Residual neuromuscular weakness in the postanesthesia care unit secondary to nondepolarizing relaxants administered intraoperatively is common1–8 and is a potentially serious patient safety issue.9,10 Expert consensus is that patients given neuromuscular blockers should receive neuromuscular monitoring; that use of a quantitative train-of-four (TOF) monitor (which measures and displays the TOF ratio in real time) is preferable to the use of a conventional nerve stimulator (that require the clinician to evaluate the evoked response by subjective means, i.e., visually or tactilely); and that if a conventional nerve stimulator is used (without objective TOF monitoring), a reversal drug (i.e., anticholinesterases) should be administered at the end of surgery.11
However, surveys12–14 of clinical practice in Europe suggest that neuromuscular blockers are often administered without proper monitoring. Surveys in Denmark,12 Germany,13 the United Kingdom,14 and Mexico15 have suggested that only 43%, 28%, 10%, and 2% of clinicians, respectively, routinely use neuromuscular monitors of any kind. No comparable study of clinical practice has been undertaken in the United States (US), but a recent US publication reported significant morbidity associated with underestimated residual neuromuscular weakness.16 If the incidence of postoperative residual muscle weakness is to be reduced significantly, we need a better understanding of clinicians' current use of neuromuscular blockers and perioperative neuromuscular monitoring.
To ascertain whether the perioperative management of neuromuscular blocking drugs differs between the US and Europe, we designed an Internet-based survey and distributed it via e-mail. At a time when changes in the use of reversal drugs are occurring,17,18 a better understanding of the clinical attitudes and practices in Europe and the US regarding neuromuscular blockers is needed to support efforts to improve clinical practice and patient safety.
After obtaining approval from the IRB at The University of Texas M.D. Anderson Cancer Center, we conducted an Internet-based survey among anesthesia practitioners in the US and Europe. Respondents gave their informed consent online before answering any questions. The Anesthesia Patient Safety Foundation (APSF) and the European Society of Anaesthesiology (ESA) e-mailed all of their active members on our behalf, inviting them to anonymously answer a brief series of questions (Appendix 1: Neuromuscular Surveys, see Supplemental Digital Content 1, http://links.lww.com/AA/A34) on a dedicated website (http://www.nmjuncture.com/). The electronic link was provided in the invitation message. A survey announcement was also published in the Anesthesia Patient Safety Foundation Summer 2008 Newsletter. The survey questionnaires were developed and assessed by all investigators. The same set of questions (except for minor word variations) was used for both the US and European participants; however, the 2 groups were assigned 2 separate Internet links (http://www.nmjuncture.com/usasurvey/usasurvey.html and http://www.nmjuncture.com/eusurvey/eusurvey.html).
No open-ended questions were included in the survey. All questions were formatted into a Hypertext Mark-up Language interface, and the survey questionnaire was designed to be completed in <5 min. Possible responses were listed for each question on the monitor, and participants interactively selected their choices. Participants could choose to complete the survey in 1 session or during >1 visit to the website, but the site was Internet Protocol address–sensitive: once a respondent completed the survey, he or she was not able to submit answers again. The acquired data were stored electronically in 2 separate customized databases, 1 for the US survey and 1 for the European survey. The survey was available online for 60 days.
The goal of our study was to determine the use of, and the attitudes about the use of, neuromuscular blocking drugs and neuromuscular monitoring in 2 cohorts of anesthesia practitioners: those in the US and in Europe. Frequency tables (including categorical percentages) and graphical representations were used to summarize the demographic data and the clinical survey details within each cohort of anesthesia practitioners. Individual clinical survey items were compared between the 2 cohorts using the χ2 test or Fisher's exact test. Logistic-regression models were used to estimate the associations between demographic characteristics (e.g., years since completing training) and respondents' attitudes about the criteria for adequate antagonism of residual neuromuscular blockade and safe tracheal extubation. All statistical analyses were performed using SAS version 9.2.0 (SAS Institute, Cary, NC), and graphs were generated by using Prism for Windows version 5.02 (GraphPad Software, La Jolla, CA).
At the time of this survey, 26,000 anesthesiologist members of the American Society of Anesthesiologists in the US had known e-mail addresses. On the basis of previously published surveys, we expected a response rate of approximately 28% (7300 US responses).13,15 With at least 1000 responses from each cohort (US and ESA members), we expected to have at least 80% power to detect a 6.4% difference between the 2 cohorts. For survey items with as many as 4 levels of categorical response, 1000 respondents from each cohort would afford us >80% power to detect a small effect size of 0.074.19 As a secondary analysis, categorical models including covariates to adjust for demographic factors (the demographic questions at the beginning of the questionnaire, Appendix 1, see Supplemental Digital Content 1, http://links.lww.com/AA/A34) were used to investigate cohort differences.
