Introduction
Inpatient surgical procedures are performed less often than outpatient procedures (42.2% vs. 57.8% in the USA) [
1], and this increasingly will be the case with growing trends towards more outpatient surgery over inpatient [
1‐
4]. This trend will not be universal; patients undergoing inpatient surgeries often have acute illnesses or comorbidities [
5]. As a result of the inherent higher-risk nature of many inpatient surgeries and the patient population, inpatient surgeries remain associated with worse outcomes and longer recovery times relative to outpatient procedures [
1].
Neuromuscular blocking agents (NMBAs) are components of balanced general anesthesia [
6], facilitating intubation and ensuring patient immobility to help optimize surgical conditions. In practice, the choice of NMB reversal agent is dependent on patient and procedure requirements such as the time to onset, depth, and duration of neuromuscular blockade (NMB) [
6‐
8]. At the end of the procedure, patients may be allowed to spontaneously recover neuromuscular function, or may be administered a pharmacological NMB reversal agent for more rapid recovery of neuromuscular function. Complete reversal of NMB is important as residual NMB in the post-anesthesia care unit (PACU) may increase the risk of complications, including serious pulmonary complications [
9‐
12].
Sugammadex, a modified gamma-cyclodextrin, reverses NMB induced by rocuronium or vecuronium by encapsulation [
13]. Recent studies have demonstrated that sugammadex provides a more rapid, predictable, and safe reversal of NMB [
14] with reduced incidence of residual NMB [
15] and reduced risk of adverse events related to the acetylcholinesterase inhibitor neostigmine [
14,
16‐
19]. There is a need to evaluate the use of NMBAs as part of balanced anesthesia and the use of NMB reversal methods for recovery, to gain a better understanding of healthcare resource utilization patterns in the inpatient setting. Since the US Food and Drug Administration (FDA) approval of sugammadex on December 15, 2015 [
20], practice patterns within inpatient settings have changed. While sugammadex may be recognized as the preferred therapy because of its better safety and efficacy [
14], it may not be universally adopted as the preferred agent in clinical practice because of its higher cost compared with generic neostigmine. Limited utilization data for NMB and reversal agents use since 2015 have indicated changes in practice patterns in the USA [
21]. However, trends and variation in the choices made in NMB management, including the use of sugammadex in the broader US community inpatient surgical settings since the market availability of the drug [
20], remain unclear. We sought to (1) describe the real-world temporal trends associated with the use of NMBAs and NMB reversal agents in adults undergoing procedures in the US hospital inpatient setting and (2) identify factors associated with the choice to pharmacologically reverse non-depolarizing NMB and, specifically, the choice of NMB reversal agent among those that are pharmacologically reversed.
Methods
Study Design
This was a retrospective longitudinal analysis of a national electronic healthcare database (Premier Healthcare Database [PHD]) of US adult (at least 18 years of age) inpatient surgical data. The Premier Healthcare Database is considered exempt from institutional review board (IRB) oversight as dictated by Title 45 Code of Federal Regulations, Part 46 of the USA, specifically 45 CFR 46.101(b)(4). In accordance with the HIPAA Privacy Rule, disclosed data from the PHD are considered de-identified per 45 CFR 164.514(b)(1) through the “Expert Determination” method. This study was also reviewed and approved by the Mass General Brigham IRB (Protocol # 2021P001328), which determined that the study does not classify as human subjects research.
This analysis was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [
22]. NMB and reversal patterns were examined for the pre-sugammadex period (prior to FDA approval of sugammadex [December 2015]), and the post-sugammadex period (after sugammadex was available at participating PHD hospital sites). Primary study outcomes included administration of NMBA and utilization of NMB reversal agent (sugammadex or neostigmine) in patients receiving non-depolarizing neuromuscular blockade agents (vecuronium or rocuronium, with or without succinylcholine). Further, among those administered rocuronium and/or vecuronium, we evaluated the association of patient, procedure, and provider characteristics with NMB reversal choices.
Patient Population
All adult cases undergoing general anesthesia and receiving NMBA by bolus or infusion, between January 1, 2014 and June 30, 2019 were eligible for the study. Patients with renal failure, myasthenia gravis, or those receiving pyridostigmine therapy were excluded. Patients administered NMB with rocuronium or vecuronium were included, and patients administered a neuromuscular block reversal agent (NMBRA) with both sugammadex and neostigmine were excluded from the main analyses evaluating reversal agent use.
Variables
Patient demographics and clinical characteristics were captured for each eligible patient (e.g., age, sex, comorbidities) and site characteristics (hospital size/number of beds, geographic and census region, urban/rural) were described for each encounter. Surgical procedures were categorized by body region, based on the ICD-PCS (International Classification of Disease Procedure Coding System), classified by the Clinical Classifications Software (CCS) developed by the Healthcare Cost and Utilization Project (HCUP) for ICD-PCS (ICD-10) after October 1, 2015 and ICD-9 prior to October 2015. Primary ICD codes were used for each encounter, and grouped on the basis on their CCS1 category: those missing any ICD procedure code, or falling within CCS1 of obstetrical procedure (used as the closest proxy as no variable for “pregnant” was available; there is neither clinical trial data on the use of sugammadex in pregnant women nor is there any relevant data on lactating women/human milk [
20]) or miscellaneous, were excluded. Remaining CCS1 categories were combined when the procedures were likely to be completed by the same clinical specialty (Supplementary Table 1 includes most frequently observed primary ICD-PCS codes within each surgical category). This resulted in each encounter being classified into one of ten procedure categories.
Data Source
The PHD is a large, US hospital-based, service-level, all-payer database of information on outpatient encounters and inpatient discharges, from non-profit, non-governmental, community and teaching hospitals. Data are derived from member hospital statistics provided through a combination of self-reporting and the American Hospital Association Annual Survey Database™ and comprise information on over 10 million inpatient admissions per year since 2012 [
23]. This is estimated to cover approximately 25% of all US inpatient admissions. Patient data are de-identified and Health Insurance Portability and Accountability Act (HIPAA)-compliant.
Analysis
NMBA utilization patterns were reported over time descriptively by patient characteristics, site characteristics, and procedure type. Utilization patterns of NMB reversal options (i.e., active pharmacologic reversal [sugammadex or neostigmine] versus spontaneous recovery) were assessed among patients treated with rocuronium or vecuronium (with or without succinylcholine).
Multivariable logistic regression analyses assessed the independent association of patient, site, and procedure characteristics with NMB reversal choice. Adjusted odds ratios (OR), 95% confidence intervals (CI), and P values were reported for the likelihood of a patient being administered active pharmacologic (either sugammadex or neostigmine) versus spontaneous NMB reversal for the entire period 2014–2019. After preliminary results showed differential associations by region, further stratification was done to assess potential for interaction. In our first model (model 1), we assessed characteristics related to active (i.e., pharmacological) reversal via administration of any reversal agent (sugammadex or neostigmine) versus spontaneous NMB recovery overall (model 1a), and by geographic region (model 1b). Our second model (model 2) examined the association of these factors with the choice of pharmacological reversal agent (sugammadex versus neostigmine) among the subset of patients receiving active reversal, overall (model 2a) and by geographic region (model 2b) for the period after which sugammadex was available (December 2015 to June 2019), and for sites in which sugammadex was available. An additional analysis investigating the effect of earlier institutional utilization of sugammadex on the reversal choice was conducted on encounters where pharmacologic reversal was used in order to understand the impact of early clinical adoption on the choice of NMB reversal agent. In this model (model 2c), the year of first institutional use of sugammadex was included among the independent variables (i.e., early [2016] versus late [2018] adoption of sugammadex), removing calendar year (due to collinearity). This model only included encounters taking place at sites (in which sugammadex was available and) with continuous presence in the PHD dataset (in the period 2016–2019).
All statistical analyses were performed using SAS® software, version 9.4 (Cary, NC, USA).
Discussion
We assessed the temporal trends in clinical practice associated with the use of NMBAs and NMB reversal approaches in adult inpatients undergoing surgery.
From 2014 to 2019, the use of active reversal continuously increased and spontaneous reversal decreased (Fig.
2). By June 2019, 3.5 years after its regulatory approval in the USA, sugammadex was available in 78% of the 927 sites in this analysis. Not surprisingly, of those surgeries using active reversal, sugammadex use increased and neostigmine decreased over time, suggesting clinical equipoise among the two active reversal agents in anesthesia practice in the inpatient setting. Indeed, the year in which the surgical procedure was performed was the most impactful factor that independently influenced the odds of selecting sugammadex vs. neostigmine (Fig.
4b). A similar trend in time was observed in the active vs. spontaneous reversal model (model 1a, Fig.
4a), although it was not as pronounced. The choice of active vs. spontaneous reversal was more strongly dependent on patient comorbidities and even more so by procedure type. While both impacted the choices made in NMB management, the direction and magnitude of effect of patient comorbidities and procedure type varied in their degree of impact on choice of mode (pharmacologic vs. spontaneous) and agent (neostigmine vs. sugammadex) of NMB reversal, independent other factors and each other (Fig.
