Optimal effect-site concentration of remifentanil for preventing cough during emergence from sevofluraneremifentanil

Transcription

1 doi: /j x ORIGINAL ARTICLE Optimal effect-site concentration of remifentanil for preventing cough during emergence from sevofluraneremifentanil anaesthesia* N. H. Jun, 1 J. W. Lee, 2 J. W. Song, 3 J. C. Koh, 4 W. S. Park 3 and Y. H. Shim 5 1 Instructor, 2 Assistant Professor, 3 Clinical Assistant Professor, 4 Resident, 5 Associate Professor, Department of Anaesthesiology and Pain Medicine and Anaesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea Summary This randomised, double-blinded, controlled trial was designed to identify the optimal dose of remifentanil for cough suppression without adverse effects during emergence from sevofluraneremifentanil anaesthesia for thyroidectomy. One hundred and four patients were randomly assigned to maintain target effect-site concentrations of remifentanil at 0 (control ), 1.0 (remifentail 1 ), or 1.5 ng.ml )1 (remifentanil 1.5 ) during emergence. The incidence of coughing was lower in the remifentanil 1.5 (31%) than in the control (74%) or remifentanil 1 (63%) (p = ). In addition, the severity of coughing during extubation was lower in the remifentanil 1.5 (median (IQR [range]) 0 (0 1 [0 1]) than in the control (1 (0 2 [0 3])) and remifentanil 1 (1 (0 2 [0 3])) (p = 0.004). Haemodynamic changes were reduced, but emergence time and stay in the post-anaesthesia care unit was prolonged in the remifentanil 1.5. Maintaining the remifentanil effect-site concentration at 1.5 ng.ml )1 during emergence from sevoflurane-remifentanil anaesthesia reduces the incidence and severity of coughing without serious adverse events and may provide haemodynamic stability in patients undergoing thyroidectomy. However, awakening may be delayed.... Correspondence to: Dr Yon Hee Shim tren125@yuhs.ac *Presented at the 86th Annual Scientific Meeting of the Korean Society of Anaesthesiologists, November 2009 Accepted: 9 June 2010 Coughing during emergence from general anaesthesia after surgery may lead to a number of potentially dangerous effects, including laryngospasm, detrimental haemodynamic changes, and increased intraocular and intracranial pressure. Post-thyroidectomy bleeding occurs in 1 4% of patients [1 4] resulting in acute airway obstruction or re-operation, and severe coughing may cause bleeding [1, 4]. Intravenous opioids delivered at the end of surgery may provide smooth emergence by reducing coughing [5, 6], agitation [6] and deleterious haemodynamic changes [7]. However, these agents can also cause depression of ventilation and delay awakening. Remifentanil may be maintained during emergence due to its rapid onset and offset of action [8, 9]. A low-dose manually controlled infusion of remifentanil has been reported to reduce the incidence and severity of coughing during emergence [10]. Due to individual variability, manually controlled infusion is not a reliable technique for determining the optimal infusion rates. Administration of drugs via a target-controlled infusion (TCI) makes it possible to reach a defined target concentration without the concerns that drug levels will rapidly change or increase beyond the intended range [11]. In this randomised, double-blinded, controlled trial, we compared the effects of three effect-site concentrations (Ce) of remifentanil TCI for the optimal dose to suppress coughing without serious adverse effects during emergence from sevoflurane-remifentanil anaesthesia in patients undergoing elective thyroidectomy. 930 Journal compilation Ó 2010 The Association of Anaesthetists of Great Britain and Ireland

