The median effective dose (ED50) of cis-Atracurium for laryngeal mask airway insertion during general Anaesthesia for patients undergoing urinary surgery

This prospective observational study was approved by the university’s institutional review board (IRB no.: CINI-AD-20180808). All individuals participating in the trial provided written informed consent. The trial is also registered at http://​ClinicalTrials.gov (registry no.: NCT-03668262; date of registration: September 11, 2018). The methodology in this study followed the international guidelines for observational studies according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 2010 statement (Supplementary-STROBE checklist). We recruited 23 prospective consecutive patients who were scheduled for elective minor urological surgery under general anaesthesia between 15 September, 2018, and 30 January, 2019, at Xuanwu Hospital (Beijing, China). All patients met the criteria for the American Society of Anesthesiologists (ASA) Physical Status I–III; Body Mass Index (BMI), 18.5–30 kg/m²; age, 20–60 years; predicted operation duration < 180 min; and estimated blood loss < 5 ml·kg^− 1. The exclusion criteria were as follows: neuromuscular diseases; metabolic diseases; preoperative condition complicated with electrolyte disorders, serious hepatic insufficiency (i.e., liver transaminase level > 40 U·L^− 1), or renal insufficiency (i.e., serum creatinine level > 1.2 mg·dL^− 1); serious heart and lung disease; predicted difficult airway; use of preoperative medications that interact with non-depolarising NMBAs (e.g., aminoglycosides, polymyxin, steroids, phenytoin sodium, neuroleptics, carbamazepine); history of allergy to NMBAs; and history of alcoholism or drug abuse.

After the patient entered the operating room, lactate Ringer’s solution was infused at a rate of 5 ml·kg^− 1·h^− 1. After 3 min of oxygen supplied via the mask, intravenous sufentanil (dose, 0.25 μg·kg^− 1; injection time, 30 s) and etomidate (dose, 0.2 mg·kg^− 1; injection time, 30 s) were administered. The bispectral index (BIS) reaching a value below 60 and loss of the eyelash reflex indicated that the patient had lost consciousness, and the train-of-four (TOF) value was calibrated. The calibration of TOF as the baseline was 100. After calibration, cis-atracurium was administered (injection time, 5 s). Three minutes after the cis-atracurium injection, and once the BIS reached a value of 40–60, an experienced anaesthesiologist placed a flexible LMA (Teleflex Medical, Wayne, PA, USA; Athlone Co., Westmeath, Ireland) of the appropriate type (LMA® Flexible criteria: 30–50 kg for No. 3; 50–70 kg for No. 4; and 70–100 kg for No. 5). The patients’ responses were jointly evaluated by another anaesthesiologist who was blinded to the cis-atracurium concentrations when the LMA was inserted. The tidal volume setting was 7 ml·kg^− 1, and the respiration rate setting was 12 RR·min^− 1. If laryngeal mask insertion was unsuccessful, anaesthesia was deepened with further increments of cis-atracurium, or an inhalation agent, or both, until the laryngeal mask was tolerated; however, the patient was placed in the “unsatisfactory” group in these cases. Propofol combined with remifentanil was used to maintain the BIS at 40–60 throughout the operation. The range of blood pressure and heart rate (HR) fluctuation did not exceed the 20% baseline value. Body temperature was maintained at > 36 °C using a warm air blanket.

The patient’s upper limb was extended and fixed. After degreasing the skin with alcohol, surface electrodes were placed on the side of the ulnar nerve of the wrist for TOF stimulation monitoring (TOF-Watch; Organon Ireland, Ltd., Swords, Dublin, Ireland). The sensor probe of the TOF monitor was placed between the thumb and forefinger with no resistance between them. When the patient lost consciousness, the calibration scale of T1 was 100, the stimulation current was 45–75 mA, the interval was 5 s, and the frequency was 2 Hz. The nasopharyngeal temperatures, electrocardiography, blood pressure, HR, pulse oxygen saturation (SpO₂), and BIS of patients were routinely monitored. We set 10 timepoints to record variations during the operation as follows: upon administration of cis-atracurium (T1), and 3 min (i.e., at LMA insertion) (T2), 10 min (at the beginning of the operation) (T3), 20 min (T4), 30 min (T5), 40 min (T6), 50 min (T7), 60 min (T8), 70 min (T9), and 80 min after the administration of cis-atracurium (T10). Systolic blood pressure (SBP), diastolic blood pressure (DBP), HR, SpO₂, BIS, TOF and airway peak pressure (Paw peak pressure) were recorded at each timepoint. Intraoperative haemodynamic changes and adverse reactions such as cough, respiratory depression, dizziness, nausea, and vomiting were also recorded.

