The novel hemoglobin-based oxygen carrier HRC 101 improves survival in murine sickle cell disease.

BACKGROUND: Erythrocyte transfusion decreases morbidity in sickle cell disease, but is not without risk. Use of a hemoglobin-based oxygen carrier could offer the benefits of erythrocyte transfusion while reducing related complications. The authors tested the hypothesis that the novel hemoglobin-based oxygen carrier, HRC 101, would improve survival during exposure to acute hypoxia in a murine model of sickle cell disease, the transgenic mouse expressing hemoglobin SAD (alpha2beta2). METHODS: Wild-type (n = 30) and transgenic SAD (n = 36) mice received 0.02 ml/g HRC 101 (hemoglobin concentration, 10 g/dl) or an equal volume of 5% albumin. Thirty percent or 6% oxygen was administered to spontaneously breathing mice during halothane anesthesia (inspired concentration, 0.5%). The time to cessation of cardiac electrical activity was recorded. Survival was compared using Kaplan-Meier analysis. RESULTS: Control mice survived the 60-min study period, whether breathing 30% or 6% oxygen. In contrast, all SAD mice given albumin and 6% oxygen died, with a median survival time of 9.0 min (interquartile range, 6.9-11.6 min; P < 0.0001). HRC 101 significantly increased survival in SAD mice breathing 6% oxygen. Of 12 SAD mice given HRC 101 and 6% oxygen, 4 survived the entire study period and 8 died, with a median survival time of 48 min (19-60 min; P < 0.0001 vs. albumin). CONCLUSION: HRC 101 significantly decreased sickle-related mortality during exposure to acute hypoxic stress in transgenic mice expressing hemoglobin SAD. HRC 101 warrants further evaluation as a therapeutic modality in sickle cell disease.

The effect of magnesium deficiency on volatile anaesthetic requirement in the rat: the role of central noradrenergic neuronal activity.

Volatile anaesthetic minimum alveolar concentration (MAC, a measure of anaesthetic requirement) increased in a time-dependent manner in rats fed a Mg2+-deficient diet. MAC values in hypomagnesemic rats were 22-30 per cent greater than those in age-matched controls at 12 and 17 days after starting the diet (p < 0.01). Noradrenergic neuronal activity, as assessed from the ratio of the concentration of 3,4-dihydroxyphenylethylene-glycol (DHPG) to that of norepinephrine (NE), decreased in the brain stem and cerebrum-cerebellum in hypomagnesemic rats owing to an increase in NE concentration in both regions of the brain (p < 0.025). We conclude that prolonged hypomagnesemia (> or = 12 days) increases volatile anaesthetic MAC in the rat. The concomitant decrease in the ratio of DHPG/NE suggests that this increase in MAC cannot be attributed to an increase in noradrenergic neuronal activity in brain.

Effects of hypoxia and isoflurane on liver blood flow: the role of adenosine.

We investigated the role of endogenous adenosine in mediating the effects of hypoxia and isoflurane on portal tributary blood flow (PTBF) and hepatic arterial blood flow (HABF) in rats. Liver blood flows were determined using radiolabelled microspheres. Hypoxia resulting from the exposure of rats to an atmosphere containing 15% oxygen for 30 min decreased PTBF (23%) (P<0.05) and cardiac index (15%) (P<0.05), and increased HABF (78%) (P<0.05). Isoflurane (1.4 vol%) increased HABF in both normoxic and hypoxic conditions but did not affect PTBF. The adenosine receptor antagonist 8-phenyltheophylline attenuated the hypoxia-induced increase in HABF but did not affect that resulting from the administration of isoflurane. In conclusion, in contrast to the increase in HABF induced by hypoxia, that induced by isoflurane appears to be independent of endogenous adenosine.

Recent developments in hemoglobin-based oxygen carriers--an update on clinical trials.

