Randomized Controlled Trial of Long-term Mild Hypothermia for Severe Traumatic Brain Injury (LTH-Ⅰ)

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

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.

Study Overview

• Status: Completed
• Conditions: Brain Injuries; Craniocerebral Trauma
• Intervention / Treatment: Other: Long-term mild hypothermia; Other: 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.

• Study Type: Interventional
• Enrollment (Actual): 312
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200127
      • Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Long-term mild hypothermia; Focused intervention	Other: Long-term mild hypothermia; Hypothermia will be induced within 6 hours of injury and maintained at 34-35℃ for 5 days.Then the patients will be passively rewarmed to a temperature of 36 to 37˚C at a rate no greater than 0.5˚C/4 hours.; Other Names: Mild hypothermia therapy
Other: Normothermia; Standard management	Other: Normothermia; Patients assigned to the normothermia group will be kept at 36-37℃.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurological function	The neurological function will be evaluated at 6 months post injury by a specialized investigator who is unaware of the patients' allocation according to five-category Glasgow Outcome Scale as follows: 1, death; 2, vegetative state - unable to interact with the environment; 3, severe disability - unable to live independently but able to follow commands; 4, moderate disability - capable of living independently but unable to return to work or school; and 5, good recovery - able to return to work or school.	6 months post injury

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracranial pressure (ICP) control	The effect of long-term hypothermia on ICP control will be determined.	Admission, day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 14, or until the monitor is removed
Glasgow Coma Score (GCS)	The neurological function improvement during study intervention will be evaluated.	Admission, day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 14, day 21, day 28 post injury
Length of ICU stay	The numbers of days in the ICU.	6 months post injury
Length of hospital stay	The numbers of days in the hospital.	6 months post injury
Frequency of complications	Frequency of complications during the the study such as pneumonia, significant bleeding, liver and kidney function abnormality will be recorded and compared between groups.	6 months post injury
Mortality rate	The proportion of death will be determined at 6 months post injury.	6 months post injury

Collaborators and Investigators

• Sponsor: RenJi Hospital
• Collaborators: Xiangya Hospital of Central South University; West China Hospital; Qilu Hospital of Shandong University; Nanfang Hospital of Southern Medical University; First Affiliated Hospital of Zhejiang University; Xuzhou Central Hospital; Second Affiliated Hospital of Wenzhou Medical University; Tang-Du Hospital; Shenzhen Second People's Hospital; Taizhou First People's Hospital; The Affiliated Hospital Of Southwest Medical University; Chongqing Emergency Medical Center; The 101st Hospital of Chinese People's Liberation Army; The 98 Hospital of People's Liberation Army; The 94 Hospital of People's Liberation Army; The Affiliated Hospital of Medical College of Chinese People's Armed Police Forces
• Investigators: Principal Investigator: Jiyao Jiang, MD, PhD, Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Helpful Links

• Shanghai Institute of Head Trauma leads the research on neurotrauma nationally and has made a lot of effort in traumatic brain injury.
• Ren Ji Hospital is one of the top medical centers across China.
• Prof. Jiang holds the title of Chairman of International Neurotrauma Society.

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2013
• Primary Completion (Actual): June 30, 2019
• Study Completion (Actual): June 30, 2019

Study Registration Dates

• First Submitted: June 17, 2013
• First Submitted That Met QC Criteria: June 21, 2013
• First Posted (Estimate): June 25, 2013

Study Record Updates

• Last Update Posted (Actual): March 12, 2020
• Last Update Submitted That Met QC Criteria: March 10, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Traumatic brain injury
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Trauma, Nervous System; Body Temperature Changes; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Craniocerebral Trauma; Hypothermia
• Other Study ID Numbers: RJNS001