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You are here: Home / Environment / Questions from the Field / EPO for altitude acclimitization

EPO for altitude acclimitization

A look at the use of exogenous erythropoietin (EPO) for faster altitude acclimatization.

From the Field

Will EPO help my performance?

Overview

EPO for altitude acclimitization

B.L.U.F.*

EPO research indicates that, while it may enhance performance under some circumstances, the use of EPO comes with potentially serious risks. Moreover, it requires both a prescription and medical supervision. Taking time to ascend gradually, which allows the body to adapt naturally, still seems the best method for Warfighters to acclimatize to altitudes of 6,000 ft or higher.

Background

Erythropoietin (EPO), a hormone produced mainly by the kidneys, stimulates the production of red blood cells (RBCs). Low oxygen partial pressure, which is found at altitude, stimulates the production of EPO and, thus, RBCs to carry more oxygen to the body’s tissues. Recombinant human (exogenous) erythropoietin (eEPO) can be manufactured and injected for the treatment of anemia and other clinical disorders. eEPO is also used illegally to enhance performance (“blood doping”).

Myths and Claims

It is popularly thought that administering eEPO to stimulate the production of RBCs will help individuals acclimatize faster and, thus, adapt more rapidly to moderate or higher altitudes.

Facts

Ascent to altitude causes physiologic stress because of the reduced air density and decreased partial pressure of oxygen, frequently resulting in altitude illness. Acute mountain sickness (AMS) can occur in un-acclimatized persons who quickly travel to altitudes of 6,000 ft (2,000 m) or greater, although not all individuals are affected to the same extent or in the same manner. AMS is characterized by headache and/or gastrointestinal distress (anorexia, nausea, or vomiting), insomnia, lightheadedness, dizziness, and fatigue. Above altitudes of 9,800 ft (3,000 m), pulmonary or cerebral edema, or damage, can ultimately occur. AMS can be made worse by strenuous exercise.

Many athletes have used eEPO illegally, and the beneficial effects at sea level due to increased hemoglobin concentration and systemic and muscular oxygen delivery suggest that it should have benefits at altitude. However, no studies have been done on individuals who took eEPO and were then rapidly sent to altitude and monitored for performance or symptoms of AMS. So the question of a beneficial effect at altitude has not been answered. Studies using simulated altitude conditions and oxygen deprivation have shown some positive results, except that eEPO seems to have no effect under conditions similar to those at altitudes of 14,700 ft (4,500 m).

The only established means of preventing or minimizing AMS is through staged acclimatization. The most accepted process is to ascend no higher than 8.000 ft (2,400 m) the first day and then sleep at that altitude for four to seven days before climbing higher. Alternatively, ascend to 8,000 ft (2,400 m) the first day and then gain no more than 500 ft (150 m) each subsequent day. Additional strategies include an iron-enriching diet, hydration, and consumption of carbohydrates.

Cautions

eEPO has not been shown to be effective at enhancing acclimatization to altitude, and it is considered a controlled substance. Studies have shown that serious side effects and even death can result from its use. On February 16, 2010, the FDA issued a safety announcement that all EPO-related drugs must be prescribed and used under a risk management program, known as a risk evaluation and mitigation strategy, to ensure their safe use.

Summary for Military Translation

Peak performance at altitude is necessary for Warfighters, yet it is known that rapid ascent to altitude results in reduced performance. No studies have shown that eEPO accelerates acclimatization to altitude or minimizes AMS. The favored method to acclimatize is through non-pharmacological behavioral strategies that promote needed adaptations; this can be done either through staging or graded ascents. If acclimatization is not possible, military leaders should limit the initial activity levels of Warfighters and watch for signs of AMS. For additional information on acclimatization strategies and detailed symptoms of AMS, see the related Research Brief.



* “Bottom Line Up Front”

Research Summary

EPO for altitude acclimitization

Key Points

  • Erythropoietin (EPO) is a hormone produced primarily by the kidneys to stimulate the production of red blood cells (RBCs), which carry oxygen in the blood. Stimulation of red blood cell production, called erythropoiesis, is central to optimizing performance at high altitude.
  • EPO is also manufactured for many clinical conditions, in particular anemia. This exogenous EPO (eEPO) is injected to artificially stimulate RBC production, a process called “blood doping; it is classified as an erythropoiesis-stimulating agent (ESA).
  • On February 16, 2010, the FDA issued a safety announcement requiring all ESA drugs to be prescribed and used under a risk management program to ensure their safe use.
  • Multiple adverse events have been noted with use of eEPO.
  • High altitude can degrade performance and induce altitude sickness: Warfighters should use approved acclimatization strategies before going to moderate to high altitude environments.
  • Administering eEPO can improve maximal aerobic performance at sea level and at simulated altitudes up to 11,000 ft (3,500 m) by increasing the oxygen-carrying capacity of the RBCs. eEPO does not appear to be effective above 11,000 ft (3,500 m).
  • No scientific studies have been conducted to determine whether eEPO can accelerate altitude acclimatization.

Background

The hormone erythropoietin (EPO) is a glycosylated protein that regulates and initiates RBC formation [1]. The production of EPO is stimulated by the concentration of oxygen in the blood—the lower the oxygen content, the greater the release of EPO—to increase the production of RBCs [1,2] and, ultimately, total hemoglobin mass and arterial oxygen content [3]. RBCs, which represent 38-45% of total blood volume, contain hemoglobin (Hb); the primary role of Hb in RBCs is to carry oxygen to tissues, all of which are dependent on oxygen.

Ascent to altitude is a physiologic stress because of the reduced air density and decreased partial pressure of oxygen. As an individual ascends in elevation, air density progressively decreases, so the amount of oxygen available decreases. For example, at 30,000 ft (9,200 m; the height of Mt. Everest), only one-third of the oxygen is present in the air than is available at sea level. Initial physiologic responses to altitude include increases in ventilation and in heart rate during rest and submaximal exercise that increase cardiac output to compensate for the decreased oxygen saturation of hemoglobin. In addition, endogenous EPO production and a decrease in plasma volume improve the oxygen-carrying capacity of the blood.

The production of EPO is rapidly stimulated with increasing altitude due to increases in oxygen demands, particularly during exercise, due to decreases in oxygen saturation. Serum EPO levels typically peak within 24–­48 h and then decline to near-baseline levels within approximately one week [4]. Despite the rapid increase in EPO, it takes approximately three weeks for RBC mass to increases by about 7% [1]. Both acute and chronic changes facilitate acclimatization with ongoing exposure. However, rapid deployment to altitude may result in adverse physiologic responses and marked decrements in physical and cognitive performance [5].

Facts and Evidence

Signs and symptoms at altitude. Acute mountain sickness (AMS) occurs frequently in persons who are not acclimatized and rapidly travel to altitudes of 6,500 ft (2,000 m) or greater [6]. AMS is characterized by headache and/or any one or more of the following: gastrointestinal distress (anorexia, nausea, and/or vomiting), insomnia, lightheadedness, dizziness, and fatigue [6]. High-altitude pulmonary edema (HAPE), which can be fatal, may occur at altitudes of 9,800 ft (3,000 m) or higher, and high-altitude cerebral edema (HACE), often considered the end-stage of AMS, is usually seen only above 13,000 ft (4,000 m) [7]. The figure above shows the highest estimated incidence and severity of AMS in persons who had not been acclimatized prior to altitude exposure. As shown, 40% of the population experiences at least mild AMS at altitudes of 12,000 ft (3,500 m), and over 70% experience severe symptoms at very high altitude (18,000 ft.) [8]. The only way to minimize these symptoms is through acclimatization. Table 1 presents the anticipated effects of altitude at various elevations [Source: USARIEM "High Altitude" Brief].

Table 1: Elevation Measurements

Altitude

Feet (meters)

Effects of Altitude

Low

Sea Level - 5,000
(SL-1,500)

None

Moderate

5,000-8,000
(1,500-2,440)

Mild, temporary altitude illness may occur

High

8,000-14,000
(2,440-4,300)

Altitude illness and decreased performance is increasingly common

Very High

14,000-18,000
(4,300-5,500)

Altitude illness and decreased performance as the rules

Extreme

18,000-higher (>5,500)

With acclimatization, humans can function for short periods of time

Symptoms generally occur as early as one hour to within six to ten hours of ascent. Risk factors for AMS include a prior history of illness at altitude, recent ascent to altitude, exertion at altitude prior to acclimatization, and certain preexisting conditions [6]. Older individuals (over 50 years) seem to be less susceptible [6]. Additionally, physical fitness does not seem to protect against AMS [9,10], and the incidence does not seem to differ by gender [10].

