The Prevalence of Distal and Proximal Gastroesophageal Reflux in Patients Awaiting Lung Transplantation

Article (PDF Available)inAnnals of Surgery 244(4):491-7 · November 2006with25 Reads
DOI: 10.1097/01.sla.0000237757.49687.03 · Source: PubMed
Abstract
To determine the prevalence and proximal extent of gastroesophageal reflux (GERD) in patients awaiting lung transplantation. GERD has been postulated to contribute to accelerated graft failure in patients who have had lung transplantations. However, the prevalence of reflux symptoms, esophageal motility abnormalities, and proximal esophageal reflux among patients with end-stage lung disease awaiting lung transplantation are unknown. A total of 109 patients with end-stage lung disease awaiting lung transplantation underwent symptomatic assessment, esophageal manometry, and esophageal pH monitoring (using a probe with 2 sensors located 5 and 20 cm above the lower esophageal sphincter). Reflux symptoms were not predictive of the presence of reflux (sensitivity, 67%; specificity, 26%). Esophageal manometry showed a high prevalence of a hypotensive lower esophageal sphincter (55%) and impaired esophageal peristalsis (47%) among patients with reflux. Distal reflux was present in 68% of patients and proximal reflux was present in 37% of patients. These data show that in patients with end-stage lung disease: 1) symptoms were insensitive and nonspecific for diagnosing reflux; 2) esophageal motility was frequently abnormal; 3) 68% of patients had GERD; 4) in 50% of the patients with GERD, acid refluxed into the proximal esophagus. We conclude that patients with end-stage lung disease should be screened with pH monitoring for GERD.
ORIGINAL ARTICLES
The Prevalence of Distal and Proximal Gastroesophageal
Reflux in Patients Awaiting Lung Transplantation
Matthew P. Sweet, MD,* Fernando A. M. Herbella, MD,* Lorriana Leard, MD,†
Charles Hoopes, MD,* Jeffrey Golden, MD,† Steven Hays, MD,† and Marco G. Patti, MD*
Objective: To determine the prevalence and proximal extent of gas-
troesophageal reflux (GERD) in patients awaiting lung transplantation.
Background: GERD has been postulated to contribute to acceler-
ated graft failure in patients who have had lung transplantations.
However, the prevalence of reflux symptoms, esophageal motility
abnormalities, and proximal esophageal reflux among patients with
end-stage lung disease awaiting lung transplantation are unknown.
Methods: A total of 109 patients with end-stage lung disease
awaiting lung transplantation underwent symptomatic assessment,
esophageal manometry, and esophageal pH monitoring (using a
probe with 2 sensors located 5 and 20 cm above the lower esoph-
ageal sphincter).
Results: Reflux symptoms were not predictive of the presence of
reflux (sensitivity, 67%; specificity, 26%). Esophageal manometry
showed a high prevalence of a hypotensive lower esophageal
sphincter (55%) and impaired esophageal peristalsis (47%) among
patients with reflux. Distal reflux was present in 68% of patients and
proximal reflux was present in 37% of patients.
Conclusions: These data show that in patients with end-stage lung
disease: 1) symptoms were insensitive and nonspecific for diagnos-
ing reflux; 2) esophageal motility was frequently abnormal; 3) 68%
of patients had GERD; 4) in 50% of the patients with GERD, acid
refluxed into the proximal esophagus. We conclude that patients
with end-stage lung disease should be screened with pH monitoring
for GERD.
(Ann Surg 2006;244: 491– 497)
C
hronic allograft dysfunction due to obliterative bronchi-
olitis remains the main complication limiting long-term
graft survival following lung transplantation. Gastroesopha-
geal reflux disease (GERD) has been implicated in causing
the bronchiolitis obliterans syndrome (BOS).
1– 6
It is postu-
lated that, in some patients, the reflux extends into the upper
esophagus and causes microaspiration.
6 –11
Analysis of bron-
choalveolar lavage fluid from 120 posttransplant patients
showed that, in those with BOS, levels of bile acids were high
compared with specimens from patients without BOS. Further-
more, the onset of BOS (early vs. late) correlated with the
amount of bile acid in the fluid.
6
There is evidence that, in lung
transplant patients with GERD, early fundoplication can im-
prove allograft function and prevent obliterative bronchiolitis.
4,5
These findings have stimulated fresh interest in the
relationship of reflux to severe pulmonary disease in adults.
At this point, little is known about esophageal function and
the prevalence of proximal reflux, a better predictor of respi-
ratory complications of GERD.
7–10
The aims of this study were to determine the prevalence
of GERD, the clinical presentation of GERD, and the man-
ometric and reflux profile among patients with end-stage lung
disease awaiting lung transplantation.
PATIENTS AND METHODS
A total of 109 patients with end-stage lung disease who
were being evaluated for transplantation at the University of
California San Francisco were referred to the UCSF Swallowing
Center for esophageal manometry and 24-hour ambulatory pH
monitoring. They were identified by cross-referencing the list of
762 patients evaluated for lung transplantation with the Swal-
lowing Center database of 4385 preoperative patient evaluations.
This yielded 109 patients, 104 of whom were studied after
esophageal studies were made a routine component of the
pretransplant evaluation in July 2003. Five additional patients
were studied before that time. Patients who were studied after a
lung transplant or who had combined heart-lung transplantation
were not included.
The patients were divided into the following lung disease
subgroups: restrictive, obstructive, mixed, pulmonary hyperten-
sion, and bronchoalveolar carcinoma, according to the principle
reason for referral for transplantation. For patients with more
than one of these conditions, the most severe one was chosen for
the group assignment. For example, patients with scleroderma
were classified as restrictive or pulmonary hypertension depend-
ing on which predominated. Patients in the restrictive group
were further divided into idiopathic pulmonary fibrosis (IPF) or
one of the following interstitial lung diseases: nonspecific inter-
stitial pneumonia, hypersensitivity pneumonitis, scleroderma, or
sarcoidosis. Specific diagnoses in the obstructive group included
chronic obstructive pulmonary disease (COPD), bronchiectasis,
alpha-1 antitrypsin deficiency (AAT), and cystic fibrosis. Pa-
tients in the mixed group had both restrictive and obstructive
From the Departments of *Surgery and †Medicine, University of California–
San Francisco, San Francisco, CA.
Reprints: Marco G. Patti, MD, Department of Surgery, University of Cali-
fornia, San Francisco, 521 Parnassus Avenue, Room C-341, San Fran-
cisco, CA 94143-0790. E-mail: pattim@surgery.ucsf.edu.
Copyright © 2006 by Lippincott Williams & Wilkins
ISSN: 0003-4932/06/24404-0491
DOI: 10.1097/01.sla.0000237757.49687.03
Annals of Surgery Volume 244, Number 4, October 2006 491
ventilatory deficits, including eosinophilic granuloma and lym-
phangiomyomatosis (LAM). Pulmonary hypertension included
primary pulmonary arterial hypertension and secondary pulmo-
nary hypertension (due to interstitial lung diseases or some other
process). One patient had bronchoalveolar carcinoma. The pa-
tient’s classification was determined by the transplant pulmo-
nologists (J.G., S.H., and L.L.).
Symptomatic Evaluation
The subjects underwent standardized interviews with
the Swallow Center physician or technician. We used a
nonvalidated, standard questionnaire in place for 16 years.
They estimated the severity of their symptoms (heartburn,
regurgitation, dysphagia, cough) using a 5-point scale ranging
from 0 (no symptom) to 4 (disabling symptom). They were
also questioned about the use of acid-reducing medications
(H2-blocking agents and proton pump inhibitors PPIs).
Esophageal Manometry
Esophageal manometry was performed after an overnight
fast using techniques previously described.
12
Medications that
might interfere with esophageal motor function (ie, calcium
channel blocking agents, nitrates, and metoclopramide) were
discontinued at least 48 hours before the study. Position, pres-
sure, length, and relaxation of the lower esophageal sphincter
(LES) were measured using the station pull through technique,
with 0.5-cm increments between stations. Esophageal body
function was recorded 3, 8, 13, and 18 cm above the upper
border of the LES by giving 10 swallows of 5 mL of water at
30-second intervals. The amplitude of peristaltic waves was
calculated independently for the distal esophagus (3 and 8 cm
above the LES) and proximal esophagus (13 and 18 cm above
the LES).
8
Esophageal length was measured from the upper
esophageal sphincter to the distal end of the LES. Ineffective
esophageal motility was defined as distal esophageal amplitude
30 mm Hg or 30% simultaneous waves in the distal esoph-
agus.
13
Ambulatory pH Monitoring
Proton pump inhibitors (PPIs) were withheld for 14 days
and histamine-2 blockers were withheld for 3 days before the
study. The pH catheters were calibrated in a standard buffer
solution at pH 1 and pH 7 before and after monitoring. A
dual-channel pH catheter with 2 antimony sensors located 15 cm
apart was placed transnasally, with the distal sensor 5 cm above
the upper border of the manometrically determined LES. Pa-
tients were instructed to consume an unrestricted diet, refrain
from taking any acid-suppressing medications, and to keep a
diary of symptoms during the pH testing. The data were incor-
porated into a composite score (ie, DeMeester score), which
takes into account 6 elements: 1) number of reflux episodes, 2)
number of reflux episodes longer than 5 minutes, 3) duration of
the longest reflux episode, 4) percentage of time the pH is 4.0
for the total duration of the study, and 5) in the upright and 6)
supine positions. A score greater than 14.7 was set as abnormal
based on the data obtained from 50 volunteers.
14
Proximal reflux
was defined as 1% total time pH 4 at the proximal sensor.
15
The data were analyzed using a commercial software program
(Gastrosoft, Medtronic Functional Diagnostic, Shoreview, MN).
Other Tests
Gastric emptying studies were performed in 17 patients.
Other studies were performed in a nonsystematic manner,
mostly in patients who were candidates for antireflux surgery.
Ten patients had upper endoscopy and 15 patients had a barium
swallow.
Statistical Analysis
Statistical analysis was performed using STATA Statisti-
cal Software: Release 9.1 (Stata Corp., College Station, TX).
Nonparametric statistical analyses were performed. Differences
between the GERD positive and negative groups were analyzed
with the
2
test for proportions or the Mann-Whitney U test for
continuous variables. Comparisons between lung disease sub-
groups were performed with the Kruskal-Wallis test. Data are
reported as number (percentage) from
2
analysis or as median
(interquartile range) for nonparametric tests. Spearman rank
correlation was used to examine associations between continu-
ous or ordinal variables.
The study protocol was reviewed and approved by the
University of California San Francisco Committee on Human
Research.
RESULTS
A total of 109 patients were evaluated with esophageal
manometry and pH studies. Seventy-four patients had reflux
(68%; DeMeester score 14.7, GERD) and 35 had normal
esophageal acid exposure (32%; DeMeester score 14.7,
GERD) (Table 1).
Symptomatic Evaluation
A total of 104 patients completed the symptom ques-
tionnaire. The main symptoms were respiratory. Seventy-two
subjects (69%) reported having at least one typical symptom
of GERD (heartburn, regurgitation, or dysphagia). There was
no difference in the prevalence of heartburn or regurgitation
among patients with and without reflux (Table 1). Although
dysphagia was more common among GERD patients, only
half of the GERD patients had dysphagia. Reflux was
asymptomatic in 33% of those with distal reflux and in 38%
of those with proximal reflux. There was no difference in the
severity of heartburn (P 0.23) and regurgitation (P 0.26)
TABLE 1. Demographics and Symptoms
GERD GERD P
Demographics
No. of patients 74 35
Median age (yr) (range) 54 (23–69) 56 (28–65) 0.54
Median BMI (IQR) 25 (23–28) 24 (21–28) 0.58
Male 42 (57%) 14 (40%) 0.10
Symptom prevalence (%)
Any typical symptom 62 66 0.43
Heartburn 27 38 0.30
Regurgitation 46 56 0.33
Dysphagia 51 23 0.02
Continuous data are presented as median and interquartile range.
Categorical data are presented as percentage.
Sweet et al Annals of Surgery Volume 244, Number 4, October 2006
© 2006 Lippincott Williams & Wilkins492
between the 2 groups. The severity of typical symptoms did
not correlate with the DeMeester score or the percentage of
time the pH was 4.0 in the proximal esophagus (Spearman
ranks r 0.09 and 0.05, P 0.35 and 0.61, respectively).
To determine the utility of symptom assessment as a
screening test for reflux, we compared typical reflux symp-
toms with the esophageal pH findings. The presence of one or
more typical reflux symptoms was compared with the esoph-
ageal pH findings for distal and proximal reflux (Table 2).
The sensitivity and specificity for distal reflux were 67% and
26%, respectively. The sensitivity and specificity for proxi-
mal reflux were 62% and 26%, respectively.
Esophageal Manometry
GERD patients had lower LES pressures. Separating
the LES pressures into normal and abnormal (ie, above or
below 14 mm Hg) demonstrated that 55% of subjects with
reflux had a hypotensive LES compared with 26% of those
without reflux (P 0.004). The groups had similar total and
abdominal LES lengths (Table 3).
The amplitude of peristalsis in the distal esophagus was
lower in GERD patients, and ineffective esophageal motil-
ity was more common. There was no difference in amplitude
of peristalsis in the proximal esophagus (Table 4).
Analysis by lung disease subgroup found that distal
esophageal amplitude was lower in the subjects with sclero-
derma (P 0.0002) and higher in those with COPD and
LAM (P 0.02 and 0.01). When a correction for multiple
comparisons was made, only the lower distal esophageal
amplitude among subjects with scleroderma remained statis-
tically significant.
The upper esophageal sphincter pressure was similar in
the 2 groups.
The ratio of esophageal length to patient height corre-
lated with type of lung disease (Kruskal-Wallis, P 0.0047).
The esophagus was shorter in patients with IPF and cystic
fibrosis and longer in those with COPD and bronchiectasis.
Esophageal length was not different between those with and
without GERD.
Ambulatory pH Monitoring
The prevalence of distal and proximal reflux was 68%
and 37%, respectively. The reflux profile of GERD and
GERD groups is given in Table 5.
The DeMeester scores separated the 2 groups, as did
the rest of reflux data (Table 5). In addition to more reflux
episodes and more time with pH 4.0 in the supine and
upright positions, GERD patients had slower acid clearance
in the lower and upper esophagus.
GERD subjects had more proximal reflux, with a
median percentage of time pH 4 of 1.2 versus 0 (P
TABLE 2. Utility of Symptomatic Screening
Distal Reflux
(%)
Proximal Reflux
(%)
Sensitivity 67 62
Specificity 26 26
Positive predictive value 64 33
Negative predictive value 28 53
Comparison of the presence or absence of any typical reflux symptoms with
esophageal pH findings. Distal Reflux: DeMeester score 14.7. Proximal Reflux:
proximal probe pH 4 for 1% of study time.
TABLE 5. Esophageal pH Findings
GERD GERD P
Distal probe
No. of reflux events 161 (105–234) 35 (22–60) 0.00005
Events 5 minutes 5 (3–9) 0 (0–1) 0.00005
Percent time pH 4 12 (6–19) 1 (0.5–1.9) 0.00005
DeMeester score 51 (30–76) 5.5 (3–10) 0.00005
Proximal probe
No. of reflux events 36 (12–65) 7 (2–16) 0.00005
Events 5 minutes 0 (0–2) 0 0.00005
Percent time pH 4 1.2 (0.3–3.4) 0.1 (0–0.6) 0.00005
Percent time upright 1.1 (0.2–3.2) 0.1 (0–0.6) 0.0001
Percent time supine 0.3 (0–3) 0.00 0.00005
Proximal reflux 37 (51%) 2 (6%) 0.00005
Clearance time
Distal clearance 1 (0.7–1.6) 0.3 (0.3–0.5) 0.00005
Proximal clearance 0.5 (0.2–1) 0 (0–0.4) 0.00005
Continuous data are presented as the median with the interquartile range. Categor-
ical data are presented as the number and percentage. Distal reflux is defined as
DeMeester score 14.7. Proximal reflux is defined as pH 4 at the proximal probe for
1% of the study time. Mean clearance times are calculated by dividing the number of
minutes pH 4 by the number of reflux episodes. Units are minutes/episode.
TABLE 3. Esophageal Sphincter Function
GERD GERD P
LES pressure (mm Hg) 13 (9–18) 18 (12–24) 0.003
Hypotensive LES
(14 mm Hg)
55% 26% 0.004
LES total length (cm) 2.7 (1.9–3) 3 (2–3) 0.37
LES abdominal length (cm) 2 (1.3–2.3) 2 (1.5–3) 0.11
UES pressure (mm Hg) 60 (39–86) 64 (43–86) 0.61
Continuous data are presented as the median with the interquartile range. Categor-
ical data are presented as the percentage.
LES, lower esophageal sphincter; UES, upper esophageal sphincter.
TABLE 4. Esophageal Body Function
GERD GERD P
Normal peristalsis 53% 69% 0.12
NSEMD 19% 20% 0.89
IEM 28% 11% 0.049
DEA (mm Hg) 77 (49–115) 132 (87–178) 0.0009
DED (s) 3.2 (2.6–4.2) 4 (3–5.1) 0.01
PEA (mm Hg) 67 (35–95) 67 (54–88) 0.32
PED (s) 2.5 (2–3.2) 2.9 (2.5–3.7) 0.06
Esophageal length (cm) 27 (25–30) 28 (26–31) 0.61
Continuous data are presented as the median with the interquartile range. Categor-
ical data are presented as the percentage.
NSEMD, nonspecific motility disorder; IEM, ineffective esophageal motility; DEA,
distal esophageal amplitude; DED, distal esophageal duration; PEA, proximal esopha-
geal amplitude; PED, proximal esophageal duration.
Annals of Surgery Volume 244, Number 4, October 2006 Gastroesophageal Reflux
© 2006 Lippincott Williams & Wilkins 493
0.00005). Proximal reflux was more common when the pa-
tients were upright.
Proximal reflux occurred in 2 patients with normal
distal esophageal acid exposure. One patient had IPF and one
had COPD. Both had normal LES and upper esophageal
sphincter pressures and normal esophageal body motility.
Reflux among lung disease subgroups is presented in
Table 6.
Other Tests
Seventeen patients with symptoms suggestive of de-
layed gastric emptying (postprandial bloating and fullness,
nausea, vomiting) had gastric emptying studies. Sixteen of
them had abnormal distal acid exposure. Among these 16
patients, 4 had delayed emptying of liquids and 10 had
delayed emptying of solids.
Ten patients had upper endoscopy. Six patients were
found to have a hiatal hernia. All patients with a hiatal hernia
had abnormal distal reflux. Four had irregular z-lines sugges-
tive of chronic inflammation and 1 patient had linear ero-
sions. Of the 4 patients without hiatal hernia, 2 had reflux.
DISCUSSION
These results show the following in patients with end-
stage lung disease (ESLD) awaiting lung transplantation: 1)
the prevalence of GERD was 68%, and in half of those with
distal reflux, acid refluxed into the proximal esophagus; 2)
GERD was associated with a hypotensive LES and abnormal
esophageal peristalsis; and 3) symptoms did not distinguish
between those with and without GERD.
Prevalence of GERD in Patients With ESLD
Awaiting Lung Transplantation
In this study, GERD was detected in 68% of patients
with ESLD awaiting lung transplantation. Our data confirm
the observation of a high prevalence of GERD similar to
cohorts of patients studied at other centers. For instance,
Cantu et al found GERD in 63% of patients who were
candidates for lung transplant,
5
whereas a prevalence of 32%
was found by D’Ovidio et al.
16
The lower prevalence found
in the latter study may be explained by the fact that PPIs were
stopped for only 5 days before the pH monitoring. Because
these medications affect the acid secretion by the parietal
cells for up to 10 days, the prevalence of GERD might have
been underestimated.
In half of the patients with GERD, reflux reached 20 cm
above the LES, similar to the findings of D’Ovidio et al.
16
Proximal reflux is more dangerous than distal reflux, for it
predisposes to microaspiration, which in time can perma-
nently damage the lungs.
6,7,8,17
Because ambulatory pH mon
-
itoring is a surrogate marker of aspiration, detecting bile acids
or pepsin in bronchoalveolar fluid would provide stronger
evidence that gastric contents are entering the tracheobron-
chial tree.
6,11
Most proximal reflux occurred during the day
(upright reflux), as reported by others.
3
Two patients with
normal distal acid exposure had abnormal proximal reflux,
suggesting that most of the “physiologic” reflux occurring in
the distal esophagus eventually reached 20 cm above the
LES. The meaning of this finding, as noted by others,
16,18
is
still unclear, but it underscores the importance of measuring
both distal and proximal reflux.
Reflux was common among all subgroups. Among 27
patients with IPF, distal and proximal reflux was found in 78%
and 33%, respectively. In another report, the prevalence was
87% among 65 patients with IPF.
18
The high prevalence of
GERD in this group of patients with idiopathic ESLD raises the
possibility that reflux plays a role in pathogenesis of IPF.
Some patients develop reflux after lung transplantation,
2,3
possibly as a consequence of vagal nerve injury and delayed
gastric emptying, or immunosuppressive medications.
19
Clinical Presentation of GERD in Patients With
ESLD Awaiting Lung Transplantation
This study confirms that the clinical history, even using
a standardized questionnaire, cannot distinguish between pa-
tients with and without GERD. Neither the presence nor the
severity of reflux symptoms predicted the presence of reflux,
which is consistent with other reports on this subject.
10,18,20
For example, among 822 patients with a clinical diagnosis of
GERD, manometry and pH monitoring showed that only 575
patients (70%) actually had reflux.
20
Furthermore, we found
reflux in 33% of patients who had none of the typical
symptoms (ie, heartburn, regurgitation) of GERD. A high
prevalence (53%) of asymptomatic reflux was also found by
Raghu et al in patients with IPF.
18
We think that every patient with ESLD should be
screened by esophageal manometry and ambulatory pH mon-
itoring to learn if abnormal reflux is present.
Pathophysiology of GERD in Patients With
ESLD Awaiting Lung Transplantation
Patients with GERD more frequently had a hypotensive
LES and low amplitude and abnormally propagating peristal-
tic waves in the distal esophagus. Almost one third of
TABLE 6. Reflux Profile by Lung Disease Subgroup
n
Distal Reflux
(%)
Proximal Reflux
(%)
Total 109 68 37
Restrictive 62 73 31
IPF 27 78 33
ILD–other 35 69 29
Obstructive 35 60 43
COPD 21 43 25
Cystic fibrosis 6 83 67
Bronchiectasis 4 75 50
AAT 4 100 100
Mixed 4 75 50
LAM 2 50 50
Eosinophilic granuloma 2 100 50
Pulmonary Hypertension 7 57 29
Primary 4 25 0
Secondary 3 100 67
BAC 1 100 100
Percentage of patients in each lung disease subgroup with distal or proximal reflux.
Distal reflux is defined as DeMeester score 14.7. Proximal reflux is defined as pH
4 at the proximal probe for 1% of the study time.
Sweet et al Annals of Surgery Volume 244, Number 4, October 2006
© 2006 Lippincott Williams & Wilkins494
GERD patients had ineffective esophageal motility, a dis-
order often associated with respiratory symptoms.
13,21
Since
peristalsis is the main determinant of esophageal acid clear-
ance, esophageal clearance in both the distal and proximal
esophagus was probably delayed in the patients with GERD.
A higher volume of refluxate may also produce this finding.
D’Ovidio et al reported that the LES was hypotensive and
motility of the body of the esophagus was abnormal in 63%
and 33% of patients with ESLD, respectively.
16
In the few patients who had upper endoscopy, a hiatal
hernia was common. This last finding, which needs confir-
mation, is important because the size of a hiatal hernia
correlates with the magnitude of the reflux and with respira-
tory symptoms.
22
In addition, gastric emptying was fre
-
quently delayed among the patients who were tested, and it
was associated with abnormal reflux. Gastric emptying usu-
ally slows after transplantation, which may contribute to the
development of BOS.
19
CONCLUSION
We recognize that this study has limitations. The study
population comprised selected patients with end-stage lung
disease who were candidates for transplantation. They were
younger and had fewer comorbidities than the general popu-
lation of patients with end-stage lung disease.
We recommend that esophageal manometry and pH
monitoring be performed in every patient with end-stage lung
disease to check for GERD and proximal reflux. Future
studies should include the use of multichannel impedance
technology to search for acid and nonacid reflux
23
and deter
-
mination of bile acids or pepsin in bronchoalveolar fluid.
6,11
The same diagnostic approach should also be used for pa-
tients with less severe lung disease, particularly in patients
with IPF. Controlling reflux at an earlier stage may improve
the lung function or stop the progression of the disease,
avoiding the need for transplantation.
Although a cause-and-effect relationship between GERD
and lung injury is not definitively proved, we recommend
antireflux surgery for the patients with reflux. A total fundopli-
cation is the treatment of choice as it is the only way to
reestablish the competence of the gastroesophageal junction and
stop any type of gastric reflux.
24
Treatment with proton pump
inhibitors should be second-line therapy for reflux persists in
most patients even though symptoms improve as the pH of the
refluxate rises.
18,23,25
REFERENCES
1. Reid KR, McKenzie FN, Menkis AH, et al. Importance of chronic aspira-
tion in recipients of heart-lung transplants. Lancet. 1990;336:206 –208.
2. Young LR, Hadjiliadis D, Davis RD, et al. Lung transplantation exac-
erbates gastroesophageal reflux disease. Chest. 2003;124:1689 –1693.
3. Hadjiliadis D, Davis RD, Steele MP, et al. Gastroesophageal reflux
disease in lung transplant recipients. Clin Transplant. 2003;17:363–368.
4. Davis RD, Lau CL, Eubanks S, et al. Improved lung allograft function after
fundoplication in patients with gastroesophageal reflux disease undergoing
lung transplantation. J Thorac Cardiovasc Surg. 2003;125:533–542.
5. Cantu E, Appel JZ, Hartwig MG, et al. Early fundoplication prevents
chronic allograft dysfunction in patients with gastroesophageal reflux
disease. Ann Thorac Surg. 2004;78:1142–1151.
6. D’Ovidio F, Mura M, Tsang M, et al. Bile acid aspiration and the
development of bronchiolitis obliterans after lung transplantation. J Tho-
rac Cardiovasc Surg. 2005;129:1144 –1152.
