Neostigmine versus sugammadex: the tide may be turning, but we still need to navigate the winds

It is now well recognised that residual neuromuscular block in the recovery room is more common after neostigmine has been used as a reversal agent than after sugammadex.1Brueckmann B. Sasaki N. Grobara P. et al.Effects of sugammadex on incidence of postoperative residual neuromuscular blockade: a randomized, controlled study.Br J Anaesth. 2015; 115: 743-751Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar The pivotal question that still remains is whether this lower incidence of residual block after sugammadex can be translated into a lower incidence of postoperative pulmonary complications (POPCs) in the days following surgery. POPCs have a deleterious effect on clinical outcomes and healthcare costs,2Shander A. Fleisher L.A. Barie P.S. Bigatello L.M. Sladen R.N. Watson C.B. Clinical and economic burden of postoperative pulmonary complications: patient safety summit on definition, risk-reducing interventions, and preventive strategies.Crit Care Med. 2011; 39: 2163-2172Crossref PubMed Scopus (144) Google Scholar,3Khuri S.F. Henderson W.G. DePalma R.G. et al.Determinants of long-term survival after major surgery and the adverse effect of postoperative complications.Ann Surg. 2005; 242: 326-341Crossref PubMed Scopus (1004) Google Scholar and the use of neuromuscular blocking drugs during anaesthesia is associated with a higher incidence of POPCs. For example, Bulka and colleagues4Bulka C.M. Terekhov M.A. Martin B.J. Dmochowski R.R. Hayes R.M. Ehrenfeld J.M. Nondepolarizing neuromuscular blocking agents, reversal, and risk of postoperative pneumonia.Anesthesiology. 2016; 125: 647-655Crossref PubMed Scopus (96) Google Scholar found a postoperative pneumonia rate of 9.00 vs 5.22 per 10 000 in a propensity-matched cohort study of patients receiving neuromuscular blocking drugs vs those who did not. Determining whether neuromuscular blocking drugs and reversal agents contribute to POPCs is made more difficult by the use of various definitions to determine such complications. One of the earlier descriptions for a composite adverse respiratory outcome is based on a prospective cohort study from Spain in 2010 of 2464 adult patients undergoing diverse surgical procedures utilising different anaesthetic techniques and requiring at least a 1-day inpatient stay.5Canet J. Gallart L. Gomar C. et al.Prediction of postoperative pulmonary complications in a population-based surgical cohort.Anesthesiology. 2010; 113: 1338-1350Crossref PubMed Scopus (699) Google Scholar The definition included respiratory infection, respiratory failure, bronchospasm, atelectasis, pleural effusion, pneumothorax, or aspiration pneumonitis, and the overall rate of POPCs was only 5%. However, age >80 yr and duration of surgery >3 h increased the odds of POPCs by 5.1-fold (95% confidence interval 1.9–13.3) and 9.7-fold (95% confidence interval 4.7–19.9), respectively. New onset hypoxaemia in addition to clinical correlates for pulmonary complications were used in the more recent prospective pan-European observational study Postanaesthesia pulmonary complications after use of muscle relaxants (POPULAR),6Kirmeier E. Eriksson L.I. Lewald H. et al.Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study.Lancet Respir Med. 2019; 7: 129-140Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar in line with the Prospective Evaluation of a Risk Score for Postoperative Pulmonary Complications in Europe (PERISCOPE) study, which was undertaken in part to define a reproducible scoring system.7Canet J. Sabate S. Mazo V. et al.Development and validation of a score to predict postoperative respiratory failure in a multicentre European cohort: a prospective, observational study.Eur J Anaesthesiol. 2015; 32: 458-470Crossref PubMed Scopus (112) Google Scholar In the POPULAR study, the use of neuromuscular blocking agents was associated with an 8.6% incidence of POPCs, whereas the incidence was only 3.3% in patients who did not receive these agents.6Kirmeier E. Eriksson L.I. Lewald H. et al.Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study.Lancet Respir Med. 2019; 7: 129-140Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar Notably, no difference in the incidence of POPCs was detected between patients who had received neostigmine compared with sugammadex, nor between those managed with qualitative vs quantitative neuromuscular monitoring. However, only 6866 out of 17 150 patients who received neuromuscular blocking drugs received any kind of monitoring in the POPULAR study.6Kirmeier E. Eriksson L.I. Lewald H. et al.Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study.Lancet Respir Med. 2019; 7: 129-140Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar The seemingly logical progression of residual muscular weakness after extubation to POPCs has undoubtedly been difficult to demonstrate. Thus far, several meta-analyses have not found a difference in the incidence of severe POPCs based on whether neostigmine or sugammadex was administered.8Hristovska A.M. Duch P. Allingstrup M. Afshari A. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults.Cochrane Database Syst Rev. 2017; 8CD012763PubMed Google Scholar, 9Abad-Gurumeta A. Ripolles-Melchor J. Casans-Frances R. et al.A systematic review of sugammadex vs neostigmine for reversal of neuromuscular blockade.Anaesthesia. 2015; 70: 1441-1452Crossref PubMed Scopus (89) Google Scholar, 10Carron M. Zarantonello F. Tellaroli P. Ori C. Efficacy and safety of sugammadex compared to neostigmine for reversal of neuromuscular blockade: a meta-analysis of randomized controlled trials.J Clin Anesth. 2016; 35: 1-12Crossref PubMed Scopus (80) Google Scholar A recent small prospective randomised single-centre trial in 130 patients undergoing major abdominal surgery with combined general and epidural anaesthesia found no differences in pulmonary function in patients receiving sugammadex or neostigmine.11Alday E. Munoz M. Planas A. Mata E. Alvarez C. Effects of neuromuscular block reversal with sugammadex versus neostigmine on postoperative respiratory outcomes after major abdominal surgery: a randomized-controlled trial.Can J Anaesth. 2019; 66: 1328-1337Crossref PubMed Scopus (21) Google Scholar However, a quasi-experimental study in 7316 patients pointed to lower rates of adverse pulmonary outcomes after sugammadex.12Krause M. McWilliams S.K. Bullard K.J. et al.Neostigmine versus sugammadex for reversal of neuromuscular blockade and effects on reintubation for respiratory failure or newly initiated noninvasive ventilation: an interrupted time series design.Anesth Analg Adv. 2019; (Access Published November 5)https://doi.org/10.1213/ANE.0000000000004505Crossref Scopus (36) Google Scholar In the latter study, an interrupted time series design was utilised to assess the effectiveness of introducing sugammadex instead of neostigmine as the primary reversal agent for inpatients receiving muscle relaxation with rocuronium or vecuronium. The higher likelihood of a composite adverse respiratory outcome in the neostigmine group compared with the sugammadex group was driven by higher rates of starting noninvasive ventilation. Interestingly, in a recent Multicenter Perioperative Outcomes Group (MPOG) observational matched-cohort study including 12 US hospitals and 45 712 patients, reversal with sugammadex was associated with a 30% reduced risk of pulmonary complications compared with neostigmine.13Kheterpal S. Vaughn M. Dubovoy T. et al.Sugammadex versus neostigmine for reversal of neuromuscular blockade and postoperative pulmonary complications (stronger): a multicenter matched cohort analysis.Anesthesiology. 2020; (In press)Crossref Scopus (114) Google Scholar A challenge of comparing the results of these studies lies not only in the absence of a universal definition for POPCs, but also in the inherent differences in measuring outcomes retrospectively based on electronic health records as opposed to using a dedicated recorder in prospective studies, which also could influence the findings (Table 1).Table 1Sugammadex vs neostigmine and adverse respiratory outcomes: summary of studies discussed.StudyDesign, participantsPrimary outcomeInferenceTogioka and colleagues,14Togioka B.M. Yanez N.D. Aziz M.F. Higgins J.R. Tekkali P. Treggiari M.M. Randomised controlled trial of sugammadex and neostigmine for reversal of neuromuscular blockade on the incidence of pulmonary complications in older adults undergoing prolonged surgery.Br J Anaesth. 