GASTROENTEROLOGY

1992;103:114-119

Intravenous Erythromycin Overcomes Small Intestinal Feedback on Antral, Pyloric, and Duodenal Motility R. FRASER, T. SHEARER, J. FULLER, M. HOROWITZ, and J. DENT Gastroenterology Unit and Department of Medicine Royal Adelaide Hospital, North Terrace, Adelaide, South Australia

The retardation of gastric emptying caused by intraduodenal lipid is associated with suppression of antral contractions and stimulation of localized pyloric contractions. Similar patterns of motility have been described in patients with gastroparesis. The effect of erythromycin on the antropyloroduodenal motor responses to intraduodenal lipid was investigated. In 17 volunteers an intraduodenal lipid infusion (10% Intralipid) was given at 1 mL/min for 50 minutes. Either erythromycin (3 mg/kg) or saline was administered IV for 15 minutes, beginning 20 minutes after the start of the intraduodenal lipid infusion. Antral, pyloric, and duodenal motility were measured with a sleeve/sidehole manometric assembly. Intraduodenal lipid stimulated localized pyloric contractions. Erythromycin suppressed localized phasic (P < 0.003) and tonic (P < 0.002) pyloric pressure waves and stimulated antral (P < 0.003) and duodenal pressure waves (P < 0.02). After erythromycin antral pressure waves were usually of high amplitude (>50 mm Hg) and often associated with duodenal pressure waves. It was concluded that erythromycin overcomes the effects of intraduodenal lipid on antral, pyloric, and duodenal motility. These effects probably contribute to the gastrokinetic properties of erythromycin. n some patients with diabetic gastroparesis, the antibiotic erythromycin, when given intravenously (IV) in a dose of 200 mg, has recently been shown to increase gastric emptying to a rate faster than that seen in healthy humans. ‘3’Similar beneficial effects have also been reported in postsurgical gastroparesisa3The motor mechanisms responsible for the accelerated emptying due to erythromycin have not been fully elucidated.4-” Recent studies indicate that the pylorus is important in the regulation of gastric emptying. In healthy subjects, infusion of nutrients into the small intestine retards gastric emptying and is associated with stimulation of localized phasic and tonic pyloric contractions and suppression of antral and duodenal contractions.7’8 Similar motor patterns have been de-

I

scribed in patients with gastroparesis.g-” Therefore, small intestinal nutrient infusion may provide a useful means to evaluate the efficacy of gastrokinetic drugs. The present study has examined in normal volunteers the effect of erythromycin on the gastroduodenal, and in particular the pyloric, motor responses to the intraduodenal infusion of a lipid emulsion. Materials and Methods Subjects Studies were carried out on 17 healthy volunteers, aged 18-32 years, weight range 47-81 kg, who had no history of gastrointestinal disease and were not taking any medication. Smoking was prohibited on the morning of the study. Subjects were warned of the possibility of nausea or abdominal cramps before each study and were questioned at the end of each study regarding these side effects. All subjects gave their written informed consent, and the study was approved by the Human Ethics Committee of the Royal Adelaide Hospital in December 1989. Equipment The manometric technique used is described in detail elsewhere.‘2-‘4 In brief the manometric assembly consisted of a 4.5-cm, long sleeve sensor in parallel with an array of perfused side holes 1.5 cm apart. Four sideholes were located in the gastric antrum, four along the sleeve, and one in the proximal duodenum. The side holes at either end of the sleeve sensor recorded transmucosal potential difference (TMPD) simultaneously with intraluminal pressure via flowing saline electrodes. Solutions of lipid or saline were infused into the duodenum through an infusion port 12.5 cm distal to the sleeve. The catheter had a maximum external diameter of 6 mm, and intubation was aided by a small articulated weight of tungsten pellets at the tip of the assembly. Pressures and TMPD measurements were recorded onto a l&channel chart (Grass polygraph model 7D; Grass Inc, Quincy, MA).

