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Anesth Analg 2006;102:1803-1808 © 2006 International Anesthesia Research Society doi: 10.1213/01.ane.0000216040.66619.7e
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Abstract |
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In this double-blind cross-over study, we assessed whether erythromycin infusion is effective as a prokinetic drug against gastroparesis from acute pain. The effect of erythromycin on gastric emptying (GE) was measured in seven volunteers subjected to a standardized acute painful stimulus. The GE rate for solids was measured using the octanoic acid breath test. An acetaminophen absorption test measured the GE rate for liquids. Five minutes after ingestion of a 13C-labeled meal, the subjects received in randomized order either a test (placebo and erythromycin groups) or a control (control group) stimulus consisting of repeated 1-min immersion of a hand into 4°C (test) or 37°C (control) water, with 15 s for recovery between immersions, for a total of 20 min. While the stimulus was applied, 250 mL saline (control and placebo groups) or 250 mg erythromycin (erythromycin group) was infused. Pain and stress were evaluated using visual analog scales, and standard hemodynamic values were recorded throughout the study. Our results show that acute stress decreased GE for solids, which was significantly accelerated in the erythromycin group in comparison with the placebo group. GE for liquids was similar in the three groups. We conclude that erythromycin is effective as a prokinetic drug for solids in acute painful situations.
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Introduction |
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Acute stress related to pain induces delayed gastric emptying (GE), partly caused by endocrinal changes such as hyperglycemia and large blood concentrations of catecholamines (1,2).
Erythromycin is a macrolide antibiotic that acts on gut motility as an agonist of the receptors for motilin and possibly via a cholinergic pathway or endogenous motilin release (3–5). Many studies have shown that its administration at smaller doses than those used for antibiotic properties enhances GE of meals in healthy volunteers, as well as in critically ill patients and those with gastroparesis related to several pathologies, including diabetes mellitus (6–11).
However, the prokinetic effects of erythromycin are inhibited through several endocrinal disruptions, such as hyperglycemia or large blood concentrations of catecholamines (12,13), which are common during acute stress. Hence, it remains uncertain that erythromycin acts as an effective prokinetic drug for patients suffering from acute stress or pain as observed before emergency anesthesia.
Few studies have evaluated the interactions between erythromycin and gut function during the perioperative period. One study showed that 200 mg of preoperative oral erythromycin significantly reduces residual gastric volume and acidity before elective surgery (14). In 1997, Kopp et al. (15) reported that in one nonfasting patient undergoing emergency anesthesia, the administration of erythromycin as a premedication had totally emptied the stomach.
The aim of this study was to assess whether the administration of 250 mg of erythromycin produces gastrokinetic effects during an acute painful situation. We used noninvasive techniques to evaluate the GE rate for liquids and solids after ingestion of a test meal in volunteers subjected to standardized cold stress.
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Methods |
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With the approval of the University of Lyon Committee on Human Research (Lyon, France), we evaluated 7 healthy volunteers (3 men and 4 women; mean age, 28 yr; range, 20–45 yr). Written informed consent was obtained from each volunteer. The criteria for exclusion from the study were upper gastrointestinal tract diseases, previous gastrointestinal surgery, history of diabetes mellitus, pregnancy, history of heart disease, and use of medication affecting gastric motility. Volunteers attended 3 separate study sessions, each at least 2 wk apart. In this crossover double-blind study, volunteers were randomly allocated by coded envelopes to the following groups: control (0.9% saline infusion and control stimulus), placebo (0.9% saline and cold stress), and erythromycin (250 mg erythromycin IV administration and cold stress).
The experimental protocol is summarized in Figure 1.
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. Acetaminophen concentrations 
. IV catheter insertion 
. Pain and stress estimation (PVAS and SVAS) *.All tests were conducted after an overnight fast. Throughout the test, the volunteers were lying in a supine position on a bed. Tests started with a period of 60 min to allow volunteers to become accustomed to the hood of the indirect calorimeter, and during this time several baseline values were collected, such as oxygen consumption (Vo2), carbon dioxide, and 13CO2 production (Vco2).
The usual physiologic measures were also recorded throughout the study, including heart rate (HR) and noninvasive brachial arterial blood pressure (NIBP: systolic, diastolic, and mean).
