disease UCD/OA (except for OTC def.)• post-treatment start coma duration

informative• total coma duration• pre-treatment start coma duration• responsiveness to pharmacological therapy

Conclusions (1)

1/3 of patients respond to pharmacological therapy alone

In our series, medium-term outcome did not depend on dialysis modality

A  pre-treatment coma duration exceeding 33-35 hours is almost invariably associated with a poor outcome, in both medically treated and dialyzed patients, irrespective of the treatment rapidity.

Plasma ammonium changes within the initial 4 hours of medical treatment seem to discriminate patients who will respond to this treatment alone from those who will need dialysis.

This point is crucial for patients who start medical treatment in peripheral hospitals before being referred to centers with neonatal dialysis facilities.

Conclusions (2)

In neonatal hyperammonemia, CVVHD provides treatment continuity, efficacy and cardiovascular stability. Higher dialysate flow rates must be investigated in order to increase ammonium clearance.

Major effort should be made for rapid identification of patients, early start of appropriate treatment & quick referral to specialized centres.

long-term outcome ? quality of life ?

Conclusions (3)

Short-term <2nd year of life

(median 1.3 yrs,range 0-2)

Mortality 27.5%

Cognitive development

Normal 71%

Mild MR 4.7%

Severe MR 23%

Outcome Neonatal Onset pts (n=29)

Long-term >2nd year of life

(median 12.5 yrs,range 3-21)

48%

28.5%

9.5%

57%

No significative difference between UCDs and OAs

ACKNOWLEDGEMENTS

• Metabolic Unit: Carlo Dionisi-Vici, MD; Andrea Bartuli, MD; Gaetano Sabetta, MD.

• NICU: Marcello Orzalesi, MD.• Clinical Biochemistry Lab: Cristiano Rizzo BSc,

PhD; Anna Pastore BSc, PhD.• Dialysis Unit: all doctors and nurses (thanks!).

EFFECT OF BLOOD AND DIALYSATE FLOW ONIN VITRO AMMONIA CLEARANCE IN CVVHD

(from Schaefer et al, 1999).

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.

0 2 4 6 8 10 12 14 16

PA

PA

MMA

MMA

PA

PA

PA

PA

PA

PA

PA

MMA

MMA

HMG

ISO

neonatal death normal mild MR severe MR

dead

alive

Neonatal Onset OAs

YEARS

0 2 4 6 8 10 12 14 16 18 20 22

OTCm

OTCm

AS

CPS

CPS

CPS

AS

AS

AL

AL

AL

AL

HHH

HHH

neonatal death normal mild MR severe MR

dead

alive

Neonatal Onset UCDs

YEARS

UCDs AND OAs: LONG-TERM OUTCOME

CVVHD

CVVHD

CAVHD

CAVHD

CVVHD

CVVHD

CVVHD

CAVHD

CAVHD

HD

HD

HD

PD

PD

PD

time

urea

PD

HD

CRRT

[C]generation rate clearance

ammonium?

TREATMENT of NEONATAL HYPERAMMONEMIA

HOSPITALIZATION

DIAGNOSISPHARMACOLOGICAL

TREATMENT

DIALYSIS

NO RESPONSE RESPONSE

RE-FEEDING

F. Deodato, S. Caviglia°, A. Bartuli, G.Sabetta, C. Dionisi-Vici

Metabolic and °Psychology Units, Bambino Gesù Hospital, IRCCS, Rome

Survival and long term neuro-developmental outcome

of Urea Cycle Disorders and Organic Acidurias

36th EMG Meeting

Rimini, May 14-16,2004

UCDs

• CPS 3

• OTC male 6

• OTC female 13

• AS 4

• AL 5

• HHHs 5

36 pts

Total number of patients = 60

OAs

• PA 12

• MMA mut -/o 8

• HMG 2

• IVA 1

• ß-KT 1

24 pts

Neonatal Onset < 28 days

Late Onset > 28 days

29 pts

31 pts

UCDs 14

OAs 15

UCDs 22

OAs 9

• Mortality-survival• neuro-developmental outcome

Baylely’s Scale of Infant Development,

Leiter International Performance Scale,

WISC-R, WAIS-R and Raven Progressive Matrices

normal development IQ>79, DQ>74

mild Mental Retardation IQ 50-79, DQ 60-74

severe Mental Retardation IQ< 49, DQ< 59

Neonatal Onset group short term outcome < 2nd year of life long term outcome > 2nd year of life

Neonatal Onset group short term outcome < 2nd year of life long term outcome > 2nd year of life

