Acute hyperammonemia

Both acute hyperammonemia (Kosenko et al., 1995) and chronic hyperammonemia resulting from portacaval anastomosis (Raghavendra Rao et al., 1997) result in increased expression of nitric oxide synthase (NOS-1 isoform) in the brain. Nitric oxide synthase activities are also increased by an ammonia-induced stimulation of L-arginine uptake into neuronal preparations both in vitro and in vivo (Raghavendra Rao et al 1997). Selective NOS-1 inhibitors, such as nitroarginine, inhibit many of the metabolic and toxic effects of acute hyperammonemia (Kosenko et al., 1995). However, NOS-I inhibitors were ineffective in the prevention of intracranial hypertension in portacaval shunted rats administered ammonium salts (Larsen et al., 2001). 

Haberle J. Role of caiglumic add in the treatment of acute hyperammonemia due to N-acetylglutamate synthase defidency. Ther Qin Risk Manag. 2011 7 327-32. 

Dialysis, including hemodialysis and peritoneal dialysis, relieves acute toxicity during fulminant hyperammonemia. Exchange transfusions also have been performed, but this technique has not been equally useful in removing ammonia. 

Acquired hyperammonemia Liver disease is a common cause of hyperammonemia in adults. It may be a result of an acute po cess, for example, viral hepatitis, ischemia, or hepatotoxins. Cirrhosis of the liver caused by alcoholism, hepatitis, or biiary obstruction may result in formation of collateral circulation around the liver. As a result, portal blood is shunted directly rto the systemic circulation and does not have access to the ter. The detoxification of ammonia (that is, its conversion to urea) is, therefore, severely impaired, leading to elevated levels of cicu lating ammonia. 

Hyperammonemia has occurred during parenteral nutrition as a component of therapy for renal insufficiency (905). The hyperammonemia presented as a change in mental status, developing about 3 weeks after initiation of parenteral nutrition therapy in most cases the episodes are of increasing duration and paroxysmal. In three of the patients, serum amino acid analysis in the acute phase showed reduced concentrations of ornithine and citrulline (the respective substrate and product of condensation with carbamyl phosphate at its entry into the urea cycle). Concentrations of arginine, the precursor to ornithine, were raised. 

Treatment for patients with a UCD can be divided into two parts acute management of hyperammonemic encephalopathy and long-term control to prevent further episodes of hyperammonemia while maintaining normal growth and development. 

Of as yet unknown consequence to the brain and nervous system, there are many studies indicating that valproic acid promotes a variety of potentially dangerous viruses (e.g., Fan et al., 2005). Both valproic acid and carbamazepine cause a small increase in the rate of major congenital malformations in infants (Wide et al., 2004). Acute and potentially fatal pancreatitis has been reported with valproic acid (e.g., Grauso-Eby et al., 2003). Liver failure is a known problem as well. Valproic acid is known to cause hyperammonemia with encephalopathy (e.g., McCall et al., 2004). Severe and even lethal skin disorders can occur with all of the antiseizure medications now used as mood stabilizers. The various adverse effects of valproic acid and other mood stabilizers are not nearly as benign as physicians believe in their eagerness to switch patients from lithium. 

Kimura A, Yoshida I, Ono E, Matsuishi T, Yoshino M, Yamashita F, Yamamoto M, Hashimoto T, Shinka T, Kuhara T, et al. Acute encephalopathy with hyperammonemia and dicarboxyhc aciduria during calcium hopantenate therapy a patient report. Brain Dev 1986 8(6) 601-5. 

Sedation, fatigue, dizziness, headache, ataxia, and insomnia are less frequent with valproate than with other anticonvulsants. However, encephalopathy, sometimes associated with hyperammonemia and/or liver failure, has been described on several occasions, with symptoms ranging from acute confusion to stnpor and even deep coma (SEDA-18, 69) (9). The stnpor tends to be associated with bilaterally synchronons high-voltage, slow-wave EEG activity. Psychiatric symptoms and increased seizure frequency can also occur. Although in some cases valproate-induced stupor can be associated with increased epileptiform activity, it appeared to be triggered by a cortical non-epileptic mechanism in six... 

Acute neonatal hyperammonemia, irrespective of cause, is a medical emergency and requires immediate and rapid lowering of ammonia levels to prevent serious effects on the brain. Useful measures include hemodialysis, exchange transfusion, peritoneal dialysis, and administration of arginine hydrochloride. The general goals of management are to... 

Other substances to which people have been exposed have been shown to alter the toxic effects of ammonia. Methionine sulfoximine, administered by intraperitoneal injection, suppressed the tonic convulsions produced by intravenous injection of ammonium chloride in mice (Hindfelt and Plum 1975 Warren and Schenker 1964). Intraperitoneal injection of alpha-methylglutamic acid also exerts a protective effect against hyperammonemia in rats (Lamar 1970). Nicotinohydroxamic acid and neomycin administered orally reduce blood ammonia levels and increase excretion of urea in treated rats (Haiada et al. 1985). Ethanol exerted a protective effect on acute ammonia intoxication in mice (O Connor et al. 

