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© 1999 International Anesthesia Research Society
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Although propofol is widely used for sedation in the intensive care unit, there are limited data on its effects on gastrointestinal motility. For that reason, we studied the in vitro effects of propofol on human gastric and colonic smooth muscle. Grossly normal human gastric and colonic muscle strips were mounted in an organ bath set-up for isometric contraction and stimulated by acetylcholine (Ach), using a cumulative dose schedule in the absence or presence of different concentrations of propofol [1.7 x 10-6 M (0.3 µg/mL) to 4.4 x 10-4 M (78 µg/mL)]. Ach led to concentration-dependent contraction of both gastric and colonic muscle strips, whereas propofol, at a concentration 6.7 x 10-6 M (1.2 µg/mL) and above, significantly depressed Ach-induced contraction in a concentration-dependent manner for both smooth muscle preparations. In addition, propofol, at a concentration 2.7 x 10-5M (4.8 µg/mL) and above, depressed spontaneous contractile activity of both smooth muscle preparations. Fat emulsion 10% (Intralipid®), the solvent for propofol, had no effect on either the spontaneous activity or the Ach-induced contraction of gastric and colonic smooth muscles.
Implications: The success of enteral feeding requires a normal gastrointestinal motility. We found that, at clinically relevant concentrations, propofol impaired gastrointestinal contractile activity. Further investigations are required to determine the clinical significance of this change.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Recognition of improvement in outcome and other benefits of enteral feeding in the critically ill has increased interest in its use compared with parenteral feeding (1). Propofol (2,6 di-isopropylphenol) is a useful drug for sedation in the intensive care unit (ICU) as it allows easy titration and rapid recovery (2). Previous investigations have reported the relaxant effects of propofol on tracheal (3), vascular (4), and uterine smooth muscles (5). However, clinical data on the effect of propofol on gastrointestinal (GI) smooth muscles are limited. Jensen et al. (6) showed that a propofol-based technique resulted in similar impairment of bowel function after major GI surgery when compared with an isoflurane-based technique. However, Hamman et al. (7) showed that gastric emptying of liquids was uninfluenced by light propofol sedation, but, in the same study, orocecal transit time was slightly prolonged. The effects of propofol on GI smooth muscle may have bearing on GI motility, and, therefore, on its use in the ICU. This in vitro study was designed to test the hypothesis that propofol produces dose-dependent depression of GI motility.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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With institutional ethical board approval and written, informed consent, we enrolled into the study patients scheduled to undergo bowel resection for carcinoma of the stomach or colon. Ten patients were recruited for each of the gastric and colonic groups. In all cases, the extent of resection was at the discretion of the attending surgeon. From the resected specimen, we obtained macroscopically normal segments of the descending colonic or gastric fundus muscles. Smooth muscle tissues from these segments were then prepared by dissection from fat and connective tissues and stored in normal saline at 4°C. Experiments were conducted within 24 h. Longitudinal and circular stomach fundus and longitudinal tenia coli muscle strips 15 mm in length and 5 mm in width, denuded of serosa and mucosa were dissected out while in Krebs-Henseleit solution (composition in mM:NaCl-117, KCl-4.8, MgSO4-1.2, KH2PO4-1.2, NaHCO3-25, CaCl2-2.5, and glucose-5.7). The muscle strips were then mounted vertically in a 25-mL organ bath containing Krebs-Henseleit solution, aerated with 95% oxygen and 5% carbon dioxide, and maintained at 37 ± 0.5°C.
The lower end of each muscle strip was fixed to a stationary point, and the top end was tied to a force displacement transducer for isometric measurements of tension. The changes were monitored and recorded on a MacLab/4e system (AD Instruments, Castlehill, Australia). Preliminary experiments were performed on human colon (n = 4) and gastric (n = 4) muscle samples to establish the optimal length, initial resting tone, time for equilibration, and dosing regimen. The optimal initial tone was determined to be 2 g and equilibration time 90 min. The 25-mL organ bath had to be washed out 4 times in order to clear as much of the propofol effects from the organ bath as possible. The time of equilibration and recovery required between experiments was at least 90 min. Muscle strips that did not exhibit spontaneous contractile activity were excluded.
Acetylcholine (Ach) was added to the bath in cumulative concentrations between 2.7 x 10-6 and 5.4 x 10-3 M, with an average contact time of 40 s for each dose, and a concentration response curve was obtained (n = 10 for human gastric and colonic smooth muscles). The maximal contraction for each strip of muscle was used as a contraction reference. Subsequent contractile responses were measured as a percentage of this control maximum. The Ach concentration-response profile formed the control curve for comparison with the preparations pretreated with propofol and fat emulsion (Intralipid®).
