Extraesophageal Reflux: When Empiric Therapy Doesn’t Work

Andrew Coughlin, MD Michael Underbrink, MD, FACS The University of Texas Medical Branch (UTMB Health) Department of Otolaryngology Grand Rounds Presentation January 29, 2013

Outline

• Scope of Extra-esophageal Reflux

• Relavent Anatomy and Physiology

• Describe Extra-esophageal Reflux Syndromes

• Workup of Empiric Treatment Failures

• Indications for Surgical Therapy

• Results of Surgical Therapy

• Discuss my approach to the PPI resistant patient

Impact of Reflux

• 25% of adults experience reflux monthly

• 5-10% experience reflux daily

• PPI’s 3rd most prescribed medication

– $13.6 billion annually 2009

Montreal Consensus 2006

• GERD defined as:

“a condition that develops when the reflux of the stomach contents causes Troublesome symptoms and/or complications”

• Troublesome:

“adversely affects an individuals well being”

Kahrilas et al.

Metaplasia

http://sitemaker.umich.edu/betrnet/significance

Montreal Classification

Yuksel et al.

Relevant Anatomy

Esophageal Anatomy

http://classconnection.s3.amazonaws.com/474/flashcards/538474/png/esophageal_anatomy1307324173480.png

Nonkeratinizing Stratified Squamous Epithelium

http://stevegallik.org/sites/histologyolm.stevegallik.org/htmlpages/HOLM_Chapter02_Page19.html

Laryngeal Mucosa

http://www.medicalhistology.us/twiki/bin/view/Main/RespiratorySystemAtlas09

Esophageal Sphincters

• Upper Esophageal Sphincter

– Inner circular layer associated with cricopharyngeus

• Lower Esophageal Sphincter

– Opens with peristalsis

– Resting tone 15-45mm Hg

Physiology of Parietal cell

http://www.hopkins-gi.org/GDL_Disease.aspx?GDL_Cat_ID=AF793A59-B736-42CB-9E1F-E79D2B9FC358&GDL_Disease_ID=80AD1118-6659-4B04-B560-71B95E3B7FA9

Empiric Therapy for Patients with Symptoms

• GERD

– Heartburn

– Epigastric pain

– Shortness of Breath

– Regurgitation

– Belching

– Chest Pain

• LPRD

– Dysphagia

– Sore Thorat

– Halitosis

– Voice Changes

– Cough

– Throat Clearing

– Globus Sensation

Cochran Review on Medical Therapy

• Review of RCT’s (van Pinxteren et al. 2006)

– PPI’s vs H2-Blockers vs Prokinetic medications

• Studies evaluating empiric therapy (19)

– PPI significantly better at relieving reflux symptoms (RR: 0.37)

• Studies evaluating ENRD (17)

– PPI significantly better at relieving reflux symptoms (RR: 0.73)

Scrutiny over reflux symptoms

Acid Overproduction

-or-

LES Dysfunction

Should we be using PPI’s so casually?

Fractures (Yu et al.)

• Meta-analysis 10 studies looking at: – PPI or H2 blocker usage versus control

– In general included postmenopausal and older men

– No RCT’s mainly case control and prospective observational

– Modest increase risk of fractures (M=F) • Hip RR = 1.3

• Spine RR = 1.56

– H2 – Blockers not associated with increased risk

Effects on Plavix (Bhatt)

• DB/PC/RCT of Clopidogrel plus PPI or placebo

• Approximately 3800 patients each arm

• Results

– GI event (1.1% vs 2.9%)

– Cardiovascular Events (4.9% vs 5.7%)

***No significant increases in the risk of cardiovascular events even in high-risk subgroups

Dependence Issues

• 2009 Reimer et al. (33) – Randomized, Double Blinded, Placebo controlled trial

of 120 normal patients • 12 weeks of placebo

• 8 weeks of Nexium 40mg/day then 4 weeks placebo

– Measured GI symptom rating scores (GSRS) weekly

– Results • Both groups similar at baseline

• Higher GSRS (worse) score at 10, 11, 12 weeks

• 44% vs 15% reported >1 acid related symptom week 9-12

*If you start a PPI, you may not be able to stop it

Extra-esophageal Syndromes

Montreal Classification

Yuksel et al.

Asthma

Reflux and Asthma Cycle

Direct Injury from Reflux

Asthma Exacerbation

Increased Cough

Increased Negative

Intrathoracic Pressure

Asthma

• Asthma not only is exacerbated by reflux but can also make it worse

– Steroids and beta agonists relax the LES

Asthma

• Leggett et al.

– 52 patients with difficult to control asthma

– Dual Probe pH monitoring

– 39 patients (75%) had evidence of reflux

• 55% at distal probe (5cm above LES)

• 34.6% at the proximal probe (15cm above distal probe)

– Only 16% of coughing episodes were associated with reflux

Asthma

• American Lung Association Asthma Clinical Research Centers – DB/PC/RCT of 412 patients with uncontrolled

asthma and no reflux symptoms

– Nexium 40mg BID versus Placebo for 24 weeks

– Ambulatory 24 hour pH monitoring at baseline

– Results • 40% of patients had asymptomatic reflux

• No significant difference in asthma exacerbations or PFT’s with treatment

Asthma

• Kiljander et al.

• DB/PC/RCT 770 subjects with moderate to severe asthma

• Nexium 40mg BID vs. Placebo for 16 weeks

• Results

– Significant improvement in PFT’s in patients with pretreatment nocturnal symptoms and GERD versus patients without pretreatment GERD or nocturnal symptoms

Asthma Recommendation

• Empiric treatment is not helpful unless patients are symptomatic for GERD

• Especially helpful with nocturnal symptoms

• Shoot for lowest effective dose

• If not responsive perform additional workup

Chronic Cough

Chronic Cough

• Present >8 weeks

• 5 most common causes (90% of cases)

– Postnasal drip

– Asthma

– Gastroesophageal reflux

– Chronic Bronchitis

– ACE inhibitor

Chronic Cough (Jacobs)

• Triggered by

– Irritation of the respiratory tract by aspiration

– Stimulation of an esophageal-bronchial cough reflex (Vagal mediated)

Chronic Cough

• 75% of patients with GER-related cough do not exhibit typical reflux symptoms

• Low specificity of studies to diagnose chronic cough – EGD showed only 15% esophagitis in patients with

chronic cough (Baldi et al.)

• Success ill-defined – Only 35% of patients with abnormal 24 hour pH

measurement showed a response to therapy (Ours et al.)

Treatment Chronic Cough

• Poe et al.

– 79% of patients with cough secondary to GER responded to daily PPI

• Baldi et al.

– 60% resolution of symptoms

– Lansoprazole 30mg BID for 4 weeks then BID or daily therapy for 12 weeks

– No difference between groups

Chronic Cough Recommendation

• Treat with BID PPI for 12 weeks and if no improvement

– Reassess for PND/Asthma/Bronchitis/etc.

– Move forward with additional studies to determine if reflux is present

Laryngitis

Laryngitis

• Symptoms

– Hoarseness

– Globus sensation

– Dysphagia

– Cough

– Mucous production

– Sore throat

– Halitosis

– Throat clearing

• Signs

– Erythema of mucosa

– Vocal cord edema

– Interarytenoid pachydermia

– Laryngeal mucous

– Subglottic edema

– Granulomas

Nonspecific Nature of LPR

• 80-90% of normal patients will have “reflux findings” on laryngoscopy (Milstein et al.)

• Hypopharyngeal reflux can be found in 19-43% of normal volunteers on pH monitoring (Joniau et al.)

• pH probe-documented LPR in 50% despite LPR symptoms in 69% (Koufman et al.)

