Journal of Clinical Anesthesia (2014) 26, 466–474
Original Contribution
Does the type of anesthetic agent affect remifentanil effect-site concentration for preventing endotracheal tube-induced cough during anesthetic emergence? Comparison of propofol, sevoflurane, and desflurane☆,☆☆ Jae Hoon Lee MD (Assistant Professor of Anesthesiology and Pain Medicine)a , Seung Ho Choi MD, PhD (Associate Professor of Anesthesiology and Pain Medicine)a , Yong Seon Choi MD, PhD (Assistant Professor of Anesthesiology and Pain Medicine)a , Bahn Lee MD (Assistant Clinical Professor of Anesthesiology and Pain Medicine)a , Shi Joon Yang MD (Resident of Anesthesiology and Pain Medicine)b , Jeong-Rim Lee MD, PhD (Assistant Professor of Anesthesiology and Pain Medicine)a,⁎ a
Department of Anesthesiology and Pain Medicine, Severance Hospital, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea b Department of Anesthesiology and Pain Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Korea Received 29 January 2013; revised 4 February 2014; accepted 12 February 2014
Keywords: Cough; Desflurane; Propofol; Remifentanil; Sevoflurane
Abstract Study Objective: To investigate whether the type of anesthetic agent administered affects the antitussive effect of remifentanil. Design: Prospective randomized study. Setting: Operating room of a university hospital. Patients: 78 ASA physical status 1 and 2 women, aged 20 to 65 years, who were scheduled to undergo a thyroidectomy. Interventions: Patients were randomly assigned to three groups to receive anesthesia with propofol (Group P), sevoflurane (Group S), or desflurane (Group D). The main anesthetics were titrated to maintain a target Bispectral Index for hypnosis of 40 to 60. Remifentanil was administered via effectsite target-controlled infusion (TCI). To determine the effective remifentanil effect-site concentration (Ce) to suppress coughing in each group, the up-and-down sequential allocation design was used.
☆
Supported by departmental funding only. The authors declare they have no conflicts of interest to disclose. ⁎ Correspondence: Jeong-Rim Lee MD, PhD, Assistant Professor of Anesthesiology and Pain Medicine, Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea. Tel.: + 82 2 2228 2420; fax: +82 2 312 7897. E-mail address: [email protected] (J.-R. Lee). ☆☆
http://dx.doi.org/10.1016/j.jclinane.2014.02.002 0952-8180/© 2014 Elsevier Inc. All rights reserved.
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Measurements: The half maximal effective concentration (EC50) values of remifentanil for preventing coughing in the groups were estimated using isotonic regression and compared among the groups. Main Results: The EC50 of remifentanil for cough suppression in Group P [1.60 ng/mL (98.3% CI, 0.92 - 1.75 ng/mL)] was statistically lower than in Group D [1.96 ng/mL (98.3% CI, 1.81 - 2.50 ng/ mL)]. The EC50 in Group S was 1.75 ng/mL (98.3% CI, 1.39 - 2.13 ng/mL), which was higher than in Group P and lower than in Group D, but did not differ significantly from either group. Conclusions: Remifentanil administration for cough suppression during emergence should be customized to the anesthetic agent. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Coughing is a normal protective reflex that is essential for removing foreign material and secretions from the airways. However, coughing against the endotracheal tube (ETT) during emergence from general anesthesia causes various adverse complications such as hypertension and tachycardia [1], intracranial hypertension [2], and increased intraocular pressure [3]. Preventing coughing during emergence from anesthesia is important in several clinical situations. Opioids are currently the most effective and widely used treatment for coughing in patients with respiratory disease [4], and codeine inhibits cough in normal volunteers [5]. Recent reports illustrated an antitussive effect of remifentanil during recovery from general anesthesia by demonstrating that a target-controlled infusion (TCI) safely and effectively suppressed coughing [6,7]. On the other hand, hypnotics may variously affect the coughing reflex according to type of hypnotic; reportedly, the incidence of coughing during anesthetic emergence is higher in patients anesthetized with sevoflurane than with propofol [8,9]. In addition, desflurane is an airway irritant [10] and may provoke coughing [11]. If various hypnotics affect the coughing reflex differently during anesthetic recovery, the effective concentration of remifentanil for cough suppression may vary according to the hypnotic agent. Therefore, we hypothesized that the effective remifentanil effect-site concentration (Ce) for preventing coughing during anesthetic emergence differed according to the anesthetic agent used. Smooth emergence without coughing against the ETT is especially important in patients undergoing thyroid surgery. Postoperative hemorrhage and the possibility of a potentially fatal cervical hematoma are well known complications of coughing after thyroidectomy [12]. Thyroid cancer is more prevalent in women [13], and a gender-related difference in cough incidence [14] and recovery time after anesthesia [15] does exist. Therefore, the present study was designed to determine the 50% effect-site concentration (EC 50 ) and 95% effect-site concentration (EC 95) of remifentanil in effect-site TCI for preventing cough when general anesthesia was performed with propofol, sevoflurane, and desflurane in women undergoing thyroidectomy. Through comparison of these EC50 levels of remifentanil according to the type of anesthetics, it was determined
whether the type of anesthetic agent would affect the ability of remifentanil to prevent cough during emergence from general anesthesia.
2. Materials and methods This study was approved by the Institutional Review Board of Severance Hospital, Yonsei University Health System (ref: 4-2011-0019), and registered at ClinicalTrials.gov (ref: NCT01351285). The authors obtained written, informed consent from all subjects to participate in the study. The investigation was conducted in the operating room (OR) of Severance Hospital, Yonsei University Health System, Seoul, Korea, from May 2011 to October 2011. About 2,400 thyroidectomies are performed every year at our center.
2.1. Patients and group allocation Seventy-eight ASA physical status 1 and 2 patients were enrolled in the study, all women, aged 20 to 65 years, who underwent general anesthesia for elective thyroidectomy due to thyroid neoplasm. Exclusion criteria included administration of an angiotensin-converting enzyme inhibitor or cough medicine, or presentation with signs of a difficult airway, increased risk of perioperative aspiration, history of chronic respiratory disease, recent respiratory tract infection, chronic coughing, current smoking, or significant cardiovascular, hepatic, or renal disease. Written, informed consent was obtained on the day before the surgery. Patients were randomly assigned to one of the three groups according to a computer-generated random numbers table on the day of the surgery. According to the allocated group, patients were anesthetized with propofol (Group P), sevoflurane (Group S), or desflurane (Group D). Remifentanil in all groups and propofol in Group P were administered by TCI. For effect-site TCI of remifentanil and propofol, a commercial TCI pump (Orchestra® Base Primea; Fresenius Kabi ELEMA, Paris, France) was used, and the pumps were operated according to the models of Schnider and colleagues [16] and Minto and colleagues [17]; the present study's protocol was based on targeted Ce.
