The Laryngoscope
C 2011 The American Laryngological,
V
Rhinological and Otological Society, Inc.
Traditional Reflux Parameters and Not Impedance Monitoring Predict
Outcome After Fundoplication in Extraesophageal Reflux
David O. Francis, MD, MS; Marion Goutte, BS; James C. Slaughter, DrPH; C. Gaelyn Garrett, MD;
David Hagaman, MD; Michael D. Holzman, MD, MPH; Michael F. Vaezi, MD, PhD
Objectives/Hypothesis: Fundoplication is considered in patients with refractory extraesophageal reflux symptoms.
However, postoperative symptom resolution is inconsistent. This analysis investigates which presenting symptoms and preoperative objective parameters predict postoperative symptom improvement.
Study Design: Retrospective cohort study.
Methods: A total of 237 patients referred for extraesophageal reflux symptoms refractory to medical therapy underwent
esophageal function testing. Fundoplication was performed in 27 patients with objective evidence of gastroesophageal reflux
disease. Symptomatic improvement was assessed at postoperative intervals. Logistic regression determined which symptoms
and objective parameters predicted improvement of the presenting extraesophageal reflux symptom.
Results: Overall, 59% of patients reported at least partial improvement of their presenting extraesophageal symptom after fundoplication. Predictors of symptomatic improvement were the presence of heartburn with or without regurgitation
concomitant to their primary presenting symptom (odds ratio [OR], 6.6; 95% confidence interval [CI], 0.97-44.9; P ¼ .05) and
pH < 4 more than 12% of a 24-hour period (OR, 10.5; 95% CI, 1.36-81.1; P ¼ .02). Probability of postoperative extraesophageal reflux symptom improvement was 90% if both conditions were present.
Conclusions: Both heartburn with or without regurgitation and esophageal pH < 4 more than 12% of a 24-hour period
predicted postfundoplication resolution of the presenting extraesophageal reflux symptom.
Key Words: Extraesophageal reflux, laryngopharyngeal reflux, gastroesophageal reflux disease, fundoplication, chronic
cough, surgery.
Level of Evidence: 2b.
Laryngoscope, 121:1902–1909, 2011
INTRODUCTION
Extraesophageal reflux (EER) is widely implicated
in the etiology of laryngeal, pharyngeal, and pulmonary
symptoms.1 Despite significant attention to this condition, controversy continues regarding its diagnosis and
management. Currently, most patients with signs and
symptoms attributed to EER are empirically treated
with proton pump inhibitors (PPIs). However, symptomatic improvement on a PPI is not as consistent in
these patients compared to those with more classic gastroesophageal reflux disease (GERD).2 Patients with
presumed EER refractory to initial empiric medical therapy are often referred for testing to evaluate for the
presence of underlying GERD and possible consideration
for surgical fundoplication.
From the Vanderbilt Voice Center, Department of Otolaryngology
(D.O.F., C.G.G.); Division of Gastroenterology, Hepatology and Nutrition
(M.G., M.F.V.); Department of Biostatistics (J.C.S.); Allergy, Sinus and Asthma
Program (D.H.); and Department of Surgery (M.D.H.), Vanderbilt University
Medical Center, Nashville, Tennessee, U.S.A.
Editor’s Note: This Manuscript was accepted for publication March
24, 2011.
The authors have no funding, financial relationships, or conflicts
of interest to disclose.
Send correspondence to David O. Francis, MD, MS, Vanderbilt
Voice Center, Department of Otolaryngology, Bill Wilkerson Center, Vanderbilt University Medical Center, Medical Center East, South Tower,
1215 21st Avenue South, Suite 7302, Nashville, TN 37232-8783.
E-mail: [email protected]
DOI: 10.1002/lary.21897
Laryngoscope 121: September 2011
1902
Surgical fundoplication may be successful in improving reflux symptoms in more than 90% of patients with
typical symptoms of GERD and, in a recent Cochrane
review, was suggested to be more effective than medical
treatment of GERD in the short to medium term.3
Although, the relative effectiveness of medical to surgical
management of GERD may be debatable, it is generally
accepted that both are effective in reducing esophageal
acid exposure and relieving patient symptoms. However,
the role of antireflux surgery for EER symptoms refractory to aggressive acid suppressive therapy is unclear. In
a systematic review by Iqbal et al., 15% to 95% of patients
with EER symptoms improved after fundoplication.4 This
broad variability underscores our poor understanding of
which patients with refractory EER symptoms might benefit from surgery.
A concurrent control study in patients with chronic
laryngeal symptoms refractory to PPI therapy did not
find Nissen fundoplication to be of benefit. One year after surgery, only 10% of patients noted improvement in
laryngeal symptoms, but signs of laryngopharyngeal
reflux on laryngoscopy improved in 80% of patients.5
Recent controversy surrounds the role of surgical fundoplication in patients with PPI-refractory symptoms who
have abnormal nonacid reflux by impedance monitoring.
In the only study assessing the role of fundoplication in
patients with chronic cough refractory to PPI therapy,
the authors suggested significant improvement of EER
Francis et al.: Fundoplication Outcome Assessment in EER
in those with abnormal impedance monitoring when
tested on therapy.6 However, this finding is yet to be independently validated.
Thus, the aims of this retrospective cohort study
were to 1) assess symptomatic response to surgical fundoplication in patients with EER who were either partial or
nonresponders to PPI therapy; and 2) to identify predictors for symptom response with fundoplication based on
patient demographics and baseline esophageal physiologic
tests including pH and impedance monitoring.
MATERIALS AND METHODS
The study was performed in accordance with the Declaration of Helsinki, good clinical practice and applicable regulatory
requirements. The Vanderbilt University Institutional Review
Board approved the study protocol (IRB#101219).
Study Design and Patient Population
The study population consisted of patients with chief complaint of EER refractory to PPI therapy referred for evaluation
and treatment for possible reflux-associated symptoms. Refractory symptom was defined as less than 50% improvement in the
chief complaint after at least 12 weeks of twice daily PPI therapy. The following information was collected for all participants:
presence, severity and frequency of GERD (heartburn 6 regurgitation) and extraesophageal symptoms (cough, hoarseness,
throat clearing, sore throat, globus sensation, postnasal drip
symptoms, chest pain), current medication as well as information on subject demographics (age, sex, race, body mass index),
history of alcohol and tobacco use, and presence of voice/laryngeal and nasal symptoms.
Patients underwent esophagogastroduodenoscopy (EGD),
wireless 48-hour pH monitoring and esophageal motility testing
off acid suppression to assess the baseline esophageal motility
and acid exposure. They also underwent 24-hour impedance/pH
monitoring while on twice daily PPI therapy to determine the
presence of nonacid reflux despite acid suppression. Symptom
index (SI) and symptom association probability (SAP) were
hand-calculated based on previously described methods for both
wireless pH monitoring off therapy and impedance/pH monitoring on therapy.7,8 Presence and size of hiatal hernia were
determined at endoscopy, and severity of esophagitis was
graded by Los Angeles Classification.9 Patients with abnormal
esophageal acid exposure at baseline (off PPI therapy) were
offered laparoscopic surgical fundoplication. Inclusion criteria
were age >18 years, chronic EER symptoms refractory to PPI
therapy, and presence of abnormal baseline esophageal acid exposure. Patients were excluded from the study for the following
reasons: Barrett’s esophagus; history of alcoholism; prior ear,
nose, and throat or gastrointestinal surgery; or unwillingness to
participate in the study. Subjects who agreed to undergo fundoplication had a complete preoperative evaluation including
chest X-ray, 12-lead electrocardiogram, blood testing (complete
blood count, basic metabolic panel, and coagulation panel), and
a consultation with the surgeon (M.D.H.) and an anesthesiologist.
Postoperatively, patients were followed both in the Surgery and Esophageal Centers to assess response of EER
symptoms to fundoplication and to identify any potential
adverse outcome from the surgical intervention. All patient
symptoms were assessed by using a standard questionnaire at
follow-up. The patients were asked to give percentage improvement of their primary symptoms on a Likert scale. Greater
than 50% improvement compared to baseline differentiated
‘‘responders’’ from ‘‘nonresponders.’’ Resolved symptoms were
Laryngoscope 121: September 2011
defined as complete resolution of the primary chief complaint,
and improvement was defined as greater than 50% symptom
improvement compared to baseline. Predictors of treatment success were determined based on presurgical demographic and
esophageal physiologic testing on and off PPI therapy.
Wireless pH Monitoring
Ambulatory pH monitoring was performed for 48 hours
using a wireless monitoring device (Given Imaging, Inc.,
Duluth, GA). Study patients were instructed to stop taking all
PPIs and H2-receptor antagonists for at least 14 days before
undergoing evaluation. Wireless capsules were calibrated by
submersion in buffer solutions at pH 7.0 and pH 1.0 and then
activated by magnet removal. Patients underwent EGD with
conscious intravenous sedation for visual anatomic inspection
and distance measurements from the incisors to the squamocolumnar junction. Capsules were then placed using the
manufacturer’s delivery system at 6 cm above the squamocolumnar junction and attached with vacuum suction of 600 mm
Hg. Capsule placement was confirmed at endoscopy. After successful placement, patients were given wireless pH recorders to
wear about their waists or to keep within 3 to 5 feet at all
times. Recording devices receive pH data sampling transmitted
by the capsule at 433 Hz with 6-second sampling intervals.
Patients were instructed to perform their normal daily activities
and dietary practices. Distal esophageal pH recording was conducted for a total of 48 hours. During this time, patients kept
diaries of meal times, symptoms, and supine position.
After completion of the 48-hour study, data were downloaded from recording devices to dedicated computers using
Datalink software (Sandhill Scientific, Inc., Highlands Ranch,
CO). Patient diary information was manually entered into the
computer-based record. Measurements of the total, upright, and
supine percentages of time when esophageal pH was below 4
were determined for day 1 and day 2 of the wireless study. Acid
exposure time (% total time pH < 4) greater than 4.2% per day
was considered abnormal.10
Esophageal Motility Testing
High-resolution manometry (Sierra Scientific Instruments,
Inc., Los Angeles, CA) was used to measure the location of the
lower esophageal sphincter (LES) before placement of the impedance pH. A solid-state assembly with 36 circumferential
sensors spaced at 1-cm intervals (outside diameter, 4.2 mm)
was used. This device detects pressure over a length of 2.5 mm
in each of the 12 radially dispersed sectors of the 36 pressuresensing elements. The sector pressures are averaged, making
the sensors a circumferential pressure detector. Before recording, the transducers were calibrated at 0 and 100 mm Hg using
externally applied pressure. Using this device, LES was measured and the proximal location noted for placement of the
impedance -pH catheter.
Combined Impedance-pH Monitoring
Patients underwent impedance-pH monitoring while on at
least twice daily PPI therapy for 1 month before evaluation.
They were instructed to fast for 4 hours before testing. Each
patient’s primary symptom complaint was recorded as part of
the preprocedure evaluation. Patients were given diaries to record time of start and end of meals, position changes (upright
or recumbent) and occurrence of symptoms during 24-hour impedance and pH monitoring.
Impedance testing was performed by using a combined impedance-pH monitoring device (Sandhill Scientific, Inc.,
Highlands Ranch, CO) comprising a data recorder (Sleuth System; Sandhill Scientific, Inc.) and a 2.1-mm-diameter polyvinyl
Francis et al.: Fundoplication Outcome Assessment in EER
1903
catheter embedded by one pH and six impedance sensors at predefined positions. The pH sensors were calibrated before
placement by using standardized buffer solutions at pH 4.0 and
7.0 as recommended by the manufacturer. The catheter was
placed intranasally so that the esophageal pH sensor was positioned 5 cm above the manometrically defined upper border of
the LES. Intraluminal impedance was measured at 3, 5, 7, 9,
15, and 17 cm above the LES. Data sampling frequency for both
impedance and pH sensors was 50 Hz. Studies were performed
for 18 to 24 hours, after which patients returned to the lab for
catheter removal and data review.
Data were downloaded from the recorder and analyzed
using BioView Analysis software (Sandhill Scientific, Inc.).
Reflux episodes were identified by computerized detection
(Autoscan; Sandhill Scientific, Inc.) of proximally directed
decreases in impedance. Tracings were also manually reviewed
by an experienced investigator (M.F.V.) to confirm accuracy and
correct any errors. Total, upright, and supine reflux events
were recorded. Acid reflux events were defined as those occurring with pH less than or equal to 4, and nonacid reflux events
were defined as those occurring at pH greater than 4. For impedance parameters, total number of reflux events greater than
48 was considered abnormal.11–14
Surgical Fundoplication
Patients with objective evidence of GERD on wireless pH
and/or endoscopy were counseled about treatment options
including continued medical management and fundoplication
surgery. Medical management involved continued twice-daily
PPI. All patients opting for surgery were evaluated and had
surgical fundoplication performed by the same surgeon (M.D.H.).
The procedure was performed on an elective basis, agreed
upon by the subject and the surgeon. A standard 360 (Nissen)
laparoscopic fundoplication was performed in all subjects. None
of the patients required conversion to an open procedure. Surgical technique used the standard five-port laparoscopic
abdominal setup. The procedure consisted of abdominal insufflation with carbon dioxide gas, retraction of the left lobe of the
liver, dissection and identification of the right and left diaphragmatic crura, and takedown of the short gastric vessels using a
harmonic scalpel. After the diaphragmatic crura were reapproximated using two to three interrupted nonabsorbable
sutures, the posterior fundus of the stomach was passed
through the retroesophageal window to create the fundoplication. A bougie was utilized in all cases to assist in calibration of
the fundoplication. All patients then received routine postoperative care.
Statistical Analysis
Fig. 1. Study flow diagram. EER ¼ extraesophageal reflux; PPI ¼
proton pump inhibitor.
yngitis, and postnasal drip. Resolution was graded by the
patients as ‘‘none,’’ ‘‘partial,’’ or ‘‘complete’’ and dichotomized for
analysis into ‘‘responders’’ (50% improvement) or ‘‘nonresponders’’ (<50% symptom improvement). Patient demographics and
presurgery esophageal physiologic test parameters were compared for those with and without symptom improvement based
on 1-year postoperative response. All statistical tests were performed using Stata/SE 10 (Stata Corporation, College Station,
TX). Univariate comparisons were performed with v2 and Wilcoxon rank sum tests. Analysis of variance or covariance was
used where appropriate and adjusted for multiple comparisons.
Multivariable logistic regression was used to estimate the effect
of covariates on the probability of presenting EER symptom
improvement.
RESULTS
Patient Population
Data were collected and stored at the secure web-based
Vanderbilt Digestive Disease Center REDCap (Research Electronic Data Capture; 1 UL1 RR024975 NCRR/NIH). REDCap is
an application designed to support data capture for research
studies providing 1) an intuitive interface for validating data
entry; 2) audit trails for tracking data manipulation and export
procedures; 3) automated export procedures for seamless data
downloads to common statistical packages; and 4) procedures
for importing data from external sources. There was strict control and supervision of the data entry and access for this study.
Both primary presenting extraesophageal symptoms and
secondary concomitant presence of heartburn with or without
regurgitation were surveyed at the initial consultation and postoperatively. Primary presenting symptoms were categorized
into ‘‘cough,’’ ‘‘asthma/wheezing,’’ or ‘‘other.’’ ‘‘Other’’ included
throat clearing, shortness of breath/pneumonia, hoarseness/lar-
A total of 335 patients were referred to Vanderbilt
Swallowing and Esophageal Disorders Clinic with refractory extraesophageal symptoms between 2005 and 2010
(Fig. 1), of which 237 underwent physiologic testing for
GERD. In this group, 182 (77%) had objective evidence
of GERD based on abnormal esophageal acid exposure
off PPI therapy of which 27 (14.8%) underwent laparoscopic surgical fundoplication; median age (interquartile
range [IQR]): 56 (49–66), BMI: 30.9 (27–34.3), 100% caucasian, 78% female. Overall, cough (44%, 12/27) and
asthma/wheezing (22%, 6/27) were the most common
presenting EER symptoms among patients who chose to
undergo surgery (Table I). Hiatal hernia was present in
63% and esophagitis in 8% of patients. Median (IQR)
LES pressure (LESp) was 10.8 mm Hg (0.0–16.2), and
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Francis et al.: Fundoplication Outcome Assessment in EER
1904
TABLE I.
