Autonomic nervous system activity and the risk of nosocomial infection in critically ill patients with brain injury.

PURPOSE: Nosocomial infection contributes to adverse outcome after brain injury. This study investigates whether autonomic nervous system activity is associated with a decreased host immune response in patients following stroke or traumatic brain injury (TBI). METHODS: A prospective study was performed in adult patients with TBI or stroke who were admitted to the Intensive Care Unit of our tertiary university hospital between 2013 and 2016. Heart rate variability (HRV) was recorded daily and assessed for autonomic nervous system activity. Outcomes were nosocomial infections and immunosuppression, which was assessed ex vivo using whole blood stimulations with plasma of patients with infections, matched non-infected patients and healthy controls. RESULTS: Out of 64 brain injured patients, 23 (36%) developed an infection during their hospital stay. The ability of brain injured patients to generate a host response to the bacterial endotoxin lipopolysaccharides (LPS) was diminished compared to healthy controls (p < 0.001). Patients who developed an infection yielded significantly lower TNF-α values (86 vs 192 pg/mL, p = 0.030) and a trend towards higher IL-10 values (122 vs 84 pg/mL, p = 0.071) following ex vivo whole blood stimulations when compared to patients not developing an infection. This decreased host immune response was associated with altered admission HRV values. Brain injured patients who developed an infection showed increased normalized high-frequency power compared to patients not developing an infection (0.54 vs 0.36, p = 0.033), whereas normalized low-frequency power was lower in infected patients (0.46 vs 0.64, p = 0.033). CONCLUSION: Brain injured patients developing a nosocomial infection show parasympathetic predominance in the acute phase following brain injury, reflected by alterations in HRV, which parallels a decreased ability to generate an immune response to stimulation with LPS.

Towards patient-specific management of trauma hemorrhage: the effect of resuscitation therapy on parameters of thromboelastometry.

Essentials The response of thromboelastometry (ROTEM) parameters to therapy is unknown. We prospectively recruited hemorrhaging trauma patients in six level-1 trauma centres in Europe. Blood products and pro-coagulants prevent further derangement of ROTEM results. ROTEM algorithms can be used to treat and monitor trauma induced coagulopathy. SUMMARY: Background Rotational thromboelastometry (ROTEM) can detect trauma-induced coagulopathy (TIC) and is used in transfusion algorithms. The response of ROTEM to transfusion therapy is unknown. Objectives To determine the response of ROTEM profiles to therapy in bleeding trauma patients. Patients/Methods A prospective multicenter study in bleeding trauma patients (receiving ≥ 4 red blood cell [RBC] units) was performed. Blood was drawn in the emergency department, after administration of 4, 8 and 12 RBC units and 24 h post-injury. The response of ROTEM to plasma, platelets (PLTs), tranexamic acid (TXA) and fibrinogen products was evaluated in the whole cohort as well as in the subgroup of patients with ROTEM values indicative of TIC. Results Three hundred and nine bleeding and shocked patients were included. A mean dose of 3.8 g of fibrinogen increased FIBTEM CA5 by 5.2 mm (IQR: 4.1-6.3 mm). TXA administration decreased lysis by 5.4% (4.3-6.5%). PLT transfusion prevented further derangement of parameters of clot formation. The effect of PLTs on EXTEM ca5 values was more pronounced in patients with a ROTEM value indicative of TIC than in the whole cohort. Plasma transfusion decreased EXTEM clotting time by 3.1 s (- 10 s to 3.9 s) in the whole cohort and by 10.6 s (- 45 s to 24 s) in the subgroup of patients with a ROTEM value indicative of TIC. Conclusion The effects of therapy on ROTEM values were small, but prevented further derangement of test results. In patients with ROTEM values indicative of TIC, the efficacy of PLTs and plasma in correcting deranged ROTEM parameters is possibly more robust.

Data-driven Development of ROTEM and TEG Algorithms for the Management of Trauma Hemorrhage: A Prospective Observational Multicenter Study.

