Sugammadex vs. Neostigmine for Neuromuscular Blockade Reversal in Thoracic Surgical Patients
Condition: Neuromuscular Blockade
Study type: Interventional
Phase: Phase 4

Summary: 
      This prospective, randomized, double blinded study is intended to enroll a total of 92
      patients undergoing thoracic surgery with general endotracheal anesthesia at Parkland
      Hospital. Patients will be randomized to receive either neostigmine or sugammadex for
      reversal of neuromuscular blockade. Merck, Inc. will supply the sugammadex through an
      agreement with Parkland Investigational Drug Services. Neostigmine is readily available for
      anesthesiologists to use and is the current standard of care for reversal of neuromuscular
      blockade. A standardized anesthetic protocol that is usual and customary for the type of
      operation the patient is having will be provided to the anesthesia teams of enrolled
      subjects. The remainder of the anesthetic care of the subject will not deviate from the
      standard of care. The surgeon, anesthesia team, postoperative recovery nurse, and research
      assistant will be blinded as to which reversal drug the patient receives. The only individual
      that will know to which drug the patient has been randomized will be the pharmacist who draws
      up the medication(s). A blinded research assistant will record postoperative outcomes and the
      patient will be followed 90 minutes postoperatively for any adverse events.
    

Detailed description: 
      Screening and Informed Consent:

      A member of the research team will use a screening form to look for surgical patients that
      meet all of the inclusion and exclusion criteria. He/she will approach potential subjects
      during pre-anesthesia evaluation clinic (PAEC). Patients who are unable to be consented in
      PAEC will be approached in the preoperative area and the study will be explained in detail in
      a private room. Patients will be informed that they will receive no compensation for
      participating in the study and there will be no adverse consequences if they choose not to
      participate. If the subjects agree to participate, informed written consent will be obtained
      prior to any study procedures and this document will be sent to
      pmhresearchparticipants@phhs.org, for inclusion in the patient's medical record, per Parkland
      regulations. The study duration is from the start of anesthesia to 90 minutes
      postoperatively.

      Anesthesia Protocol:

      The anesthesia team that will be caring for the subject during surgery will be given the
      protocol for the study, which standardizes the general anesthetic technique. All patients
      will receive 0.6 mg/kg of rocuronium for neuromuscular paralysis during induction. Additional
      rocuronium will be given in 0.15 mg/kg increments to keep the patient at a neuromuscular
      depth of 1 twitch throughout the surgery. All patients will have the depth of neuromuscular
      block monitored at the non-dominant ulnar nerve at 60 mA with a TOF Watch accelerometer
      device, which provides real time feedback of the strength of contraction and graphically
      displays the relevant ratios.

      Maintenance of anesthesia will be with sevoflurane in 70% oxygen, titrated to keep the
      bispectral index (BIS) between 40-60. All patients will have a forced air warming device
      (e.g., Bair Hugger, 3M, Maplewood, MN) used to maintain normothermia throughout the surgery.
      Subjects will be randomized to receive blinded study drug: either neostigmine or sugammadex
      for reversal of neuromuscular blockade, which will be administered intravenously at the
      beginning of skin closure. The anesthesia team will be blinded. The blinded study drug
      (reversal agent(s)) will be prepared into a 10 mL syringe by a pharmacist in Investigational
      Drug Service (IDS) Pharmacy and labeled in a blinded fashion as "sugammadex or
      neostigmine/glycopyrrolate." Any volume of blinded study drug (reversal agent(s)) that is
      less than 10 mL will be supplemented with 0.9% normal saline solution, preservation-free so
      that all syringes contain a volume of 10 mL and appear identical in order to preserve
      blinding. Any patient with clinical signs of inadequate reversal or failure of recovery of
      neuromuscular function [TOFR < 0.2] at 20 min after reversal will receive a rescue dose of
      sugammadex. The remaining aspects of the anesthetic will be standardized and not differ from
      the standard of care and will be similar for all patients.

      Randomization & Dosing:

      Patients will be randomized to one of two groups for reversal of neuromuscular paralysis:

        1. Group 1- neostigmine (NEO group)

             1. Neostigmine 50 mcg/kg, maximum 5 mg

             2. Glycopyrrolate, 8 mcg/kg, maximum 1 mg

        2. Group 2- sugammadex (SUG group). a. Sugammadex 2 mg/kg

      The research coordinator will make randomization envelopes by using a random number
      generator. These envelopes will be provided to IDS Pharmacy before any subjects are screened
      and later only as needed to replenish supply. The words 'neostigmine/glycopyrrolate' or
      'sugammadex' will be printed on a piece of paper and placed in an opaque manila envelope that
      bears a unique subject number (#). Upon receiving the physician order for the subject, the
      IDS Pharmacist will randomize the subject to a treatment group by opening the randomization
      envelope bearing the subject # corresponding to the subject # written on the physician order.

      The Investigator or Co-Investigator will write the patient's total body weight (TBW) on the
      physician order so that the pharmacist can perform necessary dose calculations and draw up
      the appropriate intravenous dose of the blinded study drug (reversal agent(s)): sugammadex OR
      neostigmine/glycopyrrolate. After the blinded study drug syringe is prepared, a pharmacist or
      pharmacy technician will deliver the syringe to the operating room to the anesthesia
      provider, who will sign for receipt of the study drug syringe.

      Blinding/Un-blinding:

      The patient, all medical providers (surgeons, anesthesia faculty, anesthesia residents,
      certified registered nurse anesthetists, nurses), and the postoperative evaluator will be
      blinded as to what reversal agent (sugammadex versus neostigmine/glycopyrrolate) the patient
      receives. A member of the research team that is not involved in the direct care or assessment
      of the patient will provide the randomization envelopes to IDS Pharmacy. IDS Pharmacy staff
      will be the only un-blinded personnel.

      In emergency scenarios where un-blinding becomes necessary (e.g., anaphylaxis), the Principal
      Investigator or Co-Investigators may call the IDS Pharmacy to ascertain which specific
      medication(s) was dispensed. A detailed log of patient enrollments, randomization assignments
      and drug accountability will be kept in Investigational Drug Service (IDS) Pharmacy, which
      has controlled security access.

      Calculation of Key Times:

      The time that the reversal agent (sugammadex versus neostigmine) is given will be marked as
      'Reversal Time', and times to last stitch, extubation, and out of OR will be ascertained from
      the electronic medical record (EMR) (i.e., Epic Systems, Verona, WI). A trained research
      assistant will assess the degree of neuromuscular function the patient has in the early
      postoperative period. Adequate reversal will be defined as a train of four ratio (TOFR) ≥
      0.9. Anything less than 0.9 will be defined as residual paralysis or inadequate reversal.

      Postoperative Recovery Assessment:

      A blinded, trained research assistant will observe and record all parameters during the early
      postoperative period. All episodes of hypoxia will be recorded and any use of supplemental
      oxygen will be recorded. A standard O2 weaning protocol will be used in the PACU. All vital
      signs will be extracted from the EMR. Any drugs given will be recorded.
    

Intervention name(s): Sugammadex; Neostigmine w/ Glycopyrrolate
Intervention type(s): Drug; Drug
Intervention description(s): Sugammadex 2 mg/kg; Neostigmine 50 mcg/kg, maximum 5 mg Glycopyrrolate, 8 mcg/kg, maximum 1 mg
Intervention MeSH terms: Glycopyrrolate; Neostigmine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment