Asymmetric and symmetric dimethylarginine in high altitude pulmonary hypertension (HAPH) and high altitude pulmonary edema (HAPE).

Introduction: High altitude exposure may lead to high altitude pulmonary hypertension (HAPH) and high altitude pulmonary edema (HAPE). The pathophysiologic processes of both entities have been linked to decreased nitric oxide (NO) availability. Methods: We studied the effect of acute high altitude exposure on the plasma concentrations of asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-arginine, L-ornithine, and L-citrulline in two independent studies. We further investigated whether these biomarkers involved in NO metabolism were related to HAPH and HAPE, respectively. Fifty (study A) and thirteen (study B) non-acclimatized lowlanders were exposed to 4,559 m for 44 and 67 h, respectively. In contrast to study A, the participants in study B were characterized by a history of at least one episode of HAPE. Arterial blood gases and biomarker concentrations in venous plasma were assessed at low altitude (baseline) and repeatedly at high altitude. HAPE was diagnosed by chest radiography, and HAPH by measuring right ventricular to atrial pressure gradient (RVPG) with transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and the AMS-C score. Results: In both studies SDMA concentration significantly increased at high altitude. ADMA baseline concentrations were higher in individuals with HAPE susceptibility (study B) compared to those without (study A). However, upon high altitude exposure ADMA only increased in individuals without HAPE susceptibility, while there was no further increase in those with HAPE susceptibility. We observed an acute and transient decrease of L-ornithine and a more delayed but prolonged reduction of L-citrulline during high altitude exposure. In both studies SDMA positively correlated and L-ornithine negatively correlated with RVPG. ADMA was significantly associated with the occurrence of HAPE (study B). ADMA and SDMA were inversely correlated with alveolar PO2, while L-ornithine was inversely correlated with blood oxygenation and haemoglobin levels, respectively. Discussion: In non-acclimatized individuals ADMA and SDMA, two biomarkers decreasing endothelial NO production, increased after acute exposure to 4,559 m. The observed biomarker changes suggest that both NO synthesis and arginase pathways are involved in the pathophysiology of HAPH and HAPE.

Serum neurofilament level increases after ascent to 4559 m but is not related to acute mountain sickness.

BACKGROUND AND PURPOSE: At high altitude the brain is exposed to hypoxic stress, which may result in neurological conditions, with acute mountain sickness (AMS) being the most common. We aimed to test the hypothesis that rapid ascent to high altitude alters neuro-axonal integrity, which can be detected by increased concentration of serum neurofilament light (sNfL) in the blood and may even be exaggerated in people with AMS. METHODS: Serum neurofilament light was measured using a single-molecule array (Simoa, Quanterix, Lexington, MA, USA) assay at low altitude (423 m) in 47 healthy study participants and 44 h after rapid and active ascent to high altitude (4559 m). Peripheral oxygen saturation (SpO2 ) and partial pressures of oxygen (pO2 ) were obtained at low and high altitude. The Acute Mountain Sickness-Cerebral (AMS-C) scoring system was used to assess AMS incidence and AMS severity. RESULTS: There was an increase in sNfL from its baseline value compared with its value at high altitude (6.34 ± 1.96 vs. 7.19 ± 3.14 pg/ml; p = 0.014), but sNfL level did not correlate with SpO2 (r = -0.19; p = 0.066) or pO2 (r = -0.19; p = 0.068). The incidence of AMS at high altitude was 62%. Neither at low altitude (p = 0.706) nor at high altitude (p = 0.985) was there a difference in sNfL between participants with and without AMS as measured 3 days after rapid ascent and 44 h of high-altitude exposure. Altitude sNfL did not correlate with AMS-C, either overall or with single-item scores such as headache severity. CONCLUSIONS: Rapid ascent of healthy people to high altitude provokes an increase in sNfL 44 h after arrival at 4559 m, which is not related to the magnitude of hypoxemia or AMS incidence and severity, suggesting that neuro-axonal injury does not directly contribute to AMS.

Rapid Ascent to 4559 m Is Associated with Increased Plasma Components of the Vascular Endothelial Glycocalyx and May Be Associated with Acute Mountain Sickness.

Background: The stress of high altitude alters vascular permeability, which may be related to structural changes in the endothelial glycocalyx. We aimed to study these changes by measuring plasma concentrations of several glycocalyx components upon exposure to high altitude. Methods: Plasma collected from 17 subjects at low altitude (423 m) and at three time points (7, 20, and 44 hours) after rapid ascent to high altitude (4559 m) were evaluated for concentrations of three glycocalyx components: syndecan-1, intercellular adhesion molecule-1 (ICAM-1), and heparan sulfate. Vital signs and echocardiographic measurement of systolic pulmonary artery pressure (sPAP) and cardiac output were also obtained at low and high altitudes. Results: Mean age of the study population was 35.5 ± 11.2 years with a body mass index of 22.7 ± 2.5 kg/m2. Concentrations of ICAM-1 and heparan sulfate increased from baseline to 7 hours after arrival at high altitude; the ICAM-1 rise persisted at 20 hours. Syndecan-1 concentrations were increased only at 44 hours. Increased ICAM-1 concentrations correlated with sPAP and peripheral edema. Elevations in heparan sulfate appeared to correlate with acute mountain sickness (AMS). Conclusions: Levels of circulating glycocalyx components increase after exposure to high altitude and may correlate with AMS. Measuring plasma concentrations of various glycocalyx components could serve as a useful tool for further evaluation of vascular endothelial injury and repair in illness at high altitude.

Preserved right ventricular function but increased right atrial contractile demand in altitude-induced pulmonary hypertension.

PURPOSE: Ascent to high altitude increases right ventricular (RV) afterload and decreases myocardial energy supply. This study evaluates physiologic variables and comprehensive echocardiographic indices of RV and right atrial (RA) function following rapid ascent to high altitude. METHODS: Fifty healthy volunteers actively ascended from 1130 to 4559 m in < 22 h. All participants underwent 2D echocardiography during baseline examination at low altitude (424 m) and at three study time-points (7, 20 and 44 h) after arrival at high altitude. In addition to systolic pulmonary artery pressure (sPAP), comprehensive 2D planimetric-, tissue Doppler- and speckle-tracking-derived strain indices of RA and RV function were obtained. RESULTS: sPAP increased from baseline (24 ± 4 mmHg) to the first altitude examination (39 ± 8 mmHg, p < 0.001) and remained elevated during the following 44 h. Global RV function did not change. RA reservoir strain showed a trend towards increase from baseline (50.2 ± 12.1%) to the first altitude examination (53.8 ± 11.0%, p = 0.07) secondary to a significant increase of RA contraction strain (19.2 ± 6.4 vs. 25.4 ± 9.6%, p < 0.001). Volumetric RA data largely paralleled RA strain results and RA active emptying volume was increased throughout the 44 h stay at high altitude. CONCLUSION: Active and rapid ascent of healthy individuals to 4559 m is associated with an increased contractile performance of the RA that compensates for the increased workload of the RV.

Endurance Athletes Are at Increased Risk for Early Acute Mountain Sickness at 3450 m.

INTRODUCTION: Acute mountain sickness (AMS) may develop in nonacclimatized individuals after exposure to altitudes ≥2500 m. Anecdotal reports suggest that endurance-trained (ET) athletes with a high maximal oxygen uptake (V˙O2max) may be at increased risk for AMS. Possible underlying mechanisms include a training-induced increase in resting parasympathetic activity, higher resting metabolic rate (RMR), and lower hypoxic ventilatory response (HVR). METHODS: In 38 healthy, nonacclimatized men (19 ET and 19 untrained controls [UT], V˙O2max 66 ± 6 mL·min·kg vs 45 ± 7 mL·min·kg; P < 0.001) peripheral oxygen saturation (SpO2), heart rate variability, RMR, and poikilocapnic HVR were assessed at 424 m and during 48 h at 3450 m after passive ascent by train (~2 h). Acute mountain sickness was evaluated by AMS cerebral (AMS-C) score. RESULTS: On day 1 at altitude, ET presented with a higher AMS incidence (42% vs 11%; P < 0.05) and severity (AMS-C score: ET, 0.48 ± 0.5 vs UT, 0.21 ± 0.2; P = 0.03), but no group difference was found on days 2 and 3. SpO2 decreased upon arrival at altitude (ET: 82% ± 6% vs UT: 83% ± 4%; ptime <0.001) with a significantly different time course between ET and UT (ptime × group = 0.045). Parasympathetic activity decreased at altitude (P < 0.001) but was always higher in ET (P < 0.05). At altitude RMR increased (P < 0.001) and was higher in ET (P < 0.001). Hypoxic ventilatory response increased only in ET (P < 0.05) and was greater than in UT after 24 and 48 h (P < 0.05). CONCLUSIONS: Endurance-trained athletes are at higher risk for developing AMS on the first day after passive and rapid ascent to 3450 m, possibly due to an increased parasympathetic activity and an increased RMR, while HVR appeared to be of minor importance. Differences in AMS time course and physiological responses should be taken into consideration when ET are planning high-altitude sojourns.

