GASTROENTEROLOGY 78:286-293,1980

Gastric Motor Abnormalities in Diabetic

and Postvagotomy Gastroparesis: Effect of
Metoclopramide and Bethanechol

JUAN-R. MALAGELADA, WYNNE D. W. REES, LAURENCE J.

MAZZOTTA, and VAY LIANG W. GO
Gastroenterology Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

Gastroparesis is a relatively uncommon but clini- zoar formation, and radiologic or endoscopic (or
cally troublesome disorder that develops in some pa- both) evidence of gastric stasis in the absence of me-
tients with diabetes mellitus or after gastric opera- chanical obstruction or mucosal abnormality.2.4.7
tions. Its pathogenesis remains obscure. We used a However, milder, even asymptomatic, gastroparesis
manometric technique to record pressure changes in has been recognized.” Gastroparesis also may be a
fasting patients in the gastric fundus, distal stomach, feature of the “intestinal pseudo-obstruction syn-
and adjacent small bowel of patients with severe drome,” a poorly defined group of disorders in-
gastroparesis, asymptomatic diabetic patients, asymp- volving the intestine, bladder, and smooth-muscle
tomatic postsurgical patients, and healthy controls. organs.” These latter types of gastroparesis will not
Patients with gastroparesis had normal inter- be discussed.
digestive motor cycles (phase III) in the intestine but The pathogenesis of diabetic and postsurgical gas-
not in the stomach. Sporadic motor activity in the troparesis is obscure and may represent a neuropa-
stomach (phase II) also was markedly reduced. thic disorder.1”m12 As its name indicates, gastric stasis
Metoclopramide and bethanecol significantly in- is believed to be caused by a failure of gastric motil-
creased gastric motor activity in these patients, of- ity to propel stomach contents into the intestine. Ra-
ten triggering an intense burst of motor activity in diologic studies have commented on the relative or
the stomach, similar to phase III. These observations total absence of gastric peristalsis in this condition.2,”
suggest that gastroparesis is a potentially reversible Drugs, like metoclopramide and bethanechol, which
disorder and should encourage further attempts for increase gastric motility, are reported to be clinically
pharmacologic control of the syndrome. helpful, although the evidence is inconc1usive.13,14
Unfortunately, the motor abnormality has not been
characterized, in part because of lack of standard-
Gastroparesis is a well-recognized complication of ized manometric methods for the study of gastric
insulin-requiring diabetes mellitus or of vagotomy, motility. Thus, we do not know whether fundal, an-
often when the latter has been performed with par- tral, or intestinal motor activities are affected differ-
tial gastric resection.‘-7 Clinically, it is characterized ently; whether interdigestive motor cycles are dis-
by intractable nausea and vomiting, recurrent be- turbed; or whether motor patterns are different in
patients with different underlying diseases (that is,
diabetes or postsurgical). In the present study, we
Received July 23, 1979. Accepted September 21, 1979.
tried to answer these questions.
Address requests for reprints to: Juan-R. Malagelada, M.D.,
Gastroenterology Unit, Mayo Clinic, Rochester, Minnesota 55901.
This study was supported in part by Grant AM 6908 from the Material and Methods
National Institutes of Health, Bethesda, Maryland. Dr. J.-R. Ma-
A total of 41 subjects were divided into five groups.
lagelada is the recipient of Research Career Development award
#1 K04 AM 00330-01 from the National Institutes of Health.
This work was presented in part at the American Gastroenter- Gastroparesis Patients
ological Association meeting, Las Vegas, 1978 (Gastroenterology
74:1083, 1978). Castroparesis was diagnosed when patients ful-
The authors wish to thank Mr. Richard Tucker for technical as- filled all of the following criteria: (a) intractable nausea
sistance and Ms. Gaurdis Grube for secretarial help. and vomiting, with or without bezoar formation; (b) radio-
0 1980 by the American Gastroenterological Association logic evidence of gastric stasis after an ordinary upper gas-
0016-5085/80/020286-08$02.25
 MANOMETRIC ABNORMALITIES 1N C;AS’I’R0t’ARl3IS 287

trointestinal series (little or no contrast medium emptied Intact Stomach:

