Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Hyperammonemia Treatment & Management

  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS  more...
 
Updated: Nov 30, 2015
 

Medical Care

The aims are to correct biochemical abnormalities and ensure adequate nutritional intake. Treatment involves compounds that increase the removal of nitrogen waste. These compounds convert nitrogen into products other than urea, which are then excreted; hence, the load on the urea cycle is reduced. The first compounds to be used were sodium benzoate and arginine. Later, phenylacetate was used, which has now been replaced by phenylbutyrate.

  • Treatment of neonatal hyperammonemic coma
    • Protein intake should be stopped.
    • Calories should be supplied by giving hypertonic 10% glucose.
    • Hemodialysis should be started promptly in all comatose neonates with plasma ammonium levels greater than 10 times reference range. Plasma ammonium levels are reduced quickly and the total dialysis time is shorter with hemodialysis than with peritoneal dialysis. Continuous arteriovenous or venovenous hemofiltration may be used as an alternative method.[27]
    • Intravenous sodium benzoate and phenylacetate should be started once the plasma ammonium level falls to 3-4 times the upper limit of the reference range.
    • Intravenous arginine should be provided.
    • Corticosteroids are not indicated for the management of increased intracranial pressure in hyperammonemia because they induce negative nitrogen balance. Mannitol is not effective in treating cerebral edema induced by hyperammonemia.
    • Valproic acid should not be used to treat seizures as it decreases urea cycle function and increases serum ammonia levels.
  • Treatment of intercurrent hyperammonemia
    • Patients with urea cycle defects may present with episodes of hyperammonemia secondary to increased protein intake, increased catabolism, or noncompliance with therapy. This should be recognized early and treated as an emergency.
    • Treatment should be started if the plasma ammonium level is 3 times the reference level.
    • All nitrogen intake should be stopped.
    • High parenteral intake of calories from 10-15% glucose and intralipids should be provided.
    • Intravenous infusion of sodium benzoate and phenylacetate should be started.
    • Plasma ammonium levels should be checked at the end of the infusion and every 8 hours.
    • Once the ammonia level is near normal, oral medication should be started.
    • If the level does not decrease in 8 hours, hemodialysis should be started.
    • Osmotic demyelination syndrome has been reported as a potential serious complication of standard therapy for hyperammonemia in patients with ornithine transcarbamylase deficiency.[28]
Next

Surgical Care

See the list below:

  • Liver transplantation: The main goal of liver transplantation is to correct the metabolic error. In one recent study of liver transplantation in patients with defects causing hyperammonemia, metabolic errors were corrected in all patients, and requirements for medication and dietary restriction were eliminated. Neurologic outcomes correlated closely with status prior to transplantation. Thus, liver transplantation is a good option for patients with urea cycle defects who have not suffered major brain injury.
  • Liver cell transplantation, administered as multiple intraportal infusions of cryopreserved hepatocytes, has been reported as a potentially less invasive alternative or bridging to liver transplantation.[2, 3]
Previous
Next

Consultations

See the list below:

  • Nephrologist for hemodialysis
  • Dietitian to help with the dietary management and education of the family
  • Geneticist for possible testing of family members and to provide genetic counseling
Previous
Next

Diet

Dietary management consists of the following:

  • Low protein intake: Current recommendation is 0.7 g/kg/day of protein and 0.7 g/kg/day of essential amino acid mixture. During the first 6 months, an infant may tolerate 1.5-2 g/kg/day of protein.
  • Arginine supplementation: Arginine is an essential amino acid in patients with urea cycle defects. In neonates and in OTC and CPSI deficiencies, citrulline can be given as a source of arginine as it gives one less nitrogen atom; in late-onset cases, however, arginine is acceptable because of increased nitrogen tolerance. Citrulline levels are elevated in ASS and ASL deficiencies and citrulline should not be administered in patients with unknown enzyme deficiency.
  • Providing enough calories to meet energy requirements
  • A tube feeding may be needed to provide a stable feeding route. A gastrostomy tube is the most reliable way to administer medications and fluids during illness and helps provide adequate nutritional support to prevent catabolism.[1]
Previous
Next

Activity

Restricting physical activity of these children is not necessary; however, caloric intake should be sufficient to avoid protein breakdown.

Previous
 
 
Contributor Information and Disclosures
Author

Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS is a member of the following medical societies: American College of International Physicians, American Heart Association, American Stroke Association, American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners Institute, National Association of Managed Care Physicians, American College of Physicians, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, Royal Society of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

J Stephen Huff, MD, FACEP Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD, FACEP is a member of the following medical societies: American Academy of Neurology, American College of Emergency Physicians, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Elena Crisan, MD Neurology Staff, Department of Neurology, Edwards Hines Veterans Affairs Hospital; Assistant Professor of Neurology, Loyola University Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Kazi Imran Majeed, MD to the development and writing of this article.

