Escalating rocuronium dosing in the era of sugammadex for neuromuscular blockade reversal

Griffith and Johnson’s introduction of neuromuscular blocking agents 83 years ago transformed anesthesia and surgery by enabling tracheal intubation, reducing upper-airway trauma, and improving operative conditions. In 1954, Beecher and Todd’s observational study of 599,500 anesthetics reported higher mortality when curare was used (1 in 360) than when it was not (1 in 2,100) (1). The later identification of postoperative adverse events associated with neuromuscular blocking agents prompted the adoption of routine pharmacologic reversal strategies beginning in the late 1950s.

Surgery triggers a homeostatic inflammatory response, which muscle relaxants may amplify by inhibiting the cholinergic anti-inflammatory pathway (CAP). Macrophages drive inflammation by releasing pro-inflammatory mediators such as tumor necrosis factor (TNF) and interleukin (IL)-1/IL-6; excessive production can contribute to tissue injury and organ dysfunction. This response is normally balanced by anti-inflammatory factors including IL-10, IL-4, and soluble TNF receptors.

A key component of the anti-inflammatory response is the vagus nerve: local cytokines activate vagal afferents, and the inflammatory reflex enhances vagal efferent signaling, leading to acetylcholine (ACh) release. Ach suppresses macrophage cytokine production via α7 nicotinic acetylcholine receptors (α7nAChRs), forming the CAP (2-4).

Vagal cholinergic signaling acts via α7nAChRs on macrophages, dendritic cells, and other immune cells. In macrophages, α7nAChR activation suppresses NF-κB activity, reducing inflammatory cytokine release. Consistently, electrical vagus nerve stimulation attenuates NF-κB-driven hepatic inflammation, lowers TNF, and improves survival in hemorrhagic shock models; these effects are abolished by vagotomy. In preclinical studies, vagotomy worsens pancreatitis and increases IL-6, whereas the α7nAChR agonist GTS-21 reduces pancreatitis severity. Similarly, subdiaphragmatic vagotomy promotes pancreatic tumor growth and impairs leukocyte phagocytosis of Escherichia coli, underscoring the role of vagal cholinergic pathways in controlling excessive inflammatory responses (5,6).

Vagus nerve stimulation has gained attention as a nonpharmacologic therapeutic approach for TNF-α-mediated conditions, such as inflammatory bowel disease and rheumatoid arthritis (7). The spleen, a key secondary lymphoid organ, functions as a substantial source of monocytes that are mobilized to areas of inflammation and infection. Stimulation of the splenic nerve leads to the release of norepinephrine, which engages β2-adrenergic receptors on cholinergic T lymphocytes and induces the secretion of ACh. Subsequently, ACh exerts anti-inflammatory effects by activating α7nAChRs on splenic macrophages (3) (Figure 1).

Figure 1 Pathways of cholinergic anti-inflammatory pathway. ACh, acetylcholine; CAP, cholinergic anti-inflammatory pathway; mAChR, muscarinic acetylcholine receptor; NE, norepinephrine; TNF, tumor necrosis factor; α7nAChR, α7 nicotine acetylcholine receptor; β2AR, β2-adrenergic receptor.

Neuromuscular blocking agents produce dose-dependent suppression of human neuronal Ach receptors, including the α7 nicotinic subtype. Inhibition of these receptors may attenuate cholinergic anti-inflammatory signaling, thereby potentiating inflammatory responses and potentially increasing susceptibility to postoperative complications (8). The use of neuromuscular blocking agents is associated with a heightened risk of residual paralysis, which may contribute to postoperative pulmonary complications. Even low degrees of persistent neuromuscular blockade can compromise pharyngeal muscle coordination, thereby elevating the likelihood of aspiration and subsequent pneumonia (9,10). Neuromuscular blocking agents may also indirectly promote postoperative hypoxemia through their effects on nicotinic receptors within the carotid bodies (11).

