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Background Elevated BNP and the N-terminal fragment of the proBNP (NT-proBNP) are hallmarks of heart failure (HF). Generally, both biomarkers parallel each other. In patients receiving sacubitril/valsartan, BNP remained stable while NT-proBNP decreased. As BNP and NT-proBNP assays have limited specificity due to cross-reactivity, we quantified by mass spectrometry (MS) the contributing molecular species. Methods We included 356 healthy volunteers, 100 patients with acute dyspnoea (49 acute decompensated HF; 51 dyspnoea of non-cardiac origin), and 73 patients with chronic HF and reduced ejection fraction treated with sacubitril/valsartan. BNP and NT-proBNP immunoreactivities (BNPir and NT-proBNPir) were measured by immunoassays (Abbott ARCHITECT and Roche Diagnostics proBNPII) and proBNP-derived peptides and glycosylation at serine 44 by MS on plasma samples. Results BNPir corresponded to the sum of proBNP1–108, BNP1–32, BNP3–32, and BNP5–32 (R2 = 0.9995), while NT-proBNPir corresponded to proBNP1–108 and NT-proBNP1–76 not glycosylated at serine 44 (R2 = 0.992). NT-proBNPir was better correlated (R2 = 0.9597) than BNPir (R2 = 0.7643) with proBNP signal peptide (a surrogate of proBNP production). In patients receiving sacubitril/valsartan, non-glycosylated NT-proBNP1–76 remained constant (P = 0.84) despite an increase in NT-proBNP1–76 and its glycosylation (P < 0.0001). ProBNP1–108 remained constant (P = 0.12) while its glycosylation increased (P < 0.0001), resulting in a decrease in non-glycosylated proBNP1–108 (P < 0.0001), and in NT-proBNPir. Conclusions Glycosylation interfered with NT-proBNPir measurement, explaining the discrepant evolution of these 2 biomarkers in patients receiving sacubitril/valsartan. Both BNPir and NT-proBNPir are surrogates of proBNP1–108 production, NT-proBNPir being more robust in the clinical contexts studied.

Aims Vericiguat reduced the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization in patients with worsening HF with reduced ejection fraction (HFrEF) and a lower limit of baseline estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m2. We evaluated the relationship between the efficacy of vericiguat and baseline and subsequent changes in renal function. Methods and results In VICTORIA, core laboratory serum creatinine was measured at baseline (n = 4956) and weeks 16, 32, and 48. Worsening renal function (WRF), defined as an increase ≥0.3 mg/dL in creatinine from baseline to week 16, was assessed via a Cox model with respect to subsequent primary events. Mean age was 69 years, 24% were female, and mean baseline eGFR was 61 mL/min/1.73 m2. During 48 weeks of treatment, the trajectories in eGFR and creatinine with vericiguat were similar to placebo (P = 0.50 and 0.18). The beneficial effects of vericiguat on the primary outcome were not influenced by baseline eGFR (interaction P = 0.48). WRF occurred in 15% of patients and was associated with worse outcomes (adjusted hazard ratio 1.28, 95% confidence interval 1.11–1.47; P, The left panel shows no differences in the change in creatinine (P = 0.18) between the vericiguat and placebo groups, as evaluated by the interaction between treatment and study visit in the model. The right panel shows a natural cubic spline plot showing that the treatment effect of vericiguat on the primary outcome was similar across the full range of estimated glomerular filtration rate (eGFR) (P = 0.23).

Biomarkers are useful for diagnosis, disease monitoring and risk stratification in cardiovascular disease. Cardiogenic shock (CS) is a medical emergency caused by a primary cardiac insult resulting in inadequate cardiac output, hypoperfusion and organ injury. The pathophysiology of CS is complex involving hemodynamic and circulatory disturbances, inflammation and organ dysfunction. CS is associated with high short-term mortality. Biomarkers such as lactate, cardiac troponins and markers of renal function are established in the diagnosis and monitoring of CS. Evaluation of organ injury and dysfunction is essential for the management. Biomarkers of inflammation and novel biomarkers such as growth differentiating factor-15 (GDF-15), sST2 and dipeptidyl dipeptidase 3 (DPP) may improve our understanding of pathophysiology and clinical course. The prognostic properties of these biomarkers aids in risk stratification and are incorporated as clinical tools for mortality risk prediction in CS. In this review, the role of biomarkers in CS will be discussed. Markers of organ injury and dysfunction, metabolism and novel biomarkers will be covered from a clinical perspective.

Background: Inflammatory responses play an important role in the pathophysiology of cardiogenic shock (CS). The aim of this study was to investigate the kinetics of procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6 (IL-6) in CS and to assess their relation to clinical presentation, other biochemical variables, and prognosis. Methods: Levels of PCT, CRP and IL-6 were analyzed in serial plasma samples (0-120h) from 183 patients in the CardShock study. The study population was dichotomized by PCTmax >= and < 0.5 mu g/L, and IL-6 and CRPmax above/below median. Results: PCT peaked already at 24 h [median PCTmax 0.71 mu g/L (IQR 0.24-3.4)], whereas CRP peaked later between 48 and 72 h [median CRPmax 137mg/L (59-247)]. PCT levels were significantly higher among non-survivors compared with survivors from 12 h on, as were CRP levels from 24 h on (p < 0.001). PCTmax >= 0.5 mu g/L (60% of patients) was associated with clinical signs of systemic hypoperfusion, cardiac and renal dysfunction, acidosis, and higher levels of blood lactate, IL-6, growth-differentiation factor 15 (GDF-15), and CRPmax. Similarly, IL-6 > median was associated with clinical signs and biochemical findings of systemic hypoperfusion. PCTmax >= 0.5 mu g/L and IL-6 > median were associated with increased 90-day mortality (50% vs. 30% and 57% vs. 22%, respectively; p < 0.01 for both), while CRPmax showed no prognostic significance. The association of inflammatory markers with clinical infections was modest. Conclusions: Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis. (C) 2020 Elsevier B.V. All rights reserved.

