The pharmacokinetics and colonic tissue concentrations of cyclosporine after i.v., oral, and enema administration.

This study compares pharmacokinetic parameters and colonic tissue concentrations of cyclosporine administered by olive-oil or water-retention enemas with conventional intravenous (i.v.) and oral dosing. Five medical students were enrolled in a prospective crossover study. All subjects received a single dose of cyclosporine on four separate occasions, once orally, once as an olive-oil enema, once as a water enema, and once i.v. Cyclosporine concentration was measured in blood and in colonic tissue obtained by flexible sigmoidoscopy. Bioavailability was 18 +/- 7% (mean +/- SD) for the oral dose and was unmeasurable for the oil and water enemas. The concentration of cyclosporine in colon tissue was 32,443 +/- 17,251 ng/g (mean +/- SD) for the i.v. dose, 2797 +/- 1812 ng/g for the oral dose, 21,727 +/- 14,090 ng/g for the oil enema, and 25,318 +/- 30,408 ng/g for the water enema. The authors conclude that the bioavailability of cyclosporine, and thus the systemic absorption after administration by a retention enema, is negligible. The colonic tissue concentration of cyclosporine after i.v. or rectal administration via an enema is tenfold higher than that for oral dosing. These findings suggest that cyclosporine-retention enemas produce high distal colonic tissue concentrations with negligible systemic absorption after a single dose in healthy subjects and should be evaluated as treatment for patients with left-sided colitis. Because cyclosporine administered by the i.v. route provided sharply higher colonic tissue concentrations than those seen with oral therapy, pulse i.v. cyclosporine should be tried for patients with severe ileitis and colitis.

Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients.

This study was done to determine if the pharmacokinetics and gastric pH response of intravenous cimetidine are superior to oral dosing in seriously ill patients. A paired study of intravenous followed by oral liquid cimetidine was given to eight men and two women who were inpatients in a VA Hospital. Treatment was prescribed for either upper gastrointestinal (GI) bleeding or prophylaxis against GI bleeding. All patients received cimetidine 300 mg every 6 hours intravenously on day 1 and orally on day 2. After the fourth dose each day, venous blood samples and gastric pH measurements were taken serially for 6 hours. Peak serum cimetidine concentration was 2.0 +/- 0.5 mg/L for the intravenous dose and 1.5 +/- 0.3 mg/L for the oral dose (P = .001). Area under the curve (AUC) of cimetidine concentration was 3.81 +/- 1.1 mg/hr/L for the intravenous dose and 4.19 +/- 1.22 mg/hr/L for the oral dose (P greater than .30). Bioavailability (AUCpo/AUCiv) was 1.13 +/- 0.25, demonstrating complete oral absorption. The time during a 6-hour dosing interval that the gastric pH remained above 3.0 was 3.3 +/- 2.1 hours for the intravenous dose and 2.5 +/- 2.3 hours for the oral dose, P = .171). The time that the serum cimetidine concentration remained above 0.5 mg/L was 2.0 +/- 0.9 hours for the intravenous dose and 2.7 +/- 1.0 hours for the oral dose (P = .055). We concluded that bioavailability, time that gastric pH is maintained greater 3.0, and time that the serum cimetidine concentration is greater than 0.5 mg/L for intravenous cimetidine are not significantly different from oral cimetidine in seriously ill patients.

Lack of predictive value of the APACHE II score in hypoalbuminemic patients.

The APACHE II score predicts mortality in severely ill patients. This score does not account for the serum albumin level. Ninety-three patients (28 with serum albumin levels less than 2.5 g/dL [group I] and 65 with serum albumin levels greater than or equal to 2.5 [group II]) were retrospectively reviewed. Patients were comparable in age, APACHE II score, and compliance with required protein needs. Patients with severe hypoalbuminemia had nearly double the death rate of patients with mildly low or normal albumin concentrations (54% compared with 29%). The death rate in the severely hypoalbuminemic patients was 5.1-fold higher than would be predicted by their APACHE II score. The death rate in those patients with mildly low or normal albumin levels had only a 1.9-fold higher rate than would be predicted by their APACHE II score. It is concluded that severe hypoalbuminemia increases the risk of death significantly higher than would be predicted by the APACHE II score. APACHE II score is not as accurate in a severely hypoalbuminemic population.

