Abstract
Sugammadex produces recovery from neuromuscular blockade more rapidly and reliably than neostigmine. We sought to determine if sugammadex is associated with improved perioperative efficiency when compared to traditional neuromuscular blockade reversal with neostigmine, potentially offsetting the higher medication cost. This retrospective analysis involved patients receiving either neostigmine or sugammadex for reversal of neuromuscular blockade at a single academic tertiary care hospital. The final propensity-matched groups consisted of 4060 in each group (neostigmine or sugammadex). The primary outcome measured was total time in the operating room. Secondary outcomes included specific measures of perioperative efficiency as well as postoperative pulmonary failure. The average operating room time for patients was 169.59 [1.27] minutes for neostigmine and 157.06 [1.33] minutes for sugammadex (P < 0.001). The difference was primarily accounted for by shorter surgical times (121.45 [1.18] vs 109.62 [1.22] minutes, P < 0.011). Sugammadex was also associated with a shorter post-anesthesia care unit length of stay (102.47 [1.04] vs 98.67 [1.02] minutes, P < 0.001). For 8120 patients, sugammadex use was associated with shorter operating room and surgical durations as well as shorter post-anesthesia care unit stay. The favorable pharmacodynamic profile of sugammadex may improve surgical and perioperative efficiency and offset higher medication cost.
Keywords: Anesthesia, anesthesiology, cost analysis, neuromuscular blocking agents, sugammadex
The primary aim of this retrospective analysis was to examine if using sugammadex compared to neostigmine for routine neuromuscular blockade reversal is associated with an improvement in perioperative efficiency by reducing total operating room (OR) time. We hypothesized that routine use of sugammadex would be associated with increased OR efficiency when compared to neostigmine. This increased efficiency could result in cost savings to the hospital.
METHODS
This retrospective observational analysis was not subject to informed written consent, as it was approved and designated as “not human research” by the University of Alabama at Birmingham institutional review board. Data were obtained via the Department of Anesthesiology and Perioperative Medicine Information Technology division by querying the CompuRecord (Phillips Healthcare) system. This study adhered to the applicable STROBE guidelines.
All eligible patients who underwent general anesthesia at the University of Alabama at Birmingham and received an intermediate-acting nondepolarizing neuromuscular blocking agent (rocuronium or vecuronium) between January 1, 2018, and December 31, 2019, were divided into two groups: those receiving neostigmine and those receiving sugammadex. This timeframe was selected as it spanned when sugammadex became commonly used at our institution until normal operational procedures were interrupted in the first quarter of 2020 due to COVID-19. Cases included in this study were from orthopedic, vascular, urologic, gynecologic, acute care, and gastrointestinal surgical services due to the frequent need for neuromuscular blockade and subsequent reversal of paralysis. Neurosurgery, cardiac surgery, transplant surgery, and otolaryngology/oral and maxillofacial surgery services were excluded due to the high incidence of patients remaining intubated postoperatively and the preferential use of certain reversal agents. Other initial exclusion criteria included patients already intubated, those with tracheostomies, and those <18 years of age. Additional exclusion criteria included missing/incomplete data, those receiving both neostigmine and sugammadex, surgery time <10 minutes (to exclude aborted procedures), and patients receiving >2 mg/kg of sugammadex and > 200 mg total dose. This cutoff was chosen as the manufacturer’s recommended dose for reversal from mild to moderate block is 2 mg/kg.1 We sought to avoid cases requiring reversal from deep neuromuscular blockade, as neostigmine could not be used until the return of two to three twitches in train-of-four monitoring with a peripheral nerve stimulator.2 For patients who had multiple procedures during the timeframe, only the first procedure was analyzed. Also, patients with multiple procedures on the same day were excluded from the final analysis (Figure 1).
Figure 1.
Assembly of the unmatched and matched cohorts.
Data were summarized using means and standard errors for continuous outcomes or counts and percentages for categorical outcomes. To account for a possible imbalance in baseline covariates between the sugammadex and neostigmine groups, propensity score matching was used to match patients receiving sugammadex to those receiving neostigmine. Patients were matched using a greedy 1:1 match using the covariates of age, sex, weight, American Society of Anesthesiologists classification, and surgical specialty.3 Absolute standardized differences were used to assess covariate imbalance before and after matching. The matched groups were considered to be sufficiently balanced if all covariates had an absolute standardized difference of <10%.3
Two-sample t tests and chi-square tests were used to compare the matched and unmatched cohorts. Normality for continuous outcomes was assessed using probability plots and the Shapiro-Wilk test for normality; for any outcomes where normality could not be reasonably assumed, the Wilcoxon rank sum test was used in place of two-sample t tests. A P value < 0.05 was considered statistically significant. SAS version 9.4 (SAS Institute Inc., Cary, NC) was used to perform the propensity score matching and conduct all statistical analyses.
RESULTS
Data were available for 12,393 procedures (7724 neostigmine, 4669 sugammadex) between January 1, 2018, and December 31, 2019. The unmatched cohort consisted of 11,112 patients (7008 neostigmine, 4104 sugammadex). Of the 4104 sugammadex patients in the unmatched cohort, 4060 (98.9%) were able to be matched with a neostigmine patient. The matched cohort therefore consisted of 8120 patients (4060 neostigmine, 4060 sugammadex).
Table 1 compares the demographic and clinical characteristics for the neostigmine and sugammadex groups, both before and after matching, including American Society of Anesthesiologists physical status classification system, weight, sex, and proportion of patients in each group by surgical subspecialty. Figure 2 shows the absolute standardized differences for covariates used to match the two groups. All absolute standardized differences were <10%, indicating that the matched cohort was adequately balanced on these covariates.
Table 1.
Demographic and clinical characteristics, before and after propensity score matching
| Variable | Before matching |
After matching |
||||
|---|---|---|---|---|---|---|
| Neostigmine (n = 7008) | Sugammadex (n = 4104) | P value* | Neostigmine (n = 4060) | Sugammadex (n = 4060) | P value* | |
| Age (years): mean (SE) | 52.39 (0.19) | 55.18 (0.25) | <0.001 | 54.76 (0.25) | 55.17 (0.25) | 0.292 |
| Weight (kg): mean (SE) | 88.74 (0.30) | 86.03 (0.39) | <0.001 | 86.16 (0.37) | 85.63 (0.37) | 0.283 |
| ASA classification: n (%) | <0.001 | – | ||||
| 1 | 207 (2.95%) | 112 (2.73%) | 107 (2.64%) | 107 (2.64%) | ||
| 2 | 2080 (29.68%) | 1121 (27.31%) | 1119 (27.56%) | 1119 (27.56%) | ||
| 3 | 4483 (63.97%) | 2676 (65.20%) | 2668 (65.71%) | 2668 (65.71%) | ||
| 4 | 238 (3.40%) | 192 (4.68%) | 166 (4.09%) | 166 (4.09%) | ||
| 5 | – | 3 (0.07%) | ||||
| Sex: n (%) | 0.213 | – | ||||
| Female | 4337 (61.89%) | 2493 (60.75%) | 2462 (60.64%) | 2462 (60.64%) | ||
| Male | 2671 (38.11%) | 1610 (39.23%) | 1598 (39.36%) | 1598 (39.36%) | ||
| Undetermined | – | 1 (0.02%) | – | – | ||
| Surgical specialty: n (%) | <0.001 | – | ||||
| Gastroenterology | 1719 (24.53%) | 1199 (29.22%) | 1190 (29.31%) | 1190 (29.31%) | ||
| Gynecology | 2203 (31.44%) | 1075 (26.19%) | 1070 (26.35%) | 1070 (26.35%) | ||
| Orthopedics | 1263 (18.02%) | 603 (14.69%) | 593 (14.61%) | 593 (14.61%) | ||
| Urology | 1183 (16.88%) | 832 (20.27%) | 825 (20.32%) | 825 (20.32%) | ||
| Vascular | 640 (9.13%) | 395 (9.62%) | 382 (9.41%) | 382 (9.41%) | ||
P values from Wilcoxon rank sum test (age, weight) or chi-square test (ASA status, sex, surgical specialty).
ASA indicates American Society of Anesthesiologists; SE, standard error.
Figure 2.
Absolute standardized differences for the unmatched and matched cohorts.
Clinical data from the two groups are presented in Table 2. Neostigmine and sugammadex were administered an average of 14.24 and 11.37 minutes prior to extubation, respectively. Volatile anesthetic concentrations (percent sevoflurane and isoflurane) were higher at the time of neuromuscular blockade reversal for the neostigmine group. The sugammadex group was associated with larger cumulative doses of rocuronium and vecuronium.
Table 2.
Surgical outcomes for matched cohort
| Outcome | Neostigmine (n = 4060) | Sugammadex (n = 4060) | P value* |
|---|---|---|---|
| OR minutes: mean (SE) | 169.59 (1.27) | 157.06 (1.33) | <0.001 |
| Surgery minutes: mean (SE) | 121.45 (1.18) | 109.62 (1.22) | <0.001 |
| Anesthesia minutes: mean (SE) | 180.60 (1.28) | 167.86 (1.35) | <0.001 |
| Reversal to extubation minutes**: mean (SE) | 14.24 (0.14) | 11.37 (0.14) | <0.001 |
| Extubation to out of OR minutes**: mean (SE) | 4.07 (0.05) | 4.27 (0.06) | 0.024 |
| Inhaled isoflurane concentration (%) during reversal: mean (SE) | 0.60 (0.01) | 0.50 (0.01) | <0.001 |
| Inhaled sevoflurane concentration (%) during reversal: mean (SE) | 1.52 (0.02) | 1.44 (0.02) | <0.001 |
| Rocuronium (mg): mean (SE) | 55.15 (0.30) | 57.65 (0.36) | 0.002 |
| Vecuronium (mg): mean (SE) | 5.63 (0.15) | 5.83 (0.15) | 0.087 |
| PACU length of stay (min): mean (SE) | 102.47 (1.04) | 98.67 (1.02) | <0.001 |
| No PACU paralytic: n (%) | 4058 (99.95%) | 4058 (99.95%) | – |
| PACU paralytic: n (%) | 2 (0.05%) | 2 (0.05%) |
P values from Wilcoxon rank sum test (minutes, isoflurane concentration, sevoflurane concentration, rocuronium, vecuronium, length of stay) or chi-square test (use of paralytic).
Negative values treated as missing.
OR indicates operating room, PACU, post-anesthesia care unit; SE, standard error.
Overall, when compared to the neostigmine group, the sugammadex group was associated with a shorter OR time of 12.53 minutes. For the analysis period, sugammadex was also associated with a shorter surgical time of 11.83 minutes. Anesthesia time, reversal to extubation time, reversal to out of OR time, and time from extubation to out of the OR are presented in Table 2. Finally, sugammadex was associated with a shorter post-anesthesia care unit (PACU) length of stay of 3.8 minutes and was not associated with decreased PACU respiratory failure requiring reintubation.
DISCUSSION
Neuromuscular blocking agents are commonly administered during surgical procedures. Adequate reversal of neuromuscular blockade is essential to restore respiratory muscular function and avoid postoperative complications.4 In this retrospective analysis, we compared neostigmine vs sugammadex for neuromuscular blockade reversal and the effect on perioperative efficiency at a single institution. We found that the use of sugammadex was associated with shorter OR time, largely accounted for by shorter surgical times, and reduced length of stay in the PACU.
The ability of sugammadex to produce faster recovery from neuromuscular blockade when compared to acetylcholine inhibition has been well established.5,6 To examine the economic impact of sugammadex, studies have often used the time from medication administration to time to train-of-four return = 0.97–9 or time from medication administration to OR exit.10 However, based on pharmacokinetics, neostigmine can and should be administered earlier to better align drug pharmacokinetics and planned extubation time. Thus, a longer reversal time does not necessarily translate into longer time in the OR. Instead, the primary outcome in this analysis was total OR time, which we believe to be a better marker for efficiency and potential cost-effectiveness.
In comparison with previous studies, our findings provide a more comprehensive analysis of the impact of sugammadex on OR and PACU efficiency. Reduction in OR minutes allows for direct savings as well as freeing up time that can be used for other productive means. The use of sugammadex was associated with a reduction in OR time by 12.53 minutes, the majority of which was a result of decreased surgical time (11.83 minutes). Although sugammadex may have been used more often for shorter procedures, we attempted to limit this effect by matching proportions of surgical subspecialties for the two groups. We hypothesize that the use of sugammadex may improve operating conditions and allow for faster completion of surgery. Despite surgeries using sugammadex being 9.26% shorter, providers administered 4.53% (2.50 mg) more rocuronium (the difference in vecuronium was not significantly different). Sugammadex may afford deeper neuromuscular blockade, through greater dosages and/or timing, which has been shown to improve surgical conditions in some populations such as laparoscopic colorectal surgery.11 Furthermore, the increased volatile anesthetic concentration at time of reversal for the neostigmine group suggests the patients may have been kept at an increased depth of anesthesia, compensating for a lack of paralysis to prevent movement and facilitate surgical conditions. These differences, however, are small and their clinical impact uncertain. Moreover, our study does not include a measurable surgical assessment of operating.
In terms of postoperative outcomes, sugammadex was associated with a reduction in PACU length of stay by 3.80 minutes. Other groups have found that sugammadex is associated with shortened PACU stay, although the cost effects of this remain unclear, while some have found no difference in PACU time.12–15 Sugammadex has been well demonstrated to reduce residual postoperative paralysis and minor respiratory events.16 Moreover, postoperative residual curarization leads to delayed recovery room discharge.17 Potential contributing factors to this reduction may include improved pulmonary function from a reduction in residual curarization as well as decreased postoperative nausea and vomiting. Finally, in agreement with a recent study by Li et al, we found no difference in the rate of postoperative respiratory failure between the two groups.18
Determining the costs of OR and PACU time is complex and varies based on factors including location, practice setting, and workforce staffing, among others. Girotto et al estimated a cost of $60/minute,19 while Childers et al found a cost of $36 to $37/minute in California’s acute care hospitals.20 Although hospital acquisition costs vary, sugammadex is significantly more expensive than neostigmine ($117 vs $21 for a single vial).21 Using an approximate average of $50/minute for OR time, a reduction of 1.92 OR minutes would lead to cost-effectiveness of sugammadex use. In addition, further cost savings are possible from reduced PACU length of stay as well as potential reductions in other side effects such as postoperative nausea and vomiting and pneumonia.
There are several limitations to this analysis. As a retrospective analysis, all findings are associations and do not prove causation, as it is subject to biases and confounding factors despite the two groups being propensity matched. The independent decision making of the anesthetist as to which medication to administer for which procedure and patient could affect the findings. The two groups were matched based on surgical subspecialty categories; however, sugammadex may still have been used preferentially for shorter procedures to facilitate faster turnover time for a busy schedule. As this analysis compares the two groups over time, it is vulnerable to being affected by other confounders occurring temporally as well, such as surgical times decreasing over the period of time due to logistical changes, case variety, surgeons and other staff, etc. Finally, this analysis from a large tertiary-care academic setting may not be applicable to other settings.
In conclusion, this single-center retrospective observational analysis of 8120 surgical patients showed an association of shorter OR times, largely due to shorter surgical times, when sugammadex was used compared to neostigmine. Sugammadex use was also associated with a shorter PACU length of stay. Further randomized and controlled studies are needed to validate our findings and determine cost-effectiveness.
ACKNOWLEDGMENTS
The authors acknowledge Dale Parks, PhD (Professor, University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine Information Technology) and David Benz, MS (Informatics Analyst, University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine Information Technology) for their assistance gathering data and Emma O’Hagan, MLIS (Associate Professor, University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine) for her assistance with literature search and manuscript formatting.
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