Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial.

IMPORTANCE: Norepinephrine, the first-line vasopressor for septic shock, is not always effective and has important catecholaminergic adverse effects. Selepressin, a selective vasopressin V1a receptor agonist, is a noncatecholaminergic vasopressor that may mitigate sepsis-induced vasodilatation, vascular leakage, and edema, with fewer adverse effects. OBJECTIVE: To test whether selepressin improves outcome in septic shock. DESIGN, SETTING, AND PARTICIPANTS: An adaptive phase 2b/3 randomized clinical trial comprising 2 parts that included adult patients (n = 868) with septic shock requiring more than 5 µg/min of norepinephrine. Part 1 used a Bayesian algorithm to adjust randomization probabilities to alternative selepressin dosing regimens and to trigger transition to part 2, which would compare the best-performing regimen with placebo. The trial was conducted between July 2015 and August 2017 in 63 hospitals in Belgium, Denmark, France, the Netherlands, and the United States, and follow-up was completed by May 2018. INTERVENTIONS: Random assignment to 1 of 3 dosing regimens of selepressin (starting infusion rates of 1.7, 2.5, and 3.5 ng/kg/min; n = 585) or to placebo (n = 283), all administered as continuous infusions titrated according to hemodynamic parameters. MAIN OUTCOMES AND MEASURES: Primary end point was ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) of commencing study drug. Key secondary end points were 90-day mortality, kidney replacement therapy-free days, and ICU-free days. RESULTS: Among 868 randomized patients, 828 received study drug (mean age, 66.3 years; 341 [41.2%] women) and comprised the primary analysis cohort, of whom 562 received 1 of 3 selepressin regimens, 266 received placebo, and 817 (98.7%) completed the trial. The trial was stopped for futility at the end of part 1. Median study drug duration was 37.8 hours (IQR, 17.8-72.4). There were no significant differences in the primary end point (ventilator- and vasopressor-free days: 15.0 vs 14.5 in the selepressin and placebo groups; difference, 0.6 [95% CI, -1.3 to 2.4]; P = .30) or key secondary end points (90-day mortality, 40.6% vs 39.4%; difference, 1.1% [95% CI, -6.5% to 8.8%]; P = .77; kidney replacement therapy-free days: 18.5 vs 18.2; difference, 0.3 [95% CI, -2.1 to 2.6]; P = .85; ICU-free days: 12.6 vs 12.2; difference, 0.5 [95% CI, -1.2 to 2.2]; P = .41). Adverse event rates included cardiac arrhythmias (27.9% vs 25.2% of patients), cardiac ischemia (6.6% vs 5.6%), mesenteric ischemia (3.2% vs 2.6%), and peripheral ischemia (2.3% vs 2.3%). CONCLUSIONS AND RELEVANCE: Among patients with septic shock receiving norepinephrine, administration of selepressin, compared with placebo, did not result in improvement in vasopressor- and ventilator-free days within 30 days. Further research would be needed to evaluate the potential role of selepressin for other patient-centered outcomes in septic shock. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02508649.

Low hemorrhage-related mortality in trauma patients in a Level I trauma center employing transfusion packages and early thromboelastography-directed hemostatic resuscitation with plasma and platelets.

BACKGROUND: Hemorrhage accounts for most preventable trauma deaths, but still the optimal strategy for hemostatic resuscitation remains debated. STUDY DESIGN AND METHODS: This was a prospective study of adult trauma patients admitted to a Level I trauma center. Demography, Injury Severity Score (ISS), transfusion therapy, and mortality were registered. Hemostatic resuscitation was based on a massive transfusion protocol encompassing transfusion packages and thromboelastography (TEG)-guided therapy. RESULTS: A total of 182 patients were included (75% males, median age 43 years, ISS of 17, 92% with blunt trauma). Overall 28-day mortality was 12% with causes of death being exsanguinations (14%), traumatic brain injury (72%, two-thirds expiring within 24 hr), and other (14%). One-fourth, 16 and 15% of the patients, received red blood cells (RBCs), plasma, or platelets (PLTs) within 2 hours from admission and 68, 71, and 75%, respectively, of patients transfused within 24 hours received the respective blood products within the first 2 hours. In patients transfused within 24 hours, the median number of blood products at 2 hours was 5 units of RBCs, 5 units of plasma, and 2 units of PLT concentrates. Nonsurvivors had lower clot strength by kaolin-activated TEG and TEG functional fibrinogen and lower kaolin-tissue factor-activated TEG α-angle and lysis after 30 minutes compared to survivors. None of the TEG variables were independent predictors of massive transfusion or mortality. CONCLUSION: Three-fourths of the patients transfused with plasma or PLTs within 24 hours received these in the first 2 hours. Hemorrhage caused 14% of the deaths. We introduced transfusion packages and early TEG-directed hemostatic resuscitation at our hospital 10 years ago and this may have contributed to reducing hemorrhagic trauma deaths.

