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Mecholyl Test: Comparison of Balloon Kymography and Intraluminal Pressure Measurement
Vol. 63, No.4
GASTROENTEROLOGY
Printed in U.S.A.
Copyright © 1972 by The Williams & Wilkins Co.
MECHOLYL TEST: COMPARISON OF BALLOON KYMOGRAPHY AND INTRALUMINAL PRESSURE MEASUREMENT J. K.
SHEPHERD,
M.D.,
AND
N. E.
DIAMANT,
M.D.
Department of Medicine, Division of Gastroenterology, Toronto Western Hospital, and Institute of Medical Science, University of Toronto , Toronto , Ontario, Canada
The positive methacholine response of the esophagus in patients with achalasia was studied by comparing simultaneous measurements obtained by balloon kymography and intraluminal esophageal manometry. Prior to this, mechanical characteristics of the balloonkymograph system were assessed, in particular the response of the system to external pressure on the balloon. The balloon-kymograph system has a nonlinear response. Little change in balloon volume occurs until external pressure reaches approximately 15 mm Hg. Thereafter, rapid emptying of the balloon occurs over the next 5 to 10 mm Hg and the balloon is totally collapsed at approximately 25 mm Hg or its water equivalent, 34 em. External pressures above this level cannot be appreciated by the collapsed balloon. These features were demonstrated in 6 patients with achalasia. It is suggested that a positive response to methacholine may be defined as a rise in esophageal intraluminal pressure to greater than 25 mm of mercury or its water equivalent. Accurate definition of esophageal sensitivity to methacholine and its usefulness as a diagnostic tool must await more quantitative studies. Increased sensitivity of the esophagus to parenterally administered methacholine (acetyl- ,B- me thy lcholine chloride, or Mecholyl) has been used as an aid to the diagnosis of achalasia 1' 3 and more recent studies indicate that patients with diffuse spasm of the esophagus, 4 carcinoma of the esophagus, 5 • 6 and Chaga's disease 7 may also show increased responses of the esophagus to methacholine. A positive methacholine response is dramatic when detected by the balloon-kymograph Received January 4, 1972. Accepted April 27, 1972.
Address requests for reprints to: Dr. N. E. Diamant, 25 Leonard Avenue, Toronto, 130 Ontario, Canada. This research was supported by Medical Research Council Grant MA 3353, The Toronto Western Hospital Medical Research Foundation, and the Elsie Watt Foundation. Dr. Shepherd's present address is: 755 Willard Road, Calgary S.E ., Alberta. 557
method and as described by Kramer and lngelfinger 2 is characterized by a " lumenobliterating contraction" which empties the balloon of its air content; a well defined end point which may be seen radiologically and have associated substernal distress. This response is not seen in normal persons. On the other hand, when intraluminal ·pressure change is used to determine the methacholine response in patients with achalasia, a wide range of values is obtained (7.6 to 57.1 em of water) which overlaps the normal range of values (1.7 to 26,1 em of water). 3 The apparent discrepancy in selectivity between the two recording methods suggests that the balloon-kymograph system is more reliable than intraluminal pressure recording as an indicator of increased sensitivity of the esophagus to methacholine. However, the relationship between results obtained by the two methods of study has not been determined.
Vol. 63, No. 4
SHEPHERD AND DIAMANT
558
This report describes a simple demonstration of mechanical characteristics of the balloon-kymograph system with particular attention to the effect of external pressure upon the balloon system. The relationship between balloon-kymograph characteristics and pressure external to the balloon is further demonstrated in 6 patients with achalasia by employing simultaneous balloon kymography and intraesophageal pressure recording during the "Mecholyl" test.
Materials and Methods For balloon kymography, the recording apparatus was constructed as described by lngelfinger and Abbott, 8 and a commercial MillerAbbott tube and balloon assembly, with tube shortened to 100 em for convenience, was connected to the recording apparatus (fig. 1). The balloon capacity employed (33 cc) was comparable to that used by Kramer et al. • in recent studies. Likewise, the hydrostatic pressure exerted on the air in the balloon was similar to that usually employed for balloon-kymograph studies.8 • • When collapsed, the balloon supported a column of water of 25 to 27.5 em, and when the balloon was distended in air, the column supported was 20 to 22.5 em. To demonstrate characteristics of the balloon-kymograph system the balloon was anchored at the bottom of a 1000-cc glass cylinder and the balloon just covered with water (fig. 2). For simulSPIROMETER-TYPE -===::::; VOLUME RECORDER-+-
40cc
UPPER CALIBRATED RESERVOIR
MILLER-ABBOTT TUBE
LOWER RESERVOIR
FIG. 1. Apparatus for balloon kymography. With the balloon collapsed, the reservoir head of water pressure supported is A; with the balloon distended in air, the pressure is B. When A is 20, 25, 27.5, and 30 cc, B is 15, 20, 22.5, and 25 cc, respectively.
