Work of BreathingPhase 4NCT07424014
The Role of Heliox in Respiratory Control
A Phase 4 study testing Heliox inspirate in people with Work of Breathing, run by Indiana University at 1 site in United States.
Trial summary
Warfighters are frequently exposed to environments and life-support systems that increase breathing resistance and the work of breathing (WOB), such as aircraft on-board oxygen generation systems and underwater breathing apparatuses. Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Work of Breathing
- What is being tested?
- Heliox inspirate
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- 1 siteUnited States
- Study dates
- 3 Feb 2026to 31 May 2027
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
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 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Between the ages of 18-40 years old.
- English speaking and reading.
- Self-reported weekly activity of at least 120 minutes/week of high intensity exercise for the previous 2 years.
- Normal pulmonary function assessed by a resting forced expiratory volume in 1 second over forced vital capacity (FEV1/FVC) > 75% of predicted.
- Normal cognitive function assessed using the Montreal cognitive function test [18].
- Body mass index (BMI) ≤ 35 kg/m2.
- Females with a regular menstrual cycle that ranges from 21-35 days (eumenorrhea)
Who cannot join
- History of smoking or recreational smoking, cardiovascular disease, renal disease, pulmonary disease (including asthma or exercise-induced asthma), neurological disease, and metabolic disease.
- Are pregnant or could possibly be pregnant by self-report.
- Are color blind.
- Known allergy or hypersensitivity latex.
- Take selective serotonin reuptake inhibitors, stimulant medication, antibiotics, and chronically consume pain medication (Aleve, Tylenol, etc.).
- Resting blood pressure of > 130mmHg systolic or 90 mmHg diastolic and/or resting pulse rate of > 100 bpm.
- Females with irregular menstrual cycles (oligomenorrhea) that ranges from 36-90 days, and females with the absence of a menstrual cycle (amenorrhea).
- Taking birth control for the sole purpose of period cessation (eg., Mirena IUD)
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Multidisciplinary Engineering and Sciences Hall (MESH)
Bloomington, Indiana, 47405
Scott M Clarke, 812-856-3244, scotclar@iu.edu
Zachary J Schalder, PhD, 812-855-6953, zschlade@iu.edu
About this study
Official title: Optimizing Mind-Body Interactions in Respiratory Control During Operationally Relevant Environmental Stressors
Warfighters are frequently exposed to environments and life-support systems that increase breathing resistance and the work of breathing (WOB), such as aircraft on-board oxygen generation systems and underwater breathing apparatuses. Elevated WOB increases the perception of breathing difficulty (dyspnea) and has been associated with impaired cognitive performance, including slower reaction time and reduced accuracy during attention-demanding tasks. These effects are particularly concerning in operational settings that require rapid decision-making and precise motor responses.
Despite growing recognition of this issue, critical gaps remain regarding strategies to mitigate the perceptual and cognitive consequences of elevated inspiratory resistance, especially under realistic operational stressors. The objective of this study is to determine whether reducing mechanical WOB alters breathing perception and cognitive performance during inspiratory resistance. Participants will breathe either normal-density air or a low-density helium-oxygen gas mixture (heliox) to determine whether reducing mechanical WOB lowers perceived breathing effort and improves cognitive function.
Read the detailed description
Increases in the WOB intensify the sensory and emotional perceptions of dyspnea, at least partly due to heightened conscious awareness of breathing. Recent data indicate that elevated WOB, and likely breathing perception, can impair cognitive function. This impairment is likely caused by negative affective sensations resulting from the increased WOB, which distracts from central information processing during complex reaction-time tasks. Additionally, both reaction time and accuracy worsen when greater loads are placed on the inspiratory muscles. However, several key knowledge gaps remain that are pertinent to Warfighters that experience elevated inspiratory resistance. This study will investigate whether reducing the WOB during inspiratory resistance can lower breathing perception and restore cognitive function.
Heliox lowers the resistive WOB and muscle load because of its low density and viscosity, allowing for higher ventilation rates than room air by reducing turbulent flow in the airways. Therefore, breathing heliox, which will lower the WOB, under high inspiratory resistance will provide critical insights into whether reducing the WOB can improve cognitive function. It's hypothesized that using heliox will decrease the WOB, lower perceived breathing effort, and improve cognitive function compared to breathing normal density air with elevated inspiratory resistance.