OBJECTIVE: Developing pragmatic data-driven algorithms for management of trauma induced coagulopathy (TIC) during trauma hemorrhage for viscoelastic hemostatic assays (VHAs). BACKGROUND: Admission data from conventional coagulation tests (CCT), rotational thrombelastometry (ROTEM) and thrombelastography (TEG) were collected prospectively at 6 European trauma centers during 2008 to 2013. METHODS: To identify significant VHA parameters capable of detecting TIC (defined as INR > 1.2), hypofibrinogenemia (< 2.0 g/L), and thrombocytopenia (< 100 x10/L), univariate regression models were constructed. Area under the curve (AUC) was calculated, and threshold values for TEG and ROTEM parameters with 70% sensitivity were included in the algorithms. RESULTS: A total of, 2287 adult trauma patients (ROTEM: 2019 and TEG: 968) were enrolled. FIBTEM clot amplitude at 5 minutes (CA5) had the largest AUC and 10 mm detected hypofibrinogenemia with 70% sensitivity. The corresponding value for functional fibrinogen (FF) TEG maximum amplitude (MA) was 19 mm. Thrombocytopenia was similarly detected using the calculated threshold EXTEM-FIBTEM CA5 30 mm. The corresponding rTEG-FF TEG MA was 46 mm. TIC was identified by EXTEM CA5 41 mm, rTEG MA 64 mm (80% sensitivity). For hyperfibrinolysis, we examined the relationship between viscoelastic lysis parameters and clinical outcomes, with resulting threshold values of 85% for EXTEM Li30 and 10% for rTEG Ly30.Based on these analyses, we constructed algorithms for ROTEM, TEG, and CCTs to be used in addition to ratio driven transfusion and tranexamic acid. CONCLUSIONS: We describe a systematic approach to define threshold parameters for ROTEM and TEG. These parameters were incorporated into algorithms to support data-driven adjustments of resuscitation with therapeutics, to optimize damage control resuscitation practice in trauma.

Hypothermia as a predictor for mortality in trauma patients at admittance to the Intensive Care Unit.

AIMS: To study the impact of hypothermia upon admission to the Intensive Care Unit (ICU) on early and late mortality and to develop a prediction model for late mortality in severely injured trauma patients. MATERIALS AND METHODS: A multicenter retrospective cohort study was performed in adult trauma patients admitted to the ICU of two Level-1 trauma centers between 2007 and 2012. Hypothermia was defined as a core body temperature of ≤35° Celsius. Logistic regression analyses were performed to quantify the effect of hypothermia on 24-hour and 28-day mortality and to develop a prediction model. RESULTS: A total of 953 patients were included, of which 354 patients had hypothermia (37%) upon ICU admission. Patients were divided into a normothermic or hypothermic group. Hypothermia was associated with a significantly increased mortality at 24 hours and 28 days (OR 2.72 (1.18-6.29 and OR 2.82 (1.83-4.35) resp.). The variables included in the final prediction model were hypothermia, age, APACHE II score (corrected for temperature), INR, platelet count, traumatic brain injury and Injury Severity Score. The final prediction model discriminated between survivors and non-survivors with high accuracy (AUC = 0.871, 95% CI 0.844-0.898). CONCLUSIONS: Hypothermia, defined as a temperature ≤35° Celsius, is common in critically ill trauma patients and is one of the most important physiological predictors for early and late mortality in trauma patients. Trauma patients admitted to the ICU may be at high risk for late mortality if the patient is hypothermic, coagulopathic, severely injured and has traumatic brain injury or an advanced age.

Are there any alternatives for transfusion of AB plasma as universal donor in an emergency release setting?

BACKGROUND: AB plasma is used as the universal donor plasma product in patients requiring massive transfusion. However, currently it is a recommended policy to transfuse plasma derived from male donors only as transfusion of plasma from HLA antibody-positive female donors is associated with an increased risk for transfusion-related acute lung injury. As a result, due to high demands, supplies of blood banks may run out of AB plasma, calling for alternatives. Therefore, the aim of this review was to investigate alternatives for emergency release of AB plasma as the universal donor. STUDY DESIGN AND METHODS: A systematic search was conducted in Embase and PubMed. Studies on adult patients, who were transfused with at least 1 unit of plasma, investigating the incidence of transfusion-related complications or mortality in patients transfused with ABO-identical, ABO-compatible, or ABO-incompatible plasma were eligible for inclusion. The primary outcomes were the incidence of transfusion-related complications and mortality. RESULTS: In total six studies were included. Transfusion of ABO-compatible plasma was associated with an increased incidence of lung injury and mortality (odds ratio, 1.10; 95% confidence interval, 1.04-1.15; p = 0.0003) compared to transfusion of ABO-identical plasma. No significant differences were observed regarding transfusion-related complications and mortality between patients transfused with ABO-compatible or ABO-incompatible plasma. DISCUSSION: Studies are insufficient to formulate advice about alternatives for transfusion of AB plasma as universal donor plasma in the emergency setting due to the small number of studies. The results of this review underline the need for further research.

Effects of a hospital-wide introduction of a massive transfusion protocol on blood product ratio and blood product waste.

BACKGROUND: Massive transfusion protocols (MTPs) are increasingly used in the transfusion practice and are developed to provide the standardized and early delivery of blood products and procoagulant agents and to supply the transfusion of blood products in a well-balanced ratio. AIM: The aim of this study was to investigate the effect of a hospital-wide introduction of an MTP on blood product ratio and a waste of blood products. MATERIALS AND METHODS: Retrospective analysis was performed to compare the transfusion practice in massive bleeding patients before and after the introduction of an MTP and between the use of an MTP and transfusion off-protocol. Massive bleeding was defined as an administration of ≥5 units of red blood cells (RBCs) within 12 h. RESULTS: Of 547 massively transfused patients, 192 patients were included in the pre-MTP period and 355 patients in the MTP period. The ratio of RBC to fresh frozen plasma (FFP) and the platelets transfused shifted significantly toward 1:1:1 in the MTP period (P = 0.012). This was mainly caused by a shift in RBC: FFP ratio (P = 0.014). An increase in the waste of blood products was observed, most notably FFPs (P = 0.026). Extending the storage time after thawing reduced the waste of FFPs from 11% to 4%. CONCLUSION: Hospital-wide introduction of an MTP is an adequate way to achieve a well-balanced transfusion ratio of 1:1:1. This comes at the cost of an increase in the waste of FFPs, which is lowered after extending the duration of storage time after thawing.

Risk factors for trauma-induced coagulopathy- and transfusion-associated multiple organ failure in severely injured trauma patients.

BACKGROUND: Both trauma-induced coagulopathy (TIC) and transfusion strategies influence early outcome in hemorrhagic trauma patients. Their impact on late outcome is less well characterized. This study systematically reviews risk factors for TIC- and transfusion-associated multiple organ failure (MOF) in severely injured trauma patients. MATERIALS AND METHODS: A systematic search was conducted in PubMed and Embase. Studies published from 1986 to 2013 on adult trauma patients with an injury severity score ≥16, investigating TIC or transfusion strategies with MOF as primary or secondary outcome, were eligible for inclusion. Results of the included studies were evaluated with meta-analyses of pooled data. RESULTS: In total, 50 studies were included with a total sample size of 63,586 patients. Due to heterogeneity of the study populations and outcome measures, results from 7 studies allowed for pooling of data. Risk factors for TIC-associated MOF were hypocoagulopathy, hemorrhagic shock, activated protein C, increased histone levels, and increased levels of markers of fibrinolysis on admission. After at least 24 h after admission, the occurrence of thromboembolic events was associated with MOF. Risk factors for transfusion-associated MOF were the administration of fluids and red blood cell units within 24 h post-injury, the age of red blood cells (>14 days) and a ratio of FFP:RBC ≥ 1:1 (OR 1.11, 95% CI 1.04-1.19). CONCLUSION: Risk factors for TIC-associated MOF in severely injured trauma patients are early hypocoagulopathy and hemorrhagic shock, while a hypercoagulable state with the occurrence of thromboembolic events later in the course of trauma predisposes to MOF. Risk factors for transfusion-associated MOF include administration of crystalloids and red blood cells and a prolonged storage time of red blood cells. Future prospective studies investigating TIC- and transfusion-associated risk factors on late outcome are required.