KYMOGRAPH APPARATUS
+-===A==~
B
--+RECORDER PRESSURE TRANSDUCER
IOOOcc GRADUATED CYLINDER
FIG. 2. Apparatus for assessing effect of pressure external to the balloon on the balloon-kymograph system. Water was added to the cylinder and simultaneous measurements obtained from an opentipped catheter B and the balloon-kymograph system A.
taneous measurement of pressure external to the balloon a single side opening water-filled catheter was positioned in the cylinder at the level of the center of the balloon, and pressure recorded by a Statham transducer (P 23AA) was graphed on a direct-writing recorder. Hydrostatic pressure external to the balloon was then raised by the addition of water to the cylinder. Intraluminal esophageal pressures were recorded by means of a single polyvinyl tube with a 1.2 mm side opening, or a two- to threelumen polyvinyl tube assembly with side openings at 5-cm intervals. The tubes were continuously perfused with water at a rate of 2.4 cc per min. Pressures were transmitted to Statham transducers (P 23AA) positioned at approximately esophageal level, which was arbitrarily chosen as the zero reference point. Transducer outputs were graphed on a directwriting recorder and pressures were read as the mean between inspiratory and expiratory deflections . Six patients with well documented achalasia were studied. All had symptoms of dysphagia with or without pain, and X-ray evidence of esophageal dilation and absent peristalsis. By intraluminal manometry, peristalsis was absent in all patients and in 5 of 6 patients when studied, the lower esophageal sphincter demonstrated normal or increased resting tone with poor relaxation on swallowing. After fasting for at least 18 hr, the patients were placed in the supine position and the kymograph balloon and distal pressure recording tip
ESOPHAGEAL SENSITIVITY TO METHACHOLINE
October 1972
positioned approximately 5 to 10 em above the manometrically determined high pressure zone at the gastroesophageal junction. Simultaneous records were then obtained from both re cording systems and compared. After 10 to 20 min of base line recording, methacholine was given in an initial dose of 1.0 mg subcutaneously. If no response occurred, the dose was increased to 2.5, 5.0, and 7.5 mg in sequence at 15- to 20-min intervals until a response sufficient to empty the balloon of its air content was noted.
Results Figure 3 shows the nonlinear relationship between external pressure exerted on the balloon and the volume of air expelled from the balloon. Initially, large increments in external pressure produce minimal balloon emptying, whereas eventually rapid and complete emptying of the balloon occurs over the next 5 to 10 mm Hg. After the balloon is completely collapsed, subsequent increases in external pressure have no further effect on the balloon system since the balloon remains collapsed. Two other features are also apparent. First, the head of the reservoir
-35 u
sI
15 30 0
.J .J
;;5
25
~
~
IJ..
f~~~?.:. " ~'
20
0
lj
15
.J
w
a.
(;5
10
PRESSURE (Cm) VOLUME (CC)
0::
(/
0 •
~
10
5
15
20
15.0 20.0 22 .5 25.0
25
27.0 31.0 33.0 35.0
30
35
mmHg
0
5
10
15
20
25
30
35
40
45
em H 20
EXTERNAL PRESSURE ON BALLOON FIG . 3. Relationship between external pressure exerted on the balloon and air expelled from the balloon, the distended balloon supporting different reservoir hydrostatic pressures (see text).
559
hydrostatic pressure on the air in the balloon affects the system. A higher pressure head produces a larger initial balloon volume, and requires a higher external pressure to collapse the balloon. Second, the amount of external pressure necessary to collapse the balloon is greater than the reservoir head of pressure supported by the collapsed balloon. More specifically, the effect of external pressure on the standard balloon-kymograph system can be predicted. When the balloon distended in air is supporting a reservoir pressure of 20 or 22.5 em of water, or, when collapsed, is supporting reservoir pressure of 25 and 27.5 em of water, respectively, little air · will be expelled until external pressures reach 12 to 15 mm Hg. Thereafter, the balloon will be rapidly emptied until the balloon is totally collapsed at external pressures of 22 to 25 mm Hg and pressures above this level will not be seen. In terms of water pressure, the balloon will not be totally collapsed until external pressures of approximately 30 to 35 em of H 2 0 are reached. These features are illustrated by the studies in the 6 patients with achalasia as shown in table 1 and figures 4, 5, and 6. All except 1 patient (H. P.) had high resting esophageal pressures. However, as predicted, intraesophageal pressures as high as 15 to 16 mm Hg produced little change in balloon volume. Simultaneous records from both recording systems, obtained during one study in patient H. P. , are shown in figures 4 and 5 and balloon volume and intraluminal pressure relate as predicted. (1) Resting intraesophageal pressure is low and the volume of air expelled from the balloon is small. (2) After 2 min, intraluminal esophageal pressure has increased to approximately 15 mm Hg, but little change is noted in balloon volume. (3) The balloon becomes completely collapsed when mean intraesophageal pressure reaches approximately 25 mm Hg (after 2 Vz to 3 min) and thereafter intraesophageal pressure shows a further increase unappreciated by the collapsed balloon.
SHEPHERD AND DIAMANT
560
In figure 6, studies from the 6 patients illustrate that complete emptying and collapse of the balloon occurs in close relationship to intraesophageal pressure of 25 mm Hg which correlates well with the experimental data presented above. However, intraesophageal pressure in all patients rose above 25 mm Hg to peak pressures between 36 and 50 mm Hg (see also 1. Balloon volume at rest and intra esophageal pressures before and after methacholine in patients with achalasia
Vol. 63, No. 4
table 1). There appeared to be no relationship between the level of resting intraesophageal pressure and the response to methacholine as judged by the rapidity of the response and peak intraluminal pressure. The maximal change in intraluminal pressure varied between 14 and 39 mm Hg and the greatest change occurred in the patient with the lowest resting pressure.
TABLE
Duration
Patient
D. T. B. C. ... H. P. I. G... R. M . . . L. T.
0 LLJ
...J
...J
Age
of disease
Volume expelled
MaxiPeak Resting methamal choline change mmHg
yr
yr
cc
17 60 44 67 40 45
13 2 28 22 1 6
28 20 4 19 8 20
40
Intraesophageal pressure
balloon at rest
from
22 18 6 20 16 22
36 40 45 45 32 50
14 24 39 25 16 28
MRS. H.P
LLJ
0... X
LLJ
a::
20
<(
u u
0
t
I.Omg. FIG. 4. Balloon-kymograph record of positive methacholine response. The balloon is collapsed approximately 3 min after 1.0 mg of Mecholyl.
Discussion This study correlates the results obtained by two different recording methods commonly used to determine increased sensitivity of the esophagus to methacholine. It becomes apparent from the mechanical properties of the balloon-kymograph system that response of the balloon system can be related to changes in intraluminal esophageal pressure, and, conversely, intraesophageal pressure measurements can predict the balloon response. In patients with achalasia, Kramer and Ingelfinger 2 defined a positive response with the balloon-kymograph system as a "lumen-obliterating contraction" sufficient to empty the balloon of its air content. If one accepts the definition of Kramer and Ingelfinger, these studies show that a positive response requires that intraluminal esophageal pressure of 25 mm Hg or greater must be obtained. The equivalent water pressure is approximately 34 em. Change in intraluminal is less meaningful in defining a positive response to methacholine as demonstrated by the overlap of the values for normal
MRS. H.P.
-----
lnma_____________________________
FIG. 5. Open-tipped pressure record of positive methacholine response obtained simultaneously with kymograph record shown in figure 5. Pressure of 25 mm Hg is reached at approximately 3 min after 1.0 mg of Mecholyl. Subsequently, pressures are higher.
I
•
E
40
w
30
•
0::
0:: 0...
•
•
• • • --.--*·---- -------
:::> 20
w
H. P ( 2.5mg)
50
_§
(/) (/)
B.C. (5.0mg)
D.T (I.Omg)
..--.. 0'1
561
ESOPHAGEAL SENSITIVITY TO METHACHOLINE
October 1972
• - -•- - - - - - - X -•- - • •
----*------
•
10
0
~--~~~~~~~~
2
0
_j
4
6
2
0
4
6
0
2
4
<(
w
I. G. ( 2.5 mg)
(!)
~
50
0... 0
40
w
30
R.M. (I.Omg)
L.T(I.Omg)
• •
•
•
•
(/)
• --- -·---. -r--• • •
------- *------
20
•
•
•
10
-.--M------
Ol-------..-----{o;i;==~
0
2
4
6
0
2
4
6
0
2
4
TIME AFTER METHACHOLINE (min) FIG. 6. Relationship between esophageal intraluminal pressure and collapse of balloon in 6 achalasia patients during the Mecholyl test. Dose of Mecholyl is in brackets. Shaded area represents collapse of the balloon. The x denotes time at which intraluminal pressure reached 25 mm Hg. Note that balloon collapse and 25 mm Hg intraluminal pressure approximate closely; intraluminal pressure rose to levels greater than 25 mm Hg in all patients.
