Altered cerebral blood flow and glucose metabolism in patients with liver disease and minimal encephalopathy.

We measured CBF and the CMRglc in normal controls and in patients with severe liver disease and evidence for minimal hepatic encephalopathy using positron emission tomography. Regions were defined in frontal, temporal, parietal, and visual cortex; the thalamus; the caudate; the cerebellum; and the white matter along with a whole-slice value obtained at the level of the thalamus. There was no difference in whole-slice CBF and CMRglc values. Individual regional values were normalized to the whole-slice value and subjected to a two-way repeated measures analysis of variance. When normalized CBF and CMRglc values for regions were compared between groups, significant differences were demonstrated (F = 5.650, p = 0.00014 and F = 4.58, p = 0.0073, respectively). These pattern differences were due to higher CBF and CMRglc in the cerebellum, thalamus, and caudate in patients and lower values in the cortex. Standardized coefficients extracted from a discriminant function analysis permitted correct group assignment for 95.5% of the CBF studies and for 92.9% of the CMRglc studies. The similarity of the altered pattern of cerebral metabolism and flow in our patients to that seen in rats subjected to portacaval shunts or ammonia infusions suggests that this toxin may alter flow and metabolism and that this, in turn, causes the clinical expression of encephalopathy.

Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy.

Cerebral ammonia metabolism was studied in five control subjects and five patients with severe liver disease exhibiting minimal hepatic encephalopathy. The arterial ammonia concentration in the control subjects was 30 +/- 7 mumol/L (mean +/- SD) and 55 +/- 13 mumol/L in the patients (p less than 0.01). In the normal subjects, the whole-brain values for cerebral blood flow, cerebral metabolic rate for ammonia, and the permeability-surface area product for ammonia were 0.58 +/- 0.12 ml g-1 min-1 0.35 +/- 0.15 mumol 100 g-1 min-1, and 0.13 +/- 0.03 ml g-1 min-1, respectively. In the patients, the respective values were 0.46 +/- 0.16 ml g-1 min-1 (not different from control), 0.91 +/- 0.36 mumol 100 g-1 min-1 (p less than 0.025), and 0.22 +/- 0.07 ml g-1 min-1 (p less than 0.05). The increased permeability-surface area product of the blood-brain barrier permits ammonia to diffuse across the blood-brain barrier into the brain more freely than normal. This may cause ammonia-induced encephalopathy even though arterial ammonia levels are normal or near normal and explain the emergence of toxin hypersensitivity as liver disease progresses. Greater emphasis on early detection of encephalopathy and aggressive treatment of minimal hyperammonemia may retard the development of ammonia-induced complications of severe liver disease.

Verapamil prevents cerebral acidosis during moderate hypoxia and hypotension.

Carotid ligation and moderate hypoxia in rats causes an increase in the glucose metabolic rate in the caudate-putamen and more widespread reductions in pH. Pretreatment of animals with verapamil did not affect the abnormality of glucose metabolism but abolished the associated acidosis. These data suggest that calcium channel blockade may protect the brain from injury during hypoxic hypoxia by preventing the development of acidosis.

Glucose metabolism and acidosis in the metabolic penumbra of rat brain.

The characterization of tissue acid-base status related to the penumbral zone of increased glucose consumption surrounding a focal cerebral ischemic lesion may suggest therapeutic techniques to maximize tissue survivability from stoke. We measured local cerebral metabolic rate for glucose (1 CMRglc) and an index of brain tissue pH (pHt) concurrently and characterized their interaction in a model of focal cerebral ischemia in rats in a double-label autoradiographic study, using [14C]2-deoxyglucose and [14C]dimethyloxazolidinedione. Computer-assisted digitization and analysis permitted the simultaneous quantification of the two variables on a pixel-by-pixel basis in the same brain slices. Hemispheres ipsilateral to intravascular tamponade-induced middle cerebral artery occlusion showed areas of normal, depressed, and elevated glucose metabolic rate (as defined by an interhemispheric asymmetry index) after 2 hr of ischemia. Regions of increased 1 CMRglc showed moderate acidosis (6.87 +/- 0.05), while regions of normal glucose metabolic rate showed normal pHt (pH +/- SD = 6.98 +/- 0.05) and regions of decreased 1 CMRglc showed severe acidosis (6.69 +/- 0.11). A repeated-measures analysis of variance found these values to differ from each other at the P less than 0.0005 significance level. The finding of moderate acidosis coupled with increased 1 CRMglc in the metabolic penumbra suggests that the excess protons may result from the anaerobic dissociation of ATP synthesis and hydrolysis.

Effects of moderate hypoxemia and unilateral carotid ligation on cerebral glucose metabolism and acid-base balance in the rat.

We used our recently developed method for the simultaneous measurement of the local CMRglc (LCMRglc) and composite tissue pH to evaluate the response to unilateral carotid ligation and moderate hypoxia [40.1 +/- 4.8 (SD) mm Hg]. The LCMRglc and tissue pH were measured simultaneously in brain slices using [14C]2-deoxy-D-glucose and [14C]5,5-dimethyl-2,4-oxazolidinedione. The ipsilateral LCMRglc was increased significantly in the caudate-putamen and medical thalamus and was surrounded by a much more extensive zone of acidosis, as shown by significant reductions in the tissue pH, which was affected in parietal cortex, caudate-putamen, lateral septal nucleus, medial geniculate, Ammon's horn, and nucleus reticularis of substantia nigra. In regions with an elevated LCMRglc and acidosis, anaerobic glycolysis combined with ATP hydrolysis are likely to co-exist. In regions characterized by normal glucose metabolism and acidosis, we hypothesize that a direct effect of hypoxia on the sodium/hydrogen ion antiporter may lead to secondary acidosis. Disturbed acid-base balance during hypoxia may have an adverse effect on cerebral function and cause clinical symptoms.

Use of Adair four-step kinetics in mathematical simulation of oxygen transport in the microcirculation.

The Adair four-step kinetic model for the reactions of haemoglobin and oxygen recognizes five haemoglobin species, corresponding to deoxyhaemoglobin and one species for each level of oxygenation of the four haem groups. Thus, an oxygen transport problem involves a system of five simultaneous non-linear partial differential equations for diffusion with chemical reaction. This mathematical complexity has impeded application of the Adair model despite its theoretical advantages over the one-step model often used in practice. The Adair kinetic model has been incorporated into a simulation of microcirculatory oxygen transport. The results show that the usual one-step kinetic model is inaccurate in comparison with the Adair model. However, an empirical modification can be made to the one-step model to ensure compatibility with the equilibrium curve. This modified one-step kinetic model (the VRC model) is much more tractable mathematically than the Adair model. In the physiological range of fluxes, the VRC kinetic model appears to be of sufficient accuracy for most purposes, and the mathematical complexity of the Adair model is not required.