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Original Article

A comparison of the effect on gastric emptying of propofol or dexmedetomidine in critically ill patients: preliminary study

Memiş, D.*; Dökmeci, D.; Karamanloğlu, B.; Turan, A.*; Türe, M.

Author Information
European Journal of Anaesthesiology: August 2006 - Volume 23 - Issue 8 - p 700-704
doi: 10.1017/S0265021506000512

Abstract

Introduction

Lack of enteral nutrition has been shown to be associated with degeneration of gut structure and possible translocation of organisms. The easiest method of feeding the intensive care patient enterally is through a gastric tube. However, gastric emptying is often inadequate in critically ill patients so that nasogastric feeding is not possible and the risk of aspiration of unabsorbed feed is increased.

Sedation is an important part of the therapy of critically ill patients in the intensive care unit (ICU). It reduces anxiety and stress, facilitates sleep, prevents injuries, accidental removal of catheters, reduces resistance to mechanical ventilation of the lungs and decreases oxygen consumption [1,2]. Hypotension, bradycardia, coma, respiratory depression, immunosuppression, paralytic ileus and renal failure are some of the risks of oversedation [2,3].

Propofol is a useful drug for sedation in the ICU. Previous investigations have reported the relaxant effects of propofol on tracheal, vascular and uterine smooth muscles [4–7]. The highly selective and potent α2 agonist dexmedetomidine is an effective agent for sedation and analgesia in the ICU. The α2 agonists reduce vagally mediated gastric and small bowel motility [8]. Electrolyte and water secretion by the large bowel is inhibited by α2 agonists and clonidine has been used successfully in the management of watery diarrhoea [8,9].

Although propofol and dexmedetomidine are widely used for sedation in the ICU, there are limited data on its effects on gastric motility. We aimed to select the least sedative drug on gastric emptying in sedation and enteral nutrition administered patients. In our preliminary study, we aimed to establish whether or not the propofol and dexmedetomidine on effect of gastric emptying is preserved in critically ill patients.

Methods

The Regional Committee on Medical Research Ethics approved the study. Written informed consent was obtained from the patients wherever possible, or from the next of kin. Randomization was achieved according to computer-steered permuted block design. The study was planned as a prospective, randomized, double-blind, placebo-controlled study. The patients were 18–65 yr of age, had no contraindications to enteral feeding and were not fed during the study period. Exclusion criteria were pregnancy, renal failure, age less than 18 yr, patients receiving paracetamol as part of routine clinical management, patients admitted following an overdose of paracetamol and previous adverse reaction to paracetamol. The acute physiology and chronic health evaluation (APACHE II) [10] score was employed to determine the initial severity of illness. Those patients who met the above criteria were enrolled into the study within 4 h of ICU admission.

Gastric emptying was measured indirectly using small bowel absorption of a single bolus of 1.5 g of paracetamol administered via the nasogastric tube [11]. On the day of the study, the absence or presence of bowel sounds was noted by auscultating over the abdomen for 1 min. The patient was placed supine with the head of the bed raised by approximately 30°. After confirming the correct position of the nasogastric tube (flocare pur tube, 12; Nutricia HealthCare S.A., Chatel-St-Denis, Switzerlend), by injecting air down the tube and auscultating over the stomach. This was timed to coincide with the beginning of a 5-h period of nasogastric feeding with the standard feeding preparation Biosorb (Biosorb; N. V. Nutricia, Zoetermer Holland) 50 mL h−1. At the start of the study period the stomach contents were aspired via the nasogastric tube. The residual volume and pH of residual gastric fluid were recorded. Following this, the patient was fed nasogastrically at a rate of 50 mL h−1 Biosorb for 5 h. At the same time 10 mL of arterial blood was removed for measurement of the baseline paracematol concentration. A 100 mL bolus of Biosorb feed was administered directly into the stomach via the nasogastric tube. This was followed by 1.5 g paracematol dissolved in 20 mL of water.

To perform the study in a double-blind fashion, drug solution and infusion set were covered with foil and administered to all patients by a nurse without any knowledge about the study protocol. Patients received either propofol (Propofol 1% Fresenius; Fresenius Kabi, Australia GmbH) 2 mg kg−1 h−1 (n = 12, Group P) or the loading dose infusion of dexmedetomidine (Precedex® 200 μg/2 mL; Abbott, North Chigaco, USA) was 2.5 μg kg−1 h−1 over 10 min followed by a maintenance 0.2 μg kg−1 h−1 (n = 12, Group D) IV over 5-h infusion. The feeding regimen was then continued at 50 mL h−1 for a further 5 h. Arterial blood samples (10 mL) were taken before the study, every 15 min during the first hour and subsequently at 90 min and 2 h for estimations of serum paracetamol concentrations. At the end of the second 5-h period, the feed was again stopped for an hour prior to aspiration of residual gastric contents and measurement of the volume and pH of the aspirate.

The patients were intubated and ventilated during the period of the study. The patients were not administered drugs known to affect gastric emptying (anticholinergic agents, dopamine, beta agonists, gastrokinetic drugs or sedative or opioid drugs) before the study and during the study period. No invasive surgery was performed during the study period and before study. No patients received inotropic agents. No patient suffered significant cardiovascular instability during the study. Glycaemic control was maintained within the normal range using our standard protocol with insulin infusions when necessary.

The rate of gastric emptying is directly proportional to the area under the plot of serum (paracetamol) against time [12]. Paracetamol concentrations were measured using a fluorescence polarization assay (TDx-Abbott; Abbot Laboratories, IL, USA). The assays were performed in the Department of Pharmacology Laboratories at Trakya University. The coefficients of variation of the method at 1.5, 3.5 and 15.0 mg L−1 were 4.92, 3.03 and 3.93%, respectively.

Statistical analysis

Before beginning the study, a power analysis indicated that α was set to 0.01, and β was set to 0.10. This power analysis required minimum nine patients in each group (in our study, 12 patients, in each group) [11]. The area under the paracetamol absorption curve at 120 min (AUC120) was used as the index of gastric emptying. All variables were tested for normal distribution by Kolmogorov–Smirnov test. Independent sample t-test was used for comparison of the means of continuous variables and normally distributed data.

Results

Clinical and patient characteristics are listed in Table 1. Baseline APACHE II (16.10 ± 4.8 and 17 ± 4.72, Group P and D, respectively). They had normal hepatic chemistry (AST 15–41 IU L−1, ALT 14–54 IU L−1, bilirubin 0.4–2 mg dL−1), renal chemistry (urea 10–50 mg dL−1, creatinin 0.6–1.1 mg), and normal electrolytes (sodium 142–145 mEq L−1, potassium 4–4.5 mEq L−1, calcium 8.9–9.2 mEq L−1).

Table 1
Table 1:
Patient and clinical characteristics.

Paracetamol absorption profiles were constructed for each patient studied. The results for all patients are presented in Table 2 as the area under the plasma paracetamol absorption curve at 120 min, measured in mg min L−1 (AUC120), and peak plasma paracetamol concentration, in mg L−1 (Cmax).

Table 2
Table 2:
Paracetamol absorption profiles, gastric residual volumes and pH of gastric residual volumes.

Gastric residual volume measured at the end of the propofol infusion (19.33 ± 11.33) was found to be higher when compared with the volume measured before infusion (11.33 ± 4.84) and after dexmedetomidine infusion (9.17 ± 4.54). There was no difference between groups in gastric emptying time (AUC120 894.53 ± 499.39 and 1113.46 ± 598.09, Groups P and D, respectively) (Table 2). There was no difference between groups in Cmax and pH (Table 2).

Measurement of residual gastric volume before and at the end of each period studied showed no clear correlation with the rate of gastric emptying.

Discussion

We aimed to select the least sedative drug on gastric emptying in sedation and enteral nutrition administered patients and aimed to establish whether or not the propofol and dexmedetomidine effect on gastric emptying is preserved in critically ill patients. Gastric residual volume measured at the end of propofol infusion was found to be higher when compared with the volume measured before infusion and after dexmedetomidine infusion but there was no difference between groups in gastric emptying time.

Critical illness can adversely affect gastrointestinal function. Food in the lumen of the gut is an important stimulus for maintaining splanchnic blood flow and hence mucosal integrity, enteral nutrients thereby exerting a cytoprotective effect throughout the gastrointestinal tract which prevents both atrophy and ulceration [13]. Aside from preventing the establishment of nasogastric feeding, impaired gastric emptying is also associated with gastro-oesophageal and duodenogastric reflux, both of which have been implicated in the development of nosocomial pneumonia [14]. Given these adverse effects of gastroparesis, it is not surprising that there is increasing interest in techniques to measure gastric emptying in the critically ill. The paracetamol absorption test is becoming increasingly popular, presumably because it is relatively easy to perform in the ICU at the bedside. Paracetamol is predominantly absorbed in the small intestine and its absorption depends on the rate of gastric emptying [15]. Given that the paracetamol plasma concentration depends not only on absorption but also on the distribution and metabolism of the drug, the test becomes limited if the latter two are abnormal, for example when hepatic function is deranged by sepsis or there is an increase in its volume of distribution.

