Comparison of equipotent doses of rocuronium and vecuronium.

BACKGROUND: Rocuronium (R) bromide and vecuronium (V) are monoquaternary aminosteroid compounds. The aim of this study was to evaluate the onset time, conditions of intubation and duration of action of equipotent doses (3ED95) of R and V.
MATERIALS AND METHODS: The study was carried out in 60 adult American Society of Anesthesiologists physical status 1-2 patients of age 20-60 years. The patients were divided into two groups of 30 each and received either 0.9 mg/kg of R (Group R) or 0.168 mg/kg of V (Group V) to facilitate endotracheal intubation. Neuromuscular blockade was assessed at corrugator supercilii and adductor pollicis muscles to evaluate onset time and duration of neuromuscular block, respectively.
RESULTS: The mean onset time was significantly rapid in Group R as compared to Group V (P -0.011). Overall intubating conditions were excellent in 100% of patients in Group R as compared to 70% in Group V. The mean duration of action did not show a significant variation between the groups.
CONCLUSION: At equipotent doses, R provides clinically acceptable intubation conditions much earlier than V without significant variation in clinical duration of action.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

An ideal neuromuscular blocking agent for intubation should have a rapid onset, brief duration of action, provide excellent intubation conditions and should be free from side-effects. For several decades, suxamethonium was the gold standard relaxant for rapid sequence intubation. However, the unintended side-effects such as muscle fasciculations, hyperkalemia, rise in intracranial and intraocular pressures led to the search of newer relaxants. Though vecuronium (V) and atracurium were found to have shorter onset times than the older nondepolarizing muscle relaxants, they did not serve the purpose of rapid sequence intubation.[12] Rocuronium (R) bromide a mono quaternary amino-steroid became available in 1994.[3] Because of its low potency (5.35 times) R is administered in a higher dose leading to high bioavailability at the neuromuscular junction resulting in rapid onset of action.[3] No previous studies compared 3ED95 (ED95 is the dose required to produce 95% depression of twitch response) of the two drugs. The purpose of this study was to compare the onset time, conditions at intubation and duration of action of 3ED95 of R and V.

MATERIALS AND METHODS

After obtaining Institutional Ethical Committee approval and written informed consent, 60 American Society of Anesthesiologists (ASA) physical status 1–2 patients of either sex aged 20–60 years scheduled for various surgical procedures under general anesthesia were enrolled in this prospective, randomized, double-blind study.

Patients with body mass index ≥40 kg/m2, anticipated difficult intubation or mask ventilation, hepatic or renal impairment, neuromuscular disorders, allergy to the study drugs and pregnancy were excluded from the study. Patients were allocated using random number tables into Group R or Group V of 30 each.

All the patients were premedicated with tablet alprazolam 0.5 mg the night before surgery.

Following placement of standard monitors and intravenous access, all the patients were preoxygenated with 100% oxygen for 3 min and received glycopyrrolate 5 μ/kg. Anesthesia was induced with 0.02 mg/kg midazolam, 1 μ/kg fentanyl and titrated doses of propofol until the loss of verbal contact. Train of four stimulus (TOF) of 4 pulses each of 0.2 ms duration at 2 Hz frequency was applied over 2 s to the temporal branch of facial nerve and the resultant twitches of corrugator supercilii (CS) muscle were observed visually. The patients were administered either 0.9 mg/kg R in Group R or 0.168 mg/kg V in Group V over 5 s into a fast flowing intravenous line to facilitate endotracheal intubation and were ventilated with 1% sevoflurane in oxygen. Onset of neuromuscular block was assessed with TOF stimulus every 15 s until the loss of visual response of CS muscle to stimulation of temporal branch of facial nerve. Onset time was the time from administration of muscle relaxant to the loss of visual response to the nerve stimulus. After achieving maximal neuromuscular block, endotracheal intubation was done within 10 s by the same skilled anesthetist who was not involved in the anesthesia technique and was consequently blinded to the neuromuscular blocking agent given and the observations. The conditions at intubation were assessed using the four-point scale of Cooper[456] [Table 1], which was a modification of Krieg's scale.[7] Intubation was graded according to the score attained on Cooper scale as excellent (8–9), good (6–9), fair (3–5) or poor (0–2). TOF stimulus was repeated every 5 min till the recovery of the first twitch. Duration of action of muscle relaxant was assessed at adductor pollicis (AP) muscle and it was the time from administration of muscle relaxant to the recovery of first twitch in response to stimulation of ulnar nerve at the wrist. Normothermia was maintained in patients of both the groups. The primary outcome measure of the study was the onset time. The secondary outcome measures were the conditions of intubation and duration of action of R.

Table 1

Criteria and score of conditions of intubation (Cooper scale)

Statistical analysis

Sample size was derived using MedCalc (trial version 11) online power and sample size calculator based on the assumption of alpha error 0.05 and power of the study were 86%. MedCalc statistical software, version (13.3) was used to analyze the data. Summary statistics, mean and standard deviation were calculated for different parameters under the study. The observed results were analyzed using Chi-square test for qualitative data and Student's t-test for quantitative data. P < 0.05 was considered as statistically significant.