After the patients were given transcutaneous local anesthesia, two peripheral venous catheters were inserted into antecubital veins of both arms. On the nondominant hand, 250 mL saline (control and placebo groups) or 250 mg erythromycin diluted with 250 mL saline (erythromycin group) was administered through the venous catheter. The infusion was started 5 min after the meal for a period of 15 min. The hand of the opposite arm was heated in a hot blanket to obtain arterialized blood samples for acetaminophen dosages. After each blood sample was taken, the IV catheter was flushed with 1 mL heparinized saline.
A breath test for the measurement of GE of solids labeled with 13C octanoic acid was used in this study, as previously established by Ghoos et al. (16). This test is based on the fact that disintegration of the labeled solid phase of the test meal, with subsequent absorption and oxidation of 13C octanoic acid to 13CO2, takes place once the meal reaches the duodenum.
The test meal consisted of a scrambled egg with the yolk labeled with 100 mg 13C-octanoic acid (Eurisotop, Saint-Aubin, France). The egg was ingested with 2 slices of white bread and 5 g margarine, followed immediately by acetaminophen 1 g diluted in 150 mL water. The yolk and the egg white were cooked separately but were administered together with the bread. The total caloric value of the meal was 250 kcal. All test meals were consumed in <10 min.
Measured Vco2 production was used for calculations. Measurements of Vo2 and Vco2 were performed by the open-circuit method of indirect calorimetry (Deltatrac; Datex; Helsinki, Finland), calibrated weekly.
Expired air was collected by having participants blow through a straw into tubes (Vacutainer; Becton Dickinson; Grenoble, France). Measurements were taken with patients lying in a semi-recumbent position (20°). Breath samples were taken over a period of 240 min at regular 15-min intervals before and after ingestion of the meal and every 5 min during the stimulus. They were analyzed for 13CO2 concentration by isotope-ratio mass spectrometry (SIRA 10; VG Isogas; Middlewich, UK) as previously described (17,18).
Breath CO2 isotopic concentrations were calculated versus breath CO2 obtained before labeled octanoic ingestion. Using nonlinear regression methods, the 13CO2 excretion curves were fitted to calculate three GE parameters: GE coefficient (GEC), gastric half emptying time (t
ß), and lag phase (tlag) (16). GEC gives an overall index of GE, and tß indicates the time at which half of the dose of 13CO2 has been excreted out of the cumulative 13CO2 excretion when time is infinite. The lag phase corresponds to the time when the peak of the 13CO2 excretion curve has been reached. These calculations were made using a homemade Excel 4.0 macro program (Microsoft, Redmond, WA) by a physician not involved in the collection of the data.
The appearance of acetaminophen in the systemic circulation is an indirect method of determining the rate of GE for liquids because acetaminophen is not absorbed in the stomach but is rapidly absorbed by the intestine (19). This test has been validated using radionucleotide techniques that quantitatively measure GE (20). Acetaminophen (1 g in 150 mL water) was given by mouth at the end of the test meal. Blood samples for acetaminophen analysis were collected at 5-min intervals throughout the stimulus and then every 15 min for 60 min. Blood samples were subsequently separated by centrifugation. The plasma was stored at –40°C until analyzed for acetaminophen concentrations.
Acetaminophen concentrations were measured in the plasma by high-performance liquid chromatography (Wisp auto injector 717, Pump 600 E, PDA 996). The limit of quantification of the assay was 100 ng/mL. The calibration curve showed a linear response (r < 0.99) for the concentration range (100–20,000 ng/mL) tested. The coefficient of variation for the calibration range was <5%.
Patient files were broken down into three groups (control, placebo, erythromycin) using the file manager program (PASTRX) included in the USC*PACK software (21). Each file contained anthropometric and treatment data, such as age, weight, administered amounts of acetaminophen, time of administration, infusion duration, blood sampling times, and drug serum concentration measurements. Pharmacokinetic parameter values were estimated in each group using the nonparametric EM algorithm NPEM2 implemented within the USC*PACK software NPEM program. The discrete joint probability density function of pharmacokinetic parameters was calculated without making any assumption of the shape of the distribution. The population parameter values obtained for each group were then used to estimate individual pharmacokinetic parameter values by using a Maximum A Posteriori Bayesian method also implemented in the USC*PACK (22). Several parameters of GE, including time to reach the peak serum concentration (Tmax), the maximum serum concentration (Cmax), and the area under the acetaminophen serum concentration-versus-time curve (AUC), were then calculated.
