Efficacy and Safety of Sugammadex versus Neostigmine in Reversing Neuromuscular Blockade in Morbidly Obese Adult Patients: A Systematic Review and Meta-Analysis.

CONTEXT: Sugammadex is known to reverse neuromuscular blockade (NMB) more rapidly and reliably than neostigmine. However, data remain limited in bariatric patients. In this review, we systematically evaluated the efficacy and safety of sugammadex versus neostigmine in reversing NMB in morbidly obese (MO) patients undergoing bariatric surgery. AIMS: Our primary objective was to determine the recovery time from drug administration to a train-of-four (TOF) ratio >0.9 from a moderate or deep NMB. SETTINGS AND
DESIGN: This systematic review and meta-analysis (SR and MA) was conducted in accordance with the Preferred Items for SRs and MAs guidelines. SUBJECTS AND METHODS: A systematic search was conducted within multiple databases for studies that compared sugammadex and neostigmine in MO patients. STATISTICAL ANALYSIS USED: We reported data as mean difference (MD) or odds ratios (OR) and corresponding 95% confidence interval (CI) using random-effects models. A two-sided P < 0.05 was considered statistically significant.
RESULTS: Seven studies with 386 participants met the inclusion criteria. Sugammadex significantly reduced the time of reversal of moderate NMB-to-TOF ratio >0.9 compared to neostigmine, with a mean time of 2.5 min (standard deviation [SD] 1.25) versus 18.2 min (SD 17.6), respectively (MD: -14.52; 95% CI: -20.08, -8.96; P < 0.00001; I 2 = 96%). The number of patients who had composite adverse events was significantly lower with sugammadex (21.2% of patients) compared to neostigmine (52.5% of patients) (OR: 0.15; 95% CI: 0.07-0.32; P < 0.00001; I 2 = 0%).
CONCLUSIONS: Sugammadex reverses NMB more rapidly with fewer adverse events than neostigmine in MO patients undergoing bariatric surgery. Copyright:

INTRODUCTION

Morbid obesity (MO), defined as body mass index (BMI) >40 kg.m−2, occurs in 2%–5% in the Western societies. The worldwide increase in the incidence of obesity has led to an increased demand for bariatric surgery, which offers an important treatment for these patients.[12] An increased risk for postoperative respiratory complications from general anesthesia and paralysis makes adequate reversal from neuromuscular blockade (NMB) crucial in MO patients. Acetylcholine inhibitors, such as neostigmine, have been conventionally used to reverse NMB. Their action on muscarinic cholinergic receptors causes undesirable side effects such as bradycardia, hypotension, bronchoconstriction, airway secretions, and increased gastrointestinal motility. They are also associated with unpredictable reversal and a risk of postoperative residual curarization (PORC).[34]

The discovery of sugammadex was considered a revolution in the domain of neuromuscular reversal.[5] Sugammadex is a synthetically modified gamma-cyclodextrin that is specifically designed to encapsulate rocuronium and vecuronium and reverse their effects. Two recent systematic review and meta-analysis (SR and MA) have compared the efficacy and safety of sugammadex and neostigmine in reversing NMB in adults and have found sugammadex to allow a faster neuromuscular recovery from rocuronium-induced NMB, with fewer adverse effects.[67] This can result in a reduced duration of anesthesia, higher flow of patients through the operating theater, and more efficient use of healthcare resources.[7] At present, there is insufficient evidence comparing sugammadex and neostigmine in MO patients. The aim of this SR and MA was to assess the efficacy and safety of sugammadex compared with neostigmine in MO adult patients.

SUBJECTS AND METHODS

This SR and MA was conducted using a predesigned protocol [Supplementary File S1], which was registered at PROSPERO (CRD42021197102). This MA was reported according to the Preferred Items for SRs and MAs guidelines.[8] The ethics approval was not required as it is an SR and MA.

Study selection

We included all randomized controlled trials (RCTs), including conference abstracts, comparing sugammadex with neostigmine in MO adult surgical patients (age >18 years and BMI ≥40 kg.m−2) receiving nondepolarizing neuromuscular blocking agents. We included any dose of sugammadex and neostigmine, at any time point of administration of the study drug. We excluded case series and case reports, observational studies, and studies that were not published in English. Recovery time was measured in minutes from administration of the study drug to a train-of-four (TOF) ratio >0.9. Adverse events were defined by study authors and assessed in the operating theater or in the postanesthetic care unit (PACU), depending on each study. Only adverse events that were possibly, probably, or definitely related to the study drug were included in the risk assessments.

