Computed Tomography to Exclude Cardiac Thrombus in Atrial Fibrillation-An 11-Year Experience from an Academic Emergency Department.

BACKGROUND: Computed tomography (CT) could be a suitable method for acute exclusion of left atrial appendage thrombus (LAAT) prior to cardioversion of atrial fibrillation (AF) and atrial flutter (AFL) at the emergency department. Our aim was to present our experiences with this modality in recent years. METHODS: This registry-based observational study was performed at the Department of Emergency Medicine at the Medical University of Vienna, Austria. We studied all consecutive patients with AF and AFL who underwent CT between January 2012 and January 2023 to rule out LAAT before cardioversion to sinus rhythm was attempted. Follow-ups were conducted by telephone and electronic medical records. The main variables of interest were the rate of LAAT and ischemic stroke at follow-up. RESULTS: A total of 234 patients (143 [61%] men; median age 68 years [IQR 57-76], median CHA2DS2-VASc 2 [IQR 1-4]) were analyzed. Follow-up was completed in 216 (92%) patients after a median of 506 (IQR 159-1391) days. LAAT was detected in eight patients (3%). A total of 163 patients (72%) in whom LAAT was excluded by CT were eventually successfully cardioverted to sinus rhythm. No adverse events occurred during their ED stay. All patients received anticoagulation according to the CHA2DS2-VASc risk stratification, and no patient had suffered an ischemic stroke at follow-up, resulting in an incidence risk of ischemic strokes of 0% (95% CI 0.0-1.2%). CONCLUSION: LAAT was rare in patients admitted to the ED with AF and AFL who underwent cardiac CT prior to attempted cardioversion. At follow-up, no patient had suffered an ischemic stroke. Prospective studies need to show whether this strategy is suitable for the acute treatment of symptomatic AF in the emergency setting.

Anticoagulation with argatroban using hemoclot™ targets is safe and effective in CARDS patients receiving venovenous extracorporeal membrane oxygenation: An exploratory bi-centric cohort study.

Direct thrombin inhibitors, including argatroban, are increasingly used for anticoagulation during venovenous extracorporeal membrane oxygenation (VV ECMO). In many centers activated partial thromboplastin time (aPTT) is used for monitoring, but it can be affected by several confounders. The aim of this study was to evaluate the safety and efficacy of anticoagulation with argatroban titrated according to diluted thrombin time targets (hemoclot™ assay) compared to anti-Xa guided anticoagulation with unfractionated heparin (UFH). METHODS: This cohort study included adults at two tertiary care centers who required VV ECMO for severe COVID-19-related acute respiratory distress syndrome (CARDS). Patients received center-dependent argatroban or UFH for anticoagulation during ECMO. Argatroban was guided following a hemoclot™ target range of 0.4-0.6 µg/ml. UFH was guided by anti-factor Xa (antiXa) levels (0.2-0.3 IU/ml). The primary outcome was safety of argatroban compared to UFH, assessed by time to first clinically relevant bleeding event or death during ECMO. Secondary outcomes included efficacy (time to thromboembolism) and feasibility (proportion of anticoagulation targets within range). RESULTS: From 2019 to 2021 57 patients were included in the study with 27 patients (47 %) receiving argatroban and 30 patients (53 %) receiving UFH. The time to the first clinically relevant bleeding or death during ECMO was similar between groups (HR (argatroban vs. UFH): 1.012, 95 % CI 0.44-2.35, p = 0.978). Argatroban was associated with a decreased risk for thromboembolism compared to UFH (HR 0.494 (95 % CI 0.26-0.95; p = 0.034)). The overall proportion of anticoagulation within target ranges was not different between groups (46 % (23-54 %) vs. 46 % (37 %-57 %), p = 0.45). CONCLUSION: Anticoagulation with argatroban according to hemoclot™ targets (0.4-0.6 µg/ml) compared to antiXa guided UFH (0.2-0.3 IU/ml) is safe and may prolong thromboembolism-free time in patients with severe ARDS requiring VV ECMO.

Algorithm for Rapid Exclusion of Clinically Relevant Plasma Levels of Direct Oral Anticoagulants in Patients Using the DOAC Dipstick: An Expert Consensus Paper.

BACKGROUND: With the widespread use of direct oral anticoagulants (DOACs), there is an urgent need for a rapid assay to exclude clinically relevant plasma levels. Accurate and rapid determination of DOAC levels would guide medical decision-making to (1) determine the potential contribution of the DOAC to spontaneous or trauma-induced hemorrhage; (2) identify appropriate candidates for reversal, or (3) optimize the timing of urgent surgery or intervention. METHODS AND RESULTS: The DOAC Dipstick test uses a disposable strip to identify factor Xa- or thrombin inhibitors in a urine sample. Based on the results of a systematic literature search followed by an analysis of a simple pooling of five retrieved clinical studies, the test strip has a high sensitivity and an acceptably high negative predictive value when compared with levels measured with liquid chromatography tandem mass spectrometry or calibrated chromogenic assays to reliably exclude plasma DOAC concentrations ≥30 ng/mL. CONCLUSION: Based on these data, a simple algorithm is proposed to enhance medical decision-making in acute care indications useful primarily in hospitals not having readily available quantitative tests and 24/7. This algorithm not only determines DOAC exposure but also differentiates between factor Xa and thrombin inhibitors to better guide clinical management.

Prevalence of FXII-Deficiency and Its Relevance to Monitoring Anticoagulation in Adults Receiving Extracorporeal Membrane Oxygenation.

During extracorporeal membrane oxygenation (ECMO) blood is exposed to artificial surfaces, resulting in contact activation of the intrinsic coagulation pathway initiated by coagulation factor XII (FXII). Little is known about the prevalence of acquired FXII-deficiency, especially during ECMO. The primary outcome was the prevalence of acquired FXII-deficiency (FXII activity <60%) during ECMO. Secondary outcomes included differences in hemorrhagic/thromboembolic complications, doses of unfractionated heparin administered, and time points of anticoagulation within target ranges between patients with and without FXII-deficiency. Of 193 adults receiving ECMO therapy between 2013 and 2021, FXII testing was performed in 64 (33%) patients. Of these, 89% ( n = 57) had an acquired FXII-deficiency. Median complication-free intervals were not different between patients with and without acquired FXII-deficiency (bleeding: 28 days [6-145] vs. 12 days [11-not available], p = 0.85; thromboembolism: 16 days [8-54] vs. 13 days [3-15], p = 0.053). Patients with acquired FXII-deficiency received less heparin (16,554 IU/day vs. 25,839 IU/day; p = 0.009) and were less likely to be within aPTT-target ranges (23.1% [14.3%-36.4%] vs. 37.8% [33.7%-58.3%], p = 0.005). Acquired FXII-deficiency is common during ECMO and may affect monitoring of anticoagulation. The impact of FXII-activity on complications needs to be determined in future studies.

Disseminated Intravascular Coagulation in Anaphylaxis.

Anaphylaxis is a life-threatening condition that involves severe cutaneous, respiratory, and cardiovascular symptoms. Disseminated intravascular coagulation (DIC) is an acquired, widespread activation of coagulation that can be caused by infectious conditions (e.g., sepsis) and noninfectious conditions. The onset of DIC following anaphylaxis is not commonly known, and information regarding the pathomechanism linking anaphylaxis to DIC is scarce. Further, demographic and clinical data in anaphylaxis-induced DIC are still missing to this day. Triggered by a case of anaphylaxis-induced DIC that seamlessly transitioned to lethal sepsis-induced DIC, we aimed to characterize the patient population affected by anaphylaxis-induced DIC by performing a review of existing literature and expand the discussion to underlying mechanisms. The overall mortality of the patient cohort (n = 30) identified by the literature review was 50%. All patients that died either suffered a bleeding event or a thrombotic event. The majority of patients (n = 25/30; 83%) had bleeding events; thrombotic events were only reported in nonsurvivors (n = 9/15 or 60% of nonsurvivors; vs. n = 0/15 in survivors; p < 0.001). Nonsurvivors of anaphylaxis-induced DIC were on average 25 years older than survivors (p = 0.068). In conclusion, DIC can complicate anaphylaxis and is expected to contribute to poor microvascular perfusion after anaphylaxis. Particularly, elderly patients with known cardiovascular disease and patients who develop thrombotic events are susceptible to lethal outcomes. As a rare and largely uncharacterized disease entity, further research is needed to investigate the link between DIC and anaphylaxis and to potentially identify better treatment strategies.

