Inhalational induction with sevoflurane has been shown to provide acceptable conditions for tracheal intubation. The end-tidal sevoflurane concentration required for intubation in adults is about twice the minimum alveolar concentration (MAC) [1,2]. Anaesthetic adjuvants such as midazolam or opioids significantly decrease the alveolar concentration needed to achieve acceptable intubating conditions [2-5]. Remifentanil 1 μg kg−1 injected for 60 s followed by an infusion of 0.25 μg kg−1 min−1 provides acceptable intubation conditions with 2% alveolar concentration sevoflurane . Tracheal intubation can be performed at 1 MAC, but significant increases in blood pressure and heart rate, movement and coughing occur in 95% of patients . On the other hand, sevoflurane at 1 MAC with fentanyl 1 μg kg−1 provides satisfactory intubating conditions in 50% of patients . The purpose of this study was to determine the target plasma concentration of remifentanil to provide satisfactory intubating conditions with sevoflurane at age-adjusted MAC in the absence of muscle relaxant.
After Institutional Ethics Committee approval and written informed consent, adult patients scheduled for elective surgery requiring tracheal intubation were consecutively studied. Eligible patients were aged 18-50 yr, ASA I or II, weighing 75-125% of ideal weight. Patients with a history of cardiac, pulmonary or renal disease, history of oesophageal reflux or hiatus hernia, contraindications for mask inhalation induction or predictive signs of difficult intubation (Mallampati classification > 2, thyromental distance < 65 mm, interincisor gap < 35 mm) were excluded from the study. Patients were given 0.5 mg alprazolam orally as prophylaxis for anxiety the evening before surgery.
No premedication was given on the day of surgery. All operations were performed in the morning. All patients were monitored with an electrocardiogram, pulse oximeter, non-invasive blood pressure device, pulse oximeter and bispectral index (BIS-XP® monitor; Aspect Medical Systems International B.V., De Meern, The Netherlands). Inspired and end-tidal concentration of oxygen, carbon dioxide and sevoflurane were also measured. All patients were preoxygenated for 5 min with 100% oxygen through a tight-fitting mask. They were then connected to a semi-closed anaesthetic circuit (Julian®; Draeger, Lübeck, Germany) prefilled with 8% sevoflurane. The fresh gas flow was set at 6 L min−1. Anaesthesia was induced through a face mask with sevoflurane 8% in 100% oxygen for 2 min. The concentration delivered was then adjusted to obtain the predetermined age-adjusted MAC (Table 1) and to keep it constant. Remifentanil was simultaneously administered using target-controlled infusion and the pharmacokinetic model of Minto . Stanpump software (written by and freely available from Steven L. Shafer, M.D., Department of Anaesthesia, Stanford University, Stanford, CA, USA) running on a commercially available laptop computer was used to drive a Pilot-Anesthesie® infusion pump (Fresenius, Vial, France). Patients were manually ventilated if needed and PCO2 was maintained at 35 ± 3 mmHg. Tracheal intubation was performed at 10 min. At this time, sevoflurane and remifentanil effect-site concentrations had reached equilibrium. The anaesthesiologist who performed and rated the intubation was blind to the target concentration of remifentanil. The target plasma concentration of remifentanil was fixed for each patient with the use of a modified Dixon's up-and-down method . The first patient was tested at a concentration of 4.5 ng mL−1 . Subsequent patients were tested at a concentration defined by the previous patient's response to intubation. If intubation failed, the remifentanil concentration was increased by 0.5 ng mL−1. If it was successful, it was decreased by 0.5 ng mL−1. Haemodynamic data, carbon dioxide end-tidal concentration, inspired and end-tidal concentration of oxygen and sevoflurane, and BIS were recorded before induction, every minute during induction until intubation, and 2 and 5 min after intubation.
The quality of intubation score was evaluated according to the consensus conference on Good Clinical Research Practice in Pharmacodynamic Studies of Neuromuscular Blocking Agents . Successful intubation corresponded to an excellent intubating score, that is all variables (laryngoscopy vocal cords, reaction to tube insertion or cuff inflation) were excellent. In case of failure, intubation was performed after injection of atracurium 0.5 mg kg−1.