Search strategy

Based on the predefined search criteria, a medical librarian systematically searched the following electronic databases: PubMed, Medline, Embase, Web of Science, and Cochrane databases. The search strategy included the following descriptors, as per the National Center for Biotechnology Information Medical Subject Headings (NCBI MeSH): Obesity/Overweight/(obes * or “morbid* obes*”)/*”)/(overweight or over-weight or overweight or overeating or over eating or over-eating)/sugammadex/selective relaxant binding agent/SRBA/bridion/neostigmine. The search was conducted in July 2020. The complete search strategy is available in the Supplementary File S2.

Two authors (YS and MN) independently scrutinized the list of titles and abstracts to identify articles that were included in the SR and MA. Full texts of the positively screened articles were retrieved and independently assessed by two reviewers (YS and MN) for the inclusion criteria. In case of any conflict, the senior author (AF) was consulted. In addition, references listed in the included studies were manually searched for any other potentially relevant articles for inclusion. All trials were evaluated for major potential sources of bias using the Cochrane risk of bias tool (random sequence generation, allocation concealment, blinding of participants, blinding of personnel, blinding of primary outcome assessor, blinding of secondary outcome assessor, incomplete outcome data, selective reporting, and other biases). We assessed each domain separately and in total and graded each domain as “high risk,” “low risk,” or “unclear risk” of bias.[910] We evaluated the evidence with GRADE methodology.[11]

Data extraction

A data collection form was designed, and data were collected regarding study characteristics, patient demographics, and intraoperative and postoperative data using a standardized data collection protocol. Study characteristics, including name of the author, publication year, and study type, were identified. Preoperative data including age, sex, and BMI of patients were recorded. Intraoperative and postoperative data included type of surgery, duration, doses of rocuronium, sugammadex, neostigmine, and glycopyrrolate, degree of NMB, timing of reversal of NMB, time to recovery from NMB, and incidence of adverse effects such as pain, bradycardia, postoperative nausea and vomiting (PONV), and postoperative residual NMB. YS, MN, and AF confirmed the accuracy and completeness of all the data.

Outcome definition

Our primary outcome was recovery time from moderate NMB (from re-appearance of second twitch to TOF ratio >0.9) or deep NMB (from re-appearance of posttetanic count 1–5 to TOF ratio >0.9) with sugammadex compared to neostigmine groups. Our secondary outcomes included the risk of composite adverse events such as pain, bradycardia, and PONV; incidence of residual NMB (desaturation >4% from baseline, need for a rescue dose of sugammadex, difficulty breathing, respiratory rate >20/min, accessory muscle use or tracheal tug, reintubation, need for invasive or noninvasive ventilation); and time to discharge from the PACU with sugammadex compared to neostigmine groups.

Statistical analysis

Continuous data were reported as mean difference (MD) and 95% confidence intervals (CIs). Dichotomous data were reported as odds ratios (ORs) and 95% CI. A two-sided P < 0.05 was considered statistically significant. The pooled incidence of outcome was estimated using a random-effects model to account for inter-study variation. Egger's test, Begg's test, fail-safe N-test, and inspection of the funnel plot were performed to assess publication bias.

Each analysis was assessed for statistical heterogeneity using the I2 statistic[12] and Chi-square tests. I2 >50% and P < 0.05 for the Chi-square test indicate significant heterogeneity. A random-effects model was used for all analyses to account for between-study heterogeneity. Heterogeneity of more than 50% was further explored with an influence analysis by excluding studies, contributing to heterogeneity in the analysis and recalculating the pooled estimates. An influence analysis was performed by excluding each study in the analysis for the significant risk factors and outcomes, and the pooled estimates were recalculated. A sensitivity analysis was performed for all outcomes, by excluding the conference abstracts from the analysis. The analysis was conducted using Review Manager Software (RevMan, V.5.3), Cochrane Canada, Health Research Methods, Evidence, and Impact, McMaster University, Hamilton ON, Canada.

