The recognition and management of life-threatening hemorrhage in the polytrauma patient poses several challenges to prehospital rescue personnel and hospital providers. First, identification of acute blood loss and the magnitude of lost volume after torso injury may not be readily apparent in the field. Because of the expression of highly effective physiological mechanisms that compensate for a sudden decrease in circulatory volume, a polytrauma patient with a significant blood loss may appear normal during examination by first responders. Consequently, for every polytrauma victim with a significant mechanism of injury we assume substantial blood loss has occurred and life-threatening hemorrhage is progressing until we can prove the contrary. Second, a decision to begin damage control resuscitation (DCR), a costly, highly complex, and potentially dangerous intervention must often be reached with little time and without sufficient clinical information about the intended recipient. Whether to begin DCR in the prehospital phase remains controversial. Furthermore, DCR executed imperfectly has the potential to worsen serious derangements including acidosis, coagulopathy, and profound homeostatic imbalances that DCR is designed to correct. Additionally, transfusion of large amounts of homologous blood during DCR potentially disrupts immune and inflammatory systems, which may induce severe systemic autoinflammatory disease in the aftermath of DCR. Third, controversy remains over the composition of components that are transfused during DCR. For practical reasons, unmatched liquid plasma or freeze-dried plasma is transfused now more commonly than ABO-matched fresh frozen plasma. Low-titer type O whole blood may prove safer than red cell components, although maintaining an inventory of whole blood for possible massive transfusion during DCR creates significant challenges for blood banks. Lastly, as the primary principle of management of life-threatening hemorrhage is surgical or angiographic control of bleeding, DCR must not eclipse these definitive interventions.

From clinical and laboratory studies of specific coagulation defects induced by injury, damage control resuscitation (DCR) emerged as the most effective management strategy for hemorrhagic shock. DCR of the trauma patient who has sustained massive blood loss consists of 1) hemorrhage control; 2) permissive hypotension; and 3) the prevention and correction of trauma-induced coagulopathies, referred to collectively here as acute coagulopathy of trauma (ACOT). Trauma patients with ACOT have higher transfusion requirements, may eventually require massive transfusion, and are at higher risk of exsanguinating. Distinct impairments in the hemostatic system associated with trauma include acquired quantitative and qualitative platelet defects, hypocoagulable and hypercoagulable states, and dysregulation of the fibrinolytic system giving rise to hyperfibrinolysis or a phenomenon referred to as fibrinolytic shutdown. Furthermore, ACOT is a component of a systemic host defense dysregulation syndrome that bears several phenotypic features comparable with other acute systemic physiological insults such as sepsis, myocardial infarction, and postcardiac arrest syndrome. Progress in the science of resuscitation has been continuing at an accelerated rate, and clinicians who manage catastrophic blood loss may be incompletely informed of important advances that pertain to DCR. Therefore, we review recent findings that further characterize the pathophysiology of ACOT and describe the application of this new information to optimization of resuscitation strategies for the patient in hemorrhagic shock.

