A blinded randomized study comparing intubating conditions after either rocuronium 0.6 mg·kg-1 or remifentanil 2 µg·kg-1 in elderly patients.

BACKGROUND: To facilitate tracheal intubation, either a neuromuscular blocking agent or a bolus dose of remifentanil can be administered. We hypothesized that rocuronium 0.6 mg·kg-1 provided a larger proportion of excellent intubating conditions compared to remifentanil 2 µg·kg-1 in patients above 80 years. METHODS: A total of 78 patients were randomized to either rocuronium 0.6 mg·kg-1 or remifentanil 2 µg·kg-1 . General anaesthesia was initiated with fentanyl and propofol. Two minutes after the administration of either rocuronium or remifentanil, tracheal intubating conditions were evaluated using the Fuchs-Buder scale by a blinded investigator, and our primary outcome was the proportion of patients presenting intubating conditions deemed as excellent. Further outcomes included the Intubating Difficulty Scale (IDS), hoarseness or sore throat 24 h postoperatively, and intervention against hypotension. RESULTS: No difference in the occurrence of excellent intubating conditions was found comparing the rocuronium group with the remifentanil group; 10 (28%) versus 15 (39%) (p = .29), respectively, relative risk = 0.72. Interventions against hypotension were used in 24 (67%) versus 28 (74%) (p = .51), respectively. Hoarseness and sore throat 24 h postoperatively were found in 37% versus 35% p = .86, and 14% versus 5% p = .20, respectively. The IDS score was 2 versus 2 p = .48. CONCLUSION: No difference in intubating conditions was found 2 min after the administration of either rocuronium 0.6 mg·kg-1 or remifentanil 2 µg·kg-1 in patients aged above 80 years. Intubation conditions were less than optimal in a large proportion of this patient population. CLINICAL TRIALS REGISTRATION: NCT04287426.

The biomarkers neuron-specific enolase and S100b measured the day following admission for severe accidental hypothermia have high predictive values for poor outcome.

AIM: The aim of the present study was to assess the ability of the biomarkers neuron-specific enolase (NSE) and S100 calcium-binding protein b (S100b) to predict mortality and poor neurologic outcome after 30days in patients admitted with severe accidental hypothermia. METHODS: Consecutive patients with severe accidental hypothermia, defined as a core temperature <32°C, were included. Patients were treated with active rewarming and/or extracorporeal life support (ECLS) using extra corporeal circulation (ECC) and/or extra corporeal membrane oxygenation (ECMO). The day following admission blood was analyzed for NSE and S100b. Follow-up was conducted after 30days and poor neurologic outcome was defined as a Cerebral Performance Category (CPC) score of 3-5. The predictive value of NSE and S100b was assessed as the area under the receiver-operating characteristics curve (AUC). RESULTS: A total of 34 patients were admitted with a diagnosis of severe accidental hypothermia and 29 (85%) were resuscitated from cardiac arrest. ECLS was initiated in 27 (79%) of patients. The day following admission three (9%) patients had died and one (3%) patient was awake, and accordingly, NSE and S100b were analyzed in 30 unconscious and/or sedated patients. NSE and S100b achieved AUCs of 0.93 and 0.88, respectively, for prediction of 30day mortality and AUCs of 0.88 and 0.87, respectively, for prediction of poor neurologic outcome. CONCLUSIONS: In patients remaining unconscious the day following admission for severe accidental hypothermia, the biomarkers NSE and S100b appear to be solid predictors of mortality and poor neurologic outcome after 30days.

Pilot Randomized trial of Fibrinogen in Trauma Haemorrhage (PRooF-iTH): study protocol for a randomized controlled trial.

