Comparison of the Optimal Effect-site Concentrations of Remifentanil for Preventing Cough during Emergence from Desflurane or Sevoflurane Anaesthesia

The Journal of International Medical Research 2012; 40: 174 183 Comparison of the Optimal Effect-site Concentrations of Remifentanil for Preventing Cough during Emergence from Desflurane or Sevoflurane Anaesthesia HB CHO, JY KIM, DH KIM, DW KIM AND YJ CHAE Department of Anaesthesiology and Pain Medicine, School of Medicine, Ajou University, Suwon, Republic of Korea OBJECTIVE: To compare the effect-site concentrations of remifentanil targetcontrolled infusion (TCI) that produced 50% and 95% of the maximal effect (EC 50, respectively) for preventing cough during emergence from desflurane or sevoflurane anaesthesia, in patients undergoing elective thyroidectomy. METHODS: Adults undergoing elective thyroidectomy were randomized to receive anaesthesia with desflurane or sevoflurane. The EC 50 values for remifentanil TCI were determined using Dixon s up-anddown method and probit analysis with sigmoid curve. RESULTS: In total, 48 patients aged 20 64 years were enrolled in the study. The EC 50 ± SD of remifentanil TCI, determined by Dixon s up-and-down method, were 1.54 ± 0.70 and 1.11 ± 0.24 ng/ml for desflurane and sevoflurane, respectively. The EC 95 of remifentanil TCI, analysed by probit analysis, were 2.88 ng/ml and 2.29 ng/ml for desflurane and sevoflurane, respectively. The effect-site concentration of remifentanil TCI for preventing cough during emergence from desflurane anaesthesia was not significantly higher than that observed for sevoflurane. CONCLUSIONS: During emergence from anaesthesia, variations in effect-site concentrations of remifentanil for preventing cough are of limited importance as they do not generate significant differences in results. KEY WORDS: DESFLURANE; SEVOFLURANE; REMIFENTANIL; ANAESTHESIA; EMERGENCE COUGH; TARGET-CONTROLLED INFUSION Introduction Smooth emergence from general anaesthesia after surgery is important to prevent potentially dangerous effects such as hypertension, tachycardia, myocardial ischaemia, arrhythmias and increased intracranial and intra-abdominal pressure. 1 In thyroidectomy, coughing during emergence from general anaesthesia may lead to postoperative bleeding, resulting in acute airway obstruction or reoperation. 2 Several methods have been employed to 174

reduce coughing during emergence from anaesthesia, including deep extubation, 3 dexmedetomidine administration, 4 intra - venous lidocaine 5 and application of lidocaine inside the tracheal tube cuff. 6 The administration of short-acting opioids, such as remifentanil, has also been shown to suppress cough during emergence. 7,8 It is widely believed that the use of desflurane for maintenance of anaesthesia is associated with a higher incidence of cough during emergence, compared with sevoflurane. 9 11 No specific studies have, however, compared the optimal effect-site concentrations of remifentanil targetcontrolled infusion (TCI), administered intravenously, for preventing cough during emergence from either desflurane or sevoflurane anaesthesia. The purpose of the present study was to compare the effect-site concentrations of remifentanil TCI that produced 50% and 95% of the maximal effect (EC 50, respectively) for prevention of cough during emergence from desflurane or sevoflurane anaesthesia, in adult patients undergoing elective thyroidectomy. Patients and methods STUDY POPULATION The study included adult patients with American Society of Anesthesiology (ASA) physical status I or II (http://www.asahq.org/ clinical/physicalstatus.htm), who were scheduled to undergo elective thyroidectomy under general anaesthesia at Ajou University Hospital, Suwon, Republic of Korea, between February 2010 and July 2010. Patients were assigned, according to a computer-generated randomization table, to receive either desflurane or sevoflurane general anaesthesia. Patients were excluded if they had received treatment with sedatives, antitussives or angiotensin-converting enzyme inhibitors 4 weeks before the start of the study. Other exclusion criteria were: allergies to any of the study drugs; chronic cough; asthma; recent respiratory tract infection (4 weeks before the start of the study); predicted difficult intubation; notable cardiopulmonary, renal or hepatic disease. All patients provided written informed consent and the study protocol was approved by the Institutional Review Board of Ajou University. ANAESTHESIA PROTOCOL No premedication was given before the induction of anaesthesia; premedication usually includes anxiolytics (sedatives), and so they were not given in order to rule out any potential effect of sedatives on cough. Patient monitoring during anaesthesia involved electrocardiography, continuous pulse oximetry (SpO 2 ), oropharyngeal temperature and noninvasive measurement of blood pressure (BP) at 1 5 min intervals. End-expiratory concentrations of carbon dioxide (ETCO 2 ) and inhalational anae - sthetics were continuously measured at the elbow of the breathing circuit with a precalibrated gas monitor included in the anaesthetic machine (Dräger Primus, Dräger Medical, Lübeck, Germany). The minimum alveolar concentration (MAC) value (a fraction of the age-adapted 1 MAC value) was calculated along with the endexpiratory concentration of inhalation anaesthetics, and was also continuously monitored with the same device. For effectsite TCI of remifentanil, a commercial TCI pump (Orchestra, Fresenius Vial S.A.S., Brézins, France) employing Minto s pharmacokinetic model, was used. 12 General anaesthesia was induced with thiopental sodium 5 µg/kg, administered intravenously. After patients were unable to respond to verbal commands, ventilation was 175

performed via a facemask with desflurane (Suprane ; Baxter Healthcare, Deerfield, IL, USA) or sevoflurane (Sevorane ; Abbott Laboratories, Abbott Park, IL, USA) at concentrations of 0.7 1.2 MAC, with 100% oxygen at a fresh gas flow (FGF) of 6.0 l/min. During facemask ventilation, rocuronium 0.6 µg/kg was given intravenously and remifentanil TCI was started at an effect-site concentration of 4.0 ng/ml. Endotracheal intubation was performed with a cuffed tracheal tube of 7.0 or 8.0 mm internal diameter for female or male patients, respectively. Cuff pressure was maintained at 20 25 mmhg throughout the procedure. The tidal volume was maintained at 8 10 ml/kg and a frequency of 8 11 breaths/min. Minute ventilation was controlled to maintain ETCO 2 between 35 and 40 mmhg during surgery. After induction, anaesthesia was maintained with desflurane or sevoflurane at 0.7 1.2 MAC with 50% oxygen at a FGF of 4.0 l/min and remifentanil effect-site TCI at 2.5 4.0 ng/ml, in order to maintain BP and heart rate (HR) within 20% of baseline values during surgery. At the end of surgery, both desflurane and sevoflurane were reduced to 0.5 MAC with 50% oxygen at a FGF of 4.0 l/min, and the effect-site concentration of remifentanil TCI was titrated to a predetermined concentration. The effect-site concentration of remifentanil used for each patient was determined by the response of the previously tested patient, using a modified Dixon s upand-down method with a step size of 0.5 ng/ml. Using this method, the first patient entering the study was tested at a remifentanil effect-site concentration of 1.0 ng/ml. If this patient experienced smooth emergence, the effect-site concentration of remifentanil was decreased by 0.5 ng/ml in the next patient and, if smooth emergence was not achieved, the effect-site concentration of remifentanil was increased by 0.5 ng/ml in the next patient. At 10 min after surgery, when the MAC value of inhalational anaesthetics and the effect-site concentration of remifentanil were judged to be in equilibrium by the attending anaesthetist (T base ), desflurane and sevoflurane were discontinued; remifentanil TCI was maintained at the predetermined concentration until extubation. After discontinuation of inhalational anaesthetics, manual ventilation was performed with 100% oxygen at a FGF of 6.0 l/min and ETCO 2 was maintained at 35 45 mmhg. When more than three responses to a trainof-four stimulation were observed, pyridostigmine 0.3 µg/kg and glycopyrrolate 0.008 µg/kg were given intravenously to reverse neuromuscular block. When the patient could breathe adequately and open his or her eyes spontaneously, or after verbal command (T before ), the tracheal tube was extubated (T after ). Immediately prior to extubation, the end-tidal concentration of inhalational anaesthetics and the MAC-awake value (MAC value when the patients could open his or her eyes on verbal command, MAC value at T before ) were recorded. Following extubation, remifentanil infusion was discontinued and time from discontinuation of inhalational anaesthetics to extubation was recorded. Body temperature was maintained at 36.5 ± 0.5 C during anaesthesia. Oxygen (100%) was applied after extubation via a facemask for 5 min and complications such as hypoventilation (respiratory rate < 8 breaths/min), desaturation (SpO 2 < 95%), and bradycardia (HR < 45 beats/min) were recorded. Mean arterial pressure (MAP) and HR were recorded at T base, T before and T after ). Duration of stay in the postanaesthetic care unit (PACU) was also recorded. 176

