We congratulate Thilen et al. for their comprehensive and pragmatic guidelines for neuromuscular blockade monitoring and antagonism. They highlight the problems associated with neuromuscular monitoring after administration of succinylcholine (a depolarizing neuromuscular blocker): the utilization of single-twitch monitoring; occurrence of fade in patients with genetic variants of butyrylcholinesterase (the enzyme that hydrolyzes succinylcholine); and the difficulties associated with monitoring. We would like to further discuss neuromuscular monitoring and antagonism of succinylcholine.

After a standard intubating dose of succinylcholine (1 mg/kg), the duration of neuromuscular blockade is 5 to 11 min in patients with normal butyrylcholinesterase levels.  As is traditionally taught, this is reflected by a depolarizing phase 1 block: depressed train-of-four twitches with no fade, and absent tetanic fade and posttetanic potentiation.  However, this is incorrect. De Jong and Freund showed that, after succinylcholine administration, fade occurred during tetanic stimulation.  Naguib et al.  also showed that boluses of succinylcholine (0.1 and 1.0 mg/kg) caused significant train-of-four fade (40 and 68%, respectively), tetanic fade and posttetanic potentiation.

With prolonged exposure to succinylcholine (e.g., butyrylcholinesterase deficiency or during succinylcholine infusions), a nondepolarizing phase 2 block occurs (i.e., marked train-of-four and tetanic fade, posttetanic potentiation, and antagonism by anticholinesterase reversal agents [e.g., neostigmine]).  Butyrylcholinesterase deficiency may be due to acquired or inherited conditions. Mutations of the gene may result in heterozygous and homozygous atypical enzymes resulting in prolonged neuromuscular blockade after succinylcholine administration (i.e., 10 to 30 min and 40 to 200 min, respectively).  Therefore, succinylcholine may cause fade in phase 1 block in phase 2 block or during mixed phase 1 and 2 block (acetylcholine receptor desensitization by succinylcholine occurring in parallel with depolarization). 

Nondepolarizing neuromuscular blockers are often given after an initial dose of succinylcholine without establishing recovery from the latter agent because neuromuscular monitoring is not commonly used. In one survey, more than 20% anesthesiologists in the United States used quantitative train-of-four monitoring routinely, and we suspect that this figure is much lower for monitoring neuromuscular blockade after succinylcholine administration..  In cases of prolonged duration of succinylcholine, subsequent train-of-four fade may erroneously be attributed to partial recovery of the nondepolarizing neuromuscular blockade but could in fact be due to succinylcholine phase 1 or 2 blocks. Neostigmine may then be given to reverse the perceived shallow block (train-of-four count 4 with fade) of the nondepolarizing neuromuscular blockade.  However, the action of neostigmine after prolonged blockade by succinylcholine is unpredictable in part, because mixed phase 1 and 2 blocks can occur. 

Options for quantitative monitoring of neuromuscular blockade, including after succinylcholine administration, should ideally be “applied throughout all phases of anesthesia from before initiation of neuromuscular blockade until recovery of the [train-of-four] ratio to greater than 0.9 has been confirmed.”  Evidence of recovery from succinylcholine blockade should be obtained before subsequent administration of a nondepolarizing neuromuscular blocker.

Depth of, and confirming recovery from, neuromuscular blockade can be assessed by qualitative devices that stimulate a nerve (“peripheral nerve stimulators”) or quantitative monitors. The former rely on subjective assessment of evoked twitches by visual or tactile means, but even experienced anesthesiologists cannot reliably detect fade greater than 0.4 (minimal block) using this method and therefore residual paralysis may be missed. In contrast, quantitative monitors can objectively and reliably measure twitches such as T1 height and train-of-four ratio. However, T1 height is not a reliable method for determining the recovery of block due to the “staircase” phenomenon, where repeated indirect stimulation causes enhanced twitch augmentation that is directly related to the frequency of stimulation.

The use of neostigmine to reverse prolonged succinylcholine-induced neuromuscular blockade is complex because it may result in blockade that is persistent or exacerbated.  Neostigmine administration may be avoided by keeping the patient sedated and ventilated (because the prolonged blockade is temporary) until full recovery has been established. If neostigmine reversal is considered, it should be administered after the appearance of four train-of-four twitches.  Both T1 and train-of-four ratio should be used to accurately assess adequate reversal by neostigmine, because there are case reports of patients with butyrylcholinesterase deficiency where, after the attempted reversal of prolonged succinylcholine duration, neostigmine had little effect on the train-of-four ratio (despite T1 100 to 120% of control) or it increased the train-of-four ratio without increasing the T1 height (remaining at 25%). 

Delayed application, or a lack, of neuromuscular monitoring when succinylcholine is used in patients with butyrylcholinesterase deficiency is associated with complications.  The latter include: perceived neuromuscular monitoring failure, delayed recovery, hypertension, airway obstruction, respiratory complications (25% in unmonitored patients [e.g., oxygen desaturation, reintubation, and pulmonary aspiration]), premature extubation, awareness, and fear of future anesthetics.  One Danish study found that that premature awakening (while paralyzed and so at increased risk of awareness) occurred in 100% of patients with suspected butyrylcholinesterase deficiency who had no intraoperative neuromuscular monitoring. In addition, delayed recovery may be misattributed to the effects of opioids and result in naloxone administration. 

Succinylcholine pharmacology is complex and poorly understood, so accurate monitoring is imperative. Subjective monitoring of fade, whether after succinylcholine or nondepolarizing neuromuscular blockers, is not reliable. Quantitative monitoring should therefore be applied when succinylcholine is administered to recognize prolonged block from butyrylcholinesterase deficiency or persistent “phase 2 block,” which if not recognized can result in serious complications.

In conclusion, if practical, neuromuscular monitoring should be applied during all phases of anesthesia when neuromuscular blockers (including succinylcholine) are administered.  This will help to prevent misinterpretation of the neuromuscular monitoring data, identify patients with undiagnosed butyrylcholinesterase deficiency, and minimize complications.