- Email: [email protected]
Reflux Monitoring: Role of Combined Multichannel Intraluminal Impedance and pH
Gastrointest Endoscopy Clin N Am 15 (2005) 361 – 371
Ref lux Monitoring: Role of Combined Multichannel Intraluminal Impedance and pH Radu Tutuian, MD*, Donald O. Castell, MD Division of Gastroenterology/Hepatology, Medical University of South Carolina, 96 Jonathan Lucas Street, 210 CSB, Charleston, SC 29425, USA
Combined multichannel intraluminal impedance and pH (MII-pH) is a recently Food and Drug Administration–approved technique for gastroesophageal reflux (GER) monitoring. Combined MII-pH represents a shift in the refluxtesting paradigm because reflux episodes are identified by the ability of MII to detect bolus volume presence and direction of bolus movement in the esophagus. Data from the pH sensor are used to characterize the chemical composition of reflux episodes and classify them as acid or nonacid based on predefined criteria.
Comparison of multichannel intraluminal impedance and pH with conventional pH monitoring Currently available systems using combined MII-pH employ impedance rings mounted on pH catheters (Sandhill Scientific, Highlands Ranch, Colorado). The dimensions of combined MII-pH catheters are similar to those of traditional pH catheters (2.1 mm diameter) and, therefore, do not change patient comfort compared with traditional pH testing. Depending on the clinical scenario, different types of MII-pH catheters should be used (Fig. 1). When placed in the esophagus, the 6MII-1pH catheter allows collecting impedance data at 3, 5, 7 and 9 cm above the lower esophageal sphincter (LES) in the distal esophagus and at 15 and 17 cm above the LES in the proximal esophagus and allows collecting pH data at 5 cm above the LES. This design can be modified to include a second pH sensor located in the stomach, 10 cm below the LES for concomitant assess-
* Corresponding author. E-mail address: [email protected] (R. Tutuian). 1052-5157/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.giec.2004.10.002 giendo.theclinics.com
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castell
Fig. 1. Placement of various combined MII-pH catheters. (A) ‘‘Classic’’ 6MII-1pH probe placed relative to LES. (B) 6MII-2pH (esophageal and gastric pH) probe placement relative to LES. (C) Bifurcated 4MII-1pH + 2MII-1pH probe placement relative to LES and upper esophageal sphincter (UES).
reflux monitoring: mii-ph
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Fig. 1 (continued).
ment of intragastric acid control on therapy. A bifurcated adjustable catheter (4MII-1pH + 2MII-1pH) may be preferred to evaluate patients with suspected laryngopharyngeal reflux because it allows the detection of bolus presence in the distal esophagus (3, 5, 7, and 9 cm above the LES) and around (2 cm above and 5 cm below) the upper esophageal sphincter and allows the collection of pH data from the distal esophagus (5 cm above the LES) and hypopharynx (2 cm above the LES). This bifurcated design is necessary for accurate placement in reference to the upper esophageal sphincter and the LES, given intersubject variation of esophageal lengths. After the catheter is placed in the esophagus, patients are instructed to have a normal day and provided a diary to record the time and content of meals, time of upright and recumbent periods, time of administration of acid-suppressive medication, and time of symptoms. The authors encourage patients to induce as many symptoms as they can by either ingesting foods or doing activities known to produce symptoms. The following day, the patient returns the logger and the diary, and data are downloaded for analysis using dedicated software (Sleuth, Sandhill Scientific). Data analysis is performed using dedicated software (BioView GER Analysis, Sandhill Scientific). Normal values for combined MII-pH testing off therapy have been established by a multicenter collaborative study in 60 healthy adult volunteers [1]. This study found that in normal volunteers, off-therapy GER is primarily acidic, with nonacid reflux episodes primarily clustered in the postprandial periods and only minor amounts and number of nonacid reflux episodes occurring at nighttime in the recumbent position. Furthermore, 37% of distal (5 cm above LES) acid or nonacid reflux episodes reach the proximal (15 cm above LES) esophagus in normal volunteers. In the same study, it was also observed that acid clearance
364
tutuian
&
castell
reflux monitoring: mii-ph
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Fig. 2. Various types of reflux episodes detected by MII-pH: acid reflux (A) nonacid reflux (B) minor acid reflux (C) acid re-reflux (D) is another type of acid reflux that occurs while intraesophageal pH is below 4.0, and the pH may go further below 4.0.
