Christoph Dehnert

Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial.

Context Very few trials have evaluated ways to prevent high-altitude pulmonary edema (HAPE). Contribution In this double-blind trial, 29 adults with a history of HAPE were randomly assigned to receive prophylactic tadalafil, dexamethasone, or placebo during a 24-hour ascent and 2-day stay at 4559 m. Compared with placebo recipients, adults taking dexamethasone less often experienced acute mountain sickness and those taking either dexamethasone or tadalafil less often had HAPE. Cautions The trial involved a small number of selected adults who rapidly ascended to a high altitude. Implications Either tadalafil or dexamethasone might help prevent HAPE in mountaineers with a history of pulmonary edema. The Editors Rapid ascent to altitudes greater than 2500 m may cause acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE). In nonacclimatized mountaineers, the prevalences of AMS and HAPE at 4559 m are approximately 50% and 4%, respectively (1). Individual susceptibility, rate of ascent, and preexposure to high altitude are major, independent determinants of the prevalence of AMS (2). Acute mountain sickness is not a prerequisite for HAPE. Acetazolamide (3, 4) or dexamethasone (5, 6) prophylaxis can prevent AMS, whereas nifedipine prophylaxis can prevent HAPE (7). Whether acetazolamide or dexamethasone also prevents HAPE has not been studied. Exaggerated hypoxic pulmonary vasoconstriction leading to elevated pulmonary capillary pressure (8) is the major pathophysiologic mechanism of HAPE. This elevated pulmonary capillary pressure may be caused by inhomogeneous hypoxic pulmonary vasoconstriction (9), which leads to areas that are subjected to high pressure and flow, consequent mechanical overdistention of pulmonary capillaries, and injury of the bloodgas barrier (10). This phenomenon causes extravasation of fluid, plasma proteins, and blood cells into the interstitial and alveolar spaces (11). Decreased bioavailability of nitric oxide might explain the elevated pulmonary artery pressure (12, 13). Therefore, phosphodiesterase-5 inhibitors are an attractive option to restore impaired effects of nitric oxide in persons susceptible to HAPE (1416). Constitutively impaired sodium and water transport in the lung has been thought to be an additional factor in the pathogenesis of HAPE (17, 18). Hypoxia also decreases water reabsorption from the alveolar space. Direct experimental evidence has been obtained from hypoxia-exposed rats (19), and indirect evidence derives from decreased sodium transport activity in cultured alveolar epithelial cells (20). Prophylactic inhalation of the 2-adrenergic agonist salmeterol to stimulate alveolar sodium transport (17) decreased the incidence of HAPE in susceptible persons. However, other mechanisms of action may also contribute to the preventive effects of salmeterol, because -adrenergics tighten the endothelial barrier and decrease pulmonary artery pressure (21). Dexamethasone may be an alternative therapy to prevent HAPE because it stimulates alveolar sodium and water reabsorption (22); may enhance nitric oxide availability in pulmonary vessels (23, 24); and is effective against AMS (5, 6), which may develop despite use of nifedipine as prophylaxis against HAPE (25). However, HAPE has occurred in persons who received dexamethasone for AMS (26, 27). We sought to test whether prophylaxis with dexamethasone or tadalafil reduces the risk for HAPE in adults with a history of HAPE on rapid ascent to 4559 m. Methods Sample and Setting Mountaineers with a history of HAPE were recruited through announcements in the journals of the Swiss Alpine Club and the German Alpine Club. Four women and 25 men with at least 1 documented episode of HAPE participated after providing written informed consent. Table 1 shows the age and average number of HAPE episodes for each participant. No participant spent more than 4 nights above 2500 m within 30 days before ascent to the Capanna Regina Margherita, Italy (altitude, 4559 m). Table 1. Participant Characteristics Two to 4 weeks before the study at the Capanna Regina Margherita, baseline evaluations were performed in Zrich, Switzerland (altitude, 490 m). For ascent, participants traveled to Alagna, Italy (altitude, 1100 m), ascended to 3200 m by cable car, and continued by foot to the Capanna Gnifetti (altitude, 3600 m), where they spent 1 night. The journey from the cable car arrival station (3200 m) to the Capanna Gnifetti took about 1.5 hours. The next morning, the participants continued to the Capanna Regina Margherita (about 4 hours), where they spent 2 nights. Figure 1 shows the study design. The institutional ethics boards of the University Hospital Zrich and University Hospital Heidelberg approved the study and its protocol, which was consistent with the principles of the Declaration of Helsinki. Figure 1. Flow diagram of the study. Twenty-nine participants were recruited and underwent prealtitude tests, after which they were randomly assigned to treatment groups. *Two participants in the tadalafil group were withdrawn from the study early because they required treatment for severe acute mountain sickness (AMS) with oxygen and dexamethasone before the first night at 4559 m, but high-altitude pulmonary edema (HAPE) was not diagnosed at the time of withdrawal. However, the duration of exposure to 4559 m may not have been long enough to develop HAPE. Randomization and Interventions Medication consisted of white gelatin capsules, identical in appearance, containing placebo; tadalafil, 10 mg (Cialis [Eli Lilly, Geneva, Switzerland]); or dexamethasone, 8 mg (Fortecortin [Merck, Dietikon, Switzerland]). Before the study, the pharmacist at the University Hospital Zrich packaged the medication into numbered bottles, which were assigned to individual participants according to a computer-generated list. Randomization was stratified by the number of previous episodes of HAPE (1 or 2) without blocking. Participants started taking the medication twice daily on the morning of the day before ascent to high altitude and continued intake until the end of the study. Primary End Point and Assessment of HAPE and AMS The primary end point was development of HAPE, which was assessed by clinical examination and chest radiography in each participant after the first and second nights at 4559 m or when HAPE or severe AMS occurred (Figure 1). Two physicians who were blinded to treatment assignment performed clinical examinations according to a predefined checklist in the mornings after the first and second night at 4559 m or when severe AMS or HAPE occurred. High-altitude pulmonary edema was clinically suspected at the appearance of dry cough, orthopnea, or pulmonary rales in at least 1 lung area. A posteroanterior thorax radiograph was then obtained by using a mobile unit (TRS [Siemens, Stockholm, Sweden]) at a fixed distance of 1.4 m at 95 kV and a charge of 3 to 6 mAs. Radiographs were scored retrospectively by a second radiologist who was blinded to other study results. After the lung was divided into 4 quadrants, the following scores were assigned: 1 for a questionable infiltrate, 2 for interstitial edema in less than 50% of the quadrant area, 3 for interstitial edema on 50% or more of the quadrant area, and 4 for alveolar edema. A radiograph showing interstitial or alveolar edema (score >1) in at least 1 quadrant (28) confirmed the diagnosis of HAPE. The severity of AMS was evaluated by clinical examination and was quantified by using the Lake Louise scoring protocol (29). Each participant answered the first 5 questions of the protocol that asked about the severity of headache, gastrointestinal symptoms, fatigue, lightheadedness or dizziness, and insomnia. A score of 0 to 3 points (0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms) was assigned for each item. In clinical examination, a score of 0 (normal) to 4 points was given for mental status (for which 4 points indicated coma) and ataxia (for which 4 points indicated inability to stand on the heel-to-toe walking test). A score of 1 was given for peripheral edema in 1 location, and a score of 2 was given for edema in more than 1 location. The sum of all points yielded the Lake Louise score (maximum score, 25 points). A Lake Louise score greater than 4 defined AMS (30). To assess possible side effects of the study medications, we separately evaluated the Lake Louise score question that asked for information on headache severity and the degree of insomnia, and we measured blood glucose levels in addition to vital signs. To test for adherence, participants were requested to document medication intake and investigators counted the remaining capsules at each visit. Blood and urine samples were collected to measure cortisol and tadalafil, respectively. Treatment of HAPE and AMS consisted of nifedipine for HAPE, dexamethasone for AMS, and supplemental oxygen for both disorders. Participants who required treatment were withdrawn from the study. Echocardiography and Measurement of Cardiac Output Doppler echocardiography was performed by using an integrated color Doppler system with a 4.0-MHz transducer (Aplio 80 [Toshiba-Medical Systems, Oetwil am See, Switzerland]) while participants were lying in a semi-supine, left-lateral position. Systolic pulmonary artery pressure was calculated from the pressure gradient across the tricuspid valve and measured with continuous-wave Doppler echocardiography by using the modified Bernoulli equation and an estimated right atrial pressure of 7 mm Hg (8). Color flow imaging was used for alignment. The recordings were stored on magneto-optical disk for evaluation by 2 investigators who were blinded to all other data. Averages of at least 3 cardiac cycles were used. Cardiac output was measured by using beat-to-beat stroke volume measurement with impedance cardiography (Task Force Monitor [CNSystems, Graz, Austria]). Nasal Potential Measurements Diffe

