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00005768-200709000-0002200005768_2007_39_1590_wilber_physiological_9report< 138_0_11_6 >Medicine & Science in Sports & Exercise© 2007 American College of Sports MedicineVolume 39(9)September 2007pp 1590-1599Effect of Hypoxic "Dose" on Physiological Responses and Sea-Level Performance[BASIC SCIENCES: Symposium: Altitude/Hypoxic Training: Research-Based Evidence and Practical Application]WILBER, RANDALL L.; STRAY-GUNDERSEN, JAMES; LEVINE, BENJAMIN D.1Athlete Performance Laboratory, United States Olympic Committee, Colorado Springs, CO; 2Department of Health, University of Utah, Salt Lake City, UT; and 3Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas, University of Texas Southwestern Medical Center, Dallas, TXAddress for correspondence: Randall L. Wilber, Ph.D., Athlete Performance Laboratory, Sport Science Division, United States Olympic Committee, One Olympic Plaza, Colorado Springs, CO 80909; E-mail: randy.wilber@usoc.org .Submitted for publication December 2006.Accepted for publication January 2007.ABSTRACTLive high-train low (LH + TL) altitude training was developed in the early 1990s in response to potential training limitations imposed on endurance athletes by traditional live high-train high (LH + TH) altitude training. The essence of LH + TL is that it allows athletes to "live high" for the purpose of facilitating altitude acclimatization, as manifest by a profound and sustained increase in endogenous erythropoietin (EPO) and ultimately an augmented erythrocyte volume, while simultaneously allowing athletes to "train low" for the purpose of replicating sea-level training intensity and oxygen flux, thereby inducing beneficial metabolic and neuromuscular adaptations. In addition to "natural/terrestrial" LH + TL, several simulated LH + TL devices have been developed to conveniently bring the mountain to the athlete, including nitrogen apartments, hypoxic tents, and hypoxicator devices. One of the key questions regarding the practical application of LH + TL is, what is the optimal hypoxic dose needed to facilitate altitude acclimatization and produce the expected beneficial physiological responses and sea-level performance effects? The purpose of this paper is to objectively answer that question, on the basis of an extensive body of research by our group in LH + TL altitude training. We will address three key questions: 1) What is the optimal altitude at which to live? 2) How many days are required at altitude? and 3) How many hours per day are required? On the basis of consistent findings from our research group, we recommend that for athletes to derive the physiological benefits of LH + TL, they need to live at a natural elevation of 2000-2500 m for ≥ 4 wk for ≥ 22 h·d−1.Altitude training has been used by endurance athletes for many years based on the belief that it serves to enhance sea-level performance. The original model of altitude training was one in which athletes lived and trained in a natural/terrestrial hypobaric hypoxic environment at moderate altitude (1500-3000 m). This method of altitude training came to be known as live high-train high (LH + TH) altitude training and is still used today by many athletes. Although LH + TH altitude training has been studied extensively over several decades, it remains unclear whether it has an enhancing effect on sea-level performance. Whereas some investigations have demonstrated significant improvements in erythrocyte parameters, maximal oxygen uptake (V˙O2max) and/or sea-level endurance performance following LH + TH altitude training, others have failed to do so (7,18,19,40,68,75).One of the potential limitations of LH + TH altitude training is related to the fact that many athletes are unable to produce the level of training intensity (e.g., running velocity) and oxygen flux necessary to bring about or preserve the physiological changes that have a positive impact on performance. It is not uncommon to hear athletes remark that they seem to lose "speed" or "turnover" as a result of doing LH + TH altitude training, which ultimately has a negative impact on their sea-level performance. In response to this potential limitation of LH + TH altitude training, the live high-train low (LH + TL) altitude training model was developed in the early 1990s by Drs. Benjamin Levine and James Stray-Gundersen of the United States. The essence of LH + TL is that it allows athletes to "live high" for the purpose of facilitating altitude acclimatization (e.g., an increase in endogenous erythropoietin (EPO) and resultant increase in erythrocyte volume) while simultaneously allowing athletes to "train low" for the purpose of replicating sea-level training intensity and oxygen flux, thereby inducing beneficial metabolic and neuromuscular adaptations. The initial series of investigations by Levine and Stray-Gundersen (12,41,60) were conducted in a natural/terrestrial altitude environment in which well-trained runners lived at 2500 m (Deer Valley, UT) and trained at 1250 m (Salt Lake City, UT). The results of those studies suggested that 4 wk of LH + TL was unique in its combined effect on accelerating erythropoiesis, increasing V˙O2max and enhancing sea-level endurance performance (5000-m run) in well-trained runners when compared with either a sea-level control group or a conventional LH + TH group (12,41,60).On the basis of the promising findings of these investigations of "natural/terrestrial" LH + TL (12,41,60), several modifications of LH + TL were developed in the 1990s. Dr. Heikki Rusko of Finland conceived the nitrogen apartment, which is a normobaric hypoxic (2500-3000 m) living/sleeping environment created via nitrogen dilution (56,67,69). Olympic cyclist Sean Wallace of the United Kingdom developed the hypoxic tent, which is a normobaric hypoxic (2000-4000 m) sleeping environment based on oxygen-filtration technology (67,69). Sport scientists at the U.S. Olympic Training Center (Colorado Springs, CO; 1860 m) began using supplemental oxygen to allow U.S. national team athletes to live high in a natural/terrestrial altitude environment (1860-3000 m) and train at "sea level" using medical-grade gas with a fraction of inspired oxygen (FIO2) approximately 0.26 (PIO2 ≈ 159 torr) (43,70-72).Research findings regarding these various modifications of LH + TL have proven to be equivocal. Whereas some investigations demonstrated significant increases in erythropoietic markers and improvements in sea-level endurance performance (10,41,50,54,60,66), others were unable to replicate those results (5,28,29,51,58). One possible explanation for these inconsistent results may have been due to the fact that some studies had a relatively small sample size, resulting in lack of statistical power and increased potential for type II error. However, a more likely explanation is that a variety of protocols have been used to administer the hypoxic dose. In other words, there has been great disparity in 1) the altitude-natural or simulated-at which the athlete was exposed, 2) number of days of altitude/hypoxic exposure, and 3) number of hours per day of altitude/hypoxic exposure. This has led researchers to focus on the question: In using LH + TL, what is the optimal hypoxic dose needed to produce the expected beneficial physiological responses and sea-level performance effects in most individuals?In this paper, we begin by proposing that altitude/hypoxic exposure can be viewed in terms of a conventional medical dose-response curve. We then present data from the series of definitive LH + TL studies by our group that strongly suggest that the primary mechanism by which LH + TL can enhance sea-level endurance performance is via accelerated erythropoiesis, provided a sufficient hypoxic dose is administered. Finally, based on the accumulated findings of our research group regarding LH + TL, we offer what we believe to be the optimal hypoxic dose for the purpose of enhancing sea-level endurance performance in most individuals. In doing so, we will focus on the following key questions: 1. What is the optimal altitude at which to live? 2. How many days are required at altitude? 3. How many hours per day are required?DOSE-RESPONSE CONCEPT APPLIED TO ALTITUDE/HYPOXIC EXPOSUREIn attempting to identify the optimal hypoxic dose, we use the analogy of a dose-response curve (Fig. 1). In a medical scenario, the physician's goal is to administer a pharmacological therapy that lies within the therapeutic range. In other words, the dose must be sufficient to induce the desired effect on at least 50% of the patients (effective dose 50, [ED 50]) without exceeding the critical level that proves lethal to 50% or more of the patients(lethal dose 50, [LD 50]). Any dose below the therapeutic range will be extremely safe but essentially ineffective in curing the illness or disease in most individuals, whereas any dose above the therapeutic range may be effective in curing the illness or disease but is likely to kill the patient in the process. In an altitude/hypoxic training scenario, the athlete's goal is to live/sleep at an altitude-natural or simulated-that is within the therapeutic range. This range should be high enough (and long enough duration) to induce the desired acclimatization effect in at least 50% of athletes (ED 50) via an acute and sustained increase in EPO and subsequent accelerated erythropoiesis, without being so high that more than 50% of athletes (LD 50) are unable to recover from daily training, or may experience symptoms of acute mountain sickness (AMS) or more debilitating high-altitude afflictions. Later in this paper, we will outline what we believe to be the optimal hypoxic dose (i.e., therapeutic range) for use in conjunction with LH + TL altitude training. However, before we present that information, we next provide an empirical base from which our recommendations for an optimal hypoxic dose have been derived.FIGURE 1-Dose-response curve showing the optimal therapeutic range: the dose amount that will surpass the effective dose 50 (ED 50) without exceeding the lethal dose 50 (LD 50). See text for details.THE LIVE HIGH-TRAIN LOW MODEL OF ALTITUDE TRAININGInitial implementation and scientific evaluation of the LH + TL model was conducted in the natural/terrestrial altitude environment of the Wasatch Mountains in the state of Utah. The original study by our group (41) evaluated the efficacy of LH + TL among 39 American female and male collegiate distance