2022 Jun 1;132(6):1361-1369. doi: 10.1152/japplphysiol.00806.2021. Epub 2022 May 5.
Effects of acetazolamide on pulmonary artery pressure and prevention of high-altitude pulmonary edema after rapid active ascent to 4,559 m
Marc Moritz Berger 1, Mahdi Sareban 2 3, Lisa Maria Schiefer 4, Kai E Swenson 5, Franziska Treff 4, Larissa Schäfer 4, Peter Schmidt 4, Magdalena M Schimke 4, Michael Paar 6, Josef Niebauer 2 3, Annalisa Cogo 7, Susi Kriemler 8, Stefan Schwery 9, Philipp A Pickerodt 10, Benjamin Mayer 11, Peter Bärtsch 12, Erik R Swenson 13
Affiliations expandPMID: 35511718
DOI: 10.1152/japplphysiol.00806.2021
Abstract
Acetazolamide prevents acute mountain sickness (AMS) by inhibition of carbonic anhydrase. Since it also reduces acute hypoxic pulmonary vasoconstriction (HPV), it may also prevent high-altitude pulmonary edema (HAPE) by lowering pulmonary artery pressure. We tested this hypothesis in a randomized, placebo-controlled, double-blind study. Thirteen healthy, nonacclimatized lowlanders with a history of HAPE ascended (<22 h) from 1,130 to 4,559 m with one overnight stay at 3,611 m. Medications were started 48 h before ascent (acetazolamide: n = 7, 250 mg 3 times/day; placebo: n = 6, 3 times/day). HAPE was diagnosed by chest radiography and pulmonary artery pressure by measurement of right ventricular to atrial pressure gradient (RVPG) by transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and AMS-C score. The incidence of HAPE was 43% versus 67% (acetazolamide vs. placebo, P = 0.39). Ascent to altitude increased RVPG from 20 ± 5 to 43 ± 10 mmHg (P < 0.001) without a group difference (P = 0.68). Arterial Po2 fell to 36 ± 9 mmHg (P < 0.001) and was 8.5 mmHg higher with acetazolamide at high altitude (P = 0.025). At high altitude, the LLS and AMS-C score remained lower in those taking acetazolamide (both P < 0.05). Although acetazolamide reduced HAPE incidence by 35%, this effect was not statistically significant, and was considerably less than reductions of about 70%-100% with prophylactic dexamethasone, tadalafil, and nifedipine performed with the same ascent profile at the same location. We could not demonstrate a reduction in RVPG compared with placebo treatment despite reductions in AMS severity and better arterial oxygenation. Limited by small sample size, our data do not support recommending acetazolamide for the prevention of HAPE in mountaineers ascending rapidly to over 4,500 m.NEW & NOTEWORTHY This randomized, placebo-controlled, double-blind study is the first to investigate whether acetazolamide, which reduces acute mountain sickness (AMS), inhibits short-term hypoxic pulmonary vasoconstriction, and also prevents high-altitude pulmonary edema (HAPE) in a fast-climbing ascent to 4,559 m. We found no statistically significant reduction in HAPE incidence or differences in hypoxic pulmonary artery pressures compared with placebo despite reductions in AMS and greater ventilation-induced arterial oxygenation. Our data do not support recommending acetazolamide for HAPE prevention.
Keywords: AMS; Diamox; HAPE; acetazolamide; acute mountain sickness.
Acetazolamide prevents acute mountain sickness (AMS) by inhibition of carbonic anhydrase. Since it also reduces acute hypoxic pulmonary vasoconstriction (HPV), it may also prevent high-altitude pulmonary edema (HAPE) by lowering pulmonary artery pressure. We tested this hypothesis in a randomized, placebo-controlled, double-blind study. Thirteen healthy, nonacclimatized lowlanders with a history of HAPE ascended (<22 h) from 1,130 to 4,559 m with one overnight stay at 3,611 m. Medications were started 48 h before ascent (acetazolamide: n = 7, 250 mg 3 times/day; placebo: n = 6, 3 times/day). HAPE was diagnosed by chest radiography and pulmonary artery pressure by measurement of right ventricular to atrial pressure gradient (RVPG) by transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and AMS-C score. The incidence of HAPE was 43% versus 67% (acetazolamide vs. placebo, P = 0.39). Ascent to altitude increased RVPG from 20 ± 5 to 43 ± 10 mmHg (P < 0.001) without a group difference (P = 0.68). Arterial Po2 fell to 36 ± 9 mmHg (P < 0.001) and was 8.5 mmHg higher with acetazolamide at high altitude (P = 0.025). At high altitude, the LLS and AMS-C score remained lower in those taking acetazolamide (both P < 0.05). Although acetazolamide reduced HAPE incidence by 35%, this effect was not statistically significant, and was considerably less than reductions of about 70%–100% with prophylactic dexamethasone, tadalafil, and nifedipine performed with the same ascent profile at the same location. We could not demonstrate a reduction in RVPG compared with placebo treatment despite reductions in AMS severity and better arterial oxygenation. Limited by small sample size, our data do not support recommending acetazolamide for the prevention of HAPE in mountaineers ascending rapidly to over 4,500 m.
NEW & NOTEWORTHY This randomized, placebo-controlled, double-blind study is the first to investigate whether acetazolamide, which reduces acute mountain sickness (AMS), inhibits short-term hypoxic pulmonary vasoconstriction, and also prevents high-altitude pulmonary edema (HAPE) in a fast-climbing ascent to 4,559 m. We found no statistically significant reduction in HAPE incidence or differences in hypoxic pulmonary artery pressures compared with placebo despite reductions in AMS and greater ventilation-induced arterial oxygenation. Our data do not support recommending acetazolamide for HAPE prevention.
