Sugammadex and Decreased Time to Extubation

Primary Efficacy Objective: To demonstrate faster time to extubation after arrival in the
cardiothoracic ICU in patients having a CABG who receive Sugammadex 2mg/kg as compared to
placebo.

Hypotheses: We hypothesize that the use of Sugammadex for reversal of residual neuromuscular
blockade in adults undergoing CABG, AVR or CABG/AVR combination surgery in the cardiothoracic
ICU will significantly decrease the time to extubation.

Prolonged intubation after cardiac surgery continues to be a common clinical challenge and is
associated with significant risks and costs(1-5). Despite a Class I recommendation by the
American College of Cardiology supporting care directed towards early postoperative
extubation after low to medium risk Coronary Artery Bypass Grafting (CABG) surgeries (6), a
sizable proportion of patients continue to have a prolonged course of cardiothoracic
intensive care unit (CTICU) intubation(1). Residual neuromuscular blockade (NMB) continues to
be one of the key factors leading to prolonged intubation after cardiac surgery(7). It is
also a significant contributor to postoperative pulmonary and respiratory complications
including hypoxia, upper airway obstruction; and decreased oxygen saturation - often
prompting reintubation in critical care units(8-10). Due to the profound effects that
neuromuscular reversal agents other than Sugammadex have when used in combination with
muscarinic acetylcholine receptor antagonists on the autonomic nervous system and patient
hemodynamics, these traditional reversal drugs are rarely used in the postoperative cardiac
surgery patient population (11) as opposed to other general surgical cases.

Sugammadex, a gamma-cyclodextrin drug, rapidly reverses neuromuscular blockade by
encapsulating the non-depolarizing amino steroids agents(12) and is not associated with
cardiovascular effects that are commonly seen with traditional NMB reversal agents(13). It
can also reverse NMB more quickly and predictably than existing agents(14). However, there
have been sporadic reports of hypotension(15), anaphylaxis(16), elongated a PTT(17) with the
use of Sugammadex. Additionally, although the FDA currently lists Sugammadex as indicated for
reversal of neuromuscular blockade induced by rocuronium and vecuronium in adults undergoing
surgery,(18) its use in the post cardiac surgery setting is limited due to lack of supportive
data. In this context, the present study aims to test the effectiveness of a pragmatic and
broadly applicable care pathway for shortening time to extubation among patients in the
cardiothoracic ICU who have undergone isolated CABG, AVR or CABG/AVR combination procedure.
The FDA-approved package insert is attached as an appendix to this application.

Study design: Prospective, randomized, double blind, single center placebo-controlled trial.

Number of participants: 110 enrolled with assumed randomization of 90 using 1:1 randomization
between active ingredient (intervention) and control arms, to be assigned randomly using a
computer generated algorithm.

Subject Recruitment: Subjects will be consented in the collaborating surgeons offices or in
pre-admission testing. Every effort will be made to consent subjects prior to day of surgery.
If a patient is referred or identified any time after those visits, they may be consented in
the preoperative area.

Anesthetic management per protocol:For enrolled patients, anesthetic management will be left
to the discretion of the attending anesthesiology provider. As per our usual clinical
practice, Rocuronium or vecuronium will be used as the non-depolarizing NMB and that where
sedation is desired and appropriate, The patients will be transferred to the CTICU intubated
and on a propofol infusion and/or dexmedetomidine per our usual clinical practice.

Upon CTICU arrival, determination of continued eligibility will be determined. If the
decision is made to continue on a fast-track extubation pathway, eligible patients will be
randomized, investigational pharmacy will be contacted for study drug. 30 minutes after the
ICU admission, propofol will be discontinued. Precedex may be continued per clinical
discretion. The participant will be randomized to either receive Sugammadex or placebo. A
qualitative train-of-four measurement will be obtained. The administration of the study and
placebo compounds will be performed by CTICU nurses who will receive the drugs in a blinded
fashion from the departmental research pharmacy. The level of neuromuscular blockade will be
measured by accelerometer before and after the drug/placebo administration by the research
coordinator. This will be done by placing a sheet over the limb being tested, so that the
clinical team remains blinded to the results of the drug /placebo administration. The study
drug will be supplied by Merck. Patients will be initiated on SIMV with 40% FiO2, tidal
volumes 8-10 ml/kg and PEEP of 5.

Ten minutes after the drug administration, if the patient is able to lift head and remains
hemodynamically stable, the patient will be switched to CPAP mode of ventilation for 30
minutes. At the end of the CPAP trial tidal volumes, Rapid Shallow Breathing Index (RSBI) and
ABG will be assessed. The patient will be extubated if he/she is not hypoxic/ hypercarbic,
has RSBI<100 and has TV >300 cc. The final clinical decision to extubate the patients will be
taken by the CTICU team.

If a patient fails the 30 minute CPAP criteria, the ICU intensivist will be immediately
notified. Every attempt will be made to correct the underlying cause of CPAP failure, and a
prompt reassessment will be made as deemed appropriate by the intensivist to reattempt CPAP
versus continuing controlled mechanical ventilation.

It is estimated conservatively that the study personnel will randomize 3 patients per week
allowing for data collection to be completed within 1 year of study commencement. Data
analysis and dissemination of findings will be conducted over the subsequent 6 months by the
study institution investigators per the publication plan below.

