CRRT for Metabolic Diseases in the Newborn and Child.

Stefano Picca, MD.

Division of Nephrology, Dialysis and Renal Transplantation. Bambino Ges Pediatric Research Hospital. ROMA, Italy.

SMALL MOLECULES DISEASES INDUCING CONGENITAL HYPERAMMONEMIA. INCIDENCE

Overall: Organic Acidurias: Urea Cycle Defects: Fatty Acids Oxidation Defects:
AGE OF ONSET Neonate: 40% Infant: 30% Child: 20% Adult: 5-10% (?)

1:9160 1:21422 1:41506 1:91599

Dionisi-Vici et al, J Pediatrics, 2002.

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

OA
Lethargy/coma Axial hypotonia Abnormal movements Feeding difficulties/vomiting Dyspnea/tachipnea
100% 100% 78% 78% 57%

UCD
100% 100% 81% 68% 56%

Dionisi-Vici et al. J Inher Met Dis 2003

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

PROGNOSIS OF HYPERAMMONEMIC COMA IS DEPENDENT ON COMA DURATION.

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

TREATMENT of SEVERE NEONATAL HYPERAMMONEMIA

IMMEDIATE MEDICAL THERAPY IMMEDIATE DIALYSIS + MEDICAL THERAPY

NO RESPONSE

RESPONSE

DIALYSIS

?
MAINTAINANCE MEDICAL THERAPY + REFEEDING

MAINTAINANCE MEDICAL THERAPY + REFEEDING

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

Bambino Ges Hospital, Rome 23/30 newborns treated according to our protocol

8 pharmacological therapy

2 citrullinemia 3 ASAuria 1 PA 1 MMA 1 CACT 3 CPS 2 citrullinemia 1 ASAuria 7 PA 2 MMA

15 pharmacological therapy + dialysis 5 CVVHD 4 CAVHD 3 HD 3 PD

0-4 HOURS MEDICAL TREATMENT IN NEONATAL

HYPERAMMONEMIA
6000 4000 2000 1000

pNH 4 ( m mol/l)

750 500
250 0 0 4 8 12 16 20 24

HOURS

0-4 HOURS MEDICAL TREATMENT IN NEONATAL

HYPERAMMONEMIA
6000 4000 2000 1000
non-responders (dialysis) responders (med. treatment alone)

pNH 4 ( m mol/l)

750 500
250 0 0 4 8 12 16 20

24

HOURS

NH4p (percent of initial value)

180

PD patients

160
140 120 100 80 60 40 20

0
0 5 10 15 20 25

Time (hours)

100 80 60 40 20 0 0 100 80 60 10

CAVHD patients

NH4p (percent of initial value)

20

30

40

50

60

CVVHD patients

40
20 0 0 100 10 20 30 40 50 60

HD patients

80
60 40 20 0

10

20

30

40

50

60

TIME (hours)

Picca et al. Ped Nephrol 2001

AMMONIUM CLEARANCE AND FILTRATION FRACTION USING DIFFERENT DIALYSIS MODALITIES.

Patient (n)

Ammonium Ammonium Clearance Filtration Dialysis (ml/min) (ml/min) (ml/min/kg Fraction BW) (%) CAVHD 10-20 8.3 (0.5 l/h) 33.3-83.3 (2-5 l/h) 500 0.87-0.97 12.5-14.3

Type of

Qb

Qd

CVVHD

20-40

2.65-6.80

53.0-58.0

HD

10-15

3.95-5.37

95.0-96.0

Picca et al., 2001

Follow-up <2 yrs in 23 patients

GOOD POOR OUTCOME OUTCOME

TOTAL (n=23) PHARMACOLOGICAL THERAPY (n=8)

14

9
(6 died)

DIALYSIS (n=15)

8
(6 died)

Coma duration (hours , median and range) & outcome in 15 dialyzed patients

GOOD POOR OUTCOME OUTCOME

TOTAL
BEFORE DIALYSIS AFTER DIALYSIS

47.5
18-99

102
72-266

0.048
0.002

14
13-36

48
40-56

34
2-85

50
32-213

NS

Coma duration (hours, median and range) & outcome in 22 patients

GOOD POOR OUTCOME OUTCOME

TOTAL BEFORE TREATMENT AFTER TREATMENT

47
18-169

113
72-266

0.009
0.004

23
1-36

53
40-79

33
2-92

65
32-213

NS

DIALYZED PATIENTS: NH4 LEVELS AND 7000 COMA DURATION BEFORE DIALYSIS
6000

peak pNH4 (mmol/l)

4500 4000 3500 3000 2500 2000 1500 1000 500 0

0
good outcome bad outcome

10 15 20 25 30 35 40 45 50 55 60

hours

n=14

ALL PATIENTS: NH4 LEVELS AND COMA DURATION BEFORE ANY TREATMENT

peak pNH4 (mmol/l)

7000 6000 4500 4000 3500 3000 2500 2000 1500 1000 500 0

good outcome bad outcome

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) 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.