The Hen or the Egg: Impaired Alveolar Oxygen Diffusion and Acute High-altitude Illness?

Individuals ascending rapidly to altitudes >2500 m may develop symptoms of acute mountain sickness (AMS) within a few hours of arrival and/or high-altitude pulmonary edema (HAPE), which occurs typically during the first three days after reaching altitudes above 3000-3500 m. Both diseases have distinct pathologies, but both present with a pronounced decrease in oxygen saturation of hemoglobin in arterial blood (SO2). This raises the question of mechanisms impairing the diffusion of oxygen (O2) across the alveolar wall and whether the higher degree of hypoxemia is in causal relationship with developing the respective symptoms. In an attempt to answer these questions this article will review factors affecting alveolar gas diffusion, such as alveolar ventilation, the alveolar-to-arterial O2-gradient, and balance between filtration of fluid into the alveolar space and its clearance, and relate them to the respective disease. The resultant analysis reveals that in both AMS and HAPE the main pathophysiologic mechanisms are activated before aggravated decrease in SO2 occurs, indicating that impaired alveolar epithelial function and the resultant diffusion limitation for oxygen may rather be a consequence, not the primary cause, of these altitude-related illnesses.

Impairment of left atrial mechanics does not contribute to the reduction in stroke volume after active ascent to 4559 m.

Hypoxia challenges left ventricular (LV) function due to reduced energy supply. Conflicting results exist whether high-altitude exposure impairs LV diastolic function and thus contributes to the high altitude-induced increase in systolic pulmonary artery pressure (sPAP) and reduction in stroke volume (SV). This study aimed to assess LV diastolic function, LV end-diastolic pressure (LVEDP), and LA mechanics using comprehensive echocardiographic imaging in healthy volunteers at 4559 m. Fifty subjects performed rapid (<20 hours) and active ascent from 1130 m to 4559 m (high). All participants underwent echocardiography during baseline examination at 424 m (low) as well as 7, 20 and 44 hours after arrival at high altitude. Heart rate (HR), sPAP, and comprehensive volumetric- and Doppler- as well as speckle tracking-derived LA strain parameters were obtained to assess LV diastolic function, LA mechanics, and LVEDP in a multiparametric approach. Data for final analyses were available in 46 subjects. HR (low: 64 ± 11 vs high: 79 ± 14 beats/min, P < 0.001) and sPAP (low: 24.4 ± 3.8 vs high: 38.5 ± 8.2 mm Hg, P < 0.001) increased following ascent and remained elevated at high altitude. Stroke volume (low: 64.5 ± 15.0 vs high: 58.1 ± 16.4 mL, P < 0.001) and EDV decreased following ascent and remained decreased at high altitude due to decreased LV passive filling volume, whereas LA mechanics were preserved. There was no case of LV diastolic dysfunction or increased LVEDP estimates. In summary, this study shows that rapid and active ascent of healthy individuals to 4559 m impairs passive filling and SV of the LV. These alterations were not related to changes in LV and LA mechanics.

Inhaled Budesonide Does Not Affect Hypoxic Pulmonary Vasoconstriction at 4559 Meters of Altitude.

