Drug-induced Hyperammonemia
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1 Drug-induced Hyperammonemia EAPCCT Madrid Pre-Congress Florian Eyer Division of Clinical Toxicology & PCC Munich School of Medicine Klinikum rechts der Isar Technical University of Munich
2 Drug-induced Hyperammonemia (HA)
3 Drug-induced Hyperammonemia (HA) Aims
4 Drug-induced Hyperammonemia (HA) Aims To provide a short overview of drugs capable to induce HA
5 Drug-induced Hyperammonemia (HA) Aims To provide a short overview of drugs capable to induce HA To show some pathophysiological background
6 Drug-induced Hyperammonemia (HA) Aims To provide a short overview of drugs capable to induce HA To show some pathophysiological background To briefly summarize treatment options for drug induced HA
7 Drug-induced Hyperammonemia (HA) Aims To provide a short overview of drugs capable to induce HA To show some pathophysiological background To briefly summarize treatment options for drug induced HA This talk will not
8 Drug-induced Hyperammonemia (HA) Aims To provide a short overview of drugs capable to induce HA To show some pathophysiological background To briefly summarize treatment options for drug induced HA This talk will not cover HA secondary to hepatic failure (including druginduced hepatic failure)
9 Drug-induced Hyperammonemia (HA) Aims To provide a short overview of drugs capable to induce HA To show some pathophysiological background To briefly summarize treatment options for drug induced HA This talk will not cover HA secondary to hepatic failure (including druginduced hepatic failure) review the role of L-carnitine in VPA-induced HA
10 Definitions
11 Definitions Plasma-ammonia can be measured in arterial or venous blood samples; capillary blood samples not reliable (hemolysis, inconstant composition)
12 Definitions Plasma-ammonia can be measured in arterial or venous blood samples; capillary blood samples not reliable (hemolysis, inconstant composition) Blood to be collected in ammonia-free heparinized or EDTA chilled tubes, placed on ice, rapidly delivered to Lab
13 Definitions Plasma-ammonia can be measured in arterial or venous blood samples; capillary blood samples not reliable (hemolysis, inconstant composition) Blood to be collected in ammonia-free heparinized or EDTA chilled tubes, placed on ice, rapidly delivered to Lab Falsely elevated by hemolysis, exposure to room temperature or delayed delivery to Lab
14 Definitions Plasma-ammonia can be measured in arterial or venous blood samples; capillary blood samples not reliable (hemolysis, inconstant composition) Blood to be collected in ammonia-free heparinized or EDTA chilled tubes, placed on ice, rapidly delivered to Lab Falsely elevated by hemolysis, exposure to room temperature or delayed delivery to Lab Normal values in adults less than µmol/l, neonates < 60 µmol/l and less than 55 µmol/l in infants 1-6 months of age; levels below 100 µmol/l only in context with clinical course
15 Common causes of HA
16 Common causes of HA Increased ammonia production: infections, increased catabolism, GI-bleeding, burns, trauma, sepsis, TPN, cancer
17 Common causes of HA Increased ammonia production: infections, increased catabolism, GI-bleeding, burns, trauma, sepsis, TPN, cancer Reduced hepatic elimination of ammonia: synthesized from bacterial species (e.g. ALF, porto-caval shunts, TIPS)
18 Common causes of HA Increased ammonia production: infections, increased catabolism, GI-bleeding, burns, trauma, sepsis, TPN, cancer Reduced hepatic elimination of ammonia: synthesized from bacterial species (e.g. ALF, porto-caval shunts, TIPS) Drug-induced HA:
19 Common causes of HA Increased ammonia production: infections, increased catabolism, GI-bleeding, burns, trauma, sepsis, TPN, cancer Reduced hepatic elimination of ammonia: synthesized from bacterial species (e.g. ALF, porto-caval shunts, TIPS) Drug-induced HA: Drugs affecting urea cycle disorders: e.g. Glucocorticoids, VPA, CBZ, ASA, AAP, chemotherapeutic agents, sulfadiazine/pyrimethamine
20 Common causes of HA Increased ammonia production: infections, increased catabolism, GI-bleeding, burns, trauma, sepsis, TPN, cancer Reduced hepatic elimination of ammonia: synthesized from bacterial species (e.g. ALF, porto-caval shunts, TIPS) Drug-induced HA: Drugs affecting urea cycle disorders: e.g. Glucocorticoids, VPA, CBZ, ASA, AAP, chemotherapeutic agents, sulfadiazine/pyrimethamine Glycine-infusion (during TURP-operations)
21 Infrequent causes of HA
22 Infrequent causes of HA Disturbed mitochondrial ß-fatty-acid-oxygenation
23 Infrequent causes of HA Disturbed mitochondrial ß-fatty-acid-oxygenation Urea cycle (UC) disorders (e.g. inborn errors of metabolism; 1:8200 U.S.; in partial insufficiency symptoms may develop late in life!)
