TitleRemifentanil is a suitable concomitant agent forpropofol during dental outpatient anaesthesiaAuthor(s), Journal, (): -URLhttp://hdl.handle.net/10130/3424Right

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Title Remifentanil is a suitable concomitant agent for propofol during dental outpatient anaesthesia Author(s) 前納, 允

Journal , (): ‑

URL http://hdl.handle.net/10130/3424 Right

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Remifentanil Remifentanil Remifentanil

Remifentanil is a suitable is a suitable is a suitable concomitant agent is a suitable concomitant agent concomitant agent concomitant agent for propofol during dental

for propofol during dental for propofol during dental

for propofol during dental outpatient outpatient outpatient outpatient anaesthesia

anaesthesia anaesthesia anaesthesia

Makoto Maeno

Department of Dental Anesthesiology, Tokyo Dental College

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Summary Summary Summary Summary

The purpose of this study was to examine which might be suitable as a

concomitant agent for propofol general anaesthesia during dental outpatient

anaesthesia. Eighty patients with severe dental avoidance were divided into

one of four groups: propofol/saline solution (PS, n=20), propofol/0.25 µg.kg^-

1.min^-1 remifentanil (PRe-0.25, n=20), propofol/0.125 µg.kg^-1.min^-1 remifentanil

(PRe-0.125, n=20), and propofol/66% nitrous oxide (PN, n=20). By maintaining

the BIS value between 40 and 60, body movement and haemodynamic changes

during the treatment, recovery process following the treatment, process

following discharge, and anaesthetic cost were investigated. Body movements

were observed in all cases in the PS group. Postoperative nausea was observed

in five cases (25%) in the PRe-0.25 group. Although PRe-0.125 and PN groups

were considered clinically available, the PRe-0.125 group was less expensive. In

conclusion, remifentanil (0.125µg.kg^-1.min^-1) is a suitable concomitant agent for

propofol during dental outpatient anaesthesia.

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Introduction Introduction Introduction Introduction

In outpatient anaesthesia, rapid emergence, absence of complications such as

nausea and vomiting and delirium, no pain after treatments, and satisfaction

by the patient as well as low anaesthetic cost, can be considered as conditions

for selecting anaesthetic methods [1]. According to studies on the recovery

process after general anaesthesia on the same patient [2], it has been reported

that the awakening time is longer after anaesthesia with propofol alone than

after anaesthesia with sevoflurane alone, while no difference is seen in the time

for total recovery, and that patient satisfaction is superior after propofol

anaesthesia. However, during treatment under propofol alone anaesthesia,

body movement and haemodynamic fluctuations may be of clinical issues.

There have been reports of the usefulness [3,4] and problems [3,5] of

concomitantly used agents that have an analgesic action, such as nitrous oxide,

fentanyl, remifentanil, or ketamine for controlling noxious stimuli and

haemodynamic fluctuations during propofol anaesthesia. [3-5] However, there

are no reports examining the usefulness and problems of concomitant use of

agents having analgesic action in outpatient propofol anaesthesia under mildly

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invasive conditions such as dental treatment. To examine which might be

suitable as a concomitant agent for propofol general anaesthesia for outpatients

undergoing dental treatment among 0.25µg.kg^-1.min^-1 remifentanil, 0.125µg.kg^-

1.min^-1 remifentanil, or nitrous oxide, we investigated body movement,

haemodynamic changes, postoperative recovery process, degree of satisfaction,

and the anaesthetic cost in patients with severe dental avoidance.

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Method Method Method Method

Subjects

This study was approved by the Ethics Review Board of Tokyo Dental College

Ethics Committee (Approval number 267). The subjects were 80 patients with

severe dental avoidance including those with dental phobia and/or gagging

problems. All subjects gave written informed consent to the study. All subjects

received general anaesthesia for the first time in this department. They were

randomly divided into one of four groups: propofol/saline solution (PS group,

n=20), propofol/0.25µg.kg^-1.min^-1 remifentanil (PRe-0.25 group, n=20),

propofol/0.125µg.kg^-1.min^-1 remifentanil (PRe-0.125 group, n=20), and

propofol/66% nitrous oxide (PN group, n=20). All subjects were classified as

ASA physical status 1 or 2. Exclusion criteria included alcohol or drug

dependent patients, patients with psychiatric diseases, and patients who

underwent invasive treatments such as impacted tooth extraction.