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.

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 ?

Outcome Neonatal Onset pts (n=29)

Short-term <2nd year of life
(median 1.3 yrs,range 0-2)

Long-term >2nd year of life

(median 12.5 yrs,range 3-21)

Mortality

27.5%

48%

Cognitive development Normal Mild MR Severe MR 71% 4.7% 23% 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 ON IN VITRO AMMONIA CLEARANCE IN CVVHD

(from Schaefer et al, 1999).

DIALYSIS IN NEONATAL HYPERAMMONEMIA. Data of the literature

Type of dialysis (No of pts.) Peritoneal dialysis (n=16) Hemodialysis (n=17) Continuous hemofiltration (n=6) Continuous hemodialysis (n=16) NH4 in vivo clearance (ml/min/kg BW) 0.71 0SD 6.4 3SD 1.2 0.1SD 4.4 1SD Pts. with Hypotensive Survivors neurological pts. (%) improvement 0-16% 0-63% 0-25%

9 (56%) 12 (70%) 4 (67%)

3 (18%) 10 (62%) 3 (50%)

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.

UCDs AND OAs: LONG-TERM OUTCOME

Neonatal Onset OAs
neonatal death
ISO HMG MMA MMA PA PA PA PA PA PA PA MMA MMA PA PA

Neonatal Onset UCDs

neonatal death
HHH HHH AL

normal mild MR

severe MR

normal mild MR

severe MR

HD CVVHD HD

AL

CVVHD

alive
PD PD

AL AL AS AS CPS CPS

alive
CVVHD

CAVHD CVVHD CVVHD

CAVHD

HD
PD
CAVHD

dead

CPS AS OTCm OTCm

dead

CAVHD

10

12

14

16

10

12

14

16

18

20

22

YEARS

YEARS

urea

PD CRRT HD

time

generation rate

[C]

clearance

ammonium?

TREATMENT of NEONATAL HYPERAMMONEMIA

HOSPITALIZATION

DIAGNOSIS

PHARMACOLOGICAL TREATMENT

NO RESPONSE

RESPONSE

DIALYSIS

RE-FEEDING

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 Ges Hospital, IRCCS, Rome

36th EMG Meeting

Rimini, May 14-16,2004

Total number of patients = 60 UCDs CPS OTC male OTC female AS AL HHHs 3 6 13 4 5 5 36 pts 24 pts PA MMA mut -/o HMG IVA -KT OAs 12 8 2 1 1

Neonatal Onset
< 28 days

UCDs 14

29 pts

OAs

15

Late Onset
> 28 days

31 pts

UCDs 22 OAs 9

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
mild Mental Retardation severe Mental Retardation short term outcome long term outcome

IQ>79, DQ>74
IQ 50-79, DQ 60-74 IQ< 49, DQ< 59 < 2nd year of life > 2nd year of life

Neonatal Onset group

Mortality rate:

Neonatal Onset 48% Late Onset 10%

Survival Function
(Kaplan- Mayer curve)

1,0

Late Onset

Survival rate

,8
,6 ,4 ,2

Neonatal Onset

p 0.0002
0

10

14

18

22

26

30

years

Neonatal Onset OAs

neonatal death
HMG
ISO

normal

mild MR

severe MR

HD

MMA MMA PA

PA HD PA
PA PA PA PA

CVVHD

alive

PD PD

MMA MMA PA PA

HD PD CAVHD

CAVHD

dead

10

12

14

16 years

mild decompensation coma

Neonatal Onset UCDs

neonatal death
HHH HHH AL AL AL AL AS AS CPS CPS AS OTCm OTCm

normal

mild MR

severe MR

CVVHD

CVVHD

alive

CVVHD
CVVHD CAVHD

CPS CAVHD

dead

10

12

14

16

18

20

22 years

mild decompensation coma

Long term outcome Late Onset UCDs

normal
HHH HHH AL AS AS OTCm OTCm OTCm OTCm OTCf OTCf OTCf OTCf OTCf OTCf OTCf OTCf OTCf OTCf OTCf

mild MR

severe MR

alive

dead
years

10 12 14 16 18 20 22 24 26 28 30 32

mild decompensation

coma

Long term outcome Late Onset OAs

normal
KT HMG PA PA PA MMA MMA MMA MMA
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 years

mild MR

severe MR

alive

mild decompensation

coma * stroke

Long term outcome Late Onset pts

Mortality

10%

(limited to 3 OTCf )

