Liver and Muscle Contribute Differently to the Plasma Acylcarnitine Pool During Fasting and Exercise in Humans.

BACKGROUND: Plasma acylcarnitine levels are elevated by physiological conditions such as fasting and exercise but also in states of insulin resistance and obesity. AIM: To elucidate the contribution of liver and skeletal muscle to plasma acylcarnitines in the fasting state and during exercise in humans. METHODS: In 2 independent studies, young healthy males were fasted overnight and performed an acute bout of exercise to investigate either acylcarnitines in skeletal muscle biopsies and arterial-to-venous plasma differences over the exercising and resting leg (n = 9) or the flux over the hepato-splanchnic bed (n = 10). RESULTS: In the fasting state, a pronounced release of C2- and C3-carnitines from the hepato-splanchnic bed and an uptake of free carnitine by the legs were detected. Exercise further increased the release of C3-carnitine from the hepato-splanchnic bed and the uptake of free carnitine in the exercising leg. In plasma and in the exercising muscle, exercise induced an increase of most acylcarnitines followed by a rapid decline to preexercise values during recovery. In contrast, free carnitine was decreased in the exercising muscle and quickly restored thereafter. C8-, C10-, C10:1-, C12-, and C12:1-carnitines were released from the exercising leg and simultaneously; C6, C8, C10, C10:1, C14, and C16:1 were taken up by the hepato-splanchnic. CONCLUSION: These data provide novel insight to the organo-specific release/uptake of acylcarnitines. The liver is a major contributor to systemic short chain acylcarnitines, whereas the muscle tissue releases mostly medium chain acylcarnitines during exercise, indicating that other tissues are contributing to the systemic increase in long chain acylcarnitines.

Attenuated hepatosplanchnic uptake of lactate during intense exercise in humans.

We evaluated whether the increase in blood lactate with intense exercise is influenced by a low hepatosplanchnic blood flow as assessed by indocyanine green dye elimination and blood sampling from an artery and the hepatic vein in eight men. The hepatosplanchnic blood flow decreased from a resting value of 1.6 +/- 0.1 to 0.7 +/- 0.1 (SE) l/min during exercise. Yet the hepatosplanchnic O2 uptake increased from 67 +/- 3 to 93 +/- 13 ml/min, and the output of glucose increased from 1.1 +/- 0.1 to 2.1 +/- 0.3 mmol/min (P < 0.05). Even at the lowest hepatosplanchnic venous hemoglobin O2 saturation during exercise of 6%, the average concentration of glucose in arterial blood was maintained close to the resting level (5.2 +/- 0.2 vs. 5.5 +/- 0.2 mmol/l), whereas the difference between arterial and hepatic venous blood glucose increased to a maximum of 22 mmol/l. In arterial blood, the concentration of lactate increased from 1.1 +/- 0.2 to 6.0 +/- 1.0 mmol/l, and the hepatosplanchnic uptake of lactate was elevated from 0.4 +/- 0.06 to 1.0 +/- 0.05 mmol/min during exercise (P < 0.05). However, when the hepatosplanchnic venous hemoglobin O2 saturation became low, the arterial and hepatosplanchnic venous blood lactate difference approached zero. Even with a marked reduction in its blood flow, exercise did not challenge the ability of the liver to maintain blood glucose homeostasis. However, it appeared that the contribution of the Cori cycle decreased, and the accumulation of lactate in blood became influenced by the reduced hepatosplanchnic blood flow.

S-100b and neuron-specific enolase in patients with fulminant hepatic failure.

Patients with fulminant hepatic failure (FHF) frequently develop cerebral edema and intracranial hypertension. The aim of this study was to evaluate circulating S-100b and neuron-specific enolase (NSE) levels as markers of neurological outcome in patients with FHF. In a subgroup of patients, the cerebral flux of S-100b and NSE was measured. We included 35 patients with FHF, 6 patients with acute on chronic liver disease (AOCLD), 13 patients with cirrhosis of the liver without hepatic encephalopathy, and 8 healthy subjects. Blood samples were obtained from catheters placed in the radial artery and internal jugular bulb. The net cerebral flux of S-100b and NSE was measured, and the effect of short-term hyperventilation, as well as the effect of high-volume plasmapheresis, on circulating levels of these two biomarkers was determined. Blood levels of S-100b were greater in patients with FHF and AOCLD than patients with cirrhosis and healthy subjects (median, 0.39 microg/L; range, 0.02 to 10.31 microg/L; and 1.11 microg/L; range, 0.19 to 4.84 microg/L v 0.05 microg/L; range, 0.02 to 0.27 microg/L; and 0.09 microg/L; range, 0.02 to 0.15 microg/L, respectively; P <.05, ANOVA). Among patients with FHF, blood levels of NSE tended to be greater in patients who subsequently developed cerebral herniation than in survivors (median, 10.5 microg/L; range, 5.2 to 15.9 microg/L v 5.1 microg/L; range, 2.8 to 12 microg/L; P =.05). There was no net cerebral flux of S-100b or NSE. Short-term hyperventilation had no effect on any of these measures, whereas high-volume plasmapheresis reduced circulating S-100b levels from 0.45 microg/L (range, 0.19 to 10.31 microg/L) to 0.42 microg/L (range, 0.11 to 6.35 microg/L; P =.01). In conclusion, blood levels of S-100b were elevated in almost all patients with FHF and AOCLD, but were unrelated to survival. Conversely, NSE showed a clear tendency toward greater circulating levels in patients with FHF who subsequently developed cerebral herniation than in survivors. This finding encourages further evaluation of NSE as a marker of neurological outcome in FHF.

Increased turnover of Gc-globulin in patients with hepatic encephalopathy.

BACKGROUND: A low serum level (< 100 mg/L) of the actin-scavenger Gc-globulin is a prognostic marker of non-survival in fulminant hepatic failure (FHF). It is unknown whether decreased production or increased consumption (or both) is responsible for the low Gc-globulin levels. METHODS: Ten patients with FHF and four patients with acute or chronic liver disease (AOCLD) with hepatic encephalopathy (HE) grades II-IV were included. Eight patients with cirrhosis (chronic liver disease, CLD) without HE served as controls. Total, free, and actin-bound Gc-globulin were measured in samples from an artery, a central vein, and a hepatic vein. In 12 patients (9 FHF, 3 AOCLD), concentrations were measured before and after high volume plasmapheresis (HVP). RESULTS: Total Gc-globulin was reduced to 21%, 40%, and 43% of the normal level in the FHF, AOCLD, and CLD groups, respectively, whereas bound Gc-globulin was within normal range in all patients. The Gc:actin complex ratio was increased 3.8, 2.5, and 1.9-fold compared with normal levels. Total, free, and bound serum Gc-globulin levels did not differ among arterial, systemic venous, or hepatic venous blood. Total Gc-globulin rose to >100 mg/L in all patients after HVP, whereas bound Gc-globulin remained unchanged. The Gc-globulin production rate in FHF and AOCLD patients was increased to 4.1 +/- 1.3 mg/min compared to literature values of 0.6 mg/min in healthy individuals. The estimated half-life of total Gc-globulin was shorter in the patients compared to healthy individuals (127 +/- 56 min and 870 min, respectively). CONCLUSIONS: Gc-globulin levels were reduced in patients with FHF and AOCLD because a 7-fold increase of Gc-globulin production rate could not compensate for the accelerated clearance. Bound Gc-globulin was maintained within normal levels in all circumstances studied, indicating a possible regulatory role of this parameter in the clearance of actin.

Effects of high-volume plasmapheresis on ammonia, urea, and amino acids in patients with acute liver failure.

OBJECTIVE: In acute liver failure (ALF), urea production is severely impaired, and detoxification of ammonia by glutamine synthesis plays an important protective role. The aim of this study was to examine the effects of therapeutic high-volume plasmapheresis (HVP) on arterial concentrations 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 exchange rates of ammonia, urea, and amino acids were measured by use of liver vein catheterization. RESULTS: HVP removed ammonia and glutamine at a rate of 1 micromol/min and 27 micromol/min, respectively. Arterial ammonia decreased from 160 +/- 65 to 114 +/- 50 micromol/L (p < 0.001). In contrast, arterial glutamine was only minimally changed from 1791 +/- 1655 to 1764 +/- 1875 micromol/L (NS). This implied that the rate of systemic glutamine synthesis was increased by 27 micromol/min. Splanchnic exchange rates (before vs after HVP) were as follows: for ammonia, -93 +/- 101 versus -70 +/- 80 micromol/min (NS); urea-nitrogen, 0.08 +/- 1.64 versus -0.31 +/- 0.45 mmol/min (NS); alanine, -73 +/- 151 versus 12 +/- 83 micromol/min (p < 0.05); and glutamine: 132 +/- 246 versus 186 +/- 285 micromol/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.

Splanchnic metabolism of fuel substrates in acute liver failure.

BACKGROUND/AIMS: This study aimed to characterize the exchange of fuel substrates in the splanchnic circulation in acute liver failure. METHODS: Liver vein catheterization was used in 22 patients with acute liver failure after development of hepatic encephalopathy grade III-IV Healthy controls, patients with cirrhosis and patients with acute on chronic liver disease were also studied. RESULTS: In acute liver failure there was splanchnic removal of glucose (0.21+/-0.44 mmol/min), release of lactate (0.34+/-0.37 mmol/min), pyruvate (0.08+/-0.06 mmol/min) and ketone bodies (0.04+/-0.02 mmol/min), while extraction of amino acids and free fatty acids was insignificant. In the acute liver failure group, a normal hepatic venous oxygen saturation (0.69+/-0.12) and normal pyruvate/lactate ratio suggested absence of hypoxia even though the acetoacetate/beta-hydroxybutyrate ratio was decreased. Only in the acute liver failure group did the measured splanchnic oxygen content difference exceed what could be accounted for even by hypothesizing complete oxidation of all extracted blood-borne fuel substrates; oxidation of endogenous substrates may be quantitatively important in this condition. CONCLUSION: Acute liver failure was associated with a state of accelerated glycolysis in the splanchnic region, leading to release of lactate in the absence of splanchnic hypoxia.

Splanchnic and leg exchange of amino acids and ammonia in acute liver failure.

BACKGROUND & AIMS: In patients with acute liver failure, hyperammonemia is associated with cerebral herniation. We examined the splanchnic and leg exchange of amino acids, urea, and ammonia in such patients. METHODS: Bedside liver vein catheterization was used in 22 patients after development of hepatic encephalopathy grades III-IV. Femoral venous blood was sampled in 7 of these patients. RESULTS: Arterial amino acid concentration (8.1 +/- 4.1 mmol/L) was increased 4-fold above normal. Glutamine (2.4 +/- 1.8 mmol/L) and alanine (0.57 +/- 0.35 mmol/L) were by far the predominant amino acids exchanged in the splanchnic and leg circulation. In the splanchnic circulation, there was a net uptake of glutamine (241 +/- 353 micromol/min) and ammonia and alanine were released in an almost 1:1 stoichiometry (r(2) = 0.47; P < 0.001). In the leg, ammonia and alanine were removed and glutamine released. The leg ammonia concentration difference was correlated to that of glutamine (r(2) = 0.80; P = 0.008) and alanine (r(2) = 0.67; P = 0.03). CONCLUSIONS: Splanchnic metabolism of glutamine in combination with decreased hepatic function was responsible for the splanchnic release of ammonia and alanine. These processes were reversed in skeletal muscle. Stimulation of skeletal muscle metabolism of ammonia could be a important target for future treatment of patients with acute liver failure.

Plasma phospholipid fatty acid pattern in severe liver disease.

