The Effect of Sugammadex Versus Neostigmine on Postoperative Pulmonary Complications

NCT ID: NCT02861131

Last Updated: 2020-03-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-24
• Study Completion Date: 2018-04-30

Brief Summary

Substantial respiratory morbidity has been associated with postoperative residual paralysis, which is fairly common after general anesthesia involving a neuromuscular blocking agent. Common practice in United States is to reverse neuromuscular blockade with neostigmine at the end of surgery. A new drug with evidence of more complete neuromuscular reversal has been developed, sugammadex. The objective of this study is to determine if a strategy of rocuronium neuromuscular reversal with sugammadex will reduce the proportion of subjects with any postoperative pulmonary complication, compared to neostigmine.

Detailed Description

This study is designed to be an assessor-blinded, randomized, controlled, single center, parallel design trial at Oregon Health and Science University (OHSU) in Portland, Oregon. The investigators will enroll patients ≥ 70 years of age that are mentally competent to consent for anesthesia with a scheduled surgical length of ≥ 180 minutes on Monday through Friday in the South Operating Room Theatre at Oregon Health and Science University.

Subjects will be screened for inclusion in the study on either the day prior or the day of surgery. The initial review will occur by a quick view of the surgical posting sheet for the South Operating Rooms. Subjects undergoing any type of surgery will be eligible as long as neuromuscular paralysis is a component of the planned anesthetic. If subjects initially seem appropriate for inclusion, a more in depth chart review will occur. The research coordinator will approach patients that meet inclusion criteria in the Pre-operative Care Unit. Initially all patients 70 years of age or older will have equal probability of being approached for the study. At the halfway point of the study the investigators will monitor enrollment, and if ahead of schedule, preferentially select older patients in the 2nd half of the study-a group that is more likely to have Postoperative Pulmonary Complications (PPCs).

All subjects that are approached for recruitment will hear a description of the study, reasons for pursuing this research question, options for opting out the research protocol or not completing data collection, and potential risks, advantages, and disadvantages from participating. Subjects that agree to participate in the study will be asked to sign a written informed consent that has been approved by our Institutional Review Board. All subjects that agree to participate in the research study will be given a form describing the research study and providing contact information for the principal investigators. The subject's status in the research project will show up clearly on our medical records in their problem list, until the subject's time of participation is complete. A progress note will be placed in the subject's chart to allow other providers to easily contact study investigators. In addition, an electronic copy of the signed consent will be scanned into the medical records system and a copy of the signed consent will be made available for the subject to take home.

All subjects enrolled will have the following characteristics recorded by the research coordinator: age, sex, weight, body mass index, American Society of Anesthesiologists physical status classification score, creatinine clearance, and Charlson comorbidity index.

Subjects will be allocated to either neuromuscular reversal with sugammadex or neostigmine. Before study activation a sample of 200 sequentially numbered opaque envelopes will be prepared by an investigator not involved in patient recruitment, allocation, consent, or assessment: 100 for the sugammadex arm and 100 for the neostigmine arm. Patient allocation will occur in the operating room when the anesthesia provider notifies the coordinator that reversal is appropriate. At that time the research coordinator will open the lowest remaining numbered free envelope. Group assignment will be determined by a computer generated random number sequence produced in Excel (Redmond, Washington). The random number sequence will be generated by an investigator not involved in either patient enrollment or patient assignment. Reversal of rocuronium neuromuscular blockade (i.e. sugammadex or neostigmine) will be defined in the opened opaque envelope. Once a study subject signs a consent form, a unique number corresponding to the opened opaque envelope will be assigned to that subject. The envelope will not be opened until the anesthesia provider is ready to prepare and administer reversal of neuromuscular blockade. This subject number will never be reused and will remain with the subject for the entirety of the study. No subject will ever be allowed to have more than one unique subject number.

The subject, anesthesia providers, and research coordinator performing consent and recruitment will not be blinded to the study drug. The anesthesiologists will not be blinded for reasons of patient safety. The assessor of PPCs, residual neuromuscular blockade, secondary outcomes, exploratory outcomes, and adverse event accounting will be blinded to study drug and will not be allowed in the operating room during surgery.

All subjects will have standard American Society of Anesthesiologists monitors plus five lead electrocardiogram applied. Additional monitoring needs will be left up the anesthesia team directing patient care. Decisions with regards to induction and maintenance of anesthesia will also be left up to the direction of the anesthesia team with the exception that rocuronium will be mandated for maintenance of neuromuscular blockade. Decisions on when to dose and what quantity of rocuronium should be dosed for maintenance of neuromuscular blockade will be left to the discretion of the anesthesia team in the operating room. The level of neuromuscular blockade will be monitored in the operating room at the adductor pollicis muscle with a basic peripheral nerve stimulator monitor that does not have train-of-four ratio capability. Train-of-four counts will be mandated every 15 minutes, which is our current practice at OHSU. Anesthesia providers will be asked to maintain neuromuscular blockade at a T2 level throughout surgery and reverse neuromuscular blockade at as close to a T2 level as safely possible. Administration of sugammadex or neostigmine will occur into a fast flowing IV that is running wide open. Sugammadex will be dosed at 2 mg/kg and neostigmine will be dosed at 0.07 mg/kg to a maximum of 5 mg. Glycopyrrolate will be co-administered in the neostigmine arm at a dose between 0.1 to 0.2 mg of glycopyrrolate per 1.0 mg of neostigmine administered.

In accordance with standard of practice at OHSU, all subjects will have convective warmers used during the case and subject temperature will be monitored. Ventilation parameters will be left to the discretion of the anesthesia team in the operating room.

A train-of-four ratio will be obtained in all subjects within 5 minutes of arrival to the Post-Anesthesia Care Unit (PACU) with a Train-of-four Watch-SX Acceleromyograph. In order to measure the train-of-four ratio in the PACU the train-of-four watch will be set up and calibrated on the subject upon arrival in the OR, prior to the administration of any neuromuscular blocking agent. The accelerometer sensor will be attached to the subject's thumb. The subject's fingers and forearm adjacent to the thumb attached to the accelerometer sensor will be fixed with tape to an arm board to minimize artifact. Ulnar nerve stimulation of the adductor pollicis muscle will be measured via the Train-of-four watch. As twitch height will vary from subject to subject, a control twitch height value of 100% for the 1 Hz mode will be calibrated after a 5 second, 50 Hz tetanic stimulation. This calibration will be used to obtain a train-of-four ratio upon 5 minutes of arrival to the PACU. A train-of-four ratio of less than 0.9 will be considered residual neuromuscular blockade.

Active monitoring of adverse events (desaturation, hypoxemia, upper airway obstruction, aspiration pneumonitis, bronchospasm, laryngospasm, drug hypersensitivity reaction, and recurarization) will be conducted on an ongoing basis until discharge with daily assessments by the research coordinator and/or principal investigator. Assessment of PACU phase 1 recovery time will occur on Post-operative day (POD) #0 or POD #1. Assessment of hospital length of stay will be assessed within a week of discharge by electronic medical record review. Hospital readmission data will be assessed within 1 to 2 months of hospital discharge. National Surgical Quality Improvement Program (NSQIP) 30-day postoperative risk-adjusted respiratory complications will be assessed and recorded prior to data analysis at the conclusion of patient enrollment and study implementation.

Conditions

Postoperative Complications; Neuromuscular Blockade

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: SINGLE

Study Groups

Sugammadex

Sugammadex 2 mg/kg IV once at the end of surgery

Group Type: EXPERIMENTAL

Sugammadex

Intervention Type: DRUG

At the end of the surgical procedure at a depth of neuromuscular blockade after the reappearance of T2 on the train-of-four, Sugammadex will be dosed once at 2 mg/kg through an intravenous line with brisk flow

Neostigmine

Neostigmine 0.07 mg/kg to a maximum of 5 mg (+ Glycopyrrolate 0.1-0.2 mg per 1 mg of Neostigmine administered) IV once at the end of surgery

Group Type: ACTIVE_COMPARATOR

Neostigmine

Intervention Type: DRUG

At the end of surgical procedure at a depth of neuromuscular blockade after the reappearance of T2 on the train-of-four, Neostigmine will be dosed once at 0.07 mg/kg to a maximum of 5 mg through an intravenous line with brisk flow. Glycopyrrolate will be administered with Neostigmine at a dose between 0.1 to 0.2 mg of Glycopyrrolate per 1.0 mg of Neostigmine administered.

Interventions

Sugammadex

At the end of the surgical procedure at a depth of neuromuscular blockade after the reappearance of T2 on the train-of-four, Sugammadex will be dosed once at 2 mg/kg through an intravenous line with brisk flow

Intervention Type: DRUG

Neostigmine

At the end of surgical procedure at a depth of neuromuscular blockade after the reappearance of T2 on the train-of-four, Neostigmine will be dosed once at 0.07 mg/kg to a maximum of 5 mg through an intravenous line with brisk flow. Glycopyrrolate will be administered with Neostigmine at a dose between 0.1 to 0.2 mg of Glycopyrrolate per 1.0 mg of Neostigmine administered.

Intervention Type: DRUG

Other Intervention Names

Org 25969; Bridion; Prostigmin; Vagostigmin

Eligibility Criteria

Inclusion Criteria

• Age ≥ 70 years
• Elective surgery Monday through Friday in the South Operating Rooms of Oregon Health and Science University (OHSU)
• Planned general endotracheal anesthesia
• Expected surgical duration ≥ 3 hours

Exclusion Criteria

• Prisoners
• An inability to consent for surgery or anesthesia
• Surgery for which neuromuscular blockade is contraindicated (e.g. neurosurgical, orthopedic, and head and neck surgery in which nerve monitoring will be employed)
• A known neuromuscular disorder
• Stage 4 chronic kidney disease or worse (estimated glomerular filtration rate < 30 ml/min)
• Liver Disease
• An allergies to Sugammadex, Rocuronium, Neostigmine, or Glycopyrrolate
• Patients taking Toremifene

• Minimum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Oregon Health and Science University

OTHER

Sponsor Role: lead

Responsible Party

Brandon M Togioka

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Brandon M Togioka, MD

Role: PRINCIPAL_INVESTIGATOR

Oregon Health and Science University

Locations

Oregon Health and Science University

Portland, Oregon, United States

Countries

United States

References

Togioka BM, Yanez D, Aziz MF, Higgins JR, Tekkali P, Treggiari MM. Randomised controlled trial of sugammadex or neostigmine for reversal of neuromuscular block on the incidence of pulmonary complications in older adults undergoing prolonged surgery. Br J Anaesth. 2020 May;124(5):553-561. doi: 10.1016/j.bja.2020.01.016. Epub 2020 Mar 2.

Reference Type: DERIVED

PMID: 32139135 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

MISP #55196

Identifier Type: -

Identifier Source: org_study_id