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Anesthesia & Analgesia:
doi: 10.1213/ANE.0b013e318292ee3c
Editorials: Editorial

Reasoning of an Anomaly: Residual Block After Sugammadex

Naguib, Mohamed MB, BCh, MSc, FCARCSI, MD*; Brull, Sorin J. MD, FCARCSI (Hon.); Arkes, Hal R. BA, PhD

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From the *Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio; Department of General Anesthesia, Mayo Clinic College of Medicine, Jacksonville, Florida; and Department of Psychology, The Ohio State University, Columbus, Ohio.

Accepted for publication March 6, 2013

Funding: None.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Mohamed Naguib, MB, BCh, MSc, FCARCSI, MD, Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Ave., NE6-306, Cleveland, OH 44195. Address e-mail to naguibm@ccf.org.

“The greatest impediment to [knowledge] is the illusion of knowledge.”

—Daniel Boorstein (The Discoverers)

In this issue of Anesthesia & Analgesia, Kotake et al.1 report an unexpectedly high incidence of postoperative residual weakness after using sugammadex for antagonism of rocuronium-induced block in a nonrandomized study conducted at 5 university-affiliated teaching hospitals in Japan. This report represents a “real world” scenario in which anesthesiologists used neither a quantitative train-of-four (TOF) monitor (which measures and displays the TOF ratio in real-time) nor a conventional nerve stimulator (which requires the clinician to evaluate the evoked response by subjective means, i.e., visually or tactilely).

Kotake et al.1 report on 2 cohorts of patients who received a general anesthetic (sevoflurane or target-controlled infusion of propofol) and were managed according to routine clinical care at the discretion of the attending anesthesiologist. All patients received, on average, a total dose of approximately 1.2 mg/kg rocuronium to provide neuromuscular blockade over a mean surgical period of 170 minutes. Before the introduction of sugammadex in Japan, the authors studied the incidence of residual block after reversal with neostigmine (in a dose of approximately 33 µg/kg) in 1 cohort of 132 patients. When sugammadex became available clinically, the authors used it in a mean dose of 2.7mg/kg to antagonize rocuronium-induced neuromuscular block in a second cohort of 117 patients. The anesthesiologists subjectively judged the timing of “adequate recovery” in both groups without guidance from either conventional peripheral nerve stimulators or neuromuscular monitors.

The report, admittedly, has several methodological flaws, and the authors omitted important details in designing this study. However, the purpose of an accompanying editorial such as this one is to offer perspectives on what is deemed novel and clinically important, not to critique all flaws. As such, we will point out what we consider to be the most significant limitations, most of which are inherent to a nonrandomized, uncontrolled investigation, and will offer insights into the potential reasons why clinicians’ practices continue to ignore some well-studied and reported recommendations regarding perioperative neuromuscular monitoring.

It is not obvious why neostigmine administration was omitted in 23 patients (the authors labeled them as “spontaneous recovery group”), while every patient in the sugammadex group received the reversal drug (in other words, there was no comparable spontaneous recovery group in the latter patient cohort). Similarly, the criteria used to administer neostigmine or sugammadex were not defined, and the adequacy of recovery was based on clinical criteria; there is ample evidence to suggest that assessments based on clinical tests of muscle strength (e.g., head lift for 5 seconds, grip strength) are not reliable predictors of neuromuscular function.2–4 Postoperatively, TOF ratios were quantified using acceleromyography (TOF-Watch SX®; Organon, Roseland, NJ). The frequency of residual postoperative weakness after tracheal extubation, which the authors defined as a TOF ratio <0.9, was 13.0%, 23.9%, and 4.3% in the spontaneous recovery, neostigmine reversal, and sugammadex reversal groups, respectively. The corresponding incidence of TOF ratio <1.0 (considering the use of accelerographic monitor without prior calibration or normalization)3 was 69.6%, 67.0%, and 46.2%, respectively. These patients received on average a total dose of rocuronium of approximately 1.2 mg/kg over about 3 hours, the last dose of which was administered an hour before reversal. Therefore, it is inconceivable that 2 mg/kg sugammadex would fail to achieve adequate recovery in nearly 50% of the patients. Sugammadex 2 mg/kg effectively reverses a rocuronium-induced block at a TOF count of 2 in <5 minutes.5 The authors’ definition of “satisfactory recovery” is ambiguous, and it is difficult to reconcile why the incidence of postoperative residual block was similar in the neostigmine and spontaneous recovery groups. Despite these unanswered questions, these findings are clinically relevant and very important from a patient safety perspective because they show, yet again, that clinical criteria are inadequate for assessing neuromuscular recovery, and this practice is not unique to Japan but is universally prevalent.6,7