Considerable progress has been made in the development of the hemoglobin based oxygen carriers (HBOCs), with a number of products in the final stages of clinical development prior to licensing application. This follows many years of concentrated study. Although there are limitations to the clinical use of the currently studied HBOCs, there are a number of advantages that suggest that these products will have an important role in future clinical practice. It is anticipated that these products will be commercially available within two years.

A phase I study of oxidized raffinose cross-linked human hemoglobin.

OBJECTIVE: To evaluate the safety of oxidized-raffinose cross-linked human hemoglobin, Hemolink, in normal healthy volunteers. DESIGN: Randomized, placebo-controlled, double-blind study. SETTING: Clinical research facility of a contract research organization. PATIENTS: Forty-two healthy adult male volunteers of which 33 received Hemolink. INTERVENTIONS: Oxidized-raffinose cross-linked and polymerized hemoglobin as a 10% (w/v) solution, in doses of 0.025-0.6 g/kg or an equivalent volume of lactated Ringer's solution, was infused intravenously on day 1, and subjects were monitored for 3 days in the clinical facility with < or =6 wks follow-up. Major organ function was assessed pre- and postinfusion, by hemodynamic, electrocardiographic, pulmonary function, and clinical chemistry measurements. MEASUREMENTS AND MAIN RESULTS: Doses of 1.7-42 g of hemoglobin were administered with no serious adverse events noted. Abdominal pain of moderate to severe intensity was seen in some subjects at doses >0.4 g/kg and was alleviated with smooth muscle relaxants. There was a dose-dependent increase in mean arterial pressure with a plateau of approximately 14% above baseline at 0.1 g/kg. There was a concomitant reduction in heart rate, with no electrocardiographic abnormalities found. Respiratory function was not affected. There was a dose-dependent increase in serum bilirubin with values above the upper limit of normal at doses of > or =0.4 g/kg. Small increases in aspartate aminotransferase and alanine aminotransferase were noted in some patients, whereas alkaline phosphatase and gamma-glutamyltransferase remained in the normal range. Serum amylase concentrations were normal in 31 of 33 patients receiving Hemolink, whereas lipase was within the normal range in 21 of 33 patients. LDH was increased in a dose-dependent fashion. Two patients had increased creatine kinase concentrations, with a normal creatine kinase-MB mass fraction. All hematologic variables were within the normal range. The half-life of the oligomeric (>64 kDa) fraction of Hemolink was 18-20 hrs. CONCLUSION: Oxidized-raffinose cross-linked hemoglobin, Hemolink, at doses < or =0.6 g/kg were well tolerated in healthy volunteers with no evidence of organ dysfunction. Further investigation of its potential use in surgical and trauma settings appears warranted.

Haemodynamic response following a 10% topload infusion of HemolinkTM in conscious, anaesthetized and treated spontaneously hypertensive rats.

HemolinkTM (HLK), a haemoglobin-based oxygen carrier (HBOC), is currently undergoing Phase II/III clinical trials in surgical patients. It causes some blood pressure rise in animal and human tests. This study was designed to investigate the systemic haemodynamic response to HemolinkTM in spontaneously hypertensive rats (SHR rats). Conscious or anaesthetized SHR rats and control Wistar Kyoto rats (WKY rats) received either HemolinkTM or homologous plasma as a 10% topload infusion. Some awake animals were pretreated with nifedipine and followed by HLK infusion. In the conscious animal study, HLK induced a greater pressure rise and less bradycardia in SHR rats than in WKY rats. In the anaesthetized animal experiment, HLK-induced pressure rise and bradycardia were similar in both strains and less pronounced than in the conscious animals. In the nifedipine pretreated SHR rats, HLK-induced pressure rise was significantly smaller than that observed in nontreated SHR rats and was not different from that of nontreated WKY rats. The HLK-induced bradycardia was significantly smaller in nifedipine-treated animals than in the nontreated SHR or WKY rats. This study suggests that the pressor effect of HemolinkTM can be attenuated in hypertensive animals with general anaesthesia or treatment with antihypertensive agents.

Neuroprotective effects of acetylsalicylic acid in an animal model of focal brain ischemia.