4a vs. b).
Over the study period, the use of NMB with rocuronium alone increased to a high of 90.3% in June 2019, with an accompanying decline in the use of short-acting agents such as succinylcholine, perhaps owing to the introduction of a faster reversal option. The use of active NMB reversal increased overall over the study period, with spontaneous recovery dropping to 27.6% in 2019. Choice of reversal with sugammadex seemed to displace, to some extent, both spontaneous recovery and active reversal with neostigmine over time. Certain patient characteristics influenced the choice of NMB reversal approach more than others. This finding was consistent with trends observed in a recent similar outpatient study [
24] as well as a recent retrospective observational study of sugammadex utilization conducted in adult general anesthesia inpatient cases from the Multicenter Perioperative Outcomes Group (MPOG), across 24 US centers between 2014 and 2018 [
21], though the association between sugammadex use and age was far more pronounced in the latter population.
Patients identifying as Black or “other” races as well as Hispanics were negatively associated with sugammadex use relative to White and non-Hispanic patients. Differences observed according to race or ethnicity were of modest magnitude, and while they were independent of other patient and site characteristics, they may reflect differences in access to care and be associated with site or regional differences in practice. Notably, we observed that in the Northeast, Hispanics were about 26% more likely to be pharmacologically reversed compared to non-Hispanics, though when reversed, they were about 16% less likely to receive sugammadex. Interestingly, in the South and West, Hispanics receiving active NMB reversal were 38–44% more likely to be reversed with sugammadex compared to non-Hispanics independent of other factors. Black and Hispanic patients made up only 10% and 7% of the population, respectively. While these are interesting observations lending insight to potential health disparities in clinical practice and access to care at a site or regional level, a follow-on sensitivity analysis (not shown) found that ethnicity was not a statistically significant contributor to NMB reversal choice (neither mode nor type of agent) when the correlation of observations within institutions was taken into account via a generalized estimating equations (GEE) model. However, race was a statistically significant contributor to choice of active vs. spontaneous reversal (but not type of agent) even after accounting for the correlation within institutions. These observations may point to some disparities in NMB treatment choices. Further research in understanding the source of these treatment disparities is both necessary and beyond the scope of this paper.
Emergency/urgent and trauma cases were all negatively associated with pharmacological reversal compared with elective cases. This is not surprising as most elective cases have planned extubation prior to operating room discharge compared to emergency cases which may be more likely to have prolonged intubation, obviating a need for NMBA reversal. However, when pharmacologically reversed, use of sugammadex was modestly, but positively associated with emergency/urgent (OR 1.10;
P < 0.0001) and trauma (OR 1.65;
P < 0.0001) cases compared to elective cases. These findings are similar to that reported in the MPOG study [
21], which reported greater use of sugammadex for emergent surgeries (OR 1.09; 95% CI 1.04–1.14;
P < 0.001). Sugammadex is indicated for urgent NMB reversal [
20] and most emergency rooms carry sugammadex, which may also influence the choice of reversal agent in emergency/trauma patients. Associations observed with trauma centers should be interpreted with caution, as the majority of trauma cases in this study came from five or fewer sites. This may, in part, account for the difference in association between choice of reversal agent and type of admission within the Northeast.
Specifically, cardiovascular procedures were also independently negatively associated with active pharmacologic reversal and were more than twice as likely to be spontaneously reversed compared to musculoskeletal procedures. This observation is consistent with the conventional practice not to extubate patients undergoing cardiovascular surgeries who remain sedated and are under prolonged ventilation following surgery (specifically this may be seen in the open approach coronary artery bypass graft and valve replacement procedures frequently observed here [Supplementary Table 1]). It is unclear whether this observed association may be despite the introduction of enhanced recovery pathways (which have endorsed early extubation as part of “Fast-Track” cardiac surgery for improved patient outcomes over the last several years, with mixed results with regard to reduction of complications [
25,
26]), or if associations would be even more pronounced in the absence of these efforts. Perhaps as a result of differences in adoption and practice of enhanced recovery pathways by site and region, interestingly, among the Midwest sites, when they chose to pharmacologically reverse in cardiovascular procedures, anesthesia providers’ preference to reverse with sugammadex was more pronounced than in other regions (Fig.
4; OR 1.27;
P < 0.0001, Supplementary Table 4, compared to musculoskeletal procedures).