INTRODUCTION
High-altitude pulmonary edema (HAPE) is a noncardiogenic pulmonary edema that develops within 1–5 days after an acute altitude exposure > 2,500 m when acclimatization is insufficient (1). The typical symptoms are an inappropriate level of dyspnea during exercise, reduced exercise performance, cough, and chest congestion. In advanced illness, dyspnea at rest, orthopnea, and expectoration of pink frothy sputum may also occur (1, 2). The main factor in the pathophysiology of HAPE is excessive hypoxic pulmonary vasoconstriction (HPV) that is regionally uneven, leading to pressure-induced fluid leakage in highly perfused and less vasoconstricted regions of the lungs (3–7). The critical role of high pulmonary vascular pressure is consistent with the fact that descent, oxygen and other drugs that lower pulmonary artery pressure (e.g., nifedipine and tadalafil) are all effective in preventing and treating HAPE (3, 8, 9).
Acetazolamide is a carbonic anhydrase (CA) inhibitor and is the mainstay of pharmacological prevention of acute mountain sickness (AMS) (1, 10), which is a syndrome of nonspecific symptoms (headache, malaise, anorexia, nausea, and dizziness) occurring in nonacclimatized individuals within 1–3 days after reaching altitudes > 2,500 m (11, 12). In addition to its AMS-preventive effects, acetazolamide has been shown to blunt acute HPV (13–16) to the same extent as nifedipine, tadalafil, and sildenafil (8, 9, 17, 18). Several mechanisms may be responsible for the HPV-lowering effect of acetazolamide: a direct effect on the pulmonary vasculature and indirectly by increasing ventilation and alveolar oxygen partial pressure (PAO2PAO2) (19), the main stimulus for HPV. It may also improve gas exchange, reduce diffusion limitation, and improve ventilation-perfusion matching in normoxic and hypoxic exercise (20). Studies in isolated pulmonary artery smooth muscle cells show that acetazolamide prevents the hypoxia-mediated increase in cytosolic calcium that initiates smooth muscle contraction and does so by a mechanism not involving CA inhibition, since a slightly modified analog of acetazolamide that is incapable of inhibiting CA, still lowers hypoxic pulmonary artery pressures (21).
Although these findings make a strong case that acetazolamide might reduce the incidence of HAPE, there have been no studies that have evaluated the effect of acetazolamide on pulmonary artery pressure and HAPE in humans in the context of alpine style climbing, i.e., during a fast ascent to altitudes above 4,000 m. We hypothesized that prophylactic acetazolamide would blunt pulmonary artery pressure elevation at high altitude and thus reduce the incidence of HAPE after rapid and active ascent to 4,559 m.
METHODS
Study Approval and Registration
The study was performed in accordance with the Declaration of Helsinki and its current amendments, and was approved by the Ethical Committee Salzburg, Austria, by the Ethical Committee of the University of Torino, Italy, and by the Austrian Competent Authority (BASG), Vienna, Austria. The trial was registered at the European Union Clinical Trials Register (2017–005166-22). The study was conducted in the summer of 2019 as a prospective, randomized, double-blind, and placebo-controlled trial.
Subjects and Treatment Groups
After written informed consent was obtained, 18 healthy, nonsmoking, and nonacclimatized native lowlanders with a previous history of radiographically documented HAPE were included in the study. Prior to the study, a sample size calculation was performed. Based on an effect size of 0.75, which was roughly that observed with nifedipine (8) and tadalafil (9), an α-error probability of 0.05, and a power (1 − β error probability) of 0.8 the required sample size for the two study groups (placebo vs. acetazolamide) analyzed by a chi-square test was calculated to be 18 participants (G*Power 3.1.9.2). Subjects with a sojourn > 2,000 m within the last 4 wk before the first study day were excluded. The analysis is based on the data obtained in 13 instead of 18 planned subjects since three participants had to be excluded due to nonspecific ST-segment depression found at maximal exercise during the pre-examination, and two other subjects withdrew their participation on short notice.
Subjects were randomly assigned to receive 250 mg acetazolamide three times per day (n = 7 subjects) or lactose-monohydrate (placebo group, n = 6 subjects). The tablets for both study groups looked identical. During the low-altitude tests, subjects were instructed on the correct intake of the study drugs and to start them 2 days before ascent and continue until the end of the study. Both the participants and the investigators were blinded with respect to the study drug. For the duration of the drug intake, carbonated beverages were forbidden and participants were informed that the placebo might cause the same side effects as acetazolamide (e.g., tingling in the fingers, feet, and perioral region, increased urine output, and nausea). Other personal medications were not allowed.
Study Protocol
Baseline measurements were performed at an altitude of 423 m (Salzburg, Austria). They consisted of a medical history review with special emphasis on HAPE, a physical examination, a ramp test protocol on a cycle ergometer until voluntary exhaustion, arterial blood drawing, chest radiography, assessment of AMS, and transthoracic echocardiography for the determination of the right ventricular pressure gradient (RVPG) as an indicator of systolic pulmonary artery pressure.
Between 2 and 4 wk later, subjects traveled to Alagna (1,130 m), Valsesia, Italy, and ascended in groups of three to five accompanied by licensed mountain guides to 4,559 m in <22 h. The ascent consisted of transport by cable car to 3,275 m, and a 90-min climb to 3,611 m (Capanna Giovanni Gnifetti), where they spent one night. On the next morning, they climbed to 4,559 m (Capanna Regina Margherita, Monte Rosa) within 4–5 h. AMS, RVPG, and hemodynamics were assessed at low altitude and at 5, 19, 29, 43, 53, and 67 h after arrival at 4,559 m. Radiographs and arterial blood samples for blood gas analyses were taken at low altitude and at 19, 43, and 67 h at high altitude, and when HAPE was clinically suspected because of dry cough, orthopnea, or pulmonary rales in at least one lung area.
Diagnosis and Treatment of HAPE and AMS
The diagnosis of HAPE was based on posteroanterior thorax radiographs that were obtained using a mobile unit (Mobilett XP, Siemens) at a fixed distance of 1.4 m at 99 or 109 kV, respectively, and a charge of 2–2.5 mA. The investigators made the initial radiological diagnosis of HAPE to treat any subject who felt ill in a way consistent with their past experience with HAPE. However, the final diagnosis was made by a radiologist blinded to the clinical and experimental data, who retrospectively analyzed all radiographs in random order. For the diagnosis of HAPE, the lung was divided into four quadrants, with the mediastinum used as a vertical axis and the hila as a horizontal axis. The four lung areas were assessed separately for the presence of edema. A score of 0 points indicated normal lung parenchyma. Questionable pathological areas were given a score of 1; definite interstitial edema of less than 50% of the area was given 2 points; nonconfluent interstitial edema of more than 50% of the area was rated with a score of 3 points; and alveolar, partly confluent edema was rated with 4 points (22). Radiographs with a score of ≥2 points in at least one lung quadrant were considered positive for HAPE. The total lung score was obtained by adding the four regional scores, yielding a possible range from 0 to 16 points as described previously (22).
AMS was evaluated using the 2018 Lake Louise score (cumulative self-report + clinical scores) and the AMS-C score of a paper-based abbreviated version of the Environmental Symptoms Questionnaire (12, 23). Individuals were considered to have AMS when they had a Lake-Louise score (LLS) ≥5 in combination with an AMS-C score ≥ 0.70 (11) at least during one evaluation while at 4,559 m. When only one of the scores was positive, subjects were classified as not having AMS (24).
Subjects with clinical and radiographic signs of HAPE were given nifedipine, supplemental oxygen, and dexamethasone (4 mg). This approach was chosen to ensure a fast and sustained release of symptoms and to improve comfort of the affected volunteers all of which also had AMS. In these subjects, final measurements were performed before treatment was initiated and data collection was terminated thereafter. If in cases of severe AMS subjects requested therapy, headache was treated with paracetamol (500–1,000 mg), and nausea was treated with metoclopramide (10 mg) according to published expert opinion (10). This was the case in two participants on the first and second study day, respectively. At this time point, they had AMS-C scores of 2.3 and 3.4 and a corresponding LLS of 8 and 13. The next recorded AMS scoring was performed at least 6 h after drug intake. Because paracetamol and metoclopramide are not known to affect pulmonary artery pressure and/or HAPE, these subjects remained in the study, and data collection was continued.
Assessment of Right Ventricular Pressure Gradient and Systemic Hemodynamics
All cardiac ultrasounds were conducted by the same experienced cardiac sonographer with the subject lying in the left lateral decubitus position after participants rested for 5 min in supine position. For the determination of RVPG, peak-flow velocities of tricuspid valve regurgitation jets were measured at the highest coherent boundary of the spectral wave using continuous-wave Doppler, guided by color-flow Doppler (Philips CX50, Philips Medical Systems, Andover, MA) with a 1.0–5.0 MHz sector array transducer (Philips S5-1, Philips Medical Systems, Andover, MA). RVPG was calculated from a modified Bernoulli equation as described previously (25–27). All images were saved in a raw Digital Imaging and Communications in Medicine (DICOM) format on a mass storage device and analyzed offline in random order by two independent sonographers using commercially available software (Philips Xcelera, Phillips Medical Systems, Andover, MA).
Heart rate and peripheral oxygen saturation (Spo2) were measured by pulse oximetry (Covidien Nellcor, Mansfield), and blood pressure was measured noninvasively by analyzing brachial artery waveforms (Pulsecor, Auckland, New Zealand).
Blood Gas Analysis
Arterial blood samples were collected from the radial artery in supine position after 10 min of rest using heparinized syringes equipped with a gold-coated mixing ball (safePICO, Radiometer, Brønshøj, Denmark). Blood samples were immediately analyzed in triplicate with a blood gas analyzer (Radiometer ABL 90 flex, Brønshøj, Denmark) for the measurement of partial pressures of oxygen (Po2) and carbon dioxide (Pco2), pH, base excess, bicarbonate (HCO3−), hemoglobin (Hb), and hemoglobin-oxygen saturation (So2). The alveolar to arterial Po2 difference (A-aDO2) was calculated from the alveolar gas equation assuming a respiratory exchange ratio of 0.85.
Statistical Analyses
Normal distribution of the data was tested using the Kolmogorov–Smirnov test. Differences in the incidence of HAPE and AMS were analyzed by the Chi-squared test. Group comparisons in Figs. 1 and 3 were made by t test. Furthermore, mixed linear regression modeling was used to analyze repeated measures data on arterial blood gases, hemoglobin, AMS score, blood pressure, and heart rate values presented in Tables 2 and 3. In these models, all available measurements up to 67 h post ascent were used, and statistical inference was made based on appropriate linear contrast hypotheses. Continuous data are either expressed as mean values and 95% confidence interval (CI) or mean values and standard deviation (SD). A P value of ≤0.05 (two-sided) was considered significant. No adjustment for multiple hypothesis testing was made since our primary research hypothesis was focused on an evaluation of HAPE incidence in the two study groups. All other results from statistical hypothesis testing are interpreted in an explorative manner only. Statistics were performed using the SigmaStat and SAS software packages (Systat Software Inc., Berkshire, UK; SAS Institute, Cary, NC).
