This article is part of a Pro and Con debate and is accompanied by the following Invited Commentary and article:
• Fuchs-Buder T, Schmartz D. The never ending story or the search for a nondepolarising alternative to succinylcholine. Eur J Anaesthesiol 2013; 30:583–584.
• Girard T. Pro: rocuronium should replace succinylcholine for rapid sequence induction. Eur J Anaesthesiol 2013; 30:585–589.
‘So long, succinylcholine!’ concluded Lee and Katz1 in a review article in 2009 after discussing why this agent should be sent out to retirement 60 years after its clinical introduction. During this time, clinical appraisal has changed from ‘close to ideal’ into ‘pharmacologically dirty and dangerous’.2 Probably unlike any other drug in clinical anaesthesia, succinylcholine has been subject to controversies due to its number of side effects. Life-threatening complications such as malignant hyperthermia or cardiac arrests are associated with this drug as well as minor problems such as postoperative myalgia. Undoubtedly, succinylcholine has taught anaesthesiologists and pharmacologists a lot about neuromuscular pharmacology, and probably, millions of patients have benefited from treatment with this agent. Now, more than 60 years after the introduction of ‘SUX’ into clinical practice, the anaesthesiologist's portfolio contains a variety of neuromuscular blocking agents and it seems that there are suitable alternatives for all clinical situations. However, several surveys have shown that the majority of anaesthesiologists still trust this old drug and that, even now, none of the newer agents can force succinylcholine out of the management of one of the most critical situations in clinical anaesthesia, the induction of the patient at a risk of pulmonary aspiration.3–5
After the failure of rapacuronium, the steroidal rocuronium introduced in 1996 remains the nondepolarising muscle relaxant with the fastest onset. It has been recommended as an alternative agent for rapid sequence induction (RSI) if there are contraindications to the use of succinylcholine.6 However, there are some good reasons why we should not completely switch to ‘ROC’.
Closer to ideal?
The aims of RSI are clearly defined. It should prevent the inhalation of gastric contents during induction of anaesthesia in at risk patients. With this aim in mind, the procedure involves the loss of consciousness, neuromuscular block without the assurance of the ability to ventilate the lungs following preoxygenation and rapid achievement of tracheal intubation. Cricoid pressure can be applied before loss of consciousness.7
The major demand on a neuromuscular blocking agent during RSI is to create optimal intubating conditions as quickly as possible. The rapid paralysing effect of succinylcholine has been attributed mainly to its ultrarapid breakdown by serum cholinesterase, additionally modified by its low potency.8 Factors such as cardiac output, circulation time and muscle blood flow might have an influence on the onset time, but these factors are independent of the agent.
Following the usual intubating dose of succinylcholine 1 mg kg−1 (which represents three times the ED95), 100% block at the adductor pollicis muscle can be expected within 1 min. Moreover, it has been demonstrated that the laryngeal muscles might be more sensitive to succinylcholine than to nondepolarising agents.9 The laryngeal muscles have been shown to be somewhat more resistant to rocuronium.10 In a direct comparison of both agents,11 the onset time of succinylcholine 1 mg kg−1 at this site was found to be significantly shorter than that of rocuronium 0.8 or 1.2 mg kg−1. The results may explain why succinylcholine might be the drug that is ‘closer to ideal’.
A number of clinical trials have considered this issue. Since the clinical introduction of rocuronium, many studies have compared the quality of intubating conditions with those associated with the use of succinylcholine. A comprehensive systematic review and meta-analysis on this topic was published for the first time in the Cochrane database by Perry et al.12 in 2003, followed by an update in 2008. This meta-analysis analysed the data from 37 randomised controlled trials, which included 2690 patients who underwent a modified or simulated RSI procedure. The majority of the studies compared intubating conditions following succinylcholine with rocuronium 0.6 to 0.7 mg kg−1. In this setting, succinylcholine produced excellent intubating conditions significantly more often, and independently of the anaesthetic induction agent (i.e. propofol or thiopentone). Overall, there was no difference in creating acceptable intubating conditions. At a higher dose of 0.9 to 1.2 mg kg−1, rocuronium was comparable with succinylcholine in producing excellent or acceptable conditions. However, in 2006, Donati13 noted that most of the studies of intubating conditions were undertaken in elective patients who underwent no, or a simulated, RSI scenario.
In their review, Perry et al.12 identified only four trials involving emergency patients and two of these used a rocuronium dose between 1 and 1.2 mg kg−1. In the analysis of this subgroup, succinylcholine was superior in creating excellent intubating conditions. Consequently, the authors concluded that succinylcholine should be the preferred muscle relaxant for RSI. Moreover, they suggested that future studies should specifically include emergency patients.
In the majority of clinical trials on intubating conditions, the insertion of a tracheal tube was usually performed after a fixed time interval of 60 to 90 s after injection of the neuromuscular blocking agent. It remains questionable whether this is a realistic scenario because many anaesthesiologists start laryngoscopy as quickly as possible after the injection of the relaxant. This is reflected in the study of Sluga et al.,14 in which the intubation process was already complete after 50 s in one-third of the patients treated with succinylcholine.
Another important group frequently scheduled for RSI is obstetric patients. Unfortunately, information on this group is also sparse. Data on placental transfer of rocuronium following a dose of more than 0.6 mg kg−1 are completely lacking. A MEDLINE search for clinical studies, performed in November 2012, revealed only one randomised controlled trial, which investigated the intubating conditions following rocuronium 1 mg kg−1 with those after succinylcholine. No differences in acceptable intubating conditions, but more frequent excellent conditions, were reported in patients treated with the depolarising agent.15 In addition, a number of case series with a total of 35 patients have reported the use of rocuronium in caesarean section.16–18 It remains questionable whether the currently available information with one controlled trial and three case series can be regarded as sufficient to recommend the use of rocuronium instead of succinylcholine in obstetric patients.
The risks of using succinylcholine
Adverse effects of succinylcholine are related mainly to its depolarising mechanism of action. Malignant hyperthermia and hyperkalaemia are potentially life-threatening complications. In Denmark, the incidence of fulminant malignant hyperthermia has been estimated to be one in 62 000 anaesthetic procedures when succinylcholine is administered in combination with a potent inhalational agent.19 The introduction of dantrolene for treatment has reduced the mortality of malignant hyperthermia from 80 to less than 10%.20
Cardiac arrest induced by hyperkalaemia has been associated with various diseases. Gronert21 identified 57 cases of cardiac arrest due to hyperkalaemia with 17 fatalities after a search of reports published over 40 years beginning in the early 1960s. The majority of cases were related to myopathies or receptor upregulation.21 Renal failure has not been identified as a risk factor for hyperkalaemic cardiac arrest.22
Clearly, the use of succinylcholine must be avoided in patients at a risk of developing malignant hyperthermia, or with known myopathies. Similarly, patients with suspected receptor upregulation through acquired pathological states should not be exposed to succinylcholine.23 However, there is a residual risk that the agent could be administered to patients with an undiagnosed predisposition.
Minor problems such as fasciculations or postoperative muscle pain can be minimised by administration of lidocaine or by precurarisation prior to the use of succinylcholine.24 Muscle pains are not exclusive to succinylcholine and have been observed also after the use of nondepolarising agents.25 For rocuronium, pain during injection is an additional issue.26
Neuromuscular blocking agents can cause anaphylactic reactions. The reported incidence varies widely. For rocuronium, the incidence has been calculated to be one in 5000 treatments in Norway but only one in 114 000 in the rest of Scandinavia.27 Data from a French survey imply that the incidence of anaphylactic reactions after succinylcholine might be comparable to those following rocuronium.28
Improved safety through a fast offset?
Another clinical characteristic that makes succinylcholine very attractive is the fast termination of its neuromuscular blocking effects. The rapid restoration of spontaneous ventilation might save a patient in a ‘can’t intubate – can’t ventilate’ (CICV) situation following RSI. However, when reviewing data from model calculations and clinical trials for succinylcholine, this faith might be misplaced in at least a number of patients.29,30
Recently, the selective relaxant binding agent sugammadex has been introduced. It allows a rapid reversal of a rocuronium-induced neuromuscular block even after the use of increased doses of this steroidal blocker.31 It has been suggested that the use of sugammadex could be a treatment option in such a situation.18 In two trials on simulated scenarios of ventilation failure after RSI with rocuronium, sugammadex resulted in restoration of spontaneous breathing faster than a spontaneous recovery from succinylcholine.32,33 However, concerns have been expressed that delays in administration may limit successful treatment.34 Meanwhile, the use of sugammadex in the treatment of CICV situations has been described in several case reports in which the administration of the agent could not rescue the situation.35,36 Currently, there is an ongoing debate on the role of sugammadex in the management of such a complication.
The famous Dutch football player Johan Cruijff once said that ‘every disadvantage has its advantage’. The disadvantage of succinylcholine as an old drug should be seen as an advantage. Over the years, the number of side effects has led to intensive research on their prevention and treatment. Anaesthesiologists are experienced and aware of the problems that the agent can cause, which may result in additional alertness and careful selection of patients.
It is reasonable to continue with the use of succinylcholine as a first choice in RSI because the agent produces excellent intubation conditions within 60 s reliably and often allows completion of the airway management process in less than a minute. A nondepolarising agent that unifies all the positive characteristics of succinylcholine without the side effects is currently not available.
For rocuronium, it must be concluded that the evidence regarding intubating conditions during RSI in emergency situations is not convincing enough. Data on specific patient populations (e.g. obstetric patients) are very sparse. Consequently, rocuronium should not be used as a first choice for RSI but remains the best alternative in the presence of specific contraindications to succinylcholine.
The potential role of the selective reversal agent sugammadex in the treatment of a CICV situation during RSI is not clear at the moment. However, there must be concern that the availability of sugammadex to reverse a deep rocuronium-induced neuromuscular block in such a scenario may create a false sense of security, which could be fatal.
Is it, therefore, now justified to say ‘so long’ to succinylcholine? In case of a RSI, the answer should be ‘not yet’.
Assistance with the editorial: none declared. This article is dedicated to the memory of Eva Mucha, MD.
Financial support and sponsorship: none declared.
Conflicts of interest: none declared.
Comment from the Editor: this editorial was checked by the editors but was not sent for external peer review.
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