BACKGROUND/AIMS: In acute liver failure the liver has to regenerate, which may increase the consumption of essential fatty acids. Nutritional support consists mainly of infusion of glucose. It is therefore possible that essential fatty acid deficiency may develop in such patients. METHODS: Plasma phospholipid composition was studied in healthy controls (n=11), in patients with acute liver failure, (n=10), in patients with stable cirrhosis (n=7), and in patients with acute on chronic liver disease with hepatic encephalopathy (n=6). The influence of 2 days of fat-free diet followed by infusion of glucose was studied in five healthy controls. RESULTS: The ratio between the sums of nonessential/ essential fatty acids, (n-7+n-9)/(n-3+n-6), was higher in patients with acute liver failure (0.73+/-0.17) compared to healthy controls (0.35+/-0.06, p<0.001). The ratio was also higher in patients with acute on chronic liver disease (1.11+/-0.39) compared to patients with cirrhosis (0.61+/-0.18, p<0.01). These differences were mainly due to low levels of linoleic acid and high levels of oleic acid in the patients with acute liver failure and acute on chronic liver disease. Two days of fat-free diet followed by infusion of glucose did not change this ratio (0.40+/-0.04 vs. 0.47+/-0.05, NS) in healthy controls. The essential fatty acid deficiency indicator eicosatrienoic acid was detectable in 2 out of 11 controls, in 5/10 with acute liver failure, in 7/7 with cirrhosis, and in 6/7 with acute on chronic liver disease. CONCLUSION: Acute severe deterioration of liver function was associated with changes in the fatty acid composition of plasma phospholipids suggestive of essential fatty acid deficiency.

The effect of increasing blood pressure with dopamine on systemic, splanchnic, and lower extremity hemodynamics in patients with acute liver failure.

BACKGROUND: Arterial hypotension occurs frequently in patients with acute liver failure (ALF). Treatment with epinephrine and norepinephrine in patients with ALF has been associated with a decrease in whole-body (systemic) oxygen consumption. We aimed to investigate the effect of increasing blood pressure with dopamine on whole-body (systemic), splanchnic, and lower extremity hemodynamics and oxygen consumption in patients with acute liver failure and hepatic encephalopathy grade III or IV. METHODS: In seven patients with ALF cardiac output (CO) was measured with the thermodilution technique, and hepatic blood flow (HBF) was estimated with infusion of sorbitol as test compound, liver vein catheterization, and calculations on the basis of Fick's principle. Lower-extremity blood flow was measured with strain-gauge plethysmography. RESULTS: During infusion of dopamine (5 +/- 2 microg kg(-1) min(-1)) mean arterial pressure (MAP) increased from 68 +/- 5 to 85 +/- 8 mmHg. CO increased from 6.8 +/- 0.8 to 9.0 +/- 2.4 l/min (P < 0.05), systemic oxygen delivery from 45 +/- 7 to 63 +/- 19 mmol/min (P < 0.05), systemic oxygen consumption from 10.2 +/- 2.0 to 11.5 +/- 3.3 mmol/min (NS). HBF increased from 2.2 +/- 0.7 to 2.7 +/- 1.0 l/ min (P < 0.05), splanchnic oxygen delivery from 14.4 +/- 5.3 to 18.5 +/- 7.2 mmol/min (P < 0.01), and splanchnic oxygen consumption decreased from 3.9 +/- 1.1 to 2.9 +/- 0.6 mmol/min (P < 0.05). No significant changes in lower extremity flow and oxygenation variables were found. CONCLUSIONS: The use of dopamine in patients with ALF to increase MAP was associated with increases in systemic and splanchnic oxygen delivery. A concomitant decrease in splanchnic oxygen consumption was observed.

Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.

Cerebral edema leading to cerebral herniation (CH) is a common cause of death in acute liver failure (ALF). Animal studies have related ammonia with this complication. During liver failure, hepatic ammonia removal can be expected to determine the arterial ammonia level. In patients with ALF, we examined the hypotheses that high arterial ammonia is related to later death by CH, and that impaired removal in the hepatic circulation is related to high arterial ammonia. Twenty-two patients with ALF were studied retrospectively. In addition, prospective studies with liver vein catheterization were performed after development of hepatic encephalopathy (HE) in 22 patients with ALF and 9 with acute on chronic liver disease (AOCLD). Cerebral arterial-venous ammonia difference was studied in 13 patients with ALF. In all patients with ALF (n = 44), those who developed CH (n = 14) had higher arterial plasma ammonia than the non-CH (n = 30) patients (230 +/- 58 vs. 118 +/- 48 micromol/L; P <. 001). In contrast, galactose elimination capacity, bilirubin, creatinine, and prothrombin time were not different (NS). Cerebral arterial-venous differences increased with increasing arterial ammonia (P <.001). Arterial plasma ammonia was lower than hepatic venous in ALF (148 +/- 73 vs. 203 +/- 108 micromol/L; P <.001). In contrast, arterial plasma ammonia was higher than hepatic venous in patients with AOCLD (91 +/- 26 vs. 66 +/- 18 micromol/L; P <.05). Net ammonia release from the hepatic-splanchnic region was 6.5 +/- 6. 4 mmol/h in ALF, and arterial ammonia increased with increasing release. In contrast, there was a net hepatic-splanchnic removal of ammonia (2.8 +/- 3.3 mmol/h) in patients with AOCLD. We interpret these data that in ALF in humans, vast amounts of ammonia escape hepatic metabolism, leading to high arterial ammonia concentrations, which in turn is associated with increased cerebral ammonia uptake and CH.

Hepatic blood flow and splanchnic oxygen consumption in patients with liver failure. Effect of high-volume plasmapheresis.

Liver failure represents a major therapeutic challenge, and yet basic pathophysiological questions about hepatic perfusion and oxygenation in this condition have been poorly investigated. In this study, hepatic blood flow (HBF) and splanchnic oxygen delivery (DO2, sp) and oxygen consumption (VO2,sp) were assessed in patients with liver failure defined as hepatic encephalopathy grade II or more. Measurements were repeated after high-volume plasmapheresis (HVP) with exchange of 8 to 10 L of plasma. HBF was estimated by use of constant infusion of D-sorbitol and calculated according to Fick's principle from peripheral artery and hepatic vein concentrations. In 14 patients with acute liver failure (ALF), HBF (1.78 +/- 0.78 L/min) and VO2,sp (3.9 +/- 0.9 mmol/min) were higher than in 11 patients without liver disease (1.07 +/- 0.19 L/min, P <.01) and (2.3 +/- 0.7 mmol/min, P <.001). In 9 patients with acute on chronic liver disease (AOCLD), HBF (1.96 +/- 1.19 L/min) and VO2,sp (3.9 +/- 2.3 mmol/min) were higher than in 18 patients with stable cirrhosis (1.00 +/- 0.36 L/min, P <.005; and 2.0 +/- 0.6 mmol/min, P <.005). During HVP, HBF increased from 1.67 +/- 0.72 to 2.07 +/- 1.11 L/min (n=11) in ALF, and from 1.89 +/- 1.32 to 2.34 +/- 1.54 L/min (n=7) in AOCLD, P <.05 in both cases. In patients with ALF, cardiac output (thermodilution) was unchanged (6.7 +/- 2.5 vs. 6.6 +/- 2.2 L/min, NS) during HVP. Blood flow was redirected to the liver as the systemic vascular resistance index increased (1,587 +/- 650 vs. 2, 020 +/- 806 Dyne. s. cm-5. m2, P <.01) whereas splanchnic vascular resistance was unchanged. In AOCLD, neither systemic nor splanchnic vascular resistance was affected by HVP, but as cardiac output increased from 9.1 +/- 2.8 to 10.1 +/- 2.9 L/min (P <.01) more blood was directed to the splanchnic region. In all liver failure patients treated with HVP (n=18), DO2,sp increased by 15% (P <.05) whereas VO2,sp was unchanged. Endothelin-1 (ET-1) and ET-3 were determined before and after HVP. Changes of ET-1 were positively correlated with changes in HBF (P <.005) and VO2,sp (P <.05), indicating a role for ET-1 in splanchnic circulation and oxygenation. ET-3 was negatively correlated with systemic vascular resistance index before HVP (P <.05) but changes during HVP did not correlate. Our data suggest that liver failure is associated with increased HBF and VO2, sp. HVP further increased HBF and DO2,sp but VO2,sp was unchanged, indicating that splanchnic hypoxia was not present.