RESULTS

From the initial study group of 68 patients, 8 patients (four from each group) were excluded from the study because the neuromuscular block was incomplete 5 min after injection of muscle relaxant. The groups were comparable with respect to demographic data, ASA physical status and Mallampati score [Table 2]. The mean onset time was significantly rapid in Group R (83.66 ± 41.73 s), compared with Group V (116.66 ± 55.37 s) [Table 3]. There was a statistically significant difference in mean onset time in both groups with rapid onset in Group R (P - 0.011). Overall intubation conditions were excellent in 100% of patients in Group R as compared to 70% patients in Group V. Intubation conditions were good in 23% and fair in 7% of patients in Group V. The mean duration of action in Group R was 49.83 ± 14.53 min, compared to Group V 52.5 ± 15.9 min. There was no statistically significant difference in mean duration of action in both groups (P - 0.50).

Table 2

Demographic data

Table 3

Onset time, duration of action and conditions of intubation in R Group and V Group

DISCUSSION

The study has confirmed the rapid onset of action of R compared with V. It also showed that the clinical conditions of intubation were better with R than V. Onset of action at CS muscle did not guarantee excellent intubation conditions in V Group. Both the groups did not show a significant difference in duration of action.

Many previous studies compared R with V. However, no study compared 3ED95 of the two drugs. Onset time at CS with either of the relaxants and its correlation with conditions at intubation were also not assessed. ED95, corresponding to 95% block, is more commonly used to compare the pharmacological profile of drugs. R bromide is 5.35 times less potent than V with an ED95 of 0.3 mg/kg and 0.056 mg/kg respectively.[3]

As the muscles of interest (diaphragm, abdominal or laryngeal muscles) are clinically not accessible, it would be appropriate to choose a site that has a similar response to the muscles of interest. We chose CS to assess the onset of action as the response of the CS is close to that of the laryngeal muscles. Even though, cessation of response of orbicularis occuli occurs earlier than CS, it does not guarantee satisfactory intubation conditions.[89] Though excellent intubation conditions were observed most frequently with neuromuscular block assessment at AP, it delays the intubation time.[8] CS can predict the presence of excellent tracheal intubation conditions and allows intubation earlier than that of AP.[810]

Conditions at intubation were assessed in our study as the muscle groups differ in their sensitivity to neuromuscular blocking agents. The central group of muscles show an early onset of action compared to the peripheral muscles. Among the central group of muscles, diaphragm and laryngeal adductors are most resistant to the action of nondepolarizing neuromuscular blockers. Hence, the results obtained from one muscle cannot be extrapolated to the other. Use of a peripheral nerve stimulator cannot replace direct observation of the muscles (larynx, and diaphragm) as the twitch height at one muscle does not parallel that of the other.[1112]

Normothermia was maintained throughout the study as twitch tension is reduced by 61%/°C decrease in temperature of the monitored muscle group due to increasing in resistance of the skin.[11]

Duration of action of muscle relaxants in the study was documented by assessing the response of AP to stimulation of ulnar nerve for two reasons. One was that head and neck surgeries were included in the study and AP provided easy access for neuromuscular monitoring. The second was that monitoring the response of AP during recovery reflects the upper airway muscles. As AP is one of the last muscles to recover from neuromuscular blockade (NMB), the recovery of the muscle indicates that diaphragm and other muscles have definitely recovered. It is essential to monitor AP to ensure full recovery of neuromuscular function.[131415]

High dose NMB (3–4 ED95) used for modified rapid sequence inductions, will prolong the duration (50–300%) of blockade compared with normal-dose (1–2 ED95). Hence, such dose cannot be used for short surgical procedures. Dosing should always be individualized to the anticipated duration of surgery.

A study done by Patel and Swadia comparing 2ED95 of R and V, showed a significantly (P - 0.001) shorter onset of rocuronim (75.66 ± 11.79 s) than V (116.66 ± 10.93) without significant variation in duration of action.[4] The response of orbicularis occuli muscle to stimulation of the facial nerve was monitored to assess the degree of NMB. Conditions at intubation were also better in R Group (excellent intubating conditions were recorded in 83.33% of R Group and 46.66% of patients in V Group). However, the intubation conditions in our study were better compared with their study and this could probably be attributed to a higher dose and the monitoring of the neuromuscular block at CS muscle. Onset time in R Group was shorter in their study despite a smaller dose compared to our study (83.66 ± 41.73 s) as orbicularis occuli is more sensitive to nondepolarizing neuromuscular blockers than CS, hence shows a rapid loss of response to TOF. Smith and Saad compared the intubating conditions after 2ED95 of R and V.[16] They judged the timing of intubation by clinical criteria and concluded that R provided better intubating conditions than V. Both the groups did not vary in hemodynamic responses to intubation. Doǧruel et al. used various doses of R (2ED95 and 4ED95) and V (2ED95 with and without priming) and neuromuscular block was monitored by the contraction of AP muscle by acceleromyography.[17] Intergroup comparisons revealed that time, to achieve complete blockade, was significantly shorter in R 4ED95 than other groups. There was no significant difference among groups with regards to the quality of intubation. A study by Sagir et al. compared 2ED95 of R, V and cisatracurium in elderly patients using accelomyography at AP and showed that intubation time was faster with R but cisatracurium had a better recovery profile and hence preferable in elderly.[18] A study by Somani et al. with 2ED95 of R and V using TOF guard monitor at AP showed early onset of action in R Group without significant difference in intubation sores.[19]

One limitation of our study is the use of electrocardiography electrodes, that is, silver - chloride electrodes and they offer greater impedance than the electrodes recommended for NMJ monitoring.[15] Because of the lack of equipment neuromuscular function was assessed visually, and quantitative devices were not used to record the contractions.

CONCLUSION

In summary, onset of action of 3ED95 R is significantly shorter than V without significant variation in duration of action. R provides better intubation conditions than V.