The Second Canadian Consensus Conference on the Management of Patients with Gastroesophageal Reflux Disease.

The Second Canadian Consensus Conference on the Management of Patients with Gastroesophageal Reflux Disease (GERD) was organized by the Canadian Association of Gastroenterology to address major advances in the understanding of the pathophysiology of GERD, to review the new methods of investigation and therapy introduced since the first conference in 1992 and to examine the issue of relevant health economics. The changes that have taken place over the past four years have been sufficiently dramatic to necessitate reassessment of the recommendations made following the first conference. The second conference dealt with the investigation and treatment of uncomplicated GERD and the complex issues of esophageal and extraesophageal complications such as chest pain, Barrett's esophagus, and reflux-related pulmonary and laryngeal disorders. The role of laparoscopic surgery was also discussed. A decision tree for investigation and treatment of patients with GERD was developed. The 38 participants represented a broad spectrum of experience, location of practice and special interests. The distribution of participants conformed to the recommendations of the Canadian Medical Association guidelines for consensus documents in that there should be input from all possible interested parties. A list of the state-of-the-art lectures presented during the conference, the small group sessions, the session chairpersons and participants are appended to this document. CONCLUSIONS. UNCOMPLICATED GERD: GERD with alarm symptoms must be investigated immediately. There was no consensus about when to investigate uncomplicated GERD, ie, whether to perform endoscopy immediately or after initial therapy fails. There was controversy regarding 'step up' (H2 receptor antagonist [H2RA] or prokinetic [PK] first therapy) versus 'step down' therapy (proton pump inhibitor [PPI] first therapy). The majority decision was for short term 'step up' therapy and investigation if symptoms do not improve or recur. Maintenance therapy should be carried out with the initial therapy that was effective. H2RAs and PKs may suffice for maintenance therapy in milder GERD; however, for severe esophagitis, PPIs should be used. SURGERY: Indications for laparoscopic surgery should be the same as for conventional antireflux operations. NONCARDIAC ANGINA-LIKE CHEST PAIN: After exclusion of nonesophageal causes, the majority decided that eight weeks of therapy with a PPI should be performed, while some suggested work-up before a therapeutic test. In the absence of response or recurrence, esophagogastroduodenoscopy (EGD) and, depending on the circumstances, 24 h ambulatory pH/motility may be indicated. BARRETT'S ESOPHAGUS: Only patients who, in case of future discovery of cancer or dysplasia, are able or willing to undergo therapy should have surveillance. In the absence of dysplasia EGD should be performed every two years, and in the presence of mild dysplasia every three to six months. All agreed that for severe dysplasia, esophagectomy or poor risk patients, esophageal mucosal ablation is indicated. ESTRAESOPHAGEAL COMPLICATONS (EECs): Asthma, chronic cough and posterior laryngitis were considered EECs. Although PPIs may decrease symptoms, improvement alone is not diagnostic of the presence of EEC. Ambulatory pH studies with two pH probes or ambulatory pH/motility may be useful in establishing causation. HEALTH ECONOMICS: There are limited data for an economic comparison among the different drugs or between medical and surgical therapy.

Prokinetic therapy in gastroesophageal reflux disease.

There is a growing body of pathophysiological evidence that gastroesophageal reflux disease (GERD) is caused by disordered motility and not acid hypersecretion. The key factor in the pathogenesis of GERD is disordered function of the lower esophageal sphincter. Other factors include delayed gastric emptying and decreased peristalsis in the body of the esophagus. The principal symptoms of GERD are heartburn and regurgitation. Studies have demonstrated that up to 50% of patients may have other symptoms of dysmotility including epigastric discomfort or fullness, nausea and early satiety. The use of a prokinetic agent in such patients seems logical. Given its proven superior efficacy over domperidone and metaclopramide in treating GERD, cisapride has become the prokinetic drug of choice for the acute management and maintenance therapy of GERD. In the acute management of GERD, cisapride is superior to placebo and has the same efficacy as H2 receptor antagonists (H2RAs) in several clinical trials. It is also effective in maintenance therapy for GERD. These studies are reviewed. Cisapride (10 mg qid or 20 mg bid) is effective in the acute treatment of mild to moderate GERD, particularly in patients with heartburn associated with other symptoms of dysmotility, and particularly in patients with heartburn associated with gastroparesis. Combination therapy with an H2RA may be considered if symptoms (particularly dysmotility symptoms) persist with H2RA alone. In severe GERD that is not responsive to conventional doses of a proton pump inhibitor, cotherapy with cisapride or increasing the dose of the proton pump inhibitor are the two therapeutic options to consider. Cisapride 20 mg at bedtime is effective maintenance therapy for patients with mild to moderate GERD.

National survey of radionuclide gastric emptying studies.

A survey was mailed to all institutions in Canada licensed to use radiopharmaceuticals. Questions addressed meal type; mode of preparation; and means, ranges and SD of emptying times. Seventy-eight per cent of 222 facilities responded, including all 55 teaching centres. Eighty-five per cent of teaching and 56% of nonteaching centres perform solid phase gastric emptying studies (GES). The majority use 99mTc sulphur colloid (Tc-SC) added to eggs before cooking as the standard meal. Twenty-five per cent of teaching and 21% of nonteaching centres perform liquid phase GES. Most use a watery solution of 111Indiethylenetriamine pentaacetic acid. Gastric emptying for solid phase GES, expressed as time for 50% emptying (mean t1/2), varied from 42 to 105 mins for centres using the Tc-SC egg meal. Twenty-eight per cent of teaching centres used +/- 2 SD to define their normal range, 26% used +/- 1 SD, 6% used +/- 1.5 SD, and 40% did not know the number of SD used. Twenty per cent of nonteaching centres used +/- 2 SD, 12% used +/- 1 SD and 68% did not know how many SD were used. For liquid phase GES, mean t1/2 varied from 20 to 60 mins. Eighteen per cent of centres used healthy volunteers to establish or validate normal ranges. There is substantial variability among the normal ranges for radionuclide solid and liquid phase GES in both teaching and nonteaching centres across Canada. A minority of facilities have established or validated their own normal ranges in healthy volunteers. There is a need for a more standardized protocol and range of normal, with internal validation by each institution.

A double-blind randomized study of cisapride in the treatment of nonulcer dyspepsia. The Canadian Cisapride Nud Study Group.

Cisapride is a substituted benzamide with gastrointestinal prokinetic effects presumed to be due to the enhancement of the physiological release of acetylcholine at the myenteric plexus. In a multicentre study, 189 patients with nonulcer dyspepsia (NUD) received single-blind placebo treatment for two weeks. A total of 123 patients with no or minimal response to placebo and epigastric pain of at least moderate severity and frequency were randomly assigned to one of the three parallel double-blind treatments for six weeks: cisapride 10 mg tid, cisapride 20 mg tid or placebo. The severity and frequency of individual symptoms (epigastric pain, heartburn, nausea, vomiting anorexia, postprandial discomfort, regurgitation, lower abdominal pain, bloating and constipation) were assessed on a four- and five-point categorical scale, respectively, by the investigator at three on treatment visits and by patients in a daily diary. Analysis of investigator and patient assessments for differences in symptom severity x frequency composite scores among the three treatment groups showed no statistically significant differences for individual symptoms or symptom clusters. As assessed by the investigator, and compared with baseline, cisapride 20 mg tid significantly (P < 0.05) improved epigastric pain, bloating and early satiety as well as improved the total symptom cluster. Investigator evaluation of the five most severe and frequent symptoms for each patient showed statistically significant improvement in each treatment group. For patient diary assessments, statistically significant within-treatment improvement of the total symptom cluster, the five most severe symptoms cluster, bloating and early satiety was observed for both cisapride 20 mg and placebo, whereas epigastric pain significantly (P < 0.05) improved in all three treatment groups. Investigator evaluation of global response (good+excellent) rate at the end of the six week treatment period was 38% for cisapride 20 mg, 47% for cisapride 10 mg and 33% for placebo. No statistically significant difference in this parameter among treatments was noted. Cisapride was well tolerated at both doses with a side effect profile comparable with that of placebo. It is concluded that in this double-blind multicentre study with a single-blind two-week placebo run in phase, cisapride 10 mg tid and 20 mg tid were not effective compared with placebo in improving symptoms in NUD patients. This study re-emphasizes the good prognosis of patients with NUD, with 14% of patients improving in the two-week placebo run-in phase and a further 33% improving in the next six weeks while on placebo. Within-treatment analysis of investigator assessments showed improvement for cisapride 20 mg tid suggesting a trend of efficacy at this dose.