There is ample evidence in the literature indicating that failure to use a simple peripheral nerve stimulator to monitor, even subjectively, the degree of paralysis or adequacy of recovery is frequently associated with clinically significant muscle weakness, critical respiratory events, and delays in postanesthesia care unit (PACU) discharge.8–13 The first report in 1979 demonstrated that the use of long-acting neuromuscular blockers was associated with a 42% incidence of residual paralysis in the PACU.14 Once intermediate-duration agents became available, clinicians and researchers alike rejoiced at the prospect of using atracurium, vecuronium, cisatracurium, and rocuronium, in the hope of avoiding residual neuromuscular weakness. Unfortunately, our optimism was short lived. After the administration of an intermediate neuromuscular blocking drug, approximately 20% of patients arrived in the PACU with TOF ratios <0.70, and 40% arrived with TOF values <0.90.15–17 Even the introduction of a short-acting neuromuscular blocker (mivacurium) did not eliminate the problem of residual postoperative weakness.18

Clearly, the incidence of residual postoperative weakness is linked to the rate of clearance of the neuromuscular blocking drug from the neuromuscular junction and the fact that neostigmine has a ceiling effect in its ability to reverse a deep block. The promise of a new class of antagonist, the selective reversal binding agent sugammadex, again ignited renewed hope that residual paralysis would be a complication of the past. In fact, when used in appropriate doses, sugammadex has been shown to predictably antagonize any level of neuromuscular blockade induced by rocuronium and vecuronium.19 However, the current report confirms, once again, that failure to use, at a minimum, a peripheral nerve stimulator to guide the timing and/or dosing of sugammadex (or neostigmine for that matter) will result in significant residual neuromuscular weakness. In fact, the package insert for sugammadex clearly indicates that the dose of sugammadex should be calculated based on the TOF count (i.e., based on the depth of block determined with a nerve stimulator).20

From a pharmacoeconomic perspective, the authors’ argument that nerve stimulators were not used because of their high cost ($300–$600/unit) makes no economic sense, given the routine use of sugammadex (at a cost of approximately $100/dose). The authors’ approach to administer sugammadex to every patient (regardless of the depth of block) without using even a simple nerve stimulator to gauge its effects or help select the appropriate dose is, of course, questionable because of its ineffectiveness in ensuring adequate recovery in all patients.

Given the predictability of the reversal action of sugammadex (when used in appropriate doses), the report by Kotake et al.1 suggests that anesthesiologists might be tempted to administer larger and more frequent doses of rocuronium closer to the expected end of surgery than if they had used neostigmine. It is interesting to note that all patients with residual weakness had received approximately 2 mg/kg sugammadex. Given this reversal agent’s documented effectiveness and reliability (when used in doses based on evoked neuromuscular responses), this suggests that a higher dose (4 mg/kg) of sugammadex might have resulted in a better outcome, but at the price of doubling the cost of such therapy.

There is no question that this report has potentially significant clinical implications, given the importance of the questions it raises: why is monitoring of indirectly evoked muscle responses to nerve stimulation still not practiced routinely, despite the plethora of studies, review articles, editorials, and case reports attesting to the improved outcome when monitoring is practiced?7,21 Less devoted clinicians might argue that in today’s world of laparoscopic surgery the patient’s hands are frequently unavailable for neuromuscular monitoring. Although this emphasizes the need for a portable, battery-operated electromyographic monitor, it does not mean that anesthesiologists should refrain from using a peripheral nerve stimulator at other sites, as long as the limitations of facial muscle monitoring and potential confounding variables associated with this monitoring site are followed;22 alternatively, the stimulator could be placed along the ulnar nerve at the end of the surgical procedure (once the patient’s hand became available) to ensure adequate recovery of neuromuscular function before tracheal extubation.

Why, then, do we clinicians consistently fall short of implementing scientific facts (related to neuromuscular monitoring) to improve patient safety? And how can we clinicians achieve a plausible rationale (or understanding) of this anomaly? One reason why neuromuscular monitoring is not used routinely is that anesthesiologists think that they do not need it. They may feel confident that their knowledge and experience can provide highly accurate “intuitive” monitoring without any technical assistance. Such confidence has been tested among other medical specialties, and the results are illuminating. For example, Dawson et al.23 asked physicians to estimate a patient’s pulmonary capillary wedge pressure, systemic vascular resistance, and cardiac index before insertion of a right-heart catheter. One of the major goals of this research was to ascertain whether physicians’ estimates were more accurate when physicians assigned higher confidence to their estimates. If confidence and accuracy were highly related, then cardiologists could avoid cardiac catheterization and its associated risk of morbidity when they felt very confident in their estimates of hemodynamic parameters. The startling finding was that there was no relation whatsoever between clinicians’ confidence and their accuracy. It should be pointed out that the confidence physicians expressed in their estimates was significantly related to 1 factor: a physician’s level of experience. More senior physicians were more confident without being any more accurate. The Nobel Prize–winning psychologist Dr. Kahneman has coined this phenomenon, “the illusion of validity” in which “predictions were unrelated to the truth.”24 The conclusion of this research is that objective monitoring of hemodynamic functioning simply cannot be abandoned in favor of intuition. By analogy, compared with “intuitive” monitoring, objective neuromuscular monitoring is likely to result in substantially less postoperative residual weakness.

A second possible contributor to the underutilization of objective neuromuscular monitoring is that an individual physician may not have had (or may not be aware of) any patients who experienced a serious adverse outcome related to postoperative residual weakness.7,21 Therefore, physicians may think that neuromuscular monitoring is unnecessary. Very similar reasoning has been cited as the cause of why automobile drivers did not use seat belts in the era before their use was made mandatory. Slovic et al.25 showed that when people considered the minute probability that any single automobile trip would result in a serious injury, their interest in wearing seat belts was negligible. However, with appropriate education, people started considering the enormously higher probability that they would have a serious injury sometime during their lifetime of driving; thus, interest in wearing seat belts became drastically greater. Of course, no one knows which one of the approximately 40,000 lifetime automobile trips will be the one in which the use of a seat belt might prove to be vital. By analogy, the potential problems of residual neuromuscular block would be probably overlooked in many patients in the PACU since their physiological reserve would tolerate such insults. However, over a career of administering anesthesia, the probability that it will be crucial at some time is vastly higher. Because anesthesiologists are understandably concerned with their current case, they may well ignore the career-long statistics, both at their own and their patients’ peril.

A third possible reason for the reluctance to adopt neuromuscular monitoring is exemplified by the legal case of Dr. Merenstein.26 In 1999, Dr. Merenstein discussed with a male patient the potential benefits and harms of a prostate specific antigen (PSA) test. The patient opted not to have the test, but some years later, he was diagnosed with advanced, incurable prostate cancer. Dr. Merenstein and his practice were sued for malpractice. Although Dr. Merenstein was found not liable, his practice was found liable for $1 million. The plaintiff’s attorney successfully argued that giving a 53-year-old man a PSA test was the standard of care in Virginia, and 4 physicians testified that this was indeed the case. Dr. Merenstein’s reliance on evidence-based medicine was deprecated, and the research documenting the dubious overall benefit of the PSA test was ignored. Dr. Merenstein26 wrote, “In our legal system, the physicians who are slow to change are the winners” (p. 15). Thus, some physicians might decide that neuromuscular monitoring is not the “standard of care” in their venue, and reliance on their intuition is. This view would discourage any practitioner from being a “first mover,” a person who adopts a new technique or procedure that is not currently in general use in their community. The scientific evidence that the PSA test is not adequately predictive of prostatic cancer seemed not to be sufficiently convincing among the members of the jury considering Dr. Merenstein’s practice.

A fourth possible reason for the reluctance to adopt neuromuscular monitoring was suggested by Aberegg et al.,27 who compared physicians’ willingness to adopt beneficial therapies with their willingness to abandon harmful ones. Pulmonary and critical care physicians were randomized into groups and then shown data depicted in 1 of 2 ways: in the first group, a common treatment was shown to increase mortality compared with a placebo, although the common treatment did result in fewer specified harmful side effects. In the second group, a novel therapy was shown to decrease mortality compared with usual care, although the novel therapy did result in more specified harmful side effects. This design allowed for a direct comparison of the rates of adoption and abandonment of therapies based on precisely identical evidence. The results showed that the physicians were less than half as likely to change practice to adopt a beneficial therapy compared with abandoning a harmful one! By analogy, if neuromuscular monitoring were recognized by clinicians as beneficial, then the Aberegg et al.27 results would suggest that this quality might not be a sufficiently powerful factor to motivate a change in physician behavior.

Why is achieving benefits not valued as highly as shedding losses? According to prospect theory,28 losses have approximately 2 to 2.5 times as much psychological impact on people as gains of equivalent magnitude. Physicians have been trained to “do no harm,” which is consistent with the willingness of practitioners to eschew any harmful therapy. But, are we not potentially imposing harm on our patients by not monitoring the adequacy of recovery from neuromuscular blocking drugs? It may well be that until and unless every clinician personally experiences a complication in a patient as a result of residual neuromuscular block, the “benefit” of changing routine practice to perioperative objective monitoring will not be appreciated. Aren’t we, then, doomed to repeat history?

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RECUSE NOTE

Dr. Sorin J. Brull is the Section Editor for Patient Safety for the Journal. This manuscript was handled by Dr. Tony Gin, Section Editor for Anesthetic Clinical Pharmacology, and Dr Brull was not involved in any way with the editorial process or decision.

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DISCLOSURES

Name: Mohamed Naguib, MB, BCh, MSc, FCARCSI, MD.

Contribution: This author helped write the manuscript and approved the final manuscript.

Conflict of interest: Dr. Naguib has received honoraria and consulting fees from GlaxoSmithKline and Merck & Co., Inc.

Name: Sorin J. Brull, MD, FCARCSI (Hon.).

Contribution: This author helped write the manuscript and approved the final manuscript.

Conflict of interest: Dr. Brull is a consultant for Merck & Co., Inc., and partner in T4 Analytics.

Name: Hal R. Arkes, BA, PhD.

Contribution: This author helped write the manuscript and approved the final manuscript.

Conflict of interest: The author has no conflicts of interest to declare.

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REFERENCES

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