Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.

CONTEXT: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown. OBJECTIVE: To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs. DESIGN: The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000. SETTING: Three hundred eighty-six clinical sites in the United States and Canada. PARTICIPANTS: A total of 8059 patients (>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months. INTERVENTIONS: Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (

Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor.

OBJECTIVE: The aim of this study was to assess the rate of upper gastrointestinal (UGI) ulcer complications (bleeding, perforation, or gastric outlet obstruction) associated with celecoxib, a specific COX-2 inhibitor, compared with the rate associated with nonspecific, nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: A pooled analysis was conducted of 14 multicenter, double-blind, randomized, controlled trials (RCTs) and a separate analysis of one long-term open label trial that assessed the efficacy and safety of celecoxib for symptomatic treatment of arthritis. The RCTs enrolled 11,008 patients with osteoarthritis or rheumatoid arthritis treated for 2-24 wk; the long-term open label trial enrolled 5,155 patients receiving celecoxib for a maximum of 2 yr. In the RCTs, patients were randomly assigned to receive placebo (n = 1,864; 208 patient-years), celecoxib 25-400 mg b.i.d. (n = 6,376; 1,020 patient-years), or a comparator NSAID (n = 2,768; 535 patient-years); NSAIDs were naproxen 500 mg b.i.d., diclofenac 50 or 75 mg b.i.d., or ibuprofen 800 mg t.i.d.). In the long-term, open-label trial, patients received celecoxib 100-400 mg b.i.d. for up to 2 yr (n = 5,155; 5,002 patient-years). The principal outcome measure of this analysis was development of a UGI ulcer complication, which was prospectively defined as bleeding, perforation, or gastric outlet obstruction. Ulcer complications were assessed and adjudicated by persons blinded to the patient's treatment assignment or the study in which the patient participated. RESULTS: In the RCTs, UGI ulcer complications occurred in no placebo patients (0 of 1,864 patients), in 2 of 6,376 celecoxib patients (0.03%), and in 9 of 2,768 patients receiving an NSAID (0.33%), corresponding to annual incidences of 0.20% for celecoxib (p > 0.05 vs placebo) and 1.68% for NSAIDs (p = 0.002 vs celecoxib and placebo). In the long-term open-label trial, nine UGI ulcer complications occurred, for an incidence of 0.17% and an annualized incidence of 0.18%. CONCLUSIONS: The incidence of UGI ulcer complications associated with celecoxib was 8-fold lower than with nonspecific NSAIDs. The incidence of ulcer complications observed in celecoxib-treated patients was similar to that in patients receiving placebo in the RCTs, and to that in non-NSAID users reported in the literature.

Magnetic detection to position human nasogastric tubes.

Placement of nasogastric tubes is one of the most commonly performed diagnostic and therapeutic medical procedures. Proper placement of the tube in the digestive tract below the diaphragm is crucial for efficacy and safety. This study evaluates a magnet detection system that allows percutaneous non-radiographic localization of the nasogastric tube tip. Each volunteer subject had the magnet detector placed over the abdomen, and was then intubated with a magnet-tagged nasogastric tube. Eighty-eight nasogastric tube placements were performed in 22 volunteers. The detection system located the nasogastric tube tip below the diaphragm in all 88 placements. Location in all attempts was confirmed by fluoroscopy. This method of correctly locating the tip of nasogastric tubes may obviate the need for radiographic imaging in most cases.

Improving the gastrointestinal safety of NSAIDs: the development of misoprostol--from hypothesis to clinical practice.

Arthritis is a major source of disability for the American population. It results in significant morbidity for the millions of patients affected and costs billions of dollars yearly for diagnosis and management. Nonsteroidal antiinflammatory drugs (NSAIDs) are the principal therapy for the majority of arthritis patients. It has been estimated that more than 15 million people with arthritis take these drugs daily. This use is predicted to increase greatly not only as a result of an aging population, with the consequent increase in the prevalence of arthritis, but also because NSAIDs may prove to have a role in decreasing colonic neoplasia and in reducing the likelihood of conditions such as Alzheimer's disease. It is therefore increasingly important to understand the nature of the side effects associated with these agents as well as ways of decreasing or preventing their occurrence. NSAIDs inhibit the enzymes cyclooxygenase-1 and cyclooxygenase-2. This reduces the synthesis of prostaglandins and therefore decreases joint inflammation, but it may also lead to the development of gastric and duodenal ulcers. For this reason, exogenous prostaglandins have been studied for their potential role in preventing NSAID-associated ulcers and ulcer complications. This paper reviews the development of the prostaglandin E1 analog misoprostol, the theory behind its use as a mucosal protective agent, and the results of studies in animals as well as in normal volunteers and patients with arthritis. Ultimately, a study was performed to evaluate whether misoprostol reduces the incidence of serious ulcer complications in patients taking NSAIDs. It is an interesting story, which promises to be of increasing importance as NSAID use expands to new indications while concern remains about their associated complications, especially those related to the gastrointestinal tract.

[High frequency ultrasonography of the gastrointestinal wall]. / Høyfrekvent ultrasonografi av gastrointestinalkanalens vegg.

If an ultrasound probe comes close to the area of interest, high ultrasound frequencies can be applied. Endoscopic ultrasonography is performed by means of echoendoscopes or miniature probes using ultrasound frequencies between 7 and 30 MHz. A high frequency ultrasound image of the normal gastrointestinal wall usually shows five layers corresponding closely to the histological layers of the wall. Corrections have to be made, however, for interface echoes between layers with different acoustic impedances. We describe studies performed with the aim of correlating ultrasound images of the normal and diseased gastrointestinal wall with the histology. Ultrasound images of the normal gastrointestinal wall and pathological changes like ischemia, ulcers, tumours and inflammation are presented.

Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To investigate whether concurrent administration of misoprostol reduces the occurrence of serious upper gastrointestinal complications, such as perforation, gastric outlet obstruction, or bleeding, in patients with rheumatoid arthritis who are receiving nonsteroidal anti-inflammatory drugs (NSAIDs). DESIGN: 6-month randomized, double-blind, placebo-controlled trial. SETTING: 664 clinical practices of family medicine, internal medicine, or rheumatology in the United States and Canada. PATIENTS: 8843 men and women (mean age, 68 years) receiving continuous therapy with any of 10 specified NSAIDs for control of symptoms of rheumatoid arthritis. Patients were enrolled between July 1991 and August 1993. INTERVENTION: Patients were randomly assigned to receive 200 micrograms of misoprostol or placebo four times a day. MEASUREMENTS: Development of serious upper gastrointestinal complications detected by clinical symptoms or findings (not by scheduled endoscopy). RESULTS: Serious upper gastrointestinal complications were reduced by 40% (odds ratio, 0.598 [95% CI, 0.364 to 0.982; P = 0.049]) among patients receiving misoprostol (25 of 4404 patients) compared with those receiving placebo (42 of 4439 patients). During the first month, more patients receiving misoprostol (20%) than placebo (15%) withdrew from the study, primarily because of diarrhea and related problems (P < 0.001). Risk factors for serious upper gastrointestinal complications were increasing age, history of peptic ulcer or bleeding, and cardiovascular disease. Patients with all four risk factors would have a 9% risk for a major complication in 6 months. CONCLUSIONS: In older patients with rheumatoid arthritis, misoprostol reduced serious NSAID-induced upper gastrointestinal complications by 40% compared with placebo.

Simultaneous M-mode echoesophagram and manometry in the sheep esophagus.

