Gianfranco Cervellin

Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features

Abstract Rhabdomyolysis, a term used to describe the rapid breakdown of striated muscle, is characterized by rupture and necrosis of muscle fibers. This process results in the release of cell breakdown products into the bloodstream and extracellular space. Although direct muscle injury remains the most common cause of muscle injury, additional causes include hereditary enzyme disorders, drugs, toxins, endocrinopathies, malignant hyperthermia, neuroleptic malignant syndrome, heatstroke, hypothermia, electrolyte alterations, diabetic ketoacidosis and non-ketotic hyperosmolar coma, severe hypo- or hyperthyroidism and bacterial or viral infections. The classic triad of symptoms includes muscle pain, weakness and dark urine, although more than 50% of the patients do not complain of muscle pain or weakness. Additional systemic symptoms include fever, general malaise, tachycardia, nausea and vomiting. The laboratory diagnosis is based essentially on the measurement of creatine kinase in serum or plasma. Plasma and urine myoglobin measurement might be useful in the early stages of the syndrome and for identifying a subset of patients with minor skeletal muscle injury. Patient monitoring is pivotal (the mortality rate is as high as 8%), and should be focused on preventing the detrimental consequences, that often include renal disease and coagulopathy. In the pre-hospital setting, forced hydration with 1.5–2 L of sterile saline solution should be started immediately, followed by 1.5–2 L/h. Following hospital admission, continuous hydration should be ensured, alternating the saline solution with a 5% glucose solution. In the presence of myoglobinuria, urine should be alkalinized by use of sodium bicarbonate solution. Clin Chem Lab Med 2010;48:749–56.

The role of red blood cell distribution width in cardiovascular and thrombotic disorders

Abstract The red blood cell (RBC) distribution width (RDW) is a measurement of the size variation as well as an index of the heterogeneity of the erythrocytes (i.e., anysocytosis), which is typically used in combination with the mean corpuscular volume to troubleshoot the cause of an underlying anemia. Reliable data emerged from a variety of clinical studies have, however, disclosed a new and unpredictable scenario in the clinical usefulness of this measure, supporting the hypothesis that RDW might be a useful parameter for gathering meaningful clinical information, either diagnostic or prognostic, on a variety of cardiovascular and thrombotic disorders. Highly significant associations have been described between RDW value and all-cause, non-cardiac and cardiac mortality in patients with coronary artery disease, acute and chronic heart failure, peripheral artery disease, stroke, pulmonary embolism and pulmonary arterial hypertension. It is however still unclear whether anysocytosis might be the cause, or a simple epiphenomenon of an underlying disease, such as inflammation, impaired renal function, undernutrition, oxidative damage, or perhaps an element of both. Nevertheless, RDW is an easy, inexpensive, routinely reported test, whose assessment might allow the acquisition of significant diagnostic and prognostic information in patients with cardiovascular and thrombotic disorders.

Hemolyzed specimens: a major challenge for emergency departments and clinical laboratories

The term hemolysis designates the pathological process of breakdown of red blood cells in blood, which is typically accompanied by varying degrees of red tinge in serum or plasma once the whole blood specimen has been centrifuged. Hemolyzed specimens are a rather frequent occurrence in laboratory practice, and the rate of hemolysis is remarkably higher in specimens obtained in the Emergency Department (ED) as compared with other wards or outpatient phlebotomy services. Although hemolyzed specimens may reflect the presence of hemolytic anemia, in most cases they are due to preanalytical sources related to incorrect procedures or failure to follow procedures for collection, handling and storage of the samples; some of these are typical of the ED. Since hemolyzed specimens are often an important cause of relationship, economic, organizational and clinical problems between the ED and the clinical laboratory, it is essential to develop effective processes for systematically identifying unsuitable specimens (e.g. by using the hemolysis index), differentiating in vitro from in vivo hemolysis, troubleshooting the potential causes, and maintaining good relations between the clinical laboratory and the ED.

Pathophysiology, clinics, diagnosis and treatment of heart involvement in carbon monoxide poisoning

