Impact of Blood Pressure Targets in Patients With Heart Failure Undergoing Postresuscitation Care: A Subgroup Analysis From a Randomized Controlled Trial.

BACKGROUND: To assess the effect of targeting higher or lower blood pressure during postresucitation intensive care among comatose patients with out-of-hospital cardiac arrest with a history of heart failure. METHODS: The BOX trial (Blood Pressure and Oxygenation Targets After Out-of-Hospital Cardiac Arrest) was a randomized, controlled, double-blinded, multicenter study comparing titration of vasopressors toward a mean arterial pressure (MAP) of 63 versus 77 mm Hg during postresuscitation intensive care. Patients with a history of heart failure were included in this substudy. Pulmonary artery catheters were inserted shortly after admission. History of heart failure was assessed through chart review of all included patients. The primary outcome was cardiac index during the first 72 hours. Secondary outcomes were left ventricular ejection fraction, heart rate, stroke volume, renal replacement therapy and all-cause mortality at 365 days. RESULTS: A total of 134 patients (17% of the BOX cohort) had a history of heart failure (patients with left ventricular ejection fraction, ≤40%: 103 [77%]) of which 71 (53%) were allocated to a MAP of 77 mm Hg. Cardiac index at intensive care unit arrival was 1.77±0.11 L/min·m-2 in the MAP63-group and 1.78±0.17 L/min·m-2 in the MAP77, P=0.92. During the next 72 hours, the mean difference was 0.15 (95% CI, -0.04 to 0.35) L/min·m-2; Pgroup=0.22. Left ventricular ejection fraction and stroke volume was similar between the groups. Patients allocated to MAP77 had significantly elevated heart rate (mean difference 6 [1-12] beats/min, Pgroup=0.03). Vasopressor usage was also significantly increased (P=0.006). At 365 days, 69 (51%) of the patients had died. The adjusted hazard ratio for 365 day mortality was 1.38 (0.84-2.27), P=0.20 and adjusted odds ratio for renal replacement therapy was 2.73 (0.84-8.89; P=0.09). CONCLUSIONS: In resuscitated patients with out-of-hospital cardiac arrest with a history of heart failure, allocation to a higher blood pressure target resulted in significantly increased heart rate in the higher blood pressure-target group. However, no certain differences was found for cardiac index, left ventricular ejection fraction or stroke volume. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03141099.

Combined effects of targeted blood pressure, oxygenation, and duration of device-based fever prevention after out-of-hospital cardiac arrest on 1-year survival: post hoc analysis of a randomized controlled trial.

BACKGROUND: The "Blood Pressure and Oxygenation Targets in Post Resuscitation Care" (BOX) trial investigated whether a low versus high blood pressure target, a restrictive versus liberal oxygenation target, and a shorter versus longer duration of device-based fever prevention in comatose patients could improve outcomes. No differences in rates of discharge from hospital with severe disability or 90-day mortality were found. However, long-term effects and potential interaction of the interventions are unknown. Accordingly, the objective of this study is to investigate both individual and combined effects of the interventions on 1-year mortality rates. METHODS: The BOX trial was a randomized controlled two-center trial that assigned comatose resuscitated out-of-hospital cardiac arrest patients to the following three interventions at admission: A blood pressure target of either 63 mmHg or 77 mmHg; An arterial oxygenation target of 9-10 kPa or 13-14 kPa; Device-based fever prevention administered as an initial 24 h at 36 °C and then either 12 or 48 h at 37 °C; totaling 36 or 72 h of temperature control. Randomization occurred in parallel and simultaneously to all interventions. Patients were followed for the occurrence of death from all causes for 1 year. Analyzes were performed by Cox proportional models, and assessment of interactions was performed with the interventions stated as an interaction term. RESULTS: Analysis for all three interventions included 789 patients. For the intervention of low compared to high blood pressure targets, 1-year mortality rates were 35% (138 of 396) and 36% (143 of 393), respectively, hazard ratio (HR) 0.92 (0.73-1.16) p = 0.47. For the restrictive compared to liberal oxygenation targets, 1-year mortality rates were 34% (135 of 394) and 37% (146 of 395), respectively, HR 0.92 (0.73-1.16) p = 0.46. For device-based fever prevention for a total of 36 compared to 72 h, 1-year mortality rates were 35% (139 of 393) and 36% (142 of 396), respectively, HR 0.98 (0.78-1.24) p = 0.89. There was no sign of interaction between the interventions, and accordingly, no combination of randomizations indicated differentiated treatment effects. CONCLUSIONS: There was no difference in 1-year mortality rates for a low compared to high blood pressure target, a liberal compared to restrictive oxygenation target, or a longer compared to shorter duration of device-based fever prevention after cardiac arrest. No combination of the interventions affected these findings. Trial registration ClinicalTrials.gov NCT03141099, Registered 30 April 2017.