24 Infrequent causes of HA Disturbed mitochondrial ß-fatty-acid-oxygenation Urea cycle (UC) disorders (e.g. inborn errors of metabolism; 1:8200 U.S.; in partial insufficiency symptoms may develop late in life!) Elevated ammonia (i.e. above µmol/l), normal blood glucose and elevated anion gap -> suggests an urea cycle disorder -> check for plasma amino acids & organic- and orotic acid in urine
25 Infrequent causes of HA Disturbed mitochondrial ß-fatty-acid-oxygenation Urea cycle (UC) disorders (e.g. inborn errors of metabolism; 1:8200 U.S.; in partial insufficiency symptoms may develop late in life!) Elevated ammonia (i.e. above µmol/l), normal blood glucose and elevated anion gap -> suggests an urea cycle disorder -> check for plasma amino acids & organic- and orotic acid in urine UC enzyme-deficiencies: e.g. determined in liver biopsy (CPS-I, OTC), red blood cells or fibroblasts (depending on enzyme-type to be determined)
26 Infrequent causes of HA Disturbed mitochondrial ß-fatty-acid-oxygenation Urea cycle (UC) disorders (e.g. inborn errors of metabolism; 1:8200 U.S.; in partial insufficiency symptoms may develop late in life!) Elevated ammonia (i.e. above µmol/l), normal blood glucose and elevated anion gap -> suggests an urea cycle disorder -> check for plasma amino acids & organic- and orotic acid in urine UC enzyme-deficiencies: e.g. determined in liver biopsy (CPS-I, OTC), red blood cells or fibroblasts (depending on enzyme-type to be determined) Idiopathic HA: normal liver function, normal amino-acid-levels - ruling out enzymatic deficiencies of UC -> acquired insufficiency of glutamine synthase: waste nitrogen circulating as ammonia not being converted to glutamine
27 Idiopathic HA e.g. as a result of CTX-induced reduced glutamine synthase expression and / or activity Glutamate Glutamine Martìnez-Lapiszina et al., JCSN, 2012
28 The urea cycle The only effective system that converts waste nitrogen (protein intake; catabolism) into urea -> excreted Machado et al., J Intensive Care, 2014
29 The urea cycle The only effective system that converts waste nitrogen (protein intake; catabolism) into urea -> excreted Machado et al., J Intensive Care, 2014
30 VPA-induced HA
31 VPA-induced HA HA and HAE is a well-known, but serious and potentially fatal complication of VPA-treatment (even under therapeutic serum levels, although uncommon) or VPA-overdose
32 VPA-induced HA HA and HAE is a well-known, but serious and potentially fatal complication of VPA-treatment (even under therapeutic serum levels, although uncommon) or VPA-overdose RF: Polypharmacy (esp. Barbiturates, Phenytoin), malnutrition, infancy
33 VPA-induced HA HA and HAE is a well-known, but serious and potentially fatal complication of VPA-treatment (even under therapeutic serum levels, although uncommon) or VPA-overdose RF: Polypharmacy (esp. Barbiturates, Phenytoin), malnutrition, infancy Several mechanisms have been postulated how VPA may induce HAE:
34 VPA-induced HA HA and HAE is a well-known, but serious and potentially fatal complication of VPA-treatment (even under therapeutic serum levels, although uncommon) or VPA-overdose RF: Polypharmacy (esp. Barbiturates, Phenytoin), malnutrition, infancy Several mechanisms have been postulated how VPA may induce HAE: VPA directly stimulates renal glutaminase: glutamine -> glutamate + NH 4 +, thereby increasing synthesis of ammonia up to 25%