2 N. H. Jun et al. Æ Preventing cough with remifentanil during emergence Methods After obtaining approval from our Institutional Review Board and written consent from all patients, a total of 105 patients (ASA physical status 1 2) aged years, scheduled for elective thyroidectomy under general anaesthesia, were randomly allocated to one of three s according to a computer-generated random table. Exclusion criteria included treatment with sedatives, antitussives, or angiotensin converting enzyme (ACE) inhibitors, allergies to any of the drugs used in the study, a history of smoking, chronic cough, asthma, recent respiratory tract infection, predicted difficult intubation, increased risk of aspiration, and significant cardiopulmonary, renal, or hepatic disease. All patients were premedicated with midazolam 0.05 mg.kg )1 intramuscularly 30 min before induction and glycopyrronium 0.2 mg IV immediately before induction of anaesthesia. Patients were monitored with ECG, arterial oxygen saturation (S p O 2 ), oropharyngeal temperature and non-invasive blood pressure. End-expiratory concentrations of carbon dioxide and sevoflurane were continuously measured at the elbow of the breathing circuit with a precalibrated gas monitor (Smart Anaesthesia Multi-Gas (SAM) TM, GE Marquette Medical Systems, Milwaukee, WI, USA) at a sampling flow rate of 250 ml.min )1. For effect-site TCI of remifentanil, a commercial TCI pump (Orchestra Base Primea, Fresenius Vial, Brézins, France) using Minto s pharmacokinetic model was used. General anaesthesia was induced with IV propofol mg.kg )1, lidocaine 20 mg and a effect-site TCI of remifentanil set at 3 ng.ml )1. After loss of verbal response and eyelash reflex, rocuronium 0.6 mg.kg )1 was administered and tracheal intubation was performed in all patients using a 6.0- and 7.0-mm tracheal tube for women and men, respectively. The cuff was inflated with air and the cuff pressure maintained at kpa. Mechanical ventilation was adjusted to maintain the endexpiratory carbon dioxide concentration at kpa. Patients temperature was maintained at 36.5 ± 0.5 C. Anaesthesia was maintained with sevoflurane % and effect-site TCI of remifentanil at ng.ml )1 to maintain blood pressure and heart rate within 20% of baseline values during the surgery. Towards the end of surgery and when suturing of the subcutaneous layer began, the concentration of sevoflurane was reduced to 1.0%. Next, tracheal and oral suctioning was performed, followed by IV administration of ketorolac 1.0 mg.kg )1 and ondansetron 4 mg for pain and postoperative nausea and vomiting. At the beginning of skin suturing, the remifentanil infusion was adjusted according to assignment. In the control the remifentanil was stopped, and the target effects-site was reduced to 1.0 and 1.5 ng.ml )1 in the remifentanil 1 and remifentanil 1.5 s, respectively. After completing skin suturing, the sevoflurane was stopped (time 0). After confirmation of four responses to a train-of-four (TOF) stimulation, glycopyrronium mg.kg )1 and neostigmine 0.02 mg.kg )1 were given to reverse neuromuscular block to an endpoint of a > 90% response in the TOF ratio. After discontinuation of sevoflurane, manual ventilation was performed with 100% oxygen at 4 l.min )1 and patients were stimulated at 30-s intervals either verbally or by gentle tactile stimulation. When patients spontaneously opened their eyes or responded to verbal commands, deep breathing was encouraged and tracheal extubation was performed. After tracheal extubation, remifentanil was stopped in the remifentanil 1 and 1.5 s, oxygen was applied via a facemask, and assisted ventilation was used to maintain end-expiratory CO 2 concentration at kpa. After adequate spontaneous respiration resumed, the patient was transferred to the post-anaesthesia care unit (PACU). The following variables were recorded at five time points: the mean arterial blood pressure, heart rate, S p O 2, spontaneous respiratory rate, end-expiratory CO 2 and sevoflurane concentrations, effect-site and plasma concentration of remifentanil, and the Ramsay Sedation Scale (1 patient is anxious and agitated or restless, or both; 2 patient is co-operative, oriented, and tranquil; 3 patient responds to commands only; 4 patient exhibits brisk response to light glabellar tap or loud auditory stimulus; 5 patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus; 