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MINERVA MEDICA RIVISTA BIMESTRALE DI MEDICINA INTERNA, INIZIATA NEL 1909 E RISORTA NEL 1921 A CURA DI GUGLIELMO OLIARO ALBO D’ONORE: E. G. OLIARO, A. CECONI F. MICHELI, O. UFFREDUZZI, A. M. DOGLIOTTI, T. OLIARO CONSIGLIO DIRETTIVO P. Arcangeli - F. Balsano - P. Boyle - G. Clemenzia - N. Dioguardi - G. Gasbarrini - P. Larizza - B. Magnani - M. Martelli W. Montorsi - F. Rossi - G. Rotondo EDITORIAL BOARD H. E. Blum (Freiburg, Germany) - P. Boyle (Milan, Italy) - J. M. Delehanty (Rochester, USA) A. Di Bisceglie (St. Louis, USA) - J. T. Grayhack (Chicago, USA) - S. T. Holgate (Southampton, UK) D. R. Jr. Holmes (Rochester, USA) - A. Jörres (Berlin, Germany) - J. H. Lazarus (Cardiff, UK) - J. Marsh (London, UK) E. E. Vokes (Chicago, USA) REDATTORI R. Bonardi - L. Bussi - G. Cariti - E. Concina - G. De Dominicis - P. A. Giudice - R. Pellicano - M. Porta - L. Premuda M. Rapellino - G. Recchia - S. Rocchietta - M. L. Soranzo - W. Torretta CORRISPONDENTI F. Bianchi - A. Cerami - V. Fabbrocini - L. Luciani - A. Monti - R. Morgante U. A. Pini - N. Simonetti - F. Tursi - V. Tursi REDATTORE CAPO M. L. Benzo DIRETTORE RESPONSABILE A. Oliaro

This journal is PEER REVIEWED Direzione, redazione, ufficio grafico, ufficio pubblicità, fotocomposizione, amministrazione - Edizioni Minerva Medica - Corso Bramante 83-85 - 10126 Torino Tel. (011) 67.82.82 - Fax (011) 67.45.02 - E-mail: minervamedica@minervamedica.it Web Site: www.minervamedica.it Stampa - Edizioni Minerva Medica - Tipografia di Saluzzo - Corso IV Novembre 29-31 - 12037 Saluzzo (CN) - Tel. (0175) 249405 - Fax (0175) 249407 Abbonamento annuo: Italia - Individuale: Cartaceo € 96,00, Cartaceo+Online € 96,00; Istituzionale: Cartaceo € 129,00, Online (Small € 230,00, Medium € 263,00, Large € 307,00), Cartaceo+Online (Small € 241,00, Medium € 289,00, Large € 337,00); il fascicolo € 25,00. Unione Europea - Individuale: Cartaceo € 166,00, Cartaceo+Online € 166,00; Istituzionale: Cartaceo € 229,00, Online (Small € 230,00, Medium € 263,00, Large € 307,00), Cartaceo+Online (Small € 241,00, Medium € 289,00, Large € 337,00); il fascicolo € 40,00. Paesi extraeuropei - Individuale: Cartaceo € 184,00, Cartaceo+Online € 184,00; Istituzionale: Cartaceo € 252,00, Online (Small € 253,00, Medium € 289,00, Large € 337,00), Cartaceo+Online (Small € 265,00, Medium € 318,00, Large € 371,00); il fascicolo € 45,00. Gli abbonati possono utilizzare le seguenti forme di pagamento: a) conto corrente postale 00279109 intestato a Edizioni Minerva Medica, Corso Bramante 83-85, 10126 Torino; b) assegno bancario; c) carte di credito Diners Club International, Master Card, VISA, American Express. I cambi di indirizzo vanno segnalati tempestivamente inviando nuovo e vecchio indirizzo e una targhetta di spedizione I reclami per i fascicoli mancanti devono pervenire entro 6 mesi I fascicoli e le annate arretrati vengono maggiorati del 50% © Edizioni Minerva Medica - Torino 2008 Tutti i diritti sono riservati. Nessuna parte di questa pubblicazione può essere riprodotta, trasmessa e memorizzata in qualsiasi forma e con qualsiasi mezzo Pubblicazione bimestrale. Autorizzazione del Tribunale di Torino n. 274 del 30-6-1948. Iscrizione nel registro nazionale della stampa di cui alla legge 5-8-1981 n. 416 art. 11 con il numero 00 148 vol. 2 foglio 377 in data 18-8-1982. Pubblicazione periodica bimestrale - Poste Italiane S.p.A. Sped. in a.p. - D. L. 353/2003 (conv. in L. 27/02/2004 N° 46) art. 1, comma 1, DCB/CN Studio grafico della copertina: Eleonora Garosci