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2.2. Anesthetic management All patients were premedicated with intravenous (IV) glycopyrrolate 0.2 mg before induction of anesthesia. Electrocardiogram, peripheral oxygen saturation, noninvasive arterial pressure (BP), end-tidal carbon dioxide (ETCO2), and nasopharyngeal temperature monitors were applied and monitored at one to 5-minute intervals in the OR. In addition, a Bispectral Index (BIS) monitor was applied by placing a cutaneous electrode according to the manufacturer's instructions. Anesthesia was induced using targeted effect-site TCI remifentanil and propofol in Group P and IV propofol of 1.5 mg/kg and effect-site TCI of remifentanil in the other groups. Remifentanil infusion began at the time of anesthetic induction with propofol administration. For all patients, IV rocuronium 0.6 mg/kg was administered after loss of consciousness, and tracheal intubation was performed using a 7.0 mm (internal diameter) reinforced ETT. Cuff pressure was maintained at 20 to 25 mmHg with a hand pressure gauge (Hi-Lo™ hand pressure gauge; VBM Medizintechnik GmbH, Sulz a.N., Germany) throughout the procedure. Anesthesia was maintained with effect-site TCI of propofol and remifentanil in Group P and the other two groups, with effect-site TCI of remifentanil and sevoflurane (Group S) or desflurane (Group D). The main anesthetics and remifentanil were titrated to maintain a BIS target level for hypnosis of 40 to 60 and to maintain BP and heart rate (HR) within 20% of preinduction values. Mechanical ventilation was maintained with a tidal volume of 8 mL/kg, and ventilator frequency was adjusted to maintain ETCO2 at 35 to 40 mmHg. During mechanical ventilation, patients received a mixture of air and oxygen (0.5 of fraction of inspired oxygen). Temperature was maintained at 36° C to 37° C. During suture of the surgical incision, effect-site TCI of remifentanil was titrated to a “predetermined concentration” (the initial concentration being 2.0 ng/mL for the first pt of each group). The “predetermined concentration” was maintained throughout emergence until extubation. In addition, the main hypnotic agent of each group was then titrated to maintain an approximate BIS level of 60. After suture completion, ketorolac 0.5 mg/kg was administered for pain control and glycopyrrolate 0.004 mg/kg with neostigmine 0.02 mg/kg was given for reversal of the neuromuscular block, which was confirmed at a greater than 90% train-offour (TOF) ratio. Immediately after the surgical dressings were applied, administration of the main hypnotic agents was discontinued, whereas remifentanil TCI was maintained until extubation. Mechanical ventilation was then converted to manual ventilation, and ETCO2 was maintained at 40 to 50 mmHg. The patient was not disturbed other than to receive continuous verbal requests to open their eyes, and all other stimulus was avoided. When patients opened their eyes on request, deep breathing was encouraged; the trachea was extubated after adequate spontaneous respiration was confirmed. Immediately after extubation, remifentanil
J.H. Lee et al. administration was discontinued, and oxygen was supplemented via facemask for 5 minutes.
2.3. Study protocol Cough was assessed during anesthetic emergence from hypnotic discontinuation to 5 minutes after extubation. Cough was defined as a sudden contraction of the abdomen. To determine the effective remifentanil Ce, the up-and-down sequential allocation design was used; if the first patient did not cough during emergence, the extubation was defined as successful and the predetermined concentration for the next patient was decreased by 0.5 ng/mL. Similarly, if the patient coughed anytime around the time of extubation, it was considered a failed attempt and the predetermined concentration for the next patient was increased by 0.5 ng/mL. These processes were performed for all three groups. After extubation, all patients received 100% oxygen by facemask, were observed for 5 minutes, then transferred to the Postanesthesia Care Unit (PACU). Bradypnea, defined as respiratory rate less than 8 breaths per minute, oxygen saturation by pulse oximetry below 95% despite oxygen supplementation, and other respiratory complications were recorded. Mean arterial pressure (MAP) and HR during emergence were recorded at three time points: when remifentanil TCI reached the predetermined concentration (at the end of surgery), then before and immediately after extubation. The intervals from the end of surgery (discontinuation of main anesthetics) to eye opening and to extubation were defined as the time periods of emergence and were recorded. Two practitioners were involved during the emergence phase. The first anesthesiologist controlled the TCI pump and anesthetic vaporizer, and recorded parameters related to emergence from anesthesia. Before anesthetic agent discontinuation, this first investigator shielded the TCI pump and the anesthetic agent monitor from the other investigator. Another anesthesiologist, who was blinded to patient group allocation, entered the OR at the time of anesthetic agent discontinuation. This second anesthesiologist assessed emergence, performed extubation, and checked patients for coughing. While remaining blinded to the anesthetic administered and the remifentanil Ce throughout the entire emergence phase, the second anesthesiologist communicated the specific time points of emergence to the first anesthesiologist, who then recorded anesthetic concentrations, time periods of emergence, MAP, and HR accordingly. A third anesthesiologist, who was also blinded to patient group allocation, assessed the degree of postoperative pain, sedation, nausea, and vomiting of patients in the PACU. The parameters of interest were defined by the following criteria: pain greater than 5 points on the visual analog scale; residual sedation higher than Grade 2 on the modified Wilson sedation scale [18] at 10 minutes after PACU admission, nausea, and need for antiemetic treatment. The modified Wilson sedation scale classifies sedation as Grade 1 (awake and responding), Grade 2 (sedated but responsive to normal voice), Grade 3 (sedated but responsive
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Fig. 1 CONSORT diagram showing the flow of participants through each stage of our randomized trial. P = propofol; S = sevoflurane; D = desflurane.
to light glabellar tap or loud voice), and Grade 4 (deeply sedated and unresponsive).
2.4. Statistical analysis For estimating EC50 of remifentanil in preventing cough, we adopted the up-and-down sequential design. According to previous studies in which EC50 was estimated by the Dixon's method [19,20], the stopping rule required at least 6 failure/success pairs. Simulation studies for the up-and-down design suggest that at least 20 patients be included to obtain stable estimates [21]. To satisfy both bases, we enrolled patients until at least 8 failure/success pairs were achieved in all groups; thus, each group contained more than 20 patients. We obtained EC50 values of remifentanil needed to suppress coughing according to Dixon's method by calculating the midpoint concentrations of patients involving crossover from failure to success. To specify the precision of the target concentration with confidence intervals (CIs), the isotonic regression method also was used for estimating EC50 and EC95 along with CIs [22]; from an observed response rate, which is the ratio of the number of successful patients to the number of subjects at each concentration level, an adjusted response probability was calculated by pooled adjacent-violators algorithm (PAVA) so as to adhere to the assumption in dose-response determinations that drug effect increases with increased dosage [21,23]. EC50 and EC95 were estimated using isotonic regression based on the PAVA adjusted response rate; and CIs were estimated by a boot strapping approach, which allows estimation of CIs of the target dose with any probability of effect [21,23].
As the principal analysis, the EC50s of remifentanil for abolishing cough by isotonic regression was compared along with the CIs between groups. Comparison of EC50 among groups was done by using the method of overlapping CIs. If 98.3% CIs were nonoverlapping in comparison of the three groups, then the null hypothesis of equal ECs was rejected at an α of 0.0167 (comparisons were performed three times, 0.05/3 = 0.0167), which is the corrected significance level by the Bonferroni method. In addition, the EC50s estimated by the Dixon's method among groups were compared using one-way analysis of variance (ANOVA) with Bonferroni post-hoc analysis. All continuous variables except the estimated EC were tested for normality using the Shapiro-Wilk test. Continuous Table 1
Patient characteristics
Age (yrs) Height (cm) Weight (kg) ASA physical status (1/2) Duration of anesthesia (min) Type of surgery (total thyroidectomy/ hemi-thyriodectomy)
Group P (n=25)
Group S (n=24)
Group D (n=27)
39.2 ± 9.0 159.6 ± 5.2 56.3 ± 8.0 22/3
39.1 ± 10.9 160.2 ± 4.3 56.6 ± 6.8 20/4
38.9 ± 8.7 161.9 ± 4.8 58.5 ± 7.6 24/3
141.9 ± 27.0 135.3 ± 30.4 141.6 ± 29.5 20/5
20/4
23/4
Values are means ± SD or numbers of patients. Group P was anesthetized with propofol, Group S was anesthetized with sevoflurane, and Group D was anesthetized with desflurane.
470 data that were normally distributed are presented as means (SD), and comparison of the three groups was done by oneway ANOVA with Bonferroni post-hoc analysis. The incidences of adverse outcomes at the PACU between groups were compared using Fisher's Exact test of χ2 analysis.
J.H. Lee et al. R statistical software (version 2.13.0), a free software environment for statistical computing and graphics, was used for calculations with the isotonic regression method, with a bootstrapping approach to produce a 98.3% CI for the estimate of EC50 and EC95. Other data were analyzed using PASW
Fig. 2 Assessment of success or failure of cough prevention under a predetermined concentration of remifentanil in consecutive patients by Dixon's method. Mean EC50 for cough prevention was calculated from midpoints of pairs (arrow) from failure (open circle) to success (closed circle) in (A) 25 Group P (propofol) patients, (B) 24 Group S (sevoflurane) patients, and (C) 27 Group D (desflurane) patients. The EC50 for cough prevention by the Dixon's method in Groups P, S, and D were 1.69 ± 0.31 ng/mL, 1.81 ± 0.46 ng/mL, and 2.13 ± 0.43 ng/mL, respectively. Ce=effect-site concentration.
