Diagnostic Testing in Patients with Refractory GERD Frank Zerbib, MD, PhD, and Arnaud Duriez, MD
Corresponding author
Frank Zerbib, MD, PhD
Gastroenterology Department, Saint Andre Hospital,
1 rue Jean Burguet, 33075 Bordeaux, France.
注射用盐酸万古霉素E-mail: bib@chu-bordeaux.fr
Current GERD Reports 2007, 1:157–7162
Current Medicine Group LLC ISSN 1934-967X
Copyright © 2007 by Current Medicine Group LLC
Refractory gastroesophageal reflux dia (GERD) usu-ally refers to patients with persisting symptoms despite proton pump inhibitor therapy. The diagnostic yield of esophageal pH monitoring is low in patients with symp-toms on proton pump inhibitors, especially for tho prenting with atypical
symptoms and no respon to adequate acid suppressive therapy. In the patients, pH monitoring should be performed off therapy to rule out pathologic GER. In contrast, in patients prenting with typical symptoms or partial respon to proton pump inhibitors, pH-monitoring studies on therapy can dem-onstrate pathologic GER in approximately 10% of the patients. However, 30% to 40% of the patients clearly have symptoms that can be associated with nonacid
reflux, detected by pH-impedance monitoring. Out-come studies will help to determine the actual impact
of pH-impedance monitoring on the management of refractory GERD.
Introduction
带月的四字词语The acid component of the refluxate plays a major role in the pathophysiology of gastroesophageal reflux dia (GERD), but although proton pump inhibitors (PPIs) have a remarkable efficacy for mucosal healing and symptom relief [1], some patients are refractory to adequate acid-suppressive therapy. “Refractoriness” to PPIs has no widely admitted definition that can be referenced in pub-lished studies regarding patients with either incomplete or no respon to therapy. The two groups of patients are probably very different with respect to GERD prevalence and underlying conditions le
ading to symptoms. More-over, the definition of refractoriness to PPIs should also include frequency and verity of persisting symptoms (ie, bothersome symptoms), as well as duration and dosing of therapy. Available data from clinical trials with PPIs as G ERD therapy suggest that up to 30% of included patients with esophagitis are considered to have inad-equate symptom relief after a 4-week cour of a single do of PPI [1]. The proportion of patients with persisting symptoms after a 4-week cour of treatment is probably much higher in patients with endoscopy-negative reflux dia [2,3]. Becau the definition of refractory GERD varies widely in the literature, the data prented in this article refer to patients with “persisting symptoms despite PPI therapy.”
In the clinical tting of “refractory GERD,” esopha-geal reflux tests are suppod to provide objective data and help physicians to answer three questions: does a pathologic GER exist, is this GER responsible for symp-toms, and should this patient be referred for surgery?
If pH monitoring has been the gold standard for esophageal reflux testing for years, combined esophageal impedance and pH monitoring is now considered to be the best technique to detect and characterize G ER [4]. The majority of published studies in this field during the past 2 years referring to this new technique is therefore not surprising. However, pH monitoring alone is still uful, especially becau wireless technology has become avail-able. We strongly encourage reading the r
ecently published recommendations of the American College of G astroen-terology on the clinical applications of esophageal reflux testing, which are supported by an in-depth review of advantages and limitations of the different techniques [5]. Esophageal pH Monitoring
Esophageal pH monitoring is uful for documenting GER in patients with typical or atypical symptoms refractory to PPIs, but whether pH testing should be performed off or on therapy is still controversial. We agree with the ACG recommendations that suggest that the decision should be made according to the pretest probability of GERD; a low probability should favor a study off therapy to rule out GERD, whereas a study on therapy should be propod if the probability of GERD is high. “Pretest probability is bad on prevalence of GERD in patient population under question, clinician’s impression, and degree of respon to empiric PPI trial” [5]. The diagnostic yield of pH monitor-
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158Diagnosis and Testing
ing is generally higher in patients with typical symptoms than in patients prenting with atypical symptoms, espe-cially ear, no, and throat (ENT) symptoms. Indeed, Vaezi et al. [6] have reported the results of a placebo-controlled randomized study that aimed to determine the efficacy of 40 mg of esomeprazole taken twice daily for 16 weeks in patients with posterior laryngitis. No difference wa
s found between esomeprazole and placebo concerning symptom relief. In this study conducted in lected patients without significant typical reflux symptoms, ambulatory pharyngo-esophageal pH monitoring demonstrated abnormal acid reflux in only 29% and 9% of patients, respectively, in dis-tal and proximal esophagus. Moreover, the results of pH monitoring could not predict the respon to therapy. There-fore, the ufulness of esophageal pH testing in patients with ENT symptoms appears questionable. Nevertheless, esophageal pH testing may help physicians, especially the gastroenterologist to whom the patient is referred, to rule out the diagnosis of G ERD in the patients with long-term difficult-to-treat symptoms but who are considered by a majority of ENT physicians as having GERD-related symptoms [7].
