Coagulation and fibrinolysis in acute mountain sickness and beginning pulmonary edema

To examine whether intravascular coagulation and/or decreased fibrinolysis precedes high-altitude pulmonary edema (HAPE) we examined 25 male mountaineers (median age 40 yr) at low altitude (550 m) and after 6, 18, and 42 h at an altitude of 4,559 m, which was climbed in 24 h. In 14 subjects, 2 of whom showed radiological evidence of HAPE after 42 h, symptoms of acute mountain sickness (AMS) were mild or absent. Eleven subjects suffered from AMS, six of whom developed radiologically documented HAPE after 18 or 42 h. In the absence of AMS there were no significant changes at high altitude, with the exception of a decrease in bleeding time from 246 +/- 18 to 212 +/- 13 (SE) (P less than 0.05). In AMS, partial thromboplastine time decreased from 34.2 +/- 0.8 to 31.1 +/- 0.5 s (P less than 0.001) and factor VIII procoagulant activity and von Willebrand factor antigen were increased by 57 +/- 12 and 70 +/- 13%, respectively (P less than 0.001), whereas there were no significant changes in beta-thromboglobulin (BTG), fibrinopeptide A (FPA), and fibrin fragment B beta 15-42. In subjects with HAPE, BTG, FPA, and B beta 15-42 were normal before and in beginning HAPE. Preceding HAPE, euglobulin clot lysis time declined at high compared with low altitude from 289 +/- 48 to 201 +/- 42 min without venous occlusion (VO) and from 107 +/- 36 to 86 +/- 31 min after VO (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence against an increase in capillary permeability in subjects exposed to high altitude

Kleger, Gian-Reto, Peter Bärtsch, Peter Vock, BernhardHeilig, L. Jackson Roberts II, and Peter E. Ballmer. Evidence against an increase in capillary permeability in subjects exposed tohigh altitude. J. Appl. Physiol.81(5): 1917-1923, 1996.A potential pathogenetic cofactor for thedevelopment of acute mountain sickness and high-altitude pulmonaryedema is an increase in capillary permeability, which could occur as aresult of an inflammatory reaction and/or free radical-mediatedinjury to the lung. We measured the systemic albumin escape byintravenously injecting 5 µCi of ¹²⁵I-labeled albumin and theplasma concentrations of cytokines, F₂-isoprostanes (products of lipidperoxidation), and acute-phase proteins in 24 subjects exposed to 4,559 m. Ten subjects developed acute mountain sickness, and four subjectsdeveloped high-altitude pulmonary edema. The transcapillary escaperate of albumin was 6.9 ± 2.0%/h (SD) at low (550 m) and 6.3 ± 1.9%/h at high (4,559 m) altitude (P = 0.23; n = 24). The subjects withhigh-altitude pulmonary edema had a modest but insignificant increasein the transcapillary escape rate of albumin (4.6 ± 1.9%/h at lowvs. 5.7 ± 1.9%/h at high altitude;P = 0.42;n = 4). Plasma concentrations offibrinogen, ₁-acidglycoprotein, C-reactive protein, and interleukin-6 were unchanged inthe early phases and significantly increased by the end of theobservation period in the subjects with high-altitude pulmonary edema,whereas tumor necrosis factor- andF₂-isoprostanes did not change atall. This suggests that the inflammatory reaction was rather aconsequence than a causative factor of high-altitude pulmonary edema.In summary, these data argue against a dominant role for increasedsystemic capillary permeability in the development of acute mountainsickness and high-altitude pulmonary edema.

     

Contact phase of blood coagulation is not activated in edema of high altitude

To examine whether bradykinin generated by the activation of the contact phase of blood coagulation is involved in the pathogenesis of edema occurring after acute exposure to high altitude, 15 mountaineers were examined at 490 m and 1, 3, and 5 days after arrival at 4,559 m. The clotting activity levels of factor XII, factor XI, plasma prekallikrein, and high-molecular-weight kininogen (HMWK) were measured, and plasma kallikrein-induced proteolytic cleavage of HMWK was assessed by ligand blotting by use of radiolabeled factor XI. After an ascent on foot from 1,170 to 4,559 m in 3 days, three subjects developed high-altitude pulmonary edema, and four subjects presented facial edema. There was no evidence for activation of the contact system in any subject as demonstrated by the lack of proteolytic cleavage of HMWK at high altitude. The absence of contact system activation was further supported by stable plasma levels of the individual factors of contact activation. Therefore, we conclude that bradykinin generated by plasma kallikrein-induced cleavage of HMWK is not involved in the pathogenesis of edema due to acute exposure to high altitude.     