Antitussive concentration of remifentanil
Fig. 3 Pooled-adjacent-violators algorithm (PAVA) response rates among the three groups. The PAVA response rate at each remifentanil effect-site concentration (Ce) shown in the graph is calculated from the observed response rate using PAVA. The observed response rate = ratio of the number of successful subjects to the number of subjects at each remifentanil Ce. Based on the PAVA response rate, the EC50 for cough prevention by isotonic regression in Groups P (propofol), S (sevoflurane), and D (desflurane) were 1.60 ng/mL, 1.75 ng/mL, and 1.96 ng/mL, respectively.
statistics, version 18 software (SPSS Inc., Chicago, IL, USA). A P-value b 0.05 was considered statistically significant.
3. Results
In women requiring thyroidectomy, the remifentanil EC50 that suppressed coughing during anesthetic emergence was 1.60 ng/mL in patients who were anesthetized with propofol, a value that was significantly lower than the 1.96 ng/mL needed with desflurane anesthesia. On the other hand, the remifentanil EC50 with sevoflurane anesthesia was 1.75 ng/mL, which was higher than that of propofol and lower than that of desflurane, but not significantly different from either. The EC95 of remifentanil for cough suppression was 1.96 ng/mL with propofol anesthesia, 2.43 ng/mL with
Remifentanil effect-site concentration (Ce) for cough prevention
Dixon's method EC50 remifentanil (ng/mL)a Isotonic regression method EC50 (ng/mL)b EC95 (ng/mL)b a,b
The sequence of success and failure for preventing cough and PAVA response rates among the three groups is shown in Figs. 2 and 3. The EC50s estimated by the Dixon's method and the EC50s and EC95s by isotonic regression are presented in Table 2. The EC50 of remifentanil for cough suppression in Group P [1.60 ng/mL (98.3% CI, 0.92 - 1.75 ng/mL)] was statistically lower than in Group D [1.96 ng/mL (98.3% CI, 1.81 - 2.50 ng/mL)] when estimated by isotonic regression. The EC50 in Group S was 1.75 ng/mL (98.3% CI, 1.39 - 2.13 ng/mL), which was not statistically different from those values in Groups P and D. The EC50 estimated by the Dixon's method for Group P was statistically lower than that of Group D (P = 0.04), as was the EC50 by isotonic regression. The EC95 of remifentanil for cough suppression, as estimated by isotonic regression, was 1.96 ng/mL (98.3% CI, 1.84 - 1.98 ng/mL) in Group P, 2.43 ng/ mL (98.3% CI, 2.15 - 2.48 ng/mL) in Group S, and 2.85 ng/mL (98.3% CI, 2.41 - 2.98 ng/mL) in Group D. The profiles of recovery from general anesthesia are shown in Table 3. Time to eye opening and extubation in Group S was longer than in Group P and Group D. However, the hemodynamic changes during extubation were more prominent in Group D than Group P. No patients suffered any respiratory complications during the emergence period. The duration of PACU stay in Group S appeared to be greater than in the other groups, though the difference was not statistically significant (P = 0.076). The adverse outcomes during the PACU stay were comparable among the three groups (Table 4).
4. Discussion
Of 89 patients assessed, 78 were enrolled in the study. Among the enrolled participants, one Group S patient was excluded from the study due to delayed recovery of more than 15 minutes after discontinuation of sevoflurane. One Group D patient was excluded from the study on the day of surgery for an upper respiratory infection. Finally, 76 patients completed all the assessments in the present study [Group P (n=25); Group S (n=24); Group D (n=27)] (Fig. 1). Physical characteristics, duration of anesthesia, and type of surgery performed were comparable among the three groups (Table 1).
Table 2
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Group P
Group S
Group D
1.69 ± 0.31
1.81 ± 0.46
2.13 ± 0.43 ⁎
1.60 (0.92 - 1.75) 1.96 (1.84 - 1.98)
1.75 (1.39 - 2.13) 2.43 (2.15 - 2.48) †
1.96 (1.81 - 2.50) † 2.85 (2.41 - 2.98) †
Values are aEC50 ± SD, EC50, or bEC95 [98.3% confidence intervals (CIs)]. Group P was anesthetized with propofol, Group S was anesthetized with sevoflurane, and Group D was anesthetized with desflurane. ⁎ P = 0.04 vs Group P (Bonferroni post hoc analysis). † Significantly higher than Group P (method of overlapping CIs).
472 Table 3
J.H. Lee et al. Parameters related to emergence from anesthesia
Anesthetic concentration at eye opening Time to eye opening (min) Time to extubation (min) Mean arterial pressure (mmHg) at end of surgery before extubation after extubation Heart rate (bpm) at end of surgery before extubation after extubation
Group P
Group S
Group D
1.09 ± 0.26 μg/mL 5.4 ± 1.8 ⁎ 6.2 ± 2.0 ⁎
0.34% ± 0.08% 7.3 ± 1.2 8.4 ± 1.5
1.08% ± 0.27% 4.9 ± 2.2 ⁎ 5.6 ± 2.3 ⁎
86.7 ± 12.5 91.4 ± 11.7 91.3 ± 9.7
87.4 ± 11.9 90.9 ± 11.8 95.0 ± 13.9
89.7 ± 13.6 97.4 ± 17.4 105.5 ± 17.7 †
62.9 ± 10.0 65.1 ± 10.0 67.6 ± 8.5
62.1 ± 13.3 69.1 ± 10.6 75.4 ± 15.7
65.2 ± 14.3 79.9 ± 16.9 † 83.4 ± 12.6 †
Values are means ± SD. Group P was anesthetized with propofol, Group S was anesthetized with sevoflurane, and Group D was anesthetized with desflurane. ⁎ P b 0.05 vs Group S. † P b 0.05 vs Group P.
sevoflurane anesthesia, and 2.85 ng/mL with desflurane anesthesia. Although the mechanism of the coughing reflex remains unclear, it is initiated by a variety of stimuli, including mechanical and chemical irritation. The stimuli trigger peripheral sensory nerve endings under the airway epithelium, relaying the information through the vagus nerve to a specific area within the brainstem. The subsequent reflex stimulation of the efferent limb results in coughing [4]. The antitussive effect of opioids generally is centrally mediated by brainstem opioid receptors [4,24], and remifentanil administration via TCI may maintain a predictable Ce with an acceptable level of bias and inaccuracy [25,26]. Therefore, the authors attempted to determine the effective remifentanil Ce for abolishing cough using the TCI in the present study. A previous study reported that the EC50 and EC95 of remifentanil for preventing cough during recovery after propofol anesthesia were 1.46 and 2.14 ng/mL, respectively [19]. Another study investigated the efficacy of 2.0 ng/mL of remifentanil for preventing cough during emergence from sevoflurane anesthesia [6]. However, although 2.0 ng/mL of remifentanil was close to the EC95 of remifentanil for preventing cough after propofol anesthesia, the incidence of cough in the patients who received 2.0 ng/mL of remifentanil after sevoflurane anesthesia was 20.6%, Table 4
which was higher than what we expected. Therefore, we hypothesized that the effective remifentanil Ce for preventing coughing during anesthetic emergence differed according to the anesthetic agent used, and thus investigated this issue in the present study. We adopted the up-and-down sequential allocation design for determining EC50 because it outperforms nonsequential designs with its smaller mean square error for the same sample size. In the up-and-down sequential allocation design, there are several ways for estimating EC50, such as the Dixon's method, logistic/probit regression, and isotonic regression. Among these methods, the estimation for target dose by isotonic regression has a smaller bias and mean square error, as well as a narrower CI when compared with the Dixon's method. In addition, isotonic regression requires no symmetry assumption, unlike regression adjusted for nonindependence of data [21]. Therefore, we adopted the isotonic regression method for estimating EC50 of remifentanil in each group. Finally, through comparison of the precise estimations, we tried to elucidate the effect of the type of anesthetics on EC50 of remifentanil for suppressing cough against the ETT during emergence from general anesthesia. Compared with desflurane, the results of our study showed that propofol anesthesia required a lower concentration of remifentanil for suppression of cough during emergence.
