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

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

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.

Study Overview

• Status: Completed
• Conditions: Respiratory Muscles; Electromyography
• Intervention / Treatment: Drug: Sugammadex; Drug: Neostigmine; Drug: Neostigmine-sugammadex

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium, 9300
    • OLV Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 39 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Onze Lieve Vrouw Hospital
• Investigators: Principal Investigator: Guy Cammu, MD, PhD, OLV Hospital, Aalst, Belgium

Publications and helpful links

General Publications

• Sasaki N, Meyer MJ, Malviya SA, Stanislaus AB, MacDonald T, Doran ME, Igumenshcheva A, Hoang AH, Eikermann M. Effects of neostigmine reversal of nondepolarizing neuromuscular blocking agents on postoperative respiratory outcomes: a prospective study. Anesthesiology. 2014 Nov;121(5):959-68. doi: 10.1097/ALN.0000000000000440.
• Eikermann M, Fassbender P, Malhotra A, Takahashi M, Kubo S, Jordan AS, Gautam S, White DP, Chamberlin NL. Unwarranted administration of acetylcholinesterase inhibitors can impair genioglossus and diaphragm muscle function. Anesthesiology. 2007 Oct;107(4):621-9. doi: 10.1097/01.anes.0000281928.88997.95.
• Herbstreit F, Zigrahn D, Ochterbeck C, Peters J, Eikermann M. Neostigmine/glycopyrrolate administered after recovery from neuromuscular block increases upper airway collapsibility by decreasing genioglossus muscle activity in response to negative pharyngeal pressure. Anesthesiology. 2010 Dec;113(6):1280-8. doi: 10.1097/ALN.0b013e3181f70f3d.
• Meyer MJ, Bateman BT, Kurth T, Eikermann M. Neostigmine reversal doesn't improve postoperative respiratory safety. BMJ. 2013 Mar 19;346:f1460. doi: 10.1136/bmj.f1460. No abstract available.
• Schepens T, Cammu G, Saldien V, De Neve N, Jorens PG, Foubert L, Vercauteren M. Electromyographic activity of the diaphragm during neostigmine or sugammadex-enhanced recovery after neuromuscular blockade with rocuronium: a randomised controlled study in healthy volunteers. Eur J Anaesthesiol. 2015 Jan;32(1):49-57. doi: 10.1097/EJA.0000000000000140.
• Fleming NW, Henderson TR, Dretchen KL. Mechanisms of respiratory failure produced by neostigmine and diisopropyl fluorophosphate. Eur J Pharmacol. 1991 Mar 19;195(1):85-91. doi: 10.1016/0014-2999(91)90384-3.
• Cammu G, Schepens T, De Neve N, Wildemeersch D, Foubert L, Jorens PG. Diaphragmatic and intercostal electromyographic activity during neostigmine, sugammadex and neostigmine-sugammadex-enhanced recovery after neuromuscular blockade: A randomised controlled volunteer study. Eur J Anaesthesiol. 2017 Jan;34(1):8-15. doi: 10.1097/EJA.0000000000000543.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: March 17, 2015
• First Submitted That Met QC Criteria: March 25, 2015
• First Posted (Estimate): March 31, 2015

Study Record Updates

• Last Update Posted (Estimate): November 20, 2015
• Last Update Submitted That Met QC Criteria: November 19, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Enzyme Inhibitors; Cholinesterase Inhibitors; Parasympathomimetics; Neostigmine
• Other Study ID Numbers: TSGC03