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Redeeming Clinical Value of Esophageal pH Impedance Monitoring
EDITORIAL Redeeming Clinical Value of Esophageal pH Impedance Monitoring sophageal ambulatory pH impedance monitoring showed much promise in the new millennium as a novel approach to quantifying reflux events irrespective of pH or antisecretory therapy.1 It was widely believed then that pH-impedance monitoring would become the standard for reflux monitoring, and would be performed on antisecretory therapy without the need for discontinuation of acid suppression.2 The method has been proven to identify higher proportions of reflux events compared with pH monitoring alone even in studies performed off antisecretory therapy, and to diagnose unusual syndromes such as rumination, supragastric belching, and aerophagy.3,4 However, there were problems within its primary role: evaluation of gastroesophageal reflux disease (GERD). Identification and characterization of reflux events had to be confirmed manually, and could be time consuming. The studies also were difficult to interpret, with even experts disagreeing on occasion on what constituted a reflux event, especially proximal esophageal events.5,6 Although normative data were collected and reported, there was scant information on whether impedance parameters predicted outcome.7 Many studies were performed on antisecretory therapy in patients with reflux symptoms but without prior confirmation of reflux; therefore, the true impact of a negative impedance study on management decisions was difficult to assess. In contrast, pH testing concurrently moved toward a less-cumbersome wireless system with the capability of collecting up to 96 hours of pH data. In the changing role of reflux monitoring, now often performed to rule out rather than quantify reflux, the easier and better-tolerated prolonged wireless pH probe started gaining value as a tool to assess reflux symptoms.8 Finally, outcome studies began to be published. It was clear that the number of reflux events could be reduced by antireflux surgery, but reflux patterns identified on pH-impedance monitoring did not necessarily translate into better patient outcomes.4,9 Reflux exposure time, bolus contact time, and bolus clearance time fell by the wayside as useful reflux parameters, and even symptom reflux correlation was questioned as not being representative because of the significant impact of uncontrolled patient factors in symptom reporting during monitoring.10 In fact, acid-based parameters from pHimpedance studies provided the best evidence for therapeutic success rather than the impedance portion of the study.4 In evaluation of reflux symptoms, the best value for impedance monitoring appeared to be limited to identification of reflux events for symptom-reflux
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association, adding confidence to the diagnosis of reflux disease in patients who were incompletely responsive to antisecretory therapy. The study by Frazzoni et al published in this issue of Clinical Gastroenterology and Hepatology is a redemption of sorts for pH-impedance monitoring, adding to its niche value in the evaluation of reflux symptoms. It has been known for some time that baseline mucosal impedance correlates with esophageal mucosal integrity, hence values can be low in severe reflux disease11; alternatively, motor disorders with a fluid-filled, dilated esophagus also can decrease values.12 Frazzoni et al13 have standardized measurement of baseline impedance by calculating the mean nocturnal baseline impedance (MNBI) across three 10-minute periods between 1 AM and 3 AM, away from daytime esophageal physiologic activity. The second measure reported by Frazzoni et al makes even more physiologic sense. After a reflux event, the refluxate is mostly cleared by a secondary peristaltic wave in response to esophageal distension, but neutralization of mucosal acidity is facilitated by a reflex primary swallow that brings salivary bicarbonate into the esophagus.14 Therefore, the postreflux swallow-induced peristaltic wave (PSPW), identified by a panesophageal antegrade decrease in impedance within 30 seconds of a reflux event, indirectly assesses