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• W1590432470 abstract "The management of acute liver failure (ALF) is complex. The simultaneous need to establish the diagnosis, to determine a prognosis, and to treat the multiple complications associated with the disease requires multidisciplinary expertise in order to maximize outcomes. Of all the problems, management of the neurological picture is particularly fraught with difficulties. The pathogenesis of hepatic encephalopathy is complex,1 and treatment of the most fearsome complication, brain edema leading to intracranial hypertension, is based on few therapeutic options.2 Tools to monitor patients for the development of brain edema are imperfect. In many instances, a physical exam is unable to detect mild elevations in intracranial pressure. Arterial ammonia levels above 200 μg/dL place the patient at risk for cerebral herniation,3 but values below this value can be associated with either a favorable or unfavorable course. Imaging of the brain lacks sensitivity and is impractical for repeated measurements. Monitoring of intracranial pressure is used by many centers, especially in patients who are candidates for emergency liver transplantation.4 However, concern with the development of intracerebral hemorrhage, which can be fatal,5 has led well-experienced centers to shy away from the procedure.6 There is a real need to develop new tools to monitor the neurological picture and improve the ability to predict neurological outcomes. Could measurements of cerebral blood flow (CBF) provide such information? Under physiological conditions, CBF is tightly coupled to cerebral metabolism (metabolic autoregulation) and remains constant during wide changes in arterial pressure (vascular autoregulation).7 Insight into cerebral metabolism can be obtained indirectly by measuring cerebral oxygen consumption, the product of CBF and the arteriovenous oxygen difference. In this issue of Liver Transplantation,8 a report of the evolution of all these parameters, together with intracranial pressure (ICP), is presented from an experience with 26 patients. The authors propose a temporal sequence, evolving in 5 stages, which proceeds from (1) a low CBF and ICP at the onset to (2) a progressive rise in CBF (without changes in ICP) that culminates with (3) the development of intracranial hypertension. Once the latter is established, (4) CBF decreases until (5) brain death ensues. The sequence is deduced retrospectively from studies of patients at different stages, rather than a continuous measurement in the same individual. In addition, therapy was variable, a factor that could also affect the results. In spite of these limitations, there are two important correlates of this purported sequence. ALF, acute liver failure; CBF, cerebral blood flow; ICP, intracranial pressure; A-VΔO2, arteriovenous oxygen difference. Previous studies have reported a decrease in cerebral oxygen consumption in ALF.9 Changes in cerebral blood flow have been also reported, with both reduction10 and increase11 of cerebral perfusion noted. An initial reduction of cerebral blood flow could be explained by two nonexclusive mechanisms. In the first, a reduction in cerebral metabolism in patients with encephalopathy, as seen in the series from Pittsburgh,8 results in a corresponding decrease in perfusion, a manifestation of metabolic autoregulation. Indeed, cerebral oxygen consumption was low at this stage (and remained decreased throughout the course). In the second, peripheral arterial vasodilatation triggers a vasoconstrictive response in the cerebral circulation, similar to what is seen in the renal territory. Such a relation has been noted in patients with cirrhosis and ascites12 and could also be present in ALF, where a hyperdynamic circulation is clearly demonstrated.13 If cerebral metabolism is decreased, any rise in CBF would be viewed as inappropriate, an example of “luxury perfusion.” Aggarwal and coworkers8 defined absolute hyperemia as values of CBF above 2 SD of the mean of a group of 42 control subjects, while relative hyperemia was defined as values between the mean and the 2SD. Using these criteria, cerebral hyperemia was seen in 65-80% of subjects. The authors raise the possibility that cerebral hyperemia could be a contributor to the development of brain edema. There is strong experimental support for this tenet. Rats after porto-caval anastomosis that receive an ammonia infusion develop brain edema and exhibit a marked increase in CBF at the time of brain swelling14 Pharmacological reduction of CBF with indomethacin15 or an increase in CBF with vasopressin16 prevents or accelerates the development of brain edema, respectively. In human ALF, similar results were seen with these drugs, using ICP as an end point. Indomethacin reduced CBF and an elevated ICP,17 while terlipressin, a vasopressin analog, caused a rise in ICP in 6 subjects, even without changes in arterial pressure.18 What is the cause of cerebral hyperemia? In the experimental animal, there is evidence to suggest that the