in born error of metabolic

8/4/2019 In Born Error of Metabolic

1/67

CRRT for Metabolic Diseasesin the Newborn and Child.

Stefano Picca, MD.Division of Nephrology, Dialysis

and Renal Transplantation.

Bambino Ges Pediatric Research Hospital.

ROMA, Italy.


2/67


3/67


4/67

INCIDENCEOverall: 1:9160Organic Acidurias: 1:21422

Urea Cycle Defects: 1:41506Fatty Acids Oxidation Defects: 1:91599

AGE OF ONSET

Neonate: 40%Infant: 30%

Child: 20%

Adult: 5-10% (?) Dionisi-Vici et al, J Pediatrics, 2002.

SMALL MOLECULES DISEASES INDUCING

CONGENITAL HYPERAMMONEMIA.


5/67

OA UCD

Lethargy/coma100% 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 IVAUCD 16 pts : 3 CPS, 4 OTC, 5 AL, 3 AS,1 HHH

Dionisi-Vici et al. J Inher Met Dis 2003


6/67

hyperammonemia is extremely toxic to thebrain (per seor through intracellular excessglutamine formation) causing astrocyte

swelling, brain edema, coma, death or severedisability,

thus:

emergency treatment has to be startedeven before having a precise diagnosis

since:

prognosis mainly depends on coma duration

KEY POINTS FACING TO A HYPERAMMONEMIC

NEWBORN


7/67

PROGNOSIS OF HYPERAMMONEMIC COMAIS DEPENDENT ON COMA DURATION.

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


8/67

TREATMENT of SEVERENEONATAL HYPERAMMONEMIA

?IMMEDIATE

MEDICAL THERAPY

NO

RESPONSE RESPONSE

DIALYSIS

MAINTAINANCEMEDICAL THERAPY

+REFEEDING

IMMEDIATE DIALYSIS+ MEDICAL THERAPY

MAINTAINANCEMEDICAL THERAPY

+REFEEDING


9/67

Pharmacological treatment

before having a diagnosis

AIMSprecursorscatabolismanabolism 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


10/67

Bambino Ges Hospital, Rome23/30 newborns treated according to our protocol

8 pharmacological therapy

15 pharmacological therapy+ dialysis

2 citrullinemia3 ASAuria1 PA

1 MMA1 CACT

3 CPS

2 citrullinemia1 ASAuria7 PA2 MMA

5 CVVHD 4 CAVHD 3 HD

3 PD


11/67

0 4 8 12 16 20 24

0

250

500

750

1000

200040006000

pNH4

(mmol/l)

HOURS

0-4 HOURS MEDICAL TREATMENT IN NEONATAL

HYPERAMMONEMIA


12/67

0 4 8 12 16 20 24

0

250

500

750

1000

200040006000

pNH4

(mmol/l)

HOURS

non-responders(dialysis)

responders

(med. treatmentalone)

0-4 HOURS MEDICAL TREATMENT IN NEONATAL

HYPERAMMONEMIA


13/67

NH4p(percento

finitialvalue)

Time (hours)

0 5 10 15 20 25

0

20

40

60

80

100

120

140

160

180PD patients


14/67

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

NH4p(percento

finitialvalue)



15/67

AMMONIUM CLEARANCE AND FILTRATION FRACTIONUSING DIFFERENT DIALYSIS MODALITIES.

Patient

(n)

Type of

Dialysis

Qb

(ml/min)

Qd

(ml/min)

AmmoniumClearance(ml/min/kg

BW)

AmmoniumFiltrationFraction

(%)

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


16/67

GOODOUTCOME

POOROUTCOME

PHARMACOLOGICAL

THERAPY (n=8)

7 1

DIALYSIS (n=15) 7 8(6 died)

TOTAL(n=23)

14 9(6 died)