Mesenteric, coeliac and splanchnic blood flow in humans during exercise.

1. Exercise reduces splanchnic blood flow, but the mesenteric contribution to this response is uncertain. 2. In nineteen humans, superior mesenteric and coeliac artery flows were determined by duplex ultrasonography during fasting and postprandial submaximal cycling and compared with the splanchnic blood flow as assessed by the Indocyanine Green dye-elimination technique. 3. Cycling increased arterial pressure, heart rate and cardiac output, while it reduced total vascular resistance. These responses were not altered in the postprandial state. During fasting, cycling increased mesenteric, coeliac and splanchnic resistances by 76, 165 and 126 %, respectively, and it reduced corresponding blood flows by 32, 50 and 43 % (by 0.18 +/- 0.04, 0.42 +/- 0.03 and 0.60 +/- 0.04 l min-1). Postprandially, mesenteric and splanchnic vascular resistances decreased, thereby elevating regional blood flow, while the coeliac circulation was not influenced. Postprandial cycling did not influence the mesenteric resistance significantly, but its blood flow decreased by 22 % (0.46 +/- 0.28 l min-1). Coeliac and splanchnic resistance increased by 150 and 63 %, respectively, and the corresponding regional blood flow decreased by 51 and 31 % (0.49 +/- 0.07 and 0.96 +/- 0.28 l min-1). Splanchnic blood flow values assessed by duplex ultrasound and by dye-elimination techniques were correlated (r = 0.70; P < 0.01). 4. During submaximal exercise in humans, splanchnic resistance increases and blood flow is reduced following a 50 % reduction in the hepato-splenic and a 25 % reduction in the mesenteric blood flow.

Hepatic plasma flow estimated according to Fick's principle in patients with hepatic encephalopathy: evaluation of indocyanine green and D-sorbitol as test substances.

The magnitude of hepatic plasma flow in patients with liver failure and hepatic encephalopathy (HE) is unknown because a reliable flow estimate has not been available. The purpose of this study was to estimate hepatic plasma flow in patients with HE and to evaluate indocyanine green (ICG) and sorbitol as test compounds. Fourteen patients with acute liver failure (ALF) and nine patients with chronic liver failure (CLF), all with HE grade II or more, were studied. After hepatic vein catheterization, hepatic plasma flow was estimated by use of constant infusion, simultaneous arterial and hepatic vein concentration measurements, and calculated according to Fick's principle. The hepatic extraction fraction of D-sorbitol 0.179+/-0.144 (mean+/-SD) was higher than the hepatic extraction fraction of ICG 0.054+/-0.085 (P < .001). The low hepatic extraction fraction of ICG rendered this compound unfit for estimation of hepatic plasma flow in these patients. In contrast, by using D-sorbitol the hepatic plasma flow could be estimated in 21 of 23 patients with a median SD of 8.4% (range, 2.6% to 29%). The D-sorbitol estimated hepatic plasma flow was 1.2+/-0.5 L/min (n = 12) in patients with ALF and 1.4+/-0.9 L/min (n = 9) in patients with CLF. These values are higher than what has been reported in normal subjects and in patients with cirrhosis without HE. An elevated hepatic flow should increase oxygen delivery and may enhance the failing liver's ability to remove substances from the blood. At the same time, hepatic first pass metabolism is reduced. We conclude that an elevated hepatic flow in these patients is of clinical importance.