Figure 1.Radiographic score at 4,559 m at the time point when HAPE was diagnosed (P < 0.001 vs. no HAPE). From one subject with HAPE, the radiographic score could not be obtained (for details, see text). Because HAPE developed between 5 and 67 h at 4,559 m, for those who did not develop HAPE, the highest radiographic score during the entire stay at high altitude is displayed. Both groups contain subjects with acetazolamide and placebo. HAPE, high-altitude pulmonary edema.
RESULTS
Baseline Characteristics
Table 1 summarizes the baseline characteristics of the two treatment groups including the number of previous HAPE episodes. There were no statistically significant group differences.
HAPE 的發生
在整個高海拔停留期間，安慰劑組的6 名參與者中有4 名(67%) 發生了HAPE，而乙酰唑胺組的7 名參與者中有3 名(43%) 發生了HAPE (P = 0.390 )。在患有HAPE的受試者中，放射照相評分顯著高於未發生HAPE的受試者中獲得的最高放射照相評分（P <0.001，圖1）。服用乙酰唑胺的 HAPE 受試者的放射學評分為 6.3 ± 0.6 分，而服用安慰劑的 HAPE 受試者的放射學評分為 5.7 ± 1.5 分（ P = 0.52），表明乙酰唑胺並未減輕HAPE 的嚴重程度。所有患有 HAPE 的參與者也患有 AMS。
Occurrence of HAPE
During the entire stay at high altitude, HAPE developed in four of six (67%) participants in the placebo group and in three of seven (43%) in the acetazolamide group (P = 0.390). In subjects with HAPE, the radiographic score was significantly higher than the highest radiographic score that was obtained in those who did not develop HAPE (P < 0.001, Fig. 1). Subjects with HAPE taking acetazolamide had a radiographic score of 6.3 ± 0.6 points compared with 5.7 ± 1.5 points for subjects with HAPE taking placebo (P = 0.52), indicating that severity of HAPE was not attenuated by acetazolamide. All participants with HAPE also had AMS.
值得注意的是，安慰劑組中的一名參與者曾有過 3 次 HAPE 病史，他在 Capanna Giovanni Gnifetti (3,611 m) 的夜間出現了 HAPE。該受試者沒有完成登上 Capanna Regina Margherita 的任務，但由一名調查員陪同前往纜車站立即下降至阿拉尼亞，並確認胸部聽診時存在爆裂聲。到達低海拔後，在阿拉尼亞附近的一家地區醫院拍了胸片，顯示有輕度肺水腫。儘管在 4,559 m 高度無法獲得用於最終分析的數據，但該參與者被評定為患有 HAPE。
Of note, one participant in the placebo group with a history of three previous episodes of HAPE developed HAPE during the night at the Capanna Giovanni Gnifetti (3,611 m). This subject did not complete the ascent to the Capanna Regina Margherita but was accompanied to the cable car station for immediate descent to Alagna by one of the investigators who confirmed the presence of crackles on chest auscultation. After arrival at low altitude, a chest radiograph was obtained in a district hospital located close to Alagna, indicating mild pulmonary edema. This participant was rated as having HAPE, although no data could be obtained at 4,559 m for the final analyses.
高海拔和 HAPE 發作時的 RVPG
在低海拔地區，兩個研究組的 RVPG 均為 20 ± 4 mmHg（P = 0.988）。在高海拔地區，乙酰唑胺組的 RVPG 增加至 43 ± 4 mmHg，安慰劑組則增加至 41 ± 5 mmHg（圖 2和表 3 ；低海拔與高海拔的P < 0.001）。兩個研究組之間 RVPG 的增加沒有差異（P = 0.677）。此外，在最後一次高海拔個體測量（即停留結束）時，乙酰唑胺組和安慰劑組之間的 RVPG 沒有差異（P = 0.466）。
RVPG at High Altitude and at the Onset of HAPE
At low-altitude RVPG was 20 ± 4 mmHg in both study groups (P = 0.988). At high altitude, RVPG was increased to 43 ± 4 mmHg in the acetazolamide group, and to 41 ± 5 mmHg in the placebo group (Fig. 2 and Table 3; both P < 0.001 for low vs. high altitude). The increase in RVPG was not different between both study groups (P = 0.677). Also, at the last individual measurement at a high altitude (i.e., end of stay), there was no difference (P = 0.466) in RVPG between those on acetazolamide and placebo, respectively.
圖 2.低海拔 (423 m) 和 4,559 m 處的單獨 RVPG 值。六個黑色圓圈表示診斷 HAPE 的時間點。安慰劑組中一名患有 HAPE 的受試者無法獲得 RVPG（詳情見正文）。5 小時內發生 HAPE 的參與者的數據點與安慰劑組中未發生 HAPE 並完成研究的另一名參與者的數據點重疊。兩個研究組間RVPG差異無統計學意義（P =0.677）。HAPE，高原肺水腫；RVPG，右心室壓力梯度。
Figure 2.Individual RVPG values at low altitude (423 m) and at 4,559 m. The six black circles indicate the time point when HAPE was diagnosed. From one subject with HAPE in the placebo group, RVPG could not be obtained (for details, see text). The data point of the participant who developed HAPE at 5 h overlays the data point of another participant in the placebo group who did not develop HAPE and completed the study. The difference in RVPG between the two study groups was not statistically significant (P = 0.677). HAPE, high-altitude pulmonary edema; RVPG, right ventricular pressure gradient.
由於一名患有 HAPE 的參與者幾乎沒有肺動脈壓力升高，因此患有和不患有 HAPE 的參與者之間的 RVPG 差異在統計學上沒有差異（P = 0.420）。從分析中排除該受試者後，HAPE 患者的 RVPG 顯著升高（P = 0.049）。該參與者之前曾兩次因急性暴露於高海拔而發生肺水腫，雙肺聽診時有羅音，放射學評分為 7 分，動脈 P o 2 為 28 mmHg， A - aDO 2升高18 mmHg、體溫正常、C 反應蛋白正常，考慮到他的病史，毫無疑問他患有肺水腫，很可能是HAPE。
Due to one participant with HAPE having virtually no pulmonary artery pressure elevation, the difference in RVPG between those with and without HAPE was statistically not different (P = 0.420). Excluding this subject from the analyses yields a significantly higher RVPG in those with HAPE (P = 0.049). This participant, who had two previous episodes of pulmonary edema with acute exposure to high altitude, had rales on lung auscultation over both lungs, a radiographic score of 7 points, an arterial Po2 of 28 mmHg, an elevated A-aDO2 of 18 mmHg, normal body temperature, and normal C-reactive protein leaving no doubt that he had pulmonary edema, most likely HAPE, considering his history.
動脈血氣分析
正如預期的那樣，上升到高海拔會降低動脈 P o 2和 S o 2 ( P < 0.001)。這種下降在安慰劑組中更為明顯（表 2）。海拔引起的動脈氧合下降伴隨著通氣量的增加，這反映在兩個研究組的動脈 P co 2水平較低（與低海拔相比，P < 0.001）。乙酰唑胺組個體的過度換氣程度較高（P = 0.001，表 2），同時碳酸氫鹽和鹼過剩的下降幅度更大。因此，服用乙酰唑胺的患者的動脈 pH 值較低（P< 0.001），反映藥物引起的碳酸氫鹽損失（代謝性酸中毒）。服用安慰劑的患者在高海拔地區的A-aDO 2略有增加（從 9.1 ± 3.0 到 13.1 ± 4.1 mmHg；與低海拔相比， P = 0.239），表明氣體交換和攝氧量受損，而乙酰唑胺組則保持不變（ 9.7 ± 2.8 與 8.7 ± 3.1 mmHg；P = 0.741 與低海拔）。然而，兩個研究組之間的差異並不具有統計學意義（表2）。在診斷出 HAPE 的時間點，A-aDO 2顯著高於在 4,559 m 的整個停留期間未發生 HAPE 的人的A-aDO 2 （圖 3））。乙酰唑胺組在高原上的血紅蛋白濃度增加（P = 0.018），但安慰劑組沒有增加，這與輕度藥物引起的利尿一致，但組間差異未達到統計學顯著性（P = 0.200） 。
Arterial Blood Gas Analysis
As expected, ascent to high altitude decreased arterial Po2 and So2 (P < 0.001). This decrease was more pronounced in the placebo group (Table 2). The altitude-induced decrease in arterial oxygenation was accompanied by an increase in ventilation, as reflected by lower arterial Pco2 levels in both study groups (P < 0.001 vs. low altitude). The degree of hyperventilation was higher in individuals in the acetazolamide group (P = 0.001, Table 2) along with a greater decrease in bicarbonate and base excess. Accordingly, arterial pH values were lower in those taking acetazolamide (P < 0.001), reflecting a drug-induced loss of bicarbonate (metabolic acidosis). The A-aDO2 at high altitude increased slightly in those taking placebo (from 9.1 ± 3.0 to 13.1 ± 4.1 mmHg; P = 0.239 vs. low altitude), indicating impaired gas exchange and oxygen uptake, and remained unchanged in the acetazolamide group (9.7 ± 2.8 vs. 8.7 ± 3.1 mmHg; P = 0.741 vs. low altitude). The difference between both study groups, however, was not statistically significant (Table 2). At the time point when HAPE was diagnosed, the A-aDO2 was significantly greater than the A-aDO2 of those who did not develop HAPE during the entire stay at 4,559 m (Fig. 3). Hemoglobin concentration at high altitude increased in the acetazolamide group (P = 0.018) but not in the placebo group consistent with a mild drug-induced diuresis, but the group difference did not reach statistical significance (P = 0.200).
圖 3.診斷 HAPE 時的肺泡與動脈氧差 (A-aD o 2 ) 為 4,559 m（ P = 0.02 對比無 HAPE）。無法獲得一名患有 HAPE 的受試者的放射學評分（詳情見正文）。對於那些沒有發生 HAPE 的人，會顯示整個高海拔停留期間的最高 A-aD o 2 。HAPE，高原肺水腫。
Figure 3.Alveolar-to-arterial oxygen difference (A-aDo2) at 4,559 m at the time point when HAPE was diagnosed (P = 0.02 vs. no HAPE). From one subject with HAPE, the radiographic score could not be obtained (for details, see text). For those who did not develop HAPE, the highest A-aDo2 during the entire stay at high altitude is shown. HAPE, high-altitude pulmonary edema.
