Anesth Analg 2004;99:429-434
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000121345.58835.93
ANESTHETIC PHARMACOLOGY
The Delay of Gastric Emptying Induced by Remifentanil Is Not Influenced by Posture
Jakob Walldén, MD*,
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Sven-Egron Thörn, MD PhD*, and
Magnus Wattwil, MD PhD*,
*Department of Anesthesia and Intensive Care, Örebro University Hospital, Örebro, Sweden; and
Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden
Address correspondence to Jakob Walldén, MD, Department of Anesthesia and Intensive Care, Örebro University Hospital, 701 85 Örebro, Sweden. Address e-mail to jakob.wallden{at}tele2.se Address reprint requests to Magnus Wattwil, MD, PhD, Department of Anesthesia and Intensive Care, Örebro University Hospital, 701 85 Örebro, Sweden. Address e-mail to magnus.wattwil@orebroll.se.
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Abstract
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Posture has an effect on gastric emptying. In this study, we investigated whether posture influences the delay in gastric emptying induced by opioid analgesics. Ten healthy male subjects underwent 4 gastric emptying studies with the acetaminophen method. On two occasions the subjects were given a continuous infusion of remifentanil (0.2 µg · kg–1 · min–1) while lying either on the right lateral side in a 20° head-up position or on the left lateral side in a 20° head-down position. On two other occasions no infusion was given, and the subjects were studied lying in the two positions. When remifentanil was given, there were no significant differences between the two postures in maximal acetaminophen concentration (right side, 34 µmol · L–1; versus left side, 16 µmol · L–1), time taken to reach the maximal concentration (94 versus 109 min), or area under the serum acetaminophen concentration time curve from 0 to 60 min (962 versus 197 min · µmol · L–1). In the control situation, there were differences between the postures in maximal acetaminophen concentration (138 versus 94 µmol · L–1; P < 0.0001) and area under the serum acetaminophen concentration time curves from 0 to 60 min (5092 versus 3793 min · µmol · L–1; P < 0.0001), but there was no significant difference in time taken to reach the maximal concentration (25 versus 47 min). Compared with the control situation, remifentanil delayed gastric emptying in both postures. We conclude that remifentanil delays gastric emptying and that this delay is not influenced by posture.
IMPLICATIONS: In healthy volunteers, remifentanil 0.2 µg · kg–1 · min–1 delayed gastric emptying, and there were no differences in this delay between 2 extreme postures (right lateral head-up and left lateral head-down position). Our results indicate that the remifentanil-induced delay in gastric emptying is not influenced by posture.
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Introduction
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The use of IV, epidural, and intrathecal opioids for postoperative pain relief causes a delay in gastric emptying (1–3). This may delay intake of fluids and food and influence the absorption of drugs administered orally. Both systemic and spinal opioids delay gastric emptying (2). This delay may be caused by decreased gastric motility and gastric tone or increased pyloric tone. The pylorus has a rich enkephalinergic innervation, and opioids may therefore increase pyloric tone (4). Posture influences gastric emptying, particularly with prolonged emptying when patients are in a left lateral position (5–7). The use of opioids also increases the risk for postoperative nausea and vomiting (8).
The effects of posture on gastric emptying during opioid administration have not been studied. If posture has an effect, then an optimal position may be found that facilitates gastric emptying and thereby reduces the negative effects. However, if opioids increase pyloric tone, gastric emptying may not be influenced by posture.
Because postoperative opioids are used in most patients undergoing major surgery, the purpose of this study was to evaluate whether posture can influence the delayed gastric emptying induced by an opioid. We compared the effects on gastric emptying of 2 extreme postures in 10 healthy volunteers with and without the administration of remifentanil. The objective for using volunteers was to eliminate other factors (e.g., surgical stress and pain) that influence gastric emptying and study the pure effect of an opioid. As an opioid, an infusion of the ultra-short-acting opioid remifentanil was chosen because of its pharmacological profile with which a predictable and constant effect could be achieved. The acetaminophen method was used to study gastric emptying.
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Methods
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After approval of the study protocol by the ethics committee of the Örebro County Council, 10 healthy male volunteers with a mean age of 23.9 yr (range, 21–31 yr), a mean weight of 80 kg (range, 71–98 kg), and a mean height of 180 cm (range, 173–188 cm) were recruited to the study. The subjects gave their informed consent to participate after receiving verbal and written information. Only men were recruited, because the menstrual cycle may alter gastric emptying (9). None of them was taking any medications, and none had a history of gastrointestinal disturbances. In a randomized order, each subject was studied on four occasions, with at least 1 day between occasions. They were given a continuous infusion of remifentanil on two occasions while lying either on the right lateral side with the bed in a 20° head-up position (RHU) or on the left lateral side with the bed in a 20° head-down position (LHD). On the other two occasions, no remifentanil infusion was given, and the subjects were studied lying in the two positions (RHU and LHD).
The subjects fasted (both liquids and solids) for at least 6 h before each study. An indwelling IV catheter was placed in one arm for the drawing of blood samples. On the occasions when remifentanil was given, an IV line was established in the opposite arm. Remifentanil was administered as a continuous infusion in a dose of 0.2 µg · kg–1 · min–1 and was started 10 min before the ingestion of acetaminophen. The infusion was terminated directly after the last blood sample (120 min) was drawn.
During the study, the usual monitors were used. Heart rate, arterial blood pressure, oxygen saturation, end-tidal carbon dioxide (CO2), respiratory rate, and sedation level were recorded every fifth minute. At the same intervals, the subjects were asked if they were experiencing nausea or any other symptoms. The sedation level was recorded as follows: no sedation = 1, light sedation = 2, moderate sedation = 3, and deep sedation = 4. The visual analog scale (VAS) 0–10 was used for nausea, where VAS 0 was no subjective symptoms and VAS 10 was the worst nausea the subjects could imagine.
If the subject showed signs of excessive sedation, respiratory depression, severe nausea, or vomiting or showed signs of other severe symptoms related to the infusion of remifentanil, the dose was reduced. During the two control situations, heart rate, arterial blood pressure, and sedation level were recorded every 15 min, and the subjects were questioned about nausea. Their level of sedation was checked at the same intervals.
The acetaminophen absorption test was used for measurement of gastric emptying. Acetaminophen 1.5 g dissolved in 200 mL of water was ingested orally, and venous blood samples were taken at 5, 10, and 15 min and then at 15-min intervals for 120 min. When remifentanil was given, acetaminophen was taken orally 10 min after the start of the infusion. Acetaminophen is not absorbed from the stomach but is rapidly absorbed from the small intestine. Consequently, the rate of gastric emptying determines the rate of absorption of acetaminophen administered into the stomach. Serum acetaminophen was determined by an immunologic method including fluorescence polarization (TDx® acetaminophen; Abbott Laboratories; North Chicago, IL). Acetaminophen concentration curves were produced, and the maximal acetaminophen concentration (Cmax), the time taken to reach the maximal concentration (Tmax), and the area under the serum acetaminophen concentration time curves from 0 to 60 min (AUC60) were calculated. Tmax was assumed to be 120 min if no acetaminophen was detected in any sample. The acetaminophen method is a well accepted method for studying the liquid phase of gastric emptying, and AUC60 correlates very well with measures of gastric emptying performed with isotope techniques (10,11).
A prior power calculation was performed and designed to detect differences in AUC60 between the 2 postures when remifentanil was given. On the basis of data from previous studies, the estimated sample size was 10 volunteers with a power of 80% at the 5% significance level.
The results are presented as means with standard deviations. Repeated-measures analysis of variance was used for overall differences between the study situations. If the analysis of variance showed differences, a paired Student’s t-test with Bonferroni’s correction was used for comparisons between the situations. The significance level was set at 5% in all tests.