LES transducer
by 30 min and contrast medium present in the stomach af-
ter 6 hr); (c) food present in morning gastric aspirate after
Fundal
overnight (more than 12 hr) fasting; and (d) endoscopic alloon &
verification of a normal configuration of the stomach ansducet

(other than surgical deformity), absence of mucosal le-

sions, and no mechanical obstruction. These criteria as-
sured that only patients with severe, unquestionable gas-
troparesis were included in the study.
Two groups of patients with gastroparesis were studied.
One group (10 patients) had undergone truncal vagotomy
with partial gastric resection and gastroenterostomy per-
Figure 1. Disposition of manometric dssembty in patients with in-
formed 6 mo to 6 yr before the study (mean 2.2 yr). There
tact gastric anatomy. Position of tubes and pressure
were 6 women and 4 men with ages ranging from 33 to 64 transducers is indicated. Fundic transducer is enclosed
yr (mean 50.7). Five patients had evidence of bezoar on ra- within a 150-ml air-filled halloon.
diologic or endoscopic examination. The other group (7
patients) had severe juvenile-onset diabetes. There were 6
women and 1 man with ages ranging from 22 to 61 yr pressure transducers (Millar Instruments, Houston, Tex.,
(mean 41.1). The duration of their diabetes ranged from 6 model PC 350) attached in series to a polyvinyl intestinal
to 38 yr (mean 17.7). All patients were taking insulin, and tube that facilitated positioning of the pressure sensors
their blood sugar levels at the time of study ranged be- within the lumen of the stomach and the adjacent small
tween 125 and 280 mg/dl (mean 215). All patients but one bowel. The sensor tips were attached 1, 5, and 20 cm from
had clinical or electromyographic evidence of peripheral the tip of the tube, with the 20.cm sensor being enclosed
neuropathy. In addition, 5 patients had diabetic reti- within a 150-ml capacity rubber balloon attached to the
nopathy, and 3 had advanced nephropathy. polyvinyl tube. The fourth transducer was attached 22 cm
from the tip of the tube and served as a marker of tube po-
sition throughout each study period (see later). Before
Disease Controls and Healthy Controls each study, the transducers were connected to a four-
Two groups of disease controls were studied. One channel pen recorder (Gould Instruments, Cleveland,
group (5 patients) had truncal vagotomy, partial gastric re- Ohio, model 2400) and calibrated using transducer control
section, and gastroenterostomy performed 6 mo to 5 yr units (Millar Instruments, model ‘IT 100).

previously (mean 2.7). There were 2 women and 3 men

with ages ranging from 30 to 58 yr (mean 46.8). The second
Procedure
group (5 patients) had advanced juvenile-onset diabetes.
There were 3 women and 2 men with ages ranging from 22 Intact stomach (diabetic patients und heulthy con-
to 52 yr (mean 31.2). The duration of their diabetes ranged trols). The tube was positioned fluoroscopically with its
from 3 tcJ 14 yr (mean 9.4). All patients were taking insulin, tip and distal transducer within the proximal duodenum,
and their blood sugar levels at the time of study ranged the second transducer within the gastric antrum, and the
from 100 to 250 mg/dl (mean 166). All but one had clinical third transducer enclosed in the 150.ml balloon at the gas-
or electromyographic evidence of peripheral neuropathy. tric fundus, which was inflated with air (Figure 1). The
Two patients also had retinopathy, and three had ad- fourth transducer was located at the lower esophageal
vanced nephropathy. As opposed to patients with gas- sphincter (LES) and enabled the continuous monitoring of
troparesis, none of these disease controls had significant the position of the tube throughout each study. Finally, a
gastrointestinal symptoms or evidence of gastric stasis on 14-F sump tube was positioned in the most dependent part
radiologic examination. They were recruited for these of the stomach.
studies as they were being investigated for other problems Postsurgicul stomach (putients with truncul vagot-
or from the Rochester community where they reside. omy and partial gastric resection with gastrojejunos-
Fourteen healthy volunteers, ages 21-74 yr (mean 31) tomy). The tip of the tube was maneuvered fluoroscopic-
also were studied. ally until the distal transducer was located within the
Patients, disease controls, and healthy volunteers fasted jejunum, approximately 3 cm distal to the surgical anasto-
for at least 12 hr before study. In addition, all patients mosis (Figure 2). The second transducer was positioned in
were given liquid diets for 48 hr or longer if morning aspi- the distal part of the gastric remnant approximately 1-2
rates still revealed retained food particles. All participants cm proximal to the anastomosis, and the third and fourth
gave informed consent, and studies had been previously transducers were positioned as descrrbed for the intact
approved by Mayo Clinic Human Studies Committee. stomach. In order to accomplish the correct positioning of
the transducers as described, the distance between trans-
ducers had to be slightly varied from patient to patient, de-
Transducers
pending on the size of the gastric remnant determined by
Gastrointestinal motor activity was measured by a prior radiologic contrast examination. A 14-F sump tube
highly sensitive transducer assembly previously de- was then placed with its tip in the most dependent portion
scribed.‘“-” It consisted of four miniature strain-gauge of the gastric pouch.
288 MALAGELADA ET AL. GASTROENTEROLOGY Vol. 78. No. 2