Altitude acclimatization. The process of altitude acclimatization requires time to induce the needed physiologic adaptations that compensate for the reduction in oxygen partial pressure [5,11]. The most accepted way to acclimatize is by ascending to no more than 8,000 ft (2,400 m) the first day and then, optimally, sleeping at that altitude for up to seven days, with four days being the minimal stay before going higher [5,11]. Alternative approaches include ascending to no more than 8,000 ft (2,400 m) the first day and then gaining no more than 500 ft (150 m) each subsequent day [8] to prevent AMS [5,8,11]. Recent work showed that spending six days at 7,200 ft (2,200 m) significantly attenuated both physical performance decrements [12] and increases in pulmonary arterial pressure [5] upon ascent to 14,000 ft (4,300 m). Importantly, strenuous exercise at altitude exacerbates symptoms of AMS, but exercise tolerance at altitude improves as time at altitude increases [5,8]. After a day or two at 8,000 ft (2,400 m), Warfighters should be able perform light to moderate physical tasks without symptoms of AMS.

Importantly, acclimatization cannot be accelerated [5,8,11]; however, some Warfighters may acclimatize rapidly and completely and others slowly and/or minimally. In addition, acclimatization to one altitude confers only partial acclimatization to a higher altitude [5]. To date, no reliable way is available for definitively identifying those who are susceptible to AMS (unless they had symptoms during previous exposures), but two ideas that involve arterial oxygen saturation (SaO2) have been put forward [13,14]. For one, SaO2 was measured before andafter running stairs (151 ft / 46 m) at peak speed [14], and for the other, SaO2 was measured 20–30 min after simulated 7,500­–14,000 ft (2,300–4,200 m) altitude exposure [13]. Such tests may become common in the future, but to date, the physiology and magnitude of the hypoxic challenge to the individual determine the degree of symptomatology and amount of time required for acclimatization [5]. Finally, the extent of acclimatization developed will be positively related to the altitude achieved and the duration of exposure [5].

Does eEPO accelerate acclimatization? In addition to EPO produced by the body, recombinant human EPO is available for exogenous (eEPO) administration [1]. eEPO is used for the treatment of anemia and other clinical disorders that result in anemia, because it increases RBC production and blood-oxygen-carrying capacity [1]. It has also been used illegally by many athletes, in particular cyclists [2]. Importantly, the FDA requires all ESA drugs to be prescribed and used under a risk management program, known as a risk evaluation and mitigation strategy, to ensure the safe use of eEPO and such drugs. This safety announcement, based on scientific evidence, was issued in February 2010.

The use of eEPO for enhancing performance is pervasive but relatively unstudied. However, the available data indicate that eEPO administration significantly improves maximal aerobic capacity and submaximal exercise performance at sea level by increasing hemoglobin concentration and systemic and muscular oxygen delivery [2]. These beneficial effects of eEPO at sea level may translate into critical adaptations needed at altitude and could potentially help Warfighters acclimatize faster and perform better.

No studies have administered eEPO to individuals and then rapidly sent them to altitude to monitor performance and symptoms of AMS. As such, the question of a beneficial effect has not been answered. However, limited information is available on how administering eEPO affects performance under simulated altitude or hypoxic conditions. One investigator compared hematologic and physiologic responses to eEPO and with those to simulated altitude exposure (8,700–9,800 ft / 2,650–3,000 m) for up to 23 nights. The results showed marked increases in serum EPO, reticulocytes, and maximal aerobic capacity in response to eEPO, versus relatively minor increases with hypoxia [15]. Another study investigated the use of eEPO during simulated altitude and showed that the maximal aerobic enhancing effect of eEPO during exercise at sea level also occurs under conditions of mild to moderate hypoxia [3]. They noted improvements in maximal aerobic capacity of 6-7% under normoxic, 8% under mild (5,000 ft/1,500 m) and 14-17% under moderate (8,000–11,000 ft/2,500-3,500 m) hypoxia [3]. In contrast, eEPO had no positive effect on exercise capacity under severe, acute hypoxia (15,000 ft / 4,500 m) [8]. However, it is important to remember that these are simulated altitude studies and did not evaluate acclimatization to actual altitude. However, given the negative effects of eEPO with severe hypoxia, it may not confer benefit at high altitude.

Cautions

eEPO has been associated with many adverse events such as clotting, thrombosis, heart attack, and stroke [16]. The increased blood viscosity from non-medical use of EPO may be exacerbated by the dehydration associated with high-intensity training and endurance sports. A number of athletes have died as the result of using eEPO to enhance performance [17].

Military Relevance

The physiologic responses described above are particularly relevant for military performance since many operations take place at high elevations. eEPO has not been studied during ascent to altitude for its role in acclimatization, but it is a prescription medication with multiple side effects, and its use at altitude should be discouraged.

Rapid exposure to altitude negatively impacts physical capacity, motor ability, and possibly mood [5,6,8,11]. Understanding the physiologic effects of altitude is necessary for mission planning and for implementing appropriate countermeasures to minimize the deleterious effects of rapid ascent to altitude. The following comments/tips should be considered for Warfighter altitude acclimatization.

Allow an individual to acclimatize at an altitude of 8,000 ft (2,400 m; moderate altitude) for at least five days before ascending higher.

AMS, pulmonary edema, and cerebral edema can be avoided with slow and gradual ascents—no more than 1,000 ft (300 m) a day above 9,800 ft (3,000 m), but only after one to seven days at 8,000 ft (2,400 m). For a more in-depth manual on how to ascend and minimize AMS, see the U.S. Army's Altitude Acclimatization Guide. Acclimatization to altitude will abate within two to three weeks upon returning to sea level.

If no time is available to acclimatize, leaders should be aware of the following signs and respond accordingly:

  • Headache, insomnia, loss of appetite, nausea, dizziness, shortness of breath, and/or vomiting (symptoms of AMS).
  • Breathlessness at rest, dry cough, bluish lips, nausea/vomiting, and/or headache (symptoms of HAPE).
  • Headache, stumbling, inability to perform, memory loss, hand coordination problems, disorientation, confusion, hallucinations, and psychotic behavior (symptoms of HACE).

For more information, see the article in the Army Times about “High Altitude” and the need for adaptation, carbohydrate loading, and drugs to treat altitude sickness.

References

EPO for altitude acclimitization

  1. Elliott S. Erythropoiesis-stimulating agents and other methods to enhance oxygen transport. Br J Pharmacol. 2008;154(3):529-41.
  2. Ekblom BT. Blood boosting and sport. Baillieres Best Pract Res Clin Endocrinol Metab. 2000;14(1):89-98.
  3. Robach P, Calbet JA, Thomsen JJ, Boushel R, et al. The ergogenic effect of recombinant human erythropoietin on VO2max depends on the severity of arterial hypoxemia. PLoS One. 2008;3(8):e2996.
  4. Sawka MN, Young AJ, Rock PB, Lyons TP, et al. Altitude acclimatization and blood volume: effects of exogenous erythrocyte volume expansion. J Appl Physiol. 1996;81(2):636-42.
  5. Muza SR, Beidleman BA, Fulco CS. Altitude preexposure recommendations for inducing acclimatization. High Alt Med Biol. 2010;11(2):87-92.
  6. Hackett PH, Roach RC. High-altitude illness. N Engl J Med. 2001;345(2):107-14.
  7. Bartsch P, Saltin B. General introduction to altitude adaptation and mountain sickness. Scand J Med Sci Sports. 2008;18 Suppl 1:1-10.
  8. Muza SR, Fulco CS, Cymerman A. Altitude acclimatization guide. Natick, MA: USARIEM;2004.
  9. Milledge JS, Beeley JM, Broome J, Luff N, et al. Acute mountain sickness susceptibility, fitness and hypoxic ventilatory response. Eur Respir J. 1991;4(8):1000-3.
  10. Palmer BF. Physiology and pathophysiology with ascent to altitude. Am J Med Sci. 2010;340(1):69-77.
  11. Muza SR. Military applications of hypoxic training for high-altitude operations. Med Sci Sports Exerc. 2007;39(9):1625-31.
  12. Fulco CS, Muza SR, Beidleman B, Jones J, et al. Exercise performance of sea-level residents at 4300 m after 6 days at 2200 m. Aviat Space Environ Med. 2009;80(11):955-61.
  13. Burtscher M, Szubski C, Faulhaber M. Prediction of the susceptibility to AMS in simulated altitude. Sleep Breath. 2008;12(2):103-8.
  14. Tannheimer M, Albertini N, Ulmer HV, Thomas A, et al. Testing individual risk of acute mountain sickness at greater altitudes. Mil Med. 2009;174(4):363-9.
  15. Ashenden MJ, Hahn AG, Martin DT, Logan P, et al. A comparison of the physiological response to simulated altitude exposure and r-HuEpo administration. J Sports Sci. 2001;19(11):831-7.
  16. Curtiss FR, Fairman KA. No TREATment with darbepoetin dosed to hemoglobin 13 grams per deciliter in type 2 diabetes with pre-dialysis chronic kidney disease--safety warnings for erythropoiesis-stimulating agents. J Manag Care Pharm. 2009;15(9):759-65.
  17. Eichner ER. Blood doping: infusions, erythropoietin and artificial blood. Sports Med. 2007;37(4-5):389-91.