急性高原病的预防性用药

急性高原病是暴露于高原时,因高原低氧而在数小时至数天内出现的临床症候群,若不及时诊治,会发展为较为严重的高原肺水肿和高原脑水肿。随着我国对西部地区投入力度的增加,内地人员进入高原地区日渐增多,因此如何保证进入高原的人员健康,是医药科研工作的一项重要任务。为使人们有效快速地预防急性高原病,本文对国内外使用较为普遍的药物以及它们的作用机制进行了概述;并对有良好应用前景的药物进行了介绍。     

High Altitude Medical Problems

Increased travel to high altitude areas by mountaineers and nonclimbing tourists has emphasized the clinical problems associated with rapid ascent. Acute mountain sickness affects most sojourners at elevations above 10,000 feet. Symptoms are usually worse on the second or third day after arrival. Gradual ascent, spending one to three days at an intermediate altitude, and the use of acetazolamide (Diamox) will prevent or ameliorate symptoms in most instances. Serious and potentially fatal problems, such as high altitude pulmonary edema or cerebral edema, occur in approximately 0.5 percent to 1.0 percent of visitors to elevations above 10,000 feet—especially with heavy physical exertion on arrival, such as climbing or skiing. Early recognition, high flow oxygen therapy and prompt descent are crucially important in management. Our knowledge of the causes of these and other high altitude problems, such as retinal hemorrhage, systemic edema and pulmonary hypertension, is still incomplete. Even less is known of the effect of high altitudes on medical conditions common at sea level or on the action of commonly used drugs.     

Pathophysiological significance of peroxidative stress, neuronal damage, and membrane permeability in acute mountain sickness.

Free radical-mediated changes in vascular permeability and subsequent inflammatory response may be a contributory pathogenetic cofactor responsible for the development of neurological sequelae associated with acute mountain sickness (AMS). To investigate this, 49 subjects were examined at sea level and serially after rapid ascent to 4,559 m. Although the venous concentration of total creatine phosphokinase activity was measured in all subjects, a complementary examination of lipid peroxidation (F(2)-isoprostanes), inflammatory (TNF-alpha, IL-1beta, IL-2, IL-6, IL-8, C-reactive protein), and cerebrovascular tissue damage (neuron-specific enolase) biomarkers was confined to a subcohort of 24 subjects. A selective increase (P < 0.05) in total creatine phosphokinase was observed in subjects diagnosed with AMS at high altitude (n = 25) compared with apparently healthy controls (n = 24). However, despite a marked increase in IL-6 and C-reactive protein attributable primarily to subjects developing high-altitude pulmonary edema, subcohort analyses demonstrated no selective differences in F(2)-isoprostanes, neuron-specific enolase, or remaining proinflammatory cytokines due to AMS (n = 14). The present findings are the first to demonstrate that free radical-mediated neuronal damage of sufficient degree to be detected in the peripheral circulation does not occur and is, therefore, unlikely to be an important, initiating event that is critical for the development of AMS. The pathophysiological significance of increased sarcolemmal membrane permeability and inflammatory response, either as a cause or epiphenomenon of AMS and/or high-altitude pulmonary edema, remains to be elucidated.     

急性高原暴露后左心功能变化及与急性高原病的关系

目的：研究青年男性由平原急进高原后心脏血流动力学变化及其与急性高原病的关系。方法：分别检测218名健康青年男性在平原及急进高原24h内的血压、心卒和血氧饱和度,使用彩色多普勒超声仪检测左心功能;根据路易斯湖评分标准将受试者分为急性高原病纽（AMS组）和无急性高原病组（无AMS组）。结果：急性高原暴露后心率、舒张压、平均动脉压、左室射血分数、每搏输出量、每博指数、心输出量、心脏指数显著增加（P〈0．05）,血氧饱和度、左室收缩末容积则显著降低（P〈0．05）;急进高原后AMS组心率、收缩压、平均动脉压显著高于无AMS组（P〈0．05）,每博指数、左室舒张末容积显著低于无AMS组（P〈0．05）。结论：健康男性青年急性高原暴露后左心室收缩功能增强,左室舒张末容积、心率、每博指数可能作为预测急性高原病的参考指标。     

Greater free plasma VEGF and lower soluble VEGF receptor-1 in acute mountain sickness.

