Effect-site concentration of remifentanil for preventing cough during emergence in elderly patients undergoing nasal surgery: a comparison with adult patients
Clinical Interventions in Aging
effect-site concentration of remifentanil for preventing cough during emergence in elderly patients undergoing nasal surgery: a comparison with adult patients
Ji Young Yoo 1
Jong Yeop Kim 1
Yun Jeong Chae 1
0 Department of Anaesthesiology and Pain Medicine, g achon University, g il Medical Center , Incheon , Korea
1 Department of Anaesthesiology and Pain Medicine, Ajou University school of Medicine , suwon
PowerdbyTCPDF(ww.tcpdf.org) hyun Jeong Kwak 2 Dong Chul lee 2 go Wun Kim 1 sook Young lee 1 Purpose: Prevention of cough during emergence after nasal surgery is important for avoiding surgical site bleeding. We investigated the remifentanil effect-site concentration in 50% (EC50) of the elderly patients undergoing nasal surgery for smooth emergence without cough and compared it with that of adult patients. Methods: Twenty-two elderly (aged 65-80 years) and 25 adult patients (aged 20-60 years) with an American Society of Anesthesiologists physical status I/II undergoing nasal surgery were enrolled. Anesthesia was maintained with sevoflurane and remifentanil. Remifentanil EC50 and EC95 for preventing cough were determined using the modified Dixon's up-and-down method and isotonic regression with bootstrapping approach. Recovery profiles were also recorded. Results: With Dixon's up-and-down method, the EC50 of remifentanil in elderly patients (2.40±0.25 ng/mL) was not significantly different from that of adults (2.33±0.30 ng/mL) (P=0.687). With isotonic regression, the EC95 of remifentanil in elderly patients (3.32 [95% confidence interval: 3.06-3.38] ng/mL) was not significantly different from that of adults (3.30 [95% confidence interval: 2.96-3.37] ng/mL). However, eye opening time (14.1±3.8 vs 12.0±2.9 seconds), extubation time (17.2±4.1 vs 14.0±3.0 seconds), and postanesthesia care unit duration (44.5±7.6 vs 38.7±3.4 minutes) in elderly patients were significantly longer than those in adults (P,0.05). Conclusion: Remifentanil EC50 for preventing cough after nasal surgery with sevoflurane anesthesia did not differ between elderly and adult patients. However, delayed awakening and respiratory adverse events may warrant attention in elderly patients.
sevoflurane; cough; remifentanil; elderly; extubation
open access to scientific and medical research
Cough suppression during emergence and tracheal extubation after general anesthesia
has become an important issue in patient safety. Cough due to mechanical irritation of
the endotracheal tube and cuff can be accompanied by various adverse effects such as
laryngospasm, hypertension, tachycardia, arrhythmia, and an increase in intracranial,
intraocular, or intra-abdominal pressure.1 Consequently, this can lead to myocardial
ischemia, disruption of wound, and bleeding at the surgical site. Alongside medical
development, an increasing number of elderly patients undergo surgery and exhibit
a greater prevalence of cardiovascular disease than younger patients.2,3 Therefore,
the application of agents for cough suppression during emergence should be
Clinical Interventions in Aging 2016:11 1247–1252 1247
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Remifentanil is a selective μ-receptor opioid agonist with
a very rapid onset time. Its extrahepatic metabolism by
nonspecific esterase results in rapid clearance.4,5 Maintenance of
remifentanil infusion during emergence has been reported to
be an effective method for reducing cough and cardiovascular
change without delay of recovery.6,7 In previous studies, the
effective effect-site concentration for 95% of adults (EC95)
for preventing cough has been shown to vary according to
anesthetic agent, type of surgery, and patient sex, and is
ranging from 2.14 to 2.94 ng/mL.8–10
The aging process may alter not only the
pharmacokinetics and pharmacodynamics,11,12 resulting in potentially
variable responses to anesthetic drugs (likely increase in
sensitivity), but also cough reflex.13 The hypothesis of this
study is that altered pharmacokinetics and cough sensitivity
in elderly patients may require the titration of remifentanil
target controlled infusion (TCI) for cough suppression during
emergence. To the best of our knowledge, no studies to date
.vdoepww l.syoeun hpraevsesicoonnfiinr
:s an is to determine the effect-site concentration of remifentanil
tthp rseo in 50% (EC50) of elderly patients undergoing nasal surgery
from ropF for cough suppression during emergence after balanced
ded anesthesia with sevoflurane and remifentanil. In addition,
laon we have compared the difference in effect-site
concentradow tion of remifentanil and recovery profiles between elderly
ign and adult patients.