Novel pharmacologic treatment options reduce mortality and morbidity in a cost-effective manner in patients with heart failure (HF). Undisputedly, the effective implementation of these agents is an essential element of good clinical practice, which is endorsed by the European Society of Cardiology (ESC) guidelines on acute and chronic HF. Yet, physicians struggle to implement these therapies as they have to balance the true and/or perceived risks versus their substantial benefits in clinical practice. Any worsening of biomarkers of renal function is often perceived as being disadvantageous and is in clinical practice one of the most common reasons for ineffective drug implementation. However, even in this context, they clearly reduce mortality and morbidity in HF with reduced ejection fraction (HFrEF) patients, even in patients with poor renal function. Furthermore these agents are also beneficial in HF with mildly reduced ejection fraction (HFmrEF) and sodium-glucose cotransporter 2 (SGLT2) inhibitors more recently demonstrated a beneficial effect in HF with preserved ejection fraction (HFpEF). The emerge of several new classes (angiotensin receptor-neprilysin inhibitor [ARNI], SGLT2 inhibitors, vericiguat, omecamtiv mecarbil) and the recommendation by the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic HF of early initiation and titration of quadruple disease-modifying therapies (ARNI/angiotensin-converting enzyme inhibitor + beta-blocker + mineralocorticoid receptor antagonist and SGLT2 inhibitor) in HFrEF increases the likelihood of treatment-induced changes in renal function. This may be (incorrectly) perceived as deleterious, resulting in inertia of starting and uptitrating these lifesaving therapies. Therefore, the objective of this consensus document is to provide advice of the effect HF drugs on renal function.

Acute coronary syndrome is a precipitant of acute heart failure in a substantial proportion of cases, and the presence of both conditions is associated with a higher risk of short-term mortality compared to acute coronary syndrome alone. The diagnosis of acute coronary syndrome in the setting of acute heart failure can be challenging. Patients may present with atypical or absent chest pain, electrocardiograms can be confounded by pre-existing abnormalities, and cardiac biomarkers are frequently elevated in patients with chronic or acute heart failure, independently of acute coronary syndrome. It is important to distinguish transient or limited myocardial injury from primary myocardial infarction due to vascular events in patients presenting with acute heart failure. This paper outlines various clinical scenarios to help differentiate between these conditions and aims to provide clinicians with tools to aid in the recognition of acute coronary syndrome as a cause of acute heart failure. Interpretation of electrocardiogram and biomarker findings, and imaging techniques that may be helpful in the diagnostic work-up are described. Guidelines recommend an immediate invasive strategy for patients with acute heart failure and acute coronary syndrome, regardless of electrocardiographic or biomarker findings. Pharmacological management of patients with acute coronary syndrome and acute heart failure should follow guidelines for each of these syndromes, with priority given to time-sensitive therapies for both. Studies conducted specifically in patients with the combination of acute coronary syndrome and acute heart failure are needed to better define the management of these patients. The authors acknowledge the Heart Failure Association of the European Society of Cardiology for organizing the meeting during which this topic was discussed. The authors acknowledge T.J. for her expert review of the manuscript, and W.G. S., PharmD (Campbell University College of Pharmacy and Health Sciences), supported by the Heart Failure Association of the European Society of Cardiology for contributions to content development, writing, and editing the manuscript. J.M., C.M. and F.P. performed their expert review of the paper on behalf of Acute Cardiovascular Care Association of the European Society of Cardiology. J.B. and T.T. were supported by the Deutsche Forschungsgemeinschaft, Clinical Research Group 311 (KFO 311) '(Pre-)terminal heart and lung failure: unloading and repair' (DFG; TP1 and TP11). Harjola, VP (corresponding author), Helsinki Univ Hosp, Dept Emergency Med & Serv, Div Emergency Med, PL 340, Helsinki 00029, Finland. veli-pekka.harjola@hus.fi

Appropriate interpretation of changes in markers of kidney function is essential during the treatment of acute and chronic heart failure. Historically, kidney function was primarily assessed by serum creatinine and the calculation of estimated glomerular filtration rate. An increase in serum creatinine, also termed worsening renal function, commonly occurs in patients with heart failure, especially during acute heart failure episodes. Even though worsening renal function is associated with worse outcome on a population level, the interpretation of such changes within the appropriate clinical context helps to correctly assess risk and determine further treatment strategies. Additionally, it is becoming increasingly recognized that assessment of kidney function is more than just glomerular filtration rate alone. As such, a better evaluation of sodium and water handling by the renal tubules allows to determine the efficiency of loop diuretics (loop diuretic response and efficiency). Also, though neurohumoral blockers may induce modest deteriorations in glomerular filtration rate, their use is associated with improved long-term outcome. Therefore, a better understanding of the role of cardio-renal interactions in heart failure in symptom development, disease progression and prognosis is essential. Indeed, perhaps even misinterpretation of kidney function is a leading cause of not attaining decongestion in acute heart failure and insufficient dosing of guideline-directed medical therapy in general. This position paper of the Heart Failure Association Working Group on Cardio-Renal Dysfunction aims at improving insights into the interpretation of renal function assessment in the different heart failure states, with the goal of improving heart failure care.

Aims Insulin-like growth factor binding protein-4 (IGFBP-4) fragments have been shown to predict the risk of major adverse cardiovascular events, including segment-elevation myocardial infarction, in patients with acute coronary syndrome. We evaluated the prognostic value of the carboxy-terminal fragment of IGFBP-4 (CT-IGFBP-4) for all-cause mortality in emergency room patients with acute heart failure (AHF). Methods and results CT-IGFBP-4, N-terminal pro brain natriuretic peptide (NT-proBNP), and C-reactive protein (CRP) were measured at admission from the lithium-heparin plasma of 156 patients with AHF. All-cause mortality was recorded for 1 year. Receiver operator characteristic (ROC) curves, Kaplan-Meier, and Cox proportional hazard ratio analyses were performed to evaluate the prognostic value of the various clinical variables, CT-IGFBP-4, NT-proBNP, CRP, and their combinations. During 1 year of follow-up, 52 (33.3%) patients died. CT-IGFBP-4 only weakly correlated with NT-proBNP (Pearson correlation coefficient r = 0.16, P = 0.044) and did not correlate with CRP (r = 0.08, P = 0.35), emphasizing the different nature of these biomarkers. The receiver operator characteristic area under the curve (ROC AUC) of CT-IGFBP-4 for the prediction of all-cause mortality (0.727) was significantly higher than that of NT-proBNP (0.680, P = 0.045) and CRP (0.669, P = 0.016). The combination of CT-IGFBP-4, NT-proBNP, and CRP predicted mortality significantly better (ROC AUC = 0.788) than any of the biomarkers alone (P

Aims: To describe the baseline characteristics of participants in the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial and compare these with other contemporary diuretic trials in acute heart failure (AHF).Methods and results: ADVOR recruited 519 patients with AHF, clinically evident volume overload, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) and maintenance loop diuretic therapy prior to admission. All participants received standardized loop diuretics and were randomized towards once daily intravenous acetazolamide (500 mg) versus placebo, stratified according to study centre and left ventricular ejection fraction (LVEF) (≤40% vs. >40%). The primary endpoint was successful decongestion assessed by a dedicated score indicating no more than trace oedema and no other signs of congestion after three consecutive days of treatment without need for escalating treatment. Mean age was 78 years, 63% were men, mean LVEF was 43%, and median NT-proBNP 6173 pg/ml. The median clinical congestion score was 4 with an EuroQol-5 dimensions health utility index of 0.6. Patients with LVEF ≤40% were more often male, had more ischaemic heart disease, higher levels of NT-proBNP and less atrial fibrillation. Compared with diuretic trials in AHF, patients enrolled in ADVOR were considerably older with higher NT-proBNP levels, reflecting the real-world clinical situation.Conclusion: ADVOR is the largest randomized diuretic trial in AHF, investigating acetazolamide to improve decongestion on top of standardized loop diuretics. The elderly enrolled population with poor quality of life provides a good representation of the real-world AHF population. The pragmatic design will provide novel insights in the diuretic treatment of patients with AHF.

Background Mortality from cardiogenic shock remains high and early recognition and risk stratification are mandatory for optimal patient allocation and to guide treatment strategy. The CardShock and the Intra-Aortic Balloon Counterpulsation in Acute Myocardial Infarction Complicated by Cardiogenic Shock (IABP-SHOCK II) risk scores have shown good results in predicting short-term mortality in cardiogenic shock. However, to date, they have not been compared in a large cohort of ischaemic and non-ischaemic real-world cardiogenic shock patients. Methods The Red-Shock is a multicentre cohort of non-selected cardiogenic shock patients. We calculated the CardShock and IABP-SHOCK II risk scores in each patient and assessed discrimination and calibration. Results We included 696 patients. The main cause of cardiogenic shock was acute coronary syndrome, occurring in 62% of the patients. Compared with acute coronary syndrome patients, non-acute coronary syndrome patients were younger and had a lower proportion of risk factors but higher rates of renal insufficiency; intra-aortic balloon pump was also less frequently used (31% vs 56%). In contrast, non-acute coronary syndrome patients were more often treated with mechanical circulatory support devices (11% vs 3%, p Conclusions In our cohort, both the CardShock and the IABP-SHOCK II risk scores were good predictors of in-hospital mortality in acute coronary syndrome-related cardiogenic shock.

Cardiogenic shock (CS) is a life-threatening emergency. New biomarkers are needed in order to detect patients at greater risk of adverse outcome. Our aim was to assess the characteristics of miR-21-5p, miR-122-5p, and miR-320a-3p in CS and evaluate the value of their expression levels in risk prediction. Circulating levels of miR-21-5p, miR-122-5p, and miR-320a-3p were measured from serial plasma samples of 179 patients during the first 5–10 days after detection of CS, derived from the CardShock study. Acute coronary syndrome was the most common cause (80%) of CS. Baseline (0 h) levels of miR-21-5p, miR-122-5p, and miR-320a-3p were all significantly elevated in nonsurvivors compared to survivors (p &lt, 0.05 for all). Above median levels at 0h of each miRNA were each significantly associated with higher lactate and alanine aminotransferase levels and decreased glomerular filtration rates. After adjusting the multivariate regression analysis with established CS risk factors, miR-21-5p and miR-320a-3p levels above median at 0 h were independently associated with 90-day all-cause mortality (adjusted hazard ratio 1.8 (95% confidence interval 1.1–3.0), p = 0.018, adjusted hazard ratio 1.9 (95% confidence interval 1.2–3.2), p = 0.009, respectively). In conclusion, circulating plasma levels of miR-21-5p, miR-122-5p, and miR-320a-3p at baseline were all elevated in nonsurvivors of CS and associated with markers of hypoperfusion. Above median levels of miR-21-5p and miR-320a-3p at baseline appear to independently predict 90-day all-cause mortality. This indicates the potential of miRNAs as biomarkers for risk assessment in cardiogenic shock.

Purpose of review Organ dysfunction is a key feature of cardiogenic shock. Active revascularization and contemporary management in intensive care has improved prognosis in cardiogenic shock, but mortality is still unacceptably high. This review will discuss the prevalence, manifestation, management and clinical impact of kidney and liver dysfunction in cardiogenic shock. Recent findings Patients with cardiogenic shock more frequently have several comorbidities that make them at risk of developing multiorgan failure, including renal and liver dysfunction. Kidney and liver injury and dysfunction will markedly increase mortality of patients with cardiogenic shock. Management requires active monitoring of organ function and knowledge of criteria for detection and classification of organ injury. The SOFA score for prediction of mortality in the critically ill incorporates organ injury and can be used also in cardiogenic shock, but risk prediction models specific for cardiogenic shock exist. Biomarkers reflecting different pathways activated in cardiogenic shock correlate with severity of organ dysfunction and may improve risk prediction in cardiogenic shock. Preliminary data suggest that they can even be future treatment targets. Summary Monitoring renal and hepatic function and identifying injury and dysfunction of these organs is essential for the management and mortality risk assessment of patients in cardiogenic shock.

Aims Decisive evidence on the optimal diuretic agent, dosing schedule, and administration route is lacking in acute heart failure (AHF) with congestion. The Acetazolamide in Decompensated heart failure with Volume OveRload (ADVOR) trial is designed to test the hypothesis that the carbonic anhydrase inhibitor acetazolamide, a potent inhibitor of proximal tubular sodium reabsorption, improves decongestion when combined with loop diuretic therapy in AHF, potentially leading to better clinical outcomes. Methods The ADVOR trial is set up as a multicentre, randomized, double-blind, placebo-controlled study, aiming to recruit 519 patients with AHF and clinically evident volume overload. All study participants receive high-dose intravenous loop diuretics as background therapy and are randomized towards intravenous acetazolamide at a dose of 500 mg once daily vs. placebo, stratified according to including study centre and ejection fraction ( 3.5 L during the first 30-48 h of decongestive treatment. Secondary endpoints include all-cause mortality or heart failure readmission after 3 months, length of hospital stay for the index admission, and longitudinal changes in the EuroQol-5 dimensions questionnaire. Conclusion ADVOR will investigate if acetazolamide combined with loop diuretic therapy improves decongestion in AHF with volume overload.

