The Effect of Sugammadex Versus Neostigmine on Postoperative Pulmonary Complications

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.

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