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Uncommon Events May Be More Common Than You Think

Kopman, Aaron F. MD

doi: 10.1213/XAA.0000000000000570
Case Reports: Editorial

Accepted for publication April 14, 2017.

Funding: None.

The author declares no conflicts of interest.

Address correspondence to Aaron F. Kopman, MD, 19970 Sawgrass Ln, Unit 4102, Boca Raton, FL 33434. Address e-mail to

As far back as 2001, there has been an editorial call for the mandatory use of qualitative neuromuscular monitors (peripheral nerve stimulators [PNS]) whenever a nondepolarizing relaxant is administered1 and by 2003, the routine use of quantitative or objective monitors (devices that could display the train-of-four [TOF] ratio in real time) was advocated.2 These suggestions have been largely ignored by many practicing anesthetists. Certainly, the latter recommendation is not widely followed. A recent but cursory literature search by the present author unearthed 7 editorials and 11 review articles published within the last 5 years in major anesthesia journals that reiterate the need for routine perioperative neuromuscular monitoring. Why then another editorial on this subject?

This issue of A&A Case Reports contains a report of 2 cases from the University of Iowa3 of unusual sensitivity to rocuronium in “normal” healthy individuals. It is not exactly breaking news that there is wide variability in the response to nondepolarizing blocking agents in the general population. As the authors note, 50 years ago, Katz4 observed that 0.10 mg/kg d-tubocurarine (about 20% of its ED95) in some individuals produced 100% block, while in others, this dose had no discernable effect on the indirectly evoked twitch height. The present communication deserves attention because it demonstrates the value of routine objective monitoring of neuromuscular function in the day-to-day practice of anesthesia. It comes from an institution with extensive experience with the intraoperative use of electromyographic monitoring.5 In both patients, neuromuscular function was monitored and recorded continuously from induction of anesthesia or shortly thereafter through return of the TOF ratio to control values. In 2014, this department of anesthesiology reported that quantitative monitoring of the TOF ratio was used to assess the need for reversal of residual neuromuscular block in >90% of their cases.

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Objective monitoring of neuromuscular block serves a function beyond giving immediate guidance as to the need for relaxant dose adjustment and/or reversal of residual block. It has a pedagogical effect as well. Routine use gives the clinician a better “feel” for the wide variability in patient sensitivity to neuromuscular blockers that is seen in every day practice.

This patient received an initial dose of 0.08 mg/kg rocuronium or about one half of an ED50 (0.016 mg/kg).6 Assuming an average slope of the dose-response curve (a gamma of 4.5), this would normally result in only about 4% or 5% twitch (T1) depression. This is not what transpired. We do not know the initial extent of twitch depression, but 17 minutes after drug administration, a TOF ratio of about 0.10 was recorded. Generally the fourth response to TOF stimulation returns at a T1 value of about 35%7 of control, so it is probable that this individual experienced more than 50% twitch depression. The coefficient of variation of the ED50 for most blocking agents approximates 25%.8 Thus, approximately 1 patient in 44 (2 SDs to the left) will be twice as sensitive to rocuronium as the average individual. Hence, because of the nonlinearity of the rocuronium’s dose-response curve, a patient 2 SDs more sensitive (an ED50 of 0.08 mg/kg) would experience 50% depression.

If one assumes that this patient exhibited this uncommon, but not rare, degree of neuromuscular sensitivity, the response to the second 0.08 mg/kg dose of rocuronium (100% twitch depression) should not be surprising. At a TOF ratio of 0.95, considerable nicotinic receptor occupancy still exists. The clinical implications of this are important. In a study now 20 years old, Kopman et al9 intubated 12 patients without relaxants and then under stable N2O—opioid anesthesia administered a small (0.025 mg/kg) dose of mivacurium, which produced an average T1 depression of 12%. A larger dose calculated to produce 95% T1 depression was then administered. After spontaneous recovery from this second dose to a TOF ratio of 0.95, a repetition of the initial dose (0.025 mg/kg) now produced 79% T1 depression, a 50% decrease in the estimated ED50. Thus, marked neuromuscular sensitivity combined with pre-existing receptor occupancy (in this case, a TOF ratio of 0.88) resulted in 0.08 mg/kg rocuronium achieving total twitch suppression.

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The patient described received a 0.70 mg/kg dose of rocuronium (based on ideal body weight). Neuromuscular recovery was somewhat delayed (time to a TOF count of 4 took 60 minutes, and absence of subjectively detectable fade [a TOF ratio of 0.40] took 2 hours). Under desflurane anesthesia, these intervals would probably not have raised any “red flags” in the absence of objective monitoring. However, for reasons not fully understood, further recovery in this individual was extremely slow. The elapsed time of spontaneous recovery from a TOF ratio of 0.40 to 0.80 was 7 hours. This was unlikely to be an artifact as neostigmine administration at the end of the procedure restored the TOF ratio to its initial value of 1.00. This unusual response to rocuronium was only identified because objective neuromuscular monitoring was “standard of care” in the authors’ department. At a TOF ratio of 0.40, most clinicians can no longer detect palpable or visual fade on TOF stimulation.10 Had this been a shorter case, in the absence of objective monitoring, there would have been a strong temptation to omit administration of a reversal agent once a reasonable interval (perhaps 30–60 minutes) had passed beyond the point where subjective fade could no longer be demonstrated. In this instance that would have resulted in the patient’s discharge to the postanesthesia care unit with a TOF ratio of 0.50, a clearly unacceptable level of residual weakness.11,12 It is for this reason that when quantitative monitoring is unavailable that routine reversal of residual block has been advocated even when subjective fade cannot be demonstrated.13 At least 2 recent (2015) editorials thus argue for the mandatory use of quantitative monitoring whenever a neuromuscular blocking drug is administered.14,15

Nevertheless, despite these repeated exhortations to implement quantitative monitoring, this practice is still widely ignored. In part, this no doubt reflects the fact that available devices are not ideal. When the arms/hands are not accessible to the clinician, acceleromyography may prove to be impractical. Also, to the best of my knowledge, there are no commercially distributed free-standing battery-operated electromyographic monitors on the market. However, an additional impediment to widespread adoption of routine monitoring needs to be recognized. Many if not most professional organizations such as the American Society of Anesthesiologists (ASA) have turned a blind eye to the importance of perioperative monitoring of neuromuscular function.16 The 2013 Practice Guidelines for Postanesthetic Care17 by the ASA states that “Assessment of neuromuscular function primarily includes physical examination and, on occasion, may include neuromuscular blockade monitoring.” The ASA’s Standards for Basic Anesthetic Monitoring (amended in 2010 and affirmed in 2015) makes no mention of the need for neuromuscular monitoring.18 A recent and welcome exception to this apparent indifference comes from the Association of Anaesthetists of Great Britain and Ireland. Their guidelines for standards of monitoring during anesthesia19 include the following statements and recommendations:

  • A PNS is mandatory for all patients receiving a neuromuscular blocking drug.
  • While a “simple” PNS allows a qualitative assessment of the degree of neuromuscular blockade, a more reliable guarantee of return of safe motor function is evidence of a TOF ratio >0.9.
  • Anesthetic departments are encouraged to replace existing qualitative nerve stimulators with quantitative devices.

Finally, a follow-up report from Todd et al5 to their 2014 article adds a cautionary note.20 Simply equipping every operating room with objective neuromuscular monitors is an insufficient initiative if the benefits of routine monitoring are to be achieved. Purchasing and distribution of equipment must be accompanied with a sustained educational effort to familiarize staff with relevant issues such as the incidence of postoperative residual neuromuscular block, or the limitations of neostigmine as an antagonist of nondepolarizing block, and the clinical implications of TOF ratios <0.90. To cite the authors: “The continued failure by some of our providers to use the available technology also reinforces the difficulties in changing long-held, but dangerously erroneous, beliefs that such monitoring is unnecessary and/or that qualitative assessment of reversal is sufficient. Some users are unable or unwilling to diagnose and correct EMG signal acquisition problems and/or to distinguish artifacts from true EMG waveforms. Users may give up and simply not use the device at all or not trust the TOF values even when they are accurate.”

The benefits of quantitative monitoring (be it electromyography, acceleromyography, or kinemyography) are real, but each modality has its own learning curve and foibles. Most of us did not learn to ride a bicycle without acquiring a few scraped knees along the way. As with most new skills, the reward is worth the effort. E

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Name: Aaron F. Kopman, MD.

Contribution: This author reviewed the literature and wrote the manuscript.

This manuscript was handled by: Hans-Joachim Priebe, MD, FRCA, FCAI.

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