INTRODUCTION: The coagulopathy of trauma, illustrated by a short R-time, is common and well understood. The physiology behind this may be early thrombin burst with rapid clot formation. Rapid consumption of fibrinogen, however, may result in weak clot and substrate depletion, resulting in low MA. While these characteristics are interesting, utilizing thromboelastography (TEG) to identify those at risk of subsequent bleeding diathesis, especially in those who do not demonstrate early signs of physiologic derangement, is challenging. We have developed a novel ratio utilizing TEG values to describe patients at specific risk of traumatic coagulopathy. The purpose of this study was to create a single TEG value, which would reflect both the hypercoagulability and hypocoagulability of TIC. We hypothesized that this ratio, at admission, would be indicative of TIC and predictive of both blood product transfusion volumes and subsequent mortality. METHODS: Patients admitted via the highest activation criteria at one of two Level I trauma centers were included if they received at least 1 unit of packed red blood cells in the first 24 hours of admission. The admission TEG was collected, and a ratio was calculated by dividing the MA by the R-time (MA-R). MA-R quartiles were developed, and multivariable logistic regression was utilized to determine odds of mortality. RESULTS: Three hundred thirty patients with admission TEG were included. In all patients, median age was 35 years (interquartile range, 25-54 years), Injury Severity Score (ISS) was 20 (interquartile range, 13-29), 76% were male, and 43% had penetrating trauma. The MA-R groups were based on quartiles. Multivariable analysis, controlling for mechanism of injury, ISS, and admission pH, showed that increasing ratios were associated with decreased odds of death. The lowest MA-R ratios were also significantly associated with higher ISS, higher rates of blunt injury, and higher plasma utilization without a significant difference in packed red blood cell administration. CONCLUSIONS: Patients with the lowest MA-R ratios demonstrated the highest mortality rates. This novel ratio may prove highly useful to predict at-risk patients early, when other physiologic indicators are absent. The mechanism driving this finding may rest in fibrinogen depletion, resulting in weak clot. Patients with low MA-R ratiosmay benefit from earlier resuscitation with cryoprecipitate, rather than the traditional use of plasma found in current massive transfusion protocols. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

BACKGROUND Early assessment of clot function identifies coagulopathies after injury. Abnormalities include a hypercoagulable state from excess thrombin generation, as well as an acquired coagulopathy. Efforts to address coagulopathy have resulted in earlier, aggressive use of plasma emphasizing 1:1 resuscitation. The purpose of this study was to describe coagulopathies in varying hemorrhagic profiles from a cohort of injured patients.METHODS All injured patients who received at least one unit of packed red blood cells (PRBC) in the first 24 hours of admission from September 2013 to May 2015 were eligible for inclusion. Group-Based Trajectory Modeling, using volume of transfusion over time, was used to identify specific hemorrhagic phenotypes. The thromboelastography profile of each subgroup was characterized and group features were compared.RESULTS Four hemorrhagic profiles were identified among 330 patientsminimal (MIN, group 1); patients with large PRBC requirements later in the hospital course (LH, group 2); massive PRBC usage (MH, group 3), and PRBC transfusion limited to shortly after injury (EH, group 4). All groups had an R-time shorter than the normal range (3.2-3.5, p = NS). Patients in group 3 had longer K-times (1.8 vs. 1.2-1.3, p < 0.05), significantly flatter -angles (66.7 vs. 70.4-72.8, p < 0.05), and significantly weaker clot strength (MA 54.6 vs. 62.3-63.6, p < 0.05). Group 3 had greater physiologic derangements at admission and worse overall outcomes.CONCLUSION Hemorrhagic profiles suggest a rapid onset of clot formation in all subgroups but significantly suppressed thrombin burst and diminished clot strength in the most injured. Patients are both hypercoagulable, with early and precipitous clot formation, and also have a demonstrable hypocoagulability. The exact cause of traumatic hypocoagulability is likely multifactorial. Goal-directed resuscitation, as early as institution of the massive transfusion protocol, may be more effective in resuscitating the most coagulopathic patients.LEVEL OF EVIDENCE Prognostic study, level III.

The recognition and management of massive blood loss as a consequence of severe facial trauma or as a complication of complex oral and maxillofacial procedures pose formidable challenges. A patient who has lost substantial amounts of blood may still present in a deceptive clinical state that suggests stability, although oxygen delivery to tissue is severely compromised. Furthermore, hemorrhagic shock may be compounded by specific hemostatic disorders induced by trauma and several extreme homeostatic imbalances that often appear during resuscitation. We review salient clinical features of these hemorrhage-induced processes and describe recent advances in damage control resuscitation for management of them.

Frantz, Travis L. MS; Steenburg, Scott D. MD; Gaski, Greg E. MD; Pohlman, Timothy H. MD, FACS; McKinley, Todd O. MD; Reed, Robert L. MD Author Information

Myocardial ischaemia remains a significant cause of morbidity and mortality due both to the initial ischaemic insult and also to subsequent reperfusion injury. Inflammatory mediators contribute to this phenomenon by a humoral cascade directly affecting myocytes, as well as by a cellular cascade activating the interactions between neutrophils, endothelial cells and myocytes. Investigation of these cellular interactions reveals a complex process of adhesion molecule expression with subsequent recruitment and activation of neutrophils to the site of ischaemia-induced inflammation. Understanding of mechanisms of cellular activation and interaction is advancing rapidly, and its applications are being recognised to have significant clinical potential. Although therapeutic interventions directed against the ischaemia/reperfusion phenomenon have traditionally involved modification of the insult, future therapeutics may more effectively target adhesion molecule expression or availability, thus modifying the creation of the injury.

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal

Background— Protease-activated receptor-1 (PAR-1) is the high-affinity receptor for the coagulation protease thrombin. It is expressed by a variety of cell types in the heart, including cardiomyocytes and cardiac fibroblasts. We have shown that tissue factor (TF) and thrombin contribute to infarct size after cardiac ischemia-reperfusion (I/R) injury. Moreover, in vitro studies have shown that PAR-1 signaling induces hypertrophy of cardiomyocytes and proliferation of cardiac fibroblasts. The purpose of the present study was to investigate the role of PAR-1 in infarction, cardiac remodeling, and hypertrophy after I/R injury. In addition, we analyzed the effect of overexpression of PAR-1 on cardiomyocytes. Methods and Results— We found that PAR-1 deficiency reduced dilation of the left ventricle and reduced impairment of left ventricular function 2 weeks after I/R injury. Activation of ERK1/2 was increased in injured PAR-1 −/− mice compared with wild-type mice; however, PAR-1 deficiency did not affect infarct size. Cardiomyocyte-specific overexpression of PAR-1 in mice induced eccentric hypertrophy (increased left ventricular dimension and normal left ventricular wall thickness) and dilated cardiomyopathy. Deletion of the TF gene in cardiomyocytes reduced the eccentric hypertrophy in mice overexpressing PAR-1. Conclusions— Our results demonstrate that PAR-1 contributes to cardiac remodeling and hypertrophy. Moreover, overexpression of PAR-1 on cardiomyocytes induced eccentric hypertrophy. Inhibition of PAR-1 after myocardial infarction may represent a novel therapy to reduce hypertrophy and heart failure in humans.

BACKGROUND:We have previously reported that nuclear factor (NF)-kappaB activation and inflammatory cytokine expression were involved in the development of lung ischemia-reperfusion injury (LIRI). Because Toll-like receptor 4 (TLR4) activates NF-kappaB-dependent transcription of inflammatory cytokine genes during myocardial ischemia-reperfusion injury, we examined whether absence of TLR4 in TLR4-deficient mice protects against LIRI. METHODS:Left lungs of wild-type (C57BL/6J) mice or TLR4-null (TLR4-/-) mice were made ischemic for 60 minutes and then reperfused for 180 minutes. Response to injury was quantified by tissue myeloperoxidase activity, vascular permeability ([125I]-bovine serum albumin extravasation), and leukocyte and inflammatory mediator accumulation in bronchoalveolar lavage expression. Lung homogenates were also analyzed for activation of mitogen-activated protein kinases and nuclear translocation of the transcription factors NF-kappaB and activator protein-1. RESULTS:After LIRI, lungs from TLR4-/- mice demonstrated a 52.4% reduction in vascular permeability (p = 0.001), a 52.6% reduction in lung myeloperoxidase activity (p = 0.006), and a marked reduction in bronchoalveolar lavage leukocyte accumulation when compared with lungs from wild-type mice. The TLR4-/- mice lungs, subjected to LIRI, also demonstrated marked reductions in amounts of several proinflammatory cytokines/chemokines in bronchoalveolar lavage samples. Phosphorylation of c-Jun NH2-terminal kinase, and activation of NF-kappaB and activator protein-1 were also significantly reduced in homogenates of lungs from TLR4-/- mice injured by ischemia and reperfusion (p < 0.05). CONCLUSIONS:These data suggest that TLR4 plays a role in LIRI. Thus, TLR4 may be a potential therapeutic target to minimize ischemic-reperfusion-induced tissue damage and organ dysfunction.

