Acetazolamide reduces exercise capacity following a 5-day ascent to 4559 m in a randomised study.

OBJECTIVE: To assess whether acetazolamide (Az), used prophylactically for acute mountain sickness (AMS), alters exercise capacity at high altitude. METHODS: Az (500 mg daily) or placebo was administered to 20 healthy adults (aged 36±20 years, range 21-77), who were paired for age, sex, AMS susceptibility and weight, in a double-blind, randomised manner. Participants ascended over 5 days to 4559 m, then exercised to exhaustion on a bicycle ergometer, while recording breath-by-breath gas measurements. Comparisons between groups and matched pairs were done via Mann-Whitney U and Pearson's χ2 tests, respectively. RESULTS: Comparing paired individuals at altitude, those on Az had greater reductions in maximum power output (Pmax) as a percentage of sea-level values (65±14.1 vs 76.6±7.4 (placebo); P=0.007), lower VO2max (20.7±5.2 vs 24.6±5.1 mL/kg/min; P<0.01), smaller changes from rest to Pmax for VO2 (9.8±6.2 vs 13.8±4.9 mL/kg/min; P=0.04) and lower heart rate at Pmax (154±25 vs 167±16, P<0.01) compared with their placebo-treated partners. Correlational analysis (Pearson's) indicated that with increasing age Pmax (r=-0.83: P<0.005) and heart rate at Pmax (r=-0.71, P=0.01) reduced more in those taking Az. CONCLUSION: Maximum exercise performance at altitude was reduced more in subjects taking Az compared with placebo, particularly in older individuals. The age-related effect may reflect higher tissue concentrations of Az due to reduced renal excretion. Future studies should explore the effectiveness of smaller Az doses (eg, 250 mg daily or less) in older individuals to optimise the altitude-Az-exercise relationships.

High-intensity intermittent exercise increases pulmonary interstitial edema at altitude but not at simulated altitude.

OBJECTIVE: Ascent to high altitude leads to a reduction in ambient pressure and a subsequent fall in available oxygen. The resulting hypoxia can lead to elevated pulmonary artery (PA) pressure, capillary stress, and an increase in interstitial fluid. This fluid can be assessed on lung ultrasound (LUS) by the presence of B-lines. We undertook a chamber and field study to assess the impact of high-intensity exercise in hypoxia on the development of pulmonary interstitial edema in healthy lowlanders. METHODS: Thirteen volunteers completed a high-intensity intermittent exercise (HIIE) test at sea level, in acute normobaric hypoxia (12% O2, approximately 4090 m equivalent altitude), and in hypobaric hypoxia during a field study at 4090 m after 6 days of acclimatization. Pulmonary interstitial edema was assessed by the evaluation of LUS B-lines. RESULTS: After HIIE, no increase in B-lines was seen in normoxia, and a small increase was seen in acute normobaric hypoxia (2 ± 2; P < .05). During the field study at 4090 m, 12 participants (92%) demonstrated 7 ± 4 B-lines at rest, which increased to 17 ± 5 immediately after the exercise test (P < .001). An increase was evident in all participants. There was a reciprocal fall in peripheral arterial oxygen saturations (Spo2) after exercise from 88% ± 4% to 80% ± 8% (P < .01). B-lines and Spo2 in all participants returned to baseline levels within 4 hours. CONCLUSIONS: HIIE led to an increase in B-lines at altitude after subacute exposure but not during acute exposure at equivalent simulated altitude. This may indicate pulmonary interstitial edema.

Exercise limitation of acetazolamide at altitude (3459 m).

OBJECTIVE: To assess the effect of acetazolamide (Az) on exercise performance during early acclimatization to altitude. METHODS: Az (250 mg twice daily) or placebo was administered for 3 days in a double-blind, randomized manner followed by a rapid ascent to 3459 m in the Italian Alps. Twenty healthy adults (age range, 18-67 years) were tested at 60% of sea-level peak power output for 15 minutes on a bicycle ergometer after 16 to 27 hours of altitude exposure. Exercise performance was measured in relation to peripheral oxygen saturations measured from pulse oximetry (Spo2), Lake Louise acute mountain sickness (AMS) score, and perceived difficulty. RESULTS: At altitude, resting Spo2 was higher in the Az group compared with placebo (P < .001). The highest AMS scores were in 4 of the placebo individuals with the lowest resting Spo2 (P < .05). During the exercise test, Spo2 fell in all but 1 subject (P < .001) and was reduced more in the Az group (P < .01). Four Az and 1 placebo subject were unable to complete the exercise test; 4 of these 5 had the largest fall in Spo2. The perception of exercise difficulty was higher in the Az subjects compared with those taking the placebo (P < .01). There was an age relationship with exercise limitation; 4 of the 9 older than 50 years failed to complete the test whereas only 1 of 11 younger than 50 years failed, and there were no failures in the 6 younger than 30 years (P < .05). CONCLUSIONS: In this study group, and despite higher resting Spo2, Az may have compromised exercise at 3459 m altitude during early acclimatization, particularly in older subjects.

Time course variations in the mechanisms by which cerebral oxygen delivery is maintained on exposure to hypoxia/altitude.

Normal cerebral function is dependent upon an adequate and continuous supply of oxygen. This study calculated cerebral blood flow based on assessment of the right middle cerebral artery (MCA) velocity (MCAVel) and MCA diameter (MCADiam) by trans-cranial Doppler and trans-cranial Duplex in normoxia, during acute exposure to 12% normobaric hypoxia for up to 6 hours, and after 3 days exposure to the equivalent altitude, 4392 m, in nine subjects. Mean (SD) MCAVel increased both after 6 hours hypoxia from 76.8 (11.4) to 97.2 (17.4) cms/sec (p<0.001), and after 3 days at altitude from 68.1 (7.5) [sea level] to 76.2 (10.2) [4392 m] (p=0.015). MCADiam increased from 5.07 (0.6) to 6.1 (0.6) mm (p<0.001) after 6 hours of 12% hypoxia. Calculated mean MCA blood flow increased after 6 hours of 12% hypoxia from 5.0 (0.6) mL/sec to 8.9 (1.2) mL/sec, but there was no difference between sea level and 4392 m. Calculated mean cerebral oxygen delivery increased from 72.4 (14.4) to 107 (20.1) mL/sec (p<0.001) after 6 hours of 12% hypoxia and was maintained unchanged at 4392 m. An increase in MCA caliber, rather than blood velocity, was a major contributor to increased oxygen delivery accompanying within the first few hours of exposure to acute hypoxia. During more long-term exposure, increases in MCA velocity and a rise in hemoglobin appeared to be the more important mechanisms in maintaining cerebral oxygen delivery. The implication of this observed change in MCA diameter questions the widely held assumption that MCA velocity is a surrogate for flow during acute hypoxic exposure.

Do changes in gastro-intestinal blood flow explain high-altitude anorexia?

BACKGROUND: Gastrointestinal symptoms are common on acute exposure to high-altitude (HA). Underlying mechanisms are not understood, but vascular shunting away from the gut could be responsible. Therefore, blood flow in the superior mesenteric artery (SMA) and hepatic portal vein (HPV) was examined at sea level (SL) and after ascent to 4392 m (HA). MATERIALS AND METHODS: Twelve subjects [eight male, mean age 40 (22-72) years] were studied following an overnight fast and a standard meal. Cross-sectional vessel area and blood velocity were measured by ultrasound, systolic and diastolic flow calculated for the SMA (HR x vessel area x velocity, cm(3) min(-1)) and mean flow for the HPV. RESULTS: All subjects experienced reduced appetite at HA. Blood flow in the SMA and HPV increased following food at SL (mean SMA systolic flow 1024 vs. 3316 cm(3) min(-1), P < 0.001; HPV 505 vs. 1789, P < 0.001) and at HA (2020 vs. 3767, P < 0.001; HPV 708 vs. 1727, P < 0.001). Pre-prandial flow in the SMA and HPV was significantly increased at HA compared with SL. The changes were due to increased vessel diameter and increased flow velocity. There was no difference in post-prandial flow between SL and HA in the HPV, although the increase in post-prandial flow was greater at SL than HA (254% increase vs. 144%). CONCLUSIONS: These results show that resting blood flow in the gastrointestinal tract is increased during exposure to high-altitude hypoxia, and that the vascular response of increased blood flow following food ingestion is maintained. Therefore, reduced flow is unlikely to cause gastrointestinal symptoms and reduced appetite at HA.

Intrapulmonary and intracardiac shunting with exercise at altitude.

Recent studies in normal participants have shown that right to left shunt blood vessels in the lung open up during exercise. We describe the first field study to investigate this phenomenon at altitude. This study aimed to assess the effect of altitude and partial acclimatization on inducible right to left shunting at rest and with exercise. A contrast-enhanced transcranial Doppler imaging technique to detect microbubbles after injection of blood and saline agitated with air was used to measure right to left shunting in 10 normal participants at rest and immediately after exercising to maximum oxygen consumption (VO(2max)) at 80 m, on acute exposure to 3450 m, and finally after a week above 3450 m. At 80 m, exercising resulted in right to left shunting via patent foramen ovale in 2 participants, but there was no evidence of shunting in the remaining 8 participants. Cerebral microbubbles were detected at rest in the 2 participants with patent foramen ovale on acute exposure to 3450 m, and the shunting increased on exercise (P = .04). In 5 of the remaining 8 participants without patent foramen ovale, cerebral microbubbles were detected on exercise (P = .04) but not at rest. Partial acclimatization had minimal effect on the prevalence or magnitude of the intrapulmonary or intracardiac shunts. Oxygenation was similar in those with shunts compared with those without shunts. Intrapulmonary shunting occurs on exercise at altitude, but the clinical and physiologic significances have yet to be determined. Despite the occurrence of shunting in most participants, our results suggest that this phenomenon is not a significant factor in altitude and exercise-induced hypoxia.

Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73.

