Oxygen Toxicity: Mechanisms in Humans

NCT05761756 | Recruiting DMC

• 1 other identifier: Pro00112396
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to learn about the mechanisms of oxygen toxicity in scuba divers. The main questions it aims to answer are:

• How does the training of respiratory muscles affect oxygen toxicity?
• How do environmental factors, such as sleep deprivation, the ingestion of commonly utilized medications, and chronic exposure to carbon dioxide, impact the risk of oxygen toxicity?
• How does immersion in water affect the development of oxygen toxicity? Participants will be asked to do the following:
• Undergo a basic screening exam composed of health history, vital signs, and some respiratory function tests
• Train their respiratory muscles at regular intervals
• Exercise on a cycle ergometer both in dry conditions and underwater/under pressure in the context of medication, sleep deprivation, or carbon dioxide exposure Researchers will compare the performance of each subject before and after the possible interventions described above to see if there are changes in exercise performance, respiratory function, cerebral blood flow, and levels of gene expression.

Conditions

Oxygen Toxicity; Hypercapnia; Seizures

Outcome Measures

Primary Outcomes (1)

• Hypercapnic ventilatory response

  3 months

Secondary Outcomes (5)

• Lactate, pyruvate

  3 months

• Arterial PCO2

  Baseline and after Intervention/arm

• Integrated diaphragmatic function (IDF) composite score

  Baseline and after Intervention/arm, which averages 3 months

• Cerebral blood oxygenation

  Baseline and after Intervention/arm, which averages 3 months

• Hormone levels (leptin, adiponectin)

  Baseline and after Intervention/arm, which averages 3 months

Study Arms (4)

Sleep Deprivation

ACTIVE COMPARATOR

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.

Behavioral: Sleep Deprivation

Caffeine

EXPERIMENTAL

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.

Drug: Caffeine

Methylphenidate

EXPERIMENTAL

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.

Drug: Methylphenidate

Carbon Dioxide Exposure

EXPERIMENTAL

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.

Drug: Carbon Dioxide

Interventions

Sleep Deprivation BEHAVIORAL

24 hours sleep deprivation

Sleep Deprivation

Caffeine DRUG

Oral administration of caffeine

Caffeine

Methylphenidate DRUG

Oral administration of methylphenidate

Methylphenidate

Carbon Dioxide DRUG

Oral administration of sodium bicarbonate to simulate carbon dioxide exposure

Carbon Dioxide Exposure

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Equal numbers of male and female
• Non-smokers
• Aged 18-45 years
• Males will be required to have VO2 peak \> or equal to mL/kg min
• and females \> or equal to 30 mL/kg min

You may not qualify if:

• Pregnancy
• Cardiorespiratory disease, including hypertension
• Neuromuscular disease
• Anemia
• History of hemoglobinopathy, including sick cell disease and trait

Sponsors & Collaborators

• Duke University: lead

Study Sites (1)

Duke University Health Sustem

Durham, North Carolina, 27705, United States

RECRUITING

Related Publications (14)

• Dunworth SA, Natoli MJ, Cooter M, Cherry AD, Peacher DF, Potter JF, Wester TE, Freiberger JJ, Moon RE. Hypercapnia in diving: a review of CO(2) retention in submersed exercise at depth. Undersea Hyperb Med. 2017 May-Jun;44(3):191-209. doi: 10.22462/5.6.2017.1.

  PMID: 28779577 BACKGROUND

• Drummond JC. Blood Pressure and the Brain: How Low Can You Go? Anesth Analg. 2019 Apr;128(4):759-771. doi: 10.1213/ANE.0000000000004034.

  PMID: 30883421 BACKGROUND

• Lucas SJ, Tzeng YC, Galvin SD, Thomas KN, Ogoh S, Ainslie PN. Influence of changes in blood pressure on cerebral perfusion and oxygenation. Hypertension. 2010 Mar;55(3):698-705. doi: 10.1161/HYPERTENSIONAHA.109.146290. Epub 2010 Jan 18.

  PMID: 20083726 BACKGROUND

• Wester TE, Cherry AD, Pollock NW, Freiberger JJ, Natoli MJ, Schinazi EA, Doar PO, Boso AE, Alford EL, Walker AJ, Uguccioni DM, Kernagis D, Moon RE. Effects of head and body cooling on hemodynamics during immersed prone exercise at 1 ATA. J Appl Physiol (1985). 2009 Feb;106(2):691-700. doi: 10.1152/japplphysiol.91237.2008. Epub 2008 Nov 20.

  PMID: 19023017 BACKGROUND

• Pendergast DR, Moon RE, Krasney JJ, Held HE, Zamparo P. Human Physiology in an Aquatic Environment. Compr Physiol. 2015 Sep 20;5(4):1705-50. doi: 10.1002/cphy.c140018.

  PMID: 26426465 BACKGROUND

• Linnarsson D, Ostlund A, Lind F, Hesser CM. Hyperbaric bradycardia and hypoventilation in exercising men: effects of ambient pressure and breathing gas. J Appl Physiol (1985). 1999 Oct;87(4):1428-32. doi: 10.1152/jappl.1999.87.4.1428.

  PMID: 10517774 BACKGROUND

• Oppersma E, Doorduin J, van der Hoeven JG, Veltink PH, van Hees HWH, Heunks LMA. The effect of metabolic alkalosis on the ventilatory response in healthy subjects. Respir Physiol Neurobiol. 2018 Feb;249:47-53. doi: 10.1016/j.resp.2018.01.002. Epub 2018 Jan 4.

  PMID: 29307724 BACKGROUND

• Cherry AD, Forkner IF, Frederick HJ, Natoli MJ, Schinazi EA, Longphre JP, Conard JL, White WD, Freiberger JJ, Stolp BW, Pollock NW, Doar PO, Boso AE, Alford EL, Walker AJ, Ma AC, Rhodes MA, Moon RE. Predictors of increased PaCO2 during immersed prone exercise at 4.7 ATA. J Appl Physiol (1985). 2009 Jan;106(1):316-25. doi: 10.1152/japplphysiol.00885.2007. Epub 2008 Sep 11.

  PMID: 18787095 BACKGROUND

• Dodson ME, Fryer JM. Postoperative effects of methylphenidate. Br J Anaesth. 1980 Dec;52(12):1265-70. doi: 10.1093/bja/52.12.1265.

  PMID: 7004471 BACKGROUND

• GALE AS. The effect of methylphenidate (ritalin) on thiopental recovery. Anesthesiology. 1958 Jul-Aug;19(4):521-31. doi: 10.1097/00000542-195807000-00009. No abstract available.

  PMID: 13545587 BACKGROUND

• Beecroft J, Duffin J, Pierratos A, Chan CT, McFarlane P, Hanly PJ. Enhanced chemo-responsiveness in patients with sleep apnoea and end-stage renal disease. Eur Respir J. 2006 Jul;28(1):151-8. doi: 10.1183/09031936.06.00075405. Epub 2006 Mar 1.

  PMID: 16510459 BACKGROUND

• Yao Q, Pho H, Kirkness J, Ladenheim EE, Bi S, Moran TH, Fuller DD, Schwartz AR, Polotsky VY. Localizing Effects of Leptin on Upper Airway and Respiratory Control during Sleep. Sleep. 2016 May 1;39(5):1097-106. doi: 10.5665/sleep.5762.

  PMID: 26951402 BACKGROUND

• Eynan M, Arieli Y, Taran B, Yanir Y. Symptoms of central nervous system oxygen toxicity during 100% oxygen breathing at normobaric pressure with increasing inspired levels of carbon dioxide: a case report. Diving Hyperb Med. 2020 Mar 31;50(1):70-74. doi: 10.28920/dhm50.1.70-74.

  PMID: 32187621 BACKGROUND

• Martin BJ. Effect of sleep deprivation on tolerance of prolonged exercise. Eur J Appl Physiol Occup Physiol. 1981;47(4):345-54. doi: 10.1007/BF02332962.

  PMID: 7199438 BACKGROUND

MeSH Terms

Conditions

Hypercapnia; Seizures

Interventions

Caffeine; Methylphenidate; Carbon Dioxide

Condition Hierarchy (Ancestors)

Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurologic Manifestations; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Carbon Compounds, Inorganic; Inorganic Chemicals; Gases; Oxides; Oxygen Compounds

Study Officials

• Derek B Covington, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Derek B Covington, MD

CONTACT

919-613-8881; derek.covington@duke.edu

Richard Moon, MD

CONTACT

919-613-8881; Richard.moon@duke.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2023
• First Posted: March 9, 2023
• Study Start: November 28, 2023
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): August 31, 2026
• Last Updated: October 23, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)