Departments of Anaesthesia, 1Technische Universität München, Klinikum r. d. Isar, Munich, Germany. 2The Queens University of Belfast, Belfast, UK. 3University Hospital of Groningen, Groningen, The Netherlands. 4University of Newcastle upon Tyne, Newcastle upon Tyne, UK. 5Helsinki University Central Hospital, Helsinki, Finland. 6Institut Gustave Roussy, Paris, France. 7Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. 8Herlev University Hospital København, Copenhagen, Denmark. 9Organon Teknika BV, Boxtel, The Netherlands. 10Leopold-Franzens Universität Innsbruck, Innsbruck, Austria
Accepted for publication: June 9, 2000
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Abstract |
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Br J Anaesth 2000; 85: 72431
Keywords: anaesthesia, rapid sequence induction; anaesthesia, intubation; neuromuscular block, rapacuronium; neuromuscular block, succinylcholine
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Introduction |
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Rapacuronium is a non-depolarizing neuromuscular blocking agent with the characteristics of rapid onset, short duration of action and the feasibility of early antagonism.8 It may be a safe and effective alternative to succinylcholine for facilitating tracheal intubation during rapid-sequence induction of anaesthesia. In a previous study, clinically acceptable intubating conditions were achieved significantly less frequently after rapacuronium 1.5 mg kg1 (89.4%) than after succinylcholine 1.0 mg kg1 (97.4%) during rapid-sequence induction of anaesthesia.9 Increasing the initial dose of a neuromuscular blocking agent is commonly used to shorten onset time and to improve intubating conditions.5 10 11 The results of a dose-finding study suggest that using higher doses of rapacuronium (2.0 or 2.5 mg kg1) results in a more rapid onset and may result in a higher number of excellent and good tracheal intubating conditions.12
The aim of the present study was to compare the intubating conditions during rapid-sequence induction after rapacuronium 2.0 and 2.5 mg kg1 with the conditions after succinylcholine 1.0 mg kg1. As equivalence was not expected,9 based on a comparison between rapacuronium 1.5 mg kg1 and succinylcholine 1.0 mg kg1, the aim of the study was to prove non-inferiority of these two doses of rapacuronium compared with a standard dose of succinylcholine (see Appendix). In addition, adverse events and the cardiovascular response to induction of anaesthesia and intubation were assessed.
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Patients and methods |
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After fentanyl 12 µg kg1 and 3 min of preoxygenation, anaesthesia was induced with thiopental 27 mg kg1 followed by the neuromuscular blocking drug. Fentanyl and thiopental doses were decided by the anaesthetist within defined ranges, according to the weight and clinical condition of the individual patient. All drugs were injected into a rapidly running infusion of lactated Ringers solution, the neuromuscular blocking drugs being injected within 5 s. Cricoid pressure was applied after loss of consciousness.
Tracheal intubation was carried out by an experienced anaesthetist who was blinded to the identity of the neuromuscular blocking drug (by remaining outside the room for 45 s after its administration). Laryngoscopy and intubation, including cuff inflation, were commenced 60 (±5) s after completion of injection of the neuromuscular blocking drug and had to be completed within 20 s. Intubating conditions were evaluated according to a standard scheme in which assessments were made of the ease of laryngoscopy, the position and movement of the vocal cords, and coughing and limb movement on insertion of the tracheal tube.13 Each variable was graded as excellent, good or poor, or not applicable if it could not be assessed. The overall intubating conditions were classified as excellent (all variables scored as excellent), good (at least one of the variables scored as good but none scored as poor) or poor (at least one variable scored as poor). Excellent or good conditions were considered clinically acceptable.
Anaesthesia for the first 5 min after intubation was maintained with 66% nitrous oxide in oxygen and isoflurane (up to 1% inspired). Heart rate, non-invasive arterial blood pressure and arterial oxygen saturation were assessed in all patients during the preoxygenation period (baseline) and 2, 3, 4 and 5 min after administration of the neuromuscular blocking agent. The study terminated at this point and anaesthesia thereafter was managed as appropriate.
Note was made of any adverse events during the intra- or postoperative periods. An adverse event was defined as an unusual or unexpected sign which manifested itself or worsened during the study and post-study periods. According to the principles of good clinical practice, the anaesthetist decided on the existence, severity and drug-relatedness of any adverse event. Particular attention was paid to skin reactions and respiratory side-effects, such as bronchospasm, increased airway pressure, wheezing on auscultation and oxygen desaturation below 95%.
