Kalil Andre C, Johnson Daniel W, Lisco Steven J, Sun Junfeng
1Infectious Disease Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.2Critical Care Division, Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE.3Critical Care Department, National Institutes of Health, Bethesda, MD.
Crit Care Med. 2017 Apr;45(4):607-614. doi: 10.1097/CCM.0000000000002235.
Early goal-directed therapy has shown discordant survival outcomes in sepsis studies. We aim to find the reasons for this discordance.
Random-effects and Bayesian hierarchical analyses.
Studies that evaluated early goal-directed therapy.
Patients with severe sepsis and/or septic shock.
Early goal-directed therapy.
A total of 19,998 patients were included in the main analysis: 31 observational (n = 15,656) and six randomized (n = 4,342) studies. The analysis from 37 studies showed that early goal-directed therapy was associated with a 23% reduction in the risk of death: relative risk = 0.77 (95% CI, 0.71-0.83); p value of less than 0.0001. Mortality reduction was seen with observational studies: relative risk = 0.73 (0.67-0.80); p value of less than 0.0001 but not with randomized studies: relative risk = 0.92 (0.78-1.07); p = 0.268. Meta-regression analysis showed lower risk of death in observational compared with randomized studies: relative risk = 0.81 (0.68-0.95); p = 0.01. Differences in age, country, hospital location, era, systolic pressure, mean arterial pressure, lactate, bundle compliance, amount of fluid administered, and hemodynamic goal achievements were not associated with survival differences between studies. Factors associated with mortality differences between early goal-directed therapy and control included Acute Physiology and Chronic Health Evaluation II (relative risk = 1.05 [1.02-1.09]; p = 0.003), Sequential Organ Failure Assessment (relative risk = 1.09 [1.00-1.18]; p = 0.04), presence of shock (relative risk = 1.007 [1.002-1.013]; p = 0.006), time-to-first antibiotic (relative risk = 1.22 [1.09-1.36]; p = 0.0006), antibiotic administration within 6 hours (relative risk = 0.20 [0.09-0.45]; p = 0.0001), 4 hours (relative risk = 0.16 [0.06-0.39]; p = 0.0001), and 3 hours (relative risk = 0.09 [0.03-0.27]; p < 0.0001). The only factors that explained mortality differences between randomized and observational studies were time-to-first antibiotic (R = 87%), antibiotic administration within 6 hours (R = 94%), 4 hours (R = 99%), 3 hours (R = 99%), and appropriate antibiotic use (R = 96%).
Survival discordance was not associated with differences in early goal-directed therapy bundle compliance or hemodynamic goal achievement. Our results suggest that it was associated with faster and more appropriate antibiotic co-intervention in the early goal-directed therapy arm compared with controls in the observational studies but not in the randomized trials. Early goal-directed therapy was associated with increased mortality in patients with high-disease severity.
早期目标导向治疗在脓毒症研究中显示出不一致的生存结果。我们旨在找出这种不一致的原因。
随机效应和贝叶斯分层分析。
评估早期目标导向治疗的研究。
严重脓毒症和/或感染性休克患者。
早期目标导向治疗。
共有19998例患者纳入主要分析，包括31项观察性研究（n = 15656）和6项随机对照研究（n = 4342）。37项研究的分析表明，早期目标导向治疗使死亡风险降低23%：相对风险=0.77（95%CI，0.71 - 0.83）；p值小于0.0001。观察性研究显示死亡率降低：相对风险=0.73（0.67 - 0.80）；p值小于0.0001，但随机对照研究未显示：相对风险=0.92（0.78 - 1.07）；p = 0.268。Meta回归分析显示，与随机对照研究相比，观察性研究的死亡风险更低：相对风险=0.81（0.68 - 0.95）；p = 0.01。年龄、国家、医院位置、时代、收缩压、平均动脉压、乳酸水平、集束治疗依从性、补液量和血流动力学目标达成情况的差异与研究间的生存差异无关。早期目标导向治疗与对照相比，与死亡率差异相关的因素包括急性生理与慢性健康状况评分系统II（相对风险=1.05[1.02 - 1.09]；p = 0.003）、序贯器官衰竭评估（相对风险=1.09[1.00 - 1.18]；p = 0.04）、休克的存在（相对风险=1.007[1.002 - 1.013]；p = 0.006）、首次使用抗生素的时间（相对风险=1.22[1.09 - 1.36]；p = 0.0006）、6小时内使用抗生素（相对风险=0.20[0.09 - 0.45]；p = 0.0001）、4小时内使用抗生素（相对风险=0.16[0.06 - 0.39]；p = 0.0001）以及3小时内使用抗生素（相对风险=0.09[0.03 - 0.27]；p < 0.0001）。唯一能解释随机对照研究和观察性研究死亡率差异的因素是首次使用抗生素的时间（R = 87%）、6小时内使用抗生素（R = 94%）、4小时内使用抗生素（R = 99%）、3小时内使用抗生素（R = 99%）以及抗生素的合理使用（R = 96%）。
生存结果的不一致与早期目标导向治疗集束治疗依从性或血流动力学目标达成情况的差异无关。我们的结果表明，与观察性研究中的对照相比，早期目标导向治疗组更快且更合理地联合使用抗生素与生存结果相关，但在随机对照试验中并非如此。早期目标导向治疗与疾病严重程度高的患者死亡率增加相关。