RESULTS

Our initial search identified 592 studies that were screened by titles and abstracts to yield 40 studies for full-text eligibility review. Seven studies with 386 participants met the inclusion criteria and were included [Figure 1].[13141516171819] All the included trials were published in English. There were four RCTs[13141516] and three conference abstracts.[171819] The participants in the included trials underwent various bariatric surgical procedures under general anesthesia, using rocuronium as a neuromuscular blocking agent and either sugammadex or neostigmine as reversal drugs. Table 1 summarizes the SR of the included studies. The quality of the studies was assessed using the Cochrane risk of bias tool, and all studies had some risks of bias in at least one domain [Figure 2]. We have also summarized the GRADE evidence [Table 2].

Figure 1

PRISMA flow diagram

Table 1

Systematic review of the included studies

Author	Type of study	Type of surgery	Number of patients Sugammadex/neostigmine	Muscle relaxant	Intensity of block at reversal	Dose of sugammadex	Dose of comparison	Body weight scalar to dose reversal	Primary outcome
Evron et al. (2017)	RCT	Laparoscopic sleeve gastrectomy	32/25	Rocuronium	Moderate (T2)	2 mg/kg	Neostigmine 2.5 mg with atropine sulfate 1 mg	TBW	Postoperative oxygen saturation
Castro et al. (2014)	RCT	Laparoscopic bariatric surgery	44/44	Rocuronium	Moderate (T2)	2 mg/kg	Neostigmine 0.05 mg/kg with Atropine 0.02 mg/kg	CBW	Postoperative pain scores
Carron et al. (2013)	RCT	Laparoscopic gastric band removal	20/20	Rocuronium	Deep (one to five PTCs)	4 mg/kg	Neostigmine 0.07 mg/kg with atropine 0.01 mg/kg	Sugammadex: TBWNeostigmine: LBW	Time to recovery from NMB
Gaszynski et al. (2012)	RCT	Bariatric surgery	35/35	Rocuronium	Moderate (T2)	2 mg/kg	Neostigmine 0.05 mg/kg with atropine 0.02 mg/kg	CBW	Time to recovery from NMB
Georgiou et al. (2013)	RCT, conference abstract	Bariatric surgery with laparotomy	28/29	Rocuronium	Moderate (T2)	2 mg/kg	Neostigmine 0.05 mg/kg with atropine 0.02 mg/kg	IBW	Time to full decurarization
Georgiou et al. (2013)	RCT, conference abstract	Bariatric Surgery with laparotomy	28/29	Rocuronium	Moderate (T2)	2 mg/kg	Neostigmine 0.05 mg/kg with atropine 0.02 mg/kg	CBW	Time to full decurarization
Foletto et al. (2014)	RCT, conference abstract	Laparoscopic sleeve gastrectomy	17/17	Rocuronium	Moderate (T2)	2 mg/kg	Neostigmine 0.05 mg/kg	TBW	Postoperative recovery of spirometric respiratory parameters
Raziel et al. (2014)	RCT, conference abstract	Bariatric surgery	21/19	Rocuronium	Moderate (T2)	Not available	Not available	Not available	Time to recovery from NMB

RCT=Randomised controlled trials, PTCs=Pass through certificates, TBW=Total body weight, LBW=Lean body weight, IBW=Ideal body weight, CBW=Current body weight, NMB=Neuromuscular blockade

Figure 2

Risks of bias. Green - low risk; yellow - unclear risk; red - high risk

Table 2

Grade of evidences

Quality assessment
Outcome	n designsample size	Summary estimate	Risk of bias	Inconsistency	Indirectness	Imprecision	Quality of evidence
Recovery time to TOF >/= 0.9 (min)	4 RCT 201	MD: −14.52; 95% CI: −20.08–−8.96; P<0.00001	Very serious	No	No	No	⊕⊕◯◯Low
Composite adverse events	3 RCT 198	OR: 0.15; 95% CI: 0.07–0.32; P<0.00001	Serious	No	No	No	⊕⊕⊕◯ Moderate
Residual neuromuscular blockade	2 RCT 97	OR: 0.11; 95% CI: 0.03–0.44; P=0.002	Serious	No	No	Serious	⊕⊕◯◯Low
Time to discharge from PACU	3 RCT 185	MD: −26.66; 95% CI: −43.72–−9.59; P=0.002	Very Serious	Serious	No	NO	⊕◯◯◯Very low