vasodilatory signal arises from the brain itself.14 Swollen astrocytes are a hallmark of the neuropathology of brain edema, the result of osmotic and metabolic alterations initiated by the accumulation of glutamine in this cell.19 Nitric oxide was the initial candidate to be the vasodilatory mediator, as increased expression of neuronal nitric oxide synthase can be detected in experimental ALF.20 However, inhibition of its activity did not prevent the rise in flow.21 Preliminary studies raise the possibility that activation of heme oxygenase 1, with production of carbon monoxide as the vasodilator, could be a cause of cerebral hyperemia. Astrocytes, but not neurons, exposed to ammonia markedly increase their expression of HO-1.22 Inhibition of HO-1 prevented cerebral hyperemia and the development of brain edema in an in vivo model.23 Why would the activity of HO-1 be increased? HO-1 is induced under conditions of oxidative stress, and there is increasing evidence that both nitrosative and oxidative stress can be detected both in vitro and in vivo under conditions of hyperammonemia.24 Does this mechanism in animals explain cerebral hyperemia in humans? The presence of oxidative stress in brain has not yet been reported in the brain of patients with ALF. Furthermore, factors other than ammonia may play a role in the neurological disturbance of this disease. The systemic inflammatory response is commonly detected in patients with ALF,25 and infection precedes the worsening of encephalopathy in both acetaminophen- and nonacetaminophen-induced ALF.26 Inflammation may play an important role in the development of intracranial hypertension.11 The mechanisms by which inflammation/infection trigger cerebral hyperemia have not been yet defined, but a synergistic role between infection and hyperammonemia has been proposed.11 While mechanistic studies will continue to dissect the origin of cerebral hyperemia, the cumulative data highlight the importance of this hemodynamic alteration in the pathogenesis of brain edema. Could CBF be used as a tool to monitor the course of the disease? Unfortunately, direct measurements of CBF are complex, require corrections for PaCO2 values and are not easily available at most units. In the paper published in this issue, radioactive xenon was injected, with detectors placed over the external brain surface; although several measurements can be obtained in the same patient, it is technically demanding and not available for routine clinical use. The Kety-Schmidt technique, based on the uptake of nitrous oxide, requires careful calibration and is problematic for repeated measurements. Indirect measurements can be obtained of parameters whose changes reflect alterations in cerebral perfusion. The arteriovenous oxygen difference (A-VΔO2), measured from the oxygen content in a peripheral artery and the internal jugular vein, has been the most commonly used. The results will vary inversely with changes in CBF: An increase of A-VΔO2 with lower values of CBF and a reduction with cerebral hyperemia. However, the A-VΔO2can be also affected by changes of brain metabolism: A decrease of A-VΔO2, used to diagnose cerebral hyperemia, may reflect an increase in cerebral oxygen consumption. In the series from Pittsburgh,8 cerebral oxygen consumption remained at low values, supporting the interpretation of changes of A-VΔO2 as a reflection of cerebral perfusion. Other techniques to monitor CBF are available. Doppler flowmetry of the middle cerebral artery can measure blood velocity, a parameter directly related to CBF. Doppler flowmetry requires technical expertise, as small variations in the angle of insonation will result in spurious values. Near-infrared spectroscopy has also been explored in a small series, where the combination of this technique with Doppler flowmetry was able to detect an increase in CBF induced by noradrenaline.27 Failure of vascular autoregulation further complicates the management of these patients, as both reductions and increases of arterial pressure will be translated into corresponding changes in CBF. In 2005, management of patients with ALF and severe encephalopathy requires attention to the nature of cerebral perfusion. The data presented in this study,8 as well as from other centers,9, 11 indicate that monitoring CBF provides additional information to that obtained from ICP alone. Tools are available to normalize cerebral hyperemia, including the use of hyperventilation,28 indomethacin,17 and application of mild hypothermia.29 At a time when the era of large clinical trials in ALF has been launched,30 prospective studies of the pathophysiology of the cerebral complications of ALF are still critical to guide the management of the critically ill patients." @default.
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• W1590432470 date "2005-10-19" @default.
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• W1590432470 title "Monitoring cerebral blood flow: A useful clinical tool in acute liver failure?" @default.
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