Hemostatic function of buffy coat platelets in additive solution treated with pathogen reduction technology.

BACKGROUND: Pathogen reduction technologies (PRTs) may influence the hemostatic potential of stored platelet (PLT) concentrates. To investigate this, buffy coat PLTs (BCPs) stored in PLT additive solution (SSP+) with or without Mirasol PRT treatment (CaridianBCT Biotechnologies) were compared by functional hemostatic assays. STUDY DESIGN AND METHODS: We performed in vitro comparison of PRT (PRT-BCP) and control pooled-and-split BCPs (CON-BCP) after 2, 3, 6, 7, and 8 days' storage. Hemostatic function was evaluated with thrombelastography (TEG) and impedance aggregometry (Multiplate), the latter also in a sample matrix (Day 2) with or without addition of red blood cells (RBCs), control plasma, and/or PRT-treated plasma. RESULTS: PRT treatment of 8-day-stored BCPs influenced clot formation (TEG) minimally, with reductions in maximum clot strength (maximum amplitude, p = 0.014) but unchanged initial fibrin formation (R), clot growth rate (α), and fibrinolysis resistance. In the absence of RBCs and plasma, PRT impaired aggregation (Multiplate) in stored BCPs, with reduced aggregation against thrombin receptor activating peptide-6 (p < 0.001), collagen (p = 0.014), adenosine 5'-diphosphate (p = 0.007), and arachidonic acid (p = 0.070). Addition of RBCs and PRT-treated or untreated plasma to PRT-BCP and CON-BCP, respectively, enhanced aggregation in both groups. CONCLUSIONS: Mirasol PRT treatment of BCPs had a minimal influence on clot formation, whereas aggregation in the absence of RBCs and plasma was significantly reduced. Addition of RBCs and plasma increased agonist-induced responses resulting in comparable aggregation between PRT-BCP and CON-BCP. The clinical relevance for PLT function in vivo of these findings will be investigated in a clinical trial.

Rationale and Design of an Adaptive Phase 2b/3 Clinical Trial of Selepressin for Adults in Septic Shock. Selepressin Evaluation Programme for Sepsis-induced Shock-Adaptive Clinical Trial.

Septic shock carries substantial morbidity and mortality. The failure of many promising therapies during late-phase clinical trials prompted calls for alternative trial designs. We describe an innovative trial evaluating selepressin, a novel selective vasopressin V1a receptor agonist, for adults with septic shock. SEPSIS-ACT (Selepressin Evaluation Programme for Sepsis-induced Shock-Adaptive Clinical Trial) is a blinded, randomized, placebo-controlled, two-part, adaptive phase 2b/3 trial, evaluating up to four selepressin dosing strategies. The primary outcome is pressor- and ventilator-free days, with a value of zero assigned for death within 30 days. We calculate Bayesian probabilities of final trial success to guide interim decision-making. Part 1 (dose-finding) has an adaptive sample size based on response-adaptive randomization and prespecified rules to determine stopping for futility or selection of the best dosing regimen for Part 2. Part 2 (confirmation) randomizes a minimum of 1,000 patients equally to the selected dosing regimen or placebo. The final estimate of treatment effect compares all selepressin-treated patients with all placebo-treated patients. The sample size of 1,800 provides 91% power to detect an increase of 1.5 pressor- and ventilator-free days with a reduction in mortality of 1.5%. The trial received a Special Protocol Assessment agreement from the U.S. Food and Drug Administration Center for Drug Evaluation and Research and is underway in Europe and the United States. SEPSIS-ACT is an innovative trial that addresses both optimal dose and confirmation of benefit, accelerating the evaluation of selepressin while mitigating risks to patients and sponsor through use of response-adaptive randomization, a novel registration endpoint, prespecified futility stopping rules, and a large sample size. Clinical Trial registered with www.clinicaltrials.gov (NCT02508649).

