Translational barriers and opportunities for emergency preservation and resuscitation in severe injuries

Alam, Hasan B.

doi:10.1002/bjs.7756

Cited by 17 publications

(8 citation statements)

References 95 publications

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“…(8) A recent case series has shown that induced hypothermia protocols may be used after traumatic cardiac arrest with positive outcomes. (9) Several laboratory studies have sought to clarify the role of hypothermia during resuscitation from hemorrhagic shock and trauma.…”

Section: Introductionmentioning

confidence: 99%

Induced Hypothermia During Resuscitation From Hemorrhagic Shock Attenuates Microvascular Inflammation in the Rat Mesenteric Microcirculation

Coyan¹,

Moncure²,

Thomas³

et al. 2014

Shock

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Introduction Microvascular inflammation occurs during resuscitation following hemorrhagic shock, causing multiple organ dysfunction and mortality. Pre-clinical evidence suggests that hypothermia may have some benefit in selected patients by decreasing this inflammation, but this effect has not been extensively studied. Methods Intravital microscopy was used to visualize mesenteric venules of anesthetized rats in real time to evaluate leukocyte adherence and mast cell degranulation. Animals were randomly allocated to normotensive or hypotensive groups, and further subdivided into hypothermic and normothermic resuscitation (N=6 per group). Animals in the shock groups underwent mean arterial blood pressure reduction to 40-45 mmHg for 1 hour via blood withdrawal. During the first two hours following resuscitation by infusion of shed blood plus double that volume of normal saline, rectal temperature of the hypothermic groups were maintained at 32-34°C, while the normothermic groups were maintained between 36-38°C. The hypothermic group was then rewarmed for the final two hours of resuscitation. Results Leukocyte adherence was significantly lower after 2 hours of hypothermic resuscitation compared with normothermic resuscitation: (2.8±0.8 vs 8.3±1.3 adherent leukocytes, p=0.004). Following rewarming, leukocyte adherence remained significantly different between hypothermic and normothermic shock groups: (4.7±1.2 vs 9.5±1.6 adherent leukocytes, p=0.038). Mast cell degranulation index (MDI) was significantly decreased in the hypothermic (1.02±0.04 MDI) vs normothermic (1.22±0.07 MDI) shock groups (p=0.038) after the experiment. Conclusions Induced hypothermia during resuscitation following hemorrhagic shock attenuates microvascular inflammation in rat mesentery. Furthermore, this decrease in inflammation is carried over after rewarming takes place.

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Section: Introductionmentioning

confidence: 99%

Induced Hypothermia During Resuscitation From Hemorrhagic Shock Attenuates Microvascular Inflammation in the Rat Mesenteric Microcirculation

Coyan¹,

Moncure²,

Thomas³

et al. 2014

Shock

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“…These include the need to decrease the core body temperature to <15°C, requirement for cardiopulmonary bypass, the very short window of time available for complex instrumentation, the need for effective heat-exchange technology or large volume of cold fluids, and the adverse effect of hypothermia on coagulopathy. 10 These limitations are especially problematic in the austere prehospital environment, where most of trauma-related deaths occur.…”

mentioning

confidence: 99%

Development of a novel neuroprotective strategy: Combined treatment with hypothermia and valproic acid improves survival in hypoxic hippocampal cells

Jin

Liu

You

et al. 2014

Surgery

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Background Therapeutic hypothermia and histone deacetylase inhibitors, such as valproic acid (VPA), independently have been shown to have neuroprotective properties in models of cerebral ischemic and traumatic brain injury. However, the depth of hypothermia and the dose of VPA needed to achieve the desired result are logistically challenging. It remains unknown whether these two promising strategies can be combined to yield synergistic results. We designed an experiment to answer this question by subjecting hippocampal-derived HT22 cells to severe hypoxia in vitro. Methods Mouse hippocampal HT22 cells were exposed to 200 µM cobalt chloride (CoCl2), which created hypoxic conditions in vitro. Cells were incubated for 6 or 30 hours under the following conditions: (1) Dulbecco’s Modified Eagle Medium; (2) 200 µM CoCl2; (3) 200 µM CoCl2 plus 1 mmol/L VPA; (4) 200 µM CoCl2 plus 32°C hypothermia; and (5) 200 µM CoCl2 plus both 1 mmol/L VPA and 32°C hypothermia. Cellular viability was evaluated by (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) and lactate dehydrogenase release assays at 30 hours after treatment. Levels of acetylated histone H3, hypoxia-inducible factor-1α, phospho-GSK-3β, β-catenin, and high-mobility group box-1 were measured by Western blotting. Results High levels of acetylated histone H3 were detected in the VPA-treated cells. The release of lactate dehydrogenase was greatly suppressed after the combined hypothermia + VPA treatment (0.269 ± 0.003) versus VPA (0.836 ± 0.026) or hypothermia (0.451 ± 0.005) treatments alone (n = 3, P = .0001). (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay showed that the number of viable cells was increased by 17.6%when VPA and hypothermia were used in combination (n = 5, P = .0001). Hypoxia-inducible factor-1α and phospho-GSK-3β expression were synergistically affected by the combination treatment, whereas high-mobility group box-1 was increased by VPA treatment, and inhibited by the hypothermia. Conclusion This is the first study to demonstrate that the neuroprotective effects of VPA and hypothermia are synergistic. This novel approach can be used to develop more effective therapies for the prevention of neuronal death.

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“…Induction of profound hypothermia (core temperature 10–15°C) requires specialized instrumentation and is therefore technically very challenging (23). Profound hypothermia may also produce adverse side effects that are proportional to the depth of hypothermia, such as inducing coagulopathy and impairing the immune response.…”

Section: Discussionmentioning

confidence: 99%

Hypothermia and valproic acid activate prosurvival pathways after hemorrhage

Bambakidis

Dekker

Liu

et al. 2015

Journal of Surgical Research

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Background Therapeutic hypothermia (Hypo) and valproic acid (VPA, a histone deacetylase inhibitor) have independently been shown to be protective in models of trauma and hemorrhagic shock (HS), but require logistically challenging doses to be effective. Theoretically, combined treatment may further enhance effectiveness, allowing us to use lower doses of each modality. The aim of this study was to determine whether a combination of mild hypothermia and VPA treatments would offer better cytoprotection compared to individual treatments in a hemorrhage model. Materials and methods Male Sprague-Dawley rats were subjected to 40% volume-controlled hemorrhage, kept in shock for 30 minutes, and assigned to one of the following treatment groups: normothermia (36–37°C), Hypo (30±2°C), normothermia+VPA (300mg/kg), and Hypo+VPA (n=5/group). After three hours of observation, the animals were sacrificed, liver tissue was harvested and subjected to whole cell lysis, and levels of key proteins in the pro-survival Akt pathway were measured using Western Blot. Results Activation of the pro-apoptotic protein cleaved-caspase-3 was significantly lower in the combined treatment group relative to normothermia (P<0.05). Levels of the pro-survival Bcl-2 was significantly higher in the combined treatment group relative to sham, normothermia, and normothermia+VPA groups (P<0.005). The downstream pro-survival protein phospho-GSK-3β was significantly higher in the sham, Hypo, and combined treatment groups compared to normothermia groups with or without VPA (P<0.05). Levels of the pro-survival β-catenin were significantly higher in the combined treatment group relative to normothermia (P<0.01). Conclusions This is the first in-vivo study to demonstrate that combined treatment with VPA and hypothermia offers better cytoprotection than these treatments given independently.

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Translational barriers and opportunities for emergency preservation and resuscitation in severe injuries

Cited by 17 publications

References 95 publications

Induced Hypothermia During Resuscitation From Hemorrhagic Shock Attenuates Microvascular Inflammation in the Rat Mesenteric Microcirculation

Induced Hypothermia During Resuscitation From Hemorrhagic Shock Attenuates Microvascular Inflammation in the Rat Mesenteric Microcirculation

Development of a novel neuroprotective strategy: Combined treatment with hypothermia and valproic acid improves survival in hypoxic hippocampal cells

Hypothermia and valproic acid activate prosurvival pathways after hemorrhage

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