35 VPA-induced HA HA and HAE is a well-known, but serious and potentially fatal complication of VPA-treatment (even under therapeutic serum levels, although uncommon) or VPA-overdose RF: Polypharmacy (esp. Barbiturates, Phenytoin), malnutrition, infancy Several mechanisms have been postulated how VPA may induce HAE: VPA directly stimulates renal glutaminase: glutamine -> glutamate + NH 4 +, thereby increasing synthesis of ammonia up to 25% VPA / metabolites directly inhibit CPS-I
36 VPA-induced HA HA and HAE is a well-known, but serious and potentially fatal complication of VPA-treatment (even under therapeutic serum levels, although uncommon) or VPA-overdose RF: Polypharmacy (esp. Barbiturates, Phenytoin), malnutrition, infancy Several mechanisms have been postulated how VPA may induce HAE: VPA directly stimulates renal glutaminase: glutamine -> glutamate + NH 4 +, thereby increasing synthesis of ammonia up to 25% VPA / metabolites directly inhibit CPS-I VPA may cause carnitine depletion, affecting ß-oxidation of fatty acids, resulting in decreased acetyl-coa, necessary for NAG synthesis
37 VPA-induced HA HA and HAE is a well-known, but serious and potentially fatal complication of VPA-treatment (even under therapeutic serum levels, although uncommon) or VPA-overdose RF: Polypharmacy (esp. Barbiturates, Phenytoin), malnutrition, infancy Several mechanisms have been postulated how VPA may induce HAE: VPA directly stimulates renal glutaminase: glutamine -> glutamate + NH 4 +, thereby increasing synthesis of ammonia up to 25% VPA / metabolites directly inhibit CPS-I VPA may cause carnitine depletion, affecting ß-oxidation of fatty acids, resulting in decreased acetyl-coa, necessary for NAG synthesis Valproyl-CoA blocks the enzyme NAGS -> NAG - an essential allosteric activator of CPS-I - decreases -> impaired metabolism of ammonia via Carbamoyl-P into the UC
38 HA secondary to chemotherapy Lazier J et al., Curr Oncol, 2014 Laemmle A et al., Mol Gen Metabol 2015
39 HA secondary to chemotherapy Functional arginine deficiency secondary to increased catabolism (overwhelming the capacity of the UC) after CTX has been proposed Lazier J et al., Curr Oncol, 2014 Laemmle A et al., Mol Gen Metabol 2015
40 HA secondary to chemotherapy Functional arginine deficiency secondary to increased catabolism (overwhelming the capacity of the UC) after CTX has been proposed CTX-induced impairment of CPS-I gene-expression and function (carboplatin and etoposide) Lazier J et al., Curr Oncol, 2014 Laemmle A et al., Mol Gen Metabol 2015
41 HA secondary to chemotherapy Functional arginine deficiency secondary to increased catabolism (overwhelming the capacity of the UC) after CTX has been proposed CTX-induced impairment of CPS-I gene-expression and function (carboplatin and etoposide) Alternatively, tumor replacement of normal (liver) cell lines may decrease expression of the OTC-gene, thereby leading to insufficient OTC enzyme synthesis Lazier J et al., Curr Oncol, 2014 Laemmle A et al., Mol Gen Metabol 2015
42 HA secondary to chemotherapy Functional arginine deficiency secondary to increased catabolism (overwhelming the capacity of the UC) after CTX has been proposed CTX-induced impairment of CPS-I gene-expression and function (carboplatin and etoposide) Alternatively, tumor replacement of normal (liver) cell lines may decrease expression of the OTC-gene, thereby leading to insufficient OTC enzyme synthesis OTC-deficiency leads to decreased synthesis of arginine (and accumulation of NH 4 + ) Lazier J et al., Curr Oncol, 2014 Laemmle A et al., Mol Gen Metabol 2015
