Comparative Clinical Pharmacology of Rocuronium, Cisatracurium, and Their Combination 

After obtaining institutional approval and informed consent, we studied 220 patients of both sexes who were classified as American Society of Anesthesiologists physical status I, had a mean age of 25.7 yr (SD, 6.4 yr), and weighed a mean of 66.8 kg (SD, 11.4 kg). all patients were undergoing elective procedures; had no neuromuscular, renal, or hepatic disease; and were not taking any drug known to interfere with neuromuscular function. All patients received 2 mg oral lorazepam 90 min before operation. An infusion of lactated Ringer's solution was started before induction of anesthesia in the arm contralateral to that used to monitor neuromuscular function. Standard monitoring was used, and the peripheral temperature was maintained at > 32.5 [degree sign]C.

Anesthesia was induced with 0.03 mg/kg midazolam, 2 to 2.5 mg/kg propofol, 4 or 5 [micro sign]g/kg fentanyl, and 70% nitrous oxide in oxygen, and it was maintained with a continuous infusion of 50-140 [micro sign]g [middle dot] kg^-1[middle dot] min^-1propofol and nitrous oxide in oxygen (70:30 ratio) supplemented with incremental doses of fentanyl. After topical anesthesia with 4 ml 4% lidocaine, the trachea was intubated without the aid of a muscle relaxant. End-tidal concentrations of nitrous oxide, oxygen, and carbon dioxide were determined continuously using a multiple-gas analyzer (Capnomac, Datex Instrumentarium, Helsinki, Finland). Ventilation was adjusted to maintain normocapnia (end-tidal carbon dioxide pressure, 36-40 mmHg).

The ulnar nerve was stimulated at the wrist with square wave supramaximal stimuli lasting 0.2 ms, delivered in a train-of-four (TOF) sequence and repeated every 12 s, using a Myotest peripheral nerve stimulator (Biometer International, Odense, Denmark). To facilitate stabilization of twitch height, we administered a 5-s, 50-Hz tetanus followed by a 2-min stabilization period. [8]The resultant contraction of the adductor pollicis muscle was recorded using a force displacement transducer and neuromuscular function analyzer (Myograph 2000, Biometer International). Approximately 200-300 g resting tension was applied to the thumb. The first twitch (T1) of the TOF was considered the twitch height. The amplitude of the first response (T1) in each TOF sequence was taken as the control to which all subsequent T1 values were compared.

The choice of drug and dose for any patient was made randomly. All patients received one dose of the neuromuscular blocker (or their combination). The time course of this dose was recorded and TOF measurements were continued until a TOF ratio had recovered spontaneously to 1.0 or had reached a maximum recovery for at least 10 consecutive stimuli.

The following predetermined doses of drugs were administered: 100, 120, 150, 180, 240, or 300 [micro sign]g/kg rocuronium and 20, 25, 30, 40, or 50 [micro sign]g/kg cisatracurium. All drugs were administered to groups of 10 patients and were injected over 5 s into a rapidly flowing intravenous line. From the dose-response curves of rocuronium and cisatracurium, we determined the respective effective doses resulting in a 50% and 95%(ED⁵⁰and ED⁹⁵) reduction of the first twitch tension (T1). The neuromuscular response was recorded as the maximum depression of T1, expressed as a percentage of the control value. Data from patients in whom the injected dose of the neuromuscular blocker caused 1-99% block were used to calculate the dose response.

The percentage values for T1 depression in each group were transformed to probits and plotted against the logarithm of the dose using PCNONLIN version 4.2A (ClinTrials, Lexington, KY). [9]Regression lines were compared using analysis of covariance [10]and the BMDP statistical package (release 7.01, University of California Press, Berkeley, CA). The ED (⁵⁰) and ED⁹⁵values were calculated from the log-probit regression lines for each group.

We investigated the time course of rocuronium- or cisatracurium-induced neuromuscular block in eight groups of patients (n = 10 in each) and compared equipotent doses of both drugs (1 x ED⁵⁰, 1 x ED (⁹⁵), 1.5 x ED⁹⁵, and 2 x ED⁹⁵).

In part 3, the dose-response curves for a combination of the two drugs were obtained by administering the following drug combinations in a constant dose ratio based on the ED⁵⁰values of the single agent:(0.25 ED⁵⁰rocuronium + 0.25 ED⁵⁰cisatracurium; 0.5 ED⁵⁰rocuronium + 0.5 ED⁵⁰cisatracurium; and 0.75 ED⁵⁰rocuronium + 0.75 ED⁵⁰cisatracurium). The neuromuscular response was recorded as the maximum depression of T1, expressed as a percentage of the control value. In these studies, cisatracurium was administered first, followed 3 min later by rocuronium to ensure that the peak effect of both drugs coincided.

