Esophageal Function and Gastroesophageal Reflux during Sleep and Waking in Patients with Chronic Obstructive Pulmonary Disease* William c. On; Ph.D.; Z. Shamma-Othman, M.D., F.C.C.E;t Melvin Allen, Ph.D.; and Malcolm G. Robinson, M.D.
This study was conducted to assess esophageal function and pulmonary resistance changes with esophageal acidi6cation in patients with COPD. Twelve patients with COPD and a mean age of 55.6 years were studied. Each patient underwent standard esophageal manometry, 24-h ambulatory pH testing, esophageal acid clearance evaluation during sleep, and an assessment ofpulmonary resistance with and without esophageal acid perfusion. Neither airway resistance nor conductance was altered by the esophageal acid infusion; LES pressures were normal and esop~ageal contractile pressures were mildly decreased. Acid exposure in the upright and supine positions was within normal limits. Acid
clearance during sleep was similar to that in DOrmal subjects; however, acid clearance during waking appeared to be somewhat prolonged in the COPD patients. We conclude that patients with COPD do not have a bronchoconstrictive reOex to distal esophageal acidi6cation, and esophageal function in these patients appears to be relatively normal. (Cheat 1992; 101:1521-25)
Numerous studies in the medical literature have strongly suggested a relationship between lung dysfunction and GER. 1 The primary mechanism for
the symptom ofnocturnal wheezing. 13-15 In one report, patients cured by antireflux surgery were those with predominantly nocturnal symptoms. 9 Other· studies have found the bronchoconstrictive response to be present only in patients with esophagitis or an acidsensitive esophagus (positive response to an acid perfusion test}. 4. 16 Clinically, it often has been suggested that patients with COPD may experience symptoms of GER, particularly when treated with drugs such as theophylline or anticholinergic compounds. The mechanism for this could relate to potential effects of these drugs in decreasing LES pressure. 17 Furthermore, it has been postulated that alterations of lung mechanisms such as hyperinBation can lower LES pressure, perhaps in part through diaphragm flattening. 18 A high incidence of GER was documented in patients with COPD in a recent report by Ducolone and colleagues. 19 However, the effect that acute or chronic reDux has on intrinsic lung functioning in patients with COPD has not been thoroughly investigated. The present study reports a comprehensive investigation of esophageal function in patients with COPD during both sleep and waking states.
this relationship initially was thought to be the microaspiration of gastric contents reBuxed into the esophagus. 2 More recent studies in asthmatic subjects have suggested a vagally mediated reflex bronchoconstriction in these patients associated with esophageal acid contact.3-5 To date, several studies have shown that empirical medical or surgical treatment of reflux disease has improved respiratory symptoms.6-11 A particularly interesting animal study has been reported recently by Tuchman et al, 12 demonstrating a gradient of bronchoconstrictive response to acid placed in the distal esophagus or in the trachea. This study indicated a tenfold increase in the bronchoconstrictive response when minute amounts of acid were placed in the trachea compared with acid instilled in the distal esophagus. Some ofthese studies have suggested that this reflex response to GER is exacerbated during sleep, or that this phenomenon occurs only during sleep, generating *From the Sleep and GI J~hysiology Laboratories, Baptist Medical Center of Oklahoma, Oklahoma City (Dr. Orr); the University of Oklahoma Health Sciences Center, Oklahoma City (Dr. ShammaOthman); the GI Physiology Laboratory, Presbyterian Hospital, Oklahoma City (Dr. Allen); and Oklahoma Center for Digestive Research, Oklahoma City (Dr. Robinson). tCurrently at Humana Hospital Greenhrier Valley, Ronceverte, WVa. Manuscript received April 1; revision accepte4 September 20. Reprint requests: Dr. On; Baptist Medical Center; 3300 NW Expressway, Oklahoma City 73112
= =
= =
EEG electroencephalogram; EMG electromrogram; EOG = electro-oculogram; GER = gastroesophagea re8ux; LES lower esophageal sphincter; Sgaw speci6c airway conductance; SOB shortness of breath; Sraw specific airway resistance
=
=
METHODS
Subjects
Twelve patients with chronic airway obstruction and a mean age of 55.6 years (range, 34 to 77 years) were studied. All patients were thought to have underlying emphysema as a result of cigarette smoking and varying degrees of reactive airway disease. As shown in Table 1, this varied from zero to 102 percent. AU patients were CHEST I 101 I 6 I JUNE, 1992
1521
Table l-Detnograplaic and ClinictJl1JGtG*
Age (yr) 53
59
60
77
72
65
66
49
59 64
42 58
FEVl before FEVl after %Cbange 2.39 2.28 -5% 1.15 1.11 -3% 1.50 1.52
I'll
1.24 1.30 5% 2.01 2.36 17% 2.02 2.52 25% 0.92 1.21 32% 0.95 1.26 32% 1.45 1.93 33%
1.58 2.30 46% 1.00 1.85 85% 0.82 1.66 102%
Resting, Awake Blood Gas Values FEV/FVC,%
pH
POOl
Po.
