Reduction In Brain Temperature Research Articles

Hypoxic irreversible brain cells damage, associated risk factors and antihypoxants

It is reported that in the final stage of many diseases the immediate cause of biological death in humans and warm-blooded animals is hypoxic irreversible damage to brain cells. This explains the fact that to prevent biological death in all critical conditions without exception, inhalation with breathing gases containing oxygen has long been successfully used. This is also why oxygenation of the blood is considered one of the main conditions for preserving human life in all critical situations and forms the basis of emergency medical care in the intensive care unit. However, inhalation of oxygen gas and increasing blood oxygen saturation should be carried out as early as possible, and more precisely - before the onset of the stage of hypoxic irreversible damage in brain cells. The fact is that after the onset of irreversible damage brain cells die even in the presence of oxygen. In this connection, the mechanisms of adaptation of the organism to oxygen deficiency play a great role for longer preservation of brain cells viability and human life in conditions of hypoxemia. In order to increase resistance to hypoxemia, antihypoxants are traditionally used. But they can preserve the viability of brain cells not always, but only if they are introduced into the body before the onset of hypoxic irreversible damage to brain cells and in the case of unused reserves of adaptation to hypoxemia in the body. Risk factors of hypoxic irreversible damage of brain cells are indicated, among which excessively long duration of hypoxemia and hyperthermia are emphasized. It is shown that the most important circumstance for the development of hypoxic irreversible damage of brain cells is not so much the degree of hypoxemia as the degree of hypoxia of brain tissue and its duration, which exceeds the period of human resistance to hypoxia. It has been shown that human resistance to hypoxia can be assessed using the Stange test. It has been reported that fever and local cerebral hyperthermia decrease, and hibernation and local cerebral hypothermia increase, the resistance of brain cells to hypoxia. In this regard, recommendations not only to eliminate fever and local inflammatory processes in the head, but also recommendations to reduce brain temperature are highly appropriate to improve resistance to hypoxia. It is pointed out that among the methods of local therapeutic hypothermia, targeted temperature management is the most advanced. In addition, it is reported that in recent years a new group of promising antihypoxants - alkaline solutions of hydrogen peroxide - has been created. It is shown that hydrogen peroxide is able to decompose very quickly into water and oxygen gas under the action of catalase, which is found in all tissues. The peculiarities of using alkaline solutions of hydrogen peroxide as antihypoxants we all have to study in the future.

Abstract TP288: Selective Brain Hypothermia Induced by Thermoelectric Cooling

Background: Stroke or Traumatic Brain Injury (TBI) are leading causes of disability and death in the United States. Hypothermia is a known neuronal protectant. Current hypothermia interventions include intravascular, intranasal, and surface brain cooling technologies but these interventions have not been well utilized clinically. Cooling the brain a few degrees below normothermia (T<36°C) has been shown to yield significant neuroprotective effects. Noninvasive surface cooling methods are most desirable given their less patient complications, provided the desired therapeutic hypothermia effect (T 33-36°C) can be maintained. Method: These investigators propose a novel noninvasive solid state technology that employs addressable Peltier thermoelectric cooling elements to generate hypothermia. ThermoPelt’s closed-looped microcontroller design provides the ability to address individual Peltier elements to selectively reduce the temperature of localized regions of the brain, thus allowing precision therapeutic hypothermic conditions to be realized. Results: Assessment of ThermoPelt performance was accomplished with use of virtual prototype (engineering mathematical model representations of the brain) and early, in vitro experimental physical prototype testing. Preliminary results obtained from virtual and physical prototype tests verify ThermoPelt feasibility to achieve hypothermic conditions. Conclusion: In this new method of generating hypothermia, the preliminary findings demonstrate that our noninvasive ThermoPelt technology is capable of reducing brain temperature at controlled rates to selectively target specific head and neck regions.

Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental Stroke.