runners who were initially matched according to fitness level and then randomly assigned to one of three experimental groups (LL + TL, LH + TL, LH + TH). After a 4-wk baseline period at sea level (Dallas, TX), the LH + TL runners (N = 13) completed a 28-d training period in which they lived at 2500 m (Deer Valley) for approximately 22 h·d−1 and trained at 1250 m (Salt Lake City) for approximately 2 h·d−1. Training consisted of alternate workouts of base training and interval training. Thirteen fitness-matched female and male collegiate runners, serving as a control group (LL + TL), followed the same training program at sea level at 150 m (San Diego, CA), as did another group of 13 female and male runners who followed a conventional LH + TH regimen at 2500 m (Deer Valley). This initial study was followed by subsequent investigations by our group (60) using a similar LH + TL approach. The details of this series of LH + TL investigations can be reviewed elsewhere (12,41,60), but the essential findings were as follows: 1) athletes living for ≥ 22 h·d−1 at a natural/terrestrial altitude of 2500 m (LH + TH and LH + TL groups) had a significant increase in serum EPO concentration, which led to a significant increase in erythrocyte volume (5%) and hemoglobin concentration (9%), neither of which was altered significantly in the sea-level control group; 2) coincident with the increase in erythrocyte volume, there was a significant increase in treadmill V˙O2max (4%) in both groups living at 2500 m (LH + TH; LH + TL) that was proportional to the increase in erythrocyte volume, none of which was observed in the sea-level control group; 3) despite an increase in V˙O2max in both groups living at 2500 m (LH + TH; LH + TL), only the group that performed all their training at 1250 m (LH + TL) significantly improved their postaltitude sea-level 5000-m-run time trial performance (13.4 s = 1.3%); and 4) there was no relationship between the skill of the athlete and the magnitude of improvement observed after 4 wk of LH + TL. Even U.S. elite runners, including U.S. Olympians, achieved on average the same 1-2% improvement in sea-level endurance performance associated with clear evidence of accelerated erythropoiesis and increased V˙O2max (60). Collectively, these robust and consistent results led us to conclude that LH + TL conducted at a natural/terrestrial living altitude of 2500 m for 4 wk, with daily hypoxic exposure of about 22 h, while simultaneously conducting daily workouts at a training altitude of 1250 m, is an effective method for enhancing sea-level endurance performance in subelite and elite endurance athletes. Furthermore, we concluded that a significant hypoxia-induced increase in serum EPO and resultant accelerated erythropoiesis was the primary physiological pathway affecting the enhancement of postaltitude sea-level endurance performance (12,41,60).The mechanism surrounding the hypoxia-induced increase in serum EPO and its subsequent effect on the augmentation of erythrocyte volume is not completely understood, but there is strong evidence to suggest that the hypoxia-inducible factor 1α (HIF-1α) complex (Fig. 2) is the primary mediator of this erythropoietic cascade (11,45,57). The HIF-1α complex is located on human chromosome 14 and belongs to a class of genetic factors that regulate DNA transcription to mRNA (57). Under normoxic conditions, HIF-1α is hydroxylated via a highly conserved prolyl hydroxylase (the putative cellular oxygen sensor in peripheral tissues), which then binds to the Von Hipple-Lindau factor, targeting the entire HIF-1α complex for rapid degradation via the ubiquitin-proteosome pathway (16,31,32) (Fig. 2). In fact, this process is so rapid that in the presence of oxygen and iron, HIF-1α has one of the shortest half-lives of any known protein (32). In contrast, under hypoxic conditions, the HIF-1α complex is stable, allowing for transcriptional activation and ultimate stimulation of proteins such as EPO and vascular endothelial growth factor (65) (Fig. 2). In addition to regulating EPO, the HIF-1α complex modulates other physiological responses at altitude including glucose transport, glycolytic enzyme activity, inflammatory responses, and bone metabolism (13,23,57).FIGURE 2-Schematic representation of the regulation of hypoxia-inducible factor-1α (HIF-1α) complex-mediated gene transcription in hypoxic conditions. See text for details. Reprinted by permission from J. Caro (11).Moreover, when altitude natives, or even altitude sojourners return to sea level, there is a suppression of EPO (12,17,24,34,41,49), a prominent reduction in iron turnover and bone marrow production of erythroid cell lines (30,46), and a marked decrease in erythrocyte survival time (46). This increase in erythrocyte destruction with concomitant suppression of EPO levels has been termed neocytolysis and has been observed under other conditions of a relative increase in FIO2 (2-4,47,48). Both the rapid ubiquitination and destruction of HIF-1α, and neocytolysis (possibly its clinical manifestation), provide evidence for the argument against the use of short-duration (1-3 h), intermittent hypoxic exposures to induce a sustained increase in the erythrocyte volume, and antithetically lend strong support in favor of administering a significantly longer and more potent hypoxic dose.Despite the documented erythropoietic and sea-level performance benefits of LH + TL altitude training (hypoxic dose = 2500 m, 22 h·d−1, 28 d), there seems to be considerable individual variation in the physiological responses of athletes using LH + TL. Dr. Robert Chapman, a member of our research group, used a retrospective research design to examine the topic of individual variation within the context of the LH + TL altitude training model (12). Well-trained runners from three training groups were evaluated: 1) LH + TH: live and train at 2500 m (Deer Valley); 2) LH + TL: live at 2500 m (Deer Valley), train at 1250 m (Salt Lake City); and 3) LH + TH + TL: live at 2500 m (Deer Valley), moderate-intensity training at 2500 m (Deer Valley), high-intensity training at 1250 m (Salt Lake City). Chapman et al. (12) retrospectively classified the subjects from all three training groups as either responders or nonresponders, according to their performance in a postaltitude sea-level 5000-m-run time trial. On average, the responders demonstrated a significant 4% improvement (−37 s) in the postaltitude sea-level 5000-m run versus their prealtitude performance, whereas the nonresponders were approximately 1% slower (+14 s).In retrospectively evaluating the hematological data, Chapman et al. (12) showed that the responders had a significantly greater acute increase (altitude 30 h) in serum EPO compared with the nonresponders (responders = 52%; nonresponders = 34%) (Fig. 3). Moreover, the responders had a significantly greater sustained increase (altitude 14 d) in serum EPO versus the nonresponders (responders = 30%; nonresponders = 12%). Consistent with the serum EPO data, postaltitude erythrocyte volume for the responders was 8% higher (P < 0.05), whereas the nonresponders' erythrocyte volume was only 1% higher (P > 0.05) compared with prealtitude values (Fig. 3). Responders were also able to maintain a higher level of training intensity (running velocity) and oxygen flux than the nonresponders, as evidenced by the fact that V˙O2 during 1000-m training intervals was 20% lower versus prealtitude values in the nonresponders, whereas it was only 6% lower in the responders (P < 0.05 vs nonresponders) (Fig. 3). Finally, the responders showed a significant improvement in postaltitude sea-level V˙O2max (6%), whereas the nonresponders showed no change (Fig. 3). On the basis of this retrospective analysis, we concluded that athletes who respond to altitude training, as evidenced by a significant improvement in postaltitude sea-level endurance performance, 1) demonstrate significantly greater acute and sustained EPO responses leading to significantly higher postaltitude erythrocyte volume versus nonresponders, and 2) are able to maintain greater interval training intensity (running velocity) and oxygen uptake/flux at altitude than nonresponders (12). Finally, it is important to note that a breakdown of the responders revealed that 18, 47, and 35% came from the LH + TH, LH + TL, and LH + TH + TL groups, respectively, which indicated that most of the responders (82%) completed a training program that included either full or partial implementation of LH + TL altitude training (12).FIGURE 3-Altitude acclimatization of responders and nonresponders relative to serum erythropoietin (EPO) (A, upper), total red cell volume (A, lower), 1000-m running velocity (B, upper), 1000-m oxygen uptake (V˙O2) (B, lower), and postaltitude maximal oxygen uptake (V˙O2max). Asterisk above standard error bar indicates P < 0.05 vs prealtitude; asterisk above bracket indicates P < 0.05 between groups. Reprinted by permission from R.F. Chapman et al. (12).Preliminary data by our group suggested that a specific allele of the EPO gene may discriminate between responders and nonresponders (73). Individuals identified as having the D7S477 allele of the EPO gene had a 135% increase in serum EPO after 24 h of simulated altitude exposure at 2800 m. By comparison, individuals who did not possess the D7S477 allele of the EPO gene had a significantly lower increase (78%) in serum EPO after 24 h of simulated altitude exposure. However, subsequent follow-up investigations by our team (33) in this area have been unable to identify a unique single-nucleotide polymorphism (SNP) in candidate genes of the hypoxia response pathway that can be linked to the individual variability in serum EPO and erythropoietic responses observed in responders versus nonresponders. Although it seems probable that genetic predisposition plays an important role in the observed individual variation in response to altitude, additional research is required to elucidate the specific gene(s) involved.PRACTICAL APPLICATION OF LIVE HIGH-TRAIN LOW: OPTIMAL HYPOXIC DOSEWe now address the practical application of LH + TL altitude training and provide recommendations for the optimal hypoxic dose needed to induce the desired physiological responses and sea-level performance effects in most individuals. Again, we emphasize that our extensive research in the area of LH + TL has led us to conclude that the primary pathway by which LH + TL can enhance sea-level