Sedation is an important part of the therapy of critically ill patients in ICU. It reduces anxiety and stress, facilitates sleep, prevents injuries, accidental removal of catheters, reduces resistance to mechanical ventilation of the lungs and decreases oxygen consumption [2]. Inhibition of intestinal peristalsis is a major side-effect of drugs used for anaesthesia or for analgesia and sedation of patients in the ICU. Propofol and dexmedetomidine are useful drugs for sedation in the ICU. Although they are widely used for sedation in the ICU, there are limited data on its effects on gastric motility.

Propofol, exhibits an inhibitory effect on spontaneous contractile activity and acetylcholine-induced contraction of human gastric and colonic smooth muscles at clinically relevant concentrations. The mechanism for depression of contraction of propofol on the stomach and colonic tissues is unknown [7]. Studies in vascular smooth muscles suggest that a calcium-related blocking activity is responsible for the relaxation mechanism of propofol [5,16]. It is possible that a similar mechanism may be responsible for the relaxation effects of propofol on stomach and colonic smooth muscle [7]. Lee and colleagues [7] found that, at clinically relevant concentrations, propofol impaired gastrointestinal contractile activity and the use of propofol, especially in the critically ill, need to be evaluated in vivo. McArthur and colleagues [17], in their study with patients who received infusions of propofol and where gastric emptying was assessed by the paracetamol absorption technique found that gastric emptying was not improved in patients with propofol infusion. In our study, gastric residual volume measured at the end of propofol infusion was found to be higher when compared with the volume measured before infusion and after dexmedetomidine infusion. But, there was no difference between groups in gastric emptying time.

The α2-adrenoceptor agonist dexmedetomidine is used in anaesthesia and ICU due its sedative, amnesic, analgesic and anaesthetic properties. Because of the lack of appropriate models, the effect of dexmedetomidine on intestinal peristalsis is unknown. Herbert and colleagues [18] found that clonidine and, much more potently dexmedetomidine, inhibit peristalsis of the guinea pig ileum and the inhibition is caused by interaction with α2-adrenoceptors and, in the case of clonidine, also involved activation of small conductance Ca2+-activated potassium channels and endogenous opioid pathways. Whether central mechanisms contribute to the inhibitory action of α2-adrenoceptor agonists under clinical conditions is speculative. Centrally mediated inhibition of small intestinal motility has been suggested from experiments in rats and mice in which inhibition of propulsion is most potent when clonidine is given intracerebroventricularly [19]. The pharmacological mechanisms behind the peripheral antiperistaltic effect of dexmedetomidine was analysed with a protocol in which transmitter antagonists were tested in parallel with vehicle. Specifically, the possibility that dexmedetomidine inhibits peristalsis by activating inhibitory α1-adrenoceptors on the smooth muscle by activating inhibitory α2-adrenoceptors on excitatory cholinergic pathways such as opioid, purinergic and nitrergic neurons [20,21]. Herbert and colleagues [18] demonstrated that intestinal peristaltis could be suppressed by α2-adrenoceptor agonists through a peripheral site of action on enteric neurons in the gut. In our study, gastric residual volume measured at the end of dexmedetomidine infusion was found to be lower when compared with the volume measured before infusion, but not found statistically significant.

High-gastric residual volumes or aspirates after a period at rest from feeding is used as a marker of gastric intolerance. In general, a range of residual volumes from 50 to 150 mL have been recommended as cut-off points for discontinuation of enteral delivery [22]. In our study, gastric residual volumes was less from 50 mL.

Enteral nutrition is often withheld from critically ill patients due to high-residual gastric aspirates. However, the results of this study show that high-residual gastric volume does not always imply gastric stasis. Other workers were also unable to demonstrate a relationship between residual volumes and gastric emptying [23].

In conclusion, measurement of residual gastric volume before and at the end of each period studied showed no clear correlation with the rate of gastric emptying although gastric residual volume measured at the end of propofol infusion was found to be higher when compared with the volume measured before infusion and after dexmedetomidine infusion. Because of the limited number of patients in our study and the short period of observation, our findings need to be confirmed by larger clinical trials.

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Keywords:

GASTRIC EMPTYING; PROPOFOL; DEXMEDETOMIDINE; CRITICAL ILLNESS; CRITICAL CARE

© 2006 European Society of Anaesthesiology