MEASUREMENT OF EMERGENCE COUGH Cough was recorded during the emergence period from discontinuation of inhalational anaesthetics to extubation (i.e. between T base and T after ) and was defined as a strong and sudden contraction of the abdomen. Smooth emergence was defined as a success if cough did not develop. Failure of smooth emergence was defined by the development of cough. Cough was recorded by an anaesthesiologist blinded to the concentration of remifentanil. STATISTICAL ANALYSES Statistical analyses were performed using the SPSS statistical package, version 11.0 (SPSS Inc., Chicago, IL, USA) for Windows. Data are reported as the mean ± SD. Normally distributed data were analysed by Student s t- test. The Mann Whitney U-test was used for data that were not normally distributed. Differences in proportions were compared by Pearson s χ 2 -test. MAP and HR during emergence were compared between treatment groups by repeated measures analysis of variance. A P-value of < 0.05 was considered to be statistically significant. The EC 50 of remifentanil was defined as the effect-site concentration that produced 50% of the maximal effect and was determined by calculating the mean of the midpoint effect-site concentration of seven independent pairs of patients (shift from failure to success of smooth emergence). Data were also analysed by probit analysis with sigmoid curve, which enabled the EC 50 of remifentanil with 95% confidence intervals (CI) to be derived. Results The study included 48 patients undergoing elective thyroidectomy, who were randomly assigned to receive desflurane (n = 27) or sevoflurane (n = 21). As shown in Table 1, there were no between-group differences in demographic or surgical characteristics and MAC-awake values. There were no differences between groups in emergence and recovery profiles with the exception of extubation time, which was significantly shorter in the desflurane group TABLE 1: Demographic and surgical characteristics of adult patients who underwent thyroidectomy with desflurane or sevoflurane (0.7 1.2 minimum alveolar concentration [MAC]) anaesthesia and remifentanil effect-site target-controlled infusion at 2.5 4.0 ng/ml Desflurane Sevoflurane Characteristic (n = 27) (n = 21) Age, years 45.3 ± 8.7 46.9 ± 9.9 Female 23 (85.2) 16 (76.2) Weight, kg 61.4 ± 8.6 60.0 ± 9.5 Height, cm 161.5 ± 5.8 163.3 ± 9.3 History of smoking 4 (14.8) 3 (14.3) Duration of surgery, min 136.9 ± 53.5 134.0 ± 48.4 MAC-awake value a 0.2 ± 0.1 0.2 ± 0.1 Data presented as mean ± SD or n (%) patients. a MAC-awake value: the fraction of age-adapted 1 MAC calculated with the end-expiratory concentration of inhalational anaesthetics when the patient could open his or her eyes on verbal command. Data were not significantly different between groups (P > 0.05); continuous variables were compared with Student s t-test or Mann Whitney U-test; categorical variables were compared using Pearson s χ 2 -test. 177

than in the sevoflurane group (P = 0.024) (Table 2). Desaturation of < 95% SpO 2 was observed in more patients in the desflurane group compared with the sevoflurane group, but this difference was not statistically significant (Table 2). Compared with baseline levels, both MAP and HR were increased during extubation, but there were no statistically significant differences between patients who received anaesthesia with desflurane or sevoflurane (Table 3). The sequences of failed and successful smooth emergence from desflurane and sevoflurane anaesthesia are shown in Figs 1 and 2, respectively. The EC 50 of remifentanil TCI, as determined by Dixon s up-and-down method, for preventing cough during emergence after desflurane was 1.54 ± 0.70 ng/ml, and after sevoflurane