Breslin, Dara S. MB, FFARCSI; Jiao, Kuiran MD; Habib, Ashraf S. MB, BCh, MSc, FRCA; Schultz, John MD; Gan, Tong J. MBBS, FRCA, FFARCSI
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina
This study was supported in part by Abbott Inc.
Presented in part at the American Society of Anesthesiologists meeting, Orlando, FL, October 12–16, 2002.
Accepted for publication August 14, 2003.
Address correspondence and reprint requests to Dr. Tong J. Gan, Department of Anesthesiology, Box 3094, DUMC, Durham, NC 27710. Address e-mail to firstname.lastname@example.org.
The onset and duration of a maintenance dose of a nondepolarizing neuromuscular blocking drug (NMB) may be influenced by the original NMB used to induce block. This interaction is not well defined when steroidal NMBs such as rocuronium and benzo-isoquinolinium compounds such as cisatracurium are combined. Potentiation of effect has been demonstrated when two NMBs from similar and different classes were combined. Lebowitz et al. (1) showed increased potency of NMBs in humans produced by combinations of pancuronium and metocurine or pancuronium and d-tubocurarine when administered simultaneously. Similarly, Kim et al. (2) also showed increased potency when cisatracurium was administered simultaneously with rocuronium, vecuronium, or mivacurium. However, in these studies, the drugs were administered as a combination simultaneously. The aim of this study was to assess the interaction between rocuronium and cisatracurium on the clinical duration of a maintenance dose of cisatracurium when administered after an intubating dose of rocuronium.
After IRB approval and written informed consent, a prospective randomized trial involving 60 ASA physical status I–III patients, aged 18 to 75 yr, scheduled for elective surgery lasting >120 min was performed. Patients known to have renal, hepatic, or neuromuscular disease and those on medications known to interfere with neuromuscular blockade were excluded from the study. Patients with a body mass index >35 were also excluded from the study.
An IV cannula was inserted in a forearm vein and an infusion of Ringer’s lactate solution commenced before the induction of anesthesia. ASA standard monitoring was used throughout the procedure. After premedication with midazolam 0.03–0.06 mg/kg IV, anesthesia was induced with fentanyl 2–4 μg/kg and propofol 1–2 mg/kg and maintained with isoflurane 0.8%–1% (end-tidal concentration) in 66% nitrous oxide and oxygen. Further increments of fentanyl were administered as required. Twenty patients were each allocated using a computer-generated randomization scheme to receive the following: rocuronium 0.6 mg/kg followed by cisatracurium 0.03 mg/kg (Group I), cisatracurium 0.15 mg/kg followed by cisatracurium 0.03 mg/kg (Group II), and rocuronium 0.6 mg/kg followed by rocuronium 0.15 mg/kg (Group III) when the first twitch (T1) in the train-of-four (TOF) recovered to 25%. Patients received further maintenance doses of cisatracurium 0.03 mg/kg or rocuronium 0.15 mg/kg on recovery to T1 25% as required. The patient’s trachea was intubated after onset of muscle relaxation and ventilation controlled to maintain normocapnia (end-tidal carbon dioxide 4.5–5.3 kPa). On completion of surgery, neostigmine 50 μg/kg with glycopyrrolate 10 μg/kg was administered if spontaneous recovery to a TOF ratio >0.8 had not occurred.
A TOF-Guard® (Boxtel, The Netherlands) monitor was applied before the induction of anesthesia and was auto-calibrated and stabilized after loss of consciousness. The ulnar nerve was stimulated transcutaneously at the wrist with supramaximal stimuli in the TOF mode of stimulation at 2 Hz every 15 s. The force of contraction of the adductor pollicis muscle was monitored using acceleromyography (TOF-Guard®). Baseline neuromuscular responses were allowed to stabilize in all 3 groups for approximately 5 min. The arm was immobilized and the movement of the thumb unimpeded throughout the study. The patient’s skin temperature over the adductor pollicis was monitored and maintained at >32°C by wrapping the arm. All patients were kept warm (>35°C) during anesthesia using forced-air warming blankets. The onset and clinical duration of the initial dose and the first three maintenance doses of muscle relaxant were recorded.
