Karim Brohi

Circulating Mitochondrial DAMPs Cause Inflammatory Responses to Injury

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 Ca2+ 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.

Acute traumatic coagulopathy

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 thousand eight hundred sixty-seven consecutive trauma patients were reviewed, of whom 1,088 had full data sets. Median Injury Severity Score was 20, and 57.7% had an Injury Severity Score > 15; 24.4% of patients had a significant coagulopathy. Patients with an acute coagulopathy had significantly higher mortality (46.0% vs. 10.9%; chi2, p < 0.001). The incidence of coagulopathy increased with severity of injury, but was not related to the volume of intravenous fluid administered (r2 = 0.25, p < 0.001). CONCLUSION There is a common and clinically important acute traumatic coagulopathy that is not related to fluid administration. This is a marker of injury severity and is related to mortality. A coagulation screen is an important early test in severely injured patients.

The coagulopathy of trauma: a review of mechanisms.

BACKGROUND Bleeding is the most frequent cause of preventable death after severe injury. Coagulopathy associated with severe injury complicates the control of bleeding and is associated with increased morbidity and mortality in trauma patients. The causes and mechanisms are multiple and yet to be clearly defined. METHODS Articles addressing the causes and consequences of trauma-associated coagulopathy were identified and reviewed. Clinical situations in which the various mechanistic causes are important were sought along with quantitative estimates of their importance. RESULTS Coagulopathy associated with traumatic injury is the result of multiple independent but interacting mechanisms. Early coagulopathy is driven by shock and requires thrombin generation from tissue injury as an initiator. Initiation of coagulation occurs with activation of anticoagulant and fibrinolytic pathways. This Acute Coagulopathy of Trauma-Shock is altered by subsequent events and medical therapies, in particular acidemia, hypothermia, and dilution. There is significant interplay between all mechanisms. CONCLUSIONS There is limited understanding of the mechanisms by which tissue trauma, shock, and inflammation initiate trauma coagulopathy. Acute Coagulopathy of Trauma-Shock should be considered distinct from disseminated intravascular coagulation as described in other conditions. Rapid diagnosis and directed interventions are important areas for future research.

The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.

Background The aim of the CRASH-2 trial was to assess the eff ects of early administration of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with signifi cant haemorrhage. Tranexamic acid signifi cantly reduced all-cause mortality. Because tranexamic acid is thought to exert its eff ect through inhibition of fi brinolysis, we undertook exploratory analyses of its eff ect on death due to bleeding.BACKGROUND The aim of the CRASH-2 trial was to assess the effects of early administration of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage. Tranexamic acid significantly reduced all-cause mortality. Because tranexamic acid is thought to exert its effect through inhibition of fibrinolysis, we undertook exploratory analyses of its effect on death due to bleeding. METHODS The CRASH-2 trial was undertaken in 274 hospitals in 40 countries. 20,211 adult trauma patients with, or at risk of, significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min followed by infusion of 1 g over 8 h) or placebo. Patients were randomly assigned by selection of the lowest numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Both participants and study staff (site investigators and trial coordinating centre staff ) were masked to treatment allocation. We examined the effect of tranexamic acid on death due to bleeding according to time to treatment, severity of haemorrhage as assessed by systolic blood pressure, Glasgow coma score (GCS), and type of injury. All analyses were by intention to treat. The trial is registered as ISRCTN86750102, ClinicalTrials.gov NCT00375258, and South African Clinical Trial Register/Department of Health DOH-27-0607-1919. FINDINGS 10,096 patients were allocated to tranexamic acid and 10,115 to placebo, of whom 10,060 and 10,067, respectively, were analysed. 1063 deaths (35%) were due to bleeding. We recorded strong evidence that the effect of tranexamic acid on death due to bleeding varied according to the time from injury to treatment (test for interaction p<0.0001). Early treatment (≤1 h from injury) significantly reduced the risk of death due to bleeding (198/3747 [5.3%] events in tranexamic acid group vs 286/3704 [7.7%] in placebo group; relative risk [RR] 0.68, 95% CI 0.57-0.82; p<0.0001). Treatment given between 1 and 3 h also reduced the risk of death due to bleeding (147/3037 [4.8%] vs 184/2996 [6.1%]; RR 0.79, 0.64-0.97; p=0.03). Treatment given after 3 h seemed to increase the risk of death due to bleeding (144/3272 [4.4%] vs 103/3362 [3.1%]; RR 1.44, 1.12-1.84; p=0.004). We recorded no evidence that the effect of tranexamic acid on death due to bleeding varied by systolic blood pressure, Glasgow coma score, or type of injury. INTERPRETATION Tranexamic acid should be given as early as possible to bleeding trauma patients. For trauma patients admitted late after injury, tranexamic acid is less effective and could be harmful. FUNDING UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation.

Acute Traumatic Coagulopathy: Initiated by Hypoperfusion Modulated Through the Protein C Pathway?

Objectives:Coagulopathy following major trauma is conventionally attributed to activation and consumption of coagulation factors. Recent studies have identified an acute coagulopathy present on admission that is independent of injury severity. We hypothesized that early coagulopathy is due to tissue hypoperfusion, and investigated derangements in coagulation associated with this. Methods:This was a prospective cohort study of major trauma patients admitted to a single trauma center. Blood was drawn within 10 minutes of arrival for analysis of partial thromboplastin and prothrombin times, prothrombin fragments 1+2, fibrinogen, thrombomodulin, protein C, plasminogen activator inhibitor-1, and d-dimers. Base deficit (BD) was used as a measure of tissue hypoperfusion. Results:A total of 208 patients were enrolled. Patients without tissue hypoperfusion were not coagulopathic, irrespective of the amount of thrombin generated. Prolongation of the partial thromboplastin and prothrombin times was only observed with an increased BD. An increasing BD was associated with high soluble thrombomodulin and low protein C levels. Low protein C levels were associated with prolongation of the partial thromboplastin and prothrombin times and hyperfibrinolysis with low levels of plasminogen activator inhibitor-1 and high d-dimer levels. High thrombomodulin and low protein C levels were significantly associated with increased mortality, blood transfusion requirements, acute renal injury, and reduced ventilator-free days. Conclusions:Early traumatic coagulopathy occurs only in the presence of tissue hypoperfusion and appears to occur without significant consumption of coagulation factors. Alterations in the thrombomodulin-protein C pathway are consistent with activated protein C activation and systemic anticoagulation. Admission plasma thrombomodulin and protein C levels are predictive of clinical outcomes following major trauma.

Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis

BACKGROUND Coagulopathy is present at admission in 25% of trauma patients, is associated with shock and a 5-fold increase in mortality. The coagulopathy has recently been associated with systemic activation of the protein C pathway. This study was designed to characterize the thrombotic, coagulant and fibrinolytic derangements of trauma-induced shock. METHODS This was a prospective cohort study of major trauma patients admitted to a single trauma center. Blood was drawn within 10 minutes of arrival for analysis of partial thromboplastin and prothrombin times, prothrombin fragments 1 + 2 (PF1 + 2), fibrinogen, factor VII, thrombomodulin, protein C, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), and D-dimers. Base deficit was used as a measure of tissue hypoperfusion. RESULTS Two hundred eight patients were studied. Systemic hypoperfusion was associated with anticoagulation and hyperfibrinolysis. Coagulation was activated and thrombin generation was related to injury severity, but acidosis did not affect Factor VII or PF1 + 2 levels. Hypoperfusion-induced increase in soluble thrombomodulin levels was associated with reduced fibrinogen utilization, reduction in protein C and an increase in TAFI. Hypoperfusion also resulted in hyperfibrinolysis, with raised tPA and D-Dimers, associated with the observed reduction in PAI-1 and not alterations in TAFI. CONCLUSIONS Acute coagulopathy of trauma is associated with systemic hypoperfusion and is characterized by anticoagulation and hyperfibrinolysis. There was no evidence of coagulation factor loss or dysfunction at this time point. Soluble thrombomodulin levels correlate with thrombomodulin activity. Thrombin binding to thrombomodulin contributes to hyperfibrinolysis via activated protein C consumption of PAI-1.

Acute coagulopathy of trauma: mechanism, identification and effect.

Purpose of reviewAcute coagulopathy of trauma has only been described relatively recently. Developing early in the postinjury phase, it is associated with increased transfusion requirements and poor outcomes. This review examines the possible initiators, mechanism and clinical importance of acute coagulopathy. Recent findingsAcute coagulopathy of trauma occurs in patients with shock and is characterized by a systemic anticoagulation and hyperfibrinolysis. Dilution, acidemia and consumption of coagulation proteases do not appear to be significant factors at this stage. There is evidence to implicate activation of the protein C pathway in this process. Diagnosis of acute coagulopathy currently relies on laboratory assessment of clotting times. These tests do not fully characterize the coagulopathy and have significant limitations, which reduce their clinical utility. SummaryAcute coagulopathy results in increased transfusion requirements, incidence of organ dysfunction, critical care stay and mortality. Recognition of an early coagulopathic state has implications for the care of shocked patients and the management of massive transfusion. Identification of novel mechanisms for traumatic coagulopathy may lead to new avenues for drug discovery and therapeutic intervention.