The most recent study on pH monitoring on therapy has been reported by Charbel et al. [8], who showed that approximately 30% of patients on daily PPI had persistent abnormal esophageal acid exposure. However, in patients with double do PPIs, only 7% with typical symptoms and 1% prenting with atypical symptoms had an abnormal esophageal acid exposure, a positive symptom index (SI), or both. The results are consistent with tho obtained with pH-impedance monitoring and confirm that, in ca of persisting symptoms while on single-do therapy, the do should be doubled and taken twice daily before con-sidering further investigations. While on twice daily PPIs, the probability of having abnormal acid reflux is very low.
The wireless pH monitoring is a telemetric catheter-free system recently developed to monitor esophageal pH. The device (Bravo pH Monitoring System; Medtronic, Minneapolis, MN, USA) is temporarily implanted in the patient’s esophageal mucosa, avoiding the inconvenience of wearing a nasopharyngeal electrode, and allows a 48-hour ambulatory pH study [9]. The potential advantages offered by this new device appear important not only for patient acceptance but also for prolonged monitor-ing under more physiologic conditions, which results in incread nsitivity and diagnostic yield [5]. Using two parate receivers calibrated to a single Bravo capsule, Hirano et al. [10•] performed a 4-day esophageal pH monitoring in 18 patients with refractory symptoms and could therefore combine off- and on-therapy testing. Day 1 was studied with the patient off therapy, and days 2 through 4 were studied with the patient on 20 mg of rabeprazole twice daily. Among the patients with abnor-mal acid exposure on day 1, only 5% failed to normalize acid exposure on day 4. Early detachment of the capsule occurred in only 5% of patients. This study demonstrates the feasibility of a 4-day pH monitoring that may help, with a single procedure, to document the prence of acid reflux–related symptoms both off and on therapy.
The overall diagnostic yield of pH monitoring is relatively low in patients with persisting symptoms on PPI therapy, provided that refractoriness refers to patients taking PPIs twice daily. In patients with a
pretest low prob-ability of GERD (eg, atypical symptoms or no respon to PPI), pH monitoring should preferably be performed off therapy to rule out the prence of pathologic G ER. By contrast, in patients with a higher probability of G ERD (eg, typical symptoms or incomplete respon to PPIs), pH monitoring should be performed on therapy and will demonstrate abnormal esophageal acid exposure in approximately 10% of them. Notably, the upper limit of esophageal acid exposure in patients on PPI remains a mat-ter of debate. While the cutoff of 5% is generally admitted as the upper normal value of esophageal acid exposure in patients off therapy, some authors have propod a value of 1.6% in patients on 40 mg of omeprazole daily [11], which has not been validated in patients with and without persist-ing symptoms. Therefore, considering symptom association analysis to determine whether symptoms can be associated with acid reflux appears more relevant [12]. Ambulatory Esophageal
pH-impedance Testing
In patients with symptoms suggestive of GERD, the failure of an adequate acid suppressive therapy suggests that other factors either in the esophagus or in the refluxate may play an additional role in eliciting symptoms. Esophageal pH monitoring does not detect all G ER events, particularly when little or no acid is prent in the refluxate. Multi-channel intraluminal impedance monitoring is a recen
tly developed technique that allows detection of virtually all reflux episodes, liquid, gas, or mixed. When combined with pH monitoring, multichannel intraluminal imped-ance monitoring allows the characterization of reflux episodes as acid or nonacid (Fig. 1) and has been consid-ered by a panel of experts in the field of GERD as the best tool to detect and characterize GER [4]. Combined pH-impedance recording enables the detection of nonacid reflux and analysis of its association with symptoms in ambulatory physiologic conditions. Recent ambulatory studies in healthy subjects have shown that nonacid reflux reprent 40% to 60% of all GER detected by impedance and have demonstrated the reproducibility of the tech-nique [13,14]. The first data available in GERD patients have suggested that nonacid reflux may be responsible for symptoms such as chronic cough [15] and regurgitation in patients on PPIs [16].
