Excellent intubating conditions are required to minimize the occurrence of injuries to the airway, the fourth leading cause of claims related to injuries as a result of general anaesthesia.1,2 The use of neuromuscular blocking drugs (NMBDs) during induction of anaesthesia provides significantly better intubating conditions and less vocal cord sequelae than relaxant-free induction of anaesthesia and, therefore, is advocated prior to tracheal intubation for elective surgery.2,3
However, patient factors may contraindicate the use of NMBDs – for example, history of allergy to NMBDs or myasthenia – and, further, administration of NMBDs may be associated with several complications, such as anaphylactic reactions, residual curarization – even after a single intubating dose of NMBD – and awareness during general anaesthesia.4–6
Several previous studies reported significantly fewer excellent intubating conditions when coadministering remifentanil 2 or 3 μg kg−1 with thiopental 5 or 6 mg kg−1 rather than with propofol 2 mg kg−1.7,8 However, a significant improvement in the quality of tracheal intubation was reported when increased doses of remifentanil were coadministered with thiopental 5 mg kg−1,9,10 reaching excellent intubating conditions in 85–89% of patients after an induction sequence of anaesthesia combining remifentanil 4 μg kg−1 with thiopental 5 mg kg−1. Hence, it can be assumed that an optimal amount of remifentanil allowing excellent intubating conditions to be reached in 95% of patients when coadministered with thiopental can be calculated by performing an appropriate dose–response study.
The aim of this dose–response study was to determine the intubating efficient dose (IED) of remifentanil coadministered with thiopental 5 mg kg−1 for providing excellent intubating conditions in 95% (IED95) of individuals undergoing elective surgery, using an optimized sequence of induction of anaesthesia and a standardized scale for the assessment of the quality of tracheal intubation.
After approval of the study by our institution ethics committee and obtaining patients' written consent, adult female patients scheduled for elective gynaecological surgery requiring tracheal intubation were enrolled. Inclusion criteria of the patients were American Society of Anesthesiologists (ASA) class 1 and 2 physical status, age ranging from 18 to 65 years and BMI ranging from 20 to 30 kg m−2. Patients with a history or evidence of a difficult airway (combination of a Mallampati score of 3 or 4 and a thyromental distance of less than 60 mm,11,12 mouth opening of less than 35 mm) were excluded.
Protocol for anaesthesia
All patients were premedicated with alprazolam 0.5 mg and hydroxyzine 1 mg kg−1 orally given 1 h before induction of anaesthesia.
Patients were randomized by a computer-generated list to receive one of four doses of remifentanil (3, 4, 5 or 6 μg kg−1). Allocation concealment was ensured by the use of coded, sealed opaque envelopes. Remifentanil was diluted with isotonic saline (50 μg ml−1) into a 50 ml syringe.
In the operating room, patients were preoxygenated until their end-tidal oxygen fraction was more than 90%, after which anaesthesia was induced. At time T0, remifentanil was infused over 60 s using a programmable device (Pilote Anesthésie 2, Fresenius Vial, Brezins, France), hidden behind a sheet, followed by a continuous infusion of 0.15 μg kg−1 min−1. Thiopental 5 mg kg−1 was administered at time T0+60 s, over 20 s. Once loss of eyelash reflex occurred, ventilation via facemask was initiated.
The same experienced senior physician, blinded to the remifentanil dose, performed all intubations using a Macintosh 3 laryngoscope metal blade and inserted an endotracheal tube of 6.5 or 7 mm at his discretion. At time T0+150 s, the physician attempted to intubate the trachea with the aim of completing tracheal intubation after 15 s. The quality of tracheal intubation was assessed as described below. If the intubating conditions were judged to be uncomfortable, supplemental boluses of remifentanil 1 μg kg−1 and/or succinylcholine 1 mg kg−1 were administered at the discretion of the intubating anaesthetist. For each patient, difficulties in ventilation through the face-mask or after tracheal intubation related to thoracic muscle rigidity were recorded. No topical anaesthesia of the larynx was performed. The tracheal tube cuff was inflated with 5–10 ml of air, while ensuring that intracuff pressure was less than 25 cmH2O, continuously monitored throughout anaesthesia.
Anaesthesia was maintained with 1.5–2% end-tidal sevoflurane in 50% oxygen and continuous infusion of remifentanil 0.15 μg kg−1 min−1. The lungs were ventilated to normocapnia. No further stimulation was applied to the patient until skin incision.
Monitors included an automated arterial pressure cuff, electrocardiogram, peripheral pulse oximeter and capnometer. Control values of arterial pressure and heart rate (HR) were recorded before induction of anaesthesia (preinduction values), 1 min after the end of thiopental infusion, and 1, 3 and 5 min following tracheal intubation. If mean arterial pressure (MAP) or HR decreased by more than 30% in comparison with corresponding preinduction values, ephedrine 3 mg or atropine 0.5 mg was administered intravenously, as needed to reach at least 70% of the preinduction value.
Assessment of intubating conditions
The quality of tracheal intubation was assessed using the qualitative scoring system proposed by the consensus conference on Good Clinical Research Practice (GCRP) in Pharmacodynamic Studies of Neuromuscular Blocking Agents.13 Six variables were recorded: jaw relaxation, resistance to the laryngoscope, vocal cord position, vocal cord movement, and the patient's response to intubation or cuff inflation (cough or movement). Each of these variables was rated as excellent, good or poor. The criteria for assigning values to each variable are set out in Table 1. Intubating conditions were excellent if all criteria were scored as excellent, good if all criteria were either excellent or good and poor if a single criterion was poor.
In a Cochran–Armitage test for trend in proportions, a sample size of 17 patients per group was obtained from four groups with remifentanil dosage values equal to 3, 4, 5 and 6 μg kg−1 and proportions of excellent intubating conditions equal to 0.40, 0.60, 0.80 and 0.90, respectively. The total sample of 68 participants achieved 81% power to detect a linear trend using a two-sided Z-test with continuity correction and a significance level of 0.05 [PASS 8.0.05 (NCSS, LCC, Kaysville, Utah, USA)].14
The Statistica version 6.0 computer software package (Statsoft, Tulsa, Oklahoma, USA) was used for analysis of the patients' characteristics and haemodynamic data. As appropriate, patients' characteristics were analysed using the Kruskal–Wallis H-test. Repeated measures of haemodynamic values were analysed by a two-way analysis of variance. Incidence data were analysed by χ2 test. The level of significance was set at a P value less than 0.05, with Bonferroni adjustment for multiple comparisons when appropriate.15
The event ‘success’ or ‘failure’ of excellent intubating conditions for each patient was analysed using the Statistical Package for Social Science version 12.0 (SPSS, Chicago, Illinois, USA) for probit regression to calculate the effective dose of remifentanil required to provide excellent intubating conditions in 50 and 95% of patients (IED50 and IED95).
Sixty-eight patients were enrolled in this study (17 patients per group). Patients' characteristics are shown in Table 2. All patients were women, as this study was performed in a gynaecological unit.
Results concerning the overall and individual intubating scores are summarized in Figs 1 and 2. Overall intubating conditions were significantly different between groups (Fig. 1). For 12 patients (seven from group 3 μg kg−1, two from group 4 μg kg−1 and three from group 5 μg kg−1), intubating conditions were judged poor (P = 0.01 between groups), and 10 of these patients could not be intubated in less than 15 s. All other patients were intubated in less than 15 s. With Bonferroni adjustments for multiple comparisons, overall intubating conditions were significantly different in group 3 μg kg−1 from those in group 6 μg kg−1, corresponding to significantly less excellent intubating conditions and less acceptable intubating conditions in group 3 μg kg−1 (Fig. 1). There was no statistical difference between groups as regards vocal cord position, jaw relaxation, resistance to the laryngoscope, movements of limbs and coughing (Fig. 2). Concerning movement of vocal cords, the significant difference between groups corresponded, with Bonferroni adjustment for multiple comparisons, to significantly less excellent conditions in group 3 μg kg−1 than in group 6 μg kg−1 (Fig. 2b). Nevertheless, there was no statistically significant difference between groups as regards the rates of moving vocal cords (P = 0.11).
