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Prehospital tranexamic acid is associated with a dose-dependent decrease in syndecan-1 after trauma: A secondary analysis of a prospective randomized trial
Gruen DS, Brown JB, Guyette FX, Johansson PI, Stensballe J, Li SR, Leeper CM, Eastridge BJ, Nirula R, Vercruysse GA, et al
The journal of trauma and acute care surgery. 2023
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Editor's Choice
Abstract
BACKGROUND In the Study of Tranexamic Acid During Air and Ground Prehospital Transport (STAAMP) Trial, prehospital tranexamic acid (TXA) was associated with lower mortality in specific patient subgroups. The underlying mechanisms responsible for a TXA benefit remain incompletely characterized. We hypothesized that TXA may mitigate endothelial injury and sought to assess whether TXA was associated with decreased endothelial or tissue damage markers among all patients enrolled in the STAAMP Trial. METHODS We collected blood samples from STAAMP Trial patients and measured markers of endothelial function and tissue damage including syndecan-1, soluble thrombomodulin (sTM), and platelet endothelial cell adhesion molecule-1 (PECAM-1) at hospital admission (0 hours) and 12, 24, and 72 hours after admission. We compared these marker values for patients in each treatment group during the first 72 hours, and modeled the relationship between TXA and marker concentration using regression analysis to control for potential confounding factors. RESULTS We analyzed samples from 766 patients: 383 placebo, 130 abbreviated dosing, 119 standard dosing, and 130 repeat dosing. Lower levels of syndecan-1, TM, and PECAM measured within the first 72 hours of hospital admission were associated with survival at 30 days (P < 0.001). At hospital admission, syndecan-1 was lower in the TXA group (28.30 [20.05, 42.75] vs. 33.50 [23.00, 54.00] P = 0.001) even after controlling for patient, injury, and prehospital factors (P = 0.001). For every 1 g increase in TXA administered over the first 8 hours of prehospital transport and hospital admission, there was a 4 ng/mL decrease in syndecan-1 at 12 hours controlling for patient, injury, and treatment factors (P = 0.03). CONCLUSIONS Prehospital TXA was associated with decreased syndecan-1 at hospital admission. Syndecan-1 measured 12 hours after admission was inversely related to the dose of TXA received. Early pre- and in-hospital TXA may decrease endothelial glycocalyx damage or upregulate vascular repair mechanisms in a dose-dependent fashion. LEVEL OF EVIDENCE Level II, Secondary analysis of a prospective randomized trial.
PICO Summary
Population
Injured patients who received prehospital tranexamic acid (TXA) and were at risk for haemorrhage enrolled in the STAAMP randomised controlled trial (n= 766).
Intervention
Abbreviated dose: 1g of TXA (n= 130). Standard dose: 2g of TXA (n= 119). Repeat dose: 3g of TXA (n= 130).
Comparison
Placebo (saline), (n= 383).
Outcome
Blood samples were collected to measure markers of endothelial function and tissue damage including syndecan-1, soluble thrombomodulin (sTM), and platelet endothelial cell adhesion molecule-1 (PECAM-1) at hospital admission and 12, 24, and 72 hours after admission. Lower levels of syndecan-1, TM, and PECAM measured within the first 72 hours of hospital admission were associated with survival at 30 days. At hospital admission (mean ng/mL [IQR]), syndecan-1 was lower in the TXA group than the placebo group (28.30 [20.05, 42.75] vs. 33.50 [23.00, 54.00]) even after controlling for patient, injury, and prehospital factors. For every 1g increase in TXA administered over the first 8 hours of prehospital transport and hospital admission, there was a 4 ng/mL decrease in syndecan-1 at 12 hours controlling for patient, injury, and treatment factors.
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Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial
Baksaas-Aasen K, Gall LS, Stensballe J, Juffermans NP, Curry N, Maegele M, Brooks A, Rourke C, Gillespie S, Murphy J, et al
Intensive care medicine. 2020
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Editor's Choice
Abstract
PURPOSE Contemporary trauma resuscitation prioritizes control of bleeding and uses major haemorrhage protocols (MHPs) to prevent and treat coagulopathy. We aimed to determine whether augmenting MHPs with Viscoelastic Haemostatic Assays (VHA) would improve outcomes compared to Conventional Coagulation Tests (CCTs). METHODS This was a multi-centre, randomized controlled trial comparing outcomes in trauma patients who received empiric MHPs, augmented by either VHA or CCT-guided interventions. Primary outcome was the proportion of subjects who, at 24 h after injury, were alive and free of massive transfusion (10 or more red cell transfusions). Secondary outcomes included 28-day mortality. Pre-specified subgroups included patients with severe traumatic brain injury (TBI). RESULTS Of 396 patients in the intention to treat analysis, 201 were allocated to VHA and 195 to CCT-guided therapy. At 24 h, there was no difference in the proportion of patients who were alive and free of massive transfusion (VHA: 67%, CCT: 64%, OR 1.15, 95% CI 0.76-1.73). 28-day mortality was not different overall (VHA: 25%, CCT: 28%, OR 0.84, 95% CI 0.54-1.31), nor were there differences in other secondary outcomes or serious adverse events. In pre-specified subgroups, there were no differences in primary outcomes. In the pre-specified subgroup of 74 patients with TBI, 64% were alive and free of massive transfusion at 24 h compared to 46% in the CCT arm (OR 2.12, 95% CI 0.84-5.34). CONCLUSION There was no difference in overall outcomes between VHA- and CCT-augmented-major haemorrhage protocols.
PICO Summary
Population
Trauma patients from the ITACTIC trial (n= 396).
Intervention
Empiric major haemorrhage protocols (MHPs) augmented by Viscoelastic Haemostatic Assays (VHA), (n= 201).
Comparison
Interventions guided by Conventional Coagulation Tests (CCTs), (n= 195).
Outcome
At 24 h, there was no difference in the proportion of patients who were alive and free of massive transfusion (VHA: 67%, CCT: 64%). 28-day mortality was not different overall (VHA: 25%, CCT: 28%), nor were there differences in other secondary outcomes or serious adverse events. In pre-specified subgroups which included patients with severe traumatic brain injury (TBI), there were no differences in primary outcomes. In the pre-specified subgroup of 74 patients with TBI, 64% were alive and free of massive transfusion at 24 h compared to 46% in the CCT arm.
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The use of viscoelastic haemostatic assays in goal-directing treatment with allogeneic blood products - a systematic review and meta-analysis
Fahrendorff M, Oliveri RS, Johansson PI
Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. 2017;25((1)):39.
Abstract
BACKGROUND Management of the critically bleeding patient can be encountered in many medical and surgical settings. Common for these patients is a high risk of dying from exsanguination secondary to developing coagulopathy. The purpose of this meta-analysis was to systematically review and assess randomised controlled trials (RCTs) performed on patients in acute need for blood transfusions due to bleeding to evaluate the effect of viscoelastic haemostatic assay (VHA) guidance on bleeding, transfusion requirements and mortality. METHODS PubMed and EMBASE were searched for RCTs that 1) randomised patients into receiving transfusions based on either a VHA-guided (thromboelastography [TEG] or rotational thromboelastometry [ROTEM]) algorithm (intervention group) or at the clinician's discretion and/or based on conventional coagulation tests (control group) and 2) adequately reported on the outcomes bleeding and/or transfusions and/or mortality. Data on bleeding, transfusions and mortality were extracted from each trial and included in a meta-analysis. RESULTS Fifteen RCTs (n = 1238 patients) were included. Nine trials referred to cardiothoracic patients, one to liver transplantation, one to surgical excision of burn wounds and one to trauma. One trial was conducted with cirrhotic patients, one with patients undergoing scoliosis surgery while one trial randomised treatment in post-partum females presenting with bleeding. The amount of transfused red blood cells (RBCs), fresh frozen plasma (FFP) and bleeding volume was found to be significantly reduced in the VHA-guided groups, whereas no significant difference was found for platelet transfusion requirements or mortality.
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Impact of albumin on coagulation competence and hemorrhage during major surgery: a randomized controlled trial
Rasmussen KC, Hojskov M, Johansson PI, Kridina I, Kistorp T, Salling L, Nielsen HB, Ruhnau B, Pedersen T, Secher NH
Medicine. 2016;95((9)):e2720.