Differences between GERD and LPRD (Koufman et al)

• Esophagitis is rare in LPRD (25%)

• Daytime vs Nighttime reflux

• UES vs LES

• Short vs Prolonged acid exposure

• Laryngeal vs Esophageal irritation

• BID vs Daily PPI therapy

Position statement by the AAO 2002

Laryngitis Recommendations

• BID PPI for 6 months

• Plus or minus H2-blocker

• Additional studies if patients do not respond

Chest Pain

Chest Pain

• Recurring chest pain with negative cardiac workup

– Burning

– Pressure-like

– Substernal

– Occurring with exercise

What makes you think reflux?

• Post-prandial pain

• Continues for hours

• Retrosternal without radiation

• Relieved with antacids

• Pain that disturbs sleep (Yuksel et al.)

***CARDIAC CAUSES RULED OUT***

Therapy for Non-Cardiac Chest Pain

• Achem et al. – 36 patients with pH study positive reflux and noncardiac chest pain – Omeprazole 20mg vs Placebo – Symptoms improvement in 81% vs 6% of patients

• Pandak et al. – 37 patients in a crossover study evaluating Omeprazole 40mg BID vs

Placebo x 14 days/21 day washout then switch. – EGD, Esophageal Manometry, Dual Probe pH evaluation at baseline – 71% of patients treated with omeprazole had significant symptoms

improvement – 95% of patients with proven GER responded – Reflux investigations not sensitive and were much more expensive

than empiric therapy

Chest Pain Recommendations

• Empiric treatement with PPI for 2-3 months

• Taper to lowest effective dose for responders

• Additional investigations for non-responders

If patients respond to treatment…Great!!!

If patients fail therapy is it:

Resistant Reflux or

Something Else

Differential Diagnosis

• Asthma/Cough/Laryngitis

– Non-acidic reflux

– Eosinophilic Esophagitis

• Chest Pain

– Achalasia

– Strictures

– Nutcracker esophagus

– Diffuse esophageal spasm

Workup

• Physiologic Testing

– EGD

– 24 hour PH Probe

– Intraluminal Impedence

– Esophageal Manometry

– Upper GI or Barium studies

EGD or TNE

• Direct visualiztion of the esophagus

• Ability to biopsy for Barrett’s or Strictures

• Does not always show esophagitis in patients with reflux symptoms

Mucosal Breaks

Epithelial slough/erythema adjacent to normal tissue

Eosinophilic Esophagitis

EE vs GERD

EE vs GERD

24 hour pH Probe Testing (Dual Probe)

• Reserved for patients who have failed therapy or if diagnosis is unclear

• Ability to

• Quantify the number and duration of reflux episodes

• Differentiate between upright and supine reflux

• Correlate these events with subjective symptoms

• No consensus on what qualifies as LPRD

• >0 reflux events/hour

• >4 reflux events/hour

Dual PH Probe Tracing

Intraluminal Impedence (Castell)

• Very helpful in evaluation of non-acidic reflux

• Measures directional electrical resistance changes to gas, liquid or solid bolus in the esophagus

• Measures level of reflux

• Can be used in conjunction with pH monitoring to determine the type of reflux that is occurring

Impedence Schematic

Impedence Graph

Impedence and pH testing

http://www.nature.com/ajg/journal/v102/n3/fig_tab/ajg2007119f5.html#figure-title

Esophageal Manometry

• Measures

• Peristalsis

• Esophageal Sphincter Pressure

• Can reveal motility problems that can cause changes in surgical plan in up to 10% of patients (i.e. subtotal fundoplication)

Manometry Example

Manometry Diseases

http://www.nature.com/gimo/contents/pt1/fig_tab/gimo20_F2.html

Upper GI Series

• Excellent for anatomic evaluation with regards to the LES and the Hiatus

• Hiatal Hernias

• Strictures

• Shortened esophagus

• Qualitative Evaluation of esophageal peristalsis

Diffuse Esophageal Spasm

Achalasia

http://www.patient.co.uk/doctor/Achalasia.htm

We have all these tests but what do the surgeons say about offering

surgery?

Nissen Fundoplication

• Dr. Rudolf Nissen

• First described in 1950’s

• Laparoscopic Nissen has come into favor (Stefanidis et al) – Improved cosmesis

– Reduced morbidity

– Decrease hospital stay

– Decreased respiratory complications

– Faster recovery

Nissen Procedure

. SAGES Consensus Statement

• GERD diagnosis with one of the following:

– Mucosal break

– Barrett’s Esophagus on biopsy

– Peptic stricture with no malignancy

– Positive pH-metry

***Grade A recommendation

SAGES: Society of American Gastrointestinal and Endoscopic Surgeons

SAGES Consensus Statement

• pH probe studies (PPI and H2-blocker free interval) – Total time with pH<4, 5cm above LES – Composite score of:

• Total esophageal acid exposure (time) • Upright acid exposure (time) • Supine acid exposure (time) • Number of episodes • Number of episodes lasting >5min. • Duration of longest episode

***Wireless 48 hour monitoring is equivalent

SAGES Consensus Statement

• No recommendation for mandatory preoperative manometry – Can identify achalasia or other surgical modifying

conditions

• Barium swallow not mandatory but can be helpful to delineate anatomy

• Gastric emptying studies to not help preoperatively, but can identify nerve injuries after the first surgery

SAGES Criteria

• Indications for surgery

– Failed medical management

– Opt for surgery instead of medical management despite success

– Complications of GERD

• Barrett’s Esophagus

• Peptic Stricture

– Have extra-esophageal manifestations

Predictors of Success

• Francis et al. • Retrospective review of 237 patients referred for

extraesophageal reflux resistant to therapy • 27 patients treated with Nissen for objective reflux findings • EGD, pH monitoring, Impedence, Manometry all performed • Results

– 59% at least partial improvement in symptoms – Better results in patients with heartburn +/- regurgitation at

initial visit, a hiatal hernia, and pH<4 for more than 12% of time on pH monitoring

– Manometry, Impedence, and EGD did not predict success

Surgery vs PPI Therapy

• Lundell et al.

• Randomized trial of Surgery vs PPI

– 155 patients in each arm

– 71 in medical group and 53 in surgical group at 12 yrs

• Reassessed by EGD and symptomatology

• Results

– 53% of patients treated with surgery in remission

– 40% of patients treated with medicine in remission

Surgery more effective than medical therapy?

• Wileman et al. Cochran review (2010) • Primary outcomes:

• Reflux Specific QOL (GSRS) • Heartburn • Regurgitation • Dysphagia

• 4 RCT studied and over 1200 patients • Significant improvement in patients treated with Surgery

• Still true at 3 months and 1 year post-op QOL measures

• Surgery more costly, low complication rate (1.7%), small % patients have persistent dysphagia (4.6%)

• Medical therapy more likely to have persistent heartburn or regurgitation issues

Cost effectiveness study of surgery versus medical therapy

• Thijssen et al. • Systematic review of cost effectiveness studies • 4 articles reviewed

– 2 favored medical management • Lower initial costs • More symptom free months

– 2 favored surgical management • More expensive • More Quality adjusted life years than PPI

• Studies looked specifically at 3rd party • Ultimately more long term data needed as most is

inconclusive

New Therapy on the Horizon

• The real problem is LES dysfunction • GABA agonists (Baclofen and R-Baclofen)

– Show excellent response at: • Decreasing transient hypotension of the LES • Decreasing reflux events

– Poorly tolerated due to central effects and dosing

• Currently developing peripheral agonists and slow-release drugs

• Good initial results in experimental trials when added to PPI

• Reduced reflux and heartburn events

Conclusions

• Start with empiric therapy and don’t order expensive tests

– If patients succeed with PPI therapy Taper LED

– If patients fail Confirm reflux with pH probe or EGD

• Impedence testing/Manometry/Upper GI/Barium Swallow are not predictors of surgical success

• Refer to General Surgeons only if you have documented reflux

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