References
  1. Haeberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, et al. Suggested Guidelines for the Diagnosis and Management of Urea Cycle Disorders. Orphanet J Rare Dis. 2012 May 29. 7(1):32. [Medline].

  2. Meyburg J, Das AM, Hoerster F, Lindner M, Kriegbaum H, Engelmann G, et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation. 2009 Mar 15. 87(5):636-41. [Medline].

  3. Meyburg J, Schmidt J, Hoffmann GF. Liver cell transplantation in children. Clin Transplant. 2009 Dec. 23 Suppl 21:75-82. [Medline].

  4. Rodrigo R, Cauli O, Boix J, ElMlili N, Agusti A, Felipo V. Role of NMDA receptors in acute liver failure and ammonia toxicity: therapeutical implications. Neurochem Int. 2009 Jul-Aug. 55(1-3):113-8. [Medline].

  5. Lichter-Konecki U, Mangin JM, Gordish-Dressman H, Hoffman EP, Gallo V. Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. Glia. 2008 Mar. 56(4):365-77. [Medline].

  6. Panickar KS, Jayakumar AR, Rao KV, Norenberg MD. Ammonia-induced activation of p53 in cultured astrocytes: role in cell swelling and glutamate uptake. Neurochem Int. 2009 Jul-Aug. 55(1-3):98-105. [Medline].

  7. Llansola M, Rodrigo R, Monfort P, Montoliu C, Kosenko E, Cauli O, et al. NMDA receptors in hyperammonemia and hepatic encephalopathy. Metab Brain Dis. 2007 Dec. 22(3-4):321-35. [Medline].

  8. Monfort P, Cauli O, Montoliu C, Rodrigo R, Llansola M, Piedrafita B, et al. Mechanisms of cognitive alterations in hyperammonemia and hepatic encephalopathy: therapeutical implications. Neurochem Int. 2009 Jul-Aug. 55(1-3):106-12. [Medline].

  9. Schliess F, Görg B, Häussinger D. RNA oxidation and zinc in hepatic encephalopathy and hyperammonemia. Metab Brain Dis. 2009 Mar. 24(1):119-34. [Medline].

  10. Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008 Oct. 97(10):1420-5. [Medline]. [Full Text].

  11. Ichikawa K, Gakumazawa M, Inaba A, Shiga K, Takeshita S, Mori M, et al. Acute encephalopathy of Bacillus cereus mimicking Reye syndrome. Brain Dev. 2009 Sep 29. [Medline].

  12. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009 Feb. 47(2):101-11. [Medline].

  13. DeWolfe JL, Knowlton RC, Beasley MT, Cofield S, Faught E, Limdi NA. Hyperammonemia following intravenous valproate loading. Epilepsy Res. 2009 Jul. 85(1):65-71. [Medline].

  14. Cheung E, Wong V, Fung CW. Topiramate-valproate-induced hyperammonemic encephalopathy syndrome: case report. J Child Neurol. 2005 Feb. 20(2):157-60. [Medline].

  15. Deutsch SI, Burket JA, Rosse RB. Valproate-induced hyperammonemic encephalopathy and normal liver functions: possible synergism with topiramate. Clin Neuropharmacol. 2009 Nov-Dec. 32(6):350-2. [Medline].

  16. Tantikittichaikul S, Johnson J, Laengvejkal P, DeToledo J. Topiramate-induced hyperammonemic encephalopathy in a patient with mental retardation: A case report and review of the literature. Epilepsy Behav Case Rep. 2015. 4:84-5. [Medline]. [Full Text].

  17. Adler LW, Regenold WT. Valproate-Related Hyperammonemia in Older Adult Psychiatric Inpatients. Prim Care Companion CNS Disord. 2015. 17 (2):[Medline].

  18. Adams EN, Marks A, Lizer MH. Carbamazepine-induced hyperammonemia. Am J Health Syst Pharm. 2009 Aug 15. 66(16):1468-70. [Medline].

  19. Yamamoto Y, Takahashi Y, Imai K, Mishima N, Yazawa R, Inoue K, et al. Risk factors for hyperammonemia in pediatric patients with epilepsy. Epilepsia. 2013 Feb 14. [Medline].

  20. Adatia S, Poladia B, Joshi SR, Panikar V, Chauhan V, Hastak SM. Hyperammonemic coma presenting as Hashimoto's encephalopathy. J Assoc Physicians India. 2008 Dec. 56:989-91. [Medline].

  21. Rimar D, Kruzel-Davila E, Dori G, Baron E, Bitterman H. Hyperammonemic coma--barking up the wrong tree. J Gen Intern Med. 2007 Apr. 22(4):549-52. [Medline].

  22. Lora-Tamayo J, Palom X, Sarrá J, Gasch O, Isern V, Fernández de Sevilla A, et al. Multiple myeloma and hyperammonemic encephalopathy: review of 27 cases. Clin Lymphoma Myeloma. 2008 Dec. 8(6):363-9. [Medline].

  23. Rovira A, Alonso J, Córdoba J. MR imaging findings in hepatic encephalopathy. AJNR Am J Neuroradiol. 2008 Oct. 29(9):1612-21. [Medline].

  24. Zwingmann C. Nuclear magnetic resonance studies of energy metabolism and glutamine shunt in hepatic encephalopathy and hyperammonemia. J Neurosci Res. 2007 Nov 15. 85(15):3429-42. [Medline].

  25. Al-Hassnan ZN, Rashed MS, Al-Dirbashi OY, Patay Z, Rahbeeni Z, Abu-Amero KK. Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with stroke-like imaging presentation: clinical, biochemical and molecular analysis. J Neurol Sci. 2008 Jan 15. 264(1-2):187-94. [Medline].

  26. Oldham MS, VanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Pediatr Neurol. 2010 Jan. 42(1):49-52. [Medline].

  27. Arbeiter AK, Kranz B, Wingen AM, Bonzel KE, Dohna-Schwake C, Hanssler L, et al. Continuous venovenous haemodialysis (CVVHD) and continuous peritoneal dialysis (CPD) in the acute management of 21 children with inborn errors of metabolism. Nephrol Dial Transplant. 2009 Nov 23. [Medline].

  28. Cardenas JF, Bodensteiner JB. Osmotic Demyelination Syndrome as a Consequence of Treating Hyperammonemia in a Patient With Ornithine Transcarbamylase Deficiency. J Child Neurol. 2009 Feb 18. [Medline].

  29. Thompson CA. Carglumic acid approved to treat genetic hyperammonemia. Am J Health Syst Pharm. 2010 May 1. 67(9):690. [Medline].

  30. Albrecht J. Roles of neuroactive amino acids in ammonia neurotoxicity. J Neurosci Res. 1998 Jan 15. 51(2):133-8. [Medline].

  31. Albrecht J, Jones EA. Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. J Neurol Sci. 1999 Nov 30. 170(2):138-46. [Medline].

  32. Batshaw ML. Hyperammonemia. Curr Probl Pediatr. 1984 Nov. 14(11):1-69. [Medline].

  33. Batshaw ML. Inborn errors of urea synthesis. Ann Neurol. 1994 Feb. 35(2):133-41. [Medline].

  34. Becker L, Prior T, Yates A. Metabolic diseases. Textbook of Neuropathology, Baltimore: Williams & Wilkins. 1997. 487.

  35. Berlot G, Battaglia K, Ukmar M. [Hyperammoniemia and central pontine myelinolysis in a patient with Sjögren syndrome and chronic valproate use]. Recenti Prog Med. 2008 Oct. 99(10):502-4. [Medline].

  36. Bhoyar A, Short A. Congenital hypopituitarism associated with hyperammonemia. Indian J Pediatr. 2009 Mar. 76(3):327-8. [Medline].

  37. Bosoi CR, Rose CF. Identifying the direct effects of ammonia on the brain. Metab Brain Dis. 2009 Mar. 24(1):95-102. [Medline].

  38. Breningstall GN. Neurologic syndromes in hyperammonemic disorders. Pediatr Neurol. 1986 Sep-Oct. 2(5):253-62. [Medline].

  39. Brusilow SW, Horwich AL. Urea cycle disorders. The Metabolic and Molecular Bases of Inherited Disease, New York: McGraw-Hill. 1995. 1:1187-1232.

  40. Chung MY, Chen CC, Huang LT, et al. Transient hyperammonemia in a neonate. Acta Paediatr Taiwan. 2005 Mar-Apr. 46(2):94-6. [Medline].

  41. Cohn RM, Roth KS. Hyperammonemia, bane of the brain. Clin Pediatr (Phila). 2004 Oct. 43(8):683-9. [Medline].

  42. Collins FS, Summer GK, Schwartz RP, Parke JC Jr. Neonatal argininosuccinic aciduria-survival after early diagnosis and dietary management. J Pediatr. 1980 Mar. 96(3 Pt 1):429-31. [Medline].

  43. del Rosario M, Werlin SL, Lauer SJ. Hyperammonemic encephalopathy after chemotherapy. Survival after treatment with sodium benzoate and sodium phenylacetate. J Clin Gastroenterol. 1997 Dec. 25(4):682-4. [Medline].

  44. Deodato F, Boenzi S, Rizzo C, et al. Inborn errors of metabolism: an update on epidemiology and on neonatal-onset hyperammonemia. Acta Paediatr Suppl. 2004 May. 93(445):18-21. [Medline].