esophageal motor peristaltic reserve.15 Esophageal motor function in this context is relevant in reducing retention of the refluxate (by secondary peristalsis), and in chemical clearance (by inducing primary peristalsis). The PSPW index proposed by Frazzoni et al13 consists of the ratio of PSPW to the total reflux events identified, and therefore adds an additional dimension to the assessment of the number of reflux events during a pH impedance study. The gist of the study findings is that both the MBNI and PSPW index showed a gradient across 289 GERD patients and 50 healthy controls, both parameters being worse in erosive esophagitis compared with nonerosive reflux disease and healthy controls. Performance characteristics of both these parameters were overall higher than that of increased acid exposure time, total reflux events, and bolus exposure time in predicting both erosive esophagitis and non-erosive reflux disease (NERD). Frazzoni et al report a modest correlation between these 2 parameters (Pearson r ¼ 0.657; P < .001). Finally, the diagnostic gain over conventional impedance parameters was substantial, especially within the NERD categories.13 There are several additional points worth mentioning. First, the interest in bolus exposure time as an impedancebased reflux parameter is dampened further by this study’s findings. Bolus exposure time has not lived up to the performance of acid exposure time, and does not add much value in reflux assessment.4 Furthermore, the Clinical Gastroenterology and Hepatology 2015;-:-–-
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C. Prakash Gyawali
number of reflux events, although needed for the PSPW index calculation, did not perform well in any disease category other than erosive esophagitis. The PSPW index and MNBI, on the other hand, had higher sensitivity and, with the former, better accuracy than abnormal acid exposure time in predicting erosive esophagitis. Within NERD categories, performance characteristics remained impressive in pH-positive NERD, but not as much in the remainder of the NERD categories. This adds further credence to the notion that true NERD is best identified with abnormal pH parameters; indeed, in the setting of abnormal pH, NERD outcomes mirror that seen with erosive esophagitis.16 It generally is accepted that negative pH parameters with or without symptom reflux association potentially represent functional hypersensitivity to mechanical or chemical aspects of reflux (reflux hypersensitivity) or to physiologic events (functional heartburn). In contradiction to this dogma, Frazzoni et al13 suggested that true reflux disease may overlap with these 2 latter categories despite normal pHimpedance data off antisecretory therapy, on the basis of the 2 new indices alone in some instances—a stand that may not be firm yet without further outcome data. Management outcomes in these difficult and refractory settings will define the true value of MNBI and PSPW index, not in erosive esophagitis or NERD with abnormal pHimpedance parameters where existing metrics are adequate for directing therapy. As with existing studies on pH-impedance parameters, there were limitations. The report was a crosssectional study describing proportions of patients with an abnormal MNBI and PSPW index among categories of GERD patients, using these proportions to project diagnostic yield. The true value of these parameters will be assessed when outcome data are collected prospectively, comparing those with and without an abnormal MNBI and PSPW index. Although Frazzoni et al13 reported high interobserver agreement for both indices, the PSPW calculation involves a manual review of the entire pHimpedance study, which is no simple task. The MNBI also requires manual calculation after identification of appropriate quiet periods, and is likely to be impacted by esophageal motor disorders associated with hypomotility and esophageal dilation, where the impedance rings may not be in firm contact with esophageal mucosa. Finally, the new kid on the block, endoscopic mucosal impedance measurement, is threatening to limit the need for ambulatory pH impedance monitoring in the very situations in which these new metrics have potential (ie, in assessing the likelihood of reflux-induced symptoms in refractory symptomatic states).17 Nevertheless, the MNBI and PSPW index make pathophysiologic sense, and certainly deserve a chance in redeeming the clinical value of ambulatory pHimpedance testing. Further research certainly is needed to determine if a normal MNBI and PSPW index in the setting of normal pH and normal conventional impedance parameters would be the benchmark for diagnosis