and abnormal by Hightower et aL 3 Hightower et aL explained their negative results on the basis of a dilated atonic esophagus, and yet a change in pressure of at least 7.6 em H 2 0 was observed in their patients after methacholine. Values for resting intraluminal pressure were not given and another explanation for the negative results is possible. Patients with achalasia frequently have resting intraesophageal pressures that are elevated above normaL Although the number of patients in this study was few, the maximal intraesophageal pressure following methacholine administration was relatively constant (table 1). Therefore, patients with high resting intraluminal pressures had a small change in pressure while those with low resting pressures had a large change in pressure. In terms of pressure change, the former values would overlap those observed in normal subjects by Hightower et
aL while the latter would not. However, maximal intraluminal pressure greater than 25 mm Hg was sufficient to produce a positive response with the balloon-kymograph system in all our cases. The literature suggests that false-positive responses are unlikely. In the studies of Kramer and Ingelfinger, 2 normal subjects failed to demonstrate collapse of the balloon with methacholine dosage as high as 10 mg. It can therefore be assumed that maximal intraluminal esophageal pressures in their normal subjects were less than 25 mm Hg or 34 em of water. Hightower et aL 3 reported that normal subjects could show a change in intraluminal pressure as high as 26.1 em of water after methacholine. Since resting intrathoracic and therefore intraesophageal pressure is usually 0 em of water or less, maximal intraesophageal pressure after methacholine in their studies should have been 26.1
562
Vol. 63, No. 4
SHEPHERD AND DIAMANT
em of water or less. If tested with the balloon-kymograph system their normal subjects would not develop pressures sufficient to collapse the balloon and would demonstrate a negative response as defined by Kramer and Ingelfinger. Although false-positive responses appear unlikely, false-negative results cannot be excluded and difficulty will arise in defining responses that are less positive than the maximal responses observed in well advanced cases. This is particularly true if normal subjects may show intraluminal pressures as high as 26.1 em of water after methacholine administration. For example, Herrera et al. 6 reported a positive response to methacholine in a patient with gastric fundal carcinoma simulating achalasia of the esophagus. However, resting intraesophageal pressure in their patient was not elevated and the maximal sustained intraluminal pressure was less than 20 mm Hg pressure. This would not produce a positive test as defined by Kramer and Ingelfinger and would fall within the normal limits defined by Hightower et al. On the other hand, a similar patient reported by Kolodny et al. 5 demonstrates an acceptable positive response by all standards. This study indicates a number of limitations of the balloon-kymograph system. (1) The nonlinear response of the balloonkymograph system makes it impossible to translate balloon volume changes linearly into units of external pressure. This problem was alluded to by Brody et al. 10 and, in addition, they pointed out that balloon size and shape will affect the kymograph response to single contractions distorting the balloon. Nevertheless, in these studies, the balloon-kymograph response related closely to the mean intraluminal esophageal pressure during repetitive contractions following the administration of methacholine. (2) Collapse of the balloon requires more external pressure than the head of pressure supported by the balloon at the time of collapse. (3) Initial large changes in external pressure to as high as 15 mm Hg cause little change in balloon volume. Therefore,
"low" intraesophageal pressure cannot be assumed in achalasia patients from the balloon-kymograph record. On the other hand, when a distended balloon is introduced into the esophagus in normal subjects, "tone" and/or repetitive secondary contractions may expell large amounts of air from the balloon simulating abnormally high resting intraluminal pressures. 9 ( 4) Collapse of the balloon indicates only that pressure external to the balloon has reached 25 mm Hg or 34 em of water. The balloon-kymograph system is unable to record quantitatively the higher values obtained after methacholine administration. The data presented here indicate that measurement of intraluminal esophageal pressure is an effective method for determining increased sensitivity of the esophagus to cholinergic stimulation. A positive response can be accepted if sustained intraluminal esophageal pressure greater than 25 mm Hg or 34 em of water is obtained. This will be equivalent to the positive response defined by Kramer and Ingelfinger with the balloon-kymograph system. False-negative results, however, cannot be excluded. It would seem, therefore, that additional study is necessary. The relationship between dose and response in normal and abnormal subjects, and the variability imposed by duration and type of disease, esophageal dilation, resting intraluminal pressure, and esophageal tone are unknown. The limitations of the balloon-kymograph system will not allow the quantitative accuracy and versatility necessary for additional study, while intraluminal pressure measurements should permit more careful assessment. REFERENCES 1. Kramer P, Ingelfinger FJ: II Cardiospasm, a generalized disorder of esophageal motility. Am J Med 7:174- 179, 1949 2. Kramer P, Ingelfinger FJ: Esophageal sensitivity to Mecholyl in cardiospasm. Gastroenterology 19:242-251, 1951 3. Hightower NC , Olsen AM, Moersch HJ: A com· parison of the effects of acetyl-beta-methylcholine chloride (Mecholyl) on esophageal intraluminal pressure in normal persons and patients
October 1972
4.
5.
6.
7.
ESOPHAGEAL SENSITIVITY TO METHACHOLINE
with cardiospasm. Gastroenterology 26:592-600, 1954 Kramer P, Fleshier B, McNally E, et al: Esophageal sensitivity to Mecholyl in symptomatic diffuse spasm. Gut 8:120-127, 1967 Kolodny M, Schrader ZR, Rubin W, et al: Esophageal achalasia probably due to gastric carcinoma. Ann Intern Med 69:569-573, 1968 Herrera AF, Colon J , Valdes-Dapena A, et al : Achalasia or carcinoma? The significance of the Mecholyl test. Am J Dig Dis 15:1073-1081, 1970 Castro L de P, Grossi CA: 0 teste do Mecolil no diagnostico de aperistalsis do esofago. Rev
563
Gioana Med 9: 3-19, 1963 8. Ingelfinger FJ, Abbott WO : Intubation studies of the human small intestine. XX. The diagnostic significance of motor disturbances. Am J Dig Dis 7:1-7, 1940 9. Kramer P, Ingelfinger FJ: I. Motility of the human esophagus in control subjects and in patients with esophageal disorders. Am J Med 7: 168-173, 1949 10. Brody DA, Werle JM, Meschan I, et al: Intraluminal pressures of the digestive tract, especially the pyloric region. Am J Physiol 130:791- 801, 1940
GASTROENTEROLOGY
Printed in U.S.A.
