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How to deal with PPIs – refractory GERD ?
Kitti Chunlertrith
Division of Gastroenterology, Faculty of Medicine,
Khon Kaen University
3 October 2013
• GERD : Definition, Pathophysiology, Diagnosis
• Recommendation for management of GERD
• Definition of PPIs-refractory GERD
• Mechanisms of PPIs-refractory GERD
• Common causes of PPIs-refractory GERD
• Diagnostic tools for PPIs-refractory GERD
• Therapeutic options for PPIs-refractory GERD
• Step-by-step management of PPIs-refractory GERD
Scope
GERD is a condition that develops when the reflux
of stomach contents causes troublesome
symptoms and/or complication
Am J Gastroenterol.2006;101:1900-20.
Heartburn Regurgitation
Definition of GERD
Pathophysiology of GERD
Impaired esophageal clearance
Impaired salivary function
Hiatal hernia
Impaired esophageal mucosal defence
Inappropiate TLESR
Reduced resting LES pressure
Gastric acid Pepsin
Bile
Gas
Delayed gastric emtying Pyloric imcompetence
Increased intraabdominal pressure
• Typical heartburn or regurgitation
• PPI – test
• Upper endoscopy
• Ambulatory reflux monitoring
Diagnosis of GERD
No sero-marker for diagnosis
• A presumptive diagnosis of GERD can be established in the
setting of typical symptoms of heartburn or regurgitation.
Empiric medical therapy with a proton pump inhibitor is
recommended
• Weight loss is recommended for GERD patients who are
overweight or have had recent weight gain
• Head of bed elevation and avoidance of meal 2-3 h. before bed
time should be recommended for patients with nocturnal GERD
• An 8-weeks course of PPIs is the therapy of choice for
symptom relief and healing of erosive esophagitis
• Non-responders to PPI should be referred for evaluation
Am J Gastroenterol.2013;108:308-28.
Recommendations for management of GERD
• The most common GI disorder : prevalence 10 – 20%
• Proton pump inhibitors is the mainstay of treatment
• 10 – 40% of GERD fail to respond to
standard dose PPIs : PPIs-Refractory
GERD
Gastroesophageal Reflux Disease
PPI Standard dose (mg/day)
Omeprazole
Lansoprazole
Rabeprazole
Pantoprazole
Esomeprazole
20
30
20
40
40
Proton pump inhibitors
• Unresponsible to 4-8 weeks treatment with proton
pump inhibitors (1)
• Symptoms (heartburn and/or regurgitation) not
responding to double dose of a proton pump
inhibitor during a treatment period of at least 12
weeks (2)
• Bothersome symptoms that are attributable to GERD
and that persist despite treatment with a proton
pump inhibitor (3) (1) Nat Clin Pract Gastroenterol Hepatol. 2007 Dec ;4(12):658-64.
(2) Gut. 2012 Sep;61(9):1340-54.
(3) Am J Gastroenterol. 2013 Mar;108(3):308-28.
Definition of PPIs-refractory GERD
• No established consensus regarding the definition of
refractory GERD in term of symptom burden, degree of
therapeutic response and PPI dose
• Refractory GERD is a patient – driver phenomenon
• Lack of satisfactory symptomatic response to PPI once a
day is sufficient to consider patients as PPI-refactory
GERD
Definition of PPIs-refractory GERD
• 38.6% of refractory GERD had abnormal pH-testing (1)
• 31–32% and 4–16% of refractory GERD had abnormal pH-testing
during on PPI once diary and twice diary, respectively (2,3)
• 40% and 7-11% of refractory GERD , positive symptom index on
PPI one and twice daily (4, 5, 6)
• The amount of residual acid reflux was not difference in
responders to PPI and non-responders (7)
Residual acid reflux Esophageal hypersensitivity
1. Dig Dis Sci 2005;50:1909-15.
2. Am J Gastroenterol 2005;100:283-9.
3. Dig Dis Sci 2008;53:2387-93.
4. Am J Gastroenterol 2001;96:2033-40.
5. Gut 2006;55:1398-402.
6. Clin Gastroenterol Hepatol 2008;6:521-4.
7. Am J Gastroenterol 2009;104:2005-13.
pH-monitoring test during on PPI
• Profound decrease in the amount of acid reflux but with
continuing postprandial of weakly acid (1)
• Proximal extent of weekly acid reflux was the most important
determinant of symptomatic reflux event in patient who failed PPI
treatment (2, 3)
• Reflux episodes that were associated with symptoms in patients
who failed PPI, composed of both gas and liquid (2, 3)
• Heartburn patients with normal endoscopy and pH testing the risk
of reflux perception was significantly higher when gas present in
the reflux (4)