Berger, Marc Moritz, Franziska Macholz, Peter Schmidt, Sebastian Fried, Tabea Perz, Daniel Dankl, Josef Niebauer, Peter Bärtsch, Heimo Mairbäurl, and Mahdi Sareban. Inhaled budesonide does not affect hypoxic pulmonary vasoconstriction at 4559 meters of altitude. High Alt Med Biol 19:52-59, 2018.-Oral intake of the corticosteroid dexamethasone has been shown to lower pulmonary artery pressure (PAP) and to prevent high-altitude pulmonary edema. This study tested whether inhalation of the corticosteroid budesonide attenuates PAP and right ventricular (RV) function after rapid ascent to 4559 m. In this prospective, randomized, double-blind, and placebo-controlled trial, 50 subjects were randomized into three groups to receive budesonide at 200 or 800 µg twice/day (n = 16 and 17, respectively) or placebo (n = 17). Inhalation was started 1 day before ascending from 1130 to 4559 m within 20 hours. Systolic PAP (SPAP) and RV function were assessed by transthoracic echocardiography at low altitude (423 m) and after 7, 20, 32, and 44 hours at 4559 m. Ascent to high altitude increased SPAP about 1.7-fold (p < 0.001), whereas RV function was preserved. There was no difference in SPAP and RV function between groups at low and high altitude (all p values >0.10). Capillary partial pressure of oxygen (PO2) and carbon dioxide as well as the alveolar to arterial PO2 difference were decreased at high altitude but not affected by budesonide. Prophylactic inhalation of budesonide does not attenuate high-altitude-induced pulmonary vasoconstriction and RV function after rapid ascent to 4559 m.

Remote ischemic preconditioning does not prevent acute mountain sickness after rapid ascent to 3,450 m.

Remote ischemic preconditioning (RIPC) has been shown to protect remote organs, such as the brain and the lung, from damage induced by subsequent hypoxia or ischemia. Acute mountain sickness (AMS) is a syndrome of nonspecific neurologic symptoms and in high-altitude pulmonary edema excessive hypoxic pulmonary vasoconstriction (HPV) plays a pivotal role. We hypothesized that RIPC protects the brain from AMS and attenuates the magnitude of HPV after rapid ascent to 3,450 m. Forty nonacclimatized volunteers were randomized into two groups. At low altitude (750 m) the RIPC group (n = 20) underwent 4 × 5 min of lower-limb ischemia (induced by inflation of bilateral thigh cuffs to 200 mmHg) followed by 5 min of reperfusion. The control group (n = 20) underwent a sham protocol (4 × 5 min of bilateral thigh cuff inflation to 20 mmHg). Thereafter, participants ascended to 3,450 m by train over 2 h and stayed there for 48 h. AMS was evaluated by the Lake Louise score (LLS) and the AMS-C score. Systolic pulmonary artery pressure (SPAP) was assessed by transthoracic Doppler echocardiography. RIPC had no effect on the overall incidence (RIPC: 35%, control: 35%, P = 1.0) and severity (RIPC vs. CONTROL: P = 0.496 for LLS; P = 0.320 for AMS-C score) of AMS. RIPC also had no significant effect on SPAP [maximum after 10 h at high altitude; RIPC: 33 (SD 8) mmHg; controls: 37 (SD 7) mmHg; P = 0.19]. This study indicates that RIPC, performed immediately before passive ascent to 3,450 m, does not attenuate AMS and the magnitude of high-altitude pulmonary hypertension.NEW & NOTEWORTHY Remote ischemic preconditioning (RIPC) has been reported to improve neurologic and pulmonary outcome following an acute ischemic or hypoxic insult, yet the effect of RIPC for protecting from high-altitude diseases remains to be determined. The present study shows that RIPC, performed immediately before passive ascent to 3,450 m, does not attenuate acute mountain sickness and the degree of high-altitude pulmonary hypertension. Therefore, RIPC cannot be recommended for prevention of high-altitude diseases.

Reliability of echocardiographic speckle-tracking derived bi-atrial strain assessment under different hemodynamic conditions.

The aim of this study was to assess intra- and inter-observer variability of left (LA) and right atrial (RA) strain indices obtained by two-dimensional speckle-tracking echocardiography (2D-STE) in a healthy group of individuals at low-altitude and after rapid ascent to high-altitude in order to provoke altered systemic and pulmonary hemodynamics otherwise seen in various cardiac diseases. Twenty healthy subjects underwent transthoracic echocardiography during a baseline examination at low-altitude (424 m) as well as 7, 20 and 44 h after arrival at high-altitude (4559 m). Atrial strain indices (i.e. reservoir, conduit and contractile strain) were determined off-line by two independent observers. Intra- and inter-observer reproducibility of variables was assessed by intra-class correlation coefficients (ICCs), coefficients of variation and Bland Altman plots. Heart rate, systemic blood pressure and pulmonary artery pressure increased significantly from low-altitude to the first examination at high-altitude. Intra-observer ICCs were ≥0.90 except for RA conduit strain with an ICC of 0.86. The mean intra-observer differences were small and limits of agreement of relative differences were narrow for all atrial strain parameters (<3 and <16%, respectively). Inter-observer ICCs (0.80-0.90), mean biases and limits of agreement (<4 and <20%, respectively) were greater than intra-observer results for all parameters. Intra- and inter-obserer ICCs for all atrial strain variables did not differ between low- and high-altitude. 2D-STE-derived bi-atrial strain indices have excellent intra- and moderate inter-observer reproducibility with no effect of high-altitude-induced hemodynamic changes on reliability results.

[Hyperoxia in Anesthesia and Intensive Care Medicine - too much of a good thing?]. / Hyperoxie in Anästhesie und Intensivmedizin - Zu viel des Guten?

For decades the administration of oxygen has been a corner stone in the treatment of various medical emergencies, e.g. acute myocardial infarction. Several arguments support the perioperative use of high oxygen concentrations (>80%) for the prevention of surgical site infections. However, effects of oxygen include an increase in systemic vascular resistance, a reduction in heart rate and stroke volume and thus an impairment of the microcirculation, e.g. in the coronary and cerebral vasculature. Adequately powered, prospective, randomized, blinded outcome studies on the effects of hyperoxia in anesthesia and intensive care medicine are scarce. Recent data suggest that hyperoxia may be more harmful than beneficial and may increase morbidity and mortality in surgical and intensive care patients. Also, the current guidelines from the European Resuscitation Council from 2015 address the potentially harmful effects of high oxygen concentrations in various emergency settings. The aim of this article is to give an overview about the physiological and clinical effects of hyperoxia with a focus on its use in perioperative and intensive care medicine.

Remote ischemic preconditioning for prevention of high-altitude diseases: fact or fiction?

Preconditioning refers to exposure to brief episodes of potentially adverse stimuli and protects against injury during subsequent exposures. This was first described in the heart, where episodes of ischemia/reperfusion render the myocardium resistant to subsequent ischemic injury, which is likely caused by reactive oxygen species (ROS) and proinflammatory processes. Protection of the heart was also found when preconditioning was performed in an organ different from the target, which is called remote ischemic preconditioning (RIPC). The mechanisms causing protection seem to include stimulation of nitric oxide (NO) synthase, increase in antioxidant enzymes, and downregulation of proinflammatory cytokines. These pathways are also thought to play a role in high-altitude diseases: high-altitude pulmonary edema (HAPE) is associated with decreased bioavailability of NO and increased generation of ROS, whereas mechanisms causing acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) seem to involve cytotoxic effects by ROS and inflammation. Based on these apparent similarities between ischemic damage and AMS, HACE, and HAPE, it is reasonable to assume that RIPC might be protective and improve altitude tolerance. In studies addressing high-altitude/hypoxia tolerance, RIPC has been shown to decrease pulmonary arterial systolic pressure in normobaric hypoxia (13% O2) and at high altitude (4,342 m). Our own results indicate that RIPC transiently decreases the severity of AMS at 12% O2. Thus preliminary studies show some benefit, but clearly, further experiments to establish the efficacy and potential mechanism of RIPC are needed.