Prevalence and Impact of Lupus Anticoagulant in Patients Receiving Extracorporeal Membrane Oxygenation.

BACKGROUND: Monitoring of blood coagulation is essential in ECMO patients. We investigated the prevalence of lupus anticoagulant (LA) and its association with coagulation testing and hemostaseologic complications in patients treated with ECMO. METHODS: This is a retrospective analysis including adult patients who received ECMO at a medical intensive care unit at the Medical University of Vienna. The primary outcome was the prevalence of LA. Secondary outcomes included conditions associated with LA positivity, rates of bleeding and thromboembolic events, as well as the proportions of aPTT and antiXa measurements within the target range. RESULTS: Between 2013 and 2021 193 patients received ECMO, in 62 (32%) of whom LA diagnostics were performed. Twenty-two (35%) patients tested positive. LA positive patients had more frequently received VV ECMO (77.3% vs 34.3%; p = 0.002), were more frequently diagnosed with viral respiratory infections (SARS-CoV2: 45.5% vs 20%; p = 0.041, influenza virus: 22.7% vs 0%; p = 0.003), had a longer ECMO treatment duration (25 vs 10 days; p = 0.011) and a longer ICU stay (48 vs 25 days; p = 0.022), but similar rates of bleeding and thromboembolic events.

Applicability of Vasopressor Trials in Adult Critical Care: A Prospective Multicentre Meta-Epidemiologic Cohort Study.

Objective: To assess the applicability of evidence from landmark randomized controlled trials (RCTs) of vasopressor treatment in critically ill adults. Study Design and Setting: This prospective, multi-center cohort study was conducted at five medical and surgical intensive care units at three tertiary care centers. Consecutive cases of newly initiated vasopressor treatment were included. The primary end point was the proportion of patients (≥18 years) who met the eligibility criteria of 25 RCTs of vasopressor therapy in critically ill adults included in the most recent Cochrane review. Multilevel Poisson regression was used to estimate the eligibility proportions with 95% confidence intervals for each trial. Secondary end points included the eligibility criteria that contributed most to trial ineligibility, and the relationship between eligibility proportions and (i) the Pragmatic-Explanatory Continuum Indicator Summary-2 (PRECIS-2) score, and (ii) the recruitment-to-screening ratio of each RCT. The PRECIS-2 score was used to assess the degree of pragmatism of each trial. Results: Between January 1, 2017, and January 1, 2019, a total of 1189 cases of newly initiated vasopressor therapy were included. The median proportion of cases meeting eligibility criteria for all 25 RCTs ranged from 1.3% to 6.0%. The eligibility criteria contributing most to trial ineligibility were the exceedance of a specific norepinephrine dose, the presence of a particular shock type, and the drop below a particular blood pressure value. Eligibility proportions increased with the PRECIS-2 score but not with the recruitment-to-screening ratio of the trials. Conclusion: The applicability of evidence from available trials on vasopressor treatment in critically ill adults to patients receiving vasopressors in daily practice is limited. Applicability increases with the degree of study pragmatism but is not reflected in a high recruitment-to-screening ratio. Our findings may help researchers design vasopressor trials and promote standardized assessment and reporting of the degree of pragmatism achieved.

Association of Intravenous Potassium and Magnesium Administration With Spontaneous Conversion of Atrial Fibrillation and Atrial Flutter in the Emergency Department.

