Elisa Ceriani

Symbolic Dynamics of Heart Rate Variability A Probe to Investigate Cardiac Autonomic Modulation

Background—Sympathetic and parasympathetic systems are considered the principal rapidly reacting systems that control heart rate. Methods and Results—We propose a symbolic analysis series to quantify the prevalence of sympathetic or parasympathetic cardiac modulation. This analysis decomposes the heart rate variability series in patterns lasting 3 beats and classifies them into 3 categories: nonvariable, variable, and very variable patterns referred to as 0V, 1V, and 2V patterns. First, we applied this method to experimental and pharmacological conditions characterized by sympathetic activation (tilt test, handgrip, nitroprusside, and high-dose atropine administration) or parasympathetic activation (phenylephrine and low-dose atropine administration) in 60 healthy subjects. An increase in sympathetic modulation and a vagal withdrawal elicited a significant increase in 0V patterns and a decrease in 2V patterns, whereas parasympathetic dominance induced the opposite, reflecting a reciprocal sympathovagal balance. The second part of the study considered a series of 300 beats before the onset of major arrhythmic events in patients with an implantable cardioverter-defibrillator. Symbolic analysis detected an increase in the percentage of 0V patterns before the onset of major arrhythmias compared with baseline (41.6±3.9% and 24.4±2.9%, respectively; P<0.01), indicating a sympathetic prevalence. On the other hand, the 2V patterns did not decrease before major arrhythmias, suggesting the presence of nonreciprocal autonomic modulations. Conclusions—Symbolic analysis of 3 beat sequences takes into account the different time course of sympathetic and parasympathetic cardiac modulations and seems appropriate for elucidating the neural pathophysiological mechanisms occurring during the short periods that precede acute cardiac events.

Lung ultrasound and short-term prognosis in heart failure patients.

BACKGROUND Heart failure (HF) is the leading cause of hospitalization for patients older than 65years, with a 30-day readmission rate of 20-25%. Although several markers have been evaluated to stratify timing of follow-up after an acute decompensation is mostly based on clinical judgment. Lung ultrasound (LUS) has been demonstrated to be a valid tool for the assessment and monitoring of pulmonary congestion. Aim of our study was to evaluate if LUS performed in HF patients at discharge could predict 100-day hospital readmission or death. METHODS One-hundred fifty patients were enrolled. The anterolateral chest was scanned to evaluate the presence of B-lines. A sonographic score was calculated attributing 1 to each positive (≥3 B-lines) sector. Clinical, biochemical and echocardiographic data were recorded. A Cox proportional hazard regression analysis was performed to evaluate the association between variables and 100-day events. RESULTS Follow-up was obtained in 149 patients. Thirty-four events were recorded. Sonographic score was significantly associated with events (HR 1.19; CI 1.05 to 1.34; p=0.005). On average, the increase of 1 point in the sonographic score was associated with an increase of approximately 24% in the risk of event within 100days. At multivariate analysis NTproBNP remained the only independent prognostic factor. CONCLUSIONS We confirmed that B-lines at discharge are a prognostic marker for hospital readmission and death at 100days in HF patients. Nevertheless, further randomized clinical studies are needed to definitely support the routine use of LUS in the clinical management of HF patients, in combination or not with NT-proBNP.

Update on bedside ultrasound diagnosis of pericardial effusion

Pericardial effusion (PE) is the presence of an excess of fluid in the pericardial cavity. PE symptoms depend from the rate of fluid accumulation, ranging from mild dyspnea on exertion to shock due to cardiac tamponade. Echocardiography is usually the primary diagnostic tool when PE is suspected, as it is accurate, non-invasive, widely available, and feasible also with pocket size devices. Studies have shown a high degree of sensitivity and specificity in the detection of PE using focused cardiac ultrasound (FOCUS), which can be performed also by non-cardiologist in emergency setting or at bedside. A PE is visualized as an echo-free space between the heart and the parietal layer of the pericardium. A semi-quantification of the PE may be obtained measuring the distance between the two pericardial layers. Once PE diagnosis has been made, characterization of fluid and search for signs of possible cardiac tamponade have to be performed. While unechogenic space is usually associated with serous fluid, hemorrhagic, and purulent effusions may be suspected in the presence of corpuscolated/echogenic fluid. Echocardiography may identify cardiac tamponade before it is clinically evident, and can guide pericardiocentesis. B-mode echocardiographic signs of cardiac tamponade include cardiac chambers collapse (with right chambers collapse occurring at earlier stages), opposite changes in right and left cardiac chamber filling during respiratory cycle, inferior vena cava and hepatic vein plethora. Doppler analysis of tricuspidalic and mitral flow velocities are used for a more detailed analysis of ventricular interdependence, even though more advanced operator expertise is required.

