The Effect of Inhaled Nitric Oxide on Maximal Oxygen Consumption During Exercise in Hypoxia
Condition: Hypoxia
MeSH terms: Hypoxia
Study type: Interventional
Phase: Phase 1/Phase 2

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).
    

Detailed 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.
    

Intervention name(s): Nitric Oxide; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 40 parts per million dosage; Inhaled placebo. Device connected to same delivery system, but does not deliver nitric oxide.
Other intervention name(s): iNO; Hypoxic Placebo
Intervention MeSH terms: Nitric Oxide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science