Erythromycin lactobionate was a gift from Abbott Australia. 0 1992by the American Gastroenterological 0016-5085/92/$3.00

Association

ERYTHROMYCIN AND PYLORIC MOTILITY 115

July 1992

Experimental

Protocol

Before intubation, an 18-gauge Jelco teflon IV catheter was inserted into an antecubital vein for the IV infusion of test solutions (erythromycin or saline). On the morning after an overnight fast the manometric assembly was passed transnasally via an anaesthetized nostril. The catheter was then positioned across the pylorus as described previously, with the correct position of the sleeve determined by measurement of the TMPD gradient at the gastroduodenal junction.‘z-‘4 The TMPD recordings were continued throughout the experiment and the catheter advanced or withdrawn to maintain the sleeve sensor across the pylorus. migratEach study began in phase I of the interdigestive ing motor cycle (IDMMC), 10 minutes after the completion of the preceding episode of duodenal phase III activity. As in previous studies this was defined by the occurrence of regular phasic pressure waves at a frequency of 210 per minute lasting for at least 2 minutes and followed by subsequent suppression of duodenal contractions.” At the beginning of each experiment, normal saline was infused at the duodenum at 1 mL per minute for 10 minutes. This was followed by an intraduodenal infusion of triglyceride (10% Intralipid-Vitrum, Stockholm, Sweden) at a rate of 1 mL per minute for 50 minutes. Twenty minutes after beginning lipid infusion, each subject received in double-blind fashion an IV infusion administered over 15 minutes of either (a) erythromycin as the lactobionate 3 mg/kg in 20 mL normal saline or (b) an equivalent volume of normal saline. Data Analysis Records were only analyzed when the sleeve sensor was placed correctly across the pylorus according to previously defined TMPD criteria. These criteria were that the duodenal TMPD was equal to or more positive than -15 mV, the antral TMPD was equal to or more negative than -20 mV, and the difference between the two readings was at least 15 mV.‘2-‘4 Manometric

Criteria

Pyloric pressure waves. PHASIC. Sleeve recorded pressure waves were classified as isolated pyloric pressure waves (IPPWs) if they were of >lO mm Hg in amplitude and satisfied the following criteria: (a) the wave was recorded by the sleeve in the absence of any wave in either of the TMPD side holes and (b) the pressure wave was recorded by no more than one of the side holes along the sleeve.‘2-‘4 TONIC. Basal pressure was calculated for each minute of the study by determination of the difference between the visual mean of the basal pressures recorded by the sleeve and the antral TMPD sidehole after editing for phasic contractions. The mean basal pyloric pressure for each 5-minute period was then calculated.‘2-‘4 Antral and duodenal pressure waves. For the purposes of analysis, a phasic contraction was defined as an increase in pressure lasting for between lo-25 seconds in the antrum and 4-10 seconds in the duodenum.14 The

number of antral pressure waves 210 mm Hg recorded by each antral side hole was counted for each 5 minutes of the study, and the result was expressed as the number of waves per minute. In addition, the mean amplitude of antral contractions recorded by the antral TMPD side hole was calculated for each 5-minute period. A high gain setting was chosen to facilitate measurement of basal pyloric pressure, and because of this the maximum pressure that could be quantified was 50 mm Hg. All antral pressure waves that went off scale (i.e., >50 mm Hg) were scored as having an amplitude of 50 mm Hg. Duodenal pressures were evaluated by counting the number of phasic pressure waves 210 mm Hg in amplitude recorded by the duodenal sidehole 1.5 cm distal to the duodenal TMPD sidehole for each 5-minute period of the study. Pressure waves were defined as “associated” if the midpoints of contractions in at least three separate but not necessarily adjacent channels occurred within 10 seconds. These associated events were divided into antral (pressure waves in at least 3 antral sideholes in the absence of pressure waves recorded by the sleeve or sideholes along the sleeve), antropyloric (pressure waves recorded by at least two antral sites and the sleeve sensor in the absence of any duodenal pressure waves), and antropyloroduodenal contractions (pressure waves in one or more antral recording sites, the sleeve sensor, and one or more duodenal sites]. Statistical

Analysis

Nonparametric analysis of the repeated measures was necessary because of the discreteness of the data. To compare the mean response curves of the two groups over specified time intervals, F-test approximations based on randomization models were used.” Comparisons of time points within groups were performed via analysis of variance (with contrasts) on the aligned ranks of raw data. A P value of co.05 was considered significant. Data are expressed as medians and interquartile ranges.

