Influence of Mild Hypothermia on Reversal of Rocuronium With Sugammadex
Condition: Underdosing of Other General Anesthetics
MeSH terms: Hypothermia
Study type: Interventional
Phase: Phase 4

Summary: 
      The primary efficacy endpoint is the time from the start of administration of sugammadex to
      recovery of the TOF ratio to 0.9 in deep neuromuscular block (1-2 twitches post-tetanic
      count) induced by rocuronium during mild hypothermia with core temperatures between 34.5°C
      and 35°C, and compared with the normal thermal condition.

      Secondary endpoints include time from the start of administration of sugammadex to recovery
      of the TOF ratio to 0.7 or 0.8 in both groups, vital signs [heart rate and blood pressure] at
      pre-reversal, post-reversal, recovery and post-anesthetic visit, the incidence of residual
      neuromuscular blockade, post-operative nausea and vomiting (PONV) and adverse events during
      mild hypothermia and the normal thermal condition.

      We hypothesize that mild hypothermia with core temperatures between 34.5°C and 35°C diminish
      the efficacy of sugammadex.
    

Detailed description: 
      This randomized, parallel-group, safety-assessor-blinded phase IV study will be conducted.
      The study is conducted in accordance with principles of Good Clinical Practice and is
      approved by the appropriate Institutional Review Boards and regulatory agencies. Written
      informed consent is obtained from all patients.

      In total, 60 patients, aged from 20 to 65 years, with an American Society of
      Anesthesiologists physical status of I or II and undergoing elective abdominal surgery with a
      general anesthesia in the supine position will be studied. Patients are excluded if they are
      expected to have a difficult airway, known neuromuscular disease, significant hepatic or
      renal dysfunction, family history of malignant hyperthermia, known allergy to one of the
      drugs used in this protocol, intake of any medication that might interact with muscle
      relaxants, pregnant, or breast feeding.

      The anesthetized patients are randomly assigned to 2 groups as normal thermal condition with
      core temperatures between 36.5°C and 37°C (C group) and mild hypothermia with core
      temperatures between 34.5°C and 35°C (H group) in deep block state (1-2 twitches post-tetanic
      count). The randomization is performed by using computer-generated sealed envelopes to
      determine which condition (normal thermal condition or mild hypothermia) the patients are
      performed during deep block state (1-2 twitches post-tetanic count). The anesthesiologist
      remains blinded to the C group or H group during deep block state (1-2 twitches post-tetanic
      count) given throughout the remaining course of anesthesia. No premedication is given. After
      arrival to the operating room, electrocardiography, non-invasive measurement of blood
      pressure and oxygen saturation are performed. All patients are connected to a bispectral
      index (BIS) monitor (Model A 2000, Aspect Medical Systems, Natick, MA, USA). Anesthesia is
      induced with remifentanil 0.5 μg/kg/min injected intravenously over 120 seconds (s) followed
      by propofol 2 - 2.5 mg/kg injected intravenously over 30 s. After loss of consciousness and
      ventilation via facemask with a fresh gas flow at 4 L/min (50% nitrous oxide in oxygen)
      control manually to maintain the end-tidal carbon dioxide (CO2) at 30 to 35 mmHg. Maintenance
      of anesthesia is with 1 - 1.5 minimum alveolar concentration (MAC) of sevoflurane in a gas
      mixture of 50% nitrous oxide in oxygen to maintain a BIS between 40 and 50 and infusion doses
      of remifentanil 0.05 - 0.2 μg/kg/min throughout surgery.

      Core body temperature is measured by a thermocouple placed in the distal esophagus (DeRoyal®,
      DeRoyal Industries Inc., Powell, TN, USA). Core temperature is manipulated in core
      temperature ranges: 36.5°C and 37°C in C group and 34.5°C and 35°C in H group by surface
      cooling with wet towels and a fan of air conditioner. The target temperature, once achieved
      and stabilized, is maintained within ± 0.1°C throughout the remainder of the study. The
      peripheral skin temperature on the wrist is maintained more than 32°C in both groups.

      Neuromuscular function is assessed using acceleromyography of the adductor pollicis muscle
      (TOF-Watch SX®, Organon Ltd., Dublin, Ireland). Before placing the surface electrodes, the
      skin overlying the ulnar nerve of the dominant hands is cleansed with isopropyl alcohol. Two
      electrodes (CleartrodeTM, Ref 1720-003, ConMed®, Utica, NY, USA) are placed over the prepared
      skin on the wrist. A force displacement transducer is attached to the thumb. No special arm
      board is used and no preload is applied to the thumb during the entire study procedure.

      After the loss of eyelash reflex is confirmed, neuromuscular monitoring begins immediately.
      For the calibration of acceleromyography, a 5-s 50-Hz supramaximal tetanic stimulus is
      administered over the ulnar nerve. Calibration is done using the CAL2 mode of the TOF-Watch
      SX. A supramaximal current is obtained after the initial single twitch calibration. After
      stabilization of control responses, rocuronium (0.6 mg/kg) is administered and tracheal
      intubation is performed at the disappearance of the TOF response. Ventilation is adjusted to
      maintain end-tidal carbon dioxide between 30 and 35 mm Hg. Train-of-four (TOF) stimulation
      (0.2 ms duration, frequency 2 Hz, 2 s duration with supramaximal current) is performed every
      15 s. When no TOF response could be detected, the investigators performed post-tetanic count
      (PTC) stimulation manually every 6 min to monitor more profound neuromuscular block. As soon
      as muscle relaxation is no longer required after surgical dressing and the TOF-Watch SX
      reading is 1 - 2 PTCs, a single IV bolus dose of sugammadex 4.0 mg/kg is administered in deep
      block state. After the recovery of the TOF ratio to 0.9 is completely confirmed, inhalation
      agent is finished. Extubation is carried out after confirming the recovery of consciousness
      and regular respiration. All neuromuscular data are collected on a computer and monitored
      throughout the study. Skin temperature on the wrist is maintained to more than 32°C using a
      wrapping cotton wool.

      Each patient is monitored for safety for up to 7 days after administration of the study drug.
      Safety variables comprise all reported adverse events (AEs)(including serious AEs), coded
      using the Medical Dictionary for Regulatory Activities, vital signs, physical examination,
      and clinical evidence of residual neuromuscular block (NMB) and recurrence of NMB. A blinded
      safety assessor performs the safety assessments in the post-operative period and in the
      follow-up period. The anesthesiologist administering the anesthesia during the surgical
      procedure is not blinded to the randomized study drug, but the safety assessor is not allowed
      to reveal the assigned treatment group.

      Risk factors for post-operative nausea and vomiting (PONV) are also assessed at baseline and
      used to assess the likelihood that any occurrences of PONV are associated with study therapy.
      Subsequent incidence of PONV is determined from AEs coded with the Medical Dictionary for
      Regulatory Activities preferred terms of nausea, procedural nausea, vomiting and procedural
      vomiting.
    

Intervention name(s): sugammadex
Intervention type(s): Drug
Intervention description(s): sugammadex 4.0 mg/kg is administered in deep block state(1 - 2 PTCs) in different temperature state
Reversal effect of sugammadex in temperature state
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment