Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, Queen Elizabeth Hospital Birmingham, University of Birmingham, Birmingham, United Kingdom.
University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom; and.
Am J Respir Crit Care Med. 2019 Nov 15;200(10):1282-1293. doi: 10.1164/rccm.201812-2328OC.
Population studies suggest improved sepsis outcomes with statins, but the results of randomized controlled trials in patients with sepsis and organ dysfunction in critical care settings have broadly been negative. data suggest that statins modulate age-related neutrophil functions, improving neutrophil responses to infection, but only in older patients and at high doses. To determine if high-dose simvastatin improves neutrophil functions and is safe and tolerated in hospitalized older adults with community-acquired pneumonia with sepsis (CAP + S) not admitted to critical care. We conducted a randomized, double-blind, placebo-controlled pilot study of simvastatin 80 mg or placebo for 7 days for patients with CAP + S aged 55 years or older admitted to a secondary care hospital. The Day 4 primary endpoint was change in neutrophil extracellular trap formation (NETosis). Day 4 secondary endpoints included neutrophil chemotaxis, safety and tolerability, Sequential Organ Failure Assessment score, mortality, readmission, and markers of tissue degradation/inflammation. Four days of simvastatin adjuvant therapy in patients with CAP + S was associated with improvements in systemic neutrophil function (NETosis and chemotaxis), a reduction in systemic neutrophil elastase burden, and improved Sequential Organ Failure Assessment scores compared with placebo. A analysis demonstrated that simvastatin therapy was associated with improved hospitalization-free survival compared with placebo. Simvastatin was well tolerated in this elderly and multimorbid patient group with common coprescription of macrolide antibiotics. This pilot study supports high-dose simvastatin as an adjuvant therapy for CAP + S in an older and milder disease cohort than assessed previously. A definitive multicenter study is now warranted in this population to assess the likelihood of benefit and harm.Clinical trial registered with EudraCT (2012-00343-29).
人群研究表明他汀类药物可改善脓毒症的结局，但在重症监护环境中存在器官功能障碍的脓毒症患者的随机对照试验结果普遍为阴性。数据表明，他汀类药物可调节与年龄相关的中性粒细胞功能，改善中性粒细胞对感染的反应，但仅在老年患者和高剂量时有效。为了确定高剂量辛伐他汀是否可改善中性粒细胞功能，并且在未入住重症监护病房的因社区获得性肺炎合并脓毒症（CAP+S）而住院的老年患者中是安全且可耐受的，我们进行了一项随机、双盲、安慰剂对照的辛伐他汀 80mg 或安慰剂治疗 7 天的研究，纳入了年龄在 55 岁及以上、因 CAP+S 而入住二级护理医院的患者。第 4 天的主要终点是中性粒细胞胞外诱捕网形成（NETosis）的变化。第 4 天的次要终点包括中性粒细胞趋化性、安全性和耐受性、序贯器官衰竭评估评分、死亡率、再入院率以及组织降解/炎症标志物。与安慰剂相比，在 CAP+S 患者中使用辛伐他汀辅助治疗 4 天可改善全身中性粒细胞功能（NETosis 和趋化性）、降低全身中性粒细胞弹性蛋白酶负荷，并改善序贯器官衰竭评估评分。一项倾向性评分匹配分析表明，与安慰剂相比，辛伐他汀治疗与改善住院无生存获益相关。在接受大环内酯类抗生素联合治疗的老年和多病共存患者中，辛伐他汀耐受性良好。这项初步研究支持在较以往评估的年龄更大、疾病更轻的 CAP+S 患者亚组中，将高剂量辛伐他汀作为辅助治疗。目前在该人群中进行一项确证性多中心研究来评估获益和危害的可能性是必要的。该临床试验已在 EudraCT 注册（2012-00343-29）。