Results The nasogastric intubation, intraduodenal lipid infusion, and IV injections of erythromycin and saline were well tolerated by all subjects. No subject reported nausea or abdominal discomfort during the study. The position of the manometric assembly was well maintained in all studies with TMPD measurements indicating the correct location of the sleeve sensor across the pylorus for 856 minutes of the 1020 minutes (84%) of recording time. Intraduodenal lipid induced the expected pattern of antral pyloric and duodenal motility7*‘2~‘6 with stimulation of localized and tonic contractions of the pylorus and virtual absence of antral and duodenal contractions (Figures l-6). An example of the motility pattern from a saline treated subject is shown in Figure 1A. There was no significant difference in the number of IPPWs, antral or duodenal contractions after saline. However, there was a time-dependent

116

FRASER ET AL.

+

GASTROENTEROLOGY

IV SalIn. -

Pr0xtm.l Antrum

40 0

1

$

IV Erythromycin

Vol. 103,No. I

3 ma/kg

A

Figure 1. Examples of tracing showing (A)the lack of response to IV saline and (II) the early response to erythromycin. abolition of IPPWs and basal pyloric pressure was seen within 10 minutes in all 8 subjects treated with erythromycin.

decrease in basal pyloric pressure following saline (P < 0.05). The initial effect of erythromycin administration on the pattern of antral, pyloric, and duodenal pressure waves is shown in Figure 1B. After erythromytin there was abolition of IPPWs and pyloric tone within 10 minutes of the commencement of the erythromycin infusion in all 8 subjects. Localized pyloric activity remained almost completely absent until the end of the study (Figure 3). The median frequency of IPPWs fell from 2.1 per minute before erythromycin to 0 per minute within 10 minutes of the start of the infusion (P < 0.0003 vs. saline, P < 0.0001 vs. pretreatment). Basal pyloric pressure decreased from 6.3 mm Hg immediately before erythro-

A complete

mycin to 0.4 mm Hg (P < 0.002 vs. saline, P < 0.0001 vs. pretreatment) (Figure 4). After the abolition of localized pyloric contractions, there was motor quiescence for l-25 minutes (median, 5 minutes). Subsequently, the frequency of pressure waves recorded by the antral TMPD side hole increased following the erythromycin infusion from 0 to 1.8 waves/min (P < 0.003 vs. saline, P -C 0.002 vs. pretreatment) (Figure 5). A similar increase was recorded by all the antral side holes. After erythromycin infusion the median amplitude of contractions recorded at the antral TMPD recording site was 50 mm Hg (i.e., 50 mm Hg or more). There was an increase in the number of duodenal infusion pressure waves following erythromycin

so..0

Figure 2. Example of manometric tracings 15 minutes before (left panel) and 20 minutes after IV erythromytin (right panel). Lefi panel shows pattern of IPPWs during intraduodenal lipid infusion. Rightpanelshows stimulation of antropyloric and antropyloroduodenal pressure waves after erythromytin. The schema between the panels shows the approximate position of sideholes relative to antrum, pylorus, and duodenum.

