Effects of dietary nitrate supplementation on microvascular physiology at 4559 m altitude - A randomised controlled trial (Xtreme Alps).

Native highlanders (e.g. Sherpa) demonstrate remarkable hypoxic tolerance, possibly secondary to higher levels of circulating nitric oxide (NO) and increased microcirculatory blood flow. As part of the Xtreme Alps study (a randomised placebo-controlled trial of dietary nitrate supplementation under field conditions of hypobaric hypoxia), we investigated whether dietary supplementation with nitrate could improve NO availability and microvascular blood flow in lowlanders. Plasma measurements of nitrate, nitrite and nitroso species were performed together with measurements of sublingual (sidestream dark-field camera) and forearm blood flow (venous occlusion plethysmography) in 28 healthy adult volunteers resident at 4559 m for 1 week; half receiving a beetroot-based high-nitrate supplement and half receiving an identically-tasting low nitrate 'placebo'. Dietary supplementation increased plasma nitrate concentrations 4-fold compared to the placebo group, both at sea level (SL; 19.2 vs 76.9 µM) and at day 5 (D5) of high altitude (22.9 vs 84.3 µM, p < 0.001). Dietary nitrate supplementation also significantly increased both plasma nitrite (0.78 vs. 0.86 µM SL, 0.31 vs. 0.41 µM D5, p = 0.03) and total nitroso product (11.3 vs. 19.7 nM SL, 9.7 vs. 12.3 nM D5, p < 0.001) levels both at sea level and at 4559 m. However, plasma nitrite concentrations were more than 50% lower at 4559 m compared to sea level in both treatment groups. Despite these significant changes, dietary nitrate supplementation had no effect on any measured read-outs of sublingual or forearm blood flow, even when environmental hypoxia was experimentally reversed using supplemental oxygen. In conclusion, dietary nitrate supplementation does not improve microcirculatory function at 4559 m.

Sustained vasomotor control of skin microcirculation in Sherpas versus altitude-naive lowlanders: Experimental evidence from Xtreme Everest 2.

NEW FINDINGS: What is the central question of this study? Do Sherpa highlanders, when exposed to graded hypobaric hypoxia, exhibit enhanced vasomotor and neurovascular control to maintain microcirculatory flux, and thus tissue oxygenation, when compared with altitude-naive lowlanders? What is the main finding and its importance? Sherpas, when exposed to hypobaric hypoxia at high altitude, demonstrated superior preservation of their peripheral microcirculatory perfusion, a greater oxygen unloading rate and sustained microvascular reactivity with enhanced vasomotion, when compared with altitude-naive lowlanders. These differences have not been reported previously and may improve our understanding of the multifactorial responses to sustained environmental hypoxia. ABSTRACT: Enhanced oxygen delivery, consequent to an increased microvascular perfusion, has been postulated to play a key role in the physiological adaptation of Tibetan highlanders to the hypobaric hypoxia encountered at high altitude. We tested the hypothesis that Sherpas, when exposed to graded hypobaric hypoxia, demonstrate enhanced vasomotor and neurovascular control to maintain microcirculatory flux, and thus tissue oxygenation, when compared with altitude-naive lowlanders. Eighty-three lowlanders [39 men and 44 women, 38.8 (13.1) years old; mean (SD)] and 61 Sherpas [28 men and 33 women, 27.9 (6.9) years old] were studied on ascent to Everest Base Camp over 11 days. Skin blood flux and tissue oxygen saturation were measured simultaneously using combined laser Doppler fluximetry and white light spectroscopy at baseline, 3500 and 5300 m. In both cohorts, ascent resulted in a decline in the sympathetically mediated microvascular constrictor response (P < 0.001), which was more marked in lowlanders than in Sherpas (P < 0.001). The microvascular dilator response evaluated by postocclusive reactive hyperaemia was significantly greater in Sherpas than in lowlanders at all sites (P < 0.002). Spectral analysis of the blood flux signals revealed enhanced myogenic (vasomotion) activity in Sherpas, which was unaffected by ascent to 5300 m. Although skin tissue oxygenation was lower in Sherpas than in lowlanders, the oxygen unloading rate was faster, and deoxyhaemoglobin levels higher, at all altitudes. Together, these data suggest that Sherpas, when exposed to hypobaric hypoxia, demonstrated superior preservation of peripheral microcirculatory perfusion compared with altitude-naive lowlanders. The physiological differences in local microvasculature vasomotor and neurovascular control may play a key role in Sherpa adaptation to high-altitude hypobaric hypoxia by sustaining local perfusion and tissue oxygenation.

