Clinical trial NCT01965067
Conditions: Underdosing of Other General Anesthetics
Sponsor: MSD Korea Ltd.
Start date: 2013-10-01; Completion date: 2014-04-01
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Arms: arm 1: normal thermal condition with core temperatures between 36.5°C and 37°C arm 2: mild hypothermia with core temperatures between 34.5°C and 35°C
Interventions: intervention 1: sugammadex
Intervention descriptions: intervention 1: 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

Protocol documents: