Hagop S. Mekhjian

Colonic secretion of water and electrolytes induced by bile acids: perfusion studies in man.

Each of the three major bile acids of man was tested for its influence on electrolyte and water absorption in the human colon. Transport from isotonic solutions, with or without added bile acids, was compared in 35 studies on 20 healthy volunteers by colonic perfusions under steady-state conditions. Electrolytes and water were always absorbed from control solutions, but dihydroxy bile acid solutions induced continuous secretion or inhibition of sodium, potassium, and water absorption, which was reversible. Deoxycholic acid caused consistent secretion at 3 mm concentrations, whereas chenodeoxycholic acid did not induce secretion until the concentration was 5 mm. The trihydroxy bile acid (cholic acid) produced no significant change in absorption at 10 mm. Inhibition of absorption was also induced by mixtures of the glycine or taurine conjugated bile acids. Secretion of sodium and chloride, induced by bile acid perfusion, was linearly correlated with secretion of water; potassium secretion was relatively constant regardless of the volume of secretion. These results establish a striking influence of bile acids on colonic absorptive activity, provide an explanation in part for the diarrhea that frequently accompanies ileal disease or resection, and imply that diarrhea should occur in other disease states that produce elevated concentrations of dihydroxy bile acids in the colonic lumen.

Chenodiol (Chenodeoxycholic Acid) for Dissolution of Gallstones: The National Cooperative Gallstone Study: A Controlled Trial of Efficacy and Safety

A double-masked study was conducted to determine the efficacy and safety of randomly allocated chenodiol (chenodeoxycholic acid, 750 mg/d or 350 mg/d) or placebo administered for 2 years to 916 patients for dissolution of radiolucent gallstones. There was confirmed complete dissolution in 13.5% of patients (750 mg/d), 5.2% (375 mg/d), and 0.8% (placebo), p less than 0.0001. Partial (over 50%) or complete dissolution (by validated roentgenographic metrology) occurred in 40.8% (750 mg/d), 23.6% (375 mg/d), and 11.0% (placebo), p less than 0.0001. Dissolution occurred more frequently in women, thin patients, or patients with small or floating gallstones or serum cholesterol greater than or equal to 227 mg/dL. Clinically significant hepatotoxicity occurred in 3% of patients (750 mg/d), 0.4% (375 mg/d), and 0.4% (placebo), p less than 0.007, and always was reversible biochemically. Elevations of 10% or more of serum cholesterol, mostly low-density lipoproteins, occurred in 85.2% of patients (750 mg/d), 82.8% (375 mg/d), and 67.0% (placebo), p less than 0.001. Chenodiol, 750 mg/d for up to 2 years, is appropriate therapy for dissolution of gallstones in selected patients who are informed of the risks and benefits.

Immediate Benefits Realized Following Implementation of Physician Order Entry at an Academic Medical Center

OBJECTIVE To evaluate the benefits of computerized physician order entry (POE) and electronic medication administration record (eMAR) on the delivery of health care. DESIGN Inpatient nursing units in an academic health system were the setting for the study. The study comprised before-and-after comparisons between phase 1, pre-implementation of POE (pre-POE) and phase 2, post-implementation of POE (post-POE) and, within phase 2, a comparison of POE and the combination of POE plus eMAR. Length of stay and cost were compared pre- and post-POE for a period of 10 to 12 months across all services in the respective hospitals. MEASUREMENTS Comparisons were made pre- and post-POE for the time intervals between initiation and completion of pharmacy (pre-POE, n=46; post-POE, n=70), radiology (pre-POE, n=11; post-POE, n=54), and laboratory orders (without POE, n=683; with POE, n=1,142); timeliness of countersignature of verbal order (University Hospitals [OSUH]: pre-POE, n=605; post-POE, n=19,225; James Cancer Hospital (James): pre-POE, n=478; post-POE, n=10,771); volume of nursing transcription errors (POE with manual MAR, n=888; POE with eMAR, n=396); length of stay and total cost (OSUH: pre-POE, n=8,228; post-POE, n=8,154; James: (pre-POE, n=6,471; post-POE, n=6,045). RESULTS Statistically significant reductions were seen following the implementation of POE for medication turn-around times (64 percent, from 5:28 hr to 1:51 hr; p<0.001), radiology procedure completion times (43 percent, from 7:37 hr to 4:21 hr; p<0.05), and laboratory result reporting times (25 percent, from 31:3 min to 23:4 min; p=0.001). In addition, POE combined with eMAR eliminated all physician and nursing transcription errors. There were 43 and 26 percent improvements in order countersignature by physicians in OSUH and James, respectively. Severity-adjusted length of stay decreased in OSUH (pre-POE, 3.91 days; post-POE, 3.71 days; p=0.002), but not significantly in James (pre-POE, 3.68 days; post-POE, 3.61 days; p=0.356). Although total cost per admission decreased significantly in selected services, it did not change significantly across either institution (OSUH: pre-POE, 5,697 dollars; post-POE, 5,661 dollars; p=0.687; James: pre-POE, 6,427 dollars; post-POE, 6,518 dollars; p=0.502). CONCLUSION Physician order entry and eMAR provided the framework for improvements in patient safety and in the timeliness of care. The significant cultural and workflow changes that accompany the implementation of POE did not adversely affect acuity-adjusted length of stay or total cost. The reductions in transcription errors, medication turn-around times, and timely reporting of results supports the view that POE and eMAR provide a good return on investment.

Impact of computerized physician order entry on clinical practice in a newborn intensive care unit.

OBJECTIVE: To study the impact of computerized physician order entry (CPOE) on selected neonatal intensive care unit (NICU) practices.DESIGN: Retrospective review.SETTING: Nursing units in an academic health system where CPOE has been implemented in adult services since 2000 and in the NICU since 2002.STUDY POPULATION: Data from 111 very-low-birth-weight (VLBW) infants born consecutively within 6 months before and 100 VLBW infants born within 6 months after the implementation of CPOE were evaluated. The study is based on pre- and post-CPOE comparisons in medication error rates and on the initiation to completion time intervals for pharmacy orders and radiology procedures. The specific data subsets that were compared included caffeine and gentamicin. Radiology turn-around time (order to image display) for the first chest and abdominal X-ray taken following endotracheal intubation and/or umbilical catheter placement was studied.RESULTS: Statistically significant (p<0.01) reductions were seen in medication turn-around times for the loading dose of caffeine in pre-CPOE (n=41, mean 10.5±9.8 SD hours) and post-CPOE (n=48, mean 2.8±3.3 SD hours). After CPOE implementation, the percentage of cases during each period where caffeine was administered before 2 and 3 hours increased from 10 to 35% and 12 to 63%, respectively. Accuracy of gentamicin dose at the time of admission for 105 (pre-CPOE) and 92 (post-CPOE) VLBW infants was determined. In the pre-CPOE period, 5% overdosages, 8% underdosages, and 87% correct dosages were identified. In the post-CPOE, no medication errors occurred. Accuracy of gentamicin dosages during hospitalization at the time of suspected late-onset sepsis for 31 pre- and 28 post-CPOE VLBW infants was studied. Gentamicin dose was calculated incorrectly in two of 31 (6%) pre-CPOE infants. No such errors were noted in the post-CPOE period. Radiology response time decreased significantly from the pre-CPOE (n=107, mean 42±12 SD minutes) to post-CPOE (n=95, mean 32±16 SD minutes).CONCLUSION: The implementation of CPOE in our NICU resulted in a significant reduction in medication turn-around times and medication errors for selected drugs, and a decrease in ancillary service (radiology) response time. In spite of the complexities of medication orders in pediatric populations, commercially available software programs for CPOE can successfully be adjusted to accommodate NICU needs and to beneficially impact clinical practice.

Colonic absorption of unconjugated bile acids: perfusion studies in man.