AMS的發生
上升到高海拔顯著增加了 LLS 和 AMS-C 分數（與低海拔相比，P < 0.001；表 3）。安慰劑組的 AMS-C 評分（P = 0.047）和 LLS（P = 0.010）均高於乙酰唑胺組（表 3）。此外，與乙酰唑胺組相比，安慰劑組基於LLS ≥ 5 和AMS-C 評分≥ 0.70 的AMS 發生率較高，但這未能達到統計學顯著性，儘管總體LLS 和AMS 均較低。服用乙酰唑胺的患者得分為 C（表 3）。研究組之間撲熱息痛和/或甲氧氯普胺的攝入總量沒有差異（未顯示）。
Occurrence of AMS
Ascent to high altitude significantly increased the LLS and the AMS-C scores (P < 0.001 vs. low altitude; Table 3). Both the AMS-C score (P = 0.047) and the LLS (P = 0.010) were higher in the placebo group than in the acetazolamide group (Table 3). Also, the incidence of AMS based on an LLS ≥ 5 in combination with an AMS-C score ≥ 0.70 was higher in the placebo group compared with the acetazolamide group, but this failed to reach statistical significance, despite both lower overall LLS and AMS-C scores in those taking acetazolamide (Table 3). The total amount of paracetamol and/or metoclopramide intake did not differ between the study groups (not shown).
全身血流動力學
儘管高海拔地區所有時間點的心率均高於低海拔地區，但各組之間在任何時間點的全身血壓和心率均無差異（表 3 ）。
Systemic Hemodynamics
Systemic blood pressure and heart rate did not differ between the groups at any time, although heart rate was higher at all time points at high altitude compared with low altitude (Table 3).
討論
這項研究的主要發現是，在攀登4,559 m 前2 天開始預防性服用乙酰唑胺（250 mg，3 次/天）並持續接下來的4 天，並沒有顯著減少HAPE 的發生，也沒有降低海拔高度儘管乙酰唑胺可降低 AMS 的嚴重程度、增加通氣量並改善肺泡和動脈氧合，但仍存在與肺動脈高壓相關的情況。
DISCUSSION
The main finding of this study was prophylactic acetazolamide (250 mg 3 times/day) started 2 days before a climbing ascent to 4,559 m and continued for the next 4 days did not significantly reduce the development of HAPE and did not reduce the degree of altitude-related pulmonary artery hypertension even though acetazolamide reduced AMS severity, increased ventilation, and improved alveolar and arterial oxygenation.
令人驚訝的是，在相同的條件下，乙酰唑胺未能證明能夠預防HAPE，而另外兩種肺血管擴張劑（硝苯地平和他達拉非）對急性HPV 具有相似的抑製作用，但被證明有80%–90% 的有效性。儘管乙酰唑胺將 HAPE 的發生率從安慰劑組的 67% 降低到 43%，但這種效果並不具有統計學意義（P = 0.390）。如果要在更大的人群中維持這種減少 35% 的差異，則需要 134 名受試者（即 67 名/組）來檢測統計上顯著的差異 ( P< 0.05），具有足夠的統計功效（≥0.80）。此外，與安慰劑組相比，乙酰唑胺組 HAPE 減少 35%（需要治療的人數 = 4.2）遠小於硝苯地平（需要治療的人數 ~1.8）（ 8）、他達拉非（需要治療的人數= 4.2）、他達拉非（需要治療的人數）的預防效果要小得多。9 ) 和地塞米松（治療 ∼1.3) ( 9 ) 所需的數量，即使乙酰唑胺刺激通氣並增加肺泡 P o 2，HPV 的主要刺激因素。儘管沒有研究得出 AMS 可能導致 HAPE 發生的結論，但人們普遍假設這一點。我們的數據並不支持這一觀點，因為儘管乙酰唑胺可以降低 AMS 的嚴重程度，但它並不能顯著預防 HAPE。這與硝苯地平 ( 28 ) 和他達拉非 ( 9 ) 尚不能刺激高海拔地區通氣或預防 AMS，但可有效預防 HAPE 的研究結果相一致。The failure to demonstrate that acetazolamide prevents HAPE under the same conditions in which two other pulmonary vasodilators with similar inhibition of acute HPV, nifedipine, and tadalafil, proved to be 80%–90% effective was surprising. Although acetazolamide reduced the incidence of HAPE from 67% in the placebo group to 43%, this effect was not statistically significant (P = 0.390). If this difference of a 35% reduction were to be sustained in a larger population, 134 subjects (i.e., 67/group) would be required to detect a statistically significant difference (P < 0.05) with sufficient statistical power (≥0.80). Furthermore, a 35% reduction of HAPE in the acetazolamide versus the placebo group is considerably smaller (number needed to treat = 4.2) than the much greater preventive effect of nifedipine (number needed to treat ∼1.8) (8), tadalafil (number needed to treat ∼1.5) (9), and dexamethasone (number needed to treat ∼1.3) (9), even though acetazolamide stimulates ventilation and increases alveolar Po2, the main stimulus for HPV. Although no studies have concluded that AMS may contribute to the development of HAPE, it is nonetheless commonly hypothesized. Our data do not support this notion since acetazolamide did not significantly protect from HAPE despite reducing AMS severity. This is in line with the findings that nifedipine (28) and tadalafil (9) are not known to stimulate ventilation at high altitudes or prevent AMS, but are effective in preventing HAPE.
許多動物和人類研究表明，乙酰唑胺是一種有效的急性HPV 抑製劑（抑制60%–90%），與鈣通道阻滯劑和磷酸二酯酶5 抑製劑相當，但這些研究中的大多數僅檢查肺動脈壓力反應超過1–3小時（13、14、16、29 – 31 ）。_ _ 與這些短期研究相反，數小時或數天后低氧肺動脈壓的結果並不一致。柯等人。( 15 ) 發現乙酰唑胺可降低人體被動上升至 3,658 m 高度後 3 天的肺動脈收縮壓，但 Basnyat 等人。（32）發現在喜馬拉雅山從 4,300 米上升到 5,000 米的部分適應環境的徒步旅行者並沒有減少。此外，在慢性高山病中，乙酰唑胺並沒有降低大鼠模型（33 ）缺氧數月和秘魯高海拔地區人類（ 34 ）多年缺氧後肺動脈壓力的輕度升高。Berg 等人在唯一一項通過乙酰唑胺預防 HAPE 的動物研究中。( 35）發現乙酰唑胺可有效預防大鼠在 5,485 m（0.5 atm）的低壓缺氧環境中暴露 24 小時後發生類似 HAPE 的肺損傷，但沒有測量肺動脈壓力。這些過去的研究結果和目前的工作相結合表明，儘管乙酰唑胺可急性抑制HPV，但其降低缺氧肺動脈壓力並從而預防HAPE 的能力會隨著時間的推移而減弱，並且可能在24 小時後不再有效，特別是在運動和其他壓力的情況下參與登山活動。我們的研究結果表明，在我們的受試者爬升超過 2 天后，肺動脈壓力沒有降低，這似乎證實了這一點，儘管維持稍高的肺泡和動脈 P o 2 可能有任何好處藥物誘導的通氣刺激和 AMS 嚴重程度的減輕。
Many studies in animals and humans have demonstrated that acetazolamide is a potent inhibitor of acute HPV (60%–90% inhibition) and on a par with calcium channel blockers and phosphodiesterase 5 inhibitors, but the majority of these studies only examined pulmonary artery pressure responses over 1–3 h (13, 14, 16, 29–31). In contrast to these short-term studies, the results on hypoxic pulmonary artery pressure after many hours or days are not consistent. Ke et al. (15) found that acetazolamide reduced pulmonary artery systolic pressure in humans up to 3 days after a passive ascent to 3,658 m, but Basnyat et al. (32) found no reduction in partially acclimatized trekkers ascending from 4,300 to 5,000 m in the Himalayas. Furthermore, in chronic mountain sickness, the mildly elevated pulmonary artery pressures after months of hypoxia in a rat model (33) and many years in humans at high altitudes in Peru (34) were not reduced with acetazolamide. In the only animal study of HAPE prevention by acetazolamide, Berg et al. (35) found that acetazolamide was effective in rats at preventing a HAPE-like lung injury 24 h after exposure to hypobaric hypoxia at 5,485 m (0.5 atm), but no pulmonary artery pressure was measured. The results of these past studies and the present work taken together suggest that although acetazolamide acutely inhibits HPV, its ability to reduce hypoxic pulmonary artery pressure and thus prevent HAPE wanes over time and may not be effective beyond 24 h, particularly if exercise and other stresses of mountaineering are involved. Our findings of no reduction in pulmonary artery pressure after our subjects had climbed over 2 days would seem to bear this out, despite whatever benefits there may have been at maintaining a slightly higher alveolar and arterial Po2 from the drug-induced ventilatory stimulation and reduction in severity of AMS.
經胸超聲心動圖由經驗豐富的超聲醫師進行，研究由第二位盲法研究者進行離線評估。儘管如此，我們必須考慮到肺動脈壓力是通過多普勒超聲心動圖估計的。儘管阿勒曼等人。（36）報導稱，該方法與高海拔地區的侵入性測量有很好的相關性，但它不能被視為黃金標準，因為多普勒超聲心動圖和侵入性測量之間可能會出現10-20 mmHg的差異。安慰劑組中一名既往發生過兩次 HAPE 的受試者可能就是這種情況，其 RVPG 在低海拔時為 19 mmHg，在診斷 HAPE 時為 22 mmHg。儘管該受試者的三尖瓣反流噴射很難識別，但它們顯示出令人滿意的包絡線。
Transthoracic echocardiography was performed by an experienced sonographer and the study was assessed off-line by a second, blinded investigator. Nevertheless, we must consider that pulmonary artery pressure was estimated by Doppler echocardiography. Although Allemann et al. (36) reported that this method correlates well with invasive measurements at high altitudes, it cannot be considered the gold standard because differences in the order of 10–20 mmHg between Doppler echocardiographic and invasive measurements may occur. This may have been the case in the one subject with two previous episodes of HAPE in the placebo group whose RVPG was 19 mmHg at low altitude and 22 mmHg at the time point when HAPE was diagnosed. Although the tricuspid regurgitation jets in this subject were difficult to identify, they showed a satisfactory envelope.
為什麼乙酰唑胺在給藥後的最初幾個小時內似乎無法減少缺氧引起的肺血管收縮和肺動脈壓力，因此不能像鈣通道阻滯劑和磷酸二酯酶 5 抑製劑那樣有效預防 HAPE。一種合理的解釋是，HPV 有幾個階段，發生在幾分鐘、幾小時和幾天內（37 – 39），其中涉及立即的非基因組反應，然後是基因組反應以及血管重塑。乙酰唑胺可能僅作用於最早的信號傳導和反應，而上述類別的藥物作用於肺血管膜離子通道、受體和酶，其功能和表達不會因缺氧持續時間而發生很大改變，並且對這些藥物保持敏感藥物。事實上，這些藥物在許多其他非缺氧情況下可降低肺動脈壓力升高，並且不是特異性或選擇性 HPV 抑製劑。相比之下，乙酰唑胺通過不依賴於 CA 活性的機制 ( 14 , 21 ) 抑制肺動脈平滑肌細胞活性氧的立即缺氧生成 ( 40）通過肌漿網鈣儲備的動員啟動細胞內鈣的增加。細胞內鈣的早期增加隨後引發一系列鈣從細胞外空間進一步流入，以增強血管收縮。但是，隨著缺氧刺激持續較長時間，收縮裝置的Ca 2+敏感性增加，並且收縮維持在正常的細胞內鈣濃度，這可能繼發於 Rho 激酶的激活 ( 21 , 37）。因此，阻斷缺氧引起的鈣增加可能會延遲但不能完全防止肺動脈壓力隨時間的推移而升高。另一種可能性是，在持續缺氧的情況下，缺氧誘導因子的激活及其基因轉錄的改變導致其他信號通路的收縮，這些信號通路變得更加占主導地位並且對乙酰唑胺不敏感。
Why acetazolamide appears unable to reduce hypoxia-induced pulmonary vasoconstriction and pulmonary artery pressure beyond the first hours of administration and thus not effective in HAPE prevention as are calcium channel blockers and phosphodiesterase 5 inhibitors is not known. One plausible explanation is that HPV has several phases occurring over minutes, hours, and days (37–39), which involve immediate nongenomic and then genomic responses as well as vascular remodeling. Acetazolamide may only act on the earliest signaling and response, whereas the aforementioned classes of drugs act on pulmonary vascular membrane ion channels, receptors, and enzymes, the function and expression of which are not altered greatly by the duration of hypoxia and remain sensitive to these drugs. In fact, these drugs reduce pulmonary artery pressure elevation in many other nonhypoxic situations and are not specific or selective HPV inhibitors. In contrast, acetazolamide, by a mechanism not dependent on CA activity (14, 21), suppresses the immediate hypoxic generation of reactive oxygen species of pulmonary artery smooth muscle cells (40) that initiates a rise in intracellular calcium from mobilization of sarcoplasmic reticulum calcium stores. This very early increase in intracellular calcium then triggers a cascade of further calcium influx from the extracellular space to augment vasoconstriction. But, as the hypoxic stimulus is sustained over a longer time, Ca2+ sensitivity of the contractile apparatus increases, and contraction is maintained at normal intracellular concentrations of calcium, likely secondary to activation of Rho kinase (21, 37). Thus, blocking the hypoxia-induced calcium increase may delay but not completely prevent higher pulmonary artery pressure over time. Another possibility is that with sustained hypoxia, activation of hypoxia-inducible factors and their alteration of gene transcription contribute to contraction by other signaling pathways, which become more dominant and not sensitive to acetazolamide.
The 8 mmHg higher and presumably an equal increase in alveolar Po2 resulting from an acetazolamide-induced ventilatory stimulation causing a 5 mmHg greater fall in should have been sufficient to reduce pulmonary artery pressure and possibly the occurrence of HAPE. Dose-response data in the Po2 range we observed in our study in humans are sparse. In anesthetized subjects (41), HPV increased by 20% when inspired O2 was lowered from 20.9% to 12%, and with a further reduction to 8%, HPV rose more steeply by 30%. In a study of awake normal subjects, reduction from an end-tidal Po2 of 75 to 50 mmHg with a fall in end-tidal Pco2 of 4 mmHg (similar to the change in our subjects) caused a 6 mmHg rise in pulmonary artery systolic pressure (42). These data predict that we should have observed some effect of the increased ventilation and changes in and to lower pulmonary artery pressure since the changes we observed are on the effect slope of the dose-response curve. We cannot exclude the possibility that despite acetazolamide-induced ventilatory stimulation and thus an effectively higher , the effect of acetazolamide to lower hypoxic pulmonary artery pressures may have been prevented by the known enhancement of HPV with metabolic acidosis (37, 43). In all acute short-duration studies of acetazolamide showing HPV inhibition, there was insufficient time to develop enough renal bicarbonate loss to lower systemic bicarbonate concentrations, but in our subjects, plasma bicarbonate fell by 9.5 mM in those taking acetazolamide versus 2.3 mM in those taking placebo. In addition, the Pco2 and pH values observed in the present study roughly match those of short-term studies that reported an HPV inhibitory effect of acetazolamide (14, 16, 31). Thus, it is unlikely that the opposing effects of lower Pco2 and lower pH and HCO3− concentration on hypoxic pulmonary artery pressure explain the absence of effect of acetazolamide on HPV suppression in our study.
數據來自 Bärtsch 等人。( 8 )表明，快速上升至4,559 m後，SO 2在4天內從70%增加到78%並不影響肺動脈壓力。在那項研究中，服用安慰劑的 HAPE 易感登山者的肺動脈壓力也保持穩定，而在高原暴露的第 1 天和第 3 天之間，SO 2從 61% 上升到 66%，P co 2從31 下降到28 mmHg （ 8 ). 這些發現支持了我們的觀察結果，即乙酰唑胺組氧合作用的改善程度與在 4,300 m 海拔 3-5 天內適應環境所預期的程度相同（44），對肺動脈壓力影響很小。
Data from Bärtsch et al. (8) showed that an increase in So2 from 70% to 78% over 4 days did not affect pulmonary artery pressure after rapid ascent to 4,559 m. In that study, pulmonary artery pressure also remained stable in HAPE-susceptible mountaineers who were on placebo, whereas So2 rose from 61% to 66% and Pco2 fell from 31 to 28 mmHg between days 1 and 3 of altitude exposure (8). These findings support our observation that the magnitude of improvement in oxygenation in the acetazolamide group, which is in the order of what can be expected by acclimatization over 3–5 days at 4,300 m (44), has only little effect on pulmonary artery pressure.
後面還有一段寫 LIMITATION 就不放上來了.
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