Effect of Neuromuscular Blockade and Reversal on Breathing (BREATH)

• ClinicalTrials.gov Identifier: NCT02845375
• Recruitment Status: Completed
• First Posted: July 27, 2016
• Results First Posted: February 19, 2020
• Last Update Posted: February 19, 2020
• Sponsor: Leiden University Medical Center
• Information provided by (Responsible Party): Albert Dahan, Leiden University Medical Center

Study Description

Brief Summary:

In this study the investigators will assess (i) the effect of partial neuromuscular blockade (NMB; TOF ratio 0.8 and 0.6) induced by low-dose rocuronium on the ventilatory response to isocapnic hypoxia and (ii) the effect over time (from TOF 0.6 to TOF 1.0) of the reversal by sugammadex, neostigmine or placebo in healthy volunteers.

Additionally the investigators will assess the effect of partial NMB (TOF ratio 0.6) induced by low-dose rocuronium on the ventilatory response to hypercapnia and effect over time (from TOF 0.6 to TOF 1.0) of the reversal by sugammadex, neostigmine or placebo in healthy volunteers.

Condition or disease	Intervention/treatment	Phase
Respiratory Insufficiency	Drug: Sugammadex; Drug: Neostigmine; Drug: Placebo	Phase 4

Detailed Description:

The carotid bodies, located at the bifurcation of the common carotid artery, play a crucial and life-saving role in the control of breathing in humans. The carotid bodies contain type 1 cells that are primarily sensitive to low oxygen concentrations in arterial blood. In response to low oxygen the carotid bodies send information to the brainstem respiratory centers and a brisk hyperventilatory response will be initiated ensuring an increase in uptake of oxygen via the lungs. Following surgery, a rapid return of the carotid body function is vital and persistent loss of carotid body function may result in respiratory complications that occur independent of the effects of anesthetics (incl. muscle relaxants) on respiratory muscles. Respiratory complications that are related to the loss of carotid body function include the inability to respond properly to hypoxia as well the inability to overcome upper airway obstruction. The latter is especially important in patients with sleep disordered-breathing and obese patients. These patients rely on the optimal function of their carotid bodies in response to hypoxia or upper airway closure.

Important neurotransmitters involved in the carotid body response to hypoxia include acetylcholine, which acts through local nicotinergic acetylcholine receptors. Apart from the observation that muscle relaxants (which are blockers of the acetylcholine receptors) affect the proper functioning of the carotid bodies, the investigators have no knowledge on the dynamic effects of muscle relaxants on carotid body function over time or on the relationship between carotid body function and Train-of-Four (TOF) ratio over time. Additionally, there is no data on the link between the use of NMB antagonists and return of carotid body function. Linking TOF ratio to carotid body function is of clinical importance as a possible relationship will allow clinicians to predict carotid body function from the TOF ratio. The latter is highly relevant as the investigators show in a previous trial that a large proportion of patients is extubated at TOF ratio's < 0.7.

Apart from the carotid bodies, chemoreceptors in the brainstem exist that are sensitive to hypercapnia. This response system is not under control of cholinergic neurotransmission. Since the investigators may assume that the hypercapnic ventilatory response is not influenced by muscle relaxants the investigators can use this response to calibrate the hypoxic ventilatory response as both responses are equally affected by the effect of muscle relaxants on muscle function.

As stated there is data on the effect of muscle relaxants on carotid body function at one fixed TOF ratio (TOF ratio fixed at 0.7). No data are available on:

1. Dynamic effect of carotid body function as measured by the hypoxic ventilatory response at TOF ratio's slowly changing from 0.6 to 1.0;
2. Dynamic effect of reversal of NMB by sugammadex versus neostigmine. Sugammadex and neostigmine are both reversal agents of neuromuscular blockade. At their institution the investigators use both agents in clinical practice but remain without knowledge on their effects on carotid body function. The current proposal is designed to study items 1 and 2 in healthy awake volunteers.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Neuromuscular Blockade and Reversal by Sugammadex Versus Neostigmine on Breathing When Hypoxic or Hypercapnic in Volunteers
• Actual Study Start Date: September 1, 2016
• Actual Primary Completion Date: September 1, 2018
• Actual Study Completion Date: September 1, 2018

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: PLACEBO; Placebo (normal saline) will be administered following a period of muscle relaxation after which respiratory measurements will be obtained.	Drug: Placebo; Placebo will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.; Other Name: Normal saline
NEOSTIGMINE; intravenous neostigmine will be administered following a period of muscle relaxation after which respiratory measurements will be obtained.	Drug: Neostigmine; Neostigmine will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.; Other Name: NEO
Experimental: SUGAMMADEX; intravenous sugammade will be administered following a period of muscle relaxation after which respiratory measurements will be obtained.	Drug: Sugammadex; Sugammadex will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.

Outcome Measures

Primary Outcome Measures :

1. Breathing Increase Due to a Reduction in Inspired Oxygen Saturation (Hypoxic Ventilatory Response) [ Time Frame: during the 1-2 hours following reversal ]
   The change in breathing response to a decrease in inspired oxygen concentration, which equals the isocapnic ventilatory response to hypoxia.
2. Breathing Increase Due to a Reduction in Inspired Oxygen Saturation (Hypoxic Ventilatory Response) [ Time Frame: 0-10 minutes following reversal ]
   The ventilatory response to a decrease in oxygen saturaytion of 80%

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• male gender
• age 18 years and older
• body mass index < 30 kg/m2.

Exclusion Criteria:

• Known or suspected neuromuscular disorders impairing neuromuscular function;
• allergies to muscle relaxants, anesthetics or narcotics;
• a (family) history of malignant hyperthermia or any other muscle disease;
• any medical, neurological or psychiatric illness (including a history of anxiety).

Contacts and Locations

Locations

Netherlands

Leiden University Medical Center

Leiden, ZH, Netherlands, 2333 ZA

Sponsors and Collaborators

Leiden University Medical Center

  Study Documents (Full-Text)

Documents provided by Albert Dahan, Leiden University Medical Center:

Study Protocol and Statistical Analysis Plan  [PDF] November 8, 2015

Informed Consent Form  [PDF] January 14, 2016

More Information

Publications:

Eriksson LI, Sato M, Severinghaus JW. Effect of a vecuronium-induced partial neuromuscular block on hypoxic ventilatory response. Anesthesiology. 1993 Apr;78(4):693-9.

Eriksson LI, Lennmarken C, Wyon N, Johnson A. Attenuated ventilatory response to hypoxaemia at vecuronium-induced partial neuromuscular block. Acta Anaesthesiol Scand. 1992 Oct;36(7):710-5.

Dahan A, Nieuwenhuijs D, Teppema L. Plasticity of central chemoreceptors: effect of bilateral carotid body resection on central CO2 sensitivity. PLoS Med. 2007 Jul 24;4(7):e239.

• Responsible Party: Albert Dahan, Professor, Leiden University Medical Center
• ClinicalTrials.gov Identifier: NCT02845375
• Other Study ID Numbers: P16.025
• First Posted: July 27, 2016
• Results First Posted: February 19, 2020
• Last Update Posted: February 19, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: We will publish the paper. After publication the data are available
• Time Frame: Mid 2019
• Access Criteria: Request to the authors and approved protocol for data analysis to be submitted. A review committee will then decide wether the data will be shared, deepening on supplementary data analyses by the authors

Additional relevant MeSH terms:

Respiratory Insufficiency; Pulmonary Valve Insufficiency; Respiration Disorders; Respiratory Tract Diseases; Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Neostigmine; Cholinesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Parasympathomimetics; Autonomic Agents; Peripheral Nervous System Agents