Acid Perfusion Test
35
7.48
35
79
+
64
7.44
35
70
36
N/At
37
Symptoms Respiratory
Esophageal
Chronic cough, SOB
Heartburn
Nocturnal wheezing
None
+
Nocturnal SOB*
Heartburn, dysphagia
N/A
+
SOB*
Heartburn, dysphagia
50
N/A
+
SOB
Heartburn
50
7.41
43
76
+
MomingSOB*
Heartburn, dysphagia
59
7.37
39
96
SOB
Heartburn, indigestion
46
7.38
55
45
Nocturnal and moming SOB*
Heartburn
47
7.37
39
78
SOB
None
34
7.53
32
66
+
SOB
Heartburn, dysphagia
38
7.40
44
80
+
Early morning SOB
Heartburn
70
7.40
44
84
+
Nocturnal and morning SOB
Heartburn
+
*Data are presented in order of increasing degrees of reversibility. tN/A =recent blood gas values not available. *Described some relationship between the occurrence of heartburn and respiratory symptoms. referred from the Chest Medicine Clinic of the Veterans Aft8irs Medical Center. At the time of the stud~ patients were free of all respiratory medication and any medication for the treatment of peptic symptoms. Pertinent patient data are presented in 18ble 1. Nine patients had reversible lung disease (as defined by at least 15 percent increase in FEV1 with bronchodilator administration), and three patients bad nonreversible lung disease. Although 10 of the 12 patients had a positive history of reflux-related symptoms (heartburn, dysphagia), only four described any noticeable relationship between their respiratory symptoms and their heartburn symptoms (Table 1). None had previously taken histamine "blockers. All subjects gave informed consent, and the study was approved by the Institutional Review Board of the University of Oklahoma Health Sciences Center. Each patient underwent the following sequence of evaluations: Placement of an esophageal manometry probe. Measurement of total pulmonary resistance. Esophageal manometric evaluation and acid perfusion test. Repeat total pulmonary resistance determination. Ambulatory 24-h esophageal pH monitoring (subsequent day).
1522
Sleep evaluation to include determination of sleep stages and esophageal acid clearance times (subsequent night). lWfIIOfUJ'1I He.riBttJnce Meauru
Measures of Raw were done with the standard plethysmographic technique. Resistance was determined using the following formula:
Raw=PJP~. RIP. V Esophagetll Manometry Esophageal pressures were measured via a small (4.5-mm diameter) probe containing three radially oriented pressure transducers located 5 em apart. Pressures were amplified and recorded on a standard recording chart (SandhiD Scienti&c, Inc.). The LES pressures were measured by the standard pull-through technique, and esophageal peristalsis was assessed by having the patients swallow a small volume (5 ml) of water ten times at 3O-s intervals. In addition, each patient ingested a meal in the form of a cup of commercial beef stew and esophageal peristalsis was assessed during food ingestion by assessing responses to swallows identified by a
Table 2-Mean Ainooy Re8iBtance and Conductance Value, with Acid Infusion in the DiBtal Eaophagua Raw
Saline O.IN HCI p value*
sGaw
Gaw
sRaw
Mean
SD
Mean
SD
Mean
SD
Mean
SD
3.75 3.87 NS
1.75 2.33
21.84 21.97 NS
9.33 9.44
0.031 0.033 NS
0.013 0.016
0.0052 0.0051 NS
0.0029 0.0030
*Wilcoxon signed rank test. submental EMG. RESULTS
Acid Perfusion Test The acid perfusion test was perfonned in accordance with a standard technique using liquid infusions of 120 drops per minute at a location 5 cm above the manometrically detennined LES. A solution ofO.lN HCI was instilled into the distal esophagus and the subjective response was monitored. This procedure continued until the patient expressed some subjective response (ie, heartburn or chest pain), or until 15 min had elapsed. Subsequently, the infusion solution was switched (without the subject's knowledge) to an infusion solution of sterile water which continued until the patient expressed a subjective response, or until 15 min had elapsed. A positive response was detennined to be provocation of substernal or epigastric pain by the acid infusion, ideally also relieved by the subsequent water infusion.