2020; (Advance Access published on March 2)https://doi.org/10.1016/j.bja.2020.01.016Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar 2020RCT, n = 200Composite of POPCNo significant effectAlday and colleagues,11Alday E. Munoz M. Planas A. Mata E. Alvarez C. Effects of neuromuscular block reversal with sugammadex versus neostigmine on postoperative respiratory outcomes after major abdominal surgery: a randomized-controlled trial.Can J Anaesth. 2019; 66: 1328-1337Crossref PubMed Scopus (21) Google Scholar 2019RCT, n = 130Forced vital capacity, one hour after surgeryNo significant effectKrause and colleagues,12Krause M. McWilliams S.K. Bullard K.J. et al.Neostigmine versus sugammadex for reversal of neuromuscular blockade and effects on reintubation for respiratory failure or newly initiated noninvasive ventilation: an interrupted time series design.Anesth Analg Adv. 2019; (Access Published November 5)https://doi.org/10.1213/ANE.0000000000004505Crossref Scopus (36) Google Scholar 2019Quasi-experimental, interrupted time series, n = 7316New noninvasive ventilation or re-intubation after surgeryFavours sugammadexKirmeier and colleagues,6Kirmeier E. Eriksson L.I. Lewald H. et al.Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study.Lancet Respir Med. 2019; 7: 129-140Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar 2019Prospective observational, logistic regression, n = 8796 (subgroup receiving any reversal agent)Composite of POPCNo significant effectKheterpal and colleagues,13Kheterpal S. Vaughn M. Dubovoy T. et al.Sugammadex versus neostigmine for reversal of neuromuscular blockade and postoperative pulmonary complications (stronger): a multicenter matched cohort analysis.Anesthesiology. 2020; (In press)Crossref Scopus (114) Google Scholar 2020Retrospective matched cohort design, logistic regression, n = 45 712Composite of POPCFavours sugammadexPOPC, postoperative pulmonary complication. Open table in a new tab POPC, postoperative pulmonary complication. In a recent issue of the British Journal of Anaesthesia, Togioka and colleagues14Togioka B.M. Yanez N.D. Aziz M.F. Higgins J.R. Tekkali P. Treggiari M.M. Randomised controlled trial of sugammadex and neostigmine for reversal of neuromuscular blockade on the incidence of pulmonary complications in older adults undergoing prolonged surgery.Br J Anaesth. 2020; (Advance Access published on March 2)https://doi.org/10.1016/j.bja.2020.01.016Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar report the results of another small single-centre prospective randomised assessor-blinded clinical trial comparing the use of neostigmine or sugammadex in 200 patients aged 70 yr or older who underwent surgery lasting at least 3 h. The primary outcome, POPCs, did not significantly differ between the two drugs. The definition of hypoxaemia in this study was stringent (patients with oxygen saturation <90% receiving new oxygen therapy after previously being weaned off oxygen) according to the established Spanish criteria.5Canet J. Gallart L. Gomar C. et al.Prediction of postoperative pulmonary complications in a population-based surgical cohort.Anesthesiology. 2010; 113: 1338-1350Crossref PubMed Scopus (699) Google Scholar However, Togioka and colleagues14Togioka B.M. Yanez N.D. Aziz M.F. Higgins J.R. Tekkali P. Treggiari M.M. Randomised controlled trial of sugammadex and neostigmine for reversal of neuromuscular blockade on the incidence of pulmonary complications in older adults undergoing prolonged surgery.Br J Anaesth. 2020; (Advance Access published on March 2)https://doi.org/10.1016/j.bja.2020.01.016Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar did find an 89% lower odds for residual neuromuscular block in the recovery room, and a lower hospital readmission rate in the sugammadex group, although as in some earlier reports this study was underpowered. These findings are in line with the concept that intraoperative anaesthetic management in general, and approaches to neuromuscular block and reversal in particular, have long-term implications that exceed the index hospitalisation.15Bose S. Xu X. Eikermann M. Does reversal of neuromuscular block with sugammadex reduce readmission rate after surgery?.Br J Anaesth. 