Volume 52, Issue 10 - Special issue: IV Italian GREAT Network Congress / Editors: Giuseppe Lippi, Salvatore Di Somma

Sepsis, severe sepsis and septic shock are among the most common conditions handled in the emergency department (ED). According to new Sepsis Guidelines, early diagnosis and treatment are the keys to improve survival. Plasma C-reactive protein (CRP) and procalcitonin (PCT) levels, when associated with documented or suspected infection, are now part of the definitions of sepsis. Blood culture is the gold standard method for detecting microorganisms but it requires too much time for results to be known. Sensitive biomarkers are required for early diagnosis and as indexes of prognosis sepsis. CRP is one of the acute phase proteins synthesized by the liver: it has a great sensitivity but a very poor specificity for bacterial infections. Moreover, the evolution of sepsis does not correlate with CRP plasma changes. In recent years PCT has been widely used for sepsis differential diagnosis, because of its close correlation with infections, but it still retains some limitations and false positivity (such as in multiple trauma and burns). Soluble CD14 subtype (sCD14-ST), also known as presepsin, is a novel and promising biomarker that has been shown to increase significantly in patients with sepsis, in comparison to the healthy population. Studies pointed out the capability of this biomarker for diagnosing sepsis, assessing the severity of the disease and providing a prognostic evaluation of patient outcome. In this mini review we mainly focused on presepsin: we evaluate its diagnostic and prognostic roles in patients presenting to the ED with systemic inflammatory response syndrome (SIRS), suspected sepsis or septic shock.

Overcrowding of the emergency department (ED) is rapidly becoming a global challenge and a major source of concern for emergency physicians. The evaluation of cardiac biomarkers is critical for confirming diagnoses and expediting treatment decisions to reduce overcrowding, however, physicians currently face the dilemma of choosing between slow and accurate central-based laboratory tests, or faster but imprecise assays. With improvements in technology, point-of-care testing (POCT) systems facilitate the efficient and high-throughput evaluation of biomarkers, such as troponin (cTn), brain natriuretic peptide (BNP) and neutrophil gelatinase-associated lipocalin (NGAL). In this context, POCT may help ED physicians to confirm a diagnosis of conditions, such as acute coronary syndrome, heart failure or kidney damage. Compared with classic laboratory methods, the use of cTn, BNP, and NGAL POCT has shown comparable sensitivity, specificity and failure rate, but with the potential to provide prompt and accurate diagnosis, shorten hospital stay, and alleviate the burden on the ED. Despite this potential, the full advantages of rapid delivery results will only be reached if POCT is implemented within hospital standardized procedures and ED staff receive appropriate training.

When considering the appropriate disposition plan in a patient presenting to the emergency department (ED) with acute heart failure (HF), the range of options includes discharge home to intensive care unit (ICU) admission. Unfortunately, there are few objective measures to insure optimal choices, and the currently available science is scant at best. The consequences of a lack of a standardized approach are nowhere more evident than as demonstrated by the worldwide 90-day heart failure rehospitalization rate that exceeds 25%. New strategies to address this important gap in clinical care are sorely needed. The measurement of galectin-3 may represent a new alternative to the historical standard of gestalt-based clinical disposition decisions. Elevated galectin-3 can identify patients at very high risk for short-term adverse outcomes, while low levels identify a population with essentially no 90-day revisits. This prospective objective measure of illness severity may aid in clinical decision making and thus represent a future where rehospitalization after HF is an unusual event.

Galectin-3 is a versatile molecule which exerts several and sometimes opposite functions in various pathophysiological processes. Recently, galectin-3 has gained attention as a powerful predictor of heart failure and mortality, thus becoming a useful prognostic marker in clinical practice. Moreover, though not specifically investigated in diabetic cohorts, plasma levels of galectin-3 correlated with the prevalence of diabetes and related metabolic conditions, thus suggesting that pharmacological blockade of this lectin might be successful for treating heart failure especially in subjects suffering from these disorders. Indeed, galectin-3 is considered not only as a marker of heart failure, but also as a mediator of the disease, due to its pro-fibrotic action, though evidence comes mainly from studies in galectin-3 deficient mice. However, these studies have provided contrasting results, with either attenuation or acceleration of organ fibrosis and inflammation, depending on the experimental setting and particularly on the levels of advanced glycation endproducts (AGEs)/advanced lipoxidation endproducts (ALEs), of which galectin-3 is a scavenging receptor. In fact, under conditions of increased AGE/ALE levels, galectin-3 ablation was associated with tissue-specific outcomes, reflecting the AGE/ALE-receptor function of this lectin. Conversely, in experimental models of acute inflammation and fibrosis, galectin-3 deficiency resulted in attenuation of tissue injury. There is a need for prospective studies in diabetic patients specifically investigating the relation of galectin-3 levels with complications and for further animal studies in order to establish the effective role of this lectin in organ damage before considering its pharmacological blockade in the clinical setting.

