Francesco Casella

San Francisco Syncope Rule, Osservatorio Epidemiologico sulla Sincope nel Lazio risk score, and clinical judgment in the assessment of short-term outcome of syncope.

OBJECTIVE The study aimed to compare the efficacy of the Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) risk score, San Francisco Syncope Rule, and clinical judgment in assessing the short-term prognosis of syncope. METHODS We studied 488 patients consecutively seen for syncope at the emergency department of 2 general hospitals between January and July 2004. Sensitivity, specificity, predictive values, and likelihood ratios for short-term (within 10 days) severe outcomes were computed for each decision rule and clinical judgment. Severe outcomes comprised death, major therapeutic procedures, and early readmission to hospital. RESULTS Clinical judgment had a sensitivity of 77%, a specificity of 69%, and would have admitted less patients (34%, P < .05 vs decision rules). The OESIL risk score was characterized by a sensitivity of 88% and a specificity of 60% (admission 43%). San Francisco Syncope Rule sensitivity was 81% and specificity was 63% (admission 40%). According to both clinical rules, no discharged patient would have died. With combined OESIL risk score and clinical judgment, the probability of adverse events was 0.7% for patients with both low risk scores, whereas that for both high risk scores was roughly 16%. CONCLUSION Because of a relatively low sensitivity, both risk scores were partially lacking in recognizing patients with short-term high-risk syncope. However, the application of the decision rules would have identified all patients who subsequently died, and OESIL risk score and clinical judgment combined seem to improve the decision-making process concerning the identification of high-risk patients who deserve admission.

Liver abscess caused by Klebsiella pneumoniae: two case reports

IntroductionThe present case reports highlight the peculiar aspect of Klebsiella pneumoniae liver abscess, an emerging disease in United States and Western countries.Case presentationWe report two cases of Asiatic patients with Klebsiella-associated liver abscesses evaluated at our institution over a one-year period. Both of them had non-specific clinical symptoms at presentation, a peculiar ultrasonographic appearance and successful treatment with early percutaneous drainage.ConclusionKlebsiella related liver abscess is an emerging disease with peculiar clinical features. As compared with other bacterial liver abscesses, Klebsiella pneumonia associated pyogenic liver abscess has distinctive risk factors, unique ultrasonographic and computed tomography features and different prognosis.

Influence of climate on emergency department visits for syncope: role of air temperature variability.

Background Syncope is a clinical event characterized by a transient loss of consciousness, estimated to affect 6.2/1000 person-years, resulting in remarkable health care and social costs. Human pathophysiology suggests that heat may promote syncope during standing. We tested the hypothesis that the increase of air temperatures from January to July would be accompanied by an increased rate of syncope resulting in a higher frequency of Emergency Department (ED) visits. We also evaluated the role of maximal temperature variability in affecting ED visits for syncope. Methodology/Principal Findings We included 770 of 2775 consecutive subjects who were seen for syncope at four EDs between January and July 2004. This period was subdivided into three epochs of similar length: 23 January–31 March, 1 April–31 May and 1 June–31 July. Spectral techniques were used to analyze oscillatory components of day by day maximal temperature and syncope variability and assess their linear relationship. There was no correlation between daily maximum temperatures and number of syncope. ED visits for syncope were lower in June and July when maximal temperature variability declined although the maximal temperatures themselves were higher. Frequency analysis of day by day maximal temperature variability showed a major non-random fluctuation characterized by a ∼23-day period and two minor oscillations with ∼3- and ∼7-day periods. This latter oscillation was correlated with a similar ∼7-day fluctuation in ED visits for syncope. Conclusions/Significance We conclude that ED visits for syncope were not predicted by daily maximal temperature but were associated with increased temperature variability. A ∼7-day rhythm characterized both maximal temperatures and ED visits for syncope variability suggesting that climate changes may have a significant effect on the mode of syncope occurrence.

Neural autonomic control in orthostatic intolerance

Inability to maintain the upright position is manifested by a number of symptoms shared by either human pathophysiology and conditions following weightlessness or bed rest. Alterations of the neural sympathetic cardiovascular control have been suggested to be one of the potential underlying etiopathogenetic mechanisms in these conditions. We hypothesize that the study of the autonomic profile of human orthostatic intolerance syndromes may furnish a valuable insight into the complexity of the sympathetic alterations leading to a reduced gravitational tolerance. In the present paper we describe abnormalities both in the magnitude and in the pattern of the sympathetic neural firing observed in patients affected by orthostatic intolerance, attending the upright position. Also, we discuss similarity and differences in the neural sympathetic mechanisms regulating the cardiovascular system during the gravitational stimulus both in clinical syndromes and in subjects returning from space.