Woodstove smoke and CO emissions: comparison of reference methods with the VIP sampler.

A new field sampler has been developed for measuring the particulate matter (PM) and carbon monoxide emissions of woodburning stoves. Particulate matter is determined by carbon balance and the workup of a sample train which is similar to a room-temperature EPA Method 5G train. A steel tank, initially evacuated, serves as the motive force for sampling and also accumulates a gas sample for post-test analysis of time-averaged stack CO and CO2 concentrations. Workup procedures can be completed within 72 hours of sampler retrieval. The system has been compared to reference methods in two laboratory test series involving six different woodburning appliances and two independent laboratories. The correlation of field sampler emission rates and reference method rates is strong.

Management of idiopathic, diabetic and miscellaneous gastroparesis with cisapride.

There have been several long term studies (greater than 4 weeks) of cisapride in a variety of gastroparetic conditions. All of these studies have used cisapride 10 mg t.i.d. or q.i.d. Chronic idiopathic dyspepsia Cisapride has been shown to be effective in both improving symptoms and also delayed gastric emptying in a six week study. In another placebo controlled study of two weeks, gastric emptying was improved but symptoms did not improve significantly. Diabetic gastroparesis In a four week study, cisapride has been shown to be effective in improving symptoms and solid phase gastric emptying. A six weeks study demonstrated both improvement of solid and liquid gastric emptying and symptoms. Progressive systemic sclerosis Cisapride was effective in improving symptoms over a four week period. Myotonic dystrophy Cisapride was effective in improving solid phase gastric emptying and symptoms over a four week period. Combined studies In two combined studies, cisapride has been shown to be effective in a variety of gastroparetic conditions. One year studies In three open long term studies, cisapride appears to be the first prokinetic agent to demonstrate long term efficacy for up to one year.

Measuring gastric contents during general anaesthesia: evaluation of blind gastric aspiration.

Various medications have been reported to decrease gastric content volume and thus risk for pulmonary aspiration. The majority of studies have used blind gastric tube aspiration of stomach contents as the method of measuring the volume of gastric contents. This study evaluated the accuracy of this method by first measuring gastric content volume using blind gastric aspiration and then aspirating residual content in the stomach, using a visually guided flexible fiberoptic gastroscope. Ten obese patients undergoing elective surgery were studied. Gastric contents were collected using a multi-orificed gastric tube and blind aspiration. Immediately after this was completed, residual gastric volume was collected using a visually guided gastroscope. The sum of these two aspirate volumes (true total gastric volume) was statistically compared with the blind aspirate volume. The blind aspirate volume underestimated true total gastric volume by an average of 14.7 ml and was significantly different from true total gastric volume (p less than 0.05). Blind gastric aspiration was thus demonstrated only to approximate true gastric volume. Its use to measure precisely gastric volume cannot, therefore, be recommended.

Variability in the clinical presentation and endoscopic findings of herpetic esophagitis.

Three cases of herpetic esophagitis are reported in which the endoscopic features were non-specific and the triad of odynophagia, retrosternal pain and fever was absent, suggesting that the endoscopic and clinical presentation may be more variable than previously described.

Cutaneous hypersensitivity to vitamin K1 injection.

Cutaneous hypersensitivity to vitamin K1 injection has been reported once in North America. This case and most of the others in European literature have been associated with alcoholic liver disease. We report six patients who developed persistent skin hypersensitivity reactions at the site of vitamin K1 injection. These cases are the first reported to occur in liver disease associated with primary biliary cirrhosis, chronic myeloid leukemia, amyloidosis, and preeclampsia. Patch and intradermal skin tests demonstrated a hypersensitivity that seems to have an immune basis and is restricted to fat-soluble vitamin K1. This finding suggests that patients with any type of liver disease may be at risk for vitamin K hypersensitivity and that the hypersensitivity may be a marker of liver disease.

