Intermittent hypoxia increases brain blood flow by 20%

Key Points

• Intermittent hypoxia (IH) increases brain blood flow, even with low CO2

• IH increases fractional oxygen extraction in the brain

• IH might be a useful before a workout, competition, or presentation to increase brain blood flow and focus

The Breathing Diabetic Summary

Your brain consumes almost 20% of your oxygen at rest.  Therefore, during intermittent hypoxia (IH), it makes sense that the body would compensate to make sure the brain gets the oxygen it needs.

However, previous studies are conflicting because when oxygen is reduced, we typically start breathing more.  This gets rid of too much carbon dioxide (CO2), leading to hypocapnia (low CO2).

CO2 is a main driver of cerebral vasodilation.  That is, it increases brain blood flow.  Thus, if CO2 is reduced, we would expect less blood flow to the brain. 

This study aimed to see how these factors played out during cyclic IH.  Would the reduced O2 increase brain blood flow, or would it be offset by reduced CO2?

They recruited 8 healthy men that were ~25 years old.  The participants inhaled O2 at 10% for 6 min to induce hypoxia.  They then breathed normal room air for 4 min.  This cycle was repeated 5 times.  Measurements were taken after the 1st and 5th bouts to see how responses changed during progressive hypoxia exposures.

During the bouts of hypoxia, blood oxygen saturation dropped to ~67%, which is below the therapeutic range of IH.  However, the authors reported that none of the subjects felt discomfort or stress.

Overall, the results revealed that brain blood flow increased by ~20%.  Increases in brain blood flow were significantly greater during the 5th vs. the 1st bout of hypoxia, suggesting a cumulative effect of hypoxia exposures.  The participants dropped CO2 by 4 mm Hg, yet their brain blood flow still increased significantly.  Thus, the increased brain blood flow from hypoxia “overpowered” the reduced blood flow from hypocapnia.

Fractional oxygen extraction in the brain also increased significantly after the 1st bout and remained elevated during the rest of the protocol.  Muscle oxygen extraction, on the other hand, dropped during the procedure, suggesting that the brain gets priority during times of hypoxia.

Statistical analysis revealed that major increases in brain blood flow occurred at about 86% SpO2.  This is something we can easily achieve using breath holds.  In fact, Principle 3 recommends hypercapnic (high CO2) breath holds.  Because both hypoxia and high CO2 cause cerebral vasodilation, we can speculate that brain blood flow would be increased even more using this protocol.

Finally, from a practical perspective, this research supports the idea of practicing breath holds before a workout, competition, or presentation. The increased brain blood flow will help focus your mind and prepare you for what’s ahead.

Abstract from Paper

Cerebral vasodilation and increased cerebral oxygen extraction help maintain cerebral oxygen uptake in the face of hypoxemia. This study examined cerebrovascular responses to intermittent hypoxemia in eight healthy men breathing 10% O2 for 5 cycles, each 6 min, interspersed with 4 min of room air breathing. Hypoxia exposures raised heart rate ( P < 0.01) without altering arterial pressure, and increased ventilation ( P < 0.01) by expanding tidal volume. Arterial oxygen saturation ([Formula: see text]) and cerebral tissue oxygenation ([Formula: see text]) fell ( P < 0.01) less appreciably in the first bout (from 97.0 ± 0.3% and 72.8 ± 1.6% to 75.5 ± 0.9% and 54.5 ± 0.9%, respectively) than the fifth bout (from 94.9 ± 0.4% and 70.8 ± 1.0% to 66.7 ± 2.3% and 49.2 ± 1.5%, respectively). Flow velocity in the middle cerebral artery ( VMCA) and cerebrovascular conductance increased in a sigmoid fashion with decreases in [Formula: see text] and [Formula: see text]. These stimulus-response curves shifted leftward and upward from the first to the fifth hypoxia bouts; thus, the centering points fell from 79.2 ± 1.4 to 74.6 ± 1.1% ( P = 0.01) and from 59.8 ± 1.0 to 56.6 ± 0.3% ( P = 0.002), and the minimum VMCA increased from 54.0 ± 0.5 to 57.2 ± 0.5 cm/s ( P = 0.0001) and from 53.9 ± 0.5 to 57.1 ± 0.3 cm/s ( P = 0.0001) for the [Formula: see text]- VMCA and [Formula: see text]- VMCA curves, respectively. Cerebral oxygen extraction increased from prehypoxia 0.22 ± 0.01 to 0.25 ± 0.02 in minute 6 of the first hypoxia bout, and remained elevated between 0.25 ± 0.01 and 0.27 ± 0.01 throughout the fifth hypoxia bout. These results demonstrate that cerebral vasodilation combined with enhanced cerebral oxygen extraction fully compensated for decreased oxygen content during acute, cyclic hypoxemia. NEW & NOTEWORTHY Five bouts of 6-min intermittent hypoxia (IH) exposures to 10% O2 progressively reduce arterial oxygen saturation ([Formula: see text]) to 67% without causing discomfort or distress. Cerebrovascular responses to hypoxemia are dynamically reset over the course of a single IH session, such that threshold and saturation for cerebral vasodilations occurred at lower [Formula: see text] and cerebral tissue oxygenation ([Formula: see text]) during the fifth vs. first hypoxia bouts. Cerebral oxygen extraction is augmented during acute hypoxemia, which compensates for decreased arterial O2 content.

Journal Reference:

Liu X, Xu D, Hall JR, et al.  Enhanced cerebral perfusion during brief exposures to cyclic intermittent hypoxemia.  J Appl Physiol.  2017;123(6):1689-1897.

The protective role of nitric oxide during adaptation to hypoxia

Key Points

• Adaptation to hypoxia increases NO production and storage

• Simultaneously, adaptation to hypoxia protects against NO over- and under-production

Breathing Blueprint Summary

A paper we recently reviewed found that the production and storage of nitric oxide (NO) increases significantly during adaptation to hypoxia.  This paper wanted to see what would happen during adaptation to hypoxia in disorders of either NO over-production or NO deficiency.

Three different types of Wistar rats were studied.  The first was a model of NO overproduction (NO+), the second a model of NO deficiency (NO-), and the third a control group.

The same protocol from their previous work was used for adaptation to hypoxia: They gradually adapted mice to hypoxia in an altitude chamber simulating ~5000 m (hypobaric hypoxia).  The mice completed 40 sessions.  They started at 10 min the first session, then 20 min the second session, and so on until they reached 5 hours of simulated altitude per session.

After the full acclimation, the control mice nearly doubled their NO metabolites.  Their NO storage had significantly increased as well.  These results indicated that NO production and storage increased due to adaptation to hypoxia.

These adaptations were beneficial for the other mice studied.  The NO+ mice that were not acclimated to hypoxia showed a drop in blood pressure of about 36 mm Hg.  The NO+ mice that were acclimated to hypoxia only showed a 19 mm Hg drop.

Similarly, adaptation to hypoxia protected the NO- mice as well.  Without hypoxia, their blood pressure increased ~80 mm Hg.  With adaptation, it only increased ~20 mm Hg.

These results indicate that adaptation to hypoxia protects against both over- and under-production of NO.

The body ramps up production of NO while simultaneously increasing NO storage to an even greater extent.  This prevents severe drops in blood pressure, but also ensures that NO is available “if needed.”

The final sentence from the abstract sums it up nicely:

“The data suggest that NO stores induced by adaptation to hypoxia can either bind excessive NO to protect the organism against NO overproduction or provide a NO reserve to be used in NO deficiency.”

Abstract

Adaptation to hypoxia is beneficial in cardiovascular pathology related to NO shortage or overproduction. However, the question about the influence of adaptation to hypoxia on NO metabolism has remained open. The present work was aimed at the relationship between processes of NO production and storage during adaptation to hypoxia and the possible protective significance of these processes. Rats were adapted to intermittent hypobaric hypoxia in an altitude chamber. NO production was determined by plasma nitrite/nitrate level. Vascular NO stores were evaluated by relaxation of the isolated aorta to diethyldithiocarbamate. Experimental myocardial infarction was used as a model of NO overproduction; stroke-prone spontaneously hypertensive rats (SHR-SP) were used as a model of NO shortage. During adaptation to hypoxia, the plasma nitrite/nitrate level progressively increased and was correlated with the increase in NO stores. Adaptation to hypoxia prevented the excessive endothelium-dependent relaxation and hypotension characteristic for myocardial infarction. At the same time, the adaptation attenuated the increase in blood pressure and prevented the impairment of endothelium-dependent relaxation in SHR-SP. The data suggest that NO stores induced by adaptation to hypoxia can either bind excessive NO to protect the organism against NO overproduction or provide a NO reserve to be used in NO deficiency.

Journal Reference:

Manukhina EB, Mashina SY, Smirin BV, et al. Role of nitric oxide in adaptation to hypoxia and adaptive defense. Physiol Res. 2000;49(1):89-97.

Intermittent hypoxia is beneficial in sedentary, non-athletic, and clinical populations

Key Points

• Intermittent hypoxia improves cardio-autonomic function and exercise tolerance

• There are several ways to achieve intermittent hypoxia and receive benefits, including prolonged hypoxic exposure, intermittent hypoxic exposure, and intermittent hypoxic training

• Intermittent hypoxia is beneficial in sedentary and clinical populations

The Breathing Diabetic Summary

I love review papers because they summarize the key findings from the scientific literature in an easy to follow manner. Therefore, anytime I find a review study on a subject of interest, I dive right in.

This one was unique because it looked at the effects of simulated altitude on non-athletic, sedentary, and clinical populations. Most studies on simulated altitude involve elite performers, so it was interesting seeing a review paper focusing on more “everyday” people.

Using different search criteria, they identified 26 studies that have looked at intermittent hypoxia in the abovementioned populations. Within those 26 studies, they then identified 3 different methods of achieving intermittent hypoxia:

1. Prolonged hypoxic exposure (PHE): Continuous hypoxic interval, such as “live high, train low”.

2. Intermittent hypoxic exposure (IHE): Short intervals (5-10 min) of hypoxic:normoxic exposure.

3. Intermittent hypoxic training (IHT): Exercising in hypoxia.

For our purposes, IHE and IHT are the only practical methods for achieving hypoxia via breath holds. However, the results for PHE will also be included for completeness (and, maybe one day altitude tents will be affordable!).

Here, I’ll summarize the benefits they found for each method of hypoxia.

IHE:

• Reduced systemic stress

• Improved heart rate variability

• Improved autonomic balance

• Reduced blood pressure

• Greater exercise tolerance

• Longer time to exhaustion while exercising

• Hematological results were mixed. Some studies showed increased red blood cells, others didn’t.

PHE:

• Improved lung ventilation

• Improved submaximal exercise performance

• Improved blood lipid profile

• Improved blood flow to the heart

IHT:

• Increased aerobic capacity

• Increased fat burning

• Increased mitochondrial density

• Improved autonomic balance

With respect to PHE, the research suggested that at least 1 hour of 12% O2 for 2 weeks would provide the greatest benefits without side effects. They did not provide recommendations for IHE or IHT.

However, a 2014 review study showed that 3-15 episodes of 9-16% O2 is the therapeutic range for IHE. This corresponds to blood O2 saturations of approximately 82-95%.

Also, from a practical perspective, we know that we can perform walking breath holds to achieve mild IHT. Essentially, we combine the IHE protocol with walking.

Overall, this paper suggests that intermittent hypoxia has many benefits in sedentary, non-athletic, and clinical populations, including improved cardiovascular and autonomic function and increased exercise capacity.

It also showed that there are several ways to achieve those benefits: Prolonged exposure, intermittent exposure, or exposure during exercise.

I recommend that you find a modality that fits you or your client’s lifestyle that can be practiced consistently.

Abstract from Paper

BACKGROUND: The reportedly beneficial improvements in an athlete's physical performance following altitude training may have merit for individuals struggling to meet physical activity guidelines.

AIM: To review the effectiveness of simulated altitude training methodologies at improving cardiovascular health in sedentary and clinical cohorts.

METHODS: Articles were selected from Science Direct, PubMed, and Google Scholar databases using a combination of the following search terms anywhere in the article: "intermittent hypoxia," "intermittent hypoxic," "normobaric hypoxia," or "altitude," and a participant descriptor including the following: "sedentary," "untrained," or "inactive."

RESULTS: 1015 articles were returned, of which 26 studies were accepted (4 clinical cohorts, 22 studies used sedentary participants). Simulated altitude methodologies included prolonged hypoxic exposure (PHE: continuous hypoxic interval), intermittent hypoxic exposure (IHE: 5-10 minutes hypoxic:normoxic intervals), and intermittent hypoxic training (IHT: exercising in hypoxia).

CONCLUSIONS: In a clinical cohort, PHE for 3-4 hours at 2700-4200 m for 2-3 weeks may improve blood lipid profile, myocardial perfusion, and exercise capacity, while 3 weeks of IHE treatment may improve baroreflex sensitivity and heart rate variability. In the sedentary population, IHE was most likely to improve submaximal exercise tolerance, time to exhaustion, and heart rate variability. Hematological adaptations were unclear. Typically, a 4-week intervention of 1-hour-long PHE intervals 5 days a week, at a fraction of inspired oxygen (FIO2) of 0.15, was beneficial for pulmonary ventilation, submaximal exercise, and maximum oxygen consumption ([Formula: see text]O2max), but an FIO2 of 0.12 reduced hyperemic response and antioxidative capacity. While IHT may be beneficial for increased lipid metabolism in the short term, it is unlikely to confer any additional advantage over normoxic exercise over the long term. IHT may improve vascular health and autonomic balance.

Journal Reference:

Lizamore CA, Hamlin MJ.  The Use of Simulated Altitude Techniques for Beneficial Cardiovascular Health Outcomes in Nonathletic, Sedentary, and Clinical Populations: A Literature Review.  High Alt Med Biol.  2017;18(4):305-321.

Hypoxia has positive impacts on insulin and blood glucose levels while also increasing energy expenditure

Key Points

• Hypoxia positively impacts insulin and blood glucose while also increasing energy use

• Hypoxia and exercise combined reduce weight and blood pressure in obese patients

• The positive effects of hypoxia are dose-dependent

Breathing Blueprint Summary

I love review studies because they save us a lot of time.  Researchers go through all of the literature on a specific topic and consolidate everything into one place for us to read. I like to think of The Breathing Diabetic as a big review of all of the research on breathing, health, and well-being…

This paper reviewed the literature on the potential therapeutic benefits of hypoxia for obese individuals.  We know from other papers we have reviewed on hypoxia that there are many benefits for diabetics as well.  And, since diabetes and obesity often occur simultaneously, this review study is relevant for us.

One important point they make, which bears repeating, is that it is not feasible for us all to have access to high altitude.  We cannot simply move to the mountains, or somewhere close enough, to periodically expose ourselves to high altitude.  But, there are ways to experience some of the effects of altitude while at sea level.  The authors specifically mention masks and tents that can reduce the amount of inspired oxygen to simulate high altitude.  However, we cannot forget that breath holds also simulate high altitude and are available to us anytime, for free!

One of the key findings was that fasting blood glucose and insulin levels were reduced in animals following intermittent hypoxia.  Additionally, energy expenditure was increased in animals following hypoxic exposure.  Finally, hypoxia combined with exercise (what they called “active hypoxia”) decreased body weight and blood pressure in obese humans.

They also found contradictory results in some studies, which appeared to be due to the severity of the hypoxia protocol used (something we have reviewed previously). Thus, again we see that the benefits of hypoxia are dose-dependent.

Overall, the authors conclude that hypoxia could be beneficial for obese populations. However, the improvements in insulin, blood glucose, weight, and blood pressure shown here are further evidence that intermittent hypoxia (Principle 3) can benefit anyone looking to improve overall health and well-being.

Abstract From Paper

Normobaric hypoxic conditioning (HC) is defined as exposure to systemic and/or local hypoxia at rest (passive) or combined with exercise training (active). HC has been previously used by healthy and athletic populations to enhance their physical capacity and improve performance in the lead up to competition. Recently, HC has also been applied acutely (single exposure) and chronically (repeated exposure over several weeks) to overweight and obese populations with the intention of managing and potentially increasing cardio-metabolic health and weight loss. At present, it is unclear what the cardio-metabolic health and weight loss responses of obese populations are in response to passive and active HC. Exploration of potential benefits of exposure to both passive and active HC may provide pivotal findings for improving health and well being in these individuals. A systematic literature search for articles published between 2000 and 2017 was carried out. Studies investigating the effects of normobaric HC as a novel therapeutic approach to elicit improvements in the cardio-metabolic health and weight loss of obese populations were included. Studies investigated passive (n = 7; 5 animals, 2 humans), active (n = 4; all humans) and a combination of passive and active (n = 4; 3 animals, 1 human) HC to an inspired oxygen fraction (FIO2) between 4.8 and 15.0%, ranging between a single session and daily sessions per week, lasting from 5 days up to 8 mo. Passive HC led to reduced insulin concentrations (-37 to -22%) in obese animals and increased energy expenditure (+12 to +16%) in obese humans, whereas active HC lead to reductions in body weight (-4 to -2%) in obese animals and humans, and blood pressure (-8 to -3%) in obese humans compared with a matched workload in normoxic conditions. Inconclusive findings, however, exist in determining the impact of acute and chronic HC on markers such as triglycerides, cholesterol levels, and fitness capacity. Importantly, most of the studies that included animal models involved exposure to severe levels of hypoxia (FIO2 = 5.0%; simulated altitude >10,000 m) that are not suitable for human populations. Overall, normobaric HC demonstrated observable positive findings in relation to insulin and energy expenditure (passive), and body weight and blood pressure (active), which may improve the cardio-metabolic health and body weight management of obese populations. However, further evidence on responses of circulating biomarkers to both passive and active HC in humans is warranted.

Journal Reference:

Hobbins L, Hunter S, Gaoua N, Girard O. Normobaric hypoxic conditioning to maximize weight loss and ameliorate cardio-metabolic health in obese populations: a systematic review. Am J Physiol Regul Integr Comp Physiol. 2017;313:R251-R264.