Establishment of an ideal time window model in hypothermic-targeted temperature management after traumatic brain injury in rats

Zhao, Wanyong; Chen, Shaobo; Wang, Jingjing; Xu, Chao; Zhao, Mei; Dong, Huajiang; Liang, Haiqian; Li, Xiaohong; Tu, Yue; Zhang, Sai; Chen, Chong; Sun, Haitao

doi:10.1016/j.brainres.2017.06.006

Cited by 22 publications

(16 citation statements)

References 41 publications

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“…The Bcl‐2 family consists of antiapoptotic (Bcl‐2) and proapoptotic (Bax) factors. The pro‐apoptotic family members trigger cytokine release into the cytoplasm, leading to caspase activation . In present study, Bax and Bcl‐2 expression levels were detected using Western blotting.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Attenuates Neuroinflammatory–Induced Apoptosis after Traumatic Brain Injury via Nrf2 signaling pathway

Xiao-dong

Zhang

et al. 2019

Ann Clin Transl Neurol

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Objective Dexmedetomidine (DEX) exhibits neuroprotective effects as a multifunctional neuroprotective agent in numerous neurological disorders. However, in traumatic brain injury (TBI), the molecular mechanisms of these neuroprotective effects remain unclear. The present study investigated whether DEX, which has been reported to exert protective effects against TBI, could attenuate neuroinflammatory‐induced apoptosis and clarified the underlying mechanisms. Methods A weight‐drop model was established, and DEX was intraperitoneally injected 30 min after inducing TBI in rats. The water content in the brain tissue was measured. Terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling (TUNEL) assays were performed on histopathological tissue sections to evaluate neuronal apoptosis. Enzyme‐linked immunosorbent assay and PCR were applied to detect the levels of the inflammatory factors, TNF‐α, IL‐1β, IL‐6, and NF‐κB. Results TBI–challenged rats exhibited significant neuronal apoptosis, which was characterized via the wet‐to‐dry weight ratio, neurobehavioral functions, TUNEL assay results and the levels of cleaved caspase‐3, Bax upregulation and Bcl‐2, which were attenuated by DEX. Western blot, immunohistochemistry, and PCR results revealed that DEX promoted Nrf2 expression and upregulated expression of the Nrf2 downstream factors, HO‐1 and NQO‐1. Furthermore, DEX treatment markedly prevented the downregulation of inflammatory response factors, TNF‐α, IL‐1β and NF‐κB, and IL‐6. Interpretation Administering DEX attenuated inflammation‐induced brain injury in a TBI model, potentially via the Nrf2 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Attenuates Neuroinflammatory–Induced Apoptosis after Traumatic Brain Injury via Nrf2 signaling pathway

Xiao-dong

Zhang

et al. 2019

Ann Clin Transl Neurol

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“…Multiple studies and meta-analyses have reported benefit for prophylactic hypothermia as a potential neuroprotectant after traumatic brain injury. 7,8,[21][22][23][24][25][26][27][28][29][30][31] Three higher-quality multicenter randomized trials of prophylactic hypothermia demonstrated no benefit, but these had methodological limitations and 2 stopped prematurely (≤50% projected sample size). [13][14][15] The most recent meta-analysis of prophylactic hypothermia after severe traumatic brain injury 8 suggested that early prophylactic hypothermia may be most beneficial when Data are presented as n/N (%) unless otherwise indicated and are presented for the intention-to-treat population.…”

Section: Discussionmentioning

confidence: 99%

Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury

Cooper

Nichol

Bailey

et al. 2018

JAMA

249

167

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IMPORTANCE After severe traumatic brain injury, induction of prophylactic hypothermia has been suggested to be neuroprotective and improve long-term neurologic outcomes. OBJECTIVE To determine the effectiveness of early prophylactic hypothermia compared with normothermic management of patients after severe traumatic brain injury. DESIGN, SETTING, AND PARTICIPANTS The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial (POLAR-RCT) was a multicenter randomized trial in 6 countries that recruited 511 patients both out-of-hospital and in emergency departments after severe traumatic brain injury. The first patient was enrolled on December 5, 2010, and the last on November 10, 2017. The final date of follow-up was May 15, 2018. INTERVENTIONS There were 266 patients randomized to the prophylactic hypothermia group and 245 to normothermic management. Prophylactic hypothermia targeted the early induction of hypothermia (33°C-35°C) for at least 72 hours and up to 7 days if intracranial pressures were elevated, followed by gradual rewarming. Normothermia targeted 37°C, using surface-cooling wraps when required. Temperature was managed in both groups for 7 days. All other care was at the discretion of the treating physician. MAIN OUTCOMES AND MEASURES The primary outcome was favorable neurologic outcomes or independent living (Glasgow Outcome Scale-Extended score, 5-8 [scale range, 1-8]) obtained by blinded assessors 6 months after injury. RESULTS Among 511 patients who were randomized, 500 provided ongoing consent (mean age, 34.5 years [SD, 13.4]; 402 men [80.2%]) and 466 completed the primary outcome evaluation. Hypothermia was initiated rapidly after injury (median, 1.8 hours [IQR, 1.0-2.7 hours]) and rewarming occurred slowly (median, 22.5 hours [IQR, 16-27 hours]). Favorable outcomes (Glasgow Outcome Scale-Extended score, 5-8) at 6 months occurred in 117 patients (48.8%) in the hypothermia group and 111 (49.1%) in the normothermia group (risk difference, 0.4% [95% CI,-9.4% to 8.7%]; relative risk with hypothermia, 0.99 [95% CI, 0.82-1.19]; P = .94). In the hypothermia and normothermia groups, the rates of pneumonia were 55.0% vs 51.3%, respectively, and rates of increased intracranial bleeding were 18.1% vs 15.4%, respectively. CONCLUSIONS AND RELEVANCE Among patients with severe traumatic brain injury, early prophylactic hypothermia compared with normothermia did not improve neurologic outcomes at 6 months. These findings do not support the use of early prophylactic hypothermia for patients with severe traumatic brain injury.

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“…14,25,26,29,31 Here, we showed that in these studies therapeutic hypothermia significantly improved the outcome in severe TBI compared to those trials which followed the protocol regardless of ICP. 8,13,17,20,23,24,27,28,30 These results highlight the importance of continuous ICP monitoring during therapeutic hypothermia and warrant for the need of adjustments in the cooling protocol based on ICP. Unfortunately, the data about the deviations from the set protocols were not reported in sufficient details in any of the studies, in order to account for the changes in our calculation of the cooling index.…”

Section: Journal Of Neurotraumamentioning

confidence: 92%

“…Therapeutic hypothermia has been investigated as a possible neuroprotective strategy to attenuate the harmful effects of severe TBI. In animal models of TBI, beneficial effects of therapeutic hypothermia have been shown repeatedly, [8][9][10][11] but clinical studies provided contradictory results. The first report of the use of hypothermia in TBI was in 1943, 12 while randomized controlled studies appeared only at the end of the 1990s.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Whole-Body Hypothermia Reduces Death in Severe Traumatic Brain Injury if the Cooling Index Is Sufficiently High: Meta-Analyses of the Effect of Single Cooling Parameters and Their Integrated Measure

Oláh

Pótó

Hegyi

et al. 2018

Journal of Neurotrauma

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Therapeutic hypothermia was investigated repeatedly as a tool to improve the outcome of severe traumatic brain injury (TBI), but previous clinical trials and meta-analyses found contradictory results. We aimed to determine the effectiveness of therapeutic whole-body hypothermia on the deaths of adult patients with severe TBI by using a novel approach of meta-analysis. We searched the PubMed, EMBASE, and Cochrane Library databases from inception to February 2017. The identified human studies were evaluated regarding statistical, clinical, and methodological designs to ensure interstudy homogeneity. We extracted data on TBI severity, body temperature, death, and cooling parameters; then we calculated the cooling index, an integrated measure of therapeutic hypothermia. Forest plot of all identified studies showed no difference in the outcome of TBI between cooled and not cooled patients, but interstudy heterogeneity was high. On the contrary, by meta-analysis of randomized clinical trials that were homogenous with regard to statistical, clinical designs, and precisely reported the cooling protocol, we showed decreased odds ratio for death in therapeutic hypothermia compared with no cooling. As independent factors, milder and longer cooling, and rewarming at <0.25°C/h were associated with better outcome. Therapeutic hypothermia was beneficial only if the cooling index (measure of combination of cooling parameters) was sufficiently high. We conclude that high methodological and statistical interstudy heterogeneity could underlie the contradictory results obtained in previous studies. By analyzing methodologically homogenous studies, we show that cooling improves the outcome of severe TBI, and this beneficial effect depends on certain cooling parameters and on their integrated measure, the cooling index.

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Establishment of an ideal time window model in hypothermic-targeted temperature management after traumatic brain injury in rats

Cited by 22 publications

References 41 publications

Dexmedetomidine Attenuates Neuroinflammatory–Induced Apoptosis after Traumatic Brain Injury via Nrf2 signaling pathway

Dexmedetomidine Attenuates Neuroinflammatory–Induced Apoptosis after Traumatic Brain Injury via Nrf2 signaling pathway

Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury

Therapeutic Whole-Body Hypothermia Reduces Death in Severe Traumatic Brain Injury if the Cooling Index Is Sufficiently High: Meta-Analyses of the Effect of Single Cooling Parameters and Their Integrated Measure

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