was 1.11 ± 0.24 ng/ml. There were no significant differences between the two treatment groups. Probit TABLE 2: Emergence and recovery profile of adult patients who underwent thyroidectomy with desflurane or sevoflurane (0.7 1.2 minimum alveolar concentration) anaesthesia and remifentanil effect-site target-controlled infusion at 2.5 4.0 ng/ml Desflurane Sevoflurane (n = 27) (n = 21) Extubation time, min 8.6 ± 3.9 12.0 ± 6.2 a Desaturation, SpO 2 < 95% 4 (14.8) 1 (4.8) Hypoventilation, RR < 8 breaths/min 3 (11.1) 3 (14.3) Bradycardia, HR < 45 beats/min 0 (0) 0 (0) Duration of PACU stay, min 35.6 ± 6.8 35.0 ± 9.2 Data presented as mean ± SD or n (%) of patients. a P = 0.024; Student s t-test. Extubation time, time from the discontinuation of inhalational anaesthetics to extubation; PACU, postanaesthetic care unit; RR, respiratory rate; HR, heart rate. TABLE 3: Comparison of haemodynamic profiles during extubation between adult patients who underwent elective thyroidectomy with desflurane or sevoflurane anaesthesia (0.7 1.2 minimum alveolar concentration) and remifentanil effect-site target-controlled infusion at 2.5 4.0 ng/ml Desflurane Sevoflurane Haemodynamic parameter (n = 27) (n = 21) MAP, mmhg T base 85.5 ± 11.9 92.5 ± 13.5 T before 102.4 ± 17.9 103.0 ± 10.8 T after 106.8 ± 16.4 110.9 ± 11.9 HR, beats/min T base 62.0 ± 9.6 63.1 ± 11.4 T before 83.5 ± 15.8 83.5 ± 12.8 T after 90.0 ± 17.5 91.7 ± 18.6 Data presented as mean ± SD. MAP, mean arterial pressure; HR, heart rate; T base, time of equilibrium of inhalational anaesthetics and remifentanil; T before, before extubation; T after, after extubation. No significant differences between groups; repeated measures analysis of variance. 178

Remifentanil effect-site concentration (ng/ml) 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Success Failure Crossover midpoint 0 0 5 10 15 20 25 Consecutive patients FIGURE 1: Consecutive successful smooth emergence and failed smooth emergence over predetermined concentrations of remifentanil (with initial predetermined concentration being 1.0 ng/ml for the first patient) after desflurane anaesthesia (n = 27). Seven pairs of failed smooth emergence successful smooth emergence sequences were received for analysis with the modified Dixon s up-and-down method. The mean ± SD effect-site concentration of remifentanil that produced 50% of the maximal effect (EC 50 ) for preventing cough during emergence after desflurane was 1.54 ± 0.70 ng/ml analysis with sigmoid curve demonstrated EC 50 of remifentanil TCI of 1.49 ng/ml (95% CI 0.9, 2.20) and 2.88 ng/ml (95% CI 2.18, 6.37) in the desflurane group, and 0.90 ng/ml (95% CI 0.17, 1.52) and 2.29 ng/ml (95% CI 1.62, 5.45) in the sevoflurane group, respectively. Again, there were no significant between-group differences. Discussion The present study demonstrated that there were no significant differences in the EC 50 of remifentanil for suppression of cough during emergence from either desflurane or sevoflurane anaesthesia after thyroidectomy, as determined using a modified Dixon s upand-down method. There were also no between-group differences in the EC 95, as determined using probit analysis with sigmoid curve. A high incidence of airway reactivity during induction with desflurane has been well documented because of its airway irritant properties. 13 Similar findings have also been reported during emergence from general anaesthesia, 9 11 when tracheal tube stimulation, noxious effects of the anaesthetic gas or uncleared secretions are all thought to increase the incidence of cough. 9,10 Protective airway reflexes return more rapidly following anaesthesia with desflurane and this may further increase the 179

