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.

Physiological responses during ascent to high altitude and the incidence of acute mountain sickness.

Acute mountain sickness (AMS) occurs when there is failure of acclimatisation to high altitude. The aim of this study was to describe the relationship between physiological variables and the incidence of AMS during ascent to 5300 m. A total of 332 lowland-dwelling volunteers followed an identical ascent profile on staggered treks. Self-reported symptoms of AMS were recorded daily using the Lake Louise score (mild 3-4; moderate-severe ≥5), alongside measurements of physiological variables (heart rate, respiratory rate (RR), peripheral oxygen saturation (SpO2 ) and blood pressure) before and after a standardised Xtreme Everest Step-Test (XEST). The overall occurrence of AMS among participants was 73.5% (23.2% mild, 50.3% moderate-severe). There was no difference in gender, age, previous AMS, weight or body mass index between participants who developed AMS and those who did not. Participants who had not previously ascended >5000 m were more likely to get moderate-to-severe AMS. Participants who suffered moderate-to-severe AMS had a lower resting SpO2 at 3500 m (88.5 vs. 89.6%, p = 0.02), while participants who suffered mild or moderate-to-severe AMS had a lower end-exercise SpO2 at 3500 m (82.2 vs. 83.8%, p = 0.027; 81.5 vs. 83.8%, p < 0.001 respectively). Participants who experienced mild AMS had lower end-exercise RR at 3500 m (19.2 vs. 21.3, p = 0.017). In a multi-variable regression model, only lower end-exercise SpO2 (OR 0.870, p < 0.001) and no previous exposure to altitude >5000 m (OR 2.740, p-value 0.003) predicted the development of moderate-to-severe AMS. The Xtreme Everest Step-Test offers a simple, reproducible field test to help predict AMS, albeit with relatively limited predictive precision.

A comparison of the quality of image acquisition between two different sidestream dark field video-microscopes.

Sidestream dark field (SDF) imaging enables direct visualisation of the microvasculature from which quantification of key variables is possible. The new MicroScan USB3 (MS-U) video-microscope is a hand-held SDF device that has undergone significant technical upgrades from its predecessor, the MicroScan Analogue (MS-A). The MS-U claims superior quality of sublingual microcirculatory image acquisition over the MS-A, however, this has yet to be robustly confirmed. In this manuscript, we therefore compare the quality of image acquisition between these two devices. The microcirculation of healthy volunteers was visualised to generate thirty video images for each device. Two independent raters, blinded to the device type, graded the quality of the images according to the six different traits in the Microcirculation Image Quality Score (MIQS) system. Chi-squared tests and Kappa statistics were used to compare not only the distribution of scores between the devices, but also agreement between raters. MS-U showed superior image quality over MS-A in three of out six MIQS traits; MS-U had significantly more optimal images by illumination (MS-U 95% optimal images, MS-A 70% optimal images (p-value 0.003)), by focus (MS-U 70% optimal images, MS-A 35% optimal images (p-value 0.002)) and by pressure (MS-U 72.5% optimal images, MS-A 47.5% optimal images (p-value 0.02)). For each trait, there was at least 85% agreement between the raters, and all the scores for each trait were independent of the rater (all p-values > 0.05). These results show that the new MS-U provides a superior quality of sublingual microcirculatory image acquisition when compared to old MS-A.

An introduction to mechanical circulatory support in cardiac intensive care.

While use of mechanical circulatory support is increasing, knowledge of its fundamental role and limitations remains poorly understood by many medical professionals. This article summarises the main types of mechanical circulatory support and how they work, particularly focusing on the key information medical professionals should know should they encounter them in hospital. Mechanical circulatory support can be an effective treatment modality in selected pathologies, including myocardial ischaemia, pulmonary congestion, massive pulmonary embolic disease, postcardiotomy cardiogenic shock with failure to wean off bypass, right ventricular failure, bridge to heart and lung transplant and, increasingly, extracorporeal cardiopulmonary resuscitation. Intra-aortic balloon pumps increase coronary perfusion and reduce myocardial oxygen demand in a variety of cardiac conditions. Extracorporeal membrane oxygenation can provide both respiratory and circulatory support to patients. Ventricular assist devices can provide support for not only patients with acute cardiogenic shock, but also for ambulant patients in the community setting.

Cannulation of the subclavian vein using real-time ultrasound guidance.

Cannulation of the subclavian vein has many advantages when compared to other anatomical sites for central venous access. Difficulty in its ultrasonic visualisation, and the perceived consequent 'higher' complication rate, mean that this approach has fallen out of favour. This barrier, however, may now have disappeared. In this article, we discuss the indications, contraindications and complications associated with subclavian vein cannulation, and present an ultrasound-guided approach to infraclavicular subclavian cannulation.

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.

Observational study of the microcirculation in patients with liver cirrhosis.

