Sugammadex exerts its effect by forming very tight complexes at a 1:1 ratio with steroidal neuromuscular blocking drugs (rocuronium > vecuronium ≫ pancuronium) (Fig. 3) (26–29). The guest–host complex exists in equilibrium with a very high association rate (an association constant of 107 M−1) and a very low dissociation rate, so the complex is tight (26).
During rocuronium-induced neuromuscular blockade, the IV administration of sugammadex results in rapid removal of free rocuronium molecules from the plasma. This creates a concentration gradient favoring the movement of the remaining rocuronium molecules from the neuromuscular junction back into the plasma, where they are encapsulated by free sugammadex molecules (38–40). The latter molecules also enter the tissues and form a complex with rocuronium. Therefore, the neuromuscular blockade of rocuronium is terminated rapidly by the diffusion of rocuronium away from the neuromuscular junction back into the plasma (38–44). This results in an increase in the total plasma concentration of rocuronium (both free and bound to sugammadex) (38). Because of the low dissociation rate, no muscle weakness has been reported in available human or animal studies (38–44). Sugammadex, therefore, acts as a binding drug and has no effect on acetylcholinesterase or any receptor system in the body. This eliminates the need for anticholinergic drugs, thus avoiding their undesirable side effects. The findings of sugammadex's reversal of rocuronium-induced neuromuscular blockade have theoretical implications as well (38–44). They disprove the historical hypothesis of Feldman and Tyrrell (45) that reducing the plasma concentration of nondepolarizing neuromuscular blockers does not reverse the neuromuscular blockade.
The compound's efficacy as an antagonist does not appear to rely on renal excretion of the cyclodextrin-relaxant complex (46). Most sugammadex is excreted unchanged in the urine in the first 8 h (40). Sugammadex also increases the amount of rocuronium excreted unchanged in the urine (40), but a change in acid–base status affects anticholinesterase activity, it appears not to influence the efficacy of sugammadex1.
Sugammadex is ineffective against succinylcholine and benzylisoquinolinium neuromuscular blockers, such as mivacurium, atracurium, and cisatracurium (44), because it cannot form inclusion complexes with these drugs. Therefore, if neuromuscular blockade must be re-established after using sugammadex, succinylcholine or one of the benzylisoquinolinium neuromuscular blockers should be considered. Under these conditions, what would be the potency of cisatracurium and succinylcholine? Sugammadex binds at a 1:1 ratio to rocuronium and vecuronium, but for effective reversal, all rocuronium or vecuronium molecules do not have to be complexed with sugammadex. The margin of safety of the neuromuscular transmission is such that only 20%–25% of postsynaptic receptors need to be free for transmission to occur (47). Therefore, sugammadex only has to reduce the occupation of these receptors from 100% to 70% to obtain complete reversal. After induction of neuromuscular blockade with rocuronium and complete reversal with sugammadex in anesthetized guinea pigs, the administration of cisatracurium caused a more intense neuromuscular blockade with a faster than normal onset (48). Kopman et al. (49) also demonstrated that the ED50 of mivacurium was 56% less if calculated after full recovery from mivacurium-induced neuromuscular blockade than after the initial blockade. When succinylcholine rather than cisatracurium was administered, complete blockade could also be induced; however, its onset was delayed in the guinea pig (48). Pretreatment with nondepolarizing neuromuscular blockers had a marked antagonistic effect on the development of the subsequent depolarizing blockade produced by succinylcholine (50).
The interaction of sugammadex with other molecules has been tested with isothermal titration microcalorimetry. This technique measures the heat production when two molecules form a complex. The ability of sugammadex to form complexes with other steroidal and nonsteroidal compounds, such as cortisone, atropine, and verapamil, is probably clinically insignificant and is approximately 120–700 times less than that of rocuronium (51). Steroidal molecules form complexes with sugammadex, but with a much lower affinity, because the high affinity of sugammadex for rocuronium and vecuronium is caused by the interaction between the negatively charged carboxyethyl side chains of sugammadex and the positively charged quaternary nitrogen of rocuronium and vecuronium. As endogenous steroidal hormones and steroidal drugs lack the quaternary nitrogen of the steroidal blockers, they show a much lower affinity. Furthermore, steroidal hormones are also bound tightly to specific protein carriers; for example, the sex hormones are bound with very high affinity to globulin.