In the US, of the 22,108 e-mails sent on August 12, 2008, 4238 (19.2%) “bounced,” indicating an incorrect e-mail address. Thus, 17,870 e-mails were delivered successfully. Of these, 4464 messages were opened, and 1792 individuals responded to the survey (a response rate of 40.1%). If the total number of e-mails successfully delivered (including the 13,406 e-mails that were never opened by recipients) was considered the denominator, the response rate would have been 10.03% (1792 of 17,870 e-mails). The list of practice locations reported by US respondents is shown in Appendix 2 (see Supplemental Digital Content 2, http://links.lww.com/AA/A35).
The ESA sent 5604 e-mails to its members (4807 active members and 797 trainees) and 844 responded to the survey. Thus, the response rate in Europe was 15.06%. However, in this dataset, 84 respondents reported a practice location outside of Europe and 21 did not report a practice location (Appendix 3: Practice Locations Reported in the European Data Set, see Supplemental Digital Content 3, http://links.lww.com/AA/A36). For that reason, the analysis was based on the remaining 739 respondents from Europe.
The demographic characteristics of the respondents are summarized in Table 1. Twenty-eight percent of the US respondents practiced at a university hospital, compared with 49% of the European respondents; and 22.1% of the US respondents practiced at a hospital affiliated with a university, compared with 30.6% of the European respondents (P < 0.0001). Thirty-seven percent of the US respondents indicated that there were >30 anesthesiologists in their department compared with 46.4% of the European respondents (P < 0.0001).
Respondents' observations and beliefs regarding the incidence and public health effects of postoperative residual paralysis and the potential of neuromuscular monitoring to decrease this problem are presented in Figure 1. A higher percentage of US respondents (88.1%) than European respondents (78.6%) had never observed patients in the postanesthesia care unit with residual neuromuscular weakness after intraoperative administration of a muscle relaxant (P < 0.0001). Respondents from the US were more likely than their European counterparts to estimate that the incidence of clinically significant postoperative residual neuromuscular weakness was <1% (64.1% vs 52.2%, respectively; P < 0.0001). Similar proportions of respondents from the US (77.7%) and Europe (75.2%) (P = not significant) believed that postoperative residual weakness was a significant anesthetic complication, and this was true regardless of the respondents' years of experience (odds ratio = 1.2; 95% confidence interval [CI], 0.96–1.45, adjusted for years since completing training). European respondents were 40% more likely than were US respondents to believe that routine use of a conventional nerve stimulator or quantitative TOF monitoring would decrease the incidence of postoperative residual paralysis after adjusting for years since completion of training (odds ratio = 1.4; 95% CI, 1.1–1.8; P = 0.007).
Data on the availability and use of neuromuscular monitoring are presented in Table 2. Significantly more European respondents (70.2%) than US respondents (22.7%) indicated that they had access to quantitative TOF monitors (P < 0.0001) (Table 2). However, when TOF monitors were available, they were more likely to be distributed 1 per operating room (vs 1 per 2, 3, or more operating rooms) in the US (71.4%) than in Europe (44.5%). Among institutions with both quantitative TOF monitors and conventional nerve stimulators, European clinicians were more likely than were US clinicians to routinely use quantitative TOF monitors alone (53.2% vs 18.8%, respectively), and US clinicians were more likely than their European counterparts were to routinely use conventional nerve stimulators alone (63.2% vs 17.1%, respectively). Of the respondents, 19.3% of those practicing in Europe and 9.4% of those practicing in the US reported that they did not routinely use a neuromuscular monitor in their practice.
Data on the availability and use of various neuromuscular blockers and reversal drugs are presented in Table 3. For example, the table shows that succinylcholine was still being used in both Europe (85.8%) and the US (92.8%) to facilitate tracheal intubation. The significantly lower rate of mivacurium use in the US reflects its lack of availability for clinical use. Additionally, most of the respondents from Europe (82%) and the US (65.8%) reported that they did not routinely administer an anticholinesterase at the end of surgery after a nondepolarizing relaxant (P < 0.0001). The positive association between years of experience and the use of an anticholinesterase was particularly evident among US respondents (odds ratio = 2.4; 95% CI, 1.9–3.0; P < 0.0001), especially among those who had 16–20 yr of experience (P = 0.0178) and regardless of the type of institution with which they were affiliated.
