Factors Affecting Oxygen Toxicity

Overseen By Richard Moon, MD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Duke University

Disqualifiers: Pregnancy, Cardiorespiratory disease, Neuromuscular disease, Anemia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

62 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how oxygen toxicity affects scuba divers. Researchers aim to understand how factors like respiratory muscle training, sleep deprivation, certain medications, and carbon dioxide exposure influence this condition. Participants will exercise under various conditions, such as with caffeine or methylphenidate (a medication often used to treat ADHD), while sleep-deprived, or exposed to carbon dioxide. This trial may suit non-smoking men and women aged 18-45 who are physically fit and have no history of heart, lung, or certain blood conditions. As an unphased trial, it offers participants the chance to contribute to foundational research that could enhance safety and performance for scuba divers.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, since the study involves the ingestion of commonly used medications, it's possible that some medications might be part of the study conditions. Please consult with the trial coordinators for specific guidance.

What prior data suggests that these trial interventions are safe?

Research shows that caffeine is generally safe when consumed in normal amounts. One study found that overdosing on caffeine requires a very large amount, about 10-14 grams, far more than most people would consume at once. Human studies have not linked methylphenidate, a medication often used for attention disorders, to increased risk in certain conditions. Following dosing instructions is important to avoid side effects.

Exposure to carbon dioxide in controlled settings is considered safe, but it can be dangerous if it significantly lowers oxygen levels. Safety data suggests that it could cause suffocation if oxygen is displaced, so careful monitoring is essential.

Researchers are studying these treatments to better understand oxygen toxicity in divers. Consulting a healthcare professional is always advisable to ensure it is safe and suitable to participate in such trials. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores how different factors like caffeine, carbon dioxide, methylphenidate, and sleep deprivation affect oxygen toxicity. Unlike traditional treatments focusing solely on managing symptoms, this study delves into how these elements influence the body's response to oxygen under stress, particularly during underwater activities. By examining these unique interactions, researchers hope to uncover new ways to enhance safety and performance in high-pressure environments, offering insights that current treatments for oxygen toxicity don't address.

What evidence suggests that this trial's treatments could be effective for understanding oxygen toxicity?

Research has shown that carbon dioxide (CO2), to which participants in this trial may be exposed, can increase stress and harm cells, potentially contributing to oxygen toxicity. Animal studies have indicated that CO2 can exacerbate problems caused by high oxygen levels, suggesting it could be a risk factor for divers.

Caffeine, another treatment option in this trial, has demonstrated protective effects in some situations, such as reducing stress-related damage in the brain. Although it hasn't been directly studied for oxygen toxicity, caffeine's benefits in other stress situations suggest it might help with oxygen-related issues.

Methylphenidate, also under study in this trial, does not appear to increase the risk of oxygen toxicity based on human studies. It has not been shown to worsen oxygen-related problems, making it worth further investigation in this area. ^{3 6 7 8 9}

Who Is on the Research Team?

Derek B Covington, MD

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

This trial is for non-smoking men and women aged 18-45 who are in good health with a specific level of cardiovascular fitness (VO2 peak). It's designed to understand oxygen toxicity in scuba divers, focusing on how respiratory training, environmental factors like sleep deprivation and CO2 exposure, affect the risk.

Inclusion Criteria

My gender has been considered for the study's balance.

People who do not smoke.

My peak oxygen intake meets the required level.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Training and Exercise

Participants train their respiratory muscles and exercise on a cycle ergometer in various conditions, including dry and underwater/under pressure, with exposure to medications, sleep deprivation, or carbon dioxide.

12 weeks

Regular intervals (in-person)

Follow-up

Participants are monitored for changes in exercise performance, respiratory function, cerebral blood flow, and levels of gene expression after interventions.

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Caffeine
• Carbon Dioxide
• Methylphenidate
• Sleep Deprivation

Trial Overview The study tests the effects of carbon dioxide, caffeine, sleep deprivation, and methylphenidate on oxygen toxicity. Participants will undergo respiratory muscle training and exercise tests both dry and underwater to measure changes in performance, lung function, brain blood flow, and gene expression.

How Is the Trial Designed?

