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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.

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Presentation on theme: "CRRT for Metabolic Diseases in the Newborn and Child. Stefano Picca, MD. Division of Nephrology, Dialysis and Renal Transplantation. Bambino Gesù Pediatric."— Presentation transcript:

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.

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4 INCIDENCE Overall: 1:9160 Organic Acidurias: 1:21422 Urea Cycle Defects: 1:41506 Fatty Acids Oxidation Defects: 1:91599 AGE OF ONSET Neonate: 40% Infant: 30% Child: 20% Adult: 5-10% (?) Dionisi-Vici et al, J Pediatrics, SMALL MOLECULES DISEASES INDUCING CONGENITAL HYPERAMMONEMIA.

5 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 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

7 PROGNOSIS OF HYPERAMMONEMIC COMA IS DEPENDENT ON COMA DURATION. from Msall M et al, N Eng J Med 1984.

8 TREATMENT of SEVERE NEONATAL HYPERAMMONEMIA ? IMMEDIATE MEDICAL THERAPY NO RESPONSE DIALYSIS MAINTAINANCE MEDICAL THERAPY + REFEEDING IMMEDIATE DIALYSIS + MEDICAL THERAPY MAINTAINANCE MEDICAL THERAPY + REFEEDING

9 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 15 pharmacological therapy + dialysis 2 citrullinemia 3 ASAuria 1 PA 1 MMA 1 CACT 3 CPS 2 citrullinemia 1 ASAuria 7 PA 2 MMA 5 CVVHD 4 CAVHD 3 HD 3 PD

11 pNH 4 ( mol/l) HOURS 0-4 HOURS MEDICAL TREATMENT IN NEONATAL HYPERAMMONEMIA

12 pNH 4 ( mol/l) HOURS non-responders (dialysis) responders (med. treatment alone) 0-4 HOURS MEDICAL TREATMENT IN NEONATAL HYPERAMMONEMIA

13 NH4p (percent of initial value) Time (hours) PD patients

14 CAVHD patients HD patients TIME (hours) CVVHD patients NH4p (percent of initial value) 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 PHARMACOLOGICAL THERAPY (n=8) 71 DIALYSIS (n=15) 7 8 (6 died) TOTAL (n=23) 14 9 (6 died) Follow-up <2 yrs in 23 patients

17 GOOD OUTCOME POOR OUTCOME p BEFORE DIALYSIS AFTER DIALYSIS TOTAL NS Coma duration (hours, median and range) & outcome in 15 dialyzed patients

18 GOOD OUTCOME POOR OUTCOME p BEFORE TREATMENT AFTER TREATMENT TOTAL NS Coma duration (hours, median and range) & outcome in 22 patients

19 hours peak pNH 4 ( mol/l) n=14 good outcome bad outcome DIALYZED PATIENTS: NH 4 LEVELS AND COMA DURATION BEFORE DIALYSIS

20 peak pNH 4 ( mol/l) hours ALL PATIENTS: NH 4 LEVELS AND COMA DURATION BEFORE ANY TREATMENT good outcome bad outcome 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 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)

24 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)

25 Short-term <2 nd 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 >2 nd year of life (median 12.5 yrs,range 3-21) 48% 28.5% 9.5% 57% 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 dead alive Neonatal Onset OAs YEARS dead alive Neonatal Onset UCDs YEARS UCDs AND OAs: LONG-TERM OUTCOME CVVHD CAVHD CVVHD CAVHD HD PD

30 time urea PD HD CRRT [C] generation rateclearance ammonium?