High-altitude pulmonary hypertension is associated with a free radical-mediated reduction in pulmonary nitric oxide bioavailability

High altitude (HA)‐induced pulmonary hypertension may be due to a free radical‐mediated reduction in pulmonary nitric oxide (NO) bioavailability. We hypothesised that the increase in pulmonary artery systolic pressure (PASP) at HA would be associated with a net transpulmonary output of free radicals and corresponding loss of bioactive NO metabolites. Twenty‐six mountaineers provided central venous and radial arterial samples at low altitude (LA) and following active ascent to 4559 m (HA). PASP was determined by Doppler echocardiography, pulmonary blood flow by inert gas re‐breathing, and vasoactive exchange via the Fick principle. Acute mountain sickness (AMS) and high‐altitude pulmonary oedema (HAPE) were diagnosed using clinical questionnaires and chest radiography. Electron paramagnetic resonance spectroscopy, ozone‐based chemiluminescence and ELISA were employed for plasma detection of the ascorbate free radical (A·−), NO metabolites and 3‐nitrotyrosine (3‐NT). Fourteen subjects were diagnosed with AMS and three of four HAPE‐susceptible subjects developed HAPE. Ascent decreased the arterio‐central venous concentration difference (a‐cvD) resulting in a net transpulmonary loss of ascorbate, α‐tocopherol and bioactive NO metabolites (P < 0.05 vs. LA). This was accompanied by an increased a‐cvD and net output of A·− and lipid hydroperoxides (P < 0.05 vs. sea level, SL) that correlated against the rise in PASP (r= 0.56–0.62, P < 0.05) and arterial 3‐NT (r= 0.48–0.63, P < 0.05) that was more pronounced in HAPE. These findings suggest that increased PASP and vascular resistance observed at HA are associated with a free radical‐mediated reduction in pulmonary NO bioavailability.

Microhemorrhages in Nonfatal High-Altitude Cerebral Edema

Vasogenic edema in the corpus callosum is a characteristic finding in high-altitude cerebral edema (HACE). Furthermore, microhemorrhages have been found at autopsies in brains of HACE victims. The objective of this study was to determine if microhemorrhages also occur in nonlethal HACE. Consequently, magnetic resonance imaging (MRI) was performed in patients who had suffered from HACE and in patients who had suffered from severe acute mountain sickness (AMS) by applying imaging techniques highly susceptible to blood or blood remnants. Two experienced neuroradiologists independently evaluated the exams blinded to clinical data. The MRI was performed 2 to 31 months after the event. The MRI of the HACE patients revealed multiple hemosiderin depositions in the brain—predominantly found in the corpus callosum—indicative of microhemorrhages. These changes were not present in the three AMS patients. In summary, hemosiderin deposits detectable by MRI predominantly in the corpus callosum indicate that microhemorrhages occur in nonlethal HACE, which may serve as a novel diagnostic MRI sign for HACE even many months after the event.

No evidence for interstitial lung oedema by extensive pulmonary function testing at 4,559 m

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.