The mean target concentration of remifentanil enabling smooth intubation with age-adjusted MAC sevoflurane was obtained from the midpoints of all independent pairs of patients involving a crossover, that is failure to success. According to the study of Paul and Fisher, patients were enrolled until six pairs were obtained . Data were also analysed using a logistic regression model to determine the effective target concentration of remifentanil needed to successfully intubate 50% and 95% of subjects (Cp50 and Cp95, respectively). In this analysis, the logit transformation of the probability of successful intubation (P), ln(P/1 − P), was expressed as a linear function of the target concentration of remifentanil. Results were expressed as mean ± SD (or SEM in Fig. 3) or as mean (95% confidence interval (CI)). Data were plotted and analysed using SigmaPlot 8.0 and Systat 10.0 (SPSS Inc., Chicago, IL). Comparison of two means was performed by t-test. Comparison of several means was performed using repeated measures analysis of variance followed by the Student-Newman-Keuls test. A P-value of <0.05 was considered statistically significant.
Twenty-four patients were enrolled in this study (Fig. 1). Patient characteristics are shown in Table 2. The mean target concentration of remifentanil for successful intubation was 3.3 ng mL−1 (95% CI: 2.6-3.9 ng mL−1). From logistic regression, the Cp50 of remifentanil was 2.9 ng mL−1 (95% CI: 2.2-3.6 ng mL−1) and the Cp95 was 5.0 ng mL−1 (95% CI: 2.4-7.7 ng mL−1) (Fig. 2).
With regard to patient characteristics (Table 2), patients were older in the failure group: 40 ± 8 yr vs. 31 ± 8 yr. The end-tidal sevoflurane concentration and the target concentration of remifentanil were significantly higher in the success group: 2.3 ± 0.3% vs. 2.1 ± 0.2% and 3.5 ± 0.7 ng mL−1 vs. 2.8 ± 0.7 ng mL−1, respectively. Arterial pressure, heart rate and BIS did not increase after intubation in the success group (Table 3 and Fig. 3). Systolic pressure and BIS significantly increased 2 min after intubation in the failure group (Table 3 and Fig. 3).
The MAC intubation of sevoflurane required to perform tracheal intubation in acceptable conditions without using a muscle relaxant varies from 4.50% to 3.55% [1,2]. The difference might be due to the choice of criteria for defining satisfactory intubation, to the pressure applied to inflate the cuff , but also to the difference in age of the patients enrolled in the study . Mollestad and colleagues showed that intubation could be achieved with sevoflurane at 1 MAC without clinical signs of wakefulness . However, 19 of 20 patients involved in that study experienced coughing, bucking or gross purposeful movement after intubation. In our study, successful intubation corresponds strictly to excellent conditions. It has been recently reported that the quality of intubation contributes to laryngeal morbidity, and excellent conditions are less frequently associated with postoperative hoarseness and vocal cord sequelae .
Opioids are known to decrease MAC intubation [2,4-6]. Katoh and colleagues reported that the MAC for acceptable intubation conditions was reduced from 3.55% to 2.07% if fentanyl 1 μg kg−1 was given intravenously 4 min before intubation . MAC intubation was markedly decreased with higher fentanyl doses: 1.45% and 1.37%, respectively, for 2 μg kg−1 and 4 μg kg−1 of fentanyl. Alfentanil 30 μg kg−1 associated with sevoflurane, set at 8% until loss of eyelash reflex and then 5% for 2 min, gives intubation conditions similar to those provided by the same protocol for sevoflurane administration associated with suxamethonium 1 mg kg−1 and alfentanil 10 μg kg−1 . Remifentanil 2 μg kg−1 associated with inhalation of sevoflurane 8% for 3 min gives optimal intubation conditions . Another study showed that remifentanil 1 μg kg−1 followed by an infusion of 0.25 μg kg−1 min−1 given 3 min before intubation is sufficient to produce satisfactory intubation conditions in association with sevoflurane at 2% alveolar concentration .