Accordingly, postoperative pulmonary complications related to residual neuromuscular blockade are primarily attributable to mechanical factors resulting from incomplete reversal of muscle paralysis. Impaired function of respiratory, pharyngeal and upper airway musculature predisposes patients to atelectasis and micro aspiration, thereby compromising pulmonary function integrity. In addition, emerging evidence suggests that neuromuscular blocking agents may exert proinflammatory effects that amplify the pulmonary inflammatory response, potentially exacerbating postoperative respiratory complications (PRCs) and compounding the initial mechanical insult.

The development of sugammadex, a modified γ-cyclodextrin, has substantially enhanced the reversal of steroidal neuromuscular blocking agents, including rocuronium and vecuronium. Sugammadex encapsulates these agents in a tight 1:1 complex, thereby reducing their free plasma concentration and facilitating recovery of nicotinic receptor function at the neuromuscular junction (12,13). Sugammadex has received regulatory approval in more than 80 countries and has been available for clinical use in Europe since 2008 and in the United States since 2016. In 2024, its indication was expanded to include reversal of rocuronium-induced neuromuscular blockade in pediatric patients across all age groups.

Clinical data indicate that sugammadex use is associated with a 34% reduction in unplanned 30-day hospital readmissions compared with neostigmine, with the most frequent reasons for readmission including pain, gastrointestinal disturbances, and fever (14).

Despite its advantages, sugammadex has certain limitations, including lack of efficacy in reversing benzylisoquinoline neuromuscular blocking agents and the risk of hypersensitivity reactions, including anaphylaxis, which has been reported in approximately 0.39% of cases (15). Importantly, sugammadex has been associated with an approximately tenfold greater risk of severe hypersensitivity reactions compared with neostigmine, although the absolute incidence of such events remains low (16). Additional reported adverse effects include bradycardia, hypotension, nausea, and potential pharmacologic interactions with concomitantly administered medication (17). Sugammadex has been shown to interact with factor Xa, resulting in transient prolongation of prothrombin time and activated partial thromboplastin time (18) or sex hormones (19), and may consequently diminish the efficacy of hormonal oral contraceptives.

Using sugammadex may encourage higher cumulative dosing of rocuronium, based on the perceived reliability of reversal with sugammadex. In a recently published retrospective analysis by Wachtendorf et al. (20), the authors evaluated 163,402 adult patients who received exclusively rocuronium during general anesthesia between 2010 and 2024. The primary outcome assessed changes in cumulative intraoperative rocuronium doses following sugammadex introduction in 2016. Secondary outcomes included the association between rocuronium exposure and PRCs—defined as postextubation desaturation <90%, reintubation within 7 days, or the need for emergency noninvasive ventilation—as well as potential effect modification by sugammadex use and by the type of neuromuscular monitoring [qualitative twitch counting versus quantitative train-of-four ratio (TOFR)]. After sugammadex introduction, the authors reported a 45.1% increase in rocuronium dosing. Although sugammadex was associated with attenuation of PRC risk, this risk was eliminated only when quantitative neuromuscular monitoring was used.

The findings of this study are consistent with those from the post hoc analysis of POPULAR (Post-anesthesia Pulmonary complications After use of muscle Relaxants), a prospective, large-scale European observational study (21). In POPULAR, intraoperative use of neuromuscular blocking agents was associated with a 4.4% absolute increase in postoperative pulmonary complications. However, the POPULAR post hoc analysis further demonstrated that extubating patients when the TOFR was >0.95 (rather than >0.9) reduced the adjusted risk of pulmonary complications by 3.5% compared with the original POPULAR estimate (11.3%). In sub-cohorts created using 1:1 propensity score matching, patients with TOFR >0.95 received sugammadex at higher doses [by 0.30 (0.13–0.48) mg/kg] (22). Collectively, these results highlight the importance of quantitative neuromuscular function monitoring to mitigate the incidence of postoperative pulmonary complications.

In our previous randomized controlled trial, no significant differences were identified in diaphragmatic contractile function or rates of postoperative pulmonary infection among patients undergoing neurointerventional procedures who received either sugammadex or neostigmine for neuromuscular blockade reversal. These results indicate that the attainment of sufficient neuromuscular recovery—such as a TOFR ≥0.9—may be more closely linked to postoperative respiratory outcomes than the particular reversal agent administered (23).

In a more recent retrospective cohort study from our group, including patients anesthetized with neuromuscular blockade in the bronchoscopy suite, the postoperative pulmonary complication rate was 2.7% with sugammadex and 1.9% with neostigmine (24). While the absolute difference of 0.8% is unlikely to be clinically meaningful on its own, it is notable that neostigmine was frequently selected only for patients demonstrating robust twitch responses according to American Society of Anesthesiologists (ASA) practice guidelines for monitoring and antagonism of neuromuscular blockade (25). Therefore, the implementation of routine quantitative neuromuscular monitoring is critical to verify full recovery from neuromuscular blockade and to minimize the likelihood of postoperative pulmonary complications.

Notably, reductions in the incidence of major postoperative pulmonary complications have been observed mainly in observational studies (26,27), but not consistently in randomized trials (28). One possible explanation is that registry-based analyses may be influenced by uncontrolled residual confounding factors (29).

The study did not evaluate the incidence of allergic reactions or anaphylaxis in the context of the increased use of rocuronium and sugammadex. In addition, it lacked subgroup analyses to determine which surgical specialties experienced the greatest increase in rocuronium use, and—most importantly—whether postoperative pulmonary complications improved most in specific specialties with the combined use of sugammadex and quantitative neuromuscular monitoring.

Another important limitation of the study is the absence of an evaluation of whether high cumulative exposure to rocuronium may precipitate systemic, multi-organ adverse effects beyond respiratory complications.

Emerging data indicate that exposure to neuromuscular blocking agents during general anesthesia is linked to a dose-related elevation in the risk of postoperative delirium; however, appropriate pharmacologic reversal may attenuate this association (30). Given that α7nAChRs upregulate the function of N-methyl-D-aspartate receptors (NMDARs) to support working memory and cognition, increased exposure to rocuronium could inhibit α7nAChR signaling and thereby potentially increase the risk of postoperative delirium (31-33).

The study should have more thoroughly addressed the cost implications of increased rocuronium dosing, as well as any cost savings associated with reducing postoperative pulmonary complications through the combined use of sugammadex and quantitative neuromuscular monitoring.

From a statistical perspective, this study employed a sophisticated statistical framework to address the impact of sugammadex on clinical practice. The use of Interrupted Time Series (ITS) Analysis provided a robust method for pinpointing the “sugammadex effect” on rocuronium dosing while controlling for baseline temporal trends. It was further strengthened by a comprehensive adjustment for pre-defined covariates, including baseline patient characteristics and intraoperative factors. However, a significant limitation persists in the co-primary analysis concerning PRCs. Approximately one-third (55,085/163,402) of the primary analytic sample was excluded from this analysis because they were not extubated in the end of anesthesia. The exclusion of these high-risk, non-extubated patients suggests that the reported 8.4% event rate may substantially underestimate the true risk of high dose rocuronium in the broader surgical population.

Patients who received higher cumulative doses of rocuronium may have been undergoing more complex or prolonged surgical procedures or may have had greater baseline perioperative risk. These factors independently increase the likelihood of PRCs and therefore represent important potential confounders that should be accounted for in the analysis.

Furthermore, for a composite outcome like PRC, which collapsed diverse events like desaturation and reintubation, a granular analysis of individual components is essential. In such outcomes, a single frequent but less severe component can often “drive” the overall effect, potentially masking the true impact on rarer, more life-threatening complications. Generalized estimating equation multivariate model is recommended to estimate both the average relative effect across components and the distinct effect for each individual event (34).

In conclusion, Wachtendorf et al. should be commended for their efforts to characterize the trend toward increasing rocuronium use following the introduction of sugammadex, and for highlighting a critical insight that pharmacological reversal alone is insufficient to mitigate risk. Their findings emphasize the importance of pairing sugammadex with quantitative neuromuscular monitoring to reduce postoperative pulmonary complications.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1221/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1221/coif). E.F. reports royalties from Elsevier as Editor of Brown’s Atlas for Regional Anesthesia; honoraria from Anesthesiology News for writing review articles; support for travel as a lecturer in the Abu Dhabi Congress for Anesthesia & Critical Care; and leadership position as Chair of Educational Track of Fundamentals of Anesthesia for the American Society of Anesthesiologists. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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