Recent studies have shown neuroprotective effects of acetylsalicylic acid (ASA) in cell cultures and hippocampal slices. The present study demonstrates similar effects in a whole-animal modal of focal ischemic stroke. Focal cortical ischemia was produced in Wistar rats by ligation of the common carotid and middle cerebral arteries. Subjects were sacrificed 8 days after ligation, and infarct volume was assessed via automated densitometry. Significant reductions in infarct volume were seen with i.p. ASA doses of 15 mg/kg and above. Reductions occurred when ASA was injected 2 h or 30 min before ligation, but not when it was injected 8 or 24 h before, or 30 min after ligation.

Hemolink-induced effects on intestinal motor function and attenuation of these effects by selected agents.

Hemolink, an oxidized, ring-opened raffinose-crosslinked hemoglobin-based oxygen carrier produced by Hemosol Inc., stimulates esophageal peristalsis, possibly by interference with neural NO-mediated effects. The effects of Hemolink on jejunal tone and contractions, arterial pressure and heart rate were measured in anesthetized rats, and the effect of selected agents in attenuating or reversing these effects was studied. Infusion of L-NAME was used to validate the study model; it caused an immediate increase in tone and initiated phasic contractions indicating that the model was responsive to NO-mediated effects. Hemolink administration caused effects on intestinal motor function similar to those caused by L-NAME, including increases in basal tone and contraction amplitude. Rat whole blood caused none of these changes. The Hemolink-induced effects were less immediate in some animals compared to those observed after L-NAME. As well there was greater inter-animal variability on the effects. Hemolink administration also caused a mild increase in arterial blood pressure and a reciprocal decrease in heart rate in some animals. Co-administration of morphine, a common analgesic that has been reported to influence the motility of the GI tract; L-arginine, a substrate for NO synthesis; and glycopyrrolate, an anti-cholinergic agent, did not significantly modulate the Hemolink effects, whereas nitroglycerin, an NO donor; and nifedipine, a slow calcium-channel blocker, attenuated or reversed these effects.

Circulating neutrophils and liver injury in rat models of experimental alcoholic liver disease.

The present study examined the relationship between circulating neutrophils and liver injury in two widely used rat models of chronic ethanol administration. Hematological alterations, liver histopathology, and biochemical indices of liver injury were assessed in rats receiving chronic ethanol by oral liquid diet feeding (Lieber-DeCarli method) or by continuous intragastric infusion (Tsukamoto-French method). Oral administration of ethanol did not affect circulating neutrophil counts, but resulted in minimal liver injury characterized by elevated serum alanine aminotransferase (79%), increased liver mass (15%), and moderate steatosis. In contrast, rats receiving ethanol by continuous intragastric infusion showed an approximately 2-fold increase in circulating neutrophils, and a moderate degree of liver injury, indicated by a 169% elevation of serum alanine aminotransferase and a 2-fold increase in liver mass. Liver biopsies from these rats showed severe steatosis and scattered necrotic hepatocytes, and some neutrophil infiltrates. To determine whether an increase in the number of circulating neutrophils could potentiate liver injury induced by oral ethanol feeding, rats were treated with human recombinant granulocyte colony-stimulating factor at a dose of 100 microg/kg/day (s.c.) for 4 days. Treatment with granulocyte colony-stimulating factor resulted in a 6- to 9-fold increase in circulating neutrophil counts. Nevertheless, this change did not enhance the minor degree of ethanol-induced liver injury in this model. Our results indicate that, whereas neutrophil leukocytosis accompanies more severe manifestations of ethanol hepatotoxicity in rats, this condition per se does not directly induce or exacerbate ethanol-induced liver injury.

Role of adenosine in the ethanol-induced potentiation of the effects of general anesthetics in rats.

