Rocuronium given in a sufficient dose results in rapid onset of neuromuscular block, which can be used for rapid sequence intubation. However, the duration of action is relatively prolonged and could be a problem in short procedures or in ambulatory surgical settings.1 Recent studies have suggested that the trachea can be intubated successfully without muscle relaxants using remifentanil in combination with propofol.2–4 Remifentanil 3 to 4 μg kg−1 and propofol 2 mg kg−1 administered intravenously reliably provide adequate conditions for tracheal intubation in healthy patients without a muscle relaxant. This combination of drugs allows the return of spontaneous ventilation within 5 min.2
The need for neuromuscular blockers to improve intubating conditions and to reduce the incidence of laryngeal morbidity is still controversial.5,6 By not using neuromuscular blocking drugs several complications, such as anaphylactic reaction, residual curarisation and awareness during general anaesthesia, can be avoided or reduced.7–9 However, the doses of remifentanil needed for acceptable intubating conditions without muscle relaxants are higher than those needed for conventional induction of anaesthesia using muscle relaxants. A remifentanil dose of only 1 μg kg−1 in combination with succinylcholine is effective in controlling the haemodynamic response to tracheal intubation.10 With higher doses of remifentanil, bradycardia or hypotension could be a concern. Additionally, there is no report on rapid sequence intubation without muscle relaxants.
Using the concept of balanced anaesthesia for rapid sequence intubation, we assumed that, at the moment of tracheal intubation after conventional induction doses of remifentanil and propofol, only a modest amount of muscle relaxation could increase the chance of acceptable intubating conditions. We tried to find the optimal dose of rocuronium needed for acceptable intubating conditions within 1 min after induction of anaesthesia with remifentanil 2 μg kg−1 and propofol 2 mg kg−1.
Ethical approval for this study (IRB Number B-1004–098–004) was provided by the Institutional Review Board of Seoul National University Bundang Hospital, Republic of Korea on 21 May 2010. Written informed consent was obtained from the study participants. American Society of Anesthesiologists (ASA) physical status 1–2 patients who were 18 to 65 years old and scheduled for general anaesthesia for elective surgery were enrolled. Exclusion criteria were factors predictive of difficult intubation (Mallampati grade ≥3 or Cormack and Lehane grade ≥3), a BMI above 30 kg m−2, a history of gastro-oesophageal reflux or reactive airway disease.
All patients were premedicated with intravenous midazolam 0.03 mg kg−1 and glycopyrrolate 0.2 mg about 10 to 15 min before anaesthesia. Standard monitoring, including electrocardiogram, oxygen saturation, non-invasive blood pressure and capnography, was undertaken. After preoxygenation through a facemask for 3 min, anaesthesia was induced with intravenous remifentanil 2 μg kg−1 given over 30 s and propofol 2 mg kg−1, followed by a predetermined dose of rocuronium. The propofol and rocuronium were administered rapidly within 5 s. The dose of rocuronium used for each patient was determined by the response of the previous patient using a modified Dixon's up-and-down method.11 The first patient received 0.8 mg kg−1 of rocuronium. If the tracheal intubation was a success, then the dose of rocuronium was decreased by 0.1 mg kg−1. If the tracheal intubation was a failure, then the dose of rocuronium was increased by 0.1 mg kg−1. Laryngoscopy was started and tracheal intubation was attempted 60 s after the start of the injection of rocuronium. After the first three such ‘failure-success’ up-and-down crossovers, the step change of dose was reduced to 0.05 mg kg−1. In accordance with the study of Paul and Fisher,12 the process was repeated until a total of six cross-over points were obtained. The drugs were prepared by an anaesthetic nurse and all intubations were performed by the same experienced anaesthesiologist who also evaluated the intubating conditions. He was blinded to the dose of rocuronium used but was aware of the results of the previous patients. Other variables were checked by another attending anaesthesiologist. Intubating conditions were evaluated using three variables:13 ease of laryngoscopy, position and/or movement of the vocal cords and reaction to intubation. Each of these variables was rated as excellent, good or poor. The criteria for assessing values to each variable are shown in Table 1. Intubating conditions were considered excellent if all variables were excellent, good if all variables were good or excellent and poor if any variable was poor. Excellent or good intubating conditions were regarded as a success and poor intubating conditions as a failure. A bolus dose of propofol 0.5 mg kg−1 was given immediately after intubation at the discretion of the intubating anaesthesiologist if intubating conditions were poor.
Patients were interviewed just before discharge from the postoperative anaesthetic care unit (PACU) to assess sore throat and memory recall.
