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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. “SMALL MOLECULES” DISEASES INDUCING CONGENITAL HYPERAMMONEMIA. INCIDENCE

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crrt for metabolic diseases in the newborn and child

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.

slide4

“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.
slide5

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

slide6

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
slide7

PROGNOSIS OF HYPERAMMONEMIC COMA

IS DEPENDENT ON COMA DURATION.

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

slide8

TREATMENT of SEVERE

NEONATAL HYPERAMMONEMIA

IMMEDIATE

MEDICAL THERAPY

NO

RESPONSERESPONSE

DIALYSIS

MAINTAINANCE

MEDICAL THERAPY

+

REFEEDING

IMMEDIATE DIALYSIS

+ MEDICAL THERAPY

MAINTAINANCE

MEDICAL THERAPY

+

REFEEDING

?

slide9

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

slide10

Bambino Gesù Hospital, Rome

23/30 newborns treated according to our protocol

8 pharmacological therapy

2 citrullinemia

3 ASAuria

1 PA

1 MMA

1 CACT

15 pharmacological therapy

+ dialysis

3 CPS

2 citrullinemia

1 ASAuria

7 PA

2 MMA

  • 5 CVVHD
  • 4 CAVHD
  • 3 HD
  • 3 PD
slide11

0-4 HOURS MEDICAL TREATMENT IN NEONATAL

HYPERAMMONEMIA

6000

4000

2000

1000

mol/l)

750

m

(

4

500

pNH

250

0

0

4

8

12

16

20

24

HOURS

slide12

non-responders

(dialysis)

mol/l)

responders

(med. treatment

alone)

m

(

0-4 HOURS MEDICAL TREATMENT IN NEONATAL

HYPERAMMONEMIA

6000

4000

2000

1000

750

4

500

pNH

250

0

0

4

8

12

16

20

24

HOURS

slide13

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)

slide14

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)

ammonium clearance and filtration fraction using different dialysis modalities
AMMONIUM CLEARANCE AND FILTRATION FRACTION USING DIFFERENT DIALYSIS MODALITIES.

Picca et al., 2001

slide16

Follow-up <2 yrs

in 23 patients

GOOD OUTCOME

POOR

OUTCOME

14

9

(6 died)

TOTAL (n=23)

PHARMACOLOGICAL THERAPY (n=8)

7

1

8

(6 died)

DIALYSIS (n=15)

7

slide17

Coma duration (hours , median and range)

& outcome in 15 dialyzed patients

GOOD OUTCOME

POOR

OUTCOME

p

102

72-266

TOTAL

0.048

47.5

18-99

BEFORE DIALYSIS

14

13-36

48

40-56

0.002

AFTER

DIALYSIS

50

32-213

NS

34

2-85

slide18

Coma duration (hours, median and range)

& outcome in 22 patients

GOOD OUTCOME

POOR

OUTCOME

p

113

72-266

0.009

TOTAL

47

18-169

BEFORE

TREATMENT

23

1-36

53

40-79

0.004

AFTER

TREATMENT

65

32-213

NS

33

2-92

slide19

mol/l)

good outcome

m

(

bad outcome

4

peak pNH

DIALYZED PATIENTS: NH4 LEVELS AND

COMA DURATION BEFORE DIALYSIS

7000

6000

4500

4000

3500

3000

2500

2000

1500

1000

500

0

0

5

10

15

20

25

30

35

40

45

50

55

60

hours

n=14

slide20

mol/l)

good outcome

m

(

bad outcome

4

peak pNH

ALL PATIENTS: NH4 LEVELS AND COMA

DURATION BEFORE ANY TREATMENT

7000

6000

4500

4000

3500

3000

2500

2000

1500

1000

500

0

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

hours

n=21

prognostic indicators at 2 yr follow up
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
slide22

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.
slide23

Conclusions (2)

  • 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.
slide24

Conclusions (3)

  • 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 ?
slide25

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

Outcome Neonatal Onset pts (n=29)

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%

acknowledgements
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!).
slide27

EFFECT OF BLOOD AND DIALYSATE FLOW ON

IN VITRO AMMONIA CLEARANCE IN CVVHD

(from Schaefer et al, 1999).

slide29

UCDs AND OAs: LONG-TERM OUTCOME

Neonatal Onset OAs

Neonatal Onset UCDs

HD

CVVHD

CVVHD

alive

alive

HD

CVVHD

PD

PD

CAVHD

CVVHD

CAVHD

dead

CVVHD

dead

HD

CAVHD

PD

CAVHD

YEARS

YEARS

slide30

urea

PD

CRRT

HD

time

ammonium?

generation rate

clearance

[C]

slide31

PHARMACOLOGICAL

TREATMENT

DIAGNOSIS

NO RESPONSE

RESPONSE

RE-FEEDING

DIALYSIS

TREATMENT of NEONATAL HYPERAMMONEMIA

HOSPITALIZATION

slide32
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

slide33

Total number of patients = 60

OAs

  • PA 12
  • MMA mut-/o 8
  • HMG 2
  • IVA 1
  • ß-KT 1

24 pts

UCDs

  • CPS 3
  • OTC male 6
  • OTC female 13
  • AS 4
  • AL 5
  • HHHs 5

36 pts

slide34
Neonatal Onset

< 28 days

Late Onset

> 28 days

UCDs 14

OAs 15

29 pts

UCDs 22

OAs 9

31 pts

slide35

Methods

  • 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

slide36

1,0

Late Onset

,8

Survival rate

,6

,4

Neonatal Onset

,2

p 0.0002

0

0

2

6

10

14

18

22

26

30

years

Mortality rate:

Neonatal Onset 48% Late Onset 10%

Survival Function

(Kaplan- Mayer curve)

slide37

   

         



    

 



      

        

                  

   

mild decompensation coma

Neonatal Onset OAs

HD

alive

CVVHD

HD

PD

PD

CAVHD

dead

HD

PD

CAVHD

years

slide38

     

       





   

             

    



mild decompensation  coma

Neonatal Onset UCDs

CVVHD

alive

CVVHD

CAVHD

CVVHD

CVVHD

dead

CAVHD

years

slide39



     

  

 

  

   

mild decompensation coma

Long term outcome Late Onset UCDs

alive

dead

years

slide40

 

  

     

 

   *  

mild decompensation coma * stroke

Long term outcome Late Onset OAs

alive

years

slide41

No significative difference between UCDs and OAs

Long term outcome Late Onset pts

Mortality 10% (limited to 3 OTCf )

Cognitive development

Normal 65.5%

Mild MR 14%

Severe MR 20.5%

NO cognitive deterioration after a normal developoment

slide42

Characteristic organ involvement

  • 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

slide43

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
slide44

DEAD

DEAD

0

5

10

15

20

25

0

5

10

15

20

25

dead neonate

normal

mild MR

Severe MR

NEONATAL ONSET

OA =13

long term survivors 8

UCD =14

long term survivors 7

Age at the end of follow-up (years)

ammonia ammonium chemistry in biological fluids

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

(ammonia) (ammonium)

[H+] = K * [ NH4+]

[ NH3 ]

At pH = 7.35-7.42 98.5% is NH4+

AMMONIA/AMMONIUM CHEMISTRY IN BIOLOGICAL FLUIDS.
slide46

Symptoms onset

(days)

median CI

3.1 2.7-3.8

5.7 4.6-9.2

median values

95% CI

UCDs

OAs

Picca, Dionisi-Vici, 2003, unpublished data

pH dependency of NH3 / NH4 ratio

Schema from Colombo JP, 1971

slide48

BENZOATE

PHENYLBUTYRATE

ALTERNATIVE

PATHWAYS

benzoyl-CoA

phenylacetate

GLYCINE

GLUTAMINE

NH4+

CPS

PHENYLACETYL

GLUTAMINE

(2 N)

+

HIPPURATE

(1 N)

UREA

CYCLE

UREA

arginine

neonatal hyperammonemia
NEONATAL HYPERAMMONEMIA

JM Saudubray

  • ORGANIC ACIDURIAS

intoxication - dehydration - tachipnea - hypotonia -coma

>NH3 - ketoacidosis - leucopenia

  • UREA CYCLE DEFECTS

intoxication - 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

slide51

PLASMA GLUTAMINE DURING

NEONATAL HYPERAMMONEMIA

from Scriver CR et al, 1995.

slide52

1419

1580

800

114

MEDIAN pNH4 and pGLN AT START AND

AT END OF DIALYSIS

1600

1400

1200

1000

mol/l

800

600

400

200

0

pNH4

pGLN

slide53

HEMODIALYSIS IN NEONATAL HYPERAMMONEMIA

3000

Pt 1

2500

Pt 2

stop HD

2000

restart HD

p (mcg/dl)

1500

4

NH

1000

500

0

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

hours

methods pd
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
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
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
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
slide58

CVVHD in the neonate

BLOOD

REINF.

DIAYSATE

DIAL.

DIAL. +

UF

dialysis in neonatal hyperammonemia dialysis related complications
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
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
HD Rx of Hyperammonemia(Gregory et al, Vol. 5,abst. 55P,1994: )

NH4 rebound with reinstitution of HD

NH4

micromoles/l

Time

(Hrs)

hd to crrt prevention of the rebound
HD to CRRT(prevention of the rebound)

Transition from HD to CVVHD

NH4

micromoles/L

Time

(Hrs)

hyperammonemia mcbryde et al paper in progress
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
hyperammonemia mcbryde et al paper in progress64
Hyperammonemia (McBryde et al, paper in progress)
  • 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 jasn 2000
Hyperammonemia (McBryde et al, JASN 2000)
  • Outcome
    • 12/18 patients survived
    • 2/12 continued to be medication and RRT dependent
arginine clearance in hyperammonemia
Arginine Clearance in Hyperammonemia

HD stopped

microM/L

Hrs

McBryde et al, J Peds in press

hyperammonemia conclusion
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