366
tutuian
&
castell
(pH) time is different than acid bolus (MII) clearance time, suggesting that neutralizing acid pH in the esophagus depends on mechanisms (ie, swallowing of saliva, mucosal characteristics, and so forth) other than only refluxate appearance and disappearance from the esophageal lumen. The difference in volume and pH clearance from the esophagus detected by combined MII-pH studies confirms data published by Helm et al [2] indicating that the scintigraphic activity of radiolabeled hydrochloric acid clears faster than the pH recovery time.
Characterization of gastroesophageal reflux by multichannel intraluminal impedance and pH With the addition of MII to pH monitoring have come new nomenclatures and classifications of GER episodes. Combined MII-pH classifies GER by (1) its content of liquid, gas, and mixed reflux events, and (2) its pH characteristics, traditionally separated into acid, nonacid, minor acid, and acid re-reflux. Using multiple impedance measuring sites, MII can also identify the height of the refluxate (ie, most proximal impedance channel in which GER impedance changes are noted). An acid GER event is an MII-detected reflux event in which a drop of pH from above 4.0 to below 4.0 is noted Fig. 2A. Nonacid reflux is an MII-detected event during which the pH stays above 4.0 and does not drop more than 1 pH unit Fig. 2B. Minor acid reflux is an MII-detected reflux event during which pH stays above 4.0 but the pH drops more than 1 unit Fig. 2C. An acid re-reflux event is another type of acid reflux that occurs while intraesophageal pH is already below 4.0. It is detected by MII, and the pH may or may not go further below 4.0 (Fig. 2D). A panel of esophageal experts recently reviewed the most current technologies to monitor GER and proposed a revised classification of GER episodes as detected by MII-pH [3]. The definition of acid GER is unchanged and refers to MII-detected reflux episodes with a concomitant drop in pH from above 4 to below 4. Arguing that any solution with a pH less than 4 contains an increased concentration of H+ ions and, from a chemist’s perspective, should be considered acidic, the panel decided to classify MII-detected GER episodes with a nadir pH between 4 and 7 as ‘‘weakly acidic.’’ MII-detected reflux episodes without a pH drop below 7 are considered nonacidic and MII-detected reflux episodes during a time when the pH is below 4.0 (ie, former acid re-reflux) are renamed ‘‘superimposed acid reflux.’’ Throughout this manuscript and until these proposed revisions become widely accepted, the authors will continue to use the traditional classification of MII-pH episodes (acid, nonacid, and acid re-reflux).
Clinical importance of nonacid reflux The ability of combined MII-pH to detect and characterize GER by the presence of liquid in the esophagus represents an important advance for clinical
reflux monitoring: mii-ph
367
testing of nonacid reflux [4]. Compared with bilirubin monitoring (Bilitec) [5], combined MII-pH is not dependent on presence of bilirubin in the refluxate and does not require a special liquid diet. In addition, Sifrim et al [6] reported that only 10% of nonacid reflux episodes are detected by bilirubin monitoring. Detection of GER by MII-pH is not affected by gastric emptying time of an ingested material and allows sampling at frequencies higher than every second, which are limitations of scintigraphic methods [7]. Overall, MII-pH reflux monitoring can be performed with ambulatory systems and does not require stationary/ supine postures (a limitation of manometric measurements detecting common cavities) [8]. Data on healing of erosive esophagitis with potent acid-suppressive therapy suggest that nonacid reflux may have a limited role in development of erosive lesions within the esophagus; however, it is likely to be clinically important in patients with early postprandial symptoms, in patients with persistent symptoms on acid-suppressive therapy, in patients with atypical (supraesophageal) symptoms, and in infants. Studying the effects of omeprazole on 2-hour postprandial GER, Vela et al [9] found that although the proton pump inhibitor (PPI) dramatically reduced the number of acid GER episodes, the total number of MII-detected GER events did not change but became predominantly nonacid. This observation underscores the effect of acid-suppressive therapy to shift the balance of acid versus nonacid reflux events without influencing the total number of GER events in the postprandial individual (Fig. 3A). Studying the effects of baclofen, a GABA antagonist that decreases the frequency of transient LES relaxations, Vela et al [10] found that this medication reduced the number of all GER episodes (acid and nonacid) in a 2-hour postprandial period. These studies suggest that combined MII-pH should be the preferred test to document reduction of GER (Fig. 3B). Data from large groups of patients treated with acid-suppressive therapy suggest that complete symptom relief during PPI treatment is less likely than might be anticipated. A study by Castell et al [11] found that despite N80% healing rates of erosive esophagitis with daily esomeprazole, 30% to 40% of patients were still symptomatic after 4 weeks of daily PPI [11]. Because the study focused primarily on esophageal healing rates, it is unclear whether these residual symptoms were due to persistent acid reflux, nonacid reflux, or no GER. Combined MII-pH studies, however, can help clinicians to clarify this. Preliminary data from a multicenter collaborative study suggest that only approximately 20% of patients with persistent symptoms on acid-suppressive therapy have symptoms related to continuing acid reflux [12]. The other 80% usually present a diagnostic dilemma as to whether their symptoms are associated with nonacid reflux or not associated with any type of GER. Combined MII-pH further clarifies this possible association, including recognition that approximately 40% of patients with persistent symptoms on therapy show no temporal correlation between their symptoms and any type of reflux. Therefore, the authors believe that combined MII-pH should be considered a key step in diagnostic approach to patients not responding to PPI therapy.
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Fig. 3. Effects of omeprazole (A) and baclofen (B) on postprandial reflux. Omeprazole shifts the balance of acid versus nonacid reflux events without influencing the total number of GER events, whereas baclofen reduces the number of acid GERs, the number of nonacid GERs, and the total number of GER events. NS, not significant. (Data from Vela MF, Camacho-Lobato L, Srinivasan R, et al. Intraesophageal impedance and pH measurement of acid and nonacid reflux: effect of omeprazole. Gastroenterology 2001;120:1599–606; and Vela M, Tutuian R, Katz P, et al. Baclofen reduces acid and nonacid postprandial gastroesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther 2003;17:243–51.)
Even though intraesophageal pH monitoring is considered the ‘‘gold standard’’ for diagnosis of GER disease (GERD) [13] and currently is the most accepted method of documenting laryngopharyngeal reflux [14], recent studies have challenged its sensitivity and specificity. Whereas in normal volunteers, GER episodes rarely reach the hypopharynx [15], patients with laryngopharyngeal reflux may or may not exhibit abnormal hypopharyngeal pH studies [16]. Recently, Kawamura et al [17] reported on a comparison of GER patterns in
reflux monitoring: mii-ph
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10 healthy volunteers, 10 patients with GERD, and 10 patients suspected of having reflux-attributed laryngitis. Using a bifurcated MII-pH reflux catheter, the investigators found that gas reflux with weak acidity appeared to be more common in patients with reflux-attributed laryngitis compared with healthy controls and patients with GERD. Of note, these patterns of GER are recognized only by combined MII-pH and would probably have been missed by conventional pH testing. The interest for nonacid GER testing in infants is sustained by the fact that the acid output is decreased compared with adults and the feeding patterns (drinking milk or formula every 2–3 hours) maintain long periods of time with the stomach full and with buffering of intragastric acid concentrations [18]. Skopnik et al [19] were the first to report using MII-pH to detect acid and nonacid reflux in the postprandial period in 17 infants with GERD. These investigators reported detection of a large number of nonacid reflux episodes that would otherwise be undetectable by conventional pH testing. Further reports in the pediatric literature have described the use of MII-pH to study the relationship between reflux (acid and nonacid) and apnea in infants and premature babies [20].
Revised approach to diagnosis of gastroesophageal reflux disease Current recommendations for GERD testing suggest an initial empiric trial of PPIs in patients with symptoms suggestive of GERD [21]. If patients respond to this trial, then the diagnosis is established and continuation of acid-suppressive therapy is recommended. Before MII-pH became available, patients not responding to the PPI trial would often undergo ambulatory pH testing while continuing therapy or after at least a 7-day ‘‘wash-out’’ period to evaluate whether their symptoms were associated with GER. This approach left the question of possible nonacid GER symptoms unresolved. Because combined MII-pH can
Fig. 4. Proposed GERD diagnostic algorithm. Rx, therapy; Dx, diagnosis.
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tutuian
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identify acid and nonacid GER, the authors propose using MII-pH testing on therapy at this point in the GERD diagnostic algorithm (Fig. 4). Combined MII-pH (using esophageal and gastric pH) identifies persistent symptoms associated with acid GER (suggesting inadequate acid control), symptoms associated with nonacid GER (suggesting the need for surgical, endoscopic, or medical strengthening of the gastroesophageal barrier), or symptoms not associated with any type of reflux (suggesting that the patient’s symptoms have a nonreflux etiology).