Methods

Survival Function (Kaplan- Mayer curve)

years

302622181410620

Sur

viva

l rat

e

1,0

,8

,6

,4

,2

0p 0.0002

Late Onset

Neonatal Onset

Mortality rate: Neonatal Onset 48% Late Onset 10%

0 2 4 6 8 10 12 14 16

PA

PA

MMA

MMA

PA

PA

PA

PA

PA

PA

PA

MMA

MMA

HMG

ISO

neonatal death normal mild MR severe MR

years

dead

alive

HD

CVVHD

HD

PD

PD

CAVHD

HD

PD

CAVHD

Neonatal Onset OAs

mild decompensation coma

0 2 4 6 8 10 12 14 16 18 20 22

OTCm

OTCm

AS

CPS

CPS

CPS

AS

AS

AL

AL

AL

AL

HHH

HHH

neonatal death normal mild MR severe MR

years

dead

alive

mild decompensation coma

CVVHD

CVVHD

CAVHD

CVVHD

CVVHD

CAVHD

Neonatal Onset UCDs

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

OTCf

OTCf

OTCf

OTCf

OTCf

OTCf

OTCf

OTCf

OTCf

OTCf

OTCf

OTCm

OTCm

OTCm

OTCm

AS

AS

AL

HHH

HHH

normal mild MR severe MR

years

Long term outcome Late Onset UCDs

dead

alive

mild decompensation coma

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

MMA

MMA

MMA

MMA

PA

PA

PA

HMG

KT

normal mild MR severe MR

years

Long term outcome Late Onset OAs

alive

*

mild decompensation coma * stroke

Mortality 10% (limited to 3 OTCf )

Cognitive development

Normal 65.5%

Mild MR 14%

Severe MR 20.5%

Long term outcome Late Onset pts

No significative difference between UCDs and OAs

NO cognitive

deterioration after a

normal developoment

CNS

Stroke in MMA - Pyramidal dysfunction in HHHs HEART

Cardiomyopathy in PA & MMA

LIVER

fibrosis in ASAuria KIDNEY

CRF in MMA PANCREAS

acute pancreatitis in PA

Characteristic organ involvement

Conclusions

Higher mortality and morbidity of Neonatal Onset compared to

Late Onset diseases

Progressive cognitive deterioration of Neonatal Onset patients

despite an early good outcome

Metabolic instability/life threatening episodes of metabolic

decompensation are associated with cognitive deterioration

and mortality, especially in Neonatal Onset patients

Risks of organ failure

Alternative therapy (liver, hepatocyte transplantation, others)

should be carefully considered at an early stage

OA =13

long term survivors 8

Age at the end of follow-up (years)

DEAD

0 5 10 15 20 25

UCD =14

long term survivors 7

DEAD

0 5 10 15 20 25

NEONATAL ONSET

dead neonate normal mild MR Severe MR

AMMONIA/AMMONIUM CHEMISTRY IN BIOLOGICAL

FLUIDS.

[H+] = K * [ NH4+]

[ NH3 ]

At pH = 7.35-7.42 98.5% is NH4+

NH3 + H+ + OH- NH4+ + OH-

(ammonia) (ammonium)

pH dependency of NH3 / NH4 ratio

Schema from Colombo JP, 1971

Symptoms onset (days) median CI 3.1 2.7-3.8 5.7 4.6-9.2

median values 95% CIUCDsOAs

Picca, Dionisi-Vici, 2003, unpublished data

DIALYSIS IN NEONATAL HYPERAMMONEM IA

Physicalprinciple

Efficiencyof small

molecules

Tolerance

Peritonealdialysis

Diffusion +ultrafiltration

poor good

Hemodialysis Diffusion very high poor

Continoushemofiltration

Ultrafiltration poor good

Continoushemodiafiltration

Diffusion +ultrafiltration

high good

GLYCINE GLUTAMINE

HIPPURATE(1 N)

PHENYLACETYLGLUTAMINE

(2 N)

benzoyl-CoA

phenylacetate

UREACYCLE

BENZOATE

PHENYLBUTYRATE

NH4+

CPS

ALTERNATIVE

PATHWAYS

UREAarginine

+

NEONATAL HYPERAMMONEMIA

JM Saudubray

• ORGANIC ACIDURIASintoxication - dehydration - tachipnea - hypotonia -coma

>NH3 - ketoacidosis - leucopenia

• UREA CYCLE DEFECTSintoxication - hepatopathy - tachipnea - hypotonia - coma

>NH3 - alkalosis S. Cederbaum

“A respiratory alkalosis points to a UCD, whereas a metabolic acidosis points to an organic acidemia” J Pediatr 138:s29;2001

median p value

%weight loss OA UCD

-12.6 -5.7

<0.00001

Base excess OA UCD

-16.4 -2.4

<0.00001

pH OA UCD

7.28 7.44

<0.02

Onset OA UCD

5.7 3.1

<0.0001

WBC OA UCD

4.96 12.7

<0.0001

RBC OA UCD

4.3 5.3

<0.001

PLT OA UCD

218 326

<0.002

PLASMA GLUTAMINE DURING NEONATAL HYPERAMMONEMIA

from Scriver CR et al, 1995.

