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Acta Anaesthesiol Scand 2008; 52: 969–976 r 2008 The Authors

Printed in Singapore. All rights reserved Journal compilation r 2008 The Acta Anaesthesiologica Scandinavica Foundation

ACTA ANAESTHESIOLOGICA SCANDINAVICA


doi: 10.1111/j.1399-6576.2008.01685.x

Effects of remifentanil on gastric tone


JAKOB WALLDÉN1,2, SVEN-EGRON THÖRN2,3, GREGER LINDBERG4 and MAGNUS WATTWIL2,3
1
Department of Anesthesia, Sundsvall Hospital, Sundsvall, Sweden, 2School of Health and Medical Sciences, Örebro University, Örebro, Sweden,
3
Department of Anesthesia and Intensive Care, Örebro University Hospital, Örebro, Sweden and 4Department of Medicine, Karolinska Institutet,
Karolinska University Hospital Huddinge, Huddinge, Sweden

Objectives: Opioids are well known for impairing gastric tone; we found two distinct patterns of reactions
motility. The mechanism is far from clear and there is wide with both increases and decreases in gastric tone and,
interindividual variability. The purpose of this study was to during the remifentanil infusion, glucagon did not affect
evaluate the effect of remifentanil on proximal gastric tone. gastric tone.
Materials and methods: Healthy volunteers were studied Conclusions: Remifentanil induced changes in gastric tone
on two occasions and proximal gastric tone was measured with both increases and decreases. The effect of remifen-
by a gastric barostat. On the first occasion (n 5 8), glucagon tanil on gastric tone is probably dependent on the current
1 mg IV was given as a reference for a maximal relaxation state of the systems involved.
of the stomach. On the second occasion (n 5 9), remifenta-
nil was given in incremental doses (0.1, 0.2 and 0.3 mg/kg/
min) for 15 min each, followed by a washout period of Accepted for publication 16 March 2008
30 min. Thereafter, remifentanil was readministered, and
Key words: Gastrointestinal motility; gastric tone; analge-
10 min later glucagon 1 mg was given. Mean intragastric
sics; opioid.
bag volumes were calculated for each 5-min interval.
Results: Glucagon decreased gastric tone in all r 2008 The Authors
subjects. Remifentanil had a marked effect on gastric Journal compilation r 2008 The Acta Anaesthesiologica Scandinavica Foundation

P RE-OPERATIVE fasting, bioavailability of drugs


given orally (i.e. pre-medication), gastric reten-
tion with the associated risk of aspiration and the
Gastric tone can be expressed as the length of the
muscle fibers in the proximal stomach. The tone is
not equivalent to pressure. As there is an adaptive
post-operative start of oral intake are examples of relaxant reflex, a volume load can maintain the
issues that are highly dependent on gastric motility. intragastric pressure. Therefore, an almost empty
Gastric motility is often impaired during and after stomach and a full stomach are able to have the
surgery/anesthesia as a result of many contribut- same intragastric pressure, but a different tone. The
ing factors. Opioids, given as part of the anesthesia gastric barostat, which maintains a constant pres-
and the post-operative analgesic regimes, play a sure in an air-filled intragastric bag, measures
major role in this impairment. gastric tone as isobaric volume variations (1).
Gastric emptying, the functional goal of gastric Opioids are well known for impairing gastric
motility, is determined by an integrative motor motility and emptying (2–4). However, knowledge
activity in the stomach. The proximal part of the of the effects of opioids on proximal gastric tone is
stomach acts as a reservoir and exhibits a constant limited and results from published research are
dynamic tone that adapts to the volume load. The divergent (5, 6). There is also little knowledge
distal part of the stomach exhibits a distinct peri- about how the highly potent m-opioid receptor
staltic activity and acts both as a pump towards the (MOR) agonist remifentanil affects gastric motility.
duodenum and as a grinding mill. The primary aim of this study was to evaluate
the effect of the MOR agonist remifentanil on
proximal gastric tone during fasting conditions.
Previous presentations: Parts of the study have been presented as The study was performed in healthy volunteers
abstracts at the Swedish Society of Anesthesiogy and Intensive Cares and the gastric barostat was used to measure
(SFAI) Annual meetings 2002 and 2006 in Örebro, Sweden. gastric tone.

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J. Walldén et al.

Methods in a review article by an international working


team, and the barostat instrument fulfilled the
Following approval of the study protocol by the
criteria determined by this group (9).
Ethics Committee of the Örebro County Council, 10
healthy male volunteers with a mean age of 24
years (range, 19–31 years), a mean weight of 75 kg Procedure
(range, 60–84 kg) and a mean height of 182 cm The subjects fasted for at least 6 h before each study.
(range, 171–185 cm) were recruited into the study. An IV line was established in one arm and an IV-
The subjects gave their informed consent to parti- infusion of 5% buffered glucose 100 ml/h was
cipate after receiving verbal and written informa- given. Before the gastric intubation, the subjects
tion. Only men were recruited, because the received a bolus dose of propofol (0.3 mg/kg IV).
menstrual cycle may alter gastric motility (7). Previous studies in volunteers have shown that this
None of them were taking any medications dose of propofol, which was given at least 30 min
and there was no history of gastrointestinal before the study started, does not influence gastric
disturbances. tone (6). The intragastric bag was folded carefully
Each subject underwent two study protocols on around the gastric tube and positioned in the
two separate days. In the first study, the effect of gastric fundus via oral intubation. Thereafter, the
glucagon on gastric tone was measured. Glucagon gastric bag was unfolded by being slowly inflated
is a potent inhibitor of gastrointestinal motility and with 300 ml of air under controlled pressure
induces a powerful relaxation of the stomach, (o20 mmHg), and the correct position of the bag
resulting in an increase in gastric volume (8). The was verified by traction of the gastric tube.
objectives were to study the effect of glucagon in The gastric bag was completely deflated and
order to obtain an estimate of maximal stomach thereafter inflated with air to a pressure 2 mmHg
relaxation and to test the performance of the gastric above the intragastric pressure. During the study the
barostat system. participants were lying down, positioned on their
In the second study, gastric tone was measured right side, and were asked to relax comfortably. The
during and after a remifentanil infusion and, after a volume and pressure in the gastric bag were con-
washout time of 30 min, also during readministra- tinuously recorded by the electronic barostat and
tion of remifentanil in combination with glucagon. sampled in the computer. The mean gastric bag
Remifentanil is an ultra-short-acting opioid (MOR volume during each 5-min interval was calculated.
agonist) with a predictable and constant effect.

Glucagon study
After 10 min of stable basal gastric tone recording,
Measurement of gastric tone the subjects were given an intravenous bolus dose
Gastric tone was measured by an electronic baro- of 1 mg glucagon. Mean gastric volumes before the
s
stat (SVS ; Synetics AB, Stockholm, Sweden). The injection, and during the time intervals 0–5 min, 5–
gastric barostat is an instrument with an electronic 10 min and 10–15 min after the injection, were
control system that maintains a constant preset calculated. For a schematic illustration of the study
pressure within an air-filled flaccid intragastric protocol, see Fig. 1.
bag by momentary changes in the volume of air
in the bag. When the stomach contracts, the baro-
stat aspirates air to maintain the constant pressure Remifentanil study
within the bag, and when the stomach relaxes, air is After 10 min of stable basal gastric tone recordings,
injected. The pressure in the bag was set at a continuous intravenous infusion of remifentanil
2 mmHg above the basal intragastric pressure. was started. The initial dose was 0.1 mg/kg/min,
The pressure change at which respiration is per- after 15 min the dose was increased to 0.2 mg/kg/
ceived on the pressure tracing – without an in- min and after a further 15 min the dose was
crease or a decrease in the average volume – is the increased to 0.3 mg/kg/min. The infusion was dis-
basal intragastric pressure. The bag, made of ultra- continued after 45 min, following which there was
thin polyethylene, has a capacity of 900 ml and is a washout period of 30 min. Thereafter, remifenta-
connected to the barostat by a double-lumen 16 Ch nil was readministered at a dose of 0.3 mg/kg/min,
gastric tube. The barostat measurements were per- and 10 min later glucagon 1 mg was given intra-
formed following the recommendations presented venously and the remifentanil infusion was

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Remifentanil and gastric tone

Glucagon Study
Propofol Glucagon
0.3 mg ·kg−1 1 mg

−40- − 80 min −10 min 0 min 15 min

Glucagon

Measurement of Gastric Tone

Remifentanil Study
Start Remifentanil
Propofol Start Remifentanil Stop Remifentanil Glucagon
0.3 mg ·kg−1 1 mg Start Remifentanil

−40- − 80 min −10 min 0 min 15 min 30 min 45 min 75 min 85 min 95 min

Remifentanil

Glucagon
Measurement of Gastric Tone

Fig. 1. Schematic illustration of the study design.