Independent negative associations with active pharmacologic reversal were also observed among ENT and endocrine procedures (which may not require as long or as deep NMB), while digestive system procedures, female genital, and urinary/male genital procedures were considerably more likely to be pharmacologically reversed compared to musculoskeletal procedures.
The pattern of active reversal versus spontaneous recovery varied with patient comorbidity profiles. While these associations were observed, independent of other patient and procedure characteristics and each other, there may be collinearity, or some degree of residual confounding between certain comorbidities, and types of procedures. Among patients receiving pharmacologic NMB reversal, there was some variability in choice of sugammadex vs. neostigmine across presence of comorbidities, though these were less pronounced than differences observed between pharmacologic and spontaneous reversal choices. Trends and magnitude of effect were similar to those observed in a previous multicenter inpatient study [
21] and slightly less pronounced compared to those observed in a similar outpatient study conducted within PHD [
24]. While it is not surprising that a number of comorbidities putting patients at increased surgical risk [
5,
24] showed trends for the preferential use of sugammadex, it is surprising that the presence of sleep apnea (a risk factor for pulmonary complications) was not [
27].
While larger academic hospitals were more likely to pharmacologically reverse patients compared to smaller non-teaching hospital, in general, these characteristics had relatively less impact than they did on choice of reversal agent once a patient was pharmacologically reversed. We observed, perhaps paradoxically, that both smaller and teaching hospitals were less likely to use sugammadex when they do reverse, though these differences were not statistically significant when correlation within sites was taken into account with GEE. This varied somewhat by region (model 2b, Supplementary Table 6), where for instance in the Midwest providers were more likely to use sugammadex when pharmacologically reversing patients in smaller hospitals. One may speculate that the relationship between NMB reversal choices and site characteristics may be related to the volume of cases seen at a hospital as well as local pharmacy budget restrictions.
When investigating the influence of hospital adoption timing and NMB choices, we found that more academic sites adopted clinical use of sugammadex within the first year of its availability (40.31% in 2016) than in later years (2.5% in 2019) (Supplementary Table 2). Observed regional imbalances in sugammadex uptake may also be related to some of the observed regional differences in practice. This may be due to restrictions at the site level as each facility undergoes its own process to add medications to inpatient formulary and make them available for use [
21]. Regional and center characteristics may also relate to care access, practice preference, or systemic trends of clinical inertia.
Among US adult inpatients administered NMBs, we observed complex relationships between patient, site, regional, procedural characteristics, and NMB management choices. Observations (Fig.
4, Supplementary Table 3–6) suggest that patient and procedural characteristics are important factors in NMB reversal choices in both whether and how a patient is pharmacologically reversed, while external factors may be more influential in impacting choice of pharmacological reversal agent once a patient is actively reversed. While observed differences in anesthesia practice by site, race, and ethnicity are not consistent across all geographic regions, sites, or clear in their root cause, they raise awareness of potential health disparities in perioperative care, access to care, and trends of clinical practice preference variability independent of those accounted for by clinical characteristics and drug availability. Our findings help us to better understand the choices made in NMB management and anesthesia trends in the inpatient setting which will likely continue to change over time. Although our study did not include data from 2020, analyzing trends is particularly pertinent, with the COVID-19 pandemic causing major changes in hospital protocols and restrictions on elective surgeries in response to the unprecedented burden on the healthcare system.
Study Strengths and Limitations
The PHD represents approximately 25% of inpatient surgical settings, covering academic and nonacademic sites [
23], and our study sample included over 4.8 million inpatient encounters. However, as already indicated, there was an overrepresentation of the South (47.7% of patient encounters) and underrepresentation of the Northeast (12.3% of patient encounters) regions of the USA, which limit the interpretation and generalizability of the results for any specific region or type of center. While most encounters originate from large, urban, academic centers, most sites originate from small nonacademic centers (Supplementary Table 2).
Inpatient status is determined by the hospital site itself, and there will likely be minor site variation in transitions from day case to inpatient surgeries. In addition, information on local policies or access restrictions for sugammadex by site, which will have impacted the choice of reversal agent, was not available. Data on drug dosing and availability of quantitative neuromuscular monitoring and on select, but important patient characteristics including ASA class, body mass index, and smoking status were also not available and may have an impact on anesthetic treatment and NMB management choices.
This analysis utilized multivariable logistic regression to help understand associations in NMB reversal. However, it is clear that clinical practice is a dynamic landscape where the reversal choices and clinical preferences are constantly shifting. We captured this broadly with a few time-dependent variables, which can reveal the overall trends but may fail to capture changes in more specific areas of clinical practice.