Opal Steven M
Medicine Infectious Disease Division, Brown University School of Medicine, Pawtucket, Rhode Island 02860, USA.
Shock. 2003 Oct;20(4):295-302. doi: 10.1097/01.shk.0000084343.58020.57.
Severe sepsis is common, frequently fatal, and expensive. Many factors related to the pathogenesis of severe sepsis have made it difficult to effectively design clinical trials for the management of this disease. Hence, multiple trials of compounds for the treatment of severe sepsis have yielded largely negative results, except in small subsets of patients. This review provides a synopsis of the complex nature of sepsis and the problems associated with sepsis trials. Emphasis is placed on the difficulties in evaluating investigational agents in patients with severe sepsis because of the heterogeneity of the disorder, lack of correlation between animal and human models, the complexity of the insult and the host reaction, and the interaction between inflammation and coagulation in severe sepsis. Additionally, positive results from trials of steroids, intensive insulin therapy, and activated protein C (drotrecogin alfa [activated]) will be discussed. Because drotrecogin alfa (activated) is the only Food and Drug Administration-approved therapy for severe sepsis, the Phase 3 Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial results will be discussed in detail to help define a model for further clinical trials on severe sepsis.
严重脓毒症很常见，常常致命且费用高昂。许多与严重脓毒症发病机制相关的因素使得难以有效设计针对该疾病治疗的临床试验。因此，除了在一小部分患者亚组中，多项用于治疗严重脓毒症的化合物试验大多得出了阴性结果。本综述概述了脓毒症的复杂本质以及与脓毒症试验相关的问题。重点在于评估严重脓毒症患者中研究药物的困难，这是由于该病症的异质性、动物模型与人类模型之间缺乏相关性、损伤及宿主反应的复杂性，以及严重脓毒症中炎症与凝血之间的相互作用。此外，还将讨论类固醇、强化胰岛素治疗和活化蛋白C（重组人活化蛋白C [drotrecogin alfa]）试验的阳性结果。由于重组人活化蛋白C（drotrecogin alfa）是美国食品药品监督管理局批准的唯一用于严重脓毒症的治疗药物，将详细讨论严重脓毒症全球蛋白C评估3期（PROWESS）试验的结果，以帮助确定进一步针对严重脓毒症进行临床试验的模式。