The toxicity of carbon monoxide has been recognized for long throughout history and is unquestionably the leading cause of unintentional poisoning deaths in the Western countries. The severity of poisoning is dependent upon environmental and human factor. The leading pathophysiological mechanism resides in the ability of carbon monoxide to bind to hemoglobin molecules with high affinity, displacing oxygen and generating carboxyhemoglobin, which is virtually ineffective to deliver oxygen to the tissues. The organs with the highest demand for oxygen such as the brain and the heart are more vulnerable to injury. Myocardial involvement is commonplace in moderate to severe carbon monoxide poisoning and is associated with a substantially higher risk of mortality. Besides hypoxic damage, carbon monoxide produces myocardium injuries with cardiospecific mechanisms, mostly attributable to direct damage at cellular or subcellular level. The clinical spectrum of heart involvement is broad and encompasses cardiomyopathy, angina attack, myocardial infarction, arrhythmias and heart failure up to myocardial stunning, cardiogenic shock and sudden death. Patients with underlying cardiac disease, especially coronary heart disease, are at greater risk of infarction and arrhythmias. Single photon emission computed tomography (SPECT) is the technique of choice for diagnosing cardiac involvement, whereas the recent introduction of the highly sensitive troponin immunoassays seems promising for the early triage of patients. No specific treatment other than oxygen delivery can be advocated for cardiac toxicity at present, and 100% oxygen therapy should be continued until the patient is asymptomatic and carboxyhemoglobin levels decrease below 5-10%.

Laboratory diagnosis of acute pancreatitis: in search of the Holy Grail

Acute pancreatitis is an acute inflammatory condition of the pancreas, which might extend to local and distant extrapancreatic tissues. The global incidence varies between 17.5 and 73.4 cases per 100,000 and the pathogenesis recognizes alcohol exposure and biliary tract disease as the leading causes, ahead of post-endoscopic retrograde cholangiopancreatography, drugs and abdominal trauma. The diagnosis of acute pancreatitis is substantially based on a combination of clinical signs and symptoms, imaging techniques and laboratory investigations. Contrast-enhanced computed tomography is the reference standard for the diagnosis, as well as for establishing disease severity. The assessment of pancreatic enzymes, early released from necrotic tissue, is the cornerstone of laboratory diagnosis in this clinical setting. Although there is no single test that shows optimal diagnostic accuracy, most current guidelines and recommendations indicate that lipase should be preferred over total and pancreatic amylase. Although a definitive diagnostic threshold cannot be identified, cut-offs comprised between ≥ 2 and ≥ 4 times the upper limit of the reference interval are preferable. The combination of amylase and lipase has been discouraged as although it marginally improves the diagnostic efficiency of either marker alone, it increases the cost of investigation. Some interesting biomarkers have been also suggested (e.g., serum and urinary trypsinogen-1, -2 and -3, phospholipase A2, pancreatic elastase, procalcitonin, trypsinogen activated protein, activation peptide of carboxypeptidase B, trypsin-2-alpha1 antitrypsin complex and circulating DNA), but none of them has found widespread application for a variety of reasons, including the inferior diagnostic accuracy when compared with the traditional enzymes, the use of cumbersome techniques, or their recent discovery. The promising results of recent proteomics studies showed that this innovative technique might allow the identification of changes characterizing pancreatic tissue injury, thus highlighting new potential biomarkers of acute pancreatitis.

The emerging role of biomarkers and bio-impedance in evaluating hydration status in patients with acute heart failure

Abstract The quantitative and qualitative estimation of total body fluid content has proven to be crucial for both diagnosis and prognosis assessment in patients with heart failure. The aim of this review is to summarize the current techniques for assessing body hydration status as well as the principal biomarkers associated with acute heart failure (AHF). Although clinical history, physical examination and classical imaging techniques (e.g., standard radiography and echocardiography) still represent the cornerstones, novel and promising tools, such as biomarkers and bio-electrical impedance are achieving an emerging role in clinical practice for the assessment of total body fluid content. In the acute setting, the leading advantages of these innovative methods over device are represented by the much lower invasiveness and the reasonable costs, coupled with an easier and faster application. This article is mainly focused on AHF patients, not only because the overall prevalence of this disease is dramatically increasing worldwide, but also because it is well-known that their fluid overload has a remarkable diagnostic and prognostic significance. It is thereby conceivable that the bio-electrical vector analysis (BIVA) coupled with laboratory biomarkers might achieve much success in AHF patient management in the future, especially for assisting diagnosis, risk stratification, and therapeutic decision-making.

Canine olfactory detection of cancer versus laboratory testing: myth or opportunity?

Abstract According to the most recent global cancer statistics, the burden of malignancies continues to increase worldwide, so that there is a compelling need to reinforce the screening strategies and implement novel diagnostic approaches for early detection. Canines are widely used by police forces and civilian services for detecting explosives and drugs due to their superior olfactive apparatus, which is characterized by a detection threshold as low as parts per trillion. There is mounting evidence that dogs might be effectively trained to detect patients with various form of cancers due to the presence of a characteristic “odor signature”. In particular, preliminary studies reported that appropriately trained dogs exhibit an extraordinary ability to detect melanoma as well as prostate, breast, ovary and lung cancers by recognizing a characteristic “odor signature” in body, urines, sweat, breath and even blood. The most problematic issue that has emerged so far is the large heterogeneity of performance across the different studies as well as within the same study, which might be dependent upon genetic characteristics or training methodology. This article is aimed to provide an overview of the available data on cancer sniffer dogs, highlighting the appealing perspectives and the potential drawbacks.

