Contemporary approaches to Pulmonary Embolism Diagnosis - a clinical review.

Introduction: The optimal diagnosis strategy for pulmonary embolism (PE) in the emergency department (ED) remains complex. This review summarizes PE diagnosis with clinical presentation, decision rules and investigations for acute PE. Methods: This review was performed using studies published between January 1, 2010, and September 1, 2023. Results: PE should be considered in ED in patients with chest pain, shortness of breath, syncope or signs of deep veinous thrombosis. Definitive diagnosis of PE relies on thoracic imaging, with the use of CTPA or ventilation/perfusion lung scintigraphy. To limit the continuous increased use of chest imaging, the clinical probability should be the first step for PE work out. The Pulmonary Embolism Rule-out Criteria (PERC rule) can rule out PE at this stage. If not, for low or intermediate probability, several clinical decision rules (CDR) have been validated, either by ruling out PE on clinical signs, or by raising D-Dimer thresholds (YEARS or PEGeD) or by combination of these different rules. It is recommended that patients with a high clinical probability of PE should undergo chest imaging without the need for D-dimer testing. The PE diagnostic approach can be tailored in specific populations such as pregnant, younger, COVID-19, or cancer patients. Conclusion: PE diagnosis workout illustrates the complexity of modern probabilistic-based approaches of decision-making in medicine. It is recommended to use a Bayesian approach with the evaluation of clinical probability, then order D-Dimer if the PERC rule is positive, then adapt the D-Dimer threshold for ordering chest imaging using CDR.

Pulmonary embolism rule-out decision-making tools for patients aged 35 years or younger in hospital emergency departments: a post-hoc analysis of performance in 3 prospective cohorts. / Capacidad de diferentes reglas de decisión clínica para descartar tromboembolismo pulmonar en pacientes de 35 o menos años atendidos en servicios de urgencias: análisis post-hoc de tres cohortes prospectivas.

OBJECTIVES: To assess the performance of the Pulmonary Embolism Rule-out Criteria (PERC) and the age-modified PERC-35 tool in hospital emergency departments (EDs) for evaluating patients aged 35 years or younger. A secondary aim was to assess other decision-making criteria. MATERIAL AND METHODS: Post-hoc analysis of 3 European cohort studies. We included data for patients aged 35 years or younger suspected of PE who were followed for 3 months. The safety and efficacy of applying the PERC and PERC-35 were assessed with the diagnostic error rate (failure to detect PE) and the proportion of patients in whom a diagnosis of PE was ruled out. We also assessed the safety and efficacy of applying the YEARS and PEGeD criteria. RESULTS: Data for 1235 patients aged 35 years or younger were analyzed. Twenty-two (1.8%; 95% CI, 1.2%-2.7%) PE cases were diagnosed at 3 months. Six (1.0%; 95% CI, 0.5%-2.2%) and 5 (0.9%; 95% CI, 0.4%-2.1%) PE cases were not diagnosed by the PERC and PERC-35 tools, respectively. These tools allowed PE to be ruled out in 591 (48.2%; 95% CI, 45.4%-51.0%) and 554 (46.2%; 95% CI, 43.4%-49.0%) cases, respectively. The error rates of the YEARS and PEGeD criteria, respectively, were 0.4% (95% CI, 0.1%-1.1%) and 0.5% (95% CI, 0.2%-1.2%); their efficacy was similar. CONCLUSION: The safety and efficacy profiles of the PERC and PERC-35 algorithms were similar in patients aged 35 years or younger. However, the large confidence intervals we report do not allow us to confirm the safety of using the tools in patients in this age group.

OBJETIVO: Evaluar la capacidad de la regla PERC (Pulmonary Embolism Rule-out Criteria) y la regla modificada por edad (PERC-35) para descartar tromboembolia pulmonar (TEP) en servicios de urgencias hospitalarios (SUH) en pacientes 35 años. El objetivo secundario fue analizar otras reglas de decisión clínica. METODO: Análisis post-hoc de 3 estudios de cohorte europeos (PROPER, PERCEPIC y MODIGLIANI). Se incluyeron pacientes 35 años con sospecha de TEP en SUH y con seguimiento a 3 meses. La seguridad y eficacia de PERC y PERC-35 se evaluaron con su tasa de error -no detectar TEP- y la proporción de pacientes con diagnóstico de TEP descartado. Se evaluó la seguridad y eficacia de las reglas YEARS y PEGeD. RESULTADOS: Se analizaron 1.235 pacientes 35 años. Hubo 22 (1,8%, IC 95%: 1,2-2,7) TEP diagnosticados a los 3 meses. Hubo 6 (1,0%, IC 95%: 0,5-2,2) y 5 (0,9%, IC 95%: 0,4-2,1) TEP no diagnosticados con las reglas PERC y PERC-35 respectivamente. Estas reglas permitieron descartar TEP en 591 (48,2%, IC 95%: 45,4- 51,0) y 554 (46,2%, IC 95%: 43,4- 49,0) respectivamente. La tasa de error de YEARS y PEGeD fue del 0,4% (IC 95%: 0,1- 1,1) y 0,5% (IC 95%: 0,2-1,2), con una eficacia similar. CONCLUSIONES: En pacientes 35 años, las reglas PERC y PERC-35 mostraron perfiles de seguridad y eficacia similares. Sin embargo, el amplio intervalo de confianza comunicado en este estudio no permite confirmar su seguridad.

Capacidad de diferentes reglas de decisión clínica para descartar tromboembolismo pulmonar en pacientes de 35 o menos años atendidos en servicios de urgencias: análisis post-hoc de tres cohortes prospectivas / Pulmonary embolism rule-out decision-making tools for patients aged 35 years or younger in hospital emergency departments: a post-hoc analysis of performance in 3 prospective cohorts

Objetivos: Evaluar la capacidad de la regla PERC (Pulmonary Embolism Rule-out Criteria) y la regla modificada por edad (PERC-35) para descartar tromboembolia pulmonar (TEP) en servicios de urgencias hospitalarios (SUH) en pacientes # 35 años. El objetivo secundario fue analizar otras reglas de decisión clínica. Método: Análisis post-hoc de 3 estudios de cohorte europeos (PROPER, PERCEPIC y MODIGLIANI). Se incluyeron pacientes # 35 años con sospecha de TEP en SUH y con seguimiento a 3 meses. La seguridad y eficacia de PERC yPERC-35 se evaluaron con su tasa de error -no detectar TEP- y la proporción de pacientes con diagnóstico de TEP descartado. Se evaluó la seguridad y eficacia de las reglas YEARS y PEGeD. Resultados: Se analizaron 1.235 pacientes # 35 años. Hubo 22 (1,8%, IC 95%: 1,2-2,7) TEP diagnosticados a los 3 meses. Hubo 6 (1,0%, IC 95%: 0,5-2,2) y 5 (0,9%, IC 95%: 0,4-2,1) TEP no diagnosticados con las reglas PERC y PERC-35 respectivamente. Estas reglas permitieron descartar TEP en 591 (48,2%, IC 95%: 45,4- 51,0) y 554 (46,2%, IC 95%: 43,4- 49,0) respectivamente. La tasa de error de YEARS y PEGeD fue del 0,4% (IC 95%: 0,1- 1,1) y 0,5% (IC 95%: 0,2-1,2), con una eficacia similar. Conclusiones: En pacientes # 35 años, las reglas PERC y PERC-35 mostraron perfiles de seguridad y eficacia similares. Sin embargo, el amplio intervalo de confianza comunicado en este estudio no permite confirmar su seguridad. (AU)

