Miller, Ronald D. MD
From the Department of Anesthesia and Perioperative Care, University of California, San Francisco, California.
Accepted for publication December 4, 2006.
Address correspondence and reprint requests to Ronald D. Miller, MD, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA. Address e-mail to firstname.lastname@example.org.
In the last 50 yr, advances in perioperative care, especially intraoperative anesthesia, have helped to increase the safety and capability of delivering anesthesia effectively to very fragile patients (i.e., ASA Class III and higher), who are often undergoing complicated procedures. Advances in technology, pharmacology, and training, have facilitated our ability to successfully meet these anesthetic challenges.
Part of our anesthetic success can be attributed to the development of many new anesthetic drugs, including volatile anesthetics, IV anesthetics, analgesics, and local anesthetics. The advances with neuromuscular blocking drugs (NMBDs) have been consistent; most certainly pancuronium, introduced in the 1970s, is better than d-tubocurarine. Atracurium and vecuronium provided pharmacokinetic and/or cardiovascular advances, as compared with pancuronium in the 1980s. Rocuronium, mivacurium, and cisatracurium provided additional clinical opportunities for flexibility over those of vecuronium and atracurium in the 1990s. Because of its onset and duration times, the most recently introduced new NMBD, rapacuronium, had the potential to partially replace succinylcholine for the first time in over 50 yr (1). However, rapacuronium’s propensity to cause bronchospasm led to its removal from the market. These newer NMBDs have improved patient care (e.g., decreased incidence of residual postoperative paralysis) mainly because of changes in their pharmacokinetic profiles and, to a lesser extent, cardiovascular effects. Amazingly, all of these pharmacologic advances over 40 yr were made with no change in the mechanism of action of NMBDs.
Regrettably, all of these NMBDs usually require pharmacologic antagonism (reversal) of neuromuscular blockade. There have been no successful creative advances, with regard to reversal of NMBDs. In the late 1970s and early 1980s, 4-aminopyridine, which facilitates release of acetylcholine from the motor nerve terminal, was considered. However, its potential central nervous system effects precluded further development.
Despite the above flirtations, neostigmine, edrophonium, and pyridostigmine have been the mainstay of pharmacologic reversal drugs of NMBDs. Of these three, neostigmine has been the dominant drug (2). However, it has severe limitations. Its ability to antagonize an intense neuromuscular blockade is often questioned. The clinical situations during which neostigmine can and cannot antagonize a nondepolarizing neuromuscular blockade has been the subject of many studies (2). Furthermore, the cardiovascular effects of neostigmine (hypotension and bradycardia) need to be counteracted by concomitant administration of glycopyrrolate or atropine.
Sugammadex is a novel selective relaxant binding drug (SRBA) which antagonizes or reverses steroidal nondepolarizing NMBDs, especially rocuronium. Sugammadex is likely the most exciting drug in clinical neuromuscular pharmacology since the introduction of atracurium and vecuronium in the middle 1980s. Of special interest is its novel and innovative mechanism of action. For over 30 yr, this author and several other investigators had many lengthy conversations and small meetings trying to devise alternate mechanisms of action to that of the nondepolarizing NMBDs and their main reversal drug, neostigmine. To transport NMBD away from the neuromuscular junction was never considered except by enhanced metabolism and/or excretion. We never considered that a mechanism of reversing a nondepolarizing neuromuscular blockade, such as with sugammadex, was possible.
Overall, clinical studies are being conducted to define the clinical pharmacology and safety profile of sugammadex. In this issue of Anesthesia & Analgesia, Naguib (2) nicely summarizes the current status of sugammadex’s development. There can be no doubt that sugammadex reliably reverses or antagonizes a very intense rocuronium neuromuscular blockade in a manner that neostigmine could never achieve. We have never had a reversal drug or antagonist this powerful and, apparently, reliable. These findings have led many authors, including Naguib (2), to speculate how sugammadex could dramatically change the practice of anesthesiology. If sugammadex can reliably reverse the neuromuscular block from a large dose of rocuronium 10–15 min (or sooner) after its administration, will succinylcholine finally begin its ultimate demise? Once the trachea has been intubated, anesthesiologists have been cautious about the total dose of NMBD given during surgery to insure that neostigmine can successfully reverse the neuromuscular block. If large doses of rocuronium can be given, the surgeons may be presented with better surgical conditions with a more intense neuromuscular block, and reversal can still be accomplished, because sugammadex is more reliable than neostigmine. To monitor the intensity and reversal of neuromuscular block, the use of peripheral nerve stimulators is widely recommended, yet many clinicians do not see the need to use such monitoring. Will sugammadex’s increased effectiveness, in comparison to neostigmine, lessen the need for or use of monitoring neuromuscular function?
