Have we learned how to relax our patients, by thinking outside the box?☆
Article Outline
- 1. Have we relaxed our patients well?
- 2. In failed pursuit of ideal relaxants
- 3. In pursuit of better relaxation with imperfect relaxants
- 4. Thinking outside of the box
- References
- Copyright
This issue of Journal of Critical Care, devoted to current concepts in neuromuscular block and reversal, is intended to update readers on the basic and clinical aspects of neuromuscular pharmacology, especially on new advances that will soon have major impacts on how anesthesiologists relax their patients. Have we finally learned how to relax our patients, by “thinking outside the box”? To help answer the question, let us look back at some critical milestones in the history of clinical neuromuscular pharmacology.
1. Have we relaxed our patients well?
Before neuromuscular blocking drugs were available, pioneering anesthesiologists provided relaxation with deep ether anesthesia. For example, after induction of anesthesia with ether by open drop, children underwent tonsillectomy and adenoidectomy while breathing spontaneously, without airway devices. After surgery, they breathed themselves out of anesthesia. Amazingly, deep ether anesthesia provided great relaxation and analgesia, with cardiovascular stability.
No one knows how the Amazonian American Indians discovered the arrow poisons. The curare compounds are harmless per os, which means these poisons serve no purpose in nature, without a method of injection. Perhaps they are just purposeless byproducts. Two molecules of laudanosine tend to align themselves in the configuration of d-tubocurarine, to be accidentally fused to become a curare. The discovery that the curare abstract works by injection was a miracle, so was the invention of the blow gun to inject it into animals for hunting purposes. The discovery of neuromuscular junction, the elucidation that d-tubocurarine blocks that junction, and the introduction of curare into clinical anesthesia were great events in modern medicine [1]. Interestingly, Beecher and Todd [2] later reported that the introduction of d-tubocurarine was associated with an increase in surgical mortality. Most likely, the increase in mortality was due to aggressive performance of more invasive surgery on sicker patients, enabled by better relaxation, and to inappropriate use and misuse of curare and its antagonists.
Succinylcholine was introduced as an improved neuromuscular blocker over d-tubocurarine. In their first report on succinylcholine, Foldes et al [3] noted that with succinylcholine, the relaxation and the changing degree of block occurred within 1 minute, and they considered succinylcholine “close to ideal.” Amazingly, an addendum to the article already stated that since the article was submitted for publication, several cases of prolonged muscle weakness after succinylcholine had been reported. Nevertheless, succinylcholine became very well accepted in clinical anesthesia. Over the subsequent decades, unfortunately, many side effects of succinylcholine surfaced. Many of these are unusual, unprecedented, unequaled in severity, and difficult to treat. Anything that can go wrong has gone wrong with succinylcholine [4]. It is inconceivable today that a compound composed of 2 acetylcholine molecules joined end on end, which succinylcholine is, has played such an important role in modern anesthesia. The molecular structure alone would predict numerous side effects. Succinylcholine is far from ideal! The only advantage that made succinylcholine irreplaceable, so far, is its ultrashort duration of action. Its rapid onset of action has been approached by safer compounds. An old soldier never dies, he just fades away. Paraphrasing this, Lee has stated that a drug capable of surviving so many controversies will never die; it will just fade away when a replacement proves itself. Perhaps, it is about time.
2. In failed pursuit of ideal relaxants
A 1975 editorial by Savarese and Kitz [5] established the concept that an ideal relaxant must be nondepolarizing, and with good pharmacology profiles. It should also be ultrafast and ultrashort, and noncumulative so that it can be used for any duration by infusion. Alternatively, relaxants of various durations of action, short, intermediate, and long, have clinical utility as long as they are safe, effective, reversible and economic to use. Since then, better relaxants that have been brought to clinical anesthesia belong to 2 chemical classes, namely, the improved curares and the aminosteroids. Significant attempts also included Russian inventions such as the truxillic derivatives, and the tropinyl di-ester congeners of TAAC3 [6].
The improved curare class includes metocurine and the long-chain bis-quaternary tetrahydroisoquinolinium compounds. Although atracurium embodies the new pharmacokinetic concept of Hofmann degradation, cisatracurium depends on it. Cisatracurium further sets standard of stereo-specificity. However, it is still far from being ideal. GW430A (GW280430A, AV430A) and AV002 exploit molecular asymmetry and a new mechanism of breakdown, namely, cysteine adduction [7]. Today, cisatracurium remains popular, whereas the new AV compounds currently under development promise great improvement in the future.
