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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© 2004 International Anesthesia Research Society
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