Clinical trial NCT05661409: Sugammadex as Rescue Therapy
Official title: The Use of Sugammadex as Rescue Therapy Following Inadequate Reversal With Neostigmine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Neuromuscular Blockade
Keywords: Neostigmine
Sugammandex
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: National Center for Advancing Translational Sciences (NCATS)
name: Georgia Clinical & Translational Science Alliance (CTSA)
First posted: 2022-12-22
Enrollment: 71
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Neuromuscular blocking agents (NMBAs) are commonly used in the practice of anesthesiology for skeletal muscle relaxation to facilitate tracheal intubation, mechanical ventilation, and to provide optimal surgical conditions. In order to prevent residual NMB, it is vital to adequately reverse any use of a non-depolarizing NMBA. This was historically done using an anticholinesterase such as neostigmine, which would increase the concentration of acetylcholine at the neuromuscular junction leading to the return of neuromuscular transmission. Unfortunately, there are disadvantages to the use of an anticholinesterase. It was in this context that sugammadex was found to be a valuable addition to the anesthesiologist's armamentarium. It is a modified γ-cyclodextrin that encapsulates the aminosteroid NMBAs rocuronium and vecuronium.

This project is a double-blind randomized placebo-controlled dose-response trial that aims to determine the time taken to achieve adequate reversal comparing five doses of sugammadex as rescue therapy following inadequate reversal with neostigmine. The study team will recruit patients aged 18 years and above from the main operating room and outpatient surgery center at Grady Memorial Hospital who are undergoing elective surgery under general anesthesia, who has received NMB, received neostigmine for NMB reversal, and achieved a TOF count ≥ 3 twitches but not a TOF ratio of 0.9 fifteen minutes after neostigmine was given. Those with a TOF count \< 3 twitches will drop out of the study as there are already specified doses of sugammadex for that level of NMB

Detailed description: Neuromuscular blocking (NMB) agents are commonly used in the practice of anesthesiology for skeletal muscle relaxation to facilitate tracheal intubation, and may require reversal in order to prevent residual NMB. This was historically done using an anticholinesterase such as neostigmine, which has many adverse effects and may not effectively reverse a deep NMB. However, the introduction of sugammadex was instrumental in allowing the rapid return of neuromuscular function. The FDA has only approved three doses of sugammadex (2 mg/kg, 4 mg/kg and 16 mg/kg) depending on the train of four (TOF) count, which is a qualitative measure of the depth of NMB and ranges from 0 to 4 twitches. Conversely, the TOF ratio is a quantitative measure, is calculated using the ratio of the amplitude of the fourth twitch to the first twitch, and ranges from 0 to 1. A TOF ratio of 0.9 is generally accepted as the minimum threshold to safely extubate a patient, but this information is not always readily accessible as many anesthesia providers do not have a quantitative NMB monitor.

In 2020, Carvalho et al. conducted a meta-analysis of 53 studies (12,664 adult patients) where the pooled residual NMB incidence ranged from 0.115 when quantitative neuromuscular monitoring was used to 0.331 where no neuromuscular monitoring was used. Ravel et al. conducted a meta-analysis of 20 randomized controlled trials (1,923 adult patients), where residual NMB was found in 2.8% of patients who received sugammadex compared to 39% of those who received neostigmine 15 minutes post administration. Concerningly, 60 minutes after administration, 2.1% of the sugammadex group versus 19% of the neostigmine group still had NMB. When expanded to observational studies (58 studies with 25,277 adult patients), the incidence of residual NMB ranged from 0% to 90.5% (median 30%), which was significantly lower (0% to 16%) in the sugammadex group compared to 3.5% to 90.5% in the neostigmine group and 15% to 89% in the spontaneous recovery group.

This project is a double-blind randomized placebo-controlled dose-response trial that aims to determine the time taken to achieve adequate reversal comparing five doses of sugammadex as rescue therapy following inadequate reversal with neostigmine. The study team will recruit patients aged 18 years and above from the main operating room and outpatient surgery center at Grady Memorial Hospital who are undergoing elective surgery under general anesthesia, who has received NMB, received neostigmine for NMB reversal, and achieved a TOF count ≥ 3 twitches but not a TOF ratio of 0.9 fifteen minutes after neostigmine was given. Those with a TOF count \< 3 twitches will drop out of the study as there are already specified doses of sugammadex for that level of NMB.

These patients will then be randomized to six groups: 2 mg/kg (the lowest dose approved by the FDA), 1 mg/kg, 0.5 mg/kg, 0.25 mg/kg, 0.125 mg/kg of sugammadex, and placebo. The time taken to reach a TOF ratio of 0.9 thereafter would be measured and compared for statistically significant differences.

Eligibility criteria: Inclusion Criteria:

* Patients aged 18 years and above who will undergo an elective surgery in the main operating room or outpatient surgery center at Grady Memorial Hospital
* Receive general anesthesia (standardized to sevoflurane for maintenance)
* Receive rocuronium for NMB
* Receive neostigmine for NMB reversal
* Achieve a TOF count of at least 3 twitches but not a TOF ratio of 0.9 fifteen minutes after neostigmine has been given
* Able and willing to provide informed consent.

Exclusion Criteria:

* Pregnancy and/or lactating
* BMI ≥ 40
* Severe renal impairment, i.e. chronic kidney disease stages IV and V as defined by GFR \< 30 ml/min/1.73 m2
* Severe hepatic impairment, i.e. Child-Pugh score C
* Pre-existing neuromuscular disease
* Anticipated need for postoperative intubation, and/or known hypersensitivity reactions to rocuronium, neostigmine and/or sugammadex.
* Adults unable to consent
* Prisoners
* Cognitively impaired or Individuals with Impaired Decision-Making Capacity
* Individuals who are not able to clearly understand English

Primary outcomes:
measure: The time taken to achieve a TOF ratio of 0.9 after administration sugammadex
timeFrame: 10 minutes post administration of study drug
Secondary outcomes:
measure: The percentage of patients who achieve a TOF ratio of 0.9
timeFrame: 1 minute, 2 minutes and 10 minutes post administration of study drug
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Grady Memorial Hospital
state: Georgia
Study officials:
affiliation: Assistant Professor
name: Rebecca Wong, MBBS, MPH
role: PRINCIPAL_INVESTIGATOR
References: