Effect of Neuromuscular Blockade and Reversal on Breathing

NCT ID: NCT02845375

Last Updated: 2020-02-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-09-01
• Study Completion Date: 2018-09-01

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.

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.

Conditions

Respiratory Insufficiency

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

PLACEBO

Placebo (normal saline) will be administered following a period of muscle relaxation after which respiratory measurements will be obtained.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.

NEOSTIGMINE

intravenous neostigmine will be administered following a period of muscle relaxation after which respiratory measurements will be obtained.

Group Type: OTHER

Neostigmine

Intervention Type: DRUG

Neostigmine will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.

SUGAMMADEX

intravenous sugammade will be administered following a period of muscle relaxation after which respiratory measurements will be obtained.

Group Type: EXPERIMENTAL

Sugammadex

Intervention Type: DRUG

Sugammadex will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.

Interventions

Sugammadex

Sugammadex will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.

Intervention Type: DRUG

Neostigmine

Neostigmine will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.

Intervention Type: DRUG

Placebo

Placebo will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.

Intervention Type: DRUG

Other Intervention Names

NEO; Normal saline

Eligibility 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Leiden University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Albert Dahan

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Leiden University Medical Center

Leiden, South Holland, Netherlands

Countries

Netherlands

References

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. doi: 10.1097/00000542-199304000-00012.

Reference Type: BACKGROUND

PMID: 8096684 (View on PubMed)

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. doi: 10.1111/j.1399-6576.1992.tb03550.x.

Reference Type: BACKGROUND

PMID: 1359723 (View on PubMed)

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. doi: 10.1371/journal.pmed.0040239.

Reference Type: BACKGROUND

PMID: 17676946 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

P16.025

Identifier Type: -

Identifier Source: org_study_id