Pulmonary vascular response of the coati to chronic hypoxia.

The unusually muscular pulmonary arteries normally present in cattle and swine residing at low altitude are associated with a rapid development of severe pulmonary hypertension when those animals are moved to high altitude. Because these species lack collateral ventilation, they appear to have an increased dependence on hypoxic vasoconstriction to maintain normal ventilation-perfusion balance, which, in turn, maintains thickened arterial walls. The only other species known to lack collateral ventilation is the coati, which, similarly, has thick-walled pulmonary arteries. We tested the hypothesis that coatis will develop severe high-altitude pulmonary hypertension by exposing six of these animals (Nasua narica) to a simulated altitude of 4,900 m for 6 wk. After the exposure, pulmonary arterial pressures were hardly elevated, right ventricular hypertrophy was minimal, there was no muscularization of pulmonary arterioles, and, most surprising of all, there was a decrease in medial thickness of muscular pulmonary arteries. These unexpected results break a consistent cross-species pattern in which animals with thick muscular pulmonary arteries at low altitude develop severe pulmonary hypertension at high altitude.     

Insights by Peruvian scientists into the pathogenesis of human chronic hypoxic pulmonary hypertension.

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.     

Inherited susceptibility of cattle to high-altitude pulmonary hypertension.

This study examines the hypothesis that susceptibility of cattle to high-altitude pulmonary hypertension and heart failure (high mountain disease) is genetically transmitted. Eight offspring of cattle recovered from high mountain disease were considered "susceptible." Eleven offspring of healthy cattle residing at high altitude were considered "resistant." At the resident altitude of 1,524 m, 10-day-old susceptible calves had higher pulmonary arterial pressures than did resistant calves (34 vs.21 mmHg), but at 90 days of age the pressures for the two groups were similar (26 vs. 24 mmHg). After 64 days of exposure to an altitude of 3,048 m, the susceptible calves (87 +/- 7 (SE) vs. 40 +/- 3 mmHg). By 124 days at 3,048 m, all susceptible but none of the resistant calves had developed heart failure. The results indicated that susceptibility to pulmonary hypertension at high altitude was inherited. Susceptible cattle may provide a useful model of human hypoxic pulmonary hypertension.     

Impact of acute hypoxic pulmonary hypertension on LV diastolic function in healthy mountaineers at high altitude

In pulmonary hypertension right ventricular pressure overload leads to abnormal left ventricular (LV) diastolic function. Acute high-altitude exposure is associated with hypoxia-induced elevation of pulmonary artery pressure particularly in the setting of high-altitude pulmonary edema. Tissue Doppler imaging (TDI) allows assessment of LV diastolic function by direct measurements of myocardial velocities independently of cardiac preload. We hypothesized that in healthy mountaineers, hypoxia-induced pulmonary artery hypertension at high altitude is quantitatively related to LV diastolic function as assessed by conventional and TDI Doppler methods. Forty-one healthy subjects (30 men and 11 women; mean age 41 +/- 12 yr) underwent transthoracic echocardiography at low altitude (550 m) and after a rapid ascent to high altitude (4,559 m). Measurements included the right ventricular to right atrial pressure gradient (DeltaP(RV-RA)), transmitral early (E) and late (A) diastolic flow velocities and mitral annular early (E(m)) and late (A(m)) diastolic velocities obtained by TDI at four locations: septal, inferior, lateral, and anterior. At a high altitude, DeltaP(RV-RA) increased from 16 +/- 7 to 44 +/- 15 mmHg (P < 0.0001), whereas the transmitral E-to-A ratio (E/A ratio) was significantly lower (1.11 +/- 0.27 vs. 1.41 +/- 0.35; P < 0.0001) due to a significant increase of A from 52 +/- 15 to 65 +/- 16 cm/s (P = 0.0001). DeltaP(RV-RA) and transmitral E/A ratio were inversely correlated (r(2) = 0.16; P = 0.0002) for the whole spectrum of measured values (low and high altitude). Diastolic mitral annular motion interrogation showed similar findings for spatially averaged (four locations) as well as for the inferior and septal locations: A(m) increased from low to high altitude (all P < 0.01); consequently, E(m)/A(m) ratio was lower at high versus low altitude (all P < 0.01). These intraindividual changes were reflected interindividually by an inverse correlation between DeltaP(RV-RA) and E(m)/A(m) (all P < 0.006) and a positive association between DeltaP(RV-RA) and A(m) (all P < 0.0009). In conclusion, high-altitude exposure led to a two- to threefold increase in pulmonary artery pressure in healthy mountaineers. This acute increase in pulmonary artery pressure led to a change in LV diastolic function that was directly correlated with the severity of pulmonary hypertension. However, in contrast to patients suffering from some form of cardiopulmonary disease and pulmonary hypertension, in these healthy subjects, overt LV diastolic dysfunction was not observed because it was prevented by augmented atrial contraction. We propose the new concept of compensated diastolic (dys)function.     

Functional morphology of resistant pulmonary vessels and capillaries in individual and species adaptation to high altitude]

Morphological and structural rearrangement of resistant pulmonary vessels and alveolar capillaries was assessed in lowland animals (rabbits) during high-altitude adaptation, in aboriginal high-altitude species (yaks, mountain goats) and on native highlanders. Structural adaptive developments in pulmonary vessels and capillaries of high-altitude animals contribute to maximal facilitation of gas diffusion. Similar adaptive changes in pulmonary resistant vessels and capillaries of laboratory animals and in native highlanders are associated with pathological alterations manifest in the elevation of pulmonary vascular resistance, right ventricular hypertrophy, increases in the thickness of the basal membrane of the air-blood barrier. In all the subjects studied the process of high-altitude adaptation is associated with hypertrophy of pulmonary endothelium. The intensification of pulmonary endothelium. The intensification of pulmonary endothelium metabolic activity may be directed at regulation of vascular tone.     

The hemodynamics of the lesser circulation and blood indices in rats under long-term high-altitude hypoxia

Pulmonary hemodynamics in anesthetized rats was studied during long-term residence (2,5 and 10 months) at high altitude (3,200 m, Tien Shan). Transbronchial regional electroplethysmography and catheterization of pulmonary artery was used. It has been shown that at all periods of adaptation there was increased systolic pressure in pulmonary artery and practically unchanged diastolic one. Some regional redistributions of pulmonary blood flow and blood volume for five different lung parts were demonstrated. Hemoglobin content in erythrocytes was steadily increased while specific electric blood resistance, hematocrit, and number of erythrocytes did not change so significantly. The role of pulmonary arterial hypertension and changes of other studied indices of hemodynamics and red blood in adaptation to chronic high-altitude hypoxia are being discussed.     

High-altitude chronic hypoxia during gestation and after birth modifies cardiovascular responses in newborn sheep

Perinatal exposure to chronic hypoxia induces sustained pulmonary hypertension and structural and functional changes in both pulmonary and systemic vascular beds. The aim of this study was to analyze consequences of high-altitude chronic hypoxia during gestation and early after birth in pulmonary and femoral vascular responses in newborn sheep. Lowland (LLNB; 580 m) and highland (HLNB; 3,600 m) newborn lambs were cathetherized under general anesthesia and submitted to acute sustained or stepwise hypoxic episodes. Contractile and dilator responses of isolated pulmonary and femoral small arteries were analyzed in a wire myograph. Under basal conditions, HLNB had a higher pulmonary arterial pressure (PAP; 20.2 +/- 2.4 vs. 13.6 +/- 0.5 mmHg, P < 0.05) and cardiac output (342 +/- 23 vs. 279 +/- 13 ml x min(-1) x kg(-1), P < 0.05) compared with LLNB. In small pulmonary arteries, HLNB showed greater contractile capacity and higher sensitivity to nitric oxide. In small femoral arteries, HLNB had lower maximal contraction than LLNB with higher maximal response and sensitivity to noradrenaline and phenylephrine. In acute superimposed hypoxia, HLNB reached higher PAP and femoral vascular resistance than LLNB. Graded hypoxia showed that average PAP was always higher in HLNB compared with LLNB at any Po2. Newborn lambs from pregnancies at high altitude have stronger pulmonary vascular responses to acute hypoxia associated with higher arterial contractile status. In addition, systemic vascular response to acute hypoxia is increased in high-altitude newborns, associated with higher arterial adrenergic responses. These responses determined in intrauterine life and early after birth could be adaptive to chronic hypoxia in the Andean altiplano.     

Blood rheology in acute mountain sickness and high-altitude pulmonary edema.

The role of blood rheology in the pathogenesis of acute mountain sickness and high-altitude pulmonary edema was investigated. Twenty-three volunteers, 12 with a history of high-altitude pulmonary edema, were studied at low altitude (490 m) and at 2 h and 18 h after arrival at 4,559 m. Eight subjects remained healthy, seven developed acute mountain sickness, and eight developed high-altitude pulmonary edema. Hematocrit, whole blood viscosity, plasma viscosity, erythrocyte aggregation, and erythrocyte deformability (filtration) were measured. Plasma viscosity and erythrocyte deformability remained unaffected. The hematocrit level was lower 2 h after the arrival at high altitude and higher after 18 h compared with low altitude. The whole blood viscosity changed accordingly. The erythrocyte aggregation was about doubled 18 h after the arrival compared with low-altitude values, which reflects the acute phase reaction. There were, however, no significant differences in any rheological parameters between healthy individuals and subjects with acute mountain sickness or high-altitude pulmonary edema, either before or during the illness. We conclude that rheological abnormalities can be excluded as an initiating event in the development of acute mountain sickness and high-altitude pulmonary edema.     

Effect of long-term high-altitude hypoxia on fetal pulmonary vascular contractility.

Hypoxia in the fetus and/or newborn is associated with an increased risk of pulmonary hypertension. The present study tested the hypothesis that long-term high-altitude hypoxemia differentially regulates contractility of fetal pulmonary arteries (PA) and veins (PV) mediated by differences in endothelial NO synthase (eNOS). PA and PV were isolated from near-term fetuses of pregnant ewes maintained at sea level (300 m) or high altitude of 3,801 m for 110 days (arterial Po(2) of 60 Torr). Hypoxia had no effect on the medial wall thickness of pulmonary vessels and did not alter KCl-induced contractions. In PA, hypoxia significantly increased norepinephrine (NE)-induced contractions, which were not affected by eNOS inhibitor N(G)-nitro-l-arginine (l-NNA). In PV, hypoxia had no effect on NE-induced contractions in the absence of l-NNA. l-NNA significantly increased NE-induced contractions in both control and hypoxic PV. In the presence of l-NNA, NE-induced contractions of PV were significantly decreased in hypoxic lambs compared with normoxic animals. Acetylcholine caused relaxations of PV but not PA, and hypoxia significantly decreased both pD(2) and the maximal response of acetylcholine-induced relaxation in PV. Additionally, hypoxia significantly decreased the maximal response of sodium nitroprusside-induced relaxations of both PA and PV. eNOS was detected in the endothelium of both PA and PV, and eNOS protein levels were significantly higher in PV than in PA in normoxic lambs. Hypoxia had no significant effect on eNOS levels in either PA or PV. The results demonstrate heterogeneity of fetal pulmonary arteries and veins in response to long-term high-altitude hypoxia and suggest a likely common mechanism downstream of NO in fetal pulmonary vessel response to chronic hypoxia in utero.     

Echocardiographic and invasive measurements of pulmonary artery pressure correlate closely at high altitude

Exaggerated hypoxia-induced pulmonary hypertension is a hallmark of high-altitude pulmonary edema (HAPE) and plays a major role in its pathogenesis. Many studies of HAPE have estimated systolic pulmonary arterial pressure (SPAP) with Doppler echocardiography. Whereas at low altitude, Doppler echocardiographic estimation of SPAP correlates closely with its invasive measurement, no such evidence exists for estimations obtained at high altitude, where alterations of blood viscosity may invalidate the simplified Bernoulli equation. We measured SPAP by Doppler echocardiography and invasively in 14 mountaineers prone to HAPE and in 14 mountaineers resistant to this condition at 4,559 m. Mountaineers prone to HAPE had more pronounced pulmonary hypertension (57 +/- 12 and 58 +/- 10 mmHg for noninvasive and invasive determination, respectively; means +/- SD) than subjects resistant to HAPE (37 +/- 8 and 37 +/- 6 mmHg, respectively), and the values measured in the two groups as a whole covered a wide range of pulmonary arterial pressures (30-83 mmHg). Spearman test showed a highly significant correlation (r = 0.89, P < 0.0001) between estimated and invasively measured SPAP values. The mean difference between invasively measured and Doppler-estimated SPAP was 0.5 +/- 8 mmHg. At high altitude, estimation of SPAP by Doppler echocardiography is an accurate and reproducible method that correlates closely with its invasive measurement.     