This issue of Anesthesia & Analgesia provides further definition of sugammadex’s clinical pharmacology. Sacan et al. (3) found that sugammadex, 4 mg/kg IV, reversed a rocuronium neuromuscular block more rapidly than neostigmine and edrophonium. Not surprisingly, endophonium’s induced reversal of rocuronium was three times more rapid than that of neostigmine (time from reversal drug administration to train-of-four ratio of 0.9). However, sugammadex was three times more rapid than edrophonium. Thus, sugammadex’s onset time is about 10 times more rapid than neostigmine. Since neither atropine nor glycopyrrolate was needed with sugammadex, these patients’ mouths were not as dry as with neostigmine or edrophonium. Vanacker et al. (4) found that the choice of anesthetic (i.e., propofol versus sevoflurane) does not influence sugammadex’s ability to reverse a rocuronium neuromuscular blockade. While this finding is not surprising, studies like this are necessary to define all the most important drug interactions. While sugammadex appears to be superior and an outstanding SRBA, the case report by Eleveld et al. (5) reminds us that all drugs have a dose–response type of pharmacology. They administered a very small dose of sugammadex (0.5 mg/kg) for a rocuronium neuromuscular block (0.9 mg/kg). Although reversal was initially successful, the neuromuscular block partially reappeared. Groudine et al. (6) focused on the 0.5 mg/kg as an ineffective dose of sugammadex, although they did not observe a reappearance of the block. None of the other authors (2–7) studied this dose.
In addition to publications such as those in this issue of Anesthesia & Analgesia, sugammadex creates excitement every time it is discussed. When the appropriate dose is used, sugammadex appears to meet every challenge presented to it. Appropriately, dose–response curves and reversal of an intense rocuronium-induced neuromuscular blockade have been emphasized. After approval by the Food and Drug Administration, routine anesthetic use of sugammadex will create additional clinical approaches and other drug interactions. For example, Lenz et al. (7) successfully gave sugammadex, 4 mg/kg, when neostigmine failed to reverse a vecuronium neuromuscular block. We all hope that some remote adverse effect will not appear with routine clinical use.
Sugammadex is clearly one of the most exciting drugs to appear in the field of anesthesia in many years. Its basic neuromuscular pharmacology is well defined and has the opportunity to change the practice of anesthesia. Large studies are required to determine whether sugammadex can demonstrate that it has minimal orno adverse effects. Such studies are often difficult to interpret, because it is hard to separate potential adverse effects of one single drug from the complex state of surgical patients. Despite excellent, well-designed clinical studies, some remote adverse effects will not appear until the new drug has been in routine practice for a while. Putting these cautionary thoughts aside, sugammadex is an exciting new SRBA for steroidal NMBDs, especially rocuronium, which clinicians should watch closely.
1. Miller RD. Will succinylcholine ever disappear? Anesth Analg 2004;98:1674–5.
2. Naguib M. Sugammadex, another milestone in clinical neuromuscular pharmacology. Anesth Analg 2007;104:575–81.
3. Sacan O, White PF, Tufanogullari B, et al. Sugammadex reversal of rocuronium-induced neuromuscular blockade: a comparison with neostigmine-glycopyrrolate and edrophonium atropine. Anesth Analg 2007;104:569–74.
4. Vanacker BF, Vermeyer KM, Struys MMRF, et al. Reversal of rocuronium-induced neuromuscular block with the novel agent sugammadex is equally under maintenance anesthesia with propofol or sevoflurane. Anesth Analg 2007;104:563–8.
5. Eleveld DJ, Kuizenga K, Proost JH, Wierda JMKH. Temporary increase in twitch response during reversal of rocuronium induced muscle relaxant with a small dose of sugammadex. Anesth Analg 2007;104:582–4.
6. Groudine SB, Soto R, Lien C, et al. A randomized dose-finding Phase II study of the first selective relaxant binding agent, sugammadex, capable of safely reversing profound rocuronium-induced neuromuscular block. Anesth Analg 2007;104:555–62.
7. Lenz A, Hill G, White PE. Emergency use of sugammadex after failure of standard reversal drugs. Anesth Analg 2007;104:585–6.