Effect of prehospital high-dose glucocorticoid on hemodynamics in patients resuscitated from out-of-hospital cardiac arrest: a sub-study of the STEROHCA trial.

BACKGROUND: Following resuscitated out-of-hospital cardiac arrest (OHCA), inflammatory markers are significantly elevated and associated with hemodynamic instability and organ dysfunction. Vasopressor support is recommended to maintain a mean arterial pressure (MAP) above 65 mmHg. Glucocorticoids have anti-inflammatory effects and may lower the need for vasopressors. This study aimed to assess the hemodynamic effects of prehospital high-dose glucocorticoid treatment in resuscitated comatose OHCA patients. METHODS: The STEROHCA trial was a randomized, placebo-controlled, phase 2 trial comparing one prehospital injection of methylprednisolone 250 mg with placebo immediately after resuscitated OHCA. In this sub-study, we included patients who remained comatose at admission and survived until intensive care unit (ICU) admission. The primary outcome was cumulated norepinephrine use from ICU admission until 48 h reported as mcg/kg/min. Secondary outcomes included hemodynamic status characterized by MAP, heart rate, vasoactive-inotropic score (VIS), and the VIS/MAP-ratio as well as cardiac function assessed by pulmonary artery catheter measurements. Linear mixed-model analyses were performed to evaluate mean differences between treatment groups at all follow-up times. RESULTS: A total of 114 comatose OHCA patients were included (glucocorticoid: n = 56, placebo: n = 58) in the sub-study. There were no differences in outcomes at ICU admission. From the time of ICU admission up to 48 h post-admission, patients in the glucocorticoid group cumulated a lower norepinephrine use (mean difference - 0.04 mcg/kg/min, 95% CI - 0.07 to - 0.01, p = 0.02). Moreover, after 12-24 h post-admission, the glucocorticoid group demonstrated a higher MAP with mean differences ranging from 6 to 7 mmHg (95% CIs from 1 to 12), a lower VIS (mean differences from - 4.2 to - 3.8, 95% CIs from - 8.1 to 0.3), and a lower VIS/MAP ratio (mean differences from - 0.10 to - 0.07, 95% CIs from - 0.16 to - 0.01), while there were no major differences in heart rate (mean differences from - 4 to - 3, 95% CIs from - 11 to 3). These treatment differences between groups were also present 30-48 h post-admission but to a smaller extent and with increased statistical uncertainty. No differences were found in pulmonary artery catheter measurements between groups. CONCLUSIONS: Prehospital treatment with high-dose glucocorticoid was associated with reduced norepinephrine use in resuscitated OHCA patients. TRIAL REGISTRATION: EudraCT number: 2020-000855-11; submitted March 30, 2020. URL: https://www. CLINICALTRIALS: gov ; Unique Identifier: NCT04624776.