Blinded analyses of the data will be performed by the study investigators along with the
departmental statistician in the Department of Anesthesiology at the Yale School of Medicine.

Variables/Time Points of Interest: The primary outcome is the time to extubation, which will
be the duration from arrival to the ICU to the extubation time. Participants' blood pressure,
heart rate, and chest tube output will be tracked from arrival to the CTICU until extubation
per ICU protocol.

Statistical Methods:Baseline comparability. We expect that the randomization process will
produce reasonably comparable groups. However, the adequacy of the randomization will be
assessed by comparing the distribution of baseline demographic and clinical characteristics
among the intervention groups. Comparability for continuous variables will be examined
graphically and by summary statistics (means, medians, quartiles, etc.). Categorical
variables will be examined by calculating frequency distributions.

Proposed statistical test/analysis: Positively skewed variables will be log-transformed prior
to hypothesis testing. For the primary outcome, a two-sided Student's t-test will be used to
compare the time to extubation between the two groups. If necessary, covariate adjustment
will be made using the multiple linear regression analysis method. Differences between means
and 95% confidence intervals will be estimated to describe the magnitude of intervention
difference between the two groups. As part of sensitivity analyses, the time-to-extubation
outcome will be also analyzed by the Cox regression model. To compare the categorical adverse
events between two groups, chi-square test or Fisher's exact test will be used.

Missing Data: Prevention is the most obvious and effective manner to control bias and loss of
power from missing data. Therefore, several strategies (e.g., timely data entry and daily
missing data report) will be imposed to limit the likelihood that missing data will occur
during this study. This protocol will follow the intention to treat principle, requiring
follow-up of all subjects randomized regardless of the actual treatment received.

Power analysis: Our 'in-house' historical data (n = 73) showed that after excluding outliers
greater than the 80th percentile, patients undergoing isolated CABG demonstrated a mean of
8.39 hours to extubation (SD 2.89). Although we anticipate a Hawthorne effect demonstrating
reduced time to extubation in both the active and placebo arms of the present study, we have
conservatively chosen to maintain power based on historical data. We therefore estimate that
45 subjects per group will give us 90% power to detect a clinically relevant effect size of
2-hours difference between active and placebo groups at an alpha value of 0.05 using a
two-sided two-sample t-test. To allow for post consent, pre-randomization study drop out, we
will aim to enroll a total of 110 (90 + 20 = 110) subjects.

Per-protocol Sensitivity Analysis: In parallel with the primary analysis, if exclusions above
occur post randomization but prior to drug administration, the investigators will conduct a
parallel "per-protocol" sensitivity analysis.

Drug supplies will be supplied by the sponsor.

Adverse Experience Reporting: Throughout the duration of the study, researchers will adhere
to good clinical practice and the guidelines of the institution. Patient vitals will be
continuously monitored during and after the administration of the test drug. A data and
safety monitoring board (DSMB) consisting of the head nurse and a senior critical care staff
will meet monthly to discuss any serious events. Any incidence of anaphylaxis or unexplained
hypotension requiring initiation of pressors or cardiac pacing within 5 minutes of drug
administration will be reported an evaluated. Increases in chest tube output considered
clinically significant by the critical care team will be noted. Any of these adverse events
will trigger an analysis by the DSMB. If the DSMB determines that study drug may be causing
an increase in adverse events, the study will be suspended until the DSMB is able to fully
review the events and make a recommendation in consultation with the Yale Human
Investigations Committee. The local Merck research representative will also be notified about
the events. If the data monitoring board and/or institutional review board (IRB) view that
the study is unsafe, the study will be discontinued.

Specific Safety Events to Be Reported During Manuscript Preparation: For manuscript
preparation, the rates of hypotension, anaphylaxis, and bleeding (i.e. Chest Tube output)
will be reported and compared between active and placebo groups.

Inclusion Criteria:

- All elective ARV, CABG cases, on-pump or off-pump, and CABG/AVR in adult patients with
preoperative left ventricular ejection fraction (LVEF) ≥45%.

Exclusion Criteria:

- Emergency/unplanned cases.

- EF<45% or moderate /severe RV dysfunction.

- Estimated GFR < 30 mL/min.

- Patients on supplemental oxygen at baseline (home oxygen).

- BMI>40 (calculated as the patient's weight in kilograms divided by the square of the
patient's height in meters).

- Patients with chronic opioid use preoperatively.

- Patients with known neuromuscular disorders preoperatively.

- Patients with a known sensitivity to Rocuronium or to Sugammadex.

- Patients with known cognitive deficits preoperatively.

Exclusions after recruitment but prior to randomization:

- Postoperative Bleeding (chest tube output >100cc/hr ).

- Treatment of anaphylactoid reaction intraoperatively.

- Patient's temperature<35.5 or >38.3 degree Celsius at the time of ICU arrival.

- Determination that the patient will require prolonged mechanical ventilation possibly
requiring muscle relaxation based on the intraoperative course and clinical judgment
of the study PI or collaborating intensivists.

- Intraoperative hypoxia or on arrival to the ICU. (Please see Study Flowchart).

- Cardiac arrest.

- Sudden arrhythmia (Ventricular tachycardia runs/sudden bradycardia with improper
pacemaker detection/function) precluding fast-track extubation protocol.

- Need for inotrope initiation precluding fast-track protocol.

- Postoperative ST changes.