Blood pressure and heart rate (HR) were recorded before the start of induction of anaesthesia as a baseline value (Base), 30 s after administration of propofol (P30) and at 1-min intervals for 3 min after intubation (INT 1, 2, 3). If mean arterial pressure (MAP) or HR decreased by more than 30% of the baseline values, or if MAP less than 60 mmHg or HR less than 50 beats min−1 was present, ephedrine 5 mg or atropine 0.5 mg was administered intravenously, as appropriate.
Statistical analysis was performed using MATLAB (The MathWorks Inc., Natick, Massachusetts, USA) and the Statistical Package for Social Sciences software (SPSS Inc., Chicago, Illinois, USA). The effective dose of rocuronium needed for acceptable intubation conditions in 50% of the participants (ED50) with 95% confidence intervals (CI) was calculated using the method of maximum likelihood with a modified up-and-down formula suggested by Jung and Choi.11 The up-and-down data were also analysed by probit analysis. The rocuronium doses needed for acceptable intubation conditions in 50 and 95% of the participants (ED50 and ED95) were estimated from the best-fit probit curve. Haemodynamic data were compared by one-way repeated measures ANOVA with a Bonferroni multiple comparison test. A P value of <0.05 was considered statistically significant.
A total of 39 patients were assessed for eligibility. Of these, five refused to participate, three were obese (BMI ≥30 kg m−2) and one was Mallampati grade 3. Two patients were excluded after enrolment because of high Cormack and Lehane grades. A total of 28 patients were needed to obtain six pairs of success-failure crossovers. Patient characteristics are shown in Table 2. The results of success or failure for each consecutive patient according to the dose of rocuronium used are shown in Fig. 1. When combined with propofol 2 mg kg−1 and remifentanil 2 μg kg−1, the dose of rocuronium for successful rapid sequence intubation in 50% of patients (ED50) was 0.20 mg kg−1 (95% CI 0.17 to 0.23 mg kg−1) using the modified Dixon's up-and-down method.
Among the 11 patients who had poor intubating conditions, poor condition for laryngoscopy was the cause in three, and a vigorous or sustained reaction to insertion of the tracheal tube or cuff inflation was the cause in eight. A bolus dose of propofol 0.5 mg kg−1 was given to two patients who had a vigorous reaction to insertion of the tracheal tube.
SBP and HR decreased significantly 30 s after injection of propofol (P30) compared with the preinduction values (Base; SBP 15.2% and HR 11.0%, respectively, P < 0.001), but both were within acceptable ranges and no significant changes occurred thereafter until 3 min after tracheal intubation (INT3; Fig. 2). No patient needed ephedrine or atropine.
In the PACU, six patients (21.4%) reported a sore throat. No patient had hoarseness or recall of intraoperative events.
This study demonstrated that, after induction of anaesthesia with remifentanil 2 μg kg−1 and propofol 2 mg kg−1, the dose of rocuronium which provided a 50% probability of acceptable intubating conditions in a rapid sequence intubation was 0.20 mg kg−1 (95% CI 0.17 to 0.23 mg kg−1). In other words, after induction with remifentanil and propofol, acceptable intubating conditions could be obtained within 60 s using rocuronium 0.8 mg kg−1.
Rapid sequence intubation was performed traditionally using thiopental and succinylcholine. When used in a large dose of 0.9 to 1.2 mg kg−1, rocuronium could replace succinylcholine in rapid sequence intubation but a prolonged duration of action could be a problem. Sugammadex can reverse the block rapidly, but it is still expensive and is not yet available to every practitioner. As a hypnotic agent, propofol is known to result in more favourable airway conditions for tracheal intubation compared to thiopental; pharyngeal and laryngeal muscle tone during laryngoscopy were more depressed14 and vocal cords were more widely open15 after induction with propofol compared with an equipotent dose of thiopental.
Recent studies into the possibility of tracheal intubation without the use of muscle relaxants show that full relaxation is not mandatory for successful tracheal intubation.16 However, caution is needed because the intubating conditions are related to laryngeal morbidity.5,17 Postoperative hoarseness and vocal cord damage were more frequent in patients who had poor intubating conditions compared to those who had excellent conditions.17
The most commonly recommended doses for acceptable intubating conditions without a neuromuscular blocker4,18 are remifentanil 4 μg kg−1 or alfentanil 40 μg kg−1 in combination with propofol 2 to 2.5 mg kg−1. The doses of opioids used are higher than those used usually at the time of induction of anaesthesia using a muscle relaxant, and significant bradycardia or hypotension can be a problem when a high dose of opioid is used. Rapid sequence intubation with propofol 2 mg kg−1 and succinylcholine 1 mg kg−1 induced a significant 14% increase in MAP and a 25 to 30% increase in HR, whereas remifentanil 4 μg kg−1 instead of succinylcholine induced a significant 24 to 31% decrease in MAP.19 In contrast, the haemodynamic changes were not so severe and were within acceptable ranges in our patients. Remifentanil 2 μg kg−1 combined with propofol 2 mg kg−1 did not decrease HR or blood pressure significantly before intubation and also prevented increases in HR and blood pressure after intubation.
There have been other studies of intubating conditions with only a small dose of rocuronium. After inhalational induction with sevoflurane, 90% of children had acceptable intubating conditions within 2 min of injection of rocuronium 0.22 mg kg−1 and the twitch tension was 26% of baseline at that point.20 In adult patients, after induction with lidocaine 1.5 mg kg−1, remifentanil 2 μg kg−1 and propofol 2 mg kg−1, intubating conditions 90 s after injection of rocuronium 0.3 mg kg−1 were comparable to those 60 s after injection of succinylcholine 1.5 mg kg−1 and the mean train-of-four (TOF) ratio was 0.65 at the time of intubation in the rocuronium group.21 After rocuronium 0.25 mg kg−1, the onset time was 1.6 and 3.0 min at the laryngeal muscles and the adductor pollicis muscle respectively, and the maximum TOF ratios achieved were 0.37 and 0.69, respectively.22 By reducing the dose of rocuronium, the duration of action could be shortened, which makes reversal of neuromuscular block easier and reduces the risk of residual paralysis after recovery. After a single intubating dose of an intermediate duration non-depolarising neuromuscular blocker, it has been reported that up to 45% of patients have residual paralysis, defined as a TOF ratio below 0.9.23 At a TOF ratio below 0.9, there are increased risks of upper airway obstruction and pulmonary aspiration due to functional impairment of pharyngeal and upper oesophageal muscles.24
The differences between our study and previous investigations are that tracheal intubation was performed only 60 s after injection of rocuronium to simulate rapid sequence intubation and we tried to find the lowest dose of rocuronium needed in this situation. It would have been better if we had measured the degree of neuromuscular block, but we could infer from previous studies that the degree of neuromuscular block obtained would be variable according to the dose of rocuronium used but could be only partial at the time of intubation. We expected a decreased incidence of residual paralysis by reducing the dose of rocuronium during induction of anaesthesia. However, the use of a nerve stimulator for management of muscle relaxation is mandatory and reducing the dose of rocuronium does not justify not using the nerve stimulator. This is a limitation of our study.
This study has several additional limitations. First, we only obtained the ED50 of rocuronium for acceptable intubating condition, even though the values of ED90 or ED95 are of clinical interest. For this purpose, we also calculated ED95 using probit analysis (Fig. 3), but the ED95 could be incorrect and the CI is wide25 because up-and-down methods do not provide an accurate estimate at the upper part of the distribution.26 The intubating dose is classically expressed as 2 x ED95 or alternatively 4 x ED50. On the basis of our ED50 results, we recommend an intubating dose of rocuronium of 0.8 mg kg−1. This is lower than previous recommendations. However, further study is needed to obtain a more accurate ED95 value. The advantage of using the modified up-and-down method is, however, that we could reduce the number of patients to converge to an ED50 and to increase the precision of the final estimate.11
Second, we regarded both excellent and good intubating condition as a success according to the Guidelines For Good Clinical Research Practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents and several related studies.1,13,20 However, it should be kept in mind that in some situations, such as trauma patients with severe head injury, excellent intubating conditions are preferable. Caution is also needed for interpretation of previous studies because some studies regarded only excellent conditions as optimal.27
Another limitation is that we evaluated recall and sore throat only in the PACU. It is known that patients who do not have recall or a sore throat in the PACU may complain of them later.28,29 It is known that only 35% of patients who had intraoperative awareness report it during their stay in the PACU.29 The incidence of postoperative sore throat varies between 14.4 and 50%.28,30,31 After rapid sequence intubation with propofol and succinylcholine, sore throat in the PACU was reported to be 22.9%.28 The incidence of sore throat in the PACU in this study was 21.4% and was similar to previous reports.
In conclusion, after induction of anaesthesia with remifentanil 2 μg kg−1 and propofol 2 mg kg−1, we recommend a dose of rocuronium of 0.8 mg kg−1 for rapid sequence intubation. Full relaxation is not mandatory for rapid sequence intubation when propofol and remifentanil are used together. Remifentanil-propofol-low dose rocuronium could be one of the alternative methods employed when rapid sequence intubation is needed.
Assistance with the study: none declared.
Financial support and sponsorship: none declared.
Conflicts of interest: none declared.
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