Domperidone, a new dopamine antagonist.

Domperidone is a dopamine antagonist that has recently been released in Canada. Unlike metoclopramide hydrochloride, the other available dopamine antagonist, it does not readily enter the central nervous system. Domperidone acts as both an antiemetic and an upper gastrointestinal tract prokinetic agent. It is rapidly absorbed after oral administration, and few side effects have been reported. Domperidone has been approved for use in Canada for the symptomatic management of upper gastrointestinal tract motility disorders and to prevent gastrointestinal symptoms associated with the use of dopamine agonist agents in Parkinson's disease. The pharmacologic features, indications and side effects of domperidone are reviewed.

The effect of cimetidine and ranitidine on serum high density lipoprotein subfractions.

Of the two major subfractions of high density lipoprotein (HDL), HDL2 cholesterol (HDL2-C) and not HDL3 cholesterol (HDL3-C) correlates negatively with coronary heart disease. To study the effect of cimetidine and ranitidine on HDL subfractions, 6 healthy males received cimetidine (600 mg bid) ranitidine (150 mg bid) and placebo (one tab bid) for 1 week each, in random order. Measurements of HDL cholesterol (HDL-C), HDL2-C, HDL3-C were made on day 7 of each week. Comparing cimetidine with placebo, HDL2-C/HDL-C, HDL2-C/total cholesterol and HDL2-C/HDL3-C increased significantly while HDL3-C/HDL-C decreased. There was no difference in HDL-C parameters between ranitidine and placebo. Cimetidine treatment results in redistribution of HDL subfractions in favour of HDL2. The mechanism is not H2-receptor antagonism as ranitidine had no such effect.

Medical education reduces inappropriate use of cimetidine in a teaching hospital.

Before and after an education program to improve appropriate prescribing of cimetidine in an 810-bed teaching hospital, all new prescriptions written during a 4-week period were investigated, and information was obtained as to the indications for use, the dosage and concurrent drug therapy. The prescriptions were judged appropriate or inappropriate according to indications for cimetidine approved by the Department of National Health and Welfare's Health Protection Branch. After the program 63% of the prescriptions were deemed appropriate, compared with 40% before the program. The proportion of patients at risk of drug interactions, however, remained virtually unchanged. The results suggest that medical education can reduce the inappropriate use of cimetidine in teaching hospitals.

Observations on control of glycemia with conventional insulin therapy or continuous subcutaneous insulin infusion.

Determination of glycemic differences between groups treated with continuous subcutaneous insulin infusion (CSII) or conventional insulin therapy (CIT) was central to the major objective of the study. Assessment of glycemia was based on 24-h inhospital profiles of plasma glucose; pre- and postprandial and bedtime (seven time points) diurnal profiles performed monthly on outpatient samples; and glycosylated hemoglobin (HbA1) measured bimonthly at each center. The correlation between plasma glucose determinations in the central laboratory and in local laboratories was 0.988. Significance of differences between treatments was by analysis of variance and least-squares regression. At baseline, mean inhospital plasma glucose and HbA1 concentrations and insulin dosages were identical in the groups randomized to CSII or CIT. A prompt decrement of indices of glycemic control during CSII was observed such that mean decrements sustained over the 8-mo treatment period in home and in hospital plasma glucose profiles and HbA1 relative to values obtained during CIT (P less than 0.0001). The likelihood of CSII-treated patients achieving glycemic indices within the normal range was increased. The standardization of the mean and the M-value calculated from inhospital glucose profiles during CSII and CIT at 4 and 8 mo indicated that there was less plasma glucose fluctuation during CSII. The method of pooling standardized local HbA1 measurements from the six centers appeared to be an adequate substitute for centrally performed HbA1 determinations. Advantages of inhospital plasma glucose measurements in terms of accuracy and ability to obtain nocturnal samples contrasted with the likelihood of increased realism and superior correlation with HbA1 in home-obtained samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Conference on insulin pump therapy in diabetes. Multicenter study of effect on microvascular disease. Recruitment, Randomization, and baseline characteristics of the treatment groups.