Indomethacin normalizes intracranial pressure in acute liver failure: a twenty-three-year-old woman treated with indomethacin.

In patients with acute liver failure, cerebral herniation is a common cause of death. The present study reports the effect of indomethacin on four occasions of intracranial hypertension, in a 23-year old previously healthy woman with severe acetaminophen poisoning. During each episode of intracranial hypertension, the patient was treated with 25 mg of indomethacin, and each time the intracranial pressure normalized. We recommend further controlled studies to determine the exact effect of indomethacin on cerebral blood flow and metabolism before it is recommended for treatment of intracranial hypertension in patients with acute liver failure.

The effect of cimetidine on ethanol concentrations in fasting women and men after two different doses of alcohol.

BACKGROUND: Serum ethanol concentrations may become higher when alcohol is consumed during treatment with histamine receptor antagonists, especially if ethanol is ingested postprandially. Only a few studies have investigated fasting subjects, and women have only been investigated sporadically. METHODS: The present study compared serum ethanol concentrations after a 4-h fast followed by a low (0.15 g/kg) and a high (0.45 g/kg) dose of ethanol, on two separate occasions in six women and six men. The study was carried out before and after treatment with 400 mg cimetidine twice daily. RESULTS: Cimetidine administration did not change the area under the concentration-time curve or the maximal serum ethanol concentration in either women or men, irrespective of ethanol dose. Ethanol elimination rate was unchanged by cimetidine. CONCLUSION: Cimetidine does not influence the ethanol concentration-time curve when ethanol is ingested on an empty stomach.

Haemodynamic changes after high-volume plasmapheresis in patients with chronic and acute liver failure.

OBJECTIVE: To evaluate the haemodynamic changes during treatment with high-volume plasmapheresis in patients with chronic liver failure compared to patients with acute liver failure. METHODS: Haemodynamic measurements were performed with a Swan-Ganz catheter and thermodilution technique. High-volume plasmapheresis (mean plasma exchange of 8.6 litres) was performed in 11 patients with chronic and 16 patients with acute liver failure. RESULTS: In patients with chronic liver failure, systemic vascular resistance index was unaltered: 1193 +/- 494 dynscm-5m2 before treatment versus 1180 +/- 399 dynscm-5m2 after. Mean arterial pressure increased from 69 +/- 11 mmHg to 78 +/- 13 mmHg (P < 0.05) and cardiac output increased from 8.1 +/- 2.4 l/min to 8.9 +/- 2.4 l/min (P < 0.05) during high-volume plasmapheresis. In patients with acute liver failure, systemic vascular resistance index increased from 1154 +/- 628 dynscm-5m2 to 1614 +/- 738 dynscm-5m2 (P < 0.001). In this group mean arterial pressure increased from 78 +/- 16 mmHg to 95 +/- 10 mmHg (P < 0.001) and cardiac output decreased from 9.6 +/- 3.7 l/min to 8.2 +/- 2.9 l/min (P < 0.01). CONCLUSION: The hyperkinetic circulation in chronic and acute patients was differently affected by high-volume plasmapheresis. We suggest that in chronic liver failure both portosystemic shunting and chronic peripheral vasodilation may contribute to the hyperkinetic syndrome, whereas in acute liver failure a humoral factor which can be removed by high-volume plasmapheresis is a main contributor.

[Recommendations for treatment of paracetamol poisoning. Danish Medical Society, Study of the Liver]. / Rekommandation for behandling af paracetamolforgiftning.

Based on recent reports concerning the efficacy of N-acetylcysteine (NAC) in paracetamol (acetaminophen) poisoning, guidelines for treatment and control of these patients are reviewed by a study group under the Danish Association for the Study of the Liver. It is recommended that NAC-treatment is initiated immediately after referral and continued for 36 hours in all cases. Further NAC-treatment should not be discontinued before a decrease in INR has been observed.

Preservation of cerebral oxidative metabolism in fulminant hepatic failure: an autoregulation study.