Abstract
For patients exposed to a massive blood loss during surgery, maintained coagulation competence is important. It is less obvious whether coagulation competence influences bleeding during elective surgery where patients are exposed to infusion of a crystalloid or a colloid.This randomized controlled trial evaluates whether administration of 5% human albumin (HA) or lactated Ringer solution (LR) affects coagulation competence and in turn blood loss during cystectomy due to bladder cancer.Forty patients undergoing radical cystectomy were included to receive either 5% HA (n = 20) or LR (n = 20). Nineteen patients were analyzed in the HA group and 20 patients in the lactated Ringer group.Blinded determination of the blood loss was similar in the 2 groups of patients: 1658 (800-3300) mL with the use of HA and 1472 (700-4330) mL in the lactated Ringer group (P = 0.45). Yet, by thrombelastography (TEG) evaluated coagulation competence, albumin affected clot growth (TEG-angle 69 +/- 5 vs 74 degrees +/- 3 degrees , P < 0.01) and strength (TEG-MA: 59 +/- 6 vs 67 +/- 6 mm, P < 0.001) more than LR. Furthermore, by multivariate linear regression analyses reduced TEG-MA was independently associated with the blood loss (P = 0.042) while administration of albumin was related to the changes in TEG-MA (P = 0.029), aPPT (P < 0.022), and INR (P < 0.033).This randomized controlled trial demonstrates that administration of HA does not affect the blood loss as compared to infusion of LR. Also the use of HA did not affect the need for blood transfusion, the incidence of postoperative complications, or the hospital in-stay. Yet, albumin decreases coagulation competence during major surgery and the blood loss is related to TEG-MA rather than to plasma coagulation variables.
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A randomized trial of the effect of low dose epinephrine infusion in addition to tranexamic acid on blood loss during total hip arthroplasty
Jans O, Grevstad U, Mandoe H, Kehlet H, Johansson PI
British Journal of Anaesthesia. 2016;116((3):):357-62
Abstract
BACKGROUND Total hip arthroplasty (THA) is associated with both intraoperative and postoperative blood loss resulting in anaemia and, in some patients, transfusion of red blood cells. Epinephrine enhances coagulation by several mechanisms. We evaluated the effect of intraoperative low dose infusion of epinephrine on intraoperative and early postoperative blood loss. METHODS After consent, 106 subjects undergoing THA under spinal anaesthesia were randomly assigned to receive an i.v. infusion of either epinephrine 0.05 microg kg-1 min-1 or placebo (saline 0.9%) during the entire surgical procedure. Intraoperative tranexamic acid (TXA) was administered to all subjects. The primary outcome was intraoperative blood loss directly measured by drains and weighing swabs. Secondary outcome was total blood loss at 24 h postoperatively calculated using the Gross formula. RESULTS Of 106 subjects randomized, 6 were excluded, leaving 100 subjects for analyses. Mean duration of surgery was 58 (21) min. Intraoperative blood loss was 343 (95% CI 300-386) ml in the epinephrine group compared with 385 (353-434) ml in the placebo group, P = 0.228. 24 h blood loss was 902 (800-1004) ml in the epinephrine group compared with 1080 (946-1220) ml in the placebo group, P = 0.038. CONCLUSION In subjects also receiving TXA, intraoperative low dose epinephrine infusion did not reduce intraoperative blood loss in THA but calculated 24 h blood loss was reduced by 180 ml compared with placebo. Further studies on low dose epinephrine in patients at high risk of significant bleeding are warranted. CLINICAL TRIAL REGISTRATION NCT 01708642.
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Intravenous iron isomaltoside 1000 (Monofer() ) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: a randomized double-blind placebo-controlled clinical trial (the PROTECT trial)
Johansson PI, Rasmussen AS, Thomsen LL
Vox Sanguinis. 2015;109((3)):257-66.
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Abstract
BACKGROUND AND OBJECTIVES This trial explores whether intravenous iron isomaltoside 1000 (Monofer() ) results in a better regeneration of haemoglobin levels and prevents anaemia compared to placebo in preoperative non-anaemic patients undergoing cardiac surgery. STUDY DESIGN AND METHODS The trial is a prospective, double-blind, comparative, placebo-controlled trial of 60 non-anaemic patients undergoing cardiac surgery. The patients were randomized 1:1 to either 1000 mg intravenous iron isomaltoside 1000 administered perioperatively by infusion or placebo. RESULTS Mean preoperative haemoglobin in the active treatment group was 143 g/dl vs. 140 g/dl in the placebo group. At discharge 5 days after surgery, haemoglobin levels were reduced to 107 and 105 g/dl, respectively. One month after surgery, haemoglobin concentration had increased to an average of 126 g/dl vs. 118 g/dl (p = 0012) and significantly more patients were non-anaemic in the intravenous iron isomaltoside 1000-treated group compared to the placebo group (385% vs. 80%; p = 0019). There were no differences in side-effects between the groups. CONCLUSION A single perioperative 1000 mg dose of intravenous iron isomaltoside 1000 significantly increased the haemoglobin level and prevented anaemia 4 weeks after surgery, with a short-term safety profile similar to placebo. Future trials on potential clinical benefits of preoperative treatment with intravenous iron in non-anaemic patients are needed.Copyright © 2015 The Authors ISBT Science Series published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.
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Lower versus higher hemoglobin threshold for transfusion in septic shock
Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S, Johansson PI, Aneman A, Vang ML, Winding R, et al
New England Journal of Medicine. 2014;371((15):):1381-91.
Abstract
BACKGROUND Blood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established. METHODS In this multicenter, parallel-group trial, we randomly assigned patients in the intensive care unit (ICU) who had septic shock and a hemoglobin concentration of 9 g per deciliter or less to receive 1 unit of leukoreduced red cells when the hemoglobin level was 7 g per deciliter or less (lower threshold) or when the level was 9 g per deciliter or less (higher threshold) during the ICU stay. The primary outcome measure was death by 90 days after randomization. RESULTS We analyzed data from 998 of 1005 patients (99.3%) who underwent randomization. The two intervention groups had similar baseline characteristics. In the ICU, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0 to 3) and the higher-threshold group received a median of 4 units (interquartile range, 2 to 7). At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P=0.44). The results were similar in analyses adjusted for risk factors at baseline and in analyses of the per-protocol populations. The numbers of patients who had ischemic events, who had severe adverse reactions, and who required life support were similar in the two intervention groups. CONCLUSIONS Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions. (Funded by the Danish Strategic Research Council and others; TRISS ClinicalTrials.gov number, NCT01485315.).
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Perioperative transfusion threshold and ambulation after hip revision surgery - a randomized trial
Nielsen K, Johansson PI, Dahl B, Wagner M, Frausing B, Borglum J, Jensen K, Sturup J, Hvolris J, Rasmussen LS
BMC Anesthesiology. 2014;14:89.
Abstract
BACKGROUND Transfusion with red blood cells (RBC) may be needed during hip revision surgery but the appropriate haemoglobin concentration (Hb) threshold for transfusion has not been well established. We hypothesized that a higher transfusion threshold would improve ambulation after hip revision surgery. METHODS The trial was registered at Clinicaltrials.gov ( NCT00906295). Sixty-six patients aged 18 years or older undergoing hip revision surgery were randomized to receive RBC at a Hb threshold of either 7.3 g/dL (restrictive group) or 8.9 g/dL (liberal group). Postoperative ambulation was assessed using Timed Up and Go-test (TUG) and ability to walk was also assessed daily by a physiotherapist blinded to the allocation. RESULTS Fifty-three patients were able to perform the TUG and included in the analysis. The TUG could be completed in a median of 36 sec vs. 30 sec in the restrictive group and the liberal group, respectively (P=0.02). The mean difference in TUG was 14.5 sec (95% CI 2.8-26.2 sec). No difference was found in the day patients could perform TUG or walk 10 meters. The Hb at the day of testing was 10.2 g/dL in the restrictive group and 9.9 g/dL in the liberal group. Only 26 patients received RBC. CONCLUSIONS A Hb transfusion threshold of 8.9 g/dL was associated with a statistically significantly faster TUG after hip revision surgery compared to a threshold of 7.3 g/dL but the clinical importance is questionable and the groups did not differ in Hb at the time of testing.
