JAMA：脓毒症休克中血管加压素的最佳启动时机

Abstract

Importance: Norepinephrine is the first-line vasopressor for patients with septic shock. When and whether a second agent, such as vasopressin, should be added is unknown.去甲肾上腺素是脓毒症休克患者的一线血管活性药物，但何时及是否应加用第二种药物（如血管加压素）仍不明确。

Objective: To derive and validate a reinforcement learning model to determine the optimal initiation rule for vasopressin in adult, critically ill patients receiving norepinephrine for septic shock.开发并验证一种强化学习模型，以确定接受去甲肾上腺素治疗的成年脓毒症休克重症患者血管加压素的最佳启动时机。

Design, setting, and participants: Reinforcement learning was used to generate the optimal rule for vasopressin initiation to improve short-term and hospital outcomes, using electronic health record data from 3608 patients who met the Sepsis-3 shock criteria at 5 California hospitals from 2012 to 2023. The rule was evaluated in 628 patients from the California dataset and 3 external datasets comprising 10 217 patients from 227 US hospitals, using weighted importance sampling and pooled logistic regression with inverse probability weighting.利用 2012-2023 年加州 5 家医院3608 例符合 Sepsis-3 休克标准患者的电子健康记录（EHR）数据，通过强化学习生成优化血管加压素启动时机（目标：改善短期死亡率及院内结局）。采用加权重要性抽样和逆概率加权合并逻辑回归，在加州数据集的 628 例患者及 3 个外部数据集（227 家美国医院，10,217 例患者）中验证该规则。

Exposures: Clinical, laboratory, and treatment variables grouped hourly for 120 hours in the electronic health record.

Main outcome and measure: The primary outcome was in-hospital mortality.主要终点院内死亡率。

Results: The derivation cohort (n = 3608) included 2075 men (57%) and had a median (IQR) age of 63 (56-70) years and Sequential Organ Failure Assessment (SOFA) score at shock onset of 5 (3-7 [range, 0-24, with higher scores associated with greater mortality]). The validation cohorts (n = 10 217) were 56% male (n = 5743) with a median (IQR) age of 67 (57-75) years and a SOFA score of 6 (4-9). In validation data, the model suggested vasopressin initiation in more patients (87% vs 31%), earlier relative to shock onset (median [IQR], 4 [1-8] vs 5 [1-14] hours), and at lower norepinephrine doses (median [IQR], 0.20 [0.08-0.45] vs 0.37 [0.17-0.69] µg/kg/min) compared with clinicians’ actions. The rule was associated with a larger expected reward in validation data compared with clinician actions (weighted importance sampling difference, 31 [95% CI, 15-52]). The adjusted odds of hospital mortality were lower if vasopressin initiation was similar to the rule compared with different (odds ratio, 0.81 [95% CI, 0.73-0.91]), a finding consistent across external validation sets.推导队列（n=3608）：男性 2075 例（57%），中位（IQR）年龄 63（56-70）岁，休克发生时序贯器官衰竭评估（SOFA）评分 5（3-7，范围 0-24，评分越高死亡率越高）。验证队列（n=10,217）：男性 56%（5743 例），中位（IQR）年龄 67（57-75）岁，SOFA 评分 6（4-9）。模型推荐 vs 临床实践：启动比例：87% vs 31%。休克发生后时间：中位（IQR）4（1-8）小时 vs 5（1-14）小时。去甲肾上腺素剂量：中位（IQR）0.20（0.08-0.45）µg/kg/min vs 0.37（0.17-0.69µg/kg/min。有效性：模型推荐方案的预期获益显著高于临床实践（加权重要性抽样差值，31 [95% CI, 15-52]）。与模型推荐一致 vs 不一致的患者，院内死亡风险降低（优势比，0.81 [95% CI, 0.73-0.91]），且在外部验证集中结果一致。

Conclusions and relevance: In adult patients with septic shock receiving norepinephrine, the use of vasopressin was variable. A reinforcement learning model developed and validated in several observational datasets recommended more frequent and earlier use of vasopressin than average care patterns and was associated with reduced mortality.在接受去甲肾上腺素治疗的成年脓毒症休克患者中，血管加压素的使用存在差异。基于多组观察性数据开发并验证的强化学习模型，推荐更频繁、更早使用血管加压素，且与死亡率降低相关。