Management of life threatening hyperammonemia in Children...• Other hyperammonemia with secondary...
Transcript of Management of life threatening hyperammonemia in Children...• Other hyperammonemia with secondary...
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Management of life threatening hyperammonemia in Children
P Jouvet MD PhDMontreal
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Conflicts of Interest Link with companies:
Consultant: Sage Therapeutics Inc Research funds: Air Liquide HC Invited speaker: Air Liquide HC
Covidien FranceMedunik Canada
Equipment:Philips Medical, Hamilton Medical, Maquet Inc, Air Liquide HC
Research salary and funds without company: FRQS MSSS Sainte-Justine Hospital NSERC CIHR
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• Definition
• Etiologies
• Therapeutic strategy
• Extra corporeal replacement therapy indications
• Conclusions
• Future
Plan
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Objectives
• To known the etiologies of hypermmonemia
• To identify the medications to decreaseammonemia in acute onset
• To know the management of severehyperammonemia
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Hyperammonemia definition
• Reference values: < 80 mol/l (135 µg/dl) ; < 1 month < 55 mol/l (95 µg/dl) ; > 1 month
• Linearity: 9 à 1000 mol/l
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NH3
PRODUCTION
Muscle
PRODUCTION
IntestineDETOXICATION
Kidney
DETOXICATION
Liver
INTOXICATIONBrain
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Endogenousproteins
Nutritional protein intake
Protein catabolism
NH3
Liver detoxificationlimitationX
Urea
Liver diseasePorto-caval shuntEnzyme deficiency
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Etiologies of hyperNH3in children
B Ozanne et al.J Hepatol 2012;56:123-8.
2000 to 20091 Pediatric Intensive Care
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B Ozanne et al.J Hepatol 2012;56:123-8.
Hyper NH3 mortality threshold
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NH3 level
Duration
Cerebral edema mainly cytotoxic
Time
[Toxic]
HyperNH3: V Felipo et al. Prog Neurobiol 2002
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Hyperammonemia and Inborn Errors of Metabolism
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G Enns et al. NEJM 2007
Urea cycle disorders
Peak NH3 < 480 µmol/LC Bachmann. Eur J Pediatr 2003
Coma duration < 33 hoursS Picca et al. Pediatr Nephrol 2001
Reduction with dialysisF Schaeffer et al. NDT 1999
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14-year-old boyNormal developmentIntermittent headaches
Headaches + visual blurred48h later vomitting and anorexia
96h later general practitioner consultation:Clinical examination normalHemoglobine : 16 g dl–1, leucocytes : 5.2.109 /L, creatininemia : 70 μmol/L, ASAT/ALAT: 22 UI/L normal
Emergency room at night:Obnubilated without neurological focal symptomBlood pressure 180/80, HR 75/min
Clinical case (1)
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• Protidemia: 78 g/L• ASAT/ALAT normal range• Cerebral TDM normal• CSF: 1 cell/mm3, 250 Red Cell/mm3
• Toxics negative (amphetamines, cannabis, cocaïne, opioids, barbiturates, benzodiazepines, carboxyhemoglobine, alcohol, paracetamol)
• EEG non specific
Clinical case (2)14-year-old boyNormal development
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• Ammonemia of 344 mumol/L and it rapidly increased to 755 μmol/L.
• Death of one uncle after a coma in the year 1992 +++
• Diagnosis of hereditary ornithine transcarbamylase deficiency was confirmed later on by liver biopsy
Clinical case (3)14-year-old boyNormal development
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Initial management
Toxic production decrease
Toxic removal therapies
Management of hyperNH3 due to Inborn Errors of Metabolism
Management of hyperNH3 due to Inborn Errors of Metabolism
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Rehydration (goal: urine output of 2-4 ml/kg/hr)
Treatment of Intracranial hypertension:Mechanical ventilation, sedation, …If deepening encephalopathy: Mannitol or NaCl 3-5%
Blood osmolarity ≥ 300 mOsm/L
NB: In hyperammonemia, hyperventilation is not recommended as blood brain barrier seems to have a lower permeability to NH4
+ than NH3JR Stabenau et al.J Clin Invest 1959.