Anaesthesia method

After patients entered the outpatient treatment room without premedication,

they were equipped with an ECG, noninvasive blood pressure (BP), SpO2, and

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bispectral index (BIS) monitor. Thereafter, an intravenous line was established

in the left cephalic vein. Acetated Ringer’s solution was infused at 2-4 ml.kg^-1.h^-

1. Anaesthesia was induced with propofol (1% Diprivan^® injection kit,

AstraZeneca, UK) by using a TCI pump (Terufusion TCI syringe pump TE-371,

TERUMO Corporation, Japan) set to a target effect-site concentration at 3.5

µg.ml^-1 with oxygen inhalation at 6 l.min^-1. Nasotracheal intubation was

facilitated with 0.9 mg.kg^-1 rocuronium bromide (Eslax^® Intravenous solution,

Schering-Plough, USA). Oxygen and nitrous oxide were delivered at 1 l.min^-1

and 2 l.min^-1, respectively, in the PN group during maintenance of anaesthesia.

In the other three groups, oxygen and air were delivered at 1 l.min^-1 and 3

l.min^-1, respectively. Propofol concentration was adjusted to keep BIS value

between 40-60. The administration rate of remifentanil and the inhalation

concentration of nitrous oxide were fixed during the treatment. Patients were

artificially ventilated, and tidal volume and respiratory rate was adjusted to

maintain end-tidal carbon dioxide tension between 35-45 mmHg. When body

movements were observed during the treatment, a bolus injection of 0.2mg.kg^-1

rocuronium bromide was administered. When the mean blood pressure dropped

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to 60 mmHg or less, a bolus injection of 4 mgephedrine hydrochloride was

performed. Local anaesthesia was administered by using lidocaine

hydrochloride solution containing 12.5 µg.ml^-1 adrenaline during dental

treatment such as caries treatment, pulp extirpation, and tooth extraction. An

intravenous injection of 50 mg flurbiprofen axetil was administered at the

completion of anaesthesia. Extubation was performed after confirming

conditions such as recovery of spontaneous breathing, reaction to the verbal

commands, and appearance of the deglutition reflex.

Observation periods and measurements

There were four observation periods: the maintenance period, emergence period,

recovery period, and period after returning home. The maintenance period was

set as the period from induction of anaesthesia to the cessation of

administration of the anaesthetic drugs. Body movements, number of

rocuronium bromide administrations, and total dosage of propofol were

recorded during this period. Changes in blood pressure and heart rate over

time were also observed. Systolic pressure, diastolic pressure, and heart rate at

the time of entry into the treatment room were set as the preanaesthesia

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values. Observations were made at 45 and 90 min after intubation, at the

completion of anaesthesia, and immediately before extubation.

The emergence period was set as the period from the cessation of

anaesthetic drug administration to extubation. The times to recovery of

spontaneous breathing, BIS value reaching 75 [6],eye-opening, and extubation

were observed during this period.

The recovery period was set as the period from extubation to discharge.

The times to ambulation and discharge were observed. Aldrete Score [7] and

modified Post Anesthesia Discharge Scoring System (mPADSS) [8] were

recorded every five minutes, and ambulatory tests were carried out when each

of the scores was 9 or greater. In addition, discharge time was determined on

the basis of the Clinical Discharge Criteria [8].

For the period after returning home, inquiries were made by telephone

about the patient's general condition 24 h after anaesthesia on the basis of a

post-general anaesthesia checklist given to the patient at the time of discharge.

Occurrences and frequency of postoperative nausea and vomiting were

evaluated.

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Anaesthetic cost was estimated by an addition of each anaesthetic value

based on the used amount. Then, anaesthetic cost per anaesthesia time and

body weight was calculated.