Importance: Whether the simultaneous intravenous administration of potassium and magnesium is associated with the probability of spontaneous conversion to sinus rhythm (SCV) in the acute treatment of atrial fibrillation (AF) and atrial flutter (AFL) is unknown. Objective: To assess potassium and magnesium administration and SCV probability in AF and AFL in the emergency department. Design, Setting, and Participants: A registry-based cohort study was conducted in the Department of Emergency Medicine of the Medical University of Vienna, Austria. All consecutive patients with AF or AFL were screened between February 6, 2009, and February 16, 2020. Interventions: Intravenous administration of potassium, 24 mEq, and magnesium, 145.8 mg. Main Outcomes and Measures: The primary outcome was the probability of SCV during the patient's stay in the emergency department. Multivariable cluster-adjusted logistic regression was used to estimate the association between potassium and magnesium administration and the probability of SCV. Results: A total of 2546 episodes of nonpermanent AF (median patient age, 68 [IQR, 58-75] years, 1411 [55.4%] men) and 573 episodes of nonpermanent AFL (median patient age, 68 [IQR, 58-75] years; 332 [57.9%] men) were observed. In AF episodes, intravenous potassium and magnesium administration vs no administration was associated with increased odds of SCV (19.2% vs 10.4%; odds ratio [OR], 1.98; 95% CI, 1.53-2.57). In AFL episodes, in contrast, no association was noted for the probability of SCV with potassium and magnesium vs no administration (13.0% vs 12.5%; OR, 1.05; 95% CI, 0.65-1.69). Conclusions and Relevance: The findings of this registry-based cohort study on intravenous administration of potassium and magnesium suggest an increased probability of SCV in nonpermanent AF, but not AFL, during a patients' stay in the emergency department.

Multi-phasic life-threatening anaphylaxis refractory to epinephrine managed by extracorporeal membrane oxygenation (ECMO): A case report.

We present a case of a 52-year-old patient suffering from multi-phasic life-threatening anaphylaxis refractory to epinephrine treatment. Extracorporeal membrane oxygenation (ECMO) therapy was initiated as the ultima ratio to stabilize the patient hemodynamically during episodic severe bronchospasm. ECMO treatment was successfully weaned after 4 days. Mastocytosis was diagnosed as the underlying condition. Although epinephrine is recommended as a first-line treatment for anaphylaxis, this impressive case provides clear evidence of its limited therapeutic success and emphasizes the need for causal therapies.

Disseminated Intravascular Coagulation Score Predicts Mortality in Patients with Liver Disease and Low Fibrinogen Level.

BACKGROUND: Alongside its original diagnostic intention, the International Society on Thrombosis and Haemostasis' (ISTH) disseminated intravascular coagulation (DIC) score predicts mortality in various patient groups. OBJECTIVES: We investigated whether coagulopathy quantified by the DIC score can predict 30-day mortality in patients with liver disease and low fibrinogen levels. METHODS: We retrospectively analyzed all patients admitted to the Vienna General Hospital between 2003 and 2014 with a fibrinogen level of <150 mg/dL, a history of liver disease, and ≥2 pathological DIC parameters. We used a Cox regression and receiver operating characteristic analysis to assess the predictive value of the ISTH DIC score in its original (DIC-2001) and revised form (DIC-2018). RESULTS: A total of 1,333 patients were screened, and 388 of these patients (38% female, median age: 58 years, interquartile range: 48-66 years) were analyzed. The DIC-2001 (hazard ratio [HR]: 2.08, 95% confidence interval [CI]: 1.78-2.59, p < 0.001) and DIC-2018 (HR: 1.73, 95% CI: 1.51-2.05, p < 0.001) predicted 30-day mortality. The results remained robust in several sensitivity analyses. CONCLUSION: The ISTH DIC-2001 and DIC-2018 scores predicted 30-day mortality in patients with liver disease and low fibrinogen levels. The DIC score deserves further investigation in this population as it likely reflects different dimensions of the underlying disease.

Performance of a Qualitative Point-of-Care Strip Test to Detect DOAC Exposure at the Emergency Department: A Cohort-Type Cross-Sectional Diagnostic Accuracy Study.

An accurate point-of-care test for detecting effective anticoagulation by direct oral anticoagulants (DOACs) in emergencies is an unmet need. We investigated the accuracy of a urinary qualitative strip test (DOAC Dipstick) to detect relevant DOAC exposure in patients who presented to an emergency department. In this prospective single-center cohort-type cross-sectional study, adults on DOAC treatment were enrolled. We assessed clinical sensitivity and specificity of DOAC Dipstick factor Xa and thrombin inhibitor pads to detect DOAC plasma levels ≥30 ng/mL using urine samples as the testing matrix. Liquid chromatography coupled with tandem-mass spectrometry was used as the reference standard method for plasma and urine measurement of DOAC concentrations. Of 293 patients enrolled, 265 patients were included in the analysis, of whom 92 were treated with rivaroxaban, 65 with apixaban, 77 with edoxaban, and 31 with dabigatran. The clinical sensitivity and specificity of the dipstick on urine samples to detect ≥30 ng/mL dabigatran plasma levels were 100% (95% confidence interval [CI]: 87-100%) and 98% (95% CI: 95-99%), respectively. The sensitivity and specificity of the dipstick to detect ≥30 ng/mL factor Xa inhibitor plasma levels were 97% (95% CI: 94-99%) and 69% (95% CI: 56-79%), respectively. The DOAC Dipstick sensitively identified effective thrombin and factor Xa inhibition in a real-world cohort of patients presenting at an emergency department. Therefore, the dipstick might provide a valuable test to detect relevant DOAC exposure in emergencies, although further studies will be needed to confirm these findings.

The ABC-Stroke Score Refines Stroke Risk Stratification in Patients With Atrial Fibrillation at the Emergency Department.

Aims: To evaluate the performance of the ABC (Age, Biomarkers, Clinical history) and CHA2DS2-VASc stroke scores under real-world conditions in an emergency setting. Methods and Results: The performance of the biomarker-based ABC-stroke score and the clinical variable-based CHA2DS2-VASc score for stroke risk assessment were prospectively evaluated in a consecutive series of 2,108 patients with acute symptomatic atrial fibrillation at a tertiary care emergency department. Performance was assessed according to methods for the development and validation of clinical prediction models by Steyerberg et al. and the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis. During a cumulative observation period of 3,686 person-years, the stroke incidence rate was 1.66 per 100 person-years. Overall, the ABC-stroke and CHA2DS2-VASc scores revealed respective c-indices of 0.64 and 0.55 for stroke prediction. Risk-class hazard ratios comparing moderate to low and high to low were 3.51 and 2.56 for the ABC-stroke score and 1.10 and 1.62 for the CHA2DS2-VASc score. The ABC-stroke score also provided improved risk stratification in patients with moderate stroke risk according to the CHA2DS2-VASc score, who lack clear recommendations regarding anticoagulation therapy (HR: 4.35, P = 0.001). Decision curve analysis indicated a superior net clinical benefit of using the ABC-stroke score. Conclusion: In a large, real-world cohort of patients with acute atrial fibrillation in the emergency department, the ABC-stroke score was superior to the guideline-recommended CHA2DS2-VASc score at predicting stroke risk and refined risk stratification of patients labeled moderate risk by the CHA2DS2-VASc score, potentially easing treatment decision-making.

Out-of-Sample Validity of the PROLOGUE Score to Predict Neurologic Function after Cardiac Arrest.

BACKGROUND: The clinical value of a prognostic score depends on its out-of-sample validity because inaccurate outcome prediction can be not only useless but potentially fatal. We aimed to evaluate the out-of-sample validity of a recently developed and highly accurate Korean prognostic score for predicting neurologic outcome after cardiac arrest in an independent, plausibly related sample of European cardiac arrest survivors. METHODS: Analysis of data from a European cardiac arrest center, certified in compliance with the specifications of the German Council for Resuscitation. The study sample included adults with nontraumatic out-of-hospital cardiac arrest admitted between 2013 and 2018. Exposure was the PROgnostication using LOGistic regression model for Unselected adult cardiac arrest patients in the Early stages (PROLOGUE) score, including 12 clinical variables readily available at hospital admission. The outcome was poor 30-day neurologic function, as assessed using the cerebral performance category scale. The risk of a poor outcome was calculated using the PROLOGUE score regression equation. Predicted risk deciles were compared to observed outcome estimates in a complete-case analysis, a best-case analysis, and a multiple-data-imputation analysis using the Markov chain Monte Carlo method. RESULTS: A total of 1051 patients (median 61 years, IQR 50-71; 29% female) were analyzed. A total of 808 patients (77%) were included in the complete-case analysis. The PROLOGUE score overestimated the risk of poor neurologic outcomes in the range of 40% to 100% predicted risk, involving 63% of patients. The model fit did not improve after missing data imputation. CONCLUSIONS: In a plausibly related sample of European cardiac arrest survivors, risk prediction by the PROLOGUE score was largely too pessimistic and failed to replicate the high accuracy found in the original study. Using the PROLOGUE score as an example, this study highlights the compelling need for independent validation of a proposed prognostic score to prevent potentially fatal mispredictions.