Colonic absorption of three major unconjugated bile acids—cholate, chenodeoxycholate, and deoxycholate—was measured under steady-state conditions using a technique of colonic perfusion in healthy volunteers. Aqueous solutions at pH 8.0 and varying in concentration from 1 mM to 10 mM were used. The rate of chenodeoxycholate absorption averaged nine times that of cholate absorption; deoxycholate absorption was somewhat less than that of chenodeoxycholate absorption, averaging six times that of cholate. At concentrations below 5 mM, the rate of absorption of bile acids was directly proportional to concentration, so that “clearance” could be calculated. Clearance values for a 1-mM solution (ml/min/colon, mean ±se) were: chenodeoxycholate, 9.84±1.0; deoxycholate, 7.0±1; and cholate, 0.82±0.10. Since absorption was proportional to concentration in the lumen, and was more rapid for the dihydroxy acids, the major mechanism of absorption was thought to be passive nonionic diffusion. Maximal rates of bile acid absorption were calculated from a 1-mM solution and found to be as high as 4.2 g/day for chenodeoxycholate, 3.2 g/day for deoxycholate, and 0.5 g/day for cholate, and the rate would be still greater for more concentrated solutions. Colonic absorption may contribute significantly to conservation of the dihydroxy bile acid pool, especially in conditions of bile acid malabsorption.

Key attributes of a successful physician order entry system implementation in a multi-hospital environment.

The benefits of computerized physician order entry have been widely recognized, although few institutions have successfully installed these systems. Obstacles to successful implementation are organizational as well as technical. In the spring of 2000, following a 4-year period of planning and customization, a 9-month pilot project, and a 14-month hiatus for year 2000, the Ohio State University Health System extensively implemented physician order entry across inpatient units. Implementation for specialty and community services is targeted for completion in 2002. On implemented units, all orders are processed through the system, with 80 percent being entered by physicians and the rest by nursing or other licensed care providers. The system is deployable across diverse clinical environments, focused on physicians as the primary users, and accepted by clinicians. These are the three criteria by which the authors measured the success of their implementation. They believe that the availability of specialty-specific order sets, the engagement of physician leadership, and a large-scale system implementation were key strategic factors that enabled physician-users to accept a physician order entry system despite significant changes in workflow.

Stimulation of Secretion of Gastric Inhibitory Polypeptide and Insulin by Intraduodenal Amino Acid Perfusion

The effect of intraduodenal or intravenous administration of a 30-gm mixed amino acid solution of serum gastric inhibitory polypeptide (GIP), alpha-amino nitrogen (AAN), glucose, and insulin concentrations was studied in 10 normal subjects. Initially, an intraduodenal amino acid perfusion (15 ml per min X 60 min) was performed in each subject and was followed in 1 to 2 weeks by an intravenous infusion. Peak AAN concentrations occurred at 60 min after both routes of administration, but were greater with intravenous infusion, 145 +/- 5.7 mug per ml vs. 89 +/- 4.4 mug per ml (P less than 0.001). Although serum AAN levels were significantly lower after intraduodenal administration, incremental insulin concentrations were greater after intraduodenal perfusion, 77.3 +/- 8.8 muM per ml vs. 43.1 +/- 5.6 muU per ml (P less than 0.005). Total integrated insulin secretion was also greater after intraduodenal amino acids, 5000 vs. 2400 muU-min ml-1 (P less than 0.005). With intravenous amino acid infusion, serum GIP concentrations remained below the assay detection limit. After intraduodenal perfusion, a mean maximum GIP increment of 468 pg per ml occurred at 15 min. In all subjects peak GIP concentrations occurred at 15 min and preceded the maximum insulin rise by 15 to 30 min. Total integrated GIP secretion was significantly greater after intraduodenal amino acid perfusion, 13,000 pg-min ml-1 vs. no measurable response with intravenous infusion. In separate studies performed in 12 subjects, no significant changes in serum GIP concentrations occurred after intraduodenal perfusion of 0.45% saline, 0.9% saline, or 10% mannitol. The results of this study demonstrate that intraduodenal amino acid administration stimulates the secretion of GIP and suggest that endogenously released GIP may be important in the enteric mediated release of insulin.