BACKGROUND: Haemorrhage remains a leading cause of morbidity and mortality in trauma patients. Fibrinogen is an essential endogenous component of haemostasis and the plasma level is associated with bleeding, transfusion and outcome. Fibrinogen concentrate is widely used to correct acquired hypofibrinogenaemia, recommended by several international guidelines for the treatment of trauma patients, but evidence is lacking regarding the treatment safety and efficacy. We aim to assess the efficacy and safety of an immediate pre-emptive first-line treatment with fibrinogen concentrate in patients with trauma haemorrhage in need of haemostatic resuscitation. METHODS/DESIGN: This is a single-centre, randomized (1:1, active:placebo), placebo-controlled, double-blinded, investigator-initiated phase II trial. The trial population consists of 40 adult patients (>18 years) with traumatic, critical bleeding admitted to the Level 1 Trauma Centre at Rigshospitalet in Copenhagen, with immediate need for blood transfusion on arrival and an expected need for haemostatic resuscitation with multiple transfusions during the initial resuscitation. Patients will receive either pre-emptive administration of a bolus dose of 60-70 mg/kg fibrinogen concentrate (Riastap®) or placebo 0.9 % saline in equal volume to active treatment, both given as intravenous infusion blinded for the person administering the infusion. The primary end point is the change in thrombelastograph (TEG®) functional fibrinogen maximum amplitude in millimetres at 15 min after the intervention. The follow-up period on safety events and mortality will be until day 30. To detect a difference in the change from baseline to the 15-minute post-randomization measurement of 6-8 mm in TEG® functional fibrinogen maximum amplitude with a power of 0.90 and alpha of 0.05, we require 19 patients in each group. We have chosen to include 40 patients, 20 evaluable patients in each randomization group in case of attrition, in the present trial. DISCUSSION: Patients considered to be included in the trial will temporarily have a compromised consciousness because of the acute, critical bleeding related to trauma, so scientific guardians will co-sign the informed consent form. Next of kin and the patients' general practitioner or the patients will co-sign as soon as possible. This trial will test whether immediate pre-emptive fibrinogen concentrate administered to adult trauma patients as first-line treatment of trauma haemorrhage will increase the clot strength as evaluated by thrombelastography, transfusion requirements and survival in patients receiving haemostatic resuscitation according to current standard of care. TRIAL REGISTRATION: EudraCT no. 2014-003978-16 (22/1 2015); ClinicalTrials.gov: NCT02344069 . Registered on 14 January 2015. Trial protocol version 4.2 (23-12-2014).

Fibrinogen in trauma, an evaluation of thrombelastography and rotational thromboelastometry fibrinogen assays.

BACKGROUND: Identifying hypofibrinogenemia in trauma is important. The optimal method of fibrinogen determination is unknown. We therefore evaluated fibrinogen levels determined by two whole blood viscoelastic hemostatic assays, thrombelastography functional fibrinogen (FF) and rotational thromboelastometry FIBTEM in trauma patients and compared these with the plasma-based Clauss method. MATERIALS AND METHODS: Prospective study of consecutive adult trauma patients admitted to a level I trauma center. Levels of fibrinogen were analyzed by Clauss, FF, and FIBTEM on arrival. These methods were compared, and we then investigated whether specific cutoffs of fibrinogen levels were indicative for an increased risk of receiving a transfusion within the initial 6 h. RESULTS: A total of 182 patients with an Injury Severity Score of 17 (9-26) were enrolled. Functional fibrinogen maximum amplitude (FF MA) and FIBTEM maximum clot firmness (MCF) had identical correlation coefficients when compared with those of Clauss fibrinogen (both ρ = 0.64, P < 0.001), and FF MA and FIBTEM MCF correlated with each other (ρ = 0.71, P < 0.001). By logistic regression, the following cutoffs of fibrinogen levels were associated with increased odds of receiving a transfusion, red blood cell concentrates: Clauss <2.5 g/L, FF MA <14.9 mm, FIBTEM MCF <10 mm; fresh frozen plasma and platelets: Clauss <2.5 g/L, FF MA <16.9 mm, FIBTEM MCF <14 mm. CONCLUSIONS: The viscoelastic hemostatic assays for determining fibrinogen levels, FIBTEM and FF, are both correlated with the Clauss fibrinogen level, and there are no differences in the strength of these correlations. In this study, specific fibrinogen levels at arrival to the emergency department were indicative, although not necessarily causal, of increased odds of receiving a transfusion.

Is there a diurnal difference in mortality of severely injured trauma patients?

BACKGROUND: Mortality may be higher for admissions at odd hours than during daytime, although for trauma patients results are conflicting. The objective of this study was to assess whether diurnal differences in mortality among severely injured trauma patients in Denmark were present. METHODS: This observational cohort study was conducted between 1 December 2009 and 30 April 2011 involving one level 1 trauma centre and seven local emergency departments in eastern Denmark. Patients were consecutively included if received by a designated trauma team. Night-time patients (20:00-07:59) were compared with daytime patients (20:00-07:59). An injury severity score (ISS) >15 defined severe injury. Patients with burns and patients who upon arrival were declared non-trauma patients were not included. The primary outcome measure was 30-day mortality. RESULTS: A total of 1985 patients were recorded, of whom 576 were admitted at night-time, 1369 at daytime and 40 not included due to missing data. There were 142 patients with ISS >15 in the daytime group and 64 at night-time. The 30-day mortality was 14.1% for admittance at night-time versus 21.3% at daytime (p=0.22). Logistic regression analysis revealed that odd-hour admission was not a significant predictor of mortality for patients with ISS >15 when adjusted for age, ISS and initial treatment facility (OR 0.71 (95% CI 0.27 to 1.90); p=0.50). CONCLUSIONS: In conclusion, we found no diurnal differences in 30-day mortality for severely injured trauma patients.

Low level of procoagulant platelet microparticles is associated with impaired coagulation and transfusion requirements in trauma patients.

BACKGROUND: Following activation, platelets release small vesicles called platelet-derived microparticles (PMPs). PMPs accelerate thrombin generation and thus clot formation at sites of injury by exposing the procoagulant membrane phospholipid phosphatidylserine (PS). The role of PMPs in coagulopathy and hemorrhage following trauma remains elusive. We hypothesized that low levels of PS-positive PMPs (PS + PMPs) would be associated with impaired clot formation. METHODS: This is a prospective observational study of 210 trauma patients admitted directly to a Level 1 trauma center. Plasma levels of PS + PMPs were determined by flow cytometry. Coagulation status was assessed by rotational thrombelastometry, and impaired clot formation was defined by an α angle less than 63 degrees using the tissue factor-based EXTEM reagent. Transfusion requirement was assessed by number of units of red blood cells (RBCs) transfused within 24 hours of admission; platelet aggregation capacity was evaluated by the Multiplate assay; and injury severity was determined by the Injury Severity Score (ISS). RESULTS: The median ISS was 17, and blood samples were obtained after a median of 65 minutes following injury. Significantly lower levels of PS + PMPs were found in patients with impaired clot formation (p < 0.001). A low level of PS + PMPs was associated with a higher number of RBCs transfused during the initial 24 hours after admission (p < 0.03) when corrected for risk factors, for example, platelet count, hemoglobin level, and ISS. Platelet aggregation and PS + PMPs did not correlate significantly. CONCLUSION: Low levels of PMPs were associated with impaired clot formation in trauma patients at admission and also with the number of RBC transfusions. This suggests that PMPs may play an important and not previously investigated role in trauma-induced coagulopathy. LEVEL OF EVIDENCE: Prognostic study, level III.

Thrombelastography and rotational thromboelastometry early amplitudes in 182 trauma patients with clinical suspicion of severe injury.

BACKGROUND: Viscoelastic hemostatic assays may provide means for earlier detection of trauma-induced coagulopathy (TIC). METHODS: This is a prospective observational study of 182 trauma patients admitted to a Level 1 trauma center. Clinical data, thrombelastography (TEG), and rotational thromboelastometry (ROTEM) parameters were recorded upon arrival. Citrated kaolin (CK), rapid TEG (rTEG), and functional fibrinogen curves were extracted, and early amplitudes A5 and A10 were registered. Patients were stratified according to international normalized ratio of 1.2 or less and international normalized ratio greater than 1.2 (TIC patients) as well as transfusion needs (no red blood cells [RBCs], 1-9 RBCs, and ≥10 RBC in 6 hours). Correlations were analyzed by Spearman's correlation. RESULTS: TIC patients had lower amplitudes than non-TIC patients in ROTEM/TEG as follows: EXTEM, INTEM, and FIBTEM: A5, A10, and maximum clot firmness (MCF); rTEG: A10; CK: maximum amplitude (MA); and functional fibrinogen: A5, A10, and MA (p < 0.05). Furthermore, A5 and A10 had a strong correlation with MA/MCF (ρ > 0.7 and p < 0.01). The A10 amplitudes were significantly lower in patients transfused with 10 or more units of RBC compared with nontransfused patients (p < 0.02). Fibrinogen concentration and platelet count had moderate correlation with A10 compared with A5 and MA/MCF (0.3 < ρ < 0.7 and p < 0.01). Time (median [interquartile range], in minutes) to obtain a reading was faster for A10 than MA/MCF (p < 0.001) (CK, 16 [15-17] vs. 27 [25-30]; rTEG, 11 [11-11] vs. 18 [17-20]; EXTEM, 11 [11-11] vs. 29 [26-31]; and INTEM 13[12-13] vs. 25 [22-29]). CONCLUSION: Early amplitudes were lower in TIC patients, had significant correlations with MA/MCF, and differentiated between nontransfused and patients receiving one to nine RBC units or 10 or more RBC units within 6 hours. A10's superior correlation with platelet count and fibrinogen concentration suggests that A10 reflects a more dynamic part of the hemostatic process rather than MA/MCF. Early amplitudes may translate into earlier goal-directed transfusion therapy and may allow refinement of existing transfusion algorithms. LEVEL OF EVIDENCE: Prognostic and diagnostic study, level III.

Impact of the severity of trauma on early retirement.

OBJECTIVE: To assess the association between Injury Severity Score (ISS) and subsequent risk of early retirement. DESIGN: Observational cohort study with follow-up based on prospectively collected data. Hospital-based data were linked to national register data on pension reception and vital status. SETTING: Level-one urban trauma centre. PARTICIPANTS: Patients aged 18-64 years entering the trauma centre in Copenhagen during 1999-2007 who were alive after three days were followed until early retirement, death or emigration. MAIN OUTCOME MEASURES: Primary outcome was early retirement, defined as receiving disability pension (unintentional) or voluntary early retirement pension (intentional) before the regular age of retirement (65 years). Relative risk of early retirement according to ISS (low, ISS 1-15 vs. high, ISS 16-75) was assessed using Cox proportional hazards regression, adjusted for age and gender. RESULTS: Of all 6687 patients admitted to the trauma centre, a total of 1722 trauma patients were included and followed for a median of 6.2 years (interquartile range (IQR) 3.7-9.1). Of these, 1305 (75.8%) were males, median age was 35.0 years (IQR 25.4-46.5), and median ISS was 16 (IQR 9-25). Three hundred and twenty-two patients retired during follow-up. Patients with high ISS, compared to patients with low ISS, had an increased risk of early retirement, adjusted hazard ratio 2.60 (95% confidence interval (CI) 2.05-3.30; p<0.001). Relative increase in retirement risk was 1.04 (95% CI 1.03-1.05) per ISS point and 1.03 (95% CI 1.03-1.04) per year older. Gender was not found to be a significant risk factor (p=0.69). Five-year absolute risks of early retirement were 9.9% (95% CI 7.8-12.0%) for the low ISS group and 24.6% (95% CI 21.6-27.5%) for the high ISS group. CONCLUSIONS: The risk of early retirement is 2.6 times higher in severely injured patients (ISS 16-75) than the risk in low to moderately injured patients (ISS 1-15) and they have a high absolute 5-year risk as well. Early, targeted interventions to assist with return to work might be able to reduce this risk.

Optimization of burn referrals.

INTRODUCTION: Correct estimation of the severity of burns is important to obtain the right treatment of the patient and to avoid over- and undertriage. In this study we aimed to assess how often the guidelines for referral of burn injured patients are met at the national burn centre (NBC), Denmark. METHODS: We included burn patients referred to the NBC in a three-months period. Patient records were systematically analyzed and compared with the national guidelines for referral of burn injured patients. RESULTS: A total of 97 burn injured patients were transferred for treatment at the NBC and the most common reason for referral was partial thickness burn exceeding 3% estimated area of burn (55% of the patients) while facial burns (32%) and inhalational injury (25%) were other common reasons. We found that 29 (30%) of the referrals were considered potentially unnecessary according to the guidelines. The overtriage was highest among patients suffering of burns due to scalding and these were mostly children below 2 years of age. CONCLUSION: An overtriage of referred burn injured patient was found and 30% of the referred patients were treated as outpatients. A telemedicine solution may be useful in the evaluation of burn injured patients before transfer.

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.

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.

Trauma-induced coagulopathy: standard coagulation tests, biomarkers of coagulopathy, and endothelial damage in patients with traumatic brain injury.

