Marshall John C, Vincent Jean-Louis, Guyatt Gordon, Angus Derek C, Abraham Edward, Bernard Gordon, Bombardier Claire, Calandra Thierry, Jørgensen Henrik Stig, Sylvester Richard, Boers Maarten
Department of Surgery, Interdepartmental Division of Critical Care Medicine, University of Toronto, St. Michael's Hospital, Canada.
Crit Care Med. 2005 Aug;33(8):1708-16. doi: 10.1097/01.ccm.0000174478.70338.03.
Sepsis is the leading cause of morbidity and mortality for patients admitted to an intensive care unit. The evaluation of new therapies has been hampered by the underdevelopment of outcome measures used to detect biological activity and patient-centered benefit in a complex and highly heterogeneous patient population. We sought to evaluate existing approaches and to draw on insights from other disciplines to propose a comprehensive approach to outcome evaluation in sepsis clinical trials.
An expert colloquium organized by the International Sepsis Forum brought together sepsis researchers, clinical epidemiologists, and experts in the development and implementation of outcome measures in rheumatology, neurology, and oncology.
The translation of an evolving understanding of the biology of sepsis into effective new therapies for critically ill patients requires a reevaluation of the end points used to determine response to intervention. These represent a continuum that measures biological activity against the target at one end and sustained improvement in survival or quality of life at the other. Early phase research should determine whether an intervention works in vivo, using measures that are responsive and informative to provide proof of principle, to aid in selecting optimal patient populations for study, and to gain insights into optimal dose and duration of therapy. After in vivo biology has been demonstrated and the possibility of efficacy inferred by plausible improvements in surrogate physiologic measures, definitive studies should seek robust evidence of benefit using end points that measure important, patient-centered benefit, including intermediate and longer term survival and health-related quality of life. Nonmortal measures of benefit assume particular importance for populations, such as children, whose mortality risk is low, or who have significant rates of comorbidities that independently limit survival. Composite measures that integrate morbidity and mortality effects may provide the most meaningful information about therapeutic efficacy.
The development of explicit, hypothesis-driven, and iterative approaches to outcome measure development, patterned on approaches used in the fields of rheumatology and oncology, may improve the conduct of clinical studies in the critically ill.
脓毒症是重症监护病房患者发病和死亡的主要原因。在复杂且高度异质的患者群体中，用于检测生物活性和以患者为中心的获益的结局指标发展不完善，这阻碍了新疗法的评估。我们旨在评估现有方法，并借鉴其他学科的见解，提出脓毒症临床试验结局评估的综合方法。
国际脓毒症论坛组织了一次专家座谈会，汇聚了脓毒症研究人员、临床流行病学家以及风湿病学、神经病学和肿瘤学领域结局指标开发与实施方面的专家。
将对脓毒症生物学不断演变的理解转化为针对重症患者的有效新疗法，需要重新评估用于确定对干预反应的终点。这些终点代表了一个连续体，一端衡量针对靶点的生物活性，另一端衡量生存或生活质量的持续改善。早期研究应使用有反应性且信息丰富的指标来确定干预措施在体内是否有效，以提供原理证明，帮助选择最佳研究患者群体，并深入了解最佳治疗剂量和疗程。在证明体内生物学效应并通过替代生理指标的合理改善推断出疗效可能性后，确定性研究应使用衡量重要的、以患者为中心的获益的终点，包括中期和长期生存以及与健康相关的生活质量，来寻求有力的获益证据。对于儿童等死亡率风险低或合并症发生率高且独立限制生存的人群，非死亡获益指标尤为重要。整合发病率和死亡率影响的综合指标可能提供有关治疗疗效最有意义的信息。
借鉴风湿病学和肿瘤学领域使用的方法，开发明确的、假设驱动的和迭代的结局指标开发方法，可能会改善重症患者临床研究的开展。