Initial management
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Initial management
Toxic production decrease
Toxic removal therapies
Management of hyperNH3 due to Inborn Errors of Metabolism
Management of hyperNH3 due to Inborn Errors of Metabolism
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Endogenousproteins
Nutritional support
Protein anabolism
NH3
Amino acidspool
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Toxic production decrease=
Nutritional support• Promote protein anabolism
IV RehydrationCaloric intake > 1500 Cal.m-2.d-1
IV switched to PO Carbohydrates (+/- Insuline) + lipids
Infection treatment, no steroid
• Protein free nutrition
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Initial management
Toxic production decrease
Toxic removal therapies
Management of hyperNH3 due to inherited enzyme deiciciency
Management of hyperNH3 due to inherited enzyme deiciciency
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NH3
Extra-corporeal removal therapies
Medications for alternative pathway
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Sodium benzoate
Benzoylglycine
NH3
Amino acids
glycineglutamine
glutamate
N-acetylglutamate
Acetyl CoA
Carbamoyl phosphate
OroticAcid
Urea
Aspartate
Urine
Urea
Nitrogen part
CO2ATPH2O
+1
2
Citrulline Ornithine
ArginineArginosuccinate
3
4
5
6
Nitrogen scavenging medications
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Episodes with NH3 > 100 μmol/l (n=69)
HyperNH3 episodes and IV Sodium Benzoate
MC Husson et al. Orphanet Journal of Rare Diseases 2016;11:127
291 μmol/L [101 –2274]
Before i.v. sodium benzoate treatment
At the end of i.v. sodium benzoate treatment
41 μmol/L [13 –181]
No severe side effects were attributed to i.v. sodium benzoate
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Sodium benzoate
Benzoylglycine
PhénylbutyratePhenylacetate
Phenylacetyl-glutamine
NH3
Amino acids
glycineglutamine
glutamate
N-acetylglutamate
Acetyl CoA
Carbamoyl phosphate
OroticAcid
Urea
Aspartate
Urine
Urea
Nitrogen part
CO2ATPH2O
+1
2
Citrulline Ornithine
ArginineArginosuccinate
3
4
5
6
Nitrogen scavenging medications
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Most of the NH3 episodes are controlled with IV Sodium Benzoate
MC Husson et al. Orphanet Journal of Rare Diseases 2016;11:127
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Lanpher et al. Nature Reviews Genetics 7, 449–459.
Phenylbutyrate Phenylacétate Phénylacétylglutamine urines
Aspartate
Ornithine
Ornithine
Citrulline
Aspartate
Arginine
Citrulline
Carglumic acid
Na+ Benzoate
+ Hippurate+
Glutamate
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Carglumic acid is an analog of N-acetylglutamate
Carglumic acid
Can avoid hemodialysis
Inborn errors of metabolism that can benefit of this treatment: • Some urea cycle defects (N-acetylglutamate synthase deficiency,
Carbamoyl-phosphate synthase I deficiency)• Organic aciduria (propionic acidemia and methylmalonic acidemia,
isovaleric acidemia), • Other hyperammonemia with secondary inhibition of NAGS
M Daniotti et al. International Journal of General Medicine 2011;4 :21
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Extra-corporeal toxic removal therapy in hyperNH3
Criteria: Two of the three following criteria : coma, gastro-intestinal intolérance, NH3 > 300-400 µmol/L
Modality: Intermittent or continuous
Solute transfer: Diffusion
Dialysis dose: ≥ 35 ml/min/1.73 m2 in neonatesand 50 ml/min/1.73 m2 in childrenIncrease until dialysate flow = twice the blood flow (Schaefer F Nephrol Dial Transplant 1999)
Duration: until NH3 in a normal range
Multidisciplinary approach : genetics, intensivist, nephrologist, biochemist
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B Ozanne et al. J Hepatol 2012;56:123-8.
Treatment of HyperNH3 in Pediatric Intensive Care
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Management consequences
Initial NH3 Level (x2)* / clinicalcondition
Intensive care admission
Central line Hemodialysiscatheter
< 150 µmol/l (250 µg/dl) without encephalopathy +/- consider -
150-300 (250 - 500 µg/dl) and/or encephalopathy + +
(jug or fem vein) -
>300 (500 µg/dl) + + +
* Due to false positives risk, 2 NH3 blood levels are required (B Maranda et al. Clin Biochem 2007;40:531)
Multidisciplinary approach : genetics, intensivist, nephrologist, biochemist
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Hypothermia?
Whitelaw A. Lancet 2001;358:36.
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Differences in the management of HyperNH3 due to liver failure
• Non-Absorbable Disaccharide (lactulose, …)
• Neomycin, Metronidazole and other Antibiotics
• Rifaximin
• Probiotics
• Zinc
• L-Ornithine L-Aspartate
• Molecular Adsorbent Recirculating System (MARS)
• Occlusion of large portosystemic shunts
May be inappropriate in acute liver failure.
W Bernal et al. N Engl J Med 2013;369:2525
No proof of efficacyM Leise et al. Mayo Clin Proc 2014;89: 241Z Poh et al. Intern J Hepatology 2012;2012,:1A Merouani et al. PCCM 2014;15:681
M Leise et al. Mayo Clin Proc 2014;89: 241
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Liver transplantation
Disease Author year n Survival(%)
UCD D Morioka 2005 51 90
MMA M Kashara 2006 18 83
PA J Meyburg 2005 21 76
MSD KA Strauss 2006 10 100
Primary goal:To restaure all liver functions (synthesis, metabolic, …)
Elective liver transplantation in some inborn errors of metabolism
Urgent liver transplantation in acute liver failure
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CONCLUSIONS
• Ammonia blood level in case of unexplained encephalopathy
• Hyperammonemia decreases with nitrogen scavenging medications, and carglumic acid can have a dramatic impact on some hyperammonemia
• Intensive care admission and hemodialysis are required in severe hyperammonemia
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Future
Development of Enzyme therapies:Enzyme replacement therapyHepatocyte transplantationGene transfer
PICU admissions
J Häberle et al. Orphanet Journal of Rare Diseases 2012;7:32.