Identification of an abnormal esophageal clearance response to intraluminal distention in patients with esophagitis

GASTROENTEROLOGY

1992;103:943-953

Identification of an Abnormal Esophageal Clearance Response to Intraluminal Dkention in Patients With Esophagitis DAVID WILLIAMS, DAVID GEORGE THOMPSON, MARGARET LESLIE HEGGIE, TIMOTHY O’HANRAHAN, VENK MANI,

MARPLES,

and JOHN BANCEWICZ Departments of Medicine and Surgery, Hope Hospital. Salford, England; and Leigh Infirmary, Lancashire, England

Esophageal clearance responses were studied by a new technique comprising a miniature electronic strain gauge attached to an inflatable balloon in 30 normal volunteers and 48 patients with gastroesophageal reflux disease. The pressure changes around the balloon and traction forces acting on the balloon were measured during graded balloon distention (o-12mL of air for 30 seconds each inflation) in the lower and midesophagus. All normal volunteers responded to distention with development of swallow independent contractions above the balloon [65 mm Hg/30 s (range, 45-100 mm Hg/ 30 s)]together with generation of an aboral traction force [15 g (range, 6-20 g)]. Patients with reflux esophagitis showed a higher distention threshold for initiation of these responses, induced fewer proximal contractions [24mm Hg/30 s (range, O-38 mm Hg/30 s); P < 0.01 vs. normal], and generated weaker traction forces [4 g (range, O-6 g) at 10 mL P < 0.01vs.normal]. Patients with the most severe esophagitis showed greatest impairment of the clearance response (correlation = 0.7,P < 0.01)and the greatest esophageal residence of refluxed acid (correlation = 0.5, P < 0.01). These abnormalities appear to be of relevance to the pathophysiology of esophageal reflux disease although it remains to be determined whether they are the cause, or the result, of the esophagitis. he pathogenesis of gastroesophageal reflux disease is recognized to be related to a number of factors including reduced lower esophageal sphincter (LES) pressure,’ increased frequency of transient LES relaxations,’ the presence of a hiatus hernia,3 and defective esophageal motility.4 However, the central factor leading to esophagitis appears to be increased esophageal exposure to injurious gastric contents resulting from an imbalance between reflux and clearance. The role of excessive reflux has been extensively studied,5.6 and the severity of esophagitis is usually

T

found to correlate with quantity of acid refluxed and reduction of LES pressure.7 In contrast to esophageal reflux, the mechanisms controlling esophageal clearance and their abnormalities in esophagitis remain poorly understood. Efficiency of acid clearance in normal individuals has been shown to depend on swallow-related peristalsis and saliva production.’ In esophagitis patients, swallow-related acid clearance has been shown to be prolonged,g and abnormally prolonged residence of ingested radionuclide is demonstrable.lO~‘l However, swallow-induced peristalsis is not the only mechanism by which esophageal clearance is achieved. Intraluminal distention of the esophagus is known to induce secondary contractions, independent of swallowing, that propel the distending material into the stomach.‘2-14 The control of this response appears to arise locally from the enteric nervous system because virtually identical responses have been reported to occur both in vitro15 and in vivo in the extrinsically denervated esophagus.= Because abnormalities of primary peristalsis have been reported in patients with esophagitis,4 we hypothesized that abnormalities of the intrinsic clearance response might contribute to the development of mucosal damage. To test this hypothesis, we developed a new method for assessing esophageal clearance forces induced by graded intraluminal distention. The results of our studies indicate that abnormalities of the clearance response do exist in patients with esophagitis and appear to be related both to the severity of mucosal damage and acid reflux. Materials and Methods Subjects Studied Thirty troesophageal

healthy reflux

volunteers and 48 patients with gaswere recruited in accordance with

C 1992 by the American

Gastroenterological

0016-5085/92/$3.00

Association

944

WILLIAMS

ET AL.

Salford Area Health Authority ethical guidelines. All gave written informed consent before the study. Control subjects. Thirty healthy asymptomatic volunteers (median age, 26 years; range, 18-58; 18 female) were recruited to act as controls. All were healthy hospital personnel with no history of gastrointestinal disease. Patients. The patient group consisted of 48 individuals (26 female) with gastroesophageal reflux symptoms and objective evidence of excessive acid reflux on standard 24-hour pH recording.” At endoscopy, 30 patients had, in addition, evidence of esophagitis. These 30 patients were designated the “esophagitis” group. They were divided into four subgroups by endoscopic grading as follows: 7 patients with grade I (erythema and edema), 11 with grade II (isolated erosions not involving the entire circumference), 6 with grade III (circumferential erosions or superficial ulceration of >2 cm in length), and 6 with grade IV (extensive circumferential erosions and or deep benign ulceration). The median age was 46 years while the range was 18-64 years. No patient had macroscopic evidence of esophagitis extending beyond 10 cm above the lower esophageal sphincter. The other 18 patients with a normal mucosal appearance at endoscopy despite excessive reflux and symptoms were designated the “reflux” group. The median age of this group was 49 years (range, 22-68 years). All patients fulfilling the above criteria were recruited for study from a consecutive series of 74 patients referred to a gastroenterological outpatient clinic for investigation of gastroesophageal reflux symptoms. Patients with evidence of esophageal strictures or with manometric evidence of primary motor disorders such as diffuse esophageal spasm and achalasia were excluded from the study. Eighteen patients with either systemic diseases, e.g., scleroderma, diabetes, or taking drugs that may have affected esophageal function, e.g., calcium channel blockers, were also excluded from the study while a further eight patients declined the offer to participate.

Techniques lntraluminal manometry. A 4-lumen manometry catheter was constructed from polyethylene tubing (Portex Ltd., Hythe, Kent, England) of internal diameter 0.63 mm, external diameter 0.8 mm, with ends opening 0, 3, 8, and 12 cm from the tip. Each lumen was perfused at a rate of 0.6 mL/min through a pneumohydraulic perfusion system (Arndorfer Medical Specialities Inc., WI). A pressure transducer (Statham P23-ID) was attached to each channel to continuously detect changes in flow resistance. Complete occlusion of each catheter lumen gave a pressure rise of >400 mm Hg per second. Recordings of each transducer output were made on a polygraph (Grass Instruments Co., Quincy, MA] run at a paper speed of 100 mm/min and calibrated so that a pen deflection of 10 mm, equalled a pressure change of 10 mm Hg. Traction force. To measure traction forces acting on a distending balloon in the esophagus, a new device was constructed. This comprised an electronic strain gauge (Gaeltec Ltd., Dunvegan, Isle of Skye, Scotland)

GASTROENTEROLOGY

Vol. 103, No. 3

mounted on a 4-mm diameter catheter. A flexible silicone extension was attached to the membrane of the strain gauge by two inelastic Kevlar threads. Traction forces applied to the extension were thus transmitted directly to the strain gauge, the electrical output of which was recorded on the polygraph after amplification. A 2-cm latex balloon (HSC II, Precision Dippings Marketing Stover Trading Estate, Yate, England) was mounted on the extension and was inflated with air via a channel running along the catheter. The performance characteristics of the device were as follows. The sensitivity of output was 22 pV* V-’ . g-‘, with a linear relationship of output to applied traction force over a range of O-150 g (linearity error 7%). The frequency of response to suspended weights was in excess of 150 g/ sec. There was a hysteresis for applied weights of 1 g for a 100-g reapplied weight and an output “creep” of 2 g for an applied weight of 200 g for 20 seconds. Forces greater than 500 g were not applied because of the likelihood of irreversible damage to the transducer. The influence of bending or twisting the extension piece between the balloon and transducer was minimal (maximum 5 g at 90’). The device thus enabled traction forces exerted on the balloon to be directly measured at varying degrees of esophageal distention. The transducer output was calibrated before each study by applying a series of known weights to the vertically suspended silicone extension. Inflation of the balloon on the bench with increasing volumes of air led to a linear increase in its diameter from 10 mm at 1 mL volume to 28 mm at 10 mL. The pressure inside the balloon was measured via an attached force transducer at each inflation volume both on the laboratory bench before each study, and inside the esophagus during each balloon distention. The difference between the two pressures at any given volume thus provided an indication of the forces applied to the balloon by the esophagus. Ambulatory esophageal pH monitoring. Twentyfour-hour ambulatory pH monitoring was performed immediately after manometry on all patients using a commercially available digital data recording and computer analysis system (Synectics Medical, 215 Willow Road, Enfield, Middlesex, England). On each occasion the recording electrode (0011 Monocrystant pH electrode, Synectics Medical) was placed 5 cm above the position of the lower esophageal sphincter manometrically defined as the upper limit of the high pressure zone. All studies were conducted during normal daily activities.

Study Protocols All patients were studied within 10 days of the diagnostic endoscopy. Those patients who were taking antacids were required to stop the medication for at least 2 days before the study. All individuals were studEsophageal manometry. ied supine after a fast of at least 6 hours. The manometry catheter was first passed nasally until all side holes lay in the stomach. The lower esophageal sphincter was next located by station pull-through of the catheter after which it was further withdrawn until the most distal channel was

