
==== Front
Medicine (Baltimore)
Medicine (Baltimore)
MD
Medicine
0025-7974
1536-5964
Lippincott Williams & Wilkins Hagerstown, MD

MD-D-24-04818
00024
10.1097/MD.0000000000039623
3
3300
Research Article
Clinical Trial/Experimental Study
Effect of sugammadex with neostigmine on postoperative bowel function and on recovery of neuromuscular functions: A randomized controlled trial
https://orcid.org/0000-0003-4455-5342
Postaci Aysun MD a*
Durgut Ridvan MD ridvandurgut35rd@gmail.com
b
Aytac Betul Guven MD drbguven@hotmail.com
a
Ceyhan Meryem MD meryem.u.ceyhan@gmail.com
c
a Department of Anesthesiology and Reanimation, Ankara City Hospital, Health Application and Research Center, University of Health Sciences, Ankara, Turkey
b Department of Anesthesiology and Reanimation, Sedirvan State Hospital, Sakarya, Turkey
c Department of Gynecology and Obstetrics, Lokman Hekim University, Faculty of Medicine, Ankara, Turkey.
* Correspondence: Aysun Postaci, Ankara Bilkent City Hospital, Bilkent Blv. No: 1, Ankara 06800, Turkey (e-mail: aysunposta@yahoo.com).
13 9 2024
13 9 2024
103 37 e3962303 5 2024
01 8 2024
19 8 2024
Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Background:

Early recovery of neuromuscular and bowel function after abdominal surgery are important clinical indicators of postoperative recovery. This study aimed to investigate the effects of sugammadex, and neostigmine added to sugammadex, on postoperative bowel function and recovery from neuromuscular blocking agents.

Methods:

Ninety gynecological surgery patients, aged 18 to 65 years, with American Society of Anesthesiologists of 1 to 2 were randomly assigned to 3 groups: sugammadex 2 mg/kg (Group S), sugammadex 1 m/kg with neostigmine 20 µg/kg + atropine 10 µg/kg (Group S1N), and sugammadex 1.5 mg/kg with neostigmine 20 µg/kg + atropine 10 µg/kg (Group S2N), for reversal at the end of surgery during moderate block (train-of-four [TOF] count 1–2). Propofol, remifentanil, rocuronium, and sevoflurane were used for general anesthesia, and neuromuscular function was assessed using kinemyography. The primary outcomes assessed the effects of sugammadex alone and in combination with neostigmine on the time to first flatus. The secondary outcomes included time to first defecation and recovery time; defined as the administration of reversal agent to TOF ratio 90%.

Results:

Data from 90 female patients who underwent abdominal gynecological surgery were analyzed. No significant differences were found between the groups in term of the time to first flatus, defecation, or postoperative nausea and vomiting after surgery. However, significant differences were observed in the time to reach a TOF ratio 90% (P < .001) and extubation time (P = .003).

Conclusion:

The addition of neostigmine to sugammadex did not affect bowel function recovery. However, combining 20 μg/kg neostigmine with 1.5 mg/kg sugammadex or 2 mg/kg sugammadex alone antagonized moderate-depth nondepolarizing neuromuscular blockade with similar efficacy.

combined use
general anesthesia
neostigmine
postoperative bowel function
postoperative residual curarization
sugammadex
OPEN-ACCESSTRUE
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pmc1. Introduction

Postoperative loss of bowel function is a common condition after surgical procedures, particularly abdominal surgeries. Small bowel motility inhibition and colonic motility are temporary, where small bowel motility inhibition returns within 24 to 48 hours and colonic motility returns within 48 to 72 hour.[1] Postoperative bowel dysfunction causes patient discomfort and prolongs hospital stay. Possible causes of bowel dysfunction include the sympathetic inhibitory pathway, enteric nervous system, hormones, and neuropeptides, inflammation, general anesthesia, and opioids.[2,3]

Nondepolarizing neuromuscular blocking agents (nNMBAs) are commonly used during general anesthesia for neuromuscular relaxation but can cause postoperative residual curarization (PORC), resulting in prolonged muscle weakness. PORC poses a significant threat to patient safety after the administration of nNMBAs.[4,5] In anesthesia practice, acetylcholinesterase inhibitors, such as neostigmine, in combination with anticholinergics like atropine or glycopyrrolate, are routinely used at the end of surgery for the reversal of nNMBAs. Neostigmine is also a prokinetic agent that causes contraction in the small and large intestines by inhibiting acetylcholinesterase; however, it may cause postoperative nausea and vomiting (PONV).[6,7] A more recent development in this context involves the use of sugammadex, a modified gamma-cyclodextrin, which acts via encapsulation to reverse the effects of steroidal nNMBAs (such as rocuronium and vecuronium).[8] Since sugammadex does not have a muscarinic effect, it is expected to show a slower recovery time in postoperative bowel function than acetylcholinesterase inhibitors administration. Although it has been reported that sugammadex leads to faster recovery of bowel function compared to neostigmine, conflicting results have been documented in this regard.[9–12]

This study aimed to investigate the effects of sugammadex and neostigmine added to sugammadex, on recovery from the nNMBAs and postoperative bowel function in patients undergoing abdominal gynecological surgery under general anesthesia.

2. Materials and methods

2.1. Study design and patient selection

This single-center, third-party-blind, prospective, randomized, study was performed at the Ankara City Hospital. This study was conducted in accordance with the principles of in the Declaration of Helsinki. This trial has been registered at ClinicalTrials.gov (ID: NCT05228223). The study protocol was approved by the Institutional Review Board Ankara City Hospital (EK-E1-21-1914).

All participants provided written informed consent before enrollment and approval of the patient consent, 96 female patients with an American Society of Anesthesiologists status of 1 to 2, aged 18 to 65 years, who underwent elective abdominal gynecological surgery, and rocuronium for tracheal intubation and maintenance of neuromuscular blockade were included in this study between October 2022 and August 2023.

Pregnant women; those at risk of malignant hyperthermia; anticipated difficult airways; evidence of neuromuscular, cardiovascular, respiratory, hepatic, or renal disease; patients with a history of gastrointestinal motility disorders; receiving medication at a dose and/or time known to interfere with nNMBAs; those in whom the use of sugammadex, neostigmine, and/or atropine were contraindicated; those with a body weight of 100 kg and above; and those who did not agree to participate in this study were not included.

Patients were randomly allocated, to 3 groups of 30 patients each using sealed envelope randomization. Patients received sugammadex 2 mg/kg (Group S), sugammadex 1 mg/kg with neostigmine 20 µg/kg + atropine 10 µg/kg (Group S1N), and sugammadex 1.5 mg/kg with neostigmine 20 µg/kg + atropine 10 µg/kg (Group S2N) (Fig. 1: flow diagram of the study).

Figure 1. The research flow diagram of the study.

2.2. Anesthetic management and data selection

Routine monitoring of blood pressure, electrocardiography, pulse oximetry (Aisys CS2 GE anesthesia device), and body temperature was initiated in the operating room. After monitoring, the patients were premedicated with intravenous midazolam (1 mg and 100 µg fentanyl) before induction. Neuromuscular function was monitored using the kinemyography electrodes of the Aisys CS2 GE anesthesia device. Before the nerve stimulator electrodes were placed for neuromuscular monitoring, the skin was cleaned and wiped with alcohol. The negative electrode of the nerve stimulator was placed 2 to 3 cm apart. proximal to the skin fold formed when the wrist was flexed, over the ulnar nerve trace, and the positive electrode was placed 2 to 3 cm proximal to the negative electrode. Pre-oxygenation with a well-fitting mask, standard supine position, and anesthetic circuit, with a 10 L/min fresh gas flow and, FiO2 = 80% for 3 minutes (tidal volume method) before anesthesia induction.

