Derivation, Validation, and Clinical Relevance of a Pediatric Sepsis Phenotype With Persistent Hypoxemia, Encephalopathy, and Shock.
Derivation, Validation, and Clinical Relevance of a Pediatric Sepsis Phenotype With Persistent Hypoxemia, Encephalopathy, and Shock.
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DOI：
10.1097/pcc.0000000000003292
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发表时间：
2023-10-01
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解开儿童脓毒症的异质性，并确定临床相关的表型可能会导致靶向治疗的发展。我们的目的是分析脓毒症相关多器官功能障碍综合征（MODS）儿童的器官功能障碍轨迹，以确定可重复的和临床相关的脓毒症表型，并确定它们是否与治疗效果（HTE）的异质性相关。多中心观察性队列研究。美国有13个PICU。2012年至2018年期间因疑似感染而入住PICU的患者。没有。我们使用子图增强的非负矩阵因子分解，根据最初72小时内器官功能障碍的类型、严重程度和进展，确定候选的基于遗传学的表型。我们分析了候选表型，以确定可重复性以及预后，治疗和生物学相关性。总的来说，38，732名儿童疑似感染，其中15，246名（39.4%）患有脓毒症相关的MODS，住院死亡率为10.1%。我们确定了一种器官功能障碍的恶性表型（我们称之为持续性低氧血症、脑病和休克），具有高度可重复性，具有全身炎症和凝血功能障碍的特征，并与较高的死亡率独立相关。在倾向评分匹配分析中，持续低氧血症、脑病和休克表型的患者似乎有HTE，并从氢化可的松和白蛋白辅助治疗中获益。与其他高危临床综合征相比，持续低氧血症、脑病和休克表型仅与50%-60%的感染性休克、中重度小儿急性呼吸窘迫综合征或器官功能障碍负荷最高的患者重叠，表明其代表了脓毒症相关MODS的非同义临床表型。我们推导并验证了持续性低氧血症、脑病和休克表型，这些表型具有高度可重复性、临床相关性，并与脓毒症儿童常见辅助治疗的HTE相关。
Untangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of targeted therapies. Our aim was to analyze the organ dysfunction trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify reproducible and clinically relevant sepsis phenotypes and determine if they are associated with heterogeneity of treatment effect (HTE) to common therapies. Multicenter observational cohort study. Thirteen PICUs in the United States. Patients admitted with suspected infections to the PICU between 2012 and 2018. None. We used subgraph-augmented nonnegative matrix factorization to identify candidate trajectory-based phenotypes based on the type, severity, and progression of organ dysfunction in the first 72 hours. We analyzed the candidate phenotypes to determine reproducibility as well as prognostic, therapeutic, and biological relevance. Overall, 38,732 children had suspected infection, of which 15,246 (39.4%) had sepsis-associated MODS with an in-hospital mortality of 10.1%. We identified an organ dysfunction trajectory-based phenotype (which we termed persistent hypoxemia, encephalopathy, and shock) that was highly reproducible, had features of systemic inflammation and coagulopathy, and was independently associated with higher mortality. In a propensity score-matched analysis, patients with persistent hypoxemia, encephalopathy, and shock phenotype appeared to have HTE and benefit from adjuvant therapy with hydrocortisone and albumin. When compared with other high-risk clinical syndromes, the persistent hypoxemia, encephalopathy, and shock phenotype only overlapped with 50%–60% of patients with septic shock, moderate-to-severe pediatric acute respiratory distress syndrome, or those in the top tier of organ dysfunction burden, suggesting that it represents a nonsynonymous clinical phenotype of sepsis-associated MODS. We derived and validated the persistent hypoxemia, encephalopathy, and shock phenotype, which is highly reproducible, clinically relevant, and associated with HTE to common adjuvant therapies in children with sepsis.