September 1992

sited 1 cm proximal to the lower esophageal sphincter. The amplitude of the peristaltic wave following each of six IO-mL water swallows performed at 30-second intervals was then measured. The occurrence of swallowing was identified on the polygraph by the patient, using a marker button pressed on swallowing, and by occurrence of interruption of respiration detected by a nasal thermistor whose output was also recorded on the polygraph. Responses to distention. LOWER ESOPHAGUS. With the manometry catheter in situ, the traction catheter was passed nasally so the balloon was sited between the second and third recording channel, 6 cm above the lower esophageal sphincter, its position being verified throughout the study by observation of the appropriate sequence of primary peristaltic pressure changes recorded from the balloon and catheter. Both catheters were then securely taped to the nose to prevent aboral movement, and the balloon was inflated with air for 30 seconds, the volumes of inflation ranging from O-12 mL (0, 1,2,3,5, 7, 10, and 12 mL). These volumes, based on pilot study data, were chosen to give the maximum number of measurable differences in the minimum number of steps. The maximum volume administered to an individual was either 12 mL or that volume which reached the limit of the subjects tolerance. All inflations were performed at least 30 seconds apart and at least 15 seconds after any preceding swallow. If swallowing occurred inadvertently during a distention period, the balloon was deflated and the inflation repeated. MIDESOPHAGUS. The above protocol was repeated after both the traction device and manometry catheter had been withdrawn 5 cm to position the balloon in the midesophagus 11 cm above the lower esophageal sphincter and above the limit of any endoscopically recognizable esophagitis. Data Analysis Manometric data. Peristaltic amplitudes following 10 water swallows were measured using the pressures obtained from the two most distal manometry channels. Values for each individual were expressed as the median and interquartile range of the 20 values recorded. Only propagated peristaltic waves were analysed. The lower esophageal sphincter pressure was defined as the median of the four values recorded at station pullthrough, each value being measured as the difference between end-expiratory gastric and the maximum endexpiratory sphincter pressures. Responses to distention. The following variables were measured. DISTENTION THRESHOLD. Distention threshold was defined as the smallest balloon volume that induced a contraction of >lO mm Hg in the adjacent proximal pressure recording channel. The values were expressed in milliliters of air. PROXIMALCONTRACTILEACTIVITY. Anassessmentof the contractile activity induced proximal to the balloon was obtained by summation of all the contractions occur-

ESOPHAGEAL CLEARANCE FORCE IN ESOPHAGITIS 945

ring at the adjacent channel during the 30 seconds of inflation. Values were expressed as mm Hg/30 s. DISTALCONTRACTILEACTIVITY. Distal contractile activity was similarly assessed using the information provided from the adjacent distal channel. Values were expressed as mm Hg/30 s. TRACTION FORCE. Because the traction force generated by distention usually continued throughout the inflation period, an assessment of the force exerted on the balloon was obtained by counting the number of l-mm squares under the traction force curve on the polygraph tracing obtained during the inflation period. This value was then divided by 30 to provide a more convenient value. THE SENSATION THRESHOLD. At each inflation volume all individuals were asked to report whether or not they were aware of the presence of the balloon. The sensation threshold was defined as the smallest balloon volume that was recognized by the individual. pH Recording data. A recording time of >22 hours was accepted for analysis. The number and duration of episodes during which the pH fell below 4 was measured. From these two values the average reflux event duration was calculated for each patient. Statistical

Methods

Comparisons between patient and volunteer data were made using nonparametric techniques” to avoid the assumption of normality of data distribution. Comparisons between subject groups were made using the Mann Whitney U test and comparisons of paired data, by the Wilcoxon Pair Test. Tests for correlation were performed using Kendalls rank correlation and the Kruskal-Wallis test was used to compare multiple group data. Values in the text correspond to median and interquartile range unless otherwise stated. Results

Volunteer Studies Standard manometry. All volunteers showed normal propagated peristalsis on swallowing. Peristaltic amplitudes in the distal esophagus were 60 mm Hg (range, 55-68 mm Hg) and lower esophageal sphincter pressures were 12 mm Hg (range, 8-18

mm Hg). Responses to distention. SENSATION. Inflation of the balloon was described as a retrosternal discomfort. The smallest volume perceived in the lower esophagus was 10 mL (range, 5-10 mL). The sensation always developed within 2 seconds of the onset of inflation, persisted for its duration, and always ceased within 2 seconds of balloon deflation. With increasing inflation, the intensity of discomfort increased; however, tolerance to the inflation procedure was always limited by nasopharyngeal discomfort induced by traction on the catheter rather than

GASTROENTEROLOGYVol.103,No.3

946 WILLIAMS ET AL.

by chest pain. All subjects tolerated lo-mL distention but only 14 tolerated 12-mL distention and for comparison with patients the 10 mL data were therefore used. No difference was found between the thresholds in the lower and mid esophagus [midsite 10 mL (range, 5-10 mL), P > 0.5 vs. lower site]. CHARACTEROFMOTORRESPONSE. Acharacteristic pattern of motor and traction responses (Figure 1) occurred. Proximal contractions were induced in all individuals, independent of swallowing. At lower volumes of distention these were identifiable as discrete contractions on a stable baseline. However, as the degree of distention increased, multipeaked contractions were generated without a return to baseline values. In association with the contractions, an aborally directed force was exerted on the balloon

rll

: :

m

12

10

00

ooo

w

Distension Threshold (n-W 7 *

8888 88

88%

888

Reflux

Oesophagitis

Figure 2. This figure shows the thresholds for induction of proximal contractions in the control, reflux, and esophagitis groups. The esophagitis group have higher thresholds than the other two groups (P < 0.05).