Treatment effects of blood pressure targets and hemodynamics according to initial blood lactate levels in comatose out-of-hospital cardiac arrest patients - A sub study of the BOX trial.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) survivors remaining comatose are often circulatory unstable with high mortality in the first days following resuscitation. Elevated lactate will reflect the severity and duration of hypoperfusion in cardiac arrest. Further, the severity of hypoperfusion could modify the effect on survival of different mean arterial blood pressure (MAP) targets. METHODS: In this sub-study of the BOX trial, adult successfully resuscitated comatose OHCA patients (n = 789) with a presumed cardiac cause were randomized to a MAP target of 63 mmHg vs. 77 mmHg. Patients were arbitrarily grouped in low-lactate: <25% of sample, medium-lactate: 25%-75%, and high >75 percentile according to blood lactate levels at hospital arrival as a surrogate of the severity of hypoperfusion. Invasive hemodynamic evaluations were performed using an arterial catheter and pulmonary artery catheter (PAC), and data from admission to 48 hours (h) were recorded. Logistic regression analysis evaluated whether lactate levels (as continuous and categorical) modify the effect of MAP targets on mortality at 365 days. RESULTS: The three lactate groups had initial lactate levels of low-lactate: <2.9 mmol/L, medium-lactate: 2.9-7.9 mmol/L, and high-lactate > 7.9 mmol/L. All patients were randomized to a 63 mmHg or 77 mmHg MAP target. The proportion of patients in the high-MAP target group was 100/201 (50%), 178/388 (46%), and 114/197 (58%) for low, medium, and high-lactate groups respectively. At admission, the high-lactate groups had a lower MAP compared to the medium-lactate (2.6 mmHg (95% CI: 0.1-5.0 mmHg, p = 0.02), and the low-lactate group, (3.6 mmHg (95% CI: 0.8-6.5 mmHg, p < 0.01). Accordingly, the vasoactive inotropic score was 79% (95%CI: 42%-124%%) higher with increasing initial lactate level (High-lactate vs. low-lactate) with the largest difference at 6 hours (110.6% (95%CI: 54.4%-187.2%) higher in high-lactate patients). No difference in the cardiac index or systemic vascular resistance was observed between lactate groups. The initial lactate level (continuous) modified the effect of the two MAP targets (p = 0.04). In the highest lactate group, the mortality was 100/197 (51%), and with an odds ratio (OR): 1.7 (95%CI: 0.9-3.0) if randomized to MAP 77 mmHg compared to MAP 63 mmHg. In the lowest lactate group, the mortality was 35/201(17%) and similar if randomized to a MAP target of 77 mmHg (OR: 1.1 (95% CI: 0.5-2.3)). CONCLUSION: Comatose OHCA patients with high initial lactate levels required more vasoactive drugs on the first two days of ICU admission to meet the blood pressure target and had a poorer prognosis. No indication that aiming for a higher MAP target is beneficial in patients with an initial high lactate level was found, however, given the post-hoc nature of this study, these results should be considered hypothesis-generating.

Prehospital high-dose methylprednisolone in resuscitated out-of-hospital cardiac arrest patients (STEROHCA): a randomized clinical trial.

PURPOSE: Patients who are successfully resuscitated following out-of-hospital cardiac arrest (OHCA) are still at a high risk of neurological damage and death. Inflammation and brain injury are components of the post-cardiac arrest syndrome, and can be assessed by systemic interleukin 6 (IL-6) and neuron-specific enolase (NSE). Anti-inflammatory treatment with methylprednisolone may dampen inflammation, thereby improving outcome. This study aimed to determine if prehospital high-dose methylprednisolone could reduce IL-6 and NSE in comatose OHCA patients. METHODS: The STEROHCA trial was a randomized, blinded, placebo-controlled, phase II prehospital trial performed at two cardiac arrest centers in Denmark. Resuscitated comatose patients with suspected cardiac etiology were randomly assigned 1:1 to a single intravenous injection of 250 mg methylprednisolone or placebo. The co-primary outcome was reduction of IL-6 and NSE-blood levels measured daily for 72 h from admission. The main secondary outcome was survival at 180 days follow-up. RESULTS: We randomized 137 patients to methylprednisolone (n = 68) or placebo (n = 69). We found reduced IL-6 levels (p < 0.0001) in the intervention group, with median (interquartile range, IQR) levels at 24 h of 2.1 pg/ml (1.0; 7.1) and 30.7 pg/ml (14.2; 59) in the placebo group. We observed no difference between groups in NSE levels (p = 0.22), with levels at 48 h of 18.8 ug/L (14.4; 24.6) and 14.8 ug/L (11.2; 19.4) in the intervention and placebo group, respectively. In the intervention group, 51 (75%) patients survived and 44 (64%) in the placebo group. CONCLUSION: Prehospital treatment with high-dose methylprednisolone to resuscitated comatose OHCA patients, resulted in reduced IL-6 levels after 24 h, but did not reduce NSE levels.

