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CRRT for Metabolic Diseases in the Newborn and Child.

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. “SMALL MOLECULES” DISEASES INDUCING CONGENITAL HYPERAMMONEMIA. INCIDENCE

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CRRT for Metabolic Diseases in the Newborn and Child.

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  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.

  2. “SMALL MOLECULES” DISEASES INDUCING CONGENITAL HYPERAMMONEMIA. • 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, 2002.

  3. 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 Dis2003

  4. 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

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

  6. TREATMENT of SEVERE NEONATAL HYPERAMMONEMIA IMMEDIATE MEDICAL THERAPY NO RESPONSERESPONSE DIALYSIS MAINTAINANCE MEDICAL THERAPY + REFEEDING IMMEDIATE DIALYSIS + MEDICAL THERAPY MAINTAINANCE MEDICAL THERAPY + REFEEDING ?

  7. 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

  8. Bambino Gesù Hospital, Rome 23/30 newborns treated according to our protocol 8 pharmacological therapy 2 citrullinemia 3 ASAuria 1 PA 1 MMA 1 CACT 15 pharmacological therapy + dialysis 3 CPS 2 citrullinemia 1 ASAuria 7 PA 2 MMA • 5 CVVHD • 4 CAVHD • 3 HD • 3 PD

  9. 0-4 HOURS MEDICAL TREATMENT IN NEONATAL HYPERAMMONEMIA 6000 4000 2000 1000 mol/l) 750 m ( 4 500 pNH 250 0 0 4 8 12 16 20 24 HOURS

  10. non-responders (dialysis) mol/l) responders (med. treatment alone) m ( 0-4 HOURS MEDICAL TREATMENT IN NEONATAL HYPERAMMONEMIA 6000 4000 2000 1000 750 4 500 pNH 250 0 0 4 8 12 16 20 24 HOURS

  11. PD patients 180 160 140 120 100 NH4p (percent of initial value) 80 60 40 20 0 0 5 10 15 20 25 Time (hours)

  12. CAVHD patients 100 80 60 40 20 0 0 10 20 30 40 50 60 100 CVVHD patients 80 NH4p (percent of initial value) 60 40 20 0 0 10 20 30 40 50 60 HD patients 100 80 60 40 20 0 0 10 20 30 40 50 60 Picca et al. Ped Nephrol 2001 TIME (hours)

  13. AMMONIUM CLEARANCE AND FILTRATION FRACTION USING DIFFERENT DIALYSIS MODALITIES. Picca et al., 2001

  14. Follow-up <2 yrs in 23 patients GOOD OUTCOME POOR OUTCOME 14 9 (6 died) TOTAL (n=23) PHARMACOLOGICAL THERAPY (n=8) 7 1 8 (6 died) DIALYSIS (n=15) 7

  15. Coma duration (hours , median and range) & outcome in 15 dialyzed patients GOOD OUTCOME POOR OUTCOME p 102 72-266 TOTAL 0.048 47.5 18-99 BEFORE DIALYSIS 14 13-36 48 40-56 0.002 AFTER DIALYSIS 50 32-213 NS 34 2-85

  16. Coma duration (hours, median and range) & outcome in 22 patients GOOD OUTCOME POOR OUTCOME p 113 72-266 0.009 TOTAL 47 18-169 BEFORE TREATMENT 23 1-36 53 40-79 0.004 AFTER TREATMENT 65 32-213 NS 33 2-92

  17. mol/l) good outcome m ( bad outcome 4 peak pNH DIALYZED PATIENTS: NH4 LEVELS AND COMA DURATION BEFORE DIALYSIS 7000 6000 4500 4000 3500 3000 2500 2000 1500 1000 500 0 0 5 10 15 20 25 30 35 40 45 50 55 60 hours n=14

  18. mol/l) good outcome m ( bad outcome 4 peak pNH ALL PATIENTS: NH4 LEVELS AND COMA DURATION BEFORE ANY TREATMENT 7000 6000 4500 4000 3500 3000 2500 2000 1500 1000 500 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 hours n=21

  19. 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

  20. 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.

  21. 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.

  22. 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 ?

  23. 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 Outcome Neonatal Onset pts (n=29) 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%

  24. 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!).

  25. EFFECT OF BLOOD AND DIALYSATE FLOW ON IN VITRO AMMONIA CLEARANCE IN CVVHD (from Schaefer et al, 1999).

  26. DIALYSIS IN NEONATAL HYPERAMMONEMIA.Data of the literature

  27. UCDs AND OAs: LONG-TERM OUTCOME Neonatal Onset OAs Neonatal Onset UCDs HD CVVHD CVVHD alive alive HD CVVHD PD PD CAVHD CVVHD CAVHD dead CVVHD dead HD CAVHD PD CAVHD YEARS YEARS

  28. urea PD CRRT HD time ammonium? generation rate clearance [C]

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

  30. 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

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

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

  33. Methods • 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

  34. 1,0 Late Onset ,8 Survival rate ,6 ,4 Neonatal Onset ,2 p 0.0002 0 0 2 6 10 14 18 22 26 30 years Mortality rate: Neonatal Onset 48% Late Onset 10% Survival Function (Kaplan- Mayer curve)

  35.                                                                mild decompensation coma Neonatal Onset OAs HD alive CVVHD HD PD PD CAVHD dead HD PD CAVHD years

  36.                                          mild decompensation  coma Neonatal Onset UCDs CVVHD alive CVVHD CAVHD CVVHD CVVHD dead CAVHD years

  37.                       mild decompensation coma Long term outcome Late Onset UCDs alive dead years

  38.                 *   mild decompensation coma * stroke Long term outcome Late Onset OAs alive years

  39. No significative difference between UCDs and OAs Long term outcome Late Onset pts Mortality 10% (limited to 3 OTCf ) Cognitive development Normal 65.5% Mild MR 14% Severe MR 20.5% NO cognitive deterioration after a normal developoment

  40. 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

  41. 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

  42. DEAD DEAD 0 5 10 15 20 25 0 5 10 15 20 25 dead neonate normal mild MR Severe MR NEONATAL ONSET OA =13 long term survivors 8 UCD =14 long term survivors 7 Age at the end of follow-up (years)

  43. NH3 + H+ + OH- NH4+ + OH- (ammonia) (ammonium) [H+] = K * [ NH4+] [ NH3 ] At pH = 7.35-7.42 98.5% is NH4+ AMMONIA/AMMONIUM CHEMISTRY IN BIOLOGICAL FLUIDS.

  44. Symptoms onset (days) median CI 3.1 2.7-3.8 5.7 4.6-9.2 median values 95% CI UCDs OAs Picca, Dionisi-Vici, 2003, unpublished data pH dependency of NH3 / NH4 ratio Schema from Colombo JP, 1971

  45. DIALYSIS IN NEONATAL HYPERAMMONEM IA

  46. BENZOATE PHENYLBUTYRATE ALTERNATIVE PATHWAYS benzoyl-CoA phenylacetate GLYCINE GLUTAMINE NH4+ CPS PHENYLACETYL GLUTAMINE (2 N) + HIPPURATE (1 N) UREA CYCLE UREA arginine

  47. 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

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