Journal of Hepatology zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 1991; 21: 231-238 Printed in Denmark All rights reserved zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Munksgaard Copenhagen Copyright 0 European Association for the Study of the Liver 1997 Journalof Hepatology ISSN 0168-8278 Review Article Pathophysiological changes in cerebral circulation, oxidative metabolism and blood-brainbarrier in patients with acute liver failure Tailored cerebral oxygen utilization Fin Stolze Larsen’, Gitte Moos Knudsen’ and Bent Adel Hansen’ Departments of ‘Hepatology and 2Neurology. Rigshospitalet. University of Copenhagen, Denmark AUNDICE zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA J associated with cerebral dysfunction has since ancient times been associated with a poor prognosis. This ancient observation is still dramatically manifested in acute liver failure with rapid develop- ment of hepatic encephalopathy, cerebral oedema and multiorgan dysfunction. Advances in intensive care management and liver transplantation have improved survival rates irrespective of almost all causes of ful- minant hepatic failure (FHF) (1). However, cerebral oedema continues to be one of the most common causes of death in FHE Considerable efforts have been put into unravelling the pathophysiological basis of intracranial hyperten- sion in FHE Although it seems well established that cerebral oedema is localised to the perivascular space and astrocytes (2,3), the pathogenesis of cerebral oede- ma seems to be multi-faceted, with alterations in brain metabolism (4,5), astrocyte osmo-regulation (3,6,7), neurotransmission (8-lo), and blood-brain barrier transport mechanisms (7,ll). However, the surges of intracranial hypertension could theoretically also result from episodes of cerebrovascular engorgement due to inappropriate vasodilatation. Although the patho- physiological importance of changes in cerebral blood volume remains to be finally determined, distinct and rapid changes in the regulation of cerebral blood flow in patients with FHF have recently been put into focus (12). In all organs, blood flow depends on vascular resis- tance and perfusion pressure. In the brain, a decrease in cerebral perfusion pressure, defined as mean arterial Correspondence: Fin Stolze Larsen, MD, Division of Hepatology A-2102, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen 0, Denmark. Tel: 45 3545 2357. Fax: 45 4922 5 115. e-mail: stolze@post3.tele.dk. pressure minus intracranial pressure, is compensated by a decrease in cerebral vascular resistance. This means that cerebral blood flow is maintained un- changed even if cerebral perfusion pressure decreases as much as 20%, i.e. down to -65 mmHg in cerebral perfusion pressure. Below this limit of cerebral per- fusion pressure, cerebral oxidative metabolism is pre- served further down to a value of 40 mmHg by increas- ing cerebral oxygen extraction (13,14). Actually, a ce- rebral perfusion pressure below 40 mmHg for more than 2 h has been suggested to contraindicate liver transplantation as the likelihood of irreversible isch- aemic brain injury has been considered overwhelming (15,16). This 40 mmHg limit of cerebral perfusion pressure does not, however, appear to be substantiated as an indicator of insufficient cerebral blood flow in patients with FHF (17), since preserved cerebral oxida- tive metabolism (5,18) and survival has been reported in patients with cerebral perfusion pressure as low as 15 mmHg (19). This paper reviews the importance of cerebral oxida- tive metabolism for brain oedema formation in acute liver failure and focuses on changes in the regulation of cerebral circulation and the blood-brain barrier per- meability. Based on these pathophysiological changes, a new concept with a pivotal focus on securing cerebral oxygen utilisation is forwarded. Basic Pathophysiology Vasogenic and cytotoxic oedema A common response of the brain to a variety of dis- eases and injuries is the formation of cerebral oedema. In 1967, Klatzo (20) advocated a classification of cer- ebral oedema into vasogenic and cytotoxic oedema, which also has been considered useful to describe structural brain changes in FHF (7). 231