2.0 Success Failure Crossover midpoint Remifentanil effect-site concentration (ng/ml) 1.5 1.0 0.5 0 0 5 10 Consecutive patients 15 20 FIGURE 2: Consecutive successful smooth emergence and failed smooth emergence over predetermined concentrations of remifentanil (with initial predetermined concentration being 1.0 ng/ml for the first patient) after sevoflurane anaesthesia (n = 21). Seven pairs of failed smooth emergence successful smooth emergence sequences were received for analysis with the modified Dixon s up-and-down method. The ± SD effect-site concentration of remifentanil that produced 50% of the maximal effect (EC 50 ) for preventing cough during emergence after sevoflurane was 1.11 ± 0.24 ng/ml likelihood of emergence cough. 14 Several studies have demonstrated a higher incidence of emergence cough with desflurane compared with sevoflurane, 9 11 although one study failed to show any differences. 15 The present study evaluated the effect of using remifentanil for preventing cough during emergence from inhalational anaesthetics. Even though there were slight variations in the use of remifentanil, no significant impact on the incidence of emergence cough was observed between patients who were anaesthetized with either desflurane or sevoflurane. The incidence of cough during emergence is known to be lower after propofol anaesthesia compared with sevoflurane anaesthesia. 16 Research has also demonstrated that the EC 50 of remifentanil TCI for suppressing cough during emergence from propofol remifentanil anaesthesia were 1.54 ng/ml and 2.14 ng/ml, respectively, using Dixon s up-and-down method. 17 Interestingly, the effect-site concentration of remifentanil after propofol remifentanil anaesthesia 17 was comparable with the results obtained in the present analysis. This suggests that the effect-site concentration of remifentanil is similar regardless of whether the background anaesthetic during emergence is an intravenous or inhalational agent, 180

implying that the depth of anaesthesia is light enough to elicit the airway reflexes. Following the publication of studies that failed to show a higher incidence of cough after desflurane, it has been proposed that the use of opioids during the intraoperative period might minimize differences between airway responses to desflurane and other volatile anaesthetics. 10,18 20 This may also be true of the present study: use of remifentanil infusion during emergence could have minimized differences in airway responsiveness to desflurane and sevoflurane, such that the remifentanil effect-site concentration for prevention of emergence cough was not significantly different in either treatment group. Administration of an opioid before emergence is effective in preventing cough reflex, 21 but can delay recovery following general anaesthesia. A single bolus administration of an opioid before emergence may frequently result in delayed emergence or failed smooth emergence, because of the difficulty in predicting plasma or effect-site concentrations. 7 Remifentanil is, however, an ultra-short-acting opioid and its context-sensitive half-life is also short. 22 In addition, it is easy to titrate the proper plasma or effect-site concentration of remifentanil TCI to maintain the antitussive effect during emergence, thereby avoiding adverse effects such as respiratory depression and profound anaesthesia. 17 Several studies have demonstrated the efficacy of remifentanil TCI for preventing cough during emergence in different clinical settings. 17,23,24 Five of the 48 patients in the present study showed transient hypo - ventilation and desaturation (SpO 2 < 95%) after extubation but they recovered easily, by encouragement, to breathe oxygen administrated via a facemask. Extubation time was significantly shorter in the desflurane group compared with the sevoflurane group, and the duration of PACU stay was around 35 min in both groups. These results are similar to previous reports. 25,26 The findings of the present study suggested that maintaining an established effect-site concentration of remifentanil during emergence may represent an efficient method for smooth emergence from sevoflurane and desflurane anaesthesia without compromising recovery. There are, however, some limitations to the present study. First, the predicted values of remifentanil using Minto s pharmacokinetic model were used, 12 rather than measured plasma concentrations. This model is, however, widely used in clinical settings with an acceptable level of bias and inaccuracy. 27 Secondly, inhalational agents in themselves have varying effects on airway reactivity at different MAC values; 28 as such, the different inhalational concentrations at discontin - uation of anaesthesia may have had an effect on the results. To minimize this effect in the present study, end-tidal and effect-site concentrations of desflurane and sevoflurane were allowed to equilibrate at 0.5 MAC with FGF 4 l/min for 10 min at the end of surgery. MAC-awake value by fast washout was not influenced by the concentration of gas or the duration of inhalation. 