From the dose-response curve of the combined drugs, the ED⁵⁰value of the total dose of the mixture was calculated, and based on the known dose ratio, the single doses of the agents in the combination were obtained for plotting on the isobologram. [11,12] 

The isobologram was constructed by plotting single-drug ED⁵⁰points on the dose coordinates of the isobologram and a combined ED⁵⁰point in the dose field. A straight line joining the single-drug ED⁵⁰points is called the “additive line.” Confidence intervals (CIs) for each point were calculated from the variances of each component alone. The confidence intervals were evaluated for statistical significance using a Student's t test.

The algebraic (fractional) analysis [13]was used to describe the magnitude of the interaction. It was based on the expression of the component doses of the two agents of the combination as fractions of the doses that produce the same effect when given separately. The sum of the fractional doses, as expressed by the following equation, indicates the type of interaction:

dr/(ED⁵⁰)^r+ dc/(ED⁵⁰)^C

Where (ED⁵⁰)^rand (ED⁵⁰)^Care, respectively, the ED⁵⁰values of rocuronium and cisatracurium given alone, and dr and dc are, respectively, the doses of rocuronium and cisatracurium that, when combined, are equipotent with (ED⁵⁰)^ror (ED⁵⁰)^C. Values near 1 indicate additive interactions; values > 1 imply an antagonistic interaction; and values < 1 indicate a synergistic interaction.

The following variables were determined for all patients: time to first depression of T1 (lag time); maximum depression of T1 and TOF; time between administration of the neuromuscular blocker and maximum depression of T1 and TOF (onset time); times from injection to 25%(clinical duration), 75%, and 100% of control recovery of twitch tension, and times from injection to 0.25, 0.75, and 1 (or maximum) recovery of TOF ratio.

Onset and recovery times were compared with a one-way analysis of variance and the Student-Newman-Keuls multiple-range test. In clinical studies, onset and recovery times of 1 x ED⁵⁰doses of rocuronium and cisatracurium were compared using the unpaired t test. Similar analyses were performed for 1 x ED⁹⁵, 1.5 x ED⁹⁵, and 2 x ED⁹⁵doses of both drugs. These analyses were done using the BMDP statistical package (release 7.01, University of California Press). Results were expressed as mean and SD or as 95% confidence intervals, and they were considered significant when P < 0.05.

The highest doses, 300 [micro sign]g/kg rocuronium and 50 [micro sign]g/kg cisatracurium, produced 100% depression of T1 in most of the patients, and these doses were excluded from the dose-response calculations. The slopes for the rocuronium-cisatracurium combination, rocuronium, and cisatracurium groups were 4.23, 5.91, and 8.75, respectively (Figure 1). The slopes of dose-response curves differed significantly. The calculated ED (⁵⁰) and ED⁹⁵values and their 95% confidence intervals for the rocuronium group were 111 (107-115)[micro sign]g/kg and 215 (207-226)[micro sign]g/kg, respectively. Corresponding values for the cisatracurium group were 26.2 (25.8-26.5)[micro sign]g/kg and 39.8 (38.7-40.9)[micro sign]g/kg, respectively.

The isobolographic analysis demonstrated a synergistic interaction with respect to the neuromuscular-blocking activity of the rocuronium and cisatracurium combination (Figure 2). The experimentally determined ED⁵⁰(and 95% CI) for the combination was 7.1 (5.4-8.7)[micro sign]g/kg for rocuronium and 1.7 (1.3-2)[micro sign]g/kg for cisatracurium. The theoretical additive ED⁵⁰(and 95% CI) was calculated to be 55.5 (53.3-57.7)[micro sign]g/kg for rocuronium and 13.1 (12.6-13.6)[micro sign]g/kg for cisatracurium. The confidence intervals of these points do not overlap, and the results of a Student's t test for the potency ratio were significant (P < 0.0001), indicating synergism. The fractional (algebraic) analysis of this interaction also demonstrated synergism (Table 1).

Data describing onset and the spontaneous recovery are presented in Table 2and Table 3. Increasing the dose of rocuronium or cisatracurium resulted in shorter mean times to onset of maximum neuromuscular block. Recovery times varied inversely with the dose administered. In the combination groups, doubling the dose resulted in potentiation of block by approximately 240% and prolongation of time to 100% T1 recovery by 130% and time to maximum TOF recovery by 165%(Table 3).