Acetate, derived from ethanol metabolism in the liver, is released into the circulation and utilized in many tissues including the brain. The subsequent metabolism of acetate results in the production of adenosine that has a number of effects in the central nervous system. The purpose of the present studies, therefore, was to investigate the contribution of metabolically generated adenosine to the ethanol-induced potentiation of the inhalational agents isoflurane and sevoflurane. Changes in the anesthetic requirement for isoflurane and sevoflurane were determined in rats using the tail-clamp procedure. Both ethanol and sodium acetate reduced anesthetic requirement for isoflurane and sevoflurane in a dose-dependent fashion. The effect of acetate on anesthetic requirement was completely blocked by the administration of the adenosine receptor blocker, 8-phenyltheophylline. The ethanol-induced reduction in anesthetic requirement, however, was only partially blocked by 8-phenyltheophylline. Direct intracerebroventricular (i.c.v.) administration of the water-soluble adenosine receptor blocker, 8-sulfophenyltheophylline, also completely blocked the effect of acetate and partially blocked the effect of ethanol. This i.c.v. administration demonstrates that the actions of ethanol and acetate on anesthetic requirement are a central nervous system effect. The i.c.v. administration of the adenosine A1 receptor subtype agonist, R-phenylisopropyl adenosine, potentiated the anesthetic effects of isoflurane and suggests that the A receptor mediates the observed potentiation of anesthetic effect. This is further supported by the concomitant administration of 5-N-ethylcarboxamido adenosine, a non-selective adenosine agonist, with the selective A1 antagonist, 8-cyclopentyltheophylline, showing A1 receptor potentiation of anesthetic requirements. The studies show that (1) acetate potentiates the anesthetic effects of the inhalational anesthetics, sevoflurane and isoflurane; (2) acetate contributes in part to the effect of ethanol on anesthetic potency through metabolically generated adenosine; (3) these effects are likely mediated via adenosine A1 receptor subtypes.

Upper airway edema after carotid endarterectomy: the effect of steroid administration.

The objective of this study was to evaluate the effect of preoperative steroid administration on the site and extent of upper airway edema after carotid endarterectomy. The design was a randomized, prospective, double-blind controlled trial. Thirty-eight patients undergoing elective carotid endarterectomy (17 patients were in the steroid-treated group and 21 in the control group) were administered either 16 mg of dexamethasone or saline placebo prior to surgery. Computed tomograms (CT) scans of the neck were performed on the patients preoperatively and 24 h postoperatively. Measurements were taken from the CT scans of the airway transverse and anterior-posterior diameters at the levels of the hyoid bone, arytenoid cartilage, and cricoid cartilage. No postoperative neck hematomas were seen on the CT scans. Although neck edema was observed postoperatively, the upper airway dimensions were not statistically significantly different between the steroid and the control groups. We conclude that steroid administration immediately preoperatively has no clinical effect in reducing edema formation in the upper airway postcarotid endarterectomy.

Cocaine toxicity and isoflurane anesthesia: hemodynamic, myocardial metabolic, and regional blood flow effects in swine.

OBJECTIVES: Increasing numbers of people use cocaine recreationally and may require anesthesia care, having recently abused the drug. However, no data currently exist concerning potential interactions between toxic levels of cocaine and volatile anesthetic agents. This study investigated the effects of cocaine infusion on systemic hemodynamics, myocardial metabolism, and regional organ blood flow in relation to depth of isoflurane anesthesia. DESIGN: Prospective, randomized, controlled trial. SETTING: A laboratory at a university medical center. PARTICIPANTS: Twelve miniature pigs. INTERVENTIONS: An open-chest swine model was used. Isoflurane (ISO) was the sole anesthetic, administered at 0.75 and 1.5 minimum alveolar concentration (MAC), and cocaine was infused (n = 6) at a rate of 0.5 mg/kg/min. Control animals (n = 6) received an equivalent amount of normal saline. MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary arterial pressures and thermodilution cardiac output data were collected at 0.75 MAC and 1.5 MAC ISC. Regional myocardial and blood flows to other organs were measured using radiolabeled microspheres. Arrhythmias and altered ventricular conduction were noted only in the cocaine group, along with significant elevations in diastolic arterial pressure, coronary perfusion pressure, and systemic vascular resistance. Increased subendocardial blood flow occurred during cocaine infusion (p = 0.03); subepicardial perfusion was unchanged. Cerebral (p < 0.01) and spinal cord (p < 0.05) blood flows were reduced in animals receiving cocaine. Other organ blood flows were unchanged with depth of anesthesia or cocaine administration, with the exception of splenic blood flow (p < 0.04). CONCLUSIONS: Moderately toxic cocaine levels occurring during isoflurane at 0.75 MAC and 1.5 MAC are associated with hemodynamic abnormalities, a marked increase in systemic vascular resistance, and a tendency to produce cardiac arrhythmias. A reversal of endo/epicardial myocardial perfusion ratio occurs associated with cocaine infusion during ISO anesthesia. This is probably not related to a primary redistribution of subendocardial blood flow and may be related to a combination of increased myocardial oxygen demand and epicardial coronary vasoconstriction. The reductions in cerebral and spinal cord perfusion observed may explain, in part, the neurologic sequelae of cocaine toxicity.