Addressing the management of atrial fibrillation - a systematic review of the role of dronedarone.

Background Atrial fibrillation (AF) is the most common sustained arrhythmia. It occurs in 1%–2% of the general population and its prevalence increases with age. Dronedarone, a noniodinated benzofuran similar to amiodarone, was developed as an antiarrhythmic agent for patients with atrial fibrillation. The aim of our systematic review was to critically evaluate randomized controlled trials that compared treatment with dronedarone versus placebo or amiodarone in patients with atrial fibrillation. Methods Electronic databases (MEDLINE, Embase, and Central) were searched up to November 2011 with no language restrictions. We included randomized controlled trials in which dronedarone was compared to placebo or other drugs in patients with AF. Internal and external validity was assessed. Results We identified seven papers corresponding to eight randomized controlled trials. The DAFNE, EURIDIS/ADONIS, and ATHENA trials demonstrated a reduction of AF recurrence with dronedarone as compared to placebo in patients with nonpermanent AF. The DIONYSOS study showed that dronedarone is less effective for the prevention of recurrent AF but improved tolerability as compared to amiodarone. Considering patients with permanent AF, the ERATO trial showed that dronedarone had rate-control effects while the PALLAS study was stopped early since stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes were significantly more frequent in subjects treated with dronedarone as compared to placebo. The ANDROMEDA trial included patients with recent hospitalization for heart failure and was terminated early because of excess of deaths in the dronedarone group. Conclusion Like most antiarrhythmic drugs, dronedarone reduces the recurrence of AF in patients with paroxysmal or persistent AF as compared to placebo. However, relapse rates in the first year of therapy are high. Moreover, dronedarone showed to be less effective than amiodarone. Finally, dronedarone should be avoided in patients with permanent AF and a high risk for cardiovascular events or severe congestive heart failure.

Is clinically indicated replacement of peripheral catheters as safe as routine replacement in preventing phlebitis and other complications

BackgroundPeripheral intravenous catheterisation is the most commoninvasive procedure in hospitalized patients. In a significantpercentage of patients it can be associated with minorcomplications such as phlebitis and infiltration. Seriouscomplications such as catheter-related bloodstream infec-tions (CRBSI) are fortunately rare, occuring in about 0.1 %of intravenous catheters [1]. A regular removal andreplacement of peripheral intravenous catheters (IVC) hasbeen recommended by the US Centers for Disease Controland Prevention (CDC) to reduce the risks of such com-plications [2].However, such approach may lead to discomfort forpatients requiring additional needdlesticks and increasedworkload for clinical staff. Furthermore, it can be a sig-nificant contributor to health-care costs. For these reasons,IVC are already frequently left in place beyond the cur-rently recommended 72–96 h for appropriate reasons suchas a treatment soon to be completed, poor veins, or noavailable staff to cannulate [3].Small randomized clinical trials showed that IVCreplacement based on clinical indication is safe in terms ofdevelopment of phlebitis and other complications as com-pared to IVC routine replacement every 72–96 h [4, 5].Despite this evidence, the 2011 CDC guidelines designateclinically indicated replacement of IVC as an unresolvedissue, indicating that more research is needed [2].SummaryIn a multicentre, non blinded, randomized controlledequivalence trial Rickard and colleagues [6] investigate thesafety, effectiveness and possible benefits of clinicallyindicated replacement of IVC as compared to routinereplacement. Patients were considered eligible if they wereat least 18 years old and they were scheduled or expectedto have a peripheral IVC in situ for 4 days or more. Theexclusion criteria were current bacteraemia, plannedremoval of IVC within 24 h, IVC already in situ for morethan 72 h, IVC inserted in an emergency. 3,283 patientswere enrolled in three university-affiliated hospitals inAustralia and randomized either to IVC replacement everythird calendar day or to a replacement only after thedevelopment of phlebitis, infusion failure or completion oftherapy (clinically indicated IVC replacement). 1,593patients were assigned to the clinically indicated replace-ment group, 1,690 patients were randomized to the routinereplacement group.The primary endpoint was phlebitis during catheterisa-tion or within 48 h after removal; there were several sec-ondary outcomes, including bloodstream infection,infusion failure and mortality. The routine replacement andclinically indicated replacement of IVC were consideredequivalent if the limits of the two-sided 95 % confidenceinterval (CI) for the absolute risk difference were includedinside the predefined equivalence margin of 3 %.

