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Effects of High-Altitude Exposure on the Pulmonary Circulation
... Su perfil clínico es de niveles elevados de Hb, menor SaO 2 , aumento de la presión arterial pulmonar (PAP) y resistencia vascular pulmonar (RVP), con hipertrofia del ventrículo derecho (VD) y aumento de volúmenes pulmonares. Desde esta perspectiva, los tibetanos se han adaptado genotípicamente, en tanto que los nativos andinos se ubican en el proceso de adaptación fenotípica dado su menor tiempo de residencia en la altitud 5,6 . ...
... Las personas expuestas a la HA requieren adaptarse a este ambiente hipóxico hipobárico de la altura. Por arriba de los 2,500 msnm, la presión barométrica y la presión inspirada de oxígeno disminuyen y el resultado es hipoxia alveolar e hipoxemia, lo que deriva en VPH, esto es, se eleva en grado moderado la PAP y la del VD, pero es compatible con una vida normal en HA 5,8,9 . La VPH permite un mejor equilibrio entre la relación ventilación/perfusión (V/Q) pulmonar y aumenta la capacidad de difusión pulmonar; en comparación con el nativo a nivel del mar, se traduce en un menor gradiente alveoloarterial de oxígeno (A-a = 3 a 5 mmHg) 1,5,15 . ...
... Por arriba de los 2,500 msnm, la presión barométrica y la presión inspirada de oxígeno disminuyen y el resultado es hipoxia alveolar e hipoxemia, lo que deriva en VPH, esto es, se eleva en grado moderado la PAP y la del VD, pero es compatible con una vida normal en HA 5,8,9 . La VPH permite un mejor equilibrio entre la relación ventilación/perfusión (V/Q) pulmonar y aumenta la capacidad de difusión pulmonar; en comparación con el nativo a nivel del mar, se traduce en un menor gradiente alveoloarterial de oxígeno (A-a = 3 a 5 mmHg) 1,5,15 . ...
Chronic exposure to altitude has been associated with hypobaric hypoxia in its inhabitants. Two entities have been associated with it, high altitude pulmonary hypertension and chronic mountain sickness. Its physiological and pulmonary circulation characteristics are described, as well as its clinical profile and diagnosis.
... The response differs between and within species and is influenced by anatomical, biochemical and physiological factors (Harris & Heath, 1986c;Voelkel, 1986;Palevsky & Fishman, 1990). Nevertheless, a sustained increase in pulmonary vascular tone, which is mediated through contraction of muscular arteries and resistance arterioles, has been demonstrated in experimental animals maintained under prolonged hypoxic conditions, in humans dwelling at high altitudes and in human disease states associated with chronic alveolar hypoxia (Harris & Heath, 1986b;Palevsky & Fishman, 1990). This prolonged vasospastic response is associated with a complex pathological structural remodelling throughout the pulmonary circulation and in all components of the vascular wall (Harris & Heath, 1986c). ...
... The PHT existing in indigenous populations living at high altitude is well documented (Harris & Heath, 1986b). Comparative examination of the pathological processes in the pulmonary circulation has demonstrated that changes observed in high-altitude dwellers are similar to those in patients with chronic lung disease (Harris & Heath, 1986b;Palevsky & Fishman, 1990). ...
... The PHT existing in indigenous populations living at high altitude is well documented (Harris & Heath, 1986b). Comparative examination of the pathological processes in the pulmonary circulation has demonstrated that changes observed in high-altitude dwellers are similar to those in patients with chronic lung disease (Harris & Heath, 1986b;Palevsky & Fishman, 1990). The increased PVR in highlanders is well tolerated, with a normal physical capacity capable of sustaining heavy labour. ...
Although frequently unrecognized, hypoxic pulmonary vascular disease is an important cofactor in the morbidity and mortality of a wide spectrum of disease processes. The hypoxic response incorporates two distinct phases, the acute hypoxic vasoconstrictor response and vascular remodelling associated with prolonged alveolar hypoxia. Understanding of the mechanisms causing both processes has increased rapidly and may result in the near future in specific treatment aimed at correcting underlying physiological abnormalities. However, currently available therapies remain limited to correction of the hypoxaemia and generalized non-specific pulmonary vasodilatation. The recent development of inhaled NO therapy represents a significant advance in the management of the acute hypoxic pulmonary vasoconstriction occurring during critical illness.
... ∼80 million of them in Asia and ∼40 million in South America (Andean mountains), where the highest population density is found above 3,500 m.a.s.l. (Penaloza, 2012;Herrera et al., 2015). The biological response to this condition leads to a reduction of inspired and alveolar oxygen pressure, which results in a decreased oxygen concentration in the blood (arterial hypoxemia) (Virués-Ortega et al., 2006). ...
... Long-term exposure induces physiological compensations such as alveolar hyperventilation and erythropoiesis that promotes oxygen transport; however, these changes are insufficient to achieve the same conditions as at sea level (Julian, 2011). Maladaptive responses could have as consequence many cardiovascular diseases, such as acute mountain sickness, pulmonary edema, subacute mountain sickness in children, or sleep apnea, all of them related to some degree of high blood pressure or cardiovascular impairment (Penaloza, 2012). ...
In this study, we assessed the effects of Atrial Natriuretic Peptide (ANP) and Cinaciguat, as experimental medicines to treat neonatal lambs exposed to chronic hypoxic conditions. To compare the different treatments, the mechanical responses of aorta, carotid, and femoral arterial walls were analyzed by means of axial pre-stretch and ring-opening tests, through a study with n = 6 animals for each group analyzed. The axial pre-stretch test measures the level of shortening in different zones of the arteries when extracted from lambs, while the ring-opening test is used to quantify the degree of residual circumferential deformation in a given zone of an artery. In addition, histological studies were carried out to measure elastin, collagen, and smooth muscle cell (SMC) nuclei densities, both in control and treated groups. The results show that mechanical response is related with histological results, specifically in the proximal abdominal aorta (PAA) and distal carotid zones (DCA), where the cell nuclei content is related to a decrease of residual deformations. The opening angle and the elastic fibers of the aorta artery were statistically correlated (p < 0.05). Specifically, in PAA zone, there are significant differences of opening angle and cell nuclei density values between control and treated groups (p-values to opening angle: Control-ANP = 2 · 10 −2 , Control-Cinaciguat = 1 · 10 −2 ; p-values to cell nuclei density: Control-ANP = 5 · 10 −4 , Control-Cinaciguat = 2 · 10 −2). Respect to distal carotid zone (DCA), significant differences between Control and Cinaciguat groups were observed to opening angle (p-value = 4 · 10 −2), and cell nuclei density (p-value = 1 · 10 −2). Our findings add evidence that medical treatments may have effects on the mechanical responses of arterial walls and should be taken into account when evaluating the complete medical outcome.
... THABUT et al. [8], investigating the two types of population, i.e. candidates for lung volume reduction surgery (LVRS) and candidates for lung transplantation, had comparable results. Mild (P pa [26][27][28][29][30][31][32][33][34][35], moderate (36)(37)(38)(39)(40)(41)(42)(43)(44)(45) and severe (.45 mmHg) PH was present in 36.7, 9.8 and 3.7% of the 215 patients, respectively. ...
... In larger pulmonary arteries (80-1,000 mm in diameter in humans) the media can be thickened or focally atrophied [31,33,34]. Muscularisation also occurs in the postcapillary vessels of patients with COPD [35] with a more important amount of extracellular matrix in veins and venules than in pulmonary arteries. ...
Mild-to-moderate pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD); such a complication is associated with increased risks of exacerbation and decreased survival. Pulmonary hypertension usually worsens during exercise, sleep and exacerbation. Pulmonary vascular remodelling in COPD is the main cause of increase in pulmonary artery pressure and is thought to result from the combined effects of hypoxia, inflammation and loss of capillaries in severe emphysema. A small proportion of COPD patients may present with "out-of-proportion" pulmonary hypertension, defined by a mean pulmonary artery pressure >35-40 mmHg (normal is no more than 20 mmHg) and a relatively preserved lung function (with low to normal arterial carbon dioxide tension) that cannot explain prominent dyspnoea and fatigue. The prevalence of out-of-proportion pulmonary hypertension in COPD is estimated to be very close to the prevalence of idiopathic pulmonary arterial hypertension. Cor pulmonale, defined as right ventricular hypertrophy and dilatation secondary to pulmonary hypertension caused by respiratory disorders, is common. More studies are needed to define the contribution of cor pulmonale to decreased exercise capacity in COPD. These studies should include improved imaging techniques and biomarkers, such as the B-type natriuretic peptide and exercise testing protocols with gas exchange measurements. The effects of drugs used in pulmonary arterial hypertension should be tested in chronic obstructive pulmonary disease patients with severe pulmonary hypertension. In the meantime, the treatment of cor pulmonale in chronic obstructive pulmonary disease continues to rest on supplemental oxygen and a variety of measures aimed at the relief of airway obstruction.
... Therefore, there is a need to adapt current or develop new algorithms and validate them at these altitudes [29]. This process will need to adequately account for the higher standard deviation [30][31][32][33][34][35] in oxygen saturation (Table 1), slower remodeling of the pulmonary vasculature [35], and higher pulmonary artery pressures seen with very high altitude [37]. Neonatal oxygen saturation increases substantially during the first hour of life during the fetal to neonatal transition period and stabilizes by the first day of life even at altitudes as high as 4330 masl [34,[38][39][40][41] (Fig. 2), therefore POS can still be performed starting at the first 24 h of life at high altitudes. ...