43 HA secondary to chemotherapy Functional arginine deficiency secondary to increased catabolism (overwhelming the capacity of the UC) after CTX has been proposed CTX-induced impairment of CPS-I gene-expression and function (carboplatin and etoposide) Alternatively, tumor replacement of normal (liver) cell lines may decrease expression of the OTC-gene, thereby leading to insufficient OTC enzyme synthesis OTC-deficiency leads to decreased synthesis of arginine (and accumulation of NH 4 + ) This could lead to inhibition of N-acetyl-glutamate synthase (NAGS), leading to HA Lazier J et al., Curr Oncol, 2014 Laemmle A et al., Mol Gen Metabol 2015
44 HA secondary to chemotherapy Espinós J et al., Bone Marrow Transplantation, 2006 Metzeler K et al., Leukemia Research, 2009 Advani P et al., Anticancer Research, 2011 Schäfer T et al.,drug and Chem Toxicol, 2010 Shea Y et al., J Clin Pharm Ther, 2013
45 HA secondary to chemotherapy CTX with trastuzumab (HER2/neu Mk-Ab) / docetaxel /melphalan/ carboplatin in HER2+ breast cancer Oxaliplatin (FOLFOX), Rituximab (CD20 Mk-Ab), Sunitinib (receptor tyrosine-kinase-inhibitor), Cytarabine, Vincristine, Etoposide, Cyclophosphamide: mechanisms largely unknown Eculizumab (C5-complement inhibitor) for paroxysmal nocturnal hemoglobinemia Cytarabine, asparaginase and mitoxantrone for AML (FAB M1) 5-Fluorouracil (5-FU, FOLFOX or Capecitabine, an oral pro-drug of 5-FU): often transient (5-FU is degraded to 5-fluoro-B-alanine, CO 2 and ammonia), and frequently triggered by infection, dehydration or renal insufficiency Fluorocitrate - an intermediate metabolite of 5-FU - inhibits enzymes of the Krebs-cycle, which in turn causes impairment of the ATP-dependent UC Espinós J et al., Bone Marrow Transplantation, 2006 Metzeler K et al., Leukemia Research, 2009 Advani P et al., Anticancer Research, 2011 Schäfer T et al.,drug and Chem Toxicol, 2010 Shea Y et al., J Clin Pharm Ther, 2013
46 VPA/CTX-induced HA ORC: Ornithine-citrulline transport protein OTC: Ornithine transcarbamylase ACS: Acyl-CoA Synthetase Adopted from Aires CC et al., J Hepatol 2011
47 HA and ASA - Reye s syndrome Reye D et al., Lancet, 1963 Deschamps D et al., J Pharmacol Exp Ther,1991 Lemberg A et al., Current Drug Safety, 2009
48 Reye D et al., Lancet, 1963 Deschamps D et al., J Pharmacol Exp Ther,1991 Lemberg A et al., Current Drug Safety, 2009 HA and ASA - Reye s syndrome Reye s syndrome: microvesicular liver steatosis and encephalopathy, elevated transaminases and occasionally hypoglycemia - first described in the Lancet 1963
49 Reye D et al., Lancet, 1963 Deschamps D et al., J Pharmacol Exp Ther,1991 Lemberg A et al., Current Drug Safety, 2009 HA and ASA - Reye s syndrome Reye s syndrome: microvesicular liver steatosis and encephalopathy, elevated transaminases and occasionally hypoglycemia - first described in the Lancet 1963 Initially attributed to virus infection (influenza A/B, varicella) treated with ASA in childhood
50 Reye D et al., Lancet, 1963 Deschamps D et al., J Pharmacol Exp Ther,1991 Lemberg A et al., Current Drug Safety, 2009 HA and ASA - Reye s syndrome Reye s syndrome: microvesicular liver steatosis and encephalopathy, elevated transaminases and occasionally hypoglycemia - first described in the Lancet 1963 Initially attributed to virus infection (influenza A/B, varicella) treated with ASA in childhood There seems a dose-response between ASA and risk of HA, suggesting a causal link
51 Reye D et al., Lancet, 1963 Deschamps D et al., J Pharmacol Exp Ther,1991 Lemberg A et al., Current Drug Safety, 2009 HA and ASA - Reye s syndrome Reye s syndrome: microvesicular liver steatosis and encephalopathy, elevated transaminases and occasionally hypoglycemia - first described in the Lancet 1963 Initially attributed to virus infection (influenza A/B, varicella) treated with ASA in childhood There seems a dose-response between ASA and risk of HA, suggesting a causal link Structural and functional changes of mitochondria
