- Email: [email protected]
The establishment of chronic acid reflux esophagitis in rats
April 2000
AGAA487
2626
2628
ACID ASSOCIATED TRANSIENT LOWER ESOPHAGEAL SPHINCTER RELAXATIONS (TLESRS) ARE THE CAUSE OF GERD IN PREMATIJRE INFANTS. Tailer Omari, Marc Benninga, Christopher Barnett, Geoffery Davidson, Ross Haslam, Ros Lontis, Louise Goodchild, John Dent, Acad and Children's Hosp, North Adelaide, Australia; Acad Med Ctr, Amsterdam,Netherlands; Acad and Children's Hosp, North Adelaide, Australia; Royal Adelaide Hosp, Adelaide, Australia. BACKGROUND: TLESR is the predominant mechanism of physiological reflux in premature infants(l). The aim of this study was measure the occurrence of TLESR and GER in premature infants with GERD. METHODS: Thirty six infants 32-39w PMA were studied. Infants were grouped as normals or GERD based on a clinical evaluation and confirmation by reflux symptom chart and pH monitoring(2). Esophageal manometry was performed for 2h after feeding using a micromanometric assembly incorporating a pH electrode. This allowed detection of TLESRs and associated changes pH. Acid 'pH down' GER episodes were identified by pH drops of >0.5 pH unit over 5s. Non acid 'pH up' GER episodes were identified by pH increases of >0.5 pH unit over 5s associated with an oesophageal common cavity episode. Half gastric emptying time (GEtl/2) was determined by 13C-octanoate breath test(3). RESULTS: The number of TLESRs overall was the same in both groups. In infants with GERD, the proportion of TLESRs associated with the occurrence of all GER episodes was greater than normals, this was predominantly due to a significant increase in the proportion of TLESRs associated with acid GER (table). Infants with GERD had similar (or faster) gastric emptying when compared to normal infants (table). CONCLUSION: Our data indicate that in premature infants with GERD, acid associated TLESRs are abnormally common and likely to be a major contributing fact to the pathphysiology of GERD. Premature infants with GERD do not have delayed GE. (I)Omari etal. 1. Pediatrics. 1998; 133: 650-654. (2)Omari etal. Improving the diagnosis of GERD in premature infants;submittedto this meeting. (3)Barnett etal. 1.P.G.N. 1999; 29:26-30
SYMPTOMATIC GERD ON PROTON PUMP INHmITOR (PPI) THERAPY: RESULTS OF 24 HR AMBULATORY PH STUDY ON MEDICATIONS. Sukhdeep Padda, Michele A. Young, Rodney L. Atkins, Francisco C. Ramirez, Carl T Hayden VA Med Ctr, Phoenix, AZ. PPI's are the most effective medications for GERD. A small percentage of Pts continue to have bothersome reflux symptoms while on PPI's and pose a therapeutic challenge. Ambulatory 24-hr pH testing in these Pts may be helpful in their subsequent management. AIM: To assess the usefulness of 24-hr pH testing in symptomatic GERD Pts despite PPI therapy. MATERIAL AND METHODS: Ambulatory 24-hr pH testing was performed in Pts who remained symptomatic despite PPI therapy. Pts were instructed to continue their PPI at the prescribed doses while undergoing pH testing. Abnormal pH was defined as total time with a pH < 4 for 2: 4.2% of the tested time. Abnormal upright reflux was defined as pH < 4 2: 6.3% time while on the upright position and abnormal supine reflux was defined as pH < 4.0 for 2:4.2% of the time in such position. RESULTS: Of 162 pH studies performedfrom Jan '99 to Nov '99,48 (29.6%) were performedfor symptomatic GERD Pts while on PPI therapy. The mean age of these Pts was 55 yrs and 15 (32%) had Barrett's esophagus.Twenty-four Pts were on single dose PPI (lansoprazole 30 mg), 21 on double dose (Iansoprazole 30 mg BID) and the remaining on higher doses. Twenty-two Pts (45.8%) had total abnormal pH results (Table). In Barrett's Pts, 8/15 (53.3%) had abnormal pH (5 were on QD and 3 on BID doses). All Pts with normal total 24-hr pH results also had normal pH profile during upright and supine periods of the study. Pts who had abnormal pH results had their medications up-regulated (PPI dose increase, addition of promotility or nocturnal H2RAs). Those with normal results had no change in their anti-reflux medication (up- or down-regulation). CONCLUSIONS: I) GERD Pts who remain symptomatic on PPI's have a high likelihood (45.5%) of having an abnormal 24 hr pH study while on medications. 2) Ambulatory 24-hr pH monitoring is a useful tool for identifying Pts with abnormal reflux despite conventional or high doses of PPI's. 3) Abnormal pH studies prompt physicians to up-regulate anti-reflux medications.
Clinical Assessment Nonnal (n=22) GERD(n=14) No.TLESRs %acldGER %non-acld GER %aIlGER GEt1/2
10.4(1.1) - 5.7% 35.8% 41.5% 33.4(3.2)
9.5(1.2) 16.5%## 42.1% 58.6%# 312(7.0)
Clinical Assessment Confinned Nonnal (n=6) GERD (n=6) 10.8(2.5) 4.6% 36.9% 41.5% 41.8(7.3)
9.8(1.8) 20.3%# 33.9% 54.2% 19.6(5.1),
Abnormal pH Study inPatients Receiving Single vs. Double Dose PPI Abnonnal pH TOTAL UPRIGHT SUPINE
Once Dally PPI
Twice Dally PPI
11/24 (45.8%) 7/22 (31.8%) 8/22 (36.4%)
11/21 (52.4%) 8/19 (42.1%) 8/19 (42.1%)
·p<0.05 using ANOVA; #p
2629 2627 THE ESTABLISHMENT OF CHRONIC ACID REFLUX ESOPHAGITIS IN RATS. Nobuo Omura, Hideyuki Kashiwagi, Fumiaki Yano, Yutaka Suzuki, Teruaki Aoki, The Jikei Univ Sch of Medicine, Tokyo, Japan; Jikei Univ Sch of Medicine, Tokyo, Japan. Purpose: The purposeof this studywas to establishan animalmodelof chronic acid reflux esophagitis which could be used for further investigations on the physiology and pathology of refluxesophagitis. Material and methods: Experiment I : The following 3 groupsof 8 rats each were prepared: group A 16Fr pyloric stenosis (PS) + limiting ridge ligation model; group B, 18Fr PS + limiting ridge ligation model; group C, 20Fr PS + limiting ridge ligation model. The PS modelwas definedas a modelin whichthe duodenum near the pyloruswas wrapped with a piece of Nelaton catheteras a ring. The transitionalregion between the forestomach and the glandular portion(the limiting ridge) was ligatedwith 2-0 silk thread. The animals were sacrificed 2 weeks lates. The presence of reflux esophagitis was examined macroscopically and the survivalrateof these animals wasdetermined. Experiment 2 : Threegroups of rats,one of fiverats(groupD) and two of 10ratseach(groupE and F), were used. Group D, control group; group E, 18Fr PS + limiting ridge ligation model,and groupF, 18FrPS + limiting ridge ligationmodel + lansoprazole. A doseof I mglkglday of lansoprazole was administered subcutaneously to the animals once daily at 9:00 a.m. for three weeks. The animalwere sacrificed 3 weeksafter the startof the experiment. Esophageal mucosaand refluxesophagitiswerehistopathologically examined. Results: Experiment I : The survival rates in groups A, B, and C were 25% (218), 75% (6/8), and 100% (8/8), respectively. The ratios of occurrence of esophagitis in groups A, B, and C, were 100% (212), 100%(6/6),and 0% (0/8),respectively. Experiment 2: The survival rates in groups D, E, and F were 100% (5/5), 90% (9/10), and 90% (9/10), respectively. The ratios of occurrence of esophagitis in groups D, E, and F were0% (0/5), 100% (919), and 11.1 % (1/9),respectively. In groupsE, the mean number of esophagitis was 4.0 sites. In group F, esophagitis was formed in only one site of only I animal. Thickness of the esophageal epithelium was markedly increased in group E. Elongation of papillaeof the laminapropriainto the epithelial surface, inflammatory cell infiltration in the lamina propria, and an increased number of collagen fibers in the lamina propriaand submucosa werealsonoted. In groupF, histopathological findings did not differfrom thoseof normalesophagus. Conclusion: This experinnental rat modelis considered useful as a modelof chronicacid-type esophagitis for the evaluation of the pathophysiology of refluxesophagitis and the evaluation of drug efficacy.