There was a significant difference between groups as concerns the requirement for supplemental boluses of remifentanil, corresponding to significantly more boluses administered in group 3 μg kg−1 than in group 6 μg kg−1 (Table 3). No difference was recorded between groups with respect to the requirement for supplemental administration of succinylcholine (Table 3).
From probit analysis, the IED50 of remifentanil was 4.7 [95% confidence interval (CI) 4.0–5.3] μg kg−1, and the IED95 was 7.8 (95% CI 5.9–10.9) μg kg−1 (Fig. 3).
Two-way analysis of variance of MAP showed a significant decrease in MAP within the four groups of patients, without any significant difference between groups (Fig. 4). The greatest decrease in mean value of MAP was recorded 3 min after intubation and ranged from 26 to 28%. A significant decrease in mean HR values was registered in group 6 μg kg−1, 3 and 5 min after intubation compared with the preinduction value of HR, decreasing from 76 beats min−1 (preinduction) to 65 beats min−1 (3 min after intubation) and 63 beats min−1 (5 min after intubation). No significant decrease in mean HR values occurred in the other groups, and there was no statistically significant difference among groups (Fig. 4). No statistical difference was found between groups as concerns ephedrine requirement and median administered doses of ephedrine (Table 3). No patient required administration of atropine.
The aim of this dose–response study was to determine the IED95 of remifentanil when coadministered with thiopental 5 mg kg−1.
The dosages of remifentanil ranged from 3 to 6 μg kg−1 in this dose–response study, as some previous trials reported significant improvement in intubating conditions when increasing the induction dose of remifentanil from 2 to 4 μg kg−1, reaching excellent conditions in 85–89% of patients after the combination of remifentanil 4 μg kg−1 with thiopental 5 mg kg−1, whereas conditions were excellent in 45–49% and 5–6% of patients after the combination of the same dose of thiopental with remifentanil 3 and 2 μg kg−1, respectively.9,10 However, in the present dose–response study, we registered excellent intubating conditions in only six patients out of 17 in group remifentanil 4 μg kg−1, that is, excellent conditions in 35% of patients, and in group remifentanil 6 μg kg−1, the rate of excellent conditions was 13 patients out of 17, that is, excellent conditions in 76% of patients. This discrepancy between our results and those previously published can be explained by the following two reasons. First, in our protocol, patients were premedicated with alprazolam 0.5 mg and hydroxyzine, given orally 1 h before induction of anaesthesia, whereas, in the studies by Durmus et al.9 and Mohammadreza and Azim,10 premedication was performed using intravenous midazolam 0.03 mg kg−1 given 5–10 min prior to induction of anaesthesia. Under these studies, the hypnotic sparing effect of midazolam probably allowed higher rates of excellent intubating conditions to be reached with a lower dose of remifentanil.16–18
Second, assessment of intubating conditions was performed using a different scale from that used in the studies by Durmus et al.9 and Mohammadreza and Azim.10 In fact, we used the standardized qualitative scoring system proposed by the consensus conference on GCRP in Pharmacodynamic Studies of Neuromuscular Blocking Agents in 1996 for the assessment of the intubating conditions.13 This scoring system was updated in 2005;19 however, we decided not to apply this more recent scoring system because of its lack of clarity and detail in comparison with the original edition. The scale described in 1996 was chosen for the assessment of the intubating conditions for the following two reasons: first, the criteria used in this scoring system are independent of the anatomical characteristics of the patients, contrary to other scales, including Cormack grade, for example; and, second, this standardized scale allows our results to be compared with those published in the literature, as it was previously applied in several studies assessing the intubating conditions under various induction sequences of anaesthesia.2,3,20,21 Thus, this standardized qualitative scoring system is more precise and reproducible than the scale used in the studies by Durmus et al.9 and Mohammadreza and Azim,10 probably explaining in part the discrepancy between our results and those published by these authors.
