四川大学华西医院游潮教授团队研究了重症监护包治疗急性脑出血降压试验的疗效与安全性。相关论文发表在2023年5月25日出版的《柳叶刀》杂志上。

早期控制血压升高是治疗急性脑出血最有前途的方法。该研究旨在确定在医院环境中实施一个目标导向的护理包，包括早期强化降压协议和高血糖、发热和异常抗凝治疗算法，是否可以改善急性自发性脑出血患者的预后。

研究组在九个中低收入国家（巴西、中国、印度、墨西哥、尼日利亚、巴基斯坦、秘鲁、斯里兰卡和越南）和一个高收入国家（智利）的医院进行了一项务实、国际性、多中心、终点盲、阶梯式楔形聚类随机对照试验。如果医院没有或不一致的相关疾病特异性方案，并且愿意对在症状出现后6小时内出现影像学确诊的自发性脑出血的连续患者（年龄≥18岁）实施一揽子护理，且有当地龙头机构，能够提供所需的研究数据，则有资格参与。

使用排列块将医院集中随机分配到三个实施序列，按国家和研究期间12个月内预计招募的患者数量进行分层。这些序列有四个时期，决定了医院从对照常规护理程序切换到干预实施护理捆绑程序的顺序，以逐步的方式对不同患者群进行护理。为了避免数据污染，在完成常规护理对照期之前，对现场隐瞒干预、顺序和分配期的细节。

一揽子护理方案包括早期强化降低收缩压（目标<140毫米汞柱）、严格控制血糖（非糖尿病患者的目标为6.1–7.8 mmol/L，糖尿病患者为7.8–10.0 mmol/L）、解热治疗（目标体温≤37.5°C），以及在这些变量异常的患者中，在治疗后1小时内快速逆转华法林相关抗凝（目标国际标准化比值<1.5）。根据具有可用结果数据的改良意向治疗人群进行分析（即排除研究期间退出的位点）。

主要结局是功能恢复，由蒙面研究人员在6个月时用改良Rankin量表（mRS；范围0[无症状]至6[死亡]）进行测量，使用比例有序逻辑回归进行分析，以评估mRS上的得分分布，并对集群（医院所在地）、每个时期的集群分组，以及时间（自2017年12月12日起6个月）进行校正。

2017年5月27日至2021年7月8日期间，206家医院接受了资格评估，其中10个国家的144家医院同意加入并被随机分配到试验中，但22家医院在开始招募患者之前退出，另一家医院因未获得监管批准而退出，其招募患者数据也被删除。2017年12月12日至2021年12月31日，共10857名患者接受了筛查，但3821名患者被排除在外。总体而言，改良意向治疗人群包括在121家医院登记的7036名患者，其中3221名被分配到护理包组，3815名被分配给常规护理组，主要结局数据可用于护理包组的2892名患者和常规护理组的3363名患者。

护理包组功能不良的可能性较低（共同优势比0.86）。在一系列敏感性分析中，包括对国家和患者变量的额外校正（0.84），以及对缺失数据使用多个输入的不同方法，护理包组mRS评分的有利变化总体上是一致的。与常规护理组相比，护理包组的患者发生的严重不良事件更少（16.0%vs 20.1%）。

研究结果表明，在症状出现后的几个小时内实施用于强化降压的护理包协议和用于生理控制的其他管理算法，改善了急性脑出血患者的功能预后。

附：英文原文

Title: The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trial

Author: Lu Ma, Xin Hu, Lili Song, Xiaoying Chen, Menglu Ouyang, Laurent Billot, Qiang Li, Alejandra Malavera, Xi Li, Paula Muoz-Venturelli, Asita de Silva, Nguyen Huy Thang, Kolawole W Wahab, Jeyaraj D Pandian, Mohammad Wasay, Octavio M Pontes-Neto, Carlos Abanto, Antonio Arauz, Haiping Shi, Guanghai Tang, Sheng Zhu, Xiaochun She, Leibo Liu, Yuki Sakamoto, Shoujiang You, Qiao Han, Bernard Crutzen, Emily Cheung, Yunke Li, Xia Wang, Chen Chen, Feifeng Liu, Yang Zhao, Hao Li, Yi Liu, Yan Jiang, Lei Chen, Bo Wu, Ming Liu, Jianguo Xu, Chao You, Craig S Anderson, Thompson Robinson, J. Jaime Miranda, Craig S. Anderson, Chao You, Lili Song, Adrian Parry-Jones, Nikola Sprigg, Sophie Durrans, Caroline Harris, Ann Bamford, Olivia Smith, Robert Herbert, Christopher Chen, William Whiteley, Rong Hu, Laurent Billot, Qiang Li, Jayanthi Mysore, Xin Hu, Yao Zhang, Feifeng Liu, Yuki Sakamoto, Shoujiang You, Qiao Han, Bernard Crutzen, Yunke Li, Emily Cheung, Stephen Jan, Hueiming Liu, Menglu Ouyang, Lingli Sun, Honglin Chu, Anila Anjum, Francisca Gonzalez Mc Cawley, Alejandra Del Rio, Bruna Rimoli, Rodrigo Cerantola, Thanushanthan Jeevarajah, Madhushani Kannangara, Andrene Joseph, Chamath Nanayakkara, Xiaoying Chen, Alejandra Malavera, Chunmiao Zhang, Zhao Yang, Brook Li, Zhuo Meng, Menglu Ouyang, Leibo Liu, Yi Ning, Le Dong, Manuela Armenis, Joyce Lim

