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Abstract：
We aimed to determine whether and how the combination of acetazolamide and remote ischemic preconditioning (RIPC) reduced the incidence and severity of acute mountain sickness (AMS).
This is a prospective, randomized, open-label, blinded endpoint (PROBE) study involving 250 healthy volunteers. Participants were randomized (1:1:1:1:1) to following five groups: Ripc (RIPC twice daily, 6 days), Rapid-Ripc (RIPC four times daily, 3 days), Acetazolamide (twice daily, 2 days), Combined (Acetazolamide plus Rapid-Ripc), and Control group. After interventions, participants entered a normobaric hypoxic chamber (equivalent to 4000 m) and stayed for 6 h. The primary outcomes included the incidence and severity of AMS, and SpO2 after hypoxic exposure. Secondary outcomes included systolic and diastolic blood pressure, and heart rate after hypoxic exposure. The mechanisms of the combined regime were investigated through exploratory outcomes, including analysis of venous blood gas, complete blood count, human cytokine antibody array, ELISA validation for PDGF-AB, and detection of PDGF gene polymorphisms.
The combination of acetazolamide and RIPC exhibited powerful efficacy in preventing AMS, reducing the incidence of AMS from 26.0 to 6.0% (Combined vs Control: RR 0.23, 95% CI 0.07-0.70, P = 0.006), without significantly increasing the incidence of adverse reactions. Combined group also showed the lowest AMS score (0.92 ± 1.10). Mechanistically, acetazolamide induced a mild metabolic acidosis (pH 7.30 ~ 7.31; HCO3- 18.1 ~ 20.8 mmol/L) and improved SpO2 (89 ~ 91%) following hypoxic exposure. Additionally, thirty differentially expressed proteins (DEPs) related to immune-inflammatory process were identified after hypoxia, among which PDGF-AB was involved. Further validation of PDGF-AB in all individuals showed that both acetazolamide and RIPC downregulated PDGF-AB before hypoxic exposure, suggesting a possible protective mechanism. Furthermore, genetic analyses demonstrated that individuals carrying the PDGFA rs2070958 C allele, rs9690350 G allele, or rs1800814 G allele did not display a decrease in PDGF-AB levels after interventions, and were associated with a higher risk of AMS.
The combination of acetazolamide and RIPC exerts a powerful anti-hypoxic effect and represents an innovative and promising strategy for rapid ascent to high altitudes. Acetazolamide improves oxygen saturation. RIPC further aids acetazolamide, which synergistically regulates PDGF-AB, potentially involved in the pathogenesis of AMS.
ClinicalTrials.gov NCT05023941.
This is a prospective, randomized, open-label, blinded endpoint (PROBE) study involving 250 healthy volunteers. Participants were randomized (1:1:1:1:1) to following five groups: Ripc (RIPC twice daily, 6 days), Rapid-Ripc (RIPC four times daily, 3 days), Acetazolamide (twice daily, 2 days), Combined (Acetazolamide plus Rapid-Ripc), and Control group. After interventions, participants entered a normobaric hypoxic chamber (equivalent to 4000 m) and stayed for 6 h. The primary outcomes included the incidence and severity of AMS, and SpO2 after hypoxic exposure. Secondary outcomes included systolic and diastolic blood pressure, and heart rate after hypoxic exposure. The mechanisms of the combined regime were investigated through exploratory outcomes, including analysis of venous blood gas, complete blood count, human cytokine antibody array, ELISA validation for PDGF-AB, and detection of PDGF gene polymorphisms.
The combination of acetazolamide and RIPC exhibited powerful efficacy in preventing AMS, reducing the incidence of AMS from 26.0 to 6.0% (Combined vs Control: RR 0.23, 95% CI 0.07-0.70, P = 0.006), without significantly increasing the incidence of adverse reactions. Combined group also showed the lowest AMS score (0.92 ± 1.10). Mechanistically, acetazolamide induced a mild metabolic acidosis (pH 7.30 ~ 7.31; HCO3- 18.1 ~ 20.8 mmol/L) and improved SpO2 (89 ~ 91%) following hypoxic exposure. Additionally, thirty differentially expressed proteins (DEPs) related to immune-inflammatory process were identified after hypoxia, among which PDGF-AB was involved. Further validation of PDGF-AB in all individuals showed that both acetazolamide and RIPC downregulated PDGF-AB before hypoxic exposure, suggesting a possible protective mechanism. Furthermore, genetic analyses demonstrated that individuals carrying the PDGFA rs2070958 C allele, rs9690350 G allele, or rs1800814 G allele did not display a decrease in PDGF-AB levels after interventions, and were associated with a higher risk of AMS.
The combination of acetazolamide and RIPC exerts a powerful anti-hypoxic effect and represents an innovative and promising strategy for rapid ascent to high altitudes. Acetazolamide improves oxygen saturation. RIPC further aids acetazolamide, which synergistically regulates PDGF-AB, potentially involved in the pathogenesis of AMS.
ClinicalTrials.gov NCT05023941.
摘要：
背景：我们旨在确定乙酰唑胺和远程缺血预处理（RIPC）的组合是否以及如何降低急性高山病（AMS）的发生率和严重程度。
方法：这是一个前瞻性的，随机化，开放标签，纳入250名健康志愿者的盲法终点(PROBE)研究。参与者被随机（1：1：1：1：1）分为以下五组：Ripc（RIPC每天两次，6天),Rapid-Ripc(RIPC每天四次,3天),乙酰唑胺（每日两次，2天),合并（乙酰唑胺加Rapid-Ripc），和对照组。干预后,参与者进入常压低氧室（相当于4000米）并停留6小时。主要结果包括AMS的发生率和严重程度，和低氧暴露后的SpO2。次要结果包括收缩压和舒张压，缺氧暴露后的心率。通过探索性结果研究了联合方案的机制，包括静脉血气分析,全血细胞计数,人细胞因子抗体阵列，PDGF-AB的ELISA验证，并检测PDGF基因多态性。
结果：乙酰唑胺和RIPC的组合在预防AMS方面表现出强大的功效，AMS的发生率从26.0％降低到6.0％（联合与对照：RR0.23，95％CI0.07-0.70，P=0.006），无显著增加不良反应发生率。联合组AMS评分最低(0.92±1.10)。机械上,乙酰唑胺引起轻度代谢性酸中毒（pH7.30〜7.31；HCO3-18.1〜20.8mmol/L），并改善了SpO2（89〜91％）。此外,缺氧后鉴定出30种与免疫炎症过程相关的差异表达蛋白(DEP),其中PDGF-AB参与其中。在所有个体中PDGF-AB的进一步验证表明，乙酰唑胺和RIPC在低氧暴露前下调PDGF-AB，提出了一种可能的保护机制。此外，遗传分析表明，携带PDGFArs2070958C等位基因的个体，rs9690350G等位基因，或rs1800814G等位基因在干预后未显示PDGF-AB水平降低，并与AMS的高风险相关。
结论：乙酰唑胺和RIPC的组合具有强大的抗缺氧作用，代表了一种创新和有希望的快速上升到高海拔地区的策略。乙酰唑胺可改善氧饱和度。RIPC进一步帮助乙酰唑胺，协同调节PDGF-AB，可能参与AMS的发病机制。
背景：ClinicalTrials.govNCT05023941。
方法：这是一个前瞻性的，随机化，开放标签，纳入250名健康志愿者的盲法终点(PROBE)研究。参与者被随机（1：1：1：1：1）分为以下五组：Ripc（RIPC每天两次，6天),Rapid-Ripc(RIPC每天四次,3天),乙酰唑胺（每日两次，2天),合并（乙酰唑胺加Rapid-Ripc），和对照组。干预后,参与者进入常压低氧室（相当于4000米）并停留6小时。主要结果包括AMS的发生率和严重程度，和低氧暴露后的SpO2。次要结果包括收缩压和舒张压，缺氧暴露后的心率。通过探索性结果研究了联合方案的机制，包括静脉血气分析,全血细胞计数,人细胞因子抗体阵列，PDGF-AB的ELISA验证，并检测PDGF基因多态性。
结果：乙酰唑胺和RIPC的组合在预防AMS方面表现出强大的功效，AMS的发生率从26.0％降低到6.0％（联合与对照：RR0.23，95％CI0.07-0.70，P=0.006），无显著增加不良反应发生率。联合组AMS评分最低(0.92±1.10)。机械上,乙酰唑胺引起轻度代谢性酸中毒（pH7.30〜7.31；HCO3-18.1〜20.8mmol/L），并改善了SpO2（89〜91％）。此外,缺氧后鉴定出30种与免疫炎症过程相关的差异表达蛋白(DEP),其中PDGF-AB参与其中。在所有个体中PDGF-AB的进一步验证表明，乙酰唑胺和RIPC在低氧暴露前下调PDGF-AB，提出了一种可能的保护机制。此外，遗传分析表明，携带PDGFArs2070958C等位基因的个体，rs9690350G等位基因，或rs1800814G等位基因在干预后未显示PDGF-AB水平降低，并与AMS的高风险相关。
结论：乙酰唑胺和RIPC的组合具有强大的抗缺氧作用，代表了一种创新和有希望的快速上升到高海拔地区的策略。乙酰唑胺可改善氧饱和度。RIPC进一步帮助乙酰唑胺，协同调节PDGF-AB，可能参与AMS的发病机制。
背景：ClinicalTrials.govNCT05023941。