Computed tomographic analysis of airway dimensions after carotid endarterectomy.

Airway obstruction is a rare but serious postoperative complication of carotid endarterectomy. We prospectively studied airway dimensions between the hyoid bone and cricoid cartilage in patients undergoing carotid endarterectomy using preoperative and postoperative computed tomographic (CT) scans of the neck. CT scans showed soft tissue swelling in all 19 patients. Five patients with clinical evidence of airway obstruction and a hematoma present on CT scan were intubated postoperatively. The three-dimensional reconstruction of the neck from the CT scans showed a reduction in the volume of the airway in all patients. This reduction was greater in the intubated (62% +/- 9%) compared to the nonintubated (32% +/- 7%) patients (P < 0.01). The anterior-posterior and transverse diameters of the airway were reduced, while retropharyngeal edema was increased after carotid endarterectomy. This change was greater for the upper airway at the level of the hyoid compared to the arytenoids and cricoid, and was significantly greater in the intubated than the nonintubated patients. Tracheal deviation was greater in the intubated than in the nonintubated patients. These results demonstrate significant soft tissue edema of the neck after carotid endarterectomy that reduces airway volume and can result in airway obstruction.

Effect of propylthiouracil treatment on NADPH-cytochrome P450 reductase levels, oxygen consumption and hydroxyl radical formation in liver microsomes from rats fed ethanol or acetone chronically.

The antithyroid drug propylthiouracil (PTU) has been shown previously to reduce hepatic oxygen utilization and to protect the liver from ethanol-induced injury. The present study examined the effect of PTU on hepatic microsomal oxygen consumption and on the activities of NADPH-cytochrome P450 reductase (CYP-reductase) and cytochrome P4502E1 (CYP2E1) in rats receiving ethanol or acetone chronically. Liver microsomes from rats treated with ethanol for 29 days displayed increases in (i) O2 consumption (70%), (ii) hydroxyl radical (.OH) production (49%) and (iii) ethanol oxidation (50%). Microsomal CYP2E1 levels were increased markedly by chronic ethanol administration, while CYP-reductase was affected marginally, but not significantly (P = 0.06). Chronic treatment with acetone for 14 days, produced similar effects, except that .OH production was not enhanced. Administration of PTU (25 mg/kg/day) to ethanol- or acetone-fed rats, for 10 and 14 days, respectively, led to a marked reduction in the levels and activity of CYP-reductase, and to a decrease in the rates of microsomal O2 consumption, .OH production and ethanol oxidation, but did not lower the levels of CYP2E1 or the metabolism of the CYP2E1 substrate N,N-nitrosodimethylamine. These data suggest that the ability of PTU to protect the liver from ethanol-induced injury may be due to a reduction in the levels of CYP-reductase, thereby minimizing the enhancement of microsomal oxygen consumption and free radical generation associated with ethanol-induced CYP2E1 activity.

Acetate-mediated effects of ethanol.

