Influence of degradable starch microspheres (Spherex) on the retention of pertechnetate in a solitary rat liver tumor.

In a model of secondary liver cancer in the rat an evaluation was made of the influence of degradable starch microspheres (Spherex) on the drug retention in tumor and liver tissue. Sodium pertechnetate was used as a drug model substance and was injected into the hepatic artery alone or with degradable starch microspheres (DSM) in a dose of 6 or 12 mg. The distribution of pertechnetate was measured by a gamma-camera equipped with a high resolution collimator. In rats with liver tumor the total elimination of pertechnetate from the liver was delayed when compared to rats without tumor. The tumor concentration of pertechnetate was higher than that of the surrounding liver tissue, irrespective of the presence of DSM. With a DSM dose of 12 mg there was a significantly higher retention of pertechnetate in the tumor during the whole observation period compared to pertechnetate only. The results of this study indicates that DSM can be of value in regional liver chemotherapy to increase liver tumor drug exposure and to reduce systemic toxicity.

Results of hepatic lobectomy for primary epithelial cancer in 31 adults.

Hepatic lobectomy for primary epithelial cancer was performed in 31 adults from 1964 through 1977 in the surgical departments of six Scandinavian hospitals. Twenty-three patients were discharged and had a 2 year survival rate of 62 per cent and a 5 year survival rate of 16 per cent. Alternatives to surgery have not yet emerged. Further progress requires centralization.

Gastric blood flow, tissue gas tension and microvascular changes during hemorrhage-induced stress ulceration in the pig.

Various features of blood supply to the gastric mucosa were studied in the piglet stomach during stress ulceration induced by hemorrhagic shock. Gastric blood flow, as measured by the radioactive microsphere technique, significantly decreased during shock, but no major change occurred in the gastric function of total cardiac output. There was no difference in the magnitude of the decrease of mucosal blood flow between the nonulcerating antral mucosa and the more readily ulcerating corpus or fundic mucosa. At the same time, a significant decrease in tissue partial pressure of oxygen and increase in tissue partial pressure of carbon dioxide occurred, but again no difference was observed between the antrum and the corpus. Microangiographic studies demonstrated a clearly diminished filling of the arterial and capillary bed of the gastric mucosa during shock, suggesting intense vasoconstriction, thrombosis of the mucosal blood vessels, or both. These changes were more prominent in the corpus portion of the stomach than in the antrum. At the site of mucosal lesions, the filling defects persisted even after the shock, suggesting permanent thrombosis of the blood vessels.

The influence of degradable starch microspheres on liver uptake of 5-fluorouracil after hepatic artery injection in the rat.

The effect of degradable starch microspheres (DSM) on the distribution of 5-fluorouracil (5-FU) after hepatic artery injection was studied in normal rats. Carbon-14-labelled 5-FU was injected separately or together with DSM into the hepatic artery. Radioactivity was measured in liver tissue, bile, peripheral blood, and urine. When microspheres were added, the liver uptake of 5-FU was increased; its peak concentration in peripheral blood decreased, as did the early urinary excretion of radioactivity. The addition of degradable starch microspheres to hepatic artery injections of cytostatic drugs might be of value in increasing the drug concentration in tumour tissue and reducing systemic toxicity.

Protease-antiprotease imbalance, hemodynamic and regional blood flow changes in experimental pancreatitis.

Pathologic proteolysis in pancreatitis is an important clue to understand the pathophysiology in pancreatitis. Impairment of pancreatic circulation is also important in the development of severe pancreatitis. In an attempt to study some of the biochemical and circulatory events in experimental pancreatitis in the pig the following experiments were undertaken. Pancreatic and splanchnic blood flow were studied in severe and mild pancreatitis with the microsphere method, together with cardiac output and mean arterial pressure. Kininogen, alpha-2-macroglobulin and alpha-1-proteinase inhibitor were measured in plasma and in peritoneal fluid. In severe pancreatitis consumption of kininogen in the peritoneal cavity was demonstrated together with a final lowering of the plasma protease inhibitors. This was accompanied by a rapid reduction of cardiac output and finally mean arterial blood pressure. Pancreatic blood flow was profoundly diminished in this group. No such changes were found in mild pancreatitis. It is concluded that pancreatic ischemia in pancreatitis is associated with protease-antiprotease imbalance.