Compared with cisatracurium, equipotent doses of rocuronium (Table 4) resulted in significantly shorter lag and onset times. For instance, onset times at 1 x ED⁵⁰and 2 x ED⁹⁵doses were, respectively, 180 s and 67 s faster with rocuronium than those observed with cisatracurium (P = 0.0001). Mean T1 recovery times to 25%, 75%, and 100% of control tension were 5.2-10.3 min faster after 1 x ED⁵⁰to 2 x ED⁹⁵doses of rocuronium compared with equipotent doses of cisatracurium (Table 4). These differences were statistically significant except at a 100% recovery time with the 2 x ED⁹⁵dose. When plotted graphically, they appear as parallel recovery patterns (Figure 3A).

Similarly, the mean TOF ratio recovery time to 0.75 was significantly faster after 1 x ED⁵⁰to 2 x ED⁹⁵doses of rocuronium compared with equipotent doses of cisatracurium (Table 4). When plotted graphically, they appear as parallel recovery patterns (Figure 3B).

Patient responses to 1 x ED⁵⁰dose of rocuronium, cisatracurium, or their combination are summarized in Table 5. T1 and TOF recovery times in the combination group were noted to be either similar or longer than that observed with rocuronium, but they were significantly shorter compared with those of cisatracurium.

In this study, the calculated ED⁵⁰and ED⁹⁵values and their 95% confidence intervals were 26.2 (25.8-26.5) and 39.8 (38.7-40.9)[micro sign]g/kg for cisatracurium group, respectively, rendering it approximately four or five times more potent than rocuronium (based on the estimate of ED⁵⁰or ED⁹⁵) in patients receiving nitrous oxide-opioid-propofol anesthesia. Corresponding values for the rocuronium group were 111 (107-115)[micro sign]g/kg and 215 (207-226)[micro sign]g/kg, respectively. In addition, isobolographic analysis (Figure 2) showed that combinations of rocuronium and cisatracurium were synergistic. The magnitude of this interaction can be appreciated by the examination of the fractional dose scores (Table 1). The measured ED⁵⁰of the mixture was only 12% of the predicted value assuming a purely additive reaction.

It is well established that the frequency of stimulation can affect the evoked response. Therefore, the mode of stimulation used in this study (TOF) could result in an apparently greater potency of neuromuscular blockers compared with the single-twitch mode. [14]Because the same pattern of stimulation was used for all patients, the relative potencies of rocuronium and cisatracurium determined in this study are valid. In fact, the ED⁵⁰and ED⁹⁵values for cisatracurium calculated in the current study corresponds with 29 (95% CI, 20-50)[micro sign]g/kg and 48 (30-80)[micro sign]g/kg, respectively, which was reported by Belmont et al., [1]who used the single-twitch mode of stimulation and mechanomyography during thiopental-fentanyl-nitrous oxide-oxygen anesthesia. For rocuronium, the ED (⁵⁰) and ED⁹⁵values of 111 (107-115)[micro sign]g/kg and 215 (207-226)[micro sign]g/kg, respectively, calculated in the present study is in keeping with 125 (109-143)[micro sign]g/kg and 257 (233-284)[micro sign]g/kg, respectively, which was reported by Cooper et al., [14]who used the TOF mode of stimulation and mechanomyography during thiopental-nitrous oxide-oxygen anesthesia, but is smaller than that reported by Bevan et al. [15](215 and 521 [micro sign]g/kg, respectively) using a similar mode of stimulation during nitrous oxide-fentanyl anesthesia.

The results of this study support the contention that combinations of structurally dissimilar neuromuscular-blocking drugs resulted in a potentiating effect. Lebowitz et al. [7]reported a greater than additive effect with pancuronium-metocurine and pancuronium-d-tubocurarine combinations but not with a metocurine-d-tubocurarine combination. Similarly, Naguib [6]and Meretoja et al. [16]showed, respectively, that rocuronium-mivacurium and vecuronium-atracurium combinations produced synergistic effects. On the other hand, combinations of structurally similar neuromuscular-blocking drugs produce an additive response in humans. [3,4,6,7] 