The UK Prospective Diabetes Study (UKPDS) showed that a more intensive glucose control policy reduced risk of diabetic complications. As hypoglycemia is a barrier to achieving glycemic targets, we examined its occurrence and contributing factors in UKPDS patients randomized to and remaining for 6 years on diet, sulfonylurea, metformin (overweight subjects only), or insulin monotherapy from diagnosis of Type 2 diabetes. Self-reported hypoglycemic episodes were categorized as (1) transient, (2) temporarily incapacitated, (3) requiring third-party assistance, and (4) requiring medical attention, recording the most severe episode each quarter. Proportions of patients reporting at least one episode per year were calculated in relation to therapy, HbA(1c), and clinical characteristics. In 5063 patients aged 25-65 years, only 2.5% per year reported substantive hypoglycemia (Grades 2-4) and 0.55% major hypoglycemia (Grade 3 or 4). Hypoglycemia was more frequent in younger (4.0% <45 years vs. 2.2% >or=45 years), female (3.0% vs. 2.2% male), normal weight (3.6% body mass index <25 kg/m(2) vs. 1.9% >or=25 kg/m(2)), less hyperglycemic (5.2% HbA(1c) <7% vs. 2.3% >or=7%), or islet autoantibody-positive patients (4.3% vs. 2.1% negative) (all P<.0001). More on basal insulin reported hypoglycemia (3.8% per year) than diet (0.1%), sulfonylurea (1.2%), or metformin (0.3%) therapy, but less than on basal and prandial insulin (5.3%) (all P<.0001). Low hypoglycemia rates seen during the first 6 years of intensive glucose lowering therapy in Type 2 diabetes are unlikely to have a major impact on attempts to achieve guideline glycemic targets when sulfonylurea, metformin, or insulin are used as monotherapy.

Medicine at high altitude.

Medicine at high altitude provides important insights into the acute and chronic effects of hypoxia. Acute mountain sickness (AMS) is a common syndrome occurring after acute ascent to over 2,500 m and is caused by increased capillary permeability. A number of factors have been identified that increase the risk of AMS, in particular exercise. Avoiding rapid ascent, undue exercise and the use of acetazolamide are useful preventative measures but severe symptoms may require oxygen, dexamethasone and descent. Acute mountain sickness is usually self-limiting but may progress into the serious syndromes of pulmonary and cerebral oedema. Acclimatisation and adaptation are important for workers and residents at high altitude and the improvement seen in maximum exercise has been incorporated into some training schedules for endurance athletes. Chronic and subacute high-altitude diseases largely result from polycythemia and pulmonary hypertension.

The sharpened Romberg test for assessing ataxia in mild acute mountain sickness.

OBJECTIVE: To evaluate the Sharpened Romberg Test (SRT) as a measure of ataxia in subjects with mild acute mountain sickness in order to determine its sensitivity and specificity. METHODS: The SRT was performed in 23 subjects during ascent to 5260 m. RESULTS: The SRT was more often abnormal than the traditional heel-to-toe test, and at the highest altitude it was related to higher median Lake Louise symptom scores with predictive values of 60% sensitivity and 89% specificity. Our evaluation of the SRT appears to agree with similar studies on ataxia showing a lack of correlation between ataxia and symptoms of acute mountain sickness at altitudes below 5260 m. CONCLUSION: The SRT was easy to perform and provided a quantitative assessment of truncal ataxia in the field without the need for specialized equipment.

Medroxyprogesterone at high altitude. The effects on blood gases, cerebral regional oxygenation, and acute mountain sickness.

OBJECTIVE: To study the effect of medroxyprogesterone on blood gases and cerebral regional oxygenation at high altitude, alone and in conjunction with acetazolamide, and to assess the effect on acute mountain sickness (AMS). DESIGN: Two placebo-controlled trials during rapid ascent to high altitude. PARTICIPANTS: In the first trial, 20 participants, and in the second trial, 24 participants. SETTING: During rapid ascent to 4680 m and on rapid ascent to 5200 m. INTERVENTION: In the first trial, participants were randomized to receive medroxyprogesterone 30 mg or a placebo twice a day. In the second trial, participants were randomly assigned to one of 4 groups: a placebo twice daily, medroxyprogesterone 30 mg twice daily, acetazolamide 250 mg plus a placebo twice daily, or acetazolamide 250 mg plus medroxyprogesterone 30 mg twice daily. MAIN OUTCOME MEASURES: Blood gas changes and symptom scores of AMS in both trials and cerebral regional oxygen saturations in the first trial only. RESULTS: Medroxyprogesterone improved peripheral oxygen saturations in both trials and improved PaO2 in combination with acetazolamide. Cerebral regional oxygen saturation was not altered by medroxyprogesterone. The reduction in symptom scores and in the extent of AMS was not significant in this limited study. CONCLUSIONS: Medroxyprogesterone acts as a respiratory stimulant, but the clinical benefit regarding the development of AMS was unproven at high altitude. Combined medroxyprogesterone and acetazolamide gave the best PaO2.