ERYTHROMYCIN

July 1992

Figure 3. Number of IPPWs during IV saline (A)and erytbromytin (B) shown as median values and interquartile ranges for B-minute segments of recording. There is abolition of IPPWs after erythromycin administration (P -C 0.0003 vs. saline, P < 0.0001 vs. pretreatment).

from 0 to 2.0 per minute (P < 0.002vs.saline, P < 0.0001 vs. pretreatment) (Figure 6). Only 4 of the 17 antral TMPD sidehole recorded pressure waves seen after intravenous saline were associated with pressure waves recorded in the duodenal channels. However, following erythromycin, 124 of the 259 pressure waves recorded by the antral TMPD sidehole were temporally associated with pressure waves recorded in the duodenal sideholes (Table 1). The increase in duodenal pressure waves following erythromycin therefore partly reflected the transpyloric propagation of antral contractions. In the erythromycin-treated subjects, 67 of these antropyloroduodenal pressure waves were recorded by antral sideholes 4.5 and 6 cm proximal to the sleeve, whereas in the saline-treated group, none of the antropyloroduodenal pressure waves were recorded by these proximal antral side holes. Discussion The major new finding in our study is that IV erythromycin rapidly abolished the pattern of phasic and tonic pyloric contractions and absence of antral contractions associated with intraduodenal lipid. Previous studies indicate that this pattern of motility

Figure 4. Basal pyloric pressure during IV saline (A)and erytbromycin (B) shown as median values and interquartile ranges for S-minute segments of recording. There is a time dependent reduction in basal pyloric pressure in the control experiments (P -C 0.06). Following erythromycin there is abolition of basal pyloric pressure (P < 0.002 vs. saline, P < 0.0001vs.pretreatment).

AND PYLORICMOTILITY 117

Figure 5. Number of pressure waves recorded by antral TMPD side hole during IV saline (A)and erythromycin (B) shown as median values and interquartile ranges for s-minute segments of recording. There is a significant stimulation of antral pressure waves after erythromycin (P < 0.003 vs. saline, P < 0.002 vs. pretreatment). A similar pattern of stimulation was seen in all antral side holes.

is associated with retardation of gastric emptying.7 In particular, fluoroscopic studies in healthy humans have shown that localized tonic and phasic pyloric contractions may result in cessation of transpyloric flow.* The induction of a vigorous pattern of high amplitude, propagated antral contractions would be expected to favor rapid gastric emptying. Because the sleeve sensor records any contraction occurring along its length, we can not be certain that IPPWs did not persist during the period of antral stimulation. However, the initial disappearance of localized pyloric contractions and subsequent motor quiescence before the stimulation of the antral contractions suggests that this abolition is real. While there have been no previous studies examining the effect of erythromycin on the pylorus, the stimulation of high amplitude antral contractions by erythromycin is consistent with previous observations.5.6 Although we did not record the maximum amplitude of these pressure waves, previous studies have shown that the mean amplitude of antral contractions after erythromycin to be >lOO mm Hg.’ Recording of pressure waves higher in the antrum after erythromycin indicates that erythromycin has pro-

A

o

snME(mln,m =

BO

TIME(mln)~ m

Figure 6. Number of duodenal pressure waves during IV saline (A)and erythromycin (B) shown as median values and interquartile ranges for S-minute segments of recording. There is a significant stimulation of duodenal pressure waves after erythromycin (P i 0.002 vs. saline, P < 0.0001vs.pretreatment).

118

FRASER ET AL.

GASTROENTEROLOGY

Table 2. Number of Associated Pressure Waves Before (-20-O Minutes), During (O-15 Minutes), and

After (15-30 Minutes) IV Infusion of Erythromycin Expressed as Number of Waves Per 5 Minutes -20-o

o-15

15-30

0.7 (O-l) 0.5 (O-1.2) 1.8 (0.54

1.0 (0.7-1.3) 0.8 (0.3-1.3) 3.3 (1.8-3.7)

Antral Antropyloric Antropyloroduodenal

0 (O-O) 0 (O-O) 0 (O-O)

NOTE. Results expressed

as median and interquartile

range.

