Date Published: July 18, 2017
Publisher: Public Library of Science
Author(s): Hasan B. Alam
Abstract: In a Perspective, Hasan Alam discusses emerging treatment approaches in trauma care.
Partial Text: Since the second half of the 20th century, we have seen revolutionary changes in medicine, and trauma care is no exception. Injuries remain the primary cause of death for Americans under 46 years of age , but the patterns are changing. Today, in massively bleeding patients without head injuries, mortality beyond the first 24 hours is under 10% . Unfortunately, the area in which we have failed to make a difference is the period immediately following the injury, including the prehospital phase. The majority of deaths in this period are due to hemorrhage and/or traumatic brain injury (TBI). Bleeding is the more treatable of these 2 causes of death, which makes it the number 1 cause of preventable deaths. Despite numerous advances in trauma care, a recent multinational trial of more than 20,000 patients  demonstrated that most deaths occur within a few hours of injury, with <2.5% of the injured succumbing to multiple organ failure. Similarly, in combat, 87% of battlefield deaths occur before reaching a medical facility ; nearly a quarter of these injuries are considered potentially survivable, and this category is largely (91%) made up of deaths due to bleeding. Thus, the current goal of early care is to keep patients alive long enough to be evacuated to higher echelons of care for definitive treatment. In the not-too-distant future, trauma care is likely to be very different from the current practice. In addition to early hemorrhage control and damage control resuscitation, we are also likely to see the following: We know that shock can disrupt cellular acetylation homeostasis by altering the balance between the histone deacetylase (HDAC) and histone acetyltransferase (HAT) families of enzymes . Valproic acid (VPA), a commonly used anti-seizure medicine, is a nonselective histone deacetylase inhibitor (HDACI) when given in larger doses (higher than the commonly used anti-seizure dose) and can cause rapid and reversible acetylation of numerous nuclear and cytoplasmic proteins to create an anti-inflammatory and prosurvival phenotype [6,7]. In fact, a single dose of VPA, even in the absence of conventional resuscitation strategies, has been shown to improve survival and mitigate organ damage in models of lethal hemorrhage , poly-trauma [9,10], septic shock , ischemia-reperfusion injury , and TBI . Using a variety of in vitro and in vivo models, we have also identified multiple molecular pathways that are modulated by VPA treatment [6,7]. These findings are potentially clinically relevant, as we have shown that expression profiles of various HDACs in circulating cells are associated with differences in clinical outcomes in trauma patients . Additionally, tissues obtained from trauma patients display decreased acetylation, which can be rapidly normalized (ex vivo) with HDACI treatment . Often, the underlying injuries are reparable, but a patient dies of irreversible shock or severe brain damage. In this setting, strategies to maintain cerebral and cardiac viability long enough to gain control of hemorrhage and restore intravascular volume could be lifesaving. This requires an entirely new approach to the problem, with emphasis on rapid total body preservation, repair of injuries during metabolic arrest, and controlled resuscitation, the process of which has been termed emergency preservation and resuscitation (EPR). Currently, hypothermia is the most effective method for preserving cellular viability during prolonged periods of ischemia . It is clear from canine models that rapid induction of deep/profound hypothermia (<15°C) can improve an otherwise dismal outcome after exsanguinating cardiac arrest [28,29]. Our team has used clinically realistic large-animal models of lethal vascular injuries and soft tissue trauma to demonstrate that profound hypothermia can be induced through an emergency thoracotomy approach for total body protection, with excellent long-term survival and no neurological damage or significant organ dysfunction, and that otherwise lethal vascular injuries, above and below the diaphragm, can be repaired under hypothermic arrest with greater than 75% long-term survival . To save the numerous lives that are lost to hemorrhage and TBI every day, new therapeutic approaches are needed. There is clearly room for improvement. According to the United States Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, about a quarter (27 million in 2013) of all emergency department visits are due to injuries , resulting in 3 million hospitalizations and nearly 193,000 deaths—1 person every 3 minutes . As opposed to cancer, cardiovascular disease, and stroke, injuries disproportionally strike people in the prime of their lives. In fact, 59% of all deaths among people 1–44 years of age in the US are due to injuries, which is a higher proportion than all noncommunicable and infectious diseases combined. In 2013, the total cost of injuries in the US was estimated to be $671 billion [41,42]. Globally, according to the World Health Organization, injuries kill more than 5 million people each year, which is nearly 1.7 times the number of fatalities from malaria, tuberculosis, and HIV combined . Many resource-constrained countries lack established trauma systems resulting in prolonged prehospital times, and the healthcare facilities lack resources that are taken for granted in resource-rich countries (e.g., well-stocked blood banks, intensive care units, advanced radiology, sophisticated monitoring tools). Arguably, easy-to-administer, cost-effective pharmacological interventions are logistically a much more attractive option in these resource-constrained settings, as we have already seen with tranexamic acid in the CRASH-2 trial . Similarly, the battlefield environment is another place where rugged, easy-to-use interventions that can keep an injured person alive long enough to get evacuated to specialized care can save numerous lives. Many such technologies are potentially within our grasp; we just need to be open to change. Source: http://doi.org/10.1371/journal.pmed.1002350