Postsurgical Stomach: 1IVES msducer Healthy subjects were similarly studied for at least a 3-
hr period, but they did not receive any drugs.

Analysis of Results

When present, fasting motor activity consisted of

well-defined interdigestive cycles’9 with three phases:
phase I (quiescence), phase II (random but persistent con-
tractions), and phase III (terminal burst of high-amplitude
and high-frequency contractions that followed phase II
and terminated in the subsequent phase I). In healthy per-
sons, it is easy to appreciate the simultaneous occurrence
of phase III in fundus and antrum (Figure 3). Duodenal
phase III starts either simultaneously or shortly afterward,
Figure 2. Disposition of manometric assembly in patients with but usually lasts longer. A phase IV is also recognized by
prior partial gastric resection and gastrojejunal anasto- some authors as the transition from phase III to phase I.
mosis. Position of two proximal pressure transducers is Each motor recording was analyzed, and the following
identical to that in patients without prior gastric sur-
parameters were measured:
gery. Two distal transducers are located one at each
side of gastrojejunal stoma. Three-hour motility index for each transducer site (ex-
cept LES)-area (mm*) occupied by all phase II and III
contractile waves during the 3-hr observation period
All studies began at 0700 hr. Intubation was carried out for the fundal, distal stomach, and small-bowel trans-
as described above. Throughout the experimental period, ducers. The frequency of phase III activity, and the
the subjects adopted a semireclining posture (45” to the number of contractions that exceeded 12 mm Hg in am-
horizontal), and gastric contents were continually aspi- plitude also were recorded (contraction frequency).
rated and discarded. Thirty-minute motility index for each transducer site
(except LES) after administration of saline metoclopra-
mide or bethanechol-area (mm’) occupied by all con-
Experimental Design
tractile waves during the 30 min after infusion for the
In patients and disease controls, each study con- fundal, distal stomach and small-bowel transducers.
sisted of two parts: first, interdigestive motor activity was The number of contractions that exceeded 12 mm Hg
recorded for at least 3 hr; and second, 10 mg of meto- also was recorded.
clopramide (A. H. Robins Co., Richmond, Va.) or saline
(placebo) were administered intravenously during a lo-
Results
min period in randomized order, and the effect on motor
activity was evaluated during the subsequent hour. In Postsurgical Gastroparesis
some patients, 5 mg of bethanechol (Merck, Sharp and
Dohme, Inc., New York, N.Y.) were given subcutaneously, In postsurgical gastroparesis, intestinal inter-
and the motor response was evaluated during the sub- digestive motor cycles developed essentially with
sequent hour. The use of bethanechol was not randomized the same frequency as in healthy controls (Table 1).
because of the uncertainty about its duration of action. Only 1 patient failed to show phase III activity in the