After anesthesia induction with propofol 1.5 to 2 mg/kg and fentanyl 100 µg, the kinemyography device was calibrated. Following the control ratio of train-of-four (TOFR), all patient groups received 0.6 mg/kg of rocuronium. Repetitive train-of-four (TOF) stimulation was applied every 20 seconds at the ulnar nerve. When the TOFR reached 0, the patients were intubated, and mechanical ventilation was initiated. Anesthesia was maintained with end-tidal sevoflurane at 1.7% and remifentanil infusion (0.1 µg/kg/min). Throughout the operation, both the patient and infusion fluids were heated. At the end of the surgery, when the TOF count was 1 to 2, patients in Group S received sugammadex at 2 mg/kg, those in Group S1N received sugammadex at 1 mg/kg with neostigmine at 20 µg/kg + atropine at 10 µg/kg, and those in Group S2N received sugammadex at 1.5 mg/kg with neostigmine at 20 µg/kg + atropine at 10 µg/kg.[13] Following the surgery, all patients received intravenous paracetamol (1 g), tramadol (100 mg), and ondansetron (4 mg) as antiemetics. Antagonist agents (sugammadex, neostigmine) were administered intravenously by a blinded anesthesiologist using pre-filled 10 mL syringes in this study. The data and clinical responses were recorded at regular intervals following administration.

The recovery time was defined as the time from the administration of reversal agents to 90% recovery of TOFR. Tracheal extubation was performed after confirming sufficient recovery, defined as a TOF ratio > 90%, the ability to open the eyes, and the ability to maintain a regular breathing pattern. Extubation time was defined as the time from administration of the antagonist agent to extubation of the patient. The parameters checked during the study were as follows.

The recovery time was defined as the time from administration of reversal agents to 90% recovery of TOFR.

Extubation time was defined as the time from the administration of an antagonist agent to extubation.

Heart rate at 5th, 10th, and 15th minutes after antagonist agent administration.

Postoperative residual curarization was defined as TOFR < 90% at the time of extubation.

PONV evaluation in the postoperative recovery unit (during the early postoperative period) was defined as the presence or absence of PONV.[13]

Postoperative first oral intake time (h), time to first passage of flatus (h), first defecation time (h), and 24-h fluid intake (mL) were recorded.

2.3. Outcomes

The primary outcomes assessed the effects of sugammadex alone and in combination with neostigmine on the time to first flatus. The secondary outcomes included time to first defecation and recovery time; defined as the administration of reversal agent to TOFR 90%.

2. 4. Sample size and power

In the study by Sen et al[14] study, assuming that the 6 hour difference in the time of first flatulence between patients would be considered significant, it was calculated that at least 84 patients should be included with an effect size of d = 0.40, 95% power, and error level of 0.05. In the study where the time to first flatus was the primary outcome, the power of the test was found to be 0.74 (74%), with an effect size of f = 0.31, Type I error = 0.05. The calculations were performed using the G*Power 3.1.9.2 package.

2.5. Statistical analyses

IBM SPSS 20 for Windows (SPSS Inc., Chicago, IL) was used for statistical analysis. Mean standard deviation and median, minimum, and maximum values were provided in descriptive statistics for continuous data, and the number and percentage values were provided in discrete data. To compare continuous data in the 3 groups, one-way analysis of variance was used for normally distributed data, and the groups that caused differences were examined using Tukey test. Kruskal–Wallis variance analysis was used for data that did not comply with the normal distribution. The groups from which the difference originated were examined using the Kruskal–Wallis multiple comparison test. To compare the measurements of the patients at different times, analysis of variance in repeated measurements was used for normally distributed data, and the times at which the difference occurred were examined using the Bonferroni test. The Frieman test was used to compare measurements at different times for data that did not comply with normal distribution. The time at which the differences occurred was examined using the Friedman multiple comparison test. Statistical significance was set at P < .05 was considered statistically significant.

3. Results

In this study, 90 of 96 participants who met the research criteria and were accepted for the study were analyzed. A research flow diagram of the study is shown in Figure 1 and the demographic characteristics of the patients and features specific to the operations are shown in Table 1. The demographic characteristics of patients in each group were similar.

Table 1 The demographic characteristics of the patients, and features specific to operations.

	Group S
Mean ± SD	Group S1N
Mean ± SD	Group S2N
Mean ± SD	P value	
Age (yr)	47.00 ± 4.15	45.87 ± 8.48	46.27 ± 7.11	.809*	
Weight (kg)	75.87 ± 10.85	73.70 ± 11.90	72.73 ± 10.69	.540*	
BMI (kg/m²)	28.93 ± 3.75	28.57 ± 3.89	28.43 ± 4.07	.877*	
Type of surgery n(%)	
Adnexal tumor	0	1 (3.3)	0		
Myomectomy	2 (6.7)	6 (20.0)	6 (20.1)		
TAH	1 (3.3)	4 (13.3)	1 (3.3)		
TAHBS	12 (40.0)	8 (26.7)	10 (33.3)		
TAHBSO	15 (50.0)	11 (36.7)	10 (33.3)		
TAH = total abdominal hysterectomy, TAHBS = total abdominal hysterectomy + bilateral salpingectomy, TAHBSO = total abdominal hysterectomy + bilateral salpingectomy oophorectomy.

* P > .05 not significantly different with one-way analysis of variance (ANOVA).

In terms of the study, no statistically significant difference was detected between the groups in terms of the time of the first postoperative oral intake, the amount of fluid intake in the first 24 hours of the postoperative period, and the time of the first postoperative flatus and defecation (P > .05). A statistically significant difference was detected between the groups in terms of the time to reach a TOFR of 90% and extubation time (P < .001 and P < .003, respectively). No statistically significant difference was detected between the groups in terms of heart rate at the 5th, 10th, and 15th minutes after the application of the antagonist agent (P > .05). PORC was not detected after extubation in any of the patients in the 3 groups. Finally, there was no significant difference in the incidence of PONV between the patient groups during the early recovery period (Table 2).

Table 2 Comparing groups in terms of anesthesia time, recovery of neuromuscular function, and postoperative bowel function.

	Group S	Group S1N	Group S2N	P value	
Median
(Min–Max)	Median
(Min–Max)	Median
(Min–Max)	
Anesthesia time (hours)	2.22 (0.50–3.59)	2.08 (1.10–4.28)	2.08 (1.10–4.28)	.850*	
TOFR % 90 (sec)	170 (75–360)	345 (150–720)	345 (150–720)	<.001 **	
Extubation time (sec)	360 (180–1260)	600 (240–1200)	600 (240–1200)	.003 **	
Prevalence of residual curarization	0	0	0	N/A	
Heart rate beats/min
 5th min
 10th min
 15th min	78 (56–111)
76.5 (56–110)
76 (55–105)	77 (52–97)
76 (50–97)
77 (51–95)	77 (52–97)
76 (50–97)
77 (51–95)	.416****
.586****
.589****	
PONV n (%)	8 (26.7)	7 (23.3)	7 (23.3)	.495***	
POP first oral intake time (hours)	6 (2–8)	6 (5–11)	6 (5–11)	.876*	
POP total fluid intake in the first 24 hours (mL)	2850 (1300–3150)	3000 (300–3650)	3000 (300–3650)	.371*	
POP time to first passage of flatus (hours)	12 (3–40)	15 (7–29)	15 (7–29)	.219*	
POP first defecation time (hours)	36 (18–79)	38 (20–60)	38 (20–60)	.054*	
	Group S1N	Group S2N	Group S	P value	
Median
(Min–Max)	Median
(Min–Max)	Median
(Min–Max)	
Anesthesia time (hours)	2.08 (1.10–4.28)	2.05 (1.15–3.05)	2.22 (0.50–3.59)	.850*	
TOFR % 90
(sec)	345 (150–720)	180 (60–600)	170 (75–360)	<.001 **	
Extubation time (sec)	600 (240–1200)	510 (180–1800)	360 (180–1260)	.003 **	
Prevalence of residual curarization	0	0	0	N/A	
Heart rate beats/min
 5th min
 10th min
 15th min	77 (52–97)
76 (50–97)
77 (51–95)	70.5 (57–110)
72 (57–111)
72 (56–109)	78 (56–111)
76.5 (56–110)
76 (55–105)	.416****
.586****
.589****	
PONV n (%)	7 (23.3)	11 (36.7)	8 (26.7)	.495***	
POP first oral intake time (hours)	6 (5–11)	6 (6–9)	6 (2–8)	.876*	
POP total fluid intake in the first 24 hours (mL)	3000 (300–3650)	2500 (1500–3850)	2850 (1300–3150)	.371*	
POP time to first passage of flatus (hours)	15 (7–29)	16 (7–28)	12 (3–40)	.219*	
POP first defecation time (hours)	38 (20–60)	24 (16–72)	36 (18–79)	.054*	
N/A = not applicable, PONV = postoperative nausea and vomiting, POP = postoperative, TOFR = train-of-four ratio.

* P > .05 not significantly different with Kruskal–Wallis variance analysis.

** P < .05 significantly different with Kruskal–Wallis variance analysis.

*** P > .05 not significantly different with Chi-square tests.

**** P > .05 not significantly different with one-way analysis of variance and variance analysis in repeated measurements.

4. Discussion

Our study found that adding neostigmine to sugammadex did not provide additional benefit in the return of bowel function for patients undergoing abdominal gynecological surgery under general anesthesia. The study found that using 2 mg/kg sugammadex or 1.5 mg/kg sugammadex in combination with 20 µg/kg neostigmine and 10 µg/kg atropine had similar effects in reversing the effects of rocuronium and in the recovery of neuromuscular function. This suggests that either combination may be beneficial for patients without compromising safety.

The return of intestinal function after abdominal surgery is crucial for postoperative recovery and impacts hospital discharge timing. It is relevant after various types of surgery and general anesthesia, and is a significant postoperative follow-up parameter.

Neostigmine is a cholinesterase inhibitor that stimulates gastrointestinal smooth muscle, promoting peristalsis in the stomach, intestines, and colon. It is used in surgical and intensive care settings to address postoperative gastrointestinal issues.[15] Sugammadex is used as an antagonist to rapidly and effectively reverse the effects of neuromuscular blockade. It achieves this by selectively encapsulating rocuronium and other nondepolarizing aminosteroid muscle relaxants.[16]

In a comprehensive exploration of neuromuscular blockade reversal agents across diverse surgical scenarios, a series of studies offers valuable insights. In a previous study by Hunt et al,[17] sugammadex led to faster bowel function recovery compared to neostigmine/glycopyrrolate in colorectal surgery, with no PORC observed in either group.

In a retrospective cohort study on intraperitoneal surgery, Deljou et al[9] found that sugammadex resulted in an earlier onset of bowel movements compared to neostigmine/glycopyrrolate. An observational study in abdominal cancer surgery suggested that sugammadex not only hastened bowel function recovery but also led to a reduction in postoperative hospital stay and overall expedited recovery.[17] The absence of a neostigmine comparison in the study raises the possibility that there are various factors that could be influencing the length of postoperative hospital stays.

Tan et al’s retrospective cohort study found that there was no significant difference in postoperative hospital stay with sugammadex compared to other interventions for major abdominal surgery. However, they did observe that patients who received sugammadex had a shorter postoperative ambulation time, earlier first bowel movement, and reduced length of post-anesthesia care unit stay. This suggests that the early and complete recovery of muscle strength in patients who received sugammadex may contribute to early mobilization and a shorter time to the first bowel movement, as opposed to those who experienced spontaneous recovery.[18]

In previous studies, PONV incidence was lower in the sugammadex group compared to the neostigmine group, but in our study, there was no difference. We believe this difference is because our study used atropine instead of glycopyrrolate.[7,13,19]

In a study by Kakinuma et al,[20] a randomized clinical trial was conducted to compare the recovery from nondepolarizing neuromuscular blockade using sugammadex alone versus the combination of sugammadex with neostigmine. In this study, patients in Group S received 1.0 mg/kg sugammadex, while Group SN received a combination of 0.5 mg/kg sugammadex, 0.04 mg/kg neostigmine, and 0.02 mg/kg atropine during deep neuromuscular blockade. The time it took for Group SN to reach 90% TOFR (18.8 ± 8.9 min) was significantly shorter than that for Group S (29.9 ± 7.5 minutes). Aouad et al[21] conducted a study comparing the use of sugammadex at doses of 4 mg/kg and 2 mg/kg with neostigmine at a dose of 50 μg/kg and glycopyrrolate at a dose of 10 μg/kg for reversing deep neuromuscular blockade after rocuronium use during general anesthesia. They found that the times to reach a TOFR of 90% were similar in both groups. The study suggests that using neostigmine and glycopyrrolate may be a safe and cost-saving alternative to sugammadex, which is an expensive agent contributing significantly to anesthesia costs. The cost of neostigmine is approximately 10% that of sugammadex. This indicates that incorporating neostigmine into clinical practice could be a financially prudent strategy.[22] Especially with the use of quantitative neuromuscular monitoring, using these 2 medications together can result in cost savings without compromising patient safety.

The study has several limitations. First, it did not directly compare sugammadex and neostigmine. Second, it did not investigate the effects of higher doses of neostigmine or its long-term postoperative use, which could impact bowel functions. Third, the assessment of PONV was limited to the early postoperative period and did not include more complex or lengthy surgeries, thus presenting a limitation. The study did not consider the cost implications of the interventions, which could limit the generalizability of the findings. Despite these limitations, the study provides valuable insights and creates a foundation for future research in this area.

5. Conclusions

Our findings demonstrate that the addition of neostigmine to sugammadex did not affect bowel function recovery. However, the incorporation of 20 µg/kg neostigmine with 1.5 mg/kg sugammadex, or the use of 2 mg/kg sugammadex alone, antagonized moderate-depth nondepolarizing neuromuscular blockade with similar efficiency. This combination maintains the efficacy of sugammadex while ensuring patient safety.

Acknowledgments

We thank Nazmiye Kursun for the Statistical Evaluation, Ankara University, Faculty of Medicine, Department of Biostatistics.

Author contributions

Conceptualization: Aysun Postaci, Ridvan Durgut.

Data curation: Aysun Postaci, Ridvan Durgut, Betul Guven Aytac.

Formal analysis: Aysun Postaci, Betul Guven Aytac.

Methodology: Aysun Postaci, Ridvan Durgut, Betul Guven Aytac, Meryem Ceyhan.

Project administration: Aysun Postaci.

Software: Aysun Postaci.

Supervision: Aysun Postaci.

Validation: Aysun Postaci, Meryem Ceyhan.

Visualization: Betul Guven Aytac.

Writing – original draft: Aysun Postaci, Ridvan Durgut, Betul Guven Aytac, Meryem Ceyhan.

Writing – review & editing: Aysun Postaci.

Abbreviations:

nNMBAs nondepolarizing neuromuscular blocking agents

PONV postoperative nausea and vomiting

PORC postoperative residual curarization

TOFC train-of-four count

TOFR train-of-four ratio

The authors have no funding and conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

How to cite this article: Postaci A, Durgut R, Aytac BG, Ceyhan M. Effect of sugammadex with neostigmine on postoperative bowel function and on recovery of neuromuscular functions: A randomized controlled trial. Medicine 2024;103:37(e39623).
==== Refs
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