1 non-renal indications: intoxications & inborn errors of metabolism stefano picca, md dialysis...
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NON-RENAL INDICATIONS: INTOXICATIONS & INBORN ERRORS OF METABOLISM
STEFANO PICCA, MDDialysis Unit- Dept of Nephrology and Urology
“Bambino Gesù” Pediatric Research HospitalROMA, Italy
• Variables in toxic agents elimination
• Exogenous toxicity: Experience with toxic agents in PICU
• Endogenous toxicity: Inborn Errors of Metabolism: which is the role of RRT in determining the outcome?
OUTLINE
DEVICE PROPERTIES
• COMPOSITION
• SURFACE AREA
• PORE SIZE
• ADSORPTION
DRUG PROPERTIES
• MOLECULAR WEIGHT
• PLASMA PROTEIN BINDING
• VOLUME OF DISTRIBUTION
• PROPORTION OF RENAL
CLEARANCE
FACTORS POTENTIALLY AFFECTING DRUG
CLEARANCE
DURING RENAL REPLACEMENT THERAPY
Adapted from Pea F and Bunchman TE, 2010
What is unique to Pediatric Intoxications?
• Vehicle in which the medication was delivered• Metabolism of drug • Volume of distribution• Variable size of the child
“MAXIMAL”(?) EFFICIENCY IN CVVHADULT-CHILD-NEONATE
BW(kg)
TBW(l)
Qb(ml/min)
UF/h(=K urea)
(l/h)
K urea per liter of TBW(l/h)
NEONATE 3 2.4 30 0.25 0.10
CHILD 25 15 80 1.2 0.08
ADULT 70 42 150 2.5 0.05
Vancomycin: • Relatively high molecular weight (1500 kDa)• High protein binding (55%) • Poorly cleared by hemodialysis and peritoneal dialysis
EXAMPLE 1: VANCOMYCIN
0 10 20 30 40 50 60 70 800
2
4
6
8
10
12
14
16
18
20
22
24
150 mg150 mg300 mg300 mg300 mg
VA
NC
O p
las
ma
e U
F (g
/ml)
TIME (hrs.)
CVVH:Mean Sieving Coefficient: 0.67
Picca, unpublished
Author n membrane modality T 1/2
Bunchman (1999) 2 cellulose triacetate
HD 31 to 1.9 hrs
Akil (2011) 1 polysulfone CVVH 231 to 31.5 hrs
Goebel (1999) 1 polysulfone CVVHD 41.5 hrs during CVVHD
Shah (2000) 1 polysulfone CVVH From 250 to 27 mcg/ml in 58 hrs
VANCOMYCIN OVERDOSE TREATMENT IN CHILDREN
EXAMPLE 2: MYOGLOBIN
Author N membrane modality
MG clearance
Picca (2009)
1 (ch) Polyethersulfone CVVH 15.8 ml/min
Sorrentino (2010)
6(ad)
Polysulfone Ultraflux®
HD 90.5 ml/min
Premru (2011)
6(5 ad, 1 ch)
Theralite® HDF 42-131 ml/min
0 50 100 150 200 250 300 3500
1000
4000
5000
6000
7000
8000
LD
H (
IU/l)
TIME (hours)
0 50 100 150 200 250 300 3500
5001000150020002500
100000
350
153500
CK
(IU
/l)
TIME (hours)
M, 46 kg, Crush Syndrome
CVVH:Membrane: PESQb: 150 ml/minQrf: 2.5 l/hKMG = 15.8 ml/min
EXAMPLE 3: BORON
• Boron (boric acid): component of topical disinfectants• Acute boron intoxication: erythematous rash (“boiled
lobster”), AKI, vomiting, diarrhea, restlessness, headache, irritability, delirium, seizure, and coma
• 65% boron acute intoxications in pediatric age (2009 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 27th Annual Report, 2009)
• Although severe toxicity is reported only with very high boron serum levels (>300 µg/ml), lethal dose in infants is considered to be 3-6 g
• Dialysis is known to be effective in adults. No data in children with extracorporeal dialysis.
• Case: 5.5 kg, three-month infant, accidental ingestion of 160 ml of milk and water saturated solution of boric acid (3,6 g). At admittance: no symptoms, normal hepatic and kidney function. Metabolic acidosis.
0 5 10 15 20 25 30 35 40
0
50
100
150
200
250
300
BO
RO
N (
µg/
mL)
TIME (hrs)
0
50
100
150
200
250
BO
RO
N m
g
CVVH IN BORON INTOXICATION TREATMENT: MASS REMOVAL AND CONCENTRATION DECAY
Picca, 2009, unpublished
• Neonatal hyperammonemia is mainly due to urea cycle defects and organic acidurias
• Hyperammonemia is extremely toxic (per se and through intracellular excess glutamine formation) to the brain causing astrocyte swelling, brain edema, coma, death or severe disability
• When hyperammonemia does not respond to medical and dietetic treatment, dialysis has to be established in order to achieve rapid ammonium removal before neurological impairment or death occur
• Ammonium easily diffuses through membranes . Extracorporeal dialysis provides higher and faster ammonium removal than peritoneal dialysis.