Statistical analysis

Repeated measures analysis of variance (ANOVA) and Dunnett's test were

used for intragroup comparisons at the various times of haemodynamic

fluctuations. M × n χ² test was used for comparison of the frequency of occurrence of nausea and vomiting. ANOVA without repeated measures and

the Student-Newman-Keuls test was used for comparison of other

measurements among the groups. P < 0.05 was considered statistically

significant. Twenty patients per group was the target sample size in this study,

because 18 was found to be sufficient for detecting differences with the power at

0.8 in an earlier study [2].

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Results Results Results Results

There were no significant differences in patient characteristics among the four

groups (Table 1).

All patients in the PS group showed body movement during anaesthesia,

while no patients in the other three groups did it. Therefore, the doses of

rocuronium bromide and the amount of propofol were significantly higher in

the PS group than in the other three groups (Table 2).

Systolic pressure, diastolic pressure, and heart rate were significantly

lower at 45 and 90 min after intubation and at the completion of anaesthesia

than those at preanaesthesia period in the PRe-0.25, PRe-0.125 and PN groups.

In contrast, no significant change was observed in the PS group at any time

point (Table 3). Ephedrine hydrochloride was not used in any of the cases.

In the emergence period, the time to the recovery of spontaneous

breathing was significantly longer in the PRe-0.25 and PRe-0.125 groups than

in the PS and PN groups. No significant differences were observed among four

groups in the times to BIS value at 75, eye-opening, or extubation (Table 4).

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In the recovery period, no significant differences were observed in the

time to ambulation and the discharge time among four groups (Table 5).

A significant difference in postoperative nausea was observed among

four groups within 24 h after anaesthesia, and there were five cases (25%) in

the PRe-0.25 group. There were no cases of other complications in any group

following discharge. (Table 5).

The anaesthetic cost was lowest in the PRe-0.125 group (Table 6).

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Discussion Discussion Discussion Discussion

This study examined which was useful among 0.25 µg.kg^-1.min^-1 remifentanil,

0.125 µg.kg^-1.min^-1 remifentanil, and nitrous oxide, when used concomitantly

with propofol in general anaesthesia for outpatients undergoing dental

treatment. Anaesthesia with propofol and 0.125µg.kg^-1.min^-1 remifentanil

completely suppressed body movements without nausea after the treatment,

and was the least expensive.

Body movements were observed during the treatment in the PS group,

and rocuronium bromide was administered in all cases. In contrast, body

movements were completely suppressed by concomitantly using remifentanil or

nitrous oxide with propofol. Propofol increases inhibitory transmission via

GABA receptors and exhibits a hypnotic action without analgesia. Remifentanil

is a µ-receptor agonist and has an analgesic effect nearly comparable to that of

fentanyl [9]. In addition, nitrous oxide exhibits analgesic effects by inhibiting

the function of N-methyl-D-aspartic acid (NMDA) receptors [10] and by

activating α2B adrenoceptors [11]. Body movement was presumably inhibited

because of their analgesic effects which suppressed noxious stimuli not

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inhibited by local anaesthesia, and because of increases in depth of anaesthesia

not reflected in BIS values [12-14]. Approximately 30% decreases in blood

pressure and heart rate was found in both PRe-0.25 and PRe-0.125 groups.

These results agree with past reports indicating that the haemodynamic

inhibition by remifentanil is dose-independent [15]. Remifentanil has been

reported to decrease heart rate and blood pressure through vagotonic and

sympatholytic effects [16]. In this study, ephedrine hydrochloride was not used,

and the severity of haemodynamic inhibition was not of clinical problems. In

addition, nitrous oxide produces haemodynamic activation by a

sympathomimetic effect [17]. However, in this study, haemodynamic inhibition

was also observed in the PN group as in PRe groups. In addition to

haemodynamic stability by the inhibition of noxious stimuli, the increase in

depth of anaesthesia not reflected in BIS values may have inhibited

haemodynamic fluctuations [12-14]. Ephedrine hydrochloride was also not used

in the PN group, and the severity of haemodynamic inhibition was not of any

clinical problems.

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The time to the recovery of spontaneous breathing was faster in the PS

and PN groups. However, this delay was not critical since there were no

sustained effects on subsequent recovery in this study.