References [1] Shay SS, Tutuian R, Sifrim D, et al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol 2004;99:1037 – 43. [2] Helm JF, Dodds WJ, Pelc LR, et al. Effect of esophageal emptying and saliva on clearance of acid from the esophagus. N Engl J Med 1983;310:284 – 8. [3] Sifrim D, Castell DO, Dent J, et al. Gastroesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid and gas reflux. Gut 2004;53:1024 – 31. [4] Shay SS, Bomeli S, Richter J. Multichannel intraluminal impedance accurately detects fasting, recumbent reflux events and their clearing. Am J Physiol Gastrointest Liver Physiol 2002; 283:G376 – 83. [5] Stein HJ, Kauer WKH, Feussner H, et al. Bile acids as components of the duodenogastric refluxate: detection, relationship to bilirubin, mechanism of injury, and clinical relevance. Hepatogastroenterology 1999;46:66 – 73. [6] Sifrim D, Holloway RH, Silny J, et al. Non-acid gastroesophageal reflux. Gastroenterology 2001;120:A436. [7] Velasco N, Pope CE, Gannan RM, et al. Measurement of esophageal reflux by scintigraphy. Dig Dis Sci 1984;29:977 – 82. [8] Shay SS, Egli D, Johnson LF. Simultaneous esophageal pH monitoring and scintigraphy during the postprandial period in patients with severe reflux esophagitis. Dig Dis Sci 1991;36:558 – 64. [9] Vela MF, Camacho-Lobato L, Srinivasan R, et al. Intraesophageal impedance and pH measurement of acid and nonacid reflux: effect of omeprazole. Gastroenterology 2001;120:1599 – 606. [10] Vela M, Tutuian R, Katz P, et al. Baclofen reduces acid and nonacid postprandial gastroesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther 2003;17:243 – 51. [11] Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol 2002;97:575 – 83. [12] Shay SS, Tutuian R, Sifrim D, et al. Twenty-four hour impedance and pH monitoring (24-hr Imp-pH) in the evaluation of GERD patients with persistent symptoms despite bid proton pump inhibitors (PPI): a multicenter study. Gastroenterology 2004;126(Suppl 2):A324. [13] Bardan E. Pharyngoesophageal pH monitoring. Am J Med 2003;115(Suppl 3A):78S – 80S. [14] Koufman JA, Wiener GJ, Wallace CW, et al. Reflux laryngitis and its sequelae. J Voice 1988; 2:78 – 9. [15] Moldanado A, Diederich L, Castell DO. Simultaneous intraesophageal and hypopharyngeal pH monitoring in normal volunteers. Laryngoscope 2003;113:349 – 55. [16] Vaezi MF, Schroeder PL, Richter JE. Reproducibility of proximal probe pH parameters in 24-hour ambulatory esophageal pH monitoring. Am J Gastroenterol 1997;92:825 – 9. [17] Kawamura O, Aslam M, Rittman T, et al. Physical and pH properties of gastroesophagopharyngeal refluxate: a 24-hour simultaneous ambulatory impedance and pH monitoring study. Am J Gastroenterol 2004;99:1000 – 10.
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[18] Newman LJ, Russe J, Glassman MS, et al. Patterns of gastroesophageal reflux (GER) in patients with apparent life-threatening events. J Pediatr Gastroenterol Nutr 1989;8:157 – 60. [19] Skopnik H, Silny J, Heiber O, et al. Gastroesophageal reflux in infants: evaluation of a new intraluminal technique. J Pediatr Gastroenterol Nutr 1996;22:591 – 8. [20] Wenzl TG, Schenke S, Peschgens T, et al. Association of apnea and nonacid gastroesophageal reflux in infants: investigations with the intraluminal impedance technique. Pediatr Pulmonol 2001;31:144 – 9. [21] Fass R, Ofman JJ, Gralnek IM, et al. Clinical and economic assessment of the omeprazole test in patients with symptoms suggestive of gastroesophageal reflux disease. Arch Intern Med 1999; 159:2161 – 8.
Ref lux Monitoring: Role of Combined Multichannel Intraluminal Impedance and pH Radu Tutuian, MD*, Donald O. Castell, MD Division of Gastroenterology/Hepatology, Medical University of South Carolina, 96 Jonathan Lucas Street, 210 CSB, Charleston, SC 29425, USA
Combined multichannel intraluminal impedance and pH (MII-pH) is a recently Food and Drug Administration–approved technique for gastroesophageal reflux (GER) monitoring. Combined MII-pH represents a shift in the refluxtesting paradigm because reflux episodes are identified by the ability of MII to detect bolus volume presence and direction of bolus movement in the esophagus. Data from the pH sensor are used to characterize the chemical composition of reflux episodes and classify them as acid or nonacid based on predefined criteria.
Comparison of multichannel intraluminal impedance and pH with conventional pH monitoring Currently available systems using combined MII-pH employ impedance rings mounted on pH catheters (Sandhill Scientific, Highlands Ranch, Colorado). The dimensions of combined MII-pH catheters are similar to those of traditional pH catheters (2.1 mm diameter) and, therefore, do not change patient comfort compared with traditional pH testing. Depending on the clinical scenario, different types of MII-pH catheters should be used (Fig. 1). When placed in the esophagus, the 6MII-1pH catheter allows collecting impedance data at 3, 5, 7 and 9 cm above the lower esophageal sphincter (LES) in the distal esophagus and at 15 and 17 cm above the LES in the proximal esophagus and allows collecting pH data at 5 cm above the LES. This design can be modified to include a second pH sensor located in the stomach, 10 cm below the LES for concomitant assess-
* Corresponding author. E-mail address: [email protected] (R. Tutuian). 1052-5157/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.giec.2004.10.002 giendo.theclinics.com
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tutuian
&
castell
Fig. 1. Placement of various combined MII-pH catheters. (A) ‘‘Classic’’ 6MII-1pH probe placed relative to LES. (B) 6MII-2pH (esophageal and gastric pH) probe placement relative to LES. (C) Bifurcated 4MII-1pH + 2MII-1pH probe placement relative to LES and upper esophageal sphincter (UES).
reflux monitoring: mii-ph
363
Fig. 1 (continued).
ment of intragastric acid control on therapy. A bifurcated adjustable catheter (4MII-1pH + 2MII-1pH) may be preferred to evaluate patients with suspected laryngopharyngeal reflux because it allows the detection of bolus presence in the distal esophagus (3, 5, 7, and 9 cm above the LES) and around (2 cm above and 5 cm below) the upper esophageal sphincter and allows the collection of pH data from the distal esophagus (5 cm above the LES) and hypopharynx (2 cm above the LES). This bifurcated design is necessary for accurate placement in reference to the upper esophageal sphincter and the LES, given intersubject variation of esophageal lengths. After the catheter is placed in the esophagus, patients are instructed to have a normal day and provided a diary to record the time and content of meals, time of upright and recumbent periods, time of administration of acid-suppressive medication, and time of symptoms. The authors encourage patients to induce as many symptoms as they can by either ingesting foods or doing activities known to produce symptoms. The following day, the patient returns the logger and the diary, and data are downloaded for analysis using dedicated software (Sleuth, Sandhill Scientific). Data analysis is performed using dedicated software (BioView GER Analysis, Sandhill Scientific). Normal values for combined MII-pH testing off therapy have been established by a multicenter collaborative study in 60 healthy adult volunteers [1]. This study found that in normal volunteers, off-therapy GER is primarily acidic, with nonacid reflux episodes primarily clustered in the postprandial periods and only minor amounts and number of nonacid reflux episodes occurring at nighttime in the recumbent position. Furthermore, 37% of distal (5 cm above LES) acid or nonacid reflux episodes reach the proximal (15 cm above LES) esophagus in normal volunteers. In the same study, it was also observed that acid clearance
364
tutuian
&
castell
reflux monitoring: mii-ph
365
Fig. 2. Various types of reflux episodes detected by MII-pH: acid reflux (A) nonacid reflux (B) minor acid reflux (C) acid re-reflux (D) is another type of acid reflux that occurs while intraesophageal pH is below 4.0, and the pH may go further below 4.0.
366
tutuian
&
castell
(pH) time is different than acid bolus (MII) clearance time, suggesting that neutralizing acid pH in the esophagus depends on mechanisms (ie, swallowing of saliva, mucosal characteristics, and so forth) other than only refluxate appearance and disappearance from the esophageal lumen. The difference in volume and pH clearance from the esophagus detected by combined MII-pH studies confirms data published by Helm et al [2] indicating that the scintigraphic activity of radiolabeled hydrochloric acid clears faster than the pH recovery time.
Characterization of gastroesophageal reflux by multichannel intraluminal impedance and pH With the addition of MII to pH monitoring have come new nomenclatures and classifications of GER episodes. Combined MII-pH classifies GER by (1) its content of liquid, gas, and mixed reflux events, and (2) its pH characteristics, traditionally separated into acid, nonacid, minor acid, and acid re-reflux. Using multiple impedance measuring sites, MII can also identify the height of the refluxate (ie, most proximal impedance channel in which GER impedance changes are noted). An acid GER event is an MII-detected reflux event in which a drop of pH from above 4.0 to below 4.0 is noted Fig. 2A. Nonacid reflux is an MII-detected event during which the pH stays above 4.0 and does not drop more than 1 pH unit Fig. 2B. Minor acid reflux is an MII-detected reflux event during which pH stays above 4.0 but the pH drops more than 1 unit Fig. 2C. An acid re-reflux event is another type of acid reflux that occurs while intraesophageal pH is already below 4.0. It is detected by MII, and the pH may or may not go further below 4.0 (Fig. 2D). A panel of esophageal experts recently reviewed the most current technologies to monitor GER and proposed a revised classification of GER episodes as detected by MII-pH [3]. The definition of acid GER is unchanged and refers to MII-detected reflux episodes with a concomitant drop in pH from above 4 to below 4. Arguing that any solution with a pH less than 4 contains an increased concentration of H+ ions and, from a chemist’s perspective, should be considered acidic, the panel decided to classify MII-detected GER episodes with a nadir pH between 4 and 7 as ‘‘weakly acidic.’’ MII-detected reflux episodes without a pH drop below 7 are considered nonacidic and MII-detected reflux episodes during a time when the pH is below 4.0 (ie, former acid re-reflux) are renamed ‘‘superimposed acid reflux.’’ Throughout this manuscript and until these proposed revisions become widely accepted, the authors will continue to use the traditional classification of MII-pH episodes (acid, nonacid, and acid re-reflux).
Clinical importance of nonacid reflux The ability of combined MII-pH to detect and characterize GER by the presence of liquid in the esophagus represents an important advance for clinical
reflux monitoring: mii-ph
367
testing of nonacid reflux [4]. Compared with bilirubin monitoring (Bilitec) [5], combined MII-pH is not dependent on presence of bilirubin in the refluxate and does not require a special liquid diet. In addition, Sifrim et al [6] reported that only 10% of nonacid reflux episodes are detected by bilirubin monitoring. Detection of GER by MII-pH is not affected by gastric emptying time of an ingested material and allows sampling at frequencies higher than every second, which are limitations of scintigraphic methods [7]. Overall, MII-pH reflux monitoring can be performed with ambulatory systems and does not require stationary/ supine postures (a limitation of manometric measurements detecting common cavities) [8]. Data on healing of erosive esophagitis with potent acid-suppressive therapy suggest that nonacid reflux may have a limited role in development of erosive lesions within the esophagus; however, it is likely to be clinically important in patients with early postprandial symptoms, in patients with persistent symptoms on acid-suppressive therapy, in patients with atypical (supraesophageal) symptoms, and in infants. Studying the effects of omeprazole on 2-hour postprandial GER, Vela et al [9] found that although the proton pump inhibitor (PPI) dramatically reduced the number of acid GER episodes, the total number of MII-detected GER events did not change but became predominantly nonacid. This observation underscores the effect of acid-suppressive therapy to shift the balance of acid versus nonacid reflux events without influencing the total number of GER events in the postprandial individual (Fig. 3A). Studying the effects of baclofen, a GABA antagonist that decreases the frequency of transient LES relaxations, Vela et al [10] found that this medication reduced the number of all GER episodes (acid and nonacid) in a 2-hour postprandial period. These studies suggest that combined MII-pH should be the preferred test to document reduction of GER (Fig. 3B). Data from large groups of patients treated with acid-suppressive therapy suggest that complete symptom relief during PPI treatment is less likely than might be anticipated. A study by Castell et al [11] found that despite N80% healing rates of erosive esophagitis with daily esomeprazole, 30% to 40% of patients were still symptomatic after 4 weeks of daily PPI [11]. Because the study focused primarily on esophageal healing rates, it is unclear whether these residual symptoms were due to persistent acid reflux, nonacid reflux, or no GER. Combined MII-pH studies, however, can help clinicians to clarify this. Preliminary data from a multicenter collaborative study suggest that only approximately 20% of patients with persistent symptoms on acid-suppressive therapy have symptoms related to continuing acid reflux [12]. The other 80% usually present a diagnostic dilemma as to whether their symptoms are associated with nonacid reflux or not associated with any type of GER. Combined MII-pH further clarifies this possible association, including recognition that approximately 40% of patients with persistent symptoms on therapy show no temporal correlation between their symptoms and any type of reflux. Therefore, the authors believe that combined MII-pH should be considered a key step in diagnostic approach to patients not responding to PPI therapy.
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tutuian
&
castell
Fig. 3. Effects of omeprazole (A) and baclofen (B) on postprandial reflux. Omeprazole shifts the balance of acid versus nonacid reflux events without influencing the total number of GER events, whereas baclofen reduces the number of acid GERs, the number of nonacid GERs, and the total number of GER events. NS, not significant. (Data from Vela MF, Camacho-Lobato L, Srinivasan R, et al. Intraesophageal impedance and pH measurement of acid and nonacid reflux: effect of omeprazole. Gastroenterology 2001;120:1599–606; and Vela M, Tutuian R, Katz P, et al. Baclofen reduces acid and nonacid postprandial gastroesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther 2003;17:243–51.)
Even though intraesophageal pH monitoring is considered the ‘‘gold standard’’ for diagnosis of GER disease (GERD) [13] and currently is the most accepted method of documenting laryngopharyngeal reflux [14], recent studies have challenged its sensitivity and specificity. Whereas in normal volunteers, GER episodes rarely reach the hypopharynx [15], patients with laryngopharyngeal reflux may or may not exhibit abnormal hypopharyngeal pH studies [16]. Recently, Kawamura et al [17] reported on a comparison of GER patterns in
reflux monitoring: mii-ph
369
10 healthy volunteers, 10 patients with GERD, and 10 patients suspected of having reflux-attributed laryngitis. Using a bifurcated MII-pH reflux catheter, the investigators found that gas reflux with weak acidity appeared to be more common in patients with reflux-attributed laryngitis compared with healthy controls and patients with GERD. Of note, these patterns of GER are recognized only by combined MII-pH and would probably have been missed by conventional pH testing. The interest for nonacid GER testing in infants is sustained by the fact that the acid output is decreased compared with adults and the feeding patterns (drinking milk or formula every 2–3 hours) maintain long periods of time with the stomach full and with buffering of intragastric acid concentrations [18]. Skopnik et al [19] were the first to report using MII-pH to detect acid and nonacid reflux in the postprandial period in 17 infants with GERD. These investigators reported detection of a large number of nonacid reflux episodes that would otherwise be undetectable by conventional pH testing. Further reports in the pediatric literature have described the use of MII-pH to study the relationship between reflux (acid and nonacid) and apnea in infants and premature babies [20].
Revised approach to diagnosis of gastroesophageal reflux disease Current recommendations for GERD testing suggest an initial empiric trial of PPIs in patients with symptoms suggestive of GERD [21]. If patients respond to this trial, then the diagnosis is established and continuation of acid-suppressive therapy is recommended. Before MII-pH became available, patients not responding to the PPI trial would often undergo ambulatory pH testing while continuing therapy or after at least a 7-day ‘‘wash-out’’ period to evaluate whether their symptoms were associated with GER. This approach left the question of possible nonacid GER symptoms unresolved. Because combined MII-pH can
Fig. 4. Proposed GERD diagnostic algorithm. Rx, therapy; Dx, diagnosis.
370
tutuian
&
castell
identify acid and nonacid GER, the authors propose using MII-pH testing on therapy at this point in the GERD diagnostic algorithm (Fig. 4). Combined MII-pH (using esophageal and gastric pH) identifies persistent symptoms associated with acid GER (suggesting inadequate acid control), symptoms associated with nonacid GER (suggesting the need for surgical, endoscopic, or medical strengthening of the gastroesophageal barrier), or symptoms not associated with any type of reflux (suggesting that the patient’s symptoms have a nonreflux etiology).
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