Vascular endothelial growth factor (VEGF) is a hypoxia-induced protein that produces vascular permeability, and limited evidence suggests a possible role for VEGF in the pathophysiology of acute mountain sickness (AMS) and/or high-altitude cerebral edema (HACE). Previous studies demonstrated that plasma VEGF alone does not correlate with AMS; however, soluble VEGF receptor (sFlt-1), not accounted for in previous studies, can bind VEGF in the circulation, reducing VEGF activity. In the present study, we hypothesized that free VEGF is greater and sFlt-1 less in subjects with AMS compared with well individuals at high altitude. Subjects were exposed to 4,300 m for 19-20 h (baseline 1,600 m). The incidence of AMS was determined by using a modified Lake Louise symptom score and the Environmental Symptoms Questionnaire for cerebral effects. Plasma was collected at low altitude and after 24 h at high altitude, or at time of illness, and then analyzed by ELISA for VEGF and for soluble VEGF receptor, sFlt-1. AMS subjects had lower sFlt-1 at both low and high altitude compared with well subjects and a significant rise in free plasma VEGF on ascent to altitude compared with well subjects. We conclude that increased free plasma VEGF on ascent to altitude is associated with AMS and may play a role in pathophysiology of AMS.     

Physicians on Mount Everest—A Clinical Account of the 1981 American Medical Research Expedition to Everest

The American Medical Research Expedition to Everest had a wide variety of medical problems, ranging from leech bites to high-altitude pulmonary edema. Preventive measures, however, such as careful attention to ingesting only pure water and food at the lower elevations and adequate personal hydration, nutrition and rest at extremely high altitude minimized the morbidity suffered by the group. Prophylactic administration of doxycycline was effective in reducing the severity of diarrheal illness in the group. Every member of the expedition suffered upper respiratory tract infections and many other infections, some of which were resistant to all therapy until the patient moved down from high altitude. Despite careful acclimatization, several cases of acute mountain sickness occurred and required descent to a lower altitude for treatment. Frostbite was avoided entirely.     

Prevalence of acute mountain sickness in the Swiss Alps.

OBJECTIVE--To assess the prevalence of symptoms and signs of acute mountain sickness of the Swiss Alps. DESIGN--A study using an interview and clinical examination in a representative population of mountaineers. Positive symptoms and signs were assigned scores to quantify the severity of acute mountain sickness. SETTING--Four huts in the Swiss Alps at 2850 m, 3050 m, 3650 m, and 4559 m. SUBJECTS--466 Climbers, mostly recreational: 47 at 2850 m, 128 at 3050 m, 82 at 3650, and 209 at 4559 m. RESULTS--In all, 117 of the subjects were entirely free of symptoms and clinical signs of acute mountain sickness; 191 had one or two symptoms and signs; and 158 had more than two. Those with more than two symptoms and signs were defined as suffering from acute mountain sickness. At 4559 m 11 climbers presented with high altitude pulmonary oedema or cerebral oedema, or both. Men and women were equally affected. The prevalence of acute mountain sickness correlated with altitude: it was 9% at 2850 m, 13% at 3050 m, 34% at 3650 m, and 53% at 4559 m. The most frequent symptoms and signs were insomnia, headache, peripheral oedema, and scanty pulmonary rales. Severe headache, vomiting, dizziness, tachypnoea, and pronounced pulmonary rales were associated with other symptoms and signs and therefore characteristic of acute mountain sickness. CONCLUSION--Acute mountain sickness is not an uncommon disease at moderately high altitude--that is, above 2800 m. Severe headache, vomiting, dizziness, tachypnoea, and pronounced pulmonary rales indicate severe acute mountain sickness, and subjects who suffer these should immediately descend to lower altitudes.     

急性高原病的预防性用药

急性高原病是暴露于高原时,因高原低氧而在数小时至数天内出现的临床症候群,若不及时诊治,会发展为较为严重的高原肺水肿和高原脑水肿。随着我国对西部地区投入力度的增加,内地人员进入高原地区日渐增多,因此如何保证进入高原的人员健康,是医药科研工作的一项重要任务。为使人们有效快速地预防急性高原病,本文对国内外使用较为普遍的药物以及它们的作用机制进行了概述;并对有良好应用前景的药物进行了介绍。     

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.     

肠淋巴液引流对失血性休克大鼠红细胞流变性的影响

目的:观察肠淋巴液引流对失血性休克大鼠红细胞流变性指标以及血液黏度的作用。方法:Wistar雄性大鼠均分为假休克组、休克组(复制失血性休克模型)、引流组(复制失血性休克模型,自低血压1 h引流休克肠淋巴液)。在低血压3 h或相应时间,经腹主动脉取血,检测红细胞参数、红细胞电泳、红细胞沉降率(ESR)以及血液黏度,计算红细胞聚集指数、红细胞变形指数。结果:与假休克组比较,休克组红细胞数量、红细胞比积(HCT)、血红蛋白(Hb)、平均红细胞血红蛋白浓度(MCHC)、红细胞电泳率与迁移率、红细胞变形指数、全血黏度、全血低切与高切相对黏度和还原黏度显著降低,休克组平均红细胞体积、红细胞电泳时间、ESR、血沉方程K值与校正K值、红细胞聚集性指数、血浆黏度显著升高;引流组MCHC、红细胞电泳率与迁移率、全血黏度、全血低切与高切还原黏度均显著降低,引流组红细胞体积分布宽度(RDW-SD)显著增加。同时,引流组HCT、RDW-SD、红细胞变形指数、全血黏度、全血低切与高切相对黏度显著高于休克组;ESR、血沉方程K值与校正K值、红细胞聚集性指数、血浆黏度显著低于休克组。结论:休克肠淋巴液引流可改善失血性休克大鼠红细胞流变行为,从而改善血液流变性。     

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.     

Platelet count and function at high altitude and in high-altitude pulmonary edema.

Platelet aggregation is the key process in primary hemostasis. Certain conditions such as hypoxia may induce platelet aggregation and lead to platelet sequestration primarily in the pulmonary microcirculation. We investigated the influence of high-altitude exposure on platelet function as part of a larger study on 30 subjects with a history of high-altitude pulmonary edema (HAPE) and 10 healthy controls. All participants were studied in the evening and the next morning at low altitude (450 m) and after an ascent to high altitude (4,559 m). Platelet count, platelet aggregation (platelet function analyzer PFA100; using epinephrine and ADP as activators), plasma soluble P (sP)-selectin, and the coagulation parameters prothrombin fragments 1+2 and thrombin-antithrombin complex were measured. High-altitude exposure decreased the platelet count, shortened the platelet function analyzer closure time by approximately 20%, indicating increased platelet aggregation, increased sP-selectin levels to approximately 250%, but left plasma coagulation unaffected. The HAPE-susceptible subjects were prophylactically treated with either tadalafil (a phosphodiesterase 5 inhibitor), dexamethasone, or placebo in a double-blind way. Subgroup analyses between these different treatments and comparisons of the seven placebo-treated individuals developing HAPE and controls revealed no differences in platelet count, platelet aggregation, or sP-selectin values. We conclude that exposure to high altitude activates platelets, which leads to platelet aggregation, platelet consumption, and decreased platelet count. These effects are, however, not more pronounced in individuals with a history of HAPE or actually suffering from HAPE than in controls and therefore may not be a pathophysiological mechanism of HAPE.     

Changes in plasma cortisol,blood antidiuretic hormone and urinary catecholamines in high—altitude pulmonary oedema

In 10 subjects susceptible to high altitude pulmonary oedema (HAPO) plasma cortisol and antidiuretic hormone (ADH) and urinary catecholamines were estimated both at sea level and daily during their stay at 3, 500 m (Leh). At high altitude 4 of the subjects developed HAPO, 2 got acute mountain sickness (AMS) and 4 remained unaffected. Plasma cortisol showed a sharp rise on the first day at high altitude in all the subjects. Thereafter, it declined gradually in the unaffected subjects. In the HAPO patients there was a sharp fall in the plasma cortisol level combined with antidiuresis. Changes in plasma ADH and urinary catecholamines were not consistent. It appears that failure in the normal adrenocortical response to altitude stress in susceptible subjects is a factor in precipitating HAPO.     

