6KEY POINTS FACING TO A HYPERAMMONEMIC NEWBORNhyperammonemia 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 startedeven before having a precise diagnosissince:prognosis mainly depends on coma duration
7PROGNOSIS OF HYPERAMMONEMIC COMA IS DEPENDENT ON COMA DURATION. from Msall M et al, N Eng J Med 1984.
8NEONATAL HYPERAMMONEMIA TREATMENT of SEVERENEONATAL HYPERAMMONEMIAIMMEDIATEMEDICAL THERAPYNORESPONSE RESPONSEDIALYSISMAINTAINANCE+REFEEDINGIMMEDIATE DIALYSIS+ MEDICAL THERAPYMAINTAINANCEMEDICAL THERAPY+REFEEDING?
17GOOD OUTCOME POOR OUTCOME Coma duration (hours , median and range)& outcome in 15 dialyzed patientsGOOD OUTCOMEPOOROUTCOMEpTOTAL47.518-9910272-2660.048BEFORE DIALYSIS1413-364840-560.002AFTERDIALYSIS5032-213342-85NS
18Coma duration (hours, median and range) & outcome in 22 patientsGOOD OUTCOMEPOOROUTCOMEpTOTAL4718-16911372-2660.009BEFORETREATMENT231-365340-790.004AFTERTREATMENT6532-213332-92NS
19DIALYZED PATIENTS: NH4 LEVELS AND COMA DURATION BEFORE DIALYSIS 70006000peak pNH4(mmol/l)4500400035003000250020001500100050051015202530354045505560good outcomebad outcomehoursn=14
20ALL PATIENTS: NH4 LEVELS AND COMA DURATION BEFORE ANY TREATMENT 70006000peak pNH4(mmol/l)45004000350030002500200015001000500510152025303540455055606570758085good outcomebad outcomehoursn=21
21PROGNOSTIC INDICATORS (at 2-yr follow-up) non-informativeammonia peakneed of ventilatory supportdialysis modetype of disease UCD/OA (except for OTC def.)post-treatment start coma durationinformativetotal coma durationpre-treatment start coma durationresponsiveness to pharmacological therapy
22Conclusions (1)1/3 of patients respond to pharmacological therapy aloneIn our series, medium-term outcome did not depend on dialysis modalityA 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.
23Conclusions (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.
24Conclusions (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 ?
25Outcome Neonatal Onset pts (n=29) Long-term>2nd year of life(median 12.5 yrs,range 3-21)48%28.5% 9.5%57%Short-term<2nd year of life(median 1.3 yrs,range 0-2)Mortality %Cognitive developmentNormal %Mild MR %Severe MR %so a t a short evaluation mortality rate was 27% and 71% of survivors with a normal development. But at a long follow-up mortality increaased up to 48% and more impressive most patients became mentally retarded. No difference was observed between UCD and OA.No significative difference between UCDs and OAs
26ACKNOWLEDGEMENTSMetabolic 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!).
27EFFECT OF BLOOD AND DIALYSATE FLOW ON IN VITRO AMMONIA CLEARANCE IN CVVHD(from Schaefer et al, 1999).
28DIALYSIS IN NEONATAL HYPERAMMONEMIA. Data of the literature
29UCDs AND OAs: LONG-TERM OUTCOME Neonatal Onset OAsNeonatal Onset UCDsHDCVVHDCVVHDalivealiveHDCVVHDPDPDCAVHDCVVHDCAVHDdeaddeadCVVHDHDCAVHDPDCAVHDYEARSYEARS
31TREATMENT of NEONATAL HYPERAMMONEMIA HOSPITALIZATIONDIAGNOSISPHARMACOLOGICALTREATMENTDIALYSISNO RESPONSERESPONSERE-FEEDING
32Survival and long term neuro-developmental outcome of Urea Cycle Disorders and Organic AciduriasF. Deodato, S. Caviglia°, A. Bartuli, G.Sabetta, C. Dionisi-Vici Metabolic and °Psychology Units, Bambino Gesù Hospital, IRCCS, Romewe report on the survival and long term outocme of UCD and OA36th EMG MeetingRimini, May 14-16,2004
33Total number of patients = 60 UCDsCPS 3OTC male 6OTC female 13AS 4AL 5HHHs 536 ptsOAsPA 12MMA mut -/o 8HMG 2IVA 1ß-KT 124 ptswe retrospectively analised 60 patients.36 with UCD and 24 with AO. Among CUD 3 were CPS deficiency, 6 males and 13 females with OTC def......Among the OA 12 were propionic, 8 MMA.....
34Neonatal Onset 29 pts Late Onset 31 pts UCDs 14 < 28 days OAs 15 based on the age of onset of symptoms we distinguished two group of patients. The group with neonatal onset in whom symptoms started before 28 d of life and the late onset one. The first group is composed by 29 pts (14 UCD and..); pts with late onset were 31 (...)
