Orotracheal intubating conditions depend on patient anatomy, experience of the anaesthesiologist and drugs administered. An appropriate induction technique should include propofol [1-4], opioids [5-7] (to decrease haemodynamic response and facilitate intubation) and neuromuscular blockers. In a non-emergency situation the choice of muscle relaxant depends on the patient's physical status. If a rapid-sequence induction is needed, suxamethonium is still the most frequently used, although it needs to be avoided at times because of its well-known side-effects. Unfortunately there is not an ideal non-depolarizing neuromuscular blocking agent for rapid-sequence induction. This drug requires a latency less than 35 s, marked pre-synaptic effect , a rate constant of equilibration between plasma and effect site (ke0) more than 0.2, a short half-life of equilibration between plasma and effect site (t1/2ke0), a low potency and high laryngeal selectivity. The best current alternative after the clinical failure of rapacuronium  is rocuronium although it has a latency more than 35 s.
In order to reduce the latency of rocuronium, it is necessary to increase the intubating dose, use either the timing principle or the priming principle. Increasing the dose of rocuronium (1.2 mg kg−1) results in an onset time of 0.9-1.1 min (compared with 0.8-1.2 min of suxamethonium 1 mg kg−1), but is associated with a prolonged recovery time and may need to be antagonized with an anticholinesterase. The timing principle needs a perfect adjustment of the induction times to avoid diplopia, dyspnoea and other major complications .
The priming principle holds that the onset may be accelerated if an intubating dose is preceded by a priming dose administered 3-6 min earlier. The aim of our study was to compare orotracheal intubating conditions between suxamethonium (1 mg kg−1), rocuronium (0.6 mg kg−1) and rocuronium with different priming techniques.
Patients and methods
After Institutional Review Board approval and informed consent from each patient we examined tracheal intubation conditions in 376 adult patients, American Society of Anesthesiologists (ASA) Grade I-III, scheduled for several types of surgery in a randomized, blind, prospective study. Exclusion criteria included patients >70 or <18 yr of age, a history of drug or alcohol abuse, psychiatric disorder, obesity (body mass index (BMI) >30 kg m−2), hepatic, renal or cardiac failure, neuromuscular diseases, ASA Grade IV-V, pregnancy, electrolyte disorders, burns, nutritional disturbances, chronic illness, treatment with drugs known to affect neuromuscular transmission, Mallampati Class III-IV, thyro-mental distance <6 cm or possible difficult intubation.
All patients were previously informed about possible signs and symptoms of pre-curarization. They were monitored in the operating room with electrocardiography (ECG), heart rate (HR), non-invasive measurement of arterial blood pressure (BP), pulse oximetry and capnography. Neuromuscular function was assessed according to the good clinical research practice international criteria . The skin of the arm and wrist was prepared by shaving, superficial abrasion, cleaning with alcohol and application of a conductive jelly to the surface electrodes to facilitate optimal monitoring. Neuromuscular monitoring was started after successful automatic calibration of an acceleromyographic monitor (TOF-watch SX®; Organon (Ireland) Ltd, Dublin, Ireland) attached to the adductor pollicis muscle and using ulnar nerve stimulation with a train-of-four for every 15 s. This muscle is considered as a standard for monitoring and is easier to monitor than masseter  or ocular muscles . The pulse oximeter and venous cannula were sited on the opposite arm and the non-invasive arterial pressure cuff on the leg.
Patients were previously assigned to seven randomized groups. There were five priming groups which received a priming dose of 0.1 × ED95 of neuromuscular blocking agent  followed by 0.57 mg kg−1 of rocuronium. The priming drugs and doses were as follows: rocuronium 0.03 mg kg−1 (Group RR), atracurium 0.025 mg kg−1 (Group AR), vecuronium 0.005 mg kg−1 (Group VR), mivacurium 0.0075 mg kg−1 (Group MR) and cis-atracurium 0.005 mg kg−1 (Group CR). There were also two control groups, the first of which received a single bolus dose of suxamethonium 1 mg kg−1 and the second of which received a single dose of rocuronium 0.6 mg kg−1 without a priming dose (Group 0R).
After baseline monitoring had been established, the priming dose was administered in 20 mL of normal saline over 30 s (the 0R and suxamethonium groups received 20 mL of normal saline as placebo). The laryngoscopist (a staff anesthesiologist with more than 10 years of experience in intubation) was blinded to the nature of the priming dose. Each patient received fentanyl (0.003 mg kg−1) 2.5 min after priming and then propofol (2.5-3.5 mg kg−1) 3 min after priming [1-7], both being drugs which do not modify neuromuscular function [15-18].
During the pre-curarization period, signs and symptoms of pre-curarization were recorded by observing and asking the patients. Atropine and benzodiazepines were not used. The intubating dose was administered in 20 mL normal saline through a large venous cannula exactly 4 min after the injection of the priming dose. The laryngoscopist remained blinded to the nature of the drug, although suxamethonium was detected due to the high incidence of fasciculations.
Laryngoscopy started 45 s after administration of the intubating dose and all patients were intubated at 60 s. Intubating conditions were assessed according to those described in the good clinical research practice international criteria  (Table 1).
The sample size of the study was calculated with a significance level (α) of 0.001 in a two-sided test, and a power (1-β) greater than 95% to detect a difference between means of at least one standardized clinical difference. Normality was tested using the Kolmogoro- Smirnov test. The different groups were compared with one-way analysis of variance (ANOVA), followed by the Tukey-B multiple comparison test if normally distributed and using the Kruskal-Wallis test followed by the Mann-Whitney U-test with Finner's modification of Bonferroni's correction if not normally distributed. Qualitative data were analysed using the χ2-test. The statistical programs SPSS 10.0 (Chicago, Illinois, USA), WinPEPI and Granmo 4.0 were used for analysis.
Patient characteristics data of all groups is shown in Table 2. We found statistically significant differences in laryngoscopy between the suxamethonium group and 0R (P = 0.0357), AR (P < 0.00001) and CR groups (P = 0.0209). There were differences in vocal cords position and movement during intubation between 0R and RR (P = 0.0192), AR (P = 0.0090), suxamethonium (P < 0.00001), CR (P = 0.0020), VR (P < 0.00001) and MR (P = 0.0192) groups. There were also differences in reaction to insertion of tracheal tube and/or cuff inflation between 0R and AR (P = 0.0015), suxamethonium (P < 0.00001), CR (P < 0.00001), VR (P < 0.00001) and MR (P = 0.0015) groups, respectively (Table 3).
When final intubation conditions were compared, we observed significant statistical differences in the percentages of patients with poor (clinically not acceptable) intubation conditions between the 0R group and the remaining ones: RR (P = 0.0210), AR (P < 0.00001), suxamethonium (P = 0.0015), CR (P < 0.00001), VR (P < 0.00001) and MR (P = 0.0060). We also found statistical differences in the percentages of patients with clinically acceptable intubation conditions between 0R group and the rest of groups. There were also differences in the percentage of patients with good intubation conditions between the 0R group and RR (P = 0.0228), AR (P = 0.0100), suxamethonium (P = 0.0228), CR (P = 0.0090), VR (P = 0.0100) or MR (P = 0.0060) groups. When only the percentages of patients with excellent intubation conditions were considered, we observed differences between 0R group and AR (P = 0.0278), suxamethonium (0.0447), CR (0.0268) or VR (0.0119) group, respectively (Fig. 1).
Of all the patients 94.7% remained asymptomatic, whereas the rest of the patients reported pre-curarization side-effects: diplopia (2.7%), palpebral ptosis (2.1%) and a single episode of dyspnoea in the MR group (0.3%). The 0R group had three patients with diplopia (6.1%), the AR group one patient with palpebral ptosis (1.9%), the CR and VR groups one case of diplopia (2%) each and the MR group three patients with diplopia (12.5%), five with palpebral ptosis (12.8%), one case of dyspnoea (4.2%) and a single episode of histamine release (4.2%). Overall, the MR group had significantly more signs and symptoms of pre-curarization than the remaining priming groups.
Although there were significant differences in age between MR and 0R groups compared with VR and suxamethonium groups we believe that this difference has no clinically relevant importance and seems to be unrelated to our study.
This study has tried to obtain the most appropriate induction technique to achieve the best orotracheal intubating conditions at the first minute after the administration of rocuronium. We selected propofol, fentanyl and rocuronium as the best combination of drugs according to data previously reported [1-8]. We used routine doses of these agents and a priming dose of 0.1 × ED95 in each case. Priming doses greater than 0.1 × ED95 are reported to cause palpebral ptosis, diplopia, hypotonia, dyspnoea, regurgitation and tracheobronchial aspiration [19,20]. A priming dose of 0.1 × ED95 is considered to be devoid of major pre-curarization symptoms and rarely produces measurable neuromuscular effects [21,22]. The priming dose and the elapsed time until administration of the main dose of rocuronium (4 min)  were selected for optimum clinical effect with minimum curarization.
