![Page 1: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/1.jpg)
The Management of PPI Refractory Gastro-Esophageal Reflux Disease
Reuben K Wong
Consultant Gastroenterologist Assistant Professor
Clinical Director GI Motility Lab National University Hospital . NUHS
Adj. Asst. Professor of Medicine UNC-Chapel Hill . NC USA
![Page 2: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/2.jpg)
Introduction
• GERD definition & terminology
• Classification
Workflow in a pt with atypical CP/reflux
• 1st line investigations - endoscopy
• In the absence of esophageal injury, how do we prove there is reflux?
• Acid suppressants – the 1st line of treatment
Failure of Acid Suppressants
• Shall we persist with acid suppressants?
• Other drugs
• Is surgery an option?
![Page 3: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/3.jpg)
Why is GERD a significant problem? USA Prevalence Study
Locke et al 1997
Prevalence
(%)
0
20
40
60
80
25–34 35–44 45–54 55–64 65–74 Age (years)
Any episode of GERD symptoms
At least weekly episodes of GERD symptoms
females
males
![Page 4: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/4.jpg)
How important an issue is GERD/NERD locally?
Singapore Community Survey
• Jurong Estate
• Enquiring about reflux symptoms
• 1994 – 4.6%
• 2000 – 10.5%
Increasing incidence that indicates we are catching up with rates in the West
Ho KY et al. Amer Journ Gastroenetrol 1998
![Page 5: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/5.jpg)
Definitions & Classification (circa. Montreal)
![Page 6: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/6.jpg)
It’s burning!
• 43yr old Female
• No significant medical history
• Episodes of heartburn and a “sourish” sensation
• Worse when stressed (vague relationship)
• Physical examination unremarkable
What would u do…
1. Trial of acid suppression
2. Send her for an OGD
3. ECG/CXR
![Page 7: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/7.jpg)
Which acid suppressant to use?
Normal zone is defined as intraesophageal pH <4 for 0–4.2% of the time over 24 hours
Time pH <4 (minutes)
120 0 80 40 200 160
Pre-treatment
Omeprazole treatment
Normal zone
**
ns
Pre-treatment
Ranitidine treatment
omeprazole, 20 mg once daily
ranitidine, 150 mg twice daily
ns, not significant
versus pre-treatment
** p <0.01 versus pre-treatment
Ruth et al 1988
![Page 8: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/8.jpg)
RF Diagnostic Algorithms Amer Journ Gastroenterol 2010; 105
![Page 9: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/9.jpg)
RF Diagnostic Algorithms Amer Journ Gastroenterol 2010; 105
![Page 10: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/10.jpg)
RF Diagnostic Algorithms Amer Journ Gastroenterol 2010; 105
![Page 12: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/12.jpg)
![Page 13: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/13.jpg)
Reflux Esophagitis Direct physical evidence of acid reflux
Lundell et al 1999; published with permission
from Professor G Tytgat and Professor J Dent
![Page 14: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/14.jpg)
Dilated Intercellular Spaces
New modality for increasing sensitivity in the diagnosis of refluxate induced damage
![Page 15: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/15.jpg)
Definitions & Classification (circa. Montreal)
![Page 16: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/16.jpg)
p<0.0005
Acid suppression remains the cornerstone in esophagitis caused by reflux
0
20
40
60
80
Esophagitis cases healed
(%)
0 2 4 6 8 10 12 Time (weeks)
PPIs
H2-receptor
antagonists
placebo
100
Chiba et al 1997
![Page 17: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/17.jpg)
The evidence for PPIs in Esophagitis
AGA technical Review and MPS on GERD. Gastroenterology 2008
![Page 18: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/18.jpg)
Omeprazole 20mg BD
• No response
Endoscopy
• Normal
• No esophagitis
Nexium 20mg BD
• Some mild, transient improvement
• Do I need to take this lifelong?
• It’s expensive
• Are there side effects?
![Page 19: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/19.jpg)
What are the issues?
• Acid suppression with a PPI and titrate dosing
• Endoscopy if there are “red flags” or non-responsive to PPI
Heartburn & GERD
• In absence of overt esophagitis, can we prove that acid is the cause?
Is acid the problem?
![Page 20: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/20.jpg)
![Page 21: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/21.jpg)
24hr pH testing
![Page 22: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/22.jpg)
48hr Wireless pH testing
![Page 23: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/23.jpg)
![Page 24: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/24.jpg)
What are the issues?
• Acid suppression with a PPI and titrate dosing
• Endoscopy if there are “red flags” or non-responsive to PPI
Heartburn & GERD
• In absence of overt esophagitis, can we prove that acid is the cause?
Is acid the problem?
• Is all reflux acidic?
• If not, how do we document non-acidic reflux?
What if there is no acidic reflux?
![Page 25: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/25.jpg)
pH-Impedance Testing
![Page 26: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/26.jpg)
April 2007 26
Measuring technique
Use a catheter with metal rings
A small electrical current is used to measure the
impedance between the 2 rings
Ring
R1
R2
Patient safe
low electrical current
![Page 27: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/27.jpg)
April 2007 27
Impedance signals
Animation
IMP
PRES
![Page 28: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/28.jpg)
April 2007 28
Impedance signals
Baseline Air Bolus Contraction Baseline
Bolus entry …. exit
![Page 29: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/29.jpg)
Gastric reflux
• / \ shaped waveform
![Page 30: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/30.jpg)
Extent of reflux Type of reflux
![Page 31: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/31.jpg)
April 2007 31
impedance
pH oes
manometry
weakly acidic reflux
(pH 5.6) cough
Ambulatory 24hr pH- impedance-manometry
reflux cough
pH fundus
Sifrim et al. Gut
![Page 32: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/32.jpg)
Does Impedance add value – i.e. does it increase yield?
Comparative study between pH and pH-Impedance • 60 patients with reflux symptoms • Off PPI • Underwent pH and impedance testing • Yield compared between acid reflux and all reflux events AJ Bredenoord et al. Am Jour Gastro 2006:101:1-7
![Page 33: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/33.jpg)
pH-Impedance measurement
Document ALL reflux
• Duration of lower esophageal acid exposure (intensity)
• No of events (frequency)
Correlation with symptoms
• Match symptoms with reflux events
• Symptom Index (SI)
• Symptom Association Probability (SAP)
Utility
• Acidic reflux
• Non-acidic reflux
• Air movement (belching)
• Explore correlates with extra-esophageal symptoms
![Page 34: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/34.jpg)
Definitions & Classification (circa. Montreal)
![Page 35: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/35.jpg)
Introduction
• GERD definition & terminology
• Classification
Workflow in a pt with atypical CP/reflux
• 1st line investigations - endoscopy
• In the absence of esophageal injury, how do we prove there is reflux?
• Acid suppressants – the 1st line of treatment
Failure of Acid Suppressants
• Shall we persist with acid suppressants?
• Other drugs
• Is surgery an option?
![Page 36: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/36.jpg)
The treatment & diagnostic conundrum
• Proven reflux – esophagitis on endoscopy or positive reflux testing
• Persistent symptoms despite acid suppression with PPIs
What are the options open to us?
1. Persist with acid suppression
2. Anti-reflux agents
3. Prokinetics
4. Surgery
![Page 37: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/37.jpg)
Risks of long-term acid suppression
![Page 38: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/38.jpg)
Prokinetics
Cisapride
• Withdrawn because of arrythmias
Mosapride
• Possible agent
Metoclopramide
• No significant efficacy data
NO PROVEN ROLE FOR PROKINETICS IN GERD!
![Page 39: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/39.jpg)
Anti-Reflux Medication
GABA-agonist • Baclofen 10-20mg TDS • Reduces TLESRs by 40-60% • Overall reflux by 40% • CNS side-effects 1. Dizziness 2. Somnolence 3. weakness • Short t-1/2 of 3-4hrs
![Page 40: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/40.jpg)
GABA-agonist (1)
Lesogabaran
• Peripherally acting agent – less CNS side-effects
• Phase 2a trials
• Show that when used concurrently with PPIs, markedly improve symptoms
GABA-agonist (2)
Arbaclofen placabril
• R-isomer of baclofen and a pro-drug
• Long t-1/2 of 12hrs
• Therefore long-lasting suppression on TLESRs
CB1 (cannabinoid receptor)
• Rimonabant (CB1 antagonist)
• D9-THC (CB1/2 agonist)
mGluR5
Glutamate as NT at vagal afferent terminals
Allosteric inhibitors at mGluR5 receptor
• ADX10059
• AZD2516
• AFQ056
TLESRs
![Page 41: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/41.jpg)
Antireflux surgery – an alternative to pharmacological therapy
• The efficacy of antireflux surgery in controlling GERD is similar to that of chronic PPI therapy.
• The outcome of antireflux surgery is highly dependent on the skill and experience of the surgeon.
• Surgery does not always end the need for antisecretory therapy to control the symptoms of GERD.
Lundell et al 2001; Spechler et al 2001
![Page 42: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/42.jpg)
Anti-reflux Surgery
Nissen fundoplication Toupet procedure
![Page 43: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/43.jpg)
Endoscopic Fundoplication EsophyX
![Page 44: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/44.jpg)
So is there a role for anti-reflux surgery?
![Page 45: The Management of PPI Refractory Gastro-Esophageal Reflux ... The Management of PPI Refractory Gastro-Esophageal Reflux Disease Reuben K Wong Consultant Gastroenterologist Assistant](https://reader035.vdocument.in/reader035/viewer/2022062506/5f02175d7e708231d40286ef/html5/thumbnails/45.jpg)
Introduction
• GERD definition & terminology
• Classification
Workflow in a pt with atypical CP/reflux
• 1st line investigations - endoscopy
• In the absence of esophageal injury, how do we prove there is reflux?
• Acid suppressants – the 1st line of treatment
Failure of Acid Suppressants
• Shall we persist with acid suppressants?
• Other drugs
• Is surgery an option?