Background Thrombolysis and endovascular thrombectomy are the primary treatment for ischemic stroke. However, due to the limited time window and the occurrence of adverse effects, only a small number of patients can genuinely benefit from recanalization. Intraarterial injection of rtPA (recombinant tissue plasminogen activator) based on arterial thrombectomy could improve the prognosis of patients with acute ischemic stroke, but it could not reduce the incidence of recanalization-related adverse effects. Recently, selective brain hypothermia has been shown to offer neuroprotection against stroke. To enhance the recanalization rate of ischemic stroke and reduce the adverse effects such as tiny thrombosis, brain edema, and hemorrhage, we described for the first time a combined approach of hypothermia and thrombolysis via intraarterial hypothermic rtPA. Methods and Results We initially established the optimal regimen of hypothermic rtPA in adult rats subjected to middle cerebral artery occlusion. Subsequently, we explored the mechanism of action mediating hypothermic rtPA by probing reduction of brain tissue temperature, attenuation of blood-brain barrier damage, and sequestration of inflammation coupled with untargeted metabolomics. Hypothermic rtPA improved neurological scores and reduced infarct volume, while limiting hemorrhagic transformation in middle cerebral artery occlusion rats. These therapeutic outcomes of hypothermic rtPA were accompanied by reduced brain temperature, glucose metabolism, and blood-brain barrier damage. A unique metabolomic profile emerged in hypothermic rtPA-treated middle cerebral artery occlusion rats characterized by downregulated markers for energy metabolism and inflammation. Conclusions The innovative use of hypothermic rtPA enhances their combined, as opposed to stand-alone, neuroprotective effects, while reducing hemorrhagic transformation in ischemic stroke.

The Complex Relationship Between Cooling Parameters and Neuroprotection in a Model of Selective Hypothermia.

BackgroundHypothermia remains the best studied neuroprotectant. Despite extensive positive large and small animal data, side effects continue to limit human applications. Selective hypothermia is an efficient way of applying neuroprotection to the brain without the systemic complications of global hypothermia. However, optimal depth and duration of therapeutic hypothermia are still unknown. We analyzed a large animal cohort study of selective hypothermia for statistical relationships between depth or duration of hypothermia and the final stroke volume.MethodsA cohort of 30 swine stroke subjects provided the dataset for normothermic and selective hypothermic animals. Hypothermic parameters including duration, temperature nadir, and an Area Under the Curve measurement for 34 and 30°C were correlated with the final infarct volumes measured by MRI and histology.ResultsBetween group comparisons continue to demonstrate a reduction in infarct volume with selective hypothermia. Histologically-derived infarct volumes were 1.2 mm3 smaller in hypothermia-treated pigs (P = 0.04) and showed a similar, but non-significant reduction in MRI (P = 0.15). However, within the selective hypothermia group, more intense cooling, as measured through increased AUC 34 and decreased temperature nadir was associated with larger infarct proportions by MRI [Pearson's r = 0.48 (p = 0.05) and r = −0.59 (p = 0.01), respectively]. Reevaluation of the entire cohort with quadratic regression demonstrated a U-shaped pattern, wherein the average infarct proportion was minimized at 515 degree-minutes (AUC34) of cooling, and increased thereafter. In a single case of direct brain tissue oxygen monitoring during selective hypothermia, brain tissue oxygen strongly correlated with brain temperature reduction over the course of selective hypothermia to 23°C.ConclusionsIn a large animal model of selective hypothermia applied to focal ischemia, there is a non-monotone relationship between duration and depth of hypothermia and stroke volume reduction. This suggests a limit to depth or duration of selective hypothermia for optimal neuroprotection. Further research is required to delineate more precise depth and duration limits for selective hypothermia.

Hybernia post-mechanical thrombectomy – Endovascular cerebral hypothermia trial in acute ischemic stroke (post-mtech trial)

Although significant clinical improvement is achieved with mechanical thrombectomy (MT) in large vessel occlusion (LVO) stroke patients, <1/4 patients have outcomes comparable to their baseline (pre-stroke) conditions. Therapeutic hypothermia is a promising method for acute neuroprotection, with multiple beneficial mechanisms, for which a reduction of brain temperature by several °C is required. Systemic hypothermia has been difficult to implement in stroke patients due to the long delay to reach target temperature, complications related to physiological counter-mechanisms to cold, and adverse events associated with whole body cooling. In contrast, targeted brain cooling may provide effective hypothermic neuroprotection, because 1) of more rapid brain cooling (minutes) and 2) it is safer (avoids systemic cooling).

Effect of selective brain cooling versus core cooling on achieving target temperature among patients with severe traumatic brain injury

BackgroundNeurotrauma is expected to become the third leading cause of death and disability worldwide. One of these serious injuries is a traumatic brain injury. It is estimated that 10 million people sustain a traumatic brain injury yearly. AimTo assess the effect of selective brain cooling versus core cooling on achieving target temperature among patients with severe traumatic brain injury. Research hypotheses: Patients subjected to selective brain cooling method exhibit a rapid temperature reduction rate than those subjected to the core cooling method. Patients subjected to selective brain cooling method show early improvement in neurological injury severities than those subjected to the core cooling method. Study designA quasi-experimental control and study group design was conducted in this study. MethodThis study was conducted at Alexandria Main University Hospital namely unit I, unit II, unit III and general ICU at Smouha University Hospital. Subject: A convenience sample of 80 newly admitted patients with severe traumatic brain injury and exhibited a refractory fever were assigned randomly into two equal groups. ResultsRegarding cooling methods success in reducing core temperature, selective brain cooling method success in achieving the target temperature was (75.0%) compared to (45.0%) of patients in the core cooling method. Regarding cooling methods success in reducing brain temperature, selective brain cooling success in achieving target temperature is (85.0%) of patients compared to (10%) of patients in the core cooling method. ConclusionThe selective brain cooling method is effective in achieving target temperature than the core cooling method.

An Observational Study on the Use of Intravenous Non-Opioid Analgesics and Antipyretics in Poor-Grade Subarachnoid Hemorrhage: Effects on Hemodynamics and Systemic and Brain Temperature.

Intravenous nonsteroidal anti-inflammatory drugs and nonopioid analgesics are used to achieve normothermia or relieve pain in patients with aneurysmal subarachnoid hemorrhage (aSAH). We investigated the effects of paracetamol (1 g), diclofenac (75 mg) and metamizole (1 g) on systemic and cerebral hemodynamics and temperature during febrile and nonfebrile episodes after aSAH. Prospectively collected data from 77 consecutive poor-grade aSAH patients with invasive neuromonitoring were included. The burden and occurrence of hypotension (mean arterial pressure <70 mmHg), brain tissue hypoxia (PbtO2 < 20 mmHg), high intracranial pressure (>22 mmHg), low cerebral perfusion pressure (CPP <70 mmHg), and cerebral autoregulation pressure (pressure reactivity index [PRx]) during baseline (1 hour before) and 6 hours after medication were analyzed in febrile (core temperature; Tcore ≥ 38.3°C) and nonfebrile episodes. Nine hundred eighty-nine infusions (278 paracetamol, 542 diclofenac, and 169 metamizole) were administered resulting in significant reduction of core and brain temperature during febrile (49%) and nonfebrile (51%) episodes (p < 0.001). In febrile cases, temperature decreased for >1 hour below 37.5°C in 36% of interventions and ≤37°C in 11%. Hemodynamic side effects with hypotension and low CPP occurred in both febrile and nonfebrile episodes (p < 0.001) prompting increased vasopressor support in 31% of cases, even more pronounced during the vasospasm period (4-12 days postictus) (OR 5.4, 95% CI 1.8-16). The magnitude of PbtO2-decrease is directly correlated with the decrease in Tcore (p = 0.002) and higher baseline PbtO2 (p < 0.001). PRx decreased in febrile and nonfebrile episodes (p < 0.001), indicating improvement of cerebrovascular autoregulation. Antipyretics were insufficient to achieve sustained normothermia in poor-grade aSAH patients. Hemodynamic side effects were common even when given as analgesic drugs. Further studies are needed to weigh hemodynamic side effects to benefits (inter alia improved cerebral autoregulation).

MR Imaging Properties of ex vivo Common Marmoset Brain after Formaldehyde Fixation.

Purpose:Ex vivo brains have different MRI properties than in vivo brains because of chemical changes caused by fixative solutions, which change the signal intensity and/or tissue contrast on MR images. In this study, we investigated and compared the MRI properties of in vivo and ex vivo brains.Methods:Using a Bruker 9.4T experimental scanner unit for animals (Biospin GmbH, Ettlingen, Germany), we performed this study on the common marmoset. We measured the relaxation and diffusion values in the white matter and cortex of common marmosets and compared these values between in vivo brains (n = 20) and ex vivo brains (n = 20). Additionally, we observed the relationship between the tissue fixation duration and MRI properties by imaging a brain that underwent long-term fixation in a preliminary examination (n = 1).Results:The T1 values of ex vivo brains were decreased compared with those of in vivo brains; however, there were no significant difference in the T2 and values of in vivo and ex vivo brains. Axial, radial, and mean diffusivity values of ex vivo brains decreased to approximately 65% and 52% of those of in vivo brains in the cortex and white matter, respectively. Conversely, fractional anisotropy values were not significantly different between in vivo and ex vivo brains.Conclusion:The T1 values and diffusion coefficient values of the ex vivo brains were strikingly different than those of the in vivo brains. Conversely, there were no significant changes in the T2, or fractional anisotropy values. Altogether, the dehydration caused by tissue fixation and the reduction in brain temperature were involved in changing the relaxation and diffusion coefficient values. Here, it was difficult to specify all factors causing these changes. Further detailed study is needed to examine changes in MRI properties.

Brain cooling marginally increases acute upper thermal tolerance in Atlantic cod.

Physiological mechanisms determining thermal limits in fishes are debated but remain elusive. It has been hypothesised that motor function loss, observed as loss of equilibrium during acute warming, is due to direct thermal effects on brain neuronal function. To test this, we mounted cooling plates on the heads of Atlantic cod (Gadus morhua) and quantified whether local brain cooling increased whole-organism acute upper thermal tolerance. Brain cooling reduced brain temperature by 2-6°C below ambient water temperature and increased thermal tolerance by 0.5 and 0.6°C on average relative to instrumented and uninstrumented controls, respectively, suggesting that direct thermal effects on brain neurons may contribute to setting upper thermal limits in fish. However, the improvement in thermal tolerance with brain cooling was small relative to the difference in brain temperature, demonstrating that other mechanisms (e.g. failure of spinal and peripheral neurons, or muscle) may also contribute to controlling acute thermal tolerance.

From Anomalous Arteries to Selective Brain Cooling: Parallel Evolution of the Artiodactyl Carotid Rete.

Terrestrial artiodactyls (even-toed ungulates) inhabit some of the world's most extreme environments, including arid deserts and high elevations. As medium-to-large-bodied mammals, artiodactyls have a suite of specialized physiologies to facilitate occupation of regions unavailable to other large mammals. One such physiology is selective brain cooling, wherein reduction of brain temperature below core body temperature has been demonstrated to reduce evaporative water loss. This physiology is enabled by an arterial heat-exchanger called the carotid rete. The ubiquity of the carotid rete throughout the clade, as well as its evolutionary history, is currently uninvestigated. Here, I use osteological correlates to survey clade-wide presence and morphology of the carotid rete, prior to conducting a preliminary evolutionary analysis. Nearly all living artiodactyls possess a carotid rete and are capable of selective brain cooling; however, major arteries supplying the rete are derived from different embryonic aortic arches on a suborder-specific basis. Ancestral character estimation infers this pattern of variation to be the result of independent evolutionary processes, suggesting carotid rete homoplasy arising via parallelism. This is a surprising finding given the role this structure plays in driving a physiology that has been implicated in mitigating artiodactylan responses to extreme environmental conditions. Future studies should incorporate extinct species represented in the fossil record to better parse between parallel and convergent mechanisms, as well as to better understand the relationship between the carotid rete, selective brain cooling, and survivorship of climate perturbation. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc. Anat Rec, 303:308-317, 2020. © 2018 American Association for Anatomy.

A thermoregulation model for whole body cooling hypothermia

This paper presents a thermoregulation model based on the finite element method to perform numerical analyses of brain cooling procedures as a contribution to the investigation on the use of therapeutic hypothermia after ischemia in adults. The use of computational methods can aid clinicians to observe body temperature using different cooling methods without the need of invasive techniques, and can thus be a valuable tool to assist clinical trials simulating different cooling options that can be used for treatment. In this work, we developed a finite element method (FEM) package using isoparametric linear three-dimensional elements which is applied to the solution of the continuum bioheat Pennes equation. Blood temperature changes were considered using a blood pool approach and a lumped analysis for intravascular catheter methods of blood cooling. Some analyses are performed using a three-dimensional mesh based on a complex geometry obtained from computed tomography medical images, considering a cooling blanket and an intravascular catheter. A comparison is made between the results obtained with the two techniques and the effects of each case in brain temperature reduction in a required period of time, maintenance of body temperature at moderate hypothermia levels and gradual rewarming.