Effects of dietary nitrate on respiratory physiology at high altitude - Results from the Xtreme Alps study.

Nitric oxide (NO) production plays a central role in conferring tolerance to hypoxia. Tibetan highlanders, successful high-altitude dwellers for millennia, have higher circulating nitrate and exhaled NO (ENO) levels than native lowlanders. Since nitrate itself can reduce the oxygen cost of exercise in normoxia it may confer additional benefits at high altitude. Xtreme Alps was a double-blinded randomised placebo-controlled trial to investigate how dietary nitrate supplementation affects physiological responses to hypoxia in 28 healthy adult volunteers resident at 4559 m for 1 week; 14 receiving a beetroot-based high-nitrate supplement and 14 receiving a low-nitrate 'placebo' of matching appearance/taste. ENO, vital signs and acute mountain sickness (AMS) severity were recorded at sea level (SL) and daily at altitude. Moreover, standard spirometric values were recorded, and saliva and exhaled breath condensate (EBC) collected. There was no significant difference in resting cardiorespiratory variables, peripheral oxygen saturation or AMS score with nitrate supplementation at SL or altitude. Median ENO levels increased from 1.5/3.0  mPa at SL, to 3.5/7.4 mPa after 5 days at altitude (D5) in the low and high-nitrate groups, respectively (p = 0.02). EBC nitrite also rose significantly with dietary nitrate (p = 0.004), 1.7-5.1  µM at SL and 1.6-6.3 µM at D5, and this rise appeared to be associated with increased levels of ENO. However, no significant changes occurred to levels of EBC nitrate or nitrosation products (RXNO). Median salivary nitrite/nitrate concentrations increased from 56.5/786 µM to 333/5,194  µM  with nitrate supplementation at SL, and changed to 85.6/641 µM and 341/4,553 µM on D5. Salivary RXNO rose markedly with treatment at SL from 0.55 µM to 5.70 µM. At D5 placebo salivary RXNO had increased to 1.90 µM whilst treatment RXNO decreased to 3.26 µM. There was no association with changes in any observation variables or AMS score. In conclusion, dietary nitrate supplementation is well tolerated at altitude and significantly increases pulmonary NO availability and both salivary and EBC NO metabolite concentrations. Surprisingly, this is not associated with changes in hemodynamics, oxygen saturation or AMS development.

Dietary Nitrate Supplementation Does Not Alter Exercise Efficiency at High Altitude - Further Results From the Xtreme Alps Study.

Introduction: Nitrate supplementation in the form of beetroot juice (BRJ) ingestion has been shown to improve exercise tolerance during acute hypoxia, but its effect on exercise physiology remains unstudied during sustained terrestrial high altitude exposure. We hypothesized that performing exercise at high altitude would lower circulating nitrate and nitrite levels and that BRJ ingestion would reverse this phenomenon while concomitantly improving key determinants of aerobic exercise performance. Methods: Twenty seven healthy volunteers (21 male) underwent a series of exercise tests at sea level (SL, London, 75 m) and again after 5-8 days at high altitude (HA, Capanna Regina Margherita or "Margherita Hut," 4,559 m). Using a double-blind protocol, participants were randomized to consume a beetroot/fruit juice beverage (three doses per day) with high levels of nitrate (∼0.18 mmol/kg/day) or a nitrate-depleted placebo (∼11.5 µmoles/kg/day) control drink, from 3 days prior to the exercise trials until completion. Submaximal constant work rate cycle tests were performed to determine exercise efficiency and a maximal incremental ramp exercise test was undertaken to measure aerobic capacity, using breath-by-breath pulmonary gas exchange measurements throughout. Concentrations of nitrate, nitrite and nitrosation products were quantified in plasma samples collected at 5 timepoints during the constant work rate tests. Linear mixed modeling was used to analyze data. Results: At both SL and HA, plasma nitrate concentrations were elevated in the nitrate supplementation group compared to placebo (P < 0.001) but did not change throughout increasing exercise work rate. Delta exercise efficiency was not altered by altitude exposure (P = 0.072) or nitrate supplementation (P = 0.836). V̇O2peak decreased by 24% at high altitude (P < 0.001) and was lower in the nitrate-supplemented group at both sea level and high altitude compared to placebo (P = 0.041). Dietary nitrate supplementation did not alter other peak exercise variables or oxygen consumption at anaerobic threshold. Circulating nitrite and S-nitrosothiol levels unexpectedly rose in a few individuals right after cessation of exercise at high altitude. Conclusion: Whilst regularly consumed during an 8 days expedition to terrestrial high altitude, nitrate supplementation did not alter exercise efficiency and other exercise physiological variables, except decreasing V̇O2peak. These results and those of others question the practical utility of BRJ consumption during prolonged altitude exposure.