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Results
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The acetaminophen concentration curves are presented in Figure 1. There were significant differences in AUC60 (P < 0.001), Cmax (P < 0.001), and Tmax (P < 0.001) among the 4 study situations. During the remifentanil infusion, AUC60 was lower, Cmax was smaller, and Tmax was longer in both postures compared with the control situations. During the control situations, there were statistically significant differences, with a higher AUC60 and a larger Cmax in the RHU position. There were no statistically significant differences in AUC60, Cmax, or Tmax between the 2 postures when remifentanil was given (Table 1).
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Table 1. Mean (SD) of AUC60, Tmax, and Cmax in Two Different Body Postures With and Without Infusion of Remifentanil 0.2 µg · kg–1 · min–1
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In 3 subjects (30%), the dose of remifentanil had to be reduced during the study because of side effects (Table 2). Six subjects (60%) experienced nausea, three subjects (30%) vomited, and six subjects (60%) had pruritus during at least one of the remifentanil situations. There was no nausea, vomiting, or pruritus during the control situations (Table 3).
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Table 2. Adjustments of the Initial Dose of Remifentanil 0.2 µg · kg–1 · min–1 in Three Subjects Because of Side Effects
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Table 3. Incidence of Nausea, Vomiting, and Pruritus for Each Posture With and Without Infusion of Remifentanil 0.2 µg · kg–1 · min–1 (n = 10)
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Systolic blood pressure and heart rate were stable in all situations during the study. Arterial blood pressure decreased slightly compared with the initial pressure in all situations, but no further changes were detected. Heart rate decreased in the LHD position when no infusion was given (Table 4).
Respiratory rate decreased in the RHU position, and end-tidal CO2 increased in both positions during the remifentanil infusion (Table 4). There was no change in oxygen saturation. In 7 subjects (70%), the respiratory rate decreased during the remifentanil infusion to <5 breaths/min. After verbally reminding the volunteers to breathe and, for one subject, reducing the infusion of remifentanil, the respiratory rate immediately returned to an acceptable level.
Seven subjects experienced difficulty swallowing during the remifentanil infusion, but the symptom ceased within minutes after the infusion was terminated. Five subjects complained of headache during and after the infusion of remifentanil, and in some subjects the headache persisted for several hours.
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Discussion
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This study has demonstrated that body position influences gastric emptying of fluids, that remifentanil in small doses delays gastric emptying of fluids, and that a change in body position does not influence the delay in gastric emptying induced by remifentanil. During the control situation, the RHU position resulted in faster gastric emptying than the LHD position.
Gastric emptying is influenced by at least three mechanisms—gastric tone, gastric motility, and pyloric tone. The proximal fundus of the stomach functions as a reservoir, and the muscles are adapted for maintaining a continuous contractile tone. The distal antrum/pyloric area of the stomach exhibits phasic and peristaltic contractile activity and functions both as a pump and a grinding mill (12). The tone of the pyloric sphincter regulates the outflow to the duodenum. Consequently, changes in any of these factors will affect the rate of gastric emptying.
There are limited reports on the effects of posture on gastric emptying. Anvari et al. (13) found that gastric emptying of nonnutrient liquids was faster in the sitting position compared with the left lateral position and that even after a delay in gastric emptying induced by atropine there were differences between the positions. The faster emptying in the sitting position before atropine was associated with increased antral peristaltic activity and increased pyloric pressure, but after atropine, no differences in antropyloroduodenal motility could be observed. The mechanism for the change in motility was thought to be due to effects of gravity rather than primarily to changes in motility. Other authors also report that the left lateral position is associated with a delay in gastric emptying (5–7), and our findings are in accordance with these results.
The effect of gravity on gastric emptying is dependent on pyloric tone. Even if posture moves the gastric contents toward the pylorus and there is a high pyloric tone, gastric emptying will be difficult. In the control situation in this study, emptying time was fast in both postures. This indicates that passage through the pyloric region was easy. Opioids decrease gastric tone (14), but even if gastric tone was decreased, gastric emptying would have been facilitated by the RHU position. Because our study showed no significant differences in gastric emptying between the RHU and LHD positions during remifentanil infusion, these results indicate that remifentanil increases pyloric tone and thereby impairs the flow into the duodenum. It has been clearly shown that the pylorus has a rich enkephalinergic innervation (4), which may explain the effect of opioids on pyloric obstruction. No conclusions about gastric motility can be drawn on the basis of the results of our study.
Several studies have demonstrated that both systemic and spinal opioids delay gastric emptying (1,15,16), and these effects are both peripherally and centrally mediated (2). Opioid receptors are present in the gastric tract, and recently developed opioid antagonists such as methylnaltrexone and alvimopan, which do not pass the blood-brain barrier, reverse the opioid-induced inhibition of gastrointestinal motility (17,18).
Opioids pass the blood-brain barrier and have the potential to regulate motility through a central mechanism. The dorsal vagal complex, located in the medullar brainstem, receives sensory information from the gastrointestinal tract through afferent vagal fibers and is also the origin of efferent vagal fibers projecting to the gastrointestinal tract. µ-Opioid receptors have been identified in the synaptic connections within this region, and opioid agonists given locally inhibit gastric motility and decrease gastric tone (19). The role of opioids in the brainstem’s normal physiological control of gastrointestinal motility is controversial, because local injection of the opioid antagonist naloxone has not been found to influence motility per se (20). However, intrathecal morphine has been shown to inhibit motility and delay gastric emptying (2), so clinical studies consequently support the findings that opioids can inhibit motility through a central mechanism.
The respiratory rate decreased and end-tidal CO2 increased during the infusion of remifentanil. CO2 induces relaxation of smooth muscle in vascular beds, but we are not aware of any reports concerning the effects of CO2 on gastrointestinal motility. However, hypercapnia also induces sympathetic stimulation, and the increased sympathetic activity may influence gastric function, with delayed gastric emptying. Soon after the infusion of remifentanil was terminated, the respiratory rate and end-tidal CO2 were normalized.
Half of the volunteers experienced nausea during the remifentanil infusion. Five subjects vomited, but this was late in the study and therefore had no major effect on the acetaminophen study. Opioids are known to cause nausea and vomiting, but the mechanisms are complex. The action is believed to be mediated through activation of the chemoreceptor trigger zone (located in the area postrema) (8).
Sixty percent of the subjects experienced pruritus. Pruritus is often seen after the administration of opioids, particularly after spinal administration, in which there are reports of incidences up to 50% (21).
Remifentanil induced difficulties in swallowing in most volunteers. Swallowing is a complex motor behavior controlled by neuronal networks in the brainstem, and after the administration of intrathecal fentanyl, there are reports of dysphagia (22). This suggests that the mechanism is mediated by a central action.
Even though remifentanil is an ultra-short-acting drug, the subjects complained of headache and late nausea after the infusion was stopped. This is probably not a direct effect of remifentanil and may instead be an effect of the increased CO2 level, with a possible cerebral influence.
Because of the extensive side effects found in volunteers, we do not consider remifentanil a suitable drug for postoperative analgesia. A multicenter evaluation of the use of remifentanil for early postoperative analgesia found an occurrence of adverse respiratory events in 29% of patients (23) and concluded that the technique is probably not practical for routine clinical use.
However, with adequate monitoring, remifentanil is a valuable drug for studying the effects of opioids in experimental setups with volunteers. With this drug, it is possible to study the dose-response effects of opioids.
In conclusion, remifentanil delays gastric emptying, and this delay is not influenced by changes in body posture. During the control situation, the RHU position facilitated gastric emptying.
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Acknowledgments
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The study was supported by grants from the Örebro County Council Research Committee.
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References
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Accepted for publication January 20, 2004.
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Abstract
Introduction