KEY POINTS OF NEONATAL HYPERAMMONEMIA
PROGNOSTIC INDICATORS IN DIALYZED NEONATES ASSOCIATED WITH SURVIVAL
Schaefer,1999
•50% pNH4 decay time < 7 hrs•(catheter > 5F)
Picca,2001
•pre-treatment coma duration < 33 hrs (no influence of post-treatment duration)•responsiveness to pharmacological therapy
McBryde, 2006
•pNH4 at admission<180 mol/L•Time to RRT<24 hrs•Medical treatment<24 hrs•BP> 5%ile at RRT initiation •HD initial RRT (trend)
Pela,2008
• pre-treatment coma duration < 10 hrs
Arbeiter,2009
• Citrullinemia
Westrope,2010
• Favorable PRISM score• Lesser cardioactive drug requirement
SINP
ITALIAN SOCIETY OF PEDIATRIC NEPHROLOGY
Italian Study Group
“Dialysis Treatment of Neonatal hyperammonemia”
(Coord.: S. Picca, MD)
Units
A.PD
B.ECD
C.PD + ECD
p value(A vs. B)
Number of patients (47) 23 22 2
Metabolic defect
Carbamoyl phosphate synthetase def. n (%) 1 (4.3) 6 (27.3) 1 <0.05
Argininosuccinic aciduria n (%) 7 (30.4) 2 (9.1) 0 n.s.
Citrullinemia n (%) 4 (17.4) 6 (27.3) 1 n.s.
Propionic aciduria n (%) 6 (26.1) 5 (22.7) 0 n.s.
Methylmalonic aciduria n (%) 5 (21.7) 3 (13.6) 0 n.s.
General characteristics
Gender M:F 16:7 13:9 2:0 n.s.
Gestational age weeks 39.0 ± 1.4 39.2 ± 1.8 37 n.s.
Agar score 1 min score 8 [6-9] 9 [7-10] 8.5 n.s.
Agar score 5 min score 10 [8-10] 10 [8-10] 9.5 n.s.
Age at admission days 3.3 [2.0-11.0] 3.8 [2.0-20.0] 2.6 n.s.
Age at start medical treatment days 3.4 [2.0-10.0] 3.7 [2.0-20.0] 3.0 n.s.
Age at start dialysis days 4.4 [3.0-12.0] 4.5 [2.0-21.0] 3.4 n.s.
Birth weight gr 3244 ± 535 3306 ± 434 3300 n.s.
Weight at admission gr 2948 ± 519 3024 ± 434 3025 n.s.
Weight loss until admission gr/day -84 ± 41 -75 ± 70 -112 n.s.
Serum creatinine mg/dl 1.22 ± 0.62 1.10 ± 0.46 1.13 n.s.
S. creatinine > 0.8 mg/dl at admission n (%) 11 (68.8) 14 (70) 2 n.s.
Base excess at admission mEq/l -12.6 ± 11.0 -7.5 ± 6.7 -3.6 n.s.
PATIENTS CHARACTERISTICS (1)
Units
A.PD
B.ECD
C.PD + ECD
p value(A vs. B)
Number of patients (47) 23 22 2
Dialysis modality
PD n (%) 23 (100) - 2 -
CAVHD n (%) - 5 (22.7) 1 -
CVVHD n (%) - 14 (63.6) 2 -
HD n (%) - 3 (13.6) 0 -
Duration of dialysis hours 55 [24-216] 21 [2-60] 26 <0.001
Ammonium levels
At admission mmol/l 725 [490-6479] 683 [289-3203] 1104 n.s.
Before dialysis mmol/l 980 [402-3212] 1185 [304-4531] 2315 n.s.
Peak mmol/l 1405 [632-7024] 1338 [590-6479] 2317 n.s.
Outcome at 4 weeks
Survived without neurological sequelae n (%) 11 (47.8) 9 (40.9) 1 n.s.
Survived with neurological sequelae n (%) 8 (34.8) 4 (18.2) 1 n.s.
Death n (%) 4 (17.4) 9 (40.9) 0 n.s.