Critical congenital heart disease (CCHD) represents a challenging problem in global health equity due to the need for specialized surgical or transcatheter intervention within the first year of life. CCHD screening using pulse oximetry (POS) has led to significant improvements in mortality due to early referral and intervention. Andean America represents one of the few regions in the world with increasing CHD deaths and variable POS implementation. In this manuscript, we review the current state of CCHD in Andean America, the challenges and opportunities for developing new POS algorithms that account for high-altitude physiology, data on regional cost-effectiveness supporting POS implementation and outline future directions to achieve equity in CHD care in this region.
... This condition of hypobaric hypoxia is what causes alveolar hypoxia and hypoxemia in humans who live at or ascend to high altitudes. There are multiple responses to the hypoxic stimulus, as well as numerous mechanisms of acclimatization [4]. The response varies with the individual and his history of places lived, fitness level and ability to adapt. ...
This paper familiarizes the reader with the concept of common diseases, symptoms and treatment at high altitudes with special focus on high altitude pulmonary edema and acute mountain sickness. It also explains the pathophysiological aspect of human body during the onset of these diseases and the co relation of acclimatization with the symptoms related to high altitude sickness. It is generally observed that people with no acclimatization at high altitude generally suffer through these diseases and people living at high altitude or people who go through a slow ascent to high altitude are able to avoid these symptoms. But in some special cases even people living at high altitude for a long period of time start showing the symptoms of high-altitude sickness as their lose the ability to adapt to these heights.
Background
Risk factors and postoperative results of the Fontan operation in patients living at high altitude (> 2500 meters above sea level) in the Andean region remains unknown. Evaluate results and risk factor for immediate postoperative outcomes and short- and long-term functional class after Fontan.
Methods
From June 2003 to February 2019, 104 patients receiving Fontan procedure at 2640 meters (8661 feet) above-sea-level were retrospectively studied. Preoperative catheterization, intraoperative variables and post-operative outcomes were described. Functional class was evaluated in patients living permanently below (Group I) and at or higher than 2500 meters (8202 feet) above sea level. (Group II) Risk factors for mortality were analyzed.
Results
Median age at operation was 8.5 ± 4.4 years; Pulmonary artery pressure 16.2 ± 3.6 mmHg; EDVP 13.3 ± 3.8mmHg, PVRI 2.1(IQR 07-3.7) Wood units. Chest tube duration was 8,5 (6-12) days. Mortality was 4.8%, with 0 in the last 5 years. Higher preoperative pulmonary pressure (16.2 ± 3.6 vs 21.2 ± 3.40mmHg, (P Value 0.01), aortic cross clamp time (P value< 0.001) and renal failure (P value <0.01) were associated with mortality. Functional class improve to class I in 86.4%. Overall survival was 90. 7 % at ten years follow up.
Conclusions
Increased pulmonary pressure and PVRI are directly related to high altitude. Fontan-Kreutzer operation performed at high altitude in the Andean region is feasible with good results. We routinely fenestrate all cases to avoid dysfunction in the early postoperative period. Functional status is adequate after the operation.
The Mining environment is hazardous for worker’s health. It can affect the mental health, triggering symptoms and diseases, such as anxiety, job stress, depression, sleep disorders, mental fatigue and other. The aim of this study was to describe and analyze the scientific literature about the mental health in mine workers and to summarize the findings. The method used was Scoping review. The principal outcomes were the following: evidence in the last 12 years in the topic was focused in four themes 1) Psychological problems & personal factors (38.2%); 2) Psychosocial problems & health related factor (23.6%); 3) Well-being (21.1%) and 4) Physical problems & organization factors (17.1%). Several affections, symptoms, characteristics or disorders were inquired about mine worker’s mental health, such as job strain, unsafety experiences, poor quality of sleep, non-subjective well-being, job unsatisfaction, social-relations conflict, risk of accidents and injuries, MSDs, substance abuse, dangerous working conditions and demanding job organization, and so on. For those factors, Mining could expose to serious mental health problems to a part of their workers. It’s necessary to deepen the elaboration of international policies and carry out more scientific research and suggestions to make programs on the topic.
This paper familiarizes the reader with the concept of common diseases, symptoms and treatment at high altitudes with special focus on high altitude pulmonary edema and acute mountain sickness. It also explains the pathophysiological aspect of human body during the onset of these diseases and the co relation of acclimatization with the symptoms related to high altitude sickness. It is generally observed that people with no acclimatization at high altitude generally suffer through these diseases and people living at high altitude or people who go through a slow ascent to high altitude are able to avoid these symptoms. But in some special cases even people living at high altitude for a long period of time start showing the symptoms of high-altitude sickness as their lose the ability to adapt to these heights.
Aim:
To study the criterion validity of three indirect maximal oxygen uptake ([Formula: see text]O2max) assessment equations at altitude.
Methods:
We studied 64 young adults (53% men) at Bogota, Colombia (2600 m altitude). Direct [Formula: see text]O2max was measured by indirect calorimetry using a maximal incremental treadmill protocol. Indirect [Formula: see text]O2max was estimated by two exercise field tests (the 20-m shuttle-run test [20-MST] and the 2-km walking test (UKK)) and one nonexercise method (the perceived functional ability-physical activity rating questionnaire [PFA-PAR]). Altitude-adjusted PFA-PAR was estimated as a 13% linear reduction in PFA-PAR. We calculated Lin concordance coefficients (LCC) and standard error of the estimates (SEEs), and we performed Bland-Altman analyses for each indirect method.
Results:
Mean [Formula: see text]O2max was 41.2 ± 5.8 mL/kg/min in men and 32.2 ± 3.6 mL/kg/min in women. We found the highest agreement with direct [Formula: see text]O2max for the 20-MST (LCC = 0.79, SEE = 3.91 mL/kg/min), followed in order by the altitude-adjusted PFA-PAR (LCC = 0.71, SEE = 4.12 mL/kg/min), the UKK (LCC = 0.67, SEE = 5.48 mL/kg/min), and the unadjusted PFA-PAR (LCC = 0.57, SEE = 4.75 mL/kg/min). The unadjusted PFA-PAR tended to overestimate [Formula: see text]O2max, but Bland-Altman analysis showed that this bias disappeared after altitude adjustment.
Conclusion:
Several maximal, submaximal, and nonexercise methods provide estimates of [Formula: see text]O2max with acceptable validity for use in epidemiological studies of populations living at moderate altitude.
Method:
Lowland and highland newborn sheep and llama were investigated near sea level and at high altitude. Blood determinations of arterial blood gases, ADMA and homocysteíne are made and the effect of these on the arginase activity was evaluated.
Results:
The basal concentrations of ADMA and homocysteine were determined in llama, and they were found to be significantly lower than those found in other species and in addition, the exposure to hypoxia is unable to increase its concentration. On the other hand, it was observed that the llama exhibited 10 times less arginase II activity as compared to sheep, and the expression was not induced by hypoxia. Finally, ADMA y Hcy, has no effect on the type II arginase pathway.
Conclusion:
Based on our results, we propose that low concentrations of ADMA and homocysteine found in llamas, the low expression of arginase type II, DDAH-2 and CBS, as well as its insensitivity to activation by homocysteine could constitute an adaptation mechanism of these animals to the hypoxia.
Aim:
Rho kinase activation plays an important role in hypoxic pulmonary vasoconstriction and increased vascular resistance. The present study investigated changes in the level and activity of rho kinase isoform 2 (ROCK2) under acute hypobaric hypoxia exposure. For this, Wistar rats were taken as the model organism.
Materials and methods:
Fifteen male Wistar rats (4-6 week old, 250 grams) were normalized with the surrounding environment by providing a 12/12 hour day and night acclimatization cycle. The rats were divided into 3 groups: (a) control group (no exposure, n = 5), (b) Group 1 (12 hour hypobaric-hypoxia exposure, n = 5) and (c) Group 2 (12 hour hypobaric hypoxia and 12 hour normobaric normoxia exposure, n = 5). A change in behavior of the animals was noted before sacrifice. Blood was collected from the beating heart of the anesthetized animal. Lungs were dissected out and used to estimate the levels and activity of ROCK2 in different groups using commercially available kits. Lung histology was evaluated by immunohistochemistry. ROCK2 gene expression was studied in the blood and lungs using quantitative PCR.
Results and conclusions:
Control and Group 2 animals had an active movement while the Group 1 animals were sluggish before the sacrifice. Formation of a large perivascular edema cuff and collagen deposition in lungs of Group 1 and a reduction in Group 2 was observed. The protein levels and activities of ROCK2 were increased in Group 1 (p < 0.05) and became normal in Group 2 which was akin to control group animals. ROCK2 expression in PBMCs was increased in Group 1 (10.7 fold, p = 0.005) and was decreased in Group 2 (5.5 fold, p = 0.02). The outcomes establish that acute hypobaric hypoxia augments ROCK2 protein level and activity.