Objectives: To assess the performance of the Pulmonary Embolism Rule-out Criteria (PERC) and the age-modified PERC-35 tool in hospital emergency departments (EDs) for evaluating patients aged 35 years or younger. A secondary aim was to assess other decision-making criteria. Method: Post-hoc analysis of 3 European cohort studies. We included data for patients aged 35 years or younger suspected of PE who were followed for 3 months. The safety and efficacy of applying the PERC and PERC-35 were assessed with the diagnostic error rate (failure to detect PE) and the proportion of patients in whom a diagnosis of PE was ruled out. We also assessed the safety and efficacy of applying the YEARS and PEGeD criteria. Results: Data for 1235 patients aged 35 years or younger were analyzed. Twenty-two (1.8%; 95% CI, 1.2%-2.7%) PE cases were diagnosed at 3 months. Six (1.0%; 95% CI, 0.5%-2.2%) and 5 (0.9%; 95% CI, 0.4%-2.1%) PE cases were not diagnosed by the PERC and PERC-35 tools, respectively. These tools allowed PE to be ruled out in 591 (48.2%; 95% CI, 45.4%-51.0%) and 554 (46.2%; 95% CI, 43.4%-49.0%) cases, respectively. The error rates of the YEARS and PEGeD criteria, respectively, were 0.4% (95% CI, 0.1%-1.1%) and 0.5% (95% CI, 0.2%-1.2%); their efficacy was similar. Conclusions: The safety and efficacy profiles of the PERC and PERC-35 algorithms were similar in patients aged 35 years or younger. However, the large confidence intervals we report do not allow us to confirm the safety of using the tools in patients in this age group. (AU)

Effect of Noninvasive Airway Management of Comatose Patients With Acute Poisoning: A Randomized Clinical Trial.

Importance: Tracheal intubation is recommended for coma patients and those with severe brain injury, but its use in patients with decreased levels of consciousness from acute poisoning is uncertain. Objective: To determine the effect of intubation withholding vs routine practice on clinical outcomes of comatose patients with acute poisoning and a Glasgow Coma Scale score less than 9. Design, Setting, and Participants: This was a multicenter, randomized trial conducted in 20 emergency departments and 1 intensive care unit (ICU) that included comatose patients with suspected acute poisoning and a Glasgow Coma Scale score less than 9 in France between May 16, 2021, and April 12, 2023, and followed up until May 12, 2023. Intervention: Patients were randomized to undergo conservative airway strategy of intubation withholding vs routine practice. Main Outcomes and Measures: The primary outcome was a hierarchical composite end point of in-hospital death, length of ICU stay, and length of hospital stay. Key secondary outcomes included adverse events resulting from intubation as well as pneumonia within 48 hours. Results: Among the 225 included patients (mean age, 33 years; 38% female), 116 were in the intervention group and 109 in the control group, with respective proportions of intubations of 16% and 58%. No patients died during the in-hospital stay. There was a significant clinical benefit for the primary end point in the intervention group, with a win ratio of 1.85 (95% CI, 1.33 to 2.58). In the intervention group, there was a lower proportion with any adverse event (6% vs 14.7%; absolute risk difference, 8.6% [95% CI, -16.6% to -0.7%]) compared with the control group, and pneumonia occurred in 8 (6.9%) and 16 (14.7%) patients, respectively (absolute risk difference, -7.8% [95% CI, -15.9% to 0.3%]). Conclusions and Relevance: Among comatose patients with suspected acute poisoning, a conservative strategy of withholding intubation was associated with a greater clinical benefit for the composite end point of in-hospital death, length of ICU stay, and length of hospital stay. Trial Registration: ClinicalTrials.gov Identifier: NCT04653597.

Overnight Stay in the Emergency Department and Mortality in Older Patients.

Importance: Patients in the emergency department (ED) who are waiting for hospital admission on a wheeled cot may be subject to harm. However, mortality and morbidity among older patients who spend the night in the ED while waiting for a bed in a medical ward are unknown. Objective: To assess whether older adults who spend a night in the ED waiting for admission to a hospital ward are at increased risk of in-hospital mortality. Design, Settings, and Participants: This was a prospective cohort study of older patients (≥75 years) who visited the ED and were admitted to the hospital on December 12 to 14, 2022, at 97 EDs across France. Two groups were defined and compared: those who stayed in the ED from midnight until 8:00 am (ED group) and those who were admitted to a ward before midnight (ward group). Main Outcomes and Measures: The primary end point was in-hospital mortality, truncated at 30 days. Secondary outcomes included in-hospital adverse events (ie, falls, infection, bleeding, myocardial infarction, stroke, thrombosis, bedsores, and dysnatremia) and hospital length of stay. A generalized linear-regression mixed model was used to compare end points between groups. Results: The total sample comprised 1598 patients (median [IQR] age, 86 [80-90] years; 880 [55%] female and 718 [45%] male), with 707 (44%) in the ED group and 891 (56%) in the ward group. Patients who spent the night in the ED had a higher in-hospital mortality rate of 15.7% vs 11.1% (adjusted risk ratio [aRR], 1.39; 95% CI, 1.07-1.81). They also had a higher risk of adverse events compared with the ward group (aRR, 1.24; 95% CI, 1.04-1.49) and increased median length of stay (9 vs 8 days; rate ratio, 1.20; 95% CI, 1.11-1.31). In a prespecified subgroup analysis of patients who required assistance with the activities of daily living, spending the night in the ED was associated with a higher in-hospital mortality rate (aRR, 1.81; 95% CI, 1.25-2.61). Conclusions and Relevance: The findings of this prospective cohort study indicate that for older patients, waiting overnight in the ED for admission to a ward was associated with increased in-hospital mortality and morbidity, particularly in patients with limited autonomy. Older adults should be prioritized for admission to a ward.

Thrombin generation in real life bleeding patients on oral anticoagulants reversed (or not) with (activated) prothrombin complex concentrate.

BACKGROUND: Bleeding during oral anticoagulant therapy is currently codified by expert guidelines. Monitoring of coagulation during bleeding events is challenging. Our study sought to assess thrombin generation assay (TGA) in direct oral anticoagulant-treated patients without bleeding (WB), bleeding without reversal therapy (BR-), and bleeding with reversal therapy (BR+). METHODS: We conducted a prospective, monocentric study from June 2015 to June 2018. For all bleeding groups, TGA was evaluated using platelet-poor plasma collected upon arrival at emergency (T0), and 30 min (T1), 6 h (T2) and 24 h (T3) after reversal therapy (if indicated) following activation by tissue factor 5 pM and phospholipids. RESULTS: Overall, 292 patients participated, including 91 BR+, 94 BR-, and 107 WB patients. At T0, vitamin K antagonist reversed (VKA-BR+) patients experienced a significant decrease in TGA parameters (ETP and peak) compared with VKA without bleeding (VKA-WB). Compared with healthy controls, VKA-BR+ patients reversed by four-factor prothrombin complex concentrate (4F-PCC) displayed comparable TGA 's ETP and peak at T1, T2, and T3, whereas direct anti-Xa BR+ patients reversed by 4F-PCC or activated prothrombin complex concentrate (aPCC) reached thrombin generation parameters that exceeded normal range at T2 and T3. CONCLUSIONS: In VKA-treated patients reversed by 4F-PCC, TGA parameters were normalized, whereas in rivaroxaban or apixaban-treated patients reversed by 4F-PCC or aPCC, TGA parameters exceeded normal range. Further studies are needed to compare the efficacy and safety of a different dose of reversal therapy and the impact on coagulation parameters.

Severe undernutrition increases bleeding risk on vitamin-K antagonists.