Weakly acidic reflux Non – acidic reflux
1. Gastroenterology 2001;120:1599-606.
2. Gut 2008;57:156-60
3. Am J Gastroenterol 2008;103:1090-6.
4. Gut 2008;57:443-7.
Impedance pH – monitoring study
• Persistent bile acid in the refluxate as a potential factor involved in
refractory heartburn
• Baclofen 20 mg three times daily significantly reduced the duodeno-
gastro-esophageal exposure as well as symptoms of heartburn (1)
• Only 9% of symptoms were correlated to DGOR suggesting that
DGOR play a limited role in symptom elicitation in refractory GERD (2)
• Successful symptomatic treatment of NERD with PPI is almost always
associated with dilated intercellular spaces (DIS) resolutions but
persistent of DIS and persistence of symptoms (3, 4)
1. Gut 2003;52:1397-402.
2. Am J Gastroenterol 2009;104:2005-13.
3. Am J Gastroenterol 2005;100:537-42.
4. Am J Gastroenterol 2011;106:844-50.
Study of refractory GERD patient
Duodeno-gastro-esophageal reflux Dilated intercellular space
• Patients who responded less well to PPI treatment were
more likely to experience psychological distress (1)
• Anxiety increased acid – induced esophageal
hyperalgesia (2)
• Acute stress is able to induce dilated intercellular space
in esophageal mucosa (3)
1. Aliment Pharmacol Ther 2008;27:473-82.
2. Psychosom Med 2010;72:802-9.
3. Gut 2007;56:1191-7.
Study of refractory GERD patient
Psychological-comorbidity
• Persistent acid reflux
• Persistent reflux of non-acid
• Persistent impairment of
esophageal mucosal integrity
• Hypersensitivity of esophagus
• Abnormal of LES
• Dysmotility of esophagus
• Esophagitis
• Functional heartburn
• Psychological co-morbidity
Reflux-related mechanism Non-reflux cause
Mechanisms of PPIs-refractory GERD
• Potassium chloride
• Ascorbic acid
• Quinidine
• Iron sulfate
• Doxycycline
• Tetracycline
• Alendronate
• Aspirin
• Naproxen
Common drug induced esophageal symptoms
• Non-compliance
• Inappropriate PPIs
administration
• Reduced PPIs
bioavailability
• Rapid PPIs metabolism
• PPIs resistance
• Non-acid reflux
• Hypersensitivity of esophagus
• Abnormal of LES
• Dysmotility of esophagus
• Esophagitis:pill,infection,
eosinophilic
• Functional heartburn
• Psychological co-morbidity
Related to PPIs Non-related to PPIs
Common causes of PPIs-refractory GERD
Poor compliance lack of response
60% adherence to PPI therapy
46% PPI taken before meal
70% primary care
20% of gastroenterologist
Advice taken at bedtime
Review PPIs used in refractory GERD
• Symptom, Medication and Lifestyle evaluation
• Upper endoscopy
• Esophageal manometry
• Ambulatory monitoring for reflux
Diagnostic tools for PPIs-refractory GERD
Lifestyle modification : weight reduction, head of bed
elevation, diet ,medication
Antisecretory drug : compliance and dosing time,
increasing dose, switching to another PPI
Add-on therapies with PPIs : alginates, H2RA at bed
time, baclofen (TLOSRs decrease)
Pain modulators : tricyclic antidepressant, trazodone,
selective serotonin reuptake inhibitors, citalopram
Endoscopic therapy : radiofrequency abration, transoral
incisionless fundoplication
Antireflux surgery : laparoscopy fundoplication
Therapeutic options for PPIs-refractory GERD
Lifestyle intervention Effect of intervention on GERD parameters
Sources of data
Recommendation
Weight loss (46,47,48) Improvement of GERD symptoms and esophageal pH
Case–Control Strong recommendation
for patients with BMI>25
or patients with recent weight gain
Head of bed elevation (50,51,52)
Improved esophageal pH and symptoms Randomized Controlled Trial
Head of bed elevation
with foam wedge or
blocks in patients with nocturnal GERD
Avoidance of late evening meals (180,181)
Improved nocturnal gastric acidity but not symptoms
Case–Control
Avoid eating meals with
high fat content within 2–3 h of reclining
Tobacco and alcohol cessation (182,183,184)
No change in symptoms or esophageal pH Case–Control
Not recommended to
improve GERD symptoms
Cessation of chocolate,
caffeine, spicy foods, citrus, carbonated beverages
No studies performed No evidence Not routinely
recommended for GERD
patients. Selective
elimination could be
considered if patients
note correlation with
GERD symptoms and
improvement with elimination
BMI, body mass index; GERD, gastroesophageal reflux disease
Am J Gastroenterol 2013; 108:308–328
Efficacy of lifestyle interventions for GERD
Gamma-aminobutyric acid B receptor agonist
Reduced TLESR rate by 40 to 60 percent
Reduced reflux episodes by 43 percent
Increased lower esophageal sphincter basal pressure
Accelerated gastric emptying
Reduced weakly acidic and bile reflux and
gastroesophageal reflux-related symptoms
Doses up to 20 mg three times daily Gastroenterology 2000;18:370
Gut 2003;52:1397
Aliment Pharmacol Ther 2012
Baclofen
Drug crosses the blood-brain barrier, a variety of
central nervous system (CNS)-related side effects
may occur
Include somnolence, confusion, dizziness,
lightheadedness, drowsiness, weakness, and
trembling.