Equal aspiration rates from postpylorus and intragastric-placed small-bore nasoenteric feeding tubes: a randomized, prospective study.

Postpylorus delivery of enteral feeding is perceived by many experts to be safer than intragastric delivery. To test this assumption, patients with similar Glasgow Coma Scores were given identical enteral formulas continuously via a 10-French nasoenteric tube, placed into the stomach or beyond the second portion of the duodenum. Observations were made for attainment of desired nutrition, bowel changes, and clinical signs of aspiration. Radiographs of the chest and abdomen were obtained every 3 days. If a tube migrated out of a chosen location, it was replaced. Thirty-three patients were studied. Seventeen patients were fed into the stomach and 16 patients were fed postpylorus. The mean duration of enteral feeding was 11.8 days for the gastric group and 10.9 days for the postpylorus group (p = NS). The time to deliver the desired kilocalories was 3.33 and 2.77 days (p = NS) for gastric and postpylorus-fed patients. Tubes displaced similarly in each group, gastric 0.647, postpylorus 0.750 per duration of feeding (p = NS). Chest radiographs met the criteria for aspiration pneumonia in 31.3% of gastric and 40% of postpylorus-fed patients (p = NS). Together, these data indicate that complications from enterally fed patients are equally common whether the distal port of the feeding tube is in the stomach or beyond the second portion of the duodenum.

Helicobacter pylori in duodenal ulcer patients with idiopathic gastric acid hypersecretion.

Thirty-three consecutive patients with idiopathic gastric acid hypersecretion (defined as a basal acid output > 10.0 meq/hr with a normal fasting serum gastrin level and negative secretin stimulation test) who were being treated for duodenal ulcer disease and other acid-peptic disorders were evaluated for the presence of Helicobacter pylori by means of a rapid urease test. Fourteen patients had duodenal ulcer and 19 had other acid-peptic disorders (gastroesophageal reflux in 14, including six with Barrett's esophagus; four with nonulcer dyspepsia; and one with erosive gastritis). Helicobacter pylori was present in 12 of the 14 ulcer patients (86%) compared to only two of the 19 nonulcer patients (11%) (P < 0.0001). The distribution of basal acid output for patients with duodenal ulcer was similar to that for nonulcer patients, and no significant difference in the mean basal acid output was found among Helicobacter pylori-positive compared to Helicobacter pylori-negative patients. Seven of the duodenal ulcer patients with a basal acid output greater than 15.0 meq/hr were Helicobacter pylori-positive, suggesting that the organism can withstand even extreme levels of gastric acidity. In conclusion, this study demonstrates that the prevalence of Helicobacter pylori infection in patients with duodenal ulcer disease associated with idiopathic gastric acid hypersecretion is not different from a majority of ulcer patients with normal acid secretory profiles and offers additional evidence that extreme levels of gastric acid are not bactericidal for the organism.

Comparison of omeprazole and ranitidine in treatment of refractory gastroesophageal reflux disease in patients with gastric acid hypersecretion.