Fundus
Phase II Phase III Phase IV Phase I

25 mm

Antrum Figure 3. Fundic, antral, and duodenal motor activi-

ties in healthy controls. Pressure sensors
are located as indicated in Figure 1. Record
100mm Hg
from LES transducer has been omitted.
I
Four characteristic phases of inter-
digestive motor cycle are shown.
Duodenum

1OOmm Hg
1-w
February 1980 MANOMETRIC ABNORMALITIES IN (:ASTROPARESIS 289

Table 1. Occurrence of Interdigestive Motor Complex was greatly reduced in comparison with that of
Cycles in Stomach and Intestine (Number of healthy controls or asymptomatic diabetic patients
Phase 111 Activity During a 3-hr Observation (Figure 6). The antral motility index also was low,
Period)
but the average percentage of decrease in fundic mo-
Stomach Intestine tility index relative to healthy controls (91.3%) and
No. of asymptomatic diabetic patients (82.1%) was greater
Condition subjects Mean Range Mean Range
than for antral motility index (83.3% and 75%, re-
Healthy control 14 2.0 l-3 2.0 1-3 spectively). The small-bowel motility index was sim-
Postsurgical ilar in healthy controls and diabetic patients, either
Gastroparesis 10 0.1 o-1 1.4 o-3
asymptomatic or with gastroparesis (Figure 6). Mea-
Asymptomatic 5 3.0 2-4 3.0 2-4
surements of contraction frequency paralleled those
Diabetic
Gastroparesis 7 0.2 O-l 1.2" l-2 of motility index (data not shown).
Asymptomatic 5 2.0 2-2 2.0 2-2

11In I patient no intestinal measurement could he obtained. Effect of Drugs on Gastrointestinal Motor
Activity

intestine. In contrast, interdigestive motor cycles In patients with diabetic gastroparesis, meto-
were not recognizable in the stomach of 8 of the 9 clopramide significantly increased fundic, antral,
patients studied. The postsurgical controls had nor- and small-bowel motility index (Figures 7 and 8).
mal or greater than normal number of phase III ac- However, gastric motility after metoclopramide con-
tivity, both in the stomach and in the duodenum. sisted of random, phasic changes in pressure with-
The fundic tone (8.0 -t 1 mm Hg, mean & SE) was out evidence of the intense, rhythmic activity of 3/
similar to healthy (7.0 f 1) and postsurgical controls min, which characterizes antral phase III activity, or
(10 + 2), P > 0.05. Besides absent phase III activity, the elevation of baseline pressure, which character-
very little spontaneous motor activity was observed izes fundic phase III activity (Figure 8). After meto-
in the fundus (balloon-enclosed pressure transducer) clopramide use, 3 of 6 patients in whom small-bowel
or distal gastric remnant (free transducer). This was recordings were available showed phase III-like ac-
reflected in a very small motility index (significantly tivity in the intestine but not in the stomach.
lower) in this group than in healthy or postsurgical In patients with postsurgical gastroparesis, meto-
controls (Figure 4). A lesser degree, but statistically clopramide also had a stimulatory effect on gastric
significant reduction in small-bowel motility index, and intestinal motility index (Figure 7). However,
was also observed (Figure 4). A parallel decrease in because of previous antrectomy, the capacity of the
the frequency of contractions (number per 3 hr) in distal gastric remnant to respond to the drug is, in
stomach and gut also was observed (data not absolute terms, small. In contrast to the findings in
shown). Postsurgical controls had a significantly diabetic gastroparesis, in 5 of 9 postsurgical patients,
lower motility index in the distal stomach (explain- phase III activity was noted in the fundus after
able on the basis of prior antrectomy) and a lower metoclopramide use, preceding the corresponding
(but not significantly so) index in the fundus. The phase III activity in the bowel. Further, unlike pa-
small-bowel motility index in postsurgical controls
was normal.

