Transient bacteremia following endoscopic injection sclerotherapy of esophageal varices.

The incidence of transient bacteremia following endoscopic injection sclerotherapy of esophageal varices was evaluated in 18 patients subjected to 40 sessions of injection sclerotherapy. Blood cultures were obtained before sclerotherapy and at five minutes, 30 minutes, and 24 hours after sclerotherapy. The injectors as well as the endoscope were cultured before and after the procedure. Blood cultures were positive in two patients after injection sclerotherapy (Enterobacter cloacae and Staphylococcus species, coagulase-negative, respectively) for an incidence of 5% of transient bacteremia. Pseudomonas aeruginosa was the most frequent bacteria isolated from the injector after sclerotherapy. We conclude that the incidence of transient bacteremia after sclerotherapy is no higher than routine upper-intestinal endoscopy.

Pharmacokinetics and pharmacodynamics of methylprednisolone in obesity.

Methylprednisolone pharmacokinetics and its directly suppressive effects on plasma cortisol, blood histamine (basophils), and circulating helper T cells were evaluated in six obese (at least 35% above ideal body weight) men and six nonobese male volunteers. Methylprednisolone doses of 0.6 mg/kg total body weight were administered as the 21-succinate sodium salt. Absolute clearance (in liters per hour) of methylprednisolone was 40% less in the obese subjects. Total volume of distribution (Vss) of methylprednisolone was unchanged (about 120 L), but when normalized for total body weight, Vss per kilogram was less in obesity. The patterns of cortisol, blood histamine, and helper T cell responses after methylprednisolone administration were similar in both groups, but more profound effects were observed in the obese subjects. Pharmacodynamic models were applied for these immediate effects of methylprednisolone based on the premise that receptor interactions of steroids are followed by rapid suppression of the circadian rhythm of cortisol and recirculation of basophils and helper T cells, which persist until inhibitory concentrations (IC50) of methylprednisolone disappear. Similar IC50 values for the three effects were obtained in both groups, indicating no intrinsic pharmacodynamic differences in sensitivity to these methylprednisolone effects in obesity. However, methylprednisolone should be administered on the basis of ideal body weight, and the dosing interval should be potentially lengthened because of decreased methylprednisolone clearance in obesity.

Immunoradiometric assay of lipid A: a test for detecting and quantitating endotoxins of various origins.

The ability to measure circulating endotoxin in various disease states has been hampered by the lack of a specific and quantitative assay. The test most commonly used has been the Limulus gelation assay, which measures an enzymatic effect of endotoxin rather than the substance itself. Based on a solid-phase immunoradiometric assay previously developed to detect the specific lipopolysaccharide from Escherichia coli 026, a similar assay has been developed for the lipid A moiety of endotoxins. The assay uses rabbit antibodies to lipid A which do not react with ketodeoxyoctonate, myristic or beta-hydroxymyristic acids, and detects lipid A obtained from endotoxins of various origins after acid hydrolysis of lipopolysaccharide. Experiments in rats given exogenous endotoxin suggest that this assay can be useful for quantitation of bacterial endotoxins in serum and for studying the pathophysiology of experimental endotoxemia.

Rapid alterations in substrate profiles after partial hepatectomy in the rat.

We compared alterations in circulating levels of insulin and glucagon and metabolic fuels in response to partial (70%) hepatectomy (HP) and sham hepatectomy (SHP) in fasting rats and in unanesthetized, fasting control rats. Within 15 minutes, animals in the HP group were hypoglycemic compared with the SHP and control groups. After 30 minutes, the insulin concentration and the insulin-glucagon molar ratio (IGR) rose in the HP group. After four hours, animals in the HP group were hyperglycemic compared with the SHP and control animals. Comparison of the lipid and amino acid profiles suggested use of these substrates by eight hours. The levels of branched-chain amino acids, although depressed early after HP, were markedly elevated later, when the IGR in the HP group had normalized. The acute loss of hepatic mass by limiting gluconeogenesis may be the cause of hypoglycemia and also could alter the plasma IGR because of the different hepatic clearance rates of these hormones. A switch to lipid and protein as metabolic fuels appears to follow these early changes.

Pharmacokinetics of methylprednisolone hemisuccinate and methylprednisolone in chronic liver disease.