We report the simultaneous measurement of esophageal wall layer thickness and intraluminal pressure in the sheep esophagus using a miniature suction device incorporating a high-frequency ultrasound transducer and a manometry system. Transnasal placement of the device into the distal esophagus of a conscious sheep allowed observation of 133 swallowing events during three trials, each lasting from 45 to 60 minutes. In a fourth trial, 11 sequential dry and 23 sequential wet swallows were compared. Maximum manometric pressure, esophageal wall layer thickness, and duration of contraction were measured. All swallowing events produced simultaneous increases in intraluminal pressure and esophageal wall thickness. Mean maximal pressures were lower for dry swallows (18 +/- 2.1 mm Hg) than wet swallows (22 +/- 3.0 mm Hg) (p < .01). Thickness of the inner (circular) muscle layer increased above baseline by 124% for dry swallows and 161% for wet swallows (p < .01). We conclude that thickening of the esophageal inner (circular) muscle layer may be important in the generation of intraluminal esophageal pressure in the sheep esophagus.

Future developments in endoscopic imaging.

Endoscopic imaging capabilities have significantly improved over the past 10 years. Improvements in fibreoptic technology have made possible the development of very thin endoscopes that can directly visualize the biliary and pancreatic ducts. The application of the CCD to endoscopy has made electronic endoscopy possible, and holds promise for stereoendoscopy. The ability to digitize endoscopic images can be developed to store, transmit, magnify, enhance and otherwise manipulate data obtained during endoscopy, and will probably be utilized routinely in the future. Laser and ultrasound technology are likely to enhance significantly our ability to examine ultrastructural aspects of gastrointestinal organs and surrounding tissues, and may play an important role in cancer surveillance programs. Vital staining techniques are likely to find widespread use in early cancer detection programmes, and may be useful to follow prospectively lesions observed or treated during endoscopy. Finally, the new developments in 'virtual imaging' may find applications in the field of gastrointestinal endoscopy and other 'minimally invasive' surgical procedures.

Chemical- and radiation-induced esophageal injury.

The esophageal wall can only respond to injury in a limited fashion. This article explores some of the protective mechanisms involved as well as current approaches to diagnosis and management of chemical- and radiation-induced esophageal injury.

Measurement of the ultrasonic attenuation of fat at high frequency.

RATIONALE AND OBJECTIVES: High-frequency ultrasound devices are often limited by a decreased depth of acoustic imaging caused by the increased attenuation of tissue at high frequencies. We investigated the role of adipose tissue in this phenomenon. METHODS: A substitution technique was used to calculate the ultrasonic attenuation (decibels per centimeter) of fresh samples of sheep rumen, omental fat, and back fat and swine back fat and various concentrations of bovine milk fat at 22 degrees C and 37 degrees C for frequencies of 15 and 20 MHz. RESULTS: The attenuation was significantly higher for sheep adipose tissue than for the intestinal wall, in descending order, omental fat, back fat, and rumen wall (P < 0.01). A correlation was found between bovine milk fat concentrations and attenuation at both frequencies (R2 > 0.9). The attenuation of adipose tissues decreased significantly with an increase in temperature (P < 0.01), whereas the attenuation of sheep rumen showed no significant change (P > 0.1). CONCLUSIONS: The ultrasonic attenuation of fat may contribute to limitations on the use of high-frequency ultrasound in clinical situations in which adipose tissue is present.

Experimental use of high-frequency ultrasound to image bowel wall after porcine intestinal transplantation.

A means to monitor intestinal allografts will be crucial for the future success of small bowel transplantation. We have previously demonstrated the ability of high-frequency ultrasound (US) to diagnose porcine intestinal ischemia in vitro. The aim of this study was to compare the histologic appearance of normal porcine small bowel versus bowel undergoing acute rejection, using 8.5-MHz US images. We allowed porcine heterotopic small bowel allograft transplants to reject and then removed, at scheduled intervals from postoperative day 0 to 12, specimens of both the transplanted bowel and the native bowel. We examined the tissues in vitro with an 8.5-MHz linear array US system then studied them histologically. Histologically, the earliest changes of rejection occurred at days 4 to 5, with mild submucosal edema, endotheliitis, and vasculitis affecting the small vessels; the mucosa remained normal. By days 7 to 8, the submucosal endotheliitis became more prominent, with focal thrombosed small vessels; the mucosa now appeared abnormal with flattened villi, erosions, and necrosis. By days 10 to 12, marked submucosal edema, vasculitis, endotheliitis, and necrotic mucosa were present. Ultrasonically, normal intestinal wall has five wall layers, corresponding to mucosa, submucosa, muscularis propria, and subserosal fat. The US criteria for abnormality were loss of folds, decreased numbers of echo layers, discontinuity of layers, and a homogeneous appearance. Using these US criteria, blinded observers differentiated normal from abnormal bowel wall after transplantation with a sensitivity of 84% and a specificity of 81%. Most of the errors occurred with the day 4 and 5 specimens, which appeared nearly normal on US.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in esophageal wall layers during motility: measurements with a new miniature ultrasound suction device.