It has been reported [24,25] that a rocuronium priming technique could be potentially dangerous and does not offer any advantages over a single bolus dose of 0.6 mg kg−1. All of the priming doses in our study appeared to be safe (94.7% of patients remained asymptomatic). Except for a single episode of dyspnoea in the MR group, these symptoms were well tolerated by patients, but all of them had been informed carefully prior to surgery. There was also one case of histamine release in the MR group following the priming dose but limited to the skin over the chest wall.
These results show that using an adequate dose and interval of pre-curarization, priming could be a possible means to obtain good intubating conditions without major risk for healthy patients. Nevertheless, this practice should always be performed carefully, according to individual patients (e.g. priming may not be a safe approach in elderly patients because it can produce greater decreases in oxygen saturation and pulmonary function) .
We observed much better intubation conditions in the priming groups (except the RR group) when compared to rocuronium alone and our results agree with those of Griffith and colleagues . It might be expected that the combination of an aminosteroid (rocuronium or vecuronium) and a benzylisoquinolinum compound (such as atracurium, cis-atracurium or mivacurium) could offer advantages (some synergism) over the priming principle using only aminosteroid neuromuscular blockers. Our results did not confirm this expectation. Redai and colleagues  reported that rocuronium was ineffective at priming rocuronium and vecuronium was effective at priming rocuronium (producing an approximate 33% reduction in onset time). They also found that rocuronium and vecuronium, when given as priming agents, both reduce the onset time of a vecuronium block .
It is generally accepted that a combination of rocuronium with a benzylisoquinolinum compound will show synergism. Experimental observations have suggested, however, that during onset, rocuronium acts synergistically with other non-depolarizing agents, but that at a steady state the combined action is additive . We did not find prolonged neuromuscular blockade in priming groups, and responses to other rocuronium doses during surgery when needed were normal.
If we are exclusively looking for the best intubating conditions, suxamethonium has a fast onset of action, rapid recovery and familiarity among anesthesiologists. Priming a rocuronium block with vecuronium , atracurium, cis-atracurium or mivacurium  resulted in a neuromuscular block comparable to that of suxamethonium in both the onset of action and intubating conditions.
Priming is a technique, which requires careful preparation (mathematical calculations, diluted doses, and strict administration time). In addition, the long duration action of rocuronium, when compared with suxamethonium is a potential problem in expected difficult intubation. Nevertheless, it is necessary to remember that even suxamethonium's duration does not completely protect a patient from hypoxia in a difficult ventilation and intubation scenario.
In general terms, there are similar intubating conditions between suxamethonium and priming rocuronium with vecuronium, rocuronium, atracurium, cis-atracurium or mivacurium. The last group had a significantly major incidence of pre-curarization side-effects and so its use could be not recommended. Nevertheless, some patients demonstrated worse conditions than others. These patients were included in the poor intubation conditions group and determine the possibility of airway management complications, caused because these patients presented muscle fasciculations on attempted intubation, and this aspect could be increased in low cardiac output and slow circulation states. It was desirable to have not only the highest percentage of excellent and good intubation conditions but also the lowest percentage of patients with poor conditions. The SX group contained more patients with poor conditions and fewer patients with excellent conditions than the VR group (Fig. 1). In these particular clinical scenarios, priming technique, particularly with vecuronium, is safe and predictable, given the same intubating conditions (statistically speaking) as the SX group and was emphasized in the majority of patients.
In conclusion, priming rocuronium with a non-depolarizing agent resulted in a neuromuscular block comparable to that of suxamethonium in both onset of action and intubating conditions. We also consider that priming rocuronium with 0.1 × ED95 of vecuronium, rocuronium, atracurium or cis-atracurium was a safe technique and did not increase risk of pre-curarization in healthy patients.
We wish to acknowledge the assistance from the nursing staff and financial support from the Department of Anesthesiology and Intensive Care, University Clinic (Navarra) and Department of Anesthesiology, Joan XXIII Hospital (Tarragona).
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Keywords:© 2005 European Society of Anaesthesiology
ANAESTHETICS; INTRAVENOUS; propofol; INTUBATION; INTRATRACHEAL; NEUROMUSCULAR NON-DEPOLARISING AGENTS; rocuronium; atracurium; vecuronium; cis-atracurium; mivacurium; NEUROMUSCULAR DEPOLARIZING AGENTS; succinylcholine; NEUROMUSCULAR BLOCKADE; onset