Therapeutic hypothermia attenuates tissue damage and cytokine expression after traumatic brain injury by inhibiting necroptosis in the rat.
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SUBMITTER: Liu T
PROVIDER: S-EPMC4832230 | biostudies-other | 2016 Apr
REPOSITORIES: biostudies-other
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Project description:Improved understanding of the molecular mechanisms of secondary brain injury has informed the optimum depth and duration of cooling and led to increased clinical interest in the therapeutic moderate hypothermia for severe traumatic brain injury over the past two decades. Although several large multi-center clinical trials have not found a treatment effect, multiple single-center trials have, and a recent meta-analysis by Crossley and colleagues now finds that the cumulative findings of those single-center trials dilute the multi-center trial results and show an overall reduction in mortality and poor outcomes associated with cooling. The need for consistent support of key physiologic parameters during cooling is emphasized by this finding.
| S-EPMC4223619 | biostudies-other
Project description:Therapeutic hypothermia promotes protection after traumatic brain injury (TBI). The mechanisms underlying hypothermic protection are multifactorial and may include the modulation of microRNA (miRNA) expression after trauma. We utilized microarrays to examine the effects of posttraumatic hypothermia on the expression of 388 rat miRNAs. Animals were subjected to sham or moderate fluid percussion brain injury, followed by 4?hours of hypothermia (33°C) or normothermia (37°C) and euthanized at 7 or 24?hours. At 7?hours, 47 miRNAs were significantly different (P<0.05) between TBI and sham (15 higher in TBI and 31 lower). After 24?hours, 15 miRNAs differed by P<0.05 (7 higher and 9 lower). The expression of miRNAs was altered by posttraumatic hypothermia. At 7?hours, seven were higher in hypothermia than normothermia and five were lower. Some miRNAs (e.g., miR-874 and miR-451) showed the most difference with hypothermia, with changes verified by quantitative reverse transcriptase-PCR. Regionally specific miRNAs also showed responses to TBI and hypothermia treatments by in situ hybridization. In addition, in vitro neuronal stretch injury studies showed similar temperature-sensitive responses to specific miRNAs. These novel data indicate that the reported beneficial effects of early hypothermia on traumatic outcome may include temperature-sensitive miRNAs involved in basic cell-processing events.
| S-EPMC3185878 | biostudies-other
Project description:ObjectivePreclinical and clinical studies have suggested that therapeutic hypothermia, while decreasing neurologic injury, may also lead to drug toxicity that may limit its benefit. Cooling decreases cytochrome P450 (CYP)-mediated drug metabolism, and limited clinical data suggest that drug levels are elevated. Fosphenytoin is metabolized by cytochrome P450 2C, has a narrow therapeutic range, and is a commonly used antiepileptic medication. The objective of this study was to evaluate the impact of therapeutic hypothermia on phenytoin levels and pharmacokinetics in children with severe traumatic brain injury.DesignPharmacokinetic analysis of subjects participating in a multicenter randomized phase III study of therapeutic hypothermia for severe traumatic brain injury.SettingICU at the Children's Hospital of Pittsburgh.PatientsNineteen children with severe traumatic brain injury.InterventionsNone.Measurements and main resultsA sum of 121 total and 114 free phenytoin levels were evaluated retrospectively in 10 hypothermia-treated and nine normothermia-treated children who were randomized to 48 hours of cooling to 32-33°C followed by slow rewarming or controlled normothermia. Drug dosing, body temperatures, and demographics were collected during cooling, rewarming, and posttreatment periods (8 d). A trend toward elevated free phenytoin levels in the hypothermia group (p=0.051) to a median of 2.2 mg/L during rewarming was observed and was not explained by dosing differences. Nonlinear mixed-effects modeling incorporating both free and total levels demonstrated that therapeutic hypothermia specifically decreased the time-variant component of the maximum velocity of phenytoin metabolism (Vmax) 4.6-fold (11.6-2.53 mg/hr) and reduced the overall Vmax by ~50%. Simulations showed that the increased risk for drug toxicity extends many days beyond the end of the cooling period.ConclusionsTherapeutic hypothermia significantly reduces phenytoin elimination in children with severe traumatic brain injury leading to increased drug levels for an extended period of time after cooling. Pharmacokinetic interactions between hypothermia and medications should be considered when caring for children receiving this therapy.
| S-EPMC3783553 | biostudies-literature
Project description:BackgroundHypothermia has been used in the treatment of brain injury for many years. Encouraging results from small trials and laboratory studies led to renewed interest in the area and some larger trials.ObjectivesTo determine the effect of mild hypothermia for traumatic brain injury (TBI) on mortality, long-term functional outcomes and complications.Search methodsWe ran and incorporated studies from database searches to 21 March 2016. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (OvidSP), Embase Classic+Embase (OvidSP), PubMed, ISI Web of science (SCI-EXPANDED, SSCI, CPCI-S & CPSI-SSH), clinical trials registers, and screened reference lists. We also re-ran these searches pre-publication in June 2017; the result from this search is presented in 'Studies awaiting classification'.Selection criteriaWe included randomised controlled trials of participants with closed TBI requiring hospitalisation who were treated with hypothermia to a maximum of 35 ºC for at least 12 consecutive hours. Treatment with hypothermia was compared to maintenance with normothermia (36.5 to 38 ºC).Data collection and analysisTwo review authors assessed data on mortality, unfavourable outcomes according to the Glasgow Outcome Scale, and pneumonia.Main resultsWe included 37 eligible trials with a total of 3110 randomised participants; nine of these were new studies since the last update (2009) and five studies had been previously excluded but were re-assessed and included during the 2017 update. We identified two ongoing studies from searches of clinical trials registers and database searches and two studies await classification.Studies included both adults and children with TBI. Most studies commenced treatment immediately on admission to hospital or after craniotomies and all treatment was maintained for at least 24 hours. Thirty-three studies reported data for mortality, 31 studies reported data for unfavourable outcomes (death, vegetative state or severe disability), and 14 studies reported pneumonia. Visual inspection of the results for these outcomes showed inconsistencies among studies, with differences in the direction of effect, and we did not pool these data for meta-analysis. We considered duration of hypothermia therapy and the length of follow-up in collected data for these subgroups; differences in study data remained such that we did not perform meta-analysis.Studies were generally poorly reported and we were unable to assess risk of bias adequately. Heterogeneity was evident both in the trial designs and participant inclusion. Inconsistencies in results may be explained by heterogeneity among study participants or bias introduced by individual study methodology but we did not explore this in detail in subgroup or sensitivity analyses. We used the GRADE approach to judge the quality of the evidence for each outcome and downgraded the evidence for mortality and unfavourable outcome to very low. We downgraded the evidence for the pneumonia outcome to low.Authors' conclusionsDespite a large number studies, there remains no high-quality evidence that hypothermia is beneficial in the treatment of people with TBI. Further research, which is methodologically robust, is required in this field to establish the effect of hypothermia for people with TBI.
| S-EPMC6483736 | biostudies-literature
Project description:Preclinical and clinical studies have shown therapeutic potential of mild-to-moderate hypothermia for treatments of stroke and traumatic brain injury (TBI). Physical cooling in humans, however, is usually slow, cumbersome, and necessitates sedation that prevents early application in clinical settings and causes several side effects. Our recent study showed that pharmacologically induced hypothermia (PIH) using a novel neurotensin receptor 1 (NTR1) agonist, HPI-201 (also known as ABS-201), is efficient and effective in inducing therapeutic hypothermia and protecting the brain from ischemic and hemorrhagic stroke in mice. The present investigation tested another second-generation NTR1 agonist, HPI-363, for its hypothermic and protective effect against TBI. Adult male mice were subjected to controlled cortical impact (CCI) (velocity=3?m/sec, depth=1.0?mm, contact time=150?msec) to the exposed cortex. Intraperitoneal administration of HPI-363 (0.3?mg/kg) reduced body temperature by 3-5°C within 30-60?min without triggering a shivering defensive reaction. An additional two injections sustained the hypothermic effect in conscious mice for up to 6?h. This PIH treatment was initiated 15, 60, or 120?min after the onset of TBI, and significantly reduced the contusion volume measured 3 days after TBI. HPI-363 attenuated caspase-3 activation, Bax expression, and TUNEL-positive cells in the pericontusion region. In blood-brain barrier assessments, HPI-363 ameliorated extravasation of Evans blue dye and immunoglobulin G, attenuated the MMP-9 expression, and decreased the number of microglia cells in the post-TBI brain. HPI-363 decreased the mRNA expression of tumor necrosis factor-? and interleukin-1? (IL-1?), but increased IL-6 and IL-10 levels. Compared with TBI control mice, HPI-363 treatments improved sensorimotor functional recovery after TBI. These findings suggest that the second generation NTR-1 agonists, such as HPI-363, are efficient hypothermic-inducing compounds that have a strong potential in the management of TBI.
| S-EPMC4132583 | biostudies-literature
Project description:Programmed necrosis or necroptosis is an inflammatory form of cell death that critically requires the receptor-interacting protein kinase 3 (RIPK3). Here we showed that RIPK3 controls a separate, necrosis-independent pathway of inflammation by regulating cytokine expression in dendritic cells (DCs). Ripk3(-/-) bone-marrow-derived dendritic cells (BMDCs) were highly defective in lipopolysaccharide (LPS)-induced expression of inflammatory cytokines. These effects were caused by impaired NF-κB subunit RelB and p50 activation and by impaired caspase 1-mediated processing of interleukin-1β (IL-1β). This DC-specific function of RIPK3 was critical for injury-induced inflammation and tissue repair in response to dextran sodium sulfate (DSS). Ripk3(-/-) mice exhibited an impaired axis of injury-induced IL-1β, IL-23, and IL-22 cytokine cascade, which was partially corrected by adoptive transfer of wild-type DCs, but not Ripk3(-/-) DCs. These results reveal an unexpected function of RIPK3 in NF-κB activation, DC biology, innate inflammatory-cytokine expression, and injury-induced tissue repair.
| S-EPMC4220270 | biostudies-literature
Project description:IntroductionResearch into therapeutic hypothermia following traumatic brain injury has been characterised by small trials of poor methodological quality, producing variable results. The Cochrane review, published in 2009, now requires updating. The aim of this systematic review is to assess the effectiveness of the application of therapeutic hypothermia to reduce death and disability when administered to adult patients who have been admitted to hospital following traumatic brain injury.MethodsTwo authors extracted data from each trial. Unless stated in the trial report, relative risks and 95% confidence intervals (CIs) were calculated for each trial. We considered P?<?0?·?05 to be statistically significant. We combined data from all trials to estimate the pooled risk ratio (RR) with 95% confidence intervals for death, unfavourable outcome, and pneumonia. All statistical analyses were performed using RevMan 5.1 (Cochrane IMS, Oxford, UK) and Stata (Intercooled Version 12.0, StataCorp LP). Pooled RRs were calculated using the Mantel-Haenszel estimator. The random effects model of DerSimonian and Laird was used to estimate variances for the Mantel-Haenszel and inverse variance estimators.ResultsTwenty studies are included in the review, while 18 provided mortality data. When the results of 18 trials that evaluated mortality as one of the outcomes were statistically aggregated, therapeutic hypothermia was associated with a significant reduction in mortality and a significant reduction in poor outcome. There was a lack of statistical evidence for an association between use of therapeutic hypothermia and increased onset of new pneumonia.ConclusionsIn contrast to previous reviews, this systematic review found some evidence to suggest that therapeutic hypothermia may be of benefit in the treatment of traumatic brain injury. The majority of trials were of low quality, with unclear allocation concealment. Low quality trials may overestimate the effectiveness of hypothermia treatment versus standard care. There remains a need for more, high quality, randomised control trials of therapeutic hypothermia after traumatic brain injury.
| S-EPMC4056614 | biostudies-literature
Project description:Traumatic brain injury (TBI) is a worldwide medical problem, and currently, there are few therapeutic interventions that can protect the brain and improve functional outcomes in patients. Over the last several decades, experimental studies have investigated the pathophysiology of TBI and tested various pharmacological treatment interventions targeting specific mechanisms of secondary damage. Although many preclinical treatment studies have been encouraging, there remains a lack of successful translation to the clinic and no therapeutic treatments have shown benefit in phase 3 multicenter trials. Therapeutic hypothermia and targeted temperature management protocols over the last several decades have demonstrated successful reduction of secondary injury mechanisms and, in some selective cases, improved outcomes in specific TBI patient populations. However, the benefits of therapeutic hypothermia have not been demonstrated in multicenter randomized trials to significantly improve neurological outcomes. Although the exact reasons underlying the inability to translate therapeutic hypothermia into a larger clinical population are unknown, this failure may reflect the suboptimal use of this potentially powerful therapeutic in potentially treatable severe trauma patients. It is known that multiple factors including patient recruitment, clinical treatment variables, and cooling methodologies are all important in yielding beneficial effects. High-quality multicenter randomized controlled trials that incorporate these factors are required to maximize the benefits of this experimental therapy. This article therefore summarizes several factors that are important in enhancing the beneficial effects of therapeutic hypothermia in TBI. The current failures of hypothermic TBI clinical trials in terms of clinical protocol design, patient section, and other considerations are discussed and future directions are emphasized.
| S-EPMC6057704 | biostudies-other
Project description:Presently, traumatic brain injury (TBI) is a leading contributor to disability and mortality that places a considerable financial burden on countries all over the world. Docosahexaenoic acid and eicosapentaenoic acid are two kinds of omega-3 polyunsaturated fatty acids (ω-3 PUFA), both of which have been shown to have beneficial biologically active anti-inflammatory and antioxidant effects. However, the neuroprotective effect of ω-3 PUFA in TBI has not been proven, and its probable mechanism remains obscure. We suppose that ω-3 PUFA can alleviate early brain injury (EBI) via regulating necroptosis and neuroinflammation after TBI. This research intended to examine the neuroprotective effect of ω-3 and its possible molecular pathways in a C57BL/6 mice model of EBI caused by TBI. Cognitive function was assessed by measuring the neuronal necroptosis, neuroinflammatory cytokine levels, brain water content, and neurological score. The findings demonstrate that administration of ω-3 remarkably elevated neurological scores, alleviated cerebral edema, and reduced inflammatory cytokine levels of NF-κB, interleukin-1β (IL-1β), IL-6, and TNF-α, illustrating that ω-3 PUFA attenuated neuroinflammation, necroptosis, and neuronal cell death following TBI. The PPARγ/NF-κB signaling pathway is partially responsible for the neuroprotective activity of ω-3. Collectively, our findings illustrate that ω-3 can alleviate EBI after TBI against neuroinflammation and necroptosis.
| S-EPMC9990778 | biostudies-literature
Project description:The use of therapeutic hypothermia (TH) and targeted temperature management (TTM) for severe traumatic brain injury (TBI) has been tested in a variety of preclinical and clinical situations. Early preclinical studies showed that mild reductions in brain temperature after moderate to severe TBI improved histopathological outcomes and reduced neurological deficits. Investigative studies have also reported that reductions in post-traumatic temperature attenuated multiple secondary injury mechanisms including excitotoxicity, free radical generation, apoptotic cell death, and inflammation. In addition, while elevations in post-traumatic temperature heightened secondary injury mechanisms, the successful implementation of TTM strategies in injured patients to reduce fever burden appear to be beneficial. While TH has been successfully tested in a number of single institutional clinical TBI studies, larger randomized multicenter trials have failed to demonstrate the benefits of therapeutic hypothermia. The use of TH and TTM for treating TBI continues to evolve and a number of factors including patient selection and the timing of the TH appear to be critical in successful trial design. Based on available data, it is apparent that TH and TTM strategies for treating severely injured patients is an important therapeutic consideration that requires more basic and clinical research. Current research involves the evaluation of alternative cooling strategies including pharmacologically-induced hypothermia and the combination of TH or TTM approaches with more selective neuroprotective or reparative treatments. This manuscript summarizes the preclinical and clinical literature emphasizing the importance of brain temperature in modifying secondary injury mechanisms and in improving traumatic outcomes in severely injured patients. This article is part of a Special Issue entitled SI:Brain injury and recovery.
| S-EPMC4870128 | biostudies-other