Prolonged weakness after succinylcholine

A 55M presented to surgery for repair of the radial head by plate and screws. The patient was induced with 290 mg of propofol (pt weight ~115 kg), and 120 mg of succinylcholine with 250 mcg of fentanyl. The patient was maintained with desflurane in oxygen with 40 mg of rocuronium up front for relaxation. The case lasted for 2 hours. At the end of the case, anesthesia was discontinued and allowed to emerge. An ultrasound guided supraclavicular local anesthetic injection was done. A catheter was left in place for post op pain control. During this time, the patient continued to be minimally responsive. After evaluating the patient after the block for another 15 minutes and supporting his respiratory effort it was clear that the patient was not improving. Hypercarbia devleoped, the patient demonstrated significant upper airway obstruction and was non responsive now even to significant sternal rub. As there was concern for CO2 induced delayed emergence it was decided that reintubation was likely. However, mild residual neuromuscular blockade could not be ruled out as the patient had not received any reversal. Since the patient had not received additional rocuronium during the case and exhibited otherwise relatively good strength, it was considered necessary to only give a small dose. 1 mg of Neostigmine was given to no avail. The patients condition continued to worsen and his breathing became less forceful. At this point, 1 attempt at DL was made without muscle relaxation. This proved futile due to the patient's gag reflex. 100 mg of succinylcholine was administered, fasciculations were observed and intubation was completed. The patient was taken to the PACU intubated. The patients BP was also significantly elevated during this time. This was treated with labetalol. In the PACU, after 15 minutes had passed, a TOF was tested. The patient had 0 twitches. His was placed on mechanical ventilation and a propofol gtt. 2 hours later his train of four demonstrated a clear fade and was slowly returning. After 4 hours the patient woke up but by this time he had already been transferred to the ICU secondary to significant respiratory acidosis.

While it was clear in the PACU that this patient had a phase II block from the dose of succinylcholine, it was not initially clear what caused the original delayed emergence. Also curious was the prolonged duration of the phase II blockade.