Cardioversion of Post-Ablation Atrial Tachyarrhythmia with Ibutilide and Amiodarone: A Registry-Based Cohort Study.

Patients with recurrence of atrial tachyarrhythmia after catheter ablation for atrial fibrillation or atrial flutter constitute a rapidly growing cohort, but study-driven treatment recommendations are lacking. The present study aimed to compare the cardioversion success of ibutilide and amiodarone in patients with post-ablation atrial tachyarrhythmia. We included all episodes of post-ablation atrial tachyarrhythmia in patients treated with either intravenous ibutilide or amiodarone at an academic emergency department from 2010 to 2018. The primary endpoint was the conversion to sinus rhythm. The conversion rates were stratified by arrhythmia type, and multivariable cluster-adjusted logistic regression was used to estimate the effect of ibutilide and amiodarone on cardioversion success, given as the odds ratio (OR) with 95% confidence intervals (95% CI). In total, 109 episodes of 72 patients were analyzed. The conversion rates were 37/49 (76%) for ibutilide and 16/60 (27%) for amiodarone. Compared to amiodarone, ibutilide was associated with higher odds of conversion (multivariable cluster-adjusted OR 5.6, 95% CI 1.3-24.3). The cardioversion success of ibutilide was the highest in atrial flutter (crude OR 19.5, 95% CI 3.4-112.5) and focal atrial tachycardia (crude OR 8.3, 95% CI 1.5-47.2), but it was less pronounced in atrial fibrillation (crude OR 4.5, 95% CI 1.2-17.2). Randomized trials are warranted to confirm our findings.

Prediction of Successful Pharmacological Cardioversion in Acute Symptomatic Atrial Fibrillation: The Successful Intravenous Cardioversion for Atrial Fibrillation (SIC-AF) Score.

Background: Modern personalised medicine requires patient-tailored decisions. This is particularly important when considering pharmacological cardioversion for the acute treatment of haemodynamically stable atrial fibrillation and atrial flutter in a shared decision-making process. We aimed to develop and validate a predictive model to estimate the individual probability of successful pharmacological cardioversion using different intravenous antiarrhythmic agents. Methods: We analysed data from a prospective atrial fibrillation registry comprising 3053 cases of first-detected or recurrent haemodynamically stable, non-permanent, symptomatic atrial fibrillation presenting to an Austrian academic emergency department between January 2012 and December 2017. Using multivariable analysis, a prediction score was developed and externally validated. The clinical utility of the score was assessed using decision curve analysis. Results: A total of 1528 cases were included in the development cohort (median age 69 years, IQR 58−76; 43.9% female), and 1525 cases were included in the validation cohort (median age 68 years, IQR (58−75); 39.5% female). Finally, 421 cases were available for score development and 330 cases for score validation The weighted score included atrial flutter (8 points), duration of symptoms associated with AF (<24 h; 8 points), absence of previous electrical cardioversion (10 points), and the specific intravenous antiarrhythmic drug (amiodarone 10 points, vernakalant 11 points, ibutilide 13 points). The final score, the "Successful Intravenous Cardioversion for Atrial Fibrillation (SIC-AF) score," showed good calibration (R2 = 0.955 and R2 = 0.954) and discrimination in both sets (c-indices: 0.68 and 0.66) and net clinical benefit. Conclusions: A predictive model was developed to estimate the success of intravenous pharmacological cardioversion using different antiarrhythmic agents in a cohort of patients with haemodynamically stable, non-permanent, symptomatic atrial fibrillation. External temporal validation confirmed good calibration, discrimination, and clinical usefulness. The SIC-AF score may help patients and physicians jointly decide on the appropriate treatment strategy for acute symptomatic atrial fibrillation. Registration: NCT03272620.

Add-On Prostaglandin E1 in Venovenous Extracorporeal Membrane Oxygenation: A Randomized, Double-Blind, Placebo-controlled Pilot Trial.

Rationale: Prostaglandin E1 (alprostadil; PGE1), in addition to low-dose unfractionated heparin, increases the biocompatibility of extracorporeal systems and enhances the efficacy of artificial organs without increasing bleeding risk. Objectives: We investigated the safety and efficacy of PGE1 in adults receiving venovenous extracorporeal membrane oxygenation (ECMO). Methods: This study was a randomized, double-blind, placebo-controlled phase II pilot trial at two medical intensive care units at the Medical University of Vienna, Austria. Adults with venovenous ECMO were randomly assigned to receive an intravenous infusion of 5 ng/kg/min PGE1 or placebo (0.9% saline) in addition to standard anticoagulation with unfractionated heparin. Measurements and Main Results: The primary outcome was the rate of transfused packed red blood cells per ECMO day. Secondary outcomes were the incidence of and time to clinically overt bleeding and thromboembolic events. A post hoc subgroup analysis included only patients with coronavirus disease (COVID-19). Between September 2016 and April 2021, of 133 screened patients, 50 patients were randomized, of whom 48 received the assigned study medication (24 per group). The transfusion rate was similar between groups (0.41 vs. 0.39; P = 0.733). PGE1 was associated with fewer thromboembolic events (7 vs. 16; P = 0.020) and longer thromboembolism-free time (hazard ratio [HR], 0.302; P = 0.01), fewer clinically overt bleeding events (2 vs. 11; P = 0.017), and longer bleeding-free time (HR, 0.213; P = 0.047). In patients with COVID-19 (n = 25), the HRs for clinically overt bleeding and thromboembolism were 0.276 (95% confidence interval, 0.035-2.186) and 0.521 (95% confidence interval, 0.149-1.825), respectively. Conclusions: Add-on treatment with PGE1 was safe but did not meet the primary endpoint of reducing the rate of red blood cell transfusions in patients receiving venovenous ECMO. Larger studies need to evaluate the safety and efficacy of additional PGE1 in ECMO. Clinical trial registered with EudraCT (2015-005014-30) and www.clinicaltrials.gov (NCT02895373).

Advanced pharmacodynamics of cangrelor in healthy volunteers: a dose-finding, open-label, pilot trial.

BACKGROUND: High on-treatment platelet reactivity (HTPR) remains a major problem in the acute management of ST-elevation myocardial infarction (STEMI), leading to higher rates of stent thrombosis and mortality. We aimed to investigate a novel, prehospital treatment strategy using cangrelor and tested its pharmacodynamic effects in a model using healthy volunteers. METHODS: We conducted a dose-finding, open-label, pilot trial including 12 healthy volunteers and tested three ascending bolus infusions of cangrelor (5 mg, 10 mg and 20 mg) and a bolus infusion followed by a continuous infusion via an intravenous (IV) flow regulator. Platelet function was assessed using multiple electrode aggregometry (MEA), vasodilator-stimulated phosphoprotein phosphorylation assay (VASP-P) and the platelet function analyzer. In an ex vivo experiment, epinephrine was used to counteract the antiplatelet effect of cangrelor. RESULTS: All cangrelor bolus infusions resulted in immediate and pronounced platelet inhibition. Bolus infusions of cangrelor 20 mg resulted in sufficient platelet inhibition assessed by MEA for 20 min in 90% of subjects. Infusion of cangrelor via the IV flow regulator resulted in sufficient platelet inhibition throughout the course of administration. Ex vivo epinephrine, in concentrations of 200 and 500 ng/mL was able to partially reverse the antiplatelet effect of cangrelor in a dose-dependent manner. CONCLUSIONS: Weight-adapted bolus infusions followed by a continuous infusion of cangrelor via IV flow regulator result in immediate and pronounced platelet inhibition in healthy subjects. Cangrelor given as weight-adapted bolus infusion followed by a continuous infusion using an IV flow regulator may be a viable treatment approach for effective and well controllable prehospital platelet inhibition. TRIAL REGISTRATION: EC (Medical University of Vienna) 1835/2019 and EudraCT 2019-002792-34 .

