We read with great interest the database study by Aoki et al. [1], published in Critical Care. As highlighted in this article, whole blood (WB) transfusion for patients with trauma or severe hemorrhage has recently attracted worldwide attention for its promising potential in reducing mortality [2,3,4]. This study examines the association between the whole blood rate (WBR), defined as the number of WB units divided by the sum of WB units and packed red blood cells (PRBCs), and 24-h mortality in trauma patients requiring massive transfusion. The results suggest that a higher WBR is associated with improved survival and a lower risk of acute kidney injury (AKI) in patients who received whole blood transfusion within 4 h of hospital arrival. The study utilized generalized estimating equations to adjust for covariates, including clustering, and conducted sensitivity analyses that accounted for the heterogeneity of the lowest WBR group, further enhancing the robustness of the results. Therefore, this study has significant implications for current trauma resuscitation strategies. However, we believe there are some untreated biases, particularly time-dependent intervention bias, which warrant careful consideration.

Firstly, the intervention in this study design is time-dependent; that is, the risk of mortality could continuously influence the physician's decision to administer WB transfusion, and WB transfusion, in turn, could influence the risk of mortality. The risk of mortality and transfusion decisions interact dynamically over time during early trauma care. Component transfusion is routinely administered and readily available at many trauma centers, whereas WB transfusion often depends on the institution's system or regional blood bank, typically making it available later. In many cases, component transfusion is administered first, followed by WB transfusion. Under this assumption, WBR would be zero in the early phase when only component transfusion is being used, and would gradually increase once WB transfusion begins, ranging from zero to one. If, as the authors assume, the intervention, expressed as a continuous variable, affects outcomes, then the time-dependent WBR would impact outcomes differently over time. Thus, evaluating the relationship between a time-dependent intervention like WBR and outcomes at a specific point in time may not fully capture the true relationship.

Additionally, the relationship between WBR and outcomes may introduce immortal time bias. This bias occurs in epidemiological and clinical studies when there is a period during which participants cannot experience the outcome of interest, such as death [5]. Patients with severe trauma are at high risk of early death. Assuming that WBR increases over time, patients with a lower WBR may be those who died early due to severity, while patients with a higher WBR may have survived longer.

Statistical models that account for time-dependent interventions and immortal time bias, such as Marginal Structural Models with Inverse Probability of Treatment Weighting (MSMs with IPTW), may be more appropriate [6, 7]. If the current data source does not sufficiently describe time-dependent interventions, prospective studies may be necessary to generate a more suitable dataset.

In conclusion, prospective studies or database studies that account for time-dependent interventions and biases such as immortal time bias are necessary. Future research incorporating these considerations will ensure results that are both statistically robust and clinically meaningful, ultimately contributing to improved trauma resuscitation strategies.

Further information on the original manuscript is available from the corresponding authors upon reasonable request. No datasets were generated or analysed during the current study.

WB:

Whole blood

WBR:

Whole blood rate

AKI:

Acute kidney injury

TTE:

Target trial emulation

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2. Torres CM, Kent A, Scantling D, Joseph B, Haut ER, Sakran JV. Association of whole blood with survival among patients presenting with severe hemorrhage in US and Canadian adult civilian trauma centers. JAMA Surg. 2023;158(5):532–40.

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4. Aoki M, Katsura M, Matsushima K. Association between whole blood transfusion and mortality among injured pediatric patients. Ann Surg. 2024;279(5):880–4.

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5. Yadav K, Lewis RJ. Immortal time bias in observational studies. JAMA. 2021;325(7):686–7.

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Authors and Affiliations

1. Department of Emergency and Trauma Medicine, Kameda Medical Center, 929 Higashi-cho, Kamogawa, Chiba, 296-8602, Japan

   Taisuke Shibata, Saburo Minami & Atsushi Shiraishi

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All authors contributed to the manuscript conception and design. The first draft of the manuscript was written by Taisuke Shibata and all authors gave critical appraisal to the initial draft. All authors read and approved the final manuscript.

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Correspondence to Atsushi Shiraishi.