Heart failure is a complex mechanical and neurohormonal syndrome where the left ventricle fails as a pump, resulting in stasis of blood in the lungs and the periphery resulting in the cardial features of effort intolerance, fatigue, and peripheral edema. As part of the neurohormonal and local mechanical strain, tissue macrophages resident in the myocardium secrete galectin-3 which is a paracrine and endocrine factor which stimulates additional macrophages, pericytes, myofibroblasts, and fibroblasts to proliferate and secrete procollagen I which is irreversibly crosslinked resulting in myocardial fibrosis. In the general population, normal plasma concentrations of galectin-3 are <11.0 ng/mL. Galectin-3 measured in blood has been shown to: 1) identify increased risk for new onset heart failure in healthy middle-aged adults; 2) predict cardiac failure in patients after acute coronary syndromes; 3) help establish the diagnosis of heart failure with preserved ejection fraction in patients presenting with exercise intolerance; and 4) aid in the prognosis of heart failure with preserved and reduced left ventricular ejection fraction. This manuscript will present practical real case management in these applications to highlight the importance of this new in vitro diagnostic test.

First isolated from human pheochromocytoma cells, adrenomedullin (ADM) is a peptide hormone with natriuretic, vasodilatory, and hypotensive effects mediated by cyclic adenosine monophosphate (cAMP), nitric oxide, and renal prostaglandin systems. ADM expression occurs in many tissues and organ systems, including cardiovascular, renal, pulmonary, cerebrovascular, gastrointestinal, and endocrine tissues where it acts as a circulating hormone and a local autocrine and paracrine hormone. ADM plasma concentrations are increased in hypertension, chronic renal disease, and heart failure. As ADM is unstable in vitro, it is necessary to measure its mid-regional pro-hormone fragment, the levels of which correspond to ADM concentration (MR-proADM). The prognostic potential of MR-proADM was recently demonstrated in the Biomarkers in Acute Heart Failure (BACH) trial. In this trial of 568 acute heart failure patients, MR-proADM was superior to both brain natriuretic peptide (BNP) and NT-proBNP in predicting mortality within 14 days. MR-proADM also provided significant additive incremental predictive value for 90-day mortality when added to BNP and NT-proBNP.

Acute heart failure (AHF) is one of the most important cardiovascular syndromes associated with high cardiovascular morbidity, and is the major cause of admission in emergency departments worldwide. The clinical complexity of AHF has significantly increased, mostly due to the comorbidities: diabetes, arterial hypertension, dyslipidemia, obesity, peripheral vascular disease, renal insufficiency and anemia. Numerous clinical trials have demonstrated a frequent association of AHF and diabetes. Since AHF is a very heterogeneous condition, it is important to identify clinical and laboratory parameters useful for risk stratification of these populations. Hyperglycemia may be one of the most convenient, since it is widely measured, easily interpreted, and inexpensive. Acute coronary syndrome (ACS), arrhythmias and poor compliance to chronic medications are considered to be the most frequent precipitating factors of AHF in diabetics. Several studies identified diabetes as the most prominent independent predictor of morbidity and mortality in both acute and chronic heart failure (HF) patients. The following parameters were identified as the independent predictors of in-hospital mortality in patients with AHF and diabetes: older age, systolic blood pressure <100 mmHg, ACS, non-compliance, history of hypertension, left ventricular ejection fraction (LVEF) <50%, serum creatinine >1.5 mg/dL, marked elevation of natriuretic peptides, hyponatremia, treatment at admission without ACE inhibitors/ARBs/β-blockers, and no percutaneous coronary intervention (PCI) as a treatment modality. The most frequent cause of AHF is ACS, both with ST segment elevation (STEMI) or without (NSTEMI). Hyperglycemia is very common in these patients and although frequently unrecognized and untreated, has a large in-hospital and mortality significance.

Arginine vasopressin (AVP) plays a key role in many physiologic and pathologic processes. The most important stimulus for AVP release is a change in plasma osmolality. AVP is also involved in the response and adaptation to stress. Reliable measurement of AVP is hindered by several factors. Over 90% of AVP is tightly bound to platelets, and its estimation is influenced by the number of platelets, incomplete removal of platelets or pre-analytical processing steps. Copeptin (CTproAVP), a 39-aminoacid glycopeptide, is a C-terminal part of the precursor pre-provasopressin (pre-proAVP). Activation of the AVP system stimulates CTproAVP secretion into the circulation from the posterior pituitary gland in equimolar amounts with AVP. Therefore CTproAVP directly reflects AVP concentration and can be used as a surrogate biomarker of AVP secretion. In many studies CTproAVP represents AVP levels and its behavior represents changes in plasma osmolality, stress and various disease states, and shows some of the various physiologic and pathophysiologic conditions associated with increased or decreased AVP. Increased CTproAVP concentration is described in several studies as a strong predictor of mortality in patients with chronic heart failure and acute heart failure. Autosomal polycystic kidney disease (ADPKD) patients have both central and nephrogenic defects in osmoregulation and CTproAVP balance. A possibility raised by these clinical observations is that CTproAVP may serve to identify patients who could benefit from an intervention aimed at countering AVP.

Background: With patients referred to emergency departments (EDs) for acute dyspnea, emergency physicians should consider all possible diagnoses and assess patients’ risk stratification. Copeptin has been shown to have prognostic power for subsequent events, such as death and rehospitalization in patients admitted for dyspnea. The aim of this study was to investigate prognostic role of copeptin variations during hospitalization in patients admitted for dyspnea. Methods: We conducted a prospective, multicentric, observational study in acute dyspneic patients in three ED centers in Italy. Clinical data and copeptin assessments were performed at admission, and at discharge. A 90-day follow-up was performed. Results: A total of 336 patients were enrolled, and on the basis of final diagnosis distinguished into two groups: acute heart failure and no acute heart failure. Compared to a control group, in all studied population copeptin values at admission resulted in a significantly (p<0.001) higher median (maximum–minimum): 31 (0–905) versus 8 (0–13) pmol/L. Median copeptin value at admission was 42 (0–905) pmol/L in acute heart failure patients and 20 (0–887) pmol/L in no acute heart failure, respectively (p<0.001). In all studied patients and in each group copeptin at admission and discharge showed significant predictive value for 90-day events (p<0.001). Furthermore, in all patients population and in both groups Δ copeptin values from admission to discharge also showed significant predictive value for 90-day events (p<0.001). Conclusions: In patients admitted for acute dyspnea, admission, discharge and Δ copeptin variations have significant prognostic value from subsequent 90-day death and rehospitalization.

Background: Procalcitonin (PCT) is currently the most studied infection biomarker and its blood levels seem to mirror the severity of illness and outcome. PCT is widely used together with other biomarkers, such as white blood cells (WBC) count and C reactive protein (CRP), in order to guide antibiotic therapy. This study aimed to verify the diagnostic and prognostic power of WBC, CRP and PCT in patients with suspected infection in emergency department (ED). Methods: A total of 513 patients presenting to the ED with signs/symptoms of local infections or sepsis were enrolled. APACHEII score and in-hospital death were recorded. Patients were subdivided into quartiles by age, and the biomarkers were measured at baseline. Receiver operating characteristics (ROC) curves for evaluating diagnostic and prognostic role of PCT, CRP and WBC were calculated for each variable alone and combined. Results: When compared each other for PCT, CRP, and WBC there was no significant difference between the four subgroups. A direct correlation between PCT and WBC was found in the II, III, and IV quartiles (the highest correlation, r=0.34, p<0.0003). PCT alone or when combined with WBC showed the best diagnostic and prognostic power at ROC analysis. Conclusions: Our data demonstrate that WBC, but more CRP and PCT are reliable diagnostic and prognostic biomarkers, when considered in combination and with severity clinical score. PCT confirms its stronger usefulness as a diagnostic marker of sepsis. A multi-diagnostic tools approach is fundamental to perform a correct and rapid diagnosis of infection and sepsis in ED.

Background: A relevant amount of patients with clinical suspect of sepsis is admitted and treated in medical wards (MW). These patients have a better prognosis but are older and with more comorbidities compared to those admitted to intensive care units (ICU). Procalcitonin (PCT) is extensively used in emergency departments for the diagnosis of sepsis, but its accuracy in the setting of a MW has not been thoroughly investigated. Predicted low PCT levels also call for the comparison of immunomagnetic-chemiluminescent (L-PCT) and time-resolved amplified cryptate emission (TRACE, K-PCT) technologies, in PCT determination. Methods: In 80 patients with systemic inflammatory response syndrome (SIRS) diagnostic criteria and suspect of sepsis newly admitted to a MW, PCT was determined with L- and K-PCT method. Results: Sixty patients were diagnosed as sepsis (20 microbiologically and 40 clinically proven) and 20 with non-infective SIRS. The sepsis group had significantly higher levels of both PCTs, with no differences between the clinically and microbiologically proven subgroups. The areas under ROC curves for L- and K-PCT were 0.72 and 0.78 (p<0.001 for each), respectively. Based on MW customized cut-off values of 0.150 (L-PCT) and 0.143 ng/mL (K-PCT), overall accuracies were 66.8 (95% CI 58.7–78.9) and 78.2% (69.8–87.2), respectively, compared to the 55% (44.2–66) of 0.5 ng/mL canonical cut-off. Neither PCT-L nor -K held prognostic value on survival. Conclusions: In MW patients, customized PCT cut-off levels provide better accuracy than customary levels adopted from ICU, and TRACE technology seems to offer a wider analysis range.

Background: Thrombopoietin (TPO), a growth factor primarily involved in regulating thrombopoiesis, has been recently implicated in the pathogenesis of sepsis. TPO levels are, indeed, greatly increased in patients with sepsis compared to control subjects, and correlate with sepsis severity. The aim of this study was to evaluate TPO as predictive biomarker of sepsis and of sepsis severity in patients entering the emergency department (ED) with systemic inflammatory response syndrome (SIRS). Methods: This was a prospective observational study. Ours is a sub-study of the ‘Need-speed trial’, a multi-center observational study involving six Italian centers affiliated to the GREAT Italian Network. TPO was measured by ELISA. Results: We enrolled 13 patients with SIRS (6 with acute pancreatitis, 3 with acute heart failure, 1 with pulmonary embolism, and 3 with allergic reactions), and 40 patients with sepsis, eight of whom had severe sepsis and three septic shock. TPO was significantly higher in patients with sepsis than with SIRS. In addition, TPO was higher in patients with severe sepsis than with sepsis, and in patients with septic shock than with severe sepsis, although these differences did not reach the statistical significance. Conclusions: Our preliminary results suggest that TPO may have the potential to be considered a promising early biomarker for both the diagnosis of sepsis and the assessment of sepsis severity in patients with SIRS entering the ED.

Background: Thrombocytopenia is the most common coagulation disorder in critically ill patients. No studies have investigated the epidemiology and clinical impact of this condition in emergency department (ED) patients. We aimed to investigate epidemiological features, incidence of bleeding, and diagnostic and therapeutic requirements of patients with thrombocytopenia admitted to the ED. Methods: We performed a retrospective observational study enrolling all patients admitted to the medical-surgical ED of the “Città della Salute e della Scienza di Torino” Hospital with a platelet count <150×10 9 PLTs/L, during four non-consecutive months. There were no exclusion criteria. Results: The study included 1218 patients. The percentage of patients with severe (<50×10 9 PLTs/L) or very severe (<20×10 9 PLTs/L) thrombocytopenia was about 12%. Thrombocytopenia associated with liver cirrhosis was the most represented etiology. On the contrary, the most frequent cause in patients with newly recognized low platelet count was disseminated intravascular coagulation/sepsis. The incidence of bleeding and hypovolemia, as well as the need of transfusional support and mechanical, surgical or endoscopic hemostasis progressively increased with the severity of thrombocytopenia. Conclusions: Our results suggest that the detection of a platelet count lower than 50×10 9 PLTs/L may help to identify patients with higher bleeding risk in the ED setting. Additional studies are required to evaluate whether, in this setting, thrombocytopenia may represent an independent risk factor for bleeding episodes and increased mortality.