INTRODUCTION: Hemorrhage occurs in 7-10% of patients treated with vitamin K antagonist (VKA), with major bleeding in 1-3%. Impact of nutritional status on the bleeding risk of patients on anticoagulants is still poorly documented. Our study aimed to analyze the link between the nutritional status of patients on VKA and the occurrence of hemorrhagic events. We also analyzed micronutrients status. METHODS: A case-control, monocentric, and prospective study was conducted from August 2012 to October 2015. The case patients were those presenting with major bleeding and control patients those without any bleeding under VKA treatment. RESULTS: Overall, 294 patients under VKA treatment were paired according to age, gender, and index normalized ratio (INR). Out of these, 98 (33.3%) had major bleeding and 196 (66.7%) did not have any bleeding. Additionally, more than two-thirds of patients displayed undernutrition, which was more prevalent in bleeding than non-bleeding patients (OR = 1.85, CI95%: 1.07-3.21). There was a higher bleeding risk for those with severe undernutrition (OR = 2.66, CI95%: 1.58-4.46), with no difference found concerning moderate undernutrition. Bleeding patients had lower plasma-zinc concentrations than non-bleeding patients (9.4 ± 3.6 vs. 10.5 ± 3.7 µmol/L, p = 0.003); among them, there was a higher rate of patients with plasma zinc under 5 µmol/L (9% vs. 2%, p < 0.001). CONCLUSION: Patients with undernutrition on VKA exhibit a significantly higher bleeding risk, which increases three-fold in case of severe undernutrition. The evaluation of nutritional status provides additional, valuable prognosis information prior to initiating VKA therapy. CLINICALTRIALS. GOV NUMBER: NCT01742871.

Impact of epicatechin on fibrin clot structure.

Fibrin clot structure and function are major determinants of thromboembolic diseases. The study aim was to determine the impact of epicatechin (a flavonoid with cardiovascular protective effects) on fibrin clot structure and permeability. Plasma samples from 12 healthy subjects were incubated with increasing concentrations of epicatechin. Turbidity of fibrin clot was analyzed by absorbance measurement at 405 nm. The fibrin clot nanostructure was determined by scanning spectrometry (wavelength from 500 to 800 nm) and fibrin fiber size by electron microscopy. Permeability was analyzed to assess the fibrin clot functional properties. Epicatechin addition increased the maximum absorbance from 0.34 ± 0.066 (vehicle) to 0.35 ± 0.077 (P = 0.1), 0.35 ± 0.072 (P < 0.05) and 0.34 ± 0.065 (P = 0.5) for 1, 10 and 100 µM epicatechin, respectively. Epicatechin increased the fibrin clot fiber radius (nm) from 109.2 ± 3.2 (vehicle) to 108.9 ± 4.3 (P = 0.9), 110.0 ± 3.6 (P < 0.05) and 109.5 ± 3.3 (P = 0.4), and the distance between protofibrils (nm) from 22.2 ± 1.5 (vehicle) to 22.1 ± 2.3 (P = 0.9), 22.6 ± 1.8 (P < 0.05) and 22.3 ± 1.8 (P = 0.9) for 1, 10 and 100 µM epicatechin respectively. Electron microscopy confirmed these changes. Fibrin clot permeability, expressed as Darcy's constant (Ks, cm2), increased from 2.97 ± 1.17 (vehicle) to 3.36 ± 1.21 (P < 0.05), 3.81 ± 1.41 (P < 0.01) and 3.38 ± 1.33 (P = 0.9). Upon epicatechin addition, the fibrin clot structure became less dense and more permeable.

Impact of Epicatechin on the Procoagulant Activities of Microparticles.

Microparticles play a role in cardiovascular disease pathology. The flavanol-like epicatechin is increasingly considered due to its cardioprotective effects. The aim of this study was to investigate the impact of epicatechin on microparticle generation, phenotype and procoagulant properties. Plasma samples from 15 healthy subjects were incubated with increasing concentrations of epicatechin (1 to 100 µM). Then, the expression of glycoprotein IIb, phosphatidylserine (PS), glycoprotein Ib (GPIb) and P-selectin was assessed by flow cytometry analysis after (or not) platelet stimulation. Microparticle procoagulant activity was determined using ZymuphenTM MP and ZymuphenTM MP-TF for phospholipid and tissue factor content, and with thrombin generation (TG) assays for procoagulant function. Platelet microparticles that express GPIb (/µL) decreased from 20,743 ± 24,985 (vehicle) to 14,939 ± 14,333 (p = 0.6), 21,366 ± 16,949 (p = 0.9) and 15,425 ± 9953 (p < 0.05) in samples incubated with 1, 10 and 100 µM epicatechin, respectively. Microparticle concentration (nM PS) decreased from 5.6 ± 2.0 (vehicle) to 5.1 ± 2.2 (p = 0.5), 4.5 ± 1.5 (p < 0.05) and 4.7 ± 2.0 (p < 0.05) in samples incubated with 1, 10 and 100µM epicatechin, respectively. Epicatechin had no impact on tissue factor-positive microparticle concentration. Epicatechin decreased TG (endogenous thrombin potential, nM.min) from 586 ± 302 to 509 ± 226 (p = 0.3), 512 ± 270 (p = 0.3) and 445 ± 283 (p < 0.05). These findings indicate that epicatechin affects microparticle release, phenotype and procoagulant properties.

