第一部分 瑞舒伐他汀对脓毒症相关性脑病的潜在保护作用
研究背景
脓毒症是急诊科常见的危重症疾病，脓毒症相关性脑病（Sepsis-Associated Encephalopathy, SAE）是脓毒症的常见并发症之一，与神经系统远期不良预后相关。瑞舒伐他汀可能对脓毒症患者的脑功能起到一定的保护作用，但其对SAE的作用尚不明确。我们的研究旨在探讨瑞舒伐他汀对SAE的潜在影响。
研究方法
本研究从随机对照研究“瑞舒伐他汀治疗脓毒症相关急性呼吸窘迫综合征”（SAILS试验，ClinicalTrials.gov编号：NCT00979121）的前瞻性队列中纳入符合条件的脓毒症患者，分为服用他汀组和安慰剂组，以格拉斯哥昏迷评分（Glasgow Coma Scale, GCS）较前次评估时下降，或ICU意识状态评分法（Confusion Assessment Method for the Intensive Care Unit, CAM-ICU）阳性为SAE的诊断标准，分析比较两组间的基线资料、SAE发生率以及药物不良反应等临床资料。
研究结果
本研究共纳入86名脓毒症患者。在这些患者中，51人接受了瑞舒伐他汀治疗。瑞舒伐他汀治疗组的SAE发生率明显低于安慰剂组（32.1% vs 57.1%，p=0.028）。然而，肌酸激酶水平在瑞舒伐他汀组高于安慰剂组（233[22–689]U/L vs 79[12–206]U/L，p=0.034）。
结论
瑞舒伐他汀可能对脓毒症患者的脑功能具有一定保护作用，但这一结论仍需大规模临床研究进一步验证。
第二部分 他汀类药物对脓毒症相关性脑病发生的影响：单中心回顾性队列研究
研究背景
前期研究提示，瑞舒伐他汀可能降低急性呼吸窘迫综合症（Acute Respiratory Distress Syndrome, ARDS）合并脓毒症患者SAE的发生率，但因入选患者人群、样本量及数据库临床资料等限制，尚无法得到明确结论。本研究旨在进一步探讨他汀类药物对脓毒症患者脑功能的保护作用。
研究方法
纳入我院符合脓毒症3.0诊断标准的患者，分为服用他汀组和不服用他汀组。SAE的定义为GCS小于15分，比较两组之间基线资料、SAE发生率、机械通气患者比例等临床资料的差异，同时分析SAE患者在服用和不服用他汀两种不同条件下的死亡率差异等。
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研究结果
本研究共纳入193名患者，其中服用他汀组92人，不服用他汀组101人。服用他汀组患者SAE发生率显著下降（15.2% vs 35.6%, p=0.016）。在SAE患者中，服用他汀类药物的患者较不服用他汀的患者死亡率显著下降（0% vs 11.0%, p=0.002）。
结论
服用他汀类药物可能减少脓毒症患者SAE的发生率，但仍需大规模、多中心随机对照实验进一步证实这一结论，他汀类药物对SAE产生影响的机制也仍需进一步探讨。
第三部分 脂质代谢异常介导的炎症反应影响脓毒症相关性脑病发生的机制探究
研究背景
前期研究结果表明，他汀类药物可能通过调节脂质代谢、减轻炎症反应等机制，减少脓毒症患者中SAE的发生率，然而，他汀类药物影响SAE发生的机制尚不明确。本研究旨在深入探讨他汀类药物对SAE产生影响的分子机制。
研究方法
通过建立前瞻性队列，纳入符合脓毒症3.0诊断标准的脓毒症患者。SAE定义为GCS小于15分或CAM-ICU阳性，按上述标准将入组患者分为非SAE队列（Non-SAE）和SAE队列。通过对两组患者血浆、脑脊液进行脂质代谢物、细胞因子等检测，探讨SAE发生的潜在机制; 并进一步将患者分为他汀组和非他汀组，探讨他汀类药物可能对SAE产生的影响及其机制。
研究结果
本研究共纳入98名患者，其中SAE组39人，Non-SAE组59人，在连续观察过程中，有12名患者由SAE好转为Non-SAE。SAE组患者血浆、脑脊液溶血磷脂酰胆碱表达下调，溶血磷脂酸表达上调，炎症因子表达较Non-SAE组有升高趋势。在SAE好转的过程中，患者血浆溶血磷脂酰胆碱水平有升高趋势，溶血磷脂酸、炎症因子水平有下降趋势。同时发现，他汀组患者部分血浆炎症因子水平、SAE发生率显著低于非他汀组患者。
结论
溶血磷脂酰胆碱代谢异常可能通过溶血磷脂酸介导的炎症反应过程，促进SAE的发生，未来仍需大规模研究和动物实验进一步明确脂质代谢异常影响SAE发生的相关机制。

Part1. Potential protective role of rosuvastatin against sepsis-associated encephalopathy
Background
Sepsis is a common cause of death in emergency departments and sepsis-associated encephalopathy (SAE) is one of major complications of sepsis. Rosuvastatin may play a neuroprotective role due to its protective effects on the vascular endothelium and its anti-inflammatory functions. Our study aimed to explore the potential protective function of rosuvastatin against SAE.
Methods
Sepsis patients without any neurological dysfunction on admission were prospectively enrolled in the “Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome” study (SAILS trial, ClinicalTrials.gov number: NCT00979121). Patients were divided into rosuvastatin and placebo groups. SAE is defined as GCS decrease or CAM-ICU (+). This is a secondary analysis of the SAILS dataset. Baseline characteristics, SAE rate, and adverse drug events were compared between groups.
Results
A total of 86 patients were eligible for our study. Of these patients, 51 were treated with rosuvastatin. There were significantly fewer cases of SAE in the rosuvastatin group than in the placebo group (32.1% vs. 57.1%, p=0.028). However, creatine kinase levels were significantly higher in the rosuvastatin group than in the placebo group (233 [22–689] U/L vs. 79 [12–206] U/L, p=0.034).
Conclusion
Rosuvastatin appears to have a protective role against SAE but may result in a higher incidence of adverse events.
Part2. Efficacy of statins on sepsis-associated encephalopathy – a single center retrospective study
Background
Our previous study indicated that rosuvastatin is probably capable of attenuating SAE in patients suffering from sepsis complicated with acute respiratory distress syndrome (ARDS). However, we could not draw a solid conclusion due to the sample size. We aimed to further confirm the efficacy of statins on SAE patients.
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Methods
Sepsis patients were enrolled retrospectively and divided into statin group and statin-free group. SAE is defined as GCS<15. Baseline characteristics, rate of SAE and mortality rate were compared between groups. Mortality rate was also compared in SAE subgroup according to statin usage.
Results
A total of 193 patients were eventually enrolled in this study. There were 92 patients in statin group and 101 patients in statin-free group. Compared with patients in statin-free group, SAE rate was significantly lower in statin group (15.2% vs 35.6%, p=0.016). In SAE subgroup, those treated with statin demonstrated a significantly lower mortality rate (0% vs 11.0%, p=0.002).
Conclusion
Statins were likely to lower SAE rate in sepsis patients. However, further large sample, multiple centers, randomized controlled trial was still needed to confirm this conclusion. The mechanism of statins’ effect on SAE still needs further investigation.
Part3. Effect of lipid metabolism modified inflammatory reaction on sepsis-associated encephalopathy
Background
Our previous clinical studies illustrated that statins were probably capable of lowering SAE rate due to its pharmacological effect such as modifying lipid metabolism and anti-inflammation functions. However, the mechanism of these effect was not fully understood currently. We aimed to further investigate the lipid metabolic and statins’ pharmacological mechanism and its effect on SAE.
Methods
Sepsis patients were enrolled prospectively and divided into SAE and non-SAE groups. SAE is defined as GCS<15 or CAM-ICU (+). Serum and cerebral spinal fluid lipid and inflammatory factors were tested and compared to explore the mechanism of lipid metabolism and SAE. Patients were further divided into statin group and statin-free group in order to investigate statin effect and its mechanism towards SAE.
Results
Overall, ninety-eight patients were enrolled in this study. Thirty-nine of whom were in SAE group while 59 were in non-SAE group. Phosphatidylcholines (PC), lysophosphatidylcholines (LPC) was lower in SAE patients while lysophosphatidic acid (LPA) and inflammatory factors were higher. We observed 12 SAE patients recovered
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and met non-SAE criteria. When SAE patients recovered, LPC level increased and LPA and inflammatory factors decreased. We observed that some inflammatory factors and SAE rate were significantly lower in statin group than statin-free group.
Conclusion
LPC/LPA modified inflammatory reaction is likely to induce SAE in sepsis patients. Further large sample and in vitro studies are still needed to confirm this mechanism.