Effects of High-Volume Plasmapheresis on Ammonia, Urea, and Amino Acids in Patients With Acute Liver Failure Jens Otto Clemmesen, M.D., Jens Kondrup, D.M.Sc., Lars Bo Nielsen, D.M.Sc., Fin Stolze Larsen, D.M.Sc., and Peter Ott, D.M.Sc. Departments of Hepatology, Clinical Nutrition, and Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark OBJECTIVE: In acute liver failure (ALF), urea production is severely impaired, and detoxification of ammonia by glu- tamine synthesis plays an important protective role. The aim of this study was to examine the effects of therapeutic high-volume plasmapheresis (HVP) on arterial concentra- tions and splanchnic exchange rates of ammonia, urea, and amino acids—in particular, glutamine. METHODS: A quantity of 8 L of plasma was exchanged over the course of 7 h in 11 patients with ALF after development of hepatic encephalopathy grade III–IV. Splanchnic ex- change rates of ammonia, urea, and amino acids were mea- sured by use of liver vein catheterization. RESULTS: HVP removed ammonia and glutamine at a rate of 1 mol/min and 27 mol/min, respectively. Arterial ammonia decreased from 160  65 to 114  50 mol/L (p  0.001). In contrast, arterial glutamine was only mini- mally changed from 1791  1655 to 1764  1875 mol/L (NS). This implied that the rate of systemic glutamine syn- thesis was increased by 27 mol/min. Splanchnic exchange rates (before vs after HVP) were as follows: for ammonia, -93  101 versus -70  80 mol/min (NS); urea-nitro- gen, 0.08  1.64 versus -0.31  0.45 mmol/min (NS); alanine, -73  151 versus 12  83 mol/min (p  0.05); and glutamine: 132  246 versus 186  285 mol/min (NS), with negative values denoting release. CONCLUSIONS: Arterial ammonia decreased during HVP in patients with ALF. The data suggest that this effect of HVP could be explained by increased hepatic urea synthesis and possibly by increased glutamine synthesis in muscle tissue. (Am J Gastroenterol 2001;96:1217–1223. © 2001 by Am. Coll. of Gastroenterology) INTRODUCTION In patients with acute liver failure (ALF), we recently re- ported that ammonia (NH 4 + + NH 3 ) was released from the splanchnic circulation and that a high arterial ammonia concentration was associated with cerebral herniation (1). This finding was in accordance with accumulating experi- mental evidence that ammonia is of pathophysiological im- portance for development of cerebral edema (2– 4). Ammo- nia is normally removed from the circulation in the liver by synthesis of urea and glutamine (5–9). The ammonia incor- porated into glutamine can be excreted by two mechanisms. Either glutamine is used in urea synthesis, or it can be metabolized in the kidneys where the ammonia can be excreted with the urine (10 –13). However, in ALF, the capacity for synthesis of urea is severely decreased (14, 15) and renal failure is frequent (16). Ammonia can also be detoxified by way of glutamine synthesis in muscle and brain tissue (5, 10, 17–22). Thus, in ALF, glutamine repre- sents a sink for ammonia but there is no means of removing glutamine and, as a consequence, it accumulates to very high concentrations (22–25). On this basis it can be hypoth- esized that a reduction in glutamine might be beneficial in ALF by facilitating additional conversion of ammonia into glutamine with a lowering of the ammonia concentration as a result. High-volume plasmapheresis (HVP) with exchange of 8 L of plasma over the course of 7 h has been used as artificial liver support in ALF. The treatment improves consciousness levels (26) and tends to normalize the hyperkinetic circula- tion in ALF (27, 28). It cannot be expected that HVP per se can lower ammonia because the plasma clearance of HVP (20 ml/min) is small compared to the large splanchnic ammonia release (22). However, because of the high level of glutamine in ALF, HVP can remove considerable amounts of glutamine from the circulation. Thus, in the present study, the therapeutic use of HVP provided a tool to study the effects of glutamine removal. Because the splanchnic han- dling of ammonia is impaired in these patients it was of special interest to assess to what extent the splanchnic metabolism of ammonia and relevant amino acids might be changed by HVP. The aim of this study was to examine the effects of HVP on arterial concentrations and splanchnic exchange rates of ammonia, urea, and amino acids—in particular, glutamine. Because ammonia is excreted in urine, urinary excretion was also measured. THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 96, No. 4, 2001 © 2001 by Am. Coll. of Gastroenterology ISSN 0002-9270/01/$20.00 Published by Elsevier Science Inc. PII S0002-9270(01)02269-9