From a broad perspective there are only three arterial systems that respond to relative hypoxia with vasoconstriction. They are the placental, the pulmonic and the renal vascular beds. The renal system's adaptation to hypoxia is markedly different from the other two circulatory beds and will not be further considered here. Regional vasoconstriction is adaptive in the placenta and lung because it redirects red blood cells from areas of relative hypoxia to more oxygenated areas thereby maximizing oxygen uptake for a given cardiac output. The fetal placental and pulmonary vascular systems are unique because their smooth muscle cells have a unique and possibly identical potassium channel that responds to hypoxia by closing, thereby depolarizing the cell membrane allowing calcium ion influx and muscle contraction. It may be that a variety of initial causes of temporary or local placental hypoxia initiate a cascade of first fetal placental then maternal vasoconstriction and endothelial activation leading to the clinical syndrome we call preeclampsia. The response cascades seen in preeclampsia, which for purposes of this article I will abbreviate as (PECL), after development of widespread vasoconstriction, will also be seen to be identical or at least parallel in pulmonary hypertension (PAH). This means that some or all of the pharmacotherapies presently used, tested or considered in early PAH may also have a therapeutic effect in PECL by reducing fetal placental arterial resistance thereby increasing fetal placental flow. This would allow increased oxygen and other nutrient uptake and possibly increased fetal cardiac output in the face of reduced fetal cardiac work. This may allow a delay in delivery in which fetuses grow and are better oxygenated in preterm PECL, improving neonatal outcomes.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Pulmonary arterial hypertension (PAH) is a syndrome characterized by lung vascular intimal lesions, smooth muscle layer hypertrophy, perivascular inflammation, and concomitant right ventricular (RV) remodeling which can ultimately lead to the RV function decline known as RV failure (RVF). A key determining factor for RVF development is the RV metabolic state defined by the level of ischemia and glycolysis which constitute a vicious cycle of hypoxia, metabolic shift from glucose oxidation (GO) to glycolysis, increased RV systolic pressure (RVSP), decreased RV output, and further myocardial ischemia. In this context, 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography (PET) has been used for the measurement of glucose uptake (GU) as an indicator of glucose metabolism in the right heart and pulmonary vasculature. The focus of this review is the application of FDG PET modality for assessing PAH severity and clinical outcome.
Altitude physiology began with Paul Bert in 1878. Chronic mountain sickness (CMS) was defined by Carlos Monge in the 1940s in the Peruvian Andes as consisting of excess polycythemia. Hurtado et al performed studies in the Peruvian Andes in the 1950s to 1960s which defined acclimatization in healthy altitude natives, including polycythemia, moderate pulmonary hypertension, and low systemic blood pressure (BP). Electrocardiographic changes of right ventricular hypertrophy (RVH) were noted. Acclimatization of newcomers to altitude involves hyperventilation stimulated by hypoxia and is usually benign. Acute mountain sickness (AMS) in travelers to altitude is characterized by hypoxia-induced anorexia, dyspnea, headache, insomnia, and nausea. The extremes of AMS are high-altitude cerebral edema and high-altitude pulmonary edema. The susceptible high-altitude resident can lose their tolerance to altitude and develop CMS, also referred to as Monge disease. The CMS includes extreme polycythemia, severe RVH, excess pulmonary hypertension, low systemic BP, arterial oxygen desaturation, and hypoventilation.
Background:
Chronic mountain sickness (CMS) is characterized by a combination of excessive erythrocytosis,severe hypoxemia, and pulmonary hypertension, all of which affect exercise capacity.
Methods:
Thirteen patients with CMS and 15 healthy highlander and 15 newcomer lowlander control subjects were investigated at an altitude of 4,350 m (Cerro de Pasco, Peru). All of them underwent measurements of diffusing capacity of lung for nitric oxide and carbon monoxide at rest, echocardiography for estimation of mean pulmonary arterial pressure and cardiac output at rest and at exercise, and an incremental cycle ergometer cardiopulmonary exercise test.
Results:
The patients with CMS, the healthy highlanders, and the newcomer lowlanders reached a similar maximal oxygen uptake at 32 1, 32 2, and 33 2 mL/min/kg, respectively, mean SE( P 5 .8), with ventilatory equivalents for C O 2 vs end-tidal P CO 2 , measured at the anaerobic threshold,of 0.9 0.1, 1.2 0.1, and 1.4 0.1 mm Hg, respectively ( P , .001); arterial oxygen content of 26 1, 21 2, and 16 1 mL/dL, respectively ( P , .001); diffusing capacity for carbon monoxide corrected for alveolar volume of 155% 4%, 150% 5%, and 120% 3% predicted, respectively( P , .001), with diffusing capacity for nitric oxide and carbon monoxide ratios of 4.7 0.1 at sea level decreased to 3.6 0.1, 3.7 0.1, and 3.9 0.1, respectively ( P , .05) and a maximal exercise mean pulmonary arterial pressure at 56 4, 42 3, and 31 2 mm Hg, respectively ( P , .001).
Conclusions:
The aerobic exercise capacity of patients with CMS is preserved in spite of severe pulmonary hypertension and relative hypoventilation, probably by a combination of increased oxygen carrying capacity of the blood and lung diffusion, the latter being predominantly due to an increased capillary blood volume.
high-altitude adaptation leads to progressive increase in arterial Pa(O2). In addition to increased ventilation, better arterial oxygenation may reflect improvements in lung gas exchange. Previous investigations reveal alterations at the alveolar-capillary barrier indicative of decreased resistance to gas exchange with prolonged hypoxia adaptation, but how quickly this occurs is unknown. Carbon monoxide lung diffusing capacity and its major determinants, hemoglobin, alveolar volume, pulmonary capillary blood volume, and alveolar-capillary membrane diffusion, have never been examined with early high-altitude adaptation.
lung diffusion was measured in 33 healthy lowlanders at sea level (Milan, Italy) and at Mount Everest South Base Camp (5,400 m) after a 9-day trek and 2-wk residence at 5,400 m. Measurements were adjusted for hemoglobin and inspired oxygen. Subjects with mountain sickness were excluded. After 2 wk at 5,400 m, hemoglobin oxygen saturation increased from 77.2 ± 6.0 to 85.3 ± 3.6%. Compared with sea level, there were increases in hemoglobin, lung diffusing capacity, membrane diffusion, and alveolar volume from 14.2 ± 1.2 to 17.2 ± 1.8 g/dl (P < 0.01), from 23.6 ± 4.4 to 25.1 ± 5.3 ml·min(-1)·mmHg(-1) (P < 0.0303), 63 ± 34 to 102 ± 65 ml·min(-1)·mmHg(-1) (P < 0.01), and 5.6 ± 1.0 to 6.3 ± 1.1 liters (P < 0.01), respectively. Pulmonary capillary blood volume was unchanged. Membrane diffusion normalized for alveolar volume was 10.9 ± 5.2 at sea level rising to 16.0 ± 9.2 ml·min(-1)·mmHg(-1)·l(-1) (P < 0.01) at 5,400 m.
at high altitude, lung diffusing capacity improves with acclimatization due to increases of hemoglobin, alveolar volume, and membrane diffusion. Reduction in alveolar-capillary barrier resistance is possibly mediated by an increase of sympathetic tone and can develop in 3 wk.
Calculating pulmonary vascular resistance is important in many fields of medicine. Although the influence of hematocrit on calculated resistance has been known for many years, it is rare to find the appropriate corrections in published articles. This review discusses the relationship between viscosity and resistance and shows how the effect of viscosity can be allowed for by calculating hindrance or relative viscosity.
Staged ascent (SA), temporary residence at moderate altitude en route to high altitude, reduces the incidence and severity of noncardiopulmonary altitude illness such as acute mountain sickness. To date, the impact of SA on pulmonary arterial pressure (PAP) is unknown. We tested the hypothesis that SA would attenuate the PAP increase that occurs during rapid, direct ascent (DA). Transthoracic echocardiography was used to estimate mean PAP in 10 healthy males at sea level (SL, P(B) approximately 760 torr), after DA to simulated high altitude (hypobaric chamber, P(B) approximately 460 torr), and at 2 times points (90 min and 4 days) during exposure to terrestrial high altitude (P(B) approximately 460 torr) after SA (7 days, moderate altitude, P(B) approximately 548 torr). Alveolar oxygen pressure (Pao(2)) and arterial oxygenation saturation (Sao(2)) were measured at each time point. Compared to mean PAP at SL (mean +/- SD, 14 +/- 3 mmHg), mean PAP increased after DA to 37 +/- 8 mmHg (Delta = 24 +/- 10 mmHg, p < 0.001) and was negatively correlated with both Pao(2) (r(2) = 0.57, p = 0.011) and Sao(2) (r(2) = 0.64, p = 0.005). In comparison, estimated mean PAP after SA increased to only 25 +/- 4 mmHg (Delta = 11 +/- 6 mmHg, p < 0.001), remained unchanged after 4 days of high altitude residence (24 +/- 5 mmHg, p = not significant, or NS), and did not correlate with either parameter of oxygenation. SA significantly attenuated the PAP increase associated with continuous direct ascent to high altitude and appeared to uncouple PAP from both alveolar hypoxia and arterial hypoxemia.
Lung carbon monoxide (CO) transfer and pulmonary capillary blood volume (Vc) at high altitudes have been reported as being higher in native highlanders compared to acclimatised lowlanders but large discrepancies appears between the studies. This finding raises the question of whether hypoxia induces pulmonary angiogenesis. Eighteen highlanders living in Bolivia and 16 European lowlander volunteers were studied. The latter were studied both at sea level and after acclimatisation to high altitude. Membrane conductance (Dm(CO)) and Vc, corrected for the haemoglobin concentration (Vc(cor)), were calculated using the NO/CO transfer technique. Pulmonary arterial pressure and left atrial pressures were estimated using echocardiography. Highlanders exhibited significantly higher NO and CO transfer than acclimatised lowlanders, with Vc(cor)/VA and Dm(CO)/VA being 49 and 17% greater (VA: alveolar volume) in highlanders, respectively. In acclimatised lowlanders, Dm(CO) and Dm(CO)/VA values were lower at high altitudes than at sea level. Echocardiographic estimates of cardiac output and pulmonary arterial pressure were significantly elevated at high altitudes as compared to sea level. The decrease in Dm(CO) in lowlanders might be due to altered gas transport in the airways due to the low density of air at high altitudes. The disproportionate increase in Vc in Andeans compared to the change in Dm(CO) suggests that the recruitment of capillaries is associated with a thickening of the blood capillary sheet. Since there was no correlation between the increase in Vc and the slight alterations in haemodynamics, this data suggests that chronic hypoxia might stimulate pulmonary angiogenesis in Andeans who live at high altitudes.
Altitude exposure is associated with decreased exercise capacity and increased pulmonary vascular resistance (PVR). Echocardiographic measurements of pulmonary haemodynamics and a cardiopulmonary exercise test were performed in 13 healthy subjects at sea level, in normoxia and during acute hypoxic breathing (1 h, 12% oxygen in nitrogen), and in 22 healthy subjects after acclimatisation to an altitude of 5,050 m. The measurements were obtained after randomisation, double-blinded to the intake of placebo or the endothelin A receptor blocker sitaxsentan (100 mg·day(-1) for 7 days). Blood and urine were sampled for renal function measurements. Normobaric as well as hypobaric hypoxia increased PVR and decreased maximum workload and oxygen uptake (V'(O(2),max)). Sitaxsentan decreased PVR in acute and chronic hypoxia (both p<0.001), and partly restored V'(O(2),max), by 30 % in acute hypoxia (p<0.001) and 10% in chronic hypoxia (p<0.05). Sitaxsentan-induced changes in PVR and V'(O(2),max) were correlated (p = 0.01). Hypoxia decreased glomerular filtration rate and free water clearance, and increased fractional sodium excretion. These indices of renal function were unaffected by sitaxsentan intake. Selective endothelin A receptor blockade with sitaxsentan improves mild pulmonary hypertension and restores exercise capacity without adverse effects on renal function in hypoxic normal subjects.
Chronic mountain sickness (CMS) is an important public health problem and is characterized by exaggerated hypoxemia, erythrocytosis, and pulmonary hypertension. While pulmonary hypertension is a leading cause of morbidity and mortality in patients with CMS, it is relatively mild and its underlying mechanisms are not known. We speculated that during mild exercise associated with daily activities, pulmonary hypertension in CMS is much more pronounced.
We estimated pulmonary artery pressure by using echocardiography at rest and during mild bicycle exercise at 50 W in 30 male patients with CMS and 32 age-matched, healthy control subjects who were born and living at an altitude of 3,600 m.
The modest, albeit significant difference of the systolic right-ventricular-to-right-atrial pressure gradient between patients with CMS and controls at rest (30.3 +/- 8.0 vs 25.4 +/- 4.5 mm Hg, P 5 .002) became more than three times larger during mild bicycle exercise (56.4 +/- 19.0 vs 39.8 +/- 8.0 mm Hg, P < .001).
Measurements of pulmonary artery pressure at rest greatly underestimate pulmonary artery pressure during daily activity in patients with CMS. The marked pulmonary hypertension during mild exercise associated with daily activity may explain why this problem is a leading cause of morbidity and mortality in patients with CMS.
This study represented an initial attempt, by means of cross-sectional investigation, to determine the effects of chronic exposure to high altitude on pulmonary gas exchange. Single-breath D(Lco) and its components were determined at rest and during muscular work in two groups of healthy, non-smoking, sea level natives who had initiated 1-16 yr of residence at 3,100 m altitude either during physical maturation (at age 10+/-4 yr) or as adults (at age 26+/-4 yr). The relative degree of acclimatization achieved in these lowland residents was assessed through their comparison both with normal sea-level values and with two additional groups of short-term sojourners and natives to 3.100 m. D(Lco) at rest and work was significantly elevated above normal and above sojourner values in both groups of resident lowlanders at 3,100 m. The high D(Lco) in the native to 3,100 m was closely approximated in the younger resident lowlander at rest, but only during exercise in the adult resident lowlander. The high D(Lco) at rest and during exercise in the resident lowlanders was not attributable to differences in Hb concentration or in alveolar lung volume: and was accompanied primarily by an increased estimated Dm(co) and to a lesser extent by an expanded Vc. The interpretation and implications of these findings were limited by the low quantitative capability of Vc and Dm(co) estimates and by the cross-sectional nature of the study. Nevertheless, the higher than normal D(Lco) and Dm(co) in the non-native, long-term resident of 3,100 m was substantial, highly significant statistically, and consistent over a wide range of metabolic rates at rest and work. These data provide, then, a reasonable rationale upon which longitudinal experiments may be based to determine the true effects of chronic hypoxia on pulmonary gas exchange in man.
An exaggerated hypoxic pulmonary vasoconstriction is essential for development of high-altitude pulmonary edema (HAPE). We hypothesized that susceptibility to HAPE may be related to decreased production of nitric oxide (NO), an endogenous modulator of pulmonary vascular resistance, and that a decrease in exhaled NO could be detected during hypoxic exposure. Therefore, we investigated respiratory tract NO excretion by chemiluminescence and pulmonary artery systolic pressure (Ppa,s) by echocardiography in nine HAPE-susceptible mountaineers and nine HAPE-resistant control subjects during normoxia and acute hypoxia (fraction of inspired oxygen [FI(O2)] = 0.12). The subjects performed oral breathing. Nasally excreted NO was separated from respiratory gas by suction via a nasal mask. In HAPE-susceptible subjects, NO excretion in expired gas significantly decreased (p < 0.05) during hypoxia of 2 h in comparison with normoxia (28 +/- 4 versus 21 +/- 2 nl/min, mean +/- SEM). In contrast, the NO excretion rate of control subjects remained unchanged (31 +/- 6 versus 33 +/- 6 nl/ min, NS). Nasal NO excretion did not differ significantly between groups during normoxia (HAPE-susceptible group, 183 +/- 16 nl/ min; control subjects, 297 +/- 55 nl/min, NS) and was not influenced by hypoxia. The changes in Ppa,s with hypoxia correlated with the percent changes in lower respiratory tract NO excretion (R = -0.49, p = 0.04). Our data provide the first evidence of decreased pulmonary NO production in HAPE-susceptible subjects during acute hypoxia that may contribute among other factors to their enhanced hypoxic pulmonary vascular response.
Peripheral chemoreflex function was studied in high-altitude (HA) natives at HA, in patients with chronic mountain sickness (CMS) at HA, and in sea-level (SL) natives at SL. Results were as follows. 1) Acute ventilatory responses to hypoxia (AHVR) in the HA and CMS groups were approximately one-third of those of the SL group. 2) In CMS patients, some indexes of AHVR were modestly, but significantly, lower than in healthy HA natives. 3) Prior oxygenation increased AHVR in all subject groups. 4) Neither low-dose dopamine nor somatostatin suppressed any component of ventilation that could not be suppressed by acute hyperoxia. 5) In all subject groups, the ventilatory response to hyperoxia was biphasic. Initially, ventilation fell but subsequently rose so that, by 20 min, ventilation was higher in hyperoxia than hypoxia for both HA and CMS subjects. 6) Peripheral chemoreflex stimulation of ventilation was modestly greater in HA and CMS subjects at an end-tidal Po(2) = 52.5 Torr than in SL natives at an end-tidal Po(2) = 100 Torr. 7) For the HA and CMS subjects combined, there was a strong correlation between end-tidal Pco(2) and hematocrit, which persisted after controlling for AHVR.
The response elicited by exercise on pulmonary pressure, cardiac output, and arterial oxygen saturation in 35 lifetime residents of high altitude has been studied at high altitude (14,900 feet above sea level), and 22 residents of low altitude have been studied at sea level. A procedure combining cardiac catheterization, arterial cannulation, and spirometry was carried out. The exercise was moderate and was performed in supine position using a bicycle ergometer, the work load being 300 kg-m/min/m, ² and the average increase of the oxygen uptake being 4.7 times at sea level and 4.8 times at high altitude.
Both at sea level and at high altitude the cardiac output augmented during exercise proportionally to the increase in oxygen uptake, and thus followed the pattern of response described by other authors. The cardiac output as well as the oxygen intake, for the magnitude of exertion performed in this study, was almost the same at sea level and at high altitude. The cardiac output rose during exercise almost exclusively as a result of an increase in the heart rate, with the stroke volume remaining practically constant.
Despite similar increase in cardiac output, the response of pulmonary pressure was smaller for sea-level subjects than for the high-altitude subjects. Increments of mean pulmonary pressure of nearly 50% and 100% were observed on exercise at sea level and at high altitude, respectively.
During exercise the arterial oxygen saturation did not change in the sea-level studies, but decreased significantly in the high-altitude studies. The decrement observed in high-altitude residents is related to a fall in arterial pO 2 which at resting conditions is placed on the steep part of the oxygen dissociation curve.
