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Department of Anesthesiology and Intensive Care, Celal Bayar University, Manisa, Turkey
Address correspondence and reprint requests to Ismet Topcu, MD, Guzelyurt Mah. Ingolstadt Cad., Anadolu Konutlari No:11, 45030 Manisa, Turkey. Address e-mail to topcuismet{at}yahoo.com.
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Abstract |
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Introduction |
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EOS may increase the incidence of duodenogastric reflux, vomiting, and pulmonary aspiration as a result of its inhibitory effect on gastric emptying and intestinal motility (5). Furthermore, EOS decreases biliary, pancreatic, and intestinal secretions and delays intestinal motility (6,7). This is especially important in septic patients, who are unable to tolerate absorptive dysfunction or motility disturbances that can accompany enteral nutrition. Consequently, duodenogastric reflux, colonization with enteric Gram-negative pathogens, or translocation may occur (8,9).
Because of the adverse effects of opioids on the gastrointestinal tract, alternative analgesic drugs that do not have significant effects on gastrointestinal motility may offer advantages, especially for patients with sepsis.
Tramadol, a synthetic analog of codeine, is a centrally acting analgesic with a low affinity for µ-opioid receptors. This affinity of tramadol at µ-opioid receptors is some 6000 times less than that of morphine (10). Tramadol also modifies pain transmission by inhibiting neuronal noradrenaline and serotonin reuptake and by stimulating serotonin release (11,12). Tramadol has an analgesic potency similar to that of meperidine, but it is associated with less respiratory depression than conventional opioids (10).
The present study was designed to determine the effects of the µ-opioid agonist fentanyl and the atypical analgesic tramadol on gastrointestinal transit (GIT) during acute systemic inflammation in an experimental model caused by surgical cecal ligation and perforation (CLP).
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Methods |
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Twenty-four hours after sham laparotomy or CLP, and 20 min before the administration of the charcoal marker, fentanyl 0.036 mg/kg or tramadol 3.5 mg/kg was given to rats in Groups II, III, V, and VI. Rats in Groups I and IV received saline injections at the same time. The drugs or saline were injected at a volume of 10 mL/kg subcutaneously. Figure 1 shows the study design on a time axis.
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A CLP model modified from Wichterman et al. (13) was used to induce sepsis. Rats were anesthetized with halothane, and a 2- to 3-cm midline abdominal incision was performed. After exposure of the cecum, the cecal mesentery was identified and cut through after vascular ligation. The devascularized cecum was punctured with a 20-gauge needle, and a small amount of feces was extracted. The bowel was returned to the abdomen and the abdominal cavity was closed in two layers. A sham operation (abdominal laparotomy and cecal manipulation) was performed on the control rats in Groups I, II, and III.
Body temperature, weight, and mortality were recorded at 24 h before the operation and 6, 12, 18, and 24 h after the operation; a peripheral blood leukocyte count was performed at 24 h before and 12 h and 24 h after the operation. Body temperatures were measured rectally using a digital thermometer (Greisinger Electronic, Bonn, Germany). The differences in body weight at specific time points after surgery were compared to those recorded before surgery.
After dissection of the rats, the degree of peritoneal inflammation was assessed according to Simon et al.'s gradation (14) (Table 1).
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GIT was measured by an intragastric meal consisting of an 0.25-mL suspension of charcoal comprising 10% vegetable charcoal in 5% gum acacia (Sigma Chemical Co, St Louis, MO). Rats were killed 20 min after the administration of the charcoal meal. The stomach and small intestine were resected, and the length of the intestine from the pyloric sphincter to the ileocecal junction (A) and the distance traveled by the charcoal through the intestine (B) were measured. GIT was calculated as the percentage of the distance traveled by the charcoal relative to the total length of the small intestine using the following formula:
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Statistical analyses were performed using Student's t-test for significant differences between two groups. When multiple groups were compared, one-way analysis of variance was used, followed by a Student-Newman-Keuls test whenever applicable. Variance analysis of survival rate, weight, temperature, and leukocyte counts were performed using a repeated-measurements of analysis of variance test. Peritoneal inflammation was analyzed using the 
2 test. A value of P < 0.05 was considered to be significant.
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Results |
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All sham-operated rats survived the experimental procedure until they were killed. In the CLP groups, 20%–30% of the rats died before the planned death 24 h after surgery. Twelve hours after the operation, 4 rats died in Group IV, 5 rats in Group V, and 1 rat in Group VI. After 18 h, one more rat died in Group V, and 3 more rats died in Group VI. Survival rates in the groups are shown in Table 2.
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Before the experiments, body weight ranged from 150 to 200 g. Mean weight loss in Groups I, II, and III was 8.1 g, 7.8 g, and 7.9 g, respectively, over the first 12 h after surgery. Thereafter, body weight increased in these rats until they achieved their initial weight by the end of the experiment. Mean body weight changes in Groups IV, V, and VI were 20.3 g, 26. 4 g, and 22.3 g at 12 h, respectively. Further loss of body weight was observed at 18 h and 24 h. Body weight changes of the groups are presented in Table 3. A significantly larger loss of body weight was observed in CLP groups at 12 h, 18 h, and 24 h compared with preoperative values.
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Before the experimental procedures, the mean body temperature of all rats was 35.67°C. Temperature measurements in sham-operated rats were approximately stable over the entire experiment. Mean body temperatures are demonstrated in Table 3. A significantly larger loss of body temperature was observed in CLP groups at 12, 18, and 24 h compared with preoperative temperatures.
There was also a decrease in peripheral blood leukocyte counts in septic rats at 12 and 24 h after CLP (Table 3).
Peritoneal inflammation was seen in only one sham-operated rat (Groups I–III), whereas all rats in the CLP groups (Groups IV–VI) had at least an abscess or localized peritonitis. The number of rats with high degrees of peritoneal inflammation was significantly larger in CLP groups than sham groups (P < 0.05) (Table 4).
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Discussion |
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Both synthetic and endogenous opioids delay gastric emptying and GIT without the presence of systemic inflammation (7,15,16). Several studies have demonstrated that both systemic and spinal opioids delay gastric emptying (5,17,18) and that the effects are both peripherally and centrally mediated (19). In our study, although no statistical differences were found between the sham + fentanyl group and the sham + saline group, there was a larger decrease in GIT in the sham + fentanyl group, which was attributed to the effect of the opioid.
In the present study, systemic inflammation was induced by CLP. This is a well-characterized animal model of bacterial peritonitis that mimics many of the features of the human form of septic syndrome (20,21).
All CLP-operated rats demonstrated a pronounced clinical response, including significantly increased weight loss and changes in body temperature and leukocyte count compared with baseline measurements. In addition, mortality in the CLP groups was significantly more frequent than in the sham-operated groups. The differences in the degree of peritoneal inflammation were found to be smaller in sham-operated groups when compared with CLP groups.
In experimental studies, it has been shown that endotoxemia causes dose-dependent changes in jejunal transit time (22) and can markedly delay gastric emptying (23). In the present study, GIT was significantly slower in the CLP + saline group than in the sham-operated + saline group, implying sepsis-induced alterations of intestinal motility. With respect to impaired GIT during sepsis, our present study correlates well with the above-mentioned literature (22,23).
Inflammation sensitizes ORs in the myenteric and submucosal plexuses and in peripheral or central terminals and also increases the effects of exogenously administered µ and 
opioids (24). In rats, it has been reported that the inhibitory effect of morphine increases threefold in the presence of intestinal inflammation (25). In another study (26), the same researchers have shown that the GIT-inhibiting effect of fentanyl increases 1.9 times in the presence of intestinal inflammation, indicating EOS activation during local inflammation occurring in the intestinal system. All these studies support the hypothesis that the sensitivity of the ORs increases under conditions of stress. In the present study, GIT decreases were larger in the CLP + fentanyl group than in the sham + fentanyl group. This result suggests that during systemic inflammation, the antitransit effect of opioids also increases, which may be caused by upregulation of EOS in systemic inflammation and in local inflammation. This experimental approach does not allow a quantitative determination of EOP release but, rather, establishes the fact that the antitransit effect of fentanyl increases during systemic inflammation.
A recently published article by Fruhwald et al. (27) showed that endotoxin pretreatment modified peristalsis of the guinea-pig small intestine in vitro over time and that the antipropulsive effect of sufentanil was marginally decreased. Peristalsis was shown to decrease temporarily in rats after treatment with endotoxin. These results seem to contradict our results and those of other studies (24–26). However, in the Fruhwald et al. study, peristalsis was evaluated in vitro. Probably the absence of systemic factors such as vascular disorders and variations in splanchnic circulation, which can inhibit propulsive motility in vivo, are responsible for these contradictory results.
Some studies (28–30) have reported that tramadol has a dose-dependent prolonging effect on GIT, whereas others (31–33) found no effect. But this inhibitory effect of tramadol has been found to be small when compared with other opioids (28).
Wilder-Smith et al. (34) showed that gastric emptying is significantly delayed by morphine in patients who have undergone abdominal surgery, whereas this has not been observed with tramadol. However, both morphine and tramadol have prolonged the orocecal and colonic transit times. It has been stated that direct inhibition of propulsive motility caused by visceral surgery causes delays in colonic transit time. In our study, a statistically insignificant reduction of GIT in the septic group was found with tramadol, whereas fentanyl caused a significant reduction.
In our study, charcoal was used to calculate GIT. This method measures the motor activity of the intestines and also shows total gastric emptying time plus GIT time. Our findings do not give the results of specific regions, such as the stomach or the small or large intestines. With our method, we are not able to reach a conclusion about the colonic transit time. In addition, with regard to the risk of bacterial translocation, the small intestine has long been considered as a reservoir for pathogens, and therefore, assessment of small bowel function might be more important than evaluation of colonic function (35).
In summary, the effects of opioids on gastrointestinal motility and transit time are clinically important. We found that fentanyl caused a statistically significant reduction of GIT, whereas tramadol had no effect on conditions without acute inflammation. Acute systemic inflammation resulted in a significant reduction of GIT. We also found that the antipropulsive effect of fentanyl, a µ-opioid receptor agonist, significantly increased under septic conditions.
Intestinal paresis can have deleterious results, especially in critically ill patients. The results of impaired intestinal motility are intolerance to enteral feeding, increased pulmonary aspiration risk, and colonization of the stomach with enteric Gram-negative organisms. It is important to choose an appropriate analgesic regimen for patients in the intensive care unit. Especially in the presence of sepsis, it is logical and prudent to avoid drugs that may cause intestinal paresis.
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Footnotes |
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This article has been cited by other articles:
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  E A Mayer, S Bradesi, L Chang, B M R Spiegel, J A Bueller, and B D Naliboff Functional GI disorders: from animal models to drug development Gut, March 1, 2008; 57(3): 384 - 404. [Abstract] [Full Text] [PDF]
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