How well do older persons tolerate moderate altitude?

We studied the physiologic and clinical responses to moderate altitude in 97 older men and women (aged 59 to 83 years) over 5 days in Vail, Colorado, at an elevation of 2,500 m (8,200 ft). The incidence of acute mountain sickness was 16%, which is slightly lower than that reported for younger persons. The occurrence of symptoms of acute mountain sickness did not parallel arterial oxygen saturation or spirometric or blood pressure measurements. Chronic diseases were present in percentages typical for ambulatory elderly persons: 19 (20%) had coronary artery disease, 33 (34%) had hypertension, and 9 (9%) had lung disease. Despite this, no adverse signs or symptoms occurred in our subjects during their stay at this altitude. Our findings suggest that persons with preexisting, generally asymptomatic, cardiovascular or pulmonary disease can safely visit moderate altitudes.     

Acute mountain sickness is not related to cerebral blood flow: a decompression chamber study.

To evaluate the pathogenetic role of cerebral blood flow (CBF) changes occurring before and during the development of acute mountain sickness (AMS), peak mean middle cerebral artery flow velocities () were assessed by transcranial Doppler sonography in 10 subjects at 490-m altitude, and during three 12-min periods immediately (SA1), 3 (SA2), and 6 (SA3) h after decompression to a simulated altitude of 4,559 m. AMS cerebral scores increased from 0. 16 +/- 0.14 at baseline to 0.44 +/- 0.31 at SA1, 1.11 +/- 0.88 at SA2 (P < 0.05), and 1.43 +/- 1.03 at SA3 (P < 0.01); correspondingly, three, seven, and eight subjects had AMS. Absolute and relative at simulated altitude, expressed as percentages of low-altitude values (%), did not correlate with AMS cerebral scores. Average % remained unchanged, because % increased in three and remained unchanged or decreased in seven subjects at SA2 and SA3. These results suggest that CBF is not important in the pathogenesis of AMS and shows substantial interindividual differences during the first hours at simulated altitude.     

Thromboembolic risk factors in kidney transplantation: hemorheologic examination in secondary polycythemia

Cardiovascular risk factors will increase the lethality of kidney patients being under dialysis treatment and after transplantation. This risk is additionally increased after transplantation by secondary polycythemia. The paper investigates the rheological properties of the blood of 20 patients affected by secondary polycythemia after kidney transplantation, 10 patients without polycythemia after kidney transplantation and 19 test persons. Plasma viscosity, erythrocyte aggregation and whole blood viscosity were determined. As a result, an increase of erythrocyte aggregation without their deformability being changed could be found in patients affected by polycythemia after kidney transplantation. The reduced thrombocyte aggregation identified in these patients can be explained by the influence of therapy.     

Internal carotid and vertebral arterial flow velocity in men at high altitude

Cerebral blood flow increases at high altitude, but the mechanism of the increase and its role in adaptation to high altitude are unclear. We hypothesized that the hypoxemia at high altitude would increase cerebral blood flow, which would in turn defend O2 delivery to the brain. Noninvasive Doppler ultrasound was used to measure the flow velocities in the internal carotid and the vertebral arteries in six healthy male subjects. Within 2-4 h of arrival on Pikes Peak (4,300 m), velocities in both arteries were slightly and not significantly increased above sea-level values. By 18-44 h a peak increase of 20% was observed (combined P less than 0.025). Subsequently (days 4-12) velocities declined to values similar to those at sea level. At altitude the lowest arterial O2 saturation (SaO2) and the highest end-tidal PCO2 was observed on arrival. By day 4 and thereafter, when the flow velocities had returned toward sea-level values, hemoglobin concentration and SaO2 were increased over initial high-altitude values such that calculated O2 transport values were even higher than those at sea level. Although the cause of the failure for cerebral flow velocity to increase on arrival is not understood, the subsequent increase may act to defend brain O2 transport. With further increase in hemoglobin and SaO2 over time at high altitude, flow velocity returned to sea-level values.