Bas L. Weusten

The symptom-association probability: An improved method for symptom analysis of 24-hour esophageal pH data

BACKGROUND/AIMS All methods currently used to quantify the temporal relationships between symptoms and episodes of gastroesophageal reflux, as assessed by 24-hour pH monitoring, have major shortcomings. The aim of this study was to develop and validate a simple, all-comprising statistical method to calculate the probability that gastroesophageal reflux episodes and symptoms are associated. METHODS The 24-hour pH signal was divided into consecutive 2-minute periods. These periods and the 2-minute periods preceding the onset of symptoms were evaluated for the occurrence of reflux. Fishers Exact Test was then applied to calculate the probability (P value) that reflux and symptom episodes were unrelated. Finally, the symptom-association probability (SAP) was calculated as (1.0 - P) x 100%. The SAP values found in 184 24-hour esophageal pH tests were compared with the symptom index and the symptom sensitivity index. RESULTS Discordance between the SAP and the symptom index was found in 21 patients (11%) and discordance between the SAP and the symptom-sensitivity index in 28 (15%). False-positive and false-negative symptom index values occurred preferentially in patients with small and large numbers of symptom episodes during the test, respectively (P < 0.05). CONCLUSIONS The SAP is a single, simple, quantitative measure of the strength of the association between symptoms and reflux episodes that is devoid of the disadvantages inherent to previously used methods.

Endoscopic Transgastric vs Surgical Necrosectomy for Infected Necrotizing Pancreatitis: A Randomized Trial

CONTEXT Most patients with infected necrotizing pancreatitis require necrosectomy. Surgical necrosectomy induces a proinflammatory response and is associated with a high complication rate. Endoscopic transgastric necrosectomy, a form of natural orifice transluminal endoscopic surgery, may reduce the proinflammatory response and reduce complications. OBJECTIVE To compare the proinflammatory response and clinical outcome of endoscopic transgastric and surgical necrosectomy. DESIGN, SETTING, AND PATIENTS Randomized controlled assessor-blinded clinical trial in 3 academic hospitals and 1 regional teaching hospital in The Netherlands between August 20, 2008, and March 3, 2010. Patients had signs of infected necrotizing pancreatitis and an indication for intervention. INTERVENTIONS Random allocation to endoscopic transgastric or surgical necrosectomy. Endoscopic necrosectomy consisted of transgastric puncture, balloon dilatation, retroperitoneal drainage, and necrosectomy. Surgical necrosectomy consisted of video-assisted retroperitoneal debridement or, if not feasible, laparotomy. MAIN OUTCOME MEASURES The primary end point was the postprocedural proinflammatory response as measured by serum interleukin 6 (IL-6) levels. Secondary clinical end points included a predefined composite end point of major complications (new-onset multiple organ failure, intra-abdominal bleeding, enterocutaneous fistula, or pancreatic fistula) or death. RESULTS We randomized 22 patients, 2 of whom did not undergo necrosectomy following percutaneous catheter drainage and could not be analyzed for the primary end point. Endoscopic transgastric necrosectomy reduced the postprocedural IL-6 levels compared with surgical necrosectomy (P = .004). The composite clinical end point occurred less often after endoscopic necrosectomy (20% vs 80%; risk difference [RD], 0.60; 95% CI, 0.16-0.80; P = .03). Endoscopic necrosectomy did not cause new-onset multiple organ failure (0% vs 50%, RD, 0.50; 95% CI, 0.12-0.76; P = .03) and reduced the number of pancreatic fistulas (10% vs 70%; RD, 0.60; 95% CI, 0.17-0.81; P = .02). CONCLUSION In patients with infected necrotizing pancreatitis, endoscopic necrosectomy reduced the proinflammatory response as well as the composite clinical end point compared with surgical necrosectomy. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN07091918.