Participants will complete two study visits: a screening/familiarization visit (Study Day 0) followed by one experimental visit (Study Day 1). Participants will be instructed to avoid caffeine, alcohol, stimulant medication, pain/anti-inflammatory medication, cannabis and cannabis related products, and vigorous exercise for at least 24 hours prior to experimental visits. On Study Day 0, participants will complete a short familiarization breathing task in which they will breathe for 10 minutes through an 8-10mm hole at the end of a customized device, generating a pre-determined inspiratory resistance of 6-9.5 centimeters of water per liter per second (cmH2O/L/s). During the breathing task, cerebral vascular, cardiovascular and autonomic activity responses will be measured. Every 5 minutes during the breathing test, participants will be asked to rate breathing intensity and unpleasantness, and perform an inspiratory capacity maneuver. Cognitive assessments will be administered every10 minutes. After the breathing task, participants will complete lung and respiratory muscle function tests.
Prior to Study Day 1 (the experimental visit), participants will be randomized to the order in which they are exposed to the interventional conditions (room air or heliox). Upon arrival, an esophageal balloon will be placed to measure the pressure around the heart and lungs. Participants will then complete two full-length breathing tasks, in which they inspire against a predetermined resistive load for 60 minutes, while breathing under the assigned conditions in the order of randomization. Biometric monitoring, cognitive tasks and participant ratings during the breathing tasks will be completed with the same frequency as Study Day 0. A 1-hour rest period will be observed between the breathing tasks.
- Conditions
- Work of Breathing
- Being tested
- Heliox inspirate
- Keywords
- Inspiratory Resistance, Dyspnea Perception, Cognitive Performance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Heliox inspirateDrug
This intervention corresponds to Arm 1 titled "room air and heliox inspirate". This corresponds with the first phase/period of this study.
| Study group | Role | What they receive |
|---|---|---|
| Room Air, then Heliox Inspirate | Active comparator | Participants will complete 2 full length breathing tasks, one under each condition. The order of condition exposure will be assigned via randomization. Receives: Drug: Heliox inspirate |
| Heliox Inspirate, then Room Air | Active comparator | Participants will complete 2 full length breathing tasks, one under each condition. The order of condition exposure will be assigned via randomization. Receives: Drug: Heliox inspirate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Stroop Color-Word Test Time Performance
Time performance on the Stroop Color-Word Test (min:sec) will be measured every 10 minutes during each breathing task.
Measured: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Stroop Color-Word Test Error Performance
The number of errors on the Stroop Color-Word Test will be measured will be measured every 10 minutes during each breathing task.
Measured: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Perception of Dyspnea Intensity
Participants will rate perception of dyspnea (breathing) intensity on a visual analog scale (VAS) every 5 minutes during each breathing task. The participant will draw a vertical marker line on a horizontal line (100mm),indicating their breathing perception from "not noticeable" (0mm) to "maximal imaginable intensity" (100mm).
Measured: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Perception of Dyspnea Unpleasantness
Participants will rate perception of dyspnea (breathing) unpleasantness on a visual analog scale (VAS) every 5 minutes during each breathing task. The participant will draw a vertical marker line on a horizontal line(100mm), indicating their breathing perception from "not unpleasant"(0mm) to "maximal imaginable unpleasantness" (100mm).
Measured: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Secondary outcomes (8)
Change in Work of Breathing - Esophageal Pressure
Heliox-induced reduction in WOB will be summarized by pre- and post-values of pressure (unit: cmH2O) via esophageal balloon pressures during the heliox condition.
Measured: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Work of Breathing - Mouth Pressure
Heliox-induced reduction in WOB will be summarized by pre- and post-values of pressure (unit: cmH2O) via esophageal balloon pressures, mouth pressure, and dynamic lung volumes during the heliox condition.
Measured: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Work of Breathing - Dynamic Lung Volume
Heliox-induced reduction in WOB will be summarized by pre- and post-values of pressure (unit: cmH2O) via dynamic lung volumes during the heliox condition.
Measured: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Cerebral Blood Velocity
Bilateral transcranial Doppler Ultrasound will be used to continuously measure middle and posterior cerebral artery blood velocity during each breathing task. The ultrasound transducers will be placed on both sides of the head at the temporal windows and the positions will be fixed using a transducer holder.
Measured: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Cerebral Blood Oxygen Kinetics
Oxyhemoglobin and deoxyhemoglobin (uptake/extraction, uM) will be measured continuously via near-infrared spectroscopy (NIRS) of the pre-frontal cortex during each breathing task.
Measured: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Heart Rate
Heart Rate will be measured continuously during each breathing task by 3-lead electrocardiograph (ECG).
Measured: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Blood Pressure - Finger Photoplethysmography
Blood pressure will be measured continuously during each breathing task via finger photoplethysmography.
Measured: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Blood Pressure - Brachial Artery
Blood pressure will be measured every 10 minutes during each breathing task via a standard blood pressure cuff and auscultation of the brachial artery.
Measured: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Feb 2026
- Study start3 Feb 2026
- Primary completion31 May 2027 (estimated)
- Study completion31 May 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Work of BreathingStudies of the same condition, open and under way.
- More trials run by Indiana UniversityThe 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
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 15 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Indiana University
- Sponsor type
- University, hospital or other
- Collaborators
- United States Department of Defense
- Responsible party
- Principal investigator, Tim Mickleborough, Indiana University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07424014
- Sponsor's protocol ID
- 28381 - Aim 1
- Other IDs
- FOAAFRLAFOSR20240007
- Status last verified
- Mar 2026
- First submitted
- 18 Dec 2025
- Last updated
- 12 Mar 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: The plan to share individual participant data (IPD) is still unknown. However, if other researchers request IPD, we will evaluate that request and determine to share IPD.
Study at a glance
From the registry record, last updated by the sponsor on 12 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimizing Mind-Body Interactions in Respiratory Control During Operationally Relevant Environmental Stressors
- ClinicalTrials.gov ID
- NCT07424014
- Acronym / sponsor ID
- 28381 - Aim 1
- Conditions
- Work of Breathing
- Keywords
- Inspiratory Resistance, Dyspnea Perception, Cognitive Performance
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 15 participants (estimated)
- Lead sponsor
- Indiana UniversityUniversity, hospital or other
- Collaborators
- United States Department of Defense
- Study start
- 3 Feb 2026 (actual)
- Primary completion
- 31 May 2027 (estimated)
- Study completion
- 31 May 2027 (estimated)
- First posted
- 20 Feb 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Warfighters are frequently exposed to environments and life-support systems that increase breathing resistance and the work of breathing (WOB), such as aircraft on-board oxygen generation systems and underwater breathing apparatuses. Elevated WOB increases the perception of breathing difficulty (dyspnea) and has been associated with impaired cognitive performance, including slower reaction time and reduced accuracy during attention-demanding tasks. These effects are particularly concerning in operational settings that require rapid decision-making and precise motor responses.
Despite growing recognition of this issue, critical gaps remain regarding strategies to mitigate the perceptual and cognitive consequences of elevated inspiratory resistance, especially under realistic operational stressors. The objective of this study is to determine whether reducing mechanical WOB alters breathing perception and cognitive performance during inspiratory resistance. Participants will breathe either normal-density air or a low-density helium-oxygen gas mixture (heliox) to determine whether reducing mechanical WOB lowers perceived breathing effort and improves cognitive function.
Detailed description
Increases in the WOB intensify the sensory and emotional perceptions of dyspnea, at least partly due to heightened conscious awareness of breathing. Recent data indicate that elevated WOB, and likely breathing perception, can impair cognitive function. This impairment is likely caused by negative affective sensations resulting from the increased WOB, which distracts from central information processing during complex reaction-time tasks. Additionally, both reaction time and accuracy worsen when greater loads are placed on the inspiratory muscles. However, several key knowledge gaps remain that are pertinent to Warfighters that experience elevated inspiratory resistance. This study will investigate whether reducing the WOB during inspiratory resistance can lower breathing perception and restore cognitive function.
Heliox lowers the resistive WOB and muscle load because of its low density and viscosity, allowing for higher ventilation rates than room air by reducing turbulent flow in the airways. Therefore, breathing heliox, which will lower the WOB, under high inspiratory resistance will provide critical insights into whether reducing the WOB can improve cognitive function. It's hypothesized that using heliox will decrease the WOB, lower perceived breathing effort, and improve cognitive function compared to breathing normal density air with elevated inspiratory resistance.
Participants will complete two study visits: a screening/familiarization visit (Study Day 0) followed by one experimental visit (Study Day 1). Participants will be instructed to avoid caffeine, alcohol, stimulant medication, pain/anti-inflammatory medication, cannabis and cannabis related products, and vigorous exercise for at least 24 hours prior to experimental visits. On Study Day 0, participants will complete a short familiarization breathing task in which they will breathe for 10 minutes through an 8-10mm hole at the end of a customized device, generating a pre-determined inspiratory resistance of 6-9.5 centimeters of water per liter per second (cmH2O/L/s). During the breathing task, cerebral vascular, cardiovascular and autonomic activity responses will be measured. Every 5 minutes during the breathing test, participants will be asked to rate breathing intensity and unpleasantness, and perform an inspiratory capacity maneuver. Cognitive assessments will be administered every10 minutes. After the breathing task, participants will complete lung and respiratory muscle function tests.
Prior to Study Day 1 (the experimental visit), participants will be randomized to the order in which they are exposed to the interventional conditions (room air or heliox). Upon arrival, an esophageal balloon will be placed to measure the pressure around the heart and lungs. Participants will then complete two full-length breathing tasks, in which they inspire against a predetermined resistive load for 60 minutes, while breathing under the assigned conditions in the order of randomization. Biometric monitoring, cognitive tasks and participant ratings during the breathing tasks will be completed with the same frequency as Study Day 0. A 1-hour rest period will be observed between the breathing tasks.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Room Air, then Heliox Inspirate | Active comparator | Drug: Heliox inspirateParticipants will complete 2 full length breathing tasks, one under each condition. The order of condition exposure will be assigned via randomization. |
| Heliox Inspirate, then Room Air | Active comparator | Drug: Heliox inspirateParticipants will complete 2 full length breathing tasks, one under each condition. The order of condition exposure will be assigned via randomization. |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Between the ages of 18-40 years old.
- English speaking and reading.
- Self-reported weekly activity of at least 120 minutes/week of high intensity exercise for the previous 2 years.
- Normal pulmonary function assessed by a resting forced expiratory volume in 1 second over forced vital capacity (FEV1/FVC) > 75% of predicted.
- Normal cognitive function assessed using the Montreal cognitive function test [18].
Key exclusion criteria (8 listed)
- History of smoking or recreational smoking, cardiovascular disease, renal disease, pulmonary disease (including asthma or exercise-induced asthma), neurological disease, and metabolic disease.
- Are pregnant or could possibly be pregnant by self-report.
- Are color blind.
- Known allergy or hypersensitivity latex.
- Take selective serotonin reuptake inhibitors, stimulant medication, antibiotics, and chronically consume pain medication (Aleve, Tylenol, etc.).
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 |
|---|---|---|
| Heliox inspirateThis intervention corresponds to Arm 1 titled "room air and heliox inspirate". This corresponds with the first phase/period of this study. | Drug | Heliox Inspirate, then Room Air, Room Air, then Heliox Inspirate |
Primary outcome
Change in Stroop Color-Word Test Time Performance
Time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Time performance on the Stroop Color-Word Test (min:sec) will be measured every 10 minutes during each breathing task.
Change in Stroop Color-Word Test Error Performance
Time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
The number of errors on the Stroop Color-Word Test will be measured will be measured every 10 minutes during each breathing task.
Change in Perception of Dyspnea Intensity
Time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Participants will rate perception of dyspnea (breathing) intensity on a visual analog scale (VAS) every 5 minutes during each breathing task. The participant will draw a vertical marker line on a horizontal line (100mm),indicating their breathing perception from "not noticeable" (0mm) to "maximal imaginable intensity" (100mm).
Change in Perception of Dyspnea Unpleasantness
Time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Participants will rate perception of dyspnea (breathing) unpleasantness on a visual analog scale (VAS) every 5 minutes during each breathing task. The participant will draw a vertical marker line on a horizontal line(100mm), indicating their breathing perception from "not unpleasant"(0mm) to "maximal imaginable unpleasantness" (100mm).
8 secondary outcomes
Change in Work of Breathing - Esophageal Pressure
Time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Work of Breathing - Mouth Pressure
Time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Work of Breathing - Dynamic Lung Volume
Time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Cerebral Blood Velocity
Time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Cerebral Blood Oxygen Kinetics
Time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Heart Rate
Time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Blood Pressure - Finger Photoplethysmography
Time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Blood Pressure - Brachial Artery
Time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Mar 2026.
- Individual participant dataSharing planned: No. The plan to share individual participant data (IPD) is still unknown. However, if other researchers request IPD, we will evaluate that request and determine to share IPD.
Related trials for Work of Breathing
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Invasive Mechanical Ventilation, Severe Respiratory Distress Syndrome
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Impact of Inspiratory Effort and Patient-Ventilator Interaction During the Transition Phase
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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.
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 Heliox inspirate in people with Work of Breathing, run by Indiana University at 1 site in United States.
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 7 inclusion and 8 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: looking for participants now, as of the sponsor's last update on 12 Mar 2026. 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 United States. 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. 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Timothy D Mickleborough, PhD (812-855-0753, tmickleb@iu.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Stroop Color-Word Test Time Performance (time frame: Before and after each Day 1 breathing task (approximately 60 minutes in duration)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 12 Mar 2026.