The aminosteroid class of muscle relaxants has also greatly improved anesthesia care in the past 4 decades. Pancuronium was investigated in the late 1960s and introduced into clinical anesthesia in 1968. It played a major role in the 1970s. Interestingly, a tertiary analogue of pancuronium, namely, vecuronium, was handed to a PhD student to study the structure-action relationship, under the presumption that mono-quaternary compounds would not make potent relaxant (Durant, personal information). To his surprise, Durant discovered that vecuronium is equipotent to pancuronium, without vagolytic side effect [8]. Vecuronium was finally brought to clinical use in the early 1980s, about the same time when atracurium was introduced. Today, vecuronium remains in use in many hospitals. It established the concept that blocking one receptive site is sufficient to block a nicotinic receptor. After vecuronium, rocuronium is the most popular relaxant at present.
TAAC3 is one of the better tropinyl di-ester compounds.6 It is ultrafast and ultrashort in action, nondepolarizing and noncumulative, with reasonably good potency and safety profiles in animals. It is the shortest and fastest noncumulative neuromuscular blocking compound tested satisfactorily in animals. It was subjected to extensive prehuman studies, including toxicity testing. Pure stereoisomers were synthesized and compared. Unfortunately, TAAC3 failed the toxicity test (personal information).
Among neuromuscular blocking drugs, a general inverse potency-onset relationship appears to hold, not only among relaxants of the same chemical class, but also across chemical classes [9]. Outstanding examples are pipecuronium and rapacuronium, both being aminosteroid relaxants. Pipecuronium is one of the most potent and cleanest neuromuscular blocking drugs known, with few side effects, but it is slow and long-acting. It was introduced to clinical use but never gained popularity. Rapacuronium, on the other hand, is weak, short-acting, but fast. It enjoyed a brief popularity, but was withdrawn from the market soon after introduction because it causes bronchospasm. In general, weak compounds are not receptor-specific and therefore prone to side effects. They achieve fast onset because they are administered in large doses so that the large number of drug molecules quickly overwhelms the receptor population. Between high potency and fast onset, successful compounds must be exceptions to the rule, such as rocuronium, which is exceptionally fast for its potency. Rocuronium appears to have reached the limit of the aminosteroid class of relaxants.
From the viewpoint of mechanism of action, the existence of 2 receptive sites allows for potent neuromuscular blocking agents to be either monoquaternary or bisquaternary, represented respectively by the aminosteroid and the tetrahydroisoquinolinium compounds. Both are derivatives of natural precursors, not de novo creation. Both have flat broad moieties to block ionic flow through the channel [10]. A 2-point conformational theory suggests that it is unlikely for a tris-quaternary or other fundamentally new class of compounds to excel as neuromuscular blocking agent [10].
From the above, it is obvious that chances are slim to have one relaxant to provide ideal relaxation. Just combining high potency and fast onset in one drug alone is already difficult. Neither will new class of chemicals besides the tetrahydroisoquinolinium and the aminosteroid produce better relaxants. To provide better relaxation, meanwhile, researchers have made efforts to better use the imperfect relaxants that are already available, as follows:
3. In pursuit of better relaxation with imperfect relaxants
From the historic perspective, we made succinylcholine safer by restricting its indications [4]. Of the numerous side effects of succinylcholine, bradycardia can be prevented or treated with atropine. De-fasciculation with a small dose of curariform nondepolarizing relaxant prior to administration of succinylcholine may be useful to prevent regurgitation. (The authors disagree on this point, with CL pro and RLK con.) Related to fasciculation is myalgia. The great number of solutions offered to prevent or treat such myalgia can only mean that none work well.
Katz introduced the nerve stimulator [11]. He also observed that given the same 0.1 mg/kg of d-tubocurarine normal individuals vary from 0% to 100% in depression of the twitch. He further showed that an 80% depression of the twitch usually provides adequate abdominal relaxation under adequate anesthesia, while spontaneous recovery of 20% improves reversibility. Lee showed that a train-of-four count of 4 corresponds roughly to this point [12]. Numerous other studies have improved upon the sophistication of neuromuscular monitoring. Unfortunately, high incidence and potential danger of residual paralysis still exist in the post-operative period.
Priming involves administering a portion (usually 20%) of the intended total intubation dose of a nondepolarizing relaxant several (2 to 6) minutes prior to the injection of the remaining main dose, for the purpose of speeding up the onset of intubation condition. Clinically, the benefit is inconsistent and hard to quantify. We have demonstrated that cats primed by individually determined ED20 always have faster onset when the subsequent ED80 is injected (unpublished data). However, predetermination of individual ED20 is not clinically feasible. Because the correct priming dose is particularly variable among individuals, priming cannot deliver consistent results. Worse, sensitive patients could be paralyzed prematurely by the priming dose.
Ideally, a relaxant should recover immediately or be completely reversible when it is time to return muscle power to the patient. Reversal greatly extends the utility of relaxants otherwise too long-acting for the occasion. Unfortunately, anesthesiologists remain dependent on antiquated cholinesterase inhibitors for reversal of the residual block. It is not difficult to see why inhibition of cholinesterase results in cholinergic excess across many organ systems. Besides, cholinesterase inhibitors are slow, with low efficacy. Germine and 4-AP (4-aminopyridine) have been tested as new reversal agents, but did not succeed clinically [13].
