Identifying critically ill patients who may benefit from adjunctive corticosteroids: not as easy as we thought.
Identifying critically ill patients who may benefit from adjunctive corticosteroids: not as easy as we thought.
复制标题
识别可能受益于辅助皮质类固醇的危重患者：并不像我们想象的那么容易。
DOI：
10.1097/pcc.0000000000000203
复制
发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Wong,HectorR
中科院分区：
文献类型：
--
作者：
Atkinson,SarahJ;Wong,HectorR
编辑770 www. PCCM杂志。org October 2014· Volume 15· Number 8 corticosteroids（1，2）.这一争论体现在医生处方皮质类固醇的差异上（3，4）。研究危重成人使用皮质类固醇的试验产生了相互矛盾的结果，儿科研究尚未达成明确的共识（5-7）。尽管最近2012年针对儿科患者的败血症生存运动指南比前几年更强烈地推荐使用糖皮质激素，但它们的措辞仍然允许实践中存在巨大的差异，并且这些建议的基础受到质疑（8，9）。不同建议的部分原因是皮质类固醇对患者的影响不一致。考虑到这种不一致性，已经尝试确定那些重症患者谁站在受益最大的糖皮质激素。第一个理论上从皮质类固醇治疗危重病中获益最多的亚群之一是相对肾上腺功能不全的患者。按理说，那些不能对压力产生足够的皮质醇反应的患者将从皮质类固醇补充剂中获益最多。Annane等人（10）的里程碑式研究表明，对促肾上腺皮质激素（ACTH）刺激试验未能产生足够皮质醇反应的脓毒性休克患者，在给予氢化可的松和氟氢可的松时具有生存获益。这项研究在重症监护医学领域获得了极大的热情，希望一个相对简单的测试可以确定一个亚群的患者最有可能受益于连续性皮质类固醇给药;重症监护医学已经进入了个性化医疗（治疗诊断学）的时代。然而，随后的一项更大规模的研究无法复制这些数据，因此很明显，识别这些患者比简单地进行ACTH刺激试验要复杂得多。在儿科文献中，相对肾上腺功能不全已被证明存在于危重人群中，但没有研究表明在该特定队列中连续使用皮质类固醇的益处（12，13）。为了进一步研究不同个体对皮质类固醇的反应，一些研究者已经开始寻找基于下丘脑-垂体-肾上腺轴其他成分的替代解释。例如，感染性休克患者的基于基因表达的分类最近已得到验证，并显示与重要表型差异的亚类相关（14-16）。这些研究确定了一种基因特征，由一组对应于糖皮质激素受体信号通路的基因组成，该基因在死亡率和器官衰竭负担最高的患者中受到抑制。最近的另一项研究表明，危重患者在负责皮质醇代谢的途径中有功能上重要的改变（17）。总的来说，这些研究表明，危重病中皮质醇相关稳态（或缺乏稳态）的问题比ACTH刺激试验提供的信息复杂得多。鉴于危重病内在的高度复杂性和异质性，这一发现不应令人惊讶。这一概念为Jardine等人（18）在本期《儿科重症监护医学》中的研究提供了基础，该研究确定了黑皮质素2受体（MC 2 R）基因非编码区内的单核苷酸多态性（SNP（rs 1941088）这可能有助于解释危重病期间皮质醇产生的不同水平。MC 2 R基因
Editorials770 www. pccmjournal. org October 2014• Volume 15• Number 8 corticosteroids (1, 2). This controversy is personified by the variability among practitioner prescription of corticosteroids (3, 4). Trials investigating corticosteroid use in critically ill adults have yielded conflicting results, and pediatric studies have yet to arrive at a clear consensus (5–7). Although recent 2012 Surviving Sepsis Campaign guidelines for pediatric patients have a stronger recommendation for adjunctive corticosteroids than in previous years, they are still worded to allow for tremendous variability in practice and the basis for these recommendations has been questioned (8, 9). Part of the reason for the varying recommendations is the inconsistent effect of corticosteroids on a patient-to-patient basis. With this inconsistency in mind, attempts have been made to identify those critically ill patients who stand to benefit the most from adjunctive corticosteroids. One of the first subpopulations theorized to benefit the most from corticosteroid therapy for critical illness was patients with relative adrenal insufficiency. It stands to reason that patients who fail to mount a sufficient cortisol response to stress would benefit the most from corticosteroid supplementation. The landmark study by Annane et al (10) demonstrated that patients with septic shock who failed to mount an adequate cortisol response to adrenocorticotropin hormone (ACTH) stimulation testing had a survival benefit when administered hydrocortisone and fludrocortisone. This study garnered much enthusiasm in the field of critical care medicine with the hope that a relatively simple test could identify a subpopulation of patients most likely to benefit from adjunctive corticosteroid administration; critical care medicine had entered the age of personalized medicine (theranostics). However, a subsequent, larger study could not replicate these data, thus making it clear that identifying such patients is much more complex than simply conducting an ACTH stimulation test (11). Within pediatric literature, relative adrenal insufficiency has been shown to exist in critically ill populations, but no studies have demonstrated a benefit from adjunctive corticosteroid usage in this particular cohort (12, 13). To further investigate the varying individual responses to corticosteroids, several investigators have started a search for alternative explanations based on other components of the hypothalamic-pituitary-adrenal axis. For example, gene expression-based classification of patients with septic shock has recently been validated and shown to correlate with subclasses of important phenotypic differences (14–16). These studies identified a gene signature, comprised of a group of genes corresponding to the glucocorticoid receptor signaling pathway, which was repressed in patients with the highest mortality and organ failure burden. Another recent study demonstrated that critically ill patients have functionally important alterations in the pathways responsible for cortisol metabolism (17). Collectively, these studies illustrate that the issue of cortisol-related homeostasis (or lack thereof) in critical illness is much more complex than the information provided by the ACTH stimulation test. This finding should not come as a surprise given the high level of complexity and heterogeneity intrinsic to critical illness.This concept provides the foundation for the study by Jardine et al (18) in this issue of Pediatric Critical Care Medicine that identifies a single-nucleotide polymorphism (SNP) within the noncoding region of the melanocortin 2 receptor (MC2R) gene (rs1941088) that may help explain the varying levels of cortisol production during critical illness. The MC2R gene …