We have developed a miniaturized ultrasound device that attaches to the gastrointestinal mucosa by suction and produces high-resolution (+/- 0.1 mm) images of the layers of the intestinal wall. The esophageal wall layers in a single sheep were measured during 20 occlusive contractions observed with simultaneous endoscopy, which revealed thickening of the inner circular muscle layer from 1.2 +/- 0.2 mm to 2.2 +/- 0.4 mm (p < 0.01), and during 20 dilations demonstrating thinning of the full thickness of the esophageal wall from 3.6 +/- 0.3 mm to 2.9 +/- 0.3 mm (p < 0.01). Safety experiments performed in two canine stomachs demonstrated no erosions or ulceration at any level of suction. Our investigations indicate that the M-mode suction ultrasound device can safely assess changes occurring in the layers of the esophageal wall during contractions and dilations and should be evaluated for the study of human intestinal motility.

Transmission of infection by gastrointestinal endoscopy and bronchoscopy.

OBJECTIVE: To review reports on the transmission of infections by flexible gastrointestinal endoscopy and bronchoscopy in order to determine common infecting microorganisms, circumstances of transmission, and methods of risk reduction. DATA SOURCES: Relevant English-language articles were identified through prominent review articles and a MEDLINE search (1966 to July 1992); additional references were selected from the bibliographies of identified articles. STUDY SELECTION: All selected articles related to transmission of infection by gastrointestinal endoscopy or bronchoscopy; 265 articles were reviewed in detail. DATA SYNTHESIS: Two hundred and eighty-one infections were transmitted by gastrointestinal endoscopy, and 96 were transmitted by gastrointestinal endoscopy, spectrum of these infections ranged from asymptomatic colonization to death. Salmonella species and Pseudomonas aeruginosa were repeatedly identified as the causative agents of infections transmitted by gastrointestinal endoscopy, and Mycobacterium tuberculosis, atypical mycobacteria, and P. aeruginosa were the most common causes of infections transmitted by bronchoscopy. One case of hepatitis B virus transmission via gastrointestinal endoscopy was documented. Major reasons for transmission were improper cleaning and disinfection procedures; the contamination of endoscopes by automatic washers; and an inability to decontaminate endoscopes, despite the use of standard disinfection techniques, because of their complex channel and valve systems. CONCLUSIONS: The most common agents of infection transmitted by endoscopy are Salmonella, Pseudomonas, and Mycobacterium species. To prevent endoscopic transmission of infections, recommended disinfection guidelines must be followed, the effectiveness of automatic washers must be carefully monitored, and improvements in endoscope design are needed to facilitate effective cleaning and disinfection.

The effects of applied pressure on the thickness, layers, and echogenicity of gastrointestinal wall ultrasound images.