Background: State-legislated trauma systems have been enacted in an attempt to improve trauma care. Blunt splenic injury incidence without a legislated trauma system was examined for changes in care with a hypothesis that a voluntary system may perform equally with a legislated system.Methods: Data from a statewide discharge database for the years 1993 to 2002 were examined.Results: There were 276,425 trauma admissions overall, with blunt splenic injury occurring in 1.76%. Average Injury Severity Score (ISS) increased in trauma centers and decreased in the community. Trauma centers (TC) had more multisystem injuries. Spenic injury diagnosis increased 44% in TC between the early and late periods but only 7% in community facilities. Splenectomies increased 16% in TC but declined 16% in community hospital. Splenic salvage rate improved at both types of facilities.Conclusions: Splenic salvage rates improved over time in hospitals with no formal trauma system. Community hospitals cared for more than 50% of splenic injuries but transferred complex multisystem injuries, including splenic injuries, suggesting evolving care. Non-invasive imaging has increased the recognition of splenic injuries in both community hospitals and TC. Splenectomies are performed less, but have increased in TC with increasing ISS scores. (c) 2006 Excerpta Medica Inc. All rights reserved.

Background-We previously reported that the functional mutation of Toll-like receptor 4 (TLR4) in C3H/HeJ mice subjected to myocardial ischemia-reperfusion (MI/R) injury resulted in an attenuation of myocardial infarction size. To investigate the ligand-activating TLR4 during MI/R injury, we evaluated the effect of eritoran, a specific TLR4 antagonist, on MI/R injury, with the goal of defining better therapeutic options for MI/R injury.Methods and Results-C57BL/6 mice received eritoran (5 mg/kg) intravenously 10 minutes before 30 minutes of in situ of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. Infarct size was measured using triphenyltetrazoliumchloride staining. A c-Jun NH2-terminal kinase (JNK) activation was determined by Western blotting, nuclear factor (NF)-kappa B activity was detected by gel-shift assay, and cytokine expression was measured by ribonuclease protection assay. Mice treated with eritoran developed significantly smaller infarcts when compared with mice treated with vehicle alone (21.0 +/- 6.4% versus 30.9 +/- 13.9%; P = 0.041). Eritoran pretreatment resulted in a reduction in JNK phosphorylation (eritoran versus vehicle: 3.98 +/- 0.81 versus 7.01 +/- 2.21-fold increase; P = 0.020), less nuclear NF-kappa B translocation (2.70 +/- 0.35 versus 7.75 +/- 0.60-fold increase; P = 0.00007), and a decrease in cytokine expression (P < 0.05).Conclusions-We conclude that inhibition of TLR4 with eritoran in an in situ murine model significantly reduces MI/R injury and markers of an inflammatory response.

