The discussion about the potential side-effects of succinylcholine has been accompanied by an interest in non-depolarizing neuromuscular blocking agents with a rapid onset and a short time of action . Rapacuronium may fulfil some of those requirements, but it is not yet available in all European countries and its potential side-effects need further investigation . Rocuronium (Esmeron®) provides the shortest onset of action of the various non-depolarizing neuromuscular blocking agents currently available. Nevertheless, its speed of onset is dose dependent such that high dosage produces a long duration of action , thus limiting its usefulness for short surgical procedures. A method for producing acceptable conditions, similar to that of succinylcholine, for intubating the trachea quickly is imperative. The search focuses on rapidly acting non-depolarizing neuromuscular relaxants, but endeavouring to avoid giving a high dose by either using a special dosage schedule [4,5] or else a combination of drugs used for the induction of anaesthesia [6–14].
Our hypothesis is that s-ketamine should be a valuable substance in this setting because of its hypnotic and analgesic effects, and also because of its cardiovascular stimulating properties that may contribute to fast distribution of a muscle relaxant. We investigated a combination of etomidate and s-ketamine using rocuronium 0.6 mg kg−1 to provide the neuromuscular blockade. For comparison, we examined a group of patients who received either placebo or fentanyl because the benefit of adding opioids in this setting has been well documented [7,9,11]. Etomidate was used as the hypnotic agent in all groups, because of its minimal cardiovascular side-effects and recommendation for rapid-sequence induction of anaesthesia .
The investigation was conducted in accordance with the recommendations outlined in Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents . After approval by our Regional Ethics Committee and written informed patients’ consent, we invited 90 male or female Caucasian patients (ASA I–II) undergoing minor elective surgery to participate in a prospective randomized double-blinded study. All patients were free from neuromuscular, cardiovascular, renal, hepatic or endocrine disease and were taking no medication known to interact with neuromuscular blocking agents. The exclusion criteria also included any patients who were judged to be at increased risk or pulmonary aspiration or anticipated airway difficulty.
All patients were premedicated with clorazepat (Tranxilium®), a benzodiazepine drug, 10 mg orally, on the evening before surgery. Blood pressure and heart rate were monitored automatically and non-invasively in the preinduction period (baseline) and every minute before (e.g. immediately before the administration of each of the drugs used in the induction sequence) and for 5 min after tracheal intubation. Anaesthesia was induced with drugs given through a port in the intravenous (i.v.) infusion of lactated Ringer’s solution administered at maximum gravity flow. Patients were assigned to one of three groups, by use of a randomization list, for induction to one of the following three groups: control, placebo + etomidate (0.3 mg kg−1); fentanyl, fentanyl (1.5 μg kg−1) + etomidate (0.3 mg kg−1); ketamine, s-ketamine (0.5 mg kg−1) + etomidate (0.3 mg kg−1). Rocuronium (0.6 mg kg−1) was used to produce muscle relaxation in all groups. Two minutes after giving placebo, or fentanyl, or s-ketamine, a hypnotic state was induced using i.v. etomidate followed by the administration of rocuronium after 60 s.
After a further 60 s, endotracheal intubation was attempted by the authors who at this time had no idea about the nature of the induction agents, because the drugs were administered by a colleague. The attempt to intubate the trachea was repeated every 30 s until tracheal intubation was successful. The intubating conditions were evaluated using a score described by Viby-Mogensen and his colleagues  (Table 1).
Statistical analysis was applied using the χ2-test or one-way ANOVA [Kruskal–Wallis-H-test with post test (Dunnett’s multiple-comparison test) using SPSS 7.5.2.G for Windows® (SPSS Inc, Chicago, USA) – α was set at 0.05. Numerical data are presented as mean ± standard deviation (SD).
Patients in all groups were similar with regard to biometric data (Table 2). Compared with placebo or fentanyl, the best scores at the first attempt at intubation (after 60 s) were achieved by co-induction with s-ketamine and etomidate (23 excellent, 7 good) (P < 0.01, χ2-test;Figure 1 and Table 3). Tracheal intubation was achieved after 60 s in all patients in the fentanyl and ketamine groups. Four patients in the control group were intubated after 90 s and one after 120 s.
The heart rate of all patients was stable at baseline. Before tracheal intubation, heart rate remained constant in the control and fentanyl groups, but increased in the ketamine group (P < 0.01, ANOVA). A similar pattern was observed in the change of systolic and diastolic arterial pressures (P < 0.01, ANOVA). After placement of the endotracheal tube, there was a distinct rise in arterial pressure and heart rate in the control group and only a moderate non-significant increase was observed in the other groups (Figure 2).
We were able to demonstrate significantly better tracheal-intubating conditions after 60 s in the s-ketamine group, though intubation was also successfully accomplished in most patients of our control groups. Many reports claim that rocuronium is an acceptable alternative to succinylcholine for rapid-sequence induction, even if it is used in a lower dosage (0.6 mg kg−1) to avoid a prolonged action. This result may not only be explained by the effect of rocuronium itself [17–21] but also by the interaction of combined anaesthetic agents . Nevertheless, often no complete neuromuscular blockade is found after 60 s using relaxometry measurements [2,18–20]. Our study supports the assumption that the method of induction of anaesthesia has a great influence on the conditions for intubating the trachea. Hans and his colleagues  and Baraka and his colleagues  reported better intubating conditions using ketamine 2.5–1.5 mg kg−1 compared with thiopental 5–4 mg kg−1 but no significant differences were found for the onset of rocuronium (0.6 mg kg−1). Other authors describe the benefit of short-acting opioids, e.g. alfentanil [7,9,14] or remifentanil , for co-induction. Fuchs-Buder and his colleagues  found similar intubating conditions using etomidate or thiopental for induction, but important differences were observed according to whether or not alfentanil was used. The present study showed significantly better intubating conditions when an opioid was added. In addition to the analgesic co-medication, the kind of hypnotic drug selected for anaesthesia induction seems to play an important role in the ease of tracheal intubation. Dobson and his colleagues  found a shorter effective time using rocuronium 0.6 mg kg−1 after propofol compared with thiopental. Skinner and his colleagues  reported better conditions after propofol compared with etomidate. In contrast, Gill and Scott  demonstrated the shortest onset time with vecuronium in a group of patients where etomidate was used for induction of anaesthesia (compared with thiopental and propofol).
In our present investigation, etomidate was selected because of its minor cardiovascular effects. The best results for endotracheal intubation were obtained in the s-ketamine/etomidate group. This was accompanied by a significant cardiovascular stimulatory effect during the induction sequence. The increases in heart rate, arterial pressure and cardiac output induced by ketamine may have contributed to a faster onset of the relaxant effect of rocuronium. Interestingly, Munoz and his colleagues  found a faster onset time for rocuronium 0.6 mg kg−1 using ephedrine 70 μg kg−1 for co-medication and thiopental for induction of anaesthesia. However, a faster distribution of rocuronium was assumed in the effect organ (muscle), without detecting any significant differences in heart rate or blood pressure between groups. In our present investigation, we are unable to confirm the results of Munoz’s group, because we did not perform relaxometric measurements of twitch depression. This needs to be the subject of further investigation. In our present study, the analgesic and hypnotic effects of s-ketamine, as well as a faster distribution of the neuromuscular blocking agent due to haemodynamic stimulation, could explain the better results for intubating conditions obtained when pretreatment with s-ketamine was used.
In conclusion, we consider a combination of etomidate and s-ketamine for modified rapid-sequence induction using a lower dosage of rocuronium for neuromuscular blockade to be an advantageous alternative for patients with normal cardiovascular reserve capacity whenever succinylcholine needs to be avoided.
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