Payen Didier, Sablotzki Armin, Barie Philip S, Ramsay Graham, Lowry Stephen, Williams Mark, Sarwat Samiha, Northrup Justin, Toland Patricia, Booth Frank V McL
Department of Anesthesiology & Critical Care, Lariboisiere University Hospital, Paris, France.
Surgery. 2007 Apr;141(4):548-61. doi: 10.1016/j.surg.2007.02.004.
The International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy includes an extensive cohort of surgical patients (1659/4459; 37%). This database broadens the experience reported on a comparatively small set of surgical patients from the pivotal Protein C Worldwide Evaluation in Severe Sepsis trial to examine issues of safety and efficacy in a much larger cohort.
We conducted a retrospective analysis of prospectively defined outcomes from 5 integrated clinical studies of severe sepsis. Multivariable analyses incorporated propensity scores, treatment, and significant baseline risk factors as independent variables in logistic regression models for 2 outcomes: serious adverse events that were observed during infusion and 28-day, all-cause mortality rates. Adjusted odds ratios were calculated for clinically important strata. Multiple subcategories of serious bleeding-event rates are presented.
Although surgical patients who were treated with drotrecogin alfa [activated] (DrotAA) experienced a greater proportion of serious bleeding events during the infusion period, most of the patients were treated without fatal consequence. A 10.7% absolute all cause mortality risk reduction (adjusted odds ratio, 0.66; 95% CI, 0.45-0.97) was observed for DrotAA-treated, high-risk (Acute Physiology and Chronic Health Evaluation II, >/= 25) surgical patients. We could not demonstrate a survival benefit in DrotAA-treated, low-risk (Acute Physiology and Chronic Health Evaluation II, <25) surgical patients. When surgical patients were stratified by number of organ dysfunctions, absolute risk reductions were observed in both categories: multiorgan (4.3%) and single (4.5%).
International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy analyses affirmed the favorable benefit/risk profile of DrotAA for surgical patients. The serious adverse event rate that was experienced by surgical patients during the study drug infusion period was 7.5% in the DrotAA-treated group versus 6.3% in the placebo-treated group (odds ratio, 1.41; 95% CI, 0.89-2.25). The clinical benefit of DrotAA therapy paralleled baseline risk of death and substantiated findings from the Protein C Worldwide Evaluation in Severe Sepsis study. Future analyses are needed to evaluate the special relationships among sepsis severity, bleeding management, and the postoperative timing of DrotAA administration.
国际严重脓毒症及活化蛋白C治疗综合数据库纳入了大量外科患者队列（1659/4459；37%）。该数据库拓展了在严重脓毒症蛋白C全球评估关键试验中相对少量外科患者所报告的经验，以在更大队列中研究安全性和有效性问题。
我们对5项严重脓毒症综合临床研究中前瞻性定义的结局进行了回顾性分析。多变量分析将倾向评分、治疗及显著的基线风险因素作为逻辑回归模型中两个结局的独立变量：输注期间观察到的严重不良事件和28天全因死亡率。计算了具有临床意义分层的调整优势比。呈现了严重出血事件发生率的多个子类别。
尽管接受活化蛋白C（DrotAA）治疗的外科患者在输注期间发生严重出血事件的比例更高，但大多数患者接受治疗后未出现致命后果。在接受DrotAA治疗的高危（急性生理与慢性健康状况评分II，≥25）外科患者中，观察到全因死亡风险绝对降低了10.7%（调整优势比，0.66；95%置信区间，0.45 - 0.97）。我们未能证明接受DrotAA治疗的低危（急性生理与慢性健康状况评分II，<25）外科患者有生存获益。当外科患者按器官功能障碍数量分层时，在多器官（4.3%）和单器官（4.5%）两类患者中均观察到绝对风险降低。
国际严重脓毒症及活化蛋白C治疗综合数据库分析证实了DrotAA对外科患者有利的获益/风险状况。在研究药物输注期间，接受DrotAA治疗的外科患者严重不良事件发生率为7.5%，而接受安慰剂治疗的患者为6.3%（优势比，1.41；95%置信区间，0.89 - 2.25）。DrotAA治疗的临床获益与基线死亡风险相当，并证实了严重脓毒症蛋白C全球评估研究的结果。未来需要进行分析以评估脓毒症严重程度、出血管理及DrotAA给药术后时机之间的特殊关系。
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