SHORT COURSE OF OMEPRAZOLE: BETTER FIRST DIAGNOSTIC AND ECONOMIC APPROACH TO NON-CARDIAC CHEST PAIN (NCCP) THAN ENDOSCOPY, MANOMETRY, OR 24 HOUR ESOPHAGEL PH MONITORING. William M. Pandak, Sharon Everette, Shaun Arezo, Robert Jesse, Gail Decosta, Michael Suita, Alvin M. Zfass, Virgina Commonwealth Univ, Richmond, VA. The advent of "resting and exercise Sestamibi scanning" (RESS) has provided a "functional" cardiac evaluation for ruling out cardiac chest pain with a negativepredictive value of >99%. This arguably is the best test for excluding the heart as a source of pain. Of the causes of NCCP, gastroesophageal reflux (GER) has been suggested to be the most frequent. SpecificAim: To test the potent acid suppressingagent, omeprazole(OMP) against the three most common diagnostic tests used to evaluate NCCP. Methods: 44 negative RESS patients were enrolled in a prospective, double-blind,placebo-controlled,cross-over trial using high dose OMP (40 mg bid) as compared to endoscopy (EGD), manometry (MAN), and 24 hour 2 channel esophagel pH (24h pH) monitoring.Patients were excluded if receiving an antireflux regimen; OMP contraindicated;had prior gastrointestinal surgery; unable to comply with the protocol. After performing EGD to rule out a gastric or duodenal ulcer, 24h pH monitoring,and MAN were performed. Patients were then randomized to either placebo or OMP for 14 days, washed out for 21 days, and then crossed over. Visual analog symptom assessment was performed pre and post OMP and placebo. Results: 37 patients completed both arms ofthe trial. 4 patients randomized to placebo first (no improvement) withdrew; only 1 treated with OMP (responded) withdrew. Of the patients who completed the trial, 78% in the OMP arm improved, whereas only 14% on placebo. An abnormal MAN (20%), 24h pH study (46%), or EGD with evidence of esophageal disease (32%) was found less frequently. Combination of the three tests increased rate to 62%. In previous observations, GER was 24h pH documented in >75% of patients with NCCP, but only found in 48% of patients in this study. Coupling EGD findings c/w esophagitis with 24h pH did not significantly increase findings of GER. Economic analysis: 14 day course of OMP (40 mg bid) - $184; EGD (facility/phys. charges) - $1,148; MAN - $546; 24h pH monitoring - $564. Conclusion: OMP as a diagnostic tool as the first step in the evaluation of Sestamibi negative NCCP is sensitive and specific for determining a cause of NCCP. EGD, MAN, and 24h pH monitoring were not only much less sensitive in making the diagnosis of NCCP, but significantly more invasive and expensive. A response with OMP represented a "cause and effect" as compared to only a correlation.
AGAA487
2626
2628
ACID ASSOCIATED TRANSIENT LOWER ESOPHAGEAL SPHINCTER RELAXATIONS (TLESRS) ARE THE CAUSE OF GERD IN PREMATIJRE INFANTS. Tailer Omari, Marc Benninga, Christopher Barnett, Geoffery Davidson, Ross Haslam, Ros Lontis, Louise Goodchild, John Dent, Acad and Children's Hosp, North Adelaide, Australia; Acad Med Ctr, Amsterdam,Netherlands; Acad and Children's Hosp, North Adelaide, Australia; Royal Adelaide Hosp, Adelaide, Australia. BACKGROUND: TLESR is the predominant mechanism of physiological reflux in premature infants(l). The aim of this study was measure the occurrence of TLESR and GER in premature infants with GERD. METHODS: Thirty six infants 32-39w PMA were studied. Infants were grouped as normals or GERD based on a clinical evaluation and confirmation by reflux symptom chart and pH monitoring(2). Esophageal manometry was performed for 2h after feeding using a micromanometric assembly incorporating a pH electrode. This allowed detection of TLESRs and associated changes pH. Acid 'pH down' GER episodes were identified by pH drops of >0.5 pH unit over 5s. Non acid 'pH up' GER episodes were identified by pH increases of >0.5 pH unit over 5s associated with an oesophageal common cavity episode. Half gastric emptying time (GEtl/2) was determined by 13C-octanoate breath test(3). RESULTS: The number of TLESRs overall was the same in both groups. In infants with GERD, the proportion of TLESRs associated with the occurrence of all GER episodes was greater than normals, this was predominantly due to a significant increase in the proportion of TLESRs associated with acid GER (table). Infants with GERD had similar (or faster) gastric emptying when compared to normal infants (table). CONCLUSION: Our data indicate that in premature infants with GERD, acid associated TLESRs are abnormally common and likely to be a major contributing fact to the pathphysiology of GERD. Premature infants with GERD do not have delayed GE. (I)Omari etal. 1. Pediatrics. 1998; 133: 650-654. (2)Omari etal. Improving the diagnosis of GERD in premature infants;submittedto this meeting. (3)Barnett etal. 1.P.G.N. 1999; 29:26-30