Secretion of gastric acid and volume, serum gastrin concentration, and ambulatory 24-hr esophageal pH monitoring were evaluated prospectively in 12 patients with idiopathic gastric acid hypersecretion (basal acid output greater than 10.0 meq/hr) undergoing treatment for refractory chronic long-standing pyrosis. Treatment lasted six months and consisted of three months of ranitidine (mean 2150 mg/day, range 1200-3000 mg/day), followed by three months of omeprazole (mean 33 mg/day, range 20-60 mg/day). Both ranitidine and omeprazole significantly reduced gastric acid output (P less than 0.001) and gastric volume output (P less than 0.001) compared to a basal evaluation and resulted in complete disappearance of pyrosis. Total reflux time (percent 24 hr intraesophageal pH less than 4) was significantly reduced by ranitidine (P less than 0.02) and omeprazole (P less than 0.001) compared to basal evaluation; however, the effects of omeprazole were significantly greater than ranitidine (P less than 0.05). Omeprazole caused a significant increase in serum gastrin concentration compared to both basal and ranitidine (P less than 0.05). Endoscopically documented erosive esophagitis was present in nine of the 12 patients, and seven of the 12 patients had Barrett's epithelium. All 12 patients had complete resolution of pyrosis and healed esophagitis by six months, but no significant endoscopic regression was observed in the extent of Barrett's epithelium. No side effects occurred with these high doses of ranitidine or omeprazole. These results indicate that high-dose ranitidine and omeprazole are effective therapy for refractory gastroesophageal reflux disease. However, with omeprazole, total reflux times are reduced more than with ranitidine, often into the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

Endotracheal intubation. Complications in neonates.

Different opinions have developed on the use of endotracheal intubation in newborns and neonates for airway distress syndrome. The ensuing complications of the prolonged use of these airway tubes are drawing increased interest. This article reviews the case reports of 88 patients who received endotracheal intubation for airway problems and evaluates the complication rate as it correlates to the various contributing factors of duration of intubation, size of endotracheal tube, frequency of intubation, concomitant infections, and age of patient, which all lead to the complication rate.

Low serum erythropoietin--a strong diagnostic criterion of primary polycythaemia even at normal haemoglobin levels.

Estimations of serum erythropoietin level by enzyme immunoassay (EIA) kit were made in 42 patients with primary polycythaemia, and in a comparison group consisting of 41 patients with secondary polycythaemia and 47 patients with idiopathic erythrocytosis. The majority of patients with primary polycythaemia were undergoing treatment by venesection and therefore had Hb levels in the normal range at the time of erythropoietin estimation. In primary polycythaemia, 64% of the first samples taken from each patient were below the reference range for serum erythropoietin in normal individuals. When two samples were taken from each patient 72% had low values in one or both samples. In the comparison group, analysis of those patients who had two samples taken showed only one individual with secondary polycythaemia and none with idiopathic erythrocytosis who had a serum erythropoietin level below the reference range. The finding of low serum erythropoietin in patients with primary polycythaemia, even when Hb levels are normal due to venesection, is of high diagnostic specificity (few false positive results) and useful diagnostic sensitivity (28% false negative results). It is proposed that future diagnostic criteria of primary polycythaemia should include the finding of a serum erythropoietin level below the lower limit of normal in at least one of two serum samples taken on different occasions.

Abnormal duodenal bile composition in patients with acalculous chronic cholecystitis.

OBJECTIVE: Our goal was to characterize biliary lipid composition in patients with the syndrome of chronic biliary pain, absence of gallstones, and inflammation of the gallbladder mucosa (acalculous chronic cholecystitis). METHODS: Duodenal bile, obtained from 27 patients with a history of right upper quadrant pain and with negative imaging studies of the biliary tract, was analyzed enzymatically for bile acids, phospholipids, and cholesterol. Fifteen patients were found to have inflammation and/or fibrosis of the gallbladder at cholecystectomy. RESULTS: The 15 patients with abnormal gallbladder histology had more dilute duodenal bile, as indicated by a low bile acid concentration and a lower proportion of phospholipids (p < 0.01) when values were compared with those of duodenal bile samples from postmenopausal women without gallbladder disease or from radiolucent gallstone subjects participating in the National Cooperative Gallstone Study. Cholecystectomy relieved pain in 9 of 14 patients. CONCLUSIONS: Some patients with acalculous chronic cholecystitis have duodenal bile samples characterized by a decreased bile acid concentration and a decreased proportion of biliary phospholipids. The low biliary bile acid concentration may result from impaired gallbladder contraction and/or secretion by the biliary tract epithelium. The low proportion of phospholipid may result from posthepatic hydrolysis of luminal phosphatidylcholine followed by absorption of the hydrolysis products. The latter process could be caused by and/or contribute to mucosal inflammation and would also elevate the cholesterol saturation of bile, increasing the risk for cholesterol gallstone formation.