Duration of PACU stay and adverse outcomes in the PACU
Duration of PACU stay (min) Postoperative pain Nausea Residual sedation
Group P (n=25)
Group S (n=24)
Group D (n=27)
39.7 ± 10.8 9 (36.0%) 0 0
47.9 ± 12.1 6 (25.0%) 4 (16.7%) 2 (8.3%)
39.8 ± 12.1 9 (33.3%) 4 (14.8%) 0
Values are means ± SD or numbers of patients (%). PACU=Postanesthesia Care Unit. Group P was anesthetized with propofol, Group S was anesthetized with sevoflurane, and Group D was anesthetized with desflurane.
Antitussive concentration of remifentanil Although several reports failed to demonstrate the effect of propofol on suppression of cough induced by artificial irritation [27,28], other investigations showed that propofol represses airway reflexes [29,30]. In addition, Hans et al [9] reported that residual concentration of propofol during emergence decreased the probability of coughing. Furthermore, propofol at a subhypnotic dose (0.5 mg/kg) decreased the likelihood of laryngospasm after extubation in pediatric tonsillectomy patients who received inhalational anesthesia [31]. In the present study, the mean propofol Ce was 1.09 μg/mL during extubation in Group P patients and the residual propofol during emergence might suppress coughing. Volatile anesthetics may have a depressant effect on the airway reflex and simplify extubation without coughing; however, this effect is observed only at higher concentrations (N 1 minimum alveolar concentration) [32]. Whether the airway reflex is suppressed at a subhypnotic dose of volatile anesthetics during emergence is controversial and depends on the drugs [33]. Generally, all volatile anesthetics have various degrees of pungency that may cause airway irritation, and desflurane is reportedly the most pungent among the volatile anesthetics [10] that cause coughing during induction and recovery from anesthesia [10,11]. Furthermore, desflurane provides fast restoration of the airway reflex and recovery of consciousness after discontinuation [34,35]. As hypothesized, the present study demonstrated that a higher concentration of remifentanil is required for cough suppression during recovery from desflurane anesthesia than from propofol anesthesia. On the other hand, sevoflurane, which is the least irritant of the volatile anesthetic agents [10,36], also provokes airway reflexes such as coughing or breath holding during inhalation [10,11]. Moreover, airway irritation during induction may result in hyperactivation of the cough reflex because exposure to irritants of the respiratory tract alters activity of the coughing reflex, thus enhancing the responsiveness of the afferent fibers that mediate cough [4]. Inhalation of sevoflurane or desflurane during induction may not only irritate but also sensitize the cough reflex, thus requiring a higher remifentanil Ce than propofol. In the present study, Group D patients recovered from general anesthesia without any respiratory compromise, even though they were given a higher concentration of remifentanil than the other groups. Conversely, Group S patients showed delayed emergence compared with the other two groups, and one Group S patient did not recover from anesthesia 15 minutes after cessation of sevoflurane administration at a remifentanil Ce of 2.0 ng/mL. Restoring consciousness and respiration may depend on the type of anesthetic agent rather than remifentanil administration, and patients who received a remifentanil Ce of 2.0 to 4.0 ng/mL reportedly did not have respiratory depression during anesthetic induction [37] or emergence [6,19]. However, the patients who were given more than 2.5 ng/mL of remifentanil underwent brief bradypnea, although desaturation or more severe respiratory complications were not
473 observed [38]; even the remifentanil Ce of 1.0 ng/mL has the potential of delaying awakening [7]. Therefore, the clinician may hesitate to administer remifentanil during anesthetic emergence, and further studies regarding the effectiveness and safety of the suggested EC95 is necessary. There were several limitations in the present study. First, only patients between the ages of 20 to 65 years were enrolled; older patients are more sensitive to opioids. This factor should be considered when interpreting the data. Second, the presented concentration is a predicted value that was calculated from a pharmacokinetic model and not an actual measurement from patient plasma sampling. This predicted Ce was estimated by Minto's pharmacokinetic model; however, remifentanil may be administered by this method with acceptable bias and accuracy in clinical situations [25]. Finally, we presented the EC95 of remifentanil for cough prevention during anesthetic emergence according to the type of anesthetic. However, the EC95 calculated in an up-anddown sequential allocation design focusing on EC50 cannot be a reliable value [21]. Therefore, the EC95 of remifentanil to prevent cough estimated in the study cannot be readily applied to clinical practice and should be confirmed in a properly designed study for determining EC95. In conclusion, in women receiving thyroidectomy, propofol anesthesia required lower remifentanil Ce than desflurane anesthesia for preventing cough due to the ETT during emergence. On the other hand, sevoflurane anesthesia seemed to require an intermediate Ce of remifentanil for abolishing cough, although there was no statistical difference compared with propofol or desflurane. Therefore, remifentanil administration for cough suppression during emergence should be customized according to the hypnotic agent.
Acknowledgments The authors thank Kyung Hwa Han, Biostatistician, Division of Biostatistics, Department of Research Affairs, Yonsei University College of Medicine, for statistical analysis.
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474 [5] Eddy NB. Codeine and its alternates for pain and cough relief. Ann Intern Med 1969;71:1209-12. [6] Lee JH, Koo BN, Jeong JJ, Kim HS, Lee JR. Differential effects of lidocaine and remifentanil on response to the tracheal tube during emergence from general anaesthesia. Br J Anaesth 2011;106:410-5. [7] Jun NH, Lee JW, Song JW, Koh JC, Park WS, Shim YH. Optimal effect-site concentration of remifentanil for preventing cough during emergence from sevoflurane-remifentanil anaesthesia. Anaesthesia 2010;65:930-5. [8] Hohlrieder M, Tiefenthaler W, Klaus H, et al. Effect of total intravenous anaesthesia and balanced anaesthesia on the frequency of coughing during emergence from the anaesthesia. Br J Anaesth 2007;99:587-91. [9] Hans P, Marechal H, Bonhomme V. Effect of propofol and sevoflurane on coughing in smokers and non-smokers awakening from general anaesthesia at the end of a cervical spine surgery. Br J Anaesth 2008;101:731-7. [10] TerRiet MF, DeSouza GJ, Jacobs JS, et al. Which is most pungent: isoflurane, sevoflurane or desflurane? Br J Anaesth 2000;85:305-7. [11] Eshima RW, Maurer A, King T, et al. A comparison of airway responses during desflurane and sevoflurane administration via a laryngeal mask airway for maintenance of anesthesia. Anesth Analg 2003;96:701-5. [12] Rosenbaum MA, Haridas M, McHenry CR. Life-threatening neck hematoma complicating thyroid and parathyroid surgery. Am J Surg 2008;195:339-43. [13] Cook MB, Dawsey SM, Freedman ND, et al. Sex disparities in cancer incidence by period and age. Cancer Epidemiol Biomarkers Prev 2009;18:1174-82. [14] Dicpinigaitis PV, Rauf K. The influence of gender on cough reflex sensitivity. Chest 1998;113:1319-21. [15] Tercan E, Kotanoglu MS, Yildiz K, Dogru K, Boyaci A. Comparison of recovery properties of desflurane and sevoflurane according to gender differences. Acta Anaesthesiol Scand 2005;49:243-7. [16] Schnider TW, Minto CF, Shafer SL, et al. The influence of age on propofol pharmacodynamics. Anesthesiology 1999;90:1502-16. [17] Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology 1997;86:10-23. [18] Némethy M, Paroli L, Williams-Russo PG, Blanck TJ. Assessing sedation with regional anesthesia: inter-rater agreement on a modified Wilson sedation scale. Anesth Analg 2002;94:723-8. [19] Lee B, Lee JR, Na S. Targeting smooth emergence: the effect site concentration of remifentanil for preventing cough during emergence during propofol-remifentanil anaesthesia for thyroid surgery. Br J Anaesth 2009;102:775-8. [20] Tsuruta S, Satsumae T, Mizutani T, et al. Minimum alveolar concentrations of sevoflurane for maintaining bispectral index below 50 in children. Paediatr Anaesth 2011;21:1124-7. [21] Pace NL, Stylianou MP. Advances in and limitations of up-and-down methodology: a précis of clinical use, study design, and dose estimation in anesthesia research. Anesthesiology 2007;107:144-52.