Cardiopulmonary exercise testing for the evaluation of perioperative risk in non-cardiopulmonary surgery.

The use of cardiopulmonary exercise testing (CPET) as a preoperative risk stratification tool for a range of non-cardiopulmonary surgery is increasing. The utility of CPET in this role is dependent on the technology being able to identify accurately and reliably those patients at increased risk of perioperative events when compared with existing risk stratification tools. This article identifies and reviews systematically the current literature regarding the use of CPET as a preoperative tool for stratifying risk in major non-cardiopulmonary surgery. Specifically, it focuses on evaluating the capacity of CPET variables to predict the risk of postoperative complications and mortality in comparison to other methods of risk assessment. Furthermore, the potential for combining results from CPET and non-CPET methods of risk prediction to enhance the capacity to identify high risk patients is considered. The review indicates that CPET can identify patients at increased risk of adverse perioperative outcomes. However, the selection of variables and threshold values to indicate high risk differ for different surgical procedures and underlying conditions. Furthermore, the available data suggest that CPET variables outperform alternative methods of preoperative risk stratification. Several studies also identify that CPET variables may be used in combination with non-CPET variables to increase perioperative risk prediction accuracy. These findings illustrate that CPET has the capacity to identify patients at increased risk of adverse outcome before a range of non-cardiopulmonary surgical procedures. Further research is required to optimise its use, potentially by combining CPET results with alternative methods of risk stratification.

Triage of intensive care patients: identifying agreement and controversy.

RATIONALE: Intensive care unit (ICU) resources are limited in many hospitals. Patients with little likelihood of surviving are often admitted to ICUs. Others who might benefit from ICU are not admitted. OBJECTIVE: To provide an updated consensus statement on the principles and recommendations for the triage of patients for ICU beds. DESIGN: The previous Society of Critical Care Medicine (SCCM) consensus statement was used to develop drafts of general and specific principles and recommendations. Investigators and consultants were sent the statements and responded with their agreement or disagreement. SETTING: The Eldicus project (triage decision making for the elderly in European intensive care units). PARTICIPANTS: Eldicus investigators, consultants, and experts consisting of intensivists, users of ICU services, ethicists, administrators, and public policy officials. INTERVENTIONS: Consensus development was used to grade the statements and recommendations. MEASUREMENTS AND MAIN RESULTS: Consensus was defined as 80% agreement or more. Consensus was obtained for 54 (87%) of 62 statements including all (19) general principles, 31 (86%) of the specific principles, and 10 (71%) of the recommendations. Inconsistencies in responses were noted for ICU admission and discharge. Despite agreement for guidelines applying to individual patients and an objective triage score, there was no agreement for a survival cutoff for triage, not even for a chance of survival of 0.1%. CONCLUSIONS: Consensus was reached for most general and specific ICU triage principles and recommendations. Further debate and discussion should help resolve the remaining discrepancies.

Design and conduct of 'Xtreme Alps': a double-blind, randomised controlled study of the effects of dietary nitrate supplementation on acclimatisation to high altitude.

The study of healthy human volunteers ascending to high altitude provides a robust model of the complex physiological interplay that emulates human adaptation to hypoxaemia in clinical conditions. Nitric oxide (NO) metabolism may play an important role in both adaptation to high altitude and response to hypoxaemia during critical illness at sea level. Circulating nitrate and nitrite concentrations can be augmented by dietary supplementation and this is associated with improved exercise performance and mitochondrial efficiency. We hypothesised that the administration of a dietary substance (beetroot juice) rich in nitrate would improve oxygen efficiency during exercise at high altitude by enhancing tissue microcirculatory blood flow and oxygenation. Furthermore, nitrate supplementation would lead to measurable increases in NO bioactivity throughout the body. This methodological manuscript describes the design and conduct of the 'Xtreme Alps' expedition, a double-blind randomised controlled trial investigating the effects of dietary nitrate supplementation on acclimatisation to hypobaric hypoxia at high altitude in healthy human volunteers. The primary outcome measure was the change in oxygen efficiency during exercise at high altitude between participants allocated to receive nitrate supplementation and those receiving a placebo. A number of secondary measures were recorded, including exercise capacity, peripheral and microcirculatory blood flow and tissue oxygenation. Results from this study will further elucidate the role of NO in adaption to hypoxaemia and guide clinical trials in critically ill patients. Improved understanding of hypoxaemia in critical illness may provide new therapeutic avenues for interventions that will improve survival in critically ill patients.