Platelet aggregation following trauma: a prospective study.

We aimed to elucidate platelet function in trauma patients, as it is pivotal for hemostasis yet remains scarcely investigated in this population. We conducted a prospective observational study of platelet aggregation capacity in 213 adult trauma patients on admission to an emergency department (ED). Inclusion criteria were trauma team activation and arterial cannula insertion on arrival. Blood samples were analyzed by multiple electrode aggregometry initiated by thrombin receptor agonist peptide 6 (TRAP) or collagen using a Multiplate device. Blood was sampled median 65 min after injury; median injury severity score (ISS) was 17; 14 (7%) patients received 10 or more units of red blood cells in the ED (massive transfusion); 24 (11%) patients died within 28 days of trauma: 17 due to cerebral injuries, four due to exsanguination, and three from other causes. No significant association was found between aggregation response and ISS. Higher TRAP values were associated with death due to cerebral injuries (P < 0.01, when corrected for ISS and platelet counts), whereas lower platelet counts were associated with massive transfusion (P < 0.01, when corrected for ISS and aggregation). An aggregation value of 145 IU by TRAP significantly identified death due to cerebral injury (sensitivity 71% and specificity 76%, P < 0.01) by receiver operating characteristic-curve analysis; the corresponding value of platelet counts for massive transfusion was 189 × 10/l (sensitivity 86%, specificity 75%, P < 0.01). We concluded there was no simple relationship between platelet aggregation and injury severity. Our results indicate that high platelet aggregation values are associated with fatality of cerebral injury.

Consecutive thrombelastography clot strength profiles in patients with severe sepsis and their association with 28-day mortality: a prospective study.

PURPOSE: The aim of this study was to assess associations between consecutive thrombelastography (TEG) profiles and standard coagulation tests and disease severity and mortality in patients with severe sepsis. MATERIALS AND METHODS: This was a prospective observational study of adults with severe sepsis admitted to the intensive care unit (ICU). Clinical scores/variables, infection, TEG, biochemistry, therapy, and overall mortality were recorded. RESULTS: Fifty patients (60% men, median age 62 years, 28-day mortality 24%) were included. At admission, 22%, 48%, and 30% had a hypocoagulable, normocoagulable, and hypercoagulable TEG clot strength (maximum amplitude [MA]), respectively. Hypocoagulable patients had higher Sequential Organ Failure Assessment and disseminated intravascular coagulation scores compared with hypercoagulable patients and higher 28-day mortality compared with normocoagulable patients (all P < .05). Most patients (73%-91%) displayed a TEG MA comparable with the admission profile during the initial 4 ICU days or until death/discharge. Patients progressing to hypocoagulable MA had a high early mortality (80%) and hypocoagulable MA independently predicted 28-day mortality (adjusted odds ratio, 4.29 [95% confidence interval, 1.35-13.65], P = .014). In hypocoagulable and hypercoagulable patients, only fibrinogen (P = .041 and P < .001, respectively) contributed independently to clot strength, whereas both platelets (P < .001) and fibrinogen (P < .001) contributed independently to clot strength in normocoagulable patients. CONCLUSIONS: The ICU admission TEG MA remained constant for several days in patients with severe sepsis and hypocoagulable MA independently predicted 28-day mortality.

Blood levels of histone-complexed DNA fragments are associated with coagulopathy, inflammation and endothelial damage early after trauma.

