Wiedermann Christian J, Wiedermann Wolfgang
Department of Internal Medicine, Central Hospital of Bolzano, Teaching Hospital of the Medical University of Innsbruck, Bolzano, Italy.
Department of Psychology, Unit of Quantitative Methods, University of Vienna, Vienna, Austria ; Department of Educational, School and Counseling Psychology, College of Education, University of Missouri, Columbia, MO, USA.
J Anaesthesiol Clin Pharmacol. 2015 Jul-Sep;31(3):394-400. doi: 10.4103/0970-9185.161680.
In anesthesia and intensive care, treatment benefits that were claimed on the basis of small or modest-sized trials have repeatedly failed to be confirmed in large randomized controlled trials. A well-designed small trial in a homogeneous patient population with high event rates could yield conclusive results; however, patient populations in anesthesia and intensive care are typically heterogeneous because of comorbidities. The size of the anticipated effects of therapeutic interventions is generally low in relation to relevant endpoints. For regulatory purposes, trials are required to demonstrate efficacy in clinically important endpoints, and therefore must be large because clinically important study endpoints such as death, sepsis, or pneumonia are dichotomous and infrequently occur. The rarer endpoint events occur in the study population; that is, the lower the signal-to-noise ratio, the larger the trials must be to prevent random events from being overemphasized. In addition to trial design, sample size determination on the basis of event rates, clinically meaningful risk ratio reductions and actual patient numbers studied are among the most important characteristics when interpreting study results. Trial size is a critical determinant of generalizability of study results to larger or general patient populations. Typical characteristics of small single-center studies responsible for their known fragility include low variability of outcome measures for surrogate parameters and selective publication and reporting. For anesthesiology and intensive care medicine, findings in volume resuscitation research on intravenous infusion of colloids exemplify this, since both the safety of albumin infusion and the adverse effects of the artificial colloid hydroxyethyl starch have been confirmed only in large-sized trials.
在麻醉和重症监护领域，基于小规模或中等规模试验所宣称的治疗益处，在大型随机对照试验中屡屡未能得到证实。在事件发生率高的同质患者群体中进行精心设计的小型试验可能会得出确凿的结果；然而，由于合并症的存在，麻醉和重症监护中的患者群体通常是异质的。治疗干预预期效果的大小相对于相关终点而言通常较低。出于监管目的，试验需要在具有临床重要意义的终点上证明疗效，因此必须规模较大，因为诸如死亡、脓毒症或肺炎等具有临床重要意义的研究终点是二分法的，且很少发生。研究人群中终点事件发生得越罕见，即信噪比越低，就必须进行越大规模的试验以防止随机事件被过度强调。除试验设计外，根据事件发生率、具有临床意义的风险比降低以及实际研究的患者数量来确定样本量，是解读研究结果时最重要的特征之一。试验规模是研究结果对更大或一般患者群体可推广性的关键决定因素。小型单中心研究因其已知的脆弱性而具有的典型特征包括替代参数结局测量的低变异性以及选择性发表和报告。对于麻醉学和重症监护医学而言，静脉输注胶体液进行容量复苏研究中的发现就是例证，因为白蛋白输注的安全性以及人工胶体羟乙基淀粉的不良反应仅在大型试验中得到了证实。