The cause of nausea and vomiting by opioids is attributed to stimulations

of central dopamine type 2 (D2) receptors, which in turn stimulates the

vomiting center in the medulla oblongata [18]. Among the opioids, nausea and

vomiting occur less often with remifentanil than with fentanyl [19]. In contrast,

propofol has been reported to reduce postoperative nausea and vomiting by an

antiemetic action mediated by antagonism of D2 receptor mechanisms [4]. In

this study, no nausea was observed in the PRe-0.125 group probably because of

the balance of the opposite pharmacological actions of remifentanil and propofol.

In contrast, nausea was observed in five cases (25%) in the PRe-0.25 group. The

effect of remifentanil on nausea may be dose-dependent. Nitrous oxide has an

emetic action [20]. The antiemetic action of propofol is reported to counteract

the emetic action of nitrous oxide [21,22]. No cases of vomiting and one case

(5%) of nausea in the PN group agrees with previous reports.

(16)

From the results of this study, we found that body movements were

sufficiently inhibited in the PRe-0.125 and PN groups, and that this did not

aggravate the emergence and recovery characteristics of propofol. In addition,

respiratory and haemodynamic depressions were minimal. However, when

anaesthetic cost is considered, PRe-0.125 group was less expensive. Therefore,

as a concomitant medication, 0.125 µg.kg^-1.min^-1 remifentanil was considered

the most useful. In addition, because nitrous oxide also might induce

environmental problems [23,24], 0.125 µg.kg^-1.min^-1 remifentanil may be

considered the most recommendable option.

In conclusion, anaesthesia with a combination of propofol and 0.125

µg.kg^-1.min^-1 remifentanil is suitable for general anaesthesia for outpatients

undergoing dental treatment.

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Acknowledgements Acknowledgements Acknowledgements Acknowledgements

The author would like to thank Associate Prof. Ken-ichi Fukuda, Prof.

Yoshihiko Koukita, and Prof. Tatsuya Ichinohe for their assistance in this

study.

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Competing interests Competing interests Competing interests Competing interests

No Competing interests declared.

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Table 1 Patient characteristics.

No significant differences in patient background among the four groups. Values are the mean (SD).

PS PRe-0.25 PRe-0.125 PN

Number 20 20 20 20

Age; years 31.9 (8.3) 32.3 (7.3) 35.2 (10.5) 35.6 (8.9)

Gender (Male：Female) 11：9 11：9 11：9 10：10

Height; cm 163.3 (6.8) 163.1 (6.8) 162.8 (9.6) 164.8 (10.1) Weight; kg 58.0 (13.6) 57.5 (10.6) 61.2 (15.8) 62.1 (16.6)

BMI 21.4 (4.1) 21.3 (3.5) 22.5 (4.5) 22.3 (4.0)

Duration of treatment; min 241.1 (39.1) 243.6 (57.5) 247.5 (73.0) 257.6 (66.2) Duration of anaesthesia; min 282.9 (37.8) 282.7 (57.4) 286.1 (75.9) 300.1 (75.8)

Number of treated teeth [under local anaesthesia]

9.4 (1.2) [4.5 (1.3)]

9.2 (1.3) [4.4 (1.1)]

9.2 (1.2) [4.3 (1.3)]

8.9 (1.9) [4.0 (1.4)]

PS: propofol/saline solution

PRe-0.25: propofol/0.25 µg.kg^-1.min^-1 remifentanil PRe-0.125: propofol/0.125 µg.kg^-1.min^-1 remifentanil PN: propofol/66% nitrous oxide

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Table 2 Body movements during anaesthesia.

Body movements were seen in the PS group during the procedure. Values are the mean (SD).

Number of cases with body movements 20 0 0 0

Number of rocuronium bromide doses [Total dose of rocuronium bromide; mg]

6.4 (2.0) [72.5±2.4]

0^＊ [0]

Propofol used; mg.kg^-1.h^-1 9.0 (1.4) 7.1 (1.0)^＊ 7.1 (0.6)^＊ 7.5 (1.0)^＊

＊p < 0.05 versus group PS PS: propofol/saline solution

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Table 3 Haemodynamic parameters during anaesthesia.