2019; 122: 294-298Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The relatively high rate (36.5%) of the primary outcome in the study by Togiaka and colleagues14Togioka B.M. Yanez N.D. Aziz M.F. Higgins J.R. Tekkali P. Treggiari M.M. Randomised controlled trial of sugammadex and neostigmine for reversal of neuromuscular blockade on the incidence of pulmonary complications in older adults undergoing prolonged surgery.Br J Anaesth. 2020; (Advance Access published on March 2)https://doi.org/10.1016/j.bja.2020.01.016Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar is likely reflective of the high-risk population studied (based on age and duration of procedures), and in accordance with contemporary studies in high-risk populations, where a clinical approach with only qualitative monitoring techniques has been used.16Fernandez-Bustamante A. Frendl G. Sprung J. et al.Postoperative pulmonary complications, early mortality, and hospital stay following noncardiothoracic surgery: a multicenter study by the perioperative research network investigators.JAMA Surg. 2017; 152: 157-166Crossref PubMed Scopus (249) Google Scholar Inadequate reversal leading to residual neuromuscular weakness after tracheal extubation is a potential mechanism for the development of POPCs.17Cedborg A.I. Sundman E. Boden K. et al.Pharyngeal function and breathing pattern during partial neuromuscular block in the elderly: effects on airway protection.Anesthesiology. 2014; 120: 312-325Crossref PubMed Scopus (55) Google Scholar, 18Plaud B. Debaene B. Donati F. Marty J. Residual paralysis after emergence from anesthesia.Anesthesiology. 2010; 112: 1013-1022Crossref PubMed Scopus (159) Google Scholar, 19Vidal Melo M.F. Musch G. Kaczka D.W. Pulmonary pathophysiology and lung mechanics in anesthesiology: a case-based overview.Anesthesiol Clin. 2012; 30: 759-784Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 20Mirzakhani H. Williams J.N. Mello J. et al.Muscle weakness predicts pharyngeal dysfunction and symptomatic aspiration in long-term ventilated patients.Anesthesiology. 2013; 119: 389-397Crossref PubMed Scopus (54) Google Scholar Despite the importance of this issue for patient outcomes, anaesthetists seem to dismiss its relevance. In 2010, a report on 2636 survey responses from anaesthesia practitioners in Europe and the USA found that routine reversal was used by only 18% and 34% of cases, respectively, and 19% of European and 9% of US anaesthetists reported never using neuromuscular monitoring.21Naguib M. Kopman A.F. Lien C.A. Hunter J.M. Lopez A. Brull S.J. A survey of current management of neuromuscular block in the United States and Europe.Anesth Analg. 2010; 111: 110-119Crossref PubMed Scopus (235) Google Scholar In a more recent, rather disturbing, survey using nine true/false questions about reversal of neuromuscular block completed by 1629 anaesthesiologists from 80 countries, respondents correctly answered only 57% of the questions, yet 84% were confident in their grasp of the topic.22Naguib M. Brull S.J. Hunter J.M. et al.Anesthesiologists' overconfidence in their perceived knowledge of neuromuscular monitoring and its relevance to all aspects of medical practice: an international survey.Anesth Analg. 2019; 128: 1118-1126Crossref PubMed Scopus (39) Google Scholar These later findings are disappointing as they occur despite detailed guidelines on the perioperative use of neuromuscular monitoring that were issued as a consensus statement in 2018.23Naguib M. Brull S.J. Kopman A.F. et al.Consensus statement on perioperative use of neuromuscular monitoring.Anesth Analg. 2018; 127: 71-80Crossref PubMed Scopus (144) Google Scholar Muscular weakness secondary to overdosing of the reversal agent could be pertinent when neostigmine is used.24Sasaki N. Meyer M.J. Malviya S.A. et al.Effects of neostigmine reversal of nondepolarizing neuromuscular blocking agents on postoperative respiratory outcomes: a prospective study.Anesthesiology. 2014; 121: 959-968Crossref PubMed Scopus (109) Google Scholar To address the risk of inappropriate doses of neostigmine leading to pulmonary complications, effective quality improvement bundles that included neostigmine dosing tables to guide appropriate dosing based on the depth of neuromuscular block have been described.25Rudolph M.I. Chitilian H.V. Ng P.Y. et al.Implementation of a new strategy to improve the peri-operative management of neuromuscular blockade and its effects on postoperative pulmonary complications.Anaesthesia. 