0

200

400

600

800

1000

1200

1400

1600

pNH4 pGLN

mol

/lMEDIAN pNH4 and pGLN AT START AND

AT END OF DIALYSIS

1419

114

1580

800

HEMODIALYSIS IN NEONATAL HYPERAMMONEMIA

0

500

1000

1500

2000

2500

3000

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

hours

NH

4 p

(m

cg/d

l)

Pt 1Pt 2

stop HD

restart HD

METHODS-PD

• Straight neonatal Tenckhoff catheter (1988-1994).

• “Curl” neonatal catheter (from 1995 on).

• Manual exchanges

• 10-30 ml/kg loading volume

• 15-30 min dwell time

METHODS-CAVHD

• 2 femoral catheters 18G (Abbocath. Abbott Ltd.)

• Amicon Minifilter Plus, 0.08 m2

polysulfone (Amicon Division, USA)

• Dialysate flow: 0.5 l/h achieved by 2 infusion pumps placed pre and post-filter (IVAC 591, 560, Lifecare Abbott)

• Dialysate: Na+ 140, Ca + + 4, HCO3- 30

mEq/l (Solubag, SIFRA)

METHODS-CVVHD

• 6.5F, 7.5 cm double-lumen cath (Hemoaccess, Hospal)

• BSM32IC (Hospal) blood monitor (1994-98), then BM25 (Baxter).

• Blood flow: 20-40 ml/min (6-13 ml/kg/min)

• Amicon Minifilter Plus, then PSHF400, 0.3 m2 polysulfone (Minntech).

• Dialysate flow: 2.0 l/h

• Dialysate: same as CAVHD

METHODS-HD

• Vascular access, dialysate: same as CVVHD

• Gambro AK100 blood monitor

• Blood flow: 10-15 ml/min (3-5 ml/kg/min)

• Pro-100: 0.3 m2, gambrane®

• Dialysate flow: 500 ml/min

• Dialysate: same as CAVHD

CVVHD in the neonate

REINF.

DIAYSATE

BLOOD

DIAL. DIAL. + UF

DIALYSIS IN NEONATAL HYPERAMMONEMIA: DIALYSIS RELATED

COMPLICATIONS• PD (n=3): - leakage from catheter exit-site in 1 pt.

• HD (n=3): - severe hypotension in 3 pts.

• CAVHD- CVVHD (n=9) : - inaccuracy of fluid balance in 4 pts. treated without fluid delivery automated system - hypotension in 1 pt.

- transitory inferior limb ischemia in 8 pts.

Picca et al. Ped Nephrol 2001

DIALYSIS IN NEONATAL HYPERAMMONEMIA:

WHEN TO STOP?• “stop dialysis after pNH4 is stable under

the “safe” level after protein reintroduction”

• “safe” level ?• In 13 pts dialysis was stopped after protein

reintroduction at pNH4 = 97±29 mol/l

• Only 1 HD-treated pt showed rebound after dialysis withdrawal

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

0200400600800

100012001400160018002000

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

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

Hyperammonemia (McBryde et al, paper in progress)

• 18 children underwent 20 therapies of RRT due to in-born error of metabolism

• mean age 56 + 7.9 mos

• mean weight 15 + 3.7 kg (smallest 1.2 kg)

• mean duration of therapy 6.1 + 1.3 days

• 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

Hyperammonemia (McBryde et al, paper in progress)

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

dependent

Hyperammonemia (McBryde et al, JASN 2000)

Arginine Clearance in Hyperammonemia

0

100

200

300

400

500

600

700

800

900

0 0.5 1 1.5 2

NH4 ( nl < 100)Arginine (? Nl?)

mic

roM

/L

Hrs

HD stopped

McBryde et al, J Peds in press

Hyperammonemia Conclusion

• Duration of coma correlates with poor neurological outcome

• Dialysis needs to be initiated early

• Need to change dialysis thought process from ARF to metabolic– K and Phos need to be physiologic in the

dialysate or replacement fluid