Through using an optimized induction sequence of anaesthesia taking into account the pharmacokinetic/pharmacodynamic parameters of thiopental and remifentanil so that tracheal intubation occurred at the effect-site peak concentration of both agents,22,23 as we also previously performed in a study assessing the IED95 of remifentanil when coadministered with propofol,21 we report a noticeably increased IED95 of remifentanil for providing excellent intubating conditions when coadministered with thiopental, compared with the IED95 of remifentanil (4 μg kg−1) when coadministered with propofol. Our results corroborate those of several previous studies reporting worse intubating conditions because of less muscular relaxation after administration of thiopental compared with propofol;7,24–26 however, some other authors have reported that thiopental rather than propofol provided more favourable intubating conditions without muscular relaxation,27 having assumed that excellent intubating conditions could be easily reached when combining remifentanil with thiopental.9,10
As the IED95 of remifentanil was more than 6 μg kg−1, we were unable to assess the haemodynamic tolerance of the IED95 of remifentanil combined with thiopental 5 mg kg−1. However, a significant decrease in HR was registered in group 6 μg kg−1, though no significant statistical difference was observed between groups during the study period.
No clinically significant muscle rigidity occurred in any of the groups. Muscle rigidity has been described after rapid infusion of a large dose of opioids.28 We, therefore, administered remifentanil over 60 s. However, muscular rigidity was not observed in previous studies with doses of remifentanil ranging from 1 to 4 μg kg−1 administered over 90 s, combined with thiopental 5 mg kg−1 or with propofol 2 mg kg−1.9,10,25 Moreover, alprazolam given 60 min prior to induction of anaesthesia may also have contributed to minimize the occurrence of muscle rigidity, as premedication with benzodiazepine is effective in preventing opioid-induced muscle rigidity.29
The IED95 of remifentanil for providing excellent intubating conditions when coadministered with thiopental was more than 7 μg kg−1, that is, noticeably larger than both the expected value and the IED95 of remifentanil when coadministered with propofol. Hence, our results question the use of thiopental for a relaxant-free protocol for anaesthesia requiring tracheal intubation.
The present study is supported solely by institutional sources.
No author has any conflict of interest to declare.
1 Domino KB, Posner KL, Caplan RA, Cheney FW. Airway injury during anesthesia: a closed claims analysis. Anesthesiology 1999; 91:1703–1711.
2 Mencke T, Echternach M, Kleinschmidt S, et al
. Laryngeal morbidity and quality of tracheal intubation
. A randomized controlled trial. Anesthesiology 2003; 98:1049–1056.
3 Combes X, Andriamifidy L, Dufresne E, et al
. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort. Br J Anaesth 2007; 99:276–281.
4 Mertes PM, Laxenaire MC, Alla F. Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999–2000. Anesthesiology 2003; 99:536–545.
5 Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology 2003; 98:1042–1048.
6 Sandin RH, Enlund G, Samuelsson P, Lennmarken C. Awareness during anaesthesia: a prospective case study. Lancet 2000; 355:707–711.
7 Erhan E, Ugur G, Gunusen I, et al
. Propofol – not thiopental
or etomidate – with remifentanil
provides adequate intubating conditions in the absence of neuromuscular blockade. Can J Anesth 2003; 50:108–115.
8 Taha S, Siddik-Sayyid S, Alameddine M, et al
. Propofol is superior to thiopental
for intubation without muscle relaxants. Can J Anesth 2005; 52:249–253.
9 Durmus M, Ender G, Kadir BA. Remifentanil
for tracheal intubation
without muscle relaxants. Anesth Analg 2003; 96:1336–1339.
