Respiratory InsufficiencyPhase 4BREATHNCT02845375
Effect of Neuromuscular Blockade and Reversal on Breathing
A Phase 4 study testing Sugammadex and Neostigmine in people with Respiratory Insufficiency, run by Leiden University Medical Center at 1 site in Netherlands.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older, men onlyHealthy volunteers can take part
- Conditions the study is for
- Respiratory Insufficiency
- What is being tested?
- Sugammadex and Neostigmine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 46 participants
- Where
- 1 siteNetherlands
- Study dates
- 1 Sep 2016to 1 Sep 2018
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Men only
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- male gender
- age 18 years and older
- body mass index < 30 kg/m2.
Who cannot join
- 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).
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Leiden University Medical Center
Leiden, South Holland, 2333 ZA
About this study
Official title: Effect of Neuromuscular Blockade and Reversal by Sugammadex Versus Neostigmine on Breathing When Hypoxic or Hypercapnic in Volunteers
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.
Read the 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:
- 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.
- Conditions
- Respiratory Insufficiency
- Being tested
- Sugammadex, Neostigmine, Placebo
- Medical subject headings
- Respiratory Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SugammadexDrug
Sugammadex will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.
NeostigmineDrug
Also called NEO
Neostigmine will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.
PlaceboDrug
Also called Normal saline
Placebo will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained.
| Study group | Role | What they receive |
|---|---|---|
| PLACEBO | Placebo comparator | Placebo (normal saline) will be administered following a period of muscle relaxation after which respiratory measurements will be obtained. Receives: Drug: Placebo |
| NEOSTIGMINE | Other | intravenous neostigmine will be administered following a period of muscle relaxation after which respiratory measurements will be obtained. Receives: Drug: Neostigmine |
| SUGAMMADEX | Experimental | intravenous sugammade will be administered following a period of muscle relaxation after which respiratory measurements will be obtained. Receives: Drug: Sugammadex |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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%
Measured: 0-10 minutes following reversal
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jul 2016 (estimated)
- Study start1 Sep 2016
- Primary completion1 Sep 2018
- Study completion1 Sep 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Respiratory InsufficiencyStudies of the same condition, open and under way.
- More trials run by Leiden University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 46 participants (actual)
Sponsor and investigators
- Lead sponsor
- Leiden University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Albert Dahan, Leiden University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02845375
- Sponsor's protocol ID
- P16.025
- Acronym
- BREATH
- Status last verified
- Feb 2020
- First submitted
- 14 Jul 2016
- Last updated
- 19 Feb 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: We will publish the paper. After publication the data are available
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. doi: 10.1097/00000542-199304000-00012.
PubMed 8096684Eriksson 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.
PubMed 1359723Dahan 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.
PubMed 17676946
Study at a glance
From the registry record, last updated by the sponsor on 19 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Neuromuscular Blockade and Reversal by Sugammadex Versus Neostigmine on Breathing When Hypoxic or Hypercapnic in Volunteers
- ClinicalTrials.gov ID
- NCT02845375
- Acronym / sponsor ID
- BREATH / P16.025
- Conditions
- Respiratory Insufficiency
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 46 participants (actual)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Study start
- 1 Sep 2016 (actual)
- Primary completion
- 1 Sep 2018 (actual)
- Study completion
- 1 Sep 2018 (actual)
- First posted
- 27 Jul 2016 (estimated)
- Results
- Posted 19 Feb 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| PLACEBO | Placebo comparator | Drug: PlaceboPlacebo (normal saline) will be administered following a period of muscle relaxation after which respiratory measurements will be obtained. |
| NEOSTIGMINE | Other | Drug: Neostigmineintravenous neostigmine will be administered following a period of muscle relaxation after which respiratory measurements will be obtained. |
| SUGAMMADEX | Experimental | Drug: Sugammadexintravenous sugammade will be administered following a period of muscle relaxation after which respiratory measurements will be obtained. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- male gender
- age 18 years and older
- body mass index < 30 kg/m2.
Key exclusion criteria (4 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SugammadexSugammadex will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained. | Drug | SUGAMMADEX |
| NeostigmineAlso: NEONeostigmine will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained. | Drug | NEOSTIGMINE |
| PlaceboAlso: Normal salinePlacebo will be administered following a period of muscle relaxation after wich respiratory measurements will be obtained. | Drug | PLACEBO |
Primary outcome
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.
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%
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Feb 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 8096684Eriksson 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.
- Background: PubMed 1359723Eriksson 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.
- Background: PubMed 17676946Dahan 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.
- Individual participant dataSharing planned: Yes. We will publish the paper. After publication the data are available
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Sugammadex and Neostigmine in people with Respiratory Insufficiency, run by Leiden University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Feb 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Breathing Increase Due to a Reduction in Inspired Oxygen Saturation (Hypoxic Ventilatory Response) (time frame: during the 1-2 hours following reversal). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02845375, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Feb 2020.