Predicting poor neurological outcomes following out-of-hospital cardiac arrest using neuron-specific enolase and neurofilament light chain in patients with and without haemolysis.

Aims: Hypoxic-ischaemic brain injury following out-of-hospital cardiac arrest (OHCA) is a common complication and a major cause of death. Neuron-specific enolase (NSE) and neurofilament light chain (NfL) are released after brain injury and elevated concentrations of both are associated with poor neurological outcome. We explored the influence of haemolysis on the prognostic performance of NSE and NfL. Methods and results: The study is based on post hoc analyses of a randomized, single-centre, double-blinded, controlled trial (IMICA), where comatose OHCA patients of presumed cardiac cause were included. Free-haemoglobin was measured at admission to quantify haemolysis. NSE and NfL were measured after 48 h to estimate the extent of brain injury. Montreal Cognitive Assessment score (MoCA) was assessed to evaluate neurocognitive impairments. Seventy-three patients were included and divided into two groups by the median free-haemoglobin at admission. No group differences in mortality or poor neurological outcome were observed. The high-admission free-haemoglobin group had a significantly higher concentration of NSE compared to the low-admission free-haemoglobin group (27.4 µmol/L vs. 19.6 µmol/L, P = 0.03), but no differences in NfL. The performance of NSE and NfL in predicting poor neurological outcome were high for both, but NfL was numerically higher [area under the ROC (AUROC) 0.90 vs. 0.96, P = 0.09]. Furthermore, NfL, but not NSE, was inversely correlated with MoCA score, R2 = 0.21, P = 0.006. Conclusion: High free-haemoglobin at admission was associated with higher NSE concentration after 48 h, but, the performance of NSE and NfL in predicting poor neurological outcome among OHCA patients were good regardless of early haemolysis. Only elevated NfL concentrations were associated with cognitive impairments.

Duration of Device-Based Fever Prevention after Cardiac Arrest.

BACKGROUND: Guidelines recommend active fever prevention for 72 hours after cardiac arrest. Data from randomized clinical trials of this intervention have been lacking. METHODS: We randomly assigned comatose patients who had been resuscitated after an out-of-hospital cardiac arrest of presumed cardiac cause to device-based temperature control targeting 36°C for 24 hours followed by targeting of 37°C for either 12 or 48 hours (for total intervention times of 36 and 72 hours, respectively) or until the patient regained consciousness. The primary outcome was a composite of death from any cause or hospital discharge with a Cerebral Performance Category of 3 or 4 (range, 1 to 5, with higher scores indicating more severe disability; a category of 3 or 4 indicates severe cerebral disability or coma) within 90 days after randomization. Secondary outcomes included death from any cause and the Montreal Cognitive Assessment score (range, 0 to 30, with higher scores indicating better cognitive ability) at 3 months. RESULTS: A total of 393 patients were randomly assigned to temperature control for 36 hours, and 396 patients were assigned to temperature control for 72 hours. At 90 days after randomization, a primary end-point event had occurred in 127 of 393 patients (32.3%) in the 36-hour group and in 133 of 396 patients (33.6%) in the 72-hour group (hazard ratio, 0.99; 95% confidence interval, 0.77 to 1.26; P = 0.70) and mortality was 29.5% in the 36-hour group and 30.3% in the 72-hour group. At 3 months, the median Montreal Cognitive Assessment score was 26 (interquartile range, 24 to 29) and 27 (interquartile range, 24 to 28), respectively. There was no significant between-group difference in the incidence of adverse events. CONCLUSIONS: Active device-based fever prevention for 36 or 72 hours after cardiac arrest did not result in significantly different percentages of patients dying or having severe disability or coma. (Funded by the Novo Nordisk Foundation; BOX ClinicalTrials.gov number, NCT03141099.).

Blood-Pressure Targets in Comatose Survivors of Cardiac Arrest.