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

32 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 36 th EMG Meeting Rimini, May 14-16,2004

33 UCDs CPS3 OTC male 6 OTC female 13 AS4 AL 5 HHH s 5 36 pts Total number of patients = 60 OAs PA12 MMA mut -/o 8 HMG2 IVA1 ß-KT1 24 pts

34 Neonatal Onset < 28 days Late Onset > 28 days 29 pts 31 pts UCDs 14 OAs 15 UCDs 22 OAs 9

35 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 severe Mental Retardation IQ< 49, DQ< 59 Neonatal Onset group short term outcome < 2 nd year of life long term outcome > 2 nd year of life Methods

36 Survival Function (Kaplan- Mayer curve) years Survival rate 1,0,8,6,4,2 0 p Late Onset Neonatal Onset Mortality rate: Neonatal Onset 48% Late Onset 10%

37 years dead alive HD CVVHD HD PD CAVHD HD PD CAVHD Neonatal Onset OAs mild decompensation coma

38 years dead alive mild decompensation coma CVVHD CAVHD CVVHD CAVHD Neonatal Onset UCDs

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

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

41 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 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

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

44 OA =13 long term survivors 8 Age at the end of follow-up (years) DEAD UCD =14 long term survivors 7 NEONATAL ONSET dead neonatenormalmild MRSevere MR

45 AMMONIA/AMMONIUM CHEMISTRY IN BIOLOGICAL FLUIDS. [H + ] = K * [ NH 4 + ] [ NH 3 ] At pH = % is NH 4 + NH 3 + H + + OH - NH OH - (ammonia) (ammonium)

46 pH dependency of NH 3 / NH 4 ratio Schema from Colombo JP, 1971 Symptoms onset (days) median CI median values 95% CI UCDs OAs Picca, Dionisi-Vici, 2003, unpublished data

47 DIALYSIS IN NEONATAL HYPERAMMONEM IA

48 GLYCINEGLUTAMINE HIPPURATE (1 N) PHENYLACETYL GLUTAMINE (2 N) benzoyl-CoAphenylacetate UREA CYCLE BENZOATEPHENYLBUTYRATE NH4+ CPS ALTERNATIVE PATHWAYS UREA arginine +

49 NEONATAL HYPERAMMONEMIA JM Saudubray ORGANIC ACIDURIAS intoxication - dehydration - tachipnea - hypotonia -coma >NH 3 - ketoacidosis - leucopenia UREA CYCLE DEFECTS intoxication - hepatopathy - tachipnea - hypotonia - coma >NH 3 - alkalosis S. Cederbaum A respiratory alkalosis points to a UCD, whereas a metabolic acidosis points to an organic acidemia J Pediatr 138:s29;2001

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51 PLASMA GLUTAMINE DURING NEONATAL HYPERAMMONEMIA from Scriver CR et al, 1995.

52 pNH4pGLN mol/l MEDIAN pNH 4 and pGLN AT START AND AT END OF DIALYSIS

53 HEMODIALYSIS IN NEONATAL HYPERAMMONEMIA hours NH 4 p (mcg/dl) Pt 1 Pt 2 stop HD restart HD

54 METHODS-PD Straight neonatal Tenckhoff catheter ( ). Curl neonatal catheter (from 1995 on). Manual exchanges ml/kg loading volume min dwell time

55 METHODS-CAVHD 2 femoral catheters 18G (Abbocath. Abbott Ltd.) Amicon Minifilter Plus, 0.08 m 2 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, HCO 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 m 2 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 m 2, gambrane® Dialysate flow: 500 ml/min Dialysate: same as CAVHD

58 CVVHD in the neonate REINF. DIAYSAT E BLOOD 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 pNH 4 is stable under the safe level after protein reintroduction safe level ? In 13 pts dialysis was stopped after protein reintroduction at pNH 4 = 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: ) NH 4 micromoles/l Time (Hrs) NH4 rebound with reinstitution of HD

62 HD to CRRT (prevention of the rebound) Time (Hrs) NH 4 micromoles/L Transition from HD to CVVHD

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 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 Hyperammonemia (McBryde et al, paper in progress)

65 Outcome –12/18 patients survived –2/12 continued to be medication and RRT dependent Hyperammonemia (McBryde et al, JASN 2000)

66 Arginine Clearance in Hyperammonemia microM/L Hrs HD stopped 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


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