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T1907 A Novel Distensibility Technique for Measuring Upper Esophageal Function-Pilot Data
AGA Abstracts
apnea or sleep disturbances were excluded. All subjects underwent an upper endoscopy to exclude silent erosive esophagitis. Subsequently subjects were randomized to either sleep deprivation protocol (4 hours of sleep on 2 consecutive nights) or good sleep protocol (at least 7 hours of sleep on 2 consecutive nights). Subjects crossed over to the other arm after 1 week. Subjects wore an actigraph to ensure compliance with sleep time. Immediately after the sleep deprivation or good sleep protocol, subjects underwent pH testing. The Sleep Quality Questionnaire on the morning of the pH test further ensured compliance with the sleep protocols. Results: Eleven subjects (M/F 5/6, mean age 40.7 yrs) were enrolled into the study. Mean % total time pH<4 was significantly higher after bad sleep as compared to good sleep (5.6 vs. 2.3, P<0.05). Mean % upright and recumbent time pH<4 were also higher after bad sleep as compared to good sleep (4.6 vs. 1.9 and 5.5 vs. 2.6, respectively, P<0.05). Five (45.5%) of the normal subjects developed an abnormal pH test after sleep deprivation (>4.2%). All pH tests after good sleep were within the normal range. The change in esophageal acid exposure after sleep deprivation was similar in both recumbent and upright positions. Conclusions: This is the first study to demonstrate that sleep deprivation per se can precipitate acid reflux and even result in abnormal pH test in normal subjects. The study also suggests that sleep status may impact pH test results.
regurgitation (n=62) and heartburn (n=51). 53% of symptoms were associated with reflux events and 52% with low pH (74% and 84% for regurgitation; 33% and 39% for heartburn, respectively). 95% of symptomatic reflux events were caused by transient lower esophageal sphincter relaxation (TLESR) (98% regurgitation; 76% heartburn). Conversely, of 139 TLESRs, 83% were symptomatic (14% heartburn, 35% regurgitation, 25% belch). The results of Fisher's exact test of symptom association are shown in the Table. Conclusions: Closely monitored GERD patients can accurately perceive a much greater proportion of reflux events that suggested by ambulatory studies. The most common mechanism of symptomatic reflux events was TLESR with the most specific associated symptom being regurgitation. Even in a closely monitored setting, less than 40% of reported heartburn could be tightly linked to either a reflux event or low esophageal pH.
T1907 A Novel Distensibility Technique for Measuring Upper Esophageal FunctionPilot Data Julie Regan, Barry P. McMahon
T1909 A Double-Blind, Randomized, Placebo-Controlled, Single Dose, 3-Period Crossover Study of Agn 203818 in Subjects With Functional Heartburn Philip B. Miner, Rozalina Dimitrova, Wayne Lam, John E. Donello, Simon Daggett, Daniel W. Gil
Impaired opening of the upper esophageal sphincter (UES) prevents food and drinks from being transported safely and efficiently from the pharynx into the esophagus during swallowing, leading to serious respiratory and nutritional complications and to compromised quality of life. Management of impaired UES opening in people with neurogenic dysphagia consists of compensatory head postures, rehabilitative techniques (Mendelsohn manoeuvre and Shaker exercises), botulinum toxin A injections into the cricopharyngeus muscle and surgical interventions (upper esophageal dilatation and cricopharyngeal myotomy). Despite numerous management options, research indicates that current evaluation of UES opening is substandard. Videofluoroscopy is prone to poor inter-rater reliability and solid state pharyngeal manometry cannot quantify extent of UES opening. People with UES impairment are subsequently being misdiagnosed and mismanaged in the clinical setting. The Functional Lumen Imaging Probe (FLIP) is an objective evaluation tool based on the principles of impedance planimetry. The FLIP probe has been proven to accurately measure multiple cross-sectional areas in the lumen of the esophogastric junction, and has since been employed to evaluate lumens in numerous anatomical sites including the sphincter of Oddi and the ano-rectal region. Authors hypothesise that the FLIP probe can be adapted to evaluate UES function. The FLIP probe was adapted in its design and constructed to ensure safe and accurate measurement of the UES region. An initial pilot study was conducted under videofluoroscopy on a forty-three year old adult male with a history of lateral medullary stroke and mild to moderate dysphagia. The adapted FLIP probe was inserted transnasally and location of the balloon on the distal end of the probe was confirmed fluoroscopically to be in the UES region. Two ramp distensions (16ml, 18ml volumes) were carried out without any airway compromise. Eight diameter measurements were obtained at each volume and mean diameters calculated (Table 1). Additionally, narrowest diameter of the UES was obtained at baseline and during a head turn maneouvre (4.04mm at rest v 5.99mm on head turn) during an 8ml step distension (Table 1). This preliminary study indicates that an adapted FLIP probe can be positioned safely in the UES and can provide clinically useful information regarding UES function. Pilot Data