Ambulatory 24-h Esophageal pH Monitoring Each patient reported to the laboratory at 7:30 A.M., and a small caliber pH catheter was placed nasally into the distal esophagus 5 cm above the manometrically detennined LES. The probe was attached to a compact data acquisition unit (Sandhill Scientific, Inc.) around the waist. The patient was instructed to avoid specifically listed acidic foods, and to keep a log of pertinent events such as pain (heartburn, dysphagia, or chest pain), meals, and sleeping times. Sleep Study
The details of this methodology have been described previously and will be briefly reviewed here. 210.21 Each patient underwent a study in the sleep laboratory which consisted of continuous monitoring of the EEG, EOG, submental EMG, and ECG. Also distal esophageal pH was monitored with a 3-mm-diameter pH catheter placed 5 cm above the manometrically detennined LES. Two to five infusions of 15 ml of O.IN HCI were accomplished during periods of polygraphically detennined sleep. Each infusion lasted approximately 1 min. In some subjects, multiple awakenings allowed only two infusions. Statistical analysis was accomplished using the Student t test for correlated means and appropriate nonparametric analysis as indicated.
Pulmonary Resistance Measures
As can be seen from Table 2, neither Raw nor Gaw was altered by the esophageal acid infusion. Similarl~ calculations of sRaw and sGaw were not appreciably altered by the acid-mucosa contact. Since this is a relatively heterogeneous population ofindividuals with regard to bronchial reactivit~ we compared the four patients with nonreversible lung disease with the four with the greatest degree of reversibility (Table 3). U sing the Mann-Whitney U test, the two groups were found to be significantly different (p
This study was conducted to assess esophageal function and pulmonary resistance changes with esophageal acidi6cation in patients with COPD. Twelve patients with COPD and a mean age of 55.6 years were studied. Each patient underwent standard esophageal manometry, 24-h ambulatory pH testing, esophageal acid clearance evaluation during sleep, and an assessment ofpulmonary resistance with and without esophageal acid perfusion. Neither airway resistance nor conductance was altered by the esophageal acid infusion; LES pressures were normal and esop~ageal contractile pressures were mildly decreased. Acid exposure in the upright and supine positions was within normal limits. Acid
clearance during sleep was similar to that in DOrmal subjects; however, acid clearance during waking appeared to be somewhat prolonged in the COPD patients. We conclude that patients with COPD do not have a bronchoconstrictive reOex to distal esophageal acidi6cation, and esophageal function in these patients appears to be relatively normal. (Cheat 1992; 101:1521-25)
Numerous studies in the medical literature have strongly suggested a relationship between lung dysfunction and GER. 1 The primary mechanism for
the symptom ofnocturnal wheezing. 13-15 In one report, patients cured by antireflux surgery were those with predominantly nocturnal symptoms. 9 Other· studies have found the bronchoconstrictive response to be present only in patients with esophagitis or an acidsensitive esophagus (positive response to an acid perfusion test}. 4. 16 Clinically, it often has been suggested that patients with COPD may experience symptoms of GER, particularly when treated with drugs such as theophylline or anticholinergic compounds. The mechanism for this could relate to potential effects of these drugs in decreasing LES pressure. 17 Furthermore, it has been postulated that alterations of lung mechanisms such as hyperinBation can lower LES pressure, perhaps in part through diaphragm flattening. 18 A high incidence of GER was documented in patients with COPD in a recent report by Ducolone and colleagues. 19 However, the effect that acute or chronic reDux has on intrinsic lung functioning in patients with COPD has not been thoroughly investigated. The present study reports a comprehensive investigation of esophageal function in patients with COPD during both sleep and waking states.