PATIENTS CHARACTERISTICS (2)
Risk of death at 4 weeks 95% CI
b S.E. O.R. Lower Upper p
Carbamoyl phosphate synthetase def. 2.24 0.93 9.37 1.52 57.6 0.016
Argininosuccinic aciduria - - 0.00 - - 0.999
Citrullinemia -0.61 0.87 0.55 0.01 3.00 0.486
Propionic aciduria -0.77 0.86 0.46 0.09 2.52 0.375
Methylmalonic aciduria 1.13 0.80 3.11 0.64 15.1 0.158
Composite end-point at 4 weeks(death + neurological sequelae)Carbamoyl phosphate synthetase def. 1.69 1.13 5.40 0.59 49.3 0.135
Argininosuccinic aciduria -0.68 0.75 0.51 0.12 2.23 0.370
Citrullinemia 0.12 0.73 1.12 0.27 4.71 0.872
Propionic aciduria -0.66 0.70 0.52 0.13 2.04 0.345
Methylmalonic aciduria 0.24 0.80 1.27 0.26 6.12 0.766
RISK OF ADVERSE OUTCOME RELATED TO THE UNDERLYING DEFECT
Risk of death at 4 weeks 95% CI
b S.E. O.R. Lower Upper pGender (male) 0.30 0.70 1.350 0.21 1.81 0.670
Gestational age (wks) 0.27 0.24 1.308 0.82 2.09 0.262Birth Weight 0.00 0.00 1.000 0.19 1.92 0.978
Apgar score at 5 min -0.45 0.56 0.641 0.70 5.36 0.431Center 0.902
Year of birth from 1990 0.02 0.08 1.02 0.86 1.20 0.831
Composite end-point at 4 weeks(death + neurological sequelae)Gender (male) 0.89 0.64 2.443 0.19 1.81 0.159
Gestational age (wks) 0.00 0.19 1.004 0.69 1.45 0.979Birth weight (gr) 0.00 0.00 1.000 0.21 1.92 0.924
Apgar score at 5 min -0.53 0.57 0.587 0.34 5.36 0.352Center 0.985
Year of birth from 1990 -0.14 0.08 .867 .734 1.023 0.091
RISK OF ADVERSE OUTCOME RELATED TO OTHER NON-MODIFIABLE VARIABLES
95% CI
b S.E. Adj. O.R. Lower Upper p
Peritoneal dialysis 0.077 0.752 1.080 0.247 4.715 0.919
Extracorporeal dialysis -0.077 0.752 0.926 0.212 4.045 0.919
Weight loss1 (% of birth weight) 0.147 0.100 1.158 0.953 1.408 0.141
Age at admission (days) 0.184 0.186 1.203 0.835 1.732 0.322
Age start medical treatment (days) 0.341 0.284 1.406 0.807 2.452 0.229
Age start dialysis (days) 0.285 0.228 1.329 0.851 2.078 0.211
Serum creatinine on admission (mg/dl) 0.764 0.853 2.146 0.404 11.413 0.370
Base excess on admission (mEq/l) 0.029 0.078 1.029 0.884 1.199 0.709
Ammonium pre-med. (x100 mmol/l) 0.189 0.100 1.208 0.993 1.470 0.059
Ammonium pre-dial. (x100 mmol/l) 0.126 0.056 1.134 1.015 1.266 0.026
Total coma duration (days) 0.785 0.685 2.192 0.572 8.396 0.252
Duration of coma before dialysis (hours) 0.166 0.201 1.181 0.797 1.750 0.408
COMPOSITE RISK: DEATH OR NEUROLOGICAL SEQUELAE
*Adjusted for metabolic defect and year of treatment
FOREST PLOT COMPOSITE END-POINT: DEATH OR NEUROLOGICAL SEQUELAE
p: NS
Uchino, 1998
• 216 pts with UCD (1978-1995)• 92 with neonatal onset• 1-yr survival: 43% (90% with severe neuro-deficit)
Kido, 2012
• 254 pts with UCD (1999-2009)• 77 with neonatal onset• 1-yr survival: 83% (neuro-deficit NA)
THE EVOLUTION OF UCD LONG TERM SURVIVAL
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
CONCLUSIONS• RRT represent a key step in the treatment of endogenous and exogenous
intoxications unresponsive to medical treatment• Compared with adults, the depuration of toxic compounds in children is facilitated by
the small patient volume • In general, extracorporeal dialysis provides higher and faster detoxification if
compared with peritoneal dialysis• In neonatal hyperammonemia, extracorporeal dialysis provides fastest ammonium
removal• However, surprisingly, in our cohort extracorporeal and peritoneal dialysis induced a
similar ammonium decay (higher glucose uptake with PD? Lesser degree of severity in PD patients?)
• Early initiation of medical treatment may be more important in decreasing ammonium generation rate than using more efficient dialysis techniques (i.e.: extracorporeal dialysis)
• Last but most important, dialysis modality did not affect the short term outcome
In light of these findings and waiting for validation of these results in other cohorts of patients, peritoneal dialysis in the treatment of neonatal hyperammonemia must be
considered as a valid alternative to extracorporeal dialysis .
ACKNOWLEDGEMENTS
Bambino Gesù Children Hospital:• Metabolic Unit: Carlo Dionisi-Vici, MD; Andrea Bartuli, MD; Gaetano
Sabetta, MD• Clinical Biochemistry Lab: Cristiano Rizzo BSc, PhD; Anna Pastore
BSc, PhD• NICU: all doctors and nurses• Dialysis Unit: Francesco Emma, MD, all doctors and nurses
(thanks!)In Italy:• SINP (Italian Society of Pediatric Nephrology)• All doctors from Pediatric Nephrology and NICUs of Genova, Milan,
Turin, Padua, Florence, Naples, Bari.
In USA• Tim Bunchman, Stuart Goldstein for this opportunity. • Thanks guys.
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