Endogenous microparticles drive the proinflammatory host immune response in severely injured trauma patients.

INTRODUCTION: Severe trauma affects the immune system, which in its turn is associated with poor outcome. The mediators driving the immune responses in trauma are largely unknown. The aim of this study was to investigate the role of endogenous microparticles (MPs) in mediating the immune response following severe trauma. METHODS: A prospective, observational substudy of the ACIT II (Activation of Coagulation and Inflammation in Trauma II) study was performed at our academic level I trauma center. Adult multiple-trauma patients with an injury severity score of 15 or higher were included between May 2012 and June 2013. Ex vivo whole-blood stimulation with lipopolysaccharide was performed on aseptically collected patient plasma containing MPs and in plasma depleted of MPs. Flow cytometry and transmission electronic microscopy were performed on plasma samples to investigate the numbers and cellular origin of MPs. Healthy individuals served as a control group. RESULTS: Ten trauma patients and 10 control subjects were included. Trauma patients were significantly injured with a median injury severity score of 19 (range, 17-45). Patients were neither in shock nor bleeding. On admission to the hospital, the host response to bacterial stimulation was blunted in trauma patients compared with control subjects, as reflected by decreased production of interleukin 6 (IL-6), IL-10, and tumor necrosis factor α (P < 0.001). In trauma patients, MP-positive plasma was associated with a significantly higher synthesis of IL-6 and tumor necrosis factor α compared with plasma depleted from MPs (P = 0.047 and 0.002, respectively). Compared with control subjects, the number of circulating MPs was significantly decreased in trauma patients (P = 0.009). Most MPs originated from platelets. Multiple cellular protrusions, which result in MP formation, were observed in plasma from trauma patients, but not in control subjects. CONCLUSIONS: On admission, trauma patients have a reduced immune response toward endotoxin challenge, which is, at least in part, mediated by MPs, which circulate in low numbers and in early stages. Most MPs originate from platelets, which indicates that these cells may be the most important source of MPs involved in initiating an inflammatory host response after injury.

Thromboelastometry and organ failure in trauma patients: a prospective cohort study.

INTRODUCTION: Data on the incidence of a hypercoagulable state in trauma, as measured by thromboelastometry (ROTEM), is limited and the prognostic value of hypercoagulability after trauma on outcome is unclear. We aimed to determine the incidence of hypercoagulability after trauma, and to assess whether early hypercoagulability has prognostic value on the occurrence of multiple organ failure (MOF) and mortality. METHODS: This was a prospective observational cohort study in trauma patients who met the highest trauma level team activation. Hypercoagulability was defined as a G value of ≥ 11.7 dynes/cm(2) and hypocoagulability as a G value of <5.0 dynes/cm(2). ROTEM was performed on admission and 24 hours later. RESULTS: A total of 1,010 patients were enrolled and 948 patients were analyzed. Median age was 38 (interquartile range (IQR) 26 to 53), 77% were male and median injury severity score was 13 (IQR 8 to 25). On admission, 7% of the patients were hypercoagulable and 8% were hypocoagulable. Altogether, 10% of patients showed hypercoagulability within the first 24 hours of trauma. Hypocoagulability, but not hypercoagulability, was associated with higher sequential organ failure assessment scores, indicating more severe MOF. Mortality in patients with hypercoagulability was 0%, compared to 7% in normocoagulable and 24% in hypocoagulable patients (P <0.001). EXTEM CT, alpha and G were predictors for occurrence of MOF and mortality. CONCLUSIONS: The incidence of a hypercoagulable state after trauma is 10% up to 24 hours after admission, which is broadly comparable to the rate of hypocoagulability. Further work in larger studies should define the clinical consequences of identifying hypercoagulability and a possible role for very early, targeted use of anticoagulants.