35Methods Neonatal Onset group Mortality-survival neuro-developmental outcomeBaylely’s Scale of Infant Development,Leiter International Performance Scale,WISC-R, WAIS-R and Raven Progressive Matricesnormal development IQ>79, DQ>74mild Mental Retardation IQ 50-79, DQ 60-74severe Mental Retardation IQ< 49, DQ< 59we evaluated mortality and survival. and neurodevelopmental outcome. Cognitve level was assessed longytudinally by using diffrent psychologcal test according to the age of pts. Based on results of IQ/DQ we classified normal development if IQ was more than 79 or DQ more than 74, mild mental retardation (IQ between 50 and 79 or DQ between 60 and 74) and severe mental retardation qith an IQ and DQ lower than 49 and 59 respectivelyAmong nenatal onset pts we considered a short term follow-up (that is before 2 y of life) and a long term follow-upNeonatal Onset groupshort term outcome < 2nd year of lifelong term outcome > 2nd year of life
36Neonatal Onset 48% Late Onset 10% Mortality rate:Neonatal Onset 48% Late Onset 10%Survival Function(Kaplan- Mayer curve)years30262218141062Survival rate1,0,8,6,4,2pLate OnsetNeonatal OnsetHere is repersented the surival function according KAplan Mayer curve and it's evident that survival is significantly hiher in pts with late onset compared to the onse with a neonatal onset
37Neonatal Onset OAs alive dead years mild decompensation coma HDaliveCVVHDHDPDPDsimilar is the results observed in nenatl patients with . Infact many patinets had a good short term ouctome followed by cognitive decline , also in these cases metabolic instability seems to correlate with mental retardation.CAVHDdeadHDPDCAVHDyears
38Neonatal Onset UCDs alive dead years mild decompensation comaCVVHDaliveCVVHDCAVHDCVVHDin this slide is illustrated the outcome of each pts with neonatal onset UCD. 4 pts did not survived neonatal period, If you look at the left side of the graph you can see that most short term survivors had an early normal psychomotr development followed by progressive decline of cognitve performance, becaming later mentally retarded.almot in all cases this progressive worsenig was associated with a history of frequent and sever episodes of metabolic decompensationCVVHDdeadCAVHDyears
41Long term outcome Late Onset pts Mortality % (limited to 3 OTCf )Cognitive developmentNormal %Mild MR %Severe MR %NO cognitive deterioration after a normal developomentSO.. among late onset pats mortilty was limited to thrre females with OTC deficiency and 65% of survivor had a normal IQ.No significative difference between UCDs and OAs
42Characteristic organ involvement CNSStroke in MMA - Pyramidal dysfunction in HHHsHEARTCardiomyopathy in PA & MMALIVERfibrosis in ASAuriaKIDNEYCRF in MMAPANCREASacute pancreatitis in PAHere we have just analysed cognitive aspcets, but if we have to think the ong term follow-ue of these pats we have to rimind that they have a high risk of organ complications that in many cases may seriously compromise thier quality of life like in case of basal ganglia stroke in MMa or
43ConclusionsHigher mortality and morbidity of Neonatal Onset compared to Late Onset diseasesProgressive cognitive deterioration of Neonatal Onset patients despite an early good outcomeMetabolic instability/life threatening episodes of metabolic decompensation are associated with cognitive deterioration and mortality, especially in Neonatal Onset patientsto concludeRisks of organ failureAlternative therapy (liver, hepatocyte transplantation, others) should be carefully considered at an early stage
44Age at the end of follow-up (years) NEONATAL ONSETOA =13long term survivors 8UCD =14long term survivors 7DEAD510152025DEAD510152025dead neonatenormalmild MRSevere MRAge at the end of follow-up (years)
45AMMONIA/AMMONIUM CHEMISTRY IN BIOLOGICAL FLUIDS. NH3 + H+ + OH NH4+ + OH-(ammonia) (ammonium)[H+] = K * [ NH4+][ NH3 ]At pH = % is NH4+
46pH dependency of NH3 / NH4 ratio Symptoms onset(days)median CImedian values95% CIUCDsOAsPicca, Dionisi-Vici, 2003, unpublished dataSchema from Colombo JP, 1971
56METHODS-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 m2 polysulfone (Minntech).Dialysate flow: 2.0 l/hDialysate: same as CAVHD
57METHODS-HD Vascular access, dialysate: same as CVVHD Gambro AK100 blood monitorBlood flow: ml/min (3-5 ml/kg/min)Pro-100: 0.3 m2, gambrane®Dialysate flow: 500 ml/minDialysate: same as CAVHD
58CVVHD in the neonateBLOODREINF.DIAYSAT EDIAL.DIAL. +UF
59DIALYSIS 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 automatedsystem- hypotension in 1 pt.- transitory inferior limb ischemia in 8 pts.Picca et al. Ped Nephrol 2001
60DIALYSIS 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 = 97±29 mol/lOnly 1 HD-treated pt showed rebound after dialysis withdrawal
61HD Rx of Hyperammonemia (Gregory et al, Vol. 5,abst. 55P,1994: ) NH4 rebound with reinstitution of HDmicromoles/lNH4Time(Hrs)
62HD to CRRT (prevention of the rebound) Transition from HD to CVVHDmicromoles/LNH4Time(Hrs)
63Hyperammonemia (McBryde et al, paper in progress) 18 children underwent 20 therapies of RRT due to in-born error of metabolismmean age mosmean weight kg (smallest 1.2 kg)mean duration of therapy days
64Hyperammonemia (McBryde et al, paper in progress) Modalities usedHD only-9time on HD daysHF only-3time on HF daysHD followed by HF-8time on HD + HF days
65Hyperammonemia (McBryde et al, JASN 2000) Outcome12/18 patients survived2/12 continued to be medication and RRT dependent
66Arginine Clearance in Hyperammonemia HD stoppedmicroM/LHrsMcBryde et al, J Peds in press
67Hyperammonemia Conclusion Duration of coma correlates with poor neurological outcomeDialysis needs to be initiated earlyNeed to change dialysis thought process from ARF to metabolicK and Phos need to be physiologic in the dialysate or replacement fluid