Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04231773 |
| Other study ID # |
Pro00092939 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
August 17, 2020 |
| Est. completion date |
December 4, 2021 |
Study information
| Verified date |
July 2022 |
| Source |
University of Alberta |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
During exercise in conditions of low oxygen (termed hypoxia), such as mountaineering at high
altitudes, the lung blood vessels constrict in an attempt to protect the body from the
negative effects of hypoxia. It appears that this blood vessel constriction may limit the
heart to pump blood during heavy exercise, leading to reductions in exercise performance.
Inhaled nitric oxide is a drug that is known to relax the lung blood vessels. Inhaled nitric
oxide has been used to relax lung blood vessels and improve exercise capacity in patients
with chronic disease. It is unknown if similar improvements would be observed during exercise
in healthy individuals when exposed to low levels of oxygen. The goal of this study is to
determine if inhaled nitric oxide can relax the lung blood vessels and improve the heart's
pumping ability during exercise in low oxygen conditions. Further, the investigators will
determine if these improvements in lung blood vessel and heart function increase exercise
performance. Participants will complete 6 sessions over a three week period where they will
perform exercise challenges while breathing low levels of oxygen with and without inhaled
nitric oxide. The low oxygen conditions will be comparable to being at an altitude of
14,000-17,000 feet. 17,000 feet would be equivalent to standing on the summit of King Peak in
the Yukon (the 4th tallest mountain in Canada).
Description:
Background
During exercise in hypoxic conditions, maximal exercise capacity, as determined by maximal
oxygen uptake (V̇O2max), is reduced progressively as inspired oxygen tension falls. It is
generally assumed that this reduction in V̇O2max results entirely from a reduction in
arterial oxygen content. However, previous work in severe cases of hypoxia have demonstrated
a larger than expected reduction in V̇O2max. Further, the hypoxia-induced impairment in
V̇O2max could not be explained entirely by the reduced inspired O2 tension and suggest that
other mechanisms contribute to the drop in V̇O2max. Previous research showed that impaired
pulmonary gas-exchange and reduced peak cardiac output, in addition to the reduced arterial
oxygen content, were key contributors to the impaired V̇O2max in severe hypoxia (10.5%
inspired oxygen). The reason for the gas-exchange impairment and reduced cardiac output is
currently unclear, however, it has been hypothesized that hypoxic pulmonary vasoconstriction
(HPV) may increase pulmonary vascular resistance and pulmonary artery pressure during very
heavy exercise. HPV-mediated increases in pulmonary vascular resistance would increase right
heart work and potentially impair the pumping capacity of the heart, leading to a reduction
in stroke volume and, ultimately, cardiac output. HPV has been detected, even in mild hypoxia
(15-18% inspired oxygen), in healthy humans. Inhaled nitric oxide (iNO) is a selective
pulmonary vasodilator and has been shown to reduce pulmonary vascular resistance during
exercise in patients with pulmonary vascular dysfunction (i.e. chronic obstructive pulmonary
disease). Further, iNO has been shown to release HPV in healthy individuals. If iNO can
prevent HPV, this would mitigate the increase in pulmonary vascular resistance in moderate
(~13.6% inspired oxygen) and more severe (~12.1% inspired oxygen) hypoxia and improve V̇O2max
during hypoxic exercise. Therefore, we hypothesize that the iNO will improve V̇O2max during
exercise in moderate and severe hypoxia, secondary to reduced pulmonary artery systolic
pressure leading to increased stroke volume and peak cardiac output. Further, larger
improvements in V̇O2max, with iNO, will be observed in severe hypoxia conditions, when
compared to the iNO-mediated change in V̇O2max in moderate hypoxia. This would provide
conclusive evidence that the pulmonary vasculature is a key contributor to reduced V̇O2max in
both moderate and severe hypoxic conditions.
Trial Objectives
Purpose: To examine the effect of iNO on maximal oxygen consumption (V̇O2max) during exercise
in hypoxia.
Hypothesis: Inhaled NO will improve V̇O2max during hypoxic exercise, secondary to increased
stroke volume and peak cardiac output. A larger improvement in V̇O2max, with iNO, will be
observed in more severe hypoxia conditions, when compared to the iNO-mediated change in
V̇O2max in moderate hypoxia.
Study Design: Randomized double-blind cross-over design.
Study Protocol: Six sessions will be completed over a 3-week period in the following order:
Day 1) Participant enrollment, medical history, standard pulmonary function (PFT) and
cardiopulmonary exercise test (CPET) breathing normoxia (21% inspired oxygen). Days 2-5)
Randomly-ordered experimental CPETs while either breathing A) moderate hypoxia (13.6%
inspired oxygen), B) severe hypoxia (12.1% inspired oxygen), C) moderate hypoxia with 40 ppm
iNO, and D) severe hypoxia with 40 ppm iNO. Day 6) Resting and exercise trials while
breathing, normoxia, moderate and severe hypoxia, and moderate and severe hypoxia with iNO,
with ultrasonography Doppler measurements to determine pulmonary arterial systolic pressure.
The hypoxia conditions will be comparable to being at an altitude of 14,000-17,000 feet.
17,000 feet would be equivalent to standing on the summit of King Peak in the Yukon (the 4th
tallest mountain in Canada).
On Day 1, participants will complete the informed consent procedure, fill out a medical
history questionnaire and be screened for exercise using a physical activity readiness
questionnaire. They will undergo lung function and cardiopulmonary exercise testing on the
same day. The participants will be spending approximately three hours in the laboratory on
this testing day.
On days 2, 3, 4 & 5 the participants will breathe A) moderate hypoxia (13.6% inspired
oxygen), B) severe hypoxia (12.1% inspired oxygen), C) moderate hypoxia with 40 ppm iNO, and
D) severe hypoxia with 40 ppm iNO and have their blood flow/cardiac output and expired gas
evaluated, and time to exhaustion determined in a standard cardiopulmonary exercise test.
Prior to day two, the order of conditions will be block randomized to ensure both CPETs from
one oxygen concentration (either 12.1 or 13.6 %) is completed before the second oxygen
concentration condition is initiated.
On day 2, the participant will lie supine and be rested for 5 minutes. Their resting blood
pressure will be determined using manual auscultation. Resting cardiac output will be
evaluated using noninvasive impedance cardiography and oxygen saturation estimated with pulse
oximetry. Ventilation will be measured from expired gas analysis. Following these
measurements, the subject will begin to breathe one of the four experimental conditions (see
above). Following a 5 minute wash-in period, ventilation, cardiac output and oxygen
saturation recordings will be repeated. Participants will then perform a standard
cardiopulmonary exercise test while continuing to breathe the normoxic air. The participants
will be spending approximately three hours in the laboratory on this testing day.
Day 3, 4 & 5 will be identical to day 2 except, participants will breathe the other
experimental conditions.
On Day 6 the subject will lie supine and be rested for 5 minutes to obtain supine baseline
measurements. Following, participants will sit upright and baseline measurements will be
recorded. Their resting systemic blood pressure will be determined using manual auscultation
and pulmonary arterial systolic arterial pressure will be determine by cardiac ultrasound
imaging. Resting cardiac output will be evaluated using noninvasive impedance cardiography.
The resting measurements will be completed while breathing while breathing, normoxia,
moderate and severe hypoxia, and moderate and severe hypoxia with iNO (order randomized).
Participants will then completed short bouts of light exercise at a fixed intensity and all
measurements will be repeated while breathing normoxia, moderate and severe hypoxia, and
moderate and severe hypoxia with iNO (order randomized). The research participants will
exercise at a light intensity for a total of ~25 minutes (5 minutes per conditions). For both
the resting and exercise measurements, a 10-minute washout time will be given when switching
between conditions.
Participant Duration: Each visit will take approximately 3 hours. The total time duration for
each participant will be approximately 18 hours.
Intervention
Inhaled Nitric Oxide Intervention: Inhaled NO is a selective pulmonary vasodilator and has
been shown to improve blood flow to well-ventilated lung areas (i.e. improve
ventilation-perfusion matching) in conditions with elevated vascular tone. Inhaled NO has
been previously shown to lower pulmonary artery pressure during exercise in lung disease
patients, while not affecting systemic blood pressure. It is important to note that a
selective pulmonary vasodilator will be used instead of an intravenously infused vasodilator
(e.g. prostacyclin) to avoid systemic vasodilation, severe arterial hypotension and syncope
19-20. Consistent with previous work, a standard 40 ppm dose of inhaled NO will be
administered using a non-rebreathing circuit.
Statistical analysis and Interpretation A 1-way repeated measures ANOVA will be used to
evaluate the changes in V̇O2max with 1) moderate and severe hypoxia and, 2) moderate and
severe hypoxia with iNO during exercise, when compared to placebo (normoxic condition).
Should a main effect be found, a Tukey post-hoc t-test with be completed to locate the
differences. Should iNO improve V̇O2max, then this would suggest that a hypoxic-mediated
increase in pulmonary vascular resistance is a key contributor to impaired cardiac output
during moderate and severe hypoxic exercise.
