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.

4. “SMALL MOLECULES” DISEASES INDUCING CONGENITAL HYPERAMMONEMIA.
INCIDENCE
Overall: :9160
Organic Acidurias: :21422
Urea Cycle Defects: :41506
Fatty Acids Oxidation Defects: 1:91599
AGE OF ONSET
Neonate: 40%
Infant: 30%
Child: %
Adult: % (?) Dionisi-Vici et al, J Pediatrics, 2002.

5. UCD 16 pts : 3 CPS, 4 OTC, 5 AL, 3 AS,1 HHH
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. NEONATAL HYPERAMMONEMIA
TREATMENT of SEVERE
NEONATAL HYPERAMMONEMIA
IMMEDIATE
MEDICAL THERAPY NO
RESPONSE RESPONSE
DIALYSIS
MAINTAINANCE +
REFEEDING
IMMEDIATE DIALYSIS
+ MEDICAL THERAPY
MAINTAINANCE
MEDICAL THERAPY +
REFEEDING ?

9. endogenous depuration
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 mg/Kg/day
carnitine 1g i.v. bolus mg/Kg/day
vitamins (B12 1 mg,biotin 5-15 mg)
benzoate 250 mg/Kg/2 hrs 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 4 8 12 16 20 24
HOURS

12. 0-4 HOURS MEDICAL TREATMENT IN NEONATAL
HYPERAMMONEMIA
6000
4000
non-responders
(dialysis)
2000 ( m
mol/l)
1000
responders
(med. treatment
alone)
750 4
500
pNH
250 4 8 12 16 20 24
HOURS

13. PD patients Time (hours) NH4p (percent of initial value) 180 160 140
120
100
NH4p (percent of initial value) 80 60 40 20 5 10 15 20 25
Time (hours)

14. NH4p (percent of initial value)
CAVHD patients
100 80 60 40 20 10 20 30 40 50 60
100
CVVHD patients 80
NH4p (percent of initial value) 60 40 20 10 20 30 40 50 60
100
HD patients 80 60 40 20 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. GOOD OUTCOME POOR OUTCOME
Follow-up <2 yrs
in 23 patients
GOOD OUTCOME
POOR
OUTCOME
TOTAL (n=23) 14 9
(6 died)
PHARMACOLOGICAL THERAPY (n=8) 7 1
DIALYSIS (n=15) 7 8
(6 died)

17. GOOD OUTCOME POOR OUTCOME
Coma duration (hours , median and range)
& outcome in 15 dialyzed patients
GOOD OUTCOME
POOR
OUTCOME p
TOTAL
47.5
18-99
102
72-266
0.048
BEFORE DIALYSIS 14
13-36 48
40-56
0.002
AFTER
DIALYSIS 50
32-213 34
2-85 NS

18. Coma duration (hours, median and range)
& outcome in 22 patients
GOOD OUTCOME
POOR
OUTCOME p
TOTAL 47
18-169
113
72-266
0.009
BEFORE
TREATMENT 23
1-36 53
40-79
0.004
AFTER
TREATMENT 65
32-213 33
2-92 NS

19. DIALYZED PATIENTS: NH4 LEVELS AND COMA DURATION BEFORE DIALYSIS
7000
6000
peak pNH 4 ( m
mol/l)
4500
4000
3500
3000
2500
2000
1500
1000
500 5 10 15 20 25 30 35 40 45 50 55 60
good outcome
bad outcome
hours
n=14

20. ALL PATIENTS: NH4 LEVELS AND COMA DURATION BEFORE ANY TREATMENT
7000
6000
peak pNH 4 ( m
mol/l)
4500
4000
3500
3000
2500
2000
1500
1000
500 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85
good outcome
bad outcome
hours
n=21

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 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 (n=29)
Long-term
>2nd year of life
(median 12.5 yrs,range 3-21)
48%
28.5% 9.5%
57%
Short-term
<2nd year of life
(median 1.3 yrs,range 0-2)
Mortality %
Cognitive development
Normal %
Mild MR %
Severe MR %
so a t a short evaluation mortality rate was 27% and 71% of survivors with a normal development. But at a long follow-up mortality increaased up to 48% and more impressive most patients became mentally retarded. No difference was observed between UCD and OA.
No significative difference between UCDs and OAs

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
dead
CVVHD HD
CAVHD PD
CAVHD
YEARS
YEARS

30. time
urea PD HD
CRRT
generation rate
[C]
clearance
ammonium?

31. TREATMENT of NEONATAL HYPERAMMONEMIA
HOSPITALIZATION
DIAGNOSIS
PHARMACOLOGICAL
TREATMENT
DIALYSIS
NO RESPONSE
RESPONSE
RE-FEEDING

32. Survival and long term neuro-developmental outcome
of Urea Cycle Disorders and Organic Acidurias
F. Deodato, S. Caviglia°, A. Bartuli, G.Sabetta, C. Dionisi-Vici Metabolic and °Psychology Units, Bambino Gesù Hospital, IRCCS, Rome
we report on the survival and long term outocme of UCD and OA
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
we retrospectively analised 60 patients.
36 with UCD and 24 with AO. Among CUD 3 were CPS deficiency, 6 males and 13 females with OTC def......
Among the OA 12 were propionic, 8 MMA.....