Can we trust in trials stopped early for benefit

In a multicenter, randomized, placebo-controlled, doubleblind clinical trial, Elmunzer et al. [1] assigned patients at elevated risk for postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis to receive a single dose of rectal indomethacin or a placebo immediately after ERCP. According to the authors’ summary, prophylactic rectal indomethacin significantly reduced the incidence of postERCP pancreatitis (PEP) in patients at elevated risk for this complication. The trial has been stopped early after an interim analysis. Is it reasonable to trust the results of this early stopped trial showing the benefit of indomethacin in preventing PEP? A randomized clinical trial (RCT) is designed and conducted to provide the answer to a relevant clinical question. The protocol of an RCT should report several details on how the researchers are going to conduct the trial. First of all, the aim of the study has to be clear. Secondly, the outcomes (primary and secondary) should be predetermined as the statistical methods used to analyze them. Next, another item to be specified in the protocol is the number of patients to be included in the study. When determining the sample size, investigators should clarify some details about the scientific hypothesis underlying the clinical question they want to answer. Large RCTs are periodically monitored as patients are enrolled, and interim analyses are performed on collected data. Sometimes, the decision of stopping a trial early is adopted as a consequence of the results of an interim analysis. There are several reasons for the early termination of a RCT. First, a trial may be stopped early for harm, if significantly worse outcomes are observed among patients receiving the experimental treatment. Another reason for early termination of a trial may be futility, when it is highly unlikely that the trial will accrue the planned number of patients, or if the interim analysis shows that it is extremely unlikely that any benefit will be seen if the study is continued. Finally, trials may be stopped for a significant benefit in the experimental arm (trial stopped early for benefit). In this case, patients receiving the non-experimental treatment may be allowed to ‘‘crossover’’ and receive the beneficial treatment. In these papers we will only focus on the trials that have been stopped early for benefit. There are several reasons for stopping an RCT for benefit. First of all, the investigators may feel ethically obligated to stop a trial showing an apparent benefit of a study treatment. An individual ethical issue may drive the decision to stop a trial before the end of the randomization of all the planned patients, since it’s considered unethical to deny a study participant an effective treatment. This issue may be compelling for investigators and patients who may be allowed to ‘‘crossover’’, and receive the more beneficial treatment after an interim analysis shows an apparent benefit of the experimental intervention. Beyond the individual ethical issues, there are some collective interests leading to the decision to stop a trial for benefit. If a new treatment is more effective than the older one, it’s a collective interest that study results spread as quickly as possible, making the treatment available for all G. Casazza (&) Dipartimento di Scienze Biomediche e Cliniche ‘‘L. Sacco’’, Universita degli Studi di Milano, Via G.B. Grassi, 74, 20157 Milan, Italy e-mail: giovanni.casazza@unimi.it

Liver abscess caused by Klebsiella pneumoniae

m l Abdominal computed tomography scan showing a 10-cm iameter Klebsiella pneumoniae abscess is given. Notice the ypodense lesion with internal septa, a distinctive feature of lebsiella related liver abscesses [1]. The image refers to a 29-year old Indian man who preented with a 4-day history of fever, chills, anorexia and atigue. An ultrasound-guided percutaneous drainage was laced yielding 150 cm3 of purulent fluid. Two out of three lood cultures grew Klebsiella pneumoniae. The patient was iven intravenous gentamicin and metronidazole leading to clinical and radiological improvement. Klebsiella pneumoniae was identified in recent studies as he most common cause of pyogenic liver abscess (PLA) in sia and United States [2]. Symptoms of PLA are often non-specific such as fever, atigue and anorexia. High fever is the most common finding t presentation (occurring in 90% of patients), while only onealf of patients present with specific signs localized to the ight upper abdominal quadrant as abdominal pain, jaundice nd hepatomegaly [2]. Klebsiella pneumoniae-associated liver abscesses have

Is it safe to withdraw etanercept in established rheumatoid arthritis after low disease activity achievement

BackgroundRheumatoid arthritis (RA) is an immunologically drivenchronic condition characterized not only by persistent jointinflammation (synovitis) but also by systemic inflammation[1].Uncontrolled active RA produces disability and areduction of the health-related quality of life that result inloss of work and high medical and social costs [2]. Theimpact of RA on patients and society justifies treatmentwith biologics [2], expensive drugs that are not free fromcomplications and adverse events, even severe [3].The target of treatment in RA is achievement of lowdisease activity or remission [4]. It is yet to be clarifiedwhether low disease activity or remission can be alsosustained, not only by maintaining the recommendedtherapy but also by reducing or discontinuing the biologictreatment. In fact, a reduction or withdrawal of suchtreatment could imply a great amount of financial savingfor the National Health Systems.Although there are many observational studies regardingwithdrawal of anti-TNF-alpha after a period of induction,evidence coming from randomized clinical trials is stilllacking.SummaryIn a randomized controlled trial, Smolen et al. [5] assessedwhether the response to conventional doses of biologicsand background methotrexate in patients with moderatelyactive disease would be sustained after etanercept reduc-tion or withdrawal. Patients aged between 18 and 70 withmoderate disease activity, defined as a disease activityscore on 28 joints (DAS28) value between 3.2 and 5.1despite treatment with methotrexate were enrolled andgiven 50 mg etanercept plus methotrexate every weekduring an open label period of 36 weeks. Patients whocompleted the open label stage and achieved a sustainedlow disease activity (DAS28\3.2) were considered eli-gible for a subsequent double-blind period of 52 weeks.They were randomized in a 1:1:1 ratio to a weekly sub-cutaneous injection of 50 mg of etanercept plus metho-trexate, 25 mg of etanercept plus methotrexate oretanercept placebo plus methotrexate.The primary endpoint was the proportion of patients atweek 88 with a low disease activity (DAS28 B 3.2) in thegroups given 50 mg of etanercept and etanercept placeboin the double-blind period. If low disease activity wasmaintained significantly more frequently when 50 mg e-tanercept was continued than with placebo, a conditionalprimary endpoint was the proportion of patients receiving25 mg etanercept who achieved low disease activity. Aconditional endpoint was the proportion of patientsreceiving 25 mg of etanercept who maintained a low dis-ease activity. Secondary endpoints were remission basedon DAS28 (\2.6) and remission based on simplified dis-ease activity index criteria (B3.3).Out of the 834 enrolled patients, 604 were eligible forthe double-blind period: 202 were assigned to 50 mg eta-nercept plus methotrexate, 202 to 25 mg of etanercept plus

Hereditary angioedema: Assessing the hypothesis for underlying autonomic dysfunction

Background Attacks of Hereditary Angioedema due to C1-inhibitor deficiency (C1-INH-HAE)are often triggered by stressful events/hormonal changes. Objective Our study evaluates the relationship between autonomic nervous system (ANS) and contact/complement system activation. Methods Twenty-three HAE patients (6 males, mean age 47.5±11.4 years) during remission and 24 healthy controls (8 males, mean age 45.3±10.6 years) were studied. ECG, beat-by-beat blood pressure, respiratory activity were continuously recorded during rest (10’) and 75-degrees-head-up tilt (10’). C1-INH, C4, cleaved high molecular weight kininogen (cHK) were assessed; in 16 patients and 11 controls plasma catecholamines were also evaluated. Spectral analysis of heart rate variability allowed extraction of low-(LF) and high-(HF) frequency components, markers of sympathetic and vagal modulation respectively. Results HAE patients showed higher mean systolic arterial pressure (SAP) than controls during both rest and tilt. Tilt induced a significant increase in SAP and its variability only in controls. Although sympathetic modulation (LFnu) increased significantly with tilt in both groups, LF/HF ratio, index of sympathovagal balance, increased significantly only in controls. At rest HAE patients showed higher noradrenaline values (301.4±132.9 pg/ml vs 210.5±89.6pg/ml, p = 0.05). Moreover, in patients tilt was associated with a significant increase in cHK, marker of contact system activation (49.5 ± 7.5% after T vs 47.1 ± 7.8% at R, p = 0.01). Conclusions Our data are consistent with altered ANS modulation in HAE patients, i.e. increased sympathetic activation at rest and blunted response to orthostatic challenge. Tilt test-induced increased HK cleavage suggests a link between stress and bradykinin production.