Percutaneous delivery of self-propelling thrombin-containing powder increases survival from noncompressible truncal hemorrhage in a swine model of coagulopathy and hypothermia.

BACKGROUND: Noncompressible truncal hemorrhage (NCTH) remains a leading cause of preventable death on the battlefield. Definitively managing severe NCTH requires surgery within the first hour after injury, which is difficult when evacuating casualties from remote and austere environments. During delays to surgery, hemostatic interventions that are performed prehospital can prevent coagulopathy and hemorrhagic shock and increase the likelihood that casualties survive to receive definitive care. We previously reported that a self-propelling thrombin-containing powder (SPTP) can be delivered percutaneously into the abdomen as a minimally invasive intervention and can self-disperse through pooled blood to deliver the hemostatic agents thrombin and tranexamic acid locally to noncompressible intracavitary wounds. We hypothesized that, in swine with massive NCTH, dilutional coagulopathy, and hypothermia, delivering SPTP could extend survival times. METHODS: Ten swine (n = 5 per group) underwent NCTH from a Grade V liver injury following a midline laparotomy. The laparotomy was closed with sutures afterwards, creating a hemoperitoneum, and animals were managed with crystalloid fluid resuscitation, or crystalloid resuscitation and SPTP. Self-propelling thrombin-containing powder was delivered into the closed abdomen using a CO 2 -powered spray device and a catheter placed into the hemoperitoneum, entering through the upper right quadrant using the Seldinger technique. Survival to 1 and 3 hours was recorded. In an additional animal, hemorrhage was created laparoscopically, and SPTP was imaged in situ within the abdomen to visually track dispersion of the particles. RESULTS: Self-propelling thrombin-containing powder dispersed as far as 35 ± 5.0 cm within the abdomen. It increased survival to 1 and 3 hours (Kaplan-Meier p = 0.007 for both). The median survival time was 61 minutes with SPTP and 31 minutes without ( p = 0.016). CONCLUSION: Self-propelling thrombin-containing powder effectively disperses medications throughout a hemoperitoneum and increases survival in a model of NCTH. It is a promising strategy for nonsurgical management of NCTH, warranting further testing of its safety and efficacy.

Repeated Occupational Exposure to Low-level Blast in the Canadian Armed Forces: Effects on Hearing, Balance, and Ataxia.

INTRODUCTION: Recently, there has been increasing concern about the adverse health effects of long-term occupational exposure to low-level blast in military personnel. Occupational blast exposure occurs routinely in garrison through use of armaments and controlled blast detonations. In the current study, we focused on a population of breaching instructors and range staff. Breaching is a tactical technique that is used to gain entry into closed spaces, often through the use of explosives. MATERIALS AND METHODS: Initial measurements of blast overpressure collected during breaching courses found that up to 10% of the blasts for range staff and up to 32% of the blasts for instructors exceeded the recommended 3 psi exposure limit. Using a cross-sectional design, we used tests of balance, ataxia, and hearing to compare a sample of breachers (n = 19) to age-and sex-matched military controls (n = 19). RESULTS: There were no significant differences between the two groups on the balance and ataxia tests, although the average scores of both groups were lower than would be expected in a normative population. The prevalence of hearing loss was low in the breacher group (4 of 19), and hearing thresholds were not significantly different from the controls. However, the prevalence of self-reported tinnitus was significantly higher in the breacher group (12 of 19) compared with the controls (4 of 19), and all breachers who were identified as having hearing loss also reported tinnitus. CONCLUSIONS: Our results suggest that basic tests of balance, ataxia, and hearing on their own were not sensitive to the effects of long-term occupational exposure to low-level blast. Some of the blast exposure levels exceeded limits, and there was a significant association of exposure with tinnitus. Future studies should supplement with additional information including exposure history and functional hearing assessments. These findings should be considered in the design of future acute and longitudinal studies of low-level blast exposure.

Blast in Context: The Neuropsychological and Neurocognitive Effects of Long-Term Occupational Exposure to Repeated Low-Level Explosives on Canadian Armed Forces' Breaching Instructors and Range Staff.

Currently, there is strong interest within the military to better understand the effects of long-term occupational exposure to repeated low-level blast on health and performance. To gain traction on the chronic sequelae of blast, we focused on breaching-a tactical technique for gaining entry into closed/blocked spaces by placing explosives and maintaining a calculated safe distance from the detonation. Using a cross-sectional design, we compared the neuropsychological and neurocognitive profiles of breaching instructors and range staff to sex- and age-matched Canadian Armed Forces (CAF) controls. Univariate tests demonstrated that breaching was associated with greater post-concussive symptoms (Rivermead Post Concussion Symptoms Questionnaire) and lower levels of energy (RAND SF-36). In addition, breaching instructors and range staff were slower on a test that requires moving and thinking simultaneously (i.e., cognitive-motor integration). Next, using a multivariate approach, we explored the impact of other possible sources of injury, including concussion and prior war-zone deployment on the same outcomes. Concussion history was associated with higher post-concussive scores and musculoskeletal problems, whereas deployment was associated with higher post-concussive scores, but lower energy and greater PTSD symptomatology (using PCL-5). Our results indicate that although breaching, concussion, and deployment were similarly correlated with greater post-concussive symptoms, concussion history appears to be uniquely associated with altered musculoskeletal function, whereas deployment history appears to be uniquely associated with lower energy and risk of PTSD. We argue that the broader injury context must, therefore, be considered when studying the impact of repetitive low-level explosives on health and performance in military members.

A comparison of live tissue training and high-fidelity patient simulator: A pilot study in battlefield trauma training.