TOF=Train of four, RCT=Randomized controlled trials, MD=Mean difference, CI=Confidence interval, OR=Odds ratio, PACU=Postanesthesia care unit

Both the sugammadex and neostigmine groups were comparable with respect to baseline characteristics in all individual trials. There was no significant difference between the mean age or BMI of the patients in the sugammadex group compared to the neostigmine group (40.7 years [standard deviation (SD) 10.7] vs. 39.3 years [SD 11], P = 0.38; BMI 46.2 [SD 7.7] vs. 45.8 [SD 7.5], P = 0.28; respectively).

Four trials consisting of 201 patients were included in the MA of recovery time of NMB-to-TOF ratio >0.9 between the two groups.[13151718] The trial by Georgiou et al.[18] compared sugammadex and neostigmine based on ideal body weight (IBW) and corrected body weight (CBW). Both datasets from this abstract were included in the analysis. Sugammadex reversed moderate NMB-to-TOF ratio >0.9 significantly faster with a mean of 2.5 min (SD 1.25) in comparison to neostigmine with a mean of 18.2 min (SD 17.6) (MD: −14.52; 95% CI: −20.08, −8.96; P < 0.001; I2 = 96%) [Figure 3a]. An influence analysis, excluding the study by Carron 2013 et al.[13] evaluating reversal of deep NMB, did not change the significance of the results, but the heterogeneity decreased to 57%. There was no difference between the two groups in the recovery time of NMB-to-TOF ratio >0.9, in a sensitivity analysis excluding conference abstracts (MD: −25.99; 95% CI: −63.82, 11.85; P = 0.18; I2 = 99%). Publication bias was investigated using a funnel plot test, Begg's test (P = 0.08), Egger's test (P = 0.06), and fail-safe N-test for each parameter, which were not significant.

Figure 3

Forest plot. CI = confidence interval; IV = Inverse Variance; MD = Mean Difference; M-H = Mantel-Haenszel; OR = Odds ratio; I2: Heterogeneity

Three trials were included in the MA of the incidence of composite adverse events, including pain, bradycardia, and PONV, between the two groups.[131415] The number of patients who had composite adverse events was significantly lower in the sugammadex group, with 21.2% of patients, compared to the neostigmine group, with 52.5% of patients (OR: 0.15; 95% CI: 0.07–0.32; P < 0.001; I2 = 0%; absolute risk decrease: 31.3%) [Figure 3b]. Publication bias was investigated using a funnel plot test, Begg's test (P = 1.00), Egger's test (P = 0.845), and fail-safe N-test for each parameter, which were not significant.

Two trials were included in the MA of the incidence of residual NMB between the two groups [Figure 3c].[1316] Compared to neostigmine, sugammadex use was associated with a significantly lower risk of residual NMB (OR: 0.11; 95% CI: 0.03–0.44; P = 0.002; I2 = 0%). Publication bias could not be investigated because only two trials reported on this outcome.

Three trials were included in the MA of time to discharge from the PACU between the two groups [Figure 3d].[131418] A trial by Georgiou et al.[18] compared sugammadex and neostigmine based on IBW and CBW. Both datasets from this abstract were included in the analysis. Sugammadex was associated with a statistically significant lower mean time of discharge from PACU compared to neostigmine, with a mean time of 89.53 min (SD 39.37) versus 112.21 min (SD 56.98), respectively (MD: −26.66; 95% CI: −43.72, −9.59; P = 0.002; I2 = 90%). A sensitivity analysis, excluding the conference abstract by Georgiou et al.,[18] which contributed to two datasets comparing sugammadex and neostigmine based on IBW and CBW, did not change the significance of the results, but the heterogeneity decreased to 0 (MD: −8.75; 95% CI: −12.96, −4.55; P < 0.001; I2 = 0%). Publication bias was investigated using a funnel plot test, Begg's test (P = 0.308), Egger's test (P = 0.057), and fail-safe N-test for each parameter, which were not significant.

DISCUSSION

Our SR provides evidence that sugammadex is faster and safer in reversing nondepolarizing NMB of rocuronium in MO patients, with fewer adverse effects compared to neostigmine.

We found that sugammadex use was associated with a faster time to recovery of TOF ≥0.9, fewer adverse effects, a significantly lower risk of residual NMB, and a shorter mean time of discharge from PACU compared to neostigmine. This finding agrees with three observational studies which found that sugammadex reversed moderate NMB significantly faster than neostigmine in MO patients.[202122] This can result in a reduced duration of anesthesia, higher flow of patients through the operating theater, and more efficient use of healthcare resources. There are also potential benefits in terms of reduced incidence of PORC[22] and various muscarinic receptor-mediated side effects associated with neostigmine.[6] Although our sensitivity analysis excluding the conference abstracts did not show any difference between the sugammadex and neostigmine groups in the time to recovery of TOF ≥0.9; this finding may be inadequately powered due to paucity in the number of published full RCTs.

A complete recovery of neuromuscular function is crucial to maintain a patent airway and adequate upper airway reflexes in MO patients because of their sometimes-borderline respiratory physiology. PORC, defined as residual paresis after emergence from general anesthesia with neuromuscular blocking drugs,[15] can occur in up to 41% of the general surgical population.[23] Interestingly, PORC occurs more often in MO patients than in nonobese surgical populations (33% vs. 26%).[24] Even a small degree of PORC increases the incidence of critical respiratory events such as acute respiratory failure.[2526] It increases the risk of aspiration due to impaired activity and coordination of the pharyngesophageal muscles.[27] Neostigmine and sugammadex have different mechanisms of NMB reversal. Neostigmine acts by inactivating the enzyme acetyl cholinesterase in the neuromuscular junction, increasing the concentration of acetylcholine to displace rocuronium from the receptors.[28] This indirect mechanism of competitive antagonism results in unpredictable and inadequate reversal of NMB and a risk of PORC.[34] PORC can also occur if reversal with neostigmine is administered too early, when the concentration of the nondepolarizing relaxant is still high in the neuromuscular junction, and the half-life of neostigmine is shorter than that of rocuronium. This improper timing of administration is common as neuromuscular function is not always routinely monitored in daily clinical practice.[15]

Sugammadex acts by a different mechanism of reversal by binding and inactivating the neuromuscular blocking agent permanently, so it can effectively reverse NMB at any stage of muscle relaxation.[6729] We found that sugammadex was associated with a decreased risk of residual NMB versus neostigmine. Johnson et al. found that patients reversed with sugammadex had a significantly higher postoperative peak expiratory flow rate (PEFR) than those reversed with neostigmine and glycopyrrolate.[22] PEFR has been shown to be a good surrogate measure of respiratory muscle strength, with low PEFR indicative of ineffective inadequate protective reflexes from the larynx and pharynx.[2527]

There has been an increase in the number of laparoscopic bariatric surgeries worldwide, as obesity has reached epidemic proportions globally. High doses of neuromuscular blocking agents may be required to facilitate some of these surgeries performed laparoscopically. Currently, laparoscopic sleeve gastrectomy is a preferred method as it is found to give similar results in terms of weight loss and improvement of comorbidities, compared to the gold standard gastric by-pass.[30] Laparoscopic sleeve gastrectomy typically requires a deep NMB.[31] Administration of neostigmine is not recommended for reversal of a deep block, especially in the absence of any sign of neuromuscular recovery. Neostigmine cannot completely reverse profound NMB, even at high doses (70 μg.kg− 1), due to its ceiling effect, when the maximal acetylcholine concentration is unable to adequately compete with the muscle relaxant.[283233] Reversal with sugammadex is found to help in faster and more reliable reversal compared to neostigmine, irrespective of the degree of block at reversal.[6] Our analysis identified one trial comparing neostigmine and sugammadex in reversing profound NMB and found that sugammadex allowed a safer and faster recovery from profound rocuronium-induced NMB compared to neostigmine.[13]

Cardiovascular adverse events such as bradycardia and other cardiac arrhythmias occur more frequently with the use of neostigmine compared to sugammadex.[343536] Muscarinic receptor antagonists such as atropine or glycopyrrolate are administered with neostigmine to counteract unwanted respiratory and cardiac effects, but they, in turn, may cause tachyarrhythmias secondary to their vagolytic effects.[37] In addition, the duration of action of neostigmine, along with its adverse effects, can exceed that of muscarinic antagonist drugs. The direct mechanism of action of sugammadex helps bypass these adverse effects.[6]

Neostigmine augments gastrointestinal motility and hence may increase movement across the surgical anastomosis, potentially causing higher pain scores in these patients. Castro et al. found that the use of sugammadex was associated with less pain in the PACU than neostigmine.[14] This has huge implications in postoperative pain management due to its potential to reduce rescue opioids and associated respiratory and gastrointestinal adverse effects. Neostigmine is also found to be associated with an increased risk of PONV requiring antiemetic drugs.[1438] On the other hand, sugammadex is found to have no effect on the rate of PONV.[39] Our review found that sugammadex was associated with a lower incidence of composite side effects of pain, bradycardia, and PONV when compared to neostigmine.

These beneficial effects of sugammadex over neostigmine would allow a quicker transfer of patients from the PACU and economically efficient care of patients. This effect is important to recognize as the cost of sugammadex has been a major deterrent for its use as an alternative to neostigmine.[40] Several cost–benefit analyses have shown potential economic benefits associated with sugammadex in promoting operating room and PACU turnover, counteracting the drawbacks of its high cost.[214041] Our MA also showed a faster discharge from PACU with sugammadex versus neostigmine. Moreover, sugammadex is superior to neostigmine in terms of patient safety, as it is associated with a lower incidence of PORC and associated complications.[22]

This MA has several potential limitations. Our evidence and interpretations are limited by both the quality and quantity of available evidence in the included trials. All trials had at least one domain at unclear risk of bias and the risk of over- or under-estimation of the true intervention effect, which is a limitation. Our findings are also limited by the availability of evidence from published trials; hence, we also included conference abstracts. The inclusion of unpublished data can have both advantages and limitations. The Cochrane Handbook for SR recommends inclusion of grey literature, such as conference abstracts, because an SR of data from only published reports can present a misleading picture of an intervention's efficacy. That said, a typical abstract may not report all of the information needed to evaluate the methodological quality of the studies.

CONCLUSIONS

With the existing evidence base, we found that sugammadex use was associated with a faster time to recovery of TOF ≥0.9 compared to neostigmine, along with a reduced incidence of residual NMB and side effects such as pain, bradycardia, and PONV. Sugammadex was also associated with faster discharge from the PACU in our analysis. However, as the available literature is presently limited, there is a need for a large RCT evaluating the clinical and cost-effectiveness of sugammadex in this population of MO patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Search history

Set	Results	Save history/Create AlertOpen Saved History	Edit sets	Combine sets ™AND ™ OR Combine	Delete Sets Select all delete
#15	90	#5 and #14 Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#14	4,317	#6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#13	684	KP=Neostigmine Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#12	1,817	AB=Neostigmine Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#11	1,557	TI=Neostigmine Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#10	3,330	TS=Neostigmine Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#9	279	KP=Sugammadex or KP=“selective relaxant binding agent” or KP=“SRBA” or KP=org 25969 or KP=bridion Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#8	711	AB=Sugammadex or AB=“selective relaxant binding agent” or AB=“SRBA” or AB=org 25969 or AB=bridion Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#7	946	TI=Sugammadex or TI=“selective relaxant binding agent” or TI=“SRBA” or TI=org 25969 or TI=bridion Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#6	1,358	TS=Sugammadex or TS=“selective relaxant binding agent” or TS=“SRBA” or TS=org 25969 or TS=bridion Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#5	430,305	#1 or #2 or #3 or #4 Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#4	176,342	KP=Obesity or KP=Obese or KP=Obesity Management or KP=Overweight or KP=Over-Weight or KP=Over Weight or KP=overeating or KP=Over Eating or KP=Over-Eating or KP=Morbidly Obese Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#3	253,078	AB=Obesity or AB=Obese or AB=Obesity Management or AB=Overweight Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#2	170,883	TI=Obesity or TI=Obese or TI=Obesity Management or TI=Overweight Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit
#1	430,256	TS=Obesity or TS=Obese or TS=Obesity Management or TS=Overweight Indexes=SCI-EXPANDED, SSCI, A and HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years	Edit