J.H. Lee et al. [22] Stylianou M, Flournoy N. Dose finding using the biased coin upand-down design and isotonic regression. Biometrics 2002;58: 171-7. [23] Dilleen M, Heimann G, Hirsch I. Non-parametric estimators of a monotonic dose-response curve and bootstrap confidence intervals. Stat Med 2003;22:869-82. [24] Mazzone SB, Undem BJ. Cough sensors. V. Pharmacological modulation of cough sensors. Handb Exp Pharmacol 2009;187:99-127. [25] Mertens MJ, Engbers FH, Burm AG, Vuyk J. Predictive performance of computer-controlled infusion of remifentanil during propofol/ remifentanil anaesthesia. Br J Anaesth 2003;90:132-41. [26] Moerman AT, Herregods LL, De Vos MM, Mortier EP, Struys MM. Manual versus target-controlled infusion remifentanil administration in spontaneously breathing patients. Anesth Analg 2009;108:828-34. [27] Tagaito Y, Isono S, Nishino T. Upper airway reflexes during a combination of propofol and fentanyl anesthesia. Anesthesiology 1998;88:1459-66. [28] Guglielminotti J, Rackelboom T, Tesniere A, et al. Assessment of the cough reflex after propofol anaesthesia for colonoscopy. Br J Anaesth 2005;95:406-9. [29] McKeating K, Bali IM, Dundee JW. The effects of thiopentone and propofol on upper airway integrity. Anaesthesia 1988;43:638-40. [30] Brown GW, Patel N, Ellis FR. Comparison of propofol and thiopentone for laryngeal mask insertion. Anaesthesia 1991;46:771-2. [31] Batra YK, Ivanova M, Ali SS, Shamsah M, Al Qattan AR, Belani KG. The efficacy of a subhypnotic dose of propofol in preventing laryngospasm following tonsillectomy and adenoidectomy in children. Paediatr Anaesth 2005;15:1094-7. [32] Smith I, Taylor E, White PF. Comparison of tracheal extubation in patients deeply anesthetized with desflurane or isoflurane. Anesth Analg 1994;79:642-5. [33] Pappas AL, Sukhani R, Lurie J, et al. Severity of airway hyperreactivity associated with laryngeal mask airway removal: correlation with volatile anesthetic choice and depth of anesthesia. J Clin Anesth 2001;13:498-503. [34] White PF, Tang J, Wender RH, et al. Desflurane versus sevoflurane for maintenance of outpatient anesthesia: the effect on early versus late recovery and perioperative coughing. Anesth Analg 2009;109: 387-93. [35] Dexter F, Bayman EO, Epstein RH. Statistical modeling of average and variability of time to extubation for meta-analysis comparing desflurane to sevoflurane. Anesth Analg 2010;110:570-80. [36] Doi M, Ikeda K. Airway irritation produced by volatile anaesthetics during brief inhalation: comparison of halothane, enflurane, isoflurane and sevoflurane. Can J Anaesth 1993;40:122-6. [37] Lee JR, Jung CW, Lee YH. Reduction of pain during induction with target-controlled propofol and remifentanil. Br J Anaesth 2007;99: 876-80. [38] Chen J, Li W, Wang D, Hu X. The effect of remifentanil on cough suppression after endoscopic sinus surgery: a randomized study. Acta Anaesthesiol Scand 2010;54:1197-203.
Original Contribution
Does the type of anesthetic agent affect remifentanil effect-site concentration for preventing endotracheal tube-induced cough during anesthetic emergence? Comparison of propofol, sevoflurane, and desflurane☆,☆☆ Jae Hoon Lee MD (Assistant Professor of Anesthesiology and Pain Medicine)a , Seung Ho Choi MD, PhD (Associate Professor of Anesthesiology and Pain Medicine)a , Yong Seon Choi MD, PhD (Assistant Professor of Anesthesiology and Pain Medicine)a , Bahn Lee MD (Assistant Clinical Professor of Anesthesiology and Pain Medicine)a , Shi Joon Yang MD (Resident of Anesthesiology and Pain Medicine)b , Jeong-Rim Lee MD, PhD (Assistant Professor of Anesthesiology and Pain Medicine)a,⁎ a
Department of Anesthesiology and Pain Medicine, Severance Hospital, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea b Department of Anesthesiology and Pain Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Korea Received 29 January 2013; revised 4 February 2014; accepted 12 February 2014
Keywords: Cough; Desflurane; Propofol; Remifentanil; Sevoflurane
Abstract Study Objective: To investigate whether the type of anesthetic agent administered affects the antitussive effect of remifentanil. Design: Prospective randomized study. Setting: Operating room of a university hospital. Patients: 78 ASA physical status 1 and 2 women, aged 20 to 65 years, who were scheduled to undergo a thyroidectomy. Interventions: Patients were randomly assigned to three groups to receive anesthesia with propofol (Group P), sevoflurane (Group S), or desflurane (Group D). The main anesthetics were titrated to maintain a target Bispectral Index for hypnosis of 40 to 60. Remifentanil was administered via effectsite target-controlled infusion (TCI). To determine the effective remifentanil effect-site concentration (Ce) to suppress coughing in each group, the up-and-down sequential allocation design was used.
☆
Supported by departmental funding only. The authors declare they have no conflicts of interest to disclose. ⁎ Correspondence: Jeong-Rim Lee MD, PhD, Assistant Professor of Anesthesiology and Pain Medicine, Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea. Tel.: + 82 2 2228 2420; fax: +82 2 312 7897. E-mail address: [email protected] (J.-R. Lee). ☆☆
http://dx.doi.org/10.1016/j.jclinane.2014.02.002 0952-8180/© 2014 Elsevier Inc. All rights reserved.
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Measurements: The half maximal effective concentration (EC50) values of remifentanil for preventing coughing in the groups were estimated using isotonic regression and compared among the groups. Main Results: The EC50 of remifentanil for cough suppression in Group P [1.60 ng/mL (98.3% CI, 0.92 - 1.75 ng/mL)] was statistically lower than in Group D [1.96 ng/mL (98.3% CI, 1.81 - 2.50 ng/ mL)]. The EC50 in Group S was 1.75 ng/mL (98.3% CI, 1.39 - 2.13 ng/mL), which was higher than in Group P and lower than in Group D, but did not differ significantly from either group. Conclusions: Remifentanil administration for cough suppression during emergence should be customized to the anesthetic agent. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Coughing is a normal protective reflex that is essential for removing foreign material and secretions from the airways. However, coughing against the endotracheal tube (ETT) during emergence from general anesthesia causes various adverse complications such as hypertension and tachycardia [1], intracranial hypertension [2], and increased intraocular pressure [3]. Preventing coughing during emergence from anesthesia is important in several clinical situations. Opioids are currently the most effective and widely used treatment for coughing in patients with respiratory disease [4], and codeine inhibits cough in normal volunteers [5]. Recent reports illustrated an antitussive effect of remifentanil during recovery from general anesthesia by demonstrating that a target-controlled infusion (TCI) safely and effectively suppressed coughing [6,7]. On the other hand, hypnotics may variously affect the coughing reflex according to type of hypnotic; reportedly, the incidence of coughing during anesthetic emergence is higher in patients anesthetized with sevoflurane than with propofol [8,9]. In addition, desflurane is an airway irritant [10] and may provoke coughing [11]. If various hypnotics affect the coughing reflex differently during anesthetic recovery, the effective concentration of remifentanil for cough suppression may vary according to the hypnotic agent. Therefore, we hypothesized that the effective remifentanil effect-site concentration (Ce) for preventing coughing during anesthetic emergence differed according to the anesthetic agent used. Smooth emergence without coughing against the ETT is especially important in patients undergoing thyroid surgery. Postoperative hemorrhage and the possibility of a potentially fatal cervical hematoma are well known complications of coughing after thyroidectomy [12]. Thyroid cancer is more prevalent in women [13], and a gender-related difference in cough incidence [14] and recovery time after anesthesia [15] does exist. Therefore, the present study was designed to determine the 50% effect-site concentration (EC 50 ) and 95% effect-site concentration (EC 95) of remifentanil in effect-site TCI for preventing cough when general anesthesia was performed with propofol, sevoflurane, and desflurane in women undergoing thyroidectomy. Through comparison of these EC50 levels of remifentanil according to the type of anesthetics, it was determined
whether the type of anesthetic agent would affect the ability of remifentanil to prevent cough during emergence from general anesthesia.