Under normal conditions cerebral blood flow (CBF) is regulated to secure oxidative brain metabolism, but in patients with fulminant hepatic failure (FHF), insufficient CBF has been suggested to precede cerebral edema and intracranial hypertension. In order to determine if insufficient CBF and hypoxia are present in patients with FHF we increased the mean arterial pressure and measured cerebral metabolism. In six patients with FHF CBF determined by 133Xenon injection technique, transcranial Doppler mean flow velocity in the middle cerebral artery (Vmean) and cerebral metabolism were determined, before and after an increase in mean arterial pressure by norepinephrine infusion. Mean arterial pressure was measured in a radial artery, and blood samples from the radial artery and internal jugular vein allowed calculation of the cerebral arteriovenous oxygen (AVDO2), -glucose (AVDgl), and -lactate (AVDlac) differences. Cerebral metabolic rates (CMRO2,-gl,-lac) were calculated as AVDO2,-gl,-lac times CBF. Mean arterial pressure was raised from 70 (54-105) to 111 (93-128) mm Hg during intravenous infusion of norepinephrine. CBF increased from 34 (12-55) to 47 (27-81) mL . 100g-1. min-1 (p < 0.05) and Vmean from 53 (42-60) to 67 (61-79) cm.s-1 (p < 0.05), whereas CMRO2 (1.4 (0.9-2.4) mL . 100g-1 . min-1), CMRgl (11 (4.8-20) mumol 100g-1 . min-1), and CMRlac (3.2 (0-8.9) mumol . 100g-1 . min-1) remained unchanged. Our finding indicates that cerebral oxidative metabolism is preserved in patients with FHF. Cerebral autoregulation is absent, however, and neuroprotective critical care is suggested to be guided by internal jugular vein oxygen saturation to secure appropriate cerebral oxygenation.

Cerebral blood flow, oxygen metabolism and transcranial Doppler sonography during high-volume plasmapheresis in fulminant hepatic failure.

OBJECTIVE: The effect of high-volume plasmapheresis on hepatic encephalopathy, cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) was investigated in patients with fulminant hepatic failure (FHF). METHODS: Twelve consecutive patients (8 women, 4 men, median age 34 years (range 19-51), were studied before and after high-volume plasmapheresis with 10-16 litres fresh frozen plasma, while PaCO2 and body temperature were maintained at 30 (23-34) mmHg and 37.6 degrees C (36.6-38.4), respectively. Blood samples from the internal jugular vein and a radial artery allowed calculation of the cerebral arteriovenous oxygen difference (AVDO2) and oxygen extraction (AVDO2 divided by arterial oxygen content). CBF was determined by a xenon-133 clearance method in eight patients and CMRO2 calculated as AVDO2 times CBF. Cerebral perfusion pressure (CPP) was determined as the difference between mean arterial and subdural pressures in eight patients. RESULTS: High-volume plasmapheresis was initiated 22 (6-168) h after the development of hepatic encephalopathy and 11 patients had grade 4 encephalopathy. Following high-volume plasmapheresis the grade of encephalopathy improved in four patients. The CBF increased from a median of 31 (16-86) to 45 (18-97) ml/100 g/min and as oxygen extraction remained unchanged (32 (9-41) vs. 29 (7-39)%), CMRO2 increased from 1.24 (0.96-1.82) to 1.86 (1.00-2.07) ml/100 g/min (P < 0.05). The CPP increased from 62 (19-76) to 92 (50-105) mmHg (P < 0.01), whereas the intracranial pressure remained unchanged (19 (3-45) vs. 11 (5-33) mmHg). No statistical difference was found between the relative changes in the above parameters in survivors compared to non-survivors. CONCLUSION: Although the clinical status did not improve in all patients, both CBF and CMRO2 increased after high-volume plasmapheresis. The alleviation of brain oxygen metabolism by high-volume plasmapheresis may reflect partial removal of neuroinhibitory plasma factors.