Follow-up


17/67

GOODOUTCOME

POOROUTCOME

p

BEFOREDIALYSIS

1413-36

4840-56

AFTERDIALYSIS 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


18/67

GOODOUTCOME

POOROUTCOME

p

BEFORETREATMENT

231-36

5340-79

AFTERTREATMENT 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


19/67

0 5 10 15 20 25 30 35 40 45 50 55 600

5001000

1500

2000

2500

3000

3500

4000

4500

6000

7000

hours

peakpNH4(mm

ol/l)

n=14

good outcome

bad outcome

DIALYZED PATIENTS: NH4 LEVELS ANDCOMA DURATION BEFORE DIALYSIS


20/67

0 5 10152025303540455055606570758085

0

5001000

1500

2000

25003000

3500

4000

4500

6000

7000

pe

akpNH4(mm

ol/l)

hours

ALL PATIENTS: NH4 LEVELS AND COMADURATION BEFORE ANY TREATMENT

good outcome

bad outcome n=21


21/67

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


22/67

Conclusions (1)

1/3 of patients respond to pharmacologicaltherapy 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 associatedwith a poor outcome, in both medicallytreated and dialyzed patients, irrespective of

the treatment rapidity.


23/67

Plasma ammonium changes within the initial 4hours of medical treatment seem to discriminatepatients who will respond to this treatment alone

from those who will need dialysis.

This point is crucial for patients who startmedical treatment in peripheral hospitals before

being referred to centers with neonatal dialysisfacilities.

Conclusions (2)


24/67

In neonatal hyperammonemia, CVVHDprovides treatment continuity, efficacy andcardiovascular stability. Higher dialysate flowrates must be investigated in order to increase

ammonium clearance.

Major effort should be made for rapididentification of patients, early start ofappropriate treatment & quick referral tospecialized centres.

long-term outcome ? quality of life ?

Conclusions (3)


25/67

Short-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


26/67

ACKNOWLEDGEMENTS

Metabolic Unit: Carlo Dionisi-Vici, MD; AndreaBartuli, 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


27/67

EFFECT OF BLOOD AND DIALYSATE FLOW ONIN VITROAMMONIA CLEARANCE IN CVVHD

(from Schaefer et al, 1999).


28/67

DIALYSIS IN NEONATAL HYPERAMMONEMIA.Data of the literature

Type of dialysis(No of pts.)

NH4 in vivo

clearance(ml/min/kgBW)

Survivors

Pts. with

neurologicalimprovement

Hypotensivepts. (%)

Peritonealdialysis(n=16)

0.71 0SD 9 (56%) 3 (18%) 0-16%

Hemodialysis(n=17) 6.4 3SD 12 (70%) 10 (62%) 0-63%

Continuoushemofiltration

(n=6)1.2 0.1SD 4 (67%) 3 (50%) 0-25%

Continuoushemodialysis

(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.


29/67

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


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


30/67

time

urea

PD

HD

CRRT

[C]generation rate clearance

ammonium?


31/67

TREATMENT of NEONATAL HYPERAMMONEMIAHOSPITALIZATION

DIAGNOSISPHARMACOLOGICAL

TREATMENT

DIALYSIS

NO RESPONSE RESPONSE

RE-FEEDING


32/67

F.Deodato, S. Caviglia, A. Bartuli, G.Sabetta, C. Dionisi-Vici

Metabolic and Psychology Units, Bambino Ges 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


33/67

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

-KT 1

24 pts


34/67

Neonatal Onset< 28 days

Late Onset> 28 days

29 pts

31 pts

UCDs 14

OAs 15

UCDs 22

OAs 9


35/67

Mortality-survival

neuro-developmental outcome

Baylelys 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

Methods


36/67

Survival Function(Kaplan- Mayer curve)

years

302622181410620

Survivalrate

1,0

,8

,6

,4

,2

0

p 0.0002

Late Onset

Neonatal Onset

Mortality rate: Neonatal Onset 48% Late Onset 10%


37/67

0 2 4 6 8 10 12 14 16

PA

PA

MMA

MMA

PA

PA

PA

PA

PA

PA

PA

MMA

MMA

HMG

ISO


years

dead

alive

HD

CVVHD

HD

PD

PD

CAVHD

HD

PD

CAVHD

Neonatal Onset OAs

mild decompensation coma

N l O UCD


38/67

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


years

dead

alive


CVVHD

CVVHD

CAVHD

CVVHD

CVVHD

CAVHD

Neonatal Onset UCDs


39/67

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

OTCfOTCm

OTCm

OTCm

OTCm

AS

AS

AL

HHH

HHH

normal mild MR severe MR

years

Long term outcome Late Onset UCDs

dead

alive



40/67

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


41/67

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


42/67

CNSStroke in MMA - Pyramidal dysfunction in HHHs

HEART

Cardiomyopathy in PA & MMALIVER

fibrosis in ASAuria

KIDNEY

CRF in MMA

PANCREAS

acute pancreatitis in PA

Characteristic organ involvement


43/67

Conclusions

Higher mortality and morbidity of Neonatal Onset compared toLate 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


44/67

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


45/67

AMMONIA/AMMONIUMCHEMISTRY IN BIOLOGICAL

FLUIDS.

[H+] = K * [ NH4+]

[ NH3 ]At pH = 7.35-7.42 98.5% is NH4

+

NH3 + H+ + OH- NH4

+ + OH-

(ammonia) (ammonium)


46/67

pH dependency of NH3/ NH4 ratio

Schema from Colombo JP, 1971

Symptoms onset(days)

median CI3.1 2.7-3.85.7 4.6-9.2

median values95% CI

UCDs

OAs

Picca, Dionisi-Vici, 2003, unpublished data


47/67

DIALYSIS IN NEONATALHYPERAMMONEM 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


48/67

GLYCINE GLUTAMINE

HIPPURATE(1 N)

PHENYLACETYLGLUTAMINE

(2 N)

benzoyl-CoA phenylacetate

UREACYCLE

BENZOATE PHENYLBUTYRATE

NH4+

CPS

ALTERNATIVEPATHWAYS

UREA

arginine

+


49/67

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 acidosispoints to an organic acidemia J Pediatr 138:s29;2001


50/67

median p value

%weight loss OAUCD

-12.6-5.7


51/67

PLASMA GLUTAMINE DURINGNEONATAL HYPERAMMONEMIA

from Scriver CR et al, 1995.


52/67

0

200

400

600

800

1000

1200

1400

1600

pNH4 pGLN

mmol/l

MEDIAN pNH4 and pGLN AT START ANDAT END OF DIALYSIS

1419

114

1580

800

HEMODIALYSIS IN NEONATAL HYPERAMMONEMIA


53/67

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

4pmcg

Pt 1

Pt 2stop HD

restart HD


54/67

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


55/67

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

- 30mEq/l (Solubag, SIFRA)


56/67

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


57/67

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


58/67

CVVHD in the neonate

REINF.

DIAYSAT

E

BLOOD

DIAL. DIAL. +

UF


59/67

DIALYSIS IN NEONATALHYPERAMMONEMIA: 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 automatedsystem

- hypotension in 1 pt.

- transitory inferior limb ischemia in 8 pts.


DIALYSIS IN NEONATAL


60/67

DIALYSIS IN NEONATALHYPERAMMONEMIA:

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


61/67

HD Rx of Hyperammonemia

(Gregory et al, Vol. 5,abst. 55P,1994: )

0

200

400

600

800

1000

12001400

1600

1800

2000

0 1 2 3 4 5 6 10 11 12 13 17 18 19 20

NH4

micromoles/l

Time

(Hrs)

NH4 rebound with reinstitution of HD


62/67

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)

NH4

micromoles/L Transition from HD to CVVHD


63/67

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


64/67

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)


65/67

Outcome

12/18 patients survived

2/12 continued to be medication and RRTdependent

Hyperammonemia(McBryde et al, JASN 2000)

Arginine Clearance in


66/67

Arginine Clearance in

Hyperammonemia

0100

200

300

400

500

600

700

800

900

0 0.5 1 1.5 2

NH4 ( nl < 100)

Arginine (? Nl?)

microM/L

Hrs

HD stopped

McBryde et al, J Peds in press


67/67

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 thedialysate or replacement fluid

in born error of metabolic

Documents