Background: Metformin is a biguanide antihyperglycemic agent that decreases insulin resistance. It is removed through renal mechanisms and its clearance is reduced in renal failure. Metformin ingestion should always be considered in the differential diagnosis of any patient with metabolic acidosis and increased lactate level. Hemodialysis and continuous veno-venous hemofiltration (CVVH) are both efficient methods to treat metformin intoxication and correct metabolic abnormalities. Methods: Patient 1: A 63-year-old man with type 2 diabetes mellitus presented to emergency department (ED) of Lodi (Italy) for dyspnea. He also reported having diarrhea for 10 days. Initial investigations revealed metabolic acidosis with hyperlactatemia and hypoglycemia (54 mg/dL), metformin concentration was 41 μg/mL (normal value <4 μg/mL). His hemodynamic condition became rapidly unstable and hypotension worsened despite CVVH being performed. Death occurred in 24 h. Patient 2: A 76-year-old man with type 2 diabetes mellitus presented to ED of Lodi for dyspnea. He referred a recent surgery amputation of the left foot’s fifth phalanx for osteomyelitis, in levofloxacin therapy. Initial investigations revealed metabolic acidosis with hyperlactatemia and severe hypoglycemia (20 mg/dL). Two hemodialysis sessions were performed with complete normalization of the serum concentration of metformin. Results and conclusions: In our two cases the genesis of metformin intoxication was clear, powered by acute renal failure, but less obvious was the etiology of acute renal damage responsible for metformin accumulation. Damage due to renal hypoperfusion or the direct toxic effect of metformin should be considered. Additionally, for the second patient, we can also hypothesize that interstitial nephritis was exacerbated by levofloxacin.

Background: Galectin-3 is a protein widely distributed in the heart, brain and blood vessels, and has a regulatory role in inflammation, immunology and cancer. Many studies demonstrated that the increased level of galectin-3 is associated with progressive fibrosis and stiffening of the myocardium. The aim of this study was to investigate the role of galectin-3 in patients with type 2 diabetes (T2D) and/or arterial hypertension (HT). Methods: Study population included 189 patients, with no coronary artery disease, divided into three groups: group 1 (T2D), group 2 (T2D+HT), and group 3 (HT). All subjects underwent routine laboratory tests, as well as specific biomarkers assessment [galectin-3, glycosylated hemoglobin (HbA 1c ), N- terminal fragment B-type natriuretic peptide (NT-proBNP)]. Cardiological evaluation included physical examination, transthoracic tissue Doppler echocardiography and stress echocardiography. Results: The results of this study demonstrated significantly increased levels of galectin-3, blood glucose, and HbA 1c in group 2. Also, echocardiographicaly, left ventricular (LV) diameters and IVS thickness were increased in this group of patients. Furthermore, in the same cohort a positive correlation between galectin-3 and NT-pro BNP, and galectin-3 and LV mass were demonstrated. In addition, a negative correlation between galectin-3 and LV end-diastolic diameter was revealed. Conclusions: This study revealed that levels of galectin-3 were higher in patients with both T2D and HT, and correlated with LV mass, indicating the potential role of this biomarker for early detection of myocardial structural and functional alterations.

Background: Urinary tract infections (UTIs) are among the most common infectious diseases. Results obtained from conventional microbiological analysis of urine and antibiotic susceptibility testing are available only after a few days, delaying precise diagnosis and appropriate therapy. Micro Biological Survey (MBS) srl (a spin-off of Roma Tre University, Rome, Italy) has developed and patented an automated colorimetric test for rapid bacterial counting. In a preliminary validation study it was demonstrated that the results obtained with the MBS method are equivalent to the results obtained with conventional culture-based microbiological analysis. Methods: In this study, sterile urine samples were artificially contaminated with bacterial species that are most frequently responsible for UTIs. The MBS method was used to evaluate the presence of bacteria and their sensitivity to some of the most commonly used antibiotics in UTIs. Results: The MBS method was able to detect in a few hours the presence or absence of bacteria at clinically significant concentrations (>10 5 CFU/mL), and to provide their susceptibility pattern to a limited panel of antibiotics. Discussion: The results obtained demonstrate that the MBS point-of-care testing (POCT) device could be developed into a valuable aid for the management of UTIs, possibly addressing more precise diagnosis and appropriate therapy.