Genetic Polymorphisms of Vitamin D Pathway Predict Antiviral Treatment Outcome in Slow Responder Naïve Patients with Chronic Hepatitis C

Vitamin D serum levels seem to influence antiviral response in chronic hepatitis C. Vitamin D pathway is controlled by genes presenting functional single nucleotide polymorphisms (SNPs). Data regarding the association between these polymorphisms and the rate of sustained viral response (SVR) following antiviral treatment in chronic hepatitis C virus (HCV) infection are largely incomplete. Aim of this study was to evaluate if the carriage of different SNPs of these genes could influence the rate of SVR in patients treated with interferon plus ribavirin. Two hundred and six HCV positive patients treated with PEG-interferon plus ribavirin were retrospectively evaluated. Polymorphic loci rs7041 G>T and rs4588 C>A of the vitamin D transporter GC-globulin, rs10741657 G>A of the vitamin D 25 hydroxylase CYP2R1 and rs10877012 G>T of vitamin D 1-hydroxylase CYP27B1 were genotyped. A genetic model named VDPFA (vitamin D Pathway Functional Alleles) was constructed considering for each patient the sum (from 0 to 8), derived from every functional allele carried, associated with the achievement of SVR. Three groups were identified: those carrying ≤4 VDPFA (N=108), those carrying 5-6 VDPFA (N=78) and those carrying ≥7 VDPFA (N=20). Significant associations were found between the rates of SVR and the VDPFA value both in all (61/108, 53/78, 17/20, p=0.009) and in 1/4-5 HCV genotypes (17/56, 23/43, 6/8, p=0.003). Moreover in patients who don’t achieve rapid viral response (RVR) SVR and VDPFA were found to be in stronger associations in all (12/55, 17/39, 7/9, p<0.001) and in 1/4-5 HCV genotypes (4/41, 12/31, 5/6, p=0.001). VDPFA value ≥7 could aid to select, among RVR negative difficult to treat 1/4-5 HCV genotypes, those achieving SVR. These observations could permit to extend the indication to adopt dual antiviral therapy beyond RVR positivity rule without reducing the chances of SVR.

Bleeding Risk during Treatment of Acute Thrombotic Events with Subcutaneous LMWH Compared to Intravenous Unfractionated Heparin; A Systematic Review

Background Low Molecular Weight Heparins (LMWH) are at least as effective antithrombotic drugs as Unfractionated Heparin (UFH). However, it is still unclear whether the safety profiles of LMWH and UFH differ. We performed a systematic review to compare the bleeding risk of fixed dose subcutaneous LMWH and adjusted dose UFH for treatment of venous thromboembolism (VTE) or acute coronary syndromes (ACS). Major bleeding was the primary end point. Methods Electronic databases (MEDLINE, EMBASE, and the Cochrane Library) were searched up to May 2010 with no language restrictions. Randomized controlled trials in which subcutaneous LMWH were compared to intravenous UFH for the treatment of acute thrombotic events were selected. Two reviewers independently screened studies and extracted data on study design, study quality, incidence of major bleeding, patients’ characteristics, type, dose and number of daily administrations of LMWH, co-treatments, study end points and efficacy outcome. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using the random effects model. Results Twenty-seven studies were included. A total of 14,002 patients received UFH and 14,635 patients LMWH. Overall, no difference in major bleeding was observed between LMWH patients and UFH (OR = 0.79, 95% CI 0.60–1.04). In patients with VTE LMWH appeared safer than UFH, (OR = 0.68, 95% CI 0.47–1.00). Conclusion The results of our systematic review suggest that the use of LMWH in the treatment of VTE might be associated with a reduction in major bleeding compared with UFH. The choice of which heparin to use to minimize bleeding risk must be based on the single patient, taking into account the bleeding profile of different heparins in different settings.

Timing of the initiation of parenteral nutrition in critically ill adults

BackgroundCritical illness in hospitalized patients induces anorexia: aninability to eat suitably, predisposing to nutritional deficit,weakness, infections, increased duration of mechanicalventilation, delayed recovery and death [1]. To date,whether artificial nutritional support improves outcomesfor critically ill patients is unclear. Enteral nutrition isassociated with fewer complications than parenteral nutri-tion, and is less expensive [2], but enteral nutrition alonedoes not often achieve caloric targets. Combining paren-teral and enteral nutrition could prevent nutritional deficit.However, this strategy may carry the risk of overfeeding,which has been associated with complications such as liverdysfunction [3]. Current clinical practice guidelines fornutritional support in critically ill patients are largely basedon expert opinion, and differ substantially across conti-nents, in particular about the timing to start parenteralnutrition. The European Society of Parenteral and EnteralNutrition (ESPEN) recommends the commencement ofparenteral nutrition within 2 days after admission to theintensive care unit (ICU) for patients who cannot be ade-quately fed enterally [4], while the American and Canadianguidelines recommend early initiation of enteral nutrition,but suggest starting parenteral nutrition after a week inpatients who are not malnourished at baseline [5].SummaryCasaer and coworkers [6] in a randomized, multicenter trial,comparedanearlytoalateinitiationofparenteralnutritioninadults admitted to the ICU who were not malnourished atbaseline [body-mass index (BMI) of C17] in order to sup-plement insufficient enteral nutrition. The primary endpoints were the number of days spent in ICU (for survivorsand non-survivors), and the time to discharge from the ICU.In 2,312 patients, parenteral nutrition was initiated within48 h after ICU admission, whereas in 2,328 patients, it wasnot initiated before the eighth day from admission. ThemedianstayintheICUwas1 dayshorterinthelate-initiationgroup than in the early-initiation group (3 vs. 4 days,respectively, P = 0.02), which was reflected in a relativeincrease of 6.3% of the likelihood of earlier discharge alivefrom the ICU [hazard ratio 1.06, 95% confidence interval(CI), 1.00–1.13, P = 0.04]. Considering the secondary out-comes, patients in the late-initiation group had fewer healthassistance related infections (22.8 vs. 26.2%, P = 0.008), alowerincidenceofcholestasis(32.6vs.38.4%,P\0.001),areduction in the proportion of patients requiring more than2 days of mechanical ventilation (36.3 vs. 40.2%,P = 0.006), a median reduction of 3 days in the duration ofrenal replacement therapy (7 vs. 10 days, P = 0.008) and areduction in mean health care costs of €1,110 as comparedwith the early-initiation group (€16863 vs. €17973,P = 0.04). The safety outcomes (in-hospital mortality rates,survival at 90 days, rates of nutrition-related complications)weresimilarinthetwogroups,buthypoglycaemiawasmorecommon in the late-initiation group patients (3.5 vs. 1.9%,P = 0.001). Although enteral nutrition was initiated if pos-sible in the majority of patients, the post hoc subgroupanalyses including patients for whom early enteral nutritionwas contraindicated showed the same results.

Highly sensitive troponin and diagnostic accuracy in acute myocardial infarction

Chest pain is one of the most common reasons for which patients seek care in the emergency department. When evaluating these patients, much effort is made to recognize cardiac causes of chest pain, in particular acute coronary syndrome (ACS), and to identify high-risk patients who may benefit from more aggressive treatments. Cardiac troponins play a pivotal role for this purpose. The diagnosis of acute myocardial infarction (AMI) is based mainly on an elevated cardiac troponin level exceeding the 99th percentile; this since 2000, when the joint committee of the European Society of Cardiology and the American College of Cardiology (ESC/ACC) published a new definition of AMI that for the first time officially included these biomarkers [1]. Recently introduced high-sensitivity troponin assays have improved the early diagnosis of acute myocardial infarction, and have a pivotal role in diagnosis, risk stratification, and management of patients with acute coronary syndromes [2–4], but their ideal cut-off and critical changes are yet to be established. Moreover, in clinical practice, the use of troponin high sensitivity is likely to increase the number of false-positive results. Summary