Test or control stimuli were applied 5 min after meal ingestion. The test stimulus consisted of repeated 1-min immersions of the nondominant hand into water at 4°C, as previously described (23). The hand was removed for 15 s between immersions, and these cycles were repeated for a period of 20 min or until the subject could no longer tolerate pain. For the control stimulus (control group), the same procedure was applied by immersing the hand into water at 37°C.
Routine physiologic values were recorded at 15 and 30 min before and after the stimulus and every 5 min during the stimulus, along with patients' pain and anxiety levels according to a Pain and Stress Visual Analog Scale (PVAS and SVAS) (24). Each volunteer was presented with a 100-mm line and was told that the left end represented no pain (or no anxiety) and the right end the worst pain (or anxiety) imaginable. Volunteers were then asked to make a mark on the line to indicate the intensity of their pain or anxiety.
The results are expressed as mean ± sd. The Statistica computer software package was used for all calculations. After a Shapiro-Wilk W test (Statsoft, Tulsa, OK) for normality of distribution of the data, continuous variables (HR, NIBP, PVAS, SVAS) were analyzed by a repeated-measures analysis of variance or by a one-way analysis of variance (GE parameters for liquids and solids) as needed. Whenever a significant difference was observed, analysis of variance was followed by a post hoc test (Bonferroni adjusted comparisons). A P value <0.05 was considered as statistically significant.
The primary outcome of the study was the change of GE rate for solids under acute stress and erythromycin administration. Change of GE rate for liquids was the secondary outcome. Hence, assuming an sd of 0.30 for GEC, as reported in a previous study performed at our institution (25), the power of the one-way analysis of variance with 7 volunteers reached 90% at a significance level of 0.05 with a goal of a 30% difference in GEC among the 3 groups.
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Results |
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All of the tests were performed with no significant incidents. In particular, no heart arrhythmia occurred. Only one volunteer complained of nausea during the cold stress as erythromycin was administered, and all subjects completed 20 min of stress.
Pain and anxiety levels as estimated by visual analog scales (PVAS and SVAS) increased significantly and similarly during the test stimulus in the placebo and erythromycin groups compared with the control group (Figs. 2 and 3).
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HR and NIBP (mean, systolic, and diastolic) increased significantly during the stimulus among the three groups, as did Vco2 and Vo2, but no statistical difference was observed among the three groups for all these variables.
The variables measured to estimate the GE rate for liquids by the acetaminophen technique (AUC, Cmax, and Tmax) were similar in all of the groups (Table 1). Concerning the GE of solids, GEC increased significantly in the erythromycin group, while lag phase and half-emptying time decreased significantly in comparison with the placebo group, which corresponds to a significant acceleration of the GE rate for solids in the erythromycin group compared with the placebo group. The GE of solids was significantly slower in the placebo group than in the control group (Table 2).
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Discussion |
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The aim of this study was to assess whether IV administration of erythromycin is effective as a prokinetic drug for gastroparesis related to acute stress from pain. Our results showed that erythromycin promotes the GE of solids in acutely stressed volunteers.
Cold stress is a reproducible, easy-to-apply, and standardized painful stimulus that disrupts upper gut motility in volunteers (1,2,23,26). The levels of pain and anxiety obtained during application of cold water in our study were similar to those reported in previous studies using volunteers (26). Scintigraphic measurements of GE or GE quantification by duodenal recovery marker and recording of gastroduodenal motor activity by the manometric method have shown that the application of a cold stress in volunteers inhibits gastric motility and induces delay in the GE of labeled meals (1,2,23,26). In particular, painful stimulus has been reported to disturb upper gut motility by increasing the number of isolated pyloric pressure waves and also by inhibiting the antral phasic and propagated antropyloroduodenal pressure waves, which are essential for trituration and emptying of solid particles (1,26). It was therefore suggested that GE of solids may be slowed in response to an acute painful stimulus (1). Our results corroborate this hypothesis by showing that the GE rate for solids was slowed by the application of cold stress.
The mechanisms by which acute pain leads to gastroparesis are still poorly known. Endocrinal changes induced by the acute stress, such as increases in plasma levels of ß-endorphin, catecholamines, or glycemia, have been suggested as mechanisms for its pathophysiology (1,2). Also, direct activation of the autonomic nervous system induced by the acute stress may be involved in the mechanism of this gastroparesis. In fact, sympathetic gastric innervation produces inhibitory effects on antral motility as well as the inhibitory neurons of the parasympathetic nervous system (27).