Functional heartburn is characterized by hypersensitivity of the esophagus to mechanical and/or chemical stimuli, without any apparent pathology. AGN 203818 is an alpha2-adrenergic agonist that reduces mechanical hypersensitivity in a rat model of chronic colonic hypersensitivity. The pharmacodynamic effect of AGN 203818 on the discomfort/pain threshold was investigated in a single dose exploratory study in patients with functional heartburn. Methods: A single-center, double-blind, randomized, placebo-controlled, single dose, 3period crossover study evaluated 2 different doses of AGN 203818 on discomfort/pain thresholds in patients with functional heartburn undergoing mechanical esophageal stimulation (volume-step and pressure-ramp balloon inflation) and chemical esophageal stimulation (Acid Perfusion Test). On each day of dosing patients received oral AGN 203818 (3 mg or 20 mg) or placebo. Patients underwent 2 balloon distention tests 60 minutes post-dose and acid perfusion 90 minutes post-dose. Safety parameters were collected throughout the study. For the volume-step balloon test stepwise increases of 5 mL per minute interval are used whereas for the pressure-ramp test gradual increases of 1 mmHg (with consequent increase in volume) are used. For the Acid Perfusion Test (APT) 0.1 N hydrochloric acid was infused at a rate of 10 mL/min. Results: One male and 17 female patients were randomized and all completed the study as planned with no serious adverse events reported. In the balloon tests, AGN 203818 20 mg and 3 mg resulted in higher volumes at discomfort/pain threshold compared to baseline and placebo treatment. The mean (standard deviation) volume to discomfort/pain threshold (mL) for pressure ramp were: Baseline 11.6 (4.8); Placebo 12.6 (9.6); 3 mg 14.3 (9.6); 20 mg 17.0 (9.2). AGN 203818 20 mg increased the pressure ramp threshold by 47% (p=0.057 vs. placebo). The mean (standard deviation) volume to discomfort/pain threshold (mL) for volume step were: Baseline 16.9 (4.6); Placebo 18.9 (9.4); 3 mg 23.1 (13.8); 20 mg 20.3 (8.8). The 3 mg dose was significantly (p=0.02) better than placebo on the volume-step, although the large increments (5 mL) used may have contributed to a smaller overall drug effect. No significant between treatment differences were noted on the APT. The mean (standard deviation) volume to discomfort/pain threshold (mL) for APT were: Baseline 38.9 (25); Placebo 63.3 (43.8); 3 mg 65.1 (53.8); 20 mg 54.1 (33.2). In concurrence with pre-clinical findings these results demonstrate that the alpha2adrenergic agonist AGN 203818 decreases mechanical hypersensitivity of the esophagus in patients with functional heartburn. T1910 Normalized High Resolution Esophageal Pressure Topography (HREPT) Data: Characterizing Peristalsis in Terms of Neuromuscular Physiology Peter J. Kahrilas, Zhiyue Lin, Monika A. Kwiatek, John E. Pandolfino
T1908 Reflux-Symptom Association and Determinants of Symptom Perception in an Investigator-Monitored Post-Prandial Study Utilizing High Resolution Impedance Manometry (Hrim) and pH Recording Anita Fareeduddin, Sabine Roman, John E. Pandolfino, Monika A. Kwiatek, Peter J. Kahrilas
BACKGROUND: Esophageal peristalsis is regionally modulated by muscle type, vagal control, and myenteric plexus innervation. The integrity of each of these can be inferred from HREPT studies by a combination of pattern recognition and computation. We hypothesized that by normalizing data among subjects in HREPT terms, peristalsis can be characterized by the integrity of physiological elements. AIM: To calculate normalized metrics for coordinatespecific (position and time) contraction, inhibition, and quiescence of peristalsis for HREPT studies. METHODS: HREPT studies of 20 normal subjects were analyzed. Data from 10 water swallows were exported from ManoView™ in ASCII format for use in MATLAB™, a computer program customized for processing binary data. Each swallow was analyzed as a 100x200 pixel grid extending from the distal pharynx to proximal stomach for a 20s period beginning 1s before UES relaxation. Each pixel thus had coordinates of 1-100th percentile of esophageal length and 0.0-20.0s in 0.1s time increments. A composite contraction was simulated for each subject based on the median pressure value within each pixel for the 10 test swallows. Similarly, deriving the 5th, 50th, and 95th percentile values for each pixel among the 20 composite simulations computed group normative values. RESULTS: Normalizing swallows for each subject filtered out pressure signals attributable to respiration, vascular structures, and the crural diaphragm as these were not consistently synchronized with UES relaxation and cancelled out with the series of swallows. 3 contractile segments (proximal, distal, and LES) and separating pressure troughs were defined in coordinates of percent length and delay from UES relaxation; S2 and S3 described by Clouse smoothly fused into a single segment as there was no consistency in this separation among subjects. A welldefined triangle of inhibition commenced at UES relaxation and progressively widened to 8s at the LES. Each percentile of esophageal length had unique quantitative and temporal
Backgrounds & Aims: According to Rome III, the significant association between symptoms and reflux events, irrespective of esophageal acid exposure, can diagnose symptomatic GERD. Current indices used to evaluate symptom association were derived from analyses of 24-h ambulatory esophageal pH monitoring. We hypothesized that investigator-monitored postprandial impedance-manometry in combination with esophageal pH monitoring could both reveal tighter reflux symptom association and improved our understanding of underlying mechanisms. Patients and methods: 7 GERD patients (1 male, mean age 39 years, range 22-66) underwent stationary HRIM combined with esophageal pH-impedance monitoring for 3 hrs after the patient consumed a refluxogenic meal. pH was monitored 5 cm proximal to the LES. The HRIM assembly had 36 pressure sensors at 1 cm spacing and 12 impedance segments at 2 cm spacing (Sierra). Reflux events were defined by impedance as a retrograde 50% drop in impedance propagating at least 2 impedance segments proximal to the LES; acid exposure was defined as esophageal pH<4. Studies were investigator-monitored and subjects were queried for symptoms both randomly and when the investigator observed manometric or reflux events. Studies were divided in 1-minute periods, each then categorized by presence or absence of symptoms, reflux events, and nadir pH. Fisher's exact test was used to evaluate the relationship between symptoms, reflux events, and periods of low pH. Results: 183 symptoms were elicited (median 22 per patient, range 4-68), most commonly
AGA Abstracts
S-604
apnea or sleep disturbances were excluded. All subjects underwent an upper endoscopy to exclude silent erosive esophagitis. Subsequently subjects were randomized to either sleep deprivation protocol (4 hours of sleep on 2 consecutive nights) or good sleep protocol (at least 7 hours of sleep on 2 consecutive nights). Subjects crossed over to the other arm after 1 week. Subjects wore an actigraph to ensure compliance with sleep time. Immediately after the sleep deprivation or good sleep protocol, subjects underwent pH testing. The Sleep Quality Questionnaire on the morning of the pH test further ensured compliance with the sleep protocols. Results: Eleven subjects (M/F 5/6, mean age 40.7 yrs) were enrolled into the study. Mean % total time pH<4 was significantly higher after bad sleep as compared to good sleep (5.6 vs. 2.3, P<0.05). Mean % upright and recumbent time pH<4 were also higher after bad sleep as compared to good sleep (4.6 vs. 1.9 and 5.5 vs. 2.6, respectively, P<0.05). Five (45.5%) of the normal subjects developed an abnormal pH test after sleep deprivation (>4.2%). All pH tests after good sleep were within the normal range. The change in esophageal acid exposure after sleep deprivation was similar in both recumbent and upright positions. Conclusions: This is the first study to demonstrate that sleep deprivation per se can precipitate acid reflux and even result in abnormal pH test in normal subjects. The study also suggests that sleep status may impact pH test results.
regurgitation (n=62) and heartburn (n=51). 53% of symptoms were associated with reflux events and 52% with low pH (74% and 84% for regurgitation; 33% and 39% for heartburn, respectively). 95% of symptomatic reflux events were caused by transient lower esophageal sphincter relaxation (TLESR) (98% regurgitation; 76% heartburn). Conversely, of 139 TLESRs, 83% were symptomatic (14% heartburn, 35% regurgitation, 25% belch). The results of Fisher's exact test of symptom association are shown in the Table. Conclusions: Closely monitored GERD patients can accurately perceive a much greater proportion of reflux events that suggested by ambulatory studies. The most common mechanism of symptomatic reflux events was TLESR with the most specific associated symptom being regurgitation. Even in a closely monitored setting, less than 40% of reported heartburn could be tightly linked to either a reflux event or low esophageal pH.
T1907 A Novel Distensibility Technique for Measuring Upper Esophageal FunctionPilot Data Julie Regan, Barry P. McMahon
T1909 A Double-Blind, Randomized, Placebo-Controlled, Single Dose, 3-Period Crossover Study of Agn 203818 in Subjects With Functional Heartburn Philip B. Miner, Rozalina Dimitrova, Wayne Lam, John E. Donello, Simon Daggett, Daniel W. Gil
Impaired opening of the upper esophageal sphincter (UES) prevents food and drinks from being transported safely and efficiently from the pharynx into the esophagus during swallowing, leading to serious respiratory and nutritional complications and to compromised quality of life. Management of impaired UES opening in people with neurogenic dysphagia consists of compensatory head postures, rehabilitative techniques (Mendelsohn manoeuvre and Shaker exercises), botulinum toxin A injections into the cricopharyngeus muscle and surgical interventions (upper esophageal dilatation and cricopharyngeal myotomy). Despite numerous management options, research indicates that current evaluation of UES opening is substandard. Videofluoroscopy is prone to poor inter-rater reliability and solid state pharyngeal manometry cannot quantify extent of UES opening. People with UES impairment are subsequently being misdiagnosed and mismanaged in the clinical setting. The Functional Lumen Imaging Probe (FLIP) is an objective evaluation tool based on the principles of impedance planimetry. The FLIP probe has been proven to accurately measure multiple cross-sectional areas in the lumen of the esophogastric junction, and has since been employed to evaluate lumens in numerous anatomical sites including the sphincter of Oddi and the ano-rectal region. Authors hypothesise that the FLIP probe can be adapted to evaluate UES function. The FLIP probe was adapted in its design and constructed to ensure safe and accurate measurement of the UES region. An initial pilot study was conducted under videofluoroscopy on a forty-three year old adult male with a history of lateral medullary stroke and mild to moderate dysphagia. The adapted FLIP probe was inserted transnasally and location of the balloon on the distal end of the probe was confirmed fluoroscopically to be in the UES region. Two ramp distensions (16ml, 18ml volumes) were carried out without any airway compromise. Eight diameter measurements were obtained at each volume and mean diameters calculated (Table 1). Additionally, narrowest diameter of the UES was obtained at baseline and during a head turn maneouvre (4.04mm at rest v 5.99mm on head turn) during an 8ml step distension (Table 1). This preliminary study indicates that an adapted FLIP probe can be positioned safely in the UES and can provide clinically useful information regarding UES function. Pilot Data
Functional heartburn is characterized by hypersensitivity of the esophagus to mechanical and/or chemical stimuli, without any apparent pathology. AGN 203818 is an alpha2-adrenergic agonist that reduces mechanical hypersensitivity in a rat model of chronic colonic hypersensitivity. The pharmacodynamic effect of AGN 203818 on the discomfort/pain threshold was investigated in a single dose exploratory study in patients with functional heartburn. Methods: A single-center, double-blind, randomized, placebo-controlled, single dose, 3period crossover study evaluated 2 different doses of AGN 203818 on discomfort/pain thresholds in patients with functional heartburn undergoing mechanical esophageal stimulation (volume-step and pressure-ramp balloon inflation) and chemical esophageal stimulation (Acid Perfusion Test). On each day of dosing patients received oral AGN 203818 (3 mg or 20 mg) or placebo. Patients underwent 2 balloon distention tests 60 minutes post-dose and acid perfusion 90 minutes post-dose. Safety parameters were collected throughout the study. For the volume-step balloon test stepwise increases of 5 mL per minute interval are used whereas for the pressure-ramp test gradual increases of 1 mmHg (with consequent increase in volume) are used. For the Acid Perfusion Test (APT) 0.1 N hydrochloric acid was infused at a rate of 10 mL/min. Results: One male and 17 female patients were randomized and all completed the study as planned with no serious adverse events reported. In the balloon tests, AGN 203818 20 mg and 3 mg resulted in higher volumes at discomfort/pain threshold compared to baseline and placebo treatment. The mean (standard deviation) volume to discomfort/pain threshold (mL) for pressure ramp were: Baseline 11.6 (4.8); Placebo 12.6 (9.6); 3 mg 14.3 (9.6); 20 mg 17.0 (9.2). AGN 203818 20 mg increased the pressure ramp threshold by 47% (p=0.057 vs. placebo). The mean (standard deviation) volume to discomfort/pain threshold (mL) for volume step were: Baseline 16.9 (4.6); Placebo 18.9 (9.4); 3 mg 23.1 (13.8); 20 mg 20.3 (8.8). The 3 mg dose was significantly (p=0.02) better than placebo on the volume-step, although the large increments (5 mL) used may have contributed to a smaller overall drug effect. No significant between treatment differences were noted on the APT. The mean (standard deviation) volume to discomfort/pain threshold (mL) for APT were: Baseline 38.9 (25); Placebo 63.3 (43.8); 3 mg 65.1 (53.8); 20 mg 54.1 (33.2). In concurrence with pre-clinical findings these results demonstrate that the alpha2adrenergic agonist AGN 203818 decreases mechanical hypersensitivity of the esophagus in patients with functional heartburn. T1910 Normalized High Resolution Esophageal Pressure Topography (HREPT) Data: Characterizing Peristalsis in Terms of Neuromuscular Physiology Peter J. Kahrilas, Zhiyue Lin, Monika A. Kwiatek, John E. Pandolfino
T1908 Reflux-Symptom Association and Determinants of Symptom Perception in an Investigator-Monitored Post-Prandial Study Utilizing High Resolution Impedance Manometry (Hrim) and pH Recording Anita Fareeduddin, Sabine Roman, John E. Pandolfino, Monika A. Kwiatek, Peter J. Kahrilas
BACKGROUND: Esophageal peristalsis is regionally modulated by muscle type, vagal control, and myenteric plexus innervation. The integrity of each of these can be inferred from HREPT studies by a combination of pattern recognition and computation. We hypothesized that by normalizing data among subjects in HREPT terms, peristalsis can be characterized by the integrity of physiological elements. AIM: To calculate normalized metrics for coordinatespecific (position and time) contraction, inhibition, and quiescence of peristalsis for HREPT studies. METHODS: HREPT studies of 20 normal subjects were analyzed. Data from 10 water swallows were exported from ManoView™ in ASCII format for use in MATLAB™, a computer program customized for processing binary data. Each swallow was analyzed as a 100x200 pixel grid extending from the distal pharynx to proximal stomach for a 20s period beginning 1s before UES relaxation. Each pixel thus had coordinates of 1-100th percentile of esophageal length and 0.0-20.0s in 0.1s time increments. A composite contraction was simulated for each subject based on the median pressure value within each pixel for the 10 test swallows. Similarly, deriving the 5th, 50th, and 95th percentile values for each pixel among the 20 composite simulations computed group normative values. RESULTS: Normalizing swallows for each subject filtered out pressure signals attributable to respiration, vascular structures, and the crural diaphragm as these were not consistently synchronized with UES relaxation and cancelled out with the series of swallows. 3 contractile segments (proximal, distal, and LES) and separating pressure troughs were defined in coordinates of percent length and delay from UES relaxation; S2 and S3 described by Clouse smoothly fused into a single segment as there was no consistency in this separation among subjects. A welldefined triangle of inhibition commenced at UES relaxation and progressively widened to 8s at the LES. Each percentile of esophageal length had unique quantitative and temporal
Backgrounds & Aims: According to Rome III, the significant association between symptoms and reflux events, irrespective of esophageal acid exposure, can diagnose symptomatic GERD. Current indices used to evaluate symptom association were derived from analyses of 24-h ambulatory esophageal pH monitoring. We hypothesized that investigator-monitored postprandial impedance-manometry in combination with esophageal pH monitoring could both reveal tighter reflux symptom association and improved our understanding of underlying mechanisms. Patients and methods: 7 GERD patients (1 male, mean age 39 years, range 22-66) underwent stationary HRIM combined with esophageal pH-impedance monitoring for 3 hrs after the patient consumed a refluxogenic meal. pH was monitored 5 cm proximal to the LES. The HRIM assembly had 36 pressure sensors at 1 cm spacing and 12 impedance segments at 2 cm spacing (Sierra). Reflux events were defined by impedance as a retrograde 50% drop in impedance propagating at least 2 impedance segments proximal to the LES; acid exposure was defined as esophageal pH<4. Studies were investigator-monitored and subjects were queried for symptoms both randomly and when the investigator observed manometric or reflux events. Studies were divided in 1-minute periods, each then categorized by presence or absence of symptoms, reflux events, and nadir pH. Fisher's exact test was used to evaluate the relationship between symptoms, reflux events, and periods of low pH. Results: 183 symptoms were elicited (median 22 per patient, range 4-68), most commonly
AGA Abstracts
S-604