Variables independently associated with admission biomarkers reflecting endothelial glycocalyx and cell activation and/or damage, and endothelial cell junction function (syndecan-1, sE-selectin, thrombomodulin and sVE-cadherin, respectively) by backwards multivariate linear regression analysis in 163 patients admitted to a tertiary university hospital after out-of-hospital cardiac arrest.

<p>Regression coefficients (β) with 95% confidence intervals (95%CI), p-values and adjusted R² are displayed, with p-values <0.05 shown in bold. Predicted changes in syndecan-1 (ng/ml, reflecting glycocalyx damage), sE-selectin (ng/ml, reflecting endothelial activation), Thrombomodulin (ng/ml, reflecting endothelial cell injury) and sVE-cadherin (ng/ml, reflecting endothelial junction disruption) associated with one unit increase in the explanatory variables (age (1 year older), BMI, number of defibrillations (NS all over, data not shown), time from OHCA to ROSC (min), pH, STEMI (yes), p-adrenaline and p-noradrenaline (10-fold higher, NS all over, data not shown), syndecan-1, thrombomodulin, sE-selectin and VE-cadherin (all 2-fold higher). NS, non-significant. NA, non-applicable.</p><p>Variables independently associated with admission biomarkers reflecting endothelial glycocalyx and cell activation and/or damage, and endothelial cell junction function (syndecan-1, sE-selectin, thrombomodulin and sVE-cadherin, respectively) by backwards multivariate linear regression analysis in 163 patients admitted to a tertiary university hospital after out-of-hospital cardiac arrest.</p

Correlations between admission levels of syndecan-1 or thrombomodulin, reflecting endothelial glycocalyx and cell damage, respectively, and plasma (p)-adrenaline (pg/ml) (A and D), administered adrenaline (mg) (B and E) and pH (C and F) in 163 OHCA patients

<p>P- and rho-values for Spearman´s correlations are displayed.</p

Kaplan-Meier plots displaying 180-day mortality in 163 OHCA patients stratified according to median levels (high vs. low) of A) plasma (p)-adrenaline and B) Serum thrombomodulin at hospital admission.

<p>Chi-square and p-values for log-rank tests are shown.</p

Demography, medical history, characteristics of the cardiac arrest, patient admission characteristics and outcome in all patients (n = 163) and in patients stratified according to admission serum thrombomodulin (high (>median) vs. low (≤median), n = 160) admitted to a tertiary university hospital after out-of-hospital cardiac arrest (OHCA).

<p>Data are presented as medians (IQR) or n (%). Patients stratified according to the median serum level of thrombomodulin at admission were compared by Mann-Whitney U test or Chi-square/Fisher´s exact tests as appropriate, with p-values <0.05 shown in bold. AMI, acute myocardial infarction. TIA, transient ischemic attack. COPD, chronic obstructive pulmonary disease. PCI, percutaneous coronary intervention. CABG, coronary artery bypass graft. Location: R, place of residence; P, public place; O, other. CPR, cardio-pulmonary resuscitation. Shockable rhythm: ventricular fibrillation, nonperfusing ventricular tachycardia, unknown rhythm responsive to shock, perfusing rhythm after bystander-initiated defibrillation; non-shockable rhythm: asystole, pulseless electrical activity, unknown rhythm not responsive to shock. ROSC, return of spontaneous circulation. ECG (electrocardiography) findings: U, unchanged from previously/normal; S, ST-segment myocardial infarction (STEMI); L, left bundle branch block; A, atrial fibrillation or flutter; O, other. Discharge facility: O, other hospital/intensive care unit; R, rehabilitation facility; H, home; CPC, Cerebral Performance Category (1–2 designates good outcome); mRS, modified Rankin Scale (0–3 designates good outcome).</p><p>Demography, medical history, characteristics of the cardiac arrest, patient admission characteristics and outcome in all patients (n = 163) and in patients stratified according to admission serum thrombomodulin (high (>median) vs. low (≤median), n = 160) admitted to a tertiary university hospital after out-of-hospital cardiac arrest (OHCA).</p

Physiology and standard biochemistry in nine healthy volunteers before (0 h), during (4 h) and after (6 h) induction of experimental endotoxemia by means of a 4 h 0.5 ng/kg/hour LPS-infusion.

<p>Data are presented as means±SD. Data from volunteers were compared by repeated-measures analyses (RM) and Tukey post hoc tests: p<0.05 for 0 h vs. 4 h^a, 0 h vs. 6 h^b and 4 h vs. 6 h^c. P-values <0.2 are shown and in bold if p<0.05.</p><p>HR, heart rate; MAP, mean arterial blood pressure; SpO₂, peripheral oxygen saturation; SBE, standard base excess; WBC, white blood cells; CRP, c-reactive protein; AT, antithrombin; APTT, activated partial thromboplastin time; INR, international normalized ratio. NS, non-significant; ND, not done.</p

Functional hemostatic assays in whole-blood (impedance aggregometry (Multiplate), Thrombelastography (TEG), Functional fibrinogen) and plasma (TEG with or without addition of tPA to induce fibrinolysis) in nine healthy volunteers before, during and after induction of experimental endotoxemia by means of a 4 h LPS-infusion (0.5 ng/kg/hour).

<p>Data are presented as means±SD. Data from volunteers were compared by repeated-measures analyses (RM) and Tukey post hoc tests: p<0.05 for 0 h vs. 4 h^a, 0h vs. 6 h^b and 4 h vs. 6 h^c. P-values <0.2 are shown and in bold if p<0.05.</p><p>Different platelet agonists were applied in the Multiplate tests: TRAPtest, thrombin-receptor activating peptide; ADPtest, ADP; COLtest, collagen; ASPItest, arachidonic acid; TEG, thrombelastography; R, reaction time; Angle, α angle; MA, maximum amplitude; G, shear elastic modulus strength; CLT, clot lysis time; Ly30/60, percent lysis 30/60 min after MA;</p><p>tPA, tissue-type plasminogen activator. NS, non-significant.</p

Representative profiles of TEG and modified TEG analyses in healthy volunteers before (t = 0), during (t = 4 h) and after (t = 6 h) experimental endotoxemia induced by a 4-hour continuous intravenous infusion of purified <i>Escherichia coli</i> LPS (infusion rate 0.5 ng/kg/hour).

<p>TEG and Functional Fibrinogen were analyzed in whole blood whereas plasma TEG was analyzed in plasma with or without addition of 1.8 nM tPA to induce lysis of the clot i.e., allowing extended evaluation of clot resistance to fibrinolysis.</p

The Potential of Antimicrobials to Induce Thrombocytopenia in Critically Ill Patients: Data from a Randomized Controlled Trial

<div><p>Background</p><p>Antimicrobial-induced thrombocytopenia is frequently described in the literature among critically ill patients. Several antimicrobials have been implicated, although experimental evidence to demonstrate causality is limited. We report, using a randomized trial, the potential of antimicrobials to induce thrombocytopenia.</p> <p>Methods</p><p>Randomized trial allocated patients to antimicrobial treatment according to standard- of-care (SOC group) or drug-escalation in case of procalcitonin increases (high-exposure group). Patients were followed until death or day 28. Thrombocytopenia defined as absolute (platelet count ≤100x109/L) or relative (≥20% decrease in platelet count). Analyses were performed in the two randomized groups and as a merged cohort. </p> <p>Results</p><p>Of the 1147 patients with platelet data available, 18% had absolute thrombocytopenia within the first 24 hours after admission to intensive care unit and additional 17% developed this complication during follow-up; 57% developed relative thrombocytopenia during follow-up. Absolute and relative thrombocytopenia day 1-4 was associated with increased mortality (HR: 1.67 [95% CI: 1.30 to 2.14]; 1.71 [95% CI: 1.30 to 2.30], P<0.0001, respectively). Patients in the high-exposure group received more antimicrobials including piperacillin/tazobactam, meropenem and ciprofloxacin compared with the SOC group, whereas cefuroxime was used more frequently in the SOC group (p<0.05). Risk of absolute and relative thrombocytopenia (RR: 0.9 [0.7-1.3], p=0.7439; 1.2 [1.0-1.4], p=0.06; respectively), as well as absolute platelet count (daily difference, high-exposure vs. SOC -1.7 [-3.8-0.5], p=0.14) was comparable between groups. In observational analyses, use of ciprofloxacin and piperacillin/tazobactam predicted risk of relative thrombocytopenia (vs. cefuroxime, RR: 2.08 [1.48-2.92]; 1.44 [1.10-1.89], respectively), however only ciprofloxacin were associated with a reduction in absolute platelet count (p=0.0005). </p> <p>Conclusion</p><p>High exposure to broad-spectrum antimicrobials does not result in a reduction in thrombocytopenia in critically ill patients. However, single use of ciprofloxacin, and less so piperacillin/tazobactam, may contribute to a lower platelet count.</p> <p>Trial Registration</p><p><a href="http://clinicaltrials.gov" target="_blank">ClinicalTrials.gov</a> NCT00271752 <a href="http://clinicaltrials.gov/ct2/show/nct00271752" target="_blank">http://clinicaltrials.gov/ct2/show/NCT00271752</a></p> </div

Estimated change in daily platelet count.

<div><p>Mixed model adjusted for the following time fixed variables: randomisation group, age, gender, BMI, severe sepsis/septic shock at ICU admission, APACHE II score, surgical vs. medical patients. </p> <p>Time-updated use of antimicrobials was included in the model.</p> <p>Ciprofloxacin, Piperacillin/tazobactam (pip/tazo) (used alone or in combinations not including cefuroxime) and none (no antimicrobials) compared to people receiving cefuroxime (used alone or in combinations non including the antibiotic in question).</p></div

Use of frequent prescribed antimicrobials in the PASS study and occurrence of absolute and relative thrombocytopenia among the two randomized groups.

<div><p>Unadjusted analysis displaying the use of antimicrobials and occurrence of thrombocytopenia among the two randomized groups displayed as relative rate ratio (RR) during 28 day follow-up.</p> <p>Absolute (one platelet count < 100 x 109/L) or relative (>=20 % decrease in platelet count from ICU admission) thrombocytopenia.</p> <p>RR-Ratio >1.0 indicates that the high-ex. group have a relatively higher risk of occurrence of the asses variable and RR-Ratio <1.0 indicates relatively higher risk of patients in the SOC group of occurrence of the asses variable. RR-ratio=0 indicates no difference between the two groups. </p></div