The possible effects of the sugammadex-induced improved solubility of propofol, midazolam, and bupivacaine on the pharmacodynamics/pharmacokinetics of these compounds have not yet been studied.
All animal studies have thus far demonstrated that sugammadex is effective in antagonizing rocuronium-induced neuromuscular blockade without any significant effects on arterial blood pressure or heart rate (39,42–44). In one study that used anesthetized guinea pigs, rocuronium was infused for 1 h to maintain a steady state 90% neuromuscular blockade (39). After 30 min, a concomitant infusion of sugammadex at a rate of 50 nmol · kg−1 · min−1 resulted in rapid reversal of the neuromuscular blockade. An average twitch recovery of approximately 80%, 90%, and 100% occurred 10, 20, and 30 min, respectively, after the start of the sugammadex infusion (39). This was accompanied by an increase in the total plasma concentration of rocuronium (free and that encapsulated by sugammadex). In contrast, the plasma concentration of rocuronium and the depth of neuromuscular blockade remained unchanged in saline-treated animals. In clinical practice, the antagonism of residual neuromuscular blockade is normally attempted after discontinuing infusion of neuromuscular blockers. The ability of sugammadex to antagonize the neuromuscular blockade despite concomitant infusion of rocuronium points out its unique characteristics. The study design also explains the prolonged recovery times noted (39).
The effectiveness of sugammadex is dose dependent. In male volunteers, the administration of 8 mg/kg sugammadex 3 min after the administration of 0.6 mg/kg rocuronium resulted in the recovery of the TOF ratio to 0.9 within 2 min (38). Decreasing the dose of sugammadex to 4 mg/kg resulted in a recovery of the TOF ratio to 0.9 in <4 min (38). In one study, different doses of sugammadex or placebo were administered to surgical patients anesthetized with total IV anesthesia who had received 0.6 mg/kg rocuronium at the reappearance of the second twitch of the TOF response (40). Sugammadex decreased the median recovery time in a dose-dependent manner from 21.0 min in the placebo group to 1.1 min in the group receiving 4.0 mg/kg sugammadex. The authors of this study concluded that doses of 2.0–4.0 mg/kg of sugammadex reversed rocuronium-induced neuromuscular blockade within 3 min (40). In another study, deep neuromuscular blockade (posttetanic count of <10) was maintained for at least 2 h in patients anesthetized with propofol–nitrous oxide– opioid anesthesia (41). After the spontaneous recovery of the second twitch of the TOF, different doses of sugammadex were administered; increasing the sugammadex dose from 0.5 to 4.0 mg/kg shortened the average recovery time to a TOF of 0.9 from 6.8 min (range, 4.8–11.4 min) to 1.4 min (range 0.95–2.3 min), respectively (41). Unexpectedly, the recovery time was longer (2.6 min [range 1.3–3.9 min]) with a 6.0 mg/kg dose (41). The reason for this deviation is unclear, but the reversal still occurred in <3 min, on average.
Currently, as a part of a multicenter study, we are comparing the speed of recovery from 1.2 mg/kg rocuronium followed 3 min later by 16 mg/kg sugammadex with that of spontaneous recovery from 1.0 mg/kg succinylcholine in surgical patients. Our initial results are very encouraging with respect to the antagonism of this profound level of rocuronium-induced neuromuscular blockade and indicate that the total duration from administration of rocuronium until a TOF ratio recovery to more than 0.9 is shorter than the time needed for spontaneous recovery from 1.0 mg/kg succinylcholine-induced blockade to a similar degree of recovery (Fig. 4).
Sugammadex is biologically inactive, does not bind to plasma proteins, and appears to be safe and well tolerated (38,40,50). The safety of sugammadex has been assessed in the phase I and II studies (in a total of 86 subjects). In one study, sugammadex was administered to awake volunteers who had received no neuromuscular blocking drugs (38). The most frequently reported side effects have been hypotension (three subjects), coughing (three subjects), movement (three subjects), nausea (three subjects), vomiting (three subjects), dry mouth (four subjects), parosmia (an abnormal smell) (two subjects), a sensation of a changed temperature (three subjects), and abnormal levels of N-acetyl-glucosaminidase in the urine (five subjects) (38,40,41). In one study, prolongation of the corrected QT interval was noted in five subjects who received placebo and in three subjects who received sugammadex (38).