Practical issues
村居这首诗Ambulatory impedance-pH devices are now commer-cially available, and increasing u of this technique is
Diagnostic Testing in Patients with Refractory GERD Zerbib and Duriez 159
expected. However, the development of pH-impedance monitoring in routine practice is still at a very
early stage; analysis of pH-impedance recordings is time con-suming and requires experience.
The duration of analysis ranges from 1 to 3 hours, depending on the experience of the investigator and the number of reflux to analyze. The Bioview (Sandhill Sci-entific, Inc., Highlands Ranch, CO) software offers the possibility of an automatic analysis for reflux detection.Our French-Belgian collaborative group (ven centers) aimed to asss the accuracy of this automatic analysis as compared with visual analysis [17•]. Seventy-three patients with suspected G ERD underwent 24-hour esophageal pH–impedance monitoring. As compared with visual analysis, we obrved that automatic analysis detected more reflux events, especially nonacid reflux events, as well as pure gas and proximal reflux episodes. The dis-crepancies were mostly related to swallow artifacts that were taken into account by the software as actual reflux episodes. The most relevant results were obtained for the diagnostic accuracy of automatic analysis for the deter-mination of a positive association between symptoms and reflux events (SI > 50%), compared with visual analysis.The diagnostic accuracy for acid G ER was excellent in patients both off and on PPI (97.6% and 100%, respec-tively). By contrast, becau of an incread detection of nonacid reflux, the accuracy of automatic analysis for nonacid reflux was 82.9% and 75% in patients off and on
therapy, respectively. This automatic analysis is not reli-able, especially in patients on PPIs, becau
25% of them would have a wrong final diagnosis. A more rapid analy-sis could be propod to asss the temporal relationship between symptoms and G ER detected by impedance; SI could be determined accurately by a visual analysis of the 5-minute period preceding each reported symptom. How-ever, this analysis cannot provide a reliable determination of the symptom association probability (SAP), which is probably a better method to asss symptom-reflux cor-relation, although both indices have limitations [12].Although significant improvements can be expected in the future, we believe that visual analysis remains the gold standard for detecting an association between symptoms and nonacid reflux events, especially in patients with per-sisting symptoms on PPIs.
Finally, becau no reliable automatic analysis is cur-rently available, standardization of impedance tracings analysis is needed. Our collaborative group organized training ssions that aimed at interpretation of recording applying similar definitions and criteria for analysis. This allowed us to standardize and homogenize the technique as much as possible [14].
Impedance studies off therapy
Compared with pH monitoring alone, pH-impedance monitoring allows the detection of nonacid reflux that may be responsible for symptoms. All recent available
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Figure 1.Combined impedance-pH recordings showing an example of liquid weakly acidic reflux. Vertical bars on impedance channels indicate the beginning and the end of bolus reflux. Horizontal bars on the pH channel indicate a pH of 4. Tracings demonstrate a retrograde drop in impedance starting distally and propagated retrogradely up to 9 cm above LES, together with a pH fall below 6.5 but above 4. LES—lower esophagus.
160Diagnosis and Testing
data from studies in patients off therapy confirm that impedance monitoring adds little value to the diagnostic yield of pH alone.
Bredenoord et al. [18••] performed a pH-impedance study in 60 patients with typical G ER symptoms off therapy. As a whole, 75% of patients had a positive symp-tom association (SAP) when all types of reflux detected by impedance were taken into account independent of pH value. The added value of impedance was less than 10%, becau 66.7% of subjects had a positive association when reflux ep
isodes defined by a pH fall below 4. Our collaborative group reported consistent results in a cohort of 79 patients with either typical or atypical symptoms [19••]. Forty-one of the symptomatic subjects (55.4%) had positive SAP, but pH-impedance monitoring allowed establishing a temporal association between reflux and symptoms in only 4.1% of patients who would have been misd by a pH study alone. Belch and cough were the most prevalent symptoms associated with nonacid reflux. The results were very similar when symptom-reflux asso-ciation was considered with the SI, which was positive (s 50%) for nonacid reflux in only 10.8% of patients. Our group also recently reported data on patients with unex-plained ENT symptoms possibly related to G ERD [20]. The link between reflux and ENT symptoms can hardly rely on symptom-reflux association analysis, becau the symptoms are usually long lasting (or permanent) and do not have a sudden ont that could be easily per-ceived by the patient. Therefore, only the number of reflux episodes was taken into account and compared with the normal values previously determined by our group [14]. In a cohort of 26 patients without PPI, four (15.3%) had an abnormal acid reflux, including two with a proximal extent (15 cm above LES), and only one (3.8%) had a number of nonacid reflux above normal values.
In clinical practice, combined pH-impedance study in patients off PPI allows the establishing of a tem
poral relationship between reflux and symptoms in only 5% to 10% more than conventional pH recording.
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Impedance studies on therapy
Becau the majority of reflux episodes that occur while on PPI therapy are nonacid (ie, nadir pH above 4), add-ing impedance to pH monitoring improves the diagnostic yield and allows better symptom analysis. This has been clearly demonstrated by two recent studies.
In the study reported by Mainie et al. [21••], 168 patients with persisting symptoms despite adequate acid suppressive therapy (double do PPIs) underwent a pH-impedance monitoring while on therapy. As expected, only 17.3% of all reflux episodes were acid, whereas 82.7% were nonacid, mainly weakly acidic (ie, with a pH drop between 4 and 7). In approximately one half of the patients, no association between symptoms and any type of GER could be demonstrated, suggesting that the hypothesis of G ER as a cau of their symptoms could be reasonably abandoned. In contrast, 11% had symp-toms associated with acid reflux (which would have been detected by a pH-alone study), and 37% had symptoms associated with nonacid reflux, mainly regurgitation, chest pain, and heartburn. In this study, the proportion of atypical symptoms associated with reflux was only 22%, including 3% and 19% associated with acid and nonacid reflux, respectively.
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Very similar results were obtained from our collab-orative group in a cohort of 71 patients with persisting symptoms on double do PPIs [19••]. We established a significant statistical association (SAP) between nonacid reflux and symptoms in 16.7% of patients who would have been misd by a pH alone study. Regurgitation and cough were the most prevalent symptoms associated with nonacid G ER. When symptom-reflux association was considered with the SI, a positive association was found for nonacid reflux in only 38.3% of patients and for acid reflux in 8% of the symptomatic subjects.
The results of the two studies are concordant and can be summarized as follows: in unlected patients with persistent symptoms on double do PPIs, 50% to 60% do not have symptoms that can be associated with GER, 30% to 40% have symptoms associated with nonacid reflux, and approximately 10% have symptoms associated with acid reflux. In both studies, the agreement between SI and SAP was poor (values of 0.26 [19••] and 0.3 [21••],
L
respectively) [21••]. If SAP is considered by some authors to be the best method to express the temporal relationship between symptoms and reflux episodes [12], SI is a simple, easy-to-determine,
and easy-to-understand parameter. Moreover, the adequate time window before the ont of symptoms to determine temporal association is still a matter of debate. The 2-minute time window was primar-ily adopted for symptom analysis, as previous works have demonstrated that it was the most appropriate, at least in patients with chest pain [22]. However, some authors ud a 5-minute time window, which may be more appropriate for certain symptoms that lack sudden ont [21••]. To date, the indices should be considered as complemen-tary, and outcome studies will probably help to identify the best way to predict respon to therapy.