6 patient exhibits no response). These variables were measured at the following time points: before induction; at discontinuation of sevoflurane; at first response to verbal commend or spontaneous eye-opening; immediately before and 5 min after extubation. Emergence time, which was defined from time zero to first response to verbal commands or spontaneous eye-opening, was also recorded. The grades of coughing episodes (0 no coughing; 1 a single cough; 2 more than one episode of non-sustained coughing; 3 sustained and repetitive coughing with head lift) were evaluated at three time points: when the tracheal tube was still present (after the discontinuation of sevoflurane but before the patient s first spontaneous eye opening or response to verbal commands); during extubation; and after extubation. Episodes of bronchospasm, laryngospasm, desaturation (S p O 2 < 90%) or hypoventilation (spontaneous respiratory rate < 8 min )1 ) during emergence were recorded. Two anaesthetists, who were blinded to allocation, independently recorded these variables and performed the extubation. Journal compilation Ó 2010 The Association of Anaesthetists of Great Britain and Ireland 931

3 N. H. Jun et al. Æ Preventing cough with remifentanil during emergence Anaesthesia, 2010, 65, pages The following variables were recorded at the time of admission to the PACU, 5 min after admission, and just before discharge: mean arterial pressure, heart rate, Ramsay Sedation Scale, S p O 2, spontaneous respiratory rate, presence of postoperative nausea and vomiting, verbal numerical rating scale scores for pain (11-point scale, 0 10), and use of analgesics. Fentanyl 1 lg.kg )1 was given when pain scores exceeded 5 or a patient requested analgesics. Patients were discharged from the PACU by a physician when their Aldrete score was 9 [12]. The incidence of coughing during emergence from sevoflurane anaesthesia has been reported as 59% [13]. Assuming that 50% reduction would be clinically significant and permitting a type-i error of a = 0.05 and a type-ii error of b = 0.2 (a power of 80%) required 31 patients per. Taking into account of the possibility of patients withdrawal, we assigned 35 patients to each. Statistical analyses were performed with the SPSS package, version 13.0 (SPSS Inc, Chicago, IL, USA). Continuous variables were analysed using analysis of variance. Categorical data were analysed using Fisher s exact test or chi-squared test as appropriate. Repeated measures ANOVA with Bonferroni correction was employed for mean arterial pressure, heart rate and respiratory rate. If significant differences were detected, differences between two s were compared by independent t-test with Bonferroni correction. Pain scores were analysed by Kruskal-Wallis tests. A value of p < 0.05 was considered significant. Results A total of 104 patients completed the study. One patient (in the remifentanil 1 ) was excluded because of a combined mastectomy. Patient and operative characteristics were similar among the three s (Table 1). When sevoflurane was discontinued, the ratio of the Cp (plasma concentration) to Ce was in the remifentanil 1 and 1.5 s, and 0.7 in the control. The mean (SD) effect-site remifentanil concentration during tracheal extubation was 0.6 (0.1) ng.ml )1 in the control, 1.0 (0.0) ng.ml )1 in the remifentatnil 1, and 1.5 (0.0) ng.ml )1 in the remifentanil 1.5. Data on emergence are given in Table 2. The number of patients with cough during emergence was lower in the remifentanil 1.5 than in the others s. There were no patients with severe cough (grade 3) in the remifentanil 1.5. The severity of cough grade Table 1 Patients characteristics and operation details. Values are mean (SD) or number. Control Remifentanil 1 (n = 34) Remifentanil 1.5 Age; years 49 (9) 48 (10) 44 (9) Sex; M F Weight; kg 60 (11) 61 (9) 62 (9) Height; cm 160 (8) 161 (8) 161 (7) Duration of surgery; min 108 (38) 111 (54) 111 (48) Duration of anaesthesia; min 137 (41) 139 (57) 136 (52) End-expiratory sevoflurane