What can we look forward to? Does the introduction of sugammadex herald the elimination of many of the shortcomings in our clinical practice with regard to antagonism of neuromuscular blockers? The deep levels of neuromuscular blockade induced by rocuronium (and possibly by vecuronium, although there is no clinical evidence for the latter drug yet) can be promptly antagonized with appropriate doses of sugammadex. This should make surgical care much easier and safer: Surgeons should no longer encounter inadequate muscle relaxation, and anesthesiologists should no more encounter patients whose neuromuscular blockade is hard to reverse at the end of surgery. The introduction of sugammadex into clinical practice would thus contribute to both increased patient safety and improved surgical conditions. One expects to see no more patients either being held in the operating room because the antagonism of residual neuromuscular blockade is incomplete, or being transferred to postoperative care units with residual neuromuscular blockade. Additionally, no anticholinesterase or anticholinergic drugs would be needed for the antagonism of residual neuromuscular blockade, which would mean the end of the cardiovascular and other side effects of these compounds (17). The postoperative nausea and vomiting associated with the use of these compounds should also be eliminated (52). Will sugammadex replace neostigmine as an antagonist for rocuronium-induced neuromuscular blockade? Kopman (53) rightly believes that this will “… depend at least in part on economic considerations.” Although concerns have been raised about the acquisition cost of new drugs (54), the economic evaluations are complex, and not simply defined by the acquisition cost (55). In the final analysis, improvements in inpatient outcome must have a dollar value that offsets the cost of the drug (56).
Do we still need to use neuromuscular function monitoring with sugammadex? Without knowing the depth of the rocuronium-induced neuromuscular blockade, it would be difficult to know the dose of sugammadex needed. Perhaps conventional nerve stimulators would be sufficient to determine the presence or absence of the twitch response, and the appropriate dose of sugammadex could be administered accordingly. In such circumstances, objective neuromuscular monitoring would no longer be needed.
Further, the use of rapid-sequence induction with rocuronium can be facilitated by the presence of sugammadex. The previously described sequence of 1.2 mg/kg rocuronium followed 3 min later by 16 mg/kg sugammadex seems to provide a faster onset-offset profile than that seen with 1.0 mg/kg succinylcholine. If the rocuronium induction/sugammadex reversal paradigm achieves the reliability of succinylcholine, will this mark the end of years of effort directed toward developing a nondepolarizing version of succinylcholine? Why would one ever give succinylcholine if one could give rocuronium and achieve reversal more quickly than the succinylcholine would wear off? Before these questions can be answered, however, we must know whether the rocuronium-sugammadex sequence will be safer than succinylcholine? In this regard, studies using succinylcholine have indicated that the risk of desaturation in the immediate postinduction period is much greater than initially recognized in “cannot intubate, cannot ventilate” situations (57,58). Nevertheless, studies are needed to address the role of sugammadex as a “rescue” reversal drug in patients with unanticipated difficult airways who received rocuronium. For now, succinylcholine is expected to remain on the hospital formulary, but its clinical use will most likely become limited to reparalyzing patients who have already received sugammadex.
The introduction of propofol almost two decades ago changed anesthetic practice (34). Nothing since then, however, has had the same effect. Unquestionably, the introduction of sugammadex is an important breakthrough, and one that is likely to change the face of clinical neuromuscular pharmacology. This molecule is specifically suited to rocuronium and vecuronium, and its future clinical use should decrease the incidence of postoperative muscle weakness caused by these drugs and facilitate the use of rocuronium for rapid sequence induction of anesthesia. For now, however, we still need benzylisoquinolinium neuromuscular blockers in our practice, so the residual postoperative muscle weakness caused by this class of drugs is likely to continue unless objective neuromuscular function monitors are routinely used, or until a molecule capable of binding to benzylisoquinolinium neuromuscular blockers is discovered.
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