duced augmentation of antral contractions to a point that lumen occlusion occurs. Our study did not examine the effect of erythromytin on the proximal stomach, which may also be important in the regulation of gastric emptying.17 Despite this limitation, the stimulation of propagated antral contractions, together with the inhibition of localized pyloric contractions provide a plausible explanation both for the beneficial effect of erythromytin on gastric emptying in patients with gastroparesislm3 and the enhancement of transpyloric tube placement.‘8~‘g The motor properties of erythromycin are unrelated to its antibiotic activity and may be a result of the stimulation of gastrointestinal receptors for motilin.20~21Motilin may be important in the initiation of gastroduodenal phase III activity of the IDMMC. Naturally occurring gastric phase III activity is associated with elevations in plasma motilin concentrations and intravenous administration of the hormone induces gastric phase III activity.” There is limited and conflicting information about the effect of motilin on postprandial gastric motor function.23-25 Although an initial study reported that intravenous motilin slowed gastric emptying in healthy humans,23 parenteral administration of lower doses of motilin has since been shown to increase the rate of gastric emptying in both healthy humansz4 and in patients with diabetes mellitus.25 The effects of erythromycin on interdigestive gastrointestinal motility are dose dependent in animals22~zsand probably in humansu4 In dogs, low doses of erythromycin stimulate phase III activity of the gastric antrum. At high doses erythromycin disrupts the electrical control activity of the small intestine and induces retrograde contractions.26 In humans, (1 mg/kg) also induces low-dose IV erythromycin phase III contractions in the antrum, similar to both spontaneously occurring and motilin-induced gastric phase 3 activity. When given postprandially, higher doses of erythromycin (3-3.5 mg/kg) stimulate high amplitude antral contractions in healthy humans,5 which, as in the current study, have a duration considerably longer than the 3-6 minutes of

Vol. 103, No. l

spontaneous gastric antral phase 3 activity. A similar response has been reported in patients with intestinal pseudo-obstructionz7 In dogs, the induction of rapid gastric emptying by erythromycin occurred at the expense of grinding and sieving of the digesta with an eightfold increase in the percentage of particles 20.5 mm emptied into the duodenum.28 Erythromycin appears to have an unusually powerful action when compared with the best currently available gastrokinetic drugs. In human studies, Urbain et al. reported that in patients with severe gastroparesis given erythromycin, there was a loss of discrimination between liquid and solid emptying.’ The rapid emptying of relatively large food particles from the stomach may theoretically impair the orderly digestion and absorption of nutrients. However, there is no gastrokinetic drug that has been shown to both stimulate gastric emptying and promote grinding and sieving. Small intestinal nutrient receptors have a major role in the regulation of gastric emptying in normal subjects. The effect of intraduodenal nutrient infusion on gastric emptying and gastric motility has been used in other studies as a model to evaluate potential gastrokinetic agents. In dogs, intravenous cisapride (0.32 mg/kg) had no effect on the inhibitory effect of small intestinal nutrient infusion on gastric emptying,” although in humans, cisapride (IO mg orally) reversed the delay in gastric emptying induced by consumption of 50 mL dairy cream before the test mea130 Basal pyloric pressure decreased following IV saline, but the fall was less marked and occurred later than after IV erythromycin. The attenuation of pyloric motor responses has previously been shown for the phasic component of the pyloric response to intraduodenal lipide3’ The mechanism responsible for this effect is unclear, but it may reflect an alteration in duodenal receptor sensitivity during prolonged stimulation. Although erythromycin is extremely effective in promoting gastric emptying when administered IV, its gastrokinetic effect appears somewhat less pronounced with oral usage.‘,32 It has been suggested that the efficacy of erythromycin in the long term will diminish because of down regulation of motilin receptors.33 Therefore further studies are necessary to determine whether erythromycin will be beneficial in the long term treatment of gastroparesis and if so, the optimum therapeutic dose. Nevertheless, IV erythromycin may be useful initial therapy in patients with gastroparesis who are unable to tolerate oral treatment because of vomiting and when facilitating transpyloric placement of nasoenteric feeding tubes and manometric catheters.

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