Pro

rocuronium should replace succinylcholine for rapid sequence induction

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.

• Schreiber J-U. Con: succinylcholine should not be replaced by rocuronium for rapid sequence induction. Eur J Anaesthesiol 2013; 30:590–593.

This discussion covers all indications for rapid sequence induction (RSI), but there will be some emphasis on general anaesthesia for caesarean section. The distinct pathophysiological properties of these patients as well as transplacental drug transfer require special consideration. In patients at a risk of pulmonary aspiration, general anaesthesia is usually induced with RSI. The key elements of RSI are preoxygenation, cricoid pressure and refraining from mask ventilation until successful tracheal intubation.¹ The rationale behind these measures is the fact that there might be some gastric insufflation with face mask ventilation and consequently an increased risk of regurgitation and pulmonary aspiration.

Preoxygenation

Preoxygenation (denitrogenation) removes as much nitrogen as possible from the functional residual capacity in order to maximise the duration of ‘safe apnoea time’. Safe apnoea time is the duration of apnoea that can be tolerated until arterial oxygen desaturation occurs. In addition to a decreased functional residual capacity by approximately 30%, pregnant women at term simultaneously have an increase in oxygen consumption of roughly 20%. These physiological changes result in a dramatic reduction of safe apnoea time even under optimal preoxygenation. In a patient simulator, the average time of a pregnant patient at term to desaturate to 90% arterial oxygen saturation was 4 min and 50 s at best.² Due to the shape of the oxygen dissociation curve, further desaturation is very rapid, and 40% was reached after another 34 s.

Cricoid pressure

External pressure on the cricoid cartilage is supposed to compress the oesophagus and consequently reduce gastric insufflation as well as regurgitation during mask ventilation. The usefulness and possible harm of cricoid pressure in itself is currently a matter of debate and will not be further discussed here.³

Apnoea

Apnoea is the logical consequence of avoiding mask ventilation until tracheal intubation.

In paediatric anaesthesia, however, this practice has undergone substantial discussion and reduced functional residual capacity paired with increased oxygen consumption of paediatric patients has led to a change in practice. The same modification has also been suggested for selected adult patients with decreased oxygen reserves and/or increased oxygen consumption.^4,5

Ideal neuromuscular blocking agent

What characteristics would the ideal neuromuscular blocking agent for RSI in obstetric patients have? This drug should

1. have a fast onset of action
2. have an easily identifiable onset of action
3. have no influence on oxygen consumption during onset
4. have a duration of action of approximately 20 min (as a minimum duration of surgery)
5. be readily reversible by a direct antagonist
6. not cross the placenta
7. not have cardiovascular or pulmonary side effects
8. not trigger malignant hyperthermia
9. have no adverse effects in myopathic patients and
10. have an easy dosage

For decades, succinylcholine has been the standard neuromuscular blocking agent for RSI.^1,6 What reasons could lead to changing such a long story of success? Succinylcholine has been repeatedly labelled a ‘dirty drug’ and has several potentially fatal side effects. The most important of these are as follows:

1. myalgia
2. massive hyperkalaemia
3. increased masseter tone, which can impair laryngoscopy
4. triggering of malignant hyperthermia
5. muscarinic effects and bradycardia
6. markedly prolonged duration of action in patients with butyrylcholinesterase deficiency

So why is succinylcholine still used for RSI? Part of the ‘success story’ of succinylcholine includes some pharmacokinetic and pharmacodynamic properties that are hard to challenge:

1. short onset time
2. fasciculations indicating the onset of action
3. optimal intubating conditions within 60 s

Short onset time

Succinylcholine has a short onset time of approximately 60 s. Onset time is crucial in RSI because the duration of apnoea is mainly determined by the onset time of the neuromuscular blocking agent. As far as onset time is concerned, rocuronium is an alternative to succinylcholine. As rocuronium has a relatively low potency, overdosing to more than twice ED₉₅ shortens the onset time significantly.⁷ The speed of onset of rocuronium is dependent on cardiac output, a fact that was confirmed in a study in which the administration of ephedrine before rocuronium significantly reduced onset time.⁸ A similar increase in cardiac output is present in pregnant women.⁹ In theory, this should reduce the onset time, although this has not yet been investigated clinically in this population.

