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Anesthesia & Analgesia, Professor and Chairman, Department of Anesthesiology and Perioperative Care University of California, San Francisco, CA
Address correspondence and reprint requests to Ronald D. Miller, chair, Department of Anesthesiology and Perioperative Care, University of California, San Francisco, CA 94143.
Succinylcholine (SCh) has been a mainstay of anesthetic practice for more than 50 years, primarily because of its rapid onset time (time from SCh administration to peak effect). This time facilitates one of the most fundamental axioms of anesthetic practice, which is that the time from induction of anesthesia to endotracheal intubation should be as short as possible. This approach theoretically should minimize the time during which the vulnerable trachea is unprotected from aspirated fluids or solids during anesthesia. However, SCh has multiple well-documented side effects and can induce fatal complications (e.g., massive hyperkalemia and malignant hyperthermia).
For more than 25 years, research has been unequivocally directed towards the development of a nondepolarizing neuromuscular blocking drug with an onset time as short as that of SCh. The assumption was that a nondepolarizing drug would have fewer adverse effects than the depolarizing SCh.
In the 1980s, the onset times of nondepolarizing long-acting drugs (e.g., pancuronium) were shortened by the introduction of intermediate duration drugs (e.g., atracurium, vecuronium). However, these times are not as short as SCh. Since the intermediate duration drugs also had shorter onset times than the longer-acting drugs, then should not even shorter-acting drugs also have quicker onset times? For a brief time, most of us believed that a shorter duration of action would automatically be associated with a quicker onset time. Mivacurium proved that concept to be incorrect (i.e., slow onset time and short duration of action).
Finally, the 1990s provided the tantalizing illusion that we were finally ridding ourselves of the "dirty" SCh by the introduction of rapacuronium and rocuronium. Rapacuronium, indeed, had an onset time comparable to SCh and a short duration of action. Finally, the search for a replacement for SCh had nearly been achieved—but only for what seemed like a fleeting moment. Regrettably, an unacceptable incidence of bronchospasm necessitated the removal of rapacuronium from clinical use. Despite many disappointing failures, Belmont et al. (1) believe that GW280430A has an onset time of 60–90 seconds in a small number of volunteers. Obviously large clinical studies will determine when its onset time is as consistent as SCh. Furthermore, Caldwell (2) cautions that its histamine release may prevent its being introduced into clinical practice. Yet, while rocuronium has the most rapid onset time of any nondepolarizing muscle relaxant currently in use clinically, only larger doses can match the quick and predictable (i.e., small variability) onset time of SCh (3).
Remarkably and regrettably, after more than 50 years of dramatic advances in anesthesia, a pharmacologically dirty and dangerous drug (SCh) is still the "gold standard" for producing paralysis during rapid sequence induction of anesthesia and endotracheal intubation—arguably one of the most dangerous moments in anesthetic practice.
A replacement for SCh does not appear to be eminent. We, therefore, have an obligation to keep trying to improve the safety of SCh. Perhaps more research may improve or attenuate the problems from SCh. Accordingly, three papers appear in this issue of Anesthesia & Analgesia. The Werawatganon et al. study (4) found that patients undergoing electroconvulsant therapy (ECT) had less muscle damage than surgical patients after SCh administration. Clearly, the types of surgery conducted produced more muscle damage than ECT. Naguib et al. (5) found that elements of a Phase II exist during onset and recovery from an initial small dose of SCh. These elements include fade to a train-of-four and tetanic stimulation, both characteristics of a Phase II block. The obvious conclusion is that some elements of a Phase II block are present from the initial dose of SCh, which intensifies with continued administration. Actually, this has been known for more than 30 years (6) and by many clinical groups, such as ours in San Francisco. The Naguib et al. (5) study was accepted for publication because it used contemporary techniques to determine the mechanisms of a frequently used drug (i.e., SCh). However, to use peripheral nerve stimulation as a method for ascertaining clinical mechanism of action is probably overly simplistic, or possibly incorrect. Hopefully, "translational" research can be used to apply sophisticated basic science techniques (e.g., direct analysis of receptors and ion channels) to clinical research. What may result is an accurate knowledge of the mechanism of action that will allow the clinician to avoid some of the complications of SCh.
The El-Orbany et al. (7) article brought the most pleasure to this author because it confirmed clinical practice derived more than 30 years ago. They (7) concluded that 0.5–0.6 mg/kg (35–42 mg/70 kg) IV dose of SCh is as effective as 1.0 mg/kg with regard to intubating conditions, but with a more rapid recovery from neuromuscular blockade and apnea time. One hopes that these smaller doses could be associated with fewer complications, although there is no guarantee of such a result. During my training from 1965 to 1968, a common IV dose of SCh was 40 mg in adults, which would be increased 60–70% when preceded by a defasciculating dose of d-tubocurarine. In 1961, Cullen (8) even recommended 10–20 mg in a properly anesthetized adult. Over the next 30 years, the defasciculating dose was gradually eliminated (although not completely) and the dose of SCh was progressively increased to 100–150 mg in adults. The El-Orbany et al. (7) data confirm that the smaller doses of SCh used in the "old days," indeed, have some logic, or even wisdom, when compared to modern anesthesiology. While this does not happen often, my generation will enjoy an occasional thought about the "good old days."
Because of the unrelenting persistence of SCh in our anesthetic practice, new, innovative research with this muscle relaxant probably should be encouraged.
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