Objectives: p38 mitogen-activated protein kinase is associated with many clinical entities characterized by inflammation. We postulated that inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates inflammation and the development of pulmonary hypertension in monocrotaline-treated rats.Methods: Rats were divided into 4 groups: (1) the control group (daily 0.9% saline), (2) the FR group (daily FR167653, 2 mg (.) kg(-1) (.) d(-1)), (3) the NICT group (daily 0.9% saline the day after a single monocrotaline dose, 60 mg/kg), and (4) the MCT+FR group (daily FR167653, 2 mg (.) kg(-1) (.) d(-1), the day after a single MCT dose). Body weight, pulmonary artery pressure, and morphometric changes of the pulmonary artery with the histopathologic method were observed weekly for 4 weeks. Also, p38 mitogen-activated protein kinase activity and inflammatory cytokine expression in the lung were measured.Results: Four weeks after monocrotaline administration, mean pulmonary artery pressure in the MCT+FR group was lower than in the MCT group (MCT+FR vs MCT: 24.7 +/- 1.9 vs 36.5 +/- 2.1 mm Hg; P <.05). In morphometric analysis the percentage of medial wall thickness and the percentage of muscularization in the MCT+FR group were reduced compared with those in the MCT group after 4 weeks (P <.05); however, the number of macrophages was not significantly different. p38 mitogen-activated protein kinase activity was significantly attenuated in the MCT+FR group compared with in the MCT group (7.2 +/- 0.52 vs 2.1 +/- 0.23 fold-increase, P <.05, at 1 week). Although mRNA levels of tumor necrosis factor alpha and interleukin 1beta were reduced in the MCT+FR group compared with in the MCT group (tumor necrosis factor alpha: 1.18 +/- 0.36 vs 3.05 +/- 1.12 fold-increase, P <.05, at 2 weeks; interleukin 1beta: 2.2 +/- 0.34 vs 4.4 +/- 1.09 fold-increase, P <.05, at 1 week), FR167653 did not suppress increased monocyte chemotactic protein 1 mRNA expression induced by monocrotaline (3.2 +/- 0.62 vs 3.1 +/- 0.42 foldincrease, at 1 week).Conclusion: FR167653 significantly attenuates the expression of inflammatory cytokines, ultimately preventing the progression of pulmonary hypertension. These results suggest that p38 mitogen-activated protein kinase might play a central role in the molecular events that underlie the development and progression of pulmonary hypertension.

OBJECTIVE:During myocardial ischemia-reperfusion injury, p38 mitogen-activated protein kinase is activated. We examined the effect of a highly specific inhibitor of p38 mitogen-activated protein kinase, FR167653, in an experimental model of regional myocardial ischemia-reperfusion.METHODS:CD-1 mice received FR167653 intraperitoneally 24 hours before 30 minutes of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. The p38 mitogen-activated protein kinase activation and kinase activity were determined by Western blotting with monoclonal antibodies for the phosphorylated from of p38 mitogen-activated protein kinase or its substrate, activating transcription factor 2. Nuclear factor kappaB activity was measured by detecting translocation of nuclear factor kappaB to the nucleus. The expression of inflammatory cytokines was measured by ribonuclease protection assay.RESULTS:Pretreatment of mice with FR167653 before myocardial ischemia-reperfusion resulted in a reduction in p38 mitogen-activated protein kinase phosphorylation (P =.018), an inhibition of p38 mitogen-activated protein kinase activity (P =.047), a smaller amount of nuclear factor kappaB (P =.001), and a decrease in the expression of inflammatory cytokines (tumor necrosis factor alpha: P =.023, interleukin 1beta: P =.038, monocyte chemotactic protein 1: P =.0001) in the heart and the development of a significantly smaller infarct (P =.0069) relative to hearts from mice treated with vehicle alone. Activation of c-Jun N-terminal kinase and extracellular signal-regulated kinase were observed after myocardial ischemia-reperfusion without inhibition by FR167653.CONCLUSION:We conclude that FR167653 selectively inhibits p38 mitogen-activated protein kinase activation and activity during regional myocardial ischemia-reperfusion injury and efficaciously reduces infarct size (by 73.6%). Thus p38 mitogen-activated protein kinase inhibition may have a role in the treatment of myocardial ischemia-reperfusion.

Fifteen controls and 22 patients with hypertrophic cardiomyopathy (HCM) underwent PET for assessment of myocardial perfusion and coronary flow reserve (CFR).CFR was reduced in patients with HCM versus controls.Septal CFR was higher in patients with HCM treated surgically (ϩ37%, P Ͻ .01)versus patients with HCM treated medically

Structural brain abnormalities in preoperative neonates with congestive heart disease are common (50%