It remains to be debated whether traumatic brain injury (TBI) induces a different coagulopathy than does non-TBI. This study investigated traditional coagulation tests, biomarkers of coagulopathy, and endothelial damage in trauma patients with and without TBI. Blood from 80 adult trauma patients was sampled (median of 68 min [IQR 48-88] post-injury) upon admission to our trauma center. Plasma/serum were retrospectively analyzed for biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), coagulation activation/inhibition and fibrinolysis (protein C, activated protein C, tissue factor pathway inhibitor, antithrombin, prothrombin fragment 1+2, thrombin/antithrombin complex, von Willebrand factor, factor XIII, d-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1), immunology (interleukin [IL]6), endothelial cell/glycocalyx damage (soluble thrombomodulin, syndecan-1), and vasculogenesis (angiopoietin-1, -2). Patients were stratified according to: (1) isolated severe head/neck injuries (Abbreviated injury score [AIS]-head/neck ≥ 3, AIS-other<3) (isoTBI); (2) severe head/neck and extracranial injuries (AIS-head/neck ≥ 3, AIS-other>3) (sTBI+other); and (3) injuries without significant head/neck injuries (AIS-head/neck<3, including all AIS-other scores) (non-TBI). Twenty-three patients presented with isoTBI, 15 with sTBI+other and 42 with non-TBI. Acute coagulopathy of trauma shock, defined as activated partial thromboplastin time (APTT) and/or international normalized ratio (INR)>35 sec and>1.2, was found in 13%, 47%, and 5%, respectively (p=0.000). sTBI+other had significantly higher plasma levels of adrenaline, noradrenaline, annexin V, d-dimer, IL-6, syndecan-1, soluble thrombomodulin, and reduced protein C and factor XIII levels (all p<0.05). No significant biomarker differences were found between isoTBI and non-TBI patients. Injury severity scale (ISS) rather than the presence or absence of head/neck injuries determined the hemostatic and biomarker response to the injury. The coagulopathy identified thus reflected the severity of injury rather than its localization.

Elderly trauma patients have high circulating noradrenaline levels but attenuated release of adrenaline, platelets, and leukocytes in response to increasing injury severity.

OBJECTIVE: High patient age is a strong predictor of poor outcome in trauma patients. The present study investigated the effect of age on mortality and biomarkers of sympathoadrenal activation, tissue, endothelial, and glycocalyx damage, coagulation activation/inhibition, fibrinolysis, and inflammation in trauma patients at admission. DESIGN: Prospective observational study. SETTING: Single level I trauma center. PATIENTS: Eighty adult trauma patients (≥18 yrs) who met criteria for full trauma team activation and had an arterial cannula. INTERVENTION: Blood sampling a median of 68 min (interquartile range 48-88) post injury. MEASUREMENTS: Data on demography, biochemistry, Injury Severity Score, and 30-day mortality were recorded and plasma/serum was analyzed for biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments, annexin V, thrombomodulin, syndecan-1), platelet activation (soluble CD40 ligand), coagulation activation/inhibition (prothrombin fragment 1.2, thrombin/antithrombin complex, antithrombin, protein C, activated protein C, protein S, soluble endothelial protein C receptor, tissue factor pathway inhibitor, von Willebrand factor, fibrinogen, factor XIII), fibrinolysis (D-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1), and inflammation (interleukin-6, terminal complement complex). Patients were stratified according to the median age (46 yrs) of the full cohort. RESULTS: Older trauma patients had markedly higher noradrenaline (p < .001) but an attenuated increase in adrenaline with increasing Injury Severity Score and lower platelets and leukocytes (both p < .05) compared to the younger patients. Older patients displayed a biomarker profile suggestive of enhanced release, activation, and consumption of the natural anticoagulants (low antithrombin, high activated protein C, protein S, and tissue factor pathway inhibitor) and hyperfibrinolysis (high tissue-type plasminogen activator) (all p < .05 vs. younger patients). Age was an independent predictor of mortality (hazard ratio 1.04 [95% confidence interval 1.01-1.07], p = .005) after adjusting for Injury Severity Score, prehospital Glasgow Coma Scale, and plasma catecholamines. CONCLUSIONS: In trauma patients, the association between age and mortality was confirmed. Older patients had high plasma noradrenaline but attenuated adrenaline release with higher Injury Severity Score, impaired platelet and leukocyte mobilization, enhanced consumption of anticoagulants, and hyperfibrinolysis, which may all contribute to the poor outcome in these patients.