From the above, one concludes that our specialty has so far failed to provide satisfactory relaxation to our patients, not to mention ideal relaxation. The failure is not caused by lack of basic research, either. Quite to the contrary, neuromuscular pharmacology has been one of the most active research areas in anesthesiology. Application of the arrow poison led to the discovery of the neuromuscular junction. Studies of the endplate nicotinic receptor led modern receptorology. Beyond structure-action relationships, molecular modeling has elucidated some aspects of conformation-action relationship and how the relaxants molecules may interact with the receptive sites [10]. Researchers have applied sophisticated synthetic chemistry to make the thousands of new compounds for pharmacological screening [6], [7], [9], [10].
4. Thinking outside of the box
Rather than lack of research, perhaps we have been too pre-occupied with the neuromuscular junction and its pharmacology. On hindsight, most breakthroughs in neuromuscular therapeutics have resulted form “thinking outside the box.” To wit, atracurium shed the dependence on plasma cholinesterase for breakdown; vecuronium overturned the doctrine of bis-quaternary molecular requirement for potency; and TAAC3, GW and AV series of compounds do not depend on organ functions for recovery. At the extreme, sugammadex reversal of rocuronium does not even involve the neuromuscular junction at all. The reversal was achieved by encapsulation of the molecules of rocuronium, not by antagonism in any sense. The concept of agonist and antagonist was developed in the early days of receptorology, and the term antagonism was introduced into neuromuscular pharmacology decades ago. This is certainly not how sugammadex works. Nor does cysteine reversal of AV002-induced neuromuscular block involve any antagonism. In other words, the new reversals are totally outside of the box—outside of neuromuscular junction, cholinesterase, and the ideation of antagonism.
In this issue, experts in several areas of organic chemistry and neuromuscular pharmacology update us on the current concepts of neuromuscular block and reversal. Many recent investigators have demonstrated how quickly, safely, and efficaciously sugammadex reverses rocuronium in various clinical situations. Up to 16 mg/kg of sugammadex has been shown safe and efficacious and up to 1.2 mg/kg of rocuronium has been reversed at a speed faster than spontaneous recovery from succinylcholine. It thus appears that rocuronium and sugammadex together practically fulfill the definition of ideal relaxant. Perhaps, even the very concept an ideal relaxant can be shed [3], [5], [6]. A 2-drug regimen, one to block one to unblock, works just fine.
It is enlightening to learn that outside of our box, cyclodextrins are by no means new. According to Uekama and Hirayama [14], “Cyclodextrins were first isolated in 1891 as degradation products of starch and were characterized as cyclic oligosaccharides. The α-, β-, and γ-cyclodextrins are the most common natural cyclodextrins, consisting of six, seven, and eight glucose units, respectively. Because of their different internal cavity diameters, each cyclodextrin shows a different degree of molecular encapsulation with different-sized guest molecules. These cyclodextrins have therefore been utilized for the modification of physical, chemical or biological properties of guest molecules…. To obtain drug carrier properties better than those of natural cyclodextrins, the hydroxyl groups of dextrins are available as starting points for structural modification.” The cavity diameter is 0.5, 0.6, and 0.8 nm for α, β, and γ-cyclodextrin, respectively. Thermodynamically, smaller rings will be hard to form because of high bond bending energy; larger rings might twist or collapse. Luckily for anesthetic care, γ-cyclodextrin has a ring size just right for the androstane nucleus, and its negatively charged side chains fit the positively charged quaternary ammonium of rocuronium and vecuronium with great precision. Adding negative charges to the side chains was the critical step in this application.
In conclusion, our specialty has finally learned to relax our patients safely and effectively, by again thinking outside the box. Our optimism is based on sugammadex encapsulation of rocuronium, and backed up by cysteine or glutathione adduction of AV002 or one of its congeners. Is it time to bid farewell to neostigmine and succinylcholine, along with all funny techniques such as priming, primed reversal, and de-fasciculation? Time will soon tell. Meanwhile, one regrets that although cyclodextrins, vecuronium, and rocuronium have been around for decades, our patients still depend on antiquated and inefficacious cholinesterase inhibitors for reversal of residual neuromuscular block. What would have happened to modern neuromuscular pharmacology were sugammadex available when vecuronium was first discovered?
References
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☆ The authors have in the past received supports for their neuromuscular researches from various sponsors including the present Sponsor, Organon, Inc, now part of Schering-Plough Corporation, owner of sugammadex. One author (CL) is coinvestigator and coinventor of the TAAC3 series of compounds (Anesth Analg. 2002;94-4:879-885; now deactivated), which was in the past sponsored in part by the Sponsor. He is also principal investigator of one of the multicenter studies on sugammadex sponsored by the Sponsor.
PII: S0883-9441(08)00182-2
doi:10.1016/j.jcrc.2008.08.006
© 2009 Published by Elsevier Inc.