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Shibata, T., Minami, S. & Shiraishi, A. Time-dependent intervention in the database study examining the efficacy of whole blood transfusion in traumatic patients. Crit Care 28, 390 (2024). https://doi.org/10.1186/s13054-024-05115-7

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• Received: 27 September 2024

• Accepted: 30 September 2024

• Published: 26 November 2024

• DOI: https://doi.org/10.1186/s13054-024-05115-7

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我们饶有兴趣地阅读了 Aoki 等人 [1] 发表在《重症监护》上的数据库研究。正如本文所强调的，创伤或严重出血患者全血 （WB） 输注最近因其在降低死亡率方面的巨大潜力而引起了全世界的关注 [2,3,4]。本研究检查了全血率 （WBR） 之间的关联，WBR 定义为 WB 单位数除以 WB 单位和浓缩红细胞 （PRBC） 之和，与需要大量输血的创伤患者 24 小时死亡率之间的关联。结果表明，在到达医院后 4 小时内接受全血输注的患者，较高的 WBR 与生存率提高和急性肾损伤 （AKI） 风险降低相关。该研究利用广义估计方程来调整协变量，包括聚类，并进行了敏感性分析，解释了最低 WBR 组的异质性，进一步增强了结果的稳健性。因此，本研究对当前的创伤复苏策略具有重要意义。然而，我们认为存在一些未经治疗的偏倚，特别是时间依赖性干预偏倚，值得仔细考虑。

首先，本研究设计的干预是时间依赖性的;也就是说，死亡风险可能会持续影响医生进行 WB 输血的决定，而 WB 输血反过来又会影响死亡风险。在早期创伤护理期间，死亡风险和输血决策会随着时间的推移动态相互作用。成分输血是常规进行的，在许多创伤中心很容易获得，而 WB 输血通常取决于机构的系统或区域血库，通常会稍后提供。在许多情况下，首先进行成分输注，然后进行 WB 输注。在此假设下，当仅使用成分输注时，WBR 在早期阶段为零，一旦 WB 输注开始，WBR 将逐渐增加，范围从 0 到 1。如果正如作者所假设的那样，以连续变量表示的干预影响结果，那么时间依赖性 WBR 会随着时间的推移对结果产生不同的影响。因此，评估像 WBR 这样的时间依赖性干预与特定时间点的结果之间的关系可能无法完全捕捉到真正的关系。

此外，WBR 与结果之间的关系可能会引入不朽的时间偏差。这种偏倚发生在流行病学和临床研究中，当参与者在一段时间内无法体验到感兴趣的结果，例如死亡 [5]。严重创伤患者过早死亡的风险很高。假设 WBR 随着时间的推移而增加，WBR 较低的患者可能是因严重程度而过早死亡的患者，而 WBR 较高的患者可能存活时间更长。

考虑时间依赖性干预和长期时间偏倚的统计模型，例如具有治疗加权逆概率的边缘结构模型 （MSMs with IPTW），可能更合适 [6， 7]。如果当前数据源不能充分描述时间依赖性干预措施，则可能需要前瞻性研究以生成更合适的数据集。

总之，有必要进行前瞻性研究或数据库研究，以解释时间依赖性干预和偏倚，例如不朽的时间偏倚。结合这些考虑因素的未来研究将确保结果在统计上具有稳健性和临床意义，最终有助于改进创伤复苏策略。

如有合理要求，可向通讯作者索取有关原始手稿的更多信息。在当前研究期间没有生成或分析数据集。

 工 务 局：

 全血

 WBR：

 全血率

 阿基：

 急性肾损伤

 TTE：

 Target Trial 仿真

1. 
   Aoki M， Abe T， Komori A， Katsura M， Matsushima K. 大量输血创伤患者全血比值与死亡风险之间的关联：回顾性队列研究。暴击护理。2024;28(1):253.

   
   文章： PubMed PubMed Central Google Scholar

2. 
   Torres CM、Kent A、Scantling D、Joseph B、Haut ER、Sakran JV。全血与美国和加拿大成人平民创伤中心严重出血患者生存率的关联。美国医学会外科杂志 2023;158(5):532–40.

   
   文章： PubMed PubMed Central Google Scholar

3. 
   Hazelton JP、Ssentongo AE、Oh JS、Ssentongo P、Seamon MJ、Byrne JP 等人。使用冷藏全血与提高大出血止血复苏的死亡率相关：一项多中心研究。安外科杂志 2022;276(4):579–88.

   
   文章 PubMed 谷歌学术

4. 
   Aoki M， Katsura M， Matsushima K. 受伤儿科患者全血输注与死亡率之间的关联。安外科杂志 2024;279(5):880–4.

    PubMed 谷歌学术

5. 
   亚达夫 K，刘易斯 RJ。观察性研究中的不朽时间偏差。美国医学会。2021;325(7):686–7.

   
   文章 PubMed 谷歌学术

6. 
   Robins JM， Hernan MA， Brumback B. 流行病学中的边缘结构模型和因果推理。流行病学。2000;11(5):550–60.

   
   论文 CAS PubMed Google Scholar

7. 
   Hernan MA， Brumback BA， Robins JM.使用重复测量的边缘结构模型估计齐多夫定对 CD4 计数的因果关系。统计医学 2002 年;21(12):1689–709.

   
   文章 PubMed 谷歌学术

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   Taisuke Shibata， Saburo Minami & Atsushi Shiraishi

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