The primary efficacy variable of the study was the intubating condition 60 s after injecting the neuromuscular blocking agent (clinically acceptable versus unacceptable). Non-inferiority of the intubating conditions for each dose of rapacuronium was determined in comparison with succinylcholine. The concept of non-inferiority (see Appendix)14 was used, as it was expected from the results of previous studies9 12 with rapacuronium that the conditions after rapacuronium would be slightly worse than those after succinylcholine. With respect to clinically acceptable intubating conditions, rapacuronium was considered to be not inferior to succinylcholine in cases where the percentage of clinically acceptable intubating conditions after rapacuronium was not more than 10% lower than the percentage after succinylcholine. Thus, the null hypothesis was defined to be Prap<Psux10%, and the alternative hypothesis to be Prap>Psux10%, where Prap and Psux are the percentages of clinically acceptable intubating conditions after rapacuronium and succinylcholine respectively.
To determine if each of the two doses of rapacuronium was not inferior to succinylcholine 1.0 mg kg1, each of the rapacuronium dose groups was tested against the succinylcholine group separately. For each of the two statistical tests, the probability of falsely claiming non-inferiority was 0.05/2 (to allow for two comparisons). To test this null hypothesis, a one-sided 97.5% confidence interval was calculated for the difference between succinylcholine and rapacuronium. The null hypothesis of inferiority was rejected in favour of the alternative hypothesis of non-inferiority when the upper limit of this one-sided 97.5% confidence interval did not exceed 10%, a difference of this size between the two neuromuscular blocking drugs being considered clinically irrelevant. An estimate of the difference in the frequency of acceptable intubating conditions between two treatment groups was calculated as follows. For each trial site, the difference in the frequency of acceptable intubating conditions was estimated separately, and the overall treatment difference was calculated by averaging these estimates using the number of subjects per trial site as a weighting factor (see Appendix). Any influence of the dosage of induction agents used, age and any centre effect was also assessed, using a logistic regression model.
Sample size calculations were based on an estimated frequency of clinically acceptable intubating conditions of 97% after succinylcholine 1.0 mg kg1 and 94% after rapacuronium. This required 184 patients in each of the three groups of the study to have a power of 90%.15 It was planned that 200 subjects should be enrolled in each group to allow for unevaluable patients.
Safety variables (cardiovascular response and adverse events) were evaluated on the basis of data of all patients receiving the neuromuscular blocking drugs. Repeated measures analysis of variance was performed with each cardiovascular variable (heart rate, mean arterial pressure) as the dependent variable, the respective baseline value as the covariable and the time of assessment, treatment group and their interaction term as independent factors. A significant interaction would indicate differences in the cardiovascular response to the neuromuscular blocking drug used. The incidence of adverse events was compared between groups using the 2 test. Significant differences were assumed if
2 exceeded 5.02389 (
= 0.05/2, to allow for two comparisons). Logistic regression analyses were performed with respiratory side-effects as the dependent variable, treatment group as the covariable and the existence of a medical history of bronchial hyper-reactivity or smoking, and the study centre (and the respective interaction terms) as independent factors. The forwards stepwise method was used for selection of the relevant variables in the model.
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Results |
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Logistic regression analysis revealed no effect of the dose of fentanyl, the dose of thiopental or age group on intubating conditions, but a centre effect was present. The percentage of acceptable intubating conditions at the different centres ranged from 83 to 100 for succinylcholine, from 67 to 100 for rapacuronium 2.0 mg kg1 and from 71 to 100 for rapacuronium 2.5 mg kg1. The reasons for non-acceptable intubating conditions are given in Table 3, the most common being closing of the vocal cords. Impossible laryngoscopy or closed vocal cords were the reasons for failed intubation.
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Discussion |
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From the results of a dose-finding study by Kahwaji and colleagues,12 it was expected that an increase in the dose of rapacuronium to 2.0 or 2.5 mg kg1 would result in an increase in the frequency of acceptable tracheal intubating conditions that were similar to or only slightly (<10%) worse than those after succinylcholine. Therefore, this clinical trial was designed to show that the conditions obtained with the doses of rapacuronium used in the present study would not be inferior to those obtained with succinylcholine 1.0 mg kg1. For such a study design, the statistical methods used to detect differences between two treatments are not appropriate (see Appendix). Thus, a statistical method was chosen which was based on the confidence interval approach. Since we wanted to prove that the intubating conditions after each of the two doses of rapacuronium were not inferior to those after succinylcholine 1.0 mg kg1, one-sided confidence intervals were used. This made it necessary to decide a limit for assuming non-inferiority in intubating conditions, which was fixed at 10% in our study. Others may consider such a difference to be too large; Goulden and Hunter stated that ... most anaesthetists would, if possible, select excellence... for intubating conditions for rapid-sequence induction.16 Because the non-inferiority of rapacuronium 2.0 and 2.5 mg kg1 could not be proven within this limit in our study, succinylcholine should be considered the neuromuscular blocking agent that provides better intubating conditions in a rapid-sequence induction setting, when compared with rapacuronium in the doses used here.