/

30 Seconds Distension

Figure 1. This figure shows the contractile activity and traction forces induced by balloon inflation with 10 mL of air in a normal volunteer. On inflation, contractions are induced above the balloon together with the generation of an aboral traction force. Actual values for the distention period are 230 mm Hg/30 set at 1 cm and 190 mm Hg/30 set at 4 cm proximal. Distal contractile activity is 36 mm Hg/30 set (1cm) at 30 mm Hg/30 s at 4 cm. Thirty-two grams of force was exerted.

whose magnitude generally matched the pattern of proximal contractions but did not return to baseline, indicating the presence of both tonic and phasic components. Both contractions and traction force ceased within 1 second of balloon deflation. The distal motor response was characterized by quiescence; however, a small number of low amplitude contractions could be seen to propagate from the proximal to distal recording site. At maximally tolerated inflation volumes, distal contractions were abolished. Responses were similar in both the mid and lower esophagus. PROXIMALCONTRACTILEACTIVITY. Thethreshold for induction of proximal contractions in the lower esophagus was 7 mL (range, 5-7 mL) (Figure 2). Thresholds in the lower and midesophagus were similar (Table 1). Contractile activity always increased with increasing inflation volume (Figure 3A). There was no difference between the contractile activity induced by similar balloon volumes at the lower or midesophageal sites (Table 1). DISTAL CONTRACTILE ACTIVITY. Distalcontractile activity decreased progressively with increasing balloon inflation and was usually absent at maximum tolerated volumes. There was no difference

ESOPHAGEALCLEARANCEFORCE IN ESOPHAGITIS 947

September 19%

Table 1. Contractile Activitv Control Inflation volume (mL)

Proximal

Reflux

Esophagitis

Distal

Proximal

0 (O-10) 20(10-25) 15 (5-20) 8 (O-14)

0 (O-5) 24(10-30) 40(20-70) 45(37-80)

0 18 10 5

0 (O-10) 15 (8-20) 9 (4-16) 5 (O-12)

0 (D-10) 30(15-35) 45(25-76) 55(28-90)

0 (O-5) 22(12-26) 14 (5-20) 10 (2-15)

Distal

Proximal

Distal

0 5 (O-25) 24 (O-38) 30 (6-55)

0 3 (O-15) 10 (O-20) 7 (O-15)

0 13 (2-58) 33(14-48) 40(10-75)

0 5 (O-12) 12 (O-20) 8 (O-15)

Lower Esophagus 0 (O-40) 40(25-75) 65 (45-100) 85 (50-155)

5 7 10 12

Midesophagus 5

0 (O-35) 35(20-70) 60(45-90) 80(45-135)

7 10 12

(O-5) (10-22) (5-15) (O-12)

NOTE. Contractile activity in mm Hg/30 seconds induced by distension in the lower and midesophagus in controls, patients with esophagi& and patients with gastroesophageal reflux. Values represent median and IQR. Values in parentheses represent range.

between the contractile (Table 1).

response

at the two sites

TRACTION FORCE. In each subject, the threshold for traction force development was identical to that for induction of proximal contractions. Commensurate with the induction of proximal contractions, an aboral traction force was exerted on the balloon, which increased with increasing inflation (P < 0.01 for comparisons between 3/5,5/7,7/10 mL inflations) (Figure 3B). There were no consistent differences between the forces induced by inflation at the lower and midesophageal sites (Table 2).

Patient Studies Standard manometry. In the esophagitis patients, amplitudes in the lower esophagus were 48 mm Hg (range, 25-60 mm Hg) with lower esophageal sphincter pressures of 4 mm Hg (range, O-12 mm Hg), both values being lower than the control group (P < 0.01). In patients with reflux but no esophagitis peristaltic amplitudes were 50 mm Hg (range, 45-60 mm Hg) with lower esophageal sphincter pressures of 8 mm Hg (range, 4-11 mm Hg), values similar to the esophagitis group (P > 0.05) but lower than the control group (P < 0.05). A negative relationship existed between the grade of esophagitis and peristaltic amplitude in the distal esophagus (r = 0.49, P < 0.01). Responses to distention. SENSATION. In both patient groups, the sensation thresholds were similar to the control group, both being 10 mL (range, 5-10 mL; P > 0.05). The description of the character of the sensations perceived by the patients was similar to that reported by the normal volunteers. All patients tolerated 12-mL distention, and it was notable that the pharyngeal discomfort induced by the traction was less than that reported by the normal subjects. PATTERN OF RESPONSE. In both patient groups, the distention response was qualitatively similar to that seen in the controls, although quantitative dif-