52 Reye D et al., Lancet, 1963 Deschamps D et al., J Pharmacol Exp Ther,1991 Lemberg A et al., Current Drug Safety, 2009 HA and ASA - Reye s syndrome Reye s syndrome: microvesicular liver steatosis and encephalopathy, elevated transaminases and occasionally hypoglycemia - first described in the Lancet 1963 Initially attributed to virus infection (influenza A/B, varicella) treated with ASA in childhood There seems a dose-response between ASA and risk of HA, suggesting a causal link Structural and functional changes of mitochondria Activation of systemic host defense mechanisms (e.g. during virus infections) may result in depression of various induced and constitutive isoforms of enzymes, e.g. in the UC (CPS-I)
53 ASA impairs mitochondrial ß-oxidation, sequestering CoA and carnitine -> HA Reye D et al., Lancet, 1963 Deschamps D et al., J Pharmacol Exp Ther,1991 Lemberg A et al., Current Drug Safety, 2009 HA and ASA - Reye s syndrome Reye s syndrome: microvesicular liver steatosis and encephalopathy, elevated transaminases and occasionally hypoglycemia - first described in the Lancet 1963 Initially attributed to virus infection (influenza A/B, varicella) treated with ASA in childhood There seems a dose-response between ASA and risk of HA, suggesting a causal link Structural and functional changes of mitochondria Activation of systemic host defense mechanisms (e.g. during virus infections) may result in depression of various induced and constitutive isoforms of enzymes, e.g. in the UC (CPS-I)
54 Topiramate (TPM) + VPA = HA? Latour P et al., Hum Psychpharmacol Clin Exp, 2004
55 Topiramate (TPM) + VPA = HA? Two proposed mechanisms: a pharmacodynamic and a direct toxic effect Latour P et al., Hum Psychpharmacol Clin Exp, 2004
56 Topiramate (TPM) + VPA = HA? Two proposed mechanisms: a pharmacodynamic and a direct toxic effect Pharmacodynamic: VPA interacts with cytochrome P-450 [CYP2C19], decreasing TPM-metabolism eventually leading to toxic levels of TPM Latour P et al., Hum Psychpharmacol Clin Exp, 2004
57 Topiramate (TPM) + VPA = HA? Two proposed mechanisms: a pharmacodynamic and a direct toxic effect Pharmacodynamic: VPA interacts with cytochrome P-450 [CYP2C19], decreasing TPM-metabolism eventually leading to toxic levels of TPM Latour P et al., Hum Psychpharmacol Clin Exp, 2004
58 Topiramate (TPM) + VPA = HA? Two proposed mechanisms: a pharmacodynamic and a direct toxic effect Pharmacodynamic: VPA interacts with cytochrome P-450 [CYP2C19], decreasing TPM-metabolism eventually leading to toxic levels of TPM Toxic: TPM inhibits type-v mitochondrial carbonic anhydrase, thereby blocking the UC by decreased synthesis of bicarbonate, necessary for synthesis of carbamoyl-phosphate via CPS-I Latour P et al., Hum Psychpharmacol Clin Exp, 2004
59 Topiramate-VPA-induced HA Valproyl-CoA Blackford MG et al., J Pediatr Pharmacol Ther, 2013
60 Glycine-infusion during TURP
61 Glycine-infusion during TURP Glycine-infusion used during transurethral resection of the prostate may contribute to TURP-syndrome
62 Glycine-infusion during TURP Glycine-infusion used during transurethral resection of the prostate may contribute to TURP-syndrome Fluid overload, electrolyte dysbalances, and CNSdepression due to HA
63 Glycine-infusion during TURP Glycine-infusion used during transurethral resection of the prostate may contribute to TURP-syndrome Fluid overload, electrolyte dysbalances, and CNSdepression due to HA Glycine acts as a donor of one carbon fragment