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of functional esophageal symptoms. Other confounders in the assessment of these parameters need to be evaluated, for instance, the contribution of abnormal motor function or esophageal dilation. Finally, software tools need to be developed by companies marketing pHimpedance to simplify the calculation of these parameters because both the MNBI and PSPW index need to be studied rigorously and potentially adapted for clinical use in the short term. C. PRAKASH GYAWALI, MD, MRCP Division of Gastroenterology Washington University School of Medicine St. Louis, Missouri
References 1. Sifrim D, Castell D, Dent J, et al. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004; 53:1024–1031. 2. Bredenoord AJ. Impedance-pH monitoring: new standard for measuring gastro-oesophageal reflux. Neurogastroenterol Motil 2008;20:434–439. 3. Vela MF, Camacho-Lobato L, Srinivasan R, et al. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology 2001;120:1599–1606. 4. Patel A, Sayuk GS, Gyawali CP. Parameters on esophageal pHimpedance monitoring that predict outcomes of patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2015;13:884–891. 5. Loots CM, van Wijk MP, Blondeau K, et al. Interobserver and intraobserver variability in pH-impedance analysis between 10 experts and automated analysis. J Pediatr 2012;160:441–446 e1. 6. Ravi K, DeVault KR, Murray JA, et al. Inter-observer agreement for multichannel intraluminal impedance-pH testing. Dis Esophagus 2010;23:540–544. 7. Zerbib F, Roman S, Bruley Des Varannes S, et al. Normal values of pharyngeal and esophageal 24-hour pH impedance in individuals on and off therapy and interobserver reproducibility. Clin Gastroenterol Hepatol 2013;11:366–372. 8. Penagini R, Sweis R, Mauro A, et al. Inconsistency in the diagnosis of functional heartburn: usefulness of prolonged wireless pH monitoring in patients with proton pump inhibitor refractory gastroesophageal reflux disease. J Neurogastroenterol Motil 2015;21:265–272. 9. Zerbib F, Belhocine K, Simon M, et al. Clinical, but not oesophageal pH-impedance, profiles predict response to proton pump inhibitors in gastro-oesophageal reflux disease. Gut 2012; 61:501–506. 10. Slaughter JC, Goutte M, Rymer JA, et al. Caution about overinterpretation of symptom indexes in reflux monitoring for refractory gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2011;9:868–874. 11. Farre R, Blondeau K, Clement D, et al. Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut 2011;60:885–892. 12. Heard R, Castell J, Castell DO, et al. Characterization of patients with low baseline impedance on multichannel intraluminal impedance-pH reflux testing. J Clin Gastroenterol 2012; 46:e55–e57.
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13. Frazzoni M, Savarino E, de Bortoli N, et al. Analyses of the postreflux swallow-induced peristaltic wave index and nocturnal baseline impedance parameters increase the diagnostic yield of patients with reflux disease. Clin Gastroenterol Hepatol 2015: Epub ahead of print. 14. Frazzoni M, Bertani H, Manta R, et al. Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis. Dig Liver Dis 2014;46:596–602. 15. Shaker A, Stoikes N, Drapekin J, et al. Multiple rapid swallow responses during esophageal high-resolution manometry reflect esophageal body peristaltic reserve. Am J Gastroenterol 2013; 108:1706–1712.
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16. Weijenborg PW, Cremonini F, Smout AJ, et al. PPI therapy is equally effective in well-defined non-erosive reflux disease and in reflux esophagitis: a meta-analysis. Neurogastroenterol Motil 2012;24:747–757, e350. 17. Ates F, Vaezi MF. New approaches to management of PPIrefractory gastroesophageal reflux disease. Curr Treat Options Gastroenterol 2014;12:18–33.
Conflicts of interest The author discloses no conflicts. http://dx.doi.org/10.1016/j.cgh.2015.08.030
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association, adding confidence to the diagnosis of reflux disease in patients who were incompletely responsive to antisecretory therapy. The study by Frazzoni et al published in this issue of Clinical Gastroenterology and Hepatology is a redemption of sorts for pH-impedance monitoring, adding to its niche value in the evaluation of reflux symptoms. It has been known for some time that baseline mucosal impedance correlates with esophageal mucosal integrity, hence values can be low in severe reflux disease11; alternatively, motor disorders with a fluid-filled, dilated esophagus also can decrease values.12 Frazzoni et al13 have standardized measurement of baseline impedance by calculating the mean nocturnal baseline impedance (MNBI) across three 10-minute periods between 1 AM and 3 AM, away from daytime esophageal physiologic activity. The second measure reported by Frazzoni et al makes even more physiologic sense. After a reflux event, the refluxate is mostly cleared by a secondary peristaltic wave in response to esophageal distension, but neutralization of mucosal acidity is facilitated by a reflex primary swallow that brings salivary bicarbonate into the esophagus.14 Therefore, the postreflux swallow-induced peristaltic wave (PSPW), identified by a panesophageal antegrade decrease in impedance within 30 seconds of a reflux event, indirectly assesses esophageal motor peristaltic reserve.15 Esophageal motor function in this context is relevant in reducing retention of the refluxate (by secondary peristalsis), and in chemical clearance (by inducing primary peristalsis). The PSPW index proposed by Frazzoni et al13 consists of the ratio of PSPW to the total reflux events identified, and therefore adds an additional dimension to the assessment of the number of reflux events during a pH impedance study. The gist of the study findings is that both the MBNI and PSPW index showed a gradient across 289 GERD patients and 50 healthy controls, both parameters being worse in erosive esophagitis compared with nonerosive reflux disease and healthy controls. Performance characteristics of both these parameters were overall higher than that of increased acid exposure time, total reflux events, and bolus exposure time in predicting both erosive esophagitis and non-erosive reflux disease (NERD). Frazzoni et al report a modest correlation between these 2 parameters (Pearson r ¼ 0.657; P < .001). Finally, the diagnostic gain over conventional impedance parameters was substantial, especially within the NERD categories.13 There are several additional points worth mentioning. First, the interest in bolus exposure time as an impedancebased reflux parameter is dampened further by this study’s findings. Bolus exposure time has not lived up to the performance of acid exposure time, and does not add much value in reflux assessment.4 Furthermore, the Clinical Gastroenterology and Hepatology 2015;-:-–-
2
C. Prakash Gyawali
number of reflux events, although needed for the PSPW index calculation, did not perform well in any disease category other than erosive esophagitis. The PSPW index and MNBI, on the other hand, had higher sensitivity and, with the former, better accuracy than abnormal acid exposure time in predicting erosive esophagitis. Within NERD categories, performance characteristics remained impressive in pH-positive NERD, but not as much in the remainder of the NERD categories. This adds further credence to the notion that true NERD is best identified with abnormal pH parameters; indeed, in the setting of abnormal pH, NERD outcomes mirror that seen with erosive esophagitis.16 It generally is accepted that negative pH parameters with or without symptom reflux association potentially represent functional hypersensitivity to mechanical or chemical aspects of reflux (reflux hypersensitivity) or to physiologic events (functional heartburn). In contradiction to this dogma, Frazzoni et al13 suggested that true reflux disease may overlap with these 2 latter categories despite normal pHimpedance data off antisecretory therapy, on the basis of the 2 new indices alone in some instances—a stand that may not be firm yet without further outcome data. Management outcomes in these difficult and refractory settings will define the true value of MNBI and PSPW index, not in erosive esophagitis or NERD with abnormal pHimpedance parameters where existing metrics are adequate for directing therapy. As with existing studies on pH-impedance parameters, there were limitations. The report was a crosssectional study describing proportions of patients with an abnormal MNBI and PSPW index among categories of GERD patients, using these proportions to project diagnostic yield. The true value of these parameters will be assessed when outcome data are collected prospectively, comparing those with and without an abnormal MNBI and PSPW index. Although Frazzoni et al13 reported high interobserver agreement for both indices, the PSPW calculation involves a manual review of the entire pHimpedance study, which is no simple task. The MNBI also requires manual calculation after identification of appropriate quiet periods, and is likely to be impacted by esophageal motor disorders associated with hypomotility and esophageal dilation, where the impedance rings may not be in firm contact with esophageal mucosa. Finally, the new kid on the block, endoscopic mucosal impedance measurement, is threatening to limit the need for ambulatory pH impedance monitoring in the very situations in which these new metrics have potential (ie, in assessing the likelihood of reflux-induced symptoms in refractory symptomatic states).17 Nevertheless, the MNBI and PSPW index make pathophysiologic sense, and certainly deserve a chance in redeeming the clinical value of ambulatory pHimpedance testing. Further research certainly is needed to determine if a normal MNBI and PSPW index in the setting of normal pH and normal conventional impedance parameters would be the benchmark for diagnosis
Clinical Gastroenterology and Hepatology Vol.
