Even though propofol can relax the jaw and suppress airway reflexes, which makes it one of the most useful induction drugs for intubation without neuromuscular blockade, adjuvants may be needed in many cases [1,2]. Opioids are suitable for this purpose, and among them remifentanil is an ultrashort-acting potent opioid metabolized by non-specific plasma and tissue esterase. Currently combinations of propofol and remifentanil using target-controlled infusion (TCI) device are more frequently used.

The Shikani Optical Stylet (SOS; Clarus Medical, Minneapolis, MN, USA), a device for difficult intubation which was approved by the Food and Drug Administration in 1996, is unfamiliar to many anesthesiologists, consequently, not only a few studies about it are available but also none of them related to intubation using propofol and remifentanil [3].

The aims of this study were to determine the clinically required effect-site concentration (Ce) of remifentanil for intubation using SOS without neuromuscular blockade and to examine to what extent propofol reduces Ce of remifentanil and improves conditions for intubation.

Once institutional review board approval from Hanyang University Guri Hospital was obtained (IRB approval no., 2010-70), we gathered 47 patients who were going to have surgery with general anesthesia and received from them written informed consent and authorization to enroll them in our study. Patients were suitable for intubation with SOS. Members of our study were between 18 and 65 years old, American Society of Anesthesiologists status I or II. Patients expected to be difficult for intubation, respiratory tract infection history, cardiovascular disease, taking pain control medications, or body mass index (BMI) >30 kg/m² were eliminated from the study.

The patients were assigned into two groups by a randomized, double-blind method: Ce of propofol 3.5 μg/mL with remifentanil (group PRO 3.5) and Ce of propofol 7.0 μg/mL with remifentanil (group PRO 7.0). All patients were previously medicated with atropine 0.5 mg and midazolam 0.05 mg/kg intramuscular injection before surgery. In the operation room, we recorded age, sex, weight, height, BMI, Mallampati class, thyromental distance, maximal mouth opening (inter-incisor distance), and standard monitoring was documented (electrocardiogram, pulse oximeter, blood pressure, and end-tidal CO₂ Ce). Anesthetic depth was checked with the bispectral index (BIS) monitor (A-2000, ver. 3.3; Aspect Medical System Inc., Natick, MA, USA).

All subjects of our study were previously oxygenated with 100% oxygen for 3 minutes. To decrease propofol-induced injection pain, 40 mg intravenous lidocaine was injected, and induction was done with Ce of propofol 3.5 or 7.0 μg/mL using a TCI device (Orchestra; Fresenius Vial, Brezins, France). We applied the Schnider pharmacokinetic model for propofol [4,5]. Immediately after starting propofol using TCI, remifentanil was infused using TCI at a predetermined Ce. We applied the Minto pharmacokinetic model for remifentanil [6].

After loss of consciousness, mask ventilation was maintained with 100% oxygen. Propofol and remifentanil infusion was done for 4 more minutes after which endotracheal intubation was done by the same anesthesiologist for all the patients. For intubating men, we used endotracheal tube internal diameter 7.5 mm and for women, 6.5 mm. The total intubation time was defined as the time elapsed between inserting the SOS into the oral cavity and the verification of tracheal intubation with the visualization of three end tidal CO₂ waveforms, during mechanical ventilation with a tidal volume of 10 mL/kg at a respiratory rate of 20 breaths/min. After intubation, BIS index was recorded and the total amount of propofol and remifentanil used till intubation was recorded. Intubating conditions were evaluated according to a scoring system described by Viby-Mogensen (Table 1) [7]. After successful or failed intubation, all data was recorded, and Ce of propofol and remifentanil was not disclosed to the intubating anesthesiologist; thus, a double-blinded method was achieved.

Successful intubation was defined as ‘excellent’ or ‘good’ intubating conditions. If intubation failed due to movement, inadequate jaw relaxation, cough, or closed vocal cords, rocuronium 0.6 mg/kg was administered and intubation was performed following neuromuscular blockade. The Ce of remifentanil for successful intubation using SOS in 50% of patients (EC₅₀) was established using the modified Dixon’s up-and-down method [8,9]. As a pilot study, we enrolled 12 patients to determine the initial Ce of remifentanil for this study. The first patients received a Ce of remifentanil of 5 ng/mL in group PRO 3.5 and 3 ng/mL in group PRO 7.0.