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PRESENTE E FUTURO DELLA FADOI TOSCANA

Il VII Congresso Regionale della nostra Società è l’occasione per tracciare un bilancio e una prospettiva per il futuro. La grande espansione di FADOI in questi anni si è basata sulla possibilità data a tutti di partecipare alla vita della società. Questo ha liberato delle energie insospettate nella Medicina Interna Ospedaliera Toscana e ne ha preparato la rinascita. Per consolidare ed espandere i risultati ottenuti non bisogna perdere l’entusiasmo creativo che ha caratterizzato i primi anni di vita della nostra organizzazione. Questo congresso di Grosseto segna un punto di svolta per l’importanza degli argomenti trattati e per lo spazio dato a tutti con numerose comunicazioni pubblicate su questo numero speciale di Minerva Medica. Devo ringraziare a nome di tutta la FADOI Toscana l’organizzatori, Marcello Cipriani e Massimo Alessandri per lo sforzo fatto e per il salto di qualità che il congresso rappresenta. I compiti per il futuro sono molti, bisogna continuare il dialogo con le istituzioni Regionali e con le altre società scientifiche sull’ospedale per intensità di cure. Nel corso del 2007 è stato fatto molto in questo ambito e il nostro impegno è continuare su questa strada. Il confronto con le altre società scientifiche toscane ha portato alla redazione di un documento comune sulla nuova organizzazione ospedaliera che è stato accolto dalla Regione e le sue istanze sono anche state in parte recepite nel nuovo piano sanitario regionale. Con il patrocinio del presidente dell’Ordine dei Medici di Firenze è stata creata una vera e propria consulta delle società scientifiche che si riunirà periodicamente presso l’Ordine con il fine di esprimere un parere tecnicoprofessionale sulle decisioni in materia sanitaria della Regione Toscana. Un altro impegno è il miglioramento dei rapporti con le società dei Medici di Medicina Generale dato che le UO di Medicina Interna sono quelle che più di altre sono interessate ai problemi di continuità assistenziale con il territorio. Non va trascurata l’attività di ricerca e di aggiornamento del Medico Internista. Sono in corso iniziative nell’ambito dello scompenso di cuore ed iniziative sulla BPCO e sulla comorbilità associata. Aree di interesse che andranno affrontate con più incisività rispetto al passato sono quelle di endocrinologia e di ematologia come non andranno dimenticati i problemi di bioetica e di risk management. Per tutti questi obiettivi è mia intenzione e del Consiglio Direttivo di coinvolgere il più possibile tutti gli iscritti lasciando spazio agli internisti più giovani e motivati. Chi fra gli iscritti voglia partecipare in maniera più attiva mi può contattare direttamente. In definitiva i compiti da svolgere saranno molti e dovranno essere affrontati localmente anche se di concerto con gli organi direttivi nazionali. Nel salutarvi auguro a tutti un buon VII Congresso Regionale. GIANCARLO LANDINI Presidente FADOI Toscana


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AI SOCI FADOI

Il programma che abbiamo messo in piedi, articolato su sei Sessioni, è molto ricco e continente argomenti non sempre sufficientemente valorizzati nei nostri incontri societari, quali l’osteoporosi e l’uso dei farmaci biologici. Alcuni relatori, oltre ad essere di grande prestigio, rappresentano l’opinion leader nel proprio campo di lavoro e di studio. Altra novità di questa VII edizione del FADOI Regionale Toscano è rappresentata dalla pubblicazione di tutti i contributi inviati al Congresso, sia gli abstracts estesi delle relazioni che gli abstracts dei poster, in questa Rivista di Medicina Interna, a tutti noi ben nota, in un numero speciale dedicato. Abbiamo cercato di sollecitare i contributi liberi (Poster) da parte dei nostri Affiliati istituendo un “Premio Fadoi” di 1000 Euro da destinare al miglior lavoro presentato. La commissione esaminatrice è composta da nostro Presidente Giancarlo Landini, coadiuvato da Gianni Meucci e da Guidantonio Rinaldi. Agli Autori dell’opera premiata sarà riservato un piccolo spazio di presentazione orale. L’evento congressuale della FADOI Toscana si tiene unitariamente a quello della sezione Toscana dell’ANIMO (Associazione Nazionale degli Infermieri della Medicina Ospedaliera), con sedute congiunte e possibilità, anche per i Colleghi Infermieri, di pubblicazione di abstracts sul volume degli Atti. Tale evento vuole essere una concreta dimostrazione di come le due professioni sanitarie, superato ormai ogni steccato, vogliano collaborare gomito a gomito, ognuna nel proprio ambito e competenza, per affrontare insieme le sfide che la difesa della salute del cittadino prospetta all’orizzonte e di cui l’Ospedale per Intensità di Cura rappresenta uno dei modelli più all’avanguardia. È doveroso esprimere un sentito ringraziamento a tutte quelle Ditte Farmaceutiche il cui contributo ci ha permesso di organizzare questo VII Congresso Toscano, e alla Ti.Gi. Congress la cui alta professionalità è garanzia di un proficuo lavoro. Colgo infine l’occasione di esprimere più sinceri ringraziamenti al Direttivo che mi ha dato la possibilità di organizzare il nostro incontro annuale in questa bella terra di Maremma. MARCELLO CIPRIANI