Cognitive development

Normal
Mild MR Severe MR

65.5%
14% 20.5%

NO cognitive deterioration after a normal developoment

No significative difference between UCDs and OAs

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

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

NEONATAL ONSET UCD =14 long term survivors 7 OA =13 long term survivors 8

DEAD
0 5 10 15 20 25
0 5

DEAD
10 15 Severe MR 20 25

dead neonate

normal

mild MR

Age at the end of follow-up (years)

AMMONIA/AMMONIUM CHEMISTRY IN BIOLOGICAL FLUIDS.

NH3 + H+ + OH(ammonia)

NH4+ + OH(ammonium)

[H+] = K * [ NH4+] [ NH3 ] At pH = 7.35-7.42 98.5% is NH4+

pH dependency of NH3 / NH4 ratio

Symptoms onset (days) median CI 3.1 2.7-3.8 5.7 4.6-9.2

median values 95% CI

UCDs

OAs

Schema from Colombo JP, 1971 Picca, Dionisi-Vici, 2003, unpublished data

DIALYSIS IN NEONATAL HYPERAMMONEM IA

Physical principle Peritoneal dialysis Hemodialysis Continous hemofiltration Continous hemodiafiltration
Diffusion + ultrafiltration Diffusion Ultrafiltration Diffusion + ultrafiltration

Efficiency Tolerance of small molecules

poor very high poor high good poor good good

BENZOATE
benzoyl-CoA

ALTERNATIVE PATHWAYS

PHENYLBUTYRATE
phenylacetate

GLYCINE

GLUTAMINE

NH4+
CPS

HIPPURATE
(1 N)

+
UREA CYCLE

PHENYLACETYL GLUTAMINE (2 N)

UREA

arginine

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

median

p value
<0.00001 <0.00001 <0.02 <0.0001 <0.0001 <0.001 <0.002

%weight loss OA
UCD

-12.6 -5.7 -16.4 -2.4 7.28 7.44 5.7 3.1 4.96 12.7 4.3 5.3 218 326

Base excess pH Onset WBC RBC PLT

OA UCD OA UCD OA UCD OA UCD OA UCD OA UCD

PLASMA GLUTAMINE DURING NEONATAL HYPERAMMONEMIA

from Scriver CR et al, 1995.

MEDIAN pNH4 and pGLN AT START AND AT END OF DIALYSIS

1600 1400

1200

mmol/l

1000 800 600

1419

1580

800
400 200 0

114

pNH4

pGLN

HEMODIALYSIS IN NEONATAL HYPERAMMONEMIA

3000 2500 stop HD 2000 1500 1000 500 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 restart HD Pt 1 Pt 2

NH 4 p (mcg/dl)

hours

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 postfilter (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

BLOOD

REINF.
DIAYSAT E

DIAL.

DIAL. + UF

DIALYSIS IN NEONATAL HYPERAMMONEMIA: DIALYSIS RELATED COMPLICATIONS

PD (n=3): HD (n=3): CAVHDCVVHD (n=9) : - leakage from catheter exit-site in 1 pt. - severe hypotension in 3 pts.

- 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 = 9729 mmol/l Only 1 HD-treated pt showed rebound after dialysis withdrawal

HD Rx of Hyperammonemia (Gregory et al, Vol. 5,abst. 55P,1994: )

2000 1800 1600 1400 1200 1000 800 600 400 200 0 0 1 2

NH4 rebound with reinstitution of HD

micromoles/l

NH4

6 10 11 12 13 17 18 19 20

Time (Hrs)

HD to CRRT (prevention of the rebound)

1200 1000

micromoles/L

800 600 400 200 0 0 1

Transition from HD to CVVHD

NH4

10

11

17

Time (Hrs)

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 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)

Outcome
12/18 patients survived 2/12 continued to be medication and RRT dependent

Arginine Clearance in Hyperammonemia

900 800 700

HD stopped
NH4 ( nl < 100) Arginine (? Nl?)

microM/L

600 500 400 300 200 100 0 0 0.5 1 1.5 2

Hrs

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