at tracheal extubation; % 0.5 (0.2) 0.4 (0.2) 0.4 (0.2) Table 2 Emergence profile in the operating room. Values are mean (SD), median (IQR [range]), or number (proportion). Control Remifentanil 1 (n = 34) Remifentanil 1.5 Total number of patients with: Cough 25 (74%) 22 (63%) 11 (31%)* Severe cough (grade 3) 8 (24%) 6 (17%) 0 (0%) Emergence time; min 5 (2) 7 (3) 7 (3) Ramsay Sedation Scale 5 min after tracheal extubation 2 (2 3 [1 3]) 2 (2 3 [2 4]) 2 (2 3 [2 4]) Spontaneous respiratory rate;.min )1 During tracheal extubation 8 (4) 8 (5) 7 (5) Five minutes after tracheal extubation 11 (4) 10 (3) 9 (4) Desaturation (S p O 2 < 90%) 0 (0%) 0 (0%) 1 (3%) *p = , p = 0.005, p = 0.008, p = 0.04 vs other two s. 932 Journal compilation Ó 2010 The Association of Anaesthetists of Great Britain and Ireland

4 N. H. Jun et al. Æ Preventing cough with remifentanil during emergence (a) (a) (b) (b) (c) Figure 2 Mean (SD) haemodynamic changes during emergence: (a) mean arterial pressure; (b) heart rate. T0 = baseline (before anaesthetic induction); T1 = at discontinuation of sevoflurane; T2 = at first response to verbal command or spontaneous eye-opening; T3 = immediately after extubation; T4 = 5 min after extubation. d, control ; s, remifentanil 1 ;., remifentanil 1.5. *p = 0.02 vs control, p = 0.01 vs control. Figure 1 Cough grade during emergence: (a) in the presence of the tracheal tube; (b) during tracheal extubation; (c) after tracheal extubation. *p = vs control and remifentanil 1 s. during tracheal extubation was lower in the remifentanil 1.5 than in the other s (Fig. 1). Emergence time was prolonged in the remifentnail s compared with the control (Table 2, p = 0.008). There were no differences in sedation. The spontaneous respiratory rate was lower in the remifentanil min after extubation, but there were no episodes of hypoventilation before leaving the theatre and no differences in the incidence of desaturation during emergence among the s (Table 2). The mean arterial pressure at emergence and the heart rate immediately after extubation were lower in the remifentanil 1.5 (Fig 2a,b). Data on recovery are given in Table 3. At admission to the PACU, there were no differences in respiratory rate and the incidence of hypoventilation among s. The PACU stay was prolonged in the remifentanil 1.5. There were no differences in postoperative nausea and vomiting, sedation and postoperative pain between the three s. Journal compilation Ó 2010 The Association of Anaesthetists of Great Britain and Ireland 933

5 N. H. Jun et al. Æ Preventing cough with remifentanil during emergence Anaesthesia, 2010, 65, pages Table 3 Recovery profile in the PACU. Values are mean (SD), median (IQR [range]) or number (proportion). Control Remifentanil 1 (n = 34) Remifentanil 1.5 PACU stay; min 43 (13) 43 (10) 51 (12)* Spontaneous respiratory rate;.min )1 17 (3) 16 (3) 16 (3) Ramsay Sedation Scale 2 (2 3 [2 4]) 2 (2 3 [1 3]) 2 (2 3 [2 3]) PONV 1 (3%) 3 (9%) 7 (20%) Pain score 5 (4 7 [3 8]) 6 (4 8 [0 8]) 6 (3 8[2 8]) Use of analgesics 12 (35%) 8 (23%) 10 (29%) *p = 0.03 vs other two s. Discussion The results of this study demonstrate that using a targetcontrolled infusion of remifentanil at an effect-site of 1.5 ng.ml )1 during emergence reduces the incidence and severity of coughing without clinically significant complications after sevoflurane-remifentanil anaesthesia in patients undergoing elective thyroidectomy. However, remifentanil 1.5 ng.ml )1 was associated with delayed emergence and discharge from the PACU. A remifentanil Ce of 1.0 ng.ml )1 delayed emergence but did not suppress coughing. Coughing is mediated by superficial receptors found throughout the trachea [14] and through vagal afferent pathways that terminate in the brainstem respiratory centre [15]. Intravenous opioids are one method for preventing cough during emergence, acting on opioid receptors in both the brainstem [16] and peripheral sensory nerve endings [17]. Sharjar et al. [18] demonstrated that a single bolus of remifentanil 