Progressive hemorrhagic injury and ischemia after severe traumatic brain injury according to hemoglobin transfusion thresholds: a post-hoc analysis of the transfusion requirements after head trauma trial,Critical Care

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Progressive hemorrhagic injury and ischemia after severe traumatic brain injury according to hemoglobin transfusion thresholds: a post-hoc analysis of the transfusion requirements after head trauma trial
Critical Care ( IF 8.8 ) Pub Date : 2024-07-03 , DOI: 10.1186/s13054-024-04981-5
André L N Gobatto ₁ , Davi Solla ₂ , Sérgio Brasil ₂ , Fabio S Taccone ₃ , Carlos G Carlotti ₂ , Luiz Marcelo S Malbouisson ₁ , Wellingson S Paiva ₂

Affiliation

Trial registration: ClinicalTrials.gov, NCT02203292. Registered on 29 July 2014.

Following severe traumatic brain injury (TBI), up to 50% of patients develop significant anemia, which compromises oxygen delivery to the cerebral tissue [1]. Furthermore, about 20–50% of TBI cases complicate with progressive hemorrhagic injuries (PHI) within the first 72 h post-injury [2] and 19–68% develop vasospasm [3]. Such combination of events increase the risks for cerebral ischemia and suggest blood transfusion as a strategy to mitigate the possibility of additional tissue hypoxia. Nevertheless, defining the optimal hemoglobin thresholds to trigger transfusion and prevent additional hypoxic damages in TBI patients remains elusive. Therefore, the purpose of the present study was to assess whether different transfusion strategies can impact hemorrhagic and ischemic outcomes in TBI.

This study presents a post hoc analysis of the Transfusion Requirements After Head Trauma (TRAHT) trial, an open-label, parallel, feasibility, randomized controlled trial investigating two red blood cell transfusion strategies: a "restrictive" approach (hemoglobin < 7 g/dL) versus a "liberal" approach (hemoglobin < 9 g/dL) [4]. Inclusion and exclusion criteria have been previously outlined [4]. Patients adhered to their assigned transfusion strategy for up to 14 days or until death or ICU discharge, whichever occurred first. All patients were monitored using serial transcranial Doppler ultrasound (TCD) examinations. TCD provides cerebral blood velocities (CBv) as surrogate measures for cerebral blood flow, with multiple applications in critical care [5]. Cerebral vasospasm was defined using Lindegaard and Soustiel indexes, based on cerebral (middle cerebral [MCA] and basilar) and extracranial (internal carotid and vertebral) arteries blood velocities [5]. All patients were submitted to brain CT at admission following the discretion of the attending teams. The primary endpoint was observing the occurrence of new ischemic events post-randomization. Also, we described the occurrence of PHI, which was defined as the appearance of new or enlarged intracerebral hematomas by a minimum of 10% its previous volume, enlargement of subdural or epidural hematomas, or unexpected post-surgical hematomas at the operative site, with no minimum volume threshold. Extensive ischemia corresponded to a hypodense area suggestive of vascular etiology on CT scans, involving more than two segments of a cerebral artery, as MCA M3 and M4 per example. All radiological evaluations were analyzed by an independent radiologist blinded to the study allocation. For descriptive purposes, categorical variables were presented through relative and absolute frequencies and compared by means of the chi-squared or Fisher exact test, as appropriate. All tests were two-sided and final p values under 0.05 were considered statistically significant. The post-hoc analysis was considered exploratory and no multiple tests correction was implemented.

Between August 2014 and June 2016, 44 patients were included in the final analysis; of these, 23 were allocated to the restrictive group and 21 to the liberal group. Mean age was 35 ± 13 years and a median admission Glasgow Coma Scale (GCS) score was 4 (3–7). The overall sample characteristics are shown in Supplementary Table whilst our main results are shown in Table 1. Pre and post-randomization head CT scans were performed in 38 out of 44 patients (86%), whilst pre and post-randomization TCD scans were performed in the entire sample for vasospasm. PHI was detected 3 patients (16.7%) in the restrictive group and 1 patient (5.0%) in the liberal group (p = 0.35). New ischemic events were identified in 3 patients (16.7%) in the restrictive group and in 4 patients (20.0%) in the liberal group and (p = 0.98). Most ischemic events in the liberal group were new injuries (3/4), whereas patients in the restrictive group showed worsening of previous ischemia alongside new infarcts. Such complications as PHI or new ischemic events were not observed in the same patients. Extensive ischemia was exclusively observed in the restrictive group (p = 0.029). Pre-randomization ischemia and vasospasm were present in 43% and 10% of patients in the liberal strategy group, respectively, compared to 70% and 22% in the restrictive group (p = 0.127 and p = 0.416, respectively). Ischemic events were more frequent among those patients with traumatic subarachnoid hemorrhage on admission and those with pre-randomization cerebral vasospasm. Although more prevalent in the restrictive group, vasospasm severity was not significantly different between groups. A negative correlation was observed between hemoglobin concentration and mean MCA blood velocities (r = − 0.265, p < 0.01).