BACKGROUND: Evidence to support the choice of blood-pressure targets for the treatment of comatose survivors of out-of-hospital cardiac arrest who are receiving intensive care is limited. METHODS: In a double-blind, randomized trial with a 2-by-2 factorial design, we evaluated a mean arterial blood-pressure target of 63 mm Hg as compared with 77 mm Hg in comatose adults who had been resuscitated after an out-of-hospital cardiac arrest of presumed cardiac cause; patients were also assigned to one of two oxygen targets (reported separately). The primary outcome was a composite of death from any cause or hospital discharge with a Cerebral Performance Category (CPC) of 3 or 4 within 90 days (range, 0 to 5, with higher categories indicating more severe disability; a category of 3 or 4 indicates severe disability or coma). Secondary outcomes included neuron-specific enolase levels at 48 hours, death from any cause, scores on the Montreal Cognitive Assessment (range, 0 to 30, with higher scores indicating better cognitive ability) and the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at 3 months, and the CPC at 3 months. RESULTS: A total of 789 patients were included in the analysis (393 in the high-target group and 396 in the low-target group). A primary-outcome event occurred in 133 patients (34%) in the high-target group and in 127 patients (32%) in the low-target group (hazard ratio, 1.08; 95% confidence interval [CI], 0.84 to 1.37; P = 0.56). At 90 days, 122 patients (31%) in the high-target group and 114 patients (29%) in the low-target group had died (hazard ratio, 1.13; 95% CI, 0.88 to 1.46). The median CPC was 1 (interquartile range, 1 to 5) in both the high-target group and the low-target group; the corresponding median modified Rankin scale scores were 1 (interquartile range, 0 to 6) and 1 (interquartile range, 0 to 6), and the corresponding median Montreal Cognitive Assessment scores were 27 (interquartile range, 24 to 29) and 26 (interquartile range, 24 to 29). The median neuron-specific enolase level at 48 hours was also similar in the two groups. The percentages of patients with adverse events did not differ significantly between the groups. CONCLUSIONS: Targeting a mean arterial blood pressure of 77 mm Hg or 63 mm Hg in patients who had been resuscitated from cardiac arrest did not result in significantly different percentages of patients dying or having severe disability or coma. (Funded by the Novo Nordisk Foundation; BOX ClinicalTrials.gov number, NCT03141099.).

Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response after Out-of-Hospital Cardiac Arrest (IMICA): study protocol for a double-blinded, placebo-controlled, single-center, randomized clinical trial.

BACKGROUND: Resuscitated out-of-hospital cardiac arrest (OHCA) patients who remain comatose at admission are at high risk of morbidity and mortality. This has been attributed to the post-cardiac arrest syndrome (PCAS) which encompasses multiple interacting components, including systemic inflammation. Elevated levels of circulating interleukin-6 (IL-6), a pro-inflammatory cytokine, is associated with worse outcomes in OHCA patients, including higher vasopressor requirements and higher mortality rates. In this study, we aim to reduce systemic inflammation after OHCA by administering a single infusion of tocilizumab, an IL-6 receptor antibody approved for use for other indications. METHODS: Investigator-initiated, double-blinded, placebo-controlled, single-center, randomized clinical trial in comatose OHCA patients admitted to an intensive cardiac care unit. Brief inclusion criteria: OHCA of presumed cardiac cause, persistent unconsciousness, age ≥ 18 years. INTERVENTION: 80 patients will be randomized in a 1:1 ratio to a single 1-h intravenous infusion of either tocilizumab or placebo (NaCl). During the study period, patients will receive standard of care, including sedation and targeted temperature management of 36 ° for at least 24 h, vasopressors and/or inotropes as/if needed, prophylactic antibiotics, and any additional treatment at the discretion of the treating physician. Blood samples are drawn for measurements of biomarkers included in the primary and secondary endpoints during the initial 72 h. Primary endpoint: reduction in C-reactive protein (CRP). Secondary endpoints (abbreviated): cytokine levels, markers of brain, cardiac, kidney and liver damage, hemodynamic and hemostatic function, adverse events, and follow-up assessment of cerebral function and mortality. DISCUSSION: We hypothesize that reducing the effect of circulating IL-6 by administering an IL-6 receptor antibody will mitigate the systemic inflammatory response and thereby modify the severity of PCAS, in turn leading to lessened vasopressor use, more normal hemodynamics, and better organ function. This will be assessed by primarily focusing on hemodynamics and biomarkers of organ damage during the initial 72 h. In addition, pro-inflammatory and anti-inflammatory cytokines will be measured to assess if cytokine patterns are modulated by IL-6 receptor blockage. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03863015 ; submitted February 22, 2019, first posted March 5, 2019. EudraCT: 2018-002686-19; date study was authorized to proceed: November 7, 2018.

