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Original Research| Volume 14, ISSUE 1, P9-16, March 2003

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Lack of Effect of Rhodiola or Oxygenated Water Supplementation on Hypoxemia and Oxidative Stress

      Objective

      This study investigated the effects of 2 potentially “oxygen promoting” dietary supplements on hypoxia and oxidative stress at a simulated altitude of 4600 m.

      Methods

      Fifteen volunteers (ages 20–33) received 3 separate 60-minute hypoxic exposures by breathing 13.6% oxygen at an ambient barometric pressure of 633 mm Hg (simulating the partial pressure of oxygen at 4600 m elevation). Each subject received, in random order, treatments of a 7-day supply of placebo, Rhodiola rosea, and an acute dose of stabilized oxygen dissolved in water. Arterialized capillary blood oxygen samples (PcO2) were measured at baseline and at 30 and 60 minutes of exposure. Pulse oximeter oxyhemoglobin saturation (SaO2) was measured at baseline and at every 10 minutes of hypoxic exposure. Oxidative stress markers measured included baseline and 60-minute exposure serum lipid peroxides (LPO) and urine malondialdehyde (MDA).

      Results

      For each treatment group, PcO2 decreased by approximately 38% from baseline to 60-minute hypoxic exposure. Similarly, SaO2 also decreased among groups from approximately 97 to 81%. Serum lipid peroxides increased significantly in the placebo group and decreased significantly from baseline in response to the stabilized oxygen treatment (P = .02); there was a trend for decreased LPO with the Rhodiola treatment (P = .10). There were no significant changes for MDA among groups.

      Conclusions

      The 2 dietary supplements investigated did not have a significant effect on blood oxygenation after 60 minutes of sedentary hypoxic exposure. Hypoxia-induced oxidative stress was observed in the control group only. Both supplements appeared not to increase oxidative stress and may decrease free radical formation after hypoxic exposure compared with the control.

      Key words

      Introduction

      Human exposure to the decrease in partial pressure of oxygen that occurs at high altitudes results in hypoxia, which presents a physiological challenge. As the partial pressure of oxygen in the atmosphere decreases, the partial pressure of oxygen in the blood also decreases. This has been shown to create deficits in physical
      • Piehl Aulin K.
      • Svendenhag J.
      • Wide L.
      • Berglund B.
      • Saltin B.
      Short-term intermittent normobaric hypoxia—haematological, physiological and mental effects.
      • Shephard R.J.
      • Bouhlel E.
      • Vandewalle H.
      • Monod H.
      Peak oxygen intake and hypoxia: influence of physical fitness.
      • Koskolou M.D.
      • McKenzie D.C.
      Arterial hypoxemia and performance during intense exercise.
      and mental
      • Kramer A.F.
      • Coyne J.T.
      • Strayer D.L.
      Cognitive function at high altitude.
      • Nicolas M.
      • Thullier-Lestienne F.
      • Bouquet C.
      • et al.
      An anxiety, personality and altitude symptomatology study during a 31-day period of hypoxia in a hypobaric chamber.
      • Bouquet C.
      • Gardett B.
      • Gortan C.
      • Therme P.
      • Abraini J.H.
      Color discrimination under chronic hypoxic conditions.
      human performance. Delayed or poor decisions as well as decreased performance can potentially compromise the safety of an individual or a group.
      • Huey R.B.
      • Eguskitza X.
      Limits to human performance: elevated risks on high mountains.
      Typically, with proper acclimatization, people can adapt to the decrease in blood oxygenation with ventilatory, circulatory, and hemopoetic changes. However, for some individuals, traveling to altitudes above 3000 m can result in acute mountain sickness (AMS) that can progress to potentially life-threatening complications such as high-altitude pulmonary edema or high-altitude cerebral edema.
      • Hultgren H.
      High Altitude Medicine.
      Very few studies have explored the use of herbal or aqueous-stabilized oxygen supplements for the improvement of altitude-induced hypoxia. Recently, Leadbetter et al
      • Leadbetter G.
      • Maakestad K.
      • Olson S.
      • Hackett P.
      Ginkgo biloba reduces incidence and severity of acture mountain sickness [abstract].
      found that 120 mg of Ginkgo biloba, taken twice a day, 5 days before ascent to high altitudes, significantly reduced both the incidence and severity of AMS. Gertsch et al
      • Gertsch J.
      • Seto T.
      • Onopa J.
      Does Ginkgo biloba prevent acute mountain sickness (AMS) if begun 1-day before rapid ascent? [abstract].
      concluded that 60 mg TID of Ginkgo, given only 1 day before ascent to high altitudes, decreased the incidence of AMS by 33%, as compared with the control group.
      Of particular interest to this study is the Chinese herb Rhodiola rosea, also known as the “artic root” or the “golden root.” This herb is indigenous to high-elevation areas in the Artic and mountain regions of Asia and eastern Europe. It has been used for centuries as a traditional medicinal plant in Asia and eastern Europe.
      • Germano C.
      • Ramazanov A.
      Rhodiola rosea: adaptogens—nature's solution to sickness.
      ,
      • Kelly G.S.
      Rodiola rosea: a possible plant adaptogen.
      Often used as a treatment for lung disease in China, Rhodiola has been purported to function as a central nervous system stimulant that improves work performance,
      • Zhaoyun Y.
      The effects of rhodiola crenulate compound on exercise performance during hypoxia.
      decreases fatigue,
      • Kteyan D.V.
      • Panossian A.
      • Gabrielian E.
      • Wikman G.
      • Wagner H.
      Rhodiola rosea in stress induced fatigue—a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty.
      ,
      • Spasov A.A.
      • Wikman G.K.
      • Mandrikov V.B.
      • Mironova L.A.
      • Neumoin V.V.
      A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen.
      improves blood circulation,
      • Peng J.N.
      • Ge Y.C.
      • Li X.H.
      Studies on the chemical constituents of Rhodiola fastigita.
      and prevents high-altitude illness.
      • Kelly G.S.
      Rodiola rosea: a possible plant adaptogen.
      In a study by Yong,
      • Yong M.
      Effect of Rhodiola and acetazolamide in improving hypoxia in high altitude.
      24 subjects living and working at an altitude of 3700 m showed improved psychological function following 24-hour sleep deprivation and physical exercise after 20 days of drug intervention with either acetazolamide or Rhodiola. Although both treatments improved vision and reaction time in subjects, the Rhodiola treatment group experienced no side effects unlike those subjects treated with acetazolamide.
      • Yong M.
      Effect of Rhodiola and acetazolamide in improving hypoxia in high altitude.
      Although more than 200 species of Rhodiola exist, R. rosea is considered to be the most biologically active.
      • Germano C.
      • Ramazanov A.
      Rhodiola rosea: adaptogens—nature's solution to sickness.
      To date, most studies on the herb have been conducted in China and Russia, with limited access to the literature in Western countries. The research available for review appears to substantiate traditional claims of Rhodiola's role as an adaptogen.
      • Kelly G.S.
      Rodiola rosea: a possible plant adaptogen.
      ,
      • Maslova L.V.
      • Kondratev B.I.
      • Maslov L.N.
      • Lishmanov I.B.
      The cardioprotective and antiadrenergic activity of an extract of Rhodiola rosea in stress.
      ,
      • Zhang Z.
      • Liu J.
      • Shang X.
      • et al.
      The effect of Rhodiola capsules on oxygen consumption of myocardium and coronary artery blood flow in dogs.
      Adaptogens are substances that normalize body functions during stress. R. rosea was found to reduce stress-induced cardiac damage by lowering levels of catecholamines and cAMP in the myocardium.
      • Maslova L.V.
      • Kondratev B.I.
      • Maslov L.N.
      • Lishmanov I.B.
      The cardioprotective and antiadrenergic activity of an extract of Rhodiola rosea in stress.
      Another study showed that Rhodiola decreased myocardial oxygen consumption in dogs.
      • Zhang Z.
      • Liu J.
      • Shang X.
      • et al.
      The effect of Rhodiola capsules on oxygen consumption of myocardium and coronary artery blood flow in dogs.
      R. rosea is a combination of many phytochemicals including phenylpropanoids, proanthocyanidins, and flavonoids. These are thought to contribute to its antioxidant properties.
      • Lee M.W.
      • Lee Y.A.
      • Park H.M.
      • et al.
      Antioxidative phenolic compounds from the roots of Rhodiola sachalinensis A.
      ,
      • Oshugi M.
      • Fan W.
      • Hase K.
      • et al.
      Active-oxygen scavenging activity of traditional nourishing-tonic herbal medicines and active constituents of Rhodiola sacra.
      Rhodioloside, similar to the glycoside salidroside, p-tyrosol, and the phenylpropanoid rosavin are considered to be the active constituents of R. rosea. Rosavin is the constituent that is currently used to standardize extracts.
      • Germano C.
      • Ramazanov A.
      Rhodiola rosea: adaptogens—nature's solution to sickness.
      ,
      • Kelly G.S.
      Rodiola rosea: a possible plant adaptogen.
      In addition to herbal products, there are a number of oxygenated water products currently in the market. These products are purported by the manufacturers to improve blood oxygenation by providing free oxygen to cells to increase oxygen saturation. Quantitatively, the amount of oxygen provided by oxygenated water through the gut compared with that supplied through the lungs appears insignificant. However, it is possible that oxygenated water may increase the free dissolved oxygen in blood by a small but physiologically significant amount or possibly trigger some other response such as increased blood flow through vasodilation. To date, there have been no studies to validate the efficacy of supplemental dissolved oxygen or to substantiate the use of oxygenated water products.
      An additional concern for travelers and residents of high elevations is oxidative stress. Oxygen, when metabolized, produces reactive oxygen species that damage cells and tissues.
      • Simon-Schass I.
      Oxidative stress at high altitudes and effects of vitamin E.
      Hypoxic cells are particularly sensitive to oxidative stress due to the reductive atmosphere created by insufficient oxygen and increased energy turnover.
      • Mohanraj P.
      • Merola A.J.
      • Wright V.P.
      • Clanton T.L.
      Antioxidants protect rat diaphragmatic muscle function under hypoxic conditions.
      In addition, hypoxia, combined with solar radiation, cold, and physical work can contribute to dangerous oxygen metabolites known as free radicals. Electrons are transferred between molecules, leading to free radical chain reactions, especially in lipid membranes.
      • Simon-Schass I.
      Oxidative stress at high altitudes and effects of vitamin E.
      In this study, we evaluated 2 dietary supplements purported to facilitate blood oxygenation for their effect on hypoxia and oxidative stress. This study tested the effects of 1) a proprietary blend of R. rosea, and 2) a dissolved oxygen supplement stabilized in water on blood oxygenation and oxidative stress, using a reduced atmospheric oxygen gas mixture with oxygen content similar to that at an altitude of 4600 m.

      Subjects and methods

      Fifteen apparently healthy men and women, aged 20 to 33 years, were recruited to participate in this double-blind, placebo-controlled crossover study. All subjects were nonsmoking and moderately active. Subjects with a self-reported history of AMS, respiratory disease, heart disease, hypertension, diabetes mellitus, kidney disease, liver disease, thyroid abnormalities, malabsorption disorders, and blood disorders such as sickle cell anemia were excluded from the study. Subjects who were currently pregnant or lactating or were planning on becoming pregnant were also excluded. A general health and medical screening questionnaire was given to all subjects to determine eligibility. All subjects signed a written consent form approved by the local institutional review board for human subjects and were informed both orally and in writing of the purpose, requirements, and potential risks involved in their participation in the study.
      Before initial testing, all subjects were instructed on the study protocol and the dietary guidelines. Subjects were instructed to discontinue any dietary supplements they were currently taking, except for general multivitamins. Subjects were counseled to limit carbohydrate intake to no more than 50% of their total calories, 3 days before each hypoxic exposure. Three-day diet records were completed for the 3 days before each hypoxic exposure to monitor compliance. Subjects were also required to eat breakfast 2 hours before each exposure. Guidelines for a 300- to 500-calorie breakfast were given to each subject. Subjects were advised to avoid taking caffeine on the morning of testing. Food records were analyzed with the Food Processor Nutrition Analysis & Fitness Software Version 7.3 (ESHA Research, Salem, OR).
      To control extraneous oxidative stress, subjects were instructed to avoid strenuous exercise on the day before and on the day of hypoxic exposure. Strenuous exercise was defined as any activity lasting longer than 30 minutes, performed for the sole purpose of exercise. This included activities such as running, swimming, biking, weightlifting, and team sports. Subjects were allowed to continue their regular exercise routine 24 hours after each hypoxic exposure. Subjects completed an activity record for the day before and for the day of testing to monitor compliance.
      On every morning of testing, subjects brought with them their food records, activity records, and a 50-mL sample of urine from their first void of the morning. Baseline measurements were recorded for heart rate, blood pressure, and SaO2. Pulse oximeter oxyhemoglobin saturation was measured using an N20 pulse oximeter placed on the index finger (Nellcor Inc, Pleasanton, CA).
      After baseline measurements were recorded, each subject's hand was warmed with a heating pad to facilitate sampling of arterialized blood from a capillary finger stick for oxygen measurement (PcO2). Once warm, blood from a finger stick was withdrawn with a 125-μL heparinized capillary tube. Arterialized capillary blood oxygen and PcCO2 were analyzed using a blood gas analyzer (ABL 700; Radiometer, Copenhagen, Denmark). A 10-mL venous blood sample was then drawn and centrifuged to collect serum. Serum blood samples were frozen at −80°F and subsequently analyzed for the oxidative stress indicator, lipid hydroperoxides (LPO), which are produced by free radical peroxidation of fatty acids (Genox Corporation, Baltimore, MD). Serum LPO was determined using a methylene blue derivative, as described by Ohishi et al.
      • Ohishi N.
      • Ohkawa H.
      • Mike A.
      • Tatano T.
      • Yagi K.
      A new assay method for lipid peroxidation using a methylene blue derivative.
      Once all baseline measurements were taken, subjects were given either 4 ounces of a saline solution (placebo) or 4 ounces of a stabilized oxygen supplement containing 30 000 ppm dissolved oxygen in water (BIO2 International Inc, San Luis Obispo, CA). A clear Plexiglas hood was then placed over each subject's head. Hoods were attached to an oxygen tank containing 13.6% oxygen balanced nitrogen (CGA 590, Praxair Distribution, Salt Lake City, UT). The decrease in oxygen combined with an ambient barometric pressure of 633 mm Hg created an oxygen content similar to that found at an elevation of 4600 m. Subjects breathed the decreased oxygen gas mixture at a flow rate of 40 L·min−1 for 1 hour. This flow rate was tested previously by Lawless et al
      • Lawless N.P.
      • Dillard T.A.
      • Torrington K.G.
      • Davis H.Q.
      • Kamimori G.
      Improvement in hypoxemia at 4600 meters of simulated altitude with carbohydrate ingestion.
      and was determined to be adequate to prevent CO2 accumulation inside the Plexiglas hood.
      Subjects were monitored throughout the 1-hour hypoxic exposure. Pulse oximeter oxyhemoglobin saturation was recorded every 10 minutes. At 30 minutes of hypoxic exposure, subjects were again redosed either with 4 ounces of saline solution or with 4 ounces of the stabilized oxygen supplement. The subject's hand was warmed again, and an arterialized finger stick blood sample was taken and analyzed for blood gases. At 60 minutes, immediately before the cessation of the hypoxic exposure, heart rate, blood pressure, and final SaO2 were recorded. A final warmed finger stick was also performed, followed by a second venous blood draw of approximately 10 mL for LPO determination. The hoods were then removed. Subjects underwent testing 3 times in this manner, with 2-week intervals between testing. Ambient temperature on different days ranged from 20°C to 22°C. Measured ambient barometric pressure averaged 633 mm Hg on different testing days. All data collection occurred between 7:30 am and 11:00 am.
      After cessation of hypoxic exposure, subjects received either a 7-day supply of placebo capsules (4 capsules per day) or a 7-day supply of R. rosea (4 capsules per day of 447 mg R. rosea each) (American Phytotherapy Research Laboratory, Provo, UT). For the next 7 days, subjects took no supplements. On the 8th day after testing, subjects began taking their 7-day supply of capsules. Subjects were reminded by telephone and in writing when to begin taking supplements. Subjects were also given 3-day food records to be completed before the next hypoxic exposure.
      In addition, each subject provided a 50-mL urine sample 1 to 2 hours after and 24 hours after hypoxic exposure. Urine samples were frozen at −80°F and subsequently analyzed for the oxidative stress indicator malondialdehyde (MDA) (Oxis Research, Portland, OR). Malondialdehyde, a product of lipid peroxidation, was analyzed using high-pressure liquid chromatography after the urine samples were reacted with thiobarbituric acid. Urine measurements were normalized to milligrams of creatinine, which was determined with the alkaline picrate method
      • Murray R.L.
      Creatinine.
      before being statistically analyzed.
      Subjects were evaluated for AMS with the Environmental Symptoms Questionnaire. Each subject completed an Environmental Symptoms Questionnaire immediately before hypoxic exposure and at 45 minutes of hypoxic exposure. Environmental Symptoms Questionnaires were scored and analyzed as described by Sampson et al.
      • Sampson J.B.
      • Cymerman A.
      • Burse R.L.
      • Maher J.T.
      • Rock P.B.
      Procedures for the measurement of acute mountain sickness.
      Weighted average scores of cerebral symptoms (AMS-C) and respiratory symptoms (AMS-R) were calculated. An AMS-C score ≥0.07 and an AMS-R score ≥0.60 were considered indicative of the presence of AMS.
      • Sampson J.B.
      • Cymerman A.
      • Burse R.L.
      • Maher J.T.
      • Rock P.B.
      Procedures for the measurement of acute mountain sickness.
      At no time did subjects receive the Rhodiola capsules and the stabilized oxygen supplement simultaneously. If subjects were taking the Rhodiola capsules, they received the saline solution during hypoxic exposure. If subjects were taking the placebo capsules, they received the stabilized oxygen supplement during exposure. Subjects always took capsules 7 days before testing and always drank the saline solution during exposure. Both the subjects and investigators were blinded to the treatments.

      Statistics

      Statistical analysis was completed using SPSS for Windows Version 10.0 (Chicago, IL). Descriptive statistics for test subjects (means ± SD) were calculated for age, height, weight, and body mass index (BMI).
      The purpose of the study was not to compare the treatments with each other, but rather to compare each treatment with the placebo (control) group. This decision was made before data collection. Change scores were first computed for each variable measured by subtracting pre–hypoxia-exposure measurements from each time point thereafter. The means were then compared between the placebo group and both the treatment groups. For those variables with 1 change score only, a nondirectional paired t test was used to assess for differences between the placebo group and the 2 treatment groups. For those variables with more than 1 change score, repeated measures analysis of variance (ANOVA) was used with change scores and grouped as within-subject factors.
      The effect of the order in which treatments were taken was examined by developing a repeated measures ANOVA model that included a variable denoting treatment order. Because no order effect reached statistical significance, treatment order was not included in subsequent analyses.
      A Bonferroni correction for simultaneous multiple comparisons was not used because the comparisons were specified in advance, and the inference did not require the simultaneous examination of the comparisons, and the comparison error rate was kept at alpha by using standard tests of significance rather than a multiple-comparison test.
      • Dunnett C.
      • Goldsmith C.
      When and how to do multiple comparisons.
      The study was designed such that the comparison of each supplement with the control was performed, reported, and discussed individually. The inference drawn from each of the 2 supplement-to-control comparisons was not influenced by or dependent on the outcome of the other. Therefore, as specified by Dunnett and Goldsmith,
      • Dunnett C.
      • Goldsmith C.
      When and how to do multiple comparisons.
      no multiple comparison procedure was called for or used.
      Differences were considered significant at P < .05. For variables analyzed with repeated measures ANOVA, the Greenhouse-Geisser degree of freedom adjustment to the ANOVA F test was used to account for any violations of the sphericity assumption.

      Results

      All the participants met the study inclusion criteria and appeared to be healthy. Physical characteristics including age, weight, height, and BMI are described in Table 1. Fifteen subjects participated. Participants included 6 male and 9 female subjects. Due to illness, 1 subject did not complete the Rhodiola treatment, but completed the placebo and stabilized oxygen treatments.
      Table 1Test subject characteristics*
      Table thumbnail fx1
      Blood pressure did not change significantly from baseline to 1-hour hypoxic exposure, and there were no statistically significant differences between groups or across time. Mean blood pressure for the placebo group at baseline was 117/72 mm Hg, with a similar measurement of 114/72 mm Hg at 1-hour hypoxic exposure. The Rhodiola and stabilized oxygen supplement groups were almost identical, with baseline blood pressures of 113/69 mm Hg and 113/74 mm Hg and post-blood pressures of 108/73 mm Hg and 108/72 mm Hg, respectively. Heart rate also did not differ significantly between the placebo group and the Rhodiola group (P = .21) or the stabilized oxygen treatment group (P = .50). However, heart rate did increase in all groups with hypoxic exposure. Heart rate increased significantly from baseline as expected, from 67.3 ± 10 beats/min to 75.9 ± 13.9 beats/min (P = .03).
      Table 2 provides the mean values and standard deviations for PcO2. For each treatment group, PcO2 decreased significantly from baseline to 60-minutes hypoxic exposure by ∼38%. There was no significant difference between the control group and either treatment group.
      Table 2Arterial blood gases at simulated altitude*
      Table thumbnail fx2
      Pulse oximeter oxyhemoglobin saturation values are depicted in Figure 1. Although the placebo, Rhodiola, and stabilized oxygen treatment groups experienced a significant decrease in SaO2 from ∼97% to 81% during the 1-hour hypoxic exposure, there was no significant treatment difference between the placebo and Rhodiola treatment groups (P = .39) and the placebo and stabilized oxygen treatment groups (P = .90).
      Figure thumbnail gr1
      Figure 1Pulse oximeter oxyhemoglobin saturation during 60 minutes hypoxic exposure. All groups decreased similarly from baseline (P < .05). There was no significant difference between treatment groups.
      The oxidative stress markers serum LPO and urine MDA were also measured for each treatment group. Serum LPO values are compared in Figure 2. The placebo LPO increased significantly from 1.43 ± 1.34 μmol·L−1 to 1.6 ± 0.15 μmol·L−1 after the 1-hour hypoxic exposure (P = .02). The Rhodiola LPO decreased slightly by 0.003 ± 0.21 μmol·L−1. Although this decrease in Rhodiola was not statistically significant (P = .10), it did indicate a trend of decreased production of LPO compared with placebo.
      Figure thumbnail gr2
      Figure 2The effects of altitude-induced hypoxia on serum LPO. Serum LPO significantly increased in the placebo group only (P < .05). The change in serum LPO from baseline to 60 minutes hypoxic exposure was significantly higher in the placebo group compared with the stabilized oxygen treatment group (P < .05).
      Although there was no statistically significant difference between the placebo and Rhodiola group, there was a significant difference between the placebo and the stabilized oxygen supplement change scores (P = .02). Serum lipid peroxide in the placebo group increased 0.17 ± 0.24 μmol·L−1, whereas the stabilized oxygen supplement decreased 0.04 ± 0.22 μmol·L−1.
      There were no statistically significant differences in urine MDA between the placebo and the treatment groups. The placebo group's MDA decreased from a baseline of 0.94 ± 0.45 μmol·mg·crt−1 to 0.90 ± 0.45 μmol·mg·crt−1 at the 24-hour post-hypoxic exposure and that of Rhodiola increased from 0.90 ± 0.60 μmol·mg·crt−1 to 0.96 ± 0.59 μmol·mg·crt−1 (P = .06). The stabilized oxygen treatment group increased from a baseline of 0.90 ± 0.35 μmol·mg·crt−1 to 0.93 ± 0.39 μmol·mg·crt−1 at the 24-hour post-hypoxic exposure (P = .65). As described previously, all urine measurements were normalized to milligrams of creatinine for statistical analysis.
      Presence of cerebral and respiratory AMS was found in 1 subject in the placebo group using the criterion outlined previously. One subject experienced respiratory AMS with all 3 treatments during hypoxic exposure. There were no significant differences between gender or treatment groups with regard to the presence of AMS.

      Discussion

      The present study contributes information on the effects of 2 dietary supplements on blood oxygenation and oxidative stress under hypoxic conditions. With interest in dietary supplements increasing, it was appropriate to investigate 2 supplements thought to have “oxygen promoting” activities. As with many dietary supplements, there was little noncommercial information available as to the functioning and effectiveness of the 2 supplements investigated in this study.
      Under the conditions of this study, Rhodiola and stabilized oxygen supplementation did not increase blood oxygenation during hypoxia and simulated high altitudes. Arterialized capillary blood gases and pulse oximeter values were almost identical for all groups. Measurements stabilized within 10 minutes of hypoxic exposure, implying that a longer exposure was not warranted. Although arterial blood samples might have been preferable, a preliminary hypoxia trial of 1 subject showed only a slight (0.04%) difference between an arterial stick and a finger stick from a warmed hand. Previous studies have also documented the validity of using warmed finger sticks to represent arterial blood.
      • Chiappini F.
      • Fuso L.
      • Pistelli R.
      Accuracy of a pulse oximeter in the measurement of the oxyhaemoglobin saturation.
      • Zello G.A.
      • Smith J.M.
      • Pencharz P.B.
      • Ball R.O.
      Development of a heating device for sampling arterialized venous blood from a hand vein.
      • Khavar D.
      • Williams T.
      • Aitken R.
      • Woods K.L.
      • Fletcher S.
      Arterial versus capillary sampling for analyzing blood gas pressures.
      It is unlikely that diet influenced these results because previous studies have shown that only diets with 68% or higher carbohydrate intake have increased PaO2 and SaO2 values, and in this study the diet was only ∼53% carbohydrates.
      • Hansen J.E.
      • Hartley L.H.
      • Hogan R.P.
      Arterial oxygen increased by high-carbohydrate diet at altitude.
      ,
      • Consolazio C.
      • Matoush L.
      • Johnson H.
      • et al.
      Effects of high carbohydrate diet on performance and clinical symptomatology after rapid ascent to high altitude.
      It is unknown whether an effect would have been detected if a greater degree of hypoxia had been induced or if subjects had exercised during hypoxic exposure. The results also suggest that neither R. rosea nor stabilized oxygen supplementation had an effect on cardiovascular response, as indicated by similar increases in heart rate among all groups.
      Because both supplements investigated were purported by the manufacturers to increase blood oxygenation, it was of further interest to investigate their effects on oxidative stress. Previous studies have shown oxidative stress to occur at high altitudes.
      • Simon-Schass I.
      Oxidative stress at high altitudes and effects of vitamin E.
      ,
      • Simon-Schnass I.
      • Pabst H.
      Influence of vitamin E on physical performance.
      Typically, oxidative stress at high altitudes includes free radical production from exercise, solar radiation, and cold exposure.
      • Simon-Schass I.
      Oxidative stress at high altitudes and effects of vitamin E.
      However, environmental hypoxia alone can also contribute to oxidative stress.
      • Mohanraj P.
      • Merola A.J.
      • Wright V.P.
      • Clanton T.L.
      Antioxidants protect rat diaphragmatic muscle function under hypoxic conditions.
      ,
      • Bailey D.M.
      • Davies B.
      • Davison G.W.
      • Young I.S.
      Oxidatively stressed out at high altitude.
      The mechanism for this is not clearly understood. It is believed that there is an accumulation of reducing equivalents. This is caused by the decreased amount of oxygen available for reduction to H2O at the terminal end of the electron transport chain. As a consequence, reactive oxygen species are formed, making cells susceptible to free radical damage.
      • Mohanraj P.
      • Merola A.J.
      • Wright V.P.
      • Clanton T.L.
      Antioxidants protect rat diaphragmatic muscle function under hypoxic conditions.
      In addition, an increase in calcium-activated proteases during hypoxia from impaired function of calcium-ATP–dependent pumps can cause an increase in the activity of free radical–producing enzymes such as xanthine oxidase and cyclooxygenase.
      • Mohanraj P.
      • Merola A.J.
      • Wright V.P.
      • Clanton T.L.
      Antioxidants protect rat diaphragmatic muscle function under hypoxic conditions.
      In this study, lipid peroxidation, as evidenced by elevated LPO, occurred in the control group only. This supports preliminary findings by Bailey et al
      • Bailey D.M.
      • Davies B.
      • Davison G.W.
      • Young I.S.
      Oxidatively stressed out at high altitude.
      that free radical lipid peroxidation occurs independently of exercise. Lipid hydroperoxides are formed from the oxidation of fatty acids. Polyunsaturated fats (PUFAS) are particularly susceptible to oxidation by free radicals. Red blood cells and cell membranes are highly concentrated with PUFAS.
      • Eberhardt M.K.
      Antioxidants.
      Given the short duration of the hypoxic exposure in this study, it is likely that the LPO increase seen in the control group may have been from lipid peroxidation of PUFAS in the red blood cells. Because both supplements had lower levels of serum LPO than the control group, it appears that the supplements were able to prevent the increase in lipid peroxidation seen in the control group. Stabilized oxygen supplementation significantly lowered LPO (P = .02) compared with control, and Rhodiola showed a trend of decreased LPO compared with control. These results differ from those found in a previous study by Askew et al
      • Askew E.W.
      • Pfeiffer J.M.
      • Roberts D.E.
      • Reading J.E.
      • Ensign W.Y.
      Does “activated stabilized oxygen” dissolved in drinking water improve aerobic metabolism at moderate altitude [abstract].
      in which a significant increase in LPO with stabilized oxygen supplementation was observed. However, the study by Askew et al
      • Askew E.W.
      • Pfeiffer J.M.
      • Roberts D.E.
      • Reading J.E.
      • Ensign W.Y.
      Does “activated stabilized oxygen” dissolved in drinking water improve aerobic metabolism at moderate altitude [abstract].
      was a long-term field study at lower elevation. It is possible that, in the current study, the stabilized oxygen was able to decrease the degree of hypoxia, and therefore lipid peroxidation, by providing more oxygen to the cells in a manner that was not detected in blood oxygen measurements such as vasodilation. In addition, it is probable that R. rosea, like many herbal products, has antioxidant properties due to its phytochemical constituents, which include flavonoids, phenylpropanoids, and proanthocyanidins.
      • Germano C.
      • Ramazanov A.
      Rhodiola rosea: adaptogens—nature's solution to sickness.
      Another marker of lipid peroxidation, MDA, was not significantly different between the control and the 2 treatment groups. Urine samples were only taken at 3 time points (pre-, 1-hour post-, and 24-hour post-hypoxia). It is possible that peak urine MDA levels were reached during a period of time that was not measured or that the 60-minute exposure was long enough to elevate the LPO precursor of urine aldehydes in the blood but was not subsequently of quantitative significance in the urine.
      In summary, the results from this study suggest that the 2 dietary supplements examined do not help attenuate hypoxia of short duration. For individuals who are sensitive to altitude-induced hypoxia, the best recommendation would be to acclimatize slowly if possible and decrease activity for the first few days of high-altitude exposure.
      • Piehl Aulin K.
      • Svendenhag J.
      • Wide L.
      • Berglund B.
      • Saltin B.
      Short-term intermittent normobaric hypoxia—haematological, physiological and mental effects.
      This study provides information for the mountain traveler who might be exploring the utility of dietary supplements to mitigate the effects of hypoxia. Although the supplements under investigation did not show any acute improvement in blood oxygenation, they did show a potential to decrease oxidative stress produced by hypoxia. It is evident from this study that lipid peroxidation occurs even with short exposure to hypoxia, without exposure to UV light or exercise that would also occur at elevation.
      Additional research is warranted on both dietary supplements to examine their effects on hypoxia, particularly with exercise. More research is also needed to evaluate other doses of Rhodiola and to explore potential synergistic interactions with other herbal compounds such as Gingko. There is also a need to examine mechanisms of action of herbal compounds such as Rhodiola. It would be of interest to conduct further research on both supplements at high altitudes, which might include a longer exposure time to hypoxia as well as dietary supplementation of longer duration.

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