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.

Detection of tPA-induced hyperfibrinolysis in whole blood by RapidTEG, KaolinTEG, and functional fibrinogenTEG in healthy individuals.

BACKGROUND: Rapid identification of clinically relevant coagulopathies in, acute coagulopathy of trauma shock (ACOTS) has led to the development of faster point-of-care viscoelastic whole-blood-based tests like rapid thrombelastography (RapidTEG). The sensitivity of RapidTEG to detect hyperfibrinolysis, as compared to standard KaolinTEG, is unknown. To investigate this, the ability of RapidTEG, KaolinTEG, and functional fibrinogenTEG (FFTEG) to detect tPA-induced (tissue plasminogen activator) lysis in whole blood from healthy individuals was investigated. Our hypothesis was that the initial powerful clot formation in the RapidTEG assay would reduce the sensitivity as compared to the normally used KaolinTEG assay. We also evaluated the FFTEG assay. METHODS: In vitro comparison of the sensitivity of RapidTEG, KaolinTEG, and FFTEG to 1.8 nmol/L tPA in citrated whole blood (299 ± 23 ng/mL plasma) induced hyperfibrinolysis in 10 healthy individuals and duplicate titration of the tPA whole blood (WB) concentration from 0.09 to 7.2 nmol/L (14-1144 ng/mL plasma) in 1 healthy donor. RESULTS: At 1.8 nmol/L tPA, KaolinTEG, RapidTEG, and FFTEG all detected fibrinolysis but with different sensitivities. In the titration study, KaolinTEG and FFTEG displayed a continuous dose-response association and RapidTEG also displayed a dose-dependent response but only for higher levels of tPA, thus yielding a smaller "dose-sensitive range" compared to KaolinTEG and FFTEG. CONCLUSION: This pilot study demonstrated that KaolinTEG, RapidTEG, and FFTEG all were able to detect lysis at 1.8 nmol/L tPA but with a difference in sensitivity. Furthermore, KaolinTEG and FFTEG showed a continuous dose dependence related to the tPA concentration, whereas RapidTEG only detected lysis at higher tPA concentrations.

Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An observational study.

INTRODUCTION: It is debated whether early trauma-induced coagulopathy (TIC) in severely injured patients reflects disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype, acute coagulopathy of trauma shock (ACoTS) or yet other entities. This study investigated the prevalence of overt DIC and ACoTS in trauma patients and characterized these conditions based on their biomarker profiles. METHODS: An observational study was carried out at a single Level I Trauma Center. Eighty adult trauma patients (≥18 years) who met criteria for full trauma team activation and had an arterial cannula inserted were included. Blood was sampled a median of 68 minutes (IQR 48 to 88) post-injury. Data on demography, biochemistry, injury severity score (ISS) and mortality were recorded. Plasma/serum was analyzed for biomarkers reflecting tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments, Annexin V, thrombomodulin, syndecan-1), coagulation activation/inhibition (prothrombinfragment 1+2, thrombin/antithrombin-complexes, antithrombin, protein C, activated protein C, endothelial protein C receptor, protein S, tissue factor pathway inhibitor, vWF), factor consumption (fibrinogen, FXIII), fibrinolysis (D-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1) and inflammation (interleukin (IL)-6, terminal complement complex (sC5b-9)). Comparison of patients stratified according to the presence or absence of overt DIC (International Society of Thrombosis and Hemostasis (ISTH) criteria) or ACoTS (activated partial thromboplastin time (APTT) and/or international normalized ratio (INR) above normal reference). RESULTS: No patients had overt DIC whereas 15% had ACoTS. ACoTS patients had higher ISS, transfusion requirements and mortality (all P < 0.01) and a biomarker profile suggestive of enhanced tissue, endothelial cell and glycocalyx damage and consumption coagulopathy with low protein C, antithrombin, fibrinogen and FXIII levels, hyperfibrinolysis and inflammation (all P < 0.05). Importantly, in non-ACoTS patients, apart from APTT/INR, higher ISS correlated with biomarkers of enhanced tissue, endothelial cell and glycocalyx damage, protein C activation, coagulation factor consumption, hyperfibrinolysis and inflammation, that is, resembling that observed in patients with ACoTS. CONCLUSIONS: ACoTS and non-ACoTS may represent a continuum of coagulopathy reflecting a progressive early evolutionarily adapted hemostatic response to the trauma hit and both are parts of TIC whereas DIC does not appear to be part of this early response.