10 Mohammadreza S, Azim H. Tracheal intubation
without muscle relaxants: a randomized study of remifentanil
or alfentanil in combination with thiopental
. Ann Saudi Med 2008; 28:89–95.
11 Mallampati SR, Gatt SP, Gugino LD, et al
. A clinical sign to predict difficult tracheal intubation
: a prospective study. Can Anaesth Soc J 1985; 32:429–434.
12 Shiga T, Wajima Z, Inoue T, Sakamoto A. Predicting difficult intubation in apparently normal patients: a meta-analysis of bedside screening test performance. Anesthesiology 2005; 103:429–437.
13 Viby-Mogensen J, Engbaek J, Eriksson LI, et al
. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996; 40:59–74.
14 Nam JM. A simple approximation for calculating sample sizes for detecting linear trend in proportions. Biometrics 1987; 43:701–705.
15 Bland JM, Altman DG. Multiple significance tests: the Bonferroni method. BMJ 1995; 310:170.
16 Adachi YU, Uchihashi Y, Watanabe K, Satoh T. Small dose midazolam or droperidol reduces the hypnotic dose of propofol at the induction of anaesthesia. Eur J Anaesthesiol 2000; 17:126–131.
17 Cressey DM, Claydon P, Bhaskaran NC, Reilly CS. Effect of midazolam pretreatment on induction dose requirements of propofol in combination with fentanyl in younger and older adults. Anaesthesia 2001; 56:108–113.
18 Sun GC, Hsu MC, Chia YY, et al
. Effects of age and gender on intravenous midazolam premedication: a randomized double-blind study. Br J Anaesth 2008; 101:632–639.
19 Fuchs-Buder T, Claudius C, Skovgaard LT, et al
. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand 2007; 51:789–808.
20 Bouvet L, Stoian A, Jacquot-Laperriere S, et al
. Laryngeal injuries and intubating conditions with or without muscular relaxation: an equivalence study. Can J Anaesth 2008; 55:674–684.
21 Bouvet L, Stoian A, Rimmelé T, et al
. Optimal remifentanil
dosage for providing excellent intubating conditions when coadministered with a single standard dose of propofol. Anaesthesia 2009; 64:719–726.
22 Glass PS, Gan TJ, Howell S. A review of the pharmacokinetics and pharmacodynamics of remifentanil
. Anesth Analg 1999; 89:S7–14.
23 Minto CF, Schnider TW, Gregg KM, et al
. Using the time of maximum effect site concentration to combine pharmacokinetics and pharmacodynamics. Anesthesiology 2003; 99:324–333.
24 McKeating K, Bali IM, Dundee JW. The effects of thiopentone and propofol on upper airway integrity. Anaesthesia 1988; 43:638–640.
25 Stevens JB, Vescovo MV, Harris KC, et al
. Tracheal intubation
using alfentanil and no muscle relaxant: is the choice of hypnotic important? Anesth Analg 1997; 84:1222–1226.
26 Barker P, Langton JA, Wilson IG, Smith G. Movements of the vocal cords on induction of anaesthesia with thiopentone or propofol. Br J Anaesth 1992; 69:23–25.
27 Hovorka J, Honkavaara P, Korttila K. Tracheal intubation
after induction of anaesthesia with thiopentone or propofol without muscle relaxants. Acta Anaesthesiol Scand 1991; 35:326–328.
28 Thompson JP, Rowbotham DJ. Remifentanil
: an opioid for the 21st century. Br J Anaesth 1996; 76:341–343.
29 Sanford TJ Jr, Weinger MB, Smith NT, et al
. Pretreatment with sedative-hypnotics, but not with nondepolarizing muscle relaxants, attenuates alfentanil-induced muscle rigidity. J Clin Anesth 1994; 6:473–480.
Keywords:© 2010 European Society of Anaesthesiology
efficient dose; general anaesthesia; remifentanil; thiopental; tracheal intubation