ferences were readily apparent. As with the control group, the threshold volumes for induction of proximal contractions and traction force were the same. DISTENTION THRESHOLD. In the esophagitis patients, the threshold for the onset of proximal contractions and traction force in the lower esophagus was 10 mL (range, 7-12 mL), which was greater than that for the control group (P < 0.01). Four patients showed no motor responses at the maximal inflation volume of 12 mL. In the reflux patients, the distention threshold was 7 mL (range, 5-10 mL), which was similar to the control group (P > 0.05). In the esophagitis patients, the distention threshold in the midesophagus was 7 mL (range, 7-12 mL), which was lower than that recorded in the lower esophagus (P = O.O2), but was still higher than that recorded in the control group (P < 0.01). In the reflux group the distention threshold was 7 mL (range, 5-10 mL), which was similar to that recorded in the lower esophagus (P > 0.05) and to the values recorded in the control group (P > 0.05). PROXIMAL CONTRACTILE ACTIVITY. In the esophagitis patients, distention in the lower esophagus induced fewer proximal contractions than the control group at all volumes exceeding the distention threshold (P < 0.01) (Figure 3A). In the reflux patients, distention induced fewer contractions than the control group (P < 0.05) but more than in esophagitis (P < 0.01) (Figure 3A). The contractile activity induced at the threshold volume was also less in the esophagitis patients. Values were 32 mm Hg/30 s (range, 15-45 mm Hg/30 s) for controls, 28 mm Hg/30 s (range, 15-48 mm Hg/30 s) in the reflux group (P > 0.01 vs. controls), and 22.5 mm Hg/30 s (range, lo-30 mm Hg/30 s) in the esophagitis group (P < 0.01 vs. reflux and control group). In the esophagitis patients, contractile activity in the midesophagus was greater than in the lower

GASTROENTEROLOGYVol.103,No.3

948 WILLIAMS ET AL.

A

100

80

Sum of Proximal Contractions 60 ImmHgi3Os)

40,

20,

?? 0m

0,

, 20-

I I !Ii

1

B

i8T 16. l4Aboral Traction Force (8)

,2_

TRACTION FORCE. In the esophagitis patients, the forces in the lower esophagus were consistently weaker than the controls throughout the range of distention (P < 0.01 for comparisons at each inflation volume) (Figure 3B). In the reflux group, the forces resembled the control group and were consistently stronger than the esophagitis group (P < 0.01 at 7 and 10 mL). In the esophagitis patients the traction forces induced at 7 and 10 mL in the midesophagus were 2.5 g/s (range, O-4 g/s) and 8 g/s (range, O-12 g/s) respectively, which exceeded those forces induced by similar volumes at the lower esophageal site (P < 0.01 each comparison). However, the forces induced were still weaker than the control group (P < 0.01) (Table 2). In the reflux group, the forces were similar to those in the lower esophagus (P > 0.05) and resembled those of the control group (P > 0.05).

Relationships Between the Severity of Esophagitis and Distention Response

10. 8. 6.

0

3

5

Balloon Volume

7

10

(ml)

Figure 3. (A) shows the amount of proximal contractile activity induced by increasing balloon volumesin the lower esophagus (median and IQR). Greater activity was induced in both the control (0) and reflux (0) group than in the esophagitis group (m) at 5-, 7-, and IO-mL volumes (P < 0.01). At 7 and 10 mL the control group also showed greater responses than the reflux group (P < 0.05). (B) shows the aboral traction force exerted on the balloon in the lower esophagus with increasing volumes of inflation (median and interquartile range). The control (0) and reflux (0) group exerted a greater force than the esophagitis group (D) at 5, 7, and 10 mL (P c 0.01) with the control group exerting greater forces (P < 0.05) than the reflux group at 10 mL.

esophagus, being 13 mm Hg/30 s (range, 5-28 mm Hg/30 s) at 7 mL and 33 mm Hg/30 s (range, 14-48 mm Hg/30 s) at 10 mL inflation (P < 0.01 vs. lower esophagus). In the reflux patients, responses in the midesophagus and lower esophagus were similar (P > 0.05) and resembled the control group (P > 0.011(Table 1). DISTAL CONTRACTILE ACTIVITY.In the esophagitis patients, activity was consistently less than the control or reflux group at either site (P -C 0.01vs. control or reflux) (Table 1).

Distention threshold. When the endoscopic grade of esophagitis was compared with distention threshold in the distal esophagus, a direct relationship between the two was found (r = 0.7, P < 0.01). Mild esophagitis (grades I and II) was associated with normal distention thresholds, whereas those patients with more severe esophagitis (grades III and IV) had either higher thresholds or showed no response to distention (Figure 4). Proximal contractile activity. The proximal contractile response also varied with the severity of esophagitis. Patients with grade I or II esophagitis showed consistently more contractile activity than those with grade III or IV (P < 0.01) at both distention sites (Figure 5A). Traction force. The traction forces induced by distention were also related to the grade of esophagitis (Figure 5B). The traction forces developed by patients with grades I or II esophagitis did not differ from controls at either inflation site, and were consistently greater than the traction forces developed in patients with grades III and IV esophagitis (P < 0.01)at either esophageal site. Relationship Between Acid Reflux and Distention ThreshoId To determine whether the reduced response to distention in the esophagitis patients was related to the magnitude of acid reflux, distention thresholds were compared both with the average reflux event duration and with the number of reflux episodes.

September

ESOPHAGEAL

1992

CLEARANCE FORCE IN ESOPHAGITIS

949

Table 2. Traction Forces Reflux

Control Mid

Volume (mL)

Lower

Mid

Esophagitis Lower

Mid

Lower

5

0 (O-Z)

0 (O-3)

0 (O-3)

0 (O-Z)

0 (O-2)

0 (O-1)

7

4 (O-10)

6 (O-12)

6 (O-12)

5 (O-8)

2.5 (O-4)

0 (O-3)

10

12 (6-16)

15 (9-20)

10 (6-18)

12

26 (15-30)

24 (14-32)

18 (10-28)

NOTE. Traction force (g) exerted represent median and IQR.

on the balloon at differing volumes

There was a positive correlation in the lower esophagus between distention threshold and median duration of reflux events (Figure 6) (r = 0.47; P < 0.01). When the patients were separated according to their endoscopic grading of esophagitis, an increased reflux duration was seen with increasing severity of esophagitis, durations being 2.3 (range, 1.6-4.1), 3 (range, l-6), 4.5 (range, 3-7), and 5.8 (range, 3-11) minutes at grades I, II, III, and IV respectively, as shown in Table 3. Kruskal-Wallis analysis showed a significant difference between the medians of the group, P = 0.04, the intergroup differences lying between grade I and IV (P = O.O15), II and IV (P = 0.035).

8 (4-16)

9 (O-12)

14 (8-18)

12 (4-24)

in the midesophagus

and lower esophagus

4 (O-6) 5 (l-8)

are shown. Values

No correlations were found between distention threshold and the total number of reflux episodes 45 (range, 30-61) per 24 hours (r = 0.04) or between peristaltic amplitude and either the duration (r = -0.16; P > 0.3) or number (r = 0.14; P > 0.4) of reflux events. When the reflux patients were analyzed in a similar manner, no correlations were found between the distention threshold and either duration or number of reflux episodes (r = 0.16, 0.1, respectively). The total number of reflux episodes [43/24 hours (range, 31-52/24 hours)] was similar to the esophagitis group(P > 0.05). Relationships Between Distention Response and Primary Peristaltic Amplitude

00

>12

00

12

0

0

?? ???

mm

00

10

0

0

00

Distension Threshold (ml)

7

5

0.0

The Effect of Age on Distention

000 000

Threshold

No significant correlations were found between age and distention threshold for any group (control group, 0.1; reflux group, 0.15; esophagitis group, 0.2) (P > 0.05).

0.0

Relationships Between Intraballoon Pressure and Inflation Volume in Patients and Controls

3

a

In the esophagitis patients, comparisons between the distention threshold and peristaltic amplitudes in the lower esophagus did show a negative relationship (0.42, P < 0.01) (Figure 7). However, 7 patients with esophagitis were found to have normal peristaltic amplitudes yet had abnormally high distention thresholds. No correlations were found in the control or reflux groups.

---m

I

II Oesophagitis

III

m

Grade

Figure 4. This figure shows the relationship between the grade of esophagitis and the distention threshold to onset of proximal contractile activity. It can be seen that a significant relationship exists between severity of esophagitis and distention threshold (r = 0.7, P < 0.01).

Because a difference in esophageal diameter or esophageal compliance could have explained the differences in the group responses to distention, the pressure/volume characteristics of the balloon during inflation were compared for each group. There were no differences between control values, reflux patients, or mild esophagitis (grades I and II) (P > 0.05). However, at higher distention volumes the patients with the most severe esophagitis showed

950

GASTROENTEROLOGYVol.103,No. 3

WILLIAMS ET AL.

A

60

50

Sum of Proximal Contraction Amplitudes (mmHgi3Os)

40

30

V-Y-

12-

B

lO=

6.

1’ : I

Traction Force (g) 6-

‘I-

2.

O-

i ! t omo

3

?? zl

I

I

5

7

Balloon

Volume

IO

16

10

1 12

(ml)

Figure 5. (A) Proximal contractile response in the lower esophagus to increasing balloon volumes for each esophagitis group (I, 0; II, 0; III, e IV, Cl). Values given are median and IQR. It can be seen that as the severity of esophagitis increases, the contractile response is reduced. (IS] shows the traction force responses in the lower esophagus with increasing balloon volumes in the patients with esophagitis. As the severity of esophagitis increases, the traction response is reduced.

lower than expected pressures, compliance (Table 4).

vous system.” In the intestine, the effector pathway of this reflex comprises an ascending limb that mediates excitation possibly through pathways using both cholinergic and noncholinergic nonadrenergic neurotransmitters (possibly substance P), and a descending limb that mediates distal inhibition, probably via the neurotransmitter VIP.201n vitro studies using human tissue also show a peristaltic reflex similar to that of intact animals21~22indicating that the response is indeed intrinsically mediated. Most studies of the peristaltic reflex in the esophagus have concentrated on events at and below the site of balloon distention rather than above it.23*24 While these distal events are known to be intrinsic in origin, the contractions seen in vivo some distance above the site of distention could also involve a vagal reflex because more distant proximal contractions may be eliminated by vagal section.” Previous studies of the contractile responses to esophageal distention appear similar to our own.12~26~27 Unlike our results, however, no relationship between degree of distention and traction force was found; possibly the relatively unsophisticated techniques available when the studies were performed prevented such analysis. Our studies also show that patients with esophagitis produce abnormal responses to distention, with a higher response threshold, induction of fewer contractions, and weaker clearance forces than controls. Furthermore, the degree of abnormality appears greatest in lower esophagus of patients with the most severe esophagitis suggesting that the severity of neuromuscular damage is related to the greater acid exposure. In patients with reflux without esophagitis, the distention responses were less abnormal than the