;
Diabetic Gastroparesis
5 3000
As observed for patients with postsurgical "E
F
gastroparesis, interdigestive motor cycles occurred _
2000 .Mean
%
with normal frequency (at least one complex every 3 s
1
hr) as determined by monitoring intestinal activity z
1000
(Table 1). In contrast, only in 1 of the 7 patients was
phase III activity recognizable in the stomach, coin-
ciding with phase III in the bowel (Figure 5). In 0
PS PSG H PS PSG H PS PSG
H
asymptomatic diabetic patients, interdigestive motor Fundus Dtstalstomach lnfestlne

cycles in the stomach and in the intestine were nor- *PC 0 02 or bettervs H or PS
+ PC 002 "S Ii only
mal. tt PC 0.02 vs H or PSG

The fundic tone in diabetic gastroparesis (11 + 1 Figure 4. lnterdigestive motor activity of upper gut in healthy
mm Hg) was similar to that of asymptomatic dia- controls (H), postsurgical asymptomatic patients (PS),
betic patients (10 + 21, but the fundic motility index and postsurgical patients with gastroparesis (PSG).
290 MALAGELADA ET AL. GASTROENTEROLOGY Vol. 78. No. 2

Fundus

25mm Hg

Figure 5. Simultaneous measurement of fundic, an-

Antrum tral, and duodenal motor activities in pa-
Cent with diabetic gastroparesis. Note ab-
1OOmm HgL _ __c_ sence of visible phasic changes in pressure
recorded by fundic and antral pressure
Duodenum transducers, whereas typical phase III ac-
tivity is observed in duodenum.
Phase II Phase III Phase IV Phase I

tients with diabetic gastroparesis, patients with chol caused mild flushing and nausea in 2 of the 5
postsurgical gastroparesis did not show phase III ac- patients who received the drug.
tivity in the intestine after metoclopramide use,
without a corresponding phase III activity in the
Discussion
fundus.
In 3 patients with diabetic gastroparesis and in 2 In this study, we examined the interdigestive
patients with postsurgical gastroparesis, the effect of motor patterns in patients with severe diabetic and
bethanechol was compared with that of metoclopra- postvagotomy gastroparesis. Although several radio-
mide and placebo. The increase in fundic motility logic studies have commented on decreased gastro-
index effected by bethanechol was significantly intestinal peristaltic activity in these patients, sys-
greater than placebo and was similar to that of meto- tematic manometric studies for diagnostic and
clopramide (Figure 9). However, in contrast to meto- therapeutic evaluation are not available.
clopramide, bethanechol did not trigger phase III ac- The results of our study must be interpreted in the
tivity in any patient, either in the stomach or in the
small bowel.
Although there were no serious side effects from PostsurgIcal Gastroparesls
Fundus
the metoclopramide infusion, some patients com- *
M t SE
plained of transient tremor, drowsiness, anxiety, or %P< 0.05
1000 I I
blurred vision, these effects being most pronounced
after infusion of the total dose and lasting only 5-10
min. The patients were unaware of the order of
metoclopramide and saline infusions and did not no- 500
tice any effects from the control infusion. Bethane-
.s
F
4
0
,‘ P M P M P M
z
1 T
Oiabetlc
Gastropares~s

- Fundus
4 IO00
Antrum lntestme
t

500

Ii 0 DG H D DG H 0 DG
Fundus Antrum lnfestlne
x PC 0 05 or better vs H or 0
0
**PC 005 or better vs H or DG P M P M P M

Figure 6. Interdigestive motor activity of upper gut in health (H), Figure 7. Fundic, distal gastric, and intestinal pressure responses
asymptomatic diabetic patients (D), and patients with to metoclopramide (M) or placebo (P) in postsurgical
diabetic gastroparesis (DG). (upper panel) or diabetic (lower panel) gastroparesis.
February 1980 MANOMETRIC ABNORMALITIES IN CASTROPARESIS 291

Metoclopramide
Fundus 1Omg i.v.