Ethanol has been shown to increase markedly portal blood flow, primarily by increasing intestinal blood flow. This effect of ethanol is reproduced by acetate, infused at rates equivalent to those leading to endogenous acetate production following ethanol administration. The physiological mediator, adenosine, is also known to increase markedly intestinal and portal tributary blood flow. We have shown that adenosine receptor blockade with 8-phenyltheophylline completely abolishes the effects of ethanol, acetate, and adenosine on intestinal and portal blood flow, suggesting that increases in adenosine tone may constitute a common mechanism mediating the actions of both ethanol and acetate on the splanchnic vasculature. Studies are also presented that show that acetate administration has marked effects on central nervous system function. On two tests, motor coordination and anesthetic potency, both ethanol and acetate showed similar effects. The effects of acetate were fully abolished by 8-phenyltheophylline. The effects of ethanol were partially blocked by 8-phenyltheophylline, with a greater effect of this blocker being seen at low doses of alcohol. Whereas ethanol at low doses increased locomotor activity in mice, acetate markedly reduced it. The effect of acetate on locomotion was fully reversed by the adenosine receptor blocker 8-phenyltheophylline, whereas the activating effect of ethanol on locomotion was markedly enhanced by this blocker. These data suggest that the actions of ethanol on locomotor activity normally result from the combination of a direct stimulatory effect of ethanol per se and an inhibitory effect of acetate, produced endogenously from ethanol. When the latter effect of acetate is abolished by adenosine receptor blockade, the activating effect of ethanol is fully expressed.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of adenosine-induced hypotension on systemic and splanchnic hemodynamics during halothane or sevoflurane anesthesia in the rat.

BACKGROUND: It has been suggested that the liver may be at risk for ischemic damage during adenosine-induced hypotension. This notion, however, is somewhat inconsistent with the understanding that adenosine is a powerful vasodilator of the splanchnic circulation. To help clarify the effect of adenosine-induced hypotension on splanchnic hemodynamics, we studied the systemic and splanchnic hemodynamic responses to adenosine, both alone and in the presence of halothane or sevoflurane. METHODS: Systemic and splanchnic hemodynamics were determined during the infusion of adenosine in 36 rats allocated randomly to one of three study groups: (1) awake, (2) halothane anesthesia (1.0 MAC), or (3) sevoflurane anesthesia (1.0 MAC). Adenosine was infused at a rate sufficient to decrease the mean arterial pressure by 35-38% from awake control values. Cardiac output and organ blood flows were measured using the radiolabeled microsphere technique. RESULTS: Adenosine infusion produced stable hypotension of rapid onset due to a reduction in systemic vascular resistance. Stroke volume increased, but cardiac output remained unchanged in the awake and sevoflurane groups because of a decrease in heart rate. Infusion of adenosine during halothane anesthesia increased cardiac output enough to compensate for the decrease in cardiac output due to halothane alone. In the splanchnic circulation, there was an increase in portal tributary (42%, P < 0.01) and hepatic arterial (38%, P < 0.05) blood flows during adenosine infusion in awake rats. This resulted in an overall increase in total liver blood flow (42%, P < 0.01). Halothane anesthesia was associated with a decrease in portal tributary blood flow (28%, P < 0.05). In contrast, sevoflurane anesthesia was associated with an increase in hepatic arterial flow (35%, P < 0.05) but with no change in portal tributary blood flow. During halothane anesthesia, adenosine infusion increased portal tributary (90%, P < 0.01) and hepatic arterial (37%, P < 0.05) blood flows, thereby increasing total liver blood flow to values similar to those in awake adenosine-infused rats. During sevoflurane anesthesia, adenosine infusion increased portal tributary blood flow (48%, P < 0.01), but hepatic arterial blood flow did not increase beyond the values observed during sevoflurane anesthesia alone. CONCLUSIONS: These findings demonstrate that adenosine is a potent vasodilator of portal tributary and hepatic arterial vasculature in the rat and that the splanchnic hemodynamic effects of adenosine predominate over those of halothane and sevoflurane.