Diagnostic accuracy of transthoracic echocardiography to identify native valve infective endocarditis: a systematic review and meta-analysis

Infective endocarditis (IE) is a serious and potentially life-threatening disease, and accurate diagnosis is essential. We performed a systematic review and meta-analysis to assess the diagnostic accuracy of transthoracic echocardiography (TTE), with transesophageal echocardiography (TEE) as the reference standard, in patients with suspected IE of the native valves. We performed a systematic search in MEDLINE, EMBASE and Cochrane Library searching for studies that enrolled adult patients with suspected native valves IE where data about both TTE and TEE could be extracted. We included 11 studies, for a total of 2209 patients. The overall sensitivity, specificity, negative and positive likelihood ratios (LR) of TTE are 0.71 (95% CI 0.56–0.82), 0.80 (95% CI 0.58–0.92), 0.37 (95% CI 0.20–0.68) and 3.56 (95% CI 1.3–9.72), respectively. The subgroup analyses of the studies considering different cut-off levels show that the strict negative criteria (i.e., managing indeterminate results as positive) have the highest sensitivity and the lowest LR−. On the contrary, when managing indeterminate results as negative (standard criteria), the specificity and LR+ are the highest. We observed no differences between the studies performed with older and more recent technologies. In conclusion, our study results support the use of a negative TTE as a single rule-out test in patients with a low pre-test probability. In selected cases, the use of strict negative criteria might exclude IE in intermediate-risk patients, and a positive TTE might be considered as a single rule-in test with no need for TEE if TEE results would not change the patient’s management.

Syncope and autonomic failure in a middle-aged man

An Albanian 54-year-old man presented to the Emergency Department (ED) after a transient loss of consciousness that occurred while walking in the street. The episode was preceded by dizziness, vertigo and palpitations, and was followed by fatigue and paraesthesia in the right arm and leg. A long-standing history (1–2 years) of lower limb fatigue with progressive walking problems, slow speech rate, confusion and severe weight loss (about 70 kg) was reported. The patient also described previous syncopal episodes similar to the present one. A patient’s friend, who had not seen him in years, noticed that the patient was more confused and slow in moving and speaking than what he recalled. His past medical history was positive for type-2 diabetes, visual impairment in the left eye and a previous vitreous haemorrhage. The family medical history was unremarkable. On admission to the Internal Medicine Unit, the patient was alert, attentive and partially oriented, with no sign of dehydration, hypo-perfusion or congestive heart failure. Chest and abdomen physical examinations were normal. Blood pressure was 95/50 mmHg in the supine position, and the systolic blood pressure dropped to 65 mmHg while standing. Heart rate was 78 beats/min and regular, peripheral oxygen saturation was 96% in room air and body temperature was 36 °C. Neurological examination showed slurred speech, severe loss of muscle mass with diffuse limb fasciculations, diffuse absence of tendon reflexes, no response to plantar cutaneous stimulation, distal anaesthesia, postural tremor along with lower limb weakness, ataxic gait, bilateral foot drop and postural instability, distal anaesthesia for epicritic and proprioceptive sensibility without any impairment in the cranial nerves. Routine blood tests and chest X-ray study were normal. The ECG showed low voltages in both precordial and limb leads. The brain computed tomography was normal.

A young man with cough, fever and epigastric pain

Dr. Wu: A 25-year-old man presented to our Emergency Department (ED) complaining of fever, productive cough, episodes of vomiting and epigastric discomfort. These symptoms had started over the previous 5 days. His prior medical history was negative. The family history was positive only for coronary artery disease. He denied any ongoing therapy, illicit drug abuse, allergy, alcohol consumption and smoking. He reported no contacts with sick persons and no recent travel. He came from a town in Southern Italy where he worked for a company of heavy goods transport. At admission, the patient was alert, well oriented and afebrile. Vital signs recorded in the ED were the following: heart rate (HR) 120 beats/min, blood pressure (BP) 140/90 mmHg, respiratory rate (RR) 28 breaths/min and SpO2 94 % while breathing ambient air. Physical examination