Sensitivity of guaiac-impregnated cards for the detection of colorectal neoplasia.

The sensitivity of the guaiac-impregnated card, hemoccult II, for the detection of colorectal neoplasia was tested in 213 patients undergoing elective colonoscopy over a 10-month period. Contrary to statements in standard texts as to the high sensitivity of guaiac-impregnated cards for the detection of these tumors, our results demonstrate only a 52% sensitivity for colorectal carcinoma and a 23% sensitivity for adenomatous polyps over 1.0 cm in diameter. We compare these results to other studies testing hemoccult sensitivity in the presence of colorectal neoplasia. This relatively low sensitivity rate emphasizes that the use of guaiac-impregnated cards alone does not exclude colorectal carcinoma in any patient.

Cholecystokinin cholecystography, sonography, and scintigraphy: detection of chronic acalculous cholecystitis.

Because the efficacy of cholecystokinin cholecystography in the detection of chronic acalculous cholecystitis remains in doubt, the procedure is rarely used in clinical practice. However, the ability to observe gallbladder contraction with sonography and 99mTc-para-isopropylacetanilido-iminodiacetic acid cholescintigraphy (PIPIDA) offers a possibility to improve the sensitivity of the test. To determine if the degree of gallbladder contraction after cholecystokinin is the same as measured by the three techniques and if it differs in symptomatic patients compared to the normal population, cholecystokinin cholecystography, cholecystokinin sonography, and cholecystokinin PIPIDA were performed in 10 symptomatic patients and 10 normal volunteers. The mean maximum contraction of the gallbladder during the three studies was 63%, 61%, and 68%, respectively, for the volunteers, and 72%, 63%, and 73%, respectively, for the patients. The mean maximum gallbladder contraction during all three procedures was 64% +/- 26% SD in the volunteers and 74% +/- 17% SD in the patients. The differences were not statistically significant. Although there was good correlation in the degree of maximum gallbladder contraction among cholecystokinin cholecystography, cholecystokinin sonography, and cholecystokinin PIPIDA, marked variation in both the volunteers and the patients makes it unlikely that the degree of contraction as observed by any of these techniques can be used to indicate the presence of chronic acalculous cholecystitis.

A multicenter, randomized, double-blind trial of somatostatin in the management of acute hemorrhage from esophageal varices.

A prospective, randomized, placebo-controlled, double-blind, multicenter clinical trial of intravenous somatostatin (Stilamin; Serono Laboratories, Inc., Randolph, MA) was performed in 102 patients with actively bleeding esophageal varices from August, 1985, to November, 1986. Patients had major hemorrhage indicated by hematemesis or melena and evidence of significant blood loss. For entry, patients had to have endoscopic demonstration of active bleeding from esophageal varices or stigmata of recent hemorrhage and bright red blood in the gastric aspirate with no other source of bleeding found. Randomized patients received identical-appearing somatostatin or placebo for a 30-hr study period. Those given somatostatin received a 250-micrograms bolus and a 250-micrograms per hr infusion with repeat bolus and doubling of the infusion if the bleeding was not controlled. In retrospect, 18 patients could not be evaluated. Of the 84 evaluable patients, 48 received somatostatin and 36 placebo. They were comparable in age, gender, severity of liver disease and history of variceal bleeding. Transfusion requirements were similar in both groups. Bleeding stopped for 12 consecutive hr during 30 hr of the study period in 31 (65%) of the somatostatin group vs. 30 (83%) of the placebo group (p = 0.06). The median time to cessation of bleeding was 2 hr in the placebo group and 3 hr in the somatostatin group. Deaths following the study period were nine (25%) in the placebo group and 15 (31%) in the somatostatin group. Within the limitations of the present study, we conclude that somatostatin was ineffective in the management of active bleeding of esophageal varices.