29 Thus, the influence of different inhalational anaesthetic concentrations between the groups was minimal in the design of the present study. Thirdly, thyroidectomy may be associated with a higher incidence of cough than other surgery because the trachea is physically manipulated during surgery. 30 Finally, the study population included a higher proportion of female patients due to the greater prevalence of thyroid cancer in females. 31 There is also a gender-related difference in recovery time after desflurane and sevoflurane. 32 Together, these limitations 181

and characteristics must be taken into account when interpreting the data. While the sample size used in the present study was not large enough to make generalizations on the absence of statistical difference in the use of remifentanil TCI, the study does offer an important starting point for further research on a wider scale. In conclusion, in spite of the greater potency and airway irritant properties of desflurane, the effect-site concentration of remifentanil TCI for preventing cough during emergence from desflurane anaesthesia was not higher than that observed for sevoflurane anaesthesia. During emergence, variations in effect-site concentrations of remifentanil for preventing cough are of limited importance, since they do not generate significant differences in results. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 19 September 2011 Accepted subject to revision 29 September 2011 Revised accepted 25 November 2011 Copyright 2012 Field House Publishing LLP References 1 Irwin RS: Complications of cough: ACCP evidence-based clinical practice guidelines. Chest 2006; 129(1 suppl): 54S 58S. 2 Harding J, Sebag F, Sierra M, et al: Thyroid surgery: postoperative hematoma prevention and treatment. Langenbecks Arch Surg 2006; 391: 169 173. 3 Neelakanta G, Miller J: Minimum alveolar concentration of isoflurane for tracheal extubation in deeply anesthetized children. Anesthesiology 1994; 80: 811 813. 4 Guler G, Akin A, Tosun Z, et al: Single-dose dexmedetomidine attenuates airway and circulatory reflexes during extubation. Acta Anaesthesiol Scand 2005; 49: 1088 1091. 5 Saghaei M, Reisinejad A, Soltani H: Prophylactic versus therapeutic administration of intravenous lidocaine for suppression of post-extubation cough following cataract surgery: a randomized double blind placebo controlled clinical trial. Acta Anaesthesiol Taiwan 2005; 43: 205 209. 6 Fagan C, Frizelle HP, Laffey J, et al: The effects of intracuff lidocaine on endotracheal-tubeinduced emergence phenomena after general anesthesia. Anesth Analg 2000; 91: 201 205. 7 Shajar MA, Thompson JP, Hall AP, et al: Effect of a remifentanil bolus dose on the cardiovascular response to emergence from anaesthesia and tracheal extubation. Br J Anaesth 1999; 83: 654 656. 8 Aouad MT, Al-Alami AA, Nasr VG, et al: The effect of low-dose remifentanil on responses to the endotracheal tube during emergence from general anesthesia. Anesth Analg 2009; 108: 1157 1160. 9 Arain SR, Shankar H, Ebert TJ: Desflurane enhances reactivity during the use of the laryngeal mask airway. Anesthesiology 2005; 103: 495 499. 10 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: 387 393. 11 Lema FE, Tafur LA, Giraldo C, et al: Incidence of cough after desflurane and sevoflurane administration through a laryngeal mask: a controlled clinical trial. Rev Esp Anestesiol Reanim 2010; 57: 141 146 [in Spanish, English abstract]. 12 Minto CF, Schnider TW, Shafer SL: Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. Anesthesiology 1997; 86: 24 33. 13 Taylor RH, Lerman J: Induction, maintenance and recovery characteristics of desflurane in infants and children. Can J Anaesth 1992; 39: 6 13. 14 McKay RE, Large MJ, Balea MC, et al: Airway reflexes return more rapidly after desflurane anesthesia than after sevoflurane anesthesia. Anesth Analg 2005; 100: 697 700. 15 McKay RE, Bostrom A, Balea MC, et al: Airway responses during desflurane versus sevoflurane administration via a laryngeal mask airway in smokers. Anesth Analg 2006; 103: 1147 1154. 16 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: 731 737. 17 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 182

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