The sequence of drug administration might also be important because remifentanil injected before propofol and rocuronium leads to a significantly longer onset time than the sequence propofol-rocuronium-remifentanil.¹⁰

Fasciculations

Oxygen consumption is determined by basic metabolism and any additional metabolic activity. Succinylcholine-induced fasciculations are obviously associated with an increased oxygen consumption. In a non-obstetric population,¹¹ the onset of oxygen desaturation was 116 s earlier following succinylcholine 1.5 mg kg⁻¹ when compared with rocuronium 1 mg kg⁻¹. Similar results were obtained in obese patients.¹²

Fasciculations mark the onset of action of succinylcholine, which can be determined without additional monitoring.

Neuromuscular monitoring at the adductor pollicis is usually used to monitor the onset of action of nondepolarising neuromuscular blocking agents. However, sensitivity of the laryngeal muscles is different to that of the adductor pollicis.¹³ Several authors^14–19 have performed tracheal intubation for RSI after a predefined period of 55 to 60 s following rocuronium 0.9 to 1.2 mg kg⁻¹. To obtain intubating conditions equal to those associated with succinylcholine after high-dose rocuronium, disappearance of twitches at the adductor pollicis is, therefore, not required. In fact, Abouleish et al.²⁰ have concluded that at least two twitches of a train of four (TOF) have to disappear after the administration of rocuronium in order to obtain good intubating conditions. This was confirmed by Heier and Caldwell,²¹ who conclude that readiness for intubation following rocuronium cannot be judged by TOF responses. The same circumstances are reflected in the case series by Williamson et al.,¹⁷ in which disappearance of the TOF response occurred as late as 150 s after administration of rocuronium and, thus, 90 s after tracheal intubation. In summary, there is no need to wait for all twitches to disappear, and the only monitoring needed for the onset of action of rocuronium 0.9 to 1.2 mg kg⁻¹ is a chronometer indicating 60 s after injection.

In conclusion, there is no difference in onset time of rocuronium 0.9 to 1.2 mg kg⁻¹ and succinylcholine 1 mg kg⁻¹.

Optimal intubating conditions

In the mid-1990s, difficult or failed intubation in the obstetric population was reported to be as frequent as one in 300.^22,23 Although more recent data still report the same prevalence,²⁴ others have found an incidence of one in 1300, which is comparable to the general surgical population.²⁵ This might result from improved identification of challenging airways resulting in early insertion of an epidural, or the use of alternative methods of intubation, such as awake fibreoptic intubation.²⁶ Therefore, optimal intubating conditions are at least as important in an obstetric population as in a general surgical population.

There has been an extensive debate about intubating conditions when comparing rocuronium with succinylcholine. The major determinant of speed of onset and, therefore, intubating conditions is the dosage of rocuronium.⁷ In 2003, a Cochrane review comparing intubating conditions between rocuronium 0.6 mg kg⁻¹ and succinylcholine 1 mg kg⁻¹ found superior intubating conditions when succinylcholine was used. In a later revision of this review, the same authors concluded²⁷ that when rocuronium is used in doses of 0.9 to 1.2 mg kg⁻¹, there is no difference in intubating conditions when compared with succinylcholine 1 mg kg⁻¹. The authors also concluded that ‘succinylcholine was clinically superior as it has a shorter duration of action’.²⁷ A subgroup analysis of induction agents revealed better intubating conditions for succinylcholine when propofol was used as an induction agent in combination with an opioid. In the absence of opioids, there was no difference between succinylcholine and rocuronium.²⁷

In conclusion, there is no difference in intubating conditions between rocuronium 0.9 to 1.2 mg kg⁻¹ and succinylcholine 1 mg kg⁻¹.