2018; 73: 1067-1078Crossref PubMed Scopus (21) Google Scholar Yet even after implementation of a protocol aimed at optimising the dose of neuromuscular blocking drug, with the dose of neostigmine based on a qualitative train-of-four-count, and requiring a 10-min wait between neostigmine administration and tracheal extubation, the incidence of postoperative residual neuromuscular block was unacceptably high at 35%.26Thilen S.R. Ng I.C. Cain K.C. Treggiari M.M. Bhananker S.M. Management of rocuronium neuromuscular block using a protocol for qualitative monitoring and reversal with neostigmine.Br J Anaesth. 2018; 121: 367-377Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar The rate of residual neuromuscular block after neostigmine vs sugammadex in the study of Togiaka and colleagues14Togioka B.M. Yanez N.D. Aziz M.F. Higgins J.R. Tekkali P. Treggiari M.M. Randomised controlled trial of sugammadex and neostigmine for reversal of neuromuscular blockade on the incidence of pulmonary complications in older adults undergoing prolonged surgery.Br J Anaesth. 2020; (Advance Access published on March 2)https://doi.org/10.1016/j.bja.2020.01.016Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar was 49% vs 10%, respectively. As the authors point out, the use of unnecessarily high doses of neostigmine (the protocol specified a neostigmine dose of 0.07 mg kg−1 of actual body weight with a maximum of 5 mg) may have contributed to the high rate of weakness observed. In contrast, under-dosing of the reversal agent may also constitute a driver for residual motor weakness, especially after sugammadex. The 10% rate of residual muscular weakness after sugammadex in the Togiaka and colleagues14Togioka B.M. Yanez N.D. Aziz M.F. Higgins J.R. Tekkali P. Treggiari M.M. Randomised controlled trial of sugammadex and neostigmine for reversal of neuromuscular blockade on the incidence of pulmonary complications in older adults undergoing prolonged surgery.Br J Anaesth. 2020; (Advance Access published on March 2)https://doi.org/10.1016/j.bja.2020.01.016Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar study was likely caused by administering insufficient doses, and underscores the need for quantitative monitoring even if sugammadex is chosen as the reversal agent.27Kotake Y. Ochiai R. Suzuki T. et al.Reversal with sugammadex in the absence of monitoring did not preclude residual neuromuscular block.Anesth Analg. 2013; 117: 345-351Crossref PubMed Scopus (130) Google Scholar Another criticism of the study by Togioka and colleagues14Togioka B.M. Yanez N.D. Aziz M.F. Higgins J.R. Tekkali P. Treggiari M.M. Randomised controlled trial of sugammadex and neostigmine for reversal of neuromuscular blockade on the incidence of pulmonary complications in older adults undergoing prolonged surgery.Br J Anaesth. 2020; (Advance Access published on March 2)https://doi.org/10.1016/j.bja.2020.01.016Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar is therefore the lack of quantitative monitoring to guide dosing of reversal drugs. Indeed, the authors acknowledge this issue. Yet, their study unfortunately reflects the reality of most patients undergoing surgery requiring neuromuscular block. For example, of the 17 150 patient subcohort in the European POPULAR study who received neuromuscular block, only 40% had any kind of neuromuscular monitoring, and just 24% had quantitative monitoring.6Kirmeier E. Eriksson L.I. Lewald H. et al.Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study.Lancet Respir Med. 2019; 7: 129-140Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar Quantitative neuromuscular monitoring enables clinicians to select even more stringent cut-offs to determine the appropriate return of muscle strength than the currently recommended train-of-four ratio of 0.9. In a recent post hoc analysis of patients receiving mainly acceleromyographic quantitative monitoring in the POPULAR study, POPCs were reduced with a train-of-four ratio cut-off of >0.95 instead of >0.9.28Blobner M. Hunter J.M. Meistelman C. et al.Use of a train-of-four ratio of 0.95 versus 0.9 for tracheal extubation: an exploratory analysis of POPULAR data.Br J Anaesth. 2020; 124: 63-72Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar These findings underscore the fact that regardless of which reversal agent is chosen, quantitative neuromuscular monitoring techniques should be used.23Naguib M. Brull S.J. Kopman A.F. et al.Consensus statement on perioperative use of neuromuscular monitoring.Anesth Analg. 2018; 127: 71-80Crossref PubMed Scopus (144) Google Scholar Unfortunately, even 20 yr after expert recommendations for quantitative monitoring,29Viby-Mogensen J. Postoperative residual curarization and evidence-based anaesthesia.Br J Anaesth. 2000; 84: 301-303Abstract Full Text PDF PubMed Scopus (107) Google Scholar adoption has been dismal.30Pandit J.J. Andrade J. Bogod D.G. et al.5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: summary of main findings and risk factors.Br J Anaesth. 2014; 113: 549-559Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar A current drawback of choosing sugammadex over neostigmine is the higher cost of sugammadex in many countries. Superior cost-effectiveness for sugammadex hinges on the assumption that time savings associated with rapid and complete reversal, even in the presence of profound neuromuscular block, can be translated into productive cost savings in clinical practice.31Paton F. Paulden M. Chambers D. et al.Sugammadex compared with neostigmine/glycopyrrolate for routine reversal of neuromuscular block: a systematic review and economic evaluation.Br J Anaesth. 2010; 105: 558-567Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Lower costs for sugammadex in the future (patents are close to their expiry date in many countries), may further shift cost-effectiveness in favour of sugammadex. However, some clinicians may be deterred from using sugammadex because of the apparently higher incidence of anaphylaxis compared with neostigmine.32Savic L. Savic S. Hopkins P.M. Anaphylaxis to sugammadex: should we be concerned by the Japanese experience?.Br J Anaesth. 2020; Jan 22; ([Epub ahead of print])Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar The study by Togioka and colleagues14Togioka B.M. Yanez N.D. Aziz M.F. Higgins J.R. Tekkali P. Treggiari M.M. Randomised controlled trial of sugammadex and neostigmine for reversal of neuromuscular blockade on the incidence of pulmonary complications in older adults undergoing prolonged surgery.Br J Anaesth. 2020; (Advance Access published on March 2)https://doi.org/10.1016/j.bja.2020.01.016Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar supports previous evidence of the more favourable profile of sugammadex in terms of efficiency and quality of neuromuscular reversal.33Geldner G. Niskanen M. Laurila P. et al.A randomised controlled trial comparing sugammadex and neostigmine at different depths of neuromuscular blockade in patients undergoing laparoscopic surgery.Anaesthesia. 2012; 67: 991-998Crossref PubMed Scopus (99) Google Scholar, 34Illman H.L. Laurila P. Antila H. Meretoja O.A. Alahuhta S. Olkkola K.T. The duration of residual neuromuscular block after administration of neostigmine or sugammadex at two visible twitches during train-of-four monitoring.Anesth Analg. 2011; 112: 63-68Crossref PubMed Scopus (34) Google Scholar Given the multifactorial causes of POPCs and the relatively small effect size of sugammadex, large observational studies may be the only achievable level of evidence to link the more desirable properties of sugammadex with improved outcomes. A RCT would likely require thousands of patients and may be impossible to execute, in part as a result of funding issues. Even if we find that sugammadex is more efficacious in terms of the incidence of POPCs, we must continue our quest for improved neuromuscular monitoring for all patients requiring muscle relaxation, regardless of the reversal medication chosen. Contributed equally to the writing of the manuscript: both authors. KB declares no conflicts of interest. JMH has received funding from MSD in the past 5 years to give lectures and chair CME meetings. She was editor-in-chief of the British Journal of Anaesthesia from 1997 to 2005, and chair of the BJA Board from 2006 to 2012. National Institutes of Health (NIH) (K23 DA040923 to KB).