Copyright © 1972 by The Williams & Wilkins Co.
MECHOLYL TEST: COMPARISON OF BALLOON KYMOGRAPHY AND INTRALUMINAL PRESSURE MEASUREMENT J. K.
SHEPHERD,
M.D.,
AND
N. E.
DIAMANT,
M.D.
Department of Medicine, Division of Gastroenterology, Toronto Western Hospital, and Institute of Medical Science, University of Toronto , Toronto , Ontario, Canada
The positive methacholine response of the esophagus in patients with achalasia was studied by comparing simultaneous measurements obtained by balloon kymography and intraluminal esophageal manometry. Prior to this, mechanical characteristics of the balloonkymograph system were assessed, in particular the response of the system to external pressure on the balloon. The balloon-kymograph system has a nonlinear response. Little change in balloon volume occurs until external pressure reaches approximately 15 mm Hg. Thereafter, rapid emptying of the balloon occurs over the next 5 to 10 mm Hg and the balloon is totally collapsed at approximately 25 mm Hg or its water equivalent, 34 em. External pressures above this level cannot be appreciated by the collapsed balloon. These features were demonstrated in 6 patients with achalasia. It is suggested that a positive response to methacholine may be defined as a rise in esophageal intraluminal pressure to greater than 25 mm of mercury or its water equivalent. Accurate definition of esophageal sensitivity to methacholine and its usefulness as a diagnostic tool must await more quantitative studies. Increased sensitivity of the esophagus to parenterally administered methacholine (acetyl- ,B- me thy lcholine chloride, or Mecholyl) has been used as an aid to the diagnosis of achalasia 1' 3 and more recent studies indicate that patients with diffuse spasm of the esophagus, 4 carcinoma of the esophagus, 5 • 6 and Chaga's disease 7 may also show increased responses of the esophagus to methacholine. A positive methacholine response is dramatic when detected by the balloon-kymograph Received January 4, 1972. Accepted April 27, 1972.
Address requests for reprints to: Dr. N. E. Diamant, 25 Leonard Avenue, Toronto, 130 Ontario, Canada. This research was supported by Medical Research Council Grant MA 3353, The Toronto Western Hospital Medical Research Foundation, and the Elsie Watt Foundation. Dr. Shepherd's present address is: 755 Willard Road, Calgary S.E ., Alberta. 557
method and as described by Kramer and lngelfinger 2 is characterized by a " lumenobliterating contraction" which empties the balloon of its air content; a well defined end point which may be seen radiologically and have associated substernal distress. This response is not seen in normal persons. On the other hand, when intraluminal ·pressure change is used to determine the methacholine response in patients with achalasia, a wide range of values is obtained (7.6 to 57.1 em of water) which overlaps the normal range of values (1.7 to 26,1 em of water). 3 The apparent discrepancy in selectivity between the two recording methods suggests that the balloon-kymograph system is more reliable than intraluminal pressure recording as an indicator of increased sensitivity of the esophagus to methacholine. However, the relationship between results obtained by the two methods of study has not been determined.
Vol. 63, No. 4
SHEPHERD AND DIAMANT
558
This report describes a simple demonstration of mechanical characteristics of the balloon-kymograph system with particular attention to the effect of external pressure upon the balloon system. The relationship between balloon-kymograph characteristics and pressure external to the balloon is further demonstrated in 6 patients with achalasia by employing simultaneous balloon kymography and intraesophageal pressure recording during the "Mecholyl" test.
Materials and Methods For balloon kymography, the recording apparatus was constructed as described by lngelfinger and Abbott, 8 and a commercial MillerAbbott tube and balloon assembly, with tube shortened to 100 em for convenience, was connected to the recording apparatus (fig. 1). The balloon capacity employed (33 cc) was comparable to that used by Kramer et al. • in recent studies. Likewise, the hydrostatic pressure exerted on the air in the balloon was similar to that usually employed for balloon-kymograph studies.8 • • When collapsed, the balloon supported a column of water of 25 to 27.5 em, and when the balloon was distended in air, the column supported was 20 to 22.5 em. To demonstrate characteristics of the balloon-kymograph system the balloon was anchored at the bottom of a 1000-cc glass cylinder and the balloon just covered with water (fig. 2). For simulSPIROMETER-TYPE -===::::; VOLUME RECORDER-+-
40cc
UPPER CALIBRATED RESERVOIR
MILLER-ABBOTT TUBE
LOWER RESERVOIR
FIG. 1. Apparatus for balloon kymography. With the balloon collapsed, the reservoir head of water pressure supported is A; with the balloon distended in air, the pressure is B. When A is 20, 25, 27.5, and 30 cc, B is 15, 20, 22.5, and 25 cc, respectively.
KYMOGRAPH APPARATUS
+-===A==~
B
--+RECORDER PRESSURE TRANSDUCER
IOOOcc GRADUATED CYLINDER
FIG. 2. Apparatus for assessing effect of pressure external to the balloon on the balloon-kymograph system. Water was added to the cylinder and simultaneous measurements obtained from an opentipped catheter B and the balloon-kymograph system A.
taneous measurement of pressure external to the balloon a single side opening water-filled catheter was positioned in the cylinder at the level of the center of the balloon, and pressure recorded by a Statham transducer (P 23AA) was graphed on a direct-writing recorder. Hydrostatic pressure external to the balloon was then raised by the addition of water to the cylinder. Intraluminal esophageal pressures were recorded by means of a single polyvinyl tube with a 1.2 mm side opening, or a two- to threelumen polyvinyl tube assembly with side openings at 5-cm intervals. The tubes were continuously perfused with water at a rate of 2.4 cc per min. Pressures were transmitted to Statham transducers (P 23AA) positioned at approximately esophageal level, which was arbitrarily chosen as the zero reference point. Transducer outputs were graphed on a directwriting recorder and pressures were read as the mean between inspiratory and expiratory deflections . Six patients with well documented achalasia were studied. All had symptoms of dysphagia with or without pain, and X-ray evidence of esophageal dilation and absent peristalsis. By intraluminal manometry, peristalsis was absent in all patients and in 5 of 6 patients when studied, the lower esophageal sphincter demonstrated normal or increased resting tone with poor relaxation on swallowing. After fasting for at least 18 hr, the patients were placed in the supine position and the kymograph balloon and distal pressure recording tip
ESOPHAGEAL SENSITIVITY TO METHACHOLINE
October 1972
positioned approximately 5 to 10 em above the manometrically determined high pressure zone at the gastroesophageal junction. Simultaneous records were then obtained from both re cording systems and compared. After 10 to 20 min of base line recording, methacholine was given in an initial dose of 1.0 mg subcutaneously. If no response occurred, the dose was increased to 2.5, 5.0, and 7.5 mg in sequence at 15- to 20-min intervals until a response sufficient to empty the balloon of its air content was noted.
Results Figure 3 shows the nonlinear relationship between external pressure exerted on the balloon and the volume of air expelled from the balloon. Initially, large increments in external pressure produce minimal balloon emptying, whereas eventually rapid and complete emptying of the balloon occurs over the next 5 to 10 mm Hg. After the balloon is completely collapsed, subsequent increases in external pressure have no further effect on the balloon system since the balloon remains collapsed. Two other features are also apparent. First, the head of the reservoir
-35 u
sI
15 30 0
.J .J
;;5
25
~
~
IJ..
f~~~?.:. " ~'
20
0
lj
15
.J
w
a.
(;5
10
PRESSURE (Cm) VOLUME (CC)
0::
(/
0 •
~
10
5
15
20
15.0 20.0 22 .5 25.0
25
27.0 31.0 33.0 35.0
30
35
mmHg
0
5
10
15
20
25
30
35
40
45
em H 20
EXTERNAL PRESSURE ON BALLOON FIG . 3. Relationship between external pressure exerted on the balloon and air expelled from the balloon, the distended balloon supporting different reservoir hydrostatic pressures (see text).
559
hydrostatic pressure on the air in the balloon affects the system. A higher pressure head produces a larger initial balloon volume, and requires a higher external pressure to collapse the balloon. Second, the amount of external pressure necessary to collapse the balloon is greater than the reservoir head of pressure supported by the collapsed balloon. More specifically, the effect of external pressure on the standard balloon-kymograph system can be predicted. When the balloon distended in air is supporting a reservoir pressure of 20 or 22.5 em of water, or, when collapsed, is supporting reservoir pressure of 25 and 27.5 em of water, respectively, little air · will be expelled until external pressures reach 12 to 15 mm Hg. Thereafter, the balloon will be rapidly emptied until the balloon is totally collapsed at external pressures of 22 to 25 mm Hg and pressures above this level will not be seen. In terms of water pressure, the balloon will not be totally collapsed until external pressures of approximately 30 to 35 em of H 2 0 are reached. These features are illustrated by the studies in the 6 patients with achalasia as shown in table 1 and figures 4, 5, and 6. All except 1 patient (H. P.) had high resting esophageal pressures. However, as predicted, intraesophageal pressures as high as 15 to 16 mm Hg produced little change in balloon volume. Simultaneous records from both recording systems, obtained during one study in patient H. P. , are shown in figures 4 and 5 and balloon volume and intraluminal pressure relate as predicted. (1) Resting intraesophageal pressure is low and the volume of air expelled from the balloon is small. (2) After 2 min, intraluminal esophageal pressure has increased to approximately 15 mm Hg, but little change is noted in balloon volume. (3) The balloon becomes completely collapsed when mean intraesophageal pressure reaches approximately 25 mm Hg (after 2 Vz to 3 min) and thereafter intraesophageal pressure shows a further increase unappreciated by the collapsed balloon.
SHEPHERD AND DIAMANT
560
In figure 6, studies from the 6 patients illustrate that complete emptying and collapse of the balloon occurs in close relationship to intraesophageal pressure of 25 mm Hg which correlates well with the experimental data presented above. However, intraesophageal pressure in all patients rose above 25 mm Hg to peak pressures between 36 and 50 mm Hg (see also 1. Balloon volume at rest and intra esophageal pressures before and after methacholine in patients with achalasia
Vol. 63, No. 4
table 1). There appeared to be no relationship between the level of resting intraesophageal pressure and the response to methacholine as judged by the rapidity of the response and peak intraluminal pressure. The maximal change in intraluminal pressure varied between 14 and 39 mm Hg and the greatest change occurred in the patient with the lowest resting pressure.
TABLE
Duration
Patient
D. T. B. C. ... H. P. I. G... R. M . . . L. T.
0 LLJ
...J
...J
Age
of disease
Volume expelled
MaxiPeak Resting methamal choline change mmHg
yr
yr
cc
17 60 44 67 40 45
13 2 28 22 1 6
28 20 4 19 8 20
40
Intraesophageal pressure
balloon at rest
from
22 18 6 20 16 22
36 40 45 45 32 50
14 24 39 25 16 28
MRS. H.P
LLJ
0... X
LLJ
a::
20
<(
u u
0
t
I.Omg. FIG. 4. Balloon-kymograph record of positive methacholine response. The balloon is collapsed approximately 3 min after 1.0 mg of Mecholyl.
Discussion This study correlates the results obtained by two different recording methods commonly used to determine increased sensitivity of the esophagus to methacholine. It becomes apparent from the mechanical properties of the balloon-kymograph system that response of the balloon system can be related to changes in intraluminal esophageal pressure, and, conversely, intraesophageal pressure measurements can predict the balloon response. In patients with achalasia, Kramer and Ingelfinger 2 defined a positive response with the balloon-kymograph system as a "lumen-obliterating contraction" sufficient to empty the balloon of its air content. If one accepts the definition of Kramer and Ingelfinger, these studies show that a positive response requires that intraluminal esophageal pressure of 25 mm Hg or greater must be obtained. The equivalent water pressure is approximately 34 em. Change in intraluminal is less meaningful in defining a positive response to methacholine as demonstrated by the overlap of the values for normal
MRS. H.P.
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FIG. 5. Open-tipped pressure record of positive methacholine response obtained simultaneously with kymograph record shown in figure 5. Pressure of 25 mm Hg is reached at approximately 3 min after 1.0 mg of Mecholyl. Subsequently, pressures are higher.
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561
ESOPHAGEAL SENSITIVITY TO METHACHOLINE
October 1972
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TIME AFTER METHACHOLINE (min) FIG. 6. Relationship between esophageal intraluminal pressure and collapse of balloon in 6 achalasia patients during the Mecholyl test. Dose of Mecholyl is in brackets. Shaded area represents collapse of the balloon. The x denotes time at which intraluminal pressure reached 25 mm Hg. Note that balloon collapse and 25 mm Hg intraluminal pressure approximate closely; intraluminal pressure rose to levels greater than 25 mm Hg in all patients.