indicating

increased

Discussion Our study has shown that distention of the normal human esophagus elicits a characteristic set of motor responses similar to those observed in vitro15 and appear to be components of the “peristaltic reflex”lg known to be a function of the enteric ner-

Duration (mins)

5

2.5

8

??

’

0

:

lb

t-2

!

5 Distension

; Threshold

Il.2

(ml)

Figure 6. Relationship between the average reflux event duration and distention thresholds in the lower esophagus for the esophagitis patients. Each symbol shows the data for a single patient. As the distention threshold increases, reflux duration becomes greater.

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CLEARANCE FORCE IN ESOPHAGITIS

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Table 3. Z&Hour pH Data Esophagitis patients

I

Reflux patients Mean event duration (min) Mean number of reflux episodes Percentage of recording time below pH 4

3 (2.3-4.3) 43 (31-52)

2.3 (1.4-5) 44(11-70)

9.5 (4.5-14)

12.6 (3.6-20)

II 3 (l-6) 53 (18-114) 10.1 (5-37)

NOTE. Twenty-four-hour pH data for the esophagitis and reflux patients are shown. Values represent Values in parentheses represent range.

esophagitis patients, and acid residence time was also shorter despite a similar number of reflux episodes. This suggests that the development of esophagitis is determined more by abnormally prolonged residence of refluxed acid than by the quantity or frequency of acid refluxed. Our data do not allow us to be certain about the precise relationship between the motor abnormalities and the presence of esophagitis; indeed some of our observations suggest a causal, and others an effect, relationship. For example, the close relationship between the severity of inflammation and degree of motor impairment, together with the finding that some esophagitis patients showed virtually normal distention responses in the midesophagus above the site of esophagitis suggests that esophagitis leads to the impaired responses. However, in other patients, quite marked abnormalities to distention were noted even above the level of the esophagitis. This latter group may include those patients with a primary disorder of esophageal clearance in whom esophagitis is the consequence of their underlying disease.

.I 20 1 :

i ; lb Distension Threshold (ml)

l-2

I’ .1;

Figure 7. This figure shows the relationship between peristaltic amplitude and distention threshold in the lower esophagus in esophagitis patients. The control range is shown by the hatched area. A relationship exists between peristaltic amplitude and distention threshold (r = 0.42; P < 0.01). Seven patients show peristaltic amplitudes within the normal range but abnormal distention thresholds.

(grade) III

4.5 (2.5-7) 45 (36-118) 14.6 (5.7-46)

IV 5.7 (3-11) 48(9-100) 19.7 (4-37)

the median and IQR for the groups.

Because acid clearance from the esophagus is likely to be dependent on factors additional to distention-induced clearance such as saliva production’ and primary peristalsis, the importance of the responses we have found need to be discussed in relation to these other factors. Although it was true that those patients with weakest clearance responses also had the most abnormal primary peristaltic function and poorest acid clearance, acid reflux duration correlated with esophageal clearance but not peristaltic amplitude, suggesting an independent, additional effect. A number of esophagitis patients were also found to have normal standard manometry but defective distention responses. These observations are consistent with the reports of impaired acid clearance,’ and isotope transit’0~2* in patients with esophagitis despite normal primary peristalsis. In animal models, abnormalities of primary peristalsis may be induced by acid2g~30and return to normal when the acid is removed.31 However, it is unclear whether this is also true in man because reports of improvement in peristaltic function with healing of esophagitis by drug therapy are contradictory, some showing improvement3’ but others finding none.33 Studies on patients following Nissen fundoplication for esophagitis have been similarly conflicting.34-3” Some report no significant improvement in peristaltic function35 or isotope clearance,” whereas others have claimed some improvement in peristaltic amplitude in milder cases despite failure to improve those patients with the most marked abnormalities.3” Because the study of esophageal clearance responses appears a more direct method for detecting clearance abnormalities in esophagitis, it would be of interest to determine whether improvement in clearance can be found following effective healing of esophagitis. Such studies might also provide useful insight into the nature of the reflux-dysfunction relationship because restoration of function after therapy would suggest that reflux-induced abnormalities were paramount whereas persistence of dysfunction would suggest that either a primary esophageal abnormality was responsible for the development of

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GASTROENTEROLOGY Vol. 103, No. 3

WILLIAMS ET AL.

