CC:早期辅助性血管加压素启动对感染性休克患者的影响：一项目标试验模拟研究

Background

In septic shock, the optimal timing of adjunctive vasopressin initiation shock is unknown. We aimed to assess the effect of its early initiation for patients with septic shock.

在感染性休克患者中，辅助性血管加压素启动的最佳时机尚不明确。我们旨在评估早期启动血管加压素对感染性休克患者的效果。

Methods

We conducted a multicenter target trial emulation to estimate the intensive care unit (ICU) mortality effect of early (≤ 6 h) adjunctive vasopressin compared with usual care. Eligible patients had septic shock diagnosed within 6 h of ICU admission. The primary outcome of this study was 30-day ICU mortality. Subgroup analyses were conducted to test the interaction of early vasopressin start with peak norepinephrine-equivalent dose (NED) at 6 h, APACHE score, peak lactate at 6 h and invasive mechanical ventilation. Secondary outcomes were the impact of delayed vasopressin introduction on 30-day ICU mortality and effect of NED at vasopressin start on 30-day ICU mortality. We used the parametric g-formula to emulate a target trial.

我们开展了一项多中心目标试验模拟研究，以估算早期（≤6小时）辅助性血管加压素与常规治疗相比对重症监护病房（ICU）死亡率的影响。符合条件的患者在入住ICU 6小时内被诊断为感染性休克。本研究的主要结局是30天ICU死亡率。我们进行了亚组分析，以检验早期启动血管加压素与6小时时去甲肾上腺素等效剂量（NED）峰值、急性生理学与慢性健康状况评分系统Ⅱ（APACHE）评分、6小时时乳酸峰值以及有创机械通气之间的相互作用。次要结局包括延迟引入血管加压素对30天ICU死亡率的影响，以及启动血管加压素时NED对30天ICU死亡率的影响。我们采用参数化g公式来模拟目标试验。

Results

Overall, 3,105 patients fulfilled the inclusion criteria. Mean age was 62 years and mean APACHE III score was 83. In the first six hours of vasopressor therapy, 1,864 (60%) patients were invasively ventilated. Estimated 30-day ICU mortality was 19.34% (95%CI, 17.0 to 21.68) in the no vasopressin group and 18.45% (95%CI, 16.26 to 20.63) in the early vasopressin group; relative risk 0.95 (95%CI, 0.93 to 0.98). The estimated 30-day ICU mortality effect of starting vasopressin was particularly strong at lower norepinephrine doses (< 0.25 µg.kg⁻¹.min⁻¹) and significant at lower norepinephrine doses than recommended by the Surviving Sepsis Campaign Guidelines. Vasopressin administration progressively increased over the study period, from 35.2% (95%CI, 30.0 to 40.5) in 2015 to 45.1% (95%CI, 40.7 to 49.6) in 2021 (ß =  + 1.3% per year; 95%CI, + 0.46 to + 2.16, p = 0.011). Patients had progressively lower norepinephrine equivalent dose (ß = − 0.05 µg.kg⁻¹.min⁻¹ per year; 95%CI, − 0.09 to − 0.002, p = 0.038) and lower total SOFA score (ß = − 0.1 point per year; 95%CI, − 0.18 to − 0.07, p < 0.001) at vasopressin start.

总体而言，共有3105例患者符合纳入标准。患者平均年龄为62岁，平均APACHEⅢ评分为83分。在血管活性药物治疗的前6小时内，1864例（60%）患者接受了有创机械通气。在未使用血管加压素组中，估算的30天ICU死亡率为19.34%（95%置信区间[CI]：17.0 – 21.68），而在早期使用血管加压素组中为18.45%（95% CI：16.26 – 20.63）；相对风险为0.95（95% CI：0.93 – 0.98）。在去甲肾上腺素剂量较低（＜0.25 μg·kg⁻¹·min⁻¹）时，启动血管加压素对估算的30天ICU死亡率的影响尤为显著，并且在低于拯救脓毒症运动指南推荐剂量的去甲肾上腺素水平下也具有统计学意义。在研究期间，血管加压素的使用率逐渐增加，从2015年的35.2%（95% CI：30.0 – 40.5）上升至2021年的45.1%（95% CI：40.7 – 49.6）（年均增长率为 +1.3%；95% CI：+0.46 – +2.16，P = 0.011）。在启动血管加压素时，患者的去甲肾上腺素等效剂量逐渐降低（年均下降0.05 μg·kg⁻¹·min⁻¹；95% CI：−0.09 – −0.002，P = 0.038），总序贯器官衰竭评估（SOFA）评分也逐渐降低（年均下降0.1分；95% CI：−0.18 – −0.07，P ＜ 0.001）。

Conclusions

In this emulation of a hypothetical target trial, patients with septic shock benefited from early vasopressin administration. These findings can help design prospective randomised-control trials of early adjunctive vasopressin use in septic shock.

在这项假设性目标试验的模拟研究中，感染性休克患者从早期使用血管加压素中获益。这些发现有助于设计关于在感染性休克中早期联合使用血管加压素的前瞻性随机对照试验。