"Endothelial Dysfunction in Resuscitated Cardiac Arrest (ENDO-RCA): Safety and efficacy of low-dose Iloprost, a prostacyclin analogue, in addition to standard therapy, as compared to standard therapy alone, in post-cardiac-arrest-syndrome patients."

OBJECTIVE: An increasingly recognized prognostic factor for out-of-hospital-cardiac-arrest (OHCA) patients is the ischemia-reperfusion injury after restored blood circulation. Endothelial injury is common in patients resuscitated from cardiac arrest and is associated with poor outcome. This study was designed to investigate if iloprost infusion, a prostacyclin analogue, reduces endothelial damage in OHCA patients. METHODS: 50 patients were randomized in a placebo controlled double-blinded trial and allocated 1:2 to 48-hours iloprost infusion, (1 ng/kg/min) or placebo (saline infusion). Endothelial biomarkers (soluble thrombomodulin (sTM), sE-selectin, syndecan-1, soluble vascular endothelial growth factor (sVEGF), vascular endothelial cadherine (VEcad), nucleosomes) and sympathoadrenal activation (epinephrine/norepinephrine) from baseline to 48 and 96-hours were evaluated. RESULTS: Iloprost infusion did not influence endothelial biomarkers by the 48-hour endpoint. A rebound effect was observed with higher biomarker plasma values in the iloprost group (sTM p=0.02; Syndecan p=0.004; nucleosomes p<0.001; VEcad p<0.03) after 96-hours. There was a significant difference in 180-day mortality in favor of placebo. There was no difference regarding total adverse events between groups (p=0.73). Two patients were withdrawn in the iloprost group due to hypotension. CONCLUSIONS: The administration of low-dose iloprost (1ng/kg/min) to OHCA patients did not significantly influence endothelial biomarkers as measured by the 48- hour endpoint. A rebound effect was however observed in the 96-hour statistical model, with increasing endothelial biomarker levels after cessation of the iloprost-infusion.

African ST173 Cryptococcus deuterogattii strains are commonly less susceptible to fluconazole: An unclear mechanism of resistance.

OBJECTIVES: Fluconazole (FCZ), either alone or in combination, is often administered for treatment of cryptococcal meningitis, especially in sub-Saharan Africa. Its extensive use has led to the emergence of FCZ-resistant strains. The mechanisms underlying FCZ resistance are poorly documented for yeasts belonging to the Cryptococcus gattii species complex. The literature suggests that resistance could be due to mutations in and/or overexpression of the ERG11 gene (encoding the 14-α-demethylase) and efflux pumps such as MDR and AFR (two subclasses of ABC transporters). Here we highlight the presence of genotype VGII strains (Cryptococcus deuterogattii) from the Ivory Coast with a rare sequence type (ST173) associated with high FCZ minimum inhibitory concentrations (MICs) compared with strains originating from the Pacific Northwest (USA). METHODS: Mechanisms of FCZ resistance were investigated in 28 Ivorian clinical C. deuterogattii isolates recovered from three patients during their antifungal treatment and follow-up. RESULTS: The results demonstrated that: (i) these strains exhibited no mutations in the ERG11 gene; (ii) some strains had increased ERG11 and MDR1 mRNA expression, whilst AFR1 and AFR2 were not overexpressed in strains with high FCZ MICs compared with the expression levels for strains with low FCZ MICs; and (iii) exposure to FCZ in strains with high MICs induced AFR1 mRNA overexpression. CONCLUSION: This study demonstrated that the FCZ resistance mechanism commonly described in Cryptococcus neoformans was not responsible for resistance to FCZ in rare subtype strains.

Thrombelastography early amplitudes in bleeding and coagulopathic trauma patients: Results from a multicenter study.

BACKGROUND: Early amplitudes in the viscoelastic hemostatic assays, thrombelastography (TEG) and rotation thromboelastometry (ROTEM), provide fast results, which is critical in the resuscitation of bleeding patients. This study investigated associations between TEG early amplitudes and standard TEG variables in a large multicenter cohort of moderately to severely injured trauma patients admitted at three North European Level I Trauma Centers. METHODS: Prospective observational study of 404 trauma patients with clinical suspicion of severe injury from London, UK, Copenhagen, Denmark and Oslo, Norway. Biochemistry and clinical data including outcome and TEG parameters were recorded upon arrival. Kaolin TEG, Rapid TEG, and TEG functional fibrinogen curves were extracted, and early amplitudes A5 and A10 (amplitude at 5 and 10 minutes) were registered. Patients were stratified according to international normalized ratio of 1.2 or less or greater than 1.2, as well as transfusion requirements (nontransfused, 1-9 red blood cell units and ≥10 red blood cell units in 12 hours). RESULTS: In total, 404 patients were included, median Injury Severity Score was 13. There were strong positive correlations between A5/A10 and maximum amplitude in all investigated assays. All TEG values except rTEG maximum amplitude and kTEG maximum amplitude correlated significantly with mortality in transfused patients. Time from initiation of assay to A5 and A10 were lowest for rapid TEG and TEG functional fibrinogen compared with kaolin TEG. Rapid TEG A5 reduced time to result with greater than 50% compared with rapid TEG maximum amplitude. CONCLUSION: We found strong associations between TEG early amplitudes A5/A10 and maximum amplitude in rapid TEG, kaolin TEG, and TEG functional fibrinogen across trauma patients with coagulopathy and massive transfusion requirements. Introducing the use of early amplitudes can reduce time to diagnosis of coagulopathy and may be used in TEG monitoring of trauma patient. Further randomized controlled trials evaluating the role of TEG in guiding hemostatic resuscitation are warranted. LEVEL OF EVIDENCE: Prognostic study, level III.

Selective complexation of divalent cations by a cyclic α,ß-peptoid hexamer: a spectroscopic and computational study.

We describe the qualitative and quantitative analysis of the complexation properties towards cations of a cyclic peptoid hexamer composed of alternating α- and ß-peptoid monomers, which bear exclusively chiral (S)-phenylethyl side chains (spe) that have no noticeable chelating properties. The binding of a series of monovalent and divalent cations was assessed by 1H NMR, circular dichroism, fluorescence and molecular modelling. In contrast to previous studies on cations binding by 18-membered α-cyclopeptoid hexamers, the 21-membered cyclopeptoid cP1 did not complex monovalent cations (Na+, K+, Ag+) but showed selectivity for divalent cations (Ca2+, Ba2+, Sr2+ and Mg2+). Hexacoordinated C-3 symmetrical complexes were demonstrated for divalent cations with ionic radii around 1 Å (Ca2+ and Ba2+), while 5-coordination is preferred for divalent cations with larger (Ba2+) or smaller ionic radii (Mg2+).

The management of unexplained collapse in service age personnel.

Unexplained collapse is a common presentation to medical practitioners, with a wide range of differential diagnoses making assessment problematic. Without a methodical approach to the patient presenting with unexplained collapse, potentially life-threatening conditions may not be recognised, whilst benign presentations can be over-investigated. This article will review the assessment, differential diagnosis and management of unexplained collapse, whilst considering the impact in the military environment.

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.

Effect of acute hypobaric hypoxia on the endothelial glycocalyx and digital reactive hyperemia in humans.

INTRODUCTION: Hypoxia is associated with increased capillary permeability. This study tested whether acute hypobaric hypoxia involves degradation of the endothelial glycocalyx. METHODS: We exposed 12 subjects to acute hypobaric hypoxia (equivalent to 4500 m for 2-4 h) and measured venous blood concentrations of biomarkers reflecting endothelial and glycocalyx degradation (catecholamines, syndecan-1, soluble CD40 ligand, protein C, soluble thrombomodulin, tissue-type plasminogen activators, histone-complexed DNA fragments, and nitrite/nitrate). Endothelial function was assessed by the hyperemic response to brachial artery occlusion by peripheral arterial tonometry. RESULTS: Compared with normoxic baseline levels, hypoxia increased concentrations of syndecan-1 from 22 (95% confidence interval: 17-27) to 25 (19-30) ng/ml (p < 0.02) and protein C from 76 (70-83)% to 81 (74-88)% (p < 0.02). Nitrite/nitrate decreased from 23 (18-27) µM at baseline to 19 (14-24) µM and 18 (14-21) µM in hypoxia and recovery, respectively (p < 0.05). Other biomarkers remained unchanged. The post-occlusion/pre-occlusion ratio (reactive hyperemia index, RHI) decreased from 1.80 (1.52-2.07) in normoxia to 1.62 (1.28-1.96) after 2-4 h of hypobaric hypoxia and thereafter increased to 2.43 (1.99-2.86) during normoxic recovery (p < 0.01). CONCLUSIONS: The increase in syndecan-1 and protein C suggests that acute hypobaric hypoxia produces a minor degree of glycocalyx degradation and overall cellular damage. After hypoxia RHI rebounded to higher than baseline levels suggesting improved endothelial functionality.