Table 1 Main results

Full size table

In this analysis, we observed higher cerebral blood velocities among patients randomized to a restrictive transfusion approach, as well as vasospasm prevalence and extensive ischemic injuries in this group. However, the occurrence of PHI and new ischemic events was similar between groups. Although causal correlations were precluded given our limitations, this study suggest an association between anemia and vasospasm. Further research to establish evidence-based guidelines for blood transfusions in TBI are warranted.

The dataset is available upon reasonable request.

GCS:: Glasgow Coma Scale
GOS:: Glasgow outcome Scale
ICP:: Intracranial pressure
ICU:: Intensive care unit
RBC:: Red blood cells
SPSS:: Statistical package for the social sciences
TBI:: Traumatic brain injury
TCD:: Transcranial Doppler
TRAHT:: Transfusion requirements after head trauma

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Authors and Affiliations

Division of Neurosurgery, Department of Neurology, School of Medicine, University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 255, São Paulo, Brazil
Davi Solla, Sérgio Brasil, Carlos G. Carlotti Jr & Wellingson S. Paiva
Surgical Intensive Care Unit, Anesthesiology Division, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, Brazil
André L. N. Gobatto & Luiz Marcelo S. Malbouisson
Department of Intensive Care, Hôpital Universitaire de Bruxelles (HUB), Université Libre de Bruxelles (ULB), Brussels, Belgium
Fabio S. Taccone

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Sérgio BrasilView author publications
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Fabio S. TacconeView author publications
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Carlos G. Carlotti JrView author publications
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Luiz Marcelo S. MalbouissonView author publications
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Contributions

ALNG collected data and take responsibility for its integrity. WP and LMSM contributed to the study conception and design. DS performed the statistical analysis. CGCJ, FST and SB contributed to the interpretation of the data and critical review of the article. All authors approved the final version to be published.

Corresponding author

Correspondence to Sérgio Brasil.

Ethics approval and consent to participate

The study was conducted in accordance with the amended Declaration of Helsinki. Local institutional review boards approved the protocol (Comissão de Ética para Análise de Projetos de Pesquisa—CAPPesq, reference number 706744) and written informed consent was obtained from all the patients or their surrogates.

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The authors declare no competing interests.

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Gobatto, A.L.N., Solla, D., Brasil, S. et al. Progressive hemorrhagic injury and ischemia after severe traumatic brain injury according to hemoglobin transfusion thresholds: a post-hoc analysis of the transfusion requirements after head trauma trial. Crit Care 28, 218 (2024). https://doi.org/10.1186/s13054-024-04981-5

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Received: 07 April 2024
Accepted: 05 June 2024
Published: 03 July 2024
DOI: https://doi.org/10.1186/s13054-024-04981-5

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中文翻译：

根据血红蛋白输血阈值，严重创伤性脑损伤后进行性出血性损伤和缺血：头部创伤试验后输血需求的事后分析

试验注册：ClinicalTrials.gov，NCT02203292。 2014年7月29日注册。

严重创伤性脑损伤 (TBI) 后，高达 50% 的患者会出现严重贫血，从而影响脑组织的氧气输送 [1]。此外，大约 20-50% 的 TBI 病例在受伤后 72 小时内并发进行性出血性损伤 (PHI) [2]，19-68% 出现血管痉挛 [3]。这些事件的组合增加了脑缺血的风险，并建议将输血作为减轻额外组织缺氧可能性的策略。然而，确定触发输血和预防 TBI 患者额外缺氧损伤的最佳血红蛋白阈值仍然难以捉摸。因此，本研究的目的是评估不同的输血策略是否会影响 TBI 的出血和缺血结局。