2. Materials and methods This study was approved by the Institutional Review Board of Severance Hospital, Yonsei University Health System (ref: 4-2011-0019), and registered at ClinicalTrials.gov (ref: NCT01351285). The authors obtained written, informed consent from all subjects to participate in the study. The investigation was conducted in the operating room (OR) of Severance Hospital, Yonsei University Health System, Seoul, Korea, from May 2011 to October 2011. About 2,400 thyroidectomies are performed every year at our center.
2.1. Patients and group allocation Seventy-eight ASA physical status 1 and 2 patients were enrolled in the study, all women, aged 20 to 65 years, who underwent general anesthesia for elective thyroidectomy due to thyroid neoplasm. Exclusion criteria included administration of an angiotensin-converting enzyme inhibitor or cough medicine, or presentation with signs of a difficult airway, increased risk of perioperative aspiration, history of chronic respiratory disease, recent respiratory tract infection, chronic coughing, current smoking, or significant cardiovascular, hepatic, or renal disease. Written, informed consent was obtained on the day before the surgery. Patients were randomly assigned to one of the three groups according to a computer-generated random numbers table on the day of the surgery. According to the allocated group, patients were anesthetized with propofol (Group P), sevoflurane (Group S), or desflurane (Group D). Remifentanil in all groups and propofol in Group P were administered by TCI. For effect-site TCI of remifentanil and propofol, a commercial TCI pump (Orchestra® Base Primea; Fresenius Kabi ELEMA, Paris, France) was used, and the pumps were operated according to the models of Schnider and colleagues [16] and Minto and colleagues [17]; the present study's protocol was based on targeted Ce.
468
2.2. Anesthetic management All patients were premedicated with intravenous (IV) glycopyrrolate 0.2 mg before induction of anesthesia. Electrocardiogram, peripheral oxygen saturation, noninvasive arterial pressure (BP), end-tidal carbon dioxide (ETCO2), and nasopharyngeal temperature monitors were applied and monitored at one to 5-minute intervals in the OR. In addition, a Bispectral Index (BIS) monitor was applied by placing a cutaneous electrode according to the manufacturer's instructions. Anesthesia was induced using targeted effect-site TCI remifentanil and propofol in Group P and IV propofol of 1.5 mg/kg and effect-site TCI of remifentanil in the other groups. Remifentanil infusion began at the time of anesthetic induction with propofol administration. For all patients, IV rocuronium 0.6 mg/kg was administered after loss of consciousness, and tracheal intubation was performed using a 7.0 mm (internal diameter) reinforced ETT. Cuff pressure was maintained at 20 to 25 mmHg with a hand pressure gauge (Hi-Lo™ hand pressure gauge; VBM Medizintechnik GmbH, Sulz a.N., Germany) throughout the procedure. Anesthesia was maintained with effect-site TCI of propofol and remifentanil in Group P and the other two groups, with effect-site TCI of remifentanil and sevoflurane (Group S) or desflurane (Group D). The main anesthetics and remifentanil were titrated to maintain a BIS target level for hypnosis of 40 to 60 and to maintain BP and heart rate (HR) within 20% of preinduction values. Mechanical ventilation was maintained with a tidal volume of 8 mL/kg, and ventilator frequency was adjusted to maintain ETCO2 at 35 to 40 mmHg. During mechanical ventilation, patients received a mixture of air and oxygen (0.5 of fraction of inspired oxygen). Temperature was maintained at 36° C to 37° C. During suture of the surgical incision, effect-site TCI of remifentanil was titrated to a “predetermined concentration” (the initial concentration being 2.0 ng/mL for the first pt of each group). The “predetermined concentration” was maintained throughout emergence until extubation. In addition, the main hypnotic agent of each group was then titrated to maintain an approximate BIS level of 60. After suture completion, ketorolac 0.5 mg/kg was administered for pain control and glycopyrrolate 0.004 mg/kg with neostigmine 0.02 mg/kg was given for reversal of the neuromuscular block, which was confirmed at a greater than 90% train-offour (TOF) ratio. Immediately after the surgical dressings were applied, administration of the main hypnotic agents was discontinued, whereas remifentanil TCI was maintained until extubation. Mechanical ventilation was then converted to manual ventilation, and ETCO2 was maintained at 40 to 50 mmHg. The patient was not disturbed other than to receive continuous verbal requests to open their eyes, and all other stimulus was avoided. When patients opened their eyes on request, deep breathing was encouraged; the trachea was extubated after adequate spontaneous respiration was confirmed. Immediately after extubation, remifentanil
J.H. Lee et al. administration was discontinued, and oxygen was supplemented via facemask for 5 minutes.
2.3. Study protocol Cough was assessed during anesthetic emergence from hypnotic discontinuation to 5 minutes after extubation. Cough was defined as a sudden contraction of the abdomen. To determine the effective remifentanil Ce, the up-and-down sequential allocation design was used; if the first patient did not cough during emergence, the extubation was defined as successful and the predetermined concentration for the next patient was decreased by 0.5 ng/mL. Similarly, if the patient coughed anytime around the time of extubation, it was considered a failed attempt and the predetermined concentration for the next patient was increased by 0.5 ng/mL. These processes were performed for all three groups. After extubation, all patients received 100% oxygen by facemask, were observed for 5 minutes, then transferred to the Postanesthesia Care Unit (PACU). Bradypnea, defined as respiratory rate less than 8 breaths per minute, oxygen saturation by pulse oximetry below 95% despite oxygen supplementation, and other respiratory complications were recorded. Mean arterial pressure (MAP) and HR during emergence were recorded at three time points: when remifentanil TCI reached the predetermined concentration (at the end of surgery), then before and immediately after extubation. The intervals from the end of surgery (discontinuation of main anesthetics) to eye opening and to extubation were defined as the time periods of emergence and were recorded. Two practitioners were involved during the emergence phase. The first anesthesiologist controlled the TCI pump and anesthetic vaporizer, and recorded parameters related to emergence from anesthesia. Before anesthetic agent discontinuation, this first investigator shielded the TCI pump and the anesthetic agent monitor from the other investigator. Another anesthesiologist, who was blinded to patient group allocation, entered the OR at the time of anesthetic agent discontinuation. This second anesthesiologist assessed emergence, performed extubation, and checked patients for coughing. While remaining blinded to the anesthetic administered and the remifentanil Ce throughout the entire emergence phase, the second anesthesiologist communicated the specific time points of emergence to the first anesthesiologist, who then recorded anesthetic concentrations, time periods of emergence, MAP, and HR accordingly. A third anesthesiologist, who was also blinded to patient group allocation, assessed the degree of postoperative pain, sedation, nausea, and vomiting of patients in the PACU. The parameters of interest were defined by the following criteria: pain greater than 5 points on the visual analog scale; residual sedation higher than Grade 2 on the modified Wilson sedation scale [18] at 10 minutes after PACU admission, nausea, and need for antiemetic treatment. The modified Wilson sedation scale classifies sedation as Grade 1 (awake and responding), Grade 2 (sedated but responsive to normal voice), Grade 3 (sedated but responsive
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Fig. 1 CONSORT diagram showing the flow of participants through each stage of our randomized trial. P = propofol; S = sevoflurane; D = desflurane.
to light glabellar tap or loud voice), and Grade 4 (deeply sedated and unresponsive).