Endoscopic ultrasound imaging of the gastrointestinal wall can be performed through intraluminal fluid or by direct transducer contact with the wall. We tested the hypothesis that the ultrasound appearance of the gastrointestinal wall is influenced by the amount of pressure applied when the transducer is in contact with the tissue. Fresh autopsy specimens from the porcine gastrointestinal tract were examined in vitro using an 8.5-MHz linear array ultrasound system. As transducer pressure against the wall was increased from 0 to 10 KPa, changes were seen on the images in wall thickness, tissue echogenicity, and the number of layers. The stomach and rectum were more resistant to compression than the esophagus, duodenum, and colon. Wall echogenicity increased with increasing degrees of applied pressure and some layers were obliterated by this pressure. The second ultrasound layer, or deep mucosa, appeared to be the most susceptible to compression. Endoscopic ultrasound imaging artifacts should be reduced by limiting the amount of pressure applied to the wall with the transducer.

Clinical application of linear ultrasound probes.

The linear ultrasound probe should be viewed as an adjunct to conventional endoscopic ultrasonography with combined ultrasound endoscopes. It certainly does not replace these instruments for staging neoplasms and imaging extraintestinal organs such as the pancreas. It can be a simpler alternative to these instruments when applied at the time of endoscopy to obtain more information about wall thickness and the cause of an intramural mass. It can add information when used to image within impassable malignant strictures. Further development of the linear probes with the addition of a balloon over the transducer and the advent of new probes that utilize other scanning mechanisms is anticipated and should make this imaging system even more useful.

Evaluation of a 20-MHz ultrasound transducer used in diagnosing porcine small bowl ischemia.

The authors have previously demonstrated the ability of an 8.5-MHz linear array to detect moderate or severe intestinal ischemia in a porcine model. This study compares the ability of the 8.5-MHz linear array with a prototype miniature 20-MHz ultrasound (US) imaging probe in detecting small bowel ischemia. Five piglets were studied in which vascular clamps were applied to isolated jejunal pedicles, then released sequentially at hourly intervals to induce ischemia from 0 to 6 hours. After 24 hours of reperfusion, the tissue was removed and examined with both the 8.5-MHz linear array and the 20-MHz probe. A histologic examination also was done. The acoustical criteria used for interpretation were presence or absence of folds, number of echo layers, relative thickness of layers and homogeneity and continuity of layers. The 8.5-MHz system predicted the duration of ischemia with a kappa value of 0.66 +/- 0.03, whereas the 20-MHz system had a kappa value of 0.49 +/- 0.03. Both systems were able to distinguish normal or mild ischemia from moderate or severe ischemia with sensitivity and specificity rates of at least 94%. Both 8.5- and 20-MHz US systems detected intestinal ischemia in vitro. Further studies are indicated to determine the ideal frequency and design for a US system that can be used clinically.

Use of ultrasound to detect intestinal wall ischemia in piglets.

To evaluate the use of ultrasound (US) to detect intestinal wall ischemia, we isolated segments of jejunum on single vascular pedicles in five piglets. We sequentially clamped these segments in intervals of 0 to 6 h, reperfused them for 24 h, and then examined them in vitro histologically and with an 8.5 MHz US scan. All segments were grossly viable except those with 6 h of ischemia. Histologically, mild submucosal edema developed after 1 to 2 h of ischemia; after 3 to 4 h, mucosal necrosis, loss of folds, worsening submucosal edema, and prominent neutrophilic infiltration occurred; after 5 to 6 h, severe mucosal necrosis with hemorrhage and submucosal edema was present. Ultrasonically, we saw five wall layers in the control group corresponding to mucosa, submucosa, muscularis propria, and subserosal fat. After mild (1 to 2 h) ischemia, all layers were present except for a discontinuity in layer 3. After moderate (3 to 4 h) ischemia, the five layers persisted but with a markedly thickened submucosal layer, reduced echogenicity, and flattened mucosal folds. With severe (5 to 6 h) ischemia, we observed a loss of all normal layers with no discernible architecture. Using these US criteria, blinded observers were able to differentiate normal/mild from moderate/severe ischemia with a sensitivity and specificity of 100%. These data suggest that US can differentiate, in vitro, normal from moderate and severe degrees of intestinal wall ischemia that correlates well with the histological appearance. Endoscopic US or surgically implantable US probes can potentially help diagnose clinical intestinal wall ischemia.