Two recent pilot studies suggested the potential interest of 100 and 200 Hz tetanic stimulations to detect with mechanomyography (MMG) very low levels of residual neuromuscular blockade (NMB). The Tetanic Fade Ratio (TFR, residual force after 5 seconds / maximal force) measured quantitatively by MMG during tetanic stimulation at 100 or 200 Hz could provide today a more consistent response than the train-of-four (TOF) ratio provided by acceleromyography (AMG) to this search for detection of low levels of residual NMB.

This study was designed to evaluate for the first time in anesthetized patients the evolution of NMB spontaneous recovery with 5-second 100 and 200 Hz tetanic stimulations compared to TOF, and to test the hypothesis that a 200 Hz TFR would better and longer detect low levels of residual paralysis than AMG TOF ratio and 100 Hz TFR.

MATERIALS AND METHODS Patient management The monocentric study protocol was approved before patients' inclusion by the Institutional Ethical Committee (CHU UCL Namur, Yvoir, Belgium, OM 050, under unique belgian registration number B0392022000035).

It was performed in accordance with the ethical standards of the Declaration of Helsinki and was included in the Clinical Trials Registry (XXX).

After obtaining written informed consent from all participants, 20 patients with American Society of Anesthesiologists (ASA) grades I to II (aged 18 to 65 years), who were scheduled to undergo rhinoplasty or rhinoseptoplasty under general anaesthesia, were included in the study. The exclusion criteria were pregnant or breastfeeding women, patients with renal or hepatic insufficiency, patients with neurological disorders, and any patient with a suspected allergy to the drugs used in the protocol or receiving medications that could interfere with neuromuscular transmission. The patient's height, weight, age, and sex were recorded in the protocol to define the population investigated.

The patients were conventionally monitored with a pulse oximeter, a three-lead electrocardiogram and a non-invasive blood pressure monitor scheduled in automatic mode at 5-minute intervals. An intravenous catheter was inserted into their forearm for crystalloid infusion (side at random). Neuromuscular transmission monitoring (NMTM) was set up according to a specific protocol.

Total intravenous anaesthesia was induced with continuous infusion of remifentanil 0.25 µg/kg/min and continuous infusion of propofol 1% to obtain theoretical plasma concentrations ranging from 3 to 6 µg/mL (Diprifusor Cardinal Health, Basingstoke, UK). Lidocaine 1 mg/kg was also given as an intravenous bolus. After loss of consciousness, manual ventilation was provided during NMTM calibration and the initial NMB baseline measurements. Then, rocuronium 0.45 mg/kg was administered. Non-invasive automatic blood pressure measurement was suspended during the neuromuscular onset to avoid dissimilar distribution of the rocuronium in the two arms. Tracheal intubation was performed when the TOF count reached zero. Automatic non-invasive blood pressure measurement was reactivated. Mechanical ventilation (closed circuit, 40% oxygen in air) maintained end-tidal CO2 within the normal range. Anesthesia was maintained with the continuous intravenous administration of remifentanil 0.15 µg/kg/min and propofol with a target plasma concentration of 2 to 4 µg/mL. Blankets prevented heat loss from the body and both arms, and the oropharyngeal temperature was kept stable. Postoperative analgesia was provided with paracetamol, tramadol and alizapride at the end of surgery.

Neuromuscular transmission monitoring

All recordings were performed during general anesthesia. The skin was cleaned with diethyl ether, and two electrodes were placed above the ulnar nerve on each wrist.

A TOF-Watch SX® (Alvesia Pharma, France) (TWSX) was set on the left hand. The accelerometric transducer was taped on the thumb's pulp, and the hand was inserted and held inside an SL TOF tube. Another TOF-Watch® (Organon-Technika, Copenhagen, Denmark) designed to deliver high-frequency tetanic stimulations (including 100 and 200 Hz) was connected to the electrodes on the right arm, which was equipped with an Isometric Thumb Force (ITF®) handgrip designed to record the force (N) of isometric thumb adduction during electrical stimulations. The Visual-ITF® software recorded all measurements for further off-line analysis. Each tetanic signal was described in a 5 sec window starting from the 1 Newton value. If this 1N threshold was not reached, the recording was excluded from the analysis.

Both arms were positioned alongside the body on soft padding to protect nerve structures from any extra focal pressure.

Supra-maximal stimulation and initial calibration were obtained using the TWSX internal automatic sequence, and the current intensity displayed was applied on both sides. Then, TOF stimulations were applied at 15-second intervals during a short stabilisation period. On the TWSX side, four T4/T1 ratios were recorded to determine the initial baseline (mean of four values) before NMBA administration. On the ITF side, two consecutive tetanic stimulations (100 and 200 Hz at random) were applied for 5 seconds, with a two-minute interval to avoid any potentiation. Consecutive TOF stimulations every 15 seconds were applied to monitor the NMB, from the onset and, during surgery, until the spontaneous recovery of a normalized TOF ratio of 0.9 on the TWSX side and even further. Both tetanic stimulations (same order as previously) were applied alternately with 2-minute intervals on several steps of recovery and until recovering 90% of the initial TFR with both stimulation patterns.

Data collection and statistical analysis On the TWSX side, the TOF ratio provided after each 2Hz TOF stimulation was displayed and recorded. We calculated 90% of the initial baseline mean value to determine the normalised TOF ratio 0.9 recovery threshold using the following formula: normalised TOF ratio 0.9 = sum of 4 TOF ratio × 9/40, with the result rounded up.

On the ITF side, a Tetanic Fade Ratio (TFR) was determined to quantify any fade occurring during the muscle contraction: referring to the resting level just before the contraction, the residual force at the end of 5 seconds of stimulation was divided by the maximal force obtained during the contraction to provide a ratio.

Based on a previous pilot study using the same material and the same stimulating patterns, a sample of 20 patients was determined to provide a significant difference between the TFRs recorded with 100 and 200 Hz tetanic stimulations at the time of AMG TOF ratio 0.9 recovery. We expected to have enough power (0.8 at that stage) to detect a significant difference during an additional period of recovery. The alpha error was 0.05.

Off-line data analysis was based on the archived files. Using R software version 3.3.6 (R Project for Statistical Computing, Vienna, Austria), Student's t-tests were performed to compare the TFR obtained after 100- or 200-Hz stimulations at initial baseline and at several classical levels of spontaneous recovery on the TWSX side:

• TOF count 1,
• TOF ratio 0.5,
• TOF ratio 0.9
• Normalized TOF ratio 0.9
• TOF ratio 0.95
• TOF ratio 1.0 Then, both tetanic stimulations were repeated every 5 minutes until TFR reached 0.9 to quantify any further period of analysis of low levels of residual blockade.

Inclusion Criteria:

• ASA I-II
• written informed consent
• general anesthesia for rhino(septo)plasty

Exclusion Criteria:

• pregnant or breastfeeding women
• patients with renal or hepatic insufficiency
• patients with neurological disorders
• patients with a suspected allergy to the drugs used in the protocol
• patients receiving medications that could interfere with neuromuscular transmission