Right heart catheterization studies were performed in 38 healthy men 17 to 34 years of age born and living at high altitudes. In order to obtain comparative data, a similar investigation was made in 25 healthy men born and living at sea level. Previously, a physical examination was performed, and roentgenograms of the chest, hematological, electrocardiographic and vectorcardiographic data were obtained. Mild pulmonary hypertension and a moderate increase of the pulmonary vascular resistance and right ventricular work were found in men living permanently at high altitudes. Pulmonary wedge pressure, cardiac output and heart rate did not show significant differences from the data obtained at sea level. The changes occurring in the heart and pulmonary circulation in men living permanently at high altitudes are not quite comparable with the changes described in temporary residents at high altitudes, nor with those experimentally obtained by acute hypoxia. This means that when studying the effects of hypoxia upon the heart and pulmonary circulation, it is important to bear in mind not only the degree of hypoxia but also the time of exposure to it. The augmented pulmonary vascular resistance in the high altitude dweller is related to the anatomic changes in the small pulmonary arteries and arterioles which have been described by other investigators. Functional factors such as vasoconstriction, hypervolemia and polycythemia do not play an important role in the mechanism of the pulmonary hypertension at high altitudes. The role of the pulmonary hypertension in the complex mechanism of acclimatization to life at high altitude is not well understood. Apparently pulmonary hypertension would not accomplish a useful part in this mechanism. It is possible, however, that pulmonary hypetension, in association with other factors such as hyperventilation and an extensive capillary bed of the lungs, does play a role in improving the arterial oxygenation in men living at high altitude.
In cattle grazing during the summer months at altitudes between 8,000 and 12,000 feet (2,500 to 3,700 meters) in Utah and Colorado severe congestive heart failure develops.The disease is apparently the consequence of severe pulmonary hypertension which develops in this species in response to moderate altitudes. This form of chronic mountain sickness has many similarities to pulmonary hypertensive heart disease in man. It differs from Monge's disease in certain significant aspects.It is assumed that the peculiar structure of the pulmonary vascular bed in this species causes an excessive vasoconstrictive response at a reduction in partial pressure of oxygen which is still easily tolerated by man.
In 9 healthy, adult males the work intensity at pulse rate 170 (PWC170) was determined before and after i. m. injection of 0.75 mg methylscopolaminenitrate (MSN). The PWC170 decreased 14 % after MSN. In 15 patients with normal circulation the effect of MSN was studied with heart catheterization at rest and during work at two progressive loads in the supine position. At rest the heart rate increased 66 %, the stroke volume decreased 34 %, and the cardiac output was unchanged. The ventricular filling pressures decreased. During work, performed after MSN, ventricular filling pressures and stroke volume increased progressively. At the highest work load the stroke volume was only 12 % lower than before MSN. Oxygen uptake, cardiac output, central blood volume and vascular resistances in the systemic and pulmonary circulations were unchanged after MSN, both at rest and during work. After MSN the heart volume, determined in the prone position, tended to decrease. The duration of the mechanical diastole, as measured from the phonocardiogram, was significantly shorter after MSN both at rest and during exercise. The investigation elucidates the relationship between the size of the stroke volume and the capacity for work at a given pulse rate and also between the size of the stroke volume and ventricular filling pressure.
Objectives:
The aim of this study was to explore the full range of tricuspid valve regurgitation velocity (TRV) at rest and with exercise in disease free individuals. Additionally we examined the relationship of stroke volume (SV), cardiac output (CO) and TRV to exercise capacity.
Background:
Doppler evaluation of TRV can be used to estimate pulmonary artery systolic pressure (PASP). Most studies have assumed TRV < or = 2.5 m/s as the upper limits of normal. The full range of TRV with exercise has been incompletely defined.
Methods:
Highly conditioned athletes (n = 26) and healthy, active, young male volunteers (n = 14) underwent standardized recumbent bicycle exercise. Exercise parameters included: TRV, SV, CO, systolic (SBP) and diastolic (DBP) systemic blood pressure.
Results:
Tricuspid valve regurgitation, SV, HR and CO were significantly higher in athletes than in nonathletes over all workloads, including rest. Systolic blood pressure and DBP did not show significant differences between the two groups.
Conclusions:
This study defines the upper physiologic limits of TRV at rest and during exercise in normals and provides a noninvasive standard for the diagnosis of pulmonary hypertension.
Lung diffusing capacity has been reported variably in high-altitude newcomers and may be in relation to different pulmonary vascular resistance (PVR). Twenty-two healthy volunteers were investigated at sea level and at 5,050 m before and after random double-blind intake of the endothelin A receptor blocker sitaxsentan (100 mg/day) vs. a placebo during 1 wk. PVR was estimated by Doppler echocardiography, and exercise capacity by maximal oxygen uptake (Vo(2 max)). The diffusing capacities for nitric oxide (DL(NO)) and carbon monoxide (DL(CO)) were measured using a single-breath method before and 30 min after maximal exercise. The membrane component of DL(CO) (Dm) and capillary volume (Vc) was calculated with corrections for hemoglobin, alveolar volume, and barometric pressure. Altitude exposure was associated with unchanged DL(CO), DL(NO), and Dm but a slight decrease in Vc. Exercise at altitude decreased DL(NO) and Dm. Sitaxsentan intake improved Vo(2 max) together with an increase in resting and postexercise DL(NO) and Dm. Sitaxsentan-induced decrease in PVR was inversely correlated to DL(NO). Both DL(CO) and DL(NO) were correlated to Vo(2 max) at sea level (r = 0.41-0.42, P < 0.1) and more so at altitude (r = 0.56-0.59, P < 0.05). Pharmacological pulmonary vasodilation improves the membrane component of lung diffusion in high-altitude newcomers, which may contribute to exercise capacity.
Exercise stress tests have been used for the diagnosis of pulmonary hypertension, but with variable protocols and uncertain limits of normal. The pulmonary haemodynamic response to progressively increased workload and recovery was investigated by Doppler echocardiography in 25 healthy volunteers aged 19-62 yrs (mean 36 yrs). Mean pulmonary artery pressure ((Ppa)) was estimated from the maximum velocity of tricuspid regurgitation. Cardiac output (Q) was calculated from the aortic velocity-time integral. Slopes and extrapolated pressure intercepts of (Ppa)-Q plots were calculated after using the adjustment of Poon for individual variability. A pulmonary vascular distensibility alpha was calculated from each (Ppa)-Q plot to estimate compliance. (Ppa) increased from 14+/-3 mmHg to 30+/-7 mmHg, and decreased to 19+/-4 mmHg after 5 min recovery. The slope of (Ppa)-Q was 1.37+/-0.65 mmHg x min(-1) x L(-1) with an extrapolated pressure intercept of 8.2+/-3.6 mmHg and an alpha of 0.017+/-0.018 mmHg(-1). These results agree with those of previous invasive studies. Multipoint (pa)-Q plots were well described by a linear approximation, from which resistance can be calulated. We conclude that exercise echocardiography of the pulmonary circulation is feasible and provides realistic resistance and compliance estimations. Measurements during recovery are unreliable because of rapid return to baseline.
The aim of the present study was to better understand previously reported changes in lung function at high altitude. Comprehensive pulmonary function testing utilising body plethysmography and assessment of changes in closing volume were carried out at sea level and repeatedly over 2 days at high altitude (4,559 m) in 34 mountaineers. In subjects without high-altitude pulmonary oedema (HAPE), there was no significant difference in total lung capacity, forced vital capacity, closing volume and lung compliance between low and high altitude, whereas lung diffusing capacity for carbon monoxide increased at high altitude. Bronchoconstriction at high altitude could be excluded as the cause of changes in closing volume because there was no difference in airway resistance and bronchodilator responsiveness to salbutamol. There were no significant differences in these parameters between mountaineers with and without acute mountain sickness. Mild alveolar oedema on radiographs in HAPE was associated only with minor decreases in forced vital capacity, diffusing capacity and lung compliance and minor increases in closing volume. Comprehensive lung function testing provided no evidence of interstitial pulmonary oedema in mountaineers without HAPE during the first 2 days at 4,559 m. Data obtained in mountaineers with early mild HAPE suggest that these methods may not be sensitive enough for the detection of interstitial pulmonary fluid accumulation.
Altitude exposure is associated with mild pulmonary hypertension and decreased exercise capacity. We tested the hypothesis that pulmonary vascular resistance (PVR) contributes to decreased exercise capacity in hypoxic healthy subjects.
An incremental cycle ergometer cardiopulmonary exercise test and echocardiographic estimation of pulmonary artery pressure (Ppa) and cardiac output to calculate total PVR were performed in 11 healthy volunteers in normoxia and after 1 h of hypoxic breathing (12% O(2)). The measurements were performed in a random order at 1-week intervals after the receiving either a placebo or bosentan, following a double-blind randomized crossover design. Bosentan was administered twice a day for 3 days, 62.5 mg on the first day and 125 mg on the next 2 days.
Hypoxic breathing decreased the mean (+/- SE) pulse oximetric saturation (Spo(2)) from 99 +/- 1% to 3 +/- 1% and increased the mean PVR from 5.6 +/- 0.3 to 7.2 +/- 0.5 mm Hg/L/min/m(2), together with a decrease in mean maximum O(2) uptake (Vo(2)max) from 47 +/- 2 to 35 +/- 2 mL/kg/min. Bosentan had no effect on normoxic measurements and did not affect hypoxic Spo(2), but decreased PVR to 5.6 +/- 0.3 mm Hg/L/min/m(2) (p < 0.01) and increased Vo(2)max to 39 +/- 2 mL/kg/min (p < 0.01) in hypoxia. Bosentan therapy, on average, restored 30% of the hypoxia-induced decrease in Vo(2)max. Bosentan-induced changes in Ppa and Vo(2)max were correlated (p = 0.01).
We conclude that hypoxic pulmonary hypertension partially limits exercise capacity in healthy subjects, and that bosentan therapy can prevent it.
There are numerous publications on altitude-related diseases in adults. In addition, an International Consensus Statement published in 2001 deals with altitude-related illnesses occurring in lowland children who travel to high altitudes. However, despite the millions of children living permanently at high altitudes around the world, there are few publications on altitude-related diseases and pulmonary hemodynamics in this pediatric population. In this paper, we review the published literature on this subject. First, the pulmonary hemodynamics of healthy children (newborns, infants, children, and adolescents) residing at altitudes above 4000 m are summarized. Asymptomatic pulmonary hypertension, which slowly declines with increasing age, is found in these children. This is followed by a discussion of the functional closure of ductus arteriosus, which is delayed at high altitude. Then, the high prevalence of patent ductus arteriosus (PDA) in highland children and the pulmonary hemodynamics in these patients are described. Next, the pulmonary hemodynamics in highland children who suffer high altitude pulmonary edema (HAPE) after a short stay at lower levels is discussed, and the possible reasons for susceptibility to reentry HAPE in this pediatric population are postulated. The pulmonary hemodynamics in children with subacute mountain sickness (SMS) are then described. Moderate to severe pulmonary hypertension is a common finding in all these altitude-related diseases. Finally, the management of these clinical conditions is outlined.
Persons residing at high altitude who develop excessive polycythemia are more hypoxemic than normal high-altitude residents. We investigated the causes of hypoxemia in 20 patients with excessive polycythemia residing at an altitude of 3,100 m. Lung disease evidenced by abnormal spirometric features and results of a respiratory questionnaire was present in 10 of 20 patients and resulted in increased alveolar-arterial difference for PO2 [(A-a)PO2]. The excessive hypoxemia in the patients with normal lungs was not due to increased (A-a)PO2. We measured ventilatory responses to hypoxia and to hypercapnia to determine whether blunting of these responses was a cause of this excessive hypoxemia. We found, however, that chemical drives to breathe, although blunted, were the same in patients with polycythemia as in high-altitude control subjects. However, an abnormal breathing pattern was observed; the polycythemic patients had a smaller tidal volume and a greater ratio of dead space to tidal volume than did the normal subjects. In addition, the polycythemic patients had increased minute ventilation on breathing 100 percent O2, whereas the normal subjects did not. Thus, hypoxic depression of ventilation may have been present. Our findings suggested that blunted chemical drives are not causative in this disease, and that some other cause of hypoxemia must be present.
A description is given of a disease of infants occurring in Lhasa, Tibet at an altitude of 3600 m. Typically if affects infants who have been born at low altitude and subsequently brought to residue in Lhasa, and it is usually fatal within a few weeks or months. There is extreme medial hypertrophy of muscular pulmonary arteries and muscularization of pulmonary arterioles, together with dilatation of the pulmonary trunk and massive hypertrophy and dilatation of the right ventricle. The disease is distinct from acute or chronic mountain sickness and appears to be the human counterpart of 'brisket disease' in cattle.
Excess CO2 is generated when lactate is increased during exercise because its [H+] is buffered primarily by HCO-3 (22 ml for each meq of lactic acid). We developed a method to detect the anaerobic threshold (AT), using computerized regression analysis of the slopes of the CO2 uptake (VCO2) vs. O2 uptake (VO2) plot, which detects the beginning of the excess CO2 output generated from the buffering of [H+], termed the V-slope method. From incremental exercise tests on 10 subjects, the point of excess CO2 output (AT) predicted closely the lactate and HCO-3 thresholds. The mean gas exchange AT was found to correspond to a small increment of lactate above the mathematically defined lactate threshold [0.50 +/- 0.34 (SD) meq/l] and not to differ significantly from the estimated HCO-3 threshold. The mean VO2 at AT computed by the V-slope analysis did not differ significantly from the mean value determined by a panel of six experienced reviewers using traditional visual methods, but the AT could be more reliably determined by the V-slope method. The respiratory compensation point, detected separately by examining the minute ventilation vs. VCO2 plot, was consistently higher than the AT (2.51 +/- 0.42 vs. 1.83 +/- 0.30 l/min of VO2). This method for determining the AT has significant advantages over others that depend on regular breathing pattern and respiratory chemosensitivity.
In a previous study of normal subjects exercising at sea level and simulated altitude, ventilation-perfusion (VA/Q) inequality and alveolar-end-capillary O2 diffusion limitation (DIFF) were found to increase on exercise at altitude, but at sea level the changes did not reach statistical significance. This paper reports additional measurements of VA/Q inequality and DIFF (at sea level and altitude) and also of pulmonary arterial pressure. This was to examine the hypothesis that VA/Q inequality is related to increased pulmonary arterial pressure. In a hypobaric chamber, eight normal subjects were exposed to barometric pressures of 752, 523, and 429 Torr (sea level, 10,000 ft, and 15,000 ft) in random order. At each altitude, inert and respiratory gas exchange and hemodynamic variables were studied at rest and during several levels of steady-state bicycle exercise. Multiple inert gas data from the previous and current studies were combined (after demonstrating no statistical difference between them) and showed increasing VA/Q inequality with sea level exercise (P = 0.02). Breathing 100% O2 did not reverse this increase. When O2 consumption exceeded about 2.7 1/min, evidence for DIFF at sea level was present (P = 0.01). VA/Q inequality and DIFF increased with exercise at altitude as found previously and was reversed by 100% O2 breathing. Indexes of VA/Q dispersion correlated well with mean pulmonary arterial pressure and also with minute ventilation. This study confirms the development of both VA/Q mismatch and DIFF in normal subjects during heavy exercise at sea level. However, the mechanism of increased VA/Q mismatch on exercise remains unclear due to the correlation with both ventilatory and circulatory variables and will require further study.
The detection of mild nonlinearities and/or state-dependent variability in otherwise linear physiological relationships is generally difficult in the presence of significant measurement errors. Conventional approaches using pooled subject data to increase the degree of freedom for statistical inference are enervated by the resultant introduction of intersubject variability. This paper proposes a new, simple method of pooling multiple subject data for linearity analysis. With the use of a special standardization procedure for the individual response curves, this method allows sensitive detection of occult nonlinearities as well as any state-dependent variability in the underlying relationship. Application of this analytic approach to reported hypercapnic exercise-response data in eight healthy subjects showed that 1) the hypercapnic ventilation-CO2 output relationship is nonlinear with a downward concavity; and 2) the ventilation-tidal volume relationship, which is linear at low tidal volume values, is similar in hypercapnic exercise as in resting hypercapnia or eucapnic exercise.
One hundred healthy subjects (50 male and 50 female), selected to provide an even distribution of age (15 to 71 yr) and height (165 to 194 cm in males and 152 to 176 cm in females), underwent a progressively incremental (100 kpm/min each min) exercise test to a symptom-limited maximum. Measurements were made of O2 intake and CO2 output, ventilation and breathing pattern, heart rate and blood pressure, and rating of perceived exertion. The ventilatory anaerobic threshold was identified. Predictive data were derived for measurements at maximal and submaximal exercise. Maximal power output (Wmax) and oxygen intake (VO2max) varied with sex (0, male; 1, female), age (yr), and height (Ht, cm): Wmax = 20.4 (Ht) - 8.74 (Age) - 288 (Sex) - 1,909 kpm/min (SEE, 216; r, 0.858); VO2max = 0.046 (Ht) - 0.021 (Age) - 0.62 (Sex) - 4.31 L/min (SEE, 0.458; r, 0.869). The extent of leisure time activity exerted a positive influence on VO2max (r, 0.47; p less than 0.001); VO2max was also related to lean thigh volume (r, 0.79). Maximal heart rate (HR) declined as a function of age: HRmax = 202 - 0.72 (Age) beats/min (SEE, 10.3; r, 0.72). Maximal O2 pulse (O2Pmax) was related to height and was systematically higher in males than in females: O2Pmax = 0.28 (Ht) - 3.3 (Sex) - 26.7 ml/beat (SEE, 2.8; r, 0.86). Ventilation was closely related to CO2 output, and the maximal tidal volume was related to vital capacity. The VO2 increased linearly with power throughout the test; in an individual subject, the intercept of this relationship was positively influenced by weight and height.(ABSTRACT TRUNCATED AT 250 WORDS)
Ten male subjects with chronic mountain sickness were studied in Cerro de Pasco, Perú at 14,200 feet above sea level. Cyanosis, extreme polycythemia and very low values of arterial oxygen saturation were frequent findings. Hypoxia and polycythemia of severe degree are related to alveolar hypoventilation demonstrated in previous studies. Roentgen examination as well as electrocardiographic and vectorcardiographic studies showed enlargement of the right cardiac chambers. Pulmonary hypertension, of greater degree than seen in healthy highlanders, was found in these patients. Muscularization of pulmonary arterioles, hypoxic arteriolar vasoconstriction and polycythemia are contributing factors to the mechanism of pulmonary hypertension. The importance of the functional factors is demonstrated by the prompt disappearance of clinical symptoms and the great reduction of right cardiac overload and pulmonary hypertension in the patients moved down to sea level. The clinical symptoms as well as the roentgenologic, electrocardiographic and hemodynamic data are similar to those occurring in cases of chronic cor pulmonale due to alveolar hypoventilation. Muscularization of the pulmonary arteries and reversion of clinical and physiologic findings are also features common to the hypoxic type of chronic cor pulmonale. There is therefore enough clinical, physiologic and anatomic basis to conclude that Monge's disease is a variety of chronic cor pulmonale due to alveolar hypoxia.
The adequacy, efficiency and control of pulmonary gas exchange during exercise was compared among groups who were exposed for various durations of time to moderate hypoxia (3100 m altitude, PiO2 100 mm Hg. These groups included native lowlanders during acute, shortterm (4 to 45 days) and long-term (1–16 yr) exposure and native highlanders of 1 to 3 generations exposure. The working sojourner depended almost entirely on his ventilatory adaptation for maintaining adequate pulmonary and systemic O2 transport at 3100 m. Exercise Dlco, VC, (A-a) DO2 and Hb concentration were unchanged from acute through 21 days exposure, although (A-a) DO2 widened after 45 days at 3100 m. In contrast to the sojourner, the resident of 3100 m hypoventilated during exercise and maintained PaCO2 at or above resting levels. He depended on a high O2 carrying capacity and most importantly on an increased Dlco and Vc and narrowed (A-a) Do2 for his enhanced systemic O2 delivery during work. No differences in the pulmonary response to work were found among long-term and native residents of 3100 m. Hence, the highlander avoided the high levels of ventilatory work and exertional dyspnea experienced by the sojourner without compromising systemic O2 delivery.
Cardiac catheterization studies have been carried out in 2 young male subjects who experienced acute pulmonary edema after a brief sojourn at sea level, when they returned to their native town located at 14,200 feet above sea level. The investigation was performed at this altitude during the acute episode and was repeated after complete recovery. Further studies were made in 1 subject after prolonged residence at sea level.Severe hypoxemia, a marked degree of pulmonary hypertension and increased pulmonary vascular resistance were found during the acute pulmonary edema. These findings were associated with low cardiac output and pulmonary wedge pressure. The degree of pulmonary hypertension was significantly reduced after inhalation of 100 per cent oxygen. Following recovery, physiologic observations were similar to those seen in healthy residents well acclimatized to high altitudes. The data obtained suggest the presence of arteriolar constriction at the precapillary level due to severe hypoxia.Several factors may explain the severe hypoxemia observed in patients with high altitude pulmonary edema. Exercise and sleeping may decrease significantly the arterial oxygen saturation at high altitudes. Pulmonary edema occurred during exercise in our first case, and during sleep in the second. However, special susceptibility appears to be present in humans who develop pulmonary edema after rapid exposure to high altitudes. The role of a sudden rise of pulmonary artery pressure in producing pulmonary edema without elevation of pulmonary wedge pressure is not clear.
Respiratory chemosensitivity was studied in Cerro de Pasco, Peru (4330 m) in 5 normal highlanders (H), 6 highlanders with chronic mountain polycythemia (CMP) without right heart failure, and 7 lowlanders (L) acclimatized for 1–40 weeks. Mean age of groups was 35 and pulmonary function was normal. Hematocrit averaged 51.7 in L, 60.1 in H and 75.4 in CMP. Paco2 was 27.8 ±0.6 mm Hg (s.e.) in L, 31.9±0.7 in H and 34.8±0.9 in CMP. Similarity of CO2 response curve slopes of 2.6 1/min/m2/mm Hg in L, 2.5 in H and 2.2 in CMP suggested that medullary chemoreceptor sensitivity was normal although set chemically, by CSF HCO3− adjustment, to operate at differing Pco2 levels in the 3 groups. However, the ventilatory response to hypoxia () at control Paco2 differed, being 211/min/m3 in L, 5.6 in H and only 2.4 in CMP, and PaO2 as low as 22 mm Hg failed to induce hyperpnea in either H or CMP. It is postulated that chronic hypoxia results in desensitization of the carotid body hypoxia chemoreceptors, and the reduced stimulus permits ventilation to fall and Pco2 to rise. This process may be etiologic in chronic mountain sickness.
The pathogenesis of high-altitude pulmonary oedema (HAPE) is disputed. Recent reports show a strong correlation between the occurrence of HAPE and pulmonary artery pressure, and it is known that the oedema is of the high-permeability type. We have, therefore, proposed that HAPE is caused by ultrastructural damage to pulmonary capillaries as a result of stress failure of their walls. However, no satisfactory electron microscopy studies are available in patients with HAPE, and animal models are difficult to find. Madison strain Sprague-Dawley rats show a brisk pulmonary pressure response to acute hypoxia and are susceptible to HAPE. We exposed 13 Madison rats to a pressure of 294 torr for up to 12.5 h, or 4 rats to 236 torr for up to 8 h. Pulmonary arterial or right ventricular systolic pressures measured with a catheter increased from 30.5 +/- 0.5 (SEM) in controls (n = 4) to 48 +/- 2 torr (n = 11). The lungs were fixed for electron microscopy with intravascular glutaraldehyde. Frothy bloodstained fluid was seen in the trachea of three animals. Ultrastructural examination showed evidence of stress failure of pulmonary capillaries, including disruption of the capillary endothelial layer, or all layers of the wall, swelling of the alveolar epithelial layer, red blood cells (RBCs) and oedematous fluid in the alveolar wall interstitium, proteinaceous fluid and RBCs in the alveolar spaces, and fluid-filled protrusions of the endothelium into the capillary lumen.(ABSTRACT TRUNCATED AT 250 WORDS)
Elevated pulmonary arterial pressure in high-altitude residents may be a maladaptive response to chronic hypoxia. If so, well-adapted populations would be expected to have pulmonary arterial pressures that are similar to sea-level values. Five normal male 22-yr-old lifelong residents of > or = 3,600 m who were of Tibetan descent were studied in Lhasa (3,658 m) at rest and during near-maximal upright ergometer exercise. We found that resting mean pulmonary arterial pressure [15 +/- 1 (SE) mmHg] and pulmonary vascular resistance (1.8 +/- 0.2 Wood units) were within sea-level norms and were little changed while subjects breathed a hypoxic gas mixture [arterial O2 pressure (PaO2) = 36 +/- 2 Torr]. Near-maximal exercise [87 +/- 13% maximal O2 uptake (VO2max)] increased cardiac output more than threefold to values of 18.3 +/- 1.2 l/min but did not elevate pulmonary vascular resistance. Breathing 100% O2 during near-maximal exercise did not reduce pulmonary arterial pressure or vascular resistance. We concluded that this small sample of healthy Tibetans with lifelong residence > or = 3,658 m had resting pulmonary arterial pressures that were normal by sea-level standards and exhibited minimal hypoxic pulmonary vasoconstriction, both at rest and during exercise. These findings are consistent with remarkable cardiac performance and high-altitude adaptation.
This study was conducted to investigate whether the changes in the pulmonary diffusing capacity found in individuals with acute mountain sickness (AMS) reflect the early stage of high-altitude pulmonary edema (HAPE). We measured the pulmonary diffusion capacity for carbon monoxide (DCO) by the single-breath method, arterialized capillary blood gas, and spirometry in a group of 32 healthy subjects (24 men, eight women) at an altitude of 2,260 m and after ascent to 4,700 m. Twelve subjects (10 men, two women) had symptoms of AMS (AMS group) by the second day after arrival at 4,700 m, but none had clinical signs of pulmonary or cerebral edema. In the non-AMS group, almost all subjects exhibited an increase in DCO at 2,260 to 4,700 m (delta DCO, 10.7 +/- 1.25 mL/min/mm Hg), while the degree of increase in DCO in the AMS group (n = 12) was significantly lower (delta DCO, 1.26 +/- 1.74 mL/min/mm Hg) than that of the non-AMS group (p < 0.01). In four of the 12 subjects with AMS who had a high AMS score, DCO decreased from 38.4 +/- 4.5 to 33.2 +/- 5.3 mL/min/mm Hg (delta DCO, -5.84 +/- 1.1 mL/min/mm Hg). The AMS group showed significantly lower vital capacity, forced expiratory flow during the middle half of FVC, PaO2, and a greater alveolar-arterial oxygen pressure difference at 4,700 m compared with the non-AMS group. DCO showed a significant negative correlation with AMS score (r = -0.885) and a positive correlation with PaO2 (r = 0.757) at 4,700 m. These results suggest that the decreased pulmonary diffusing capacity in subjects with AMS reflects the presence of pulmonary gas exchange abnormality, which is probably due to subclinical interstitial edema of the lung.
Pulmonary hypertension is a hallmark of high-altitude pulmonary edema and may contribute to its pathogenesis. Cardiovascular adjustments to hypoxia are mediated, at least in part, by the sympathetic nervous system, and sympathetic activation promotes pulmonary vasoconstriction and alveolar fluid flooding in experimental animals.