this relationship initially was thought to be the microaspiration of gastric contents reBuxed into the esophagus. 2 More recent studies in asthmatic subjects have suggested a vagally mediated reflex bronchoconstriction in these patients associated with esophageal acid contact.3-5 To date, several studies have shown that empirical medical or surgical treatment of reflux disease has improved respiratory symptoms.6-11 A particularly interesting animal study has been reported recently by Tuchman et al, 12 demonstrating a gradient of bronchoconstrictive response to acid placed in the distal esophagus or in the trachea. This study indicated a tenfold increase in the bronchoconstrictive response when minute amounts of acid were placed in the trachea compared with acid instilled in the distal esophagus. Some ofthese studies have suggested that this reflex response to GER is exacerbated during sleep, or that this phenomenon occurs only during sleep, generating *From the Sleep and GI J~hysiology Laboratories, Baptist Medical Center of Oklahoma, Oklahoma City (Dr. Orr); the University of Oklahoma Health Sciences Center, Oklahoma City (Dr. ShammaOthman); the GI Physiology Laboratory, Presbyterian Hospital, Oklahoma City (Dr. Allen); and Oklahoma Center for Digestive Research, Oklahoma City (Dr. Robinson). tCurrently at Humana Hospital Greenhrier Valley, Ronceverte, WVa. Manuscript received April 1; revision accepte4 September 20. Reprint requests: Dr. On; Baptist Medical Center; 3300 NW Expressway, Oklahoma City 73112
= =
= =
EEG electroencephalogram; EMG electromrogram; EOG = electro-oculogram; GER = gastroesophagea re8ux; LES lower esophageal sphincter; Sgaw speci6c airway conductance; SOB shortness of breath; Sraw specific airway resistance
=
=
METHODS
Subjects
Twelve patients with chronic airway obstruction and a mean age of 55.6 years (range, 34 to 77 years) were studied. All patients were thought to have underlying emphysema as a result of cigarette smoking and varying degrees of reactive airway disease. As shown in Table 1, this varied from zero to 102 percent. AU patients were CHEST I 101 I 6 I JUNE, 1992
1521
Table l-Detnograplaic and ClinictJl1JGtG*
Age (yr) 53
59
60
77
72
65
66
49
59 64
42 58
FEVl before FEVl after %Cbange 2.39 2.28 -5% 1.15 1.11 -3% 1.50 1.52
I'll
1.24 1.30 5% 2.01 2.36 17% 2.02 2.52 25% 0.92 1.21 32% 0.95 1.26 32% 1.45 1.93 33%
1.58 2.30 46% 1.00 1.85 85% 0.82 1.66 102%
Resting, Awake Blood Gas Values FEV/FVC,%
pH
POOl
Po.
Acid Perfusion Test
35
7.48
35
79
+
64
7.44
35
70
36
N/At
37
Symptoms Respiratory
Esophageal
Chronic cough, SOB
Heartburn
Nocturnal wheezing
None
+
Nocturnal SOB*
Heartburn, dysphagia
N/A
+
SOB*
Heartburn, dysphagia
50
N/A
+
SOB
Heartburn
50
7.41
43
76
+
MomingSOB*
Heartburn, dysphagia
59
7.37
39
96
SOB
Heartburn, indigestion
46
7.38
55
45
Nocturnal and moming SOB*
Heartburn
47
7.37
39
78
SOB
None
34
7.53
32
66
+
SOB
Heartburn, dysphagia
38
7.40
44
80
+
Early morning SOB
Heartburn
70
7.40
44
84
+
Nocturnal and morning SOB
Heartburn
+
*Data are presented in order of increasing degrees of reversibility. tN/A =recent blood gas values not available. *Described some relationship between the occurrence of heartburn and respiratory symptoms. referred from the Chest Medicine Clinic of the Veterans Aft8irs Medical Center. At the time of the stud~ patients were free of all respiratory medication and any medication for the treatment of peptic symptoms. Pertinent patient data are presented in 18ble 1. Nine patients had reversible lung disease (as defined by at least 15 percent increase in FEV1 with bronchodilator administration), and three patients bad nonreversible lung disease. Although 10 of the 12 patients had a positive history of reflux-related symptoms (heartburn, dysphagia), only four described any noticeable relationship between their respiratory symptoms and their heartburn symptoms (Table 1). None had previously taken histamine "blockers. All subjects gave informed consent, and the study was approved by the Institutional Review Board of the University of Oklahoma Health Sciences Center. Each patient underwent the following sequence of evaluations: Placement of an esophageal manometry probe. Measurement of total pulmonary resistance. Esophageal manometric evaluation and acid perfusion test. Repeat total pulmonary resistance determination. Ambulatory 24-h esophageal pH monitoring (subsequent day).