If the response of patient was good or excellent, the next Ce of remifentanil was decreased by a step of 1.0 ng/mL. If patient response was ‘poor,’ the Ce was increased by 1.0 ng/mL. The step-change of Ce was decreased to 0.5 ng/mL, following the initial three ‘negative-positive up-and-down’ cross-overs. Same method was done again until seven cross-over midpoints (poor/excellent or good) were acquired. Tracheal intubation in 50% of patients (EC₅₀) of remifentanil was determined by calculating the mean of the midpoint Ce of all independent pairs of patients who manifested a cross-over from a negative to a positive response [8]. In the post anesthetic care unit patients were asked if they had any memory recall.

SPSS ver. 17.0 for Windows (SPSS Inc., Chicago, IL, USA) and SigmaStat ver. 3.5 (Systat Software Inc., San Jose, CA, USA) was used to do statistical analysis. Probit analysis in PASW ver. 18.0 (SPSS Inc.) was used to establish EC₅₀ and EC₉₅ with 95% confidence intervals (CI). Age, weight, height, BMI, thyromental distance, maximal mouth opening (inter-incisor distance), total intubation time, BIS after intubation, and total dose of propofol and remifentanil were analyzed with t-test. Sex, Mallampati class, and intubating condition of successful intubation patients were analyzed with Fisher’s exact test. Values are denominated as mean± standard deviation or number of patients and P<0.05 was considered significant.

There were no significant differences between the two groups in age, sex, weight, height, BMI, Mallampati class, thyromental distance, and maximal mouth opening (inter-incisor distance) (Table 2).

There were no cases of airway trauma, memory recall, or significant hypotension or bradycardia. In group PRO 3.5, 25 patients were enrolled of which 13 were successfully intubated, and in group PRO 7.0, 22 patients were enrolled into this study in which 12 were successfully intubated. There were no significant differences in response to successful intubation in group PRO 3.5 and group PRO 7.0, but BIS after intubation were significantly elevated in group PRO 3.5 (P<0.001) (Table 3).

Figs. 1 and 2 show individual Ce-responses according to the up-and-down sequence in group PRO 3.5 and group PRO 7.0. From the modified Dixon’s up-and-down method, EC₅₀ of remifentanil for intubation using SOS was 5.07±0.40 ng/mL in group PRO 3.5 and 1.79±0.44 in group PRO 7.0.

From probit analysis, EC₅₀ and EC₉₅ were 4.85 ng/mL (95% CI, 4.44–5.16 ng/mL) and 5.42 ng/mL (95% CI, 5.13–7.47 ng/mL) in group PRO 3.5, respectively, and EC₅₀ and EC₉₅ were 1.68 ng/mL (95% CI, 1.22–2.01 ng/mL) and 2.29 ng/mL (95% CI, 1.98–4.05 ng/mL) in group PRO 7.0, respectively. Dose-response curves for each patient obtained by the up-and-down method are shown in Fig. 3.

Using the modified Dixon’s up-and-down method, this study demonstrated that the required Ce of remifentanil at which successful intubation is possible in 50% of patients was 5.07±0.40 ng/mL during a TCI of propofol 3.5 μg/mL, and 1.79±0.44 ng/mL during a TCI of propofol 7.0 μg/mL.

During induction of anesthesia using propofol, combined use of opioids is needed to suppress hemodynamic instability [10]. Recently among opioids, remifentanil is used as an adjuvant more frequently because it has a fast onset time and no accumulation effect due to continuous infusion. Also, its context-sensitive half-life is shorter; therefore, emergence is faster [11].

In this study, we used TCI for continuous infusion because it results in fewer overdose-linked adverse effects and provides greater cardiovascular stability compared with traditional weigh-adjusted infusions. Also, TCI targets the Ce rather than the plasma Ce because it more accurately reproduces the desired time course of drug effect [4,12].

There are many studies related to propofol-remifentanil TCI induction methods to suppress hemodynamic instability [13–15]. Albertin et al. [13] suggested that EC₅₀ of remifentanil during intubation is 5.0 ng/mL (95% CI, 4.7–5.4 ng/mL) while using Ce of propofol 4 μg/mL, which is similar to the results of our study in group PRO 3.5. Mustola and Toivonen [14] suggested that EC₅₀ and EC₉₅ of remifentanil is 3.17 ng/mL and 3.79 ng/mL, respectively, during intubation while using Ce of propofol 4 μg/mL, and this study showed lower Ce compared with our group PRO 3.5. Troy et al. [15] consider that a Ce of remifentanil 8 ng/mL along with a Ce of propofol 3 μg/mL may provide satisfactory conditions for intubation while avoiding major adverse effect, compared with our study in group PRO 3.5 in which EC₉₅ was 5.42 ng/mL (95% CI, 5.13–7.47 ng/mL), showing a higher Ce.