0.1 lg.kg )1 reduces haemodynamic instability during emergence and delays emergence from isoflurane-based anaesthesia, but fails to reduce coughing. The high clearance of remifentanil [8, 9], combined with its small steady-state distribution volume, makes it difficult to maintain a sufficient plasma or effect-site concentration to suppress coughing after a single bolus dose. Continuous remifentanil infusion has been widely used as an adjunct to general anaesthesia and may be more appropriate during emergence. Aouad et al. [10] demonstrated that a low-dose infusion of remifentanil during emergence suppresses coughing and provides a smooth emergence from isoflurane-based anaesthesia. They maintained remifentanil at one tenth of the mean dose, which was calculated at the end of the surgery by dividing the total dose administered during maintenance by the patient s weight and the duration of surgery. Calculation of the mean dose is problematic and due to individual variability a manually controlled infusion is not a reliable technique for determining the optimal infusion rate. For continuous infusion of remifentanil, TCI is a safer and more predictable method to avoid overdosing compared with a manually controlled infusion [19]. We found that maintaining remifentanil Ce at 1.5 ng.ml )1 during emergence resulted in a 50% reduction in the incidence of coughing and no episodes of severe coughing (grade 3). In contrast, maintaining remifentanil Ce at 1.0 ng.ml )1 did not reduce the incidence or severity of coughing. Although remifentanil was discontinued before emergence in the control, the predicted effect-site concentration was not zero at extubation. Lee et al. [20] demonstrated that the EC 50 and EC 95 of remifentanil Ce for suppressing cough during emergence from propofol-remifentanil anaesthesia was 1.54 and 2.14 ng.ml )1 respectively, using Dixon s up and down method. The incidence of coughing at an effect site concentration of 1.5 ng.ml )1 in our study was lower than in Lee s study, although coughs during emergence are more frequent [21] or more severe [13] after sevoflurane than after propofol-based anaesthesia. Patient and anaesthetic characteristics in both studies were similar except the inclusion of male patients in our study. The factors responsible for differences between our study and others include the sample size and the methodology used to investigate the optimal effect-site of remifentanil, as well as the smaller tracheal tube size used in this study. We found that maintaining a low (1.0 and 1.5 ng.ml )1 ) effect-site concentration of remifentanil during emergence did not affect the level of sedation after extubation. It did delay emergence, but there was no clinical significance. However, a remifentanil Ce of 1.5 ng.ml )1 prolonged PACU stay. Although the spontaneous respiratory rate was slightly reduced with a remifentanil effect-site concentration of 1.5 ng.ml )1 compared with the control at 5 min after extubation, respiratory rate recovered after awakening the patient. A target Ce 1.5 ng.ml )1 of remifentanil during emergence 934 Journal compilation Ó 2010 The Association of Anaesthetists of Great Britain and Ireland

6 N. H. Jun et al. Æ Preventing cough with remifentanil during emergence may attenuate haemodynamic disturbance, especially tachycardia [10, 18, 20]. Maintaining a remifentanil Ce of 1.5 ng.ml )1 did not increase the incidence of nausea and vomiting, and all patients were discharged from the PACU without experiencing any adverse events. There are some limitations to the present study. Firstly, we did not measure plasma concentrations of remifentanil. Rather, we used the predicted value using Minto s pharmacokinetic model which is widely used in clinical settings with an acceptable level of bias and inaccuracy [22]. Secondly, pharmacogenetic characteristics such as opioid sensitivity may exhibit ethnic variations and our study sample was of Asian descent. Third, we tested only two concentrations of remifentanil. Based on the