We thank Drs. Phillips and Stewart for their interest in our article.1 The effect of neostigmine when given at the time neuromuscular recovery remains controversial, and Drs. Phillips and Stewart raise some important questions. We welcome the opportunity to respond to their queries.
We agree that we did not determine whether neostigmine induced depolarizing neuromuscular blockade. In order to assess this outcome measure, single twitch height must be recorded before and after muscle relaxant administration. In our clinical trial, we objectively evaluated muscle strength recovery by determining train-of-four ratios.1 No patient exhibited evidence of neostigmine-induced muscle weakness, as train-of-four ratios did not decrease in any subject. Both quantitative techniques (single twitch height and train-of-four ratios) are effective in objectively measuring muscle strength, and further studies are needed to assess the effect of neostigmine on single twitch height.
We also agree that standard clinical tests of signs of muscle weakness (5-s head lift) are unreliable in determining the presence of full neuromuscular recovery.2 However, we have previously determined that symptoms of muscle weakness (subjective feeling of difficulty performing the 5-s head lift) may be present when all clinical signs suggest full neuromuscular recovery has occurred, and may be more predictive of incomplete recovery.3,4 In our investigation, more symptoms of muscle weakness were present in the group randomized to receive saline, compared to neostigmine, which suggests that neostigmine did not produce clinical evidence of muscle weakness. We hypothesize that the reason that all patients were able to perform the 5-s head lift before extubation, and nine patients were unable to complete the test after admission to the recovery room, was related to the stimulation of an endotracheal tube at the time of extubation.
The peak effect of the neostigmine occurs 5 to 10 min after administration. This typically corresponds to the time of tracheal extubation. It would not be possible to conduct a comprehensive examination of patients for signs and symptoms of muscle weakness immediately before or after the removal of the endotracheal tube. This assessment was performed 15 min after postanesthesia care unit (PACU) admission, at a time when patients were sufficiently awake to cooperate with the research team. Given the duration of effect of neostigmine (typically 40 min or longer),5 we would likely have observed neostigmine-induced muscle weakness, if it were present, in the PACU. In contrast, patients who were administered neostigmine exhibited fewer symptoms of impaired neuromuscular recovery, compared to the control group. Furthermore, patients were carefully examined for any evidence of airway obstruction or hypoxemic events from the time of tracheal extubation until 30 min after PACU arrival. No clinical evidence of an adverse effect of neostigmine on airway function was observed. In fact, the incidence of hypoxemic events in the PACU was twice as high in the control-saline group.
Acceleromyography may recover slightly earlier than electromyography or mechanomyography. However, stand-alone electromyography and mechanomyography are no longer commercially manufactured, and acceleromyography is now considered the “gold standard” for clinical trials. As Drs. Phillips and Stewart note, some patients may have received neostigmine before full neuromuscular recovery had occurred, as documented with acceleromyography. However, many likely recovered hours before neostigmine was administered, since a small dose of rocuronium was given for induction and none thereafter; no clinical evidence of neostigmine-induced muscle weakness was observed in any of these subjects. In addition, as the authors note, two acceleromyography measurements made in the PACU may be discordant in awake patients; however, most of our acceleromyography assessments were performed in patients before emergence, and those measured in the PACU that differed by more than 10% were not recorded.
In our clinical investigation, with a careful examination of patients for adverse respiratory events and a thorough assessment for signs and symptoms of incomplete neuromuscular recovery, we were unable to detect any evidence of neostigmine-induced muscle weakness. Given the relatively high incidence of residual neuromuscular blockade observed in our study (21%), despite the low doses of rocuronium administered (25 mg) and long duration of cases (163 min), we believe our findings support the routine use of reversal agents, unless quantitative monitoring is used.
Dr. Murphy has received speaking fees and has served on the advisory board for Merck (Kenilworth, New Jersey). The remaining authors declare no competing interests.