This paper provides a practical clinical application of guideline recommendations relating to the inpatient monitoring of patients with acute heart failure, through the evaluation of various clinical, biomarker, imaging, invasive and non-invasive approaches. Comprehensive inpatient monitoring is crucial to the optimal management of acute heart failure patients. The European Society of Cardiology heart failure guidelines provide recommendations for the inpatient monitoring of acute heart failure, but the level of evidence underpinning most recommendations is limited. Many tools are available for the in-hospital monitoring of patients with acute heart failure, and each plays a role at various points throughout the patient's treatment course, including the emergency department, intensive care or coronary care unit, and the general ward. Clinical judgment is the preeminent factor guiding application of inpatient monitoring tools, as the various techniques have different patient population targets. When applied appropriately, these techniques enable decision making. However, there is limited evidence demonstrating that implementation of these tools improves patient outcome. Research priorities are identified to address these gaps in evidence. Future research initiatives should aim to identify the optimal in-hospital monitoring strategies that decrease morbidity and prolong survival in patients with acute heart failure. The authors acknowledge the Heart Failure Association of theEuropean Society of Cardiology for organizing the meeting duringwhich this topic was discussed.The authors acknowledge Wendy Gattis Stough, PharmD(Campbell University College of Pharmacy and Health Sciences),supported by the Heart Failure Association of the EuropeanSociety of Cardiology for contributions to content development,writing, and editing the manuscript.The work of JelenaˇCelutkien ̇e was supported by the grant fromLithuanian Research Council Nr. MIP-049/2015.

Background: It is unclear how to optimally monitor acute heart failure (AHF) patients. We evaluated the timely interplay of cardiac filling pressures, brain natriuretic peptides (BNPs), lung ultrasound (LUS) and symptoms during AHF treatment. Methods: We enrolled 60 patients who had been hospitalised for AHF. Patients were examined with a rapid cardiothoracic ultrasound (CaTUS) protocol, combining LUS and focused echocardiographic evaluation of cardiac filling pressures (i.e. medial E/e’ and inferior vena cava index [IVCi]). CaTUS was done at 0, 12, 24 and 48 hours (±3 hours) and on the day of discharge, alongside clinical evaluation and laboratory samples. Patients free of congestion (B lines or pleural fluid) on LUS at discharge were categorised as responders, whereas the rest were categorised as non-responders. Improvement in congestion parameters was evaluated separately in these groups. The effect of congestion parameters on prognosis was also analysed. Results: Responders experienced a significantly larger decline in E/e’ (2.58 vs. 0.38, p = 0.037) and dyspnoea visual analogue scale (1–10) score (7.68 vs. 3.57, p = 0.007) during the first 12 hours of treatment, while IVCi and BNPs declined later without no such rapid initial decline. Among patients experiencing a >3 U decline in E/e’ during the first 12 hours of treatment, 18/21 were to become responders ( p Conclusion: E/e’ seemed like the most useful congestion parameter for monitoring early treatment response, predicting prognostically beneficial resolution of pulmonary congestion.

Aims There is little evidence-based therapy existing for acute heart failure (AHF), hospitalizations are lengthy and expensive, and optimal monitoring of AHF patients during in-hospital treatment is poorly defined. We evaluated a rapid cardiothoracic ultrasound (CaTUS) protocol, combining focused echocardiographic evaluation of cardiac filling pressures, that is, medial E/e′ and inferior vena cava index, with lung ultrasound (LUS) for guiding treatment in hospitalized AHF patients. Methods and results We enrolled 20 consecutive patients hospitalized for AHF, whose in-hospital treatment was guided using the CaTUS protocol according to a pre-specified treatment protocol targeting resolution of pulmonary congestion on LUS and lowering cardiac filling pressures. Treatment results of these 20 patients were compared with those of a standard care sample of 100 patients, enrolled previously for follow-up purposes. The standard care sample had CaTUS performed daily for follow-up and received standard in-hospital treatment without ultrasound guidance. All CaTUS exams were performed by a single experienced sonographer. The CaTUS-guided therapy resulted in significantly larger decongestion as defined by reduction in symptoms, cardiac filling pressures, natriuretic peptides, cumulative fluid loss, and resolution of pulmonary congestion (P

Aims To investigate the incidence, haemodynamic alterations and 90-day mortality of acute kidney injury (AKI) in patients with cardiogenic shock. We assessed the utility of creatinine, urine output (UO) and cystatin C (CysC) definitions of AKI in prognostication. Methods and results Cardiogenic shock patients with serial plasma samples (n = 154) from the prospective multicenter CardShock study were included in the analysis. Acute kidney injury was defined and staged according to the KDIGO criteria by creatinine (AKI(crea)) and/or UO (AKI(UO)). CysC-based AKI (AKI(CysC)) was defined similarly to AKI(crea). Changes in haemodynamic parameters were assessed over time from baseline until 96 h. Mean age of the study population was 66 +/- 12 years and 74% were men. Median baseline creatinine was 1.12 [interquartile range (IQR) 0.87-1.54] mg/dL and CysC 1.19 (IQR 0.90-1.69) mg/L. The 90-day mortality was 38%. The incidences for AKI were: AKI(crea) 31%, AKI(UO) 50%, and AKI(Cysc) 33%. AKI(crea) [odds ratio (OR) 12.2, 95% confidence interval (CI) 4.1-36.0] and AKI(CysC) (OR 2.5, 95% CI 1.1-6.1), but not AKI(UO), were independent predictors of mortality. However, a stricter UO cut-off of < 0.3 mL/kg/h for 6 h was independently associated with 90-day mortality (OR 3.6, 95% CI 1.4-9.3). Development of AKI was associated with persistently elevated central venous pressure and decreased cardiac index and mean arterial pressure. Conclusions Acute kidney injury is frequent in patients with cardiogenic shock and especially AKI(crea) predicts poor outcome. The KDIGO UO criterion seems, however, rather liberal and a stricter AKI definition of UO