7. Johnson DA, Drane WE, Curran J, et al. Pulmonary disease in progres-
sive systemic sclerosis: a complication of gastroesophageal reflux and
occult aspiration? Arch Intern Med. 1989;149:589 –593.
8. Patti MG, Debas HT, Pellegrini CA. Clinical and functional character-
ization of high gastroesophageal reflux. Am J Surg. 1993;165:163–168.
9. Patti MG, Debas HT, Pellegrini CA. Esophageal manometry and 24-
hour pH monitoring in the diagnosis of pulmonary aspiration secondary
to gastroesophageal reflux. Am J Surg. 1992;163:401–406.
10. Oelschlager BK, Chang L, Pope CE, et al. Typical GERD symptoms and
esophageal pH monitoring are not enough to diagnose pharyngeal reflux.
J Surg Res. 2005;128:55– 60.
11. Farrell S, McMaster C, Gibson D, et al. Pepsin in bronchoalveolar lavage
fluid: a specific and sensitive method of diagnosing gastroesophageal
reflux-related pulmonary aspiration. J Pediatr Surg. 2006;41:289 –293.
12. Patti MG, Fisichella PM, Perretta S. Preoperative evaluation of patients
with gastroesophageal reflux disease. J Laparoendosc Adv Surg Tech.
2001;11:327–331.
13. Diener U, Patti MG, Molena D, et al. Esophageal dysmotility and
gastroesophageal reflux disease. J Gastrointest Surg. 2001;5:260–265.
14. Jamieson JR, Stein HJ, DeMeester TR, et al. Ambulatory pH monitor-
ing: normal values, optimal thresholds, specificity, sensitivity and repro-
ducibility. Am J Gastroenterol. 1992;87:1102–1111.
15. Dobhan R, Castell DO. Normal and abnormal proximal esophageal acid
exposure: results of ambulatory dual-probe pH monitoring. Am J Gas-
troenterol. 1993;88:25–29.
16. D’Ovidio F, Singer LG, Hadjiliadis D, et al. Prevalence of gastroesoph-
ageal reflux in end-stage lung disease candidates for lung transplant. Ann
Thorac Surg. 2005;80:1254 –1261.
17. Patti MG, Arcerito M, Tamburini A, et al. Effect of laparoscopic
fundoplication on gastroesophageal reflux-induced respiratory symp-
toms. J Gastrointest Surg. 2000;4:143–149.
18. Raghu G, Fredenberger TD, Yang S, et al. High prevalence of abnormal
acid gastroesophageal reflux in idiopathic pulmonary fibrosis. Eur Re-
spir J. 2006;27:136 –142.
19. Berkowitz N, Schulman LL, McGregory C, et al. Gastroparesis after
lung transplantation: potential role in postoperative respiratory compli-
cations. Chest. 1995;108:1602–1607.
20. Patti MG, Diener U, Tamburini A, et al. Role of esophageal function
tests in diagnosis of gastroesophageal reflux disease. Dig Dis Sci.
2001;46:597– 602.
21. Fouad YM, Katz PO, Hatlebakk JG, et al. Ineffective esophageal
motility: the most common abnormality in patients with GERD-associ-
ated respiratory symptoms. Am J Gastroenterol. 1999;94:1464–1467.
22. Patti MG, Goldberg H, Arcerito M, et al. Hiatal hernia size affects lower
esophageal sphincter function, esophageal acid exposure, and the degree
of mucosal injury. Am J Surg. 1996;171:182–186.
23. Tamhankar AP, Peters JH, Portale G, et al. Omeprazole does not reduce
gastroesophageal reflux: new insights using multichannel intraluminal
technology. J Gastrointest Surg. 2004;8:888 896.
24. Patti MG, Robinson T, Galvani C, et al. Total fundoplication is superior
to partial fundoplication even when peristalsis is weak. J Am Coll Surg.
2004;198:863– 870.
25. Milkes D, Gerson LB, Triadafilopoulos G. Complete elimination of
reflux symptoms does not guarantee normalization of intraesophageal
and intragastric pH in patients with gastroesophageal reflux disease.
Am J Gastroenterol. 2004;99:991–996.
Discussions
DR.TOM R. DEMEESTER (LOS ANGELES,CALIFORNIA): Dr.
Sweet’s paper focuses on the relationship of esophageal
disease to pulmonary disease, a fascinating development in
our understanding of pulmonary disease. It is the second
paper in the literature that documents this very high preva-
lence of reflux in patients with end-stage lung disease. In fact,
Annals of Surgery Volume 244, Number 4, October 2006 Gastroesophageal Reflux
© 2006 Lippincott Williams & Wilkins 495
the percentages are almost identical in the 2 papers, this one
and the previous one from Duke.
Now, that opens up a very exciting area of new dimen-
sions in pulmonary disease, as was pointed out, our president
pointed out, the relationship between reflux disease and pulmo-
nary fibrosis, idiopathic pulmonary fibrosis. When one thinks
about 80% of asthmatics have reflux disease and then when one
thinks about pulmonary hypertension and the association with
reflux disease, this is a very fruitful area for study.
I have a couple of questions. First of all, the problem is,
which comes first? Is it the reflux disease that induces the
pulmonary disease? Or is it the exaggerated dynamics of
breathing with pulmonary disease that induces the reflux
disease? Did you have anybody who had a positive 24-hour
but had normal manometry? That would kind of suggest that
maybe it was the pulmonary disease encouraging it. Give us
some insight into that. And how sure are we that reflux does
really cause bronchiolitis obliterans syndrome? Could you
comment on that a little bit?