Demographic and Physiologic Parameters of Surgery Versus Continued Medical Therapy.
Surgery (N ¼ 27)
Medication (N ¼ 155)
P
56 (49–66)
54 (42–61)
.20
100
78
91
69
.11
.36
30.9 (27–34.3)
28.4 (25.2–32.6)
.09
44.4
30.2
.01
22.2
7.3
33.3
62.4
Demographics
Age*
Caucasian, %
Female, %
BMI*
1 symptom, %
Cough
Asthma/wheezing
Other†
EGD
Hiatal hernia, %
Hernia size (cm)*
Hernia size >4 cm, %
63
33
.04
3.5 (2–5)
26.7
3 (2–4)
20
.39
.57
8
22
.12
Esophagitis, %
Wireless pH (% off therapy)‡
Total time pH < 4*
12.8 (6.2–15.7)
8.6 (5.8–12.6)
.09
Upright time pH < 4
16.1 (9.5–23.8)
11.3 (7.6–17.4)
.05
Supine time pH < 4
Abnormal SI, %*
1.8 (0.5–11.6)
7.7
2.5 (0–8.2)
20.8
.48
.26
38.5
35.0
.80
59.5 (45–86)
36 (16–48)
<.01
8 (3–26)
6 (2–15)
.40
43.5 (26–56)
40.9
24 (9–43)
16.7
<.01
.03
36.4
20.8
.17
Abnormal SAP, %*
Impedance (on therapy)
No. of reflux episodes (acid þ nonacid)*
No. acid reflux episodes*
No. nonacid reflux episodes*
Abnormal SI, %
Abnormal SAP, %
*Median (interquartile range).
†
Throat clearing, shortness of breath, hoarseness, laryngitis, postnasal drip.
‡
Values represent mean of the 2-day monitoring period.
BMI ¼ body mass index; EGD ¼ esophagogastroduodenoscopy; SI ¼ symptom index; SAP ¼ symptom association probability.
Postfundoplication patients were followed for a median (IQR) of 33 months (14–40). Response to surgery
was assessed at each visit and on an interval basis based
on clinic-visit symptom report. Initial visit was defined
as the first postoperative visit and occurred a median
(IQR) of 1 month after surgery (1–1). Last visit/contact
was the patient’s follow-up furthest from the surgery
date (median [IQR], 33 months [14–40]).
Incremental postoperative symptom improvement is
shown in Figure 2. The percentage of patients reporting
improvement at initial, 1-year, and last visit/contact
were 81%, 59%, and 56%, respectively (Fig. 2). Predictive model analyses were performed based on response
at 1-year after fundoplication because report of patient
improvement stabilized by this time point. At 1-year follow-up, 16 of 27 (59%) patients reported improvement in
their chief presenting symptom (48% complete resolution, 11% partial resolution). There was no difference in
length of follow-up between patients with and without
symptomatic improvement (median months of follow-up
[IQR]: responders, 27.5 (15–39) vs. nonresponders, 38
[14–40]; P ¼ .60).
There was no difference in response to surgery
based on primary presenting EER symptom (analysis of
variance, P ¼ .78; Table II) or patient demographics,
EGD, pH, impedance, or SI/SAP parameters between responders and nonresponders postfundoplication (Table II).
Manometry measurements were also not different
between groups (median LES pressure [IQR]: responders,
11.8 mm Hg [0–20] vs. nonresponders, 5.4 mm Hg [0–16];
P ¼ .56, median mean esophageal amplitude [IQR]: responders, 83.5 [56–102] vs. nonresponders, 71.5 [53–102];
P ¼ .95). However, among patients with postfundoplication symptom improvement, 85% had concomitant
baseline heartburn with or without regurgitation
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Francis et al.: Fundoplication Outcome Assessment in EER
percentage of time pH was less than 4 was 12.1% (8.5%–
15.6%). Compared to patients who continued medical
management (n ¼ 155), the surgery group had a higher
rate of hiatal hernia (63% vs. 33%, P ¼ .04) and upright
percentage time pH < 4 (16.1% vs. 11.3%, P ¼ .05; Table
I). Patients in the surgery group also had more total
reflux episodes (59.5 vs. 36, P < .01) and nonacid reflux
episodes (43.5 vs. 24, P < .01) as well as higher percentage abnormal SI and SAP. Demographic and physiologic
parameters for the two groups were otherwise similar.