Moreover, 24.2% of European respondents compared with only 7.9% of US respondents completely omitted a reversal drug in most (76%–100%) of their patients (odds ratio = 2.6; 95% CI, 2.2–3.2; P < 0.0001), and these differences between European and the US respondents were even more pronounced among those who had 11–15 yr of experience (odds ratio = 1.9; 95% CI, 1.4–2.5; P = 0.0176) and those who were practicing at university hospitals (P = 0.0001) (Table 3). No reversal drugs were used in the practices of 2.7% of European respondents or in 0.2% of US respondents (Table 4). The respondents who reported not using a reversal drug after the use of a nondepolarizing neuromuscular blocker reported several factors that they considered relevant in making their decision (Table 3).
The respondents' attitudes about the criteria for the adequacy of neuromuscular recovery and safe tracheal extubation are summarized in Table 4. Most respondents from both Europe (77.7%) and the US (78.5%) agreed that a sustained response to 50-Hz tetanic stimulation did not exclude the presence of residual neuromuscular weakness. Significantly, more respondents from the US (68.2%) than from Europe (43.5%) (odds ratio = 2.7; 95% CI, 2.32–3.2; P < 0.0001) reported that clinical signs (such as the ability to sustain a 5-s head lift) were reliable indicators of the adequacy of neuromuscular recovery (Table 4), and this trend was especially pronounced among those who had 6–10 yr of experience (P = 0.03) and those practicing at university hospitals (P = 0.005).
There was wide divergence in opinion with respect to the question “In your view, at what TOF count would neostigmine produce reliable and rapid reversal?” (Table 4). With respect to the neostigmine dose, most respondents from Europe (60.4%) administered a dose of 2.5 mg, whereas half of the respondents from the US (49%) administered this drug on a milligram per kilogram basis rather than a fixed 2.5-mg dose. Most respondents from both Europe (83.7%) and the US (86.2%) reported concerns about the adverse effects of anticholinesterases and antimuscarinic drugs. Significantly more respondents from the US (78.9%) than from Europe (57.1%) reported that the TOF ratio should be in the 91%–100% range before tracheal extubation (odds ratio = 2.5; 95% CI, 2.1–3.1; P < 0.0001, based on the proportional odds model and adjusted for years since completing training) (Table 4). Most respondents from both Europe and the US did not believe that either conventional nerve stimulators or quantitative TOF monitors should be part of minimal monitoring standards.
The first neuromuscular blocking drug, d-tubocurarine, was introduced into the anesthesiologist's armamentarium >6 decades ago,20 but little information was available to the clinician at that time about the depth of neuromuscular block or the adequacy of recovery. In 1953, Morris et al.21 accurately reflected the best clinical advice of that period: at the end of surgery, small doses of an anticholinesterase were administered until “ventilatory exchange seemed improved, and additional doses administered at 5 min intervals achieved no detectable change for the better.” In 1958, Christie and Churchill-Davidson22 suggested that the indirectly evoked mechanical response to nerve stimulation might prove to be a useful clinical tool in the diagnosis of prolonged apnea after the use of muscle relaxants, and they described a small battery-powered peripheral nerve stimulator that they used for this purpose. By 1965, an editorial in Anesthesiology23 opined, “The only satisfactory method of determining the degree of neuromuscular block is to stimulate a motor nerve with an electric current and observe the contraction of the muscles innervated by that nerve.”
More than 40 yr later, as indicated in our survey, there is little agreement about “best practices” in the use of neuromuscular blocking drugs, their reversal drugs, or the monitoring of depth of neuromuscular blockade. This survey gives credence to the notion that many clinicians (21.4% of European and 11.9% of US respondents) have witnessed significant patient weakness in the recovery room associated with the residual effects of neuromuscular blocking drugs. However, it is disappointing that 50 yr after peripheral nerve stimulators were first suggested as aids in monitoring neuromuscular function, many clinicians do not want to include these stimulators as part of their minimal monitoring standards. This is perhaps to be expected, as the utility of these instruments is still being discussed.24,25
Our survey results confirmed that there are differences between US and European clinicians in the perioperative management of neuromuscular blockade. Routine reversal of residual neuromuscular block is less common in parts of Europe than in the US, yet Europeans are less likely to have witnessed postoperative residual paralysis; perhaps they have not looked for it. In the US, however, quantitative monitors for neuromuscular block are less likely to be available.
Our results suggest that anesthesia providers have very different opinions about the best way to clinically demonstrate adequate recovery from neuromuscular block. One example is the lack of agreement about the 5-s head lift as an indicator of adequate neuromuscular recovery. Ninety percent of US respondents answered that the TOF ratio should be 0.8 or more before tracheal extubation, yet almost 70% (but only 44% of European respondents) also believed that a 5-s head lift was a reliable indicator of adequate recovery26; the latter premise is no longer considered correct. El Mikatti et al.,27 in a study of 7 awake volunteers given small increments of pipecuronium, reported that at an electromyographic TOF ratio of 0.5, 6 of the 7 volunteers could still sustain a 5-s head lift, and that at a TOF ratio of 0.6, this test was accomplished by all 7 volunteers. Englbaek et al.28 found that the head lift was somewhat more sensitive to residual weakness but still reported that 8 of 16 patients could perform a 5-s head lift at a TOF ratio of 0.6. Thus, there may be considerable residual weakness despite the ability of a patient to “pass” the most widely cited bedside test of clinical recovery, the 5-s head lift.26
We realize that our study had limitations, such as the response rate. Our survey consisted of only 1 set of e-mails that was sent to clinicians; no reminders or follow-up e-mails were sent to avoid complaints from recipients about “spam” mail and to comply with the Federal Trade Commission's rules under the Controlling the Assault of Non-Solicited Pornography and Marketing Act of 2003.* Of the 4464 e-mails that were opened (and presumably read) by US recipients, we received 1792 completed surveys, resulting in a response rate of 40.1%. This figure compares favorably with another reported figure of 29.9%.29 Our survey was voluntary and anonymous, not designed to ascertain the identities of the responders. Therefore, respondent selection bias cannot be excluded, although the physician population (anesthesiologists from each of the 50 US states) was likely to have been heterogeneous.
A second limitation was that we did not ask, “What is the TOF ratio at which one can reliably detect the presence of fade by palpation of the thumb?” The answer, however, has been reported, and we know from a previous study that the ability to reliably detect fade is lost at a TOF ratio of approximately 0.4.30 Thus, clinicians may incorrectly believe that reversal of residual block is unnecessary once all 4 TOF responses are subjectively equal (despite the actual TOF ratio being as low as 0.4).
A third limitation was that we should have asked whether a conventional peripheral nerve stimulator and/or a quantitative (objective) TOF monitor were available in every operating room. Thus, our finding that only 38% of European respondents stated that conventional peripheral nerve stimulators were available in each operating room does not necessarily indicate that no neuromuscular monitor was present; a quantitative TOF monitor may have been available instead.
A fourth limitation was that we were not more specific when we asked which quantitative monitors were available in the practitioners' departments. Of US respondents who stated that quantitative TOF monitors were available, 44.8% also stated that they used a unit other than the TOF-Guard, TOF-Watch, or Datex NMT. We were unable to determine which monitors the respondents were referring to, but we suspect that they may have misunderstood the difference between a nerve “stimulator” and a (quantitative) “TOF monitor.”
A further limitation of our study was that it was underpowered to identify significant regional differences in attitudes and practices related to neuromuscular monitoring and reversal of residual block. We had, for example, only 26 responses from France, 20 from Italy, and 60 from Germany (Appendix 3: Practice Locations Reported in the European Data Set, online supplementary content). This could be attributable to the fact that the survey was available only in the English language. However, from Denmark, a much smaller country with a considerable scientific interest in this subject,4,30,31 we received 113 responses.
Nevertheless, comparison of our findings with results from other studies indicates that there are regional differences. A survey of Danish anesthesiologists12 indicated that 85% of respondents had access to a quantitative monitor of neuromuscular function, whereas only 22% of US respondents claimed to have access to these devices. In our study, only 18% of the European respondents routinely administered anticholinesterases when a nondepolarizing relaxant had been used. Similarly, in a survey of German anesthesiologists (n = 574), only 25% of respondents routinely reversed residual block with neostigmine.13 The incidence of failure to reverse residual block was even <25% in central Europe. In contrast, approximately 90% of the Danish anesthetists in our survey routinely administered neostigmine if a nondepolarizing blocker had been given; in Denmark, extensive education on neuromuscular monitoring is provided regularly.
