Effects of Pre-dive Ketone Food Products on Latency to CNS Oxygen Toxicity (Aim 2)

Effects of Pre-dive Ketone Food Products on Latency to Central Nervous System Oxygen Toxicity

The purpose of this study is to understand how ketogenic food products affect oxygen toxicity in undersea divers. Oxygen toxicity affecting the central nervous system, mainly the brain, is a result of breathing higher than normal oxygen levels at elevated pressures as can be seen in SCUBA diving or inside a hyperbaric (pressure) chamber. This is a condition that may cause a wide variety of symptoms such as: vision disturbances, ear-ringing, nausea, twitching, irritability, dizziness, and potentially loss of consciousness or seizure. Because nutritional ketosis has been used to reduce or eliminate seizures in humans, it may be beneficial to reduce oxygen toxicity as well. The investigators hope this study will provide a help to develop practical and useful methods for improving the safety of undersea Navy divers, warfighters and submariners.

Study Overview

• Status: Completed
• Conditions: Oxygen Toxicity
• Intervention / Treatment: Dietary supplement: Ketogenic food products; Dietary supplement: Control: Placebo

Detailed Description

Central nervous system (CNS) oxygen toxicity continues to be a risk for military divers and constrains their operations. Manifestations of this condition range from nausea, twitching, and tinnitus to seizures and unresponsiveness, and the latter may lead to death by drowning. The NAVY has a need for better methods to prevent or delay the onset of CNS oxygen toxicity (CNSOT) and to safely expand the scope of diving operations. It is the broad objective of this study to generate information that will enhance warfighter safety and performance in relevant NAVY operations by reducing the risk of CNS oxygen toxicity.

It is known that nutritional ketosis through a diet with a high fat-to-carbohydrate ratio (ketogenic diet) can reduce the frequency and severity of epileptic seizures in humans, and a recent animal study has shown that dietary ketosis also delays the onset of CNSOT. In recent years, ketone ester food products ketone esters have been made commercially available which may elevate circulating ketone levels. The investigators aim to investigate whether ketosis from commercially available ketogenic food products prior to a dive will delay the onset of CNSOT.

The first aim of this study will be to determine the effect of ketone food product ingestion on serum ketone levels, and document any relevant side effects. Post-ingestion ketone levels will be trended for 3 different ketone food product regimens in 15 total subjects. Data will be used to select the optimal ketone food product strategy to investigate in the second aim.

This second aim will be to evaluate the primary hypothesis, that pre-dive ketone food products will prolong latency to CNSOT. To assess this, 20 subjects will be studied in a randomized, controlled, double-blind, crossover methodology. After consuming either the ketone food product or placebo, each subject will complete an immersed, head out hyperbaric oxygen exposure while exercising on an underwater cycle ergometer at 2.06 ATA (35 fsw) until oxygen toxicity symptoms develop or the maximum time limit of 120 minutes is reached. The experiment will be repeated on a different day by each subject after consuming the opposite (ketone food products or placebo). Primary outcome will be time to manifestation of CNSOT. Physiologic monitoring throughout the study will provide secondary endpoints such as cognitive performance, sympathetic nervous system stimulation via electrodermal activity, electroencephalography, cardiorespiratory measures and end-tidal CO2/O2/N2; all adding to our understanding of CNSOT physiology which may guide future mitigation and monitoring strategies.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Males & females between 18 and 39 years old.
• Measured (Phase 2) VO2max ≥ 30 ml/kg/min (female) or 35 ml/kg/min (male).
• BMI ≤ 30.0 unless VO2max and baseline exercise profile is deemed appropriate for the study by the PI.
• (Phase 2 only) Able to exercise continuously on cycle ergometer for 2 hours.
• (Phase 2 only) Able to equalize middle ears and tolerate hyperbaric chamber exposure test.

Exclusion Criteria:

• Prolonged QTc on initial ECG
• Currently pregnant or attempting to become pregnant.

• Have a medical history of:

  1. Smoking history deemed significant by PI
  2. Known significant electrolyte disorders
  3. Coronary artery disease
  4. Cardiac arrhythmia deemed significant by PI
  5. Lung disease
  6. Hypertension
  7. Seizures
  8. Exercise intolerance or inability to meet inclusion requirements
  9. Psychiatric disorder deemed significant by PI
  10. Previous pneumothorax or pneumomediastinum
  11. Hypo- or hyperglycemia
  12. Diabetes
  13. Inability to equalize middle ear spaces during hyperbaric compression
  14. Claustrophobia
• Regularly take any medications which may alter heart rate, blood pressure, neurotransmitter function, alter seizure threshold, mood or affect per PI discretion.
• Any other condition limiting ability to perform exercise testing or dive profile as determined by the investigators.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental: Ketogenic food products; Dietary Supplement: Ketogenic food products Participants will be given a ketogenic food product prior to the hyperbaric oxygen exposure.	Dietary supplement: Ketogenic food products; Participants will be given a ketogenic food product prior to the hyperbaric oxygen exposure.
Placebo Comparator: Control: Placebo; Dietary Supplement comparator	Dietary supplement: Control: Placebo; Participants will be given a dietary supplement comparator prior to the hyperbaric oxygen exposure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Latency to central nervous system oxygen toxicity (CNSOT)	Assessment of latency to CNSOT in a simulated working dive breathing 100% oxygen at 2.06 ATA, immersed in water (head out), in a hyperbaric chamber while performing exercise. Endpoint is time to development of signs or symptoms of CNSOT. Maximum duration 120 minutes.	2 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive performance	Changes in Multi Attribute Test battery scores prior to and during hyperbaric exposure. Tracking score pixel distance from target center, scale min = 0, no defined maximum.	Day 1
Level of nutritional ketosis as detected by serume beta hydroxybutyrate levels	Measure serume beta hydroxybutyrate levels in blood samples	Day 1
Number of participants with change in EEG	Changes in visual EEG inspection prior to and during hyperbaric exposure.	Day 1
Change in qEEG alpha/delta power ratio (ratio of power in alpha frequency band to power in delta frequency band)	Changes in qEEG readings prior to and during hyperbaric exposure	Day 1
Change in end-tidal CO2	Changes in end-tidal CO2 levels in blood samples prior to and during hyperbaric exposure	Day 1
Change in venous CO2	Changes in CO2 levels in blood samples prior to and during hyperbaric exposure	Day 1
Change in heart rate	Changes in heart rate prior to and during hyperbaric exposure	Day 1
Change in ventilatory rate	Changes in ventilatory rate prior to and during hyperbaric exposure	Day 1
Number of participants who develop CNS oxygen toxicity	Any symptoms of CNSOT during hyperbaric exposure as described by participants will be recorded.	Day 1

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: United States Navy
• Investigators: Principal Investigator: Bruce Derrick, MD, Duke Health

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2023
• Primary Completion (Actual): March 31, 2025
• Study Completion (Actual): March 31, 2025

Study Registration Dates

• First Submitted: March 24, 2023
• First Submitted That Met QC Criteria: April 14, 2023
• First Posted (Actual): April 26, 2023

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Signs and Symptoms, Respiratory; Hyperoxia
• Other Study ID Numbers: Pro00111000_1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No