Outcome and Predictors of Response
1905
In this study, we sought to quantify the effectiveness of surgical fundoplication among patients with both
medication-refractory EER symptoms and physiologic
evidence of GERD and, further, to identify what preoperative parameters enhance the probability of
surgical success at treating EER symptoms. Overall,
59% of patients experienced postoperative symptom
improvement. We also found that patients with concomitant classical GERD signs and symptoms were more
likely to experience EER symptom improvement postfundoplication than those with ‘‘silent reflux.’’ Preoperative
heartburn with or without regurgitation and esophageal
acid exposure of greater than 12% at baseline were significant predictors of response of the primary EER
symptom to antireflux surgery. In fact, there was a 90%
probability of symptom improvement if both were present. Impedance-pH parameters performed on therapy
were not predictive of EER symptom improvement
postfundoplication.
Our data provide unique and important insights
into the effectiveness of fundoplication surgery in a
select population of patients with medication-refractory
EER and objective GERD. To date, no study has applied
such strict inclusion criteria and has performed both impedance-pH on and wireless pH monitoring off therapy
with the goal of predicting what physiologic esophageal
parameters predispose to postoperative EER symptomatic improvement. Creating a predictive model to
identify who will benefit from surgical intervention for
EER symptoms is critical. Patients presenting with
chronic cough, refractory asthma, and other atypical
reflux symptoms are often desperate for a ‘‘magic bullet’’
to resolve their condition. We need to be educated and
realistic about surgery’s effectiveness and better understand who might benefit before exposing them to
associated risks. The role of surgical fundoplication in
treating EER patients refractory to PPI therapy remains
nebulous.15,16
Reported effectiveness of fundoplication for EER
symptoms varies from 15% to 95%4 and is largely attributable to disparate study design, patient selection, and
outcome metrics. In our population limited to subjects
with refractory reflux symptoms and objective evidence
of GERD, 59% had EER symptom improvement after
surgery. Other studies have used similar inclusion criteria.6,17 For example, Iqbal et al. identified 50 patients
meeting the same inclusion criteria and found that, at a
median follow-up of 41 weeks, 85% reported their result
as ‘‘satisfactory’’ with a mean reflux SI (RSI)18 decrement of 10 points.17 Although these results are subject
to recall bias due to retrospective outcome assessment, it
is interesting that 85% of patients had baseline concomitant heartburn with or without regurgitation and that
most of these patients (84%) had improved EER symptoms after fundoplication. This relationship is consistent
with our findings and those of previous studies.16,19
Mainie et al.6 used similar patient selection but did not
limit to patients with EER symptoms. Instead, their 19
subjects were heterogeneous: nine with typical (i.e.,
heartburn, regurgitation) and 10 with atypical presenting reflux symptoms (i.e., cough, asthma, throat
clearing). Power limitations prevented separate analysis
of these groups. Although 94% of subjects were asymptomatic at a mean of 14 months postoperatively, patient
heterogeneity restricts the ability to extrapolate their
findings to all patients with refractory EER symptoms.
Other studies differed in both patient selection and
outcome metrics. Westcott et al. identified 41 patients
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Francis et al.: Fundoplication Outcome Assessment in EER
Fig. 2. Incremental postoperative symptomatic improvement during follow-up period: 1-month, 12-month, and 33-month postoperative symptom report from surgery date.
compared to 55% who had no improvement (P ¼ .04).
Similarly, 44% of the responders had a hiatal hernia > 4
cm compared with 0% in nonresponders (P ¼ .06).
