Hypothermia In Traumatic Brain Injury Research Articles

Long-term hypothermia amplified neuroprotection by antagonizing intracranial pressure rebound after severe traumatic brain injury in rats.

Long-term hypothermia has been reported to prevent intracranial pressure (ICP) rebound in clinical patients, but the duration for hypothermia and the corresponding ICP data are not available. This study investigated the optimal duration of long-term hypothermia in traumatic brain injury (TBI) rats, and observed the effect on ICP and neurological function. In this study, we established a rat severe TBI model with electronic Controlled Cortical Injury device, and implemented hypothermia (33 °C) for different durations. The motor function of the rats in each group was evaluated by beam walking test and inclined-grid climbing test, brain water content was calculated by the wet-dry weight method, Evan's blue staining was used to measure the blood-brain barrier (BBB) permeability, the change of hippocampal neurons was observed by Nissl staining, the expressions of BrdU, NeuN, and CD86 positive cells were detected by immunofluorescence staining, and the expressions of Bcl-2, Bax, iNOS, IL-10, and Arg-1 were detected by Western blot. We found that therapeutic hypothermia improved neurological recovery after TBI with declining ICP, reducing brain edema, decreasing BBB permeability, promoting neurogenesis, inhibiting apoptosis, and regulating inflammation. Moreover, 48 h hypothermia amplified the neuroprotective effect after injury on the basis of 4 or 24 h hypothermic treatment. Both 4 and 24 h hypothermia led to ICP rebound during or after rewarming, whereas 48 h hypothermia completely abolished ICP rebound. Our study suggests that long-term hypothermia amplifies neuroprotection after TBI by antagonizing ICP rebound.

Analysis of rebound intracranial pressure occurring during rewarming after therapeutic hypothermia in traumatic brain injury patients

ObjectiveTo investigate the risk factors associated with rebound intracranial pressure (ICP), a phenomenon that occurs when brain swelling reprogresses rapidly during rewarming in patients who have undergone therapeutic hypothermia for traumatic brain injury (TBI). MethodsThis study analyzed 42 patients who underwent therapeutic hypothermia among 172 patients with severe TBI admitted to a single regional trauma center between January 2017 and December 2020. Forty-two patients were classified into 34.5 °C (mild) and 33 °C (moderate) hypothermia groups according to the therapeutic hypothermia protocol for TBI. Rewarming was initiated post-hypothermia, wherein ICP was maintained at ≤ 20 mmHg and cerebral perfusion pressure was maintained at ≥ 50 mmHg for ≥ 24 h. In the rewarming protocol, the target core temperature was increased to 36.5 °C at 0.1 °C/h. ResultsOf the 42 patients who underwent therapeutic hypothermia, 27 did not survive: 9 in the mild and 18 in the moderate hypothermia groups. The moderate hypothermia group had a significantly higher mortality rate than the mild hypothermia group (p = 0.013). Rebound ICP occurred in 9 of 25 patients: 2 in the mild and 7 in the moderate hypothermia groups. In the risk factor analysis of rebound ICP, only the degree of hypothermia was statistically significant, and rebound ICP was observed more frequently in the moderate than in the mild hypothermia group (p = 0.025). ConclusionsIn patients who underwent rewarming after therapeutic hypothermia, rebound ICP presented a higher risk at 33 °C than at 34.5 °C. Therefore, more careful rewarming is needed in patients receiving therapeutic hypothermia at 33 °C.

Overview of Hypothermia, Its Role in Neuroprotection, and the Application of Prophylactic Hypothermia in Traumatic Brain Injury.

The current standard of practice is to maintain normothermia in traumatic brain injury (TBI) patients despite the theoretical benefits of hypothermia and numerous animal studies with promising results. While targeted temperature management or induced hypothermia to support neurological function is recommended for a select patient population postcardiac arrest, similar guidelines have not been instituted for TBI. In this review, we will examine the pathophysiology of TBI and discuss the benefits and risks of induced hypothermia in this patient population. In addition, we provide an overview of the largest randomized controlled trials testing-induced hypothermia. Our literature review on hypothermia returned a myriad of studies and trials, many of which have inconclusive results. The aim of this review was to recognize the effects of hypothermia, summarize the latest trials, address the inconsistencies, and discuss future directions for the study of hypothermia in TBI.

Correction to “Recombinant High-Density Lipoprotein Boosts the Therapeutic Efficacy of Mild Hypothermia in Traumatic Brain Injury”

Correction to “Recombinant High-Density Lipoprotein Boosts the Therapeutic Efficacy of Mild Hypothermia in Traumatic Brain Injury”

Hypothermia impairs glymphatic drainage in traumatic brain injury as assessed by dynamic contrast-enhanced MRI with intrathecal contrast.

The impact of hypothermia on the impaired drainage function of the glymphatic system in traumatic brain injury (TBI) is not understood. Male Sprague-Dawley rats undergoing controlled cortical impact injury (CCI) were subjected to hypothermia or normothermia treatment. The rats undergoing sham surgery without CCI were used as the control. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with intrathecal administration of low- and high-molecular-weight contrast agents (Gd-DTPA and hyaluronic acid conjugated Gd-DTPA) was performed after TBI and head temperature management. The semiquantitative kinetic parameters characterizing the contrast infusion and cleanout in the brain, including influx rate, efflux rate, and clearance duration, were calculated from the average time-intensity curves. The qualitative and semiquantitative results of DCE-MRI obtained from all examined perivascular spaces and most brain tissue regions showed a significantly increased influx rate and efflux rate and decreased clearance duration among all TBI animals, demonstrating a significant impairment of glymphatic drainage function. This glymphatic drainage dysfunction was exacerbated when additional hypothermia was applied. The early glymphatic drainage reduction induced by TBI and aggravated by hypothermia was linearly related to the late increased deposition of p-tau and beta-amyloid revealed by histopathologic and biochemical analysis and cognitive impairment assessed by the Barnes maze and novel object recognition test. The glymphatic system dysfunction induced by hypothermia may be an indirect alternative pathophysiological factor indicating injury to the brain after TBI. Longitudinal studies and targeted glymphatic dysfunction management are recommended to explore the potential effect of hypothermia in TBI.

Recombinant High-Density Lipoprotein Boosts the Therapeutic Efficacy of Mild Hypothermia in Traumatic Brain Injury.

Traumatic brain injury (TBI) leads to neuropsychiatric symptoms and increased risk of neurodegenerative disorders. Mild hypothermia is commonly used in patients suffering from severe TBI. However, its effect for long-term protection is limited, mostly because of its insufficient anti-inflammatory and neuroprotective efficacy and restricted treatment duration. Recombinant high-density lipoprotein (rHDL), which possesses anti-inflammatory and antioxidant activity and blood-brain barrier (BBB) permeability, was expected to potentially strengthen the therapeutic effect of mild hypothermia in TBI treatment. To test this hypothesis and optimize the regimen for combination therapy, the efficacy of mild hypothermia plus concurrent or sequential rHDL on oxidative stress, inflammatory reaction, and cell survival in the damaged brain cells was evaluated. It was found that the effect of combining mild hypothermia with concurrent rHDL was modest, as mild hypothermia inhibited the cellular uptake and lesion-site-targeting delivery of rHDL. In contrast, the combination of mild hypothermia with sequential rHDL more powerfully improved the anti-inflammatory and antioxidant activities, promoted nerve cell survival and BBB restoration, and ameliorated neurologic changes, which thus remarkably restored the spatial learning and memory ability of TBI mice. Collectively, these findings suggest that rHDL may serve as a novel nanomedicine for adjunctive therapy of TBI and highlight the importance of timing of combination therapy for optimal treatment outcome.

Selective Brain Cooling Reduces Motor Deficits Induced by Combined Traumatic Brain Injury, Hypoxemia and Hemorrhagic Shock.

Selective brain cooling (SBC) can potentially maximize the neuroprotective benefits of hypothermia for traumatic brain injury (TBI) patients without the complications of whole body cooling. We have previously developed a method that involved extraluminal cooling of common carotid arteries, and demonstrated the feasibility, safety and efficacy for treating isolated TBI in rats. The present study evaluated the neuroprotective effects of 4-h SBC in a rat model of penetrating ballistic-like brain injury (PBBI) combined with hypoxemic and hypotensive insults (polytrauma). Rats were randomly assigned into two groups: PBBI+polytrauma without SBC (PHH) and PBBI+polytrauma with SBC treatment (PHH+SBC). All animals received unilateral PBBI, followed by 30-min hypoxemia (fraction of inspired oxygen = 0.1) and then 30-min hemorrhagic hypotension (mean arterial pressure = 40 mmHg). Fluid resuscitation was given immediately following hypotension. SBC was initiated 15 min after fluid resuscitation and brain temperature was maintained at 32–33°C (core temperature at ~36.5°C) for 4 h under isoflurane anesthesia. The PHH group received the same procedures minus the cooling. At 7, 10, and 21 days post-injury, motor function was assessed using the rotarod task. Cognitive function was assessed using the Morris water maze at 13–17 days post-injury. At 21 days post-injury, blood samples were collected and the animals were transcardially perfused for subsequent histological analyses. SBC transiently augmented cardiovascular function, as indicated by the increase in mean arterial pressure and heart rate during cooling. Significant improvement in motor functions were detected in SBC-treated polytrauma animals at 7, 10, and 21 days post-injury compared to the control group (p < 0.05). However, no significant beneficial effects were detected on cognitive measures following SBC treatment in the polytrauma animals. In addition, the blood serum and plasma levels of cytokines interleukin-1 and −10 were comparable between the two groups. Histological results also did not reveal any between-group differences in subacute neurodegeneration and astrocyte/ microglial activation. In summary, 4-h SBC delivered through extraluminal cooling of the common carotid arteries effectively ameliorated motor deficits induced by PBBI and polytrauma. Improving cognitive function or mitigating subacute neurodegeneration and neuroinflammation might require a different cooling regimen such as extended cooling, a slow rewarming period and a lower temperature.

Hypothermia for traumatic brain injury.

Hypothermia 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. To determine the effect of mild hypothermia for traumatic brain injury (TBI) on mortality, long-term functional outcomes and complications. We 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'. We 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). Two review authors assessed data on mortality, unfavourable outcomes according to the Glasgow Outcome Scale, and pneumonia. We 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. Despite 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.

Meta-Analysis of Therapeutic Hypothermia for Traumatic Brain Injury in Adult and Pediatric Patients.

Therapeutic hypothermia has been used to attenuate the effects of traumatic brain injuries. However, the required degree of hypothermia, length of its use, and its timing are uncertain. We undertook a comprehensive meta-analysis to quantify benefits of hypothermia therapy for traumatic brain injuries in adults and children by analyzing mortality rates, neurologic outcomes, and adverse effects. Electronic databases PubMed, Google Scholar, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov and manual searches of studies were conducted for relevant publications up until February 2016. Forty-one studies in adults (n = 3,109; age range, 18-81 yr) and eight studies in children (n = 454; age range, 3 mo to 18 yr) met eligibility criteria. Baseline patient characteristics, enrollment time, methodology of cooling, target temperature, duration of hypothermia, and rewarming protocols were extracted. Risk ratios with 95% CIs were calculated. Compared with adults who were kept normothermic, those who underwent therapeutic hypothermia were associated with 18% reduction in mortality (risk ratio, 0.82; 95% CI, 0.70-0.96; p = 0.01) and a 35% improvement in neurologic outcome (risk ratio, 1.35; 95% CI, 1.18-1.54; p < 0.00001). The optimal management strategy for adult patients included cooling patients to a minimum of 33°C for 72 hours, followed by spontaneous, natural rewarming. In contrast, adverse outcomes were observed in children who underwent hypothermic treatment with a 66% increase in mortality (risk ratio, 1.66; 95% CI, 1.06-2.59; p = 0.03) and a marginal deterioration of neurologic outcome (risk ratio, 0.90; 95% CI, 0.80-1.01; p = 0.06). Therapeutic hypothermia is likely a beneficial treatment following traumatic brain injuries in adults but cannot be recommended in children.

Therapeutic hypothermia and targeted temperature management for traumatic brain injury: Experimental and clinical experience

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.

Hypothermia for Increased Intracranial Pressure: Is It Dead?

Mild to moderate therapeutic hypothermia (HT) has been used to alleviate intracranial hypertension in traumatic brain injury (TBI). Its main contribution is thought to be via reduction in cerebral metabolic requirement leading both to favorable oxygen/metabolic delivery-demand ratios as well as a reduction of cerebral blood volume resulting in decreased ICP. Nevertheless, HT is a clinically complex, labor-intensive procedure with numerous potential adverse effects. Furthermore, randomized controlled trials suggest either no effect or harm. These facts challenge the role of HT in TBI. We address this challenge by posing three questions that relate to the overarching value of controlling ICP, the effectiveness of HT in reducing ICP, and the benefit-risk ratio of the intervention. We conclude that HT should not be used as an "early" intervention unless as a part of a clinical trial, although it may still have a role in patients with refractory intracranial hypertension.

Hypothermia for Traumatic Brain Injury in Children—A Phase II Randomized Controlled Trial

Surv Anesthesiol 2016;60(2):73–74 This pilot study was undertaken to test the hypothesis that early and prolonged therapeutic hypothermia (TH; continued for a minimum of 72 hours, with rate of rewarming guided by intracranial pressure [ICP] and cerebral perfusion pressure [CPP]) would improve the outcome in children with traumatic brain injury (TBI). This multicenter trial, conducted in all 8 of the pediatric intensive care units (PICUs) in Australia and New Zealand and 1 in Canada, tested the protocol (including adherence, safety, and outcomes) in order to assess the feasibility of a phase III randomized controlled trial (RCT).

Hypothermia not Supported as a Therapeutic Option for Traumatic Brain Injury in Recent Randomized Trial

Traumatic brain injury (TBI) is a leading cause of permanent disability in people younger than 40 years of age. An increase in intracranial pressure (ICP) during hospitalization for a TBI has been associated with poor long-term neurologic outcomes. On the basis of encouraging research, hypothermia has been embraced by some centers as an innovative way to treat high ICP. More recent trials, however, have hinted that therapeutic hypothermia might contribute to poor neurologic outcomes. In an attempt to define the role of hypothermia in TBI, the Eurotherm 3235 Trial collaborators conducted a randomized controlled trial, which was published October 7, 2015 in the New England Journal of Medicine. The inclusion criteria included patients with closed head injury who sustained an ICP >20 mm Hg for >5 minutes. For the purpose of creating a framework for study analysis, treatments for TBI were divided into stage 1, 2, and 3 therapies (Table 1). Eligible patients were randomized to an experimental arm, hypothermia (32 C 35 C) in addition to best management practice, and a control arm that consisted of best management practices alone. Statistical analysis was performed using ordinal logistic regression to compare the Extended Glasgow Outcome Scale scores between the hypothermia and control groups at 6 months. Only 25.7% of patients from the hypothermia group (49/191) had favorable outcomes at

Hypothermia for traumatic brain injury in children - A phase II randomized controlled trial

Hypothermia for traumatic brain injury in children - A phase II randomized controlled trial

Neuroprotective effects of cold-inducible RNA-binding protein during mild hypothermia on traumatic brain injury.

Cold-inducible RNA-binding protein (CIRP), a key regulatory protein, could be facilitated by mild hypothermia in the brain, heart and liver. This study observed the effects of mild hypothermia at 31 ± 0.5°C on traumatic brain injury in rats. Results demonstrated that mild hypothermia suppressed apoptosis in the cortex, hippocampus and hypothalamus, facilitated CIRP mRNA and protein expression in these regions, especially in the hypothalamus. The anti-apoptotic effect of mild hypothermia disappeared after CIRP silencing. There was no correlation between mitogen-activated extracellular signal-regulated kinase activation and CIRP silencing. CIRP silencing inhibited extracellular signal-regulated kinase-1/2 activation. These indicate that CIRP inhibits apoptosis by affecting extracellular signal-regulated kinase-1/2 activation, and exerts a neuroprotective effect during mild hypothermia for traumatic brain injury.

