Fibrinogen depletion in trauma: early, easy to estimate and central to trauma-induced coagulopathy

RD and KB both received departmental funding for study support costs from Haemonetics Corporation (Braintree, MA, USA) and equipment/reagent grants from Tem Innovations GmbH (Munich, Germany)

The acute management of trauma hemorrhage: a systematic review of randomized controlled trials.

PublishedResearch Support, Non-U.S. Gov'tReviewINTRODUCTION: Worldwide, trauma is a leading cause of death and disability. Haemorrhage is responsible for up to 40% of trauma deaths. Recent strategies to improve mortality rates have focused on optimal methods of early hemorrhage control and correction of coagulopathy. We undertook a systematic review of randomized controlled trials (RCT) which evaluated trauma patients with hemorrhagic shock within the first 24 hours of injury and appraised how the interventions affected three outcomes: bleeding and/or transfusion requirements; correction of trauma induced coagulopathy and mortality. METHODS: Comprehensive searches were performed of MEDLINE, EMBASE, CENTRAL (The Cochrane Library Issue 7, 2010), Current Controlled Trials, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) and the National Health Service Blood and Transplant Systematic Review Initiative (NHSBT SRI) RCT Handsearch Database. RESULTS: A total of 35 RCTs were identified which evaluated a wide range of clinical interventions in trauma hemorrhage. Many of the included studies were of low methodological quality and participant numbers were small. Bleeding outcomes were reported in 32 studies; 7 reported significantly reduced transfusion use following a variety of clinical interventions, but this was not accompanied by improved survival. Minimal information was found on traumatic coagulopathy across the identified RCTs. Overall survival was improved in only three RCTs: two small studies and a large study evaluating the use of tranexamic acid. CONCLUSIONS: Despite 35 RCTs there has been little improvement in outcomes over the last few decades. No clear correlation has been demonstrated between transfusion requirements and mortality. The global trauma community should consider a coordinated and strategic approach to conduct well designed studies with pragmatic endpoints.This research project was funded by the National Institute for Health Research Programme Grant for Applied Research (RP-PG-0407-10036)

Epigenetic regulatory pathways involving microRNAs may modulate the host immune response following major trauma

BACKGROUND Posttraumatic nosocomial pneumonia is a common complication resulting in significant morbidity. Trauma-induced immunocompromise is associated with an enhanced susceptibility to pneumonia. In this study, we explore the hypothesis that posttranscriptional epigenetic regulation of gene expression may be an important factor in determining this immune phenotype. We describe the pattern of production of microRNAss (miRs) and their association with nosocomial pneumonia following severe trauma. METHODS A convenience sample of 30 ventilated polytrauma patients (UKCRN ID: 5637) and 16 healthy controls were recruited. Messenger RNA and protein levels of key cytokines were quantified within 2 hours of the injury and at 24 hours. Three miRs per cytokine were then selected based on miRBase target prediction scores and quantified using polymerase chain reaction. Nosocomial pneumonia was defined using the Centers for Disease Control and Prevention definitions. RESULTS Median Injury Severity Score (ISS) was 29, and 47% of the patients developed nosocomial pneumonia. miR-125a and miR-202 decreased by 34% and 77%, respectively, immediately following injury, whereas their target, IL-10, increased messenger RNA levels 3-fold and protein levels 180 fold. Tumor necrosis factor α (TNF-α) and IL-12 gene expression decreased by 68% and 43%, respectively, following injury, and this was mirrored by a 10-fold increase in miR-181, an miR predicted to target TNF-α transcripts. Lower levels of miR-125a and miR-374b were associated with the later acquisition of hospital-acquired pneumonia. CONCLUSION Alteration in the expression of miRs with highly predicted complementarity to IL-10 and TNF-α may be an important mechanism regulating the posttraumatic immunosuppressive phenotype in intensive care unit patients. LEVEL OF EVIDENCE Retrospective observational study, level III

T-helper cell polarisation following severe polytrauma

Introduction Severe polytrauma induces an immunosuppressive response and is associated with a very high incidence of nosocomial infections. Previous studies have inferred that this detrimental immune response results from polarisation of the T helper (Th) response towards an anti-inflammatory, TH2 dominated, response at the expense of a bactericidal, Th1 response [1]. Objectives 1) To define alterations in TH cell subsets following severe blunt polytrauma. Methods Patients presenting to the emergency department within 2 hours of severe polytrauma were eligible if intubated either at the scene or in ED. Isolated head injuries and those not expected to survive 24 hours were excluded. EDTA anti-coagulated blood was drawn at 0hr (within 2 hours of injury), at 24 and 72hrs. Samples were immediately lysed, washed, stained and analysed using a standardised human 8-colour TH 1, 2 & 17 panel [2] on an LSR II flow cytometer. A paired white cell count differential was obtained at each sampling point. Patients were followed until discharge or death. Data were analysed using non-parametric statistics, with results presented as median and IQR. Results 15 consecutive severe polytrauma patients requiring Intensive Care Unit (ICU) admission were recruited. Demographic and clinical data are outlined in Figure 1. Twelve (80%) lymphocytosis (3.3x109/L, 2.5 - 4.4x109/L) (Figyre 2A). At 72 hours leukocytes had fallen (P < 0.01, figure 2A) such that 6 (54%) of those surviving were lymphopenic (0.9x109/L, 0.6 - 1.2x109/L). Circulating CD4+ (P = 0.01; Figure 2B) and CD4+CD25+ (P < 0.05) lymphocytes increased over 72 hours. When expressed as a percentage of total circulating lymphocytes no significant change in the proportions of the TH 1, 2 & 17 subpopulations was detected (Figure 2C-E). Conclusions Severe polytrauma patients swiftly become lymphopenic. Although a failure to normalise this during the ICU stay correlates with higher mortality [3] our study of TH cell subtypes demonstrates no evidence of a switch to a detrimental anti-inflammatory TH2 subtype at the expense of the potentially protective bactericidal TH1 subtype

The role of micrornas in the development of hospital acquired infection in polytrauma patients

Introduction Traumatic injury is associated with immunosuppression and an increased risk of developing nosocomial infections. However, the immune regulatory mechanisms involved remain unclear. Objectives 1) To describe genome-wide alterations in micro RNA (miRNA) expression following severe trauma. 2) To explore the potential role of miRNAs in mediating the post-traumatic immunosuppressive phenotype and their potential role in enhancing the risk of nosocomial infections. Methods Patients requiring ICU care following traumatic injury were recruited. Whole blood was collected within 2 hours of injury and 24 hours later. Total RNA (containing miRNAs) was isolated utilising PAX Gene and RNA extraction kits (Qiagen). miRNA-sequencing was performed with the Illumina HiSeq2500, and sequences were aligned to the human GRCh37 reference genome. Data analysis was carried out using the DESEQ2 package in R, and miRNAs were considered significantly altered with an adjusted p value of < 0.05. Functional enrichment analysis was performed using Ingenuity Pathway Analysis (IPA) on all miRNAs reaching an adjusted p value of < 0.1. mRNA targets of interest were identified using miRBase and TargetScan (http://www.mirbase.org, http://www.targetscan.org). Results 49 patients were recruited and 25 patients developed nosocomial infections. Expression of 139 miRNAs was significantly altered between 2 hours and 24 hours following injury, with miR-146b, a key inhibitor of pro-inflammatory pathways[1], upregulated to the greatest degree. Figure 1 presents miRNAs that differ between those patients who developed nosocomial infections and those who did not. miR-144-5p was significantly different between the two groups at both time points. a large percentage of mRNA targets for miR-144 are involved the Cell-mediated Immune Response (Figure 2), including the B-cell receptor complex, p38MAPK, GATA3, IgG, BCL6 and the T-cell receptor. in addition, we have previously shown that the miR-374 family of miRNAs is linked to increased IL-10 expression in trauma patients[2]. IPA highlights Cancer, Haematological Disease, Immunological and Inflammatory Disease and Organismal Injury and Abnormalities as important pathways altered between infected and non-infected patients. Conclusions These data provide a miRNA signature of severely injured trauma patients who develop hospital acquired infection compared to those who do not, and identify the miR-144 and miR-374b families as being of particular interest for future studies of trauma-induced immune dysfunction