Safety and efficacy of long-term mild hypothermia for severe traumatic brain injury with refractory intracranial hypertension (LTH-1): A multicenter randomized controlled trial

Jiyuan Hui, Junfeng Feng, Yue Tu, Weituo Zhang, Chunlong Zhong, Min Liu, Yuhai Wang, Liansheng Long, Ligang Chen, Jinfang Liu, Chaohui Mou, Binghui Qiu, Xianjian Huang, Qibing Huang, Nu Zhang, Xiaofeng Yang, Chaohua Yang, Lihong Li, Rong Ma, Xiang Wu, Jin Lei, Yong Jiang, Liang Liu, Guoyi Gao, Jiyao Jiang, LTH-1 Trial collaborators, Jiyuan Hui, Junfeng Feng, Yue Tu, Weituo Zhang, Chunlong Zhong, Min Liu, Yuhai Wang, Liansheng Long, Ligang Chen, Jinfang Liu, Chaohui Mou, Binghui Qiu, Xianjian Huang, Qibing Huang, Nu Zhang, Xiaofeng Yang, Chaohua Yang, Lihong Li, Rong Ma, Xiang Wu, Jin Lei, Yong Jiang, Liang Liu, Guoyi Gao, Jiyao Jiang, LTH-1 Trial collaborators

Abstract

Background: Therapeutic hypothermia may need prolonged duration for the patients with severe traumatic brain injury (sTBI).

Methods: The Long-Term Hypothermia trial was a prospective, multicenter, randomized, controlled clinical trial to examine the safety and efficacy in adults with sTBI. Eligible patients were 18-65, Glasgow Coma Scale score at 4 to 8, and initial intracranial pressure (ICP) ≥ 25 mm Hg, randomly assigned to the long-term mild hypothermia group (34-35 °C for 5 days) or normothermia group at 37 °C. The primary outcome was the Glasgow outcome scale (GOS) at 6 months. Secondary outcomes included ICP control, complications and laboratory findings, the length of ICU and hospital stay, and GOS at 6 months in patients with initial ICP ≥ 30 mm Hg. This trial is registered with ClinicalTrials.gov, NCT01886222.

Findings: 302 patients were enrolled from June 25, 2013, to December 31, 2018, with 6 months follow-up in 14 hospitals, 156 in hypothermia group and 146 in normothermia group. There was no difference in favorable outcome (OR 1·55, 95%CI 0·91-2·64; P = 0·105) and in mortality (P = 0·111) between groups. In patients with an initial ICP ≥ 30 mm Hg, hypothermic treatment significantly increased favorable outcome over normothermia group (60·82%, 42·71%, respectively; OR 1·861, 95%CI 1·031-3·361; P = 0·039). Long-term mild hypothermia did not increase the incidences of complications.

Interpretation: Long-term mild hypothermia did not improve the neurological outcomes. However, it may be a potential option in sTBI patients with initial ICP ≥ 30 mm Hg.

Funding: : Shanghai municipal government and Shanghai Jiao Tong University/School of Medicine.

Keywords: Efficacy; Prolonged hypothermia; Randomized controlled trial; Safety; Traumatic brain injury.

Conflict of interest statement

GG, JH, JF, RM, XW, JL, and JJ declare support from the Shanghai municipal government and Shanghai Jiao Tong University/School of Medicine. All other authors declare no competing interests.

© 2021 The Author(s).

Figures

Fig. 1
Fig. 1
Trial profile. GCS=Glasgow coma scale. CT=computerized tomography. ICP=intracranial pressure. TBI=traumatic brain injury. Initial ICP refers to the ICP value firstly measured pre-operation.
Fig. 2
Fig. 2
Core temperature for the first 7 days after randomization. The core temperature of the patients randomized to normothermia was maintained at 37 °C during the entire study period. While the patients assigned to hypothermia group were cooled to the target temperature of 34–35 °C after randomization for 5 days. Data were represented with mean and SE.
Fig. 3
Fig. 3
Distribution of GOS at 6 months after randomization. Each cell corresponded to a GOS score, and the width of the cell represented the proportion of patients. GOS=Glasgow outcome scale.

References

    1. Jiang J.Y., Gao G.Y., Feng J.F. Traumatic brain injury in China. Lancet Neurol. 2019;18(3):286–295.
    1. Injury GBDTB Spinal Cord Injury C. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(1):56–87.
    1. Stocchetti N., Carbonara M., Citerio G. Severe traumatic brain injury: targeted management in the intensive care unit. Lancet Neurol. 2017;16(6):452–464.
    1. C P. Traumatic injuries of the brain and its membranes. D. Appleton & Co; New York, NY: 1897. Principles of treatment.
    1. Clifton G.L., Miller E.R., Choi S.C. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344(8):556–563.
    1. Clifton G.L., Valadka A., Zygun D. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: hypothermia II): a randomised trial. Lancet Neurol. 2011;10(2):131–139.
    1. Clifton G.L. A review of clinical trials of hypothermia treatment for severe traumatic brain injury. Ther Hypothermia Temp Manag. 2011;1(3):143–149.
    1. Clifton M.G., Valadka P.A., Aisuku I.P., Okonkwo D.O. Future of rewarming in therapeutic hypothermia for traumatic brain injury: a personalized plan. Ther Hypothermia Temp Manag. 2011;1(1):3–7.
    1. Andrews P.J., Sinclair H.L., Rodriguez A. Therapeutic hypothermia to reduce intracranial pressure after traumatic brain injury: the Eurotherm3235 RCT. Health Technol Assess. 2018;22(45):1–134.
    1. Cooper D.J., Nichol A.D., Bailey M. Effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: the POLAR randomized clinical trial. JAMA. 2018;320(21):2211–2220.
    1. Maekawa T., Yamashita S., Nagao S. Prolonged mild therapeutic hypothermia versus fever control with tight hemodynamic monitoring and slow rewarming in patients with severe traumatic brain injury: a randomized controlled trial. J Neurotrauma. 2015;32(7):422–429.
    1. Lewis S.R., Evans D.J., Butler A.R., Schofield-Robinson O.J., Alderson P. Hypothermia for traumatic brain injury. Cochrane Database Syst Rev. 2017;9
    1. Jiang J.Y., Lyeth B.G., Kapasi M.Z., Jenkins L.W., Povlishock J.T. Moderate hypothermia reduces blood-brain barrier disruption following traumatic brain injury in the rat. Acta Neuropathol. 1992;84(5):495–500.
    1. Jiang J., Yu M., Zhu C. Effect of long-term mild hypothermia therapy in patients with severe traumatic brain injury: 1-year follow-up review of 87 cases. J Neurosurg. 2000;93(4):546–549.
    1. Qiu W., Shen H., Zhang Y. Noninvasive selective brain cooling by head and neck cooling is protective in severe traumatic brain injury. J Clin Neurosci. 2006;13(10):995–1000.
    1. Zhi D., Zhang S., Lin X. Study on therapeutic mechanism and clinical effect of mild hypothermia in patients with severe head injury. Surg Neurol. 2003;59(5):381–385.
    1. Zhi D.S., Zhang S., Zhou L.G. Continuous monitoring of brain tissue oxygen pressure in patients with severe head injury during moderate hypothermia. Surg Neurol. 1999;52(4):393–396.
    1. Jiang J.Y. Mild-to-Moderate Hypothermia for Management of Severe Traumatic Brain Injury in China: history, Current Status, and Future. Ther Hypothermia Temp Manag. 2013;3(3):120–121.
    1. Stocchetti N., Colombo A., Ortolano F. Time course of intracranial hypertension after traumatic brain injury. J Neurotrauma. 2007;24(8):1339–1346.
    1. Jiang J.Y., Xu W., Li W.P. 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;26(6):771–776.
    1. Andrews P.J., Sinclair H.L., Rodriguez A. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med. 2015;373(25):2403–2412.
    1. Geurts M., Macleod M.R., Kollmar R., Kremer P.H., van der Worp H.B. Therapeutic hypothermia and the risk of infection: a systematic review and meta-analysis. Crit Care Med. 2014;42(2):231–242.
    1. Polderman K.H. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009;37(7 Suppl):S186–S202.
    1. Teasdale G., Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974;2(7872):81–84.
    1. CCoN Surgeons. Chinese surgical guidelines for management of traumatic brain injury. Chin J Neurosurg. 2009;25:100–101.
    1. Lei J., Gao G., Mao Q. 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;40:9–14.
    1. Marion D.W., Penrod L.E., Kelsey S.F. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med. 1997;336(8):540–546.
    1. Brain Trauma F. American Association of Neurological S, Congress of Neurological S. Guidelines for the management of severe traumatic brain injury. J Neurotrauma. 2007;24(Suppl 1):S1–106.
    1. Wilson J.T., Pettigrew L.E., Teasdale G.M. Structured interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use. J Neurotrauma. 1998;15(8):573–585.
    1. Weir J., Steyerberg E.W., Butcher I. Does the extended Glasgow Outcome Scale add value to the conventional Glasgow Outcome Scale? J Neurotrauma. 2012;29(1):53–58.

Source: PubMed

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