We measured sympathetic nerve activity (using intraneural microelectrodes) in 8 mountaineers susceptible to high-altitude pulmonary edema and 7 mountaineers resistant to this condition during short-term hypoxic breathing at low altitude and at rest at a high-altitude laboratory (4559 m). We also measured systolic pulmonary artery pressure to examine the relationship between sympathetic activation and pulmonary vasoconstriction. In subjects prone to pulmonary edema, short-term hypoxic breathing at low altitude evoked comparable hypoxemia but a 2- to 3-times-larger increase in the rate of the sympathetic nerve discharge than in subjects resistant to edema (P<0.001). At high altitude, in subjects prone to edema, the increase in the mean+/-SE sympathetic firing rate was >2 times larger than in those resistant to edema (36+/-7 versus 15+/-4 bursts per minute, P<0.001) and preceded the development of lung edema. We observed a direct relationship between sympathetic nerve activity and pulmonary artery pressure measured at low and high altitude in the 2 groups (r=0.83, P<0.0001).
With the use of direct measurements of postganglionic sympathetic nerve discharge, these data provide the first evidence for an exaggerated sympathetic activation in subjects prone to high-altitude pulmonary edema both during short-term hypoxic breathing at low altitude and during actual high-altitude exposure. Sympathetic overactivation may contribute to high-altitude pulmonary edema.
Exaggerated pulmonary hypertension is thought to play an important part in the pathogenesis of high-altitude pulmonary edema (HAPE). Endothelin-1 is a potent pulmonary vasoconstrictor peptide that also augments microvascular permeability.
We measured endothelin-1 plasma levels and pulmonary artery pressure in 16 mountaineers prone to HAPE and in 16 mountaineers resistant to this condition at low (580 m) and high (4559 m) altitudes. At high altitude, in mountaineers prone to HAPE, mean (+/-SE) endothelin-1 plasma levels were approximately 33% higher than in HAPE-resistant mountaineers (22.2+/-1.1 versus 16.8+/-1.1 pg/mL, P<0.01). There was a direct relationship between the changes from low to high altitude in endothelin-1 plasma levels and systolic pulmonary artery pressure (r=0.82, P<0.01) and between endothelin-1 plasma levels and pulmonary artery pressure measured at high altitude (r=0.35, P=0.05).
These findings suggest that in HAPE-susceptible mountaineers, an augmented release of the potent pulmonary vasoconstrictor peptide endothelin-1 and/or its reduced pulmonary clearance could represent one of the mechanisms contributing to exaggerated pulmonary hypertension at high altitude.
High-altitude pulmonary edema (HAPE) is characterized by severe pulmonary hypertension and bronchoalveolar lavage fluid changes indicative of inflammation. It is not known, however, whether the primary event is an increase in pressure or an increase in permeability of the pulmonary capillaries.
We studied pulmonary hemodynamics, including capillary pressure determined by the occlusion method, and capillary permeability evaluated by the pulmonary transvascular escape of 67Ga-labeled transferrin, in 16 subjects with a previous HAPE and in 14 control subjects, first at low altitude (490 m) and then within the first 48 hours of ascent to a high-altitude laboratory (4559 m). The HAPE-susceptible subjects, compared with the control subjects, had an enhanced pulmonary vasoreactivity to inspiratory hypoxia at low altitude and higher mean pulmonary artery pressures (37 +/- 2 versus 26 +/- 1 mmHg, P<0.001) and pulmonary capillary pressures (19 +/- 1 versus 13 +/- 1 mmHg, P < 0.001) at high altitude. Nine of the susceptible subjects developed HAPE. All of them had a pulmonary capillary pressure >19 mm Hg (range 20 to 26 mmHg), whereas all 7 susceptible subjects without HAPE had a pulmonary capillary pressure < 19 mm Hg (range 14 to 18 mm Hg). The pulmonary transcapillary escape of radiolabeled transferrin increased slightly from low to high altitude in the HAPE-susceptible subjects but remained within the limits of normal and did not differ significantly from the control subjects.
HAPE is initially caused by an increase in pulmonary capillary pressure.
Twenty-eight normal residents of Leadville, Colorado, elevation 10, 150 feet, ranging in age from 13 to 17 years, underwent right heart catheterization. Significant pulmonary hypertension was found: mean pulmonary arterial pressures at rest averaged 25 mm Hg and rose to 54 mm Hg during vigorous supine exercise. It appears that for this population, the altitude of 10,150 feet provides a degree of alveolar hypoxia which is critical for the development of pulmonary hypertension, since no such hypertension is seen 2,800 feet lower.
Acute pulmonary edema was observed in 36 young healthy persons after ascending to altitudes 13,700 feet or more above sea level. Most of them were born and living permanently at high altitudes and developed pulmonary edema on returning to the mountains after a relatively short stay at lower or sea levels.
The clinical manifestations were usually severe and rapidly progressive disappearing in 24 to 48 hours with oxygen administration. The predominant roentgenologic appearance was a coarse mottling exudate, more confluent in both parahilar regions. The heart size remained normal. The electrocardiogram showed acute right ventricular overloading and primary disturbances of repolarization probably related to right ventricular myocardial ischemia. Cardiac catheterization performed in one patient during the recovery period at sea level, revealed normal pressures in the pulmonary artery and capillary bed. Necropsies performed in two patients showed severe pulmonary edema, extensive areas with hyaline membrane, thrombosis of distal arteries and septal capillaries and multiple preterminal arterioles. The left atrium and ventricle were normal and there was a moderate right ventricular hypertrophy usually found in the high altitude resident.
Pulmonary edema of high altitude appears to be the result of a magnification of the hemodynamic changes occurring during a rapid exposure to an environment of hypoxia and low temperature. These changes would be an increase in cardiac output and pulmonary blood volume, pulmonary vasoconstriction at pre-capillary level with secondary pulmonary hypertension, and increased pulmonary capillary permeability.
High-altitude pulmonary oedema (HAPE) occurs in predisposed individuals at altitudes >2,500 m. Defective alveolar fluid clearance secondary to a constitutive impairment of the respiratory transepithelial sodium transport contributes to its pathogenesis. Hypoxia impairs the transepithelial sodium transport in alveolar epithelial type II cells in vitro. If this impairment is also present in vivo, high-altitude exposure could aggravate the constitutive defect in sodium transport in HAPE-prone subjects, and thereby further facilitate pulmonary oedema. Therefore, the aim of the current study was to measure the nasal potential difference (PD) in 21 HAPE-prone and 29 HAPE-resistant subjects at low altitude and 30 h after arrival at high altitude (4,559 m). High-altitude exposure significantly decreased the mean +/- SD nasal PD in HAPE-prone (18.0 +/- 6.2 versus 12.5 +/- 6.8 mV) but not in HAPE-resistant subjects (25.6 +/- 9.4 versus 22.9 +/- 9.2 mV). This altitude-induced decrease was not associated with an altered amiloride-sensitive fraction, but was associated with a significantly lower amiloride-insensitive fraction of the nasal PD. These findings provide evidence in vivo that an environmental factor may impair respiratory transepithelial sodium transport in humans. They are consistent with the concept that in high-altitude pulmonary oedema-susceptible subjects, the combination of a constitutive and an acquired defect in this transport mechanism facilitates the development of pulmonary oedema during high-altitude exposure.
Pulmonary hypertension had long been suspected in high-altitude natives of the Andes. However, it remained for a team of Peruvian scientists led by Dante Penaloza to provide not only the first clear evidence that humans living at high altitude did indeed have chronic, and occasionally severe, pulmonary hypertension, but more importantly, that this was a consequence of structural changes in the pulmonary vascular bed. Novel histological findings by one of the team, Javier Arias-Stella, indicated that hypoxia-induced thickening of the pulmonary arteriolar walls was the primary cause of the elevated pressure. Because the hypertension was not promptly reversed by vasodilators (oxygen inhalation or acetylcholine infusion), they found it differed from acute hypoxic pulmonary vasoconstriction. The team's other novel findings included a delay in the normal fall in pulmonary vascular resistance after birth and, in adults, a lack of vasodilation with muscular exercise. Furthermore, the altitude-related pulmonary hypertension resolved over time at sea level.
Increasing pulmonary arterial (Ppa) and wedge (Pw) pressures at high flow (Q) during exercise could distend the thin-walled vessels. A mechanical descriptor of vascular distension, the distensibility (alpha, fractional diameter change/mmHg pressure), has been reported to be approximately 0.02 for isolated large and small arteries, i.e., a 2% change in diameter per millimeter mercury pressure. In this review we used a pulmonary hemodynamic model to estimate alpha for data from exercising humans to determine whether interpretable results might be obtained. In 59 normal sea level subjects having published measurements of Ppa and Pw over a range of Q, we found values of alpha (0.02 +/- 0.002) giving calculated Ppa, which matched measured Ppa to within 1.3 +/- 0.1 (SE) mmHg. When subjects were exposed to chronic hypoxia (n = 6, in Operation Everest II), alpha decreased (0.022 +/- 0.002 vs. 0.008 +/- 0.001, P < 0.05), but when subjects were exposed to acute hypoxia (Duke chamber study, n = 8), alpha did not decrease (0.014 +/- 0.002 vs. 0.012 +/- 0.002, P = not significant). Values of alpha tended to decrease with age in men >60 yr. Thus at rest and during exercise, normal values of alpha in young persons were similar to those measured in vitro, and the values decreased in chronic hypoxia and with aging where vascular remodeling or vascular wall stiffening was expected. We propose that the estimation of pulmonary vascular distensibility in humans may be a useful descriptor of pulmonary hemodynamics.