Induced Hypothermia Can Worsen Outcomes After Traumatic Brain Injury

Induced hypothermia has become popular for treating cerebral edema from traumatic brain injury (TBI), but we do not know the effect on long-term outcomes. Therefore, European investigators performed a multicenter randomized trial of hypothermia for TBI. The authors recruited patients with TBI and intracranial pressure >20 mm Hg for ≥5 minutes despite first-line therapy with mechanical ventilation, sedation, analgesia, head-of-bed elevation, cerebrospinal fluid drainage, and surgical removal of space-occupying lesions. Participants …

Therapeutic Hypothermia in Traumatic Brain injury; Review of History, Pathophysiology and Current Studies

The fact that therapeutic hypothermia (TH) has lowered intracranial pressure and protected brain in severe traumatic brain injury (TBI) is well known throughout past sources and experimental data. In this paper, the result of TH in TBI needs to be confirmed. The result of North American Brain Injury Study; Hypothermia (NAVIS-H) 1 and 2, Eurotherm3235, Japan trauma society study was reviewed throughout randomized controlled study which performed recently. The prognosis was not confirmed throughout TH in NAVIS-H1; however, there was statistical significance among the group of 45 years or less and below 35 degree in celcius which checked when he or she visited initially. Hence, NAVIS-H2 study was preceded. In patient who had surgically removed hematoma, the effects of TH were proved compared to diffuse brain damage in NAVIS-H2 study. This was found in the result of Japan neurotrauma data bank. Eurotherm study has been doing, which leads to collect many data later on. The TBI of TH makes them better prognosis in patients who had surgically removed hematoma and lowered initial body temperature. Later on, it is considered further study is necessary.

Therapeutic hypothermia for elevated intracranial pressure in traumatic brain injury: does it do more harm than good?

I have reviewed above article by Andrews et al. [1] with great interest. Reading this article has evidently produced me with a mixed feeling of both satisfying and unsatisfying emotional feedback for the reasons I have carefully outlined below. This is yet another disappointment to the multisubspecialty medical and surgical communities, because now the concept and application of hypothermia, or perhaps better termed as targeted temperature modulation, seems to be failing in neuro applications. As many readers are likely aware of, Nielsen et al. [2] have reported a negative trial of comparing 33 degrees Celsius versus 36 degrees Celsius after cardiac arrest at the end of 2013. After questioning the true value of hypothermia in cardiac arrest victims, it is now being questioned as to whether applying hypothermia in traumatic brain injury (TBI) would confer any benefits in long term outcomes.

Therapeutic hypothermia for neuroprotection: history, mechanisms, risks, and clinical applications.

The earliest recorded application of therapeutic hypothermia in medicine spans about 5000 years; however, its use has become widespread since 2002, following the demonstration of both safety and efficacy of regimens requiring only a mild (32°C-35°C) degree of cooling after cardiac arrest. We review the mechanisms by which hypothermia confers neuroprotection as well as its physiological effects by body system and its associated risks. With regard to clinical applications, we present evidence on the role of hypothermia in traumatic brain injury, intracranial pressure elevation, stroke, subarachnoid hemorrhage, spinal cord injury, hepatic encephalopathy, and neonatal peripartum encephalopathy. Based on the current knowledge and areas undergoing or in need of further exploration, we feel that therapeutic hypothermia holds promise in the treatment of patients with various forms of neurologic injury; however, additional quality studies are needed before its true role is fully known.

Therapeutic Hypothermia for Traumatic Brain Injury

Experimental evidence demonstrates that therapeutic temperature modulation with the use of mild induced hypothermia (MIH, defined as the maintenance of body temperature at 32-35 °C) exerts significant neuroprotection and attenuates secondary cerebral insults after traumatic brain injury (TBI). In adult TBI patients, MIH has been used during the acute "early" phase as prophylactic neuroprotectant and in the sub-acute "late" phase to control brain edema. When used to control brain edema, MIH is effective in reducing elevated intracranial pressure (ICP), and is a valid therapy of refractory intracranial hypertension in TBI patients. Based on the available evidence, we recommend: applying standardized algorithms for the management of induced cooling; paying attention to limit potential side effects (shivering, infections, electrolyte disorders, arrhythmias, reduced cardiac output); and using controlled, slow (0.1-0.2 °C/h) rewarming, to avoid rebound ICP. The optimal temperature target should be titrated to maintain ICP <20 mmHg and to avoid temperatures <35 °C. The duration of cooling should be individualized until the resolution of brain edema, and may be longer than 48 h. Patients with refractory elevated ICP following focal TBI (e.g. hemorrhagic contusions) may respond better to MIH than those with diffuse injury. Randomized controlled trials are underway to evaluate the impact of MIH on neurological outcome in adult TBI patients with elevated ICP. The use of MIH as prophylactic neuroprotectant in the early phase of adult TBI is not supported by clinical evidence and is not recommended.