Distribution of baseline percent time pH < 4 for the
group is shown in Figure 3. Threshold of 12% for percentage time pH < 4 identified a significant difference
between responders and nonresponders. Specifically,
acid exposure greater than 12% was higher in the responder (75%) compared with nonresponder (22%) group
(P ¼ .02). Patients with greater than 12% baseline acid
reflux had 10.5-fold increased odds of improvement
(odds ratio [OR], 10.5; 95% confidence interval [CI],
1.36-81.1; P ¼ .02), and those with concomitant heartburn with or without regurgitation had 6.6-times
increased odds of postoperative symptomatic improvement (OR, 6.60; 95% CI, 0.97-44.9; P ¼ .05).
Based on multivariable logistic regression the probability of the primary EER symptom improvement
postfundoplication increased significantly from 8.5% in
those without heartburn/regurgitation or acid exposure
greater than 12% (95% CI, 0.6-58.2) to 90.7% if patients
experienced both conditions (95% CI, 53.3-98.8; P ¼ .01)
(Fig. 4).
DISCUSSION
1906
TABLE II.
Demographic and Physiologic Parameters of Responders Versus Nonresponders After Fundoplication.
Responders (n ¼ 16)
Nonresponders (n ¼ 11)
P
58 (52–67)
53 (40–62)
.21
100
77
100
81.8
1.00
.77
30.9 (27–34)
30.7 (27–35)
.64
56.3
45.5
.78
25.0
27.3
18.8
85
27.3
55
.04
58.3
3.5 (3–5)
66.7
3 (2–4)
.74
.28
Hernia size > 4 cm, %
44.4
0
.06
Esophagitis, %
Wireless pH (off therapy)‡
13.3
0
.26
Total time pH < 4, %*
14.8 (11.4–17.3)
8 (6–10.6)
.13
Upright time pH < 4, %
Supine time pH < 4, %
19.4 (15.2–23.9)
1.6 (0.9–10.4)
11.8 (8.4–19)
2 (0–12.7)
.24
.65
Demographics
Age*
Caucasian, %
Female, %
BMI*
1 symptoms, %
Cough
Asthma/wheezing
Other†
Baseline heartburn 6 regurgitation, %
EGD
Hiatal hernia, %
Hernia size (cm)*
Abnormal SI, %
Abnormal SAP, %
Impedance (on therapy)
No. reflux episodes (acid þ nonacid)*
No. acid reflux episodes*
No. nonacid reflux episodes*
0
20
.19
50
20
.28
53 (45–82)
65.5 (37–100)
.60
7 (1–32.5)
43.5 (25–52)
9 (4–14)
46 (36–71)
.77
.60
Abnormal SI, %
41.7
40.0
.94
Abnormal SAP, %
33.3
40.0
.75
*Median (interquartile range).
†
Throat clearing, shortness of breath, hoarseness, laryngitis, postnasal drip.
‡
Values represent mean of the 2-day monitoring period.
BMI ¼ body mass index; EGD ¼ esophagogastroduodenoscopy; SI ¼ symptom index; SAP ¼ symptom association probability.
Fig. 3. Distribution of preoperative percentage time pH > 4 based
on primary extraesophageal reflux symptom response to surgical
fundoplication. Solid lines mark medians (responders 14.8% vs.
nonresponders 8%) and dotted line represents 12% threshold.
who underwent fundoplication: 27% for presumed EER
signs (i.e., subglottic stenosis, laryngeal leukoplakia/cancer) and 73% for medication-refractory EER symptoms.20
Of these, less than half had preoperative evidence of
GERD on physiologic testing. The primary outcome measure was change in RSI.18 Defined a priori as a
reduction in RSI of 5 points, 84% had symptom
improvement. Interestingly, preoperative PPI therapy
provided at least partial symptomatic improvement for
86% of responders to fundoplication compared with only
12% of nonresponders. The findings of theirs and other
studies15 suggest that patients with EER who respond
to medical therapy have a greater likelihood of symptomatic improvement from antireflux surgery. PPI therapy
is more consistently effective in patients with typical
GERD2; therefore, many argue that patients with preoperative symptom response to PPI may have undiagnosed
underlying GERD responsible for the EER symptoms/
manifestations. To eliminate potential confounding, our
analysis was limited to patients with medication-refractory EER and objectively diagnosed GERD.