Aims Heart failure oral therapies (HFOTs), including beta-blockers (BB), renin–angiotensin system inhibitors (RASi) and mineralocorticoid receptor antagonists, administered before hospital discharge after acute heart failure (AHF) might improve outcome. However, concerns have been raised because early administration of HFOTs may worsen patient's condition. We hypothesized that HFOTs at hospital discharge might be associated with better post-discharge survival. Methods and results The study population was composed of 19 980 AHF patients from the GREAT registry. The primary and secondary outcomes were 90-day and 1-year all-cause mortality, respectively. Survival was estimated with univariate and covariate-adjusted Cox proportional hazards regression models for the whole population and after propensity-score matching. HFOTs at discharge were consistently associated with no excess mortality in the unadjusted and adjusted analyses of the whole and matched cohorts. In the matched cohort, BB and RASi at discharge were associated with lower 90-day mortality risks compared to the respective untreated groups [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46–0.69; and HR 0.53, 95% CI 0.42–0.66, respectively]. The favourable associations of BB and RASi at discharge with 90-day mortality were present in many subgroups including patients with reduced or preserved left ventricular ejection fraction and persisted up to 1 year after discharge. The combination of RASi and BB was associated with an even lower risk of death than RASi or BB alone. Conclusions Administration of HFOTs at hospital discharge is associated with better survival of AHF patients.

Background: Critically ill patients often present with hyperglycemia, regardless of previous history of diabetes mellitus (DM). Hyperglycemia has been associated with adverse outcome in acute myocardial infarction and acute heart failure. We investigated the association of admission blood glucose level with the clinical picture and short-term mortality in cardiogenic shock (CS). Methods: Consecutively enrolled CS patients were divided into five categories according to plasma glucose level at the time of enrolment: hypoglycemia (glucose = 16.0 mmol/L) hyperglycemia. Clinical presentation, biochemistry, and short-term mortality were compared between the groups. Results: Plasma glucose level of 211 CS patients was recorded. Glucose levels were distributed equally between normoglycemia (26% of patients), mild (27%), moderate (19%) and severe (25%) hyperglycemia, while hypoglycemia (2%) was rare. Severe hyperglycemia was associated with higher blood leukocyte count (17.3 (5.8) E9/L), higher lactate level (4.4 (3.3-8.4) mmol/L) and lower arterial pH (7.23 (0.14)) compared with normoglycemia or mild to moderate hyperglycemia (p

Background Hyperglycemia is common, regardless of diabetes mellitus (DM), and is associated with increased mortality in patients with acute heart failure (AHF). Current oral heart failure (HF) medications improve the outcome in patients with AHF. However, the relationships between HF medications, admission glucose levels, and prognosis in AHF patients remained unknown. Purpose This study sought to investigate the effect of oral HF medications on relationships between hyperglycemia at admission and 1-year all-cause mortality in patients with AHF. Methods From the GREAT (Global Research on Acute Conditions Team) registry, 13840 patients presenting with AHF whose admission glucose levels were available were included and followed up for 1-year all-cause mortality. Hyperglycemia was defined as a glucose levels of ≥7 mmol/L for patients without history of DM and ≥10 mmol/L for those with history of DM. Patients with hypoglycemia (defined as a glucose levels of ≤4 mmol/L, n=193, 1.4%) were excluded in this analysis. Results There were 6418 (%) patients with hyperglycemia and 7229 (%) patients with normoglycemia. One-year mortality was higher in patients with hyperglycemia than those with normoglycemia (1911 [30%] and 1821 [25%], respectively). Even after adjustment, the risk for 1-year mortality was significantly higher in hyperglycemia (HR 1.14, 95%-CI 1.04–1.26, P=0.008) compared with normoglycemia. Detrimental effects of hyperglycemia on 1-year mortality were more severe in de novo AHF patients than in patients with history of HF (p for interaction 0.004). Oral HF medications (beta blockers and/or angiotensin converting enzyme inhibitors/angiotensin receptor blockers) at discharge were effective in AHF patients with normoglycemia regardless of history of HF. Oral HF medications at discharge are very effective in de novo AHF patients with hyperglycemia and less effective in acute decompensated HF patients with hyperglycemia (Figure). HF medications and 1-year mortality Conclusions Hyperglycemia at admission is associated with increased risk for 1-year mortality. Current oral HF medications are effective in most of subgroups, though they were less effective in patients with acute decompensated HF and hyperglycemia. These patients might need more aggressive therapies to improve outcomes. Acknowledgement/Funding This work was supported by a research fellowship from Japan Heart Foundation (E.A.)

Aims Recent data from national registries suggest that acute heart failure (AHF) outcomes might vary in men and women, however, it is not known whether this observation is universal. The aim of this study was to evaluate the association of biological sex and 1-year all-cause mortality in patients with AHF in various regions of the world. Methods and results We analysed several AHF cohorts including GREAT registry (22 523 patients, mostly from Europe and Asia) and OPTIMIZE-HF (26 376 patients from the USA). Clinical characteristics and medication use at discharge were collected. Hazard ratios (HRs) for 1-year mortality according to biological sex were calculated using a Cox proportional hazards regression model with adjustment for baseline characteristics (e.g. age, comorbidities, clinical and laboratory parameters at admission, left ventricular ejection fraction). In the GREAT registry, women had a lower risk of death in the year following AHF [HR 0.86 (0.79–0.94), P Conclusion Globally women with AHF have a lower 1-year mortality and less evidenced-based treatment than men. Differences among countries need further investigation. Our findings merit consideration when designing future global clinical trials in AHF.

Aims Acute heart failure is a high mortality disease and its pathophysiology is not completely understood. Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in angiotensin II and enkephalins cleavage. The aim of this study was to investigate the association of circulating DPP3 (cDPP3) levels and mortality in cardiogenic shock patients and to determine the effects of high cDPP3 on organ function in a heart failure (HF) model in mice. Methods and results cDPP3 was measured in 174 patients in cardiogenic shock and high cDPP3 levels were associated with an increased short-term mortality risk (standardized hazard ratio: 1.4 (1.1-1.8)) and severe organ dysfunction. Additionally, a rapid decrease in cDPP3 in cardiogenic shock patients within 24 h of admission was associated with a favourable outcome. This study showed that injection of DPP3 induced myocardial depression (-10 ± 2% of shortening fraction) and impaired kidney haemodynamics (+0.30 ± 0.02 of renal resistive index) in healthy mice. cDPP3 inhibition by Procizumab, a specific antibody directed against cDPP3, promptly normalized cardiac function and kidney haemodynamics in an acute heart failure mouse model, with a marked reduction in oxidative stress and inflammatory signalling. Conclusion Our study demonstrated cDPP3 is a newly discovered myocardial depressant factor, the levels of which at admission are associated with mortality in severe HF patients. Furthermore, inhibition of cDPP3 by Procizumab improved haemodynamics in a mouse model of HF. Our results suggest that DPP3 could be a new biomarker and biotarget for severe HF.

Introduction: Cardiogenic shock complicating acute myocardial infarction has a very high mortality. Our present study focuses on serial measurement of lactate during admission due to cardiogenic shock and the prognostic effect of lactate and a relative change in lactate in patients after admission and the institution of intensive care treatment. Methods and Results: This is a secondary analysis of the CardShock study. Data on lactate at baseline were available on 217 of 219 patients. In the study population, the median baseline lactate was 2.8 mmol/L (min-max range, 0.5-23.1 mmol/L). At admission, lactate was predictive of 30-day mortality with an adjusted Hazard ratio (HR) of 1.20 mmol/L (95% confidence interval, CI 1.14-1.27). Within the first 24 h of admission, baseline lactate remained predictive of 30-day mortality. Lactate at 6 h had a HR of 1.14 (95% CI 1.06-1.24) and corresponding values at 12 and 24 h had a HR of 1.10 (1.04-1.17), and of HR 1.19 (95% CI 1.07-1.32), respectively. A 50% reduction in lactate within 6 h resulted in a HR of 0.82 (95% CI 0.72-0.94). Corresponding hazard ratios at 12 and 24 h, were 0.87 (95% CI 0.76-0.98) and 0.74 (95% CI 0.60-0.91), respectively. Conclusion: The main findings of the present study are that baseline lactate is a powerful predictor of 30-day mortality, lactate at 6, 12, and 24 h after admission are predictors of 30-day mortality, and a relative change in lactate is a significant predictor of survival within the first 24 h after instituting intensive care treatment adding information beyond the information from baseline values.

Background: Cardiogenic shock (CS) is the most life-threatening manifestation of acute heart failure. Its complexity and high in-hospital mortality may justify the need for invasive monitoring with a pulmonary artery catheter (PAC). Methods: Patients with CS included in the CardShock Study, an observational, prospective, multicenter, European registry, were analyzed, aiming to describe the real-world use of PAC, evaluate its impact on 30-day mortality, and the ability of different hemodynamic parameters to predict outcomes. Results: Pulmonary artery catheter was used in 82 (37.4%) of the 219 patients. Cardiogenic shock patients who managed with a PAC received more frequently treatment with inotropes and vasopressors, mechanical ventilation, renal replacement therapy, and mechanical assist devices ( P < .01). Overall 30-day mortality was 36.5%. Pulmonary artery catheter use did not affect mortality even after propensity score matching analysis (hazard ratio = 1.17 [0.59-2.32], P = .66). Cardiac index, cardiac power index (CPI), and stroke volume index (SVI) showed the highest areas under the curve for 30-day mortality (ranging from 0.752-0.803) and allowed for a significant net reclassification improvement of 0.467 (0.083-1.180), 0.700 (0.185-1.282), 0.683 (0.168-1.141), respectively, when added to the CardShock risk score. Conclusions: In our contemporary cohort of CS, over one-third of patients were managed with a PAC. Pulmonary artery catheter use was associated with a more aggressive treatment strategy. Nevertheless, PAC use was not associated with 30-day mortality. Cardiac index, CPI, and SVI were the strongest 30-day mortality predictors on top of the previously validated CardShock risk score.

ObjectivesThe aim of this study was to evaluate the performance of a rapid cardiothoracic ultrasound protocol (CaTUS), combining echocardiographically derived E/e’ and lung ultrasound (LUS), for diagnosing acute heart failure (AHF) in patients with undifferentiated dyspnea in an emergency department

Background: The aim of this study was to assess the levels, kinetics, and prognostic value of growth differentiation factor 15 (GDF-15) in cardiogenic shock (CS). Methods and Results: Levels of GDF-15 were determined in serial plasma samples (0-120 h) from 177 CS patients in the CardShock study. Kinetics of GDF-15, its association with 90-day mortality, and incremental value for risk stratification were assessed. The median GDF-15(0h) level was 9647 ng/L (IQR 4500-19,270 ng/L) and levels above median were significantly associated with acidosis, hyperlactatemia, renal dysfunction, and higher 90-day mortality (56% vs 28%, P7000 ng/L was identified as a strong predictor of death (OR 5.0; 95% CI 1.9-3.8, P=.002). Adding GDF-15(12h) >7000 ng/L to the CardShock risk score improved discrimination and risk stratification for 90-day mortality. Conclusions: GDF-15 levels are highly elevated in CS and associated with markers of systemic hypoperfusion and end-organ dysfunction. GDF-15 helps to discriminate survivors from non-survivors very early in CS.

Acute right ventricular (RV) failure is a complex clinical syndrome that results from many causes. Research efforts have disproportionately focused on the failing left ventricle, but recently the need has been recognized to achieve a more comprehensive understanding of RV anatomy, physiology, and pathophysiology, and of management approaches. Right ventricular mechanics and function are altered in the setting of either pressure overload or volume overload. Failure may also result from a primary reduction of myocardial contractility owing to ischaemia, cardiomyopathy, or arrhythmia. Dysfunction leads to impaired RV filling and increased right atrial pressures. As dysfunction progresses to overt RV failure, the RV chamber becomes more spherical and tricuspid regurgitation is aggravated, a cascade leading to increasing venous congestion. Ventricular interdependence results in impaired left ventricular filling, a decrease in left ventricular stroke volume, and ultimately low cardiac output and cardiogenic shock. Identification and treatment of the underlying cause of RV failure, such as acute pulmonary embolism, acute respiratory distress syndrome, acute decompensation of chronic pulmonary hypertension, RV infarction, or arrhythmia, is the primary management strategy. Judicious fluid management, use of inotropes and vasopressors, assist devices, and a strategy focusing on RV protection for mechanical ventilation if required all play a role in the clinical care of these patients. Future research should aim to address the remaining areas of uncertainty which result from the complexity of RV haemodynamics and lack of conclusive evidence regarding RV-specific treatment approaches.