Table 4. Pressures

Exerted

During

Balloon

Inflation Distention

Subject category Control Reflux I II III IV

1 5 (3-8) 5 (3-8) 5 (3-8) 5 (3-8) 5 (3-8) 5 (3-8)

3

2 12(10-15) 12(10-14) 12(10-13) 12(10-14) 11 (9-13) 11 (9-13)

23(20-26) 24(20-25) 24(20-25) 24(21-26) 23 (19-25) 22(18-24)

volume JmL (range)) 5

34(30-38) 35(29-38) 34(30-36) 33(29-35) 31(28-33) 29(27-32)

7 39(35-43) 40(36-44) 38(35-42) 38(34-42) 36 (30-36)' 34 (30-3710

10 45 (40-50) 47(42-42) 43(35-48) 42(35-51) 35 (30-3910 34 (29-39y

12 48(43-53) 50(44-56) 46(40-51) 45(40-51) 36(32-42) 35(29-38)

"P < 0.05vs.control.

the esophagitis or that permanent esophageal age had been caused by the reflux.

dam-

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16. Ryan JP, Snape WJ, Cohen S. Influence of vagal cooling on esophageal function. Am J Physiol 1977;223:E159-164. 17. DeMeester TR, Wang CL Wernley JA, Pellegrini CA, Little AG, Klementschitsch P, Bermudez G, Johnson LF, Skinner DB. Technique, indications and clinical use of 24 Hr esophageal pH monitoring. J Thorac Cardiovasc Surg 1980;79:656672. 18. Leach C. Introduction to Statistics. Chichester, England: Wiley, 1979. 19. Bayliss WM, Starling EH. The movements and innervation of the small intestines. J Physiol Lond 1899;24:100-143. 20. North RA. Electrophysiology of the enteric nervous system. Neuroscience 1982;7:315-325. 21. Grider JR. Identification of neurotransmitters regulating intestinal peristaltic reflex in humans. Gastroenterology 1989;97:1414-1419. 22.Wattchow DA, Furness JB, Costa M, O’Brien PE, Peacock M. Distribution of neuropeptides in the human esophagus. Gastroenterology 1987;93:1363-1371. 23. Christensen J, Lund GF. Esophageal responses to distension and electrical stimulation. J Clin Invest 1969;48:408-419. 24. Paterson WG, Rattan S, Goyal RK. Esophageal responses to transient and sustained esophageal distension. Am J Physiol 1988;255:G587-G595. mechanisms of esophageal re25. Paterson WG. Neuromuscular sponses at and proximal to a distending balloon. Am J Physiol 1991;160:148-155. 26. Winship DH, Zboralske FF. The esophageal propulsive force: Esophageal response to acute obstruction. J Clin Invest 1967;46:1391-1401. 27. Helm JK, Dodds WJ, Pelt LR, Palmer DW, Hogan WJ, Teeter BC. Effect of esophageal emptying and saliva on clearance of acid from the esophagus. New Engl J Med 1984;310:284-288. 28. Kjellen G, Svedberg JB, Tibbling L. Solid bolus transit by esophageal scintigraphy in patients with dysphagia and normal manometry and radiography. Dig Dis Sci 1984;29:1-5. K, Custer-Hagen T, Brown CK, 29. Shirazi S, Schultze-Delrieu Ren J. Motility changes in the esophagus from experimental esophagitis. Dig Dis Sci 1989;34:1668-1676. 30. Sinar DR, Fletcher JR, Cordova CC, Eastwood GL, Caste11 DO. Acute acid-induced esophagitis impairs esophageal peristalsis in baboons. Gastroenterology 1980;80:A1286. 31. Henderson RD, Mugashe F, Jeejeebhoy KN, Cullen J, Boszko A, Szczpanski M, Marryatt G. The motor effect of esophagitis. Can J Surg 1974;17:112-116. 32. Marshall JB, Gerhardt DC. Improvement in esophageal motor dysfunction with treatment of reflux esophagitis: a report of two cases. Am J Gastroenterol 1982;77:351-354. 33. Barlow AP, Norris TL, Watson A. Influences of treatment on

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oesophageal motility in gastro-oesophageal reflux disease. Gut 1989;30:A1145-A1446 34. Johnson F, Joelsson B, Gudmundsson K, Floren CH, Walther B. Effects of fundoplication on the anti-reflux mechanism. Br J Surg 1987;74:1111-1114. 35. Gill RC. Bowes KL, Murphy PD, Kingma YJ. Oesophageal motor abnormalities in gastroesophageal reflux and the effects of fundoplication. Gastroenterology 1986;91:364-369. 36. Watson A, Jenkinson LR, Norris TL. Reflux oesophagitis and oesophageal transit. Gut 1988;29:1426-1427.

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Received October 28, 1991. Accepted March 31, 1992. Address requests for reprints to: D. G. Thompson, M.D., Department of Medicine, Hope Hospital, Eccles Old Road, Salford, M6 8HD, England. The authors wish to acknowledge the secretarial support of J. D. Hamilton, J. Young, and Gaeltec Ltd. for help in the design and construction of the force transducer. The research was conducted with the help of a project grant from the North West Regional Health Authority.