The disposition of methylprednisolone (MP) and its prodrug hemisuccinate (MPHS) was assessed in six middle-aged patients with chronic liver disease (CLD) and compared with six younger, healthy subjects after a single IV dose of 25.4 mg of MPHS. Blood and urine samples were collected over 12 hours. Plasma and urine concentrations of MPHS and MP and plasma cortisol were measured by HPLC. MPHS clearance (CL) was significantly reduced in the CLD group (495 vs. 1389 mL/hr/kg) whereas volume of distribution (Vss) of MPHS (about 0.35 1/kg) did not differ. The elimination half-life, t1/2 beta, was significantly longer in CLD (0.61 vs. 0.32 hr). The percent recovery of unchanged MPHS in urine was similar (about 9%) in both groups. The kinetic parameters of MP did not differ between the two groups for: clearance (about 370 L/hr/kg IBW), Vss (about 1.3 L/kg), and t1/2 beta (about 3.0 hr). The suppression t1/2 of cortisol after MPHS was longer (3.9 vs. 1.9 hr) indicating metabolic pathways for cortisol and MP are affected differently in CLD. Reduction in MPHS CL may reflect altered hepatic blood flow due to both cirrhosis and age effects. However, good availability of MP from MPHS and lack of perturbation of MP pharmacokinetics in CLD patients may provide therapeutic advantages in selection of this glucocorticoid. This is the first study that characterizes the disposition of the prodrug MPHS and the formation of MP simultaneously in CLD patients.

Simplified portoazygous disconnection (Tanner's operation) combined with operative sclerotherapy for bleeding varices.

A simplified method of portoazygous disconnection employing the linear stapler and operative sclerotherapy was employed in six patients. Endoscopic maintenance sclerotherapy was instituted for five patients in the follow-up period. Combining the operative and endoscopic modalities is attractive, since the deficiencies of each tend to be offset by the other.

Intestinal endotoxins as co-factors in liver injury.

The interaction between sinusoidal cells of the liver and endotoxins absorbed from the gut may be critical in causing liver cell injury due to a variety of toxins. Both fixed liver macrophages, and those recruited during injury may be important to this process either by their inability to detoxify increased amounts of LPS presented from the intestinal track, or because of the release of potent effectors under its influence. Evidence that intestinal endotoxins are an important co-factor in both experimental and clinical liver injury is discussed. Mechanisms responsible for macrophage mediation of endotoxin injury are proposed, and preliminary evidence that tumor necrosis factor levels are elevated in human liver disease is presented.

The importance of intestinal endotoxins in liver disease.

The development and wider use of the Limulus amoebocyte lysate assay (LAL) for the detection of endotoxin, has led to renewed interest in the link between gut-derived endotoxin, liver injury and the extra-hepatic manifestations of clinical liver disease. The concept that endotoxemia may occur and be harmful in clinical states without the concomitant presence of Gram-negative bacteria is a relatively recent one and has been most intensively studied in the context of liver injury. Since the liver stands between the gut and the systemic circulation, it has been postulated that failure to detoxify endotoxins absorbed into the portal circulation after hepatic injury might lead to further liver damage and escape of this toxic material into the general circulation. The present review will update the status of this hypothesis, discuss mechanisms proposed for the damage and present evidence for the association in animal models. Finally, studies both positive and negative, will be cited that have used the LAL to detect endotoxemia and its consequences in human liver disease.

Complications of gastrostomy.

Despite its simplicity, gastrostomy has been associated with a relatively high incidence of complications. We have described two unusual complications: inadvertent duodenostomy, resulting in gastric outlet obstruction, and the migration of a gastrostomy feeding tube into the midportion of the jejunum, resulting in obstruction of the small bowel.

Persistent bradyarrhythmia after sclerotherapy for esophageal varices.

Sclerotherapy for esophageal varices has recently gained wide acceptance in major medical centers for the control of bleeding esophageal varices. We have described two elderly patients with preexisting cardiac disease (right bundle branch block) in whom persistent bradyarrhythmia followed sclerotherapy using 5% sodium morrhuate. Both patients required insertion of a permanent pacemaker. This is the first report associating sclerotherapy with significant bradyarrhythmias.