Changes in cardiac output distribution after liver dearterialization in the rat.

The changes in cardiac output distribution in rats have been studied after hepatic artery ligation and additional ligament division. These procedures resulted initially in a marked decrease in the arterial blood supply to the liver and this effect was pronounced still four weeks after the operation. Evidence was found that the decrease in liver blood supply induced by the procedure was in part counterbalanced by arteriovenous shunting in the preportal region. Furthermore, a temporary redistribution of cardiac output with reduced fractions to colon and spleen was found two weeks after these operations.

Microsomal hexobarbital metabolizing enzymes in regenerating cholestatic rat liver.

Microsomal changes were studied in regenerating liver cholestatic rats by measuring hexobarbital metabolzing capacity (HMC) in vitro. Total extrahepatic biliary obstruction was induced by ligating the common duct, 3 days later, a 70% liver resection was performed. Sham-operated animals served as controls. Analysis of HMC showed a similar pattern of microsomal regeneration in cholestatic as in sham-operated rats. This indicates that in the rat, cholestasis per se does not interfere with the development of this enzyme system during regeneration.

Effects of lysine-vasopressin treatment on renal function in burned pigs.

The effects of lysine vasopressin (LVP) on renal excretory function and renal blood flow were studied in anesthetized and burned pigs either treated conservatively or by early excision 5 hours after burn. Renal perfusion was measured with radioactive microspheres. Diuresis and the urinary excretion of sodium and potassium were determined. Glomerular filtration rate (GFR) was measured either as the endogenous creatinine clearance rate or the clearance rate of 51Cr-EDTA. LVP-treatment in pharmacologic doses after burn caused larger diuresis, and larger sodium and potassium excretion rates than in unburned controls and animals submitted to burn only, Renal blood flow decreased significantly early after burn whether LVP was given or not. After burn, GFR was moderately higher in the LVP-treated pigs than in the animals submitted to burn only. After 24 hours S-creatinine was lower in the pigs treated by LVP and excision of the burned tissues after 5 hours, compared with the conservatively treated animals. This implies that an active surgical approach to full thickness skin burns might support renal function. LVP-induced intrarenal effects causing increased GFR and secondary medullary interstitial electrolyte concentration and osmolar changes could be the mechanisms causing the renal functional changes found in this investigation.

Lysine-vasopressin in excisional treatment of burns in pigs. Decreased blood loss and earlier circulatory recovery.

The hemodynamics were monitored during 24 hours in piglets anesthetized with Pentothal-N2O/O2, submitted to 33% full-thickness skin burn and resuscitated with 2.4 ml/kg/% burn of 100 mmol NaCl in 2.5% glucose. Three groups were studied: (I) standardized burn, (II) standardized burn and excision after 5 hours, (III) standardized burn, excision and lysine-vasopressin (LVP) given as intravenous infusion in a vasopressor dose. All groups showed similar decrease of cardiac output (CO), which was about 30% 4 hours after burn. In the two groups with burn excision, however, CO recovery was earlier than in the conservatively treated group I. The improvement was significant between group III and group I. LVP led to higher CO fraction and greater blood flow to hepatic artery, reduced flow to proximal gastrointestinal tract and skin and unchanged flow to heart, kidneys and other organs 24 hours after burn. The mean blood loss during and after burn excision was greatly reduced in group III (50 g/25 kg) compared with group II (146 g/25 kg). The therapeutic implications of LVP in excisional burn treatment are discussed.

Pharmacodynamic and pharmacokinetic interactions between ketamine and diazepam.

Anaesthesia with continuous i.v. ketamine and 65% nitrous oxide in oxygen was given to a total of 49 patients undergoing major abdominal surgery. A control group was premedicated with atropine and other groups received in addition rectal diazepam or clorazepate i.v. For further patients had been on oral diazepam or barbiturates for 1-14 years; as premedication they received atropine alone. The anaesthetic technique gave good operative conditions in the 4 groups of patients. The haemodynamic stimulation of ketamine was significantly reduced in patients premedicated with diazepam. Psychotomimetic side effects were not prominent in any of the groups. Patients premedicated with diazepam required a lower rate of ketamine infusion as compared to controls during the initial 30 min of anaesthesia. The patients in the other groups did not differ from the control group in this respect. There were large differences in metabolic pattern between the groups. As compared to the controls, the patients on long-term diazepam or barbiturates had high concentrations of hydroxylated metabolites, with levels higher than that of norketamine. The patients pretreated with diazepam had very low plasma levels of hydroxylated metabolites. Clorazepate premedication did not significantly affect the metabolism of ketamine. The biological half-life of ketamine was significantly increased in the diazepam-treated group, and it was shortened in those on long term treatment with barbiturates or diazepam.