Patients and methods
Approval was obtained from the Institutional Review
Board of Ajou University Hospital (Suwon, Korea), and
the study was registered with ClinicalTrials.gov (NCT No:
02334046). All patients provided informed written consent.
Twenty-two elderly patients (aged 65–80 years) and 25 adult
patients (aged 20–60 years) with an American Society of
Anesthesiologists physical status I or II undergoing nasal
surgery (endoscopic sinus surgery or septoplasty) were
enrolled in this study. The following patients were excluded
from the study: those with predicted difficult airway, body
mass index .30 kg/m2, history of obstructive sleep apnea,
chronic respiratory disease or coughing, current smokers, and
angiotensin-converting enzyme inhibitor users.
Patients were not administered with any premedication. Upon
arrival in the operating theater, all patients were monitored
via electrocardiography, pulse oximetry, automated
noninvasive blood pressure measurement, and bispectral index (BIS)
using the BIS™ Quatro Sensor (Covidien, Boulder, CO,
USA) applied to the forehead of each patient. After
preoxygenation with 100% oxygen for 1 minute, anesthesia was
induced with a bolus injection of 1.5–2.0 mg/kg propofol
and 2.0–3.0 ng/mL effect-site concentration of remifentanil
via a TCI system (Orchestra®, Fresenius Vial, France) using
Minto’s model.14 After loss of consciousness, 0.6 mg/kg
rocuronium was injected and then intubation was performed
with a cuffed endotracheal tube (internal diameter 7.5 mm for
males and 7.0 mm for females). The intracuff pressure was
adjusted to 20–25 mmHg using a pressure gauge (Hi-Lo Hand
Pressure Gauge, VBM Medizintechnik, GmbH, Germany).
Anesthesia was maintained with 1.5–2.5 vol% sevoflurane
and 2.0–4.0 ng/mL of remifentanil to target a BIS between
40 and 60, and a mean blood pressure and heart rate within
20% of baseline values. Mechanical ventilation was adjusted
to maintain an end-tidal CO2 between 35 and 40 mmHg
using 0.5 fraction of inspired oxygen. Corticosteroids which
could affect the results were not administered during surgery.
Approximately 15 minutes before the end of surgery,
sevoflurane was adjusted to 1–1.2 vol% to achieve a BIS of ~60,
and remifentanil was set at the predetermined effect-site
concentration for obtaining equilibrium between plasma and
effect-site at the time of surgery completion. After surgery,
sevoflurane was discontinued and 0.004 mg/kg
glycopyrrolate and 0.02 mg/kg neostigmine were injected for reversal
of residual muscle relaxation after achieving a train-of-four
ratio of 0.9. Oropharyngeal suction was gently performed
before injection of reversal agents. Mechanical ventilation
was switched to manual ventilation to maintain an end-tidal
CO2 between 40 and 45 mmHg. Extubation was performed
when patients were able to open their eyes on command
and following the recovery of adequate spontaneous
ventilation. Immediately after extubation, remifentanil infusion
was stopped and 100% oxygen was administered via a face
mask for 5 minutes. The presence of cough was recorded
by the investigator who was unaware of the concentration
of remifentanil. After confirmation of consciousness and
adequate respiration, patients were transferred to the
postanesthetic care unit (PACU). In the PACU, fentanyl 1 μg/kg
was administered when the pain score exceeded 5 points on
the numerical rating scale. Patients were discharged from
the PACU when Aldrete score was $9.15
Determination of effect-site
concentration and recovery profiles
The Dixon’s up-and-down method was used to determine
the effect-site concentration of remifentanil for cough
suppression during the emergence period (in the presence of
endotracheal tube, during tracheal extubation, and 5 minutes
after extubation).16 If coughing occurred during the
emergence period, it was considered a failure of cough
suppression. The initial effect-site concentration of remifentanil was
1.8 ng/mL. In the next patient, the effect-site concentration
of remifentanil was determined by the success or failure of
cough suppression of the previous patient. If cough
suppression was a success, then the effect-site concentration
of remifentanil was reduced by 0.4 ng/mL, while in case
of failure it was increased by 0.4 ng/mL. The
remifentanil EC50 of patients, which enabled successful cough
suppression, was determined by calculating the mean of
the midpoint effect-site concentration of all independent
pairs after six crossover points were obtained (ie, success
Hemodynamic data and respiratory profiles were recorded
before anesthesia induction (baseline), at the end of surgery,
at eye opening, immediately after extubation, and 5 minutes
after extubation. The eye opening and extubation times were
also measured and events of hypoventilation ,8 breaths/min
or oxygen saturation (SaO2) below 95% were recorded.