Effect of propofol infusion on splanchnic hemodynamics and liver oxygen consumption in the rat. A dose-response study.

BACKGROUND: Propofol has been used for the maintenance of anesthesia. The effects of propofol infusion on splanchnic hemodynamics and liver oxygen consumption, however, have not been reported. In the current investigation, the authors studied the effects of a continuous infusion of propofol on systemic and splanchnic hemodynamics using a new method to measure liver oxygen consumption in awake control and anesthetized rats. METHODS: Cannulas were inserted into the left ventricle, femoral artery, portal vein, and hepatic vein during ether anesthesia, and the rats were allowed to awaken and recover for 3-4 h before study. Animals were infused for 30 min with either saline (controls) or propofol at a rate of 300, 600, 900, or 1,200 micrograms.kg-1 x min-1. Cardiac output and organ blood flows were measured using radiolabelled microspheres, and blood samples from the femoral artery, portal vein, and hepatic vein were used to determine liver oxygen consumption. RESULTS: Mean arterial pressure decreased in a dose-dependent manner with a 25% reduction at the highest infusion rate. Systemic vascular resistance similarly decreased, whereas cardiac output remained unchanged at all the infusion rates. Hepatic arterial blood flow increased in a dose-dependent fashion over the dose range studied, to a maximum increase of 120%. Portal tributary blood flow increased by 30% at the highest infusion rate. Total liver blood flow increased in a dose-dependent manner to a maximum of 38%. Total oxygen delivery to the liver by the hepatic artery and portal vein increased in a dose-dependent fashion. Liver oxygen consumption increased in a dose-dependent fashion to a maximum increase of 51% at an infusion rate of 1,200 micrograms.kg-1 x min-1. The percent of oxygen extracted by the liver was not altered by propofol infusion, and hepatic venous oxygen saturation did not decrease at any dose studied. Coronary and renal blood flows were not altered. Arterial PaCO2, increased from 31 +/- 2 mmHg in awake control rats to 41 +/- 2 mmHg in spontaneously breathing rats infused with 1,200 micrograms.kg-1 x min-1 propofol. CONCLUSIONS: The maintenance of anesthesia using an infusion of propofol resulted in an increase in liver oxygen consumption that was fully compensated for by an increase in oxygen delivery to the liver. Splanchnic hemodynamics and liver oxygenation are not adversely affected during maintenance of anesthesia with propofol in the normal rat.

Effect of propylthiouracil on the ethanol-induced increase in liver oxygen consumption in awake rats.

It has been postulated that the beneficial effects of the antithyroid drug propylthiouracil in the treatment of alcoholic liver disease depend primarily on the action of propylthiouracil in suppressing the increase in hepatic oxygen consumption induced by ethanol. The evidence for this effect of propylthiouracil is derived from studies in which liver oxygen consumption has been determined in in vitro preparations. In our study the effects of ethanol and propylthiouracil on liver oxygen consumption were assessed in vivo in an unrestrained and unanesthetized rat model, where liver blood flow and hepatic vein and portal vein oxygen content can be measured. Data show that the liver oxygen consumption increased in rats treated with ethanol-containing liquid diets for 4 to 6 wk, both on withdrawal of alcohol (30%, p < 0.01), and after readministration of ethanol (50%, p < 0.01). Single-dose ethanol administration increased portal tributary blood flow without affecting hepatic arterial blood flow in both controls and rats withdrawn from long-term ethanol treatment. Long-term ethanol administration per se had no effect on portal tributary blood flow; however, hepatic arterial blood flow was increased by 38% (p < 0.01). Treatment with propylthiouracil for 5 days resulted in complete suppression of the increase in liver oxygen consumption induced by long-term ethanol administration. Propylthiouracil treatment also attenuated the increase in portal tributary blood flow after the administration of a single dose of ethanol. These determinations were made 24 hr after the last dose of propylthiouracil.(ABSTRACT TRUNCATED AT 250 WORDS)