Efforts to identify preoperative predictors of symptomatic improvement of EER symptoms from
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Francis et al.: Fundoplication Outcome Assessment in EER
1907
Fig. 4. Probability of primary extraesophageal reflux symptom
improvement 1 year postoperatively based on presence or absence of concomitant baseline heartburn/regurgitation and acid
exposure greater than 12%.
fundoplication surgery have been similarly hampered by
inconsistent methodology. Consistent with prior studies16,21 we found concomitant baseline heartburn with or
without regurgitation to be predictive of postoperative
EER symptom improvement. Heartburn with or without
regurgitation is the quintessential symptom of typical
GERD but is considered a less prominent symptom of
EER.22 It is, however, included in the RSI, which grades
patient complaints from 0 to 5 on several different
domains.18 It is unclear from studies that have used RSI
as the metric for effectiveness of fundoplication whether
the demonstrated improvement was primarily due to resolution/improvement of this classic symptom or some
combination of other domains. We also found patients
experiencing pH < 4 for more than 12% over 24 hours
had higher likelihood of postoperative EER symptom
improvement. Longer duration of pH < 4 is an indicator
of higher GERD severity. Our findings corroborate those
of previous studies demonstrating the effectiveness of
fundoplication in treatment of EER symptoms in
patients who also have typical signs and symptoms of
reflux.16,23
Preoperative presence of a large hiatal hernia (> 4
cm) was associated, albeit not significantly, with symptomatic improvement after fundoplication. In our
population, approximately two thirds of both responders
and nonresponders to surgery had a hiatal hernia.
Among those, 44% of hiatal hernias in the responder
were > 4 cm compared with 0% in the nonresponder
group. Owing to power limitations, this relationship did
not achieve statistical significance (P ¼ .06). However, it
is worth mention. Previous studies have found that
patients with larger hiatal hernias were more likely to
have abnormal findings on pH monitoring.24,25 Hiatal
hernia is a known risk factor for GERD as it effectively
impairs or eliminates the native high-pressure zone at
the distal esophagus and lower esophageal sphincter.
This association further supports our assertion that
patients with medication-refractory EER symptoms who
have coexistent objective GERD (more likely in presence
of a large hiatal hernia) have greater likelihood of symptom improvement postoperatively.
Laryngoscope 121: September 2011
1908
We did not find any relationship between preoperative impedance-pH parameters on therapy and
postoperative symptomatic improvement. Such a relationship had previously been proposed by Mainie et al.6
They concluded that detection of GERD could be done
independent of pH by recording electrical stimulation
within the esophagus, thereby contending that impedance pH is ideal for evaluating patients with residual
symptoms while on acid-suppression therapy. This is an
attractive possibility because weakly acidic and nonacidic reflux is often implicated as the explanation for why
standard pH testing does not identify all patients presumed to have EER.26 However, our results are unable
to substantiate their findings.
Our study has some limitations, which need mention. Inherent to any retrospective study is possible
selection bias. Patients with refractory EER and objective evidence of GERD were counseled about treatment
options including continued medical therapy and fundoplication. Randomization to surgery was not possible;
however, a comparison of the demographic and physiologic parameters of those who underwent fundoplication
versus those who continued on medical therapy showed
similar findings. Power limitation secondary to sample
size may have restricted our ability to identify other less
robust predictors. Thus our analysis focused on only
large effect sizes. Therefore, the presence of heartburn
with or without regurgitation and pH < 4 for 12% over
24 hours should be considered strong predictors of postoperative
EER
symptom
improvement.
Larger
prospective multicenter trials will be required to confirm
these findings and better define which patients might
benefit from surgery.
CONCLUSION
This study aimed to quantify response of patients
with refractory EER to surgical fundoplication and to
identify predictors of response to surgery. We found that
59% of patients with refractory EER symptoms experienced symptom improvement postsurgery. Those with
concomitant classical GERD signs and symptoms were
more likely to experience EER symptom improvement
postoperatively compared with those with ‘‘silent reflux.’’
We could not confirm that impedance-pH parameter performed on therapy is predictive of symptom response
postfundoplication, as previously suggested. Based on
our findings, we recommend surgical fundoplication be
considered judiciously in EER patients refractory to PPI
therapy.
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