Monitoring of dabigatran anticoagulation and its reversal in vitro by thrombelastography.

BACKGROUND: Dabigatran etexilate, a pro-drug of a direct thrombin inhibitor, was approved a few years ago for non-valvular atrial fibrillation and deep venous thrombosis. Rapid monitoring of the dabigatran level is essential in trauma and bleeding patients but the traditional plasma-based assays may not sufficiently display the effect. Furthermore, no antidote exists and reversal of the anticoagulant effect is impossible or difficult. The present study investigated the in vitro effect of dabigatran on whole blood thromboelastography (TEG) and its reversal by recombinant activated factor VII and prothrombin complex concentrate. METHODS: Blood was collected from 10 healthy donors and spiked in vitro with therapeutic doses of dabigatran to a plasma concentration of 200 ng/ml, followed by therapeutic doses of recombinant activated factor VII (corresponding to 100 µg/kg) and prothrombin complex concentrate (corresponding to 50 IE/kg) and evaluated by TEG. RESULTS: Compared to baseline, dabigatran changed all TEG parameters in a hypocoagulable direction corresponding to increased R time and time to maximum rate of thrombus generation, reduced angle, A5, A10, maximum amplitude and maximum rate of thrombin formation. Recombinant activated factor VII had a procoagulant effect on the majority of the investigated TEG parameters when added to dabigatran spiked samples. Prothrombin complex concentrate appeared not to have a procoagulant effect on TEG even when the heparin content in the formulation was neutralized by heparinase. CONCLUSIONS: TEG displays the presence of dabigatran in whole blood in vitro and the anticoagulant effect of dabigatran is partly reversed by spiking with recombinant activated factor VII.

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.

Hypercoagulability in response to elevated body temperature and central hypovolemia.

BACKGROUND: Coagulation abnormalities contribute to poor outcomes in critically ill patients. In trauma patients exposed to a hot environment, a systemic inflammatory response syndrome, elevated body temperature, and reduced central blood volume occur in parallel with changes in hemostasis and endothelial damage. The objective of this study was to evaluate whether experimentally elevated body temperature and reduced central blood volume (CBV) per se affects hemostasis and endothelial activation. METHODS: Eleven healthy volunteers were subjected to heat stress, sufficient to elevate core temperature, and progressive reductions in CBV by lower body negative pressure (LBNP). Changes in hemostasis were evaluated by whole blood haemostatic assays, standard hematologic tests and by plasma biomarkers of coagulation and endothelial activation/disruption. RESULTS: Elevated body temperature and decreased CBV resulted in coagulation activation evidenced by shortened activated partial tromboplastin time (-9% [IQR -7; -4]), thrombelastography: reduced reaction time (-15% [-24; -4]) and increased maximum amplitude (+4% (2; 6)), all P < 0.05. Increased fibrinolysis was documented by elevation of D-dimer (+53% (12; 59), P = 0.016). Plasma adrenaline and noradrenaline increased 198% (83; 346) and 234% (174; 363) respectively (P = 0.006 and P = 0.003). CONCLUSIONS: This experiment revealed emerging hypercoagulability in response to elevated body temperature and decreased CBV, whereas no effect on the endothelium was observed. We hypothesize that elevated body temperature and reduced CBV contributes to hypercoagulability, possibly due to moderate sympathetic activation, in critically ill patients and speculate that normalization of body temperature and CBV may attenuate this hypercoagulable response.

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.