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Transfusion requirements in septic shock (TRISS) trial - comparing the effects and safety of liberal versus restrictive red blood cell transfusion in septic shock patients in the ICU: protocol for a randomised controlled trial
Holst LB, Haase N, Wetterslev J, Wernerman J, Aneman A, Guttormsen AB, Johansson PI, Karlsson S, Klemenzson G, Winding R, et al
Trials [Electronic Resource]. 2013;14:150
Abstract
BACKGROUND Transfusion of red blood cells (RBC) is recommended in septic shock and the majority of these patients receive RBC transfusion in the intensive care unit (ICU). However, benefit and harm of RBCs have not been established in this group of high-risk patients. METHODS/DESIGN The Transfusion Requirements in Septic Shock (TRISS) trial is a multicenter trial with assessor-blinded outcome assessment, randomising 1,000 patients with septic shock in 30 Scandinavian ICUs to receive transfusion with pre-storage leuko-depleted RBC suspended in saline-adenine-glucose and mannitol (SAGM) at haemoglobin level (Hb) of 7 g/dl or 9 g/dl, stratified by the presence of haematological malignancy and centre. The primary outcome measure is 90-day mortality. Secondary outcome measures are organ failure, ischaemic events, severe adverse reactions (SARs: anaphylactic reaction, acute haemolytic reaction and transfusion-related circulatory overload, and acute lung injury) and mortality at 28 days, 6 months and 1 year.The sample size will enable us to detect a 9% absolute difference in 90-day mortality assuming a 45% event rate with a type 1 error rate of 5% and power of 80%. An interim analysis will be performed after 500 patients, and the Data Monitoring and Safety Committee will recommend the trial be stopped if a group difference in 90-day mortality with P <=0.001 is present at this point. DISCUSSION The TRISS trial may bridge the gap between clinical practice and the lack of efficacy and safety data on RBC transfusion in septic shock patients. The effect of restrictive versus liberal RBC transfusion strategy on mortality, organ failure, ischaemic events and SARs will be evaluated. TRIAL REGISTRATION ClinicalTrials.gov: NCT01485315. Registration date 30 November 2011. First patient was randomised 3 December 2011.
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Hemostatic resuscitation with plasma and platelets in trauma
Johansson PI, Oliveri RS, Ostrowski SR
Journal of Emergencies Trauma & Shock. 2012;5((2):):120-5.
Abstract
BACKGROUND Continued hemorrhage remains a major contributor of mortality in massively transfused patients and controversy regarding the optimal management exists although recently, the concept of hemostatic resuscitation, i.e., providing large amount of blood products to critically injured patients in an immediate and sustained manner as part of an early massive transfusion protocol has been introduced. The aim of the present review was to investigate the potential effect on survival of proactive administration of plasma and/or platelets (PLT) in trauma patients with massive bleeding. MATERIALS AND METHODS English databases were searched for reports of trauma patients receiving massive transfusion (10 or more red blood cell (RBC) within 24 hours or less from admission) that tested the effects of administration of plasma and/or PLT in relation to RBC concentrates on survival from January 2005 to November 2010. Comparison between highest vs lowest blood product ratios and 30-day mortality was performed. RESULTS Sixteen studies encompassing 3,663 patients receiving high vs low ratios were included. This meta-analysis of the pooled results revealed a substantial statistical heterogeneity (I(2) = 58%) and that the highest ratio of plasma and/or PLT or to RBC was associated with a significantly decreased mortality (OR: 0.49; 95% confidence interval: 0.43-0.57; P<0.0001) when compared with lowest ratio. CONCLUSION Meta-analysis of 16 retrospective studies concerning massively transfused trauma patients confirms a significantly lower mortality in patients treated with the highest fresh frozen plasma (FFP) and/or PLT ratio when compared with the lowest FFP and/or PLT ratio. However, optimal ranges of FFP: RBC and PLT RBC should be established in randomized controlled trials.