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EPO and Intermittent Hypoxic Exposure: How to Defy Trends in Clinical Data


Photo by Sarah Ackerman

Intermittent Hypoxic Exposure: How to Defy Trends in Clinical Data

This post is both a comprehensive analysis of intermittent hypoxic exposure.  This technique is becoming one of the most popular types of simulated altitude training.  It is also the only form of altitude training that is likely to become popular in the NFL or UFC, because of the need to maintain superior anaerobic fitness and muscle size.  However, the scientific support for IHE is very inconsistent.  Having developed truly successful IHE protocols and measured astounding results on athletes, I believe that the lack of clinical support is derived from the fact that most studies were not designed for optimizing performance gains.  In this post our research team will break down the science behind exactly how to do this and show you how to actually use a hypoxicator as an effective training tool.

The Basics of Intermittent Hypoxic Exposure: Definitions and Evidence

Intermittent hypoxic exposure (IHE) consists of brief periods of exposure to severe altitudes at rest designed to induce biological adaptations that improve sea-level performance or prepare the body for high altitude.  We will discuss a similar technique, intermittent hypoxic training (IHT), in a separate post because IHT protocols are designed differently to achieve different goals.

The clinical studies on IHE typically involve sessions of 1-3 hours in duration at simulated altitudes of 12,000-21,000 ft (3,658-6,401 m).  Session frequency ranges from consecutive multiple times daily to 3 times per week, and experiments will last from 10 days up to 5 weeks.  Though few studies show performance gains, the majority show no performance improvement at sea-level and no increase in red blood cell markers.  Studies conducted on IHE for high altitude performance, however, often have positive results such as a more responsive ventilatory drive and improved skeletal muscle resistance to the hypoxic degradation caused by extreme altitudes.

IHE for High Altitude Vs. Sea-Level Performance

As you may have gleaned from above, there are two major applications for IHE: 1) high altitude pre-conditioning and 2) sea-level performance enhancement.  In terms of clinical support, IHE is far more promising as a means to prepare the body for high altitude.  This is likely because it induces the short-term components of acclimatization as well as primes various physiological/genetic mechanisms to react more quickly to successive high altitude exposures.  For example, at high altitude, a heightened respiratory drive is the primary adaptation for improved performance because it best compensates for drops in blood 02 levels.  At sea-level, Sp02 tends to only drop during maximal exercise, rendering enhanced ventilation less useful for overall endurance performance.

IHE’s ability to improve sea-level performance does not have a lot of support from clinical studies.  This is because, compared to other types of high altitude training, the hypoxic stimulus seems to not be significant enough to bring about increases in blood oxygen carrying capacity.  Furthermore the enzymatic and PH buffering adaptations commonly reported in intermittent hypoxic training studies, do not seem to be effectively provided by IHE.

So how do we defy clinical findings and create a sea-level performance enhancing IHE protocol?

First of all, there have been numerous clinical studies in which IHE improved red blood cell growth as well as performance.  Furthermore, every single IHE study that measured levels of EPO in the blood did show significant increases.  So it seems entirely possible that IHE has the potential to increase red blood cell production.  By the way, the majority of these studies are available in a book called Intermittent Hypoxia: From Molecular Mechanisms to Clinical Applications  by Lei Xi and Tatiana Serebrovskaya.

Early IHE Session Scheduling to Combat Neocytolysis

The problem in translating spikes in EPO production to RBC growth is a process called neocytolysis, which is the selective destruction of young and pre-mature red blood cells.  This process is also the reason that your blood markers will return to baseline in 10-14 days post sea-level return from an altitude camp despite the fact that the average red blood cell lives 120 days.  Neocytolysis is initiated when EPO drops below a baseline level.  As a premature RBC transforms into the later stages of development, there are various receptor changes that take place.  These changes render premature RBC’s less EPO dependent for survival and less EPO sensitive it is for growth.  This early EPO dependence and growth sensitivity suggests that a continuously elevated level of EPO would be required to nurture premature RBC’s into infancy.  Interestingly, several studies on kidney deficient anemics have shown that small and frequent EPO injections are significantly more cost-effective than relatively infrequent large dose injections.

IHE by nature induces large spikes in EPO, that may not remain elevated long enough to nurture pre-mature red blood cells into infancy.  From the limited number of studies that measured EPO fluctuations, post IHE EPO production follows a somewhat predictable pattern:

  • EPO seems to peak 2-4 hours post exposure
  • It then recedes to baseline 5-8 hours post exposure
  • The magnitude of EPO production, as well as the duration before baseline return is directly proportional to both the level of absolute altitude and length of a session

Now lets combine these observations with the others we made above:

  • The majority of IHE studies show no impact on performance or blood oxygen carrying capacity
  • The studies that do show sea-level performance improvement also show increases in red blood cell production
  • Pre-mature red blood cells are highly EPO dependent and require continuously elevated levels of EPO for continued growth and survival
  • One daily IHE session may not be sufficient to maintain EPO levels, prevent neocytolysis, and form mature RBC’s
  • It takes 5-10 days for RBC’s to fully mature

Using this logic we designed an IHE program developed to specifically increase blood oxygen carry capacity and enhance sea-level performance.

Multi-Daily IHE Protocol:

Session Description:

  • 80 minutes of 8:2 exposure pattern to 19,000-21,000 ft using Higher Peak Normobaric Hypoxicator
  • 8:2 refers to 8 minutes under hypoxia followed by 2 minutes of rest; these patterns seem to reduce adverse symptoms while not compromising the hypoxic stimulus

Session Scheduling:

  • Minimum of 2 sessions daily for the first 10 days
  • Maximum of 3 sessions daily overall
  • Sessions are held 4-6 hours apart
  • Exercise is not performed within 2 hours prior to session or 1 hour post-session
  • 10 days out we allow more flexibility in session frequency; Minimum of 5 sessions per week

Evidence of the Multi-daily Session Approach

That is the general protocol that we put our athletes through.  We have not done sufficient hematological testing pre and post protocol to unequivocally say that it will increase performance and blood markers.  However, I have witnessed 12-14% increases in hematocrit after 12 days in four of my athletes.  These increases would rank in the top 97% of success rates in terms on improving blood markers.  Furthermore of the 4 clinical studies I have examined that demonstrated red blood cell improvements, 3 of them utilized a multi-daily protocol structure (Hellemans 1999, Rodriguez et al. 1999, Casas et al. 2000).

There has been one study that used the multi-daily approach, and did not report any significant changes in RBC markers (Glyde-Julian et al. 2003).  However, the sessions used a 5:5 ratio, lasted 70 minutes, and were only performed 5 days per week.  This is a considerably lower frequency and total duration than our protocol utilizes.

More “Air” For Thought

Overall, there is a considerable amount anecdotal and mechanistic support for multiple daily IHE sessions as the most effective technique for improving both red blood cell markers and performance.  I also believe that if done properly IHE may be an even more effective stimulus for hypoxic adaptations than living at altitude.  This is because you can expose athletes to considerably higher altitudes and produce even larger increases in EPO.  These larger increases can accelerate the development of premature RBC’s and even allow them to skip intermediary stages of development.  This phenomenon is consistent by the fact that large increases in hematocrit have been reported in as quickly as 9 days in multi-daily IHE studies.  EPO production tends to taper back to baseline rather quickly with traditional live high train high and live high train low models.

We encourage any comments or experiences you may have had with intermittent hypoxic exposure!


  • R.M.Mahindrakar

    Thank you for the information. this really helped me to explain to my students of how people get adapted to live at higher altitudes.