Fur Seals Suppress REM Sleep for Very Long Periods without Subsequent Rebound

Virtually all land mammals and birds have two sleep states: slow-wave sleep (SWS) and rapid eye movement (REM) sleep [1, 2]. After deprivation of REM sleep by repeated awakenings, mammals increase REM sleep time [3], supporting the idea that REM sleep is homeostatically regulated. Some evidence suggests that periods of REM sleep deprivation for a week or more cause physiological dysfunction and eventual death [4, 5]. However, separating the effects of REM sleep loss from the stress of repeated awakening is difficult [2, 6]. The northern fur seal (Callorhinus ursinus) is a semiaquatic mammal [7]. It can sleep on land and in seawater. The fur seal is unique in showing both the bilateral SWS seen in most mammals and the asymmetric sleep previously reported in cetaceans [8]. Here we show that when the fur seal stays in seawater, where it spends most of its life [7], it goes without or greatly reduces REM sleep for days or weeks. After this nearly complete elimination of REM, it displays minimal or no REM rebound upon returning to baseline conditions. Our data are consistent with the hypothesis that REM sleep may serve to reverse the reduced brain temperature and metabolism effects of bilateral nonREM sleep, a state that is greatly reduced when the fur seal is in the seawater, rather than REM sleep being directly homeostatically regulated. This can explain the absence of REM sleep in the dolphin and other cetaceans and its increasing proportion as the end of thesleep period approaches in humans and other mammals.

How does blood regulate cerebral temperatures during hypothermia?

Macro-modeling of cerebral blood flow can help determine the impact of thermal intervention during instances of head trauma to mitigate tissue damage. This work presents a bioheat model using a 3D fluid-porous domain coupled with intersecting 1D arterial and venous vessel trees. This combined vascular porous (VaPor) model resolves both cerebral blood flow and energy equations, including heat generated by metabolism, using vasculature extracted from MRI data and is extended using a tree generation algorithm. Counter-current flows are expected to increase thermal transfer within the brain and are enforced using either the vascular structure or flow reversal, represented by a flow reversal constant, CR. These methods exhibit larger average brain cooling (from 0.56 °C ± <0.01 °C to 0.58 °C ± <0.01 °C) compared with previous models (0.39 °C) when scalp temperature is reduced. An greater reduction in core brain temperature is observed (from 0.29 °C ± <0.01 °C to 0.45 °C ± <0.01 °C) compared to previous models (0.11 °C) due to the inclusion of counter-current cooling effects. The VaPor model also predicts that a hypothermic average temperature (<36 °C) can be reached in core regions of neonatal models using scalp cooling alone.

Ice slurry ingestion reduces human brain temperature measured using non-invasive magnetic resonance spectroscopy

We previously reported that ice slurry ingestion reduced forehead skin temperature, thereby potentially reducing brain temperature (Tbrain). Therefore, in the current study, we investigated the effect of ice slurry ingestion on Tbrain using proton magnetic resonance spectroscopy, which is a robust, non-invasive method. Eight male participants ingested 7.5 g/kg of either a thermoneutral drink (37 °C; CON) or ice slurry (−1 °C; ICE) for about 5 min following a 15-min baseline period. Then, participants remained at rest for 30 min. As physiological indices, Tbrain, rectal temperature (Tre), mean skin temperature, nude body mass, and urine specific gravity were measured. Subjective thermal sensation (TS) and thermal comfort (TC) were measured before and after the experiment. Tbrain and Tre significantly reduced after ingestion of ICE compared with after ingestion of CON, and there was a significant correlation between Tbrain and Tre. The other physiological indices were not significantly different between beverage conditions. TS and TC were significantly lower with ICE than with CON (p < 0.05). These results indicate that ice slurry ingestion can cool the brain, as well as the body’s core.

An experimental study and finite element modeling of head and neck cooling for brain hypothermia

Reducing brain temperature by head and neck cooling is likely to be the protective treatment for humans when subjects to sudden cardiac arrest. This study develops the experimental validation model and finite element modeling (FEM) to study the head and neck cooling separately, which can induce therapeutic hypothermia focused on the brain. Anatomically accurate geometries based on CT images of the skull and carotid artery are utilized to find the 3D geometry for FEM to analyze the temperature distributions and 3D-printing to build the physical model for experiment. The results show that FEM predicted and experimentally measured temperatures have good agreement, which can be used to predict the temporal and spatial temperature distributions of the tissue and blood during the head and neck cooling process. Effects of boundary condition, perfusion, blood flow rate, and size of cooling area are studied. For head cooling, the cooling penetration depth is greatly depending on the blood perfusion in the brain. In the normal blood flow condition, the neck internal carotid artery temperature is decreased only by about 0.13°C after 60min of hypothermia. In an ischemic (low blood flow rate) condition, such temperature can be decreased by about 1.0°C. In conclusion, decreasing the blood perfusion and metabolic reduction factor could be more beneficial to cool the core zone. The results also suggest that more SBC researches should be explored, such as the optimization of simulation and experimental models, and to perform the experiment on human subjects.

5-HT1a activation in PO/AH area induces therapeutic hypothermia in a rat model of intracerebral hemorrhage.

Therapeutic hypothermia is widely applied as a neuroprotective measure on intracerebral hemorrhage (ICH). However, several clinical trials regarding physical hypothermia encountered successive failures because of its side-effects in recent years. Increasing evidences indicate that chemical hypothermia that targets hypothalamic 5-HT1a has potential to down-regulate temperature set point without major side-effects. Thus, this study examined the efficacy and safety of 5-HT1a stimulation in PO/AH area for treating ICH rats. First, the relationship between head temperature and clinical outcomes was investigated in ICH patients and rat models, respectively. Second, the expression and distribution of 5-HT1a receptor in PO/AH area was explored by using whole-cell patch and confocal microscopy. In the meantime, the whole-cell patch was subsequently applied to investigate the involvement of 5-HT1a receptors in temperature regulation. Third, we compared the efficacy between traditional PH and 5-HT1a activation-induced hypothermia for ICH rats. Our data showed that more severe perihematomal edema (PHE) and neurological deficits was associated with increased head temperature following ICH. 5-HT1a receptor was located on warm-sensitive neurons in PO/AH area and 8-OH-DPAT (5-HT1a receptor agonist) significantly enhanced the firing rate of warm-sensitive neurons. 8-OH-DPAT treatment provided a steadier reduction in brain temperature without a withdrawal rebound, which also exhibited a superior neuroprotective effect on ICH-induced neurological dysfunction, white matter injury and BBB damage compared with physical hypothermia. These findings suggest that chemical hypothermia targeting 5-HT1a receptor in PO/AH area could act as a novel therapeutic manner against ICH, which may provide a breakthrough for therapeutic hypothermia.

Feasibility of profound hypothermia as part of extracorporeal life support in a pig model

ObjectiveTo investigate the feasibility of a refined aortic flush catheter and pump system to induce emergency preservation and resuscitation before extracorporeal cardiopulmonary resuscitation in a normovolemic cardiac arrest swine model simulating near real size/weight conditions of adults. MethodsIn this feasibility study, 8 female Large White breed pigs weighing 70 to 80 kg underwent ventricular fibrillation cardiac arrest for 15 minutes, followed by 4°C aortic flush (150 mL/kg for the brain; 50 mL/kg for the spine) via a new hardware ensued by resuscitation with extracorporeal cardiopulmonary resuscitation. ResultsBrain temperature was lowered from 39.9°C (interquartile range [IQR] 39.6-40.3) to 24.0°C (IQR 20.8-28.9) in 12 minutes (IQR 11-16) with a median cooling rate of 1.3°C (IQR 0.7-1.6) per minute. A median of 776 mL (IQR 673-840) per minute with a median pump pressure of 1487 mm Hg (IQR 1324-1545) were pumped to the brain. ConclusionsWith the new hardware, we were able to cool the brain within a few minutes in a large pig cardiac arrest model. The exact position; the design, diameter, and length of the flush catheter; and the brain perfusion pressure seem to be critical to effectively reduce brain temperature. Redistribution of peripheral blood could lead to sterile inflammation again and might be avoided.

Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats

Neonatal brain trauma is linked to higher risks of mortality and neurological disability. The use of mild to moderate hypothermia has shown promising potential against brain injuries induced by stroke and traumatic brain injury (TBI) in various experimental models and in clinical trials. Conventional methods of physical cooling, however, are difficult to use in acute treatments and in induction of regulated hypothermia. In addition, general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Our recent investigations demonstrate the potential therapeutic benefits of pharmacologically induced hypothermia (PIH) using the neurotensin receptor (NTR) agonist HPI201 (formerly known as ABS201) in stroke and TBI models of adult rodents. The present investigation explored the brain protective effects of HPI201 in a P14 rat pediatric model of TBI induced by controlled cortical impact. When administered via intraperitoneal (i.p.) injection, HPI201 induced dose-dependent reduction of body and brain temperature. A 6-h hypothermic treatment, providing an overall 2–3°C reduction of brain and body temperature, showed significant effect of attenuating the contusion volume versus TBI controls. Attenuation occurs whether hypothermia is initiated 15min or 2h after TBI. No shivering response was seen in HPI201-treated animals. HPI201 treatment also reduced TUNEL-positive and TUNEL/NeuN-colabeled cells in the contusion area and peri-injury regions. TBI-induced blood–brain barrier damage was attenuated by HPI201 treatment, evaluated using the Evans Blue assay. HPI201 significantly decreased MMP-9 levels and caspase-3 activation, both of which are pro-apototic, while it increased anti-apoptotic Bcl-2 gene expression in the peri-contusion region. In addition, HPI201 prevented the up-regulation of pro-inflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6. In sensorimotor activity assessments, rats in the HPI201 treated group exhibited improved functional recovery after TBI versus controls. These data support that PIH therapy using our NTR agonist is effective in reducing neuronal and BBB damage, attenuating inflammatory response and detrimental cellular signaling, and promoting functional recovery after TBI in the developing brain, supporting its potential for further evaluation towards clinical development.

Extracranial hypothermia during cardiac arrest and cardiopulmonary resuscitation is neuroprotective in vivo.

There is increasing evidence that ischemic brain injury is modulated by peripheral signaling. Peripheral organ ischemia can induce brain inflammation and injury. We therefore hypothesized that brain injury sustained after cardiac arrest (CA) is influenced by peripheral organ ischemia and that peripheral organ protection can reduce brain injury after CA and cardiopulmonary resuscitation (CPR). Male C57Bl/6 mice were subjected to CA/CPR. Brain temperature was maintained at 37.5°C ± 0.0°C in all animals. Body temperature was maintained at 35.1°C ± 0.1°C (normothermia) or 28.8°C ± 1.5°C (extracranial hypothermia [ExHy]) during CA. Body temperature after resuscitation was maintained at 35°C in all animals. Behavioral testing was performed at 1, 3, 5, and 7 days after CA/CPR. Either 3 or 7 days after CA/CPR, blood was analyzed for serum urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, and interleukin-1β; mice were euthanized; and brains were sectioned. CA/CPR caused peripheral organ and brain injury. ExHy animals experienced transient reduction in brain temperature after resuscitation (2.1°C ± 0.5°C for 4 minutes). Surprisingly, ExHy did not change peripheral organ damage. In contrast, hippocampal injury was reduced at 3 days after CA/CPR in ExHy animals (22.4% ± 6.2% vs. 45.7% ± 9.1%, p=0.04, n=15/group). This study has two main findings. Hypothermia limited to CA does not reduce peripheral organ injury. This unexpected finding suggests that after brief ischemia, such as during CA/CPR, signaling or events after reperfusion may be more injurious than those during the ischemic period. Second, peripheral organ hypothermia during CA reduces hippocampal injury independent of peripheral organ protection. While it is possible that this protection is due to subtle differences in brain temperature during early reperfusion, we speculate that additional mechanisms may be involved. Our findings add to the growing understanding of brain-body cross-talk by suggesting that peripheral interventions can protect the brain even if peripheral organ injury is not altered.

Pharyngeal Cooling, Brain Temperature Reduction and a Neglect of History

Pharyngeal Cooling, Brain Temperature Reduction and a Neglect of History