BACKGROUND: Tissue injury increases blood levels of extracellular histones and nucleic acids, and these may influence hemostasis, promote inflammation and damage the endothelium. Trauma-induced coagulopathy (TIC) may result from an endogenous response to the injury that involves the neurohumoral, inflammatory and hemostatic systems. AIMS: To study the contribution of extracellular nucleic constituents to TIC, inflammation and endothelial damage. SETTING AND DESIGN: Prospective observational study. MATERIALS AND METHODS: We investigated histone-complexed DNA fragments (hcDNA) along with biomarkers of coagulopathy, inflammation and endothelial damage in plasma from 80 trauma patients admitted directly to the Trauma Centre from the scene of the accident. Blood was sampled a median of 68 min (IQR 48-88) post injury. Trauma patients with hcDNA levels >median or ≤median were compared. RESULTS: Trauma patients with high plasma hcDNA had higher Injury Severity Score (ISS) and level of sympathoadrenal activation (higher adrenaline and noradrenaline) and a higher proportion of prolonged activated partial thromboplastin time (APTT) and higher D-dimer, tissue-type plasminogen activator (tPA), Annexin V and soluble CD40 ligand (sCD40L) concurrent with lower plasminogen activator inhibitor (PAI)-1) and prothrombin fragment (PF) 1 + 2 (all P < 0.05), all indicative of impaired thrombin generation, hyperfibrinolysis and platelet activation. Furthermore, patients with high hcDNA had enhanced inflammation and endothelial damage evidenced by higher plasma levels of terminal complement complex (sC5b-9), IL-6, syndecan-1, thrombomodulin and tissue factor pathway inhibitor (all P < 0.05). CONCLUSIONS: Excessive release of extracellular histones and nucleic acids seems to contribute to the hypocoagulability, inflammation and endothelial damage observed early after trauma.

Discrepant fibrinolytic response in plasma and whole blood during experimental endotoxemia in healthy volunteers.

BACKGROUND: Sepsis induces early activation of coagulation and fibrinolysis followed by late fibrinolytic shutdown and progressive endothelial damage. The aim of the present study was to investigate and compare the functional hemostatic response in whole blood and plasma during experimental human endotoxemia by the platelet function analyzer, Multiplate and by standard and modified thrombelastography (TEG). METHODS: Prospective physiologic study of nine healthy male volunteers undergoing endotoxemia by means of a 4-hour infusion of E. coli lipopolysaccharide (LPS, 0.5 ng/kg/hour), with blood sampled at baseline and at 4 h and 6 h. Physiological and standard biochemical data and coagulation tests, TEG (whole blood: TEG, heparinase-TEG, Functional Fibrinogen; plasma: TEG±tissue-type plasminogen activator (tPA)) and Multiplate (TRAPtest, ADPtest, ASPItest, COLtest) were recorded. Mixed models with Tukey post hoc tests and correlations were applied. RESULTS: Endotoxemia induced acute SIRS with increased HR, temperature, WBC, CRP and procalcitonin and decreased blood pressure. It also induced a hemostatic response with platelet consumption and reduced APTT while INR increased (all p<0.05). Platelet aggregation decreased (all tests, p<0.05), whereas TEG whole blood clot firmness increased (G, p = 0.05). Furthermore, during endotoxemia (4 h), whole blood fibrinolysis increased (clot lysis time (CLT), p<0.001) and Functional Fibrinogen clot strength decreased (p = 0.049). After endotoxemia (6 h), whole blood fibrinolysis was reduced (CLT, p<0.05). In contrast to findings in whole blood, the plasma fibrin clot became progressively more resistant towards tPA-induced fibrinolysis at both 4 h and 6 h (p<0.001). CONCLUSIONS: Endotoxemia induced a hemostatic response with reduced primary but enhanced secondary hemostasis, enhanced early fibrinolysis and fibrinogen consumption followed by downregulation of fibrinolysis, with a discrepant fibrinolytic response in plasma and whole blood. The finding that blood cells are critically involved in the vasculo-fibrinolytic response to acute inflammation is important given that disturbances in the vascular system contribute significantly to morbidity and mortality in critically ill patients.

Coagulopathy, catecholamines, and biomarkers of endothelial damage in experimental human endotoxemia and in patients with severe sepsis: a prospective study.

PURPOSE: The aim of this study was to investigate associations between circulating catecholamines, endothelial damage, and coagulopathy in experimental human endotoxemia and septic patients. MATERIALS AND METHODS: Nine healthy male volunteers undergoing endotoxemia (4-hour 0.5 ng/kg/hour infusion of E. coli lipopolysaccharide, blood sampling at 0, 4, and 6 hours) and 20 patients with severe sepsis. Analysis of plasma biomarkers (adrenaline, noradrenaline, thrombomodulin, syndecan-1, soluble vascular endothelial cadherin, histone-complexed DNA fragments, soluble CD40 ligand [sCD40L], protein C, tissue-type plasminogen activator, plasminogen activator inhibitor 1) and routine coagulation tests. RESULTS: Endotoxemia increased heart rate, temperature, white blood cell count, C-reactive protein and procalcitonin, decreased blood pressure and induced a hemostatic response with platelet consumption, reduced protein C and sCD40L levels and enhanced tissue-type plasminogen activator release (all P<.05). Septic patients had increased levels of noradrenaline, syndecan-1, thrombomodulin, histone-complexed DNA and sCD40L but reduced soluble vascular endothelial cadherin and plasminogen activator inhibitor 1 (all P<.05) and plasma catecholamines correlated positively with syndecan-1 (adrenaline and noradrenaline) and sTM (only noradrenaline) (all P<.05), biomarkers reflecting endothelial damage. Furthermore, noradrenaline, syndecan-1 and thrombomodulin levels correlated with INR and disease severity scores (noradrenaline and thrombomodulin) (all P<.05). CONCLUSIONS: Experimental endotoxemia induced a discrete hemostatic response without sympathoadrenal activation or endothelial damage. Septic patients had high levels of catecholamines and endothelial damage biomarkers that correlated with each other and with markers of hypocoagulability and disease severity.

Evaluation of TEG(®) and RoTEM(®) inter-changeability in trauma patients.

BACKGROUND: Massive haemorrhage is a leading cause of preventable deaths in trauma. Traumatic coagulopathy is frequently present early after trauma, and is associated with increased mortality. A number of recent trials suggest that viscoelastic haemostatic assays (VHA), such as thromboelastography and thromboelastometry, are useful tools in guiding transfusion. Treatment algorithms exist for the use of VHAs but are not validated in traumatic haemorrhage. In this study we examined the inter-changeability of two commonly used VHAs, TEG(®) and RoTEM(®). METHODS: A total of 184 trauma patients over the age of 18, requiring full trauma team activation, were included at three different hospitals in three different countries (Copenhagen, Denmark, San Francisco, CA, USA and Oslo, Norway). Blood samples were drawn immediately upon arrival, and TEG(®) and RoTEM(®) analyzed simultaneously. Correlations were calculated using. Spearman's rank correlation coefficient. Agreement was evaluated by Bland-Altman plots and calculation of limits of agreement. RESULTS: The mean ISS in the total population was 17, and the mortality was 16.5%. Mean base excess was -2.8 (SD: 4.2). The correlation coefficient for corresponding values for the two devices was 0.24 for the R-time vs CT in all centres combined. For the K-time vs CFT the correlation was 0.48, for the α-angleTEG vs α-angleRoTEM 0.44, and for MA vs MCF 0.76. Limits of agreement exceeded the preset clinically acceptable deviation of 10% for all variables in all centres except for MA/MCF in one centre (Copenhagen). Generally, correlation coefficients were lower and agreement poorer in the one centre (Oslo) where measurements were performed bedside by clinicians. CONCLUSION: Inter-changeability between TEG(®) and RoTEM(®) is limited in the trauma setting. Agreement seems poorer when clinicians operate the devices. Development and validation of separate treatment algorithms for the two devices is required.

In-vitro comparison of free oscillation rheometry (ReoRox) and rotational thromboelastometry (ROTEM) in trauma patients upon hospital admission.

Plasma-based assays do not provide accurate information on haemostatic resuscitation hence viscoelastic point-of-care haemostatic assays such as rotational thromboelastometry (ROTEM Delta, Pentapharm) are used to monitor coagulopathy in trauma patients. Free oscillation rheometry (FOR) is a new whole blood haemostatic assay that measures not only the clot-forming process but also the initial viscous phase; this could potentially be of value when assessing traumatic coagulopathy. A comparative analysis between FOR and ROTEM was therefore performed. This is a prospective observational study of 40 adult trauma patients admitted to a level 1 trauma centre. Citrated whole blood was analysed with ROTEM EXTEM and FIBTEM assays and FOR Fibscreen1 and Fibscreen2 assays. Predefined variables of ROTEM and FOR were compared using Spearman's ρ. ROTEM maximum clot function (MCF) in both EXTEM and FIBTEM correlated (P < 0.0001 for both) with FOR maximum elasticity Fibscreen1 and Fibscreen2, respectively. Interestingly, ROTEM EXTEM clotting time did not correlate with any of the FOR clot initiation parameters COT1, COT2 or COT2-1 of Fibscreen1. A correlation between ROTEM EXTEM and FIBTEM and FOR Fibscreen1 and Fibscreen2 clot formation and clot strength was found as was a significant correlation between lysis index after 60 min and ClotSR30. ROTEM EXTEM did not correlate with COT1, COT2 or COT2-1 of Fibscreen1 and this warrants further investigation.