Thrombelastography and biomarker profiles in acute coagulopathy of trauma: a prospective study.

BACKGROUND: Severe injury induces an acute coagulopathy associated with increased mortality. This study compared the Thrombelastography (TEG) and biomarker profiles upon admission in trauma patients. METHODS: Prospective observational study of 80 trauma patients admitted to a Level I Trauma Centre. Data on demography, biochemistry including standard coagulation tests, hematology, transfusions, Injury Severity Score (ISS) and TEG were recorded. Retrospective analysis of thawed plasma/serum for biomarkers reflecting tissue injury (histone-complexed DNA fragments), sympathoadrenal activation (adrenaline, noradrenaline), coagulation activation/inhibition and fibrinolysis (sCD40L, protein C, activated Protein C, tissue-type plasminogen activator, plasminogen activator inhibitor-1, D-dimer, prothrombinfragment 1+2, plasmin/α2-antiplasmin complex, thrombin/antithrombin complex, tissue factor pathway inhibitor, antithrombin, von willebrand factor, factor XIII). Comparison of patients stratified according to ISS/TEG maximum clot strength. Linear regression analysis of variables associated with clot strength. RESULTS: Trauma patients had normal (86%), hypercoagulable (11%) or hypocoagulable (1%) TEG clot strength; one had primary hyperfibrinolysis. Hypercoagulable patients had higher age, fibrinogen and platelet count (all p < 0.05), none had increased activated partial thromboplastin time (APTT) or international normalized ratio (INR) and none required massive transfusion (> 10 red blood cells the initial 24 h). Patients with normal or hypercoagulable TEG clot strength had comparable biomarker profiles, but the few patients with hypocoagulable TEG clot strength and/or hyperfibrinolysis had very different biomarker profiles.Increasing ISS was associated with higher levels of catecholamines, histone-complexed DNA fragments, sCD40L, activated protein C and D-dimer and reduced levels of non-activated protein C, antithrombin, fibrinogen and factor XIII (all p < 0.05). Fibrinogen and platelet count were associated independently with clot strength in patients with ISS ≤ 26 whereas only fibrinogen was associated independently with clot strength in patients with ISS > 26. In patients with ISS > 26, adrenaline and sCD40L were independently negatively associated with clot strength. CONCLUSIONS: Trauma patients displayed different coagulopathies by TEG and variables independently associated with clot strength changed with ISS. In the highest ISS group, adrenaline and sCD40L were independently negatively associated with clot strength indicating that these may contribute to acute coagulopathy.

[Prehospital treatment of severely injured patients with focus on damage control-surgery]. / Præhospital behandling af svært tilskadekomne patienter med fokus på damage control-kirurgi.

The majority of patients undergoing damage control surgery initially receive prehospital treatment. Bleeding causes 40% of trauma deaths, half of which happen in the prehospital setting. Future research and improved treatment before hospital admission should focus on control of the bleeding, avoidance of hypothermia, minimising the time to definitive surgery, and a restrictive and goal directed therapy with regard to the intake of fluids. On occasion, lifesaving procedures could be performed during transport to the hospital.

Resuscitation, prolonged cardiac arrest, and an automated chest compression device.

BACKGROUND: The European Resuscitation Council's 2005 guidelines for cardiopulmonary resuscitation (CPR) emphasize the delivery of uninterrupted chest compressions of adequate depth during cardiac arrest. OBJECTIVES: To describe how the circumstances of out-of-hospital cardiac arrest can impede the performance of CPR, and how this situation can be overcome. CASE REPORT: The presentation of two cases of prolonged CPR (48 min and 120 min, respectively) with an automated chest compression device, the AutoPulse, under difficult circumstances. Both patients survived without neurological sequelae. CONCLUSION: Prolonged chest compressions may be necessary in some cardiac arrests. These cases suggest that automated chest compression devices may increase the chance of a favorable outcome in these rare situations.