Trauma and Hemorrhagic Shock (T-HS) in the Battlefield

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Timothy Billiar, MD

University of Pittsburgh

Traumatic injury is the leading cause of morbidity and mortality for individuals under age 44 in the United States, with associated societal costs that exceed US$469 billion annually and resulting in approximately 150,000 deaths per year (data from the US National Safety Council). Indeed, according to the best available data, trauma will equal or surpass communicable disease in the year 2020 as the number one cause of disability-adjusted-life-years worldwide. Trauma is also a major cause of morbidity and mortality for the armed forces, especially in recent situations such as Operation Enduring Freedom in Iraq.The prevention and treatment of injury-induced organ dysfunction is therefore both a military and civilian priority.

Massive bleeding is the major cause of out-of-hospital deaths occurring early after injury. In a study by Acosta et al., deaths occurring during the first 24 hours after admission accounted for 70% (631 of 900) of all deaths. Of all these patients, 35% (222 of 631) died due to uncontrolled hemorrhage within the first 15 minutes after arrival to a level I emergency facility. Likewise, the distribution of battlefield injuries in the Vietnam War showed that 25 percent of the deaths occurred as a result of uncontrolled blood loss and were not salvageable. An additional 19 percent of deaths were deemed salvageable and these were the result of torso (10%) and peripheral blood loss (19%) respectively. As evidenced recently in the Iraq campaign, the fighting of the future is likely to involve terrorists and guerrilla interdictions, and will be fought by small groups of combatants over shorter time periods with smaller numbers of casualties at any point in time. However, because of the likely locations of these conflicts, evacuation by air may be difficult or impossible as it occurred in Somalia in 1993. As a result, immediate and even ongoing treatment of casualties may be significantly extended.

Initial survivors of acute trauma-hemorrhagic shock (T-HS) pose a tremendous challenge to physicians. They are particularly susceptible to developing an acute inflammatory response that is thought to trigger a syndrome characterized by sequential and gradual loss of organ function (multiple organ dysfunction syndrome, or MODS). MODS is the most common complication after injury, accounting for substantial morbidity and mortality. Shock-induced reduced splanchnic blood flow is considered an important etiological factor in the development of organ dysfunction and the splanchnic bed is capable of producing large amounts of cytokines in response to shock 10;13. In general, MODS is thought to be caused, at least partially, by excessive or maladaptive activation of inflammatory pathways. Due to generalized dysregulation of homeostatic mechanisms, trauma patients often become susceptible to infection (the so-called “second hit”), which further complicates attempts at immune-modulation in the early clinical course. Recently, a study has shown that ileal mucosal expression of ZO-1, a tight junction protein, is decreased and the intestinal barrier function is altered after T-HS, a phenomenon possibly regulated by the inflammatory cytokine Interleukin (IL)-6. Additionally, we have shown that HS induces profound physiological changes in liver, resulting in the activation of important inflammatory cascades accompanied by acute organ damage. The inducible nitric oxide synthase (iNOS) and IL-6 are expressed in the gut and liver, and seem to be important mediators of inflammation and organ damage in shock.

Despite remarkable strides made towards understanding the pathophysiology of the host’s acute inflammatory response to T-HS, our knowledge is still rudimentary. Until recently, questions regarding acute inflammation and MODS have been approached mainly by studying the function(s) of individual gene and gene products, one or a few at time. This mechanism-driven, reductionist approach has identified some key pathways, mediators, and events of the acute inflammatory response; in so doing, these studies have shown that these elements are time-driven, highly interconnected (sometimes simultaneous) and evidently nonlinear. Furthermore, there is potential for considerable redundancy and variability, which is characteristic of all complex systems. As such, it should not be surprising that reductionist approaches have overwhelmingly failed when subjected to the ultimate test: the randomized, double-blinded, placebo-controlled clinical trials using mediator-targeted therapies.

We believe that the failure of such clinical trials doesn’t relate only to study design problems; rather, because the acute inflammatory response to T-HS behaves as a complex nonlinear system, the current Newtonian [reductionist] assumptions underlying it may be inaccurate. Because the majority of gene products function together with other gene products, biological processes must be explored as complex networks of interconnected components. Therefore, the need to pursue a complementary, more complex level of understanding of the host’s response to injury has become inevitable. By employing high-throughput technologies, “System Biology” has emerged as a new paradigm that allows the study of large portions of physiological networks simultaneously. In this context, DNA microarray analysis has been initiated by several groups, including ours, in an attempt to address acute inflammation and organ injury. This new approach allows the analysis of complex, large scale data sets and hopefully, might provide a more complete picture of the host’s response to trauma, shock and infection.