The putative association between G ER and ENT symptoms is still a matter of debate. The temporal rela-tionship between the types of symptoms and G ER is difficult to establish. The potential role of acid reflux has been recently challenged (negative randomized studies with PPIs), suggesting that other factors like nonacid GER may play a role in eliciting such symptoms. As compared with pH monitoring alone, impedance not only allows detection of nonacid reflux episodes but also determines the proximal extent of the refluxate, which is also sup-pod to play a role in ENT and respiratory symptoms. In a cohort of 21 patients with persistent globus on PPI, Anandasabapathy et al. [23•] recently reported that nonacid reflux was not associated with symptoms but
Diagnostic Testing in Patients with Refractory GERD Zerbib and Duriez161
that proximal extent may play a role. As compared with patients with heartburn alone, patients with globus had significantly more reflux episodes with a proximal extent (27.8% vs 15.6%;P = 0.04). Our group reported the results obtained in a cohort of patients with ENT symptoms despite double-do PPIs in whom a pH-impedance study was performed on therapy [20]. We obrved that 17.2% of patients had a number of proximal reflux episodes above normal values [20] established in healthy subjects on double-do PPI therapy [24]. As a whole, 27.4% of the patients had abnormal GER, 13.7% acid reflux, and 13.7% nonacid reflux. Therefore, a pathological acid or nonacid G ER can be demonstrated in a subgroup of patients with ENT symptoms on therapy. However, the results are quite difficult to interpret, becau no temporal relationship can be established between the symptoms and GER detected by impedance. Moreover, the studied populations are probably very heterogeneous and prent with symptoms difficult to characterize. We believe that only prospective interventional studies will help to estab-lish the role of nonacid reflux in the occurrence of ENT symptoms, and 24-hour pH-impedance monitoring may help to identify a small subgroup of patients with exces-sive or proximal reflux who may have ENT symptoms related to GERD.
Outcome Studies with pH-impedance
Adding impedance to pH monitoring clearly improves the diagnostic yield and allows better symptom
analysis than pH-metry alone, but the actual impact of pH-impedance on G ERD management derves to be investigated by prospective outcome studies bad on symptom-reflux association analysis. Two studies from Castell’s group in Charleston are currently available.
Mainie et al. [25•] have reported the results of lapa-roscopic fundoplication in 19 patients with persistent symptoms despite PPI therapy. Ten patients had atypi-cal symptoms, and nine had typical symptoms, but only 18 out of 19 patients had a positive SI on preoperative pH-impedance study on therapy. One patient was lost to follow-up, but 16 out of 17 patients with a positive SI were asymptomatic and no longer taking any antire-flux medication or markedly improved after a follow-up of 14 months. Fundoplication failed to improve symp-toms in one patient with heartburn and negative SI and in one patient with hoarness despite positive SI, thus confirming that asssment of temporal relationship between ENT symptoms and reflux is difficult. The same group reported similar results in six patients with cough associated with nonacid reflux (positive SI) during pH-impedance monitoring on therapy [26•]. Laparo-scopic Nisn fundoplication led to the disappearance of symptoms in all patients who stopped receiving acid-suppressive therapy during evaluations of a median follow-up of 17 months.
The two studies have veral limitations, such as a small number of patients, probable lection bi
as, no control arm, and the abnce of postoperative data confirming reflux control. However, they are currently the only available data suggesting that pH-impedance could have a significant impact on the management of GERD in patients who failed adequate acid suppres-sive therapy. This technique could help to identify the patients who are more likely to benefit from antireflux surgery (ie, tho who have a positive SI), becau simi-lar data do not yet exist for SAP. Further controlled prospective studies are warranted to confirm the very promising results.
Conclusions
The development of 24-hour esophageal pH-impedance monitoring reprents a significant advance in diagnostic testing in patients with persisting symptoms on PPIs. This technique can clearly identify symptoms associated with nonacid reflux in patients on acid suppressive therapy. The added value of esophageal pH-impedance monitoring in patients studied off therapy is low, so we recommend a pH monitoring alone, especially in patients with a low prob-ability of having G ERD in whom this hypothesis needs to be ruled out. In contrast, on-therapy pH-impedance monitoring should preferably be performed in patients with refractory typical symptoms or partial respon to PPIs. However, outcome studies are warranted to deter-mine the actual impact of this technique on refractory GERD management.
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