Dabigatran Level Before Reversal Can Predict Hemostatic Effectiveness of Idarucizumab in a Real-World Setting.

Background: Idarucizumab has been included in guidelines for the management of bleeding or surgical procedure in dabigatran-treated patients without need for biological monitoring. The aim of the study was to assess the prognostic value of dabigatran plasma level before reversal to test the hemostatic efficacy of idarucizumab. The secondary objectives were (i) to analyze plasma dabigatran level according to the risk of rebound and (ii) to evaluate the incidence of post-reversal non-favorable clinical outcomes (including thromboembolism, bleeding, antithrombotic, and death) and antithrombotic resumption. Methods and Results: This was an observational multicentric cohort study, which included all French patients who required idarucizumab for dabigatran reversal. Between May 2016 and April 2019, 87 patients from 21 French centers were enrolled. Patients received idarucizumab for overt bleeding (n = 61), urgent procedures (n = 24), or overdose without bleeding (n = 2). Among patients with major bleeding (n = 57), treatment with idarucizumab was considered effective in 44 (77.2%) of them. Patients who did not achieve effective hemostasis after reversal had a significantly higher mean level of plasma dabigatran at baseline (524.5 ± 386 vs. 252.8 ng/mL ± 235, p = 0.033). Furthermore, patients who did not achieve effective hemostasis after reversal had less favorable outcomes during follow-up (46.2 vs. 81.8%, p = 0.027). ROC curve identified a cutoff of 264 ng/mL for dabigatran level at admission to be predictive of ineffective hemostasis. No plasma dabigatran rebound was observed after reversal in patients with dabigatran plasma level < 264 ng/mL at baseline. Conclusion: This retrospective study shows that dabigatran level before reversal could predict hemostatic effectiveness and dabigatran plasma rebound after idarucizumab injection.

Epicatechin influences primary hemostasis, coagulation and fibrinolysis.

The different stages of hemostasis (i.e., primary hemostasis, coagulation and fibrinolysis) are involved in the early atherothrombosis steps. The aim of this study was to investigate the effect of epicatechin, a major flavonoid compound, on the hemostasis phenotype using clinically relevant in vitro global assays that mimic the complexity of the in vivo hemostasis systems. Plasma samples from 10 healthy volunteers were spiked with increasing concentrations of epicatechin (1 to 100 µM). Epicatechin effect on primary hemostasis, coagulation and fibrinolysis was assessed by measuring platelet aggregation using light transmission aggregometry, thrombin generation and clot lysis time (CLT), respectively. Epicatechin (100 µM) significantly decreased the maximal platelet aggregation induced by adenosine diphosphate (-39%), thrombin receptor activating peptide (-48%), epinephrine (-30%), and collagen (-30%). The endogenous thrombin potential was significantly reduced starting from 1 µM epicatechin (1332 ± 230 versus 1548 ± 241 nM min for control) (p < 0.01). Fibrinolysis was promoted by epicatechin, as indicated by CLT decrease by 16 and 33% with 10 and 100 µM epicatechin respectively, compared with control (1271 ± 775 s). These findings show that epicatechin reduces platelet function and leads to an anticoagulant and pro-fibrinolytic profile, providing new evidence of its interest for cardiovascular disease prevention.