The side effects are an important limiting factor in the
routine usage of baclofen in clinical practice.
Usually begin by giving 10 mg twice daily
Baclofen
1. Optimize PPI therapy + Lifestyle modification
Careful to interview to assess symptom, med, LSM
Good compliance and appropriate dosing
Once daily dose, before meal (15 – 30 min)
Increase PPI to twice daily (morning and evening)
Switching to another PPI
Add-on-therapy with alginates or H2-RA at bedtime
20-30% symptomatic improvement
If symptoms persist
Step-by-step management of PPIs-refractory GERD
Typical esophageal symptom
Upper endoscopy
-Erosive esophagitis
-Eosinophilic esophagitis
-Abnormal anatomy
-Specific treatment
Atypical symptoms
Refer to ENT, pulmonary or
allergy
2. Further work – up
Step-by-step management of PPIs-refractory GERD
Upper endoscopy Erosive esophagitis
CMV esophagitis
Candida esophagitis
Herpetic esophagitis
Normal If normal finding
3. Further work - up
• Reflux monitoring : 2 key issues to consider
» PPI : Stop or on PPI during reflux monitoring
» Technique : Catheter – base pH
Wireless pH
Impedance – pH
• Result from reflux monitoring may reveal
A. PPI failure with ongoing acid reflux
B. Adequate acid control but ongoing symptomatic non
acid reflux
C. No reflux
Step – by – step management of PPIs – refractory GERD
Establish diagnosis, pathophysiology or mechanism
Step-by-step management of PPIs-refractory GERD
4. Treatment : should be tailored to the specific
underlying mechanism
Step-by-step management of PPIs-refractory GERD
Functional
heartburn
Acid sensitive
esophagus
NERD
Pain modulator
SSRIs
Tricyclic
SSRIs
(Citalopram)
Surgery
TLOSR inhibitor
(Baclofen)
Surgery
Algorithm for refractory GERD management
Am J Gastroenterol.2013;108:308-28.
REFRACTORY GERD
Optimize PPI therapy
Exclude other etiologies
No response
Typical symptoms Atypical symptoms
Upper Endoscopy
Normal
Specific treatment REFLUX
MONITORING
Referral to ENT, pulmonary, allergy
Abnormal (ENT, pulmonary, Or allergic disorder)
Specific treatment
High pre test probability of GERD Low pre test
probability of GERD
Test off medication with pH or impedance-pH
Test on medication with impedance-pH
Abnormal (eosinophilic
esophagitis, erosive esophagitis, other)
REFRACTORY GERD
Algorithm for refractory GERD management
Gut. 2012;61(9):1340-54.
Functional
heartburn
Acid sensitive
esophagus
NERD
Positive
Negative
Pain modulator
SSRIs
Tricyclic
SSRIs
(Citalopram)
Surgery
TLOSR inhibitor
(Baclofen)
Surgery
Pain modulator
SSRIs
Tricyclic
Test “off” PPI with pH
or impedance pH
Test “on” PPI with
impedance pH
SS
Management of PPIs-refractory GERD are
1.Careful history,optimization of PPIs therapy and
lifestyle modification.
2.If non-responder; consider investigation for others
diagnosis and mechanism of GERD by upper
endoscope and ambulatory reflux monitoring.
3.Treatment should be tailored to the specific underlying mechanism of patient PPIs failure.
Summary
Thank you
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