Short duration of action

One of the main advantages of succinylcholine is its short duration of action. Should neither intubation nor ventilation be possible, then the neuromuscular block induced by succinylcholine should disappear fast enough to enable spontaneous ventilation before severe desaturation. However, this view has been widely challenged. One of the first challenges was by Benumof et al.²⁸ using a mathematical model. Later, Heier et al.²⁹ confirmed that severe desaturation can occur after a single dose of succinylcholine 1 mg kg⁻¹. The logical conclusion was to reduce the dose of succinylcholine in order to decrease the duration of action. Kopman et al.³⁰ elegantly confirmed this theory by using succinylcholine 0.4, 0.6 and 1.0 mg kg⁻¹. Although the mean duration of action of succinylcholine was clearly dose-dependent, the individual maximal duration of action was between 10 and 11 min in all three groups. This huge interindividual variability in the duration of action is in accordance with the results from Heier et al.,²⁹ who reported that the maximal duration of action varied between 3.5 and 9 min. This is not surprising, because genetic variants of the butyrylcholinestease gene are known to be as frequent as one in eight or one in 25 individuals for the K-variant and A-variant, respectively.³¹ The duration of action of succinylcholine is, on average quite short, but without prior genetic testing, the individual duration of action is unpredictable.

Since its introduction, the use of sugammadex in combination with rocuronium has changed the situation. High-dose rocuronium can be immediately reversed by sugammadex 16 mg kg⁻¹. Several studies have proved such a reversal to be faster and more reliable than waiting for succinylcholine to wear off.^14,32 The key element in such situations is the immediate availability of sugammadex. It is inappropriate to store sugammadex in a remote location, and those who use high-dose rocuronium for RSI should also be familiar with sugammadex. Otherwise, trying to find sugammadex and guessing about drug dosage might introduce severe delays.³³ Sugammadex has not been investigated in pregnant patients, and its use before delivery is unlicensed.

When using high-dose sugammadex as a potentially life-saving treatment, the relatively high cost of the drug is of little importance.

In conclusion, the option to awaken a patient and re-establish spontaneous ventilation is faster and more reliable after rocuronium and sugammadex than relying on the short duration of action of succinylcholine.

Renal insufficiency

There is, however, one caveat: in patients with severe renal insufficiency, the duration of action of rocuronium is substantially prolonged.³⁴ Sugammadex is not licensed for patients with a creatinine clearance below 30 ml min⁻¹, and there is only limited experience in this patient population.³⁵ There is no ideal neuromuscular blocking agent for patients with severe renal impairment, because these patients often have an elevated serum potassium concentration and succinylcholine is not the best alternative.

Mask ventilation

It has been demonstrated that mask ventilation is significantly improved following the administration of rocuronium 0.6 mg kg⁻¹.³⁶ When comparing rocuronium with succinylcholine, improved airflow through the oral cavity was seen after succinylcholine.³⁷ This apparent advantage of succinylcholine is debatable at best. In the event of failed intubation, the oral route might not be open and – more importantly – the effect of succinylcholine is likely to have already vanished. As a consequence, a patient who has received rocuronium is likely to benefit from the facilitated mask ventilation, whilst this would not be the case for those who had received succinylcholine.

Is the short duration of action of succinylcholine really an advantage? The concept of awakening the patient and re-establishing spontaneous ventilation in case of impossible intubation and ventilation is more than 50 years old. This concept was established at a time before fibreoptic intubation, laryngeal mask airways and any of the latest videolaryngoscopes were invented.

Today, general anaesthesia for caesarean section is usually reserved for emergency cases or for patients in whom regional anaesthesia has failed. Awakening the patient is no real option for those in whom surgery has been initiated and regional blockade proves to be inadequate. In emergency cases, a delay incurred by awakening the patient is possibly harmful to the foetus.

Such a hypothetical scenario might start with the classical RSI. The first attempt to intubate the trachea begins 60 s after administration of succinylcholine. This attempt lasts, perhaps, 30 s and fails. After another 30 s, oxygen saturation starts to decrease below 95%. Mask ventilation is difficult but possible. The second attempt to intubate the trachea also fails. By then, 5 min have passed since injection of succinylcholine. The neuromuscular block starts to wear off and mask ventilation becomes impossible.

An alternative equally hypothetical scenario could be one in which rocuronium 1 mg kg⁻¹ is used as a neuromuscular blocking agent starting an additional 116 s before oxygen saturation drops. The other difference compared with the first scenario is that mask ventilation is difficult but remains possible, because neuromuscular block facilitates mask ventilation. Eventually, a laryngeal mask airway is inserted, and the surgical procedure is started.