Now, the real advantage of all of this would be that if
indeed reflux causes pulmonary disease, can we detect it
earlier and prevent end-stage pulmonary disease? And that is
going to be a problem when I look at your relationship of
symptoms to something to apply to the score. So how would
you anticipate picking up these patients earlier? Would you
extend the criterion to more cases of pulmonary problems or
have you got a way of grappling that? Obviously we don’t
want to wait until end-stage lung disease to pick them up.
It is a very good paper and opens up a big, wide area.
I congratulate you for presenting it.
D
R.MARCO G. PATTI (SAN FRANCISCO,CALIFORNIA): I
want to thank Dr. DeMeester for reviewing the manuscript
and for his questions. It was about 3 decades ago that Dr.
DeMeester postulated that aspiration secondary to gastro-
esophageal reflux disease could cause lung fibrosis. Our work
is a tribute to his ideas.
It is very difficult to know whether or not the reflux
precedes the lung disease. A theory that has been around for
a long time is that the altered respiratory mechanics in
patients with end-stage lung disease may cause the reflux.
Specifically, the increased negative pressure in the chest
during inspiration could cause a gradient favoring reflux. We
examined this issue in our patients and found very contrasting
data that did not support this hypothesis. It appears as though
transplantation increases the percentage of patients who re-
flux. If reflux was indeed due to the altered respiratory
mechanics, we should see a decrease after transplantation.
In some patients reflux occurred despite the presence of a
mechanically competent lower esophageal sphincter and normal
esophageal peristalsis. It is possible that reflux occurred because
of transient relaxations of the LES and a higher volume of
refluxate, which were not measured in our study.
There are data in the literature that suggests that aspi-
ration of gastric contents can cause the bronchiolitis obliter-
ans syndrome (BOS). The lung transplant group from To-
ronto examined the bronchoalveolar lavage fluid from 120
posttransplant patients. They found that in those patients with
BOS, levels of bile acids were high compared with specimens
from patients without BOS. In addition, the group from Duke
University has shown that in lung transplant patients with
GERD early fundoplication may improve allograft function
and prevent BOS.
Based on these data and on the findings of our study,
we think that every patient awaiting lung transplant should
undergo esophageal manometry and ambulatory pH monitor-
ing, regardless of the presence of symptoms. We recommend
a total fundoplication for the patients with reflux, as it is the
only way to re-establish the competence of the gastroesoph-
ageal junction and stop any type of gastric reflux. We think
that the same protocol should be used in any patient with IPF.
The high prevalence of reflux in patients with IPF suggests a
possible cause and effect relationship, and early intervention
might alter the natural history of this disease. Further studies
are required to elucidate this association.
D
R.RICHARD J. FINLEY (VANCOUVER,BRITISH COLUMBIA,
C
ANADA): Great paper. I have 2 questions.
Do you have any objective information such as trache-
itis or laryngitis to suggest these patients are aspirating?
It appears that some of these patients have decreased
peristalsis. Do you have any other objective information such as
a nuclear medicine esophageal transit or a timed barium swallow
to suggest that these patients have decreased transits?
D
R.MARCO G. PATTI (SAN FRANCISCO,CALIFORNIA):
Some of these patients had laryngitis but they were not
uniformly studied. We plan to study pepsin in the bronchoal-
veolar lavage for evidence of microaspiration. We did not
perform nuclear medicine studies.
D
R.JEFFREY H. PETERS (ROCHESTER,NEW YORK): Very
nice study, Dr. Patti. I have a quick question about PPI
therapy and how its use or not may relate to the problem of
recognizing reflux-pulmonary disease associations. You
didn’t give us data on how many patients were receiving PPI
therapy pre-op. If patients were on it, it suggests they still
have reflux and continue to destroy their lungs. And if they
are not on PPI therapy, it suggests we have a fundamental
problem relating reflux and respiratory disease. Can you
comment regarding PPI use?
D
R.MARCO G. PATTI (SAN FRANCISCO,CALIFORNIA): Most
patients were on proton pump inhibitors because they were treated
with steroids. They were taken off proton pump inhibitors for 2
weeks before the 24-hour pH monitoring study. Most patients were
asymptomatic before and they remained asymptomatic after. We
Sweet et al Annals of Surgery Volume 244, Number 4, October 2006
© 2006 Lippincott Williams & Wilkins496
believe that proton pump inhibitors should not be the first line of
therapy because reflux persists in most patients.
DR.LEE L. SWANSTROM (PORTLAND,OREGON): Very nice
study, Dr. Patti. Could you comment briefly on the use of imped-
ance pH and whether that might contribute in evaluating these
patients? Also, there is a lot of other information on 24-hour pH
testing aside from pure acid exposure such as correlation with
coughing episodes, supine versus upright reflux, and issues like that.
Is there data to be gained by looking at that as well?
DR.MARCO G. PATTI (SAN FRANCISCO,CALIFORNIA): We
did not perform impedance. This test is very important as it
clearly shows that reflux still occurs during treatment with
proton pump inhibitors. As shown by Drs. Peters and De-
Meester, proton pump inhibitors just change the pH of the
gastric refluxate so that the number of the acid reflux episodes
decreases while the number of nonacid episodes increases. It
was difficult to establish a correlation with symptoms. For
instance, coughing was very common in these patients. We
felt that sometimes reflux caused the cough and sometimes
the cough actually caused the reflux because of the increase in
intra-abdominal pressure. As other groups have shown, most
of the reflux to the proximal esophagus occurred in the
upright position.