The sample size was decided based on prior literature about
the modified Dixon’s up-and-down method. To minimize the
inaccuracy of the individual study, more than the minimum
six crossover points are required in this method.17
Statistical analyses were performed using the Statistical
Package for Social Sciences (version 20.0 for Windows;
IBM Corporation, Armonk, NY, USA) and R for Windows
(version 3.0.1; The R Foundation for Statistical Computing;
https://www.r-project.org). The EC50 calculated from the
modified Dixon’s up-and-down method was compared
between the two patient groups using a t-test. For backup
analysis, the data were analyzed using the isotonic
regression method to estimate EC50 and EC95 along with 95%
confidence intervals (CIs). The isotonic regression is a variant
of restricted least squares regression to constrain the point
estimates to either increase or decrease monotonically, which
has favorable statistical properties.18 The CI was estimated
using the bootstrapping approach.18 All other variables were
compared between groups using an independent t-test,
chisquare test, Fisher’s exact test, or Mann–Whitney U statistic,
where appropriate. Hemodynamic data were analyzed
with repeated measures of analysis of variance. Data were
presented as the mean ± standard deviation or the number
of patients. Statistical significance was accepted when the
P-value was ,0.05.
In total, 47 patients completed the study (Figure 1). The
elderly patient group comprised 22 patients with a mean age
of 69 (range: 65–80 years) and the adult patient group
comprised 25 patients with a mean age of 35 (range: 20–60 years).
Patient characteristics are presented in Table 1. There were
significantly more patients in the elderly groups with an
American Society of Anesthesiologists physical status of II
than in the adult group (P,0.001). During mask ventilation
and intubation, there was no unpredicted difficult airway.
The sequence of dose–response data for each patient is
.vdoepww l.syoeun shown in Figure 2. Using the modified Dixon’s up-and-down
//w l method, the EC50 of remifentanil was not significantly
dif:s an ferent between the elderly and adult groups (2.40±0.25 vs
tth re 2.33±0.30 ng/mL, respectively, P=0.687). With isotonic
from ropF regression and the bootstrapping approach, the EC50 of
daed remifentanil was similar between the elderly and adult
lon groups (2.50 [95% CI: 2.38–2.75] ng/mL and 2.52 [95% CI:
dow 2.29–2.78] ng/mL, respectively). The EC95 of remifentanil
iggn was also similar between the elderly and adult groups (3.32
inA [95% CI: 3.06–3.38] ng/mL and 3.30 [95% CI: 2.96–3.37]
itvsoenn ng/mRLec,orevsepreyctpivreolfyil)e.s are presented in Table 2. While
liilItrcane tshitee ncuomncbeenrtroaftiopnatioefntrsempriefesnentatninilg
were similar between patient groups, eye opening time
(14.1±3.8 vs 12.0±2.9 seconds), extubation time (17.2±4.1
vs 14.0±3.0 seconds), and PACU duration (44.5±7.6 vs
38.7±3.4 minutes) in the elderly group were significantly
longer than those in the adult group (all P,0.05). There
were no significant differences in pain score and additional
analgesic requirement in the PACU between groups.
There were no significant differences in hemodynamic
data between elderly and adult patient groups (data not
shown). In the present study, the highest concentration of
remifentanil used was 3.4 ng/mL and the lowest concentration
was 1.8 ng/mL. Hypoventilation (,8 breaths/min, respiratory
rate) occurred in 8/22 (36%) patients in the elderly group and
6/25 (24%) patients in the adult group. Oxygen desaturation
(SaO2 ,95%) occurred in one patient in the elderly group, but
did not occur in the adult patient group. While these adverse
events occurred more frequently in the elderly group, there
were no significant intergroup differences.
Our results showed that maintaining remifentanil during
emergence was an effective method for smooth emergence and the
required effect-site concentration of remifentanil in elderly
patients was not different from that of the adult patients.