-,
No.
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of functional esophageal symptoms. Other confounders in the assessment of these parameters need to be evaluated, for instance, the contribution of abnormal motor function or esophageal dilation. Finally, software tools need to be developed by companies marketing pHimpedance to simplify the calculation of these parameters because both the MNBI and PSPW index need to be studied rigorously and potentially adapted for clinical use in the short term. C. PRAKASH GYAWALI, MD, MRCP Division of Gastroenterology Washington University School of Medicine St. Louis, Missouri
References 1. Sifrim D, Castell D, Dent J, et al. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004; 53:1024–1031. 2. Bredenoord AJ. Impedance-pH monitoring: new standard for measuring gastro-oesophageal reflux. Neurogastroenterol Motil 2008;20:434–439. 3. Vela MF, Camacho-Lobato L, Srinivasan R, et al. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology 2001;120:1599–1606. 4. Patel A, Sayuk GS, Gyawali CP. Parameters on esophageal pHimpedance monitoring that predict outcomes of patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2015;13:884–891. 5. Loots CM, van Wijk MP, Blondeau K, et al. Interobserver and intraobserver variability in pH-impedance analysis between 10 experts and automated analysis. J Pediatr 2012;160:441–446 e1. 6. Ravi K, DeVault KR, Murray JA, et al. Inter-observer agreement for multichannel intraluminal impedance-pH testing. Dis Esophagus 2010;23:540–544. 7. Zerbib F, Roman S, Bruley Des Varannes S, et al. Normal values of pharyngeal and esophageal 24-hour pH impedance in individuals on and off therapy and interobserver reproducibility. Clin Gastroenterol Hepatol 2013;11:366–372. 8. Penagini R, Sweis R, Mauro A, et al. Inconsistency in the diagnosis of functional heartburn: usefulness of prolonged wireless pH monitoring in patients with proton pump inhibitor refractory gastroesophageal reflux disease. J Neurogastroenterol Motil 2015;21:265–272. 9. Zerbib F, Belhocine K, Simon M, et al. Clinical, but not oesophageal pH-impedance, profiles predict response to proton pump inhibitors in gastro-oesophageal reflux disease. Gut 2012; 61:501–506. 10. Slaughter JC, Goutte M, Rymer JA, et al. Caution about overinterpretation of symptom indexes in reflux monitoring for refractory gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2011;9:868–874. 11. Farre R, Blondeau K, Clement D, et al. Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut 2011;60:885–892. 12. Heard R, Castell J, Castell DO, et al. Characterization of patients with low baseline impedance on multichannel intraluminal impedance-pH reflux testing. J Clin Gastroenterol 2012; 46:e55–e57.
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2015
13. Frazzoni M, Savarino E, de Bortoli N, et al. Analyses of the postreflux swallow-induced peristaltic wave index and nocturnal baseline impedance parameters increase the diagnostic yield of patients with reflux disease. Clin Gastroenterol Hepatol 2015: Epub ahead of print. 14. Frazzoni M, Bertani H, Manta R, et al. Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis. Dig Liver Dis 2014;46:596–602. 15. Shaker A, Stoikes N, Drapekin J, et al. Multiple rapid swallow responses during esophageal high-resolution manometry reflect esophageal body peristaltic reserve. Am J Gastroenterol 2013; 108:1706–1712.
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16. Weijenborg PW, Cremonini F, Smout AJ, et al. PPI therapy is equally effective in well-defined non-erosive reflux disease and in reflux esophagitis: a meta-analysis. Neurogastroenterol Motil 2012;24:747–757, e350. 17. Ates F, Vaezi MF. New approaches to management of PPIrefractory gastroesophageal reflux disease. Curr Treat Options Gastroenterol 2014;12:18–33.
Conflicts of interest The author discloses no conflicts. http://dx.doi.org/10.1016/j.cgh.2015.08.030