Clinical trial NCT01886222: Randomized Controlled Trial of Long-term Mild Hypothermia for Severe Traumatic Brain Injury
Official title: A Multi-center, Randomized, Controlled Trial to Evaluate the Efficacy and Safety of Long-term Mild Hypothermia in Adult Patients With Severe Traumatic Brain Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Brain Injuries
Craniocerebral Trauma
Keywords: Traumatic brain injury
Lead sponsor: RenJi Hospital
Sponsor class: OTHER
Collaborators: name: First Affiliated Hospital of Zhejiang University
name: West China Hospital
name: Second Affiliated Hospital of Wenzhou Medical University
name: The 101st Hospital of Chinese People's Liberation Army
name: The 98 Hospital of People's Liberation Army
name: Shenzhen Second People's Hospital
name: The 94 Hospital of People's Liberation Army
name: Nanfang Hospital, Southern Medical University
name: The Affiliated Hospital of Medical College of Chinese People's Armed Police Forces
name: Xiangya Hospital of Central South University
name: Taizhou First People's Hospital
name: Tang-Du Hospital
name: Qilu Hospital of Shandong University
name: Chongqing Emergency Medical Center
name: Xuzhou Central Hospital
name: The Affiliated Hospital Of Southwest Medical University
First posted: 2013-06-25
Enrollment: 312
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is a prospective multi-centre randomized trial to compare the effect of long-term mild hypothermia versus routine normothermic intensive management in patients with severe traumatic brain injury.

The primary hypothesis is that the induction of mild hypothermia (maintained at 34-35℃) for 5 days will improve the outcome of patients at six months post injury compared with normothermia.

Detailed description: Traumatic brain injury (TBI) remains a leading cause of death and disability in people with injuries and constitutes a major public health concern both in developed and developing countries. There are multiple clinical trials of hypothermia therapy for TBI conducted, however, with conflicting results. Subgroup analysis of most meta-analysis showed that therapeutic effect was significant when hypothermia was maintained more than 48 hours. We have previously reported a multicenter trial of mild hypothermia (33-35℃) for severe traumatic brain injury, in which 215 patients was randomized to long-term mild hypothermia group (n = 108) for 5 ±1.3 days mild hypothermia therapy and short-term mild hypothermia group ( n = 107) for 2±0.6 days mild hypothermia therapy. The results shown improved outcomes in patients with long-term mild hypothermia and similar frequency of complications. Therefore we concluded that long-term hypothermia, which maintains at 33-35℃ for 5 days, could be considered in the management of severe traumatic brain injury.

Hypothermia therapy was recommend as the level III evidence by the 2007 Brain Trauma Foundation's guideline and this treatment is currently used in our department and other large neurosurgical centers across China, with the aim to decrease the high intracranial pressure (ICP) and improve the functional outcome of TBI patients. When the decision was made, the injured patients would be placed on cooling blankets, tracheotomized and ventilated. The patients would receive continuous infusions of a paralytic drug (Tracrium 10-40 mg/hour) and chlorpromazine (5-10 mg/hour) administered using an infusion pump to prevent shivering. The dosage was given according to each patient's temperature, blood pressure, heart rate, and muscular tone. Once the patient's rectal temperature reached 33˚C, it was kept at approximately that temperature (33-35˚C) 5 to 7 days. Then the patients were passively rewarmed to a temperature of 37 to 38˚C at a rate no greater than 1˚C/hour, by gradual adjustment of the blanket thermostat.

The present multi-center, randomized controlled trials is designed to investigate the efficacy and safety of long-term (5 days) mild hypothermia versus normothermia on the outcome of patients following severe traumatic brain injury. The primary outcome is the neurological function assessed at 1, 6 months post injury with the Glasgow Outcome Score (GOS). Additionally, the following data will also be recorded and compared: the baseline data, Glasgow Coma Score,imaging examination (e.g. CT scan), need of surgery, intracranial pressure, laboratory tests (e.g. blood routine test, liver and kidney function, blood gas analysis, etc), the complications (e.g. pneumonia, significant bleeding) and so on.

Eligibility criteria: Inclusion Criteria:

* Age 18 - 65 years within 6 hours post injury;
* Closed head injury;
* Glasgow Coma Scale(GCS) score 4 to 8 after resuscitation;
* The intracranial pressure is more than 25 mmHg;
* Cerebral contusion on computed tomographic scan.

Exclusion Criteria:

* GCS of 3 with bilateral fixed and dilated pupils;
* A life-threatening injury to an organ other than the brain;
* No spontaneous breathing or cardiac arrest at the scene of the injury;
* No consent;
* Pregnancy.

Primary outcomes:
measure: Neurological function
timeFrame: 6 months post injury
Secondary outcomes:
measure: Intracranial pressure (ICP) control
timeFrame: Admission, day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 14, or until the monitor is removed
measure: Glasgow Coma Score (GCS)
timeFrame: Admission, day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 14, day 21, day 28 post injury
measure: Length of ICU stay
timeFrame: 6 months post injury
measure: Length of hospital stay
timeFrame: 6 months post injury
measure: Frequency of complications
timeFrame: 6 months post injury
measure: Mortality rate
timeFrame: 6 months post injury
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University
state: Shanghai
Study officials:
affiliation: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China
name: Jiyao Jiang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jiang JY, Xu W, Li WP, Gao GY, Bao YH, Liang YM, Luo QZ. Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury. J Cereb Blood Flow Metab. 2006 Jun;26(6):771-6. doi: 10.1038/sj.jcbfm.9600253.
citation: Lei J, Gao G, Mao Q, Feng J, Wang L, You W, Jiang J; LTH-1 trial collaborators. Rationale, methodology, and implementation of a nationwide multicenter randomized controlled trial of long-term mild hypothermia for severe traumatic brain injury (the LTH-1 trial). Contemp Clin Trials. 2015 Jan;40:9-14. doi: 10.1016/j.cct.2014.11.008. Epub 2014 Nov 12.
citation: Hui J, Feng J, Tu Y, Zhang W, Zhong C, Liu M, Wang Y, Long L, Chen L, Liu J, Mou C, Qiu B, Huang X, Huang Q, Zhang N, Yang X, Yang C, Li L, Ma R, Wu X, Lei J, Jiang Y, Liu L, Gao G, Jiang J; LTH-1 Trial collaborators. Safety and efficacy of long-term mild hypothermia for severe traumatic brain injury with refractory intracranial hypertension (LTH-1): A multicenter randomized controlled trial. EClinicalMedicine. 2021 Jan 28;32:100732. doi: 10.1016/j.eclinm.2021.100732. eCollection 2021 Feb.