Central haemodynamics and regional blood flow during halothane-nitrous oxide anaesthesia and controlled ventilation. An experimental study in the rat.

The haemodynamic effects of halothane-N2O/O2 anaesthesia with controlled ventilation were studied in rats, using the microsphere method. Mean arterial blood pressure was significantly reduced but only minor effects on cardiac output (CO), heart rate, and systemic vascular resistance were seen. During anaesthesia, there were significantly increased fractions of CO delivered to brain, lungs, small intestine and liver (hepatic artery), while the fractions to spleen, stomach and carcass were decreased. Fractional distribution and regional blood flow to heart, kidneys, adrenals and preportal area remained unchanged. When anaesthesia was prolonged from 60 to 90 min, no further changes in central or regional haemodynamics were seen. Considering the minor effects on central haemodynamics and the absence of changes in central and regional haemodynamics at 60 and 90 min, this anaesthesia model should be useful in experimental research.

The effect of halothane on the distribution of cardiac output and organ blood flows in the hemorrhagic, hypotensive dog.

Halothane was given to dogs which had been bled to an arterial mean blood pressure of 60 mmHg, and the circulatory effects were studied with the aid of the radioactive microsphere technique. The cardiac output and coronary blood flow were well maintained, whereas the arterial mean blood pressure was slightly, and the stroke volume markedly increased, indicating an improved heart function. The blood flows to the brain, lungs, liver and kidneys were well preserved throughout the anesthesia. The effect of retransfusing the withdrawn blood was also studied, and it resulted in an increased cardiac output, arterial mean blood pressure and increased blood flows to the heart, lungs, spleen, bowel and liver.

The effect of halothane on the distribution of cardiac output and organ blood flow in the hypovolemic dog.

The circulatory effect of halothane anesthesia given to moderately hypovolemic dogs (blood loss 25 ml/kg b.w.) was investigated using the radioactive microsphere technique. The effect of the anesthetic was reflected by a decrease in the arterial mean blood pressure and a reduced blood flow to the heart, whereas the blood flows to other organs did not change significantly but were well preserved in vital organs (brain, kidneys, liver and lungs). The effect on the circulation of reinfusing the withdrawn blood was also studied.

Tissue perfusion and distribution of cardiac output during ketamine anesthesia in normovolemic rats.

Based on previous clinical experience, an anesthetic technique for the rat, using ketamine, has been evaluated. The method comprised an i.v. bolus injection of 30 mg/kg for induction and an i.v. continuous infusion of 1.5 mg/kg/min for maintenance of anesthesia. Minor differences in ketamine metabolism between man and the rat are discussed. It appears that a higher ketamine concentration at the receptor site was required in the rat as compared to man. During ketamine anesthesia in the rat, fractional distribution of cardiac output and regional tissue perfusion were determined with the aid of the microsphere method. The study showed increased fractions to the heart, brain and tongue. The carcass fraction was elevated shortly after induction but reduced during steady-state anesthesia. Stomach, bowel and kidneys received reduced fractions early, but after these fractions returned to their initial levels. As a consequence of the increased cardiac output, regional tissue perfusion was increased in practically all organs.

Evaluation of the microsphere method for determination of cardiac output and flow distribution in the rat.

The radioactive microsphere technique was applied to determine simultaneous cardiac output and flow distribution in the rat. Left ventricular injections of large numbers of microspheres were given, without significant adverse effects, allowing determination of flow to organs and tissues with low perfusion rates. In order to determine coronary blood flow it was necessary to excise the inner lining of the left ventricle, thus eliminating activity from deposits of microspheres. Cardiac output determination showed less variation with the sampling catheter in the abdominal aorta than in the femoral artery. It is concluded that the microsphere method can be conveniently used for hemodynamic studies in the rat, and that the abdominal aorta is the preferred site for the placement of the reference catheter in the rat.