Advanced trauma life support, 8th edition, the evidence for change.

The American College of Surgeons Committee on Traumas Advanced Trauma Life Support Course is currently taught in 50 countries. The 8th edition has been revised following broad input by the International ATLS subcommittee. Graded levels of evidence were used to evaluate and approve changes to the course content. New materials related to principles of disaster management have been added. ATLS is a common language teaching one safe way of initial trauma assessment and management.

Functional definition and characterization of acute traumatic coagulopathy.

Objective:To identify an appropriate diagnostic tool for the early diagnosis of acute traumatic coagulopathy and validate this modality through prediction of transfusion requirements in trauma hemorrhage. Design:Prospective observational cohort study. Setting:Level 1 trauma center. Patients:Adult trauma patients who met the local criteria for full trauma team activation. Exclusion criteria included emergency department arrival >2 hrs after injury, >2000 mL of intravenous fluid before emergency department arrival, or transfer from another hospital. Interventions:None. Measurements:Blood was collected on arrival in the emergency department and analyzed with laboratory prothrombin time, point-of-care prothrombin time, and rotational thromboelastometry. Prothrombin time ratio was calculated and acute traumatic coagulopathy defined as laboratory prothrombin time ratio >1.2. Transfusion requirements were recorded for the first 12 hrs following admission. Main Results:Three hundred patients were included in the study. Laboratory prothrombin time results were available at a median of 78 (62–103) mins. Point-of-care prothrombin time ratio had reduced agreement with laboratory prothrombin time ratio in patients with acute traumatic coagulopathy, with 29% false-negative results. In acute traumatic coagulopathy, the rotational thromboelastometry clot amplitude at 5 mins was diminished by 42%, and this persisted throughout clot maturation. Rotational thromboelastometry clotting time was not significantly prolonged. Clot amplitude at a 5-min threshold of ≤35 mm had a detection rate of 77% for acute traumatic coagulopathy with a false-positive rate of 13%. Patients with clot amplitude at 5 mins ≤35 mm were more likely to receive red cell (46% vs. 17%, p < .001) and plasma (37% vs. 11%, p < .001) transfusions. The clot amplitude at 5 mins could identify patients who would require massive transfusion (detection rate of 71%, vs. 43% for prothrombin time ratio >1.2, p < .001). Conclusions:In trauma hemorrhage, prothrombin time ratio is not rapidly available from the laboratory and point-of-care devices can be inaccurate. Acute traumatic coagulopathy is functionally characterized by a reduction in clot strength. With a threshold of clot amplitude at 5 mins of ≤35 mm, rotational thromboelastometry can identify acute traumatic coagulopathy at 5 mins and predict the need for massive transfusion.

Reduction in critical mortality in urban mass casualty incidents: analysis of triage, surge, and resource use after the London bombings on July 7, 2005

BACKGROUND The terrorist bombings in London on July 7, 2005, produced the largest mass casualty event in the UK since World War 2. The aim of this study was to analyse the prehospital and in-hospital response to the incident and identify system processes that optimise resource use and reduce critical mortality. METHODS This study was a retrospective analysis of the London-wide prehospital response and the in-hospital response of one academic trauma centre. Data for injuries, outcome, triage, patient flow, and resource use were obtained by the review of emergency services and hospital records. FINDINGS There were 775 casualties and 56 deaths, 53 at scene. 55 patients were triaged to priority dispatch and 20 patients were critically injured. Critical mortality was low at 15% and not due to poor availability of resources. Over-triage rates were reduced where advanced prehospital teams did initial scene triage. The Royal London Hospital received 194 casualties, 27 arrived as seriously injured. Maximum surge rate was 18 seriously injured patients per hour and resuscitation room capacity was reached within 15 min. 17 patients needed surgery and 264 units of blood products were used in the first 15 h, close to the hospitals routine daily blood use. INTERPRETATION Critical mortality was reduced by rapid advanced major incident management and seems unrelated to over-triage. Hospital surge capacity can be maintained by repeated effective triage and implementing a hospital-wide damage control philosophy, keeping investigations to a minimum, and transferring patients rapidly to definitive care.