The ED50 of cis-atracurium was determined by calculating the midpoint concentration of the crossover point from the “satisfactory” or “unsatisfactory” responses. To facilitate the dose-response analysis, the laryngeal mask insertion conditions were recorded as dichotomous outcomes. A probit analysis linear regression plot of the log dose versus the percentage response was generated, and interpolation (with 95% CIs) was used to determine the laryngeal mask condition. The average of the midpoints of all pairs was used to calculate the ED50 using Dixon’s up-and-down method. The number of responders at each dose was used to plot a sigmoid dose-response curve and a log-dose probit response relation. The other parameters were analysed using repeated measures ANOVA. The patient characteristics are presented as the mean (± SD) or the number (proportion). A P-value of < 0.05 was considered to represent significant difference among outcomes. These data were analysed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). The sample size of 23 patients was based on α = 0.05 for the two-sided chi-square test to analyse trends in proportions and a logistic model of β = 0.1 to detect the insertion success rates. The sample size of this study also was based on the fact that a minimum of seven independent pairs of participants exhibited a crossover point from a “satisfactory” response to an “unsatisfactory” response. In similar studies in the field of airway device insertion, the number of crossover points varied from six to eight, with six crossover points being the most common. For this study, seven crossovers were sufficient to determine the ED50 of cis-atracurium required to insert a laryngeal mask. A minimum of seven pairs of failure-success was required for the statistical analysis. The total score for the insertion conditions was calculated by addition. A score of ≥16 represented the optimal condition for LMA insertion.

Age, sex, weight, height, BMI, and the ASA Physical Status were similar among the three groups (Table 1). No significant differences were noted in the pH values and nasopharyngeal temperatures in all patients. Haemoglobin values, globulin fraction of plasma protein, and albumin fraction of plasma protein were similar among the groups (Table 1). The preoperative Mallampati variable did not differ among the groups. The operation duration, anaesthesia duration, and blood loss were non-significantly different among groups (Table 1). There was no statistical difference in the DBP among groups. The SBP was significantly decreased in the 20 μg·kg^− 1 group compared with the 50 μg·kg^− 1 group at T2, T3, and T4 (P = 0.0159, P = 0.0233, and P = 0.0428, respectively; Fig. 2a and b). For each group, the HR did not significantly differ at most timepoints; however, the HR was significantly decreased at T7, T8, and T10 in the 50 μg·kg^− 1 group compared to the 30 μg·kg^− 1 group (P = 0.0482, P = 0.0460, and P = 0.0236, respectively). This finding indirectly reflected the lower stress at these timepoints (Fig. 2c).

The BIS value did not significantly differ among the three groups and was maintained at 40–60 during surgery (Fig. 2d). TOF and airway peak pressure (Paw peak pressure) were recorded at T1-T8, because after T8, muscle relaxation subsided in most cases in the 20 μg·kg^− 1 group, and participants were unable to tolerate the laryngeal mask. Additional doses of cis-atracurium were re-administered to patients after the T8 timepoint. TOF and airway peak pressure (Paw peak pressure) were affected by re-administration of cis-atracurium; therefore, we did not include the TOF and airway peak pressure (Paw peak pressure) at T9 and T10 in the statistical analysis. The TOF value at T3 was significantly lower in the 50 μg·kg^− 1 group than that in the 30 μg·kg^− 1 group (P = 0.0226) (Fig. 2e). The TOF values in the 30 μg·kg^− 1 group and in the 20 μg·kg^− 1 group showed no difference at each timepoint, and the TOF values in the 50 μg·kg^− 1 group and in the 20 μg·kg^− 1 group also showed no difference at each timepoint (Fig. 2e). The Paw pressure is indicative of airway protection and the supraglottic airway device placement condition. In this study, the airway peak pressure (i.e., mean Paw pressure) did not significantly differ between the 50 μg·kg^− 1 group and the 30 μg·kg^− 1 group at any timepoint. However, it was significantly higher at T8 in the 20 μg·kg^− 1 group than that in the 30 μg·kg^− 1 group (P = 0.0423; Fig. 2f). There were no severe intraoperative haemodynamic changes or adverse reactions such as respiratory depression, nausea, or vomiting in any group.

In our patients, the ED50 (95% CI) of cis-atracurium for laryngeal mask insertion, which was obtained using the up-and-down method, was 26.5 μg·kg^− 1 (95% CI, 23.6–29.8). We found that the laryngeal mask, based on a probit regression analysis, can be successfully inserted in 50% (95% CI) of anaesthetised adults at a cis-atracurium concentration of 26.5 μg·kg^− 1 (95% CI, 23.6 μg·kg^− 1-29.8 μg·kg^− 1). The log dosage probit response curves for cis-atracurium for the insertion of the laryngeal mask (probability unit vs. concentration) are shown in Fig. 3. We generated the dose response curves and determined the effective doses of cis-atracurium required for the insertion of the laryngeal mask in adult patients (Fig. 3).