We performed a pharmacokinetic simulation of the sevoflurane administration protocol of these different studies with Gas Man® (MedMan Simulations, Inc., Chesnut Hill, MA, USA). The cerebral concentration of sevoflurane at the moment of intubation was about 2%. However, in those studies, as the cerebral concentrations of sevoflurane and opioids were not at steady state, the MAC intubation of sevoflurane and the plasma concentration of opioids required to perform intubation could not be precisely determined [4-6]. In the study by Kimura and colleagues , the end-tidal sevoflurane concentration was maintained for at least 20 and for 10 min in that of Katoh and colleagues . In both, the authors thought that cerebral and arterial blood gas pressure were in equilibrium. In our protocol, the pharmacokinetic simulation of sevoflurane administration using Gas Man® showed that the cerebral sevoflurane concentration was at equilibrium when intubation was performed. Moreover, the BIS was stable for several minutes during this period.
In our study, the MAC was age adjusted because it decreases significantly in the age range of the patients included in the study. Mapleson showed that the changes in MAC with age correspond approximately to a 6% decrease per decade of age . In our study, the patients in the success group were younger than those in the failure group. This cannot be explained by the differences in end-tidal sevoflurane concentration which, although significant, was negligible considering the margin of error for measuring this parameter (±20%). Moreover, the BIS values before intubation were not different between the two groups. However, we cannot exclude that the pharmacodynamic interactions between volatile agents and opioids change with age of patients.
Remifentanil was administered using a target-controlled infusion and the effect-site and plasma concentrations were at steady state at the time of intubation according to the pharmacokinetic model. In patients anaesthetized with sevoflurane at age-adjusted MAC, the Cp50 of remifentanil to obtain excellent intubation conditions was 2.9 ng mL−1. This is in agreement with other published studies [5,6]. Joo and colleagues showed that 1 μg kg−1 remifentanil in association with approximately 2% sevoflurane gives optimal intubating conditions in 54% of patients . The pharmacokinetic simulation shows that at the time of intubation the effect-site concentration of remifentanil was approximately 3 ng mL−1. Cros and colleagues showed that the MAC of sevoflurane for intubation was equal to 2% with an effect-site concentration of remifentanil of 4.5 ng mL−1 .
The haemodynamic variations before intubation were comparable in both groups. Systolic arterial pressure (SAP) decreased by about 25% and heart rate did not significantly change in either group during induction. Intubation resulted in an increase in SAP and heart rate only in the failure group, findings consistent with those of Katoh and colleagues who found that haemodynamic responses to intubation were attenuated by fentanyl in a dose-dependent manner . Sivalingam and colleagues also found a significant increase in mean blood pressure at 2 min after intubation in patients receiving sevoflurane combined with suxamethonium and alfentanil 10 μg kg−1, whereas no variations occurred in patients receiving alfentanil 20 μg kg−1 . The dose-dependent suppression of the haemodynamic response to intubation is probably due to the analgesic properties of opioids that may block afferent nerve impulses resulting from the stimulatory effect of laryngoscopy and intubation. Moreover, in the present study, the BIS was also significantly higher in the failure group after intubation. In every patient, BIS remained below 50 prior to laryngoscopy which suggests a sufficient anaesthetic depth in both groups. Therefore, in the failure group, the level of analgesia was perhaps insufficient to blunt the reaction to intubation, that is coughing and vocal cord closure.
In summary, remifentanil at 3 and 5 ng mL−1 associated with sevoflurane at 1 MAC provides excellent intubating conditions in 50% and 95% of adult patients respectively. In routine clinical practice, an effect-site concentration of 5 ng mL−1 can be achieved in 3 min with infusing a 1 μg kg−1 bolus of remifentanil over a 60 s period followed by a continuous infusion of 0.23 μg kg−1 min−1 remifentanil.
The authors thank Ray Cooke (Assistant Professor, DLVP, Université Victor Segalen Bordeaux 2) for correcting the English.
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