results of Lee et al. [20], higher effect-site concentrations of remifentanil may be more effective without increasing side effects. In conclusion, maintaining the predicted effect-site concentration of remifentanil at 1.5 ng.ml )1 during emergence from sevoflurane-remifentanil anaesthesia suppressed coughing without serious adverse events in patients undergoing elective thyroidectomy. However, this was associated with delayed awakening. Competing interests No external funding and no competing interests declared. References 1 Lee HS, Lee BJ, Kim SW, et al. Patterns of post-thyroidectomy hemorrhage. Clinical and Experimental Otorhinolaryngology 2009; 2: Godballe C, Madsen AR, Pedersen HB, et al. Postthyroidectomy hemorrhage: a national study of patients treated at the Danish departments of ENT Head and Neck Surgery. European Archives of Oto-Rhino-Laryngology 2009; 266: Leyre P, Desurmont T, Lacoste L, et al. Does the risk of compressive hematoma after thyroidectomy authorize 1- day surgery? Langenbecks Archives of Surgery 2008; 393: Harding J, Sebag F, Sierra M, Palazzo FF, Henry JF. Thyroid surgery: postoperative hematoma prevention and treatment. Langenbecks Archives of Surgery 2006; 391: Tagaito Y, Isono S, Nishino T. Upper airway reflexes during a combination of propofol and fentanyl anesthesia. Anesthesiology 1998; 88: Mendel P, Fredman B, White PF. Alfentanil suppresses coughing and agitation during emergence from isoflurane anesthesia. Journal of Clinical Anesthesia. 1995; 7: Nishina K, Mikawa K, Maekawa N, Obara H. Fentanyl attenuates cardiovascular responses to tracheal extubation. Acta Anaesthesiologica Scandinavica 1995; 39: Egan TD, Minto CF, Hermann DJ, Barr J, Muir KT, Shafer SL. Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. Anesthesiology 1996; 84: Westmoreland CL, Hoke JF, Sebel PS, Hug CC, Muir KT. Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. Anesthesiology 1993; 79: Aouad MT, Al-Alami AA, Nasr VG, Souki FG, Zbeidy RA, Siddik-Sayyid SM. The effect of low-dose remifentanil on responses to the endotracheal tube during emergence from general anesthesia. Anesthesia and Analgesia 2009; 108: Egan TD. Target-controlled drug delivery: progress toward an intravenous vaporizer and automated anesthetic administration. Anesthesiology 2003; 99: Aldrete JA. The post-anesthesia recovery score revisited. Journal of Clinical Anesthesia. 1995; 7: 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. British Journal of Anaesthesia 2008; 101: Fagan C, Frizelle HP, Laffey J, Hannon V, Carey M. The effects of intracuff lidocaine on endotracheal-tube-induced emergence phenomena after general anesthesia. Anesthesia and Analgesia 2000; 91: Belvisi MG, Hele DJ. Cough sensors. III. Opioid and cannabinoid receptors on vagal sensory nerves. Handbook of Experimental Pharmacology 2009; 187: Bolser DC. Central mechanisms II: pharmacology of brainstem pathways. Handbook of Experimental Pharmacology 2009; 187: Spina D, McFadzean I, Bertram FK, Page CP. Peripheral mechanisms II: the pharmacology of peripherally active antitussive drugs. Handbook of Experimental Pharmacology 2009; 187: Shajar MA, Thompson JP, Hall AP, Leslie NA, Fox AJ. Effect of a remifentanil bolus dose on the cardiovascular response to emergence from anaesthesia and tracheal extubation. British Journal of Anaesthesia 1999; 83: Moerman AT, Herregods LL, De Vos MM, Mortier EP, Struys MM. Manual versus target-controlled infusion remifentanil administration in spontaneously breathing patients. Anesthesia and Analgesia 2009; 108: 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. British Journal of Anaesthesia 2009; 102: 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. British Journal of Anaesthesia 2007; 99: Mertens MJ, Engbers FH, Burm AG, Vuyk J. Predictive performance of computer-controlled infusion of remifentanil during propofol remifentanil anaesthesia. British Journal of Anaesthesia 2003; 90: Journal compilation Ó 2010 The Association of Anaesthetists of Great Britain and Ireland 935