25 mmHg
Figure 8. Effect of intravenous metoclopra- 0-
mide on fundic, antral, and duode-
nal motor activities in patient with
Antrum
diabetic gastroparesis. Note ab-
sence of pressure changes in stom-
ach, with normal phase II activity
in duodenum. Metoclopramide, 10
mg intravenously, causes onset of
fundic and antral pressure waves.
Duodenum

1OOmmHg
n -I

light of current physiologic knowledge on inter- asymptomatic, variations in gastric motor activity
digestive motor patterns. Cycles of myoelectrical ac- may occur without clinical manifestation.
tivity during prolonged fasting were originally de- The function of interdigestive cycles is unknown,
scribed in the canine small bowel by Szurszewski” but the propagated phase III activity may act as an
and have since been reported in a number of animal “intestinal housekeeper,““.‘” periodically sweeping
species and in humans.2’-23 These motor cycles ap- luminal contents, bacteria, and debris into the colon.
pear to originate in the upper gut (maybe as proxi- Perhaps more relevant to patients with gastroparesis
mal as in the lower esophageal sphincter) and are is the observation that gastric phase III activity
propagated distally to the terminal ileum.‘8~*oThe plays a role in the evacuation of nondigestible solids
mechanisms that regulate cycle periodicity and from the stomach.30 Nondigestible solids can be de-
propagation remain unknown, although intrinsic in- fined as particulate dietary components which, be-
nervation of the gut appears to be essential for prop- cause of their size and mechanical resistance to an-
agation.z4 In the dog, cyclic variation in plasma moti- tral grinding and to acid-peptic degradation, are
lin is closely correlated with antroduodenal phase III selectively discriminated by the distal stomach and
activity,“” but such an association occurs infre- not allowed to pass into the duodenum with other
quently in humans (Rees, Malagelada, Go, unpub- components of the meal. Nondigestible solids are
lished data). evacuated later with the return of the interdigestive
A key finding of our study is that interdigestive motor complex.3o In light of these concepts, it is in-
motor cycles were absent in the stomach, whereas triguing that “bezoars” often found in patients with
they were essentially intact in the small bowel. This chronic gastroparesis (as it was true in 5 of 10 of our
suggests that the mechanisms responsible for this patients with postsurgical gastroparesis) are com-
cyclic activity continue operating in these patients, posed largely of nondigestible solids such as vege-
yet the stomach is not responsive to the action of table fibrous material and other debris. One ex-
these mechanisms. Furthermore, our study shows
that the absence of interdigestive motor complexes
is not the consequence of diabetes or vagotomy, be-
cause the disease control groups (diabetic and post-
surgical) also had essentially normal cyclic activity.
It is intriguing that postsurgical controls showed a
trend toward both increased frequency of inter-
digestive motor cycles and decreased gastric motility
index. The significance of this is unclear for, at least
in the dog, truncal vagotomy causes a slight decrease
or no effect on the incidence and propagation of a Placebo Metoclopramide* Bethanechol*
1Omg IV 5mg SC
complex.2”~27 The asymptomatic diabetic controls
showed a decrease in gastric motility index, and oth-
Figure 9. Comparative effect of placebo, metoclopramide, and
ers have commented on the decreased gastric empty-
bethanechol on fundic motor activity in diabetic (DG)
ing in such patients,‘” although this finding has not and postsurgical gastroparesis (PSG). Lines connect
been universal.z9 Because al1 these subjects were data from each individual patient.
292 MALAGELADA ET AL. GASTROENTEROLOGY Vol. 76, No. 2

planatit,n for the formation of these bezoars could emptying after vagotomy for obstructing ulcer. Am J Surg
be the absence of gastric interdigestive motor com- 98:612-616, 1959
6. Hermann G, Johnson V: Management of prolonged gastric re-
plex leading to their selective accumulation in the
tention after vagotomy and drainage. Surg Gynecol Obstet
stomach. 130:1044-1048, 1970
Metoclopramide significantly increased motor ac- 7. Kraft RO, Fry WJ, DeWeese MS: Postvagotomy gastric atony.
tivity in the proximal gastric, distal gastric, and Arch Surg 68865-871, 1964
small bowel in both groups of patients with gas- 8. Kassander P: Asymptomatic gastric retention in diabetics
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an earlier study”’ on the antral motor response to 9. Faulk DL, Anuras S, Christensen J: Chronic intestinal pseudo-
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may involve cholinergic36-38 and antidopaminergic”“~‘”
13. Pinder RM, Brogden RN, Sawyer PR, et al: Metoclopramide: a
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Only in the former did metoclopramide restore the housekeeper: motor correlates of the interdigestive myo-
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