34. Neonatal Onset 29 pts Late Onset 31 pts UCDs 14 < 28 days OAs 15
based on the age of onset of symptoms we distinguished two group of patients. The group with neonatal onset in whom symptoms started before 28 d of life and the late onset one. The first group is composed by 29 pts (14 UCD and..); pts with late onset were 31 (...)

35. Methods Neonatal Onset group 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
we evaluated mortality and survival. and neurodevelopmental outcome. Cognitve level was assessed longytudinally by using diffrent psychologcal test according to the age of pts. Based on results of IQ/DQ we classified normal development if IQ was more than 79 or DQ more than 74, mild mental retardation (IQ between 50 and 79 or DQ between 60 and 74) and severe mental retardation qith an IQ and DQ lower than 49 and 59 respectively
Among nenatal onset pts we considered a short term follow-up (that is before 2 y of life) and a long term follow-up
Neonatal Onset group
short term outcome < 2nd year of life
long term outcome > 2nd year of life

36. Neonatal Onset 48% Late Onset 10%
Mortality rate:
Neonatal Onset 48% Late Onset 10%
Survival Function
(Kaplan- Mayer curve)
years 30 26 22 18 14 10 6 2
Survival rate
1,0 ,8 ,6 ,4 ,2 p
Late Onset
Neonatal Onset
Here is repersented the surival function according KAplan Mayer curve and it's evident that survival is significantly hiher in pts with late onset compared to the onse with a neonatal onset

37. Neonatal Onset OAs alive dead  years  mild decompensation coma
                  


 
   
   
      
    
          
          HD
alive
CVVHD HD PD PD
similar is the results observed in nenatl patients with . Infact many patinets had a good short term ouctome followed by cognitive decline , also in these cases metabolic instability seems to correlate with mental retardation.
CAVHD
dead HD PD
CAVHD
years

38. Neonatal Onset UCDs alive dead      years
     
             
       
     
   


 mild decompensation  coma
CVVHD
alive
CVVHD
CAVHD
CVVHD
in this slide is illustrated the outcome of each pts with neonatal onset UCD. 4 pts did not survived neonatal period, If you look at the left side of the graph you can see that most short term survivors had an early normal psychomotr development followed by progressive decline of cognitve performance, becaming later mentally retarded.
almot in all cases this progressive worsenig was associated with a history of frequent and sever episodes of metabolic decompensation
CVVHD
dead
CAVHD
years

39. Long term outcome Late Onset UCDs
   
  
 
  
       
 mild decompensation coma
alive
dead
years

40. Long term outcome Late Onset OAs
   *    
  
          
    
 
 mild decompensation coma * stroke
alive
years

41. Long term outcome Late Onset pts
Mortality % (limited to 3 OTCf )
Cognitive development
Normal %
Mild MR %
Severe MR %
NO cognitive deterioration after a normal developoment
SO.. among late onset pats mortilty was limited to thrre females with OTC deficiency and 65% of survivor had a normal IQ.
No significative difference between UCDs and OAs

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
Here we have just analysed cognitive aspcets, but if we have to think the ong term follow-ue of these pats we have to rimind that they have a high risk of organ complications that in many cases may seriously compromise thier quality of life like in case of basal ganglia stroke in MMa or

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
to conclude
Risks of organ failure
Alternative therapy (liver, hepatocyte transplantation, others) should be carefully considered at an early stage

44. Age at the end of follow-up (years)
NEONATAL ONSET
OA =13
long term survivors 8
UCD =14
long term survivors 7
DEAD 5 10 15 20 25
DEAD 5 10 15 20 25
dead neonate
normal
mild MR
Severe MR
Age at the end of follow-up (years)

45. AMMONIA/AMMONIUM CHEMISTRY IN BIOLOGICAL FLUIDS.
NH3 + H+ + OH NH4+ + OH-
(ammonia) (ammonium)
[H+] = K * [ NH4+]
[ NH3 ]
At pH = % is NH4+

46. pH dependency of NH3 / NH4 ratio
Symptoms onset
(days)
median CI
median values
95% CI
UCDs
OAs
Picca, Dionisi-Vici, 2003, unpublished data
Schema from Colombo JP, 1971

47. DIALYSIS IN NEONATAL HYPERAMMONEM IA

48. NH4+ BENZOATE ALTERNATIVE PATHWAYS PHENYLBUTYRATE 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
>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

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
1580
800
1419
114
1400
1200
1000
mol/l
800
600
400
200
pNH4
pGLN

53. hours HEMODIALYSIS IN NEONATAL HYPERAMMONEMIA 3000 Pt 1 2500 Pt 2
stop HD
2000
restart HD
p (mcg/dl)
1500 4 NH
1000
500 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 ( ), then BM25 (Baxter).
Blood flow: 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: 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.
DIAYSAT E
DIAL.
DIAL. + UF

59. 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

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 = 97±29 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
micromoles/l
NH4
Time
(Hrs)

62. HD to CRRT (prevention of the rebound)
Transition from HD to CVVHD
micromoles/L
NH4
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 mos
mean weight kg (smallest 1.2 kg)
mean duration of therapy days

64. Hyperammonemia (McBryde et al, paper in progress)
Modalities used
HD only-9
time on HD days
HF only-3
time on HF days
HD followed by HF-8
time on HD + HF 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