Combat & Casualty Care

Q2 2016

Military Magazines in the United States and Canada, Covering Combat and Casualty Care, first responders, rescue and medical products programs and news\Tactical Defense Media

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Page 9 of 39 8 | Combat & Casualty Care | Summer 2016 and twofold higher plasma fibrinogen. Right heart enlargement (failure) in controls after 4 hours was particularly interesting but did not occur in ALM-treated animals. Clinically, it has recently been reported that neurogenic cardiac and pulmonary dysfunction is often under-diagnosed in head injury patients, and our data may have clinical and military significance. Further mechanistic studies and post-injury cognition tests are required in larger clinically relevant models. In our third model of combined mTBI and internal hemorrhage, ALM therapy resulted in 50% survivability and 50% less internal blood loss compared to 100% mortality in 3% NaCl controls. Death was associated with progressive shock and cardiovascular collapse. Untreated animals and controls also developed a profound hypocoagulopathy, which was corrected in ALM-treated animals. The ongoing challenge in this area has been to design a therapy that does not raise the blood pressure too high and the casualty dies from "popping-the-clot", or too low, causing the brain and body to become starved of oxygen. Our early data show that we have partially succeeded in helping the body to help itself in this model. As with non-compressible blood loss alone (Model 1) ALM therapy reduced blood loss in animals that survived (or died) by 50% compared to controls. Whole Body Protection: A Systems-based Approach to Hemorrhage and TBI The multiple benefits from the ALM fluid therapy appear to arise from the drug's ability to improve CNS-Cardiovascular Endothelium coupling which assists to correct coagulopathy, reduce inflammation and maintain adequate tissue oxygenation. The therapy appears to achieve a more natural homeostatic, restorative steady-state without depleting the body's energy reserves. The advantage of using ultra small-volumes cannot be overstated, since many fluid therapies shock the body a second time, rather than being therapeutic and protective. There is the further complication that some casualties in shock do not respond to current saline or colloidal fluid-based therapies with an increase in stroke volume to improve blood supply to the tissues. This problem of knowing who will or will not be a "responder" is challenging, and does not appear to have been adequately addressed in civilian or military combat medicine. From the above USSOCOM funded study, the total ALM volume administered over the entire 3-4 hours was about 1.0 ml or < 5% of the animal's normal total blood volume despite liver resection. In human terms this volume would be equivalent to ~150 ml for a 70kg human over 4 hours. The logistical advantage of small cube- weight cannot be overemphasized for military use in remote, austere environments or during evacuation to definitive care. Timing is Everything Most, if not all, combat medics or trauma surgeons would agree that the best survival outcomes occur when retrieval times from point- of-injury to definitive care are short as possible, which led R Adams Cowley to propose the "golden hour" concept in the 1960s. Time, however, is a curious concept. As St. Augustine wrote in the 5th century and paraphrased here: "Everyone knows what time is until someone asks you the question". Biological time is more complex. A small mammal, for example, can go through 50 generations, as a single elephant grows old. Hibernators or summer estivators can drop off the 'standard' Kleiber line of metabolic rate and body mass, and drop their metabolic rate by over 90%, then return to the 'line' when conditions are more favorable. Humans, like all non- hibernating mammals, are believed to possess the 'hibernating' genes but to date they remain hidden deep in our genome. Trying to pharmacologically extend physiological or biological time relative to clock time with new therapies has proven to be extremely challenging. Translation to the Field: Where the Action Is! An ongoing challenge is selecting the right animal model to test new drugs. The mouse model is problematic for severe trauma studies because under stress it can enter torpor (overnight hibernation), and therefore may not be directly applicable to humans. The rat, guinea-pig, rabbit, dog and pig cannot enter torpor during stress, and may be better models for translation. Selecting the right model is further complicated by the graveyard of clinical studies trialing new drugs that previously have shown promising results. In the USA alone, less than 10% of drugs entering clinical trials become an approved drug. Possible reasons for failure to translate appear to relate to: 1) the heterogeneity of the human condition compared to animal models; individuals may have different responses to the same trauma stressor, 2) regulatory hurdles, and 3) poor trial design and 4) ongoing difficulty of trial design in the real-world environment. For example, thirty-day mortality for a particular drug trial may be a meaningless end-point when death from a catastrophic injury occurs in minutes to hours. Furthermore, a drug may buy biological time and prevent death early, but the patient dies from unrelated secondary 'hit' complications within the 30-day period. Another possible reason for lack of translation is that many new drugs target downstream single nodal steps or pathways "after the horse has bolted". Reductionism is important in breaking a system into its constituent parts, however, focusing a drug therapy on a single nodal target 'downstream' does not do away with the system. The current practice of identifying, documenting and treating a single perturbation during or following an operation, and then the next defect, and so on down the line, may result in what the famous U.S. surgeon William C. Shoemaker termed "an uncoordinated and sometimes contradictory therapeutic outcome". It is our view that near-term drug breakthroughs are more likely to originate from 'upstream' systems-based approaches, rather than 'downstream' single-nodal targets. The ALM therapy, for example, has a number of advantages for possible translation and field adoption: • The drug combination is currently used at higher concentrations in cardiac surgery, and is safe, • Administration time is short (up to 4 hours) • Volumes are low removing the need for untoward aggressive fluid therapy • Logistics advantages in forward, resource limited-environments where resupply is problematic. To help with translation into the field, we have recently teamed up with trauma surgeons of the Expeditionary and Trauma Medicine Department, Combat Casualty Care and Operational Medicine, Naval Medical Research Unit, San Antonio, (NAMRU-SA), and Level 1 trauma team at the Department of Surgery headquartered at Denver Health Medical Center, Colorado. Only time will tell if small volume ALM therapy has raised the bar high enough to translate into military (and civilian) medicine with improved outcomes. Prolonged Field Care Hemorrhage and TBI

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