and abnormal by Hightower et aL 3 Hightower et aL explained their negative results on the basis of a dilated atonic esophagus, and yet a change in pressure of at least 7.6 em H 2 0 was observed in their patients after methacholine. Values for resting intraluminal pressure were not given and another explanation for the negative results is possible. Patients with achalasia frequently have resting intraesophageal pressures that are elevated above normaL Although the number of patients in this study was few, the maximal intraesophageal pressure following methacholine administration was relatively constant (table 1). Therefore, patients with high resting intraluminal pressures had a small change in pressure while those with low resting pressures had a large change in pressure. In terms of pressure change, the former values would overlap those observed in normal subjects by Hightower et
aL while the latter would not. However, maximal intraluminal pressure greater than 25 mm Hg was sufficient to produce a positive response with the balloon-kymograph system in all our cases. The literature suggests that false-positive responses are unlikely. In the studies of Kramer and Ingelfinger, 2 normal subjects failed to demonstrate collapse of the balloon with methacholine dosage as high as 10 mg. It can therefore be assumed that maximal intraluminal esophageal pressures in their normal subjects were less than 25 mm Hg or 34 em of water. Hightower et aL 3 reported that normal subjects could show a change in intraluminal pressure as high as 26.1 em of water after methacholine. Since resting intrathoracic and therefore intraesophageal pressure is usually 0 em of water or less, maximal intraesophageal pressure after methacholine in their studies should have been 26.1
562
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SHEPHERD AND DIAMANT
em of water or less. If tested with the balloon-kymograph system their normal subjects would not develop pressures sufficient to collapse the balloon and would demonstrate a negative response as defined by Kramer and Ingelfinger. Although false-positive responses appear unlikely, false-negative results cannot be excluded and difficulty will arise in defining responses that are less positive than the maximal responses observed in well advanced cases. This is particularly true if normal subjects may show intraluminal pressures as high as 26.1 em of water after methacholine administration. For example, Herrera et al. 6 reported a positive response to methacholine in a patient with gastric fundal carcinoma simulating achalasia of the esophagus. However, resting intraesophageal pressure in their patient was not elevated and the maximal sustained intraluminal pressure was less than 20 mm Hg pressure. This would not produce a positive test as defined by Kramer and Ingelfinger and would fall within the normal limits defined by Hightower et al. On the other hand, a similar patient reported by Kolodny et al. 5 demonstrates an acceptable positive response by all standards. This study indicates a number of limitations of the balloon-kymograph system. (1) The nonlinear response of the balloonkymograph system makes it impossible to translate balloon volume changes linearly into units of external pressure. This problem was alluded to by Brody et al. 10 and, in addition, they pointed out that balloon size and shape will affect the kymograph response to single contractions distorting the balloon. Nevertheless, in these studies, the balloon-kymograph response related closely to the mean intraluminal esophageal pressure during repetitive contractions following the administration of methacholine. (2) Collapse of the balloon requires more external pressure than the head of pressure supported by the balloon at the time of collapse. (3) Initial large changes in external pressure to as high as 15 mm Hg cause little change in balloon volume. Therefore,
"low" intraesophageal pressure cannot be assumed in achalasia patients from the balloon-kymograph record. On the other hand, when a distended balloon is introduced into the esophagus in normal subjects, "tone" and/or repetitive secondary contractions may expell large amounts of air from the balloon simulating abnormally high resting intraluminal pressures. 9 ( 4) Collapse of the balloon indicates only that pressure external to the balloon has reached 25 mm Hg or 34 em of water. The balloon-kymograph system is unable to record quantitatively the higher values obtained after methacholine administration. The data presented here indicate that measurement of intraluminal esophageal pressure is an effective method for determining increased sensitivity of the esophagus to cholinergic stimulation. A positive response can be accepted if sustained intraluminal esophageal pressure greater than 25 mm Hg or 34 em of water is obtained. This will be equivalent to the positive response defined by Kramer and Ingelfinger with the balloon-kymograph system. False-negative results, however, cannot be excluded. It would seem, therefore, that additional study is necessary. The relationship between dose and response in normal and abnormal subjects, and the variability imposed by duration and type of disease, esophageal dilation, resting intraluminal pressure, and esophageal tone are unknown. The limitations of the balloon-kymograph system will not allow the quantitative accuracy and versatility necessary for additional study, while intraluminal pressure measurements should permit more careful assessment. REFERENCES 1. Kramer P, Ingelfinger FJ: II Cardiospasm, a generalized disorder of esophageal motility. Am J Med 7:174- 179, 1949 2. Kramer P, Ingelfinger FJ: Esophageal sensitivity to Mecholyl in cardiospasm. Gastroenterology 19:242-251, 1951 3. Hightower NC , Olsen AM, Moersch HJ: A com· parison of the effects of acetyl-beta-methylcholine chloride (Mecholyl) on esophageal intraluminal pressure in normal persons and patients
October 1972
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5.
6.
7.
ESOPHAGEAL SENSITIVITY TO METHACHOLINE
with cardiospasm. Gastroenterology 26:592-600, 1954 Kramer P, Fleshier B, McNally E, et al: Esophageal sensitivity to Mecholyl in symptomatic diffuse spasm. Gut 8:120-127, 1967 Kolodny M, Schrader ZR, Rubin W, et al: Esophageal achalasia probably due to gastric carcinoma. Ann Intern Med 69:569-573, 1968 Herrera AF, Colon J , Valdes-Dapena A, et al : Achalasia or carcinoma? The significance of the Mecholyl test. Am J Dig Dis 15:1073-1081, 1970 Castro L de P, Grossi CA: 0 teste do Mecolil no diagnostico de aperistalsis do esofago. Rev
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Gioana Med 9: 3-19, 1963 8. Ingelfinger FJ, Abbott WO : Intubation studies of the human small intestine. XX. The diagnostic significance of motor disturbances. Am J Dig Dis 7:1-7, 1940 9. Kramer P, Ingelfinger FJ: I. Motility of the human esophagus in control subjects and in patients with esophageal disorders. Am J Med 7: 168-173, 1949 10. Brody DA, Werle JM, Meschan I, et al: Intraluminal pressures of the digestive tract, especially the pyloric region. Am J Physiol 130:791- 801, 1940