Cain David J, Del Arroyo Ana Gutierrez, Ackland Gareth L
Clinical Physiology, Wolfson Institute for Biomedical Research, Department of Medicine, University College London, London, WC1E 6BT, UK,
Intensive Care Med Exp. 2014 Dec;2(1):6. doi: 10.1186/2197-425X-2-6. Epub 2014 Feb 27.
The design of clinical immunology studies in sepsis presents several fundamental challenges to improving the translational understanding of pathologic mechanisms. We undertook a systematic review of bed-to-benchside studies to test the hypothesis that variable clinical design methodologies used to investigate immunologic function in sepsis contribute to apparently conflicting laboratory data, and identify potential alternatives that overcome various obstacles to improve experimental design.
We performed a systematic review of the design methodology employed to study neutrophil function (respiratory burst), monocyte endotoxin tolerance and lymphocyte apoptosis in the intensive care setting, over the past 15 years. We specifically focussed on how control samples were defined, taking into account age, gender, ethnicity, concomitant therapies, timing of sample collection and the criteria used to diagnose sepsis.
We identified 57 eligible studies, the majority of which (74%) used case-control methodology. Healthy volunteers represented the control population selected in 83% of studies. Comprehensive demographic data on age, gender and ethnicity were provided in ≤48% of case control studies. Documentation of diseases associated with immunosuppression, malignancy and immunomodulatory therapies was rare. Less than half (44%) of studies undertook independent adjudication for the diagnosis of sepsis while 68% provided microbiological data. The timing of sample collection was defined by highly variable clinical criteria. By contrast, surgical studies avoided many such confounders, although only one study in surgical patients monitored the study group for development of sepsis.
We found several important and common limitations in the clinical design of translational immunologic studies in human sepsis. Major elective surgery overcame many of these methodological limitations. The failure of adequate clinical design in mechanistic studies may contribute to the lack of translational therapeutic progress in intensive care medicine.
脓毒症临床免疫学研究的设计在提高对病理机制的转化理解方面面临若干基本挑战。我们对从病床到实验室的研究进行了系统综述，以检验以下假设：用于研究脓毒症免疫功能的可变临床设计方法导致了明显相互矛盾的实验室数据，并确定克服各种障碍以改进实验设计的潜在替代方法。
我们对过去15年在重症监护环境中用于研究中性粒细胞功能（呼吸爆发）、单核细胞内毒素耐受性和淋巴细胞凋亡的设计方法进行了系统综述。我们特别关注对照样本的定义方式，同时考虑年龄、性别、种族、伴随治疗、样本采集时间以及用于诊断脓毒症的标准。
我们确定了57项符合条件的研究，其中大多数（74%）采用病例对照方法。83%的研究选择健康志愿者作为对照人群。在≤48%的病例对照研究中提供了关于年龄、性别和种族的综合人口统计学数据。与免疫抑制、恶性肿瘤和免疫调节治疗相关疾病的记录很少。不到一半（44%）的研究对脓毒症诊断进行了独立判定，而68%的研究提供了微生物学数据。样本采集时间由高度可变的临床标准定义。相比之下，外科研究避免了许多此类混杂因素，尽管外科患者中只有一项研究对研究组进行了脓毒症发生情况监测。
我们发现在人类脓毒症转化免疫学研究的临床设计中存在几个重要且常见的局限性。大的择期手术克服了许多这些方法学上的局限性。机制研究中临床设计不足可能导致重症监护医学在转化治疗方面缺乏进展。
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