Haemodynamic parameters during the procedure were significantly lower than the control.

Values are the mean (SD).

preanaesthesia

45min after intubation

90min after intubation

completion of anaesthesia

directly before extubation

SBP

PS 128.3 (24.0) 121.3 (14.6) 116.4 (17.0) 117.7 (17.8) 118.8 (16.8) PRe0.25 122.8 (22.2) 83.3 (8.7)^＊ 85.9 (7.8)^＊ 95.5 (18.0)^＊ 114.7 (14.6) PRe0.125 131.7 (21.9) 87.0 (11.3)^＊ 87.3 (7.8)^＊ 91.5 (13.6)^＊ 122.9 (15.3) PN 119.4 (19.0) 98.1 (15.2)^＊ 94.1 (12.0)^＊ 100.4 (11.6)^＊ 111.4 (20.6)

DBP

PS 79.1 (15.8) 76.7 (11.3) 70.8 (10.5) 70.7 (14.7) 72.2 (13.9) PRe0.25 76.4 (17.5) 49.7 (5.7)^＊ 50.0 (5.0)^＊ 56.7 (11.8)^＊ 73.3 (12.4) PRe0.125 81.4 (18.2) 50.5 (8.7)^＊ 49.2 (9.0)^＊ 51.6 (9.6)^＊ 64.0 (13.9) PN 73.7 (11.3) 58.7 (12.3)^＊ 56.4 (9.8)^＊ 59.3 (8.3)^＊ 69.9 (15.1)

HR

PS 94.4 (19.3) 98.4 (16.5) 92.0 (16.6) 87.2 (12.2) 86.0 (13.0) PRe0.25 87.3 (17.5) 62.2 (9.8)^＊ 56.0 (7.6)^＊ 62.8 (17.4)^＊ 81.2 (14.4) PRe0.125 87.5 (18.4) 64.7 (10.0)^＊ 58.1 (10.6)^＊ 57.3 (9.8)^＊ 82.8 (15.4) PN 86.9 (19.1) 75.6 (10.4)^＊ 70.6 (9.8)^＊ 69.6 (11.8)^＊ 87.0 (17.1)

＊p < 0.05 versus control PS: propofol/saline solution

SBB: Systolic blood pressure DBP: Diastolic blood pressure HR: Heart rate

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Table 4 Emergence profiles.

The time to the appearance of spontaneous breathing was significantly longer in the PRe-0.25 group and PRe-0.125 group than in the PS group and PN group. Values are the mean (SD).

Spontaneous

respiration; sec 255.3 (154.1) 660.8 (358.4)^＊ 647.8 (149.9)^＊ 326.7 (235.9) BIS≧75; sec 634.4 (345.7) 757.9 (344.2) 751.9 (193.7) 744.9 (464.5) Eye opening; sec 670.2 (325.0) 862.7 (430.2) 778.1 (302.2) 825.5 (395.8) Extubation; sec 817.0 (326.2) 1094.8 (475.8) 1010.8 (313.0) 1002.8 (459.6)

＊p < 0.05 versus group PS and PN PS: propofol/saline solution

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Table 5 Recovery profiles.

No significant difference was found among the four groups in the time to ambulation, the discharge time, or patient satisfaction. Postoperative nausea was observed in five cases (25%) in the PRe-0.25 group. Values are the mean (SD).

PS PRe-0.25 PRe-0.125 PN p value

Time to ambulation; min 43.7 (12.5) 51.4 (24.3) 44.3 (16.6) 49.6 (48.7) n.s.

Discharge time; min 193.9 (44.7) 198.2 (47.3) 161.5 (40.6) 169.2 (70.1) n.s.

Incidence of nausea; number 0 5 0 1 p < 0.05

PS: propofol/saline solution

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Table 6 Anaesthetic cost.

The anaesthetic cost was lowest for the PRe-0.125 group. Values are the mean (SD).

1 £ = 150 Japanese Yen

Propofol; £.kg^-1.h^-1 0.26 (0.04) 0.21 (0.03)^＊ 0.21 (0.02)^＊ 0.21 (0.03)^＊ Additional rocuronium bromide