Also see:
Carbon Dioxide Basics
Comparison: Carbon Dioxide v. Lactic Acid
Carbonic Anhydrase Inhibitors as Cancer Therapy
Comparison: Oxidative Metabolism v. Glycolytic Metabolic
Promoters of Efficient v. Inefficient Metabolism
Low CO2 in Hypothyroidism
Protective Altitude
Lactate Paradox: High Altitude and Exercise
Protective Carbon Dioxide, Exercise, and Performance
Synergistic Effect of Creatine and Baking Soda on Performance
Ray Peat, PhD on Carbon Dioxide, Longevity, and Regeneration
Altitude Improves T3 Levels
High altitude sickness is now treated with acetazolamide (which causes carbon dioxide retention, and respiratory acidosis), or with direct inhalation of carbon dioxide. …Carbon dioxide, progesterone, and the carbonic anhydrase inhibitors stabilize and protect cells in very general ways. -Ray Peat, PhD
The now-standard treatment for mountain sickness is the drug acetazolamide, which causes the body to retain carbon dioxide. Despite the drug’s success in preventing and curing altitude sickness, there is a weird reluctance to acknowledge that mountain sickness is produced by an insufficiency of carbon dioxide. -Ray Peat, PhD
Schweiz Med Wochenschr. 1982 Apr 3;112(14):492-5.
[Incidence, prevention and therapy of acute mountain sickness].
[Article in German]
Oelz O.
The symptoms and signs of acute mountain sickness are present in about half of the tourists trekking in Nepal to an altitude of 42000 m. The most common symptoms are headache and nausea. Pulmonary rales are found in more than 10% of trekkers, while high altitude pulmonary edema is rare. Retinal hemorrhages occur almost exclusively above 5000 m. A careful history and physical examination are generally sufficient for medical evaluation of fitness for high altitude. There are no specific tests to predict performance at altitude. The most effective prophylaxis of acute mountain sickness is “slow” ascent, which is arbitrarily defined as an increase in sleeping altitude of 300-400 m per 24 hours. Sufficient fluid intake is also very important. Prophylactic administration of acetazolamide reduces the incidence and severity of acute mountain sickness. Mild forms of acute mountain sickness are treated by a rest day, whereas patients with severe disease should descend as soon as possible.
Fortschr Med. 1975 Oct 16;93(29):1415-22.
[Prevention of altitude sickness].
[Article in German]
Olzowy M.
In experimental and clinical studies the effect of Acetazolamide (Diamox) on acute mountain sickness was investigated. It could be established that Acetazolamide does influence the symptoms, the man effect seems to be a reduction of the respiratory alkalosis, which is found in control persons in high altitudes. Observations made with a group of 25 tourists mountaineering in the Cordilleras (South America) over 24 days in altitudes between 3200 and 6000 m are described. In accordance with other published data the favorable influence of Acetazolamide on acute mountain sickness could be confirmed. Persons taking Acetazolamide were more efficient and better prepared to cope with the extreme situations in high altitude. They also showed to be more resistent to other diseases, which are following the stress in high altitude and are caused by the different climate and food.
Lancet. 1981 Jan 24;1(8213):180-3.
Acetazolamide in control of acute mountain sickness.
[No authors listed]
As part of a double-blind trial slow-release acetazolamide (500 mg daily) or placebo was given to 20 men ascending to 5000 m. In the 18 who attained this altitude, those on acetazolamide had fewer symptoms of acute mountain sickness (AMS) than those on placebo (p < 0.02). 10 of the men had been to 5400 m on a previous expedition. 5 of these men took acetazolamide and 5 took placebo. Those on the drug performed better than those on placebo (p < 0.005). Furthermore, the performance of the 5 men on acetazolamide during the second expedition had improved more than that of the men on placebo (p < 0.01). In the group as a whole the symptoms of AMS were negatively correlated with arterial oxygen tensions (p < 0.001) which were higher in the drug group (p < 0.001). Acetazolamide probably had its effect by causing a metabolic acidosis with a resultant increase in respiratory drive and arterial oxygen tension.
J Int Med Res. 1986;14(5):285-7.
Acetazolamide in prevention of acute mountain sickness.
McIntosh IB, Prescott RJ.
