1. Il sottoscritto EDOARDO SAVARINO in qualit à di docente dell evento sopra indicato, ai sensi dell art. 3.3 sul Conflitto di Interessi, pag. 17 del Reg. Applicativo dell Accordo Stato-Regioni del 5/11/09, per conto del provider I&C srl dichiara che negli ultimi due anni non ha avuto rapporti con soggetti portatori di interessi commerciali in campo sanitario NOME E NUMERO DEL PROVIDER: I&C SRL - 7598- ECM N°: 11005555 TITOLO: XIV CONGRESSO NAZIONALE GISMAD SEDE: VENEZIA-MESTRE DATA: 18-19 MARZO 2011

2. Impatto delle Tecnologie sulla gestione clinica: pH e Manometry-Impedance Dott. Edoardo V. Savarino Dipartimento di Medicina Interna, Clinica di Gastroenterologia con Endoscopia Digestiva, Università di Genova (Resp. Prof. V. Savarino)

3. NEW TECHNOLOGIES Esophageal pH monitoring without catheter 3 cm 5 cm 7 cm 9 cm 15 cm 17 cm pH - 5 cm 6 impedance channels 1 pH channel LES 5cm 10cm 15cm 20cm 15cm 10cm 5cm Combined impedance-manometry

4. Impedance Monitoring Kahrilas PJ.

5. Impedance Monitoring: When? Impedance Monitoring: When? Evaluation of patients with difficult symptoms Evaluation of patients with difficult symptoms Evaluation of symptomatic patients despite PPI therapy Evaluation of symptomatic patients despite PPI therapy Evaluation of atypical GERD (Correlate acid & nonacid GER episodes to Sx and quantify proximal extent of GER) Evaluation of atypical GERD (Correlate acid & nonacid GER episodes to Sx and quantify proximal extent of GER) Pre and Post-operative evaluation of patients considered for surgery Pre and Post-operative evaluation of patients considered for surgery Evaluation of GERD in infants and pediatric patients Evaluation of GERD in infants and pediatric patients Evaluation of new medical or endoscopic therapies for GERD Evaluation of new medical or endoscopic therapies for GERD (Baclofen, Esophyx, Arbaclofen, Lesogaberan etc.) Cough – Asthma – Laryngitis – Hoarseness – Bronchitis - Dysfonia – Interstitial Lung Disease Non-Cardiac Chest Pain – Disphagia – Globus Efficacy of Medical Therapy – Correlate Acid & Non-Acid GER to Sx – Absence of abnormal GER Pathological acid exposure – Symptom-reflux Association – Efficacy of surgery Pathological non-acid exposure – Nocturnal apnea

6. Main Diagnostic Advantage Does patient have a reflux disease? Positive Symptom Association Negative Symptom Association Identify Non-Acid Reflux Disease Identify Functional Diseases or search for other causes MII-pH Impedance Monitoring In case of normal acid exposure

7. Clinical Utility of Impedance-pH in NERD patients NERD Patients (N = 150) Abnormal Acid Exposure Time 63 (42%) Normal Acid Exposure Time 87 (58%) Positive SI 54 (36%) Negative SI 9 (6%) Positive SI 45 (30%) Negative SI 42 (28%) Acid Only 20 (13%) Acid and Nonacid 7 (5%) Nonacid Only 18 (12%) Total Acid 27 (18%) Total Nonacid 25 (17%) Acid Only 48 (32%) Acid and Nonacid 4 (3%) Nonacid Only 2 (1%) Total Acid 52 (35%) Total Nonacid 6 (4%) Functional Heartburn 42 (28%) Savarino E et al. Am J Gastroenterology 2008;103:1-9

8. The Added Value of Impedance-pH to Rome III Criteria in NERD patients (N=219) % of patients Savarino E et al. Dig Liv Dis 2011; March 2 NARD 3%10%

9. Rome Criteria 3 ½ Kahrilas PJ et al. Am J Gastroenterology 2010;747:756

10. Clinical Utility of Impedance-pH in EE patients EE Patients (N = 58) Abnormal Acid Exposure Time 47 (81%) Normal Acid Exposure Time 11 (19%) Positive SAP 44 (76%) Negative SAP 3 (5%) Positive SAP 10 (17%) Negative SAP 1 (2%) Acid Only 3 (5%) Acid and Nonacid 3 (5%) Nonacid Only 4 (7%) Total Acid 6 (10%) Total Nonacid 7 (12%) Acid Only 35 (60%) Acid and Nonacid 5 (9%) Nonacid Only 4 (7%) Total Acid 40 (69%) Total Nonacid 9 (16%) Savarino E et al. Am J Gastroenterology 2010; 105:1053-61

11. Clinical Utility of Impedance-pH in EE patients Frazzoni M et al. APT 2011; 33:601-606 Gastric acid secretion persists despite ongoing PPI therapy and activated pepsins may well be present in weakly acidic refluxes. Therefore, they may be responsible for mucosal damage. Therapeutic interventions in patients with PPI- resistant reflux oesophagitis should be tailored on the basis of impedance–pH- monitoring results

12. Impedance-pH and overlap syndromes Savarino E et al. Gut 2009; 58:1185-1191

13. Impedance-pH and overlap syndromes * = p <0.01 * * * * % of patients HEFH NERD Savarino E et al. Gut 2009; 58:1185-1191

14. Impedance-pH and new drugs *p<0.05 * * * *

15. Impedance-pH and new drugs

16. Impedance-pH and surgery

17. Patients selection: 15 had erosive esophagitis 16 had non-erosive reflux disease Number of total, acid and weakly acidic reflux episodes Acid exposure time, liquid and mixed reflux events Gatric belching, but Supragastric belching 16 Patients were asymptomatic 15 Patients were symptomatic, but with negative SI for acid or weakly acidic reflux Laparoscopic Nissen Fundoplication

18. Impedance-pH and surgery No symptom was registered during the study performed after intervention 38 were totally asymptomatic Subtotal symptom remission was reported by two patients, one with a postoperative heartburn score of 1 (3 before intervention) and one with a post-operative regurgitation score of 1 (3 before intervention)

19. Impedance-pH: On or Off-PPI Therapy? Twice-daily PPI Therapy for at least 2 months Impedance-pH Testing On Therapy

20. Impedance-pH: On or Off-PPI Therapy? Hemmink et al. Am J Gastroenterology 2008; 103:2446-53 N=30

21. Impedance-pH: On or Off-PPI Therapy? Modified by Tutuian R. J Gastrointestin Liver Dis 2009; 1:9-10 Impedance Impedance-pH as the gold standard to test if the patient has or not GERD in the first place Impedance-pH as the gold standard to clarify the relationship between symptoms and reflux Off TherapyOn Therapy History of Erosive esophagitis or Barrett Esophagus Previous positive conventional pH monitoring

22. IEM – ineffective esophageal motility DES – distal esophageal spasm LES – lower esophageal sphincter Spechler & Castell. Gut 2001; 49:145-51 Definition of Motility Abnormalities Esophageal bodyLES resting pressureLES residual pressure Achalasia 100% aperistalsiselevated / normal IEM >30% ineffective contractions normal / lownormal DES >20% simultaneous swallows normal / elevatednormal Normal < 30% ineffectivenormal < 20% simultaneous Nutcracker normal; DEA >180mmHgnormal / elevated Hypertensive LES normal > 45 mmHg elevated / normal Poorly relaxing LES normal > 8 mmHg Hypotensive LES normal< 10 mmHgnormal

23. Meaning of esophageal motility abnormalities ?

24. Esophageal Function Testing Combined Impedance-Manometry Comprehensively Assesses Esophageal Function Motility Assessment Criteria Pressure Measurements Esophageal Body Contraction AmplitudeLES Resting Pressure LES Residual Pressure Bolus Transit Measurements Esophageal Body Contraction Velocity Complete Incomplete

25. Impedance-Manometry Testing LES 5cm 10cm 15cm 20cm 5cm 10cm 15cm 20cm

26. Simren et al. Gut 2003; 52:784-790 Video-fluoro vs. Impedance r = 0.94

27. Bolus Transit Complete bolus transit Bolus retention at 15cm 20 cm 15 cm 10 cm 5 cm 2 cm

28. Patients with esophageal motility abnormalities 350 patients 350 patients Females 220 (63%), males 130 (37%) Females 220 (63%), males 130 (37%) Age: mean 53.5 years, range 12-86 years Age: mean 53.5 years, range 12-86 years Tutuian R et al. Am J Gastroenterology 2004; 99:1011-9

29. Percentage of Patients with normal bolus transit for liquid based on manometric diagnosis (n=350) Tutuian R et al. Am J Gastroenterology 2004; 99:1011-9

30. Impedance-manometry classification of motility abnormalities MildModerateSevere Achalasia Scleroderma Nutcracker Hypertensive LES Hypotensive LES Poor relaxing LES IEM DES Pressure only Pressure and Transit Tutuian R et al. Am J Gastroenterology 2004; 99:1011-9

31. Frequency of bolus retention at different levels in the esophagus (n=85 patients) (Saline) 20 15 10 5 2 Chest pain Dysphagia GERD % swallows with bolus retention p<0.05 at each level 40%30%20%10%0%10%20%30%40% 30%20%10%0%10%20%30%40% 30%20%10%0%10%20%30%40% DDW 2007, Washington, USA

32. Frequency of bolus retention at different levels in the esophagus (n=67 patients) (Bread) 20 15 10 5 2 Chest-pain Dysphagia GERD % swallows with bolus retention p<0.05 at each level 40%30%20%10%0%10%20%30%40% 30%20%10%0%10%20%30%40% 30%20%10%0%10%20%30%40% DDW 2007, Washington, USA

33. Manometric Findings in 755 GERD Patients and 48 HVs N=48 N=70 N=239 N=340 N=106 Simile prevalenza di IEM tra HV e FH AUMENTO DELLINCIDENZA DI IEM CON LAUMENTARE DELLA SEVERITA DELLE LESIONI FISMAD 2011, Torino, Italy

34. Bolus Transit alterato in Pazienti con lesioni visibili endoscopicamente Valori simili tra FH e NERD Bolus Transit for Liquid Swallows in GERD Patients FISMAD 2011, Torino, Italy

35. Manometric Diagnosis with Bolus Transit in GERD Patients Patients (%) FISMAD 2011, Torino, Italy

36. Future Issues to be Elucidated The impact of Bolus Transit assessment in patients undergoing esophageal surgery (Fundoplication, Heller Miotomy, Trans-oral esophageal diverticulectomy etc.) The diagnostic utility of Bolus Transit assessment in patients with non-obstructive dysphagia (functional dysphagia etc.) The impact of Bolus Transit assessment in studies aimed at testing future drugs for improving gastro-esophageal emptying (Bolus transit time)