Driving Residual Neuromuscular Blockade to Zero: Precision Matters

Professional practice guidelines and consensus statements developed during the last 10 years recommend the use of quantitative neuromuscular monitors (NMMs) when neuromuscular blocking (NMB) drugs are used.1–4 In the era of sugammadex, anesthesia providers may wonder why to use a more complex monitor when sugammadex is such an effective reversal agent unless an agent like atracurium is used? Advanced monitoring techniques are an interesting academic exercise but can be a nuisance in a busy clinical practical. This level of skepticism may present a significant hurdle to their widespread adoption. In this issue of Anesthesia & Analgesia, Thilen et al5 provide additional evidence that quantitative NMM may indeed be the best way forward in the realm of NMM even with the ready availability of sugammadex. With the growing popularity of personalized medicine, their work illustrates how NMB management is poised to be an exemplar of precision drug delivery that improves outcomes. NMB drugs are unique in that there is a direct measure of their effect. With considerable variability in the duration of effect from patient comorbidities, interactions with other medications, more accurate NMM would only improve NMB dosing precision to achieve or reverse desired drug effects. PRECISION THROUGH PROTOCOLS Thilen et al5 conducted 2 prospective single-center observational studies to evaluate 2 protocols for NMB management and reversal with neostigmine or sugammadex. One protocol guides reversal with qualitative NMM and the other with quantitative electromyographic (EMG) based NMM. Their results challenge assumptions regarding NMM and sugammadex and confirm quantitative NMM is worth using, THE QUALITATIVE NMM PROTOCOL All NMM measurements were made by visual assessment of movement at the adductor pollicis muscle. This protocol called for the administration of neostigmine for a train-of-four count (TOFc) of 4 with no appreciable fade and sugammadex for deeper levels of blockade.6 Selected results merit emphasis. Five patients (95% confidence interval, 1.0% to 7.0%) presented to the postanesthesia care unit (PACU) with residual NMB. Four had been reversed with neostigmine and one with sugammadex. In a setting, where investigators were on hand to answer questions and prompt anesthesia providers to use the protocol, residual NMB persisted. In addition, several patients were extubated before adequate reversal. How could that be? Do nerve stimulators perform that poorly? This was likely due to a limitation of qualitative NMM to distinguish between adequate reversal and shallow or minimal blockade based on visual observations. Clinicians may have assumed adequate reversal. Residual NMB can be difficult to detect with qualitative NMMs and can go undetected. THE QUANTITATIVE NMM PROTOCOL This protocol called for the administration of neostigmine for a TOFc of 4 with a train-of-four ratio between 0.4 and 0.9 and sugammadex for deeper levels of blockade.5 No reversal agent was judged necessary and there not administered to 33 patients; 66 and 90 patients were reversed with neostigmine and sugammadex, respectively. Again, selected results merit emphasis. There was no residual NMB regardless of the reversal technique. Not all patients required reversal. Some anesthesia providers may find withholding reversal too cavalier. Their mistrust of quantitative NMMs, especially newer EMG-based monitors, and their perception of little consequence to administering sugammadex even if the NMM indicates adequate reversal may compel them to ignore monitor output. Some patients were adequately reversed with neostigmine. Sugammadex has gained popularity and may have reduced the use of neostigmine in some centers. In the context of their quantitative NMM protocol, Thilen et al5 demonstrated how neostigmine can be an effective reversal agent and have a zero incidence of residual neuromuscular blockade. The authors reported significant cost savings when using neostigmine under appropriate conditions instead of administering sugammadex to all patients who received rocuronium. This compelling result illustrates how appropriate monitoring can improve value by achieving the same quality, zero residual neuromuscular blockade, at a reduced cost. MISLEADING ASSUMPTIONS Despite the superiority of quantitative NMM, clinicians remain slow to adopt it into routine practice. For decades, anesthesia providers successfully used nerve stimulators and neostigmine and considered them reliable and effective. Several assumptions and limitations may contribute to the point of view that with sugammadex, quantitative NMM is not necessary. One assumption is that the clinical consequences of residual NMB are rare. Large multicenter retro and prospective observational studies have explored the contribution of residual NMB to postoperative pulmonary complications suggesting this assumption may be flawed. In this body of work, patients undergoing general anesthesia with NMB have an almost unbelievably high rate (4% to 5%) of postoperative pulmonary complications.7–10 That 1 in twenty patients has a postoperative pulmonary complication is hard for a diligent anesthesia provider to concede. That residual NMB contributes to this high rate of pulmonary complication may even be more difficult to accept. In a reanalysis of data collected in a prospective multicenter investigation entitled "Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR)," investigators established that using quantitative NMM to ensure adequate reversal before extubation reduced the risk of postoperative pulmonary complications.7 Results from the Sugammadex versus Neostigmine for Reversal of Neuromuscular Blockade and Postoperative Pulmonary Complications (STRONGER) and Still STRONGER studies based on multicenter retrospective observational data found that choice of reversal agent dropped the frequency of postoperative pulmonary complications from 4.8% with neostigmine to 3.5% with sugammadex.9 A subset analysis of this data focusing on vulnerable patients found a drop from 5.9% with neostigmine to 2.6% with sugammadex.8 Vulnerable patients included those age >80 years, American Society of Anesthesiologist physical status III or IV, or surgeries lasting longer than 2 hours. These studies emphasize 2 points: (i) quantitative NMM reduces the risk of postoperative pulmonary complications and (ii) in vulnerable patients, poor pulmonary outcomes were likely associated with residual blockade in 1 of every 30 patients. If the prevalence of adverse outcomes is accurate, it is likely many anesthesia providers have cared for patients who develop this outcome. Clinicians may wonder if this were truly the case, why have not they been made aware of these complications in the patients they cared for? Another misleading assumption may be that the adverse impact of residual anesthetics is thought to be confined to the immediate postoperative period as the effects of anesthetics dissipate. The idea that residual effects contribute to postoperative pulmonary complications beyond the early recovery period is perhaps not adequately recognized by anesthesia providers to compel a change in practice. Selected pulmonary complications may manifest long after anesthesia care has ended. As an example, atelectasis may go undetected in the presence of supplemental oxygen but eventually lead to a postoperative pneumonia days after surgery.11 Furthermore, adverse synergistic interactions between anesthetics and NMB agents may contribute to this problem. Anesthetics, including opioids in the presence of NMB agents, synergistically depress carotid body responses to hypoxia even after acceptable reversal to a TOF ratio of 100%.12,13 These adverse conditions may be perceived as having nothing to do with anesthetic technique, but rather a preexisting patient condition or a consequence of the surgical procedure. Anesthesia providers may never learn about them. Another complication is a patient's perception of inadequate reversal as awareness under anesthesia. This phenomenon was described in the UK National Audit Project #5 exploring accidental awareness during general anesthesia.14 In this report analyzing 2.8 million anesthetics, when NMB drugs were administered, not monitored, nor reversed, there was an increased risk of accidental awareness. The postoperative adverse event information pipeline is perhaps too immature to provide meaningful feedback with enough emphasis to link them to anesthetic technique and in particular management of NMB. Perhaps quantitative NMM will not be fully embraced until warning systems become available that alert providers of adverse postoperative pulmonary complications in the presence of inadequate reversal. Another misleading assumption is that there is little downside to administering sugammadex. It is well known that sugammadex is a better reversal agent than neostigmine, but it may also better mask poor NMM technique. It has the potential to lull anesthesia providers into a false sense of confidence and erode their rigor and vigilance in proper NMM. To emphasize this point, consider work by Kotake et al.15 In a cohort of 117 patients reversed with sugammadex in the absence of NMM, they reported 5 (4%) patients had residual NMB. This compliments the finding by Thilen et al.5 One patient in 71 was found to have residual NMB after reversal with sugammadex guided by a nerve stimulator. Clearly, sugammadex is better at preventing residual NMB, but it does not eradicate it and qualitative NMM is not effective at catching all patients with residual NMB. LIMITATIONS OF QUANTITATIVE NMM Some clinicians find EMG-based quantitative NMM output to be inconsistent with their clinical assessment of the depth of NMB. Like other physiologic monitors, they fall subject to artifacts and improper placement. They can present misleading information that requires discernment to sort out. To build confidence in their output requires a working knowledge of their limitations. They are primarily a function of the muscles used to assess blockade and the ability to sense low voltage signals at the neuromuscular junction that detect shallow levels of blockade. The adductor pollicis muscle or other muscle groups innervated by the ulnar nerve are more accurate than the orbicularis oculi or corrugator supercilli muscles on the face. Facial muscles, however, are often used when the adductor pollicis is not available. Nevertheless, facial muscles overestimate blockade recovery and if used to guide reversal, can lead to unanticipated residual NMB. Quantitative measurements may indicate a deep blockade when other data suggest a moderate or shallow blockade. This discrepancy can be so compelling that anesthesia providers lose confidence in monitoring output. If voltage signals detected at the neuromuscular junction are below the device detection limit, the monitor will overestimate the depth of NMB. Profound or deep blockade will be displayed for much longer than anticipated. Low signal strength may be due to poor electrode placement or inadequate skin contact. Troubleshooting sources of signal quality will often improve signal detection. In addition, signal strength is more easily interpreted when a baseline assessment is made before the administration of an NMB drug. Adapting workflow to include the placement of an NMM sensor while placing other monitors before induction addresses this issue. NEXT STEPS Although the quantitative NMM protocol put forth by Thilen et al5 is straightforward to understand, a first step to maximizing its ability to drive the incidence of residual neuromuscular blockade to zero and reduce costs is to make available quantitative NMMs and both sugammadex and neostigmine in all operating rooms where NMB drugs are administered. It is important to acknowledge that the US patent protection for sugammadex ends in 2026. More affordable generic products may enter the market at that time. Another important step for quantitative NMM to become firmly established is a widespread education campaign that addresses misconceptions surrounding NMM and clinician proficiency in this monitor modality. Another step is to further the scientific foundation through research that confirms the relationship between residual NMB and postoperative pulmonary complications. In sum, to lower the frequency of poor outcomes related to residual NMB, precision in NMM matters. DISCLOSURES Name: Ken B. Johnson, MD. Contribution: This author helped prepare the editorial text. Conflicts of Interest: K. B. Johnson is an equity partner of Applied Medical Visualizations and Respiration AI, consultant to Haisco, Masimo, and Senzime, and provided professional services to IARS, ABA, ASA, and Epperson & Owens, P.C. This manuscript was handled by: Thomas M. Hemmerling, MSc, MD, DEAA.