A controlled comparative between-group study of 48 climbers ascending Kilimanjaro (5895m) was designed as an extension to our previous double-blind cross-over trial on the same peak in 1980, using acetazolamide to decrease the incidence and effects of Acute Mountain Sickness. A group taking acetazolamide 500 mg each morning for one day before reaching 3000m were compared with 3 control groups of Caucasian subjects and lowland and highland Africans. Efficacy was assessed on climbing performance and scores derived from symptoms recorded daily by subjects. Those taking acetazolamide reached higher altitudes and had lower symptom scores than those in control groups. The results support the use of acetazolamide as an effective prophylactic for Acute Mountain Sickness, for most people in a dose of 500 mg in the morning starting one day before ascent above 3000m. The optimal dose of prophylactic acetazolamide is not established, nor is the most appropriate time for medication prior to ascent.
Aviat Space Environ Med. 1976 May;47(5):512-6.
Amelioration of the symptoms of acute mountain sickness by staging and acetazolamide.
Evans WO, Robinson SM, Horstman DH, Jackson RE, Weiskopf RB.
Treatment by 4 d of residence at 1600 m plus the administration of 500 mg acetazolamide b.i.d. for the last 2 d at 1600 m and the first 2 d at 4300 m was compared with no treatment prior to ascent to 4300 m for prophylaxis of acute mountain sickness. The treatment successfully prevented almost all symptoms of acute mountain sickness. It had no effect on the diminished capacity for maximal or prolonged heavy physical work. The treatment produced a relative acidosis and a comparatively greater arterial oxygen tension at 4300 m.
Lancet. 1986 May 3;1(8488):1001-5.
Effect of acetazolamide on exercise performance and muscle mass at high altitude.
Bradwell AR, Dykes PW, Coote JH, Forster PJ, Milles JJ, Chesner I, Richardson NV.
The effect of acetazolamide (Az) on exercise performance and muscle mass in acclimatised subjects at an altitude of 4846 m was assessed in 11 subjects and compared with the effect of placebo on 10 other subjects. Exercise performance at 85% maximum heart rate fell by 37% in the Az group and by 45% in controls (p less than 0.05). Weight loss was greater in the placebo group at high altitude (p less than 0.01) and this correlated with the fall in exercise performance (p less than 0.001). During the expedition anterior quadriceps muscle thickness fell by 12.9% in the control group and 8.5% in the Az group (p less than 0.001), while biceps muscle thickness fell by 8.6% in controls and 2.3% in the Az group (p less than 0.001). Measurements of skin-fold thickness indicated a loss of 18% of total body fat in the placebo group and 5% in the Az group by the end of the expedition (p less than 0.001). Calorie intakes at altitudes above 3000 m were low and similar for the two groups. The Az group had fewer symptoms of acute mountain sickness but differences between the two groups were not statistically significant. Acetazolamide is therefore useful for climbers and trekkers who are acclimatised to high altitudes. It could be most useful at extreme altitudes, where maintenance of exercise performance and muscle mass are important.
Lancet. 1988 Sep 17;2(8612):639-41.
Effect of carbon dioxide in acute mountain sickness: a rediscovery.
Harvey TC, Raichle ME, Winterborn MH, Jensen J, Lassen NA, Richardson NV, Bradwell AR.
The effect of adding CO2 to inhaled air in six subjects with acute mountain sickness was investigated during a medical expedition to 5400m. 3% CO2 in ambient air increased ventilation and resulted in a rise in PaO2 of between 24% and 40%. There was a 9-28% increase in PaCO2 and a reduction of the respiratory alkalosis normally seen at high altitude. Symptoms of acute mountain sickness were rapidly relieved. In three subjects cerebral blood flow increased by 17-39%, so that oxygen delivery to the brain would have been considerably improved. This study confirms earlier suggestions of the beneficial effect of CO2 inhalation at high altitude.
Am J Respir Crit Care Med. 2007 Feb 1;175(3):277-81. Epub 2006 Nov 9.
Effects of acetazolamide on ventilatory, cerebrovascular, and pulmonary vascular responses to hypoxia.
Teppema LJ, Balanos GM, Steinback CD, Brown AD, Foster GE, Duff HJ, Leigh R, Poulin MJ.
RATIONALE:
Acute mountain sickness (AMS) may affect individuals who (rapidly) ascend to altitudes higher than 2,000-3,000 m. A more serious consequence of rapid ascent may be high-altitude pulmonary edema, a hydrostatic edema associated with increased pulmonary capillary pressures. Acetazolamide is effective against AMS, possibly by increasing ventilation and cerebral blood flow (CBF). In animals, it inhibits hypoxic pulmonary vasoconstriction.
OBJECTIVES:
We examined the influence of acetazolamide on the response to hypoxia of ventilation, CBF, and pulmonary vascular resistance (PVR).
METHODS:
In this double-blind, placebo-controlled, randomized study, nine subjects ingested 250 mg acetazolamide every 8 h for 3 d. On the fourth test day, we measured the responses of ventilation, PVR, and CBF to acute isocapnic hypoxia (20 min) and sustained poikilocapnic hypoxia (4 h). Ventilation was measured with pneumotachography. Hypoxia was achieved with dynamic end-tidal forcing. The maximum pressure difference across the tricuspid valve (DeltaPmax, a good index of PVR) was measured with Doppler echocardiography. CBF was measured by transcranial Doppler ultrasound.
RESULTS:
In normoxia, acetazolamide increased ventilation and reduced DeltaPmax, but did not influence CBF. The ventilatory and CBF responses to acute isocapnic hypoxia were unaltered, but the rise in DeltaPmax was reduced by 57%. The increase in DeltaPmax by sustained poikilocapnic hypoxia observed after placebo was reduced by 34% after acetazolamide, the ventilatory response was increased, but the CBF response remained unaltered.
CONCLUSIONS:
Acetazolamide has complex effects on ventilation, PVR, and CBF that converge to optimize brain oxygenation and may be a valuable means to prevent/treat high-altitude pulmonary edema.
Clin Sci (Lond). 2003 Mar;104(3):203-10.
Effects of breathing air containing 3% carbon dioxide, 35% oxygen or a mixture of 3% carbon dioxide/35% oxygen on cerebral and peripheral oxygenation at 150 m and 3459 m.
Imray CH, Walsh S, Clarke T, Tiivas C, Hoar H, Harvey TC, Chan CW, Forster PJ, Bradwell AR, Wright AD; Birmingham Medical Research Expeditionary Society.
The effects of gas mixtures comprising supplementary 3% carbon dioxide, 35% oxygen or a combination of 3% CO(2) plus 35% O(2) in ambient air have been compared on arterial blood gases, peripheral and cerebral oxygenation and middle cerebral artery velocity (MCAV) at 150 m and on acute exposure to 3459 m in 12 healthy subjects. Breathing 3% CO(2) or 35% O(2) increased arterial blood oxygen at both altitudes, and the CO(2)/O(2) combination resulted in the most marked rise. MCAV increased on ascent to 3459 m, increasing further with 3% CO(2) and decreasing with 35% O(2) at both altitudes. The CO(2)/O(2) combination resulted in an increase in MCAV at 150 m, but not at 3549 m. Cerebral regional oxygenation fell on ascent to 3459 m. Breathing 3% CO(2) or 35% O(2) increased cerebral oxygenation at both altitudes, and the CO(2)/O(2) combination resulted in the greatest rise at both altitudes. The combination also resulted in significant rises in cutaneous and muscle oxygenation at 3459 m. The key role of carbon dioxide in oxygenation at altitude is confirmed, and the importance of this gas for tissue oxygenation is demonstrated.
High Alt Med Biol. 2003 Spring;4(1):45-52.
Efficacy of low-dose acetazolamide (125 mg BID) for the prophylaxis of acute mountain sickness: a prospective, double-blind, randomized, placebo-controlled trial.
Basnyat B, Gertsch JH, Johnson EW, Castro-Marin F, Inoue Y, Yeh C.
The objective of this study was to determine the efficacy of low-dose acetazolamide (125 mg twice daily) for the prevention of acute mountain sickness (AMS). The design was a prospective, double-blind, randomized, placebo-controlled trial in the Mt. Everest region of Nepal between Pheriche (4243 m), the study enrollment site, and Lobuje (4937 m), the study endpoint. The participants were 197 healthy male and female trekkers of diverse background, and they were evaluated with the Lake Louise Acute Mountain Sickness Scoring System and pulse oximetry. The main outcome measures were incidence and severity of AMS as judged by the Lake Louise Questionnaire score at Lobuje. Of the 197 participants enrolled, 155 returned their data sheets at Lobuje. In the treatment group there was a statistically significant reduction in incidence of AMS (placebo group, 24.7%, 20 out of 81 subjects; acetazolamide group, 12.2%, 9 out of 74 subjects). Prophylaxis with acetazolamide conferred a 50.6% relative risk reduction, and the number needed to treat in order to prevent one instance of AMS was 8. Of those with AMS, 30% in the placebo group (6 of 20) versus 0% in the acetazolamide group (0 of 9) experienced a more severe degree of AMS as defined by a Lake Louise Questionnaire score of 5 or greater (p = 0.14). Secondary outcome measures associated with statistically significant findings favoring the treatment group included decrease in headache and a greater increase in final oxygen saturation at Lobuje. We concluded that acetazolamide 125 mg twice daily was effective in decreasing the incidence of AMS in this Himalayan trekking population.
Arch Intern Med. 2005 Feb 14;165(3):296-301.
Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial.
Chow T, Browne V, Heileson HL, Wallace D, Anholm J, Green SM.
BACKGROUND:
Acute mountain sickness (AMS) commonly occurs when unacclimatized individuals ascend to altitudes above 2000 m. Acetazolamide and Ginkgo biloba have both been recommended for AMS prophylaxis; however, there is conflicting evidence regarding the efficacy of Ginkgo biloba use. We performed a randomized, placebo-controlled trial of acetazolamide vs Ginkgo biloba for AMS prophylaxis.
METHODS:
We randomized unacclimatized adults to receive acetazolamide, Ginkgo biloba, or placebo in double-blind fashion and took them to an elevation of 3800 m for 24 hours. We graded AMS symptoms using the Lake Louise Acute Mountain Sickness Scoring System (LLS) and compared the incidence of AMS (defined as LLS score > or =3 and headache).
RESULTS:
Fifty-seven subjects completed the trial (20 received acetazolamide; 17, Ginkgo biloba, and 20, placebo). The LLS scores were significantly different between groups; the median score of the acetazolamide group was significantly lower than that of the placebo group (P=.01; effect size, 2; and 95% confidence interval [CI], 0 to 3), unlike that of the Ginkgo biloba group (P=.89; effect size, 0; and 95% CI, -2 to 2). Acute mountain sickness occurred less frequently in the acetazolamide group than in the placebo group (effect size, 30%; 95% CI, 61% to -15%), and the frequency of occurrence was similar between the Ginkgo biloba group and the placebo group (effect size, -5%; 95% CI, -37% to 28%).
CONCLUSIONS:
In this study, prophylactic acetazolamide therapy decreased the symptoms of AMS and trended toward reducing its incidence. We found no evidence of similar efficacy for Ginkgo biloba.
Expert Opin Pharmacother. 2008 Jan;9(1):119-27.
High hopes at high altitudes: pharmacotherapy for acute mountain sickness and high-altitude cerebral and pulmonary oedema.
Wright A, Brearey S, Imray C.
The pharmacotherapy of prevention and treatment of acute altitude- related problems – acute mountain sickness, high-altitude cerebral oedema and high-altitude pulmonary oedema – is reviewed. Drug therapy is only part of the answer to the medical problems of high altitude; prevention should include slow ascent and treatment of the more severe illnesses should include appropriate descent. Carbonic anhydrase inhibitors, in particular acetazolamide, remain the most effective drugs in preventing, to a large extent, the symptoms of acute mountain sickness, and can be used in the immediate management of the more severe forms of altitude-related illnesses. Glucocorticoids in relatively large doses are also effective preventative drugs, but at present are largely reserved for the treatment of the more severe acute mountain sickness and acute cerebral oedema. Calcium channel blockers and PDE-5 inhibitors are effective in the management of acute pulmonary oedema. Further work is required to establish the role of antioxidants and anticytokines in these syndromes.
BMJ. 2004 Apr 3;328(7443):797. Epub 2004 Mar 11.
Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT).
Gertsch JH, Basnyat B, Johnson EW, Onopa J, Holck PS.
OBJECTIVE:
To evaluate the efficacy of ginkgo biloba, acetazolamide, and their combination as prophylaxis against acute mountain sickness.
DESIGN:
Prospective, double blind, randomised, placebo controlled trial.
SETTING:
Approach to Mount Everest base camp in the Nepal Himalayas at 4280 m or 4358 m and study end point at 4928 m during October and November 2002.
PARTICIPANTS:
614 healthy western trekkers (487 completed the trial) assigned to receive ginkgo, acetazolamide, combined acetazolamide and ginkgo, or placebo, initially taking at least three or four doses before continued ascent.
MAIN OUTCOME MEASURES:
Incidence measured by Lake Louise acute mountain sickness score > or = 3 with headache and one other symptom. Secondary outcome measures included blood oxygen content, severity of syndrome (Lake Louise scores > or = 5), incidence of headache, and severity of headache.
RESULTS:
Ginkgo was not significantly different from placebo for any outcome; however participants in the acetazolamide group showed significant levels of protection. The incidence of acute mountain sickness was 34% for placebo, 12% for acetazolamide (odds ratio 3.76, 95% confidence interval 1.91 to 7.39, number needed to treat 4), 35% for ginkgo (0.95, 0.56 to 1.62), and 14% for combined ginkgo and acetazolamide (3.04, 1.62 to 5.69). The proportion of patients with increased severity of acute mountain sickness was 18% for placebo, 3% for acetazoalmide (6.46, 2.15 to 19.40, number needed to treat 7), 18% for ginkgo (1, 0.52 to 1.90), and 7% for combined ginkgo and acetazolamide (2.95, 1.30 to 6.70).
CONCLUSIONS:
When compared with placebo, ginkgo is not effective at preventing acute mountain sickness. Acetazolamide 250 mg twice daily afforded robust protection against symptoms of acute mountain sickness.
Chest. 1992 Mar;101(3):736-41.
The effects of acetazolamide on the ventilatory response to high altitude hypoxia.
Burki NK, Khan SA, Hameed MA.
Acetazolamide treatment ameliorates the symptoms of AMS; however, the mechanism by which this occurs is unclear. To examine the effects of acetazolamide on oxygenation, CO2 responsiveness and ventilatory pattern during acute exposure to HA, we studied two groups of subjects at SL and following rapid (less than 8 h) transport to HA. Acetazolamide or placebo tablets were given to groups 1 and 2, respectively, in a double-blind manner after baseline SL measurements; treatment was continued during HA exposure. There was no difference in the ventilatory pattern at HA, between the two groups. While the Ve achieved in response to CO2 at HA vs SL was much greater in each group the percent change from baseline at HA versus that at SL was not significantly different. The beneficial effects of acetazolamide in AMS are associated with a higher level of ventilation at HA and better oxygenation: CO2 chemosensitivity is not affected by acetazolamide at HA
Respiration. 1980;39(3):121-30.
Ventilatory acclimatization to high altitude is prevented by CO2 breathing.
Cruz JC, Reeves JT, Grover RF, Maher JT, McCullough RE, Cymerman A, Denniston JC.
The hypoxia of high altitude stimulates ventilation. If the resultant respiratory alkalosis inhibits the initial increase in ventilation, then with prevention of alkalosis, ventilation should rise immediately to a stable plateau. 4 subjects inspired CO2 (3.77%) from ambient air in a hypobaric chamber (PB = 440-455 Torr) during 100 h at high altitude. Ventilation (for given oxygen uptakes at rest and during exercise) increased promptly and remained stable. 4 control subjects exposed to high altitude without CO2 supplementation showed the expected progressive increases in ventilation with time. The hyperoxic CO2 ventilatory response curve shifted progressively to the left with time in the control subjects, but not in those given supplemental CO2. The latter group also failed to increase the ventilatory response to isocapnic hypoxia. Thus, CO2 supplementation at high altitude prevented the so-called “ventilatory acclimatization’ from occurring. Prevention of respiratory alkalosis at high altitude probably permitted maintenance of [H+] at some central nervous system locus, thus allowing an uninhibited hypoxic stimulation of ventilation.
==========================
Heart protective effects of acetazolamide:
Neurol Res. 1997 Apr;19(2):139-44.
Comparison of vasodilatory effect of carbon dioxide inhalation and intravenous acetazolamide on brain vasculature using positron emission tomography.
Gambhir S, Inao S, Tadokoro M, Nishino M, Ito K, Ishigaki T, Kuchiwaki H, Yoshida J.
Carbon dioxide (CO2) and acetazolamide are increasingly being used as vasodilators to detect cerebrovascular reserve capacity in patients of chronic cerebrovascular disease. The functional cerebrovascular reserve or ability of cerebral vessels to lower their resistance in response to decrease in cerebral perfusion pressure is expressed as change in cerebral blood flow from baseline under a vasodilatory stimuli. Theoretically a vasodilator causing maximum vasodilation, and thereby expressing complete reserve capacity would be more suitable for such a purpose. We quantitatively compared the vasodilating effect of 5% CO2 inhalation and 1 g of intravenous acetazolamide by positron emission tomography. Cerebrovascular reserve was quantified in six patients with chronic cerebrovascular disease in the same sitting, using oxygen-15 labeled water (H2(15)O) positron emission tomography at rest, during 5% CO2 inhalation and after 1 g intravenous acetazolamide. A significant linear correlation in both nonlesion hemisphere (r = 0.701, p < 0.001) and in lesion hemisphere (r = 0.626, p < 0.005) was found between CO2 and acetazolamide for cerebrovascular reserve capacity. This correlation improved by considering cerebrovascular reserve per unit change in arterial carbon dioxide (r = 0.744, p < 0.001 in nonlesion hemisphere and r = 0.721, p < 0.001 in lesion hemisphere). The quantitative value of global reserve capacity was different by CO2 stimuli (5.2%) and acetazolamide (49.7%). Though a similar vasodilatory response is elicited by both vasodilators, acetazolamide seems to be more potent and therefore should be preferred to detect patients with exhausted cerebrovascular reserve capacity.