BACKGROUND AND AIM: Liver cirrhosis is associated with widespread microcirculatory dysfunction and hemodynamic derangement, which may play a role in the pathogenesis of multiple organ failure. Little is known, however, about the progression of microvascular alterations as the severity of liver disease worsens. Therefore, our aim is to quantify the peripheral systemic microcirculatory changes associated with increasing severity of liver cirrhosis. METHODS: Forty patients with liver cirrhosis were studied and divided into groups based on Child-Pugh classes A (n = 9), B (n = 18), and C (n = 13) for comparison. Incident dark field imaging was used to evaluate the sublingual microcirculation and near-infrared spectroscopy at the thenar eminence to assess microvascular reactivity and function. RESULTS: There was no difference in microcirculatory flow index (P = 0.655), heterogeneity index (P = 0.702), or vessel density (P = 0.923) between the different Child-Pugh groups. Microvascular reactivity did not change as the severity of liver disease worsened. CONCLUSIONS: This study showed no association between peripheral systemic microcirculatory alterations and the severity of liver disease. Further research with larger study cohorts are needed to clarify the relationship between microcirculatory abnormalities and disease progression and to establish if the peripheral microcirculation is affected by the pathophysiology of worsening cirrhosis.

The effect of normobaric hypoxic exposure on coagulation as measured by thromboelastography.

INTRODUCTION: The physiological impact of hypoxia on coagulation has significant importance in the clinical setting, but it is not yet fully understood. Various static methods exist to investigate the process of coagulation, however, thromboelastography (TEG) provides a dynamic assessment of clot formation that can be quantitatively assessed. METHOD: Twenty-five participants were exposed to normobaric hypoxia (12.5% oxygen) for 8 h. Venous blood was taken from the participants directly pre- and post-hypoxic exposure, and coagulation was tested using TEG. Coagulation variables assessed included reaction time, split point, alpha angle, kinetics and maximum amplitude. RESULTS: Time taken for clot initiation, (assessed using the split point and reaction time) was significantly reduced after 8 h of hypoxic exposure. The split point reduced from a mean of 5.20 to 4.23 min (p = 0.022), whilst the reaction time reduced from 6.09 to 4.94 min (p = 0.004). Maximum amplitude, alpha angle and kinetics did not change significantly after hypoxic exposure. CONCLUSION: The results demonstrate that subacute normobaric hypoxic exposure increases the tendency for whole blood to coagulate, as demonstrated by a reduced split and reaction time using TEG.

Enhanced flow-motion complexity of skin microvascular perfusion in Sherpas and lowlanders during ascent to high altitude.

An increased and more effective microvascular perfusion is postulated to play a key role in the physiological adaptation of Sherpa highlanders to the hypobaric hypoxia encountered at high altitude. To investigate this, we used Lempel-Ziv complexity (LZC) analysis to explore the spatiotemporal dynamics of the variability of the skin microvascular blood flux (BF) signals measured at the forearm and finger, in 32 lowlanders (LL) and 46 Sherpa highlanders (SH) during the Xtreme Everest 2 expedition. Measurements were made at baseline (BL) (LL: London 35 m; SH: Kathmandu 1300 m) and at Everest base camp (LL and SH: EBC 5,300 m). We found that BF signal content increased with ascent to EBC in both SH and LL. At both altitudes, LZC of the BF signals was significantly higher in SH, and was related to local slow-wave flow-motion activity over multiple spatial and temporal scales. In SH, BF LZC was also positively associated with LZC of the simultaneously measured tissue oxygenation signals. These data provide robust mechanistic information of microvascular network functionality and flexibility during hypoxic exposure on ascent to high altitude. They demonstrate the importance of a sustained heterogeneity of network perfusion, associated with local vaso-control mechanisms, to effective tissue oxygenation during hypobaric hypoxia.

Renal replacement therapy for acute kidney injury in intensive care.

Acute kidney injury is a common occurrence on the intensive care unit and is associated with incremental risk of death and chronic kidney disease. Renal replacement therapy has become an essential tool in the intensive care management of patients with severe acute kidney injury and its use is rising. A basic understanding of renal replacement therapy is essential for all doctors treating acutely unwell patients. This article provides a brief overview of the principles and important considerations for the provision of renal replacement therapy for critically ill patients with acute kidney injury.

The Smell of Hypoxia: using an electronic nose at altitude and proof of concept of its role in the prediction and diagnosis of acute mountain sickness.