Konsenko E, Kaminsky YG, Felipo V, et al. 1993. Chronic hyperammonemia prevents changes in brain energy and ammonia metabolites induced by acute ammonium intoxication. Biochim Biophys Acta... 

A rare complication is fulminant hepatitis. Children <2 years of age with other medical conditions who were given multiple antiseizure agents were especially likely to suffer fatal hepatic injury there were no deaths reported for patients >10 years old who received only valproate. Acute pancreatitis and hyperammonemia have been associated with the use of valproic acid. Valproic acid can produce teratogenic effects such as neural tube defects. 

A. Severe valproate-induced hepatotoxicity, hyperammonemia, coma, or acute valproic acid overdose. Early intervention with iV (rather than orai)... 

However, encephalopathies with a metabohc basis tend to be the most problanatic for infants or children, with functional outcomes dependent upon timely and pradent interventions. Three varieties of metabolic encephalopathy in children are discussed here. The first two are closely related. Inborn (genetic) errors of metabolism can present in the newborn as severe encephalopathy from hyperammonemia alone. When a metabolic error presents months to years later, a degree of hepatic insufficiency may complicate the metabolic derangement. In acute or fulminant hepatic failure of any etiology (i.e., infections, drug-induced, toxin-related), the rise in serum ammonia may be only moderate but other factors contribute to the ensuing encephalopathy, which may be devastating within days. 

Als-Nielsen, B., L.L. Gluud, and C. Gluud, 2004. Non-absorbable disaccharides for hepatic encephalopathy Systematic review of randomised trials. Bmj, 328(7447) p. 1046 Azzopardi, J., et al.2002. Lack of evidence of cerebral oedema in adults treated for diabetic ketoacidosis with fluids of different tonicity. Diabetes Res CUn Pract, 57(2) pp. 87-92 Bachmann, C., 2002. Mechanisms of hyperammonemia. CUn Chem Lab Med, 40(7) pp. 653-662 Bhowmick, S.K., Levens, K.L. andRettig, K.R. 2005. Hyperosmolar hyperglycemic crisis An acute life-threatening event in children and adolescents with type 2 diabetes mellitus. Endocr Pract, 11(1) pp. 23-29... 

Verkhratsky A, Kirchhoff F. NMDA receptors in gUa. The Neuroscientist, 13(1), 2S-37, 2007 Vogels BA, Maas MA, Daalhuisen J, Quack G, Chamuleau RA. Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats. Hepatology, 25, 820-827, 1997 Weber EL Jr, Veach GL. The importance of the small intestine in gut ammonium production in the fasting dog. Gastroenterology, 77, 235-240, 1979... 

Seizures can be induced by hyperammonemia, relative ischemia and hypogly-caemia in patients with acute fiver failure. In addition, they can be induced by the development of brain edema, while on the other hand they increase brain edema. 

The symptoms of acute intoxication may be very similar to that of other diseases (Box 5.3), may often lead to a misdiagnosis and, at times, death. On the other hand, some metabolic disorders can predispose a neonate to frequent neonatal period complications such as infections like E. coli sepsis in children with galactosemia or hematological complications such as central nervous system hemorrhage in hyperammonemia or thrombocytopeiua due to bone marrow suppresion in some aminoacidurias [2,7],... 

Prevent Catabolism. Catabolic stress is a major source of waste nitrogen. Episodes of hyperammonemia are often precipitated by an acute infectious illness coupled with poor feeding. It can be challenging to provide sufficient calories to patients with UCD because they often have very poor appetites. The reason for anorexia in UCD may be twofold. One theory is that elevated blood... 

In the patient who is not dialyzed, protein should be limited for no more than 24-48 h to prevent further catabolism [21]. Some advocate providing essential amino acids even during an acute illness in order to prevent branched-chain amino acid deficiency that can occur with hyperammonemia and be further exacerbated by nitrogen-scavenging medications [28]. There is no consensus about whether protein should be reintroduced in the diet in 24 or 48 hours in acutely ill patients with UCD, and the decision is made by the medical team depending on the patient s ammonia, plasma amino acids, nutritional intake, and neurological status. 

FiUppi L, et al. N-carbamylgluteunate in emergency management of hyperammonemia in neonatal acute onset propionic and methylmalonic aciduria. Neonatology. 2010 97(3) 286-90. 

Kasapkara CS, et al. N-caibamylglutamate treatment for acute neonatal hyperammonemia in isovaleric acidemia. Eur J Pediatr. 2011 170(6) 799-801. 

---