Pretreatment biliary lipid composition in white patients with radiolucent gallstones in the National Cooperative Gallstone Study

Biliary lipid classes (bile acids, phospholipids, cholesterol) as well as individual biliary bile acids were measured in duodenal bile samples obtained before treatment from 284 white men and 264 white women participating in the National Cooperative Gallstone Study. The patients had radiolucent gallstones present in visualizing gallbladders. Calculated biliary cholesterol saturation was significantly higher in women (143 +/- 43, mean +/- SD, vs. 132 +/- 39 for men). Chenodeoxycholic acid was the major biliary bile acid in both sexes (40.0 +/- 9.9 in men; 38.8 +/- 9.3 in women, NS). Cholic acid was the second most common bile acid, constituting 32.9 +/- 8.8 in men and 31.8 +/- 8.9 in women (NS). When other demographic and clinical characteristics, including serum lipids, were related with biliary lipid composition, only percent ideal body weight correlated significantly. The partial correlation coefficient adjusted for percent ideal body weight indicated that the proportion of chenodeoxycholic acid correlated negatively with the mole fraction of cholesterol in bile in men, but not in women. Multiple regression analyses showed that bile saturation could not be predicted reliably from any clinical, chemical, or radiologic measurement in either sex. Published data for biliary lipid composition in individuals with biliary disease showed considerable overlap with the National Cooperative Gallstone Study data reported here, suggesting that cholesterol gallstone disease is not caused solely by increased biliary cholesterol saturation.

Localization of Gastric Inhibitory Polypeptide Release by Intestinal Glucose Perfusion in Man

To determine the site of endogenous release of gastric inhibitory polypeptide (GIP), glucose perfusions (556 mmoles per liter) of duodenum, proximal jejunum, midjejunum, and ileum were performed in human volunteers using an occluding balloon perfusion technique. Preperfusion GIP concentrations were below assay sensitivity (125 pg per ml) in all subjects. After glucose perfusion, maximal serum GIP concentrations for the four groups were: duodenum, 1383 +/- 152 pg per ml; proximal jejunum, 904 +/- 87 pg per ml; midjejunum, 545 +/- 91 pg per ml, and ileum 305 +/- 38 pg per ml. Integrated GIP secretion was significantly greater with duodenal perfusion (111 +/- 21 ng-min ml-1) d proximal jejunal perfusion (69 +/- 5 ng-min ml-1), as compared to either midjejunal (47 +/- 7 ng-min ml-1) or ileal (25 +/- 6 ng-min ml-1) perfusions. Peak serum insulin concentrations and integrated insulin secretion were also significantly greater with perfusion of the duodenum or proximal jejunum. Serum glucose concentrations, integrated serum glucose, and glucose absorption were similar for the four areas perfused. The results of this study indicate that the proximal small intestine is the primary site of endogenous GIP release in man, but that smaller quantities are also released by the distal small bowel.

Effects of pancreatic polypeptide and vasoactive intestinal polypeptide on rat ileal and colonic water and electrolyte transportin vivo

Two gastrointestinal peptides, vasoactive intestinal polypeptide (VIP) and pancreatic polypeptide, suspected of being associated with symptoms of WDHA syndrome (pancreatic cholera) were tested on the rat small and large intestine for their effects on water and electrolyte transport. Intravenous infusion of VIP (14.3 μg/kg/hr) inhibited net absorption of water and electrolytes in the ileum and reversed net absorption to net secretion in the colon. In contrast, bovine pancreatic polypeptide (52 μg/kg/hr) did not inhibit absorption or stimulate secretion. These data indicate VIP causes colonic secretionin vivo, an effect previously shown onlyin vitro, and that bovine pancreatic polypeptide (at this dose) is not a secretagogue in the small or large intestine of the rat. Thus, while consistent with VIP being a contributory agent to the secretion of pancreatic cholera, the data do not support the notion that pancreatic polypeptide might be a causative agent in this syndrome.