Previous studies have investigated the EC50 and EC95
of remifentanil TCI for cough prevention in various
surgeries.8,9 Choi et al8 reported the EC50 and EC95 of
remifentanil at 2.17 and 2.94 ng/mL, respectively, in males
aged 18–60 years (median age 35 years) undergoing nasal
surgery after balanced anesthesia with sevoflurane. These
results are comparable to the present findings. Our study
demonstrated that the EC50 of remifentanil in adult and
elderly patients was 2.33 and 2.40 ng/mL, respectively,
without significant intergroup differences. In another study,9
the EC95 of remifentanil TCI was 2.51 ng/mL in patients
(aged 20–65 years; mean: 43 years) undergoing
transsphenoidal surgery during propofol and remifentanil anesthesia,
using biased coin up-and-down sequential allocation and the
isotonic regression method.
T h e e f f e c t o f a g i n g o n c o u g h r e f l e x r e m a i n s
controversial.13,19,20 A previous study demonstrated that the
sensitivity of cough reflex significantly decreased in the
elderly patients compared with that in the young patients,13
whereas other studies failed to detect this association.19,20
The aging process may also alter pharmacokinetics and
pharmacodynamics,11,12 and can affect clinical responses to
drugs. In general, the elderly are expected to be more
sensitive to many drugs, especially opioids. Sensitivity to
remifentanil has been reported to be high in elderly patients.14,21 The
TCI of remifentanil is age variable-adjusted because Minto’s
model was based on the electroencephalogram (EEG) effect
of remifentanil using a three-compartment model with height,
weight, and age as covariates.14
The present study demonstrated that there was no
agerelated difference in the effect-site concentration of
remifentanil for cough suppression during emergence. This suggests
that remifentanil TCI using Minto’s model is appropriate to
predict the clinical performance on cough suppression;
therefore, there is no need to reduce the effect-site concentration of
remifentanil in the elderly. The antitussive effect of narcotics
appears to be via opioid receptors such as μ- and κ-receptors22,23
and, at the subtype level, the antitussive effect of μ-receptors
is depressed via μ2-receptors.24 However, the opioid receptors
involved in the EEG effect in Minto’s model may be different
from those involved with antitussive action. Therefore, the
explanation for the good clinical performance is unclear.
In contrast, recovery profiles such as eye opening time,
extubation time, and PACU duration differed between
elderly and adult patients in the present study. Although the
clinical significance of the prolongation of recovery in the
elderly group was relatively minor, it should be treated with
caution to some extent. This difference between the elderly
and adult patients may be due to several reasons. First, the
reduced predictive clinical performance of Minto’s model of
remifentanil TCI on recovery profiles. As mentioned earlier,
Minto’s model is based on the EEG effect of remifentanil;14
therefore, the influence of age on other clinical variables
such as respiration and analgesia may be different. Second,
the interpatient variability of remifentanil was larger in the
elderly patient group than in the adult group.14 Third,
sevoflurane may have affected the results because the
elimination rate of sevoflurane can be influenced by variations in
the respiratory effect of remifentanil according to age or
because the minimal alveolar concentration of sevoflurane
for awakening also decreases with age.25 Therefore, further
studies are required to establish a definite conclusion on the
influence of age on the clinical performance of remifentanil
TCI with regard to recovery profiles.
Hypoventilation ,8 breaths/min occurred in one-third
of patients and desaturation below 95% in one patient in the
elderly group. These adverse events were more frequent in
the elderly group, although this difference lacked statistical
significance. Remifentanil produces respiratory depression
in a dose-dependent manner.26 Chang et al27 demonstrated
that 2 ng/mL remifentanil is associated with a significant
increase in hypoventilation episodes and delayed emergence.
The EC95 of remifentanil for cough suppression during
emergence would be more susceptible to respiratory
depression. Therefore, when a remifentanil EC95 is administered,
caution is required with regard to potential hypoventilation
This study has a few limitations. First, patient sex
differences at the enrollment stage were not accounted for; the
proportion of males in this study was 72%. According to the
results of Soh et al,28 the effect-site concentration of
remifentanil TCI for antitussive effect is higher in males than in
females. Therefore, variations in the dose–response
according to sex may have affected this sequential data. Second,
the type of surgery was limited to nasal surgery (endoscopic
sinus surgery or septoplasty). Based on the differences in the
effect-site concentration of remifentanil in previous studies
of a similar design,10,27 surgery type is likely to influence
the effect-site concentration of remifentanil. Therefore, the
application of the current findings to other types of surgery
should be considered carefully.
The effect-site concentration of remifentanil for
preventing cough after nasal surgery (endoscopic sinus surgery or
septoplasty) with sevoflurane anesthesia in elderly patients
did not differ from that in adult patients. However, delayed
awakening and respiratory adverse events may warrant
special attention in elderly patients.
The authors report no conflicts of interest in this work.
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