Electromyographic Activity of the Respiratory Muscles During Neostigmine or Sugammadex Enhanced Recovery After Neuromuscular Blockade

Study Overview
=================
Brief Summary
-----------------
It was recently shown that neostigmine reversal was associated with increased atelectasis and that high-dose neostigmine was associated with longer postoperative length of stay and with an increased incidence of pulmonary edema and reintubation. These study results were consistent with findings from a previous epidemiological study which revealed an absence of beneficial effects of neostigmine on postoperative oxygenation and reintubation. In our previous study, the effects of neostigmine / glycopyrrolate and sugammadex on the electromyographic activity of the diaphragm showed beneficial effects for sugammadex. This could be explained by a possible effect on neuromuscular transmission at the muscle level, but can also be explained by a neostigmine-induced decrease in total nerve activity. In a study in cats, neostigmine has been shown to reduce efferent phrenic nerve activity. The investigators aim to show a difference in phrenic nerve activity between neostigmine and sugammadex, administered alone or in combination, in healthy male volunteers.

Detailed Description
-----------------
An auxiliary surface EMG will be recorded via ordinary skin electrodes at the diaphragm, and intercostal and rectus abdominis muscles. The degree of neuromuscular blockade is continuously measured by accelerometry of the adductor pollicis muscle with ulnar nerve stimulation (TOF-watch SX®). Anesthesia is induced with propofol and remifentanil. Manually assisted ventilation with an air/oxygen mixture of 40% oxygen is started as soon as patients are becoming apnoeic. Train-of-four (TOF) monitoring starts after the induction of anesthesia (before rocuronium administration) and continues until awakening. The investigators will insert a 16 Fr. nasogastric catheter which allows electrical activity of the diaphragm (Edi) registration (NAVA, Maquet, Solna, Sweden). After baseline measurements, 0.6 mg/kg rocuronium is injected. After tracheal intubation, subjects will be ventilated by a standard ventilation mode (tidal volume 7 ml/kg, frequency of 12 breaths per minute, inspired oxygen fraction of 30%), with end-tidal PCO2 targets of 30-35 mmHg and a PEEP of 5 cmH2O. SpO2 values will be maintained at ≥98%. Spontaneous recovery is allowed to progress until the re-appearance of the second twitch of the TOF. The volunteers will then receive either sugammadex 2mg/kg or neostigmine 50µg/kg + glycopyrrolate 10µg/kg (using the commercially available 5:1 co-formulation) or neostigmine 50µg/kg followed 3 minutes later by administration of sugammadex 2mg/kg. At the onset of spontaneous respiration, an arterial blood gas sample will be drawn. NAVA catheter positioning will be confirmed using the 'Edi catheter positioning' tool as soon as a signal is received. A second arterial blood gas sample will be drawn at the moment of awakening. Diaphragm electromyographic activity (Edi, obtained from the NAVA catheter), airway pressure and flow are acquired at 100 Hz from the ventilator via an interface connected to a computer using commercially available software (Maquet Critical Care, Solna, Sweden). The auxiliary surface EMG will be recorded with a dedicated device (Dipha16, InBiolab, Groningen, The Netherlands) at the diaphragm, and intercostal and rectus abdominis muscles. All data will be stored and later analysed.

Official Title
-----------------
Electromyographic Activity of the Diaphragm and of the Rectus Abdominis and Intercostal Muscles During Neostigmine, Sugammadex, or Neostigmine-sugammadex Enhanced Recovery After Neuromuscular Blockade With Rocuronium. A Randomised Controlled Study in Healthy Volunteers

Conditions
-----------------
Respiratory Muscles, Electromyography

Intervention / Treatment
-----------------
* Drug: Sugammadex
* Drug: Neostigmine
* Drug: Neostigmine-sugammadex


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Only male, healthy volunteers will be enrolled after an in-depth interview. Each participant must have the mental capacity to decide whether he takes part in the trial or not. Each participant must voluntarily give his written informed consent. Each participant must be between 18 and 40 years of age. Each participant must meet the American Society of Anaesthesiologists class I criteria. Exclusion Criteria: The participant is known or suspected to have a neuromuscular disorder. The participant is known or suspected to have an allergic reaction to sugammadex, rocuronium, anaesthetic medications, or any drugs used during general anaesthesia. The participant is known or suspected to have an anatomical malformation impeding a proper intubation. The participant is known or suspected to have a history of malignant hyperthermia. The participant is known to have a renal insufficiency . The participant is known or suspected to have a chronic obstructive pulmonary disease GOLD classification 2 or higher. The participant is known to have an infection of the upper or lower airways, as diagnosed by clinical findings.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: sugammadex<br>Selective relaxant binding agent | Drug: Sugammadex<br>* Administration of sugammadex 2mg/kg for enhanced recovery after neuromuscular blockade with rocuronium<br>* Other names: Bridion;|
| Active Comparator: neostigmine<br>Acetylcholinesterase inhibitor | Drug: Neostigmine<br>* Administration of neostigmine 50µg/kg for enhanced recovery after neuromuscular blockade with rocuronium<br>* Other names: Robinul-neostigmine;|
| Experimental: neostigmine-sugammadex<br>Acetylcholinesterase inhibitor followed by a selective relaxant binding agent | Drug: Neostigmine-sugammadex<br>* Administration of neostigmine 50µg/kg followed 3 minutes later by administration of sugammadex 2mg/kg for enhanced recovery after neuromuscular blockade with rocuronium<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Electromyographic activity of the respiratory muscles during recovery enhanced by sugammadex, neostigmine or neostigmine followed by sugammadex | EMG activity of the diaphragm (EMGdi), and of the rectus abdominis and of the intercostal muscles during recovery enhanced by sugammadex 2mg/kg or neostigmine 50µg/kg or neostigmine 50µg/kg followed 3 minutes later by administration of sugammadex 2mg/kg | Participants will be followed from administration of study drug until tracheal extubation, an expected average of 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tidal volume of breaths recorded by the ventilator |  | Participants will be followed from administration of study drug until tracheal extubation, an expected average of 1 hour | 
| The partial pressure of O2 and of carbon dioxide in arterial blood |  | Participants will be followed from administration of study drug until tracheal extubation, an expected average of 1 hour | 
| The arterial oxygen saturation | Saturation of hemoglobin with oxygen as measured by Pulse Oximetry | Participants will be followed from induction of anesthesia until two hours after extubation of the trachea, an expected average of 3 hours |