crrt for metabolic diseases in the newborn and child. stefano picca, md. division of nephrology,...
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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.
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