64 Glycine-infusion during TURP Glycine-infusion used during transurethral resection of the prostate may contribute to TURP-syndrome Fluid overload, electrolyte dysbalances, and CNSdepression due to HA Glycine acts as a donor of one carbon fragment Pathway of glycine catabolism involves the cleavage of glycine to form CO 2, Ammonia and N 5 N 10 Methylene-tetra-hydro-folate
65 Glycine-infusion during TURP Glycine-infusion used during transurethral resection of the prostate may contribute to TURP-syndrome Fluid overload, electrolyte dysbalances, and CNSdepression due to HA Glycine acts as a donor of one carbon fragment Pathway of glycine catabolism involves the cleavage of glycine to form CO 2, Ammonia and N 5 N 10 Methylene-tetra-hydro-folate
66 Acetaminophen-induced HA Gupta S et al., Toxicol Appl Pharmacol,1997
67 Acetaminophen-induced HA Acetaminophen as the parent drug has been demonstrated to induce decreased activity of both, CPS-I and glutamine synthase, as assayed in liver homogenates in vitro. Gupta S et al., Toxicol Appl Pharmacol,1997
68 Acetaminophen-induced HA Acetaminophen as the parent drug has been demonstrated to induce decreased activity of both, CPS-I and glutamine synthase, as assayed in liver homogenates in vitro. This was accompanied by HA indicating that CPS-I and/or glutamine synthase were inhibited in vivo to an extent sufficient to compromise ammonia clearance. Gupta S et al., Toxicol Appl Pharmacol,1997
69 Acetaminophen-induced HA Acetaminophen as the parent drug has been demonstrated to induce decreased activity of both, CPS-I and glutamine synthase, as assayed in liver homogenates in vitro. This was accompanied by HA indicating that CPS-I and/or glutamine synthase were inhibited in vivo to an extent sufficient to compromise ammonia clearance. Thus, acetaminophen may additionally contribute to HA, irrespective of NAPQI-induced liver failure Gupta S et al., Toxicol Appl Pharmacol,1997
70 Treatment of drug-induced HA
71 General treatment options for HA
72 General treatment options for HA Stop the offending drug (!)
73 General treatment options for HA Stop the offending drug (!) Reduce or temporarily stop protein intake (max. 2 d)
74 General treatment options for HA Stop the offending drug (!) Reduce or temporarily stop protein intake (max. 2 d) Infusion of dextrose / insulin to avoid catabolism and establish anabolism
75 General treatment options for HA Stop the offending drug (!) Reduce or temporarily stop protein intake (max. 2 d) Infusion of dextrose / insulin to avoid catabolism and establish anabolism Correction of acid-base-disorders
76 General treatment options for HA Stop the offending drug (!) Reduce or temporarily stop protein intake (max. 2 d) Infusion of dextrose / insulin to avoid catabolism and establish anabolism Correction of acid-base-disorders Reduction of bacterial grow (e.g. rifaximine)
77 General treatment options for HA Stop the offending drug (!) Reduce or temporarily stop protein intake (max. 2 d) Infusion of dextrose / insulin to avoid catabolism and establish anabolism Correction of acid-base-disorders Reduction of bacterial grow (e.g. rifaximine) Lactulose p.o. and / or Lactulose-enema:
78 General treatment options for HA Stop the offending drug (!) Reduce or temporarily stop protein intake (max. 2 d) Infusion of dextrose / insulin to avoid catabolism and establish anabolism Correction of acid-base-disorders Reduction of bacterial grow (e.g. rifaximine) Lactulose p.o. and / or Lactulose-enema: Entrapment of NH 3 as ammonium ions by lowering ph, increasing fecal nitrogen excretion and inhibiting glutaminase, thereby inhibiting intestinal wall uptake of glutamine and subsequent metabolism to NH 3
79 General treatment options for HA Brusilow SW et al., Lancet, 1979 Metzeler K et al., Leukemia Research, 2009
80 General treatment options for HA Reduce ammonia-synthesis with Phenylacetate or Benzoate, which diverts nitrogen from UC to alternative routes of excretion Brusilow SW et al., Lancet, 1979 Metzeler K et al., Leukemia Research, 2009
81 General treatment options for HA Reduce ammonia-synthesis with Phenylacetate or Benzoate, which diverts nitrogen from UC to alternative routes of excretion Loading dose 5.5 g/m 2 each, followed by an equivalent maintenance infusion over 24 hrs; costs 10.- /day) Brusilow SW et al., Lancet, 1979 Metzeler K et al., Leukemia Research, 2009
82 General treatment options for HA Reduce ammonia-synthesis with Phenylacetate or Benzoate, which diverts nitrogen from UC to alternative routes of excretion Loading dose 5.5 g/m 2 each, followed by an equivalent maintenance infusion over 24 hrs; costs 10.- /day) Brusilow SW et al., Lancet, 1979 Metzeler K et al., Leukemia Research, 2009
83 General treatment options for HA Rahimi R et al., Clin Liver Dis, 2015 Warrillow SJ et al., Anaesth Intensive Care, 2014 Ghannoum M et al. (EXTRIP), Clin Toxicology, 2015
84 General treatment options for HA Quadruple-H-therapy : Rahimi R et al., Clin Liver Dis, 2015 Warrillow SJ et al., Anaesth Intensive Care, 2014 Ghannoum M et al. (EXTRIP), Clin Toxicology, 2015
85 General treatment options for HA Quadruple-H-therapy : Hyperventilation: to minimize hyperemic cerebral edema Rahimi R et al., Clin Liver Dis, 2015 Warrillow SJ et al., Anaesth Intensive Care, 2014 Ghannoum M et al. (EXTRIP), Clin Toxicology, 2015
86 General treatment options for HA Quadruple-H-therapy : Hyperventilation: to minimize hyperemic cerebral edema Hemodialysis / MARS : rapid reduction of ammonia and reduced production by lowering core temperature (no established cut-off for ammonia; ECTR suggested at VPA conc. >900 [1D] and recommended at VPA con. >1.300 mg/l [1D] Rahimi R et al., Clin Liver Dis, 2015 Warrillow SJ et al., Anaesth Intensive Care, 2014 Ghannoum M et al. (EXTRIP), Clin Toxicology, 2015
87 General treatment options for HA Quadruple-H-therapy : Hyperventilation: to minimize hyperemic cerebral edema Hemodialysis / MARS : rapid reduction of ammonia and reduced production by lowering core temperature (no established cut-off for ammonia; ECTR suggested at VPA conc. >900 [1D] and recommended at VPA con. >1.300 mg/l [1D] Hypernatremia: increases serum tonicity and reduces cerebral swelling Rahimi R et al., Clin Liver Dis, 2015 Warrillow SJ et al., Anaesth Intensive Care, 2014 Ghannoum M et al. (EXTRIP), Clin Toxicology, 2015
88 General treatment options for HA Quadruple-H-therapy : Hyperventilation: to minimize hyperemic cerebral edema Hemodialysis / MARS : rapid reduction of ammonia and reduced production by lowering core temperature (no established cut-off for ammonia; ECTR suggested at VPA conc. >900 [1D] and recommended at VPA con. >1.300 mg/l [1D] Hypernatremia: increases serum tonicity and reduces cerebral swelling Hypothermia: reduces pathologically increased cerebral blood-flow Rahimi R et al., Clin Liver Dis, 2015 Warrillow SJ et al., Anaesth Intensive Care, 2014 Ghannoum M et al. (EXTRIP), Clin Toxicology, 2015
89 General treatment options for HA Quadruple-H-therapy : Hyperventilation: to minimize hyperemic cerebral edema Hemodialysis / MARS : rapid reduction of ammonia and reduced production by lowering core temperature (no established cut-off for ammonia; ECTR suggested at VPA conc. >900 [1D] and recommended at VPA con. >1.300 mg/l [1D] Hypernatremia: increases serum tonicity and reduces cerebral swelling Hypothermia: reduces pathologically increased cerebral blood-flow Carglumic acid (CA; N-Carbamylglutamate; Carbaglu, mg/kg), a synthetic analog of NAG that activates CPS-I; Caveat: CA is approved for NAGS-deficiency (U.S./EU), but not labeled for secondary UC disorders; costs: /day Rahimi R et al., Clin Liver Dis, 2015 Warrillow SJ et al., Anaesth Intensive Care, 2014 Ghannoum M et al. (EXTRIP), Clin Toxicology, 2015
90 Specific treatment options for VPA-induced HA Nissim I et al., J Biol Chem, 2005 Bachmann C et al., Mol Genet Metab, 2004 Häberle J et al., Orphanet J Rare Dis, 2012
91 Specific treatment options for VPA-induced HA Consider infusion of L-carnitine - an essential cofactor in the beta-oxidation of fatty acids in deficient patients: 100 mg/kg as a bolus, followed by 50 mg/kg every 8 hours with a maximum of 3 g - although a matter of debate Nissim I et al., J Biol Chem, 2005 Bachmann C et al., Mol Genet Metab, 2004 Häberle J et al., Orphanet J Rare Dis, 2012
92 Specific treatment options for VPA-induced HA Consider infusion of L-carnitine - an essential cofactor in the beta-oxidation of fatty acids in deficient patients: 100 mg/kg as a bolus, followed by 50 mg/kg every 8 hours with a maximum of 3 g - although a matter of debate Infusion of L-Arginine-HCl (1.2 mmol/kg within min, followed by 1.2 mmol/kg/day; costs 15.- /day) Nissim I et al., J Biol Chem, 2005 Bachmann C et al., Mol Genet Metab, 2004 Häberle J et al., Orphanet J Rare Dis, 2012
93 Specific treatment options for VPA-induced HA Consider infusion of L-carnitine - an essential cofactor in the beta-oxidation of fatty acids in deficient patients: 100 mg/kg as a bolus, followed by 50 mg/kg every 8 hours with a maximum of 3 g - although a matter of debate Infusion of L-Arginine-HCl (1.2 mmol/kg within min, followed by 1.2 mmol/kg/day; costs 15.- /day) L-Arginine is metabolized to provide ornithine for citrullinesynthesis, priming the urea cycle; additionally, OTC is the most common type of late-onset UCD s. Nissim I et al., J Biol Chem, 2005 Bachmann C et al., Mol Genet Metab, 2004 Häberle J et al., Orphanet J Rare Dis, 2012
94 Specific treatment options for VPA-induced HA Consider infusion of L-carnitine - an essential cofactor in the beta-oxidation of fatty acids in deficient patients: 100 mg/kg as a bolus, followed by 50 mg/kg every 8 hours with a maximum of 3 g - although a matter of debate Infusion of L-Arginine-HCl (1.2 mmol/kg within min, followed by 1.2 mmol/kg/day; costs 15.- /day) L-Arginine is metabolized to provide ornithine for citrullinesynthesis, priming the urea cycle; additionally, OTC is the most common type of late-onset UCD s. Side effects of arginine administration include metabolic acidosis, nausea, numbness, headache, thrombocytopenia, and low blood pressure Nissim I et al., J Biol Chem, 2005 Bachmann C et al., Mol Genet Metab, 2004 Häberle J et al., Orphanet J Rare Dis, 2012
95 Summary of VPA-induced HA L-Carnitine Pedron GC et al., J Inherit Metab Dis, 2008 Colomer BF et al., An Pediatr (Barc.) 2014
96 Summary of VPA-induced HA L-Carnitine contributes to 25% of VPA-induced ammonia increase Pedron GC et al., J Inherit Metab Dis, 2008 Colomer BF et al., An Pediatr (Barc.) 2014
97 Thank you for your kind attention!
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