The Therapeutic Hypothermia in Treatment of Hyperammonemic Encephalopathy due to Urea Cycle Disorders and Organic Acidemias

Abstract

Background Hyperammonemic encephalopathy in newborns with urea cycle disorders and certain organic acidurias can cause severe brain injury, coma and death. Standard therapy includes protein restriction, nitrogen-scavenging drugs, prevention of catabolism and hemodialysis. Neuroprotective hypothermia as part of the treatment has been reported only 3 times. It has been suggested that mild systemic hypothermia can contribute to better neurological outcomes in hyperammonemic encephalopathy. However, the limited experience precludes accurate conclusions on safety and efficacy.

Methods Whole body therapeutic hypothermia was included in the standard treatment of hyperammonemic encephalopathy in 4 neonates with urea cycle disorder or organic aciduria.

Results Two patients survived the initial crisis. One patient has a developmental quotient of 0.8, while the other shows severe developmental delay. The cooling protocol had to be discontinued in 3 patients due to the otherwise untreatable complications (hypotension and hemorrhage).

Conclusion The efficacy and safety of therapeutic hypothermia in the treatment of neonatal hyperammonemic encephalopathy depend on various factors, requiring further evaluation.

Zusammenfassung

Hintergrund Die hyperammonämische Enzephalopathie bei Neugeborenen mit Harnstoffzyklusstörungen und bestimmten organischen Azidämien kann zu schweren Hirnverletzungen, Koma und Tod führen. Die Standardbehandlung umfasst Proteinrestriktion, „Stickstoff-fangenden“ Medikamente, Katabolismusprävention und die Hämodialyse. Die neuroprotektive Hypothermie wurde als Teil der Behandlung nur 3-mal berichtet. Es wurde vorgeschlagen, dass die milde systemische Hypothermie für bessere neurologische Ergebnisse bei der hyperammonämischen Enzephalopathie beitragen kann. Die begrenzte Erfahrung schließt jedoch die genauen Schlussfolgerungen zu Sicherheit und Wirksamkeit aus.

Methoden Bei 4 Neugeborenen mit Harnstoffzyklusstörung oder organischer Azidämie wurde die Ganzkörper-Hypothermie in die Standardbehandlung der hyperammonämischen Enzephalopathie eingezogen.

Ergebnisse Zwei Patienten überlebten die erste Krise. Ein Patient hat einen Entwicklungsquotient von 0,8, während der andere schwere Entwicklungsverzögerung zeigt. Das Kühlungsprotokoll musste bei 3 Patienten wegen der nicht behandelbaren Komplikationen (niedriger Blutdruck und Blutungen) abgebrochen werden.

Schlussfolgerung Die Wirksamkeit und Sicherheit der therapeutischen Hypothermie bei der Behandlung der neonatalen hyperammonämischen Enzephalopathie hängt von verschiedenen Faktoren ab, die eine weitere Evaluierung erfordern.

Key words

hyperammonemic coma - encephalopathy - urea cycle disorders - organic acidurias - therapeutic hypothermia - hypotension

Schlüsselwörter

hyperammonämisches Koma - Enzephalopathie - Harnstoffzyklusstörungen - organische Acidurias - therapeutische Hypothermie - Hypotonie

• References

• 1 Albrecht J, Zielińska M, Norenberg MD. Glutamine as a mediator of ammonia neurotoxicity: A critical appraisal. Biochem Pharmacol 2010; 80: 1303-1308
• 2 Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr 2003; 162: 410-416
• 3 Baumgartner MR, Hörster F, Dionisi-Vici C. et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis 2014; 9: 130
• 4 Braissant O, McLin VA, Cudalb C. Ammonia toxicity to the brain. J Inherit Metab Dis 2013; 36: 595-612
• 5 Enns GM. Neurologic damage and neurocognitive dysfunction in urea cycle disorders. Semin Pediatr Neurol 2008; 15: 132-139
• 6 Enns MS. Nitrogen sparing therapy revisited 2009. Mol Genet Metab 2010; 100: 65-71
• 7 Felipo V, Butterworth RF. Neurobiology of ammonia. Prog Neurobiol 2002; 67: 259-279
• 8 Haeberle J. et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 2012; 7: 32
• 9 Hallberg B, Grossmann K, Bartocci M. et al. The prognostic value of early aEEG in asphyxiated infants undergoing systemic hypothermia treatment. Act Paediatr 2010; 4: 531-536
• 10 lzke SM, Rao S, Patole SK. A systematic review of cooling for neuroprotection with hypoxic-ischemic encephalopathy – are we there yet?. BMC Pediatr 2007; 7: 1-30
• 11 Jacob S, Hunt R, Tarnow-Mordi W. et al. Cooling for newborns with hypoxic-ischemic encephalopathy. Cochrane Database Syst Rev 2007; 4: 1-46
• 12 Jalan R, Damink S, Deutz N. et al. Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet 1999; 354: 1164-1168
• 13 Jalan R, Damink S. Hypothermia for the management of intracranial hypertension in acute liver failure. Curr Opin Crit Care 2001; 7: 257-262
• 14 Kölker S, Cazorla AG, Valayannopoulos V. et al. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis 2015; 38: 1041-1057
• 15 Leonard JV, Morris AA. Urea cycle disorders. Semin Neonatol 2002; 7: 27-35
• 16 Lichter-Konecki U. Profiling of astrocyte properties in the hyperammonaemic brain: shedding new light on the pathophysiology of the brain damage in hyperammonaemia. J Inherit Metab Dis 2008; 31: 492-502
• 17 Lichter-Konecki U, Nadkarni V, Moudgil A. et al. Feasibility of adjunct therapeutic hypothermia treatment for hyperammonemia and encephalopathy due to urea cycle disorders and organic acidemias. Mol Genet Metab 2013; 109: 354-359
• 18 Majoie C, Mourmans J, Akkerman E. et al. Neonatal citrullinemia: comparison of conventional MR, diffusion-weighted, and diffusion tensor findings. Am J Neuroradiol 2004; 25: 32-35
• 19 Mehta S, Stewart DJ, Levy RD. The hypotensive effect of L-arginine is associated with increased expired nitric oxide in humans. Chest 1996; 109: 1550-1555
• 20 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; 310: 1500-1505
• 21 Nassogne MC, Heron B, Touati G. et al. Urea cycle defects: management and outcome. J Inherit Metab Dis 2005; 28: 407-414
• 22 Ott P, Vilstrup H. Cerebral effects of ammonia in liver disease: current hypotheses. Metabolic Brain Disease 2014; 29: 901-911
• 23 Picca S, Dionisi-Vici C, Abeni D. et al. Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Pediatr Nephrol 2001; 16: 862-867
• 24 Schaefer F, Straube E, Oh J. et al. Dialysis in neonates with inborn errors of metabolism. Nephrol Dial Transplant 1999; 14: 910-918
• 25 Shankaran S. Therapeutic hypothermia for neonatal encephalopathy. Curr Treat Options Neurol 2012; 14: 608-619
• 26 Takanashi J, Barkovich JA, Cheng SF. et al. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. Am J Neuroradiol 2003; 24: 1184-1187
• 27 Takeoka M, Soman TB, Shih VE. et al. Carbamyl phosphate synthetase 1 deficiency: a destructive encephalopathy. Pediatr Neurol 2001; 24: 193-199
• 28 The Urea Cycle Disorders group. Ahrens M, Barsotti R, Batshaw M. et a). Consensus statement from a Conference for the Management of Patients with Urea Cycle Disorders. J Pediatr 2001; 138: S1-S5
• 29 Vargha R, Möslinger D, Wagner O. et al. Venovenous hemodiafiltration and hypothermia for treatment of cerebral edema associated with hyperammonemia. Indian Pediatr 2012; 49: 60-62
• 30 Walker V. Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab 2009; 11: 82-87
• 31 Westrope C, Morris K, Burford D. et al. Continuous hemofiltration in the control of neonatal hyperammonemia: a 10-year experience. Pediatr Nephrol 2010; 25: 1725-1730
• 32 Whitelaw A, Bridges S, Leaf A. et al. Emergency treatment of neonatal hyperammonaemic coma with mild systemic hypothermia. Lancet 2001; 358: 36-38