Issue&Volume: 2023-05-25

Abstract:

Background

Early control of elevated blood pressure is the most promising treatment for acute intracerebral haemorrhage. We aimed to establish whether implementing a goal-directed care bundle incorporating protocols for early intensive blood pressure lowering and management algorithms for hyperglycaemia, pyrexia, and abnormal anticoagulation, implemented in a hospital setting, could improve outcomes for patients with acute spontaneous intracerebral haemorrhage.

Methods

We performed a pragmatic, international, multicentre, blinded endpoint, stepped wedge cluster randomised controlled trial at hospitals in nine low-income and middle-income countries (Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, and Viet Nam) and one high-income country (Chile). Hospitals were eligible if they had no or inconsistent relevant, disease-specific protocols, and were willing to implement the care bundle to consecutive patients (aged ≥18 years) with imaging-confirmed spontaneous intracerebral haemorrhage presenting within 6 h of the onset of symptoms, had a local champion, and could provide the required study data. Hospitals were centrally randomly allocated using permuted blocks to three sequences of implementation, stratified by country and the projected number of patients to be recruited over the 12 months of the study period. These sequences had four periods that dictated the order in which the hospitals were to switch from the control usual care procedure to the intervention implementation of the care bundle procedure to different clusters of patients in a stepped manner. To avoid contamination, details of the intervention, sequence, and allocation periods were concealed from sites until they had completed the usual care control periods. The care bundle protocol included the early intensive lowering of systolic blood pressure (target <140 mm Hg), strict glucose control (target 6·1–7·8 mmol/L in those without diabetes and 7·8–10·0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature ≤37·5°C), and rapid reversal of warfarin-related anticoagulation (target international normalised ratio <1·5) within 1 h of treatment, in patients where these variables were abnormal. Analyses were performed according to a modified intention-to-treat population with available outcome data (ie, excluding sites that withdrew during the study). The primary outcome was functional recovery, measured with the modified Rankin scale (mRS; range 0 [no symptoms] to 6 [death]) at 6 months by masked research staff, analysed using proportional ordinal logistic regression to assess the distribution in scores on the mRS, with adjustments for cluster (hospital site), group assignment of cluster per period, and time (6-month periods from Dec 12, 2017). This trial is registered at Clinicaltrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787) and is completed.

Findings

Between May 27, 2017, and July 8, 2021, 206 hospitals were assessed for eligibility, of which 144 hospitals in ten countries agreed to join and were randomly assigned in the trial, but 22 hospitals withdrew before starting to enrol patients and another hospital was withdrawn and their data on enrolled patients was deleted because regulatory approval was not obtained. Between Dec 12, 2017, and Dec 31, 2021, 10857 patients were screened but 3821 were excluded. Overall, the modified intention-to-treat population included 7036 patients enrolled at 121 hospitals, with 3221 assigned to the care bundle group and 3815 to the usual care group, with primary outcome data available in 2892 patients in the care bundle group and 3363 patients in the usual care group. The likelihood of a poor functional outcome was lower in the care bundle group (common odds ratio 0·86; 95% CI 0·76–0·97; p=0·015). The favourable shift in mRS scores in the care bundle group was generally consistent across a range of sensitivity analyses that included additional adjustments for country and patient variables (0·84; 0·73–0·97; p=0·017), and with different approaches to the use of multiple imputations for missing data. Patients in the care bundle group had fewer serious adverse events than those in the usual care group (16·0% vs 20·1%; p=0·0098).

Interpretation

Implementation of a care bundle protocol for intensive blood pressure lowering and other management algorithms for physiological control within several hours of the onset of symptoms resulted in improved functional outcome for patients with acute intracerebral haemorrhage. Hospitals should incorporate this approach into clinical practice as part of active management for this serious condition.

DOI: 10.1016/S0140-6736(23)00806-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00806-1/fulltext