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Inhibitory Action of Clonidine on Intestinal Peristalsis Is Not Augmented by Co-Administration of Fentanyl, S+ Ketamine, and Midazolam
Susanne Roth-Goldbrunner, M.D.; Michael K. Herbert, M.D.; Peter Holzer, Ph.D.; Norbert Roewer, M.D.
Dept. of Anesthesiology, University of Wuerzburg, Wuerzburg, Germany
Introduction: Inhibition of gastrointestinal motility is a major side effect of alpha-adrenoceptor agonists such as clonidine. To provide sufficient analgosedation in clinical routine clonidine is often combined with potent analgesics such as fentanyl or ketamine or with other sedatives such as midazolam. Since all these drugs exert an inhibitory action on intestinal peristalsis by themselves it is important to know whether the inhibitory action of clonidine on peristalsis is augmented by the co-administration of fentanyl, S+ ketamine, or midazolam.

Methods: Ileal segments of adult guine-pigs were mounted in silanized organ baths that contained oxygenated Tyrode solution (30 ml, 37°C). Prewarmed Tyrode solution was infused into the intestinal lumen, the infusion rate being 0.5 ml/ min. The fluid passing the gut lumen was directed into a vertical outlet tubing which ended 4 cm (reflecting a pressure of 400 Pa) above the fluid level of the organ bath. This arrangement caused gradual filling of the intestine. When the intraluminal pressure reached a threshold, an aborally moving wave of circular muscle contraction, measured as a spike-like increase in intraluminal pressure , propelled the intraluminal fluid to leave the system and thus caused emptying of the segment. The pressure threshold for eliciting peristaltic waves (peristaltic pressure threshold - PPT) was used to quantify the effect of the drugs on peristaltic activity. Inhibition of peristalsis was reflected by an increase of PPT. After recording of normal peristalsis the segments were pretreated with either (i) Tyrode solution (vehicle), (ii) fentanyl (1 or 3 nM), (iii) S+ ketamine (5 or 15 μM) or (iv) midazolam (10 μM) prior to the addition of clonidine (1-100 nM), which was administered cumulatively into the bath, i.e., to the serosal surface of 8 intestinal segments from 8 different guinea-pigs. In another series of experiments 100 nM clonidine or the vehicle (Tyrode solution) was given 20 min before exposure to 10 μM midazolam. For each combination of clonidine with one dose of an analgesic or sedative a concentration-response-curve was constructed and the area under the curve (AUC) for the clonidine-induced increase of PPT was determined. Statistical analysis was performed with the Kruskal-Wallis and Mann-Whitney-U test with a significance level of P<0.05.

Results: The AUC of clonidine induced increase of PPT was not influenced by pre-treatment with 5 and 15 μM S+ ketamine (197±45; 177±35) or 1 and 3 nM fentanyl (162±63; 179±61) compared to the control with vehicle pre-treatment (162±21). Similarly, 10 μM midazolam did not significantly enhance the inhibitory effect of clonidine (540±255 vs. the control after vehicle pre-treatment 289±110). The midazolam induced increase of PPT was also not augmented by clonidine (1578±122) compared to vehicle pre-treatment (1276±80).

Conclusion: The widely used co-administration of potent analgesics such as fentanyl or ketamine or of other sedatives such as midazolam together with clonidine does not enhance the inhibitory effect of clonidine on intestinal motility.

Anesthesiology 2001; 95:A420