Postoperative pulmonary complications after neuromuscular blockade: what does the recent evidence demonstrate?

The iPROVE-OLV (individualized PeRioperative Open-lung Ventilatory stratEgy in patients submitted to One-Lung Ventilation) trial is an international, multicenter, randomized, controlled clinical trial (NCT03182062) (1). The study involved 25 hospitals in five countries (Spain, Italy, Turkey, Egypt, and Ecuador) and aimed to determine whether an individualized perioperative open-lung ventilation strategy during one-lung ventilation (OLV) would reduce severe postoperative pulmonary complications (PPCs). Severe PPCs were defined as a composite of atelectasis requiring bronchoscopy, severe respiratory failure, contralateral pneumothorax, early extubation failure (rescue with continuous positive airway pressure, non-invasive ventilation, invasive mechanical ventilation, or reintubation), acute respiratory distress syndrome, pulmonary infection, bronchopleural fistula and pleural empyema within the first seven postoperative days. In the individualized open-lung approach (iOLA), patients received an alveolar recruitment maneuver to 40 cmH₂O of end-inspiratory pressure followed by positive end-expiratory pressure (PEEP) titrated to best respiratory system compliance and postoperative high-flow oxygen therapy. The standard group received intraoperative PEEP of 4 cmH₂O and conventional postoperative oxygen therapy. Among 1,308 enrolled patients, the incidence of severe PPCs was significantly lower in the iOLA arm (6%) compared with the standard arm (15%), supporting the role of perioperative respiratory optimization in reducing pulmonary morbidity.

In the analysis of the iPROVE-OLV trial, Mazzinari et al. compared 657 patients who received neuromuscular monitoring combined with pharmacologic reversal with 41 subjects who received neither, using a Bayesian random effect logistic regression model (2). The authors tested the sensitivity of their conclusions using three distinct priors. A neutral prior reflected no expectation of benefit or harm. A pessimistic prior was biased toward the null hypothesis. An optimistic prior was biased toward benefit. Across all three priors, the estimated odds ratios consistently favored neuromuscular monitoring with reversal, with point estimates suggesting modest to moderate reductions in the risk of PPCs. The estimated size of the benefit was smaller under the pessimistic prior and larger under the optimistic prior. Even under the pessimistic prior, the posterior probability of benefit remained substantial. The corresponding credible intervals were wide and crossed unity, indicating imprecision in effect size. This approach is well suited for the present analysis, where the comparison is observational, the groups are markedly imbalanced (657 vs. 41), and residual confounding cannot be ruled out.

In clinical terms, the observed incidence of severe PPCs was roughly 10% in the monitored/reversed group versus roughly 20% in the unmonitored group. This translates to an approximate absolute risk reduction (ARR) of about 10% and an estimated number needed to treat (NNT) of about 10, suggesting that for every 10 patients who receive neuromuscular monitoring with pharmacologic reversal, one additional patient may be spared a severe PPC. However, these figures should be interpreted cautiously given the observational design, the small comparator group (n=41), and the wide credible intervals. In addition, within the monitored and reversed cohort, the use of sugammadex was associated with a higher probability of benefit compared with neostigmine, supporting the biological plausibility that more complete and reliable reversal of neuromuscular blockade may translate into improved postoperative pulmonary outcomes. These findings raise important questions regarding the adequacy of neuromuscular recovery at the time of extubation, particularly in relation to residual neuromuscular blockade (RNMB) and current monitoring practice.

High incidence of RNMB has been reported in many recent studies ranging from 14% to 32% (3-8). The utility of neuromuscular monitoring and reversal agents to reduce the incidence of PPCs has not been consistently supported in the literature. For example, a multicenter study involving 22,803 European patients (POPULAR study) reported that the use of neuromuscular monitoring or reversal agents did not reduce PPCs (9). A single center study in the U.S. involving 10,491 patients did not find that neuromuscular blockade reversal agents would reduce PPCs (10). A U.S. multicenter study involving 45,712 patients supported that sugammadex use reduced PPCs by 30% compared to neostigmine use (11). The choice of reversal agent has also been studied in thoracic surgical populations specifically. Murphy et al. found that thoracoscopic patients reversed with neostigmine had substantially higher rates of residual paralysis at post-anesthesia care unit (PACU) admission compared to those given sugammadex (12). Ledowski et al. conducted a prospective randomized trial of high-risk older patients [American Society of Anesthesiologists (ASA) physical status III, age 75 or older] and reported that sugammadex was associated with a reduced probability of impaired pulmonary outcomes by postoperative day 7 compared with neostigmine (13). In morbidly obese patients, sugammadex use was associated with lower rates of decreased percutaneous oxygen saturation and critical respiratory events compared to neostigmine (14).