2.4. Statistical analysis For estimating EC50 of remifentanil in preventing cough, we adopted the up-and-down sequential design. According to previous studies in which EC50 was estimated by the Dixon's method [19,20], the stopping rule required at least 6 failure/success pairs. Simulation studies for the up-and-down design suggest that at least 20 patients be included to obtain stable estimates [21]. To satisfy both bases, we enrolled patients until at least 8 failure/success pairs were achieved in all groups; thus, each group contained more than 20 patients. We obtained EC50 values of remifentanil needed to suppress coughing according to Dixon's method by calculating the midpoint concentrations of patients involving crossover from failure to success. To specify the precision of the target concentration with confidence intervals (CIs), the isotonic regression method also was used for estimating EC50 and EC95 along with CIs [22]; from an observed response rate, which is the ratio of the number of successful patients to the number of subjects at each concentration level, an adjusted response probability was calculated by pooled adjacent-violators algorithm (PAVA) so as to adhere to the assumption in dose-response determinations that drug effect increases with increased dosage [21,23]. EC50 and EC95 were estimated using isotonic regression based on the PAVA adjusted response rate; and CIs were estimated by a boot strapping approach, which allows estimation of CIs of the target dose with any probability of effect [21,23].
As the principal analysis, the EC50s of remifentanil for abolishing cough by isotonic regression was compared along with the CIs between groups. Comparison of EC50 among groups was done by using the method of overlapping CIs. If 98.3% CIs were nonoverlapping in comparison of the three groups, then the null hypothesis of equal ECs was rejected at an α of 0.0167 (comparisons were performed three times, 0.05/3 = 0.0167), which is the corrected significance level by the Bonferroni method. In addition, the EC50s estimated by the Dixon's method among groups were compared using one-way analysis of variance (ANOVA) with Bonferroni post-hoc analysis. All continuous variables except the estimated EC were tested for normality using the Shapiro-Wilk test. Continuous Table 1
Patient characteristics
Age (yrs) Height (cm) Weight (kg) ASA physical status (1/2) Duration of anesthesia (min) Type of surgery (total thyroidectomy/ hemi-thyriodectomy)
Group P (n=25)
Group S (n=24)
Group D (n=27)
39.2 ± 9.0 159.6 ± 5.2 56.3 ± 8.0 22/3
39.1 ± 10.9 160.2 ± 4.3 56.6 ± 6.8 20/4
38.9 ± 8.7 161.9 ± 4.8 58.5 ± 7.6 24/3
141.9 ± 27.0 135.3 ± 30.4 141.6 ± 29.5 20/5
20/4
23/4
Values are means ± SD or numbers of patients. Group P was anesthetized with propofol, Group S was anesthetized with sevoflurane, and Group D was anesthetized with desflurane.
470 data that were normally distributed are presented as means (SD), and comparison of the three groups was done by oneway ANOVA with Bonferroni post-hoc analysis. The incidences of adverse outcomes at the PACU between groups were compared using Fisher's Exact test of χ2 analysis.
J.H. Lee et al. R statistical software (version 2.13.0), a free software environment for statistical computing and graphics, was used for calculations with the isotonic regression method, with a bootstrapping approach to produce a 98.3% CI for the estimate of EC50 and EC95. Other data were analyzed using PASW
Fig. 2 Assessment of success or failure of cough prevention under a predetermined concentration of remifentanil in consecutive patients by Dixon's method. Mean EC50 for cough prevention was calculated from midpoints of pairs (arrow) from failure (open circle) to success (closed circle) in (A) 25 Group P (propofol) patients, (B) 24 Group S (sevoflurane) patients, and (C) 27 Group D (desflurane) patients. The EC50 for cough prevention by the Dixon's method in Groups P, S, and D were 1.69 ± 0.31 ng/mL, 1.81 ± 0.46 ng/mL, and 2.13 ± 0.43 ng/mL, respectively. Ce=effect-site concentration.
Antitussive concentration of remifentanil
Fig. 3 Pooled-adjacent-violators algorithm (PAVA) response rates among the three groups. The PAVA response rate at each remifentanil effect-site concentration (Ce) shown in the graph is calculated from the observed response rate using PAVA. The observed response rate = ratio of the number of successful subjects to the number of subjects at each remifentanil Ce. Based on the PAVA response rate, the EC50 for cough prevention by isotonic regression in Groups P (propofol), S (sevoflurane), and D (desflurane) were 1.60 ng/mL, 1.75 ng/mL, and 1.96 ng/mL, respectively.
statistics, version 18 software (SPSS Inc., Chicago, IL, USA). A P-value b 0.05 was considered statistically significant.
3. Results
In women requiring thyroidectomy, the remifentanil EC50 that suppressed coughing during anesthetic emergence was 1.60 ng/mL in patients who were anesthetized with propofol, a value that was significantly lower than the 1.96 ng/mL needed with desflurane anesthesia. On the other hand, the remifentanil EC50 with sevoflurane anesthesia was 1.75 ng/mL, which was higher than that of propofol and lower than that of desflurane, but not significantly different from either. The EC95 of remifentanil for cough suppression was 1.96 ng/mL with propofol anesthesia, 2.43 ng/mL with
Remifentanil effect-site concentration (Ce) for cough prevention
Dixon's method EC50 remifentanil (ng/mL)a Isotonic regression method EC50 (ng/mL)b EC95 (ng/mL)b a,b
The sequence of success and failure for preventing cough and PAVA response rates among the three groups is shown in Figs. 2 and 3. The EC50s estimated by the Dixon's method and the EC50s and EC95s by isotonic regression are presented in Table 2. The EC50 of remifentanil for cough suppression in Group P [1.60 ng/mL (98.3% CI, 0.92 - 1.75 ng/mL)] was statistically lower than in Group D [1.96 ng/mL (98.3% CI, 1.81 - 2.50 ng/mL)] when estimated by isotonic regression. The EC50 in Group S was 1.75 ng/mL (98.3% CI, 1.39 - 2.13 ng/mL), which was not statistically different from those values in Groups P and D. The EC50 estimated by the Dixon's method for Group P was statistically lower than that of Group D (P = 0.04), as was the EC50 by isotonic regression. The EC95 of remifentanil for cough suppression, as estimated by isotonic regression, was 1.96 ng/mL (98.3% CI, 1.84 - 1.98 ng/mL) in Group P, 2.43 ng/ mL (98.3% CI, 2.15 - 2.48 ng/mL) in Group S, and 2.85 ng/mL (98.3% CI, 2.41 - 2.98 ng/mL) in Group D. The profiles of recovery from general anesthesia are shown in Table 3. Time to eye opening and extubation in Group S was longer than in Group P and Group D. However, the hemodynamic changes during extubation were more prominent in Group D than Group P. No patients suffered any respiratory complications during the emergence period. The duration of PACU stay in Group S appeared to be greater than in the other groups, though the difference was not statistically significant (P = 0.076). The adverse outcomes during the PACU stay were comparable among the three groups (Table 4).
4. Discussion
Of 89 patients assessed, 78 were enrolled in the study. Among the enrolled participants, one Group S patient was excluded from the study due to delayed recovery of more than 15 minutes after discontinuation of sevoflurane. One Group D patient was excluded from the study on the day of surgery for an upper respiratory infection. Finally, 76 patients completed all the assessments in the present study [Group P (n=25); Group S (n=24); Group D (n=27)] (Fig. 1). Physical characteristics, duration of anesthesia, and type of surgery performed were comparable among the three groups (Table 1).
Table 2
471
Group P
Group S
Group D
1.69 ± 0.31
1.81 ± 0.46
2.13 ± 0.43 ⁎
1.60 (0.92 - 1.75) 1.96 (1.84 - 1.98)
1.75 (1.39 - 2.13) 2.43 (2.15 - 2.48) †
1.96 (1.81 - 2.50) † 2.85 (2.41 - 2.98) †
Values are aEC50 ± SD, EC50, or bEC95 [98.3% confidence intervals (CIs)]. Group P was anesthetized with propofol, Group S was anesthetized with sevoflurane, and Group D was anesthetized with desflurane. ⁎ P = 0.04 vs Group P (Bonferroni post hoc analysis). † Significantly higher than Group P (method of overlapping CIs).
