Therapeutic hypothermia to reduce intracranial pressure after traumatic brain injury: the Eurotherm3235 RCT
Therapeutic hypothermia to reduce intracranial pressure after traumatic brain injury: the Eurotherm3235 RCT
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DOI：
10.3310/hta22450
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发表时间：
2018-08-01
影响因子：
3.6
通讯作者：
Murray, Gordon
中科院分区：
文献类型：
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作者：
Andrews, Peter J. D.;Sinclair, H. Louise;Murray, Gordon
背景：创伤性脑损伤（TBI）是全世界年轻人致残和死亡的主要原因。它导致欧盟（EU）每年约有100万人入院，造成50，000人死于道路交通事故中的大部分死亡，并导致约10，000人严重残疾。目标：Eurotherm 3235试验是一项检验低温治疗有效性的实用性试验（32-35 ℃）降低严重脑外伤后颅内压升高（ICP），降低脑外伤后6个月的发病率和死亡率。设计：一项国际性、多中心、随机对照试验。参与者我们纳入了TBI后的成人参与者。合格的患者进行了ICP监测，尽管进行了一线治疗，但ICP> 20 mmHg。参与者被随机分配接受标准护理，并添加低温（32-35摄氏度）或仅接受标准护理。在线随机化和电子病例报告表（CRF）的使用确保了随机治疗分配的隐蔽性。不可能对当地研究者的分配设盲，因为很明显哪些受试者正在接受低温治疗。我们收集了参与者在受伤后6个月恢复情况的信息。这些信息由参与者自己（如果他们能够）和/或他们身边的人通过完成格拉斯哥结局量表-扩展（GOSE）问卷提供。干预措施：在随机分组后，低温组降低ICP的主要干预措施是诱导低温。核心温度最初降低至35 ℃，如果需要，则逐渐降低至32 ℃的下限，以将ICP维持在< 20 mmHg。如果ICP保持受控，则在48小时后开始复温。标准治疗组的参与者在该中心接受常规治疗，但没有hypothermia.Main结局measures：主要结局指标为GOSE [范围1（死亡）至8（上部良好恢复）]，由独立合作者在损伤后6个月评估，对干预措施不知情。先验亚组分析测试了最小化因素之间的关系，包括年龄< 45岁，入院时复苏后格拉斯哥昏迷量表（GCS）运动评分< 2，受伤时间< 12小时和患者outcome.Results：我们招募了来自18个国家47个中心的387例患者。在数据和安全性监查委员会于2014年10月提出问题后，该试验停止招募。在意向治疗的基础上，195名参与者被随机分配到低温治疗组，192名参与者接受标准治疗。关于参与者的结局，低温组6个月时的死亡率较高，功能恢复较差。GOSE主要统计分析的校正常见比值比（OR）为1.54 [95%置信区间（CI）1.03 - 2.31];当GOSE被二分时，OR为1.74（95% CI 1.09 - 2.77）。这两个结果都有利于单独的标准治疗。在这项务实的研究中，我们没有收集不良事件的数据。收集了严重不良事件（SAE）的数据，但存在报告偏倚，大多数SAE发生在低温组。在TBI后且ICP> 20 mmHg的参与者中，滴定治疗性低温成功地降低了ICP，但导致更高的死亡率和更差的功能结局。低温组;低温组严重不良事件记录存在偏倚。我们现在认为，需要对用于降低ICP的常见疗法（如高渗治疗、巴比妥类药物和过度通气）进行更充分的临床试验，以评估其对患者的潜在获益和风险。
Background: Traumatic brain injury (TBI) is a major cause of disability and death in young adults worldwide. It results in around 1 million hospital admissions annually in the European Union (EU), causes a majority of the 50,000 deaths from road traffic accidents and leaves a further approximate to 10,000 people severely disabled.Objective: The Eurotherm3235 Trial was a pragmatic trial examining the effectiveness of hypothermia (32-35 degrees C) to reduce raised intracranial pressure (ICP) following severe TBI and reduce morbidity and mortality 6 months after TBI.Design: An international, multicentre, randomised controlled trial.Setting: Specialist neurological critical care units.Participant We included adult participants following TBI. Eligible patients had ICP monitoring in place with an ICP of > 20 mmHg despite first-line treatments. Participants were randomised to receive standard care with the addition of hypothermia (32-35 degrees C) or standard care alone. Online randomisation and the use of an electronic case report form (CRF) ensured concealment of random treatment allocation. It was not possible to blind local investigators to allocation as it was obvious which participants were receiving hypothermia. We collected information on how well the participant had recovered 6 months after injury. This information was provided either by the participant themself (if they were able) and/or a person close to them by completing the Glasgow Outcome Scale - Extended (GOSE) questionnaire. Telephone follow-up was carried out by a blinded independent clinician.interventions: The primary intervention to reduce ICP in the hypothermia group after randomisation was induction of hypothermia. Core temperature was initially reduced to 35 degrees C and decreased incrementally to a lower limit of 32 degrees C if necessary to maintain ICP at < 20 mmHg. Rewarming began after 48 hours if ICP remained controlled. Participants in the standard-care group received usual care at that centre, but without hypothermia.Main outcome measures: The primary outcome measure was the GOSE [range 1 (dead) to 8 (upper good recovery)] at 6 months after the injury as assessed by an independent collaborator, blind to the intervention. A priori subgroup analysis tested the relationship between minimisation factors including being aged < 45 years, having a post-resuscitation Glasgow Coma Scale (GCS) motor score of < 2 on admission, having a time from injury of < 12 hours and patient outcome.Results: We enrolled 387 patients from 47 centres in 18 countries. The trial was closed to recruitment following concerns raised by the Data and Safety Monitoring Committee in October 2014. On an intentionto-treat basis, 195 participants were randomised to hypothermia treatment and 192 to standard care. Regarding participant outcome, there was a higher mortality rate and poorer functional recovery at 6 months in the hypothermia group. The adjusted common odds ratio (OR) for the primary statistical analysis of the GOSE was 1.54 [95% confidence interval (CI) 1.03 to 2.31]; when the GOSE was dichotomised the OR was 1.74 (95% CI 1.09 to 2.77). Both results favoured standard care alone. In this pragmatic study, we did not collect data on adverse events. Data on serious adverse events (SAEs) were collected but were subject to reporting bias, with most SAEs being reported in the hypothermia group.Conclusion: In participants following TBI and with an ICP of > 20 mmHg, titrated therapeutic hypothermia successfully reduced ICP but led to a higher mortality rate and worse functional outcome.limitation Inability to blind treatment allocation as it was obvious which participants were randomised to the hypothermia group; there was biased recording of SAEs in the hypothermia group. We now believe that more adequately powered clinical trials of common therapies used to reduce ICP, such as hypertonic therapy, barbiturates and hyperventilation, are required to assess their potential benefits and risks to patients.