continued for a further 10 min. For a schematic Statistics


illustration of the study protocol, see Fig. 1. The results are presented as means with standard
deviations and medians with ranges. Repeated
Monitoring and safety measures ANOVA was used for evaluating overall
During both studies, the usual monitors were used. differences between the study situations. If the
Heart rate, blood pressure, oxygen saturation, end- statistical analysis showed differences, Fisher’s
tidal carbon dioxide (CO2), respiratory rate and PLSD was used for comparisons between the situa-
sedation level were recorded every fifth minute. At tions. For the analysis, the remifentanil study was
the same intervals, the subjects were asked whether divided into two parts. The significance level was
they were experiencing nausea or any other symp- set at 5% in all tests.
toms. The sedation level was recorded as follows:
no sedation 5 1, light sedation 5 2, moderate seda-
tion 5 3 and deep sedation 5 4. A visual analog
Results
scale (VAS) ranging from 0 to 10 indicated used Eight subjects completed the glucagon study and
for nausea, where VAS 0 was no subjective symp- nine subjects completed the remifentanil study.
toms and VAS 10 indicated the worst nausea the One subject (no. 8) did not tolerate the gastric
subjects could imagine. Blood glucose was fol- tube during the glucagon study and terminated
lowed during both studies. In the glucagon study, participation in both study protocols. One subject
blood glucose was measured just before and 15 min refused to participate in the glucagon study after
after the administration of glucagon. In the remi- completing the remifentanil study.
fentanil study, blood glucose was measured during
the baseline period and just before and 15 min after
the administration of glucagon. Glucagon study
If the subject showed signs of excessive sedation, Glucagon induced a significant decrease in gastric
respiratory depression, severe nausea or vomiting, tone (increase in volume) in all subjects (n 5 8)
or showed signs of other severe symptoms related (Table 1 and Fig. 2).
to the infusion of remifentanil, the dose was re- There was a temporary increase in the heart
duced or discontinued. rate after the injection of glucagon [before: 70

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J. Walldén et al.

(6.1) min 1; 0–5 min: 87 (8.7) min 1; Po0.001]; the the subsequent washout period of 30 min (Table 2
other vital variables were normal and stable. Blood and Fig. 2). Four subjects (no. 1, 2, 3, 7) responded
glucose increased after receiving glucagon [before: to remifentanil with a marked increase in gastric
5.4 (1.4) mmol/l; after: 11.1 (2.2) mmol/l; Po0.001]. tone (decreased volume) that decreased during
Five subjects experienced nausea [VAS 4 (2–8)] washout. Four subjects (no. 4, 6, 8, 10) responded
after receiving glucagon. to remifentanil with a marked decrease in gastric
tone (increased volume) and maintained a low
Remifentanil study gastric tone during the washout period. In one
There were variable responses in gastric tone dur- subject (no. 5) gastric tone was almost unaffected.
ing the initial 45-min infusion of remifentanil and The mean gastric tone was significantly lower
during the washout period than before starting
Table 1 the infusion.
Gastric tone in healthy volunteers (n 5 8) studied with a baro- During the initial remifentanil infusion, there
stat. were significant decreases in the heart rate [before:
Mean ANOVA Median 67 (4.9) min 1; minimum during Remi 0.1: 61
(SD) (ml) (range) (ml) (4.6) min 1; Po0.001] and the respiratory rate
Before glucagon [before: 12 (1.8) min 1; minimum during Remi
10 to 5 min 138 (16) 168 (65 224) 0.2: 8 (2.3) min 1; Po0.001] and significant in-
5 to 0 min 156 (20) 158 (68–192)
After glucagon 1 mg Po0.0001 creases in end-tidal CO2 [before: 5.4 (0.3)%; max-
0–5 min 362 (40)* 329 (230–454) imum during Remi 0.3: 7.4 (1.3)%; Po0.001] and
5–10 min 456 (47)* 410 (299–701) sedation level [before: 1 (0); maximum during Remi
10–15 min 448 (50)* 387 (330–714)
0.3: 2 (0.7); Po0.05]. The administration of gluca-
Intragastric bag volumes (ml) after intravenous glucagon 1 mg. gon at the end of the study induced a significant
Change over time evaluated with repeated measures ANOVA. increase in systolic blood pressure [before: 122
Pairwise comparison between the periods with Fisher’s PLSD.
*Significant difference (Po0.05) compared with ‘before gluca- (9) mmHg; after: 137 (22) mmHg; Po0.001], heart
gon 5 to 0 min.’ rate [before: 61 (4.1) min 1; after: 85 (22) min 1;

Fig. 2. Gastric tone measured with a gastric barostat. The curves represent individual intragastric bag volumes during the studies. In the
first part, glucagon 1 mg was given as an intravenous bolus injection. In the second part, remifentanil was given at doses of 0.1, 0.2 and
0.3 mg/kg/min.

