Effects of Melatonin on Sleep, Ventilatory Control and Cognition at Altitude

• ClinicalTrials.gov Identifier: NCT03588676
• Recruitment Status: Completed
• First Posted: July 17, 2018
• Last Update Posted: August 14, 2019
• Sponsor: Robert L. Owens
• Information provided by (Responsible Party): Robert L. Owens, University of California, San Diego

Study Description

Brief Summary:

Low oxygen at altitude causes pauses in breathing during sleep, called central sleep apnea. Central sleep apnea causes repeated awakenings and poor sleep. Low oxygen itself and the induced oxidative stress can damage mental function which is likely worsened by poor sleep. Reduced mental function due to low oxygen can pose a serious danger to mountain climbers. However there is also mounting evidence that even in populations of people that live at high altitudes and are considered adapted, low oxygen contributes to reductions in learning and memory. Therefore there is a serious need for treatments which may improve sleep, control of breathing and mental function during low oxygen.Therefore this study aims to determine how melatonin effects control of breathing, sleep and mental performance during exposure to low oxygen.

Condition or disease	Intervention/treatment	Phase
Intermittent Hypoxia	Other: Melatonin; Other: Placebo	Not Applicable

Detailed Description:

Research has shown that exposure to low oxygen at altitude causes neurocognitive impairment (impaired mental processing, memory, attention, learning, etc). This impairment in cognitive performance poses a serious risk to mountain climbers and while it has traditionally been thought that people who live at high altitude have adapted to it, evidence shows there is still considerable damage to the brain and impairments in cognitive function of people who live and work at high altitude.

As every cell in the body requires oxygen to survive and function, impairment in cognitive performance at altitude is thought mainly due to reduced oxygen availability to the central nervous system. However, low oxygen at altitude also causes unstable breathing during sleep which results in short periods where the brain stops sending the signal to breath, called central sleep apnea (CSA). During apneas (pauses in breathing) blood oxygen drops even lower and people typically wake up briefly and hyperventilate after apneas. Therefore at altitude people usually get less sleep, their sleep is broken with periods of wakefulness during the night and they experience repeated bouts of severe low blood oxygen levels. Sleep plays a critical role in how the brain repairs and also converts newly acquired information into long-term memory. Therefore broken and reduced sleep can impair cognitive performance, memory and learning. Repeated bouts of severe low oxygen also produces highly reactive molecules that cause damage to cells, called oxidative stress. Oxidative stress also prevents the brain from forming long-term memories and in severe cases (such as extremely high altitude and long duration exposure) can cause neurons in the brain to die. Therefore although sustained low oxygen at altitude likely impairs cognitive function, disturbed sleep and repeated bouts of severely low oxygen likely also contribute to causing brain damage and impaired cognitive performance.

Melatonin is a hormone produced in the pineal gland of the brain during the night which signals to the brain that it is time to sleep. Melatonin is also a very powerful antioxidant which naturally helps to prevent damage in the body from oxidative stress. A study previously reported that melatonin taken 90 mins before bed at 4,300 m (14,200 ft) reduced the time taken to fall asleep, it reduced the number of times people woke up during sleep and improved cognitive performance the following day. However how melatonin caused these effects was not determined. Therefore this study aims to determine how melatonin affects ventilatory control, sleep and neurocognitive performance during sustained hypoxia.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 39 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: randomized, placebo controlled, double blind, cross-over trial
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of Melatonin on Sleep, Ventilatory Control and Cognition at Altitude
• Actual Study Start Date: January 10, 2018
• Actual Primary Completion Date: December 10, 2018
• Actual Study Completion Date: December 10, 2018

Arms and Interventions

Arm	Intervention/treatment
No Intervention: Normoxia; Participants will sleep in room air and receive no melatonin.
Placebo Comparator: Hypoxia and Placebo; 5mg placebo before sleep study	Other: Placebo; 5mg Placebo capsule
Experimental: Hypoxia and Melatonin; 5mg melatonin before sleep study	Other: Melatonin; 5mg Melatonin

Outcome Measures

Primary Outcome Measures :

1. Change in Apnea Hypopnea Index [ Time Frame: 6 weeks ]
   Measure of Sleep Apnea severity
2. Neurocognitive Scores [ Time Frame: 6 weeks ]
   Reflex changes between conditions

Secondary Outcome Measures :

1. Loop Gain [ Time Frame: 6 weeks ]
   Measurement of breathing characteristics during sleep using a flow meter attached to a CPAP mask that allows the measurement of expiratory flow
2. Arousal Threshold [ Time Frame: 6 weeks ]
   requirements for sleep arousal to occur
3. Sleep Efficiency [ Time Frame: 6 weeks ]
   Time in bed divided by total sleep time
4. Total Antioxidant Status [ Time Frame: 6 weeks ]
   Measurement taken from blood draw
5. Hypoxic Ventilatory Response [ Time Frame: 6 weeks ]
   Change in breathing response while breathing low oxygen
6. Hypercapnic Ventilatory Response [ Time Frame: 6 weeks ]
   Change in breathing response while breathing high carbon dioxide

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Healthy Males and Females
• Age:18-65 years

Exclusion Criteria:

• Sleep Disorders
• Pregnant Females
• Smokers (quit ≥ 1 year ago acceptable)
• Cardiovascular, Pulmonary, Renal, Neurologic, Neuromuscular, or Hepatic Issues
• Diabetes
• Psychiatric disorder, other than mild depression
• Recent exposure to altitude (>8000ft) in the last month or having slept at an altitude >6000ft in the last month

Contacts and Locations

Locations

United States, California

University of California, San Diego

San Diego, California, United States, 92093

Sponsors and Collaborators

Robert L. Owens

Investigators

• Principal Investigator: Atul Malhotra, MD; Professor
• Study Director: Naomi L Deacon, Ph.D.; Research Associate
• Study Chair: Pamela De Young; Research Associate

More Information

Additional Information:

Study Website 

• Responsible Party: Robert L. Owens, Associate Physician, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT03588676
• Other Study ID Numbers: UCSD170200
• First Posted: July 17, 2018
• Last Update Posted: August 14, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Robert L. Owens, University of California, San Diego:

Hypoxia; High Altitude; Melatonin; Neurocognitive

Additional relevant MeSH terms:

Hypoxia; Signs and Symptoms, Respiratory; Melatonin; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs; Central Nervous System Depressants