Pulmonary artery pressure and cardiac function in children and adolescents after rapid ascent to 3,450 m

High-altitude destinations are visited by increasing numbers of children and adolescents. High-altitude hypoxia triggers pulmonary hypertension that in turn may have adverse effects on cardiac function and may induce life-threatening high-altitude pulmonary edema (HAPE), but there are limited data in this young population. We, therefore, assessed in 118 nonacclimatized healthy children and adolescents (mean ± SD; age: 11 ± 2 yr) the effects of rapid ascent to high altitude on pulmonary artery pressure and right and left ventricular function by echocardiography. Pulmonary artery pressure was estimated by measuring the systolic right ventricular to right atrial pressure gradient. The echocardiography was performed at low altitude and 40 h after rapid ascent to 3,450 m. Pulmonary artery pressure was more than twofold higher at high than at low altitude (35 ± 11 vs. 16 ± 3 mmHg; P < 0.0001), and there existed a wide variability of pulmonary artery pressure at high altitude with an estimated upper 95% limit of 52 mmHg. Moreover, pulmonary artery pressure and its altitude-induced increase were inversely related to age, resulting in an almost twofold larger increase in the 6- to 9- than in the 14- to 16-yr-old participants (24 ± 12 vs. 13 ± 8 mmHg; P = 0.004). Even in children with the most severe altitude-induced pulmonary hypertension, right ventricular systolic function did not decrease, but increased, and none of the children developed HAPE. HAPE appears to be a rare event in this young population after rapid ascent to this altitude at which major tourist destinations are located.     

Correlation of acute with chronic hypoxic pulmonary hypertension in cattle.

We investigated acute and chronic hypoxic pulmonary pressor responses in two groups of calves, one bred to be susceptible, the other resistant to high-altitude pulmonary hypertension. Twelve 5-mo-old susceptible calves residing at 1,524 m increased their mean pulmonary arterial pressure from 26 +/- 2 (SE) to 55 +/- 4 mmHg during 2 h at a simulated altitude of 4,572 m. In 10 resistant calves pressure increased from 22 +/- 1 to 37 +/- 2 mmHg. Five calves were selected from each group for further study. When 9 mo old, the 5 susceptible calves again showed a greater pressor response to acute hypoxia (27 +/- 1 to 55 +/- 4 mmHg) than did 5 resistant calves (23 +/- 1 to 41 +/- 3 mmHg). When 12 mo old, the 5 susceptible calves also developed a greater increase in pulmonary arterial pressure (21 +/- 2 to 9 +/- 4 mmHg) during 18 days at 4,572 m than did the 5 resistant calves (21 +/- 1 to 64 +/- 4 mmHg). Acute and chronic hypoxic pulmonary pressor responses were highly correlated (r = 0.91; P less than 0.001) indicating that they were probably produced through a common mechanism.     

Effect of Frusemide on Pulmonary Blood Volume

Intracardiac frusemide given to seven patients recovering from high-altitude pulmonary oedema caused a significant reduction in the pulmonary blood volume before the onset of diuresis. This supports the suggestion that the mobilization of fluid from the pulmonary circuit is responsible for the relief of symptoms in some patients with pulmonary oedema even when a diuresis does not occur.     

Abnormalities of blood coagulation at high altitude

Immediately on arrival of man at 3,600 m altitude there was a tendency towards hypercoagulation with increase in the platelet count, factor X, factor XII, thrombotest activity and thrombin clotting time with compensatory increase in fibrinolysis and reduction in factor VIII. During continuous stay there was a regression of the hypercoagulation state with reduction in platelet count, platelet factor 3, clot retraction, factor X, factor XII, thrombotest activity and persistence of increased fibrinolytic activity. The main difference in the hypercoagulation state in high-altitude pulmonary oedema and the corresponding highaltitude controls was the absence of a compensatory increase in fibrinolysis and increase in factor VIII. The main difference in the hypercoagulation state in highaltitude pulmonary hypertension and the corresponding high-altitude controls was an increase in platelet adhesiveness, platelet factor 3, factor V and factor VIII. The outstanding difference between high-altitude pulmonary oedema and highaltitude pulmonary hypertension was in the fibrinolytic activity and thrombin clotting time which were reduced in pulmonary oedema but were increased in pulmonary hypertension.

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Zusammenfassung Unmittelbar nach der Ankunft von Männern in 3.600 m Höhe zeigte sich eine Hyperkoagulation mit Anstieg der Plättchenzahl, Faktor X und Faktor XII, Thrombotest-Aktivität und Thrombin-Gerinnungszeit mit kompensatorischem Anstieg der Fibrinolyse und Verminderung von Faktor VIII. Bei längerem Aufenthalt ging der Hyperkoagulationszustand zurück mit verminderter Plättchenzahl, Plättchenfaktor 3, Thrombusretraktion, Faktor X, Faktor XII, Thrombotest-Aktivität und Verbleiben oder Anstieg der fibrinolytischen Aktivität. Der Hauptunterschied in der Hyperkoagulationsphase von Personen mit Lungenoedem und Gesunden in der Höhe war das Fehlen eines kompensatorischen Anstieges der Fibrinolyse und Faktor VIII. Der Hauptunterschied in der Hyperkoagulationsphase von Personen mit pulmonalem Hochdruck und Gesunden in der Höhe war ein Anstieg der Klebrigkeit der Plättchen, Plättchenfaktor 3, Faktor V und Faktor VIII. Die fibrinolytische Aktivität und die Thrombin-Gerinnungszeit waren bei Lungenoedem vermindert und bei pulmonalem Hochdruck erhöht.

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Resume A l'arrivée à 3.600 m d'altitude, on constate chez des sujets d'expérience une hypercoagulation accompagnée d'une hausse du nombre de plaquettes, du facteur X et du facteur XII, de l'activité du thrombotest et du temps de réaction de la thrombine. En compensation, on note une hausse de la fibrinolyse et une baisse du facteur VIII. Un séjour prolongé en altitude a pour conséquence une normalisation des réactions sanguines. Dans la phase d'hypercoagulation, la principale différence observée entre les personnes souffrant d'oedème pulmonaire et les personnes en bonne santé a été que, chez les premières, on n'a pas constaté de hausse compensatoire de la fibrinolyse ni de baisse du facteur VIII. Dans cette même phase, les personnes souffrant d'hypertension pulmonaires se distinguent des gens en bonne santé par le fait que les plaquettes collent entre elles et par une augmentation du facteur de plaques 3, du facteur V et du facteur VIII. L'activité fibrinolytique et le temps de coagulation de la thrombine sont diminués par l'oedème et augmentés par l'hypertension pulmonaire.

     

Mast cells in the human lung at high altitude

Mast cell densities in the lung were measured in five native highlanders of La Paz (3600 m) and in one lowlander dying from high-altitude pulmonary oedema (HAPO) at 3440 m. Two of the highlanders were mestizos with normal pulmonary arteries and the others were Aymara Indians with muscular remodelling of their pulmonary vasculature. The aim of the investigation was to determine if accumulation of mast cells in the lung at high altitude (HA) is related to alveolar hypoxia alone, to a combination of hypoxia and muscularization of the pulmonary arterial tree, or to oedema of the lung. The lungs of four lowlanders were used as normoxic controls. The results showed that the mast cell density of the two Mestizos was in the normal range of lowlanders (0.6–8.8 cells/mm²). In the Aymara Indians the mast cell counts were raised (25.6–26.0 cells/mm²). In the lowlander dying from HAPO the mast cell count was greatly raised to 70.1 cells/mm² lung tissue. The results show that in native highlanders an accumulation of mast cells in the lung is not related to hypoxia alone but to a combination of hypoxia and muscular remodelling of the pulmonary arteries. However, the most potent cause of increased mast cell density in the lung at high altitude appears to be high-altitude pulmonary oedema.     

Viral respiratory infection increases susceptibility of young rats to hypoxia-induced pulmonary edema

Recentclinical observations of a high incidence of preexisting respiratoryinfections in pediatric cases of high-altitude pulmonary edema promptedus to ask whether such infections would increase the susceptibility tohypoxia-induced pulmonary edema in young rats. We infected weanlingrats with Sendai virus, thus causing a mild respiratory infection.Within 7 days of infection, Sendai virus was essentially undetectableby using viral culture and immunohistochemical techniques. Animals atday 7 of Sendai virus infection werethen exposed to normobaric hypoxia (fraction of inspiredO₂ = 0.1) for 24 h and examinedfor increases in gravimetric lung water and in vascular permeability,as well as for histological evidence of increased lung water.Bronchoalveolar lavage was performed on a separate series of animals.Compared with control groups, infected hypoxic animals showedsignificant increases in perivascular cuffing, gravimetric lung water,and lung protein leak. In addition, infected hypoxic animals hadincreases in lavage fluid cell counts and protein content compared withcontrols. We conclude that young rats, exposed to moderate hypoxiawhile recovering from a mild viral respiratory infection, maydemonstrate evidence of early pulmonary edema formation, a finding ofpotential relevance to human high-altitude pulmonary edema.

     

Perfusion Lung Scans Provide a Guide to Which Patients With Apparent Primary Pulmonary Hypertension Merit Angiography

There is hesitancy, based on the perceived risk, to do pulmonary angiography in patients believed to have primary pulmonary hypertension. Yet pulmonary hypertension due to major-vessel, chronic thromboembolism mimics primary pulmonary hypertension clinically and on standard laboratory tests. Because thromboembolic pulmonary hypertension is potentially remediable by thromboendarterectomy and primary pulmonary hypertension is not, differentiating between these disorders is essential. Angiography is required in patients with thromboembolic pulmonary hypertension to define the anatomic location of the thrombi. In evaluating perfusion lung scans of 110 patients with pulmonary hypertension to determine whether the scan might provide a guide to selecting those patients who merit angiography, no segmentalsize perfusion defects were noted on the scans of 64 patients with primary pulmonary hypertension, whereas all 46 patients with thromboembolic hypertension had one or more defects that were segmental in size or larger. These data indicate that a perfusion lung scan should be done in patients with pulmonary hypertension of uncertain cause and that those with one or more segmental or larger defects merit pulmonary angiography before being diagnosed as having primary pulmonary hypertension.     

Effects of altitude and exercise on pulmonary capillary integrity: evidence for subclinical high-altitude pulmonary edema.

Strenuous exercise may be a significant contributing factor for development of high-altitude pulmonary edema, particularly at low or moderate altitudes. Thus we investigated the effects of heavy cycle ergometer exercise (90% maximal effort) under hypoxic conditions in which the combined effects of a marked increase in pulmonary blood flow and nonuniform hypoxic pulmonary vasoconstriction could add significantly to augment the mechanical stress on the pulmonary microcirculation. We postulated that intense exercise at altitude would result in an augmented permeability edema. We recruited eight endurance athletes and examined their bronchoalveolar lavage fluid (BALF) for red blood cells (RBCs), protein, inflammatory cells, and soluble mediators at 2 and 26 h after intense exercise under normoxic and hypoxic conditions. After heavy exercise, under all conditions, the athletes developed a permeability edema with high BALF RBC and protein concentrations in the absence of inflammation. We found that exercise at altitude (3,810 m) caused significantly greater leakage of RBCs [9.2 (SD 3.1)x10(4) cells/ml] into the alveolar space than that seen with normoxic exercise [5.4 (SD 1.2)x10(4) cells/ml]. At altitude, the 26-h postexercise BALF revealed significantly higher RBC and protein concentrations, suggesting an ongoing capillary leak. Interestingly, the BALF profiles following exercise at altitude are similar to that of early high-altitude pulmonary edema. These findings suggest that pulmonary capillary disruption occurs with intense exercise in healthy humans and that hypoxia augments the mechanical stresses on the pulmonary microcirculation.     

Cerebral blood flow velocity responses to hypoxia in subjects who are susceptible to high-altitude pulmonary oedema

Cerebral blood flow increases on exposure to high altitude, and perhaps more so in subjects who develop acute mountain sickness. We determined cerebral blood flow by transcranial Doppler ultrasound of the middle cerebral artery at sea level, in normoxia (fraction of inspired O2, F(I)O2 0.21), and during 15-min periods of either hypoxic (F(I)O2 0.125) or hyperoxic (F(I)O2 1.0) breathing, in 7 subjects with previous high-altitude pulmonary oedema, 6 climbers who had previously tolerated altitudes between 6000 m and 8150 m, and in 20 unselected controls. Hypoxia increased mean middle cerebral artery flow velocity from 69 (3) to 83 (4) cm x s(-1) (P<0.001) in the controls, from 63 (3) to 75 (3) cm x s(-1) (P<0.001) in the high-altitude pulmonary-oedema-susceptible subjects, and from 58 (4) to 70 (4) cm x s(-1) (P<0.001) in the successful high-altitude climbers. Hyperoxia decreased mean middle cerebral flow velocity to 60 (3) cm x s(-1) (P<0.001), 53 (3) cm x s(-1) (P<0.01), and 49 (3) cm x s(-1) (P<0.01) in the controls, high-altitude pulmonary-oedema-susceptible, and high-altitude climbers, respectively. We conclude that a transcranial Doppler-based estimate of cerebral blood flow is affected by hypoxic and hyperoxic breathing, and that it is not predictive of tolerance to high altitude.