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Remifentanil and gastric tone

Table 2
Gastric tone in healthy volunteers (n 5 9) studied with a gastric barostat.
Intragastric bag volumes (ml)
Mean (SD) (ml) Median (range) Interval during Period for volume Repeated
the study measurement measure
ANOVA
Before remifentanil 117 (44) 107 (62–192) 10 to 0 min 5 to 0 min
During remifentanil 0–45 min
0.1 mg/kg/min 156 (170) 114 (1–473) 0–15 min 10–15 min
0.2 mg/kg/min 219 (240) 70 (1–542) 15–30 min 25–30 min P 5 0.0012
0.3 mg/kg/min 250 (291) 59 (0–722) 30–45 min 40–45 min
Washout period 1 320 (276)* 304 (25–785) 45–75 min 55–60 min
394 (237)* 379 (90–820) 70–75 min
Readmin remifentanil
0.3 mg/kg/min 342 (314) 367 (0–856) 75–95 min 80–85 min P 5 0.6
1 Glucagon 1 mg 308 (316) 339 (0–879) At 85 min 90–95 min
Washout period 2 347 (310) 242 (1–839) 95–105 min 100–105 min

Intragastric bag volumes (ml) during infusion of remifentanil and in combination with intravenous glucagon 1 mg.
Change over time evaluated with repeated measures ANOVA. Pairwise comparison between the periods with Fisher’s PLSD.
*Significant difference (Po0.05) compared with ‘before remifentanil.’

Po0.001] and blood glucose [before: 6.2 infusion of remifentanil. However, the gastric tone
(1.1) mmol/l; after: 10.3 (1.1) mmol/l; Po0.001]. was significantly lower (higher volume) after the
One subject (no. 3) became too sedated during infusion of remifentanil compared with the base-
the highest dose of remifentanil and the infusion line period. We believe these are important find-
was discontinued. During readministration, this ings, as they show that opioid effects on human
subject received remifentanil 0.2 mg/kg/min. gastric motility are variable and complex. As ex-
Subjects experienced pruritus (n 5 7), nausea pected, we found that glucagon decreased gastric
[n 5 3, VAS 1 (1–3)], headache (n 5 3) and difficul- tone in all subjects.
ties swallowing (n 5 2) during the remifentanil We have attempted to explain the variability in
infusion. After glucagon, the incidence of nausea gastric tone during the remifentanil infusion. We
increased [n 5 6; VAS 4.5 (2–7)]. do not believe this is due to a methodological
During the readministration of remifentanil, problem with the gastric barostat. During the
there were increases in gastric tone among subjects glucagon part of the study, all subjects responded
with increased tone during the previous remifen- with a clear decrease in tone (increased volume).
tanil infusion. The subject with unaffected tone This validates that the gastric barostat was working
during the previous infusion had an increase in properly; as expected relaxant stimulus, glucagon,
gastric tone. The subjects who maintained a low decreased tone in all subjects. Also, the same
gastric tone during washout continued to maintain barostat equipment and setup have been used in
a low gastric tone. previous studies by our group (6, 10) and we have
Only one subject (no. 5) responded with a de- not observed this kind of variation.
crease in gastric tone after the injection of glucagon There are several limitations in our study. There
during the readministration of remifentanil. was no control group, and we cannot completely
rule out that there was a time effect involved for the
change in gastric tone. However, there was a stable
baseline level in gastric tone before remifentanil,
Discussion and the distinct changes in gastric tone after the
The major finding in this study is the marked effect start of the infusion, as well as the changes after
of remifentanil on gastric tone. We found two discontinuation, are in agreement with the timing
distinctly different patterns of reactions, with about of the pharmacodynamic properties of remifentanil
half of the subjects showing an increase in gastric (11). This provides us with evidence that the effects
tone (decreased volume) and about half of the are mediated by remifentanil.
subjects showing a decrease in gastric tone (in- The number of subjects in this study was small.
creased volume). Owing to this variability, we were We expected a similar response to remifentanil in
not able to statistically prove a response during all subjects, but instead there were two kinds of

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J. Walldén et al.