This study showed that rocuronium was associated with a significantly faster onset than cisatracurium. Rocuronium in doses twice the ED⁹⁵produced maximal block in 1.3 (0.3) min compared with 2.4 (0.6) min (P < 0.0001) with equipotent doses of cisatracurium. Another important observation was related to the recovery characteristics of the two drugs. Compared with cisatracurium, rocuronium had significantly shorter T1 and TOF spontaneous recovery times at 1 x ED⁵⁰, 1 x ED⁹⁵, and 1.5 x ED⁹⁵doses (Table 4). At these doses, clinical duration and time to complete TOF recovery were noted to be, on average, 10 min longer with cisatracurium (Table 4). Although at 2 x ED⁹⁵doses the differences in recovery times (8 or 9 min) were not statistically significant, it could be viewed as clinically important. The reason for this alteration in the recovery characteristics with 2 x ED⁹⁵doses is not apparent, but it could be attributed to changes in the pharmacokinetics of rocuronium at higher doses. For instance, Wright et al. [17]showed that the cumulative effects of both vecuronium and atracurium with increasing dose (within the clinical dose range) could be explained in part by a shift in recovery from the distribution phase to the elimination phase of the plasma concentration-versus-time curve. Further, unlike rocuronium, we found that the times to complete spontaneous recovery of T1 and the TOF ratio with subparalyzing doses (1 x ED⁵⁰) of the rocuronium-cisatracurium combination was significantly shorter than that observed with equipotent doses of cisatracurium (Table 5).

Because cisatracurium is four or five times more potent than rocuronium (as shown in this study), it is not unexpected that its onset was slower than that of rocuronium (Table 2and Table 4). Rocuronium offers the fastest onset time of all currently available nondepolarizing neuromuscular blockers, [2]and this has been attributed to its low potency, [18]different buffering mechanism (i.e., the repetitive binding of relaxant molecules), [19]or both. Although fast onset of rocuronium cannot be satisfactorily explained by the difference in molar potency, [20]lower potency correlated with a faster onset of action. [21,22] 

The onset time and maximum twitch suppression for cisatracurium and rocuronium reported in this study is consistent with other published studies. [1,14]Belmont et al. [1]noted that the mean onset time and mean percentage twitch suppression for 20, 30, 40, and 50 [micro sign]g/kg cisatracurium were 7.4, 7.9, 7.7, and 7.6 min, and 13.2%, 70.7%, 80.7%, and 93%, respectively. Corresponding data reported in this study (Table 2) were 8, 7.3, 7, and 4.8 min, and 16%, 66%, 90%, and 98%, respectively. With rocuronium, Cooper et al. [14]noted that the mean onset time and the mean percentage twitch suppression (using TOF stimulation) for 100, 150, and 300 [micro sign]g/kg doses were 2.2, 2.8, and 1.7 min, and 28%, 76%, and 97%, respectively. Corresponding values in this study (Table 2) were 3.3, 3.3, and 2 min and 40%, 79%, and 99%, respectively. Detailed spontaneous recovery characteristics of subparalyzing doses of rocuronium and cisatracurium have not been studied previously.

In Figure 3, spontaneous T1 and TOF recovery appear as parallel recovery patterns. It has been shown that the clearance of two times the ED (⁹⁵) of cisatracurium was similar to that reported with equipotent doses of rocuronium (5.28 and 5.03 ml [middle dot] kg^-1[middle dot] min^-1, respectively) in young adults free of hepatic or renal disease. [23,24] 

In conclusion, this study shows that cisatracurium and rocuronium have different pharmacodynamic profiles. Based on the estimate of ED⁵⁰, the relative potency for rocuronium:cisatracurium was 1:4.2. As expected, the onset time to neuromuscular block after rocuronium was significantly shorter than after comparable doses of cisatracurium. Compared with cisatracurium, rocuronium had significantly shorter T1 and TOF spontaneous recovery times at 1 x ED⁵⁰, 1 x ED⁹⁵, and 1.5 x ED⁹⁵doses. At these doses, clinical duration and time to complete TOF recovery were noted to be, on average, 10 min longer with cisatracurium. However, the differences in the maximum recovery times (8 or 9 min) noted at the 2 x ED⁹⁵dose were not statistically significant. Isobolographic and algebraic analyses showed that the interaction of the rocuronium and cisatracurium combination is the result of a synergistic action at the neuromuscular junction. Comparison of the clinical profiles of equipotent doses (1 x ED⁵⁰) of rocuronium, cisatracurium, or their combination revealed that the times to complete spontaneous recovery of T1 and the TOF ratio with the rocuronium-cisatracurium combination were significantly shorter than that observed with cisatracurium, but they were similar to longer than that of rocuronium.