Different concentrations of propofol [1.7 x 10-6 (0.3), 6.7 x 10-6 (1.2), 2.7 x 10-5 (4.8), 1.1 x 10-4 (19), and 4.4 x 10-4 M (78 µg/mL)] were added to the organ bath and allowed to equilibrate for 10 min before cumulative doses of Ach (2.7 x 10-6 to 5.4 x 10-3 M) were added. To eliminate the effects of the solvent for propofol, gastric and colonic muscle strips (n = 10 for each group) were exposed to the solvent of propofol, Intralipid® 10% 0.2 mL, a volume equivalent to the maximal concentration of propofol followed by Ach dosing as above. Each strip of muscle was used only once to study the effect of Intralipid® and five different concentrations of propofol. To observe any effect of propofol on spontaneous contractile activity and the tone of GI muscles, gastric and colonic muscle strips (n = 5 for each group) were exposed to different concentrations of propofol (as above) for up to 30 min.
Propofol 1% (molecular weight 178) was used as supplied (i.e., 1% emulsion of 10% soya bean oil, 2.25% glycerol, and 1.2% purified egg phosphatide in water). The vehicle for propofol was Intralipid® 10%. Ach (molecular weight 147) was from Sigma (St Lois, MO). The compounds were dissolved and diluted in physiologic saline. Dilutions of drugs were made fresh for each experiment and kept on ice.
The maximal force of contraction with Ach for a particular strip of muscle was taken as 100%. All other measurements of changes in contraction force for that muscle strip were calculated as a percentage of this maximum. Measurements from different strips of the same patient were averaged before use for analysis.
The values were expressed as mean ± SEM. The statistical analysis of Ach-induced contractions was accomplished by using two-way analysis of variance with Dunnett’s test for multiple comparisons (SPSS 7.5 software package, SPSS Inc., Chicago, IL) with the criteria that P < 0.05 is significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Ach, when added cumulatively between concentrations 2.7 x 10-6 and 5.4 x 10-3 M, enhanced spontaneous activity and led to a concentration-dependent increase in contraction of both gastric and colonic smooth muscles (n = 10). (Fig. 1). Intralipid® 10% had no effect on spontaneous contractile activity, resting tone, or Ach-induced muscle contraction. Five individual propofol concentrations (1.7 x 10-6, 6.7 x 10-6, 2.7 x 10-5, 1.1 x 10-4, and 4.4 x 10-4 M) had no effect on resting tone of both gastric and colonic muscle strips (n = 5 each) when the incubation period was lengthened to 30 min. However, propofol, at a concentration 2.7 x 10-5M and above, demonstrated some depression of the spontaneous contractile activity of both gastric and colonic muscle strips (Fig. 2).
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Ten minutes after the addition of a concentration of propofol (no effect was demonstrated on the spontaneous activity of the smooth muscles), cumulative doses of Ach 2.7 x 10-6 to 5.4 x 10-3 M were added (n = 10 at each concentration of propofol or Intralipid® 10%). A concentration-dependent depression of gastric and colonic smooth muscles was observed. At propofol concentrations 6.7x 10-6 M and above, the contractile response to Ach was significantly reduced for both gastric and colonic muscles (P < 0.05) (Fig. 3). Propofol induced a similar pattern of depression in both Ach-stimulated gastric and colonic muscles.
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) Control; (
) Intralipid® 10% 0.2 mL; X-X Propofol 1.7 x 10-6 M; (
) Propofol 6.7 x 10-6 M; + - + Propofol 2.7 x 10-5 M; (
) Propofol 1.1 x 10-4 M; 
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our findings show that propofol exhibits an inhibitory effect on spontaneous contractile activity and Ach-induced contraction on human gastric and colonic smooth muscles at clinically relevant concentrations. This is similar to the known relaxant effects of propofol on other smooth muscle tissues, such as the tracheal (3), vascular (4), and uterine smooth muscles (5). The concentration response curves of Ach on gastric and colonic smooth muscles pretreated with various concentrations of propofol show that the depression was significant at 6.7 x 10-6 M of propofol and above (Fig. 3). In addition, propofol, at a concentration 2.7 x 10-5 M and above, depressed spontaneous contractile activity after an incubation time of 30 minutes (Fig. 2). These concentrations of propofol lie within therapeutic blood concentrations for sedation in the ICU (up to 72 hours) of 2 µg/mL (3.3 x 10-6M) (8) and for total IV anesthesia of 4.1 µg/mL (2.2 x 10-5M) (9).
A clinical study involving human volunteers lightly sedated with propofol demonstrated a significant increase in the orocecal transit time (6). However, the duration of infusion in this study was short (30 minutes) and does not reflect the blood and tissue levels of long-term infusion. Propofol, when given as an infusion for a duration of 99 minutes, has a short elimination time of 116 ± 34 minutes (9). During longer periods of infusion (over days), the terminal elimination phase has been found to be prolonged (T1/2= 1878 ± 672 min) (8), the volume of distribution is extensive (1666 ± 756L), and there may be accumulation in a deep compartment (8,9). This would allow for the possibility of tissue accumulation, tissue contact, and effect on motility.