The general and ophthalmologic eligibility criteria were applied in the course of formal screening of selected members of clinic populations at the six treatment centers between August 1980 and November 1981. Patients eligible on the grounds of the history and general physical examination underwent a detailed ophthalmologic examination and determination of C-peptide status. Initial rates of recruitment were slow, which occasioned modifications of the eligibility criteria and a prolongation of the recruitment phase. All six clinics approached their goal of at least six patients in each of the continuous subcutaneous insulin infusion (CSII) and conventional insulin treatment (CIT) groups, with a final total of 70 randomized subjects. The method of paired randomization was acceptable, but led to some delay during periods of slow recruitment activity. Data from two patients who chose to drop out of the study shortly after randomization are included in the baseline characteristics. There was no difference between treatment groups with respect to age or duration of known diabetes, body weight, systolic blood pressure, proportion of cigarette smokers, retinopathy level as assigned by analysis of stereofundus photographs, or microaneurysm counts performed on fluorescein angiograms. A trend toward milder retinopathy in the CIT group proved to be statistically insignificant. Subsequent assessment of stereofundus photographs at the Fundus Photograph Reading Center indicated that six patients were misclassified by treatment center ophthalmologists with respect to ophthalmologic eligibility. We conclude that recruitment goals were met and randomization was successful.

Conference on insulin pump therapy in diabetes. Multicenter study of effect on microvascular disease. Origin and design of the Kroc Collaborative Study.

Although the benefits of metabolic intervention on the microvascular complications of diabetes mellitus remain unproven, it is generally assumed though not proven that prognosis in terms of blindness and renal failure will reflect the long-term glycemic response to therapy. Treatment goals however remain poorly defined. Costs and hazards of achieving near-normoglycemia in insulin-dependent diabetes mellitus (IDDM) are major. A multicenter trial was proposed to test the hypothesis that in IDDM two levels of mean glycemia, sufficiently separated to examine the control/complications relationship, could be maintained by the six collaborating centers, using randomized patient allocation to conventional insulin therapy (CIT) and continuous subcutaneous insulin infusion (CSII) as the alternative treatment modalities. Methods of maintaining and monitoring metabolic control and of assessing renal and retinal responses were to be applied, evaluated, and possibly improved. All clinics shared a common experimental protocol, which received ethical approval at each treatment center. Retinal assessment facilities were provided by the Fundus Photograph Reading Center at the University of Wisconsin in Madison, and at the Diabetic Retinopathy Department, Royal Postgraduate Medical School, Hammersmith, United Kingdom. The Central Biochemistry Laboratory was at the University of Newcastle, United Kingdom. Collaborators agreed on policy for recruitment, baseline assessment, and randomization of patients with IDDM, complicated by early microvascular disease. CIT took the form of the unchanged prestudy regimen; glycemic goals were set for CSII and their achievement based on inpatient and outpatient sampling of plasma glucose. Glycosylated hemoglobin was measured, retinal abnormalities recorded photographically, and urinary albumin excretion quantitated at baseline, 4, and 8 mo in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Is cimetidine being prescribed indiscriminately? An analytic survey of patients who present with symptoms of peptic ulcer disease.

An analytic survey was done to determine the influence of previously documented peptic ulcer disease (PUD) on the frequency of prescribing cimetidine to patients who present at a family medicine centre with symptoms of PUD. It was found that of 293 patients who presented with such symptoms over 1 year cimetidine was prescribed to 57 (19%). From the 236 patients who did not receive cimetidine 57 patients were selected at random for comparison. Information on these two groups of patients was obtained by chart review. The patients who received cimetidine were found to be significantly more likely (p less than 0.001) to have previously documented PUD than those who did not receive cimetidine. In patients in whom subsequent confirmation of PUD was not obtained, either because the results of investigations were negative or because the investigations were not ordered, cimetidine was prescribed to 63% of those who had previously documented PUD, compared with only 6% of those who did not. Of the patients who were investigated 73% of those with previously documented PUD had positive results, compared with 8% of those without previously documented PUD. The positive results were obtained by endoscopic examination in 88% of the patients with previously documented PUD, whereas upper gastrointestinal tract roentgenography was the definitive test in 73% of the patients without previously documented PUD. These findings suggest that previously documented PUD influences both the frequency of prescribing cimetidine and the investigations that are carried out.