Placental transfer

The placental transfer and foetal uptake of succinylcholine is clinically irrelevant. The neonate is normally unaffected, unless mother and child have a significant inherited decrease in butyrylcholinesterase activity.³⁸

For rocuronium, the only information about placental transfer is from an early study with rocuronium 0.6 mg kg⁻¹, in which plasma concentrations in the umbilical vein:maternal vein had a ratio of 0.16.²⁰ It was, in fact, the concern about increased transplacental transfer that prevented the authors from using a higher dose.²⁰ The influence of higher doses on this ratio is unknown. So far the only sources of information are two case series with a total of 25 patients, in which rocuronium 1 to 1.2 mg kg⁻¹ was used for caesarean section without obvious signs of neonatal paralysis.^16,17 Unfortunately, two other case series of 70 women completely lack data on neonatal well being.^15,18

There is an evident need for more data, and hopefully, all future studies will report on the neonate, and possibly about rocuronium concentration in the umbilical vein. It must be concluded that data on the safety of high-dose rocuronium (1 to 1.2 mg kg⁻¹) are still scarce as far as transplacental transfer is concerned.

Myopathies and malignant hyperthermia

Succinylcholine must not be used in myopathic patients, because the agonistic effect on nicotinic acetylcholine receptors can lead to rhabdomyolysis and life-threatening increases in serum potassium concentration.³⁹

Succinylcholine triggers malignant hyperthermia.⁴⁰ Malignant hyperthermia is thought to be a rare condition, but more recent data have hypothesised that malignant hyperthermia mutations may be as frequent as one in 2000.⁴¹ This is even more important in general anaesthesia for caesarean section, because the standard anaesthetic technique comprises two triggering agents: succinylcholine and a potent volatile anaesthetic.⁴²

Sugammadex reversal

At a dose of 0.9 to 1.2 mg kg⁻¹, rocuronium has a prolonged duration of action. Neuromuscular monitoring is mandatory towards the end of surgery because the depth of neuromuscular block determines the most effective and most affordable mode of reversal. It is, of course, always an option to keep the patient sedated and ventilated until spontaneous recovery with four twitches is reached and then revert with neostigmine.⁴³ Obviously, reversal with sugammadex is substantially faster,^16–18 and if the costs of the staff are taken into account, cheaper than waiting for spontaneous recovery, although more expensive compared with the use of succinylcholine. If general anaesthesia is reserved for selected cases and accounts for less than 10% of caesarean sections,⁴⁴ then the financial impact of sugammadex is minimal.

Conclusion

To conclude, I would like to reiterate the properties of an ideal neuromuscular blocking agent for RSI, summarised in Table 1.

Table 1: Comparison of succinylcholine and rocuronium with respect to their properties as an ‘ideal’ muscle relaxant for rapid sequence induction

It is possible that future discussion on the best neuromuscular blocking agents for RSI will be based on facts that we cannot influence. For example, for decades, thiopental has been the induction drug for general anaesthesia in caesarean section. However, its availability has dramatically decreased in some countries.⁴⁵ This has led to a change in the choice of induction agent for general anaesthesia for caesarean section from thiopental to propofol.⁴⁶ In some hospitals, thiopental is only used for caesarean section, whereas propofol is the routine induction drug for all other anaesthetic procedures. Should we use an unfamiliar drug in infrequent situations with an increased risk of difficult airway management? Interestingly, the choice of induction agent is already judged to be ‘based on its availability and the overall clinical condition of the patient’.⁵ When will similar words be used for the neuromuscular blocking agent? How soon will succinylcholine disappear from routine use but remain in the drawer of the obstetric anaesthesiologist? Although succinylcholine has some distinct properties,⁶ the combination of rocuronium 0.9 to 1.2 mg kg⁻¹ and sugammadex seems to be at least equivalent.

Acknowledgements

Assistance with the editorial: none declared.

Financial support and sponsorship: the author has received an honorarium from MSD (Merck Sharp & Dohme) for lecturing on sugammadex.

Conflicts of interest: none declared.

Comment from the Editor: this editorial was checked by the editors but was not sent for external peer review.