High levels of soluble VEGF receptor 1 early after trauma are associated with shock, sympathoadrenal activation, glycocalyx degradation and inflammation in severely injured patients: a prospective study.

BACKGROUND: The level of soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is increased in sepsis and strongly associated with disease severity and mortality. Endothelial activation and damage contribute to both sepsis and trauma pathology. Therefore, this study measured sVEGFR1 levels in trauma patients upon hospital admission hypothesizing that sVEGFR1 would increase with higher injury severity and predict a poor outcome. METHODS: Prospective observational study of 80 trauma patients admitted to a Level I Trauma Centre. Data on demography, biochemistry, Injury Severity Score (ISS), transfusions and 30-day mortality were recorded and plasma/serum (sampled a median of 68 min (IQR 48-88) post-injury) was analyzed for sVEGFR1 and biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue injury (histone-complexed DNA fragments, hcDNA), endothelial activation and damage (von Willebrand Factor Antigen, Angiopoietin-2, soluble endothelial protein C receptor, syndecan-1, soluble thrombomodulin (sTM)), coagulation activation/inhibition and fibrinolysis (prothrombinfragment 1 + 2, protein C, activated Protein C, tissue-type plasminogen activator, plasminogen activator inhibitor-1, D-dimer) and inflammation (interleukin-6). Spearman correlations and regression analyses to identify variables associated with sVEGFR1 and its predictive value. RESULTS: Circulating sVEGFR1 correlated with injury severity (ISS, rho = 0.46), shock (SBE, rho = -0.38; adrenaline, rho = 0.47), tissue injury (hcDNA, rho = 0.44) and inflammation (IL-6, rho = 0.54) (all p < 0.01) but by multivariate linear regression analysis only lower SBE and higher adrenaline and IL-6 were independent predictors of higher sVEGFR1. sVEGFR1 also correlated with biomarkers indicative of endothelial glycocalyx degradation (syndecan-1, rho = 0.67), endothelial cell damage (sTM, rho = 0.66) and activation (Ang-2, rho = 0.31) and hyperfibrinolysis (tPA, rho = 0.39; D-dimer, rho = 0.58) and with activated protein C (rho = 0.31) (all p < 0.01). High circulating sVEGFR1 correlated with high early and late transfusion requirements (number of packed red blood cells (RBC) at 1 h (rho = 0.27, p = 0.016), 6 h (rho = 0.27, p = 0.017) and 24 h (rho = 0.31, p = 0.004) but was not associated with mortality. CONCLUSIONS: sVEGFR1 increased with increasing injury severity, shock and inflammation early after trauma but only sympathoadrenal activation, hypoperfusion, and inflammation were independent predictors of sVEGFR1 levels. sVEGFR1 correlated strongly with other biomarkers of endothelial activation and damage and with RBC transfusion requirements. Sympathoadrenal activation, shock and inflammation may be critical drivers of endothelial activation and damage early after trauma.

The prognostic value of thrombelastography in identifying neurosurgical patients with worse prognosis.

Coagulopathy in patients with intracranial haemorrhage or traumatic brain injury (TBI) is associated with clinical deterioration and worse outcome. Whole blood viscoelastic haemostatic assays, like thrombelastography (TEG), might aid conventional coagulation assays in identification of patients with worse prognosis. We performed a review of patients (totalling 78 patients) with primary acute intracranial haemorrhage or isolated TBI admitted to a neurointensive care unit (NICU) for more than 24 h during a period of 9 months, who had TEG analysis performed at admission. Primary outcome was all-cause 30-day mortality, whereas decline in Glasgow Coma Scale (GCS) score at 24 h after admission or death due to cerebral incarceration were secondary outcomes. Patients were defined as hypocoaguable if TEG reaction time was more than 8 min, angle less than 55° and/or maximal amplitude less than 51 mm. Patients were defined hypocoaguable according to conventional coagulation assays if international normalized ratio was more than 1.3, platelet counts less than 100×10/l and/or activated partial thromboplastine time more than 35 s. Eight patients were hypocoaguable by TEG on admission to NICU and had higher 30-day mortality (63% vs. 16%, P=0.008), more often declined in GCS (57% vs. 16%, P=0.02) and expired due to cerebral incarceration (50% vs. 6%, P=0.02). Hypocoagulability by TEG, lower admission GCS and subarachnoid haemorrhage were independently associated with higher 30-day mortality [TEG: odds ratio (OR) 14.8 (2.2-100.1), P=0.006; GCS: OR 1.3 (1.1-1.5), P=0.006; subarachnoid haemorrhage: OR: 5.3 (1.3-22.3), P=0.02]. Only two patients were hypocoaguable by both conventional coagulation assays and TEG. The current data indicate that hypocoagulability by TEG at admission to NICU predicts worse prognosis. Low concordance with conventional coagulation assays indicates that TEG might be valuable in identifying patients with clinically relevant coagulopathy.