Electronic nose (e-nose) devices may be used to identify volatile organic compounds (VOCs) in exhaled breath. VOCs generated via metabolic processes are candidate biomarkers of (patho)physiological pathways. We explored the feasibility of using an e-nose to generate human "breathprints" at high altitude. Furthermore, we explored the hypothesis that pathophysiological processes involved in the development of acute mountain sickness (AMS) would manifest as altered VOC profiles. Breath analysis was performed on Sherpa and lowlander trekkers at high altitude (3500 m). The Lake Louise Scoring (LLS) system was used to diagnose AMS. Raw data were reduced by principal component (PC) analysis (PCA). Cross validated linear discriminant analysis (CV-LDA) and receiver-operating characteristic area under curve (ROC-AUC) assessed discriminative function. Breathprints suitable for analysis were obtained from 58% (37/64) of samples. PCA showed significant differences between breathprints from participants with, and without, AMS; CV-LDA showed correct classification of 83.8%, ROC-AUC 0.86; PC 1 correlated with AMS severity. There were significant differences between breathprints of participants who remained AMS negative and those whom later developed AMS (CV-LDA 68.8%, ROC-AUC 0.76). PCA demonstrated discrimination between Sherpas and lowlanders (CV-LDA 89.2%, ROC-AUC 0.936). This study demonstrated the feasibility of breath analysis for VOCs using an e-nose at high altitude. Furthermore, it provided proof-of-concept data supporting e-nose utility as an objective tool in the prediction and diagnosis of AMS. E-nose technology may have substantial utility both in altitude medicine and under other circumstances where (mal)adaptation to hypoxia may be important (e.g., critically ill patients).

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.

Severe Postpartum Headache and Hypertension Caused by Reversible Cerebral Vasoconstriction Syndrome: A Case Report.

Reversible cerebrovascular vasoconstriction syndrome is an uncommon condition that presents as severe headache and hypertension. Recent literature suggests a 1% incidence in postpartum headache cases. It can cause subarachnoid hemorrhages, cerebral ischemia, and seizures. It is often misdiagnosed as postdural puncture headache or preeclampsia. In this case, a postpartum woman, who had received epidural anesthesia for labor, presented 5 days postpartum with severe headache that did not resolve with an epidural blood patch. She then became more hypertensive and suffered a grand mal seizure. When treatment for eclampsia failed to resolve her symptoms, magnetic resonance angiography was performed. It demonstrated the pathognomic signs of reversible cerebrovascular vasoconstriction syndrome. Her symptoms resolved with nimodipine.

Cardiovascular assessment for non-cardiac surgery: European guidelines.

In 2014, a joint task force involving the European Society of Cardiology and European Society of Anaesthesiology assembled 'Guidelines on non-cardiac surgery: cardiovascular assessment and management'. The guidelines, subsequently published in the European Heart Journal, are intended for physicians and collaborators involved in the perioperative care of patients undergoing non-cardiac surgery, in whom heart disease is a potential source of complications. While the guidelines are an extremely relevant and useful aid for most, if not all, medics within the hospital environment, the sheer size of the document (49 pages) renders it a feat to read and digest. Given the importance of the document for optimizing patient care, this article condenses the guidelines down to help highlight the important details.

Metabolic basis to Sherpa altitude adaptation.

The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature.

Sublingual microcirculatory blood flow and vessel density in Sherpas at high altitude.

Anecdotal reports suggest that Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitude, despite exhibiting lower arterial oxygen content than acclimatized lowlanders. This study tested the hypothesis that Sherpas exposed to hypobaric hypoxia on ascent to 5,300 m develop increased microcirculatory blood flow as a means of maintaining tissue oxygen delivery. Incident dark-field imaging was used to obtain images of the sublingual microcirculation from 64 Sherpas and 69 lowlanders. Serial measurements were obtained from participants undertaking an ascent from baseline testing (35 m or 1,300 m) to Everest base camp (5,300 m) and following subsequent descent in Kathmandu (1,300 m). Microcirculatory flow index and heterogeneity index were used to provide indexes of microcirculatory flow, while capillary density was assessed using small vessel density. Sherpas demonstrated significantly greater microcirculatory blood flow at Everest base camp, but not at baseline testing or on return in Kathmandu, than lowlanders. Additionally, blood flow exhibited greater homogeneity at 5,300 and 1,300 m (descent) in Sherpas than lowlanders. Sublingual small vessel density was not different between the two cohorts at baseline testing or at 1,300 m; however, at 5,300 m, capillary density was up to 30% greater in Sherpas. These data suggest that Sherpas can maintain a significantly greater microcirculatory flow per unit time and flow per unit volume of tissue at high altitude than lowlanders. These findings support the notion that peripheral vascular factors at the microcirculatory level may be important in the process of adaptation to hypoxia.NEW & NOTEWORTHY Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitude, yet the physiological mechanisms underlying this tolerance remain unknown. In our prospective study, conducted on healthy volunteers ascending to Everest base camp (5,300 m), we demonstrated that Sherpas have a higher sublingual microcirculatory blood flow and greater capillary density at high altitude than lowlanders. These findings support the notion that the peripheral microcirculation plays a key role in the process of long-term adaptation to hypoxia.