The neuromuscular junction is important in anesthesia practice since we are often required to completely ablate all neuromuscular function. The acetylcholine (nAChr) receptor plays the dominant role in the neuromuscular juntion and is composed of 5 subunits. Two of this are alpha subunits, both of which must be occupied by acetylcholine in order for Na+ ions to be allowed to pass through the protein pore causing depolarization of the sarcolemma. Non depolarizing neuromuscular blockers can bind to the alpha subunit and thus compete with acetylcholine for the receptor effectively shutting down the ability for the muscle cell to depolarize. Succinylcholine on the other hand mimics acetylcholine because it is essentially two acetylcholine molecules hooked together. Succinylcholine, thus, binds to the alpha subunits of the receptor, causes an initial depolarization, but then due to the fact that it is not rapidly cleaved like acetylcholine is, it remains in place causing the cell to remain depolarized and thus paralyzed. This is what we refer to as a Phase I block. A phase II block may occur after the succinylcholine overwhelms the neurmomuscular junction by sheer numbers. After a time, the receptor itself undergoes changes which make it less susceptible to stimulation by acetylcholine. Clinically this will present with a fade on train of four with a twitch monitor which resembles the non depolarizaing muscle relaxants. At least two studies have found that a prolonged duration of succinylcholine resulting in a phase II block can be reversed by neostigmine. In both studies a phase II block was induced by a large dose (infusion) of succinylcholine. The dosages that will put the patient at risk for development of phase II block are in the area of 5 mg/kg. This suggests that the receptor and end plate are capable of being depolarized (and thus the cell had repolarized), but that a larger number of acetylcholine receptors were necessary. In my patient, he had received a single dose of succinylcholine followed by rocuroium from which he had recovered. Therefore, plasma cholinesterase deficiency (the enzyme responsible for degrading succinylcholine) was unlikely. He appeared to have some residual weakness from the rocuronium. This was apparent from pharyngeal muscle weakness. The pharyngeal muscles are more susceptible to neuromuscular blockers than many other muscles, and therefore, although your patient may appear to be strong, they may still obstruct if extubated with a mild even subclinical neuromuscular block. Therefore neostigmine 1 mg was administered. This did not help. Now, the neuromuscular junction was exposed to excessive acetylcholine. Furthermore, neostigmine has the secondary effect of inhibiting plasma cholinesterase. Thus, any succinylcholine administered will be degraded at a lower rate. There is one case report [3] published where a dose of neostigmine 2 hours prior to a dose of succinylcholine resulted in prolonged neuromuscular blockade. The published case report was similar to our situation in every way except three points. 1) The published case had renal insufficiency, 2) The dose of neostigmine was larger but given 2 hours prior not 5 minutes prior, and 3) The patient in the case report received two doses of neostigmine (total 5 mg) in an attempt to reverse the phase II block which caused the patient to develop severe (complete) neuromuscular blockade and go apneic. Fortunately, authors published the dibucaine number and plasma cholinesterase levels during the period of weakness and after recovery. During the period of weakness they found the dibucaine number to be 76% acutely (normal is > 80%) and 86% 24 hours later. No explanation is given for the improvement in the dibucaine number except that perhaps it was affected to a small degree by the neostigmine. However, the plasma cholinesterase level was 1.36 U/mL acutely (normal is 7 to 19 U/mL), but 10.48 U/mL after 24 hours. The authors conclude that the patient did not have a phase II block, (since it couldn't be reversed with neostigmine), but suffered from severe inhibition of plasma cholinesterase activity by neostigmine. The duration of weakness of their patient was about 3 hours from the dose of succinylcholine (this mirrors our time frame). However, in controlled clinical trials, neostigmine given prior to succinylcholine induces a weakness that is only about 35 min in duration [1]. It should be noted that careful measurements of plamsa (pseudo) cholinesterase activity in this study did show a 80% decrement in enzyme in plasma 5 min after neostigmine or pyridostigmine was administered. However, at full muscle recovery, plasma cholinesterase levels are still decreased by about 60% [1]. Therefore, giving neostigmine to a patient who has apparent clinical recovery from succinylcholine, may result in a prolonged block. These authors and others have found that while pyridostigmine reduces plasma cholinesterase levels to the same degree as neostigmine, the clinical prolongation of muscular relaxation is not as much as with neostigimie (23 min vs. 35 min). Thus, the prolonged neuromuscular block seen with anticholinesterase medications is not solely resulting from their inhibition of plasma cholinesterase enzymatic activity. This was made more apparent by Fleming et al. [2], when they compared edrophonium, pyridostigmine and neostigmine. They showed that while edrophonium did not decrease plasma cholinesterase, both pyridostigmine and neostigmine did decrease plasma cholinesterase activity. This group also showed that giving succinylcholine after edrophonium did not result in a prolonged block. However, if pyridostigmine or neostigmine were followed by succinylcholine, the block duration lasted about 18 min with pyridostigmine and 23 min after neostigmine. These data to not fit with the clinical scenario I encountered however. Furthermore, the authors in the studies cited do not indicate whether a phase II block developed or not. In the published case report cited [3], the authors ruled out a phase II block in their patient by virtue of the fact that it was not reversible with neostigmine. However, it is not clear to me that this fact is sufficient evidence to rule out a phase II block. The sine qua non of a phase two block is a TOF fade and evidence of posttetanic potentiation. It has been noted by some authors [4] that indeed patients with atypical plasma cholinesterase enzymes (or inhibited enzymes) will be more susceptible to a phase II block. It is speculated that the reason for this is excessive amounts of succinylcholine reaching the nAChR. Indeed, the vast majority of succinylcholine molecules are enzymatically cleared by plasma cholinesterase activity in normal patients. Therefore, if you give a standard dose of succinylcholine to a patient who has minimal functioning enzyme, then you might expect to develop a phase II block. However, the phase II block characteristics in this scenario may be different from that which develops when succinylcholine is given in a large dose over an long period of time (1 to 2 hours). The mechanism of a phase II block is not certain and there are 2 basic hypotheses. 1) channel blockade by succinylcholine molecules and 2) desensitization of the receptor in the presence of excessive agonists. A third hypothesis is distortion of the junctional membrane from excessive ion fluxes. In patients who receive a large dose of succinylcholine over a prolonged period, the mechanism might involve ion fluxes more than channel blockade. While, if a large influx of succinylcholine all at once occurs, as would be the case in someone who has severely inhibited plasma cholinesterase activity, then a phase II block may result, but the underlying mechanism may differ and thus, reversal with neostigmine (or other anticholinesterase may not be possible).

Still enigmatic however in the case presented is the fact that the dose of neostigmine (1mg) was very small relative to the patients body size (>100kg). The duration of block was greater than what should be expected given previous studies (about 35 min). If our patient had renal insufficiency this would be a could explanation for the prolonged duration of block as neostigmine is cleared by the kidneys. Some explanation for the somewhat enigmatic reaction seen in the above case described could be explained by other actions of anticholinesterases. Indeed, Flemming et al. [2] demonstrated that inhibition of plasma cholinesterase is only a partial explanation for the increased duration of succinylcholine after anticholinesterases. They showed that while pyridostigmine decreased measurable plasma cholinesterase to a much greater degree than did neostigmine, the duration of muscular blockade was shorter than after neostigmine. It is known for example that neostigmine has a direct depolarizing effect at the neuromuscular end plate (the others do not). Also, neostigmine has a very rapid onset (relative to the other anticholinesterases) and this could change the dynamics of a succinylcholine block.

In any case, given that edrophonium has been shown to not cause a prolonged block of succinylcholine (as well as to not inhibit plasma cholinesterase activity), a trial of reversal in the above scenario would have likely resulted in reduced chances for prolonged weakness.

1. Sunew KY et al. Effects of Neostigmine and Pyridostigmine on duration of Succinylcholine action and pseudocholinesterase activity. Anesthesiology. 1978; 49:188.

2. Fleming NW et al. Neuromuscular blocking action of suxamethonium after atagonism of vecuronium after edrophonium, pyridostigmine, or neostigmine. BJA. 1996; 77: 492.

3. Williams AR, et al. Marked Prolongation of the succinylcholine effect two hours after neostigmine reversal of neuromuscular blockade in a patient with chronic renal insufficiency. Southern Med Journal. 1999; 92(1): 77

4. Abel M. Depolarizing neuromuscular blockade. Clincal Cases in Anesthesiology. Reed A (ed.). Philadelphia, Churchill Livingstone, 3rd ed. 2005. p.117