本研究对头部创伤后输血要求 (TRAHT) 试验进行了事后分析，这是一项开放标签、平行、可行性、随机对照试验，研究了两种红细胞输注策略：“限制性”方法（血红蛋白 < 7 g/ dL) 与“自由”方法（血红蛋白 < 9 g/dL）[4]。之前已经概述了纳入和排除标准[4]。患者遵守指定的输血策略长达 14 天，或直至死亡或出院 ICU（以先发生者为准）。所有患者均使用连续经颅多普勒超声（TCD）检查进行监测。 TCD 提供脑血流速度 (CBv) 作为脑血流的替代指标，在重症监护中具有多种应用 [5]。脑血管痉挛是根据脑动脉（大脑中动脉 [MCA] 和基底动脉）和颅外动脉（颈内动脉和椎动脉）血流速度，使用 Lindegaard 和 Soustiel 指数来定义的 [5]。根据主治团队的判断，所有患者在入院时均接受了脑部 CT 检查。主要终点是观察随机化后新的缺血事件的发生。此外，我们还描述了 PHI 的发生，其定义为出现新的或扩大的脑内血肿，其体积至少为先前体积的 10%，硬膜下或硬膜外血肿扩大，或手术部位意外的术后血肿，没有最小音量阈值。广泛的缺血对应于 CT 扫描上提示血管病因的低密度区域，涉及大脑动脉的两段以上，例如 MCA M3 和 M4。所有放射学评估均由对研究分配不知情的独立放射科医生进行分析。出于描述目的，通过相对和绝对频率呈现分类变量，并酌情通过卡方或费舍尔精确检验进行比较。所有测试都是双边的，最终 p 值低于 0.05 被认为具有统计显着性。事后分析被认为是探索性的，没有实施多重测试校正。

2014年8月至2016年6月，最终分析患者44例；其中，23 个被分配给限制性组，21 个被分配给自由组。平均年龄为 35 ± 13 岁，入院格拉斯哥昏迷量表 (GCS) 评分中位数为 4 (3-7)。总体样本特征如补充表所示，而我们的主要结果如表 1 所示。 44 名患者中，有 38 名 (86%) 进行了随机化前和随机化后的头部 CT 扫描，同时进行了随机化前和随机化后的 TCD 扫描在整个样本中观察血管痉挛。限制性组中有 3 名患者 (16.7%) 检测到 PHI，自由组有 1 名患者 (5.0%) 检测到 PHI ( p = 0.35)。限制性组中的 3 名患者 (16.7%) 和自由组中的 4 名患者 (20.0%) 中发现了新的缺血事件 ( p = 0.98)。自由组中的大多数缺血事件是新损伤（3/4），而限制组中的患者则表现出先前缺血的恶化以及新的梗塞。在同一患者中未观察到 PHI 或新的缺血事件等并发症。仅在限制组中观察到广泛的缺血（ p = 0.029）。自由策略组中分别有 43% 和 10% 的患者出现随机分组前缺血和血管痉挛，而限制组中这一比例为 70% 和 22%（分别为p = 0.127 和p = 0.416）。入院时患有创伤性蛛网膜下腔出血的患者和随机分组前脑血管痉挛的患者中，缺血事件更为频繁。尽管在限制组中更为普遍，但血管痉挛的严重程度在各组之间没有显着差异。血红蛋白浓度与平均 MCA 血流速度之间存在负相关（ r = − 0.265， p < 0.01）。

表1 主要结果

全尺寸桌子

在这项分析中，我们观察到随机接受限制性输血方法的患者的脑血流速度较高，以及该组中血管痉挛的患病率和广泛的缺血性损伤。然而，各组之间 PHI 和新缺血事件的发生率相似。尽管由于我们的局限性排除了因果关系，但这项研究表明贫血和血管痉挛之间存在关联。需要进一步研究建立 TBI 输血循证指南。

该数据集可根据合理请求提供。

地面站：: 格拉斯哥昏迷量表
客户服务：: 格拉斯哥结果量表
ICP:: 颅内压
重症监护病房：: 重症监护病房
红细胞：: 红细胞
统计软件：: 社会科学统计包
创伤性脑损伤：: 脑外伤
TCD：: 经颅多普勒
特拉特：: 头部外伤后的输血要求

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PubMed PubMed 中心 Google 学术搜索
Gobatto ALN、Link MA、Solla DJ、Bassi E、Tierno PF、Paiva W、Taccone FS、Malbouisson LM。头部外伤后的输血要求：随机可行性对照试验。危重护理。 2019；23(1):89。

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作者和单位

圣保罗大学医学院神经外科，Av. Dr. Eneas de Carvalho Aguiar 255，圣保罗，巴西

Davi Solla、Sérgio Brasil、Carlos G. Carlotti Jr 和 Wellingson S. Paiva
巴西圣保罗大学医学院临床医院麻醉科外科重症监护室

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贡献

ALNG 收集数据并对其完整性负责。 WP 和 LMSM 为研究的构思和设计做出了贡献。 DS 进行了统计分析。 CGCJ、FST 和 SB 为数据的解释和文章的批判性审查做出了贡献。所有作者都批准了最终版本的发布。

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道德批准并同意参与

该研究是根据修订后的赫尔辛基宣言进行的。当地机构审查委员会批准了该方案（Commissão de Ética para Análise de Projetos de Pesquisa—CAPPesq，参考号 706744），并获得了所有患者或其代理人的书面知情同意书。

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作者声明没有竞争利益。

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