In the current study, we assessed the prokinetic effects of erythromycin on gastroparesis related to acute stress. Erythromycin mimics exogenous motilin in gastrointestinal contractile activity in an animal model and has been shown to act as an agonist of smooth muscle motilin receptors present in both proximal and distal stomach in humans (28). It could also act on upper gut motility via the activation of cholinergic neurons of the myenteric plexus by serotoninergic neurons (29) or via a central cholinergic pathway (4). Its effects on upper gut motility have been well described: its IV administration at doses larger than 3 mg/kg in fasting volunteers and patients with diabetic gastroparesis induces burst phase-3-like rhythmic antral contractions not propagated to the small intestine and not followed by a phase-1 but instead by a prolonged period of increased antral contractile motility (30). In nonfasting volunteers, 200 mg of IV erythromycin induces powerful peristaltic antral contractions accompanied by improved antroduodenal coordination during the first postprandial hour (31). Erythromycin also strongly reduces the duration of postprandial relaxation by acting on proximal gastric tone (5) and increases lower esophageal sphincter pressure (3). Furthermore, clinical studies have reported that erythromycin enhances GE in healthy and diabetic patients who suffer from gastroparesis (7,9,11) and that it promotes GE in critically ill patients (6,8,10).
We chose to administer 250 mg of erythromycin to the volunteers in the erythromycin group. This corresponds to a microbiologically ineffective dose but is sufficient to be effective on GE. Many studies have shown that erythromycin has dose-related effects on the interdigestive and postprandial motility of the stomach and the small bowel (3,30). Doses that are at least equal to 3 mg/kg are required to obtain significant effects on GE in a postprandial state (7).
In our study, only one volunteer suffered from nausea during the cold stress as erythromycin was administered. In previous studies, no side effects were described as a result of the administration of doses of approximately 3 mg/kg of erythromycin (3,4,9,30,31). Thus, digestive side effects from erythromycin at doses of approximately 3 mg/kg are probably infrequent but may cause discomfort for patients and should be avoided if possible. It would be interesting in further trials to assess whether smaller doses of erythromycin are effective on gastroparesis resulting from stress, in particular in terms of reducing the incidence of digestive dose-related side effects such as epigastric ache, nausea, and diarrhea resulting from erythromycin administration.
The GE rate for solids was only accelerated by erythromycin in stressed volunteers in our study, whereas the rate for liquids did not change. These results contradict those reported by other authors, who found that GE of both liquids and solids was strongly accelerated in healthy and diabetic patients after erythromycin administration (9,11). The lack of power of our study to show a significant change in the GE of liquids under acute stress and erythromycin administration could in part explain this finding. Our study design could also explain the lack of significant effect of erythromycin on GE for liquids. It has been shown that the gastrointestinal motor effect of erythromycin appears within 10 minutes of the commencement of an IV infusion and that 20%–30% of liquids are emptied in 15 minutes, compared with 10% of solids (32). These observations could, at least in part, explain the lack of significance for liquids despite a 28% decrease in the area under concentration-time of acetaminophen with erythromycin. It is likely that the maximum GE effect of erythromycin could not occur until 15 minutes after ingestion of acetaminophen in our protocol, at a time when a significant portion of the liquid had already left the stomach.
Our results showing that erythromycin was effective as a prokinetic drug on GE of solids for gastroparesis related to acute painful cold stress in volunteers may be important for clinical practice because gastroparesis contributing to an increase in the volume of gastric contents could be one of the factors involved in the pathophysiology of pulmonary aspiration in nonfasting patients suffering from pain during emergency anesthesia (33). Aspiration of solid food particles, whose GE rate is especially altered by an acute painful stimulus, can lead to acute airway obstruction and thereby to death by asphyxia. It can also contribute to an increase in the rate of infectious pulmonary complications (33). Erythromycin, therefore, may be useful for increasing GE of solids in nonfasting patients who are undergoing emergency procedures and anesthesia, as previously suggested by Kopp et al. (15). Further studies are required to assess whether administering erythromycin as premedication reduces the occurrence of pulmonary aspiration and to compare its prokinetic effects with those of other more commonly used drugs such as metoclopramide.
The authors thank Peter Tucker (American translator, University of Aix-Marseille, France) for assistance in the preparation of the manuscript.
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Footnotes |
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Accepted for publication January 26, 2006.
Address reprint requests to: Prof. Dominique Chassard, Service d'Anesthésie-Réanimation, Hôpital de l'Hôtel-Dieu, 69002 Lyon, France. Address e-mail to dominique.chassard{at}chu-lyon.fr.
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