脂蛋白、Apo脂蛋白與重度敗血症患者預後之相關性

Association of Serum Lipoprotein and Apolipoprotein Levels with the Prognosis of Patients with Severe Sepsis

簡榮彥(Jung-Yien Chien)

指導教授 ： 余忠仁 ； 楊泮池

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2004年)

https://doi.org/10.6342/NTU.2004.01475

摘要

研究目的：
評估脂蛋白(Lipoprotein)、Apo脂蛋白(Apolipoprotein)濃度與重度敗血症病人預後之相關性。
研究設計：前瞻性觀察研究。
病人來源：因重度敗血症轉入內科加護病房住院的病人。
研究方法與結果：
民國2002年十月至2003年一月間，63名罹患嚴重敗血症的患者進入本研究，於30日的觀察期中，共有19位病人死亡，整體30日死亡率為30.2%。本研究於嚴重敗血症發病後第1-4天，第7天和第14天連續測量空腹時血中總膽固醇、三酸甘油脂、高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C)、apolipoprotein A-I、apolipoprotein B 和apolipoprotein E濃度。於嚴重敗血症發生30日內死亡的病人，其嚴重敗血症發生前四天血中高密度脂蛋白(HDL)和apolipoprotein A-I濃度較存活超過30日的患者明顯來的低。在發生嚴重敗血症的第一天，血中高密度脂蛋白和apolipoprotein A-I的濃度和患者的APACHEII score成明顯的負相關(高密度脂蛋白和APACHEII score r=-0.31, P<0.01; apolipoprotein A-I和APACHEII score r=-0.25, P=0.03)。藉由建構receiver-operator-characteristic (ROC)curve，我們發現：使用敗血症發病第一天高密度脂蛋白=20mg/dl和apolipoprotein A-I=100mg/dl作為切點，可準確預測嚴重敗血症後30日整體死亡率(高密度脂蛋白, sensitivity=92%, specificity=80%, accuracy=83%; apolipoprotein A-I, sensitivity=83%, specificity=73%, accuracy=76%)。對於嚴重敗血症發生第一天血中高密度脂蛋白濃度<20mg/dl和apolipoprotein A-I濃度<100mg/dl的患者來說，不但其整體死亡率和感染相關死亡率上升，需長期滯留加護病房治療及得到次發性院內感染的機會也大為上升。經由多變數分析，我們發現：唯有在嚴重敗血症發生第一天的APACHEII score高低(odds ratio, 1.15; 95%信賴區間：1.04-1.26)和高密度脂蛋白濃度<20mg/dl(odds ratio, 12.92 ; 95%信賴區間：2.73-61.29)是可獨立預測嚴重敗血症發生後30日整體死亡率的獨立因子。另外，我們發現，除了三酸甘油脂以外，不論是總膽固醇、高、低密度脂蛋白，或是apolipoprotein A-I、apolipoprotein B和apolipoprotein E的濃度皆和兩種pro-inflammatory細胞素(interleukin-6 and tumor necrosis factor-

關鍵字

脂蛋白 ； 敗血症

並列摘要

INTRODUCTION
Sepsis and its sequelae are still the leading causes of death in critically ill patients. Even given appropriate antibiotics and the best available supportive care, the overall mortality of severe sepsis is still up to approximately 30-50% (Angus et al. 2001). The reduction in lipid and lipoprotein levels has been found in patients with a variety of inflammatory states(Alvarez and Ramos 1986; Gordon et al. 2001), but the prognostic implications in patients with sepsis are still uncertain. Recently, the ability of lipoproteins to bind and neutralize toxic bacterial substance has received more and more attention(Ulevitch et al. 1981; Harris et al. 1993; Read et al. 1993; Grunfeld et al. 1999; Van Amersfoort et al. 2003). Transgenic mice with increased levels of high-density lipoprotein (HDL) or low-density lipoprotein (LDL) are all resistant to endotoxin challenge(Levine et al. 1993; Netea et al. 1996). Infusion of reconstituted HDL suppressed cytokine production induced by bacterial lipopolysaccharide (LPS, toxic bacterial substance from gram-negative microorganism cell wall) in rabbits(Hubsch et al. 1995) and also blocked many of physiologic effects during endotoxemia in human volunteers (Pajkrt et al. 1996).
The aim of this study was to investigate the association between sequential levels of lipids, including lipoproteins and apolipoproteins, and clinical outcomes in patients with severe sepsis. In addition, we examined the possible mechanisms about the ability of HDL in inhibition of lipopolysaccharide-induced cytokine production in cultured human macrophage.

METHODS
Patients
The study was performed in the medical intensive care units (ICU) of a 2,000-bed university hospital, a tertiary referral center. The 34-bed medical ICUs were staffed by certified critical care specialists and medical residents who provided 24-hr in-unit coverage. Between October 2002 and January 2003, all patients admitted to the units were enrolled consecutively into this study if they fulfilled the criteria for severe sepsis, as defined by the American College of Chest Physicians/Society of Critical Care Medicine consensus conference(Bone et al. 1992). Patients were eligible for this study if they had a known or suspected infection on the basis of clinical data at the time of screening and if they met the following criteria : three or more signs of systemic inflammation and the sepsis-induced dysfunction of at least one organ or system. Patients with cirrhosis of the liver, terminal stage cancer, a history of hyperlipidemia or receiving total parenteral nutrition at the time of blood sampling were excluded. Informed written consent was obtained from the patient or his or her legal representatives. The study was approved by the Institutional Review Board of the National Taiwan University Hospital.

Data Collection.
Patients were followed for at least 30 days after recruitment or until death. Base-line characteristics, including demographic data, organ function, disease severity, causative microorganisms, and blood chemistry, were recorded within 24 hours after the patient was found to meet the criteria for severe sepsis. Severity of disease was assessed using the Acute Physiology and Chronic Health Evaluation II (APACHE II) score(Knaus et al. 1985) with higher scores indicating more severe disease. Dysfunction of organ systems were defined as previously described(Bernard et al. 2001). Microbiological culture results were assessed daily from the start of observation until day 30.
Fasting blood samples were obtained in the morning on the 1st– 4th, 7th, and 14th day of severe sepsis and allowed to clot at refrigerator (40C), and then the serum was separated and immediately stored at –800C until analysis. Total cholesterol and triglyceride levels were measured enzymatically using kits (Denka Seiken, Tokyo, Japan). HDL and LDL cholesterol concentrations were measured by the homogeneous method(Okada et al. 1998; Okada et al. 2001) using kits (Denka Seiken, Tokyo, Japan) and a model 200FR automatic analyzer (TOSHIBA, Tokyo, Japan). Apolipoprotein A-I (Apo-AI), apolipoprotein B (Apo-B), and apolipoprotein E (Apo-E) levels were measured turbidimetrically on a Roche Cobas Fara clinical chemistry analyzer (Roche Diagnostic Systems, Branchburg, NJ) using a polyclonal Apo-AI, Apo-B, or Apo-E antiserum (Daiichi Pure Chemical, Tokyo, Japan), respectively. TNF-

並列關鍵字

Lipoprotein ； Sepsis

參考文獻

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