A power calculation revealed that 17 patients were required per group to detect a mean difference of 5 min in the time to recovery of T1 25% assuming that α = 0.05 and β = 0.20 (3). We included 20 patients per group to allow for patients whose surgery finished before receiving maintenance doses of NMB. After checking for normality and equality of variance, the data were analyzed using analysis of variance and Newman-Keuls post test as appropriate (GraphPad Prism® software version 3.02; GraphPad Software, Inc., San Diego, CA). A value of P < 0.05 was considered statistically significant.
Sixty patients (31 men, 29 women) participated in the study. The data of 3 patients were excluded from analysis (1 in each of Groups I–III) for either protocol violation or equipment failure. The 3 groups were comparable clinically with regard to patient characteristics and ASA physical status (Table 1). As expected, the onset and duration of the initial dose of rocuronium was shorter compared with cisatracurium (Table 2). The clinical duration (mean ± sd) of the first maintenance dose of NMB in Group I (rocuronium/cisatracurium) was significantly longer than the other 2 groups (41 ± 10 versus 31 ± 7‡ and 25 ± 8‡ min in Groups I–III, respectively, ‡P < 0.001) (Table 2). This was still significant after the second maintenance dose (P < 0.05) (Table 2). Seven, twelve, and nine patients received a third maintenance dose of NMB with a clinical duration of 33 ± 6, 33 ± 7, 28 ± 11 min in Groups I–III, respectively. The (mean ± sd) time to onset of the first maintenance dose of NMB was 3.5 ± 1.6†, 2.3 ± 1.2, and 2.0 ± 0.8 min in Groups I–III, respectively (†P < 0.01). Subsequent maintenance doses had similar onset times.
There were no adverse events related to this study.
The clinical duration of the first two maintenance doses of cisatracurium was prolonged when administered after an intubating dose of rocuronium. The mean time to recovery of T1 25% was 33% longer in the rocuronium/cisatracurium group compared with the cisatracurium/cisatracurium group (41 versus 31 min, P < 0.001) after the first maintenance dose. This was still significantly longer after the second maintenance dose between these two groups.
Interestingly, rocuronium plus 2 maintenance doses of cisatracurium (Group I) had a mean clinical duration of 124 min compared with 126 min for cisatracurium followed by 2 maintenance doses of cisatracurium (Group II). This may suggest that prolonged block was no more likely to occur in Group I compared with Group II. However, as expected in Group II, the initial dose of cisatracurium had a longer clinical duration compared with rocuronium in Group I (65 versus 44 min), whereas the first 2 maintenance doses of cisatracurium had a mean combined time of 80 versus 61 min in Groups I and II, respectively (Table 2).
These results suggest a synergistic interaction between cisatracurium and the steroidal NMB rocuronium. Previous authors have shown a synergistic effect when muscle relaxants of different classes were combined. Lebowitz et al. (1) showed increased potency in humans produced by combinations of pancuronium and metocurine or pancuronium and d-tubocurarine when administered simultaneously. The effect of the drug combinations produced a more intense effect (synergistic) than the additive effect of each of the drugs given alone. However, the duration of blockade in their study was not prolonged. Ghoneim et al. (4) also showed synergistic interactions when d-tubocurarine and gallamine were combined for muscle relaxation. Again, the duration of blockade was not prolonged. Animal studies also confirmed a synergistic interaction. Pollard and Jones (5) assessed the interaction of tubocurarine, pancuronium, and alcuronium on neuromuscular transmission in a rat phrenic nerve-hemidiaphragm preparation. Although mixtures of d-tubocurarine and the steroidal NMBs were synergistic, they failed to show synergy between pancuronium and alcuronium. Because this was an isolated preparation, pharmacokinetic interactions could not explain their finding and it was proposed that this interaction therefore must largely occur within the neuromuscular junction. In a similar in vitro model, Van Der Spek et al. (6) showed synergy between vecuronium and atracurium. The combination was more potent than equivalent doses of either vecuronium or atracurium alone.
Kim et al. (2) showed a synergistic interaction between cisatracurium and rocuronium, vecuronium, and to a lesser extent mivacurium, when administered as a combination. Further studies assessing the interactions between vecuronium/atracurium and rocuronium/mivacurium combinations also showed synergistic effects (7,8). This is in contrast to studies assessing the combinations of structurally similar NMBs, which have generally been shown to only produce an additive effect (1,2,5,9).
In the studies discussed above (1,2,4–8), the combination of different types of competitive NMBs were more potent than equivalent doses of the individual drugs. The NMBs in these studies were administered simultaneously as a combination. Although this may have been common clinical practice in the past to decrease dose requirements and side effects and to improve the speed of onset, it is rarely done today. This is largely because of the wide variety of NMBs presently available compared with a limited variety of slow and long-acting drugs that were available then (10). However, it is still common practice to administer a maintenance dose of NMB different from that used to facilitate tracheal intubation. In particular, this may be done in patients with hepatic or renal impairment where a drug with a rapid onset of action such as succinylcholine, rocuronium, or, previously, rapacuronium, may be used to facilitate intubation, and where an NMB that does not rely on hepatic metabolism or renal excretion such as cisatracurium is used to facilitate muscle relaxation during surgery. Others used a short-acting NMB, such as mivacurium, after longer-acting drugs, like pancuronium, to try to avoid postoperative residual curarization (11).
In two studies assessing the effect of the initial NMB used on the duration of subsequent maintenance doses, the authors showed that the clinical duration of the first and first two maintenance doses was prolonged (9,12). Similarly, in our study, the first two maintenance doses of cisatracurium were prolonged when administered after rocuronium. With more maintenance doses and less intubating NMB, the interaction between drugs may become less significant. In this study, insufficient numbers of patients received a third maintenance dose to allow statistical analysis.
All patients received isoflurane in nitrous oxide and oxygen for maintenance of anesthesia. The volatile anesthetics sevoflurane, desflurane, and to a lesser extent isoflurane prolong the duration of action of both rocuronium and cisatracurium (13–15). As expected in the cisatracurium/cisatracurium group (Group II), an intubating dose of cisatracurium 0.15 mg/kg had a significantly longer clinical duration compared with rocuronium 0.6 mg/kg in Groups I and III, thus exposing this group to isoflurane for a longer time. This could potentially prolong the duration of subsequent NMB maintenance doses. However, the clinical duration of the first two maintenance doses of cisatracurium in Group II were still significantly shorter than when administered after rocuronium (Group I).
NMBs act at several sites in the neuromuscular junction (16). The exact mechanism of the synergistic interactions between different groups of NMBs has not been fully elucidated. Current theories include the notion potentiation arising from combined pre- and postsynaptic n-acetylcholine receptor effects, or that potentiation may result from altered affinities of the different NMBs for the two binding sites formed by α-subunits of the postsynaptic n-acetylcholine receptor. Additional theories include multiple receptor sites and different modes of action of competitive NMBs (6). Altered protein binding and tissue binding by either drug may also result in a larger proportion of the NMB reaching its site of action (1,17). However, other studies have suggested that alterations in pharmacokinetic characteristics are likely to have a lesser effect (5,6).
We used automatic calibration setup for the TOF-Guard® as described in the operating manual followed by a 5-min period of stabilization of the control response. Kopman et al. (18) showed significant increases in T1 height and prolonged times to stabilization of the T1 twitch height with the TOF-Guard®. The TOF fade did not vary with the duration of stabilization. They found that a 5-s, 50-Hz tetanic stimulation administered before initial twitch calibration considerably shortened the time to achieve baseline stabilization. Although drift of the T1 height may have affected the results of our study, it would have affected all three groups equally.
In this study, we administered the maintenance doses of NMBs at recovery of T1 to 25%. This represents the duration of moderate surgical block and also represents the clinical duration of a muscle relaxant (19). The synergistic interaction prolonged the clinical duration of cisatracurium, and it also likely resulted in prolonged times to attain full recovery after neuromuscular blockade.
In conclusion, we have shown that when a maintenance dose of cisatracurium is administered after an intubating dose of rocuronium the clinical duration is prolonged by 33%. This prolongation is still evident after the second maintenance dose. This finding supports the contention that combinations of structurally dissimilar NMBs result in a synergistic effect.
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