High altitude pulmonary edema: A pressure-induced leak

High altitude pulmonary edema (HAPE) is a non-cardiogenic pulmonary edema that can occur in healthy individuals who ascend rapidly to altitudes above 3000-4000m. Excessive pulmonary artery pressure (PAP) is crucial for the development of HAPE, since lowering pulmonary artery pressure by nifedipine or tadalafil (phosphodiesterase-5-inhibitor) will in most cases prevent HAPE. Recent studies using microspheres in swine and magnetic resonance imaging in humans strongly support the concept and primacy of nonuniform hypoxic arteriolar vasoconstriction to explain how hypoxic pulmonary vasoconstriction occurring predominantly at the arteriolar level can cause leakage. Evidence is accumulating that the excessive PAP response in HAPE-susceptible individuals is due to a reduced NO bioavailability. HAPE-susceptible individuals show an endothelial dysfunction in the systemic circulation in hypoxia. Lower levels of exhaled NO in hypoxia before and during HAPE suggest that this abnormality also occurs in the lungs and polymorphisms of the eNOS gene are associated with susceptibility to HAPE in the Indian and Japanese population.

Transpulmonary Plasma ET-1 and Nitrite Differences in High Altitude Pulmonary Hypertension

The efficacy and safety of intermittent hypoxia training (IHT) were investigated in healthy, 60- to 74-yr-old men. Fourteen men (Gr 1) who routinely exercised daily for 20 to 30 min were compared with 21 (Gr 2) who avoided exercise. Their submaximal work-load power values before the IHT training were 94 +/- 3.7 and 66 +/- 3.1, respectively. Before and after 10 days of IHT, the ventilatory response to sustained hypoxia (SH; 12% O(2) for 10 min), work capacity (bicycle ergometer), and forearm cutaneous perfusion (laser Doppler) were determined. During SH, no negative electrocardiogram (ECG) changes were observed in either group, and the ventilatory response to SH was unaltered by IHT. In Gr 1, IHT (normobaric rebreathing for 5 min, final Sa(O(2)) = 85% to 86%, followed by 5 min normoxia, 4/day) produced no changes in hemodynamic indixes and work capacity. In Gr 2, IHT decreased blood pressure (BP) by 7.9 +/- 3.1 mmHg (p < 0.05) and increased submaximal work by 11.3% (p < 0.05) and anaerobic threshold by 12.7% (p < 0.05). The increase in HR and BP caused by a 55 W-work load was reduced by 5% and 6.5%, respectively (p < 0.05). Cutaneous perfusion increased by 0.06 +/- 0.04 mL/min/100 g in Gr 1 and by 0.11 +/- 0.04 mL/min/100 g in Gr 2 (p < 0.05). Hyperemia recovery time increased significantly by 15.3 +/- 4.6 sec in Gr 1 and by 25.2 +/- 11.2 sec in Gr 2. Thus, healthy senior men well tolerate IHT as performed in this investigation. In untrained, healthy senior men, IHT had greater positive effects on hemodynamics, microvascular endothelial function, and work capacity.

Can patients with coronary heart disease go to high altitude

Tourism to high altitude is very popular and includes elderly people with both manifest and subclinical coronary heart disease (CHD). Thus, risk assessment regarding high altitude exposure of patients with CHD is of increasing interest, and individual recommendations are expected despite the lack of sufficient scientific evidence. The major factor increasing cardiac stress is hypoxia. At rest and for a given external workload, myocardial oxygen demand is increased at altitude, particularly in nonacclimatized individuals, and there is some evidence that blood-flow reserve is reduced in atherosclerotic coronary arteries even in the absence of severe stenosis. Despite a possible imbalance between oxygen demand and oxygen delivery, studies on selected patients have shown that exposure and exercise at altitudes of 3000 to 3500 m is generally safe for patients with stable CHD and sufficient work capacity. During the first days at altitude, patients with stable angina may develop symptoms of myocardial ischemia at slightly lower heart rate x  blood-pressure products. Adverse cardiac events, however, such as unstable angina coronary syndromes, do not occur more frequently compared with sea level except for those who are unaccustomed to exercise. Therefore, training should start before going to altitude, and the altitude-related decrease in exercise capacity should be considered. Travel to 3500 m should be avoided unless patients have stable disease, preserved left ventricular function without residual capacity, and above-normal exercise capacity. CHD patients should avoid travel to elevations above 4500 m owing to severe hypoxia at these altitudes. The risk assessment of CHD patients at altitude should always consider a possible absence of medical support and that cardiovascular events may turn into disaster.

