Okinawa Nanbu Prefectural Medical Center and Children's Medical Center, Haebaru, Okinawa, Japan.
Tokyo Foundation for Policy Research, Minato-ku, Tokyo, Japan.
Crit Care. 2023 Feb 8;27(1):53. doi: 10.1186/s13054-023-04337-5.
Steroids are widely used to modulate the inflammatory reactions associated with coronavirus disease 2019 (COVID-19); however, the optimal upper limit dose of steroid use for acute COVID-19 care remains unclear and currently available data may suffer from a time-dependent bias of no effectiveness or reversed causation given the desperate situation of treatment during this pandemic. Accordingly, the aim of this study was to elucidate the impact of intravenous pulse therapy with methylprednisolone (500 mg or greater per day) on the risk of in-hospital mortality among patients with COVID-19 by controlling for time-dependent bias.
We performed a prospective cohort study with 67,348 hospitalised acute COVID-19 patients at 438 hospitals during 2020-2021 in Japan. The impact of intravenous methylprednisolone pulse therapy on the risk of in-hospital mortality was examined based on hazard ratios (HRs) and 95% confidence intervals (95% CIs), with stratification according to the status of invasive mechanical ventilation (iMV). Time-dependent bias was controlled for in a marginal structural model analysis, with reference to patients without methylprednisolone therapy.
During the study period, 2400 patients died. In-hospital mortality rates of iMV-free patients without or with methylprednisolone pulse therapy were 2.3% and 19.5%, and the corresponding values for iMV-receiving patients were 24.7% and 28.6%, respectively. The marginal structural model analysis showed that intravenous pulse therapy with methylprednisolone was associated with a lower risk of in-hospital mortality among patients receiving-iMV (HR 0.59; 95% CI 0.52-0.68). In contrast, pulse therapy with methylprednisolone increased the risk of in-hospital mortality among iMV-free patients (HR 3.38; 95% CI 3.02-3.79). The benefits of pulse therapy for iMV-receiving patients were greater than in those treated with intermediate/higher doses (40-250 mg intravenously) of methylprednisolone (HR 0.80; 95% CI 0.71-0.89).
The results of our study suggest that intravenous methylprednisolone showed dose-response efficiencies, and pulse therapy may benefit critically ill patients with acute COVID-19, such as those requiring iMV.
类固醇被广泛用于调节与 2019 年冠状病毒病（COVID-19）相关的炎症反应；然而，急性 COVID-19 护理中类固醇使用的最佳上限剂量仍不清楚，并且由于在大流行期间治疗的紧急情况，目前可用的数据可能存在无效或因果关系逆转的时间依赖性偏差。因此，本研究旨在通过控制时间依赖性偏差，阐明静脉注射甲泼尼龙脉冲疗法（每天 500 毫克或更高剂量）对 COVID-19 住院患者院内死亡率风险的影响。
我们在 2020 年至 2021 年期间，在日本的 438 家医院对 67348 例住院急性 COVID-19 患者进行了前瞻性队列研究。根据风险比（HRs）和 95%置信区间（95%CI），并根据有创机械通气（iMV）的状态进行分层，检查静脉内甲泼尼龙脉冲疗法对院内死亡率风险的影响。通过参考未接受甲泼尼龙治疗的患者，在边缘结构模型分析中控制时间依赖性偏差。
在研究期间，有 2400 名患者死亡。无 iMV 接受者和接受 iMV 接受者中未接受或接受甲泼尼龙脉冲治疗的患者的院内死亡率分别为 2.3%和 19.5%，相应的患者为 24.7%和 28.6%。边缘结构模型分析表明，静脉内甲泼尼龙脉冲疗法与接受 iMV 的患者的院内死亡率降低相关（HR 0.59；95%CI 0.52-0.68）。相比之下，甲泼尼龙脉冲治疗增加了无 iMV 接受者的院内死亡率风险（HR 3.38；95%CI 3.02-3.79）。接受 iMV 的患者接受甲泼尼龙脉冲治疗的益处大于接受中等/高剂量（40-250 毫克静脉内）的患者（HR 0.80；95%CI 0.71-0.89）。
我们的研究结果表明，静脉内甲泼尼龙显示出剂量反应效率，脉冲疗法可能有益于急性 COVID-19 的重症患者，例如需要 iMV 的患者。