Aims Cardiogenic shock (CS) is associated with high short-term mortality and a precise CS risk stratification could guide interventions to improve patient outcome. Here, we developed a circulating protein-based score to predict short-term mortality risk among patients with CS. Methods and results Mass spectrometry analysis of 2654 proteins was used for screening in the Barcelona discovery cohort (n = 48). Targeted quantitative proteomics analyses (n = 51 proteins) were used in the independent CardShock cohort (n = 97) to derive and cross-validate the protein classifier. The combination of four circulating proteins (Cardiogenic Shock 4 proteins—CS4P), discriminated patients with low and high 90-day risk of mortality. CS4P comprises the abundances of liver-type fatty acid-binding protein, beta-2-microglobulin, fructose-bisphosphate aldolase B, and SerpinG1. Within the CardShock cohort used for internal validation, the C-statistic was 0.78 for the CardShock risk score, 0.83 for the CS4P model, and 0.84 (P = 0.033 vs. CardShock risk score) for the combination of CardShock risk score with the CS4P model. The CardShock risk score with the CS4P model showed a marked benefit in patient reclassification, with a net reclassification improvement (NRI) of 0.49 (P = 0.020) compared with CardShock risk score. Similar reclassification metrics were observed in the IABP-SHOCK II risk score combined with CS4P (NRI =0.57; P = 0.032). The CS4P patient classification power was confirmed by enzyme-linked immunosorbent assay (ELISA). Conclusion A new protein-based CS patient classifier, the CS4P, was developed for short-term mortality risk stratification. CS4P improved predictive metrics in combination with contemporary risk scores, which may guide clinicians in selecting patients for advanced therapies.

Because of a technical error, the code corresponding to the outcome for the Basir et al. cohort was mis-implemented in the original version of our article. Characteristics of the cohort are in fact the followings.

IF 16.834 (2017); International audience; BACKGROUND Vasopressor agents could have certain specific effects in patients with cardiogenic shock (CS) after myocardial infarction, which may influence outcome. Although norepinephrine and epinephrine are currently the most commonly used agents, no randomized trial has compared their effects, and intervention data are lacking. OBJECTIVES The goal of this paper was to compare in a prospective, double-blind, multicenter, randomized study, the efficacy and safety of epinephrine and norepinephrine in patients with CS after acute myocardial infarction. METHODS The primary efficacy outcome was cardiac index evolution, and the primary safety outcome was the occurrence of refractory CS. Refractory CS was defined as CS with sustained hypotension, end-organ hypoperfusion and hyperlactatemia, and high inotrope and vasopressor doses. RESULTS Fifty-seven patients were randomized into 2 study arms, epinephrine and norepinephrine. For the primary efficacy endpoint, cardiac index evolution was similar between the 2 groups (p = 0.43) from baseline (H0) to H72. For the main safety endpoint, the observed higher incidence of refractory shock in the epinephrine group (10 of 27 [37%] vs. norepinephrine 2 of 30 [7%]; p = 0.008) led to early termination of the study. Heart rate increased significantly with epinephrine from H2 to H24 while remaining unchanged with norepinephrine (p < 0.0001). Several metabolic changes were unfavorable to epinephrine compared with norepinephrine, including an increase in cardiac double product (p = 0.0002) and lactic acidosis from H2 to H24 (p < 0.0001). CONCLUSIONS In patients with CS secondary to acute myocardial infarction, the use of epinephrine compared with norepinephrine was associated with similar effects on arterial pressure and cardiac index and a higher incidence of refractory shock. (Study Comparing the Efficacy and Tolerability of Epinephrine and Norepinephrine in Cardiogenic Shock [OptimaCC]; NCT01367743) (J AmColl Cardiol 2018; 72: 173-82) (C) 2018 by the American College of Cardiology Foundation.

Decisive evidence on the optimal diuretic agent, dosing schedule, and administration route is lacking in acute heart failure (AHF) with congestion. The Acetazolamide in Decompensated heart failure with Volume OveRload (ADVOR) trial is designed to test the hypothesis that the carbonic anhydrase inhibitor acetazolamide, a potent inhibitor of proximal tubular sodium reabsorption, improves decongestion when combined with loop diuretic therapy in AHF, potentially leading to better clinical outcomes.The ADVOR trial is set up as a multicentre, randomized, double-blind, placebo-controlled study, aiming to recruit 519 patients with AHF and clinically evident volume overload. All study participants receive high-dose intravenous loop diuretics as background therapy and are randomized towards intravenous acetazolamide at a dose of 500 mg once daily vs. placebo, stratified according to including study centre and ejection fraction ( 40% vs. ≥ 40%). The primary endpoint is successful decongestion with no more than trace oedema assessed on the third morning after hospital admission, with good diuretic efficacy defined as a urine output 3.5 L during the first 30-48 h of decongestive treatment. Secondary endpoints include all-cause mortality or heart failure readmission after 3 months, length of hospital stay for the index admission, and longitudinal changes in the EuroQol-5 dimensions questionnaire.ADVOR will investigate if acetazolamide combined with loop diuretic therapy improves decongestion in AHF with volume overload.

Acute heart failure (AHF) is a major health problem worldwide and trials to assess novel therapies are increasingly global, as a means to reduce costs, expedite timelines, provide broad applicability, and satisfy regulatory authorities.The significant geographic differences in patient characteristics, outcomes, and treatment effect may affect trial results and raise important questions about generalizability of the results to a broader population.