Assessment of High Altitude Tolerance in Healthy Individuals

The most reliable prediction of high altitude tolerance can be derived from the clinical history of previous comparable exposures. Unfortunately, there are no reliable tests for prediction prior to first-time ascents. Although susceptibility to AMS is usually associated with a low hypoxic ventilatory response (HVR), there is too much overlap with the range of normal values, which precludes measuring HVR or O(2) saturation during brief hypoxia for reliable identification of susceptibility to AMS. A low HVR and an exaggerated rise in pulmonary artery pressure with (prolonged) hypoxia, or exercise in normoxia, are markers of susceptibility to high altitude pulmonary edema (HAPE). These tests can not be recommended for routinely determining high altitude tolerance because the prevalence of susceptibility to HAPE is low and because specificity and sensitivity of these tests are not sufficiently established. On the other hand, HAPE may be avoided in susceptible individuals by ascent rates of 300 m per day above an altitude of 2000 m. Since prediction of risk of mountain sickness is difficult, it is important during the physician consultation prior to ascent to consider the altitude profile, the type of ascent, the performance capacity, the history of previous exposures, and the medical infrastructure of the area.

Training in Normobaric Hypoxia and Its Effects on Acute Mountain Sickness after Rapid Ascent to 4559 m

In a randomized, placebo-controlled, double-blind study, we tested a 4-week program in normobaric hypoxia that is commercially offered for the prevention of acute mountain sickness (AMS). Twenty-two male and 18 female healthy subjects [mean age 33 +/- 7 (SD) years] exercised 70 min, 3 x /week for 3 weeks on a bicycle ergometer at workloads of 60% VO2max either in normoxia (normoxia group, NG) or in normobaric hypoxia (hypoxia group, HG), corresponding to altitudes of 2500, 3000, and 3500 m during weeks 1, 2, and 3, respectively. Four passive exposures of 90 min in normoxia (NG) or hypoxia corresponding to 4500 m (HG) followed in week 4. Five days after the last session, subjects ascended within 24 h from sea level to 4559 m (one overnight stay at 3611 m) and stayed there for 24 h. AMS was defined as LL (Lake Louise score) > or =5 and AMS-C > or =0.70. The AMS incidence (70% in NG vs. 60% in HG, p = 0.74), LL scores (7.1 +/- 4.3 vs. 5.9 +/- 3.4, p = 0.34), and AMS-C scores (1.50 +/- 1.22 vs. 0.93 +/- 0.81, p = 0.25) at the study endpoint were not significantly different between the groups. However, the incidence of AMS at 3611 m (6% vs. 47%, p = 0.01) and the functional LL score at 4559 m were lower in HG. SpO2 at 3611 m, heart rate during ascents, and arterial blood gases at 4559 m were not different between groups. We conclude that the tested program does not reduce the incidence of AMS within a rapid ascent to 4559 m, but our data show that it prevents AMS at lower altitudes. Whether such a program would prevent AMS at higher altitudes, but with slower ascent, remains to be tested.

Exercise reduces airway sodium ion reabsorption in cystic fibrosis but not in exercise asthma

When ventilating large volumes of air during exercise, airway fluid secretion is essential for airway function. Since these are impaired in cystic fibrosis and exercise-induced asthma, it was the aim of this study to determine how exercise affects airway Na+ and Cl- transport and whether changes depend on exercise intensity. Nasal potential was measured in Ringer’s solution, with amiloride to block Na+ transport, and in low chloride-containing isoproterenol to assess Cl- channels. Nasal potential was measured at rest and during submaximal and maximal bicycle ergometer exercise in individuals with cystic fibrosis, exercise-induced asthma and controls. At rest, nasal potential was significantly higher in cystic fibroses than in the others. Maximal exercise decreased nasal potentials in cystic fibrosis and controls but not in exercise asthma. Submaximal exercise decreased nasal potentials only in cystic fibrosis. Cl- transport was not affected. Our results indicate that nasal potentials and Na+ transport were decreased by maximal exercise in healthy and cystic fibrosis, whereas submaximal exercise decreased potentials in cystic fibrosis only. Exercise did not affect nasal potentials in asthmatics. Decreased reabsorption during exercise might favour airway fluid secretion during hyperpnoea. This protective effect appears blunted in patients with exercise-induced asthma.