Meat consumption and cancer risk: a critical review of published meta-analyses.

Dietary habits play a substantial role for increasing or reducing cancer risk. We performed a critical review of scientific literature, to describe the findings of meta-analyses that explored the association between meat consumption and cancer risk. Overall, 42 eligible meta-analyses were included in this review, in which meat consumption was assumed from sheer statistics. Convincing association was found between larger intake of red meat and cancer, especially with colorectal, lung, esophageal and gastric malignancies. Increased consumption of processed meat was also found to be associated with colorectal, esophageal, gastric and bladder cancers. Enhanced intake of white meat or poultry was found to be negatively associated with some types of cancers. Larger beef consumption was significantly associated with cancer, whereas the risk was not increased consuming high amounts of pork. Our analysis suggest increased risk of cancer in subjects consuming large amounts of red and processed meat, but not in those with high intake of white meat or poultry.

Opinion paper on innovative approach of biomarkers for infectious diseases and sepsis management in the emergency department.

Abstract Sepsis is a leading healthcare problem, accounting for the vast majority of fatal events in critically ill patients. Beyond early diagnosis and appropriate treatment, this condition requires a multifaceted approach for monitoring the severity, the potential organ failure as well as the risk of death. Monitoring of the efficacy of treatment is also a major issue in the emergency department (ED). The assessment of critically ill conditions and the prognosis of patients with sepsis is currently based on some scoring systems, which are, however, inefficient to provide definite clues about organ failure and prognosis in general. The discretionary and appropriate use of some selected biomarkers such as procalcitonin, inducible protein 10 (IP10), Group IV phospholipase A2 type II (PLA2 II), neutrophil gelatinase-associated lipocalin (NGAL), natriuretic peptides, mature adrenomedullin (ADM), mid-regional pro-adrenomedullin (MR-proADM), copeptin, thrombopoietin, Mer receptor and even red blood cell distribution width (RDW) represent thereby an appealing perspective in the diagnosis and management of patients with sepsis. Nevertheless, at the moment, it is not still clear if it is better to use a multimarkers approach or if a single, most appropriate, biomarker exists. This collective opinion paper is aimed at providing an overview about the potential clinical usefulness of some innovative biomarkers of sepsis in its diagnosis and prognosis, but also in the treatment management of the disease. This manuscript represents a synopsis of the lectures of Third Italian GREAT Network Congress, that was hold in Rome, 15–19 October 2012.

Critical review and meta-analysis on the combination of heart-type fatty acid binding protein (H-FABP) and troponin for early diagnosis of acute myocardial infarction

An early diagnosis is crucial for effective triage and management of patients with suspected acute myocardial infarction (AMI). Although troponin testing is the cornerstone of diagnosis, the sensitivity of this biomarker is still suboptimal at patient admission. The heart-type fatty acid binding protein (H-FABP) is an early and sensitive biomarker of myocardial ischemia, whose appropriate setting is in combination with troponin testing. We performed a systematic review and meta-analysis of articles that have assessed the combination of troponin and H-FABP in the early diagnosis of AMI. Eight studies, totaling 2735 patients, met the inclusion criteria but none of them used a high-sensitivity troponin immunoassay. The between-study variation was high (98.5%), and attributable to heterogeneity. When considered alone, troponin exhibited a significantly greater pooled area under the curve (AUC) than H-FABP alone (0.820 versus 0.784; p<0.001). The pooled specificity was also higher for troponin alone than for H-FABP alone (0.94 versus 0.83; p<0.001), whereas the cumulative sensitivity was lower for troponin than for H-FABP (0.73 versus 0.80; p=0.02). The combination of both biomarkers exhibited a greater AUC than troponin alone (0.881; p<0.001), as well as a higher pooled sensitivity (0.91; p<0.001), which was however counterbalanced by a lower specificity (0.82; p<0.001). These results attest that the combination of H-FABP with a conventional troponin immunoassay seems advantageous for increasing the sensitivity of the former biomarker, at the expense of a lower specificity. The introduction of H-FABP testing would hence require careful assessment of laboratory data or clinical signs and symptoms for excluding sources of elevation different from AMI. Further studies are needed to assess the diagnostic effectiveness of combining H-FABP with a high-sensitivity troponin immunoassay.