1522
Sleep evaluation to include determination of sleep stages and esophageal acid clearance times (subsequent night). lWfIIOfUJ'1I He.riBttJnce Meauru
Measures of Raw were done with the standard plethysmographic technique. Resistance was determined using the following formula:
Raw=PJP~. RIP. V Esophagetll Manometry Esophageal pressures were measured via a small (4.5-mm diameter) probe containing three radially oriented pressure transducers located 5 em apart. Pressures were amplified and recorded on a standard recording chart (SandhiD Scienti&c, Inc.). The LES pressures were measured by the standard pull-through technique, and esophageal peristalsis was assessed by having the patients swallow a small volume (5 ml) of water ten times at 3O-s intervals. In addition, each patient ingested a meal in the form of a cup of commercial beef stew and esophageal peristalsis was assessed during food ingestion by assessing responses to swallows identified by a
Table 2-Mean Ainooy Re8iBtance and Conductance Value, with Acid Infusion in the DiBtal Eaophagua Raw
Saline O.IN HCI p value*
sGaw
Gaw
sRaw
Mean
SD
Mean
SD
Mean
SD
Mean
SD
3.75 3.87 NS
1.75 2.33
21.84 21.97 NS
9.33 9.44
0.031 0.033 NS
0.013 0.016
0.0052 0.0051 NS
0.0029 0.0030
*Wilcoxon signed rank test. submental EMG. RESULTS
Acid Perfusion Test The acid perfusion test was perfonned in accordance with a standard technique using liquid infusions of 120 drops per minute at a location 5 cm above the manometrically detennined LES. A solution ofO.lN HCI was instilled into the distal esophagus and the subjective response was monitored. This procedure continued until the patient expressed some subjective response (ie, heartburn or chest pain), or until 15 min had elapsed. Subsequently, the infusion solution was switched (without the subject's knowledge) to an infusion solution of sterile water which continued until the patient expressed a subjective response, or until 15 min had elapsed. A positive response was detennined to be provocation of substernal or epigastric pain by the acid infusion, ideally also relieved by the subsequent water infusion.
Ambulatory 24-h Esophageal pH Monitoring Each patient reported to the laboratory at 7:30 A.M., and a small caliber pH catheter was placed nasally into the distal esophagus 5 cm above the manometrically detennined LES. The probe was attached to a compact data acquisition unit (Sandhill Scientific, Inc.) around the waist. The patient was instructed to avoid specifically listed acidic foods, and to keep a log of pertinent events such as pain (heartburn, dysphagia, or chest pain), meals, and sleeping times. Sleep Study
The details of this methodology have been described previously and will be briefly reviewed here. 210.21 Each patient underwent a study in the sleep laboratory which consisted of continuous monitoring of the EEG, EOG, submental EMG, and ECG. Also distal esophageal pH was monitored with a 3-mm-diameter pH catheter placed 5 cm above the manometrically detennined LES. Two to five infusions of 15 ml of O.IN HCI were accomplished during periods of polygraphically detennined sleep. Each infusion lasted approximately 1 min. In some subjects, multiple awakenings allowed only two infusions. Statistical analysis was accomplished using the Student t test for correlated means and appropriate nonparametric analysis as indicated.
Pulmonary Resistance Measures
As can be seen from Table 2, neither Raw nor Gaw was altered by the esophageal acid infusion. Similarl~ calculations of sRaw and sGaw were not appreciably altered by the acid-mucosa contact. Since this is a relatively heterogeneous population ofindividuals with regard to bronchial reactivit~ we compared the four patients with nonreversible lung disease with the four with the greatest degree of reversibility (Table 3). U sing the Mann-Whitney U test, the two groups were found to be significantly different (p