One major issue in neuromuscular monitoring is the lack of consistency in threshold. The reanalysis of the POPULAR study showed that a train-of-four (TOF) ratio of >0.95 at the time of tracheal extubation significantly reduced PPCs compared to a TOF ratio of >0.9 (15). This distinction matters given that upper airway muscles are more sensitive to RNMB than peripheral muscles like the adductor pollicis. Thus, a patient can reach a TOF of 0.9 and still have impaired pharyngeal function, reduced upper esophageal sphincter tone, and blunted protective airway reflexes. After thoracic surgery with OLV, where pulmonary reserve is already limited, even minimal residual blockade may contribute to atelectasis, impaired cough, and hypoxemia. This is further supported by evidence that up to 80% of acetylcholine receptors can be occupied by a neuromuscular blocking agent without any detectable clinical weakness (15). From a monitoring standpoint, we may need to perform more quantitative TOF assessment to reduce PPCs. TOF value at the time of extubation was not recorded in iPROVE-OLV trial. Thus, it is difficult to draw a firm conclusion from this dataset.

Another issue is that different combinations of neuromuscular blockade and reversal agents are often included in the same study. Neostigmine, which is the only anticholinesterase in routine clinical use, has a ceiling effect. Giving more does not necessarily increase its efficacy. It may even cause depolarizing block if given in excess (16). Sugammadex is a gamma cyclodextrin and encapsulates aminosteroidal neuromuscular blocking drugs (vecuronium, rocuronium) in a 1:1 ratio. However, it does not reverse residual blockade by other non-depolarizing agents such as cis-atracurium and mivacurium. Different from neostigmine, it does not have a ceiling effect, and can reverse any degree of neuromuscular block produced by rocuronium or vecuronium (17). Thus, it may be reasonable to assume that sugammadex is more efficient in reversing muscle blockade compared to neostigmine if a reversal agent is given. However, cis-atracurium, if used, may not necessarily be reversed due to its metabolic profiles (18).

It is also worth considering that the association between neuromuscular monitoring with reversal and reduced PPCs may be confounded by practice patterns. Anesthesiologists who routinely perform quantitative neuromuscular monitoring may also be more likely to follow other evidence-based perioperative practices, such as lung-protective ventilation, goal-directed fluid management, and multimodal analgesia. In other words, neuromuscular monitoring and reversal could be a marker of overall anesthetic quality rather than an independent contributor to improved pulmonary outcomes. The observational design of this analysis does not allow us to separate these effects.

Baseline differences between the monitored/reversed and non-monitored groups in this analysis are also notable. Differences in the prevalence of obstructive sleep apnea syndrome (OSAS) and duration of surgery persisted between groups, and both are established risk factors for PPCs. Given the small size of the non-monitored group (n=41), propensity score adjustment has limited ability to fully balance all relevant covariates, and residual confounding remains a possibility. A further limitation is the lack of a standardized PPC definition across the literature. The composite endpoint used in the iPROVE-OLV trial is specific to this study and does not correspond to widely accepted consensus definitions from a systematic review and Delphi process (19). This inconsistency potentially makes direct comparison of findings across studies difficult and limits the generalizability of these results.

Despite these limitations, the analysis by Mazzinari et al. underscores an often-overlooked contributor to postoperative pulmonary outcomes. Neuromuscular monitoring is non-invasive, readily available, and easy to incorporate into routine anesthetic practice. Until higher-quality prospective data are available, a stringent approach to neuromuscular monitoring and extubation criteria appears reasonable, particularly in patients undergoing thoracic surgery who are inherently at higher risk for PPCs. This strategy may serve as an important adjunct to established lung-protective and individualized ventilatory approaches.

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