The mechanism for depression of contraction of propofol on the stomach and colonic tissues is unknown. There was a reduction in the maximal response attainable in the presence of propofol 6.7 x 10-6 M and above. The curves do not resemble those of the competitive antagonist, atropine, which causes a parallel shift of the curve to the right but has the same maximal response (10). Studies in vascular smooth muscles suggest that a calcium-related blocking activity is responsible for the relaxation mechanism of propofol (4,11). It is possible that a similar mechanism may be responsible for the relaxation effects of propofol on stomach and colonic smooth muscles.
However, it is difficult to translate organ bath concentrations and in vitro conditions to in vivo conditions, in which concentrations at tissue or cell level, plasma protein binding, tissue transfer, and compartment kinetics play important roles. Furthermore, multiple other factors in the intact stomach contribute to the complex physiology of gastric and colonic motility (12). These would include mechanical and gastroenteric reflexes, hormonal influences, and input via neural pathways from higher centers of taste and smell. Such influences in the intact human may surmount the depressing influence of propofol on gastrointestinal contractility.
Another limitation of this study was that the specimens were obtained from selected areas of the GI tract. The gastric specimens were obtained from the fundus; this was necessary to ensure an adequate tumor-free margin as carcinoma of the stomach commonly occurs in the antrum. The antrum and pylorus are more active in gastric emptying and are areas in which the musculature is more developed. However, gastric emptying of liquids, but not solids, is controlled mainly by the gastric fundus. Similarly, the colonic tissues were obtained from the descending colon because of the relative frequency of sigmoid tumors. It is arguable whether the nature of muscle activity in these areas is representative of the entire viscera, which perhaps limits the anatomical area of inference from our study. The division of circular and longitudinal fibers is less well defined in the stomach fundus, and obtaining transverse or longitudinal strips makes little difference in this area (12). The colonic tissues longitudinal and circular muscles would include the muscularis externa in this area (12). The longitudinal tenia coli muscles were obtained from here to facilitate consistency of sampling.
In conclusion, in vitro propofol exhibits inhibitory effect on spontaneous contractile activity and concentration-dependent depression of Ach-induced contraction on human gastric and colonic smooth muscles. The clinical relevance of these findings on GI motility and their implications for the use of propofol, especially in the critically ill, need to be evaluated in vivo.
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Acknowledgments |
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This study was supported by National Medical Research Council, Singapore.
The authors would like to thank Ms. Karen Ho for technical assistance and Dr. Dong for his help with the statistical analysis.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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- Kearney PA, Annis K. Perioperative nutrition support in critical illness. Curr Opin Anaesth 1994;7:305–9.
- Newman LH, Macdonald JC, Wallace PGM, Ledingham IM. Propofol infusion for sedation in the intensive care. Anaesthesia 1987;142:929–37.
- Lee TL, Adaikan PG, Lau LC, et al. Effects of propofol on guinea pig respiratory smooth muscles. J Anesth 1995;9:265–70.
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Chang KSK, Davis RF. Propofol produces endothelium dependent vasodilation and may act as a calcium channel blocker. Anesth Analg 1993;76:24–32.
[Abstract/Free Full Text] - Lee TL, Adaikan PG, Lau LC, et al. Effects of propofol on gravid human uterine muscle. J Anesth 1997;11:71–4.
- Jensen AG, Kalman SH, Nystrom PO, Eintrei C. Anesthesia technique does not influence postoperative bowel function: a comparison of propofol, nitrous oxide and isoflurane. Can J Anaesth 1992;39:938–43.[Web of Science][Medline]
- Hamman B, Harvarfner A, Thorn E, Wattwil M. Propofol sedation and gastric emptying in volunteers. Anaesthesiol Scand 1998;42:102–5.
- Albanese J, Martin C, Lacarella B, et al. Pharmacokinetics of long term propofol infusion used for sedation in ICU patients. Anesthesiology 1990;73:214–7.[Web of Science][Medline]
- Shafer A, Doze VA, Shafer SL, White PL. Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. Anesthesiology 1988;69:348–56.[Web of Science][Medline]
- Kerr PM, Hillier K, Wallis RM, Garland JC. Characterization of muscarinic receptors mediating contractions of circular and longitudinal muscle of human isolated colon. Br J Pharmacol 1995;115:1518–24.[Web of Science][Medline]
- Wallerstedt SM, Bodelsson M. Effects of propofol on isolated human omental arteries and veins. Anaesth 1997;78:296–300.
- Gray H. Splanchnology. In: Williams PL, Warwick R, eds. Grays anatomy. 36th ed. Edinburg:Churchill Livingston, 1980:1336–63.
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