472 Table 3
J.H. Lee et al. Parameters related to emergence from anesthesia
Anesthetic concentration at eye opening Time to eye opening (min) Time to extubation (min) Mean arterial pressure (mmHg) at end of surgery before extubation after extubation Heart rate (bpm) at end of surgery before extubation after extubation
Group P
Group S
Group D
1.09 ± 0.26 μg/mL 5.4 ± 1.8 ⁎ 6.2 ± 2.0 ⁎
0.34% ± 0.08% 7.3 ± 1.2 8.4 ± 1.5
1.08% ± 0.27% 4.9 ± 2.2 ⁎ 5.6 ± 2.3 ⁎
86.7 ± 12.5 91.4 ± 11.7 91.3 ± 9.7
87.4 ± 11.9 90.9 ± 11.8 95.0 ± 13.9
89.7 ± 13.6 97.4 ± 17.4 105.5 ± 17.7 †
62.9 ± 10.0 65.1 ± 10.0 67.6 ± 8.5
62.1 ± 13.3 69.1 ± 10.6 75.4 ± 15.7
65.2 ± 14.3 79.9 ± 16.9 † 83.4 ± 12.6 †
Values are means ± SD. Group P was anesthetized with propofol, Group S was anesthetized with sevoflurane, and Group D was anesthetized with desflurane. ⁎ P b 0.05 vs Group S. † P b 0.05 vs Group P.
sevoflurane anesthesia, and 2.85 ng/mL with desflurane anesthesia. Although the mechanism of the coughing reflex remains unclear, it is initiated by a variety of stimuli, including mechanical and chemical irritation. The stimuli trigger peripheral sensory nerve endings under the airway epithelium, relaying the information through the vagus nerve to a specific area within the brainstem. The subsequent reflex stimulation of the efferent limb results in coughing [4]. The antitussive effect of opioids generally is centrally mediated by brainstem opioid receptors [4,24], and remifentanil administration via TCI may maintain a predictable Ce with an acceptable level of bias and inaccuracy [25,26]. Therefore, the authors attempted to determine the effective remifentanil Ce for abolishing cough using the TCI in the present study. A previous study reported that the EC50 and EC95 of remifentanil for preventing cough during recovery after propofol anesthesia were 1.46 and 2.14 ng/mL, respectively [19]. Another study investigated the efficacy of 2.0 ng/mL of remifentanil for preventing cough during emergence from sevoflurane anesthesia [6]. However, although 2.0 ng/mL of remifentanil was close to the EC95 of remifentanil for preventing cough after propofol anesthesia, the incidence of cough in the patients who received 2.0 ng/mL of remifentanil after sevoflurane anesthesia was 20.6%, Table 4
which was higher than what we expected. Therefore, we hypothesized that the effective remifentanil Ce for preventing coughing during anesthetic emergence differed according to the anesthetic agent used, and thus investigated this issue in the present study. We adopted the up-and-down sequential allocation design for determining EC50 because it outperforms nonsequential designs with its smaller mean square error for the same sample size. In the up-and-down sequential allocation design, there are several ways for estimating EC50, such as the Dixon's method, logistic/probit regression, and isotonic regression. Among these methods, the estimation for target dose by isotonic regression has a smaller bias and mean square error, as well as a narrower CI when compared with the Dixon's method. In addition, isotonic regression requires no symmetry assumption, unlike regression adjusted for nonindependence of data [21]. Therefore, we adopted the isotonic regression method for estimating EC50 of remifentanil in each group. Finally, through comparison of the precise estimations, we tried to elucidate the effect of the type of anesthetics on EC50 of remifentanil for suppressing cough against the ETT during emergence from general anesthesia. Compared with desflurane, the results of our study showed that propofol anesthesia required a lower concentration of remifentanil for suppression of cough during emergence.
Duration of PACU stay and adverse outcomes in the PACU
Duration of PACU stay (min) Postoperative pain Nausea Residual sedation
Group P (n=25)
Group S (n=24)
Group D (n=27)
39.7 ± 10.8 9 (36.0%) 0 0
47.9 ± 12.1 6 (25.0%) 4 (16.7%) 2 (8.3%)
39.8 ± 12.1 9 (33.3%) 4 (14.8%) 0
Values are means ± SD or numbers of patients (%). PACU=Postanesthesia Care Unit. Group P was anesthetized with propofol, Group S was anesthetized with sevoflurane, and Group D was anesthetized with desflurane.
Antitussive concentration of remifentanil Although several reports failed to demonstrate the effect of propofol on suppression of cough induced by artificial irritation [27,28], other investigations showed that propofol represses airway reflexes [29,30]. In addition, Hans et al [9] reported that residual concentration of propofol during emergence decreased the probability of coughing. Furthermore, propofol at a subhypnotic dose (0.5 mg/kg) decreased the likelihood of laryngospasm after extubation in pediatric tonsillectomy patients who received inhalational anesthesia [31]. In the present study, the mean propofol Ce was 1.09 μg/mL during extubation in Group P patients and the residual propofol during emergence might suppress coughing. Volatile anesthetics may have a depressant effect on the airway reflex and simplify extubation without coughing; however, this effect is observed only at higher concentrations (N 1 minimum alveolar concentration) [32]. Whether the airway reflex is suppressed at a subhypnotic dose of volatile anesthetics during emergence is controversial and depends on the drugs [33]. Generally, all volatile anesthetics have various degrees of pungency that may cause airway irritation, and desflurane is reportedly the most pungent among the volatile anesthetics [10] that cause coughing during induction and recovery from anesthesia [10,11]. Furthermore, desflurane provides fast restoration of the airway reflex and recovery of consciousness after discontinuation [34,35]. As hypothesized, the present study demonstrated that a higher concentration of remifentanil is required for cough suppression during recovery from desflurane anesthesia than from propofol anesthesia. On the other hand, sevoflurane, which is the least irritant of the volatile anesthetic agents [10,36], also provokes airway reflexes such as coughing or breath holding during inhalation [10,11]. Moreover, airway irritation during induction may result in hyperactivation of the cough reflex because exposure to irritants of the respiratory tract alters activity of the coughing reflex, thus enhancing the responsiveness of the afferent fibers that mediate cough [4]. Inhalation of sevoflurane or desflurane during induction may not only irritate but also sensitize the cough reflex, thus requiring a higher remifentanil Ce than propofol. In the present study, Group D patients recovered from general anesthesia without any respiratory compromise, even though they were given a higher concentration of remifentanil than the other groups. Conversely, Group S patients showed delayed emergence compared with the other two groups, and one Group S patient did not recover from anesthesia 15 minutes after cessation of sevoflurane administration at a remifentanil Ce of 2.0 ng/mL. Restoring consciousness and respiration may depend on the type of anesthetic agent rather than remifentanil administration, and patients who received a remifentanil Ce of 2.0 to 4.0 ng/mL reportedly did not have respiratory depression during anesthetic induction [37] or emergence [6,19]. However, the patients who were given more than 2.5 ng/mL of remifentanil underwent brief bradypnea, although desaturation or more severe respiratory complications were not
473 observed [38]; even the remifentanil Ce of 1.0 ng/mL has the potential of delaying awakening [7]. Therefore, the clinician may hesitate to administer remifentanil during anesthetic emergence, and further studies regarding the effectiveness and safety of the suggested EC95 is necessary. There were several limitations in the present study. First, only patients between the ages of 20 to 65 years were enrolled; older patients are more sensitive to opioids. This factor should be considered when interpreting the data. Second, the presented concentration is a predicted value that was calculated from a pharmacokinetic model and not an actual measurement from patient plasma sampling. This predicted Ce was estimated by Minto's pharmacokinetic model; however, remifentanil may be administered by this method with acceptable bias and accuracy in clinical situations [25]. Finally, we presented the EC95 of remifentanil for cough prevention during anesthetic emergence according to the type of anesthetic. However, the EC95 calculated in an up-anddown sequential allocation design focusing on EC50 cannot be a reliable value [21]. Therefore, the EC95 of remifentanil to prevent cough estimated in the study cannot be readily applied to clinical practice and should be confirmed in a properly designed study for determining EC95. In conclusion, in women receiving thyroidectomy, propofol anesthesia required lower remifentanil Ce than desflurane anesthesia for preventing cough due to the ETT during emergence. On the other hand, sevoflurane anesthesia seemed to require an intermediate Ce of remifentanil for abolishing cough, although there was no statistical difference compared with propofol or desflurane. Therefore, remifentanil administration for cough suppression during emergence should be customized according to the hypnotic agent.
Acknowledgments The authors thank Kyung Hwa Han, Biostatistician, Division of Biostatistics, Department of Research Affairs, Yonsei University College of Medicine, for statistical analysis.
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