divergent responses. As this is the first study to set to resemble a gastric load of a meal and in the
describe this dual effect, we consider our observa- second study, baseline was set to fasting condi-
tions as important despite the lack of statistical tions. The stomach wall was probably more dis-
power. Future studies may evaluate the quantita- tended (higher volumes in the intragastric bag)
tive relation between the responses, and the me- before morphine was adminstered in Penagani’s
chanisms behind them, in a larger group of study compared with Hammas’ study, resulting in
subjects. an activated adaptive reflex. This leads to comple-
Basic knowledge about the regulation of gastric tely different baseline conditions. In Penagini’s
tone is needed to explain the effects of opioids. subjects, there were probably low cholinergic and
Proximal gastric tone is an important part of gastric high NANC vagal inputs to the stomach and the
motility and is mainly controlled by the autono- reverse baseline conditions were probably present
mous nerve system. Vagal cholinergic nerves in Hammas’ subjects. This might explain why an
mediate excitation (contraction) while vagal non- MOR antagonist contracted the stomach (through
cholinergic non-adrenergic (NANC) nerves med- NANC inhibition) in one study and relaxed the
iate inhibition (relaxation) (12). Recent studies have stomach (through cholinergic inhibition) in the
identified nitrous oxide as one of the main trans- other study.
mitters in the NANC pathway. In humans, the An interesting finding in Hammas’ study was
NANC pathway is believed to be silent during that the concurrent administration of propofol
fasting conditions and to be activated by the altered the effect of morphine on gastric tone.
adaptive reflex (13). In addition, there are sympa- Propofol per se had no effect on gastric tone, but
thetic adrenergic spinal nerves that inhibit motility after the subsequent administration of morphine,
mainly through cholinergic inhibition (14). gastric tone increased (volume decreased), contrary
Several animal studies have attempted to iden- to the response of morphine alone. We cannot
tify targets for the opioid-induced inhibition of explain the mechanism behind this modulation,
gastric motility. It is widely believed that MOR but there is evidence for central interactions and
agonists inhibit the release of Ach in the stomach modulations between GABAergic and opioid path-
(15), and there is also evidence that MOR agonists ways (20). Other types of modulations of gastric
reduce the relaxation induced by the NANC path- tone have also been described; in animals with an
way (16). Opioids might also have a direct excita- intact vagus nerve, noradrenaline relaxed the prox-
tory effect on gastric smooth muscles (17). Hence, imal stomach while vagotomy reversed this re-
depending on the current state of autonomous and sponse (12).
enteric nerve systems and the main effect site, Can we explain the variable responses seen in
opioids have the potential to both relax and con- our study within this context? Remifentanil is a
tract the stomach. potent MOR agonist and the effect sites are prob-
Opioids also act in the central nervous system ably both at the stomach level and in the CNS. We
(CNS). There is evidence that MORs are present on speculate that the ‘normal’ opioid response during
and inhibit excitatory neurons projecting to gastro- fasting conditions, as seen in Hammas’ study, is a
intestinal motor neurons in the dorsal motor com- decreased cholinergic activity resulting in a de-
plex of the medulla (18). In this way, activation of crease in gastric tone. However, due to the high
central MORs inhibits the excitatory vagal output, potency of remifentanil, direct smooth muscle ef-
leading to inhibition of intestinal transit and in- fects might predominate in some subjects, resulting
duction of gastric relaxation in animal models. In in an increase in tone. Like propofol, remifentanil
humans, there is evidence that opioids inhibit might also have properties that modulate the
gastric motility through a central mechanism (19). opioid response. The focus of these speculations
There are diverging results in the literature is that opioid effects on gastric tone are variable
regarding the effects of opioids on gastric tone in and depend on factors like the state of the subject
humans. Penagini et al. (5) found that morphine and the current status of the neural pathways and
increased gastric tone while Hammas et al. (6) smooth muscles involved. This might be an expla-
reported a decrease in gastric tone. Both studies nation for the variable results in our study.
used the same dose of intravenous morphine As expected, glucagon decreased gastric tone in
(0.1 mg/kg) and both used a gastric barostat. How- all subjects. The effect of glucagon is believed to be
ever, there were important differences between the an indirect inhibition of cholinergic activity (21).
studies. In the first study, baseline gastric tone was Among those subjects who already had a low

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Remifentanil and gastric tone

gastric tone, a further decrease was not expected. 5. Penagini R, Allocca M, Cantu P et al. Relationship between
With the exception of one subject, the administra- motor function of the proximal stomach and transient
lower oesophageal sphincter relaxation after morphine.
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