Clinically acceptable intubating conditions were present in 91.8% of patients after succinylcholine 1.0 mg kg1 in the present study. This was lower than the 97.0 and 96.9% reported in two recent studies comparing succinylcholine with rocuronium or rapacuronium, in which some of the present investigators were involved.3 9 However, it is difficult to compare intubating conditions from different studies because of variation in the protocols. This becomes more obvious when considering American17 and European9 studies, in both of which the intubating conditions were compared after succinylcholine 1.0 mg kg1 and rapacuronium 1.5 mg kg1. Although the patients in the American study were probably intubated under deeper anaesthesia, the rate of acceptable intubating conditions was 23% lower in both groups of the American study.
Depth of anaesthesia affects the quality of intubation conditions, as shown by previous studies with rocuronium in which a dose that provided acceptable intubating conditions under stable anaesthesia was found to be inadequate when administered under the conditions of rapid-sequence induction.3 18 In the present study, patients received no sedative premedication and anaesthesia was induced with thiopental and fentanyl in relatively small doses, in order to carry out a typical rapid-sequence induction. This technique (using relatively light anaesthesia) may have contributed to the overall slightly lower incidence of acceptable intubating conditions.
The higher frequency of non-acceptable intubating conditions in the rapacuronium groups may have resulted from incomplete neuromuscular block in the laryngeal muscles, as the vocal cords were closed more often in patients receiving rapacuronium. Previous studies with other neuromuscular blocking drugs such as vecuronium and rocuronium have demonstrated relative resistance but earlier onset of block in the muscles of the vocal cords compared with the adductor pollicis.19 20 One study has shown similar results for rapacuronium.21 Two recent studies, however, challenge the concept of the relative resistance of the laryngeal muscles and shorter onset times of neuromuscular blocking drugs in laryngeal compared with peripheral muscles. DHonneur and colleagues were unable to demonstrate differences between onset times in laryngeal and peripheral muscles for rocuronium and succinylcholine22, and Wright and colleagues were unable to do so for rapacuronium.23 The latter authors explained the rapid onset of rapacuronium by the rapid equilibration between concentrations in the plasma and at the effect site.23 This may indicate the need for doses of rapacuronium larger than those used in the present study, or for more time to elapse so that a better quality of block can develop in the laryngeal muscles.
It is possible that the doses of rapacuronium used in the present study were less potent than the dose of succinylcholine used. Information about the potency of rapacuronium is very sparse. Using electromyography, Kahwaji and colleagues reported maximum blocks of 57, 91 and 98% with rapacuronium 0.5, 1.0 and 1.5 mg kg1 respectively.12 Debaene and colleagues, using mechanomyography, reported maximum blocks of 94, 97 and 99% respectively with rapacuronium 0.75, 1.5 and 2.0 mg kg1.21 Regression analysis of these data (carried out by the authors of the present study) yielded ED95 values of approximately 1.16 and 0.90 mg kg1 respectively. Thus, the doses of rapacuronium used in the present study were approximately 2.0 and 2.5 times its ED95, whereas the dose of succinylcholine used, 1.0 mg kg1, is just under four times the ED95.24
Increasing the dose of rapacuronium beyond those used in the present study would undoubtedly result in a further increase in the incidence of side-effects. The frequency of pulmonary side-effects of 18.5% that we found with rapacuronium 2.5 mg kg1 would be considered unacceptable. In addition, we observed a significant increase in the heart rate in both the rapacuronium groups. Taken in conjunction with the study of Sparr and colleagues9, the frequencies of respiratory side-effects of 10.7, 13.5 and 18.5% after rapacuronium 1.5, 2.0 and 2.5 mg kg1 respectively indicates a dose-related effect. Another disadvantage of using larger doses of rapacuronium is the longer time it will take to antagonize the block.25
Respiratory complications such as bronchospasm, wheezing and increased airway pressure are of obvious concern, but their cause cannot be determined from the present study. Their occurrence along with erythema and an increase in heart rate may indicate histamine release. Their frequency is dose-related and there is some evidence of a dose-related increase in histamine levels after the administration of rapacuronium.26 They may also be related to the technique of induction of anaesthesia or to predisposing factors in the patient. Fleming and colleagues, who did not perform a rapid-sequence induction technique, reported an incidence of bronchospasm of only 3.6 and 1.2% after administration of rapacuronium 1.5 mg kg1 and succinylcholine 1.0 mg kg1 respectively.17 Our results also show that such untoward respiratory effects are more likely to occur in patients with a history of smoking and a tendency to bronchial hyper-reactivity.
In conclusion, the side-effects of succinylcholine make it desirable to have a non-depolarizing relaxant which pro vides good intubating conditions rapidly. Rapacuronium in the doses used in this study was shown not to be as good as succinylcholine, and the higher dose was associated with significant side-effects. A range of 1.52.0 mg kg1 may be safer with rapacuronium, but this drug does not induce intubating conditions as good as those obtained with succinylcholine.
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Acknowledgements |
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Appendix |
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It is important to emphasize that absolute equivalence can never be demonstrated: it is possible only to assert that the true difference is unlikely to be outside a predefined interval, say (,
). The limits of this interval should be chosen so that differences smaller than these values are considered not clinically relevant.
Statistical testing for equivalence or non-inferiority is generally based on the use of confidence intervals. A confidence interval defines a range for the possible true differences between the treatments. If every point within this interval corresponds to a difference of no clinical importance, then the treatments may be considered to be equivalent or one treatment is considered not to be inferior to the other.
For equivalence trials, it is important to use two-sided confidence intervals. If the predefined range of equivalence is defined as the interval from to +
, it is possible to check whether the confidence interval centred around the observed difference lies entirely between
and +
. If it does, equivalence is demonstrated; if not, equivalence cannot be claimed.
For non-inferiority trials, one-sided confidence intervals should be used to show that the experimental treatment is not worse than the reference treatment. Non-inferiority is inferred if the upper one-sided confidence limit for the difference between the experimental and the reference agent does not exceed . For a non-inferiority trial, the hypotheses are defined as follows:
H0: µe<µr
Ha: µe>µr
where µe and µr are the test statistics in the experimental and reference groups respectively.
These null and alternative hypotheses are not equal to those used in superiority trials, in which one wants to show that one treatment is superior to the other one. For a superiority trial they are defined as:
H0: µrµe=0
Ha: µrµe0.
For testing of equivalence or non-inferiority, the usual significance tests cannot be used because they do not test the correct null hypothesis. Furthermore, one does not demonstrate equivalence by not rejecting the null hypothesis, because absence of evidence is not evidence of absence. Not rejecting H0 can, for instance, be the result of an underpowered study, because the number of subjects enrolled was too low or because the variability observed in the data was larger then expected. In both cases it will not, in general, be possible to draw meaningful conclusions from the trial.
Topic E9 of the international conference on harmonization, Statistical principles for clinical trials, states: Concluding equivalence or non-inferiority based on observing a non-significant test result of the null hypothesis that there is no difference between the investigational product and the active comparator is inappropriate.27
On the basis of results obtained from previous studies, showing a lower frequency of acceptable intubating conditions with rapacuronium than with succinylcholine, it could not have been expected that the frequency with rapacuronium would be higher in the present study. Therefore, the objective of the present study was to show that the frequency of acceptable intubating conditions after rapacuronium was only slightly lower (more precisely, it was not more than 10% worse) than the frequency after succinylcholine. For statistical analysis, the objective of a study should be translated into the alternative hypothesis. Let Prap and Psux be the percentages of clinically acceptable (excellent or good) intubating conditions after rapacuronium and succinylcholine respectively. The alternative hypothesis is now H1: Prap>Psux10%. Consequently, the null hypothesis, which is the opposite of the alternative hypothesis, becomes: H0: Prap<Psux10%. In other words, a non-inferiority trial was called for.
Estimate and variance of the difference between two treatments
The present trial is a multi-centre trial in which nine centres participated. Within each centre, the subjects were allocated randomly to treatment group 1, 2 or 3. For each subject, the success (success/failure) of the treatment is recorded. Two comparisons were made: succinylcholine versus each of the doses of rapacuronium.
We were interested in the difference between the probability of success of treatment 1 and the probability of success of treatment 2. An unbiased estimate (Q) of this difference is:
where nij is the number of subjects in centre i receiving treatment j, and xij is the number of successful treatments in centre i receiving treatment j (i=1,...,C, j=1,2, where C is the number of centres).
Using the CochranMantelHaenszel estimate, we can estimate Var[Q] as
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Footnotes |
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References |
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