Annals of Surgery Volume 244, Number 4, October 2006 Gastroesophageal Reflux
© 2006 Lippincott Williams & Wilkins 497
    • "For several decades, esophageal specialists have postulated that altered respiratory mechanics in patients with end-stage lung disease may cause reflux. Specifically, increases in positive intra-abdominal pressure and negative intrathoracic pressure (with a corresponding increase in the transdiaphragmatic pressure gradient) could cause a gradient-favoring reflux [23,24]. Survival analysis [25] showed that identifying the presence of gastro-esophageal symptoms, providing a reflux diagnosis, medication use, and Nissen fundoplication were all collectively associated with longer survival in IPF. "
    [Show abstract] [Hide abstract] ABSTRACT: The cause of idiopathic pulmonary fibrosis (IPF) remains unknown, yet gastro-esophageal reflux disease (GERD) is highly prevalent in this population. GERD prevalence was studied, and esophageal function tests (EFT) were assessed in Chinese IPF patients. We prospectively studied 69 IPF patients who undertook both stationary High Resolution esophageal Manometry/Impedance (HRiM) and 24-hour esophageal Multi-Channel Intraluminal Impedance with pH Recordings (MII/pH). Patients were divided into GERD+ and GERD- groups according to pH results. Controls were HRiM treated healthy volunteers, and patients without IPF received HRiM and MII/pH diagnosed with GERD. 69 IPF patients, 62 healthy volunteers, and 88 IPF negative GERD patients were selected. GERD prevalence in IPF was 43/69 (62.3%), and 58.1% of patients presented with at least one typical symptom. Symptoms had a sensitivity of 58.1%, a specificity of 61.6%, a positive predictive value of 71.4% and a negative predictive of 47.1%. Compared with healthy volunteers, IPF patients had significantly decreased lower esophageal sphincter pressure (LESP), upper esophageal sphincter pressure (UESP) and complete bolus transit rate (CBTR). By contrast, IPF patients had increased total bolus transit time and prevalence of weak peristalsis. MII/pH showed that one third of IPF patients had abnormal distal and proximal reflux, especially non-acid reflux. Compared with GERD patients without IPF, GERD patients with IPF had significantly decreased CBTR and UESP with increased bolus exposure time. GERD prevalence in IPF was high, but symptoms alone were an unreliable predictor of reflux. IPF patients had lower LESP and UESP, impaired esophageal peristalsis and bolus clearance function with more proximal reflux events.
    Full-text · Article · Dec 2015
    • "In addition, manometry studies showed LOS hypotonia in 57% of those patients with upper oesophageal sphincter hypotonia in 14% of patients. This suggests that the gastrointestinal contributions to GOR which have been identified in patients with chronic obstructive pulmonary disease, cystic fibrosis, and interstitial lung disease [54, 55] may also be apparent in bronchiectasis. In the largest prospective study to date of a group of 58 patients with nontuberculous mycobacterium lung disease with associated bronchiectasis, GOR was diagnosed in 26%, with clinically silent reflux in 73% [56]. "
    [Show abstract] [Hide abstract] ABSTRACT: The clinical presentation of noncystic fibrosis bronchiectasis may be complicated by concomitant conditions, including gastro-oesophageal reflux (GOR). Increased acidic GOR is principally caused by gastro-oesophageal junction incompetence and may arise from lower oesophageal sphincter hypotension, including transient relaxations, hiatus hernia, and oesophageal dysmotility. Specific pathophysiological features which are characteristic of respiratory diseases including coughing may further increase the risk of GOR in bronchiectasis. Reflux may impact on lung disease severity by two mechanisms, reflex bronchoconstriction and pulmonary microaspiration. Symptomatic and clinically silent reflux has been detected in bronchiectasis, with the prevalence of 26 to 75%. The cause and effect relationship has not been established, but preliminary reports suggest that GOR may influence the severity of bronchiectasis. Further studies examining the implications of GOR in this condition, including its effect across the disease spectrum using a combination of diagnostic tools, will clarify the clinical significance of this comorbidity.
    Full-text · Article · Nov 2011
    • "Currently, it is well known that both conditions can exist independently. However, it is recognized that hiatal hernia disrupts most of the natural antireflux mechanisms, and is considered an independent factor for GERD [26] . The simple presence of an abdominal portion of the esophagus is considered an antireflux mechanism, because it is submitted to positive abdominal pressure and acts as a valve [34] . "
    [Show abstract] [Hide abstract] ABSTRACT: This review focuses on the pathophysiology of gastroesophageal reflux disease (GERD) and its implications for treatment. The role of the natural anti-reflux mechanism (lower esophageal sphincter, esophageal peristalsis, diaphragm, and trans-diaphragmatic pressure gradient), mucosal damage, type of refluxate, presence and size of hiatal hernia, Helicobacter pylori infection, and Barrett's esophagus are reviewed. The conclusions drawn from this review are: (1) the pathophysiology of GERD is multifactorial; (2) because of the pathophysiology of the disease, surgical therapy for GERD is the most appropriate treatment; and (3) the genesis of esophageal adenocarcinoma is associated with GERD.
    Article · Aug 2010
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