Background The interaction between chronic medications on admission and the association between serum potassium level and outcome in patients with acute heart failure (AHF) are unknown. Methods Observational intercontinental study of patients admitted with AHF. 15954 patients were included from 12 cohorts in 4 continents. Main outcome was 90-day mortality. Clinical presentation (medication use, hemodynamics, comorbidities), demographic, echocardiographic, and biochemical data on admission were recorded prospectively in each cohort, with prospective adjudication of outcomes. Results Positive and negative linear relationships between 90-day mortality and sK+ above 4.5 mmol/L (hyperkalemia) and below 3.5 mmol/L (hypo-kalemia) were observed. Hazard ratio for death was 1.46 [1.34-1.58] for hyperkalemia and 1.22 [1.06-1.40] for hypokalemia. In a fully adjusted model, only hyperkalemia remained associated with mortality (HR 1.03 [1.02-1.04] for each 0.1 mmol/l change of sK+ above 4.5 mmol/L). Interaction tests revealed that the association between hyperkalemia and outcome was significantly affected by chronic medications. The association between hyperkalemia and mortality was absent for patients treated with beta blockers and in those with preserved renal function. Conclusions In patients with AHF, sK+ > 4.5 mmol/L appears to be associated with 90-day mortality. B-blockers have potentially a protective effect in the setting of hyperkalemia.

Changes in QRS duration and pattern are regarded to reflect severe ischemia in acute coronary syndromes (ACS), and ventricular conduction blocks (VCBs) are recognized high-risk markers in both ACS and acute heart failure. Our aim was to evaluate the prevalence, temporal evolution, association with clinical and angiographic parameters, and impact on mortality of VCBs in ACS-related cardiogenic shock (CS). Data of 199 patients with ACS-related CS from a prospective multinational cohort were evaluated with electrocardiogram data from baseline and day 3. VCBs including left or right bundle branch block, right bundle branch block and hemiblock, isolated hemiblocks, and unspecified intraventricular conduction delay were assessed. Fifty percent of patients had a VCB at baseline; these patients were older, had poorer left ventricular function and had more often left main disease compared with those without VCB. One-year mortality was over 2-fold in patients with VCB compared with those without VCB (68% vs 32%, p

Up to 10% of acute coronary syndromes are complicated by cardiogenic shock (CS) with contemporary mortality rates of 40–50%. The extent of ischemic myocardium has a profound impact on the initial, in-hospital, and post-discharge management and prognosis in this patient population. Individualized patient risk assessment plays an important role in determining appropriate revascularization, drug treatment with inotropes and vasopressors, mechanical circulatory support, intensive care support of other organ systems, hospital level of care triage, and allocation of clinical resources. This review will outline the underlying causes and diagnostic criteria, pathophysiology, and treatment of CS complicating acute coronary syndromes with a focus on (a) potential therapeutic issues from the perspective an interventional cardiologist, an emergency physician, and an intensive care physician, (b) the type of revascularization, and (c) new therapeutic advancements in pharmacologic and mechanical percutaneous circulatory support.

BackgroundThe most common aetiology of cardiogenic shock (CS) is acute coronary syndrome (ACS), but even up to 20%-50% of CS is caused by other disorders. ST-segment deviations in the electrocardiogram (ECG) have been investigated in patients with ACS-related CS, but not in those with other CS aetiologies. We set out to explore the prevalence of different ST-segment patterns and their associations with the CS aetiology, clinical findings and 90-day mortality. MethodsWe analysed the baseline ECG of 196 patients who were included in a multinational prospective study of CS. The patients were divided into 3 groups: (a) ST-segment elevation (STE). (b) ST-segment depression (STDEP). (c) No ST-segment deviation or ST-segment impossible to analyse (NSTD). A subgroup analysis of the ACS patients was conducted. ResultsST-segment deviations were present in 80% of the patients: 52% had STE and 29% had STDEP. STE was associated with the ACS aetiology, but one-fourth of the STDEP patients had aetiology other than ACS. The overall 90-day mortality was 41%: in STE 47%, STDEP 36% and NSTD 33%. In the multivariate mortality analysis, only STE predicted mortality (HR 1.74, CI95 1.07-2.84). In the ACS subgroup, the patients were equally effectively revascularized, and no differences in the survival were noted between the study groups. ConclusionST-segment elevation is associated with the ACS aetiology and high mortality in the unselected CS population. If STE is not present, other aetiologies must be considered. When effectively revascularized, the prognosis is similar regardless of the ST-segment pattern in ACS-related CS.

Correction Volume: 44 Issue: 11 Pages: 2022-2023 DOI: 10.1007/s00134-018-5372-9 Catecholamines have been the mainstay of pharmacological treatment of cardiogenic shock (CS). Recently, use of epinephrine has been associated with detrimental outcomes. In the present study we aimed to evaluate the association between epinephrine use and short-term mortality in all-cause CS patients. We performed a meta-analysis of individual data with prespecified inclusion criteria: (1) patients in non-surgical CS treated with inotropes and/or vasopressors and (2) at least 15% of patients treated with epinephrine administrated alone or in association with other inotropes/vasopressors. The primary outcome was short-term mortality. Fourteen published cohorts and two unpublished data sets were included. We studied 2583 patients. Across all cohorts of patients, the incidence of epinephrine use was 37% (17-76%) and short-term mortality rate was 49% (21-69%). A positive correlation was found between percentages of epinephrine use and short-term mortality in the CS cohort. The risk of death was higher in epinephrine-treated CS patients (OR [CI] = 3.3 [2.8-3.9]) compared to patients treated with other drug regimens. Adjusted mortality risk remained striking in epinephrine-treated patients (n = 1227) (adjusted OR = 4.7 [3.4-6.4]). After propensity score matching, two sets of 338 matched patients were identified and epinephrine use remained associated with a strong detrimental impact on short-term mortality (OR = 4.2 [3.0-6.0]). In this very large cohort, epinephrine use for hemodynamic management of CS patients is associated with a threefold increase of risk of death.

Aims Data on the prognostic role of left and right bundle branch blocks (LBBB and RBBB), and nonspecific intraventricular conduction delay (IVCD; QRS ≥ 110 ms, no BBB) in acute heart failure (AHF) are controversial. Our aim was to investigate electrocardiographic predictors of long‐term survival in patients with de novo AHF and acutely decompensated chronic heart failure (ADCHF). Methods and Results We analysed the admission electrocardiogram of 982 patients from a multicenter European cohort of AHF with 3.9 years' mean follow‐up. Half (51.5%, n = 506) of the patients had de novo AHF. LBBB, and IVCD were more common in ADCHF than in de novo AHF: 17.2% vs. 8.7% (P

To assess, according to age groups, patients' characteristics according to region of origin, the chronic therapeutic management, prognostic utility of clinical variables, and natriuretic peptides. Methods and results The GREAT registry consisted of patients identified as presenting with acute heart failure at the emergency department. Four groups of patients were defined according to age: the young patient group (