Radiofrequency Ablation vs Endoscopic Surveillance for Patients With Barrett Esophagus and Low-Grade Dysplasia: A Randomized Clinical Trial

IMPORTANCE Barrett esophagus containing low-grade dysplasia is associated with an increased risk of developing esophageal adenocarcinoma, a cancer with a rapidly increasing incidence in the western world. OBJECTIVE To investigate whether endoscopic radiofrequency ablation could decrease the rate of neoplastic progression. DESIGN, SETTING, AND PARTICIPANTS Multicenter randomized clinical trial that enrolled 136 patients with a confirmed diagnosis of Barrett esophagus containing low-grade dysplasia at 9 European sites between June 2007 and June 2011. Patient follow-up ended May 2013. INTERVENTIONS Eligible patients were randomly assigned in a 1:1 ratio to either endoscopic treatment with radiofrequency ablation (ablation) or endoscopic surveillance (control). Ablation was performed with the balloon device for circumferential ablation of the esophagus or the focal device for targeted ablation, with a maximum of 5 sessions allowed. MAIN OUTCOMES AND MEASURES The primary outcome was neoplastic progression to high-grade dysplasia or adenocarcinoma during a 3-year follow-up since randomization. Secondary outcomes were complete eradication of dysplasia and intestinal metaplasia and adverse events. RESULTS Sixty-eight patients were randomized to receive ablation and 68 to receive control. Ablation reduced the risk of progression to high-grade dysplasia or adenocarcinoma by 25.0% (1.5% for ablation vs 26.5% for control; 95% CI, 14.1%-35.9%; P < .001) and the risk of progression to adenocarcinoma by 7.4% (1.5% for ablation vs 8.8% for control; 95% CI, 0%-14.7%; P = .03). Among patients in the ablation group, complete eradication occurred in 92.6% for dysplasia and 88.2% for intestinal metaplasia compared with 27.9% for dysplasia and 0.0% for intestinal metaplasia among patients in the control group (P < .001). Treatment-related adverse events occurred in 19.1% of patients receiving ablation (P < .001). The most common adverse event was stricture, occurring in 8 patients receiving ablation (11.8%), all resolved by endoscopic dilation (median, 1 session). The data and safety monitoring board recommended early termination of the trial due to superiority of ablation for the primary outcome and the potential for patient safety issues if the trial continued. CONCLUSIONS AND RELEVANCE In this randomized trial of patients with Barrett esophagus and a confirmed diagnosis of low-grade dysplasia, radiofrequency ablation resulted in a reduced risk of neoplastic progression over 3 years of follow-up. TRIAL REGISTRATION trialregister.nl Identifier: NTR1198.

Determinants of perception of heartburn and regurgitation

Background and aim: It is not known why some reflux episodes evoke symptoms and others do not. We investigated the determinants of perception of gastro-oesophageal reflux. Methods: In 32 patients with symptoms suggestive of gastro-oesophageal reflux, 24 hour ambulatory pH and impedance monitoring was performed after cessation of acid suppressive therapy. In the 20 patients who had at least one symptomatic reflux episode, characteristics of symptomatic and asymptomatic reflux episodes were compared. Results: A total of 1807 reflux episodes were detected, 203 of which were symptomatic. Compared with asymptomatic episodes, symptomatic episodes were associated with a larger pH drop (p<0.001), lower nadir pH (p<0.05), and higher proximal extent (p<0.005). Symptomatic reflux episodes had a longer volume and acid clearance time (p<0.05 and p<0.002). Symptomatic episodes were preceded by a higher oesophageal cumulative acid exposure time (p<0.05). The proximal extent of episodes preceding regurgitation was larger than those preceding heartburn; 14.8% of the symptomatic reflux episodes were weakly acidic. In total, 426 pure gas reflux episodes occurred, of which 12 were symptomatic. Symptomatic pure gas reflux was more frequently accompanied by a pH drop than asymptomatic gas reflux (p<0.05). Conclusions: Heartburn and regurgitation are more likely to be evoked when the pH drop is large, proximal extent of the refluxate is high, and volume and acid clearance is delayed. Sensitisation of the oesophagus occurs by preceding acid exposure. Weakly acidic reflux is responsible for only a minority of symptoms in patients off therapy. Pure gas reflux associated with a pH drop (“acid vapour”) can be perceived as heartburn and regurgitation.

Stepwise radical endoscopic resection versus radiofrequency ablation for Barrett's oesophagus with high-grade dysplasia or early cancer: a multicentre randomised trial

Objective After focal endoscopic resection (ER) of high-grade dysplasia (HGD) or early cancer (EC) in Barretts oesophagus (BO), eradication of all remaining BO reduces the recurrence risk. The aim of this study was to compare the safety of stepwise radical ER (SRER) versus focal ER followed by radiofrequency ablation (RFA) for complete eradication of BO containing HGD/EC. Methods A multicentre randomised clinical trial was carried out in three tertiary centres. Patients with BO ≤5 cm containing HGD/EC were randomised to SRER or ER/RFA. Patients in the SRER group underwent piecemeal ER of 50% of BO followed by serial ER. Patients in the ER/RFA group underwent focal ER for visible lesions followed by serial RFA. Follow-up endoscopy with biopsies (four-quadrant/2 cm BO) was performed at 6 and 12 months and then annually. The main outcome measures were: stenosis rate; complications; complete histological response for neoplasia (CR-neoplasia); and complete histological response for intestinal metaplasia (CR-IM). Results CR-neoplasia was achieved in 25/25 (100%) SRER and in 21/22 (96%) ER/RFA patients. CR-IM was achieved in 23 (92%) SRER and 21 (96%) ER/RFA patients. The stenosis rate was significantly higher in SRER (88%) versus ER/RFA (14%; p<0.001), resulting in more therapeutic sessions in SRER (6 vs 3; p<0.001) due to dilations. After median 24 months follow-up, one SRER patient had recurrence of EC, requiring ER. Conclusions In patients with BO ≤5 cm containing HGD/EC, SRER and ER/RFA achieved comparably high rates of CR-IM and CR-neoplasia. However, SRER was associated with a higher number of complications and therapeutic sessions. For these patients, a combined endoscopic approach of focal ER followed by RFA may thus be preferred over SRER. Clinical trial number NTR1337.

Esophageal pH-Impedance Monitoring in Patients With Therapy-Resistant Reflux Symptoms: 'On' or 'Off' Proton Pump Inhibitor?

BACKGROUND:In patients with proton pump inhibitor (PPI)-resistant symptoms, ambulatory 24-h pH-impedance monitoring can be used to assess whether a relationship exists between symptoms and reflux episodes. Until now, it is unclear whether combined pH-impedance monitoring in these patients should be performed on or off PPI.METHODS:Thirty patients with symptoms of heartburn, chest pain, and/or regurgitation despite PPI twice daily underwent ambulatory 24-h pH-impedance monitoring twice, once on PPI and once after cessation of the PPI for 7 days. The order of the measurements was randomized. Reflux episodes were identified and classified as acid, weakly acidic, or weakly alkaline reflux. In addition, the symptom association probability (SAP) was calculated for each measurement.RESULTS:The total number of reflux episodes and proximal extent were not affected by PPI therapy. On PPI, there were fewer acid reflux episodes (49 ± 34 off PPI vs 20 ± 25 on PPI) while more weakly acidic reflux episodes were identified (24 ± 17 off PPI vs 48 ± 31 on PPI). Symptom association analysis identified 15 and 11 patients with a positive SAP in the measurement off and on PPI, respectively, the difference in yield of the SAP not being statistically significant. Eight of the 19 patients who had no symptoms or a negative SAP during measurement on PPI had a positive SAP off PPI therapy. In contrast, only 4 patients with a positive SAP on PPI were missed in the measurement off PPI therapy.CONCLUSIONS:In order to demonstrate or exclude GERD in patients with PPI-resistant symptoms, ambulatory 24-h pH-impedance monitoring should preferably be performed after cessation of PPI therapy because this approach seems to offer the best chance to assess a relationship between symptoms and reflux episodes.

Addition of esophageal impedance monitoring to pH monitoring increases the yield of symptom association analysis in patients off PPI therapy

BACKGROUND:The additional yield of esophageal impedance monitoring in identification of reflux as the cause of reflux symptoms is unknown.OBJECTIVES:To compare the yield of symptom–reflux association analysis of combined esophageal pH-impedance data with the yield of analysis of pH data alone.METHODS:In 60 patients with symptoms of heartburn and regurgitation combined, 24-h pH-impedance monitoring was performed. Acid-suppressive medication was stopped 1 wk in advance. Patients (48) with at least one symptom during the measurement period were selected for further analysis. Patients were instructed to note the time and nature of their symptoms. Eleven types of reflux episodes were defined, based on combinations of magnitude of the pH drop, nadir pH, and nature of the refluxate (gas and liquid) on impedance tracings. Symptom association analysis—symptom index, the symptom sensitivity index, and the symptom association probability (SAP)—was performed for each definition of reflux.RESULTS:The proportion of patients with a positive SAP (≥95.0%) varied between 62.5% and 77.1%, depending on the definition of reflux episodes. When both pH and impedance parameters were used to identify reflux, a higher proportion of patients had a positive SAP than with pH alone (77.1%vs 66.7%, p < 0.05). Symptom association analysis for acidic and weakly acidic reflux separately did not result in a higher yield than analysis with all reflux episodes pooled, regardless of pH.CONCLUSION:In patients off proton pump inhibitor, the addition of impedance monitoring to esophageal pH monitoring leads to an increase in the proportion of patients in whom an association between reflux episodes and symptoms can be identified.

Symptom association analysis in ambulatory gastro-oesophageal reflux monitoring

During the past three decades, prolonged monitoring of oesophageal pH has become increasingly popular among physicians. Most of the studies carried out with this technique focused on oesophageal acid exposure, defined as percentage of time with pH below 4. However, in most cases acid exposure variables are not very useful in the evaluation of patients with symptoms and signs of gastro-oesophageal reflux disease (GORD). An often neglected aspect of 24 hour pH recording is assessment of the temporal relation between reflux and symptoms. Various methods to quantify this relationship were developed. Here, we review these methods and the contribution of symptom association analysis to the evaluation of patients with symptoms suggestive of GORD.

Aerophagia, gastric, and supragastric belching: a study using intraluminal electrical impedance monitoring

Background: Patients with aerophagia are believed to have excessive belches due to air swallowing. Intraluminal impedance monitoring has made it possible to investigate the validity of this concept. Methods: The authors measured oesophageal pH and electrical impedance before and after a meal in 14 patients with excessive belching and 14 healthy controls and identified patterns of air transport through the oesophagus. The size of the gastric air bubble was measured radiographically. In four patients prolonged oesophageal manometry was performed simultaneously. Results: In all subjects, impedance tracings showed that a significant amount of air is propulsed in front of about a third of the swallow induced peristaltic waves. Two types of retrograde gas flow through the oesophagus (belch) were observed. In the first type air flowed from the stomach through the oesophagus in oral direction (“gastric belch”). In the second type air entered the oesophagus rapidly from proximal and was expulsed almost immediately in oral direction (“supragastric belch”). The incidence of air-containing swallows and gastric belches was similar in patients and controls but supragastric belches occurred exclusively in patients. There was no evidence of lower oesophageal sphincter relaxation during supragastric belches. Gastric air bubble size was not different between the two groups. Conclusions: In patients with excessive belching the incidence of gaseous reflux from stomach to oesophagus is similar to that in healthy subjects. Their excess belching activity follows a distinct pattern, characterised by rapid antegrade and retrograde flow of air in the oesophagus that does not reach the stomach.

Endoscopic Tri-Modal Imaging Is More Effective Than Standard Endoscopy in Identifying Early-Stage Neoplasia in Barrett's Esophagus

BACKGROUND & AIMS Endoscopic tri-modal imaging (ETMI) incorporates high-resolution endoscopy (HRE), autofluorescence imaging (AFI), and narrow band imaging (NBI). A recent uncontrolled study found that ETMI improved the detection of high-grade dysplasia (HGD) and early carcinoma (Ca) in Barretts esophagus (BE). The aim was to compare ETMI with standard video endoscopy (SVE) for the detection of HGD/Ca with the use of a randomized cross-over design. METHODS Patients referred for work-up of inconspicuous HGD/Ca were eligible and underwent both SVE and ETMI in randomized order within an interval of 6-12 weeks. During ETMI, inspection with HRE was followed by AFI. Detected lesions were inspected in detail with NBI and biopsied, followed by random biopsies. During SVE, any visible lesion was biopsied followed by random biopsies. RESULTS Eighty-seven patients with BE underwent ETMI and SVE. No significant difference was observed in overall histologic yield between ETMI and SVE. ETMI had a significantly higher targeted yield compared with SVE because of AFI. However, the yield of targeted biopsies of ETMI was significantly inferior to the overall yield of SVE. Detailed inspection with NBI reduced the false-positive rate of HRE + AFI from 71% to 48% but misclassified 17% of HGD/Ca lesions as not suspicious. CONCLUSIONS ETMI statistically significant improves the targeted detection of HGD/Ca compared with SVE. Subsequent characterization of lesions with NBI appears to be of limited value. At this stage, ETMI cannot replace random biopsies for detection of lesions or targeted biopsies for characterization of lesions in a high-risk population.