endurance performance is via accelerated erythropoiesis, provided a sufficient hypoxic dose is administered. In defining the optimal hypoxic dose, we will focus on answering questions related to optimal altitude and optimal duration.What is the optimal altitude at which to live?Keeping in mind our analogy of a medically-based dose-response curve, we now offer recommendations regarding the optimal altitude for athletes to live/sleep when utilizing LH + TL altitude training. By optimal altitude, we are referring to a specific range of altitude, and this optimal altitude range is analogous to the therapeutic range of a dose-response curve. In other words, the optimal altitude range should be high enough (and long enough duration) to induce the desired acclimatization effect in at least 50% of athletes (ED 50) as manifest by a significant and sustained increase in serum EPO and subsequent accelerated erythropoiesis, without being so high that more than 50% of athletes (LD 50) are unable to recover from daily training, or may experience AMS or more debilitating high-altitude afflictions.We have previously examined the question of optimal altitude range (20,74). Forty-eight competitive runners were initially evaluated for serum EPO response after 24 h of exposure to each of four elevations (1780, 2085, 2454, and 2800 m) via simulated hypobaric hypoxia. Subjects were then randomly assigned to live for 4 wk at one of four natural/terrestrial altitudes (1780, 2085, 2454, and 2800 m) after being matched for gender, prealtitude running performance, and the percent increase in serum EPO at a simulated altitude of 2454 m. All four groups trained together at 1250-1780 m (high-intensity training) or 1700-3000 m (moderate-intensity training).Hematological results indicated that serum EPO increased significantly after 6 h at all four simulated altitudes and then remained at the same level after 24 h at the two lowest elevations, 1780 and 2085 m (20) (Fig. 4). In contrast, serum EPO continued to increase significantly after 24 h at the two highest elevations, 2454 and 2800 m (Fig. 4), although there was no difference between 2454 and 2800 m. Substantial individual variability in serum EPO response was demonstrated across the range of the four simulated altitudes, with some individuals exhibiting approximately 400% increments in serum EPO levels, whereas others did not increase serum EPO levels in response to 2800 m (20). After 4 wk of LH + TL, V˙O2max increased in the runners who lived at the three highest elevations (2085, 2454, and 2800 m) (74). The runners who lived at the two middle elevations, 2085 and 2454 m, significantly improved their postaltitude sea-level 3000-m-run performance by 2.8% (15.7 s) and 2.7% (16.6 s), respectively. In contrast, the runners who lived at the lowest altitude (1780 m) did not significantly improve their postaltitude sea-level 3000-m-run time (6.3 s = 1.1%), nor did the runners who lived at the highest altitude (2800 m) (7.1 s = 1.4%) (74).FIGURE 4-Percent changes in serum erythropoietin (Epo) after 6 and 24 h at simulated altitudes of 1780, 2085, 2454, and 2800 m. ** P < 0.05 vs baseline (BL); ## P < 0.05 vs 2454 and 2800 m. Reprinted by permission from R.L. Ge (20).Collectively, these results led us to conclude that the optimal altitude range for LH + TL altitude training is approximately 2000-2500 m. Our serum EPO data suggest that elevations ≤ 1780 m may be too low for effective acclimatization and stimulation of a significant and sustained erythropoietic response in most individuals. Considering that serum EPO response at 2800 m was not different versus 2454 m, along with the fact that postaltitude sea-level running performance was enhanced after living for 4 wk at 2085 and 2454 m, but not at 2800 m, we further concluded that elevations ≥ 2800 m do not seem to provide an additional erythropoietic effect (vs 2500 m) and may, in fact, be too high and potentially induce some negative acclimatization effects that ultimately compromise sea-level endurance performance (74). Thus, on the basis of these data, we recommend that the optimal altitude range (therapeutic range) for use in conjunction with the LH + TL model is approximately 2000-2500 m for most athletes, keeping in mind that there is considerable individual variability in the altitude acclimatization response (20).How many days are required at altitude?Next we address the question of time duration at altitude, specifically, how many days are required to induce the desired physiological responses and sea-level performance effects. Our series of LH + TL investigations has consistently employed an altitude exposure of 28 consecutive days at moderate altitude (2500 m). Incorporation of this 4-wk duration in our research design is based in large part on previous studies in the area of exogenous EPO supplementation and its effect on erythropoiesis (6,8). It has been shown that, even when recombinant human EPO is injected directly three times per week, there is no change in hemoglobin concentration or hematocrit for the first 7-10 d, and then only a minimal increase after 2 wk (6,8). However, there is accelerated erythropoiesis during weeks 3 and 4 after EPO injection, as evidenced by significant increments in hemoglobin concentration and hematocrit. Thus, these data suggest that hypoxic exposure ≤ 2 wk in duration will probably not increase erythrocyte volume; rather, a minimum of 3-4 wk seems necessary for accelerated erythropoiesis to occur.This 4-wk-minimum guideline is supported by a number of published and unpublished studies as shown in Figure 5. Note that there is a minimal increase (≤ 2.2%) in erythrocyte volume resulting from less than 2 wk of natural or simulated (normobaric hypoxia via nitrogen dilution) altitude exposure. However, with an increase in altitude exposure beyond 2 wk, there is a prominent increase in the magnitude of the erythropoietic response, particularly as the hypoxic exposure increases to 4 wk (7.1-7.9%). This effect seems to be true whether the altitude is natural/terrestrial or simulated via nitrogen dilution technology. As shown on the right side of Figure 5, the effect of 4 wk of hypoxic exposure (~2500 m) on erythrocyte volume is relatively comparable in magnitude with that of a similar duration of low-dose EPO injection (50 IU·kg−1, 3× wk−1, for 3 wk, followed by 20 IU·kg−1, 3× wk−1, for 3 wk). The fact that the effect of 4 wk of exposure to moderate altitude on erythrocyte volume (as well as V˙O2max and endurance performance) is similar in magnitude to low-dose EPO injection provides further evidence for our contention that the postaltitude enhancement of performance is influenced primarily by accelerated erythropoiesis.FIGURE 5-The columns indicate percent change in the erythrocyte volume from before to after the particular perturbation. The error bars represent the standard deviation of the percent change. Erythrocyte volume was estimated by Evans blue dye technique. All subjects were male and female currently endurance training athletes (age 18-30). Starting on the far left, control (N = 11) represents 11 athletes who were measured twice with 4-6 wk of time in between. The second column represents before and after 1 wk of 12 h·d−1 in a nitrogen room (N = 7). The third column represents the change associated with 1 wk in a nitrogen room and a 2-wk stay at 2100-m altitude (N = 7). The fourth column (N = 24) represents before and after a 3-wk stay (~12 h·d−1) in a nitrogen room. The fifth column represents the change after a 3-wk stay at natural altitude (N = 35). Living altitudes ranged from 2000 to 2500 m. The sixth column represents the change after a 4-wk stay at natural altitude (N = 43). Living altitudes ranged from 1800 to 2800 m. The seventh column represents the change after a 4-wk stay at 2500 m (N = 26). The far right column represents the change after a 4-wk course of low-dose rhEPO (50 IU·kg−1, 3× wk−1, for 3 wk, followed by 20 IU·kg−1, 3× wk−1, for 3 wk, staying below the regulatory limits for hematocrit (female = 47%; male = 50%) or hemoglobin (female = 17.0 g·dL−1; male = 18.5 g·dL−1) set by international organizations for the purposes of doping control. Reprinted by permission from B.D. Levine and J. Stray-Gundersen (42).How many hours per day are required?To this point, we have recommended that the optimal hypoxic dose consists of living at a natural/terrestrial altitude of 2000-2500 m, for a minimum of 4 wk. Lastly, we address the question of how many hours of hypoxic exposure per day are needed to induce the desired physiological responses and sea-level performance effects.On the basis of our findings (12,20,41,60), it seems that at a natural/terrestrial altitude of 2000-2500 m with hypoxic exposure ≥ 22 h·d−1 is sufficient to stimulate an accelerated erythropoiesis and enhance postaltitude sea-level endurance performance. There is also evidence that when using simulated altitude (normobaric hypoxia via nitrogen dilution or oxygen filtration), hypoxic exposure of 12-16 h·d−1 may have similar erythropoietic effects, provided athletes are exposed to higher altitudes (2500-3000 m) (10,50,55). However, it seems that there is an additive effect as hypoxic exposure increases beyond 12-16 h·d−1, as illustrated in Figure 6, which shows the effect of three different hypoxic exposure protocols on erythrocyte volume. The data shown on the left side of Figure 6 (mountain house) come from the initial LH + TL study of Levine and Stray-Gundersen (41). That study employed a hypoxic exposure of approximately 22 h·d−1 for 4 wk at a natural altitude of 2500 m, resulting in significant pre-versus postaltitude increases in erythrocyte volume (8%), treadmill V˙O2max (4%), and 5000-m-run performance (1.3%) at sea level. The middle set of data in Figure 6 (nitrogen house, 16 h·d−1) is taken from the investigation of Rusko et al. (55) that evaluated the efficacy of LH + TL altitude training in Finnish endurance athletes using a nitrogen house. The hypoxic exposure was 12-16 h·d−1 for 25 d at a simulated altitude of 2500 m, resulting in significant pre- versus postaltitude increases in erythrocyte volume (5%) and treadmill V˙O2max (3%), which were slightly lower than the increments seen in the 22-h·d−1 protocol used by Levine and Stray-Gundersen (41). Finally, the data shown on the right side of Figure 6 (nitrogen house, 8-10 h·d−1) come from the study of Ashenden et al. (5) that evaluated the efficacy of LH + TL altitude training in Australian national team cyclists using a nitrogen house. The athletes completed a daily hypoxic exposure of 8-10 h for 12 d at a simulated altitude of 2650 m, which did not significantly alter hemoglobin mass (V˙O2max not measured/reported) (5). Collectively, the data from these three representative investigations suggest that 1) a daily hypoxic exposure of ≤ 8-10 h is inadequate to stimulate erythropoiesis; 2) a daily hypoxic exposure to simulated altitude of 12-16 h seems sufficient to stimulate erythropoiesis in most individuals, provided the simulated altitude is 2500-3000 m; and 3) a daily hypoxic exposure ≥ 22 h·d−1 at a natural altitude of 2000-2500 m is both sufficient and optimal for accelerated erythropoiesis and enhanced postaltitude sea-level performance in most individuals.FIGURE 6-Comparison of three live high-train low protocols of varying duration of daily hypoxic exposure. Mountain house ≈ 22 h·d−1 in hypobaric hypoxia via natural/terrestrial altitude (41); nitrogen house (16 h·d−1) = 12-16 h·d−1 in normobaric hypoxia via nitrogen dilution (55); nitrogen house (8-10 h·d−1) = 8-10 h·d−1 in normobaric hypoxia via nitrogen dilution (5). Reprinted by permission from B.D. Levine and J. Stray-Gundersen (42).These observations were confirmed in recent investigations (10,50,66) of elite endurance athletes. Wehrlin et al. (66) evaluated LH + TL altitude training in Swiss national team orienteers who underwent hypoxic exposure 18 h·d−1 for 24 d at a natural altitude of 2500 m. This hypoxic exposure protocol resulted in significant pre- versus postaltitude increments in erythrocyte volume (5%), hemoglobin mass (5%), treadmill V˙O2max (4%) and sea-level 5000-m-run time trial performance (2%) (66). Similar results in total hemoglobin mass were reported by the French investigative group of Dr. Jean-Paul Richalet in French national team runners and swimmers who completed a daily hypoxic exposure of 14 h for 5-6 d at simulated 2500 m (normobaric hypoxia via oxygen filtration), followed by 8-12 d at simulated 3000 m (normobaric hypoxia via oxygen filtration) (10,50).In the past decade, intermittent hypoxic exposure (IHE) and intermittent hypoxic training (IHT) have become viable altitude training options for athletes because they can be done with minimal travel or inconvenience. In using IHE, athletes live in a natural, normobaric normoxic environment, and are exposed in a resting state to discrete and relatively short intervals (5-180 min) of simulated normobaric hypoxia or hypobaric hypoxia. Normobaric hypoxia can be simulated via nitrogen dilution (e.g., Altitrainer 200 hypoxicator), oxygen filtration (e.g., Go2Altitude hypoxicator), or inspiration of hypoxic gas (69). IHT is essentially IHE done in conjunction with an exercise/training session (69). It is purported that IHE/IHT can enhance athletic performance by stimulating an increase in serum EPO and erythrocyte volume (15,39,44,59), and can augment skeletal muscle mitochondrial density, capillary-to-fiber ratio, and fiber cross-sectional area (14,64) via up-regulation of HIF-1α (64). The key research findings regarding the efficacy of IHE/IHT are reviewed in detail in an accompanying paper in this symposium (Dr. Wilber). However, we will mention here that in our opinion, the empirical evidence regarding the efficacy of IHE/IHT on erythropoietic response and sea-level endurance performance is not exceptionally compelling. Only a minimal number of well-designed, well-controlled studies on trained or elite athletes have reported increments in hemoglobin concentration (9,26), and to our knowledge none have evaluated or reported any increases in robust erythropoietic markers such as soluble transferrin receptor (sTfR), erythrocyte volume, and/or hemoglobin mass. Furthermore, no IHE/IHT study has demonstrated improvements in V˙O2max, and only 31% have reported that sea-level athletic performance was enhanced after IHE/IHT (9,27,36,37,61). In contrast, several studies, including many conducted by our group, have failed to demonstrate significant alterations in erythropoietic acceleration, V˙O2max or post-IHE/IHT performance at sea level (1,21,22,25,35,38,52,53,61-63).In one of our initial investigations of intermittent hypoxic exposure, Glyde-Julian et al. (21) evaluated the effects of passive IHE in U.S. national team distance runners using a very resolute matched-pairs, randomized and double-blind design. IHE was administered using normobaric hypoxia via oxygen filtration (Go2Altitude hypoxicator). Subjects completed a resting IHE regimen consisting of 70 min of hypoxic exposure per day (hypoxia:normoxia ratio = 5 min:5 min), 5 d·wk−1 for 4 wk. The IHE regimen was selected based on the recommendations of the hypoxic device's manufacturer, along with anecdotal evidence which suggested that this particular protocol was effective in enhancing performance. The IHE group was exposed progressively to a simulated altitude of 4000-5000 m, whereas a fitness-matched, normoxic control group was exposed to a simulated altitude equivalent to sea level. External from the experimental IHE sessions, both groups completed similar run training programs in preparation for impending national and international competition. Compared with the fitness-matched control group, 4 wk of passive IHE did not result in any significant changes in serum EPO, sTfR, V˙O2max, or sea-level 3000-m-run time trial performance (21).In a follow-up study by our group (52), we examined the hypothesis that a longer and more potent hypoxic dose (36,37) exceeding the relatively limited hypoxic dose used in our initial IHE study (70 min·d−1, consisting of a hypoxia:normoxia ratio of 5 min:5 min) (21) might be sufficient to produce an influential erythropoietic response and ultimately enhance sea-level performance, as suggested in previous research by others (36,37). A matched-pairs, randomized and double-blind design was used to evaluate passive IHE in well-trained swimmers and runners. The IHE group was exposed progressively to a simulated altitude of 4000-5500 m via hypobaric hypoxia (barometric pressure chamber) for 3 h·d−1, 5 d·wk−1 for 4 wk, whereas the normobaric normoxia control group was exposed to a simulated altitude of 0-500 m. It should be noted that to maintain the blinding effect, subjects in the normobaric normoxia control group experienced rapid increases and decreases in chamber pressure (i.e., they were "bounced") so that they would feel pressure changes in their ears and other air containing spaces, thereby masking the experimental treatment. Despite the longer and more potent hypoxic dose employed in this investigation (52), we were still unable to demonstrate any significant changes in erythrocyte volume or total hemoglobin mass (measured via carbon monoxide rebreathing and Evans blue dye), or several other measures of erythropoiesis after 4 wk of passive IHE (22). It is also important to note that although we did not see any increments in erythrocyte volume or total hemoglobin mass, we did observe a significant increase in serum EPO as a result of IHE (22). A significant increase in serum EPO is frequently, and erroneously, associated with an equivalent significant increase in erythrocyte volume. Our hematological data (22) served to clearly dispel this common misconception. Finally, consistent with the hematological results, there were no significant differences between the IHE and control groups in 100- and 400-m swim time trial performance, or 3000-m-run time trial performance when measured at sea level 1 wk and 3 wk after 4 wk of passive IHE (52).Collectively, these findings support our recommendation that a daily hypoxic exposure of about 22 h at a natural altitude of 2000-2500 m will be both sufficient and optimal to provide effective altitude acclimatization and to significantly stimulate the erythropoietic pathway to the point that it enhances postaltitude sea-level endurance performance. There is also evidence that when utilizing simulated altitude (normobaric hypoxia via nitrogen dilution or oxygen filtration), hypoxic exposure of 12-16 h·d−1 may have similar erythropoietic effects provided athletes are exposed to higher altitudes (2500-3000 m). Daily hypoxic exposures of ≤ 8 to 10 h seem ineffective in terms of affecting erythropoietic response and sea-level endurance performance. Finally, there is minimal evidence that IHE/IHT-either alternate hypoxia/normoxia short-interval (5 min) sessions, or longer (1-3 h) continuous sessions-provide the necessary acclimatization and physiological stimuli to produce beneficial changes in erythrocyte volume, V˙O2max, and sea-level performance.CONCLUSIONThe purpose of this paper was to objectively evaluate the important question: In using LH + TL, what is the optimal hypoxic dose needed to facilitate altitude acclimatization and produce the expected beneficial physiological responses and sea-level performance effects in most individuals? In attempting to define the optimal hypoxic dose, we have addressed three key questions: 1) What is the optimal altitude at which to live? 2) How many days are required at altitude? and 3) How many hours per day are required? On the basis of our extensive research findings, we recommend that for most athletes to effectively acclimatize and derive the physiological benefits of LH + TL, they need to live at a natural/terrestrial altitude of 2000-2500 m, for a minimum of 4 wk to include a daily hypoxic exposure of ≥ 22 h. On the basis of investigations of LH + TL using simulated altitude, however, it seems that fewer hours of hypoxic exposure may be necessary (12-16 h) but that a higher elevation (2500-3000 m) is required to achieve similar erythropoietic effects. Our research also suggests that a significant hypoxia-induced increase in serum EPO and resultant accelerated erythropoiesis is the primary physiological pathway affecting the enhancement of postaltitude sea-level endurance performance, and that the HIF-1α complex seems to be the primary mediator of this erythropoietic cascade. 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Conditioning Research10.1519/JSC.0b013e3181c4d2d32010244985-991APR 2010Two Days of Hypoxic Exposure Increased Ventilation Without Affecting PerformanceRacinais, S; Millet, GP; Li, C; Masters, B; Grantham, Jhttp://journals.lww.com/nsca-jscr/Fulltext/2010/04000/Two_Days_of_Hypoxic_Exposure_Increased_Ventilation.14.aspx168disablehttp://dx.doi.org/10.1519%2fJSC.0b013e3181c4d2d3