Reduced clot strength upon admission, evaluated by thrombelastography (TEG), in trauma patients is independently associated with increased 30-day mortality.

INTRODUCTION: Exsanguination due to uncontrolled bleeding is the leading cause of potentially preventable deaths among trauma patients. About one third of trauma patients present with coagulopathy on admission, which is associated with increased mortality and will aggravate bleeding in a traumatized patient. Thrombelastographic (TEG) clot strength has previously been shown to predict outcome in critically ill patients. The aim of the present study was to investigate this relation in the trauma setting. METHODS: A retrospective study of trauma patients with an injury severity qualifying them for inclusion in the European Trauma Audit and Research Network (TARN) and a TEG analysis performed upon arrival at the trauma centre. RESULTS: Eighty-nine patients were included. The mean Injury Severity Score (ISS) was 21 with a 30-day mortality of 17%. Patients with a reduced clot strength (maximal amplitude < 50 mm) evaluated by TEG, presented with a higher ISS 27 (95% CI, 20-34) vs. 19 (95% CI, 17-22), p = 0.006 than the rest of the cohort. Clot strength correlated with the amount of packed red blood cells (p = 0.01), fresh frozen plasma (p = 0.04) and platelet concentrates (p = 0.03) transfused during the first 24 hours of admission. Patients with low clot strength demonstrated increased 30-day mortality (47% vs. 10%, p < 0.001). By logistic regression analysis reduced clot strength was an independent predictor of increased mortality after adjusting for age and ISS. CONCLUSION: Low clot strength upon admission is independently associated with increased 30-day mortality in trauma patients and it could be speculated that targeted interventions based on the result of the TEG analysis may improve patient outcome. Prospective randomized trials investigating this potential are highly warranted.

Transfusion requirements and clinical outcome in intensive care patients receiving continuous renal replacement therapy: comparison of prostacyclin vs. heparin prefilter administration.

Prostacyclin (PGI(2)) analogous are potent antithrombotics recommended as prefilter infusion during renal replacement therapy (RRT) when heparin is contraindicated. It is debated whether PGI(2) administration during RRT affects transfusion requirements and outcome. Retrospective cohort study of all patients at a general intensive care unit (ICU) receiving continuous RRT (CRRT) in a 14-month period. Patients were stratified according to the used anticoagulant, that is prefilter PGI(2) group (n=24) and prefilter heparin group (n=70). The ICU stay of the patients was divided into three time periods: before, during and after CRRT. For each time period, laboratory values were analysed as changes/day and blood transfusion requirements as absolute values. Organ failures during the ICU stay and 1 year all-cause mortality were registered. During CRRT the PGI(2) group had a higher incidence of disseminated intravascular coagulation (DIC) (P=0.006), severe thrombocytopenia (P=0.03), higher maximum Sequential Organ Failure Assessment score (P<0.001) and higher rate of blood transfusions (P=0.006) compared to the heparin group. However, patients in the PGI(2) group tended to have lower mortality rates compared to those in the heparin group (30 days, 21 vs. 39%, P=0.12; 90 days, 34 vs. 53%, P=0.10 and 365 days, 38 vs. 57%, P=0.09). Patients receiving prefilter PGI(2) during CRRT were more severely ill and required more blood transfusions. Despite this, a trend towards lower mortality was observed in the PGI(2) group suggesting beneficial effects of PGI(2) administration in ICU patients undergoing CRRT.