Group I: Methylphenidate Experimental Treatment 1 Intervention

Effect of caffeine and methylphenidate on HCVR and arterial PCO2 during submersed rest and exercise at 98 fsw. Twenty subjects will be similarly sleep-deprived, tested as above and then re-tested tested following oral administration of administration of either oral caffeine (N=10) or methylphenidate (N=10). Pre-dive caffeine will be administered 500 mg orally \[59\]. Pre-dive methylphenidate will be administered as a single dose of 5 mg \[60\]. The order of drug administration vs. control will be randomized. Measurements at 98 fsw will be obtained at rest and during 10 minutes of moderate exercise in thermoneutral (29-30°C) water. fNIRS will be used to assess cerebral oxygenation and regional blood volume.

Group II: Carbon Dioxide Exposure Experimental Treatment 1 Intervention

Effect of simulated chronic CO2 exposure on HCVR and arterial PCO2 during submersed rest and exercise at 98 fsw. Ten subjects will be studied before and after induction of metabolic alkalosis as described above with daily oral administration of sodium bicarbonate. Oral bicarbonate to simulate hypercapnia exposure will seek to increase serum bicarbonate to 30 mM/L via daily oral intake of 6 teaspoons of NaHCO3 for five days. Subsequently, blood will be drawn and intake adjusted as necessary \[61\]. The order of alkalization vs. control will be randomized. Measurements at 98 fsw will be obtained at rest and during 10 minutes of moderate exercise in thermoneutral (29-30°C) water.

Group III: Caffeine Experimental Treatment 1 Intervention

Effect of caffeine and methylphenidate on HCVR and arterial PCO2 during submersed rest and exercise at 98 fsw. Twenty subjects will be similarly sleep-deprived, tested as above and then re-tested tested following oral administration of administration of either oral caffeine (N=10) or methylphenidate (N=10). Pre-dive caffeine will be administered 500 mg orally \[59\]. Pre-dive methylphenidate will be administered as a single dose of 5 mg \[60\]. The order of drug administration vs. control will be randomized. Measurements at 98 fsw will be obtained at rest and during 10 minutes of moderate exercise in thermoneutral (29-30°C) water. fNIRS will be used to assess cerebral oxygenation and regional blood volume.

Group IV: Sleep Deprivation Active Control 1 Intervention

Effect of sleep deprivation on HCVR and arterial PCO2 during submersed rest and exercise at 98 fsw. Ten subjects will be tested before and after 24 hours of sleep deprivation. The order of sleep deprivation vs. control will be randomized. Measurements at 98 fsw will be obtained at rest and during 10 minutes of moderate exercise in thermoneutral (29-30°C) water.

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

Published Research Related to This Trial

The A(2A) receptor agonist CGS21680 promotes sleep in rats by inhibiting histamine release in the brain, which is negatively correlated with non-rapid eye movement sleep.

CGS21680 increases GABA release in the histaminergic tuberomammillary nucleus, suggesting that enhanced GABA activity is a key mechanism through which A(2A)R activation induces sleep.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An adenosine A receptor agonist induces sleep by increasing GABA release in the tuberomammillary nucleus to inhibit histaminergic systems in rats. Hong, ZY., Huang, ZL., Qu, WM., et al.[2013]

In a study of 135 healthy adult men experiencing 24-hour sleep loss, lisdexamfetamine dimesylate significantly improved daytime alertness and performance compared to placebo, with longer sleep latency times observed at doses of 20, 50, and 70 mg.

The safety profile of lisdexamfetamine dimesylate was favorable, with only mild to moderate treatment-emergent adverse events reported, and no serious adverse events, indicating it may be a safe option for enhancing alertness during sleep deprivation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maintenance of wakefulness with lisdexamfetamine dimesylate, compared with placebo and armodafinil in healthy adult males undergoing acute sleep loss. Gasior, M., Freeman, J., Zammit, G., et al.[2018]

In a rat model, 6 hours of sleep deprivation before surgery significantly increased postoperative pain sensitivity and delayed recovery, indicating that even short-term sleep loss can worsen pain outcomes.

