Abstract
Background:
Studies have proposed that the routine use of sugammadex could provide perioperative time savings and a reduction in the incidence of postoperative nausea and vomiting. The purpose of this study was to test the effectiveness of sugammadex on perioperative times and on the incidences of adverse events when compared with the active control, neostigmine, for minimally invasive gastric sleeve surgery.
Methods:
Following institutional review board approval, patient characteristics, type of primary neuromuscular blocking reversal agents, operating room discharge times, post-anaesthesia care unit recovery times, and incidences of and treatment for postoperative nausea and vomiting and orotracheal reintubation were the measures of interest. Superiority testing determined the between-group means differences of the reversal agents on the two perioperative time periods of interest.
Results:
Superiority testing demonstrated no improvement of the two perioperative times with sugammadex. There was no clinical difference in the incidence of postoperative nausea and vomiting or in the number of antiemetic doses received in the post-anaesthesia care unit between the two groups. Finally, the two orotracheal reintubations in the post-anaesthesia care unit were in the sugammadex administered group.
Conclusion:
These results with sugammadex provide no perioperative time savings or reduce the incidence and treatment for postoperative nausea and vomiting in the post-anaesthesia care unit when compared with neostigmine.
Keywords
Introduction
The development of conventional laparoscopic and robotic–assisted surgeries has advanced the practice of bariatric surgery (Acevedo et al 2020, Ahmad et al 2016, Bertoni et al 2021, Gill et al 2011, Joselyn et al 2015). Studies have shown that deep neuromuscular blockade can effectively lower intra-abdominal pressure and improve the operating conditions during these minimally invasive surgeries (Li et al 2021, Lindekaer et al 2013, Loupec et al 2016, Sun et al 2021). However, the need for deep neuromuscular blockade often results in postoperative residual neuromuscular blockade requiring unplanned airway support (Baete et al 2017, Brueckmann et al 2015, Ledowski et al 2014, Lee et al 2020).
Studies have examined the role of sugammadex, a synthetic gamma-cyclodextrin, in the reversal of neuromuscular blockade induced by rocuronium or by vecuronium (Sacan et al 2007, Sparr et al 2007, Suy et al 2007, Vanacker et al 2007). Studies have supported perioperative time savings with sugammadex in bariatric surgery but have been limited to small group analyses (Carron et al 2013, Castro et al 2014), meta-analyses (Carron et al 2017, Subramani et al 2021), or in hypothetical time efficiency models (Jiang et al 2021, Insinga et al 2016, Paton et al 2010).
The neuromuscular blocking reversal agent, neostigmine, has been reported to increase the incidence of postoperative nausea and vomiting (PONV) following intra-abdominal surgery (Ding et al 2023, Koyuncu et al 2015, Lee et al 2017). The purpose of this study was to determine the clinical effectiveness of sugammadex when compared with neostigmine in patients undergoing minimally invasive gastric sleeve surgery under general or everyday practice conditions.
Methods
Following institutional review board approval, a K-nearest neighbours algorithm (Hastie et al 2009) developed equal sets of patients receiving either the active control, neostigmine (394 patients) or sugammadex (394 patients) developed from a dataset of 1235 consecutive surgical records following minimally invasive sleeve gastrectomy from August 2020 to April 2022. Patient characteristics including the American Society of Anesthesiologists Physical Status scores (ASA PS), type of primary neuromuscular blocking reversal agents, operating room (OR) discharge times, post-anaesthesia care unit (PACU) recovery times (Boggs et al 2018), incidences of and treatment for PONV, and the number of orotracheal reintubations in the PACU were the measures of interest.
Statistics
Categorical variables were presented as counts and percentages with 95% confidence intervals (CIs) with group differences assessed using chi-square (χ2) tests or the Cochrane Armitage Trend test. Continuous variables with skewed distributions were presented as medians with 25%–75% interquartile range (IQR) with differences between the two groups assessed by the Wilcoxon rank sum test. Key analyses were expressed with associated CI when indicated. Balance diagnostics (Austin 2009) assessed differences in the distributions of the baseline patient characteristics between the two propensity-matched neuromuscular blocking reversal agent groups (Hastie et al 2009). Superiority testing was utilised to determine if sugammadex had clinically important time differences when compared with the active control, neostigmine (Flight & Julious 2016, Lesaffre 2008). P values for associated frequentist tests were set <0.005 for statistical significance to minimise the risk of false discovery rates or in declaring associations significant by chance alone (Benjamin et al 2018, Colquhoun 2014, Glickman et al 2014). The statistical programme, JMP Pro 17.2 (SAS Institute, Cary, NC) was utilised for this study.
Sample size calculations
Based upon pilot data obtained from laparoscopic bariatric surgeries (Nossaman et al 2015, Nossaman et al 2017) performed before the introduction of sugammadex and not included in these data, the standard deviation for OR discharge times was 8.8 minutes. For the statistical tests for superiority testing, assuming a 0.90 power, a two-sided type I error rate of 0.01, a clinical difference to detect of 3 minutes (Lee et al 2022), and a minimum of 333 completed medical records would be needed each for the two groups of interest (Hulley et al 2007).
Results
Baseline patient characteristics are shown in Table 1. There were no important imbalances in the summation values of age, sex, body mass index, and ASA PS scores between the two neuromuscular blocking reversal agent groups (Table 1).
Patient characteristics in 788 patients following primary neuromuscular blocking reversal in minimally invasive gastric sleeve surgery
IQR: 25-75% interquartile range; Sex, f: female; BMI: body mass index; ASA PS: American Society of Anesthesiologists Physical Status Score.
Standardised differences were calculated between the two neuromuscular blocking reversal groups. An absolute standardised difference of >0.1 suggests imbalance. Austin PC. Statistics in Medicine 2009.
All patients underwent successful orotracheal extubation in the OR. The ranges of OR discharge times are shown in Table 2. Median OR discharge times were 9 minutes [IQR 6–13 minutes] for sugammadex and 9 minutes [IQR 6–12 minutes] for neostigmine (Table 2).
Ranges of operating room discharge times when expressed in quantiles following gastric sleeve surgery
Operating room discharge times are the time intervals, expressed in minutes, from the time stamp for end of surgical procedure to the time stamp for out of the operating room. Boggs SD, et. al. Journal of Medical Systems. 2018. Chi-square = 0.0001, p = 0.9912. Three time intervals were not recorded in this dataset.
The results of superiority testing on OR discharge times for the reversal agents are shown in Figure 1. When the delta (∆) time interval was set for ±3 minutes of the mean target value for the active control, neostigmine (Lee et al 2022); OR discharge times for sugammadex were not superior to those observed with neostigmine (Figure 1).
Sugammadex to neostigmine means comparison: superiority testing of sugammadex to the active control, neostigmine by OR discharge times; 3 min time interval range, (Lee et al 2022) alpha level = 0.05; means difference = 0.48 minutes; SE 0.49 minutes; 90% CI −0.33 to 1.3 minutes. Upper Bound t-ratio 7.0, p = 1.000. Sugammadex is not superior to neostigmine under these target range clinical conditions (Lesaffre 2008)
The ranges of PACU recovery times are shown in Table 3. Median PACU recovery times were 70 min IQR 43-113 min for sugammadex and 82 min IQR 53-138 min for neostigmine (Table 3).
Ranges of post-anaesthesia care unit recovery times when expressed in quantiles following gastric sleeve surgery
Post-anaesthesia care unit times are the time interval, expressed in minutes, from the time stamp for entrance into this care unit to the time stamp ready for exit from this care unit.31.Chi-square = 10.4, p = 0.0012. Two time intervals were not recorded in this dataset.
The results of superiority testing of the reversal agents on means PACU recovery times are shown in Figure 2. When the delta (∆) time interval was ±15 min of the mean value for the active control, neostigmine (Lee et al 2022); the PACU recovery times for sugammadex were not superior to the PACU recovery times observed with neostigmine (Figure 2).
Sugammadex to neostigmine means comparison: superiority testing of sugammadex to the active control, neostigmine by PACU recovery times; 15-minute time interval range (Lee et al 2022); alpha level = 0.05; means difference = −23.7 minutes; SE 6.5 minutes, 90% CI −34.7 to −12.9 minutes. Upper Bound t-ratio = −1.3, p = 0.0916. Sugammadex is not superior to neostigmine under these target range conditions (Lesaffre 2008)
The incidences of PONV are shown in Table 4. There was no clinical improvement in the incidence of PONV with sugammadex when compared with neostigmine (Table 4). The number of antiemetic doses patients received in the PACU is shown in Figure 3. There were no clinical differences in the number of antiemetics administered between the two reversal agents (Figure 3). There were two orotracheal reintubations in the PACU. Both were within the sugammadex group.
Incidence of PONV by primary neuromuscular reversal agent during minimally invasive gastric sleeve surgery
PONV: postoperative nausea and vomiting. 95% CI: 95% confidence interval.
The calculated risk difference of the incidences of PONV between the two primary neuromuscular reversal agents, sugammadex and neostigmine.
Comparison mosaic plot of number of antiemetic doses administered in the PACU. Patients were grouped by primary neuromuscular reversal agent, either sugammadex or neostigmine. The Cochran Armitage trend test examined the ordinal trends in the number of antiemetic doses administered in the two groups and was not statistically significant nor clinically important (Z = −0.25, p = 0.4026)
Discussion
Neuromuscular blocking agents improve operative conditions for laparoscopic surgery (Baete et al 2017, Lindekaer et al 2013, Sun et al 2021). Since the 1950s, the acetylcholinesterase inhibitor, neostigmine, has been used to reverse neuromuscular blockade (Srivastava & Hunter 2009, Zafirova & Dalton 2018). However, the neuromuscular blocking reversal agent, neostigmine, has been reported to increase the incidence of PONV following intra-abdominal surgery (Koyuncu et al 2015, Lee et al 2017).
In 2015, the FDA approved sugammadex (Thompson 2016). Sugammadex is a modified gamma-cyclodextrin ring with a central core designed to bind either rocuronium or vecuronium. Studies have suggested that sugammadex could provide shorter OR discharge times and shorter PACU recovery times in bariatric surgery (Carron et al 2013, Castro et al 2014). Carron et al (2013) reported an improvement in OR discharge and PACU recovery times. Castro et al (2014) reported an improvement in PACU recovery times and a lower incidence of PONV. However, these studies were conducted in small bariatric cohorts (Carron et al 2013, Castro et al 2014). Ding et al (2023) examined the incidence of PONV within 48 hours, whereas this study was limited to the immediate postoperative period.
In our study, we did not observe the OR discharge or PACU recovery time savings using superiority testing methods as both 90% CI for sugammadex for the time intervals of interest were within the target intervals set for neostigmine (Lee et al 2022). The differences between these studies and ours are unknown, although it is possible that inclusion and exclusion criteria played a role (Carron et al 2013, Castro et al 2014). Another reason could be that an observational bias or Hawthorne-like effect (Frieden 2017, McCambridge et al 2014, Nossaman & Nossaman 2022, Sedgwick & Greenwood 2015, Vetter & Mascha 2017) was introduced during the conduct of these studies (Carron et al 2013, Castro et al 2014) that influenced the outcomes.
The Hawthorne effect occurs in clinical studies when participants are aware of the study conditions (Sedgwick & Greenwood 2015). Nakayama et al (2014), Teernstra et al (2003), and (Kwann et al (2016) observed unexpected improvements in their control groups when compared with similar control groups from earlier pilot or published studies (Meyhoff et al 2009). However, in everyday clinical conditions, patient and physician preferences influence therapeutic decisions which introduces confounding by indication (Schober & Vetter 2020a, Vetter & Mascha 2017). Thus, the introduction of a novel therapeutic needs to rise above this background noise of confounders to be an effective signal in demonstrating improvement in patient care.
Eventually, the clinical effectiveness of any new medication will need re-examination under real-world, non-Hawthorne effect conditions (Frieden 2017, McCambridge et al 2014, Nossaman & Nossaman 2022, Sedgwick & Greenwood 2015, Vetter & Mascha 2017). Our data analyses under these conditions suggest that the administration of sugammadex for reversal of neuromuscular blockade does not provide clinically important improvements in the time intervals of interest. The use of sugammadex did not improve the incidences of adverse events of PONV or the need for orotracheal reintubation in the PACU following minimally invasive gastric sleeve surgery.
Limitations
One limitation of this study is that the patients did not undergo preprocedural randomisation, which would minimise the imbalance of unmeasured confounders. This study did compare two groups of patients who underwent propensity score matching with balance diagnostics. The analysis of a propensity score-matched group helps to approximate that of a randomised trial when comparing outcomes in treatment methods. Although observational studies with these balance methods do not establish causal relationships, these matching techniques do provide useful approximations of treatment effects (Haukoos & Lewis 2015).
Clinical judgement is an important component in individualised clinical care, which is limited in randomised controlled clinical trials (Bothwell et al 2016, Chavez-MacGregor & Giordano 2016, Rothwell 2006). Another strength of this study was the application of balance diagnostics in propensity matched samples to minimise confounding by indication (Austin 2009, Hastie et al 2009, Schober & Vetter 2020a, 2020b). Although group differences can still exist when unknown confounders are not measured, the introduction of new therapies need to clearly demonstrate superiority in general practice conditions.
Conclusion
These results failed to demonstrate improved perioperative time savings with sugammadex when compared with neostigmine following laparoscopic gastric sleeve surgery under general clinical practice conditions. These results did not indicate improved clinical benefit of sugammadex on the incidence of PONV or the treatment for PONV in patients undergoing gastric sleeve surgery. Although initial studies reported favourable effects of sugammadex in perioperative time savings and in reducing incidences of PONV, these studies may have suffered from Hawthorne-effect conditions. Future clinical trials may need to incorporate mixed models, a hybrid of both fixed and random effects, which may lead to more reliable conclusions when investigating the effects of novel therapies.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship and/or publication of this article.