  45. Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, et al. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology. 2012 Sep 7. [Medline]. [Full Text].

  46. Feillet F, Leonard JV. Alternative pathway therapy for urea cycle disorders. J Inherit Metab Dis. 1998. 21 Suppl 1:101-11. [Medline].

  47. Felipo V, Kosenko E, Minana MD, et al. Molecular mechanism of acute ammonia toxicity and of its prevention by L-carnitine. Adv Exp Med Biol. 1994. 368:65-77. [Medline].

  48. Hamed SA, Abdella MM. The risk of asymptomatic hyperammonemia in children with idiopathic epilepsy treated with valproate: Relationship to blood carnitine status. Epilepsy Res. 2009 May 13. [Medline].

  49. Hauser ER, Finkelstein JE, Valle D, Brusilow SW. Allopurinol-induced orotidinuria. A test for mutations at the ornithine carbamoyltransferase locus in women. N Engl J Med. 1990 Jun 7. 322(23):1641-5. [Medline].

  50. Jalan R, Lee WM. Treatment of Hyperammonemia in Liver Failure: A Tale of Two Enzymes. Gastroenterology. 2009 Apr 28. [Medline].

  51. Kuntze JR, Weinberg AC, Ahlering TE. Hyperammonemic coma due to Proteus infection. J Urol. 1985 Nov. 134(5):972-3. [Medline].

  52. Logan W. Neonatal hyperammonemic encephalopathy. Topics in Neonatal Neurology, Orlando: Grune & Stratton. 1984. 137-157.

  53. Maestri NE, McGowan KD, Brusilow SW. Plasma glutamine concentration: a guide in the management of urea cycle disorders. J Pediatr. 1992 Aug. 121(2):259-61. [Medline].

  54. McCall M, Bourgeois JA. Valproic acid-induced hyperammonemia: a case report. J Clin Psychopharmacol. 2004 Oct. 24(5):521-6. [Medline].

  55. McGuire PJ, Lee HS, Summar ML. Infectious Precipitants of Acute Hyperammonemia Are Associated with Indicators of Increased Morbidity in Patients with Urea Cycle Disorders. J Pediatr. 2013 Sep 28. [Medline].

  56. Msall M, Batshaw ML, Suss R, et al. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med. 1984 Jun 7. 310(23):1500-5. [Medline].

  57. Prasad AN, Breen JC, Ampola MG, Rosman NP. Argininemia: a treatable genetic cause of progressive spastic diplegia simulating cerebral palsy: case reports and literature review. J Child Neurol. 1997 Aug. 12(5):301-9. [Medline].

  58. Rajpoot DK, Gargus JJ. Acute hemodialysis for hyperammonemia in small neonates. Pediatr Nephrol. 2004 Apr. 19(4):390-5. [Medline].

  59. Ratnaike RN, Schapel GJ, Purdie G, et al. Hyperammonaemia and hepatotoxicity during chronic valproate therapy: enhancement by combination with other antiepileptic drugs. Br J Clin Pharmacol. 1986 Jul. 22(1):100-3. [Medline].

  60. Schaefer F, Straube E, Oh J, et al. Dialysis in neonates with inborn errors of metabolism. Nephrol Dial Transplant. 1999 Apr. 14(4):910-8. [Medline].

  61. Schutze GE, Edwards MS, Adham BI, Belmont JW. Hyperammonemia and neonatal herpes simplex pneumonitis. Pediatr Infect Dis J. 1990 Oct. 9(10):749-50. [Medline].

  62. Smith W, Diaz GA, Lichter-Konecki U, Berry SA, Harding CO, McCandless SE, et al. Ammonia Control in Children Ages 2 Months through 5 Years with Urea Cycle Disorders: Comparison of Sodium Phenylbutyrate and Glycerol Phenylbutyrate. J Pediatr. 2013 Jan 13. [Medline].

  63. Smith W, Kishnani PS, Lee B, et al. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin. 2005 Oct. 21(4 Suppl):S9-17. [Medline].

  64. Summar ML, Barr F, Dawling S, et al. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin. 2005 Oct. 21(4 Suppl):S1-8. [Medline].

  65. Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis. 1998. 21 Suppl 1:151-9. [Medline].

  66. Weng TI, Shih FF, Chen WJ. Unusual causes of hyperammonemia in the ED. Am J Emerg Med. 2004 Mar. 22(2):105-7. [Medline].

  67. Whitington PF, Alonso EM, Boyle JT, et al. Liver transplantation for the treatment of urea cycle disorders. J Inherit Metab Dis. 1998. 21 Suppl 1:112-8. [Medline].

  68. Williams CA, Tiefenbach S, McReynolds JW. Valproic acid-induced hyperammonemia in mentally retarded adults. Neurology. 1984 Apr. 34(4):550-3. [Medline].

Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.