The study suggests that adenosine A2A receptors in the median preoptic nucleus play a crucial role in mediating the relationship between sleep loss and increased pain sensitivity, as blocking these receptors reduced pain levels associated with sleep deprivation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preemptive Caffeine Administration Blocks the Increase in Postoperative Pain Caused by Previous Sleep Loss in the Rat: A Potential Role for Preoptic Adenosine A2A Receptors in Sleep-Pain Interactions. Hambrecht-Wiedbusch, VS., Gabel, M., Liu, LJ., et al.[2018]

In a study involving 48 healthy young adults undergoing 85 hours of sleep deprivation, caffeine (600 mg), dextroamphetamine (20 mg), and modafinil (400 mg) were found to equally enhance performance on simple psychomotor tasks and alertness for about 2-4 hours after administration.

While all three stimulants improved basic performance and alertness, their effects on executive function tasks were inconsistent, with caffeine and modafinil showing some improvements, while dextroamphetamine led to declines in performance on certain tasks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation. Wesensten, NJ., Killgore, WD., Balkin, TJ.[2022]

Armodafinil significantly improved alertness in healthy volunteers experiencing sleep loss, with all doses tested showing increased wakefulness and reduced lapses in attention compared to placebo and modafinil.

At a dose of 200 mg, armodafinil demonstrated a longer duration of effect and higher plasma concentrations 6-14 hours post-administration compared to modafinil, indicating it may provide sustained alertness benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamic effects on alertness of single doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss. Dinges, DF., Arora, S., Darwish, M., et al.[2018]

In healthy mice, sleep loss increases sensitivity to pain without causing general sensory hyper-responsiveness, indicating that insufficient sleep can directly worsen pain perception.

Wake-promoting agents like caffeine and modafinil can normalize pain sensitivity in sleep-deprived mice, suggesting that improving alertness may be a more effective strategy for managing pain related to sleep deficiency than traditional analgesics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decreased alertness due to sleep loss increases pain sensitivity in mice. Alexandre, C., Latremoliere, A., Ferreira, A., et al.[2022]

In a study of 53 healthy adults after 44 hours of wakefulness, all three stimulants—modafinil, dextroamphetamine, and caffeine—were equally effective in restoring alertness and reducing lapses in attention compared to placebo.

Caffeine had the shortest duration of action and was linked to the highest side effects, while dextroamphetamine negatively impacted recovery sleep, suggesting that the choice of stimulant should consider factors like side effects and sleep disruption in specific situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of dextroamphetamine, caffeine and modafinil on psychomotor vigilance test performance after 44 h of continuous wakefulness. Killgore, WD., Rupp, TL., Grugle, NL., et al.[2018]

In a study involving 16 healthy males, slow-release caffeine (SRC) did not negatively affect recovery sleep or cognitive performance after 64 hours of continuous wakefulness, suggesting it is safe for use during long work schedules.

Both SRC and placebo groups showed similar sleep patterns and cognitive impairments initially, but SRC may be a better option than other stimulants since it does not disrupt recovery sleep.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recovery after prolonged sleep deprivation: residual effects of slow-release caffeine on recovery sleep, sleepiness and cognitive functions. Beaumont, M., Batéjat, D., Coste, O., et al.[2013]

This study successfully used computational methods to analyze the mechanisms of action for CNS-active drugs, validating predictions with in vitro and in vivo tests on 491 compounds in rats, which helped define an 'optimal' sleeping pattern.

Several compounds not previously recognized as sedative-hypnotics, such as alcaftadine and ecopipam, were found to promote sleep, demonstrating the effectiveness of the in silico approach in discovering new therapeutic uses for existing drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polypharmacological in Silico Bioactivity Profiling and Experimental Validation Uncovers Sedative-Hypnotic Effects of Approved and Experimental Drugs in Rat. Drakakis, G., Wafford, KA., Brewerton, SC., et al.[2018]

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Caffeine: Uses, Interactions, Mechanism of Action The oral LD50 of caffeine in rats is 192 mg/kg. An acute fatal overdose of caffeine in humans is about 10–14 grams (equivalent to 150–200 mg/kg of body weight) ...

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Caffeine | C8H10N4O2 | CID 2519 - PubChem - NIH Caffeine is a drug of the methylxanthine class used for a variety of purposes, including certain respiratory conditions of the premature newborn, pain relief, ...

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Caffeine effects on systemic metabolism, oxidative- ... These data show that the inflammation process is linked to caffeine-dependent doses, as data presented by Huang and colleagues [170] show a reduced IL-6, IL-3, ...