D-Galactosamine liver injury: absorption of endotoxin and protective effect of small bowel and colon resection in rabbits.

D-Galactosamine is an amino sugar with unique hepatotoxic properties in animals. Although the mechanism of liver injury by galactosamine remains controversial, a role for bacterial endotoxin has been suggested. In the present study, using New Zealand rabbits, we show that the significant increase in serum glutamic oxaloacetic transaminase which followed the injection of 4.25 mmole/kg of D-galactosamine was completely prevented in animals subjected to resection of small bowel and colon. Using an immunoradiometric assay specific for E. coli 026 endotoxin we showed that after instillation of 50 mg of E. coli into the colon, serum levels of this endotoxin were higher in the animals injected with galactosamine than the controls injected with saline. However, the differences in endotoxin concentration between the two groups of animals was statistically significant only at 30 and 60 min. The role of endotoxin in the pathogenesis of galactosamine liver injury is reviewed and discussed.

Streptococcus pneumoniae meningitis in two patients with peritoneovenous shunts.

We report two patients with cirrhosis and peritoneovenous shunts (LeVeen) in whom fatal Streptococcus pneumoniae sepsis and meningitis developed 10 months and 22 days, respectively, after insertion of the shunts. The association between pneumococcal bacteremia and meningitis is well established. The potential implications of a LeVeen shunt in increasing risk for meningitis are discussed.

The clearance capacity of the canine liver for a portal vein endotoxin infusion.

The capacity of the livers of anesthetized dogs to clear a portal vein infusion of Escherichia coli 026 endotoxin was evaluated. Appearance of the endotoxin in arterial blood was quantitated by immunoradiometric assay. Various hemodynamic and metabolic parameters were monitored throughout the infusion to corroborate the development of systemic endotoxemia. Significant amounts of E. coli 026 endotoxin were detected in arterial blood after infusion of 240 micrograms endotoxin. As expected, systemic endotoxemia was associated with decreased cardiac index, mean arterial blood pressure, heart rate, and splanchnic (portal vein) blood flow. Changes in plasma levels of glucose, insulin, and glucagon and in the pancreatic outputs of insulin and glucagon did not occur before the development of severe hypotension and the termination of the study. It was concluded that the liver clearance capacity for endotoxin in the dog is 0.72 microgram/gm liver/hour and that severe hemodynamic alterations develop in this animal model before changes in carbohydrate balance.

Insulin, glucagon and glucose in the regeneration response of the liver.

The effects of intraduodenal glucose load on the hepatic uptake of insulin, glucagon and glucose after a 70 per cent hepatectomy were studies in anesthetized dogs. Dogs without a hepatectomy served as the control study. Data were derived from plasma concentrations in the portal vein, aorta and hepatic vein with simultaneous portal vein and hepatic artery plasma flow measurements. The concentrations of glucose in the arterial blood of dogs after a hepatectomy were less than those for the controls throughout the study, while insulin and glucagon concentrations showed no differences between the groups. Hepatic uptakes of insulin, glucagon and glucose per gram of liver perfused were significantly greater in the hepatectomy group and occurred because the amounts of these substances reaching the liver remnant were the same as those for the controls. The increased uptake of insulin and glucagon after partial hepatectomy may reflect increased binding of these hormones to the liver cell receptors, by which hepatic regeneration is induced. Increased glucose uptake could serve as the substrate for the accelerated anabolic processes.

Safety and pharmacokinetics of ceftazidime in patients with chronic hepatic dysfunction.

Safety and pharmacokinetic parameters of ceftazidime were evaluated in twelve male volunteers mean age 54.6 +/- 9.2 years. All had chronically impaired hepatic function which remained stable or normalized during ceftazidime administration. There was neither nephrotoxicity nor haematological toxicity. Serum concentration time curves of ceftazidime exhibited a biexponential decline. Drug accumulation was not apparent. Following doses 4 and 13, mean serum half-lives were 2.8 and 2.9 h, volumes of distribution 0.15 +/- 0.04 l/kg and 0.17 +/- 0.041 l/kg and plasma clearance values 1.320 +/- 0.50 ml/min/kg and 1.096 +/- 0.48 ml/min/kg, respectively. Dose modification based on hepatic dysfunction is unnecessary.