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Title: CRRT for Metabolic Diseases in the Newborn and Child.


1
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.

2
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3
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4
SMALL MOLECULES DISEASES INDUCING CONGENITAL
HYPERAMMONEMIA.
  • INCIDENCE
  • Overall
    19160
  • Organic Acidurias 121422
  • Urea Cycle Defects 141506
  • Fatty Acids Oxidation Defects 191599
  • AGE OF ONSET
  • Neonate 40
  • Infant 30
  • Child 20
  • Adult 5-10 (?)
    Dionisi-Vici et al, J Pediatrics, 2002.

5
  • 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
6
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

7
PROGNOSIS OF HYPERAMMONEMIC COMA IS DEPENDENT ON
COMA DURATION.
from Msall M et al, N Eng J Med 1984.
8
TREATMENT of SEVERE NEONATAL HYPERAMMONEMIA
IMMEDIATE MEDICAL THERAPY
NO RESPONSE RESPONSE
DIALYSIS MAINTAINANCE
MEDICAL THERAPY
REFEEDING
IMMEDIATE DIALYSIS MEDICAL THERAPY MAI
NTAINANCE MEDICAL THERAPY REFEEDING
?
9
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
10
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

11
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
12
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
13
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)
14
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
TIME (hours)
Picca et al. Ped Nephrol 2001
15
AMMONIUM CLEARANCE AND FILTRATION FRACTION USING
DIFFERENT DIALYSIS MODALITIES.
Picca et al., 2001
16
Follow-up lt2 yrs in 23 patients
GOOD OUTCOME
POOR OUTCOME
14
9 (6 died)
TOTAL (n23)
PHARMACOLOGICAL THERAPY (n8)
7
1
8 (6 died)
DIALYSIS (n15)
7
17
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
18
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
19
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
n14
20
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
n21
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

22
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.

23
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.

24
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 ?

25
Outcome Neonatal Onset pts (n29)
Short-term lt2nd year of life (median 1.3
yrs,range 0-2)
Mortality 27.5 Cognitive
development Normal 71
Mild MR 4.7 Severe MR
23
26
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!).

27
EFFECT OF BLOOD AND DIALYSATE FLOW ON IN VITRO
AMMONIA CLEARANCE IN CVVHD
(from Schaefer et al, 1999).
28
DIALYSIS IN NEONATAL HYPERAMMONEMIA.Data of the
literature
29
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
CAVHD
HD
PD
CAVHD
YEARS
YEARS
30
generation rate
clearance
C
31
TREATMENT of NEONATAL HYPERAMMONEMIA
HOSPITALIZATION
32
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
33
Total number of patients 60
  • UCDs
  • CPS 3
  • OTC male 6
  • OTC female 13
  • AS 4
  • AL 5
  • HHHs 5
  • 36 pts
  • OAs
  • PA 12
  • MMA mut -/o 8
  • HMG 2
  • IVA 1
  • ß-KT 1
  • 24 pts

34
  • Neonatal Onset
  • lt 28 days
  • Late Onset
  • gt 28 days

UCDs 14 OAs 15
29 pts
UCDs 22 OAs 9
31 pts
35
Methods
  • Mortality-survival
  • neuro-developmental outcome
  • Baylelys Scale of Infant Development,
  • Leiter International Performance Scale,
  • WISC-R, WAIS-R and Raven Progressive Matrices
  • normal development IQgt79, DQgt74
  • mild Mental Retardation IQ 50-79, DQ 60-74
  • severe Mental Retardation IQlt 49, DQlt 59

Neonatal Onset group short term outcome lt
2nd year of life long term outcome gt 2nd
year of life
36
Mortality rate
Neonatal Onset 48 Late Onset 10
Survival Function (Kaplan- Mayer curve)
37
Neonatal Onset OAs
HD
alive
CVVHD
HD
PD
PD
CAVHD
dead
HD
PD
CAVHD
years
38
Neonatal Onset UCDs
CVVHD
alive
CVVHD
CAVHD
CVVHD
CVVHD
dead
CAVHD
years
39
Long term outcome Late Onset UCDs
alive
dead
years
40
Long term outcome Late Onset OAs
alive
years
41
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
42
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

43
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

44
NEONATAL ONSET
OA 13 long term survivors 8
UCD 14 long term survivors 7
Age at the end of follow-up (years)
45
AMMONIA/AMMONIUM CHEMISTRY IN BIOLOGICAL FLUIDS.
46
pH dependency of NH3 / NH4 ratio
Schema from Colombo JP, 1971
47
DIALYSIS IN NEONATAL HYPERAMMONEM IA
48
BENZOATE
PHENYLBUTYRATE
ALTERNATIVE PATHWAYS
benzoyl-CoA
phenylacetate
GLYCINE
GLUTAMINE
NH4
CPS
PHENYLACETYL GLUTAMINE (2 N)


HIPPURATE (1 N)
UREA CYCLE
UREA

arginine
49
NEONATAL HYPERAMMONEMIA
  • JM Saudubray
  • ORGANIC ACIDURIAS
  • intoxication - dehydration - tachipnea -
    hypotonia -coma
  • gtNH3 - ketoacidosis - leucopenia
  • UREA CYCLE DEFECTS
  • intoxication - hepatopathy - tachipnea -
    hypotonia - coma
  • gtNH3 - alkalosis
  • S. Cederbaum
  • A respiratory alkalosis points to a UCD, whereas
    a metabolic acidosis points to an organic
    acidemia J Pediatr 138s292001

50
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51
PLASMA GLUTAMINE DURING NEONATAL HYPERAMMONEMIA
from Scriver CR et al, 1995.
52
MEDIAN pNH4 and pGLN AT START AND AT END OF
DIALYSIS
1600
1400
1200
1000
?mol/l
800
600
400
200
0
pNH4
pGLN
53
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
54
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

55
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)

56
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

57
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

58
CVVHD in the neonate
BLOOD
REINF.
DIAYSATE
DIAL.
DIAL. UF
59
DIALYSIS IN NEONATAL HYPERAMMONEMIA DIALYSIS
RELATED COMPLICATIONS
  • PD (n3) - leakage from catheter exit-site in 1
    pt.
  • HD (n3) - severe hypotension in 3 pts.
  • CAVHD-
  • CVVHD
  • (n9) - 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
60
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 9729 ?mol/l
  • Only 1 HD-treated pt showed rebound after
    dialysis withdrawal

61
HD Rx of Hyperammonemia(Gregory et al, Vol.
5,abst. 55P,1994 )
NH4 rebound with reinstitution of HD
NH4 micromoles/l
Time (Hrs)
62
HD to CRRT(prevention of the rebound)
Transition from HD to CVVHD
NH4 micromoles/L
Time (Hrs)
63
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

64
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

65
Hyperammonemia (McBryde et al, JASN 2000)
  • Outcome
  • 12/18 patients survived
  • 2/12 continued to be medication and RRT dependent

66
Arginine Clearance in Hyperammonemia
HD stopped
microM/L
Hrs
McBryde et al, J Peds in press
67
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
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