Finally, institutional differences within a country may also vary widely according to their interest in this subject. A personal communication with Dr. Rajinder K. Mirakhur on May 7, 2009, from the Department of Anesthetics and Intensive Care Medicine, The Queen's University of Belfast in Northern Ireland, which has a longstanding research interest in neuromuscular pharmacology, indicated that 90%–95% of the department's staff routinely administer acetylcholinesterase antagonists, whereas our survey results for the United Kingdom suggested that the overall incidence in this country is <30%.
The specialty of anesthesiology has historically been an early adopter of new technology. For example, pulse oximetry, capnography, and end-tidal anesthetic gas analysis all rapidly became standards for patient monitoring, despite relatively high initial acquisition costs. Thus, the fact that not even conventional peripheral nerve stimulators have achieved universal acceptance is intriguing. It has been shown that the incidence of residual weakness in postoperative patients is 33%–64%,1,2,32 and that the incidence of critical respiratory events related to the administration of nondepolarizing relaxants is approximately 0.8%.16 Thus, it is possible that as many as 112,000 patients annually in the US are at risk of adverse events associated with undetected neuromuscular blockade.10 To contrast this relatively frequent occurrence with another well-recognized (but rare) event, the incidence of malignant hyperthermia is about 1 case per 5000–65,000 anesthetics† (approximately 1300 cases per year in the US, or a frequency 100 times less than that of residual paralysis); however, few hospitals would find it acceptable to not have a malignant hyperthermia cart and dantrolene readily available, and no hospital without these precautions in place would be deemed certifiable by government agencies. This suggests that much rarer life-threatening events receive far more attention and better support than does residual paralysis.
It is clear that despite the voluminous literature published on the subject of neuromuscular monitoring and postoperative residual neuromuscular block, considerable confusion remains within the anesthesia community about the proper clinical use of muscle relaxants. Three-quarters of responders reported postoperative residual weakness as a significant anesthetic complication, and at least 20% of responders believed that the incidence of residual weakness in their institution was >1% (Fig. 1). Although moderate residual weakness on admission to the postanesthesia care unit after the administration of nondepolarizing relaxants is not uncommon, the incidence of adverse consequences is still poorly documented and probably quite low.33 Relaxant-related complications, when they do occur, may easily be attributed to other perioperative factors, such as hypoxia, hypercarbia, hypoventilation, acidosis, and administration of other drugs (e.g., narcotics, antibiotics). However, undetected postoperative residual weakness clearly has the potential to increase postoperative morbidity,16,31,34 and there is growing evidence that the risk of adverse respiratory events during early recovery from anesthesia can be reduced by quantitative monitoring.4,5,35,36
Almost 70 yr after the introduction of d-tubocurarine into the anesthesiologist's armamentarium, 10%–20% of clinicians still see no need to monitor the evoked response to indirect nerve stimulation in the perioperative period. The remaining 80%–90% often do so with instruments poorly designed for the task. In the absence of “official” guidelines from professional organizations, we do not expect current clinical attitudes toward monitoring to change. We recommend that professional organizations develop formal training and publish official guidelines on best practices for perioperative neuromuscular monitoring. Such efforts should help to reduce the incidence of undetected postoperative neuromuscular block and reduce patient morbidity.
New reversal options (such as sugammadex encapsulation of rocuronium or vecuronium) or cysteine adduction of asymmetrical fumarates37 are promising alternatives. They will not, however, obviate the need for intelligent monitoring of neuromuscular function. The correct dose of sugammadex, for example, is a function of the extent of existing neuromuscular block.38 These alternatives are likely to remain only partial and insufficient solutions; incomplete reversal of neuromuscular block will remain a problem until all clinical care involves use of neuromuscular blocking drugs that have well-documented, specific, reliable, and completely effective antagonists.17,18
The authors gratefully acknowledge the cooperation of the Anesthesia Patient Safety Foundation and the European Society of Anaesthesiology for inviting their members to participate in this survey.
* http://www.ftc.gov/opa/2008/05/canspam.shtm—“FTC approves new rule provision.” Accessed December 7, 2009.
† Malignant Hyperthermia Association or the United States (MHAUS). Available at: http://www.mhaus.org/index.cfm/fuseaction/OnlineBrochures.Display/BrochurePK/8AABF3FB-13B0–430F-BE20FB32516B02D6.cfm. Accessed May 27, 2009.
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