Neostigmine: You Can’t Have It Both Ways

We read the recent study by Sasaki et al.¹  with interest but were confused by its clinical take-home message (or lack thereof). This article represents the logical extension of previous work by Eikermann and coworkers, which states that “… neostigmine and qualitative neuromuscular transmission monitoring did not mitigate the increased risk of postoperative respiratory complications linked to the use of non-depolarizing neuromuscular blocking agents. Furthermore, neostigmine may [adversely] affect postoperative respiratory function…”^2,3  In their current study, the authors conclude “Neostigmine reversal … was associated with increased atelectasis. High-dose neostigmine or unwarranted use of neostigmine may translate to increased postoperative respiratory morbidity.” We find the authors’ discussion highly unbalanced. They spend considerable time reviewing the well-known limitations of neostigmine as an antagonist of moderate to deep neuromuscular block but essentially ignored the clinical reality that for those clinicians who do not have access to sugammadex, neostigmine represents a valuable and necessary addition to our armamentarium.

In a prominent place under the heading What This Article Tells Us That Is New is the statement “Neostigmine reversal did not reduce signs and symptoms of postoperative respiratory failure, and was associated with an increased incidence of atelectasis.” We think this message may be easily misinterpreted by the naïve reader. At the end of surgery when the train-of-four (TOF) count has returned to three palpable responses or four with fade, do the authors imply that the risks of neostigmine administration outweigh its benefits? We would hope not.

In addition, we find several aspects of the protocol of authors problematic. For example, the authors define unwarranted use of neostigmine as “neostigmine administration in the absence of neuromuscular transmission monitoring or if the last documented TOF [train-of-four] before neostigmine administration was 0 of 4 twitches.” These are hardly comparable situations. It is certainly no surprise that attempted reversal of residual nondepolarizing block with neostigmine at a TOF count of 0 will result in slow and inadequate return of neuromuscular function. However, is neostigmine antagonism 45 to 60 min after rocuronium 0.60 mg/kg (in the absence of neuromuscular monitoring) unwarranted? Although we would agree that qualitative monitoring (at a minimum) should be universally used, we also know that this standard is far from generally practiced. Thus, we question automatically labeling neostigmine administration unwarranted in these circumstances. Certainly, at this point in time, the majority of patients will have TOF ratios less than 0.90, and perhaps 30% will have TOF ratios less than 0.70.⁴ 

Similarly, the authors lump all individuals who required reintubation within 7 days of surgery into one group. We do not think this is sensible. Furthermore, the incidence of postoperative pulmonary complications was taken from hospital billing records. Did the authors ever review the actual patient charts to examine these outcomes more closely?

More importantly, patients who received neostigmine were three times more likely to have had abdominal or thoracic surgery than were those who did not receive this drug. Thus, is it really a surprise that the incidence of atelectasis was higher in the neostigmine group? If the TOF ratios on admission to the postanesthesia care unit were identical and the incidence of postoperative residual neuromuscular block in both groups was also the same, to attribute an increase in pulmonary complications to neostigmine is unjustified when the case mixes were not identical. The authors present the association between the dose of neostigmine (0 to 60 vs. >60 μg/kg) and increased incidence of atelectasis and hospital length of stay in figs. 1 and 2, respectively. We wonder whether a similar association could be found by looking at the abdominal and thoracic surgery in relation to atelectasis and hospital length of stay.

Trying to extract a take-home message from this article is particularly difficult when it is read in the context of other investigations from Dr. Eikermann’s department. Sample conclusions: “upper airway obstruction frequently occurs during minimal neuromuscular blockade (TOF ratio 0.8), and extubation may put the patient at risk.”⁵ ; “The clinician should consider that post-operative recovery of the TOF ratio to 0.9 does not exclude an impairment of neuromuscular transmission.”⁶ ; “impaired neuromuscular transmission, even to a degree insufficient to evoke respiratory symptoms, markedly impairs upper airway dimensions and function.”⁷ ; “Minimal neuromuscular blockade markedly increases upper airway closing pressure... Increased airway collapsibility despite unaffected values for resting ventilation may predispose patients to postoperative respiratory complications.”⁸  These opinions suggest that this research group is quite concerned with the potentially adverse effects of even very modest levels of residual neuromuscular block on respiratory function and airway patency. The current authors need to explain how the preceding conclusions should be interpreted in relation to their current caveats regarding neostigmine. If one is apprehensive about the sequelae of even very shallow residual paralysis, then, for those clinicians without access to sugammadex, reversal with an appropriate dose of neostigmine⁹  should be routine. However, if concern about potential adverse respiratory effects of neostigmine is primary, we are at a loss as to how the authors would have the clinician proceed. A clearer clinical directive is called for. You can’t have it both ways.

The authors declare no competing interests.