Effect of Neuromuscular Blockade and Reversal on Breathing

Study Overview
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Brief Summary
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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.

Detailed Description
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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: 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; 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.

Official Title
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Effect of Neuromuscular Blockade and Reversal by Sugammadex Versus Neostigmine on Breathing When Hypoxic or Hypercapnic in Volunteers

Conditions
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Respiratory Insufficiency

Intervention / Treatment
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* Drug: Sugammadex
* Drug: Neostigmine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: PLACEBO<br>Placebo (normal saline) will be administered following a period of muscle relaxation after which respiratory measurements will be obtained. | Drug: Placebo<br>* Placebo will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.<br>* Other names: Normal saline;|
| Other: NEOSTIGMINE<br>intravenous neostigmine will be administered following a period of muscle relaxation after which respiratory measurements will be obtained. | Drug: Neostigmine<br>* Neostigmine will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.<br>* Other names: NEO;|
| Experimental: SUGAMMADEX<br>intravenous sugammade will be administered following a period of muscle relaxation after which respiratory measurements will be obtained. | Drug: Sugammadex<br>* Sugammadex will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.<br>|

What is the study measuring?
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Primary Outcome Measures

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