Underdosing of Other General Anesthetics Clinical Trial
Official title:
A Randomized, Parallel-group, Safety-assessor-blinded Phase IV Study to Estimate the Influence of Mild Hypothermia on Reversal of Rocuronium-induced Neuromuscular Block With Sugammadex
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.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT02886806 -
Fully Automated Anesthesia, Analgesia and Fluid Management
|
Phase 1 |