SYMPTOMATIC GERD ON PROTON PUMP INHmITOR (PPI) THERAPY: RESULTS OF 24 HR AMBULATORY PH STUDY ON MEDICATIONS. Sukhdeep Padda, Michele A. Young, Rodney L. Atkins, Francisco C. Ramirez, Carl T Hayden VA Med Ctr, Phoenix, AZ. PPI's are the most effective medications for GERD. A small percentage of Pts continue to have bothersome reflux symptoms while on PPI's and pose a therapeutic challenge. Ambulatory 24-hr pH testing in these Pts may be helpful in their subsequent management. AIM: To assess the usefulness of 24-hr pH testing in symptomatic GERD Pts despite PPI therapy. MATERIAL AND METHODS: Ambulatory 24-hr pH testing was performed in Pts who remained symptomatic despite PPI therapy. Pts were instructed to continue their PPI at the prescribed doses while undergoing pH testing. Abnormal pH was defined as total time with a pH < 4 for 2: 4.2% of the tested time. Abnormal upright reflux was defined as pH < 4 2: 6.3% time while on the upright position and abnormal supine reflux was defined as pH < 4.0 for 2:4.2% of the time in such position. RESULTS: Of 162 pH studies performedfrom Jan '99 to Nov '99,48 (29.6%) were performedfor symptomatic GERD Pts while on PPI therapy. The mean age of these Pts was 55 yrs and 15 (32%) had Barrett's esophagus.Twenty-four Pts were on single dose PPI (lansoprazole 30 mg), 21 on double dose (Iansoprazole 30 mg BID) and the remaining on higher doses. Twenty-two Pts (45.8%) had total abnormal pH results (Table). In Barrett's Pts, 8/15 (53.3%) had abnormal pH (5 were on QD and 3 on BID doses). All Pts with normal total 24-hr pH results also had normal pH profile during upright and supine periods of the study. Pts who had abnormal pH results had their medications up-regulated (PPI dose increase, addition of promotility or nocturnal H2RAs). Those with normal results had no change in their anti-reflux medication (up- or down-regulation). CONCLUSIONS: I) GERD Pts who remain symptomatic on PPI's have a high likelihood (45.5%) of having an abnormal 24 hr pH study while on medications. 2) Ambulatory 24-hr pH monitoring is a useful tool for identifying Pts with abnormal reflux despite conventional or high doses of PPI's. 3) Abnormal pH studies prompt physicians to up-regulate anti-reflux medications.
Clinical Assessment Nonnal (n=22) GERD(n=14) No.TLESRs %acldGER %non-acld GER %aIlGER GEt1/2
10.4(1.1) - 5.7% 35.8% 41.5% 33.4(3.2)
9.5(1.2) 16.5%## 42.1% 58.6%# 312(7.0)
Clinical Assessment Confinned Nonnal (n=6) GERD (n=6) 10.8(2.5) 4.6% 36.9% 41.5% 41.8(7.3)
9.8(1.8) 20.3%# 33.9% 54.2% 19.6(5.1),
Abnormal pH Study inPatients Receiving Single vs. Double Dose PPI Abnonnal pH TOTAL UPRIGHT SUPINE
Once Dally PPI
Twice Dally PPI
11/24 (45.8%) 7/22 (31.8%) 8/22 (36.4%)
11/21 (52.4%) 8/19 (42.1%) 8/19 (42.1%)
·p<0.05 using ANOVA; #p
2629 2627 THE ESTABLISHMENT OF CHRONIC ACID REFLUX ESOPHAGITIS IN RATS. Nobuo Omura, Hideyuki Kashiwagi, Fumiaki Yano, Yutaka Suzuki, Teruaki Aoki, The Jikei Univ Sch of Medicine, Tokyo, Japan; Jikei Univ Sch of Medicine, Tokyo, Japan. Purpose: The purposeof this studywas to establishan animalmodelof chronic acid reflux esophagitis which could be used for further investigations on the physiology and pathology of refluxesophagitis. Material and methods: Experiment I : The following 3 groupsof 8 rats each were prepared: group A 16Fr pyloric stenosis (PS) + limiting ridge ligation model; group B, 18Fr PS + limiting ridge ligation model; group C, 20Fr PS + limiting ridge ligation model. The PS modelwas definedas a modelin whichthe duodenum near the pyloruswas wrapped with a piece of Nelaton catheteras a ring. The transitionalregion between the forestomach and the glandular portion(the limiting ridge) was ligatedwith 2-0 silk thread. The animals were sacrificed 2 weeks lates. The presence of reflux esophagitis was examined macroscopically and the survivalrateof these animals wasdetermined. Experiment 2 : Threegroups of rats,one of fiverats(groupD) and two of 10ratseach(groupE and F), were used. Group D, control group; group E, 18Fr PS + limiting ridge ligation model,and groupF, 18FrPS + limiting ridge ligationmodel + lansoprazole. A doseof I mglkglday of lansoprazole was administered subcutaneously to the animals once daily at 9:00 a.m. for three weeks. The animalwere sacrificed 3 weeksafter the startof the experiment. Esophageal mucosaand refluxesophagitiswerehistopathologically examined. Results: Experiment I : The survival rates in groups A, B, and C were 25% (218), 75% (6/8), and 100% (8/8), respectively. The ratios of occurrence of esophagitis in groups A, B, and C, were 100% (212), 100%(6/6),and 0% (0/8),respectively. Experiment 2: The survival rates in groups D, E, and F were 100% (5/5), 90% (9/10), and 90% (9/10), respectively. The ratios of occurrence of esophagitis in groups D, E, and F were0% (0/5), 100% (919), and 11.1 % (1/9),respectively. In groupsE, the mean number of esophagitis was 4.0 sites. In group F, esophagitis was formed in only one site of only I animal. Thickness of the esophageal epithelium was markedly increased in group E. Elongation of papillaeof the laminapropriainto the epithelial surface, inflammatory cell infiltration in the lamina propria, and an increased number of collagen fibers in the lamina propriaand submucosa werealsonoted. In groupF, histopathological findings did not differfrom thoseof normalesophagus. Conclusion: This experinnental rat modelis considered useful as a modelof chronicacid-type esophagitis for the evaluation of the pathophysiology of refluxesophagitis and the evaluation of drug efficacy.
SHORT COURSE OF OMEPRAZOLE: BETTER FIRST DIAGNOSTIC AND ECONOMIC APPROACH TO NON-CARDIAC CHEST PAIN (NCCP) THAN ENDOSCOPY, MANOMETRY, OR 24 HOUR ESOPHAGEL PH MONITORING. William M. Pandak, Sharon Everette, Shaun Arezo, Robert Jesse, Gail Decosta, Michael Suita, Alvin M. Zfass, Virgina Commonwealth Univ, Richmond, VA. The advent of "resting and exercise Sestamibi scanning" (RESS) has provided a "functional" cardiac evaluation for ruling out cardiac chest pain with a negativepredictive value of >99%. This arguably is the best test for excluding the heart as a source of pain. Of the causes of NCCP, gastroesophageal reflux (GER) has been suggested to be the most frequent. SpecificAim: To test the potent acid suppressingagent, omeprazole(OMP) against the three most common diagnostic tests used to evaluate NCCP. Methods: 44 negative RESS patients were enrolled in a prospective, double-blind,placebo-controlled,cross-over trial using high dose OMP (40 mg bid) as compared to endoscopy (EGD), manometry (MAN), and 24 hour 2 channel esophagel pH (24h pH) monitoring.Patients were excluded if receiving an antireflux regimen; OMP contraindicated;had prior gastrointestinal surgery; unable to comply with the protocol. After performing EGD to rule out a gastric or duodenal ulcer, 24h pH monitoring,and MAN were performed. Patients were then randomized to either placebo or OMP for 14 days, washed out for 21 days, and then crossed over. Visual analog symptom assessment was performed pre and post OMP and placebo. Results: 37 patients completed both arms ofthe trial. 4 patients randomized to placebo first (no improvement) withdrew; only 1 treated with OMP (responded) withdrew. Of the patients who completed the trial, 78% in the OMP arm improved, whereas only 14% on placebo. An abnormal MAN (20%), 24h pH study (46%), or EGD with evidence of esophageal disease (32%) was found less frequently. Combination of the three tests increased rate to 62%. In previous observations, GER was 24h pH documented in >75% of patients with NCCP, but only found in 48% of patients in this study. Coupling EGD findings c/w esophagitis with 24h pH did not significantly increase findings of GER. Economic analysis: 14 day course of OMP (40 mg bid) - $184; EGD (facility/phys. charges) - $1,148; MAN - $546; 24h pH monitoring - $564. Conclusion: OMP as a diagnostic tool as the first step in the evaluation of Sestamibi negative NCCP is sensitive and specific for determining a cause of NCCP. EGD, MAN, and 24h pH monitoring were not only much less sensitive in making the diagnosis of NCCP, but significantly more invasive and expensive. A response with OMP represented a "cause and effect" as compared to only a correlation.