In a pilot study, we enrolled 12 patients to determine the initial Ce of remifentanil for successful intubation, in which hypotension or bradycardia was minimal. Initial Ce of remifentanil for group PRO 3.5 and group PRO 7.0 was 5 ng/mL and 3 ng/mL, respectively.

Recently, many devices are used for intubation. Aside from the traditional Macintosh laryngoscope, the GlideScope is one of the latest devices for intubation. Ithnin et al. [16] suggested that when Ce of propofol 3 μg/mL was used for intubation using a Macintosh laryngoscope, EC₅₀ of remifentanil was 4.41 ng/mL, and using the GlideScope, EC₅₀ of remifentanil was 5.45 ng/mL, showing that EC₅₀ of remifentanil was higher in the latter one. Comparing this with our study (EC₅₀ of remifentanil 5.07 ng/mL in group PRO 3.5), EC₅₀ using the Macintosh laryngoscope was lower and using the GlideScope, it was higher. The lightwand is the most similar to SOS, and Masso et al. [17] made a study using continuous infusion of propofol and remifentanil using a lightwand for intubation, but we could not compare our study with it because they did not use TCI.

Even though it is not intubation, Kim et al. [18] used Ce of propofol 3.5 μg/mL for laryngeal mask airway (LMA) insertion requiring EC₅₀ of remifentanil 3.04±0.49 ng/mL. Comparing it with our study, LMA insertion requires lower EC₅₀ of remifentanil than intubation using the SOS because the former one is less painful. And Jeon et al. [19] suggested that optimal Ce of remifentanil using Ce of 6 μg/mL propofol for Cobra perilarygeal airway insertion is 4 ng/mL. Although Ce of propofol is different from our study, comparing it with group PRO 7.0 the Ce was higher.

SOS is a novel fiberoptic endoscopy. It consists of a malleable stainless steel fiberoptic stylet and an eyepiece which can either be connected to a video camera and monitor or used on its own with the light source. This device has both features of fiberoptic bronchoscope and lightwand. The endotracheal tube is inserted in the stylet and like using a lightwand, the oropharynx is opened and looking through the bronchoscope vocal cord and trachea can be confirmed [3,20]. The device is lightweight, portable, sturdy, and can be used by a single operator. Yao et al. [21], after comparing intubation using SOS versus Macintosh laryngoscope, suggested that SOS airway trauma is less and intubation time is faster; also, hemodynamics are more stable.

Kil et al. [22] suggested that optimal Ce to maintain adequate BIS and hemodynamic stability with propofol for Koreans was 3.5 μg/mL, thus in this study using SOS for intubation, we used a Ce of 3.5 μg/mL and 7.0 μg/mL to find the optimal Ce of remifentanil. In this study, BIS after intubation in group PRO 3.5 was higher than in group PRO 7.0, 56.2±14.0, and 30.1±10.2, respectively. Especially, six patients among 25 showed BIS higher than 65 in group PRO 3.5 compared to none among 22 patients in group PRO 7.0 (P= 0.023). In this study, none of the patients had memory recalls, but it should be noticed that there can be memory recalls if Ce of propofol 3.5 μg/mL.

Park et al. [23] suggested that during insertion of LMA and laryngeal tube, Ce of propofol can be decreased by half when Ce of remifentanil is doubled. In our study EC₅₀, of remifentanil in group PRO 3.5 was 5.07±0.40 μg/mL and EC₅₀ of remifentanil in group PRO 7.0 was 1.79±0.44 μg/mL, showing that doubling the Ce of propofol allowed us to reduce the Ce of remifentanil by more than half. We recommend a Ce of 7.0 μg/mL rather than 3.5 μg/mL propofol because Ce of remifentanil can be lowered and no elevations of BIS are shown after intubation using SOS.

In conclusion, the Ce of remifentanil for successful intubation using SOS without neuromuscular blockade in 50% of patients (EC₅₀) in group PRO 3.5 was 5.07±0.40 ng/mL and in group PRO 7.0 was 1.79±0.44 ng/mL. From probit analysis, the EC₅₀ and EC₉₅ in group PRO 3.5 were 4.85 ng/mL (95% CI, 4.44–5.16 ng/mL) and 5.42 ng/mL (95% CI, 5.13–7.47 ng/mL), respectively, and the EC₅₀ and EC₉₅ in group PRO 7.0 were 1.68 ng/mL (95% CI, 1.22–2.01 ng/mL) and 2.29 ng/mL (95% CI, 1.98–4.05 ng/mL), respectively. Increased Ce of propofol reduced the EC₅₀ of remifentanil for successful intubation using SOS without neuromuscular blockade.