Targeted temperature management after cardiac arrest is associated with reduced metabolism of pantoprazole - A probe drug of CYP2C19 metabolism.

OBJECTIVE: Targeted temperature management (TTM) is part of standard post-resuscitation care. TTM may downregulate cytochrome enzyme activity and thus impact drug metabolism. This study compared the pharmacokinetics (PK) of pantoprazole, a probe drug of CYP2C19-dependent metabolism, at different stages of TTM following cardiac arrest. METHODS: This prospective controlled study was performed at the Medical University of Vienna and enrolled 16 patients following cardiac arrest. The patients completed up to three study periods (each lasting 24 h) in which plasma concentrations of pantoprazole were quantified: (P1) hypothermia (33 °C) after admission, (P2) normothermia after rewarming (36 °C, intensive care), and (P3) normothermia during recovery (normal ward, control group). PK was analysed using non-compartmental analysis and nonlinear mixed-effects modelling. RESULTS: 16 patients completed periods P1 and P2; ten completed P3. The median half-life of pantoprazole was 2.4 h (quartiles: 1.8-4.8 h) in P1, 2.8 h (2.1-6.8 h, p = 0.046 vs. P1, p = 0.005 vs. P3) in P2 and 1.2 h (0.9 - 2.3 h, p = 0.007 vs. P1) in P3. A two-compartment model described the PK data best. Typical values for clearance were estimated separately for each study period, indicating 40% and 29% reductions during P1 and P2, respectively, compared to P3. The central volume of distribution was estimated separately for P2, indicating a 64% increase compared to P1 and P3. CONCLUSION: CYP2C19-dependent drug metabolism is downregulated during TTM following cardiac arrest. These results may influence drug choice and dosing of similarly metabolized drugs and may be helpful for designing studies in similar clinical situations.

The association of early diarrhea after successful resuscitation following out-of-hospital cardiac arrest with neurological outcome: A retrospective observational study.

ABSTRACT: Gastrointestinal ischemia with reperfusion tissue injury contributes to post-cardiac arrest syndrome. We hypothesized that diarrhea is a symptom of intestinal ischemia/reperfusion injury and investigated whether the occurrence of early diarrhea (≤12 hours) after successful cardiopulmonary resuscitation is associated with an unfavorable neurological outcome.We analyzed data from the Vienna Clinical Cardiac Arrest Registry. Inclusion criteria comprised ≥18 years of age, a witnessed, non-traumatic out-of-hospital cardiac arrest, return of spontaneous circulation (ROSC), initial shockable rhythm, and ST-segment elevation in electrocardiogram after ROSC with consecutive coronary angiography. Patients with diarrhea caused by other factors (e.g., infections, antibiotic treatment, or chronic diseases) were excluded. The primary endpoint was neurological function between patients with or without "early diarrhea" (≤12 hours after ROSC) according to cerebral performance categories.We included 156 patients between 2005 and 2012. The rate of unfavorable neurologic outcome was higher in patients with early diarrhea (67% vs 37%). In univariate analysis, the crude odds ratio for unfavorable neurologic outcome was 3.42 (95% confidence interval, 1.11-10.56, P = .03) for early diarrhea. After multivariate adjustment for traditional prognostication markers the odds ratio of early diarrhea was 5.90 (95% confidence interval, 1.28-27.06, P = .02).In conclusion, early diarrhea within 12 hours after successful cardiopulmonary resuscitation was associated with an unfavorable neurological outcome.