Karsten Bartels,Ana Fernandez-Bustamante,Marcos F. Vidal Melo
Reversal of neuromuscular block: what are the costs?
health economics,neostigmine,neuromuscular blocking agent,outcomes,postoperative pulmonary complications,sugammadex
Patients requiring neuromuscular block for anaesthesia have a higher risk of adverse postoperative outcomes. The choice of reversal drug and its corresponding dose is critical for improving clinical outcomes. Although drug costs are higher for sugammadex relative to neostigmine, additional factors need to be considered when choosing one drug over the other. New data from a recent study in the British Journal of Anaesthesia indicate cost advantages for sugammadex in low-risk and ambulatory patients, but for neostigmine in high-risk patients. These findings highlight the need to take local and temporal factors into consideration in addition to clinical effectiveness when performing cost analyses for administrative decision-making.
Reversal of neuromuscular block: what are the costs?

Patients requiring neuromuscular block for anaesthesia have a higher risk of adverse postoperative outcomes. The choice of reversal drug and its corresponding dose is critical for improving clinical outcomes. Although drug costs are higher for sugammadex relative to neostigmine, additional factors need to be considered when choosing one drug over the other. New data from a recent study in the British Journal of Anaesthesia indicate cost advantages for sugammadex in low-risk and ambulatory patients, but for neostigmine in high-risk patients. These findings highlight the need to take local and temporal factors into consideration in addition to clinical effectiveness when performing cost analyses for administrative decision-making.

In 1934, the Scottish physician Mary Broadfoot Walker noticed that patients with myasthenia gravis presented signs and symptoms comparable to those with curare poisoning. Dr Walker used subcutaneous physostigmine in a patient with severe disease and documented transient symptom improvement. Remarkably, the initial reports describing the use of curare rarely mentioned the need for reversal of neuromuscular block. Griffith and Johnson in 1942 recommended having prostigmine available, but the 25 anaesthetised patients they described remained spontaneously breathing, despite curare rendering the abdomen ‘soft as dough’ for the surgeon. In a case series of 1500 patients receiving d-tubocurarine published in 1946, Gray and Halton concluded that ‘there are rare occasions when physostigmine, the physiological antidote to curarine, may be useful.’ Beecher and Todd’s seminal observational study of 599,500 anaesthetics published in 1954 found a death rate of 1 in 360 for cases that included curare, but ‘only' 1 in 2100 for anaesthetics that did not include curare. Recognition of increased postoperative complications after the use of neuromuscular blocking agents led to the routine use of reversal agents for neuromuscular block in the late 1950s.

Much has been learned since the 1950s on neuromuscular blocking agents and their antidotes. Two articles published recently in the British Journal of Anaesthesia compared the effects of using sugammadex with those of neostigmine for the pharmacologic reversal of neuromuscular block with respect to relevant health economic outcomes: hospital length of stay and costs of care. These reports are welcome additions to the literature with direct implications for clinical practice, as cost has been a major factor restricting the use of sugammadex. Wachtendorf and colleagues report their findings of direct and total healthcare costs in a registry-based cohort of 79,474 patients from two institutions in the USA. In a large and broad sample of patients undergoing surgery with general anaesthesia, they found lower direct costs (232 USD) in those receiving sugammadex for reversal of neuromuscular block than those who received neostigmine for reversal. The lower direct costs were detected despite a higher drug cost for sugammadex. Direct cost assumptions need to be made for personnel, supplies, and other resources that are directly attributable to patient hospitalisation. Although different medication costs (Table 1 ) account for some of the direct costs, factors such as operating room personnel and supply costs required to perform the operation, staff costs for postoperative care, and other supply costs also contribute. Notably, pharmacy costs for cholecystectomy surgery comprise only 2% of total hospital costs. Furthermore, acquisition cost comparisons between neostigmine and sugammadex are in constant flux because of price swings in generic drugs and expiration of patent protection of sugammadex in the coming years. Another important caveat is that costs for hospital stay before or after surgery are related not only to complications but also to other logistic issues (e.g. delays in the transfer of surgical patients from the postanaesthesia care unit to the hospital ward). In fact, it is possible that the greater cost observed in sicker patients with longer perioperative hospital stays, intensive care unit stays, and longer surgeries was influenced by a substantial health burden and increased postoperative complications unrelated to residual neuromuscular weakness or postoperative pulmonary complications. In these more ill patients, improved reversal of neuromuscular block at the end of surgery might be unable to reduce the direct or total costs of care significantly. Interestingly, the cost advantage of sugammadex was specific to low-risk patients (a reduction of 1042 USD), whereas total costs were higher for sugammadex than for neostigmine in sicker patients (American Society of Anesthesiologists [ASA] physical status ≥3) with preoperative hospitalisation. This is a perplexing and unexpected finding that deserves deeper examination. The authors speculate that the observation of higher costs in sicker patients might be attributable to greater susceptibility to laryngospasm and other sugammadex-specific side-effects such as a rapid increase in airway reflexes or sugammadex binding to coagulation factors causing bleeding in sicker patients. Although such explanations are intriguing, the finding comes as a surprise. If the known side-effects of sugammadex actually manifest as adverse outcomes responsible for the higher direct costs found in this study is a question that remains to be answered. Prevailing thought is that patients at high risk for postoperative pulmonary complications would benefit more from the use of sugammadex than low-risk patients. Despite sugammadex being more effective than neostigmine at reducing residual neuromuscular weakness, reductions in the incidence of major pulmonary complications have been found mostly in observational studies, , but not consistently in randomised trials. A possible explanation could be the presence of uncontrolled residual confounding factors in registry-based data, possibly explaining higher costs in high-risk patients, despite the extensive and careful analysis performed by the investigators. Although there has been a general expectation of a benefit of sugammadex compared with neostigmine for reducing postoperative pulmonary complications, current data are equivocal. Indeed, the recent 2023 ASA Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade classifies the evidence for any differences between sugammadex and neostigmine in affecting respiratory adverse events as low or very low. Inherent limitations of statistical approaches to the analysis of observational data have highlighted the need to rely not solely on the favourable pharmacodynamic profile of sugammadex. Rather, clinicians should maintain a high index of suspicion for residual neuromuscular block and utilise quantitative neuromuscular monitoring to assess for weakness. Whether difficulties in establishing a differential benefit of sugammadex in respiratory outcomes are related to currently unrecognised effects that manifested as increased costs in the study from Wachtendorf and colleagues will require further investigation. The 2023 ASA Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade explicitly state that an analysis of economic considerations was beyond the scope of their guidelines.

In another article in the British Journal of Anaesthesia, Azimaraghi and colleagues found that sugammadex relative to neostigmine use was associated with reduced postoperative length of stay in an ambulatory care facility (9.5 min), which was possibly mediated by a reduction in the incidence of postoperative nausea and vomiting (19.6% for neostigmine vs 17.2% for sugammadex). The large sample of patients studied encompassed predominantly ASA physical status 1 and 2 patients, reflecting a low comorbidity burden as expected in this setting. One of the earlier economic evaluations of sugammadex use analysed the reduction in recovery time and the ‘value of time saved’ as a surrogate of establishing cost-effectiveness for neostigmine. The authors concluded that sugammadex would be cost-effective if such time savings were achieved in the operating theatre but not in the recovery unit, as cost per time is substantially higher in the operating theatre. Despite the high costs of operating room and recovery room time, savings in time might not translate directly to financial gain. The primary savings of reducing recovery unit time stem from prevention of patients staying longer in the operating theatre awaiting a recovery room bed. In a scenario where a staffed recovery unit is not at capacity (i.e. there are open and staffed beds available and no backlog of waiting operating room patients exists), reducing recovery time might not translate to cost savings. The studies by Wachtendorf and colleagues and Azimaragi and colleagues describe in detail the associations of neostigmine and sugammadex use with costs and hospital length of stay. When comparing sugammadex with neostigmine use, multiple economic outcomes, such as drug cost, recovery time, and costs for managing postoperative complications including those occurring after discharge, must be considered. In light of recent guidelines and the nearing patent expiration for sugammadex, it is likely that the choice of sugammadex for reversal after rocuronium and vecuronium will continue to increase. Although this change in practice appears to be based on best available data, we should prioritise efforts to conduct rigorous health economic assessments of current practice and emerging changes in how we deliver perioperative care.

AFB reports additional research funding from the US Department of Defense, the Merck Investigator-initiated Studies Program and the Institute for Healthcare Quality, Safety and Efficiency for projects unrelated to the discussed work. KB and MFVM declare that they have no conflicts of interest.

US National Institutes of Health National Heart, Lung and Blood Institute (NHLBI) (UH3HL140177 to AFB and MFVM), and the 10.13039/100000133Agency for Healthcare Research and Quality (AHRQ) (award number R01HS027795 to KB). This report is solely the authors’ responsibility and does not represent the official views of NIH or AHRQ. NIH and AHRQ had no involvement in writing the report or the decision to submit the article for publication.