Injury causes a systemic inflammatory response syndrome (SIRS) that is clinically much like sepsis. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors. Similarly, cellular injury can release endogenous 'damage'-associated molecular patterns (DAMPs) that activate innate immunity. Mitochondria are evolutionary endosymbionts that were derived from bacteria and so might bear bacterial molecular motifs. Here we show that injury releases mitochondrial DAMPs (MTDs) into the circulation with functionally important immune consequences. MTDs include formyl peptides and mitochondrial DNA. These activate human polymorphonuclear neutrophils (PMNs) through formyl peptide receptor-1 and Toll-like receptor (TLR) 9, respectively. MTDs promote PMN Ca(2+) flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo. Circulating MTDs can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. The release of such mitochondrial 'enemies within' by cellular injury is a key link between trauma, inflammation and SIRS.

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Circulating mitochondrial DAMPs cause inflammatory responses to injury

BACKGROUND Hospitals have difficulty justifying the expense of maintaining trauma centers without strong evidence of their effectiveness. To address this gap, we examined differences in mortality between level 1 trauma centers and hospitals without a trauma center (non-trauma centers). METHODS Mortality outcomes were compared among patients treated in 18 hospitals with a level 1 trauma center and 51 hospitals non-trauma centers located in 14 states. Patients 18 to 84 years old with a moderate-to-severe injury were eligible. Complete data were obtained for 1104 patients who died in the hospital and 4087 patients who were discharged alive. We used propensity-score weighting to adjust for observable differences between patients treated at trauma centers and those treated at non-trauma centers. RESULTS After adjustment for differences in the case mix, the in-hospital mortality rate was significantly lower at trauma centers than at non-trauma centers (7.6 percent vs. 9.5 percent; relative risk, 0.80; 95 percent confidence interval, 0.66 to 0.98), as was the one-year mortality rate (10.4 percent vs. 13.8 percent; relative risk, 0.75; 95 percent confidence interval, 0.60 to 0.95). The effects of treatment at a trauma center varied according to the severity of injury, with evidence to suggest that differences in mortality rates were primarily confined to patients with more severe injuries. CONCLUSIONS Our findings show that the risk of death is significantly lower when care is provided in a trauma center than in a non-trauma center and argue for continued efforts at regionalization.

https://www.nejm.org/doi/pdf/10.1056/NEJMsa052049

A National Evaluation of the Effect of Trauma-Center Care on Mortality

OBJECTIVE: Recognizing the impact of the 1977 San Francisco study of trauma deaths in trauma care, our purpose was to reassess those findings in a contemporary trauma system. DESIGN: Cross-sectional. MATERIAL AND METHODS: All trauma deaths occurring in Denver City and County during 1992 were reviewed; data were obtained by cross-referencing four databases: paramedic trip reports, trauma registries, coroner autopsy reports and police reports. MEASUREMENTS AND MAIN RESULTS: There were 289 postinjury fatalities; mean age was 36.8 +/- 1.2 years and mean Injury Severity Score (ISS) was 35.7 +/- 1.2. Predominant injury mechanisms were gunshot wounds in 121 (42%), motorvehicle accidents in 75 (38%) and falls in 23 (8%) cases. Seven (2%) individuals sustained lethal burns. Ninety eight (34%) deaths occurred in the pre-hospital setting. The remaining 191 (66%) patients were transported to the hospital. Of these, 154 (81%) died in the first 48 hours (acute), 11 (6%) within three to seven days (early) and 26 (14%) after seven days (late). Central nervous system injuries were the most frequent cause of death (42%), followed by exsanguination (39%) and organ failure (7%). While acute and early deaths were mostly due to the first two causes, organ failure was the most common cause of late death (61%). CONCLUSIONS: In comparison with the previous report, we observed similar injury mechanisms, demographics and causes of death. However, in our experience, there was an improved access to the medical system, greater proportion of late deaths due to brain injury and lack of the classic trimodal distribution.

Epidemiology of trauma deaths: a reassessment

Importance Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. Objective To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. Design, Setting, and Participants Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. Interventions Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). Main Outcomes and Measures Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. Results No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, −4.2% [95% CI, −9.6% to 1.1%]; P  = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, −3.7% [95% CI, −10.2% to 2.7%]; P  = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, −5.4% [95% CI, −10.4% to −0.5%]; P  = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P  = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P P Conclusions and Relevance Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. Trial Registration clinicaltrials.gov Identifier:NCT01545232

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Transfusion of plasma, platelets, and red blood cells in a 1: 1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: The PROPPR randomized clinical trial

Background:Traumatic coagulopathy is thought to be caused primarily by fluid administration and hypothermia.Methods:A retrospective study was performed to determine whether coagulopathy resulting from the injury itself is a clinically important entity in severely injured patients.Results:One thousan

Acute traumatic coagulopathy.

A method for comparing death rates of groups of injured persons was developed, using hospital and medical examiner data for more than two thousand persons. The first step was determination of the extent to which injury severity as rated by the Abbreviated Injury Scale correlates with patient survival. Substantial correlation was demonstrated. Controlling for severity of the primary injury made it possible to measure the effect on mortality of additional injuries. Injuries that in themselves would not normally be life-threatening were shown to have a marked effect on mortality when they occurred in combination with other injuries. An Injury Severity Score was developed that correlates well with survival and provides a numerical description of the overall severity of injury for patients with multiple trauma. Results of this investigation indicate that the Injury Severity Score represents an important step in solving the problem of summarizing injury severity, especially in patients with multiple trauma.

The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care

The problem of human injury has been misunderstood and neglectedfor too long. Although scientific approaches have been applied to the problem of human damage from traditionally recognized environmental hazards-such as lead and pathogenic organisms-analogous approaches for controlling injuries have been largely ignored. This paper describes the etiologic agents of injuries and methods of preventing or reducing their harmful effects on man. Effective strategies for reducing human losses due to injuries go far beyond traditional concepts of "accident prevention ": even when "accidents" cannot be prevented, there are many ways to prevent or reduce the frequency and severity of injuries and their sequelae. Important considerations in choosing injury countermeasures include effectiveness, economic constraints, and reduction of the amount of individual cooperation that is necessary. As infectious diseases gradually yield to scientific approaches, injuries assume increasing importance as a major health problem. In many countries, injuries are now the leading cause of death from early childhood through most of the fourth decade of life. Among the very young and the aged, injury deaths are primarily due to non-motor-vehicle accidents such as falls and fires. During the most productive years of life, and in many countries during childhood as well, motor-vehicle fatalities comprise the largest category of injury deaths. Increases in the number and use of motor vehicles have been accompanied by dramatic increases in the number of deaths and injuries, especially among teen-agers and young adults (Aldman and Thorson, 1971). Despite its magnitude, the problem of injury has been the subject of more folklore and less competent scientific attention than has any other serious problem in medicine. Most of the folklore has been associated with the word "accident," with its connotations of fate, chance, and unexpectedness. However, the notion of "fate" is inappropriate, because injuries can be prevented or reduced in their severity; they are not "chance" or random events but the predictable results of specific combinations of human and environmental factors; and they are no more "unexpected" than most diseases.

William Haddon

Papers

The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care

Reducing Injuries and Their Results: The Scientific Approach