BACKGROUND: Trauma procedural and management skills are often learned on live tissue. However, there is increasing pressure to use simulators because their fidelity improves and as ethical concerns increase. We randomized military medical technicians (medics) to training on either simulators or live tissue to learn combat casualty care skills to determine if the choice of modality was associated with differences in skill uptake. METHODS: Twenty medics were randomized to trauma training using either simulators or live tissue. Medics were trained to perform five combat casualty care tasks (surgical airway, needle decompression, tourniquet application, wound packing, and intraosseous line insertion). We measured skill uptake using a structured assessment tool. The medics also completed exit questionnaires and interviews to determine which modality they preferred. RESULTS: We found no difference between groups trained with live tissue versus simulators in how they completed each combat casualty care skill. However, we did find that the modality of assessment affected the assessment score. Finally, we found that medics preferred trauma training on live tissue because of the fidelity of tissue handling in live tissue models. However, they also felt that training on simulators also provided additional training value. CONCLUSION: We found no difference in performance between medics trained on simulators versus live tissue models. Even so, medics preferred live tissue training over simulation. However, more studies are required, and future studies need to address the measurement bias of measuring outcomes in the same model on which the study participants are trained. LEVEL OF EVIDENCE: Therapeutic/care management study, level II.

Role of the sodium hydrogen exchanger in maitotoxin-induced cell death in cultured rat cortical neurons.

Maitotoxin (MTX) is one of the most potent toxins known to date. It causes massive calcium (Ca(2+)) influx and necrotic cell death in various tissues. However, the exact mechanism(s) underlying its cellular toxicity is not fully understood. In the present study, the role of the sodium hydrogen exchanger (NHE) in MTX-induced increases in intracellular Ca(2+) and subsequent cell death were investigated in cultured rat cortical neurons. Intracellular Ca(2+) concentrations ([Ca(2+)](i)) were measured fluorimetrically using FURA-2 as the fluorescence indicator. Cell death was measured with the alamarBlue cell viability assay and the vital dye ethidium bromide (EB) uptake assay. Results showed that MTX increased, in a concentration dependent manner, both [Ca(2+)](i) and cell death in cortical neurons. Decreasing the pH of the treatment medium from 7.5 to 6.0 diminished MTX-induced cell death. The protection offered by lowering extracellular pH was not due to MTX degradation, because it was still effective even if the cells were treated with MTX in normal pH and then switched to a lower pH. Pretreatment of cells with the specific NHE inhibitor, 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), prevented MTX-induced increases in [Ca(2+)](i), as well as cell death in a concentration dependent manner. Furthermore, knockdown of NHE1 by SiRNA transfection suppressed MTX-induced cell death in human embryonic kidney (HEK) cells. Together, these results suggest that NHE1 plays a major role in MTX-induced neurotoxicity.

VX-induced cell death involves activation of caspase-3 in cultured rat cortical neurons.

Exposure of cell cultures to organophosphorous compounds such as VX can result in cell death. However, it is not clear whether VX-induced cell death is necrotic or involves programmed cell death mechanisms. Activation of caspases, a family of cysteine proteases, is often involved in cell death, and in particular, caspase-3 activation appears to be a key event in programmed cell death processes including apoptosis. In this study, we investigated VX-induced neuronal cell death, as well as the underlying mechanism in terms of its effect on caspase-3 activity. Primary cortical neuronal cultures were prepared from gestational days 17 to 19 Sprague Dawley rat fetuses. At maturation, the cells were treated with varying concentrations of VX and cell death was evaluated by lactate dehydrogenase (LDH) release. VX induced an increase in LDH release in a concentration-dependent manner. Morphological VX-induced cell death was also characterized by using nuclear staining with propidium iodide and Hoechst 33342. VX induced a concentration- and time-dependent increase in caspase-3 activation. Caspase-3 activation was also confirmed by the proteolytic cleavage of poly(ADP-ribose)polymerase (PARP), an endogenous caspase-3 substrate. These data suggested that in rat cortical neurons, VX-induced cell death via a programmed cell death pathway that involves changes in caspase-3 protease.

Physiological neuroprotection by melatonin in a 6-hydroxydopamine model of Parkinson's disease.

There is considerable evidence that pharmacological doses of the pineal hormone, melatonin, are neuroprotective in diverse models of neurodegeneration including Parkinson's disease. However, there is limited information about the effects of physiological doses of this hormone in similar models. In this study, rats were chronically treated with melatonin via drinking water following partial 6-hydroxydopamine lesioning in the striatum. The two doses of melatonin (0.4 microg/ml and 4.0 microg/ml) were within the reported physiological concentrations present in the serum and cerebrospinal fluid respectively. At 2 weeks after surgery, the higher dose of melatonin significantly attenuated rotational behavior in hemi-parkinsonian rats compared to similarly lesioned animals receiving either vehicle (P < 0.001) or the lower dose of melatonin (P < 0.01). Animals were perfused or sacrificed 10 weeks after commencing melatonin treatment for immunohistochemical or mRNA studies. Animals treated with 4.0 microg/ml melatonin exhibited normal tyrosine hydroxylase (TH) immunoreactivity in the lesioned striatum, whereas little or no TH immunofluorescence was visible in similarly lesioned animals receiving vehicle. In contrast, semiquantitative RT-PCR analysis revealed no group differences in TH mRNA, suggesting spontaneous recovery of this transcript as observed previously in partially lesioned animals. There were no significant differences in striatal GDNF mRNA levels between sham and lesioned animals. However, there was a significant (P < 0.01) increase in GDNF mRNA expression in the intact contralateral striata of lesioned animals treated with vehicle. Interestingly, melatonin treatment attenuated this novel compensatory contralateral increase in striatal GDNF expression, presumably due to its neuroprotective effect. These findings support a physiological role for melatonin in protecting against parkinsonian neurodegeneration in the nigrostriatal system.