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MINERVA MEDICA Vol. 99

October 2008

Suppl. 1 to No. 5

CONTENTS

VII CONGRESSO REGIONALE FADOI TOSCANA Castiglione della Pescaia (GR), October 10-11, 2008

SEGRETERIA SCIENTIFICA Dott. Marcello Cipriani Dott. Massimo Alessandri Consiglio Direttivo FADOI Toscana

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Oral communications

Bone metabolism

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New frontiers on anti-platelet and antithrombotic therapy

Emerging issues in internal medicine

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Free communications

Chronic pain in internal medicine

19 Biologic drugs

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Posters

24 Cardiovascular disease

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NEW FRONTIERS ON ANTI-PLATELET AND ANTITHROMBOTIC THERAPY Old and new anti-platelet drugs R. Abbate, A. Cordisco, R. Marcucci Thrombosis Center, Departments of Medical and Surgical Critical Area, University of Florence, Azienda Ospedaliera Universitaria di Careggi, Italy

Cardiovascular diseases (CVDs) are major causes of death in the developed world, and are becoming an increasing burden in a number of developing countries. In the UK, CVDs, predominantly myocardial infarction (MI), ischaemic stroke and peripheral vascular disease, contribute towards more than one in three deaths, affecting both men and woman. Thrombosis, the formation of a blood clot within the blood vessel resulting in occlusion of blood flow, is the major problem that triggers both MI and stroke. Platelets form a first line of defence, triggering haemostasis on encountering damaged tissue. The aetiologies of cardiovascular disorders are complex and controversial, but the underlying conditions such as atherosclerosis are commonly the precipitating factor. The rupturing of instable lesions results in the release of prothrombotic factor, such as oxidized lipids, and the exposure of collagen, which triggers thrombosis. Furthermore, the presence of adhesive substrates within the lesion and rheological disturbances caused by the narrowed artery lumen may contribute to pathological platelet recruitment. The therapeutic targeting of platelets is recognized as effective in the prevention and treatment of CVD. The morbidity and mortality figures, however, indicate that current anti-platelet strategies (and anti-coagulant therapy) are far from a panacea. Current anti-platelet therapy 1. Inhibition of thromboxane A2 production First generated in 1897, aspirin has been used as an anti-inflammatory, analgesic and anti-pyretic for many decades. In 1971, its mechanism of action to inhibit prostaglandin formation was elucidated. Taken orally, aspirin irreversibly acetylates and inactivates the enzyme COX, primarily COX-1, preventing the conversion of arachidonic acid to prostacyclin (PGI2) in endothelial cells. The benefit of aspirin use in the prevention and treatment of various chronic or acute CVDs is widely recognized and supported by extensive clinical data. The Antithrombotic Trialist’ Collaboration1 compared several studies and concluded that 75-375 mg aspirin per day was at least as effective as higher doses. 2. ADP receptor antagonists Clopidogrel, a thienopyridine, is an irreversible antagonist of the ADP receptor P2Y12. When taken at 75

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mg day, it is able to reduce ADP-induced aggregation by 40-60% and is reported to be more effective than aspirin (325 mg day) in preventing vascular death, MI or ischaemic stroke but with reduced gastric irritation2. The overall effects of clopidogrel have been examined extensively in several clinical trials involving more than 80000 patients demonstrating the ability of clopidogrel to reduce the incidence of vascular death, MI or ischaemic stroke. 3. Integrin αII bβ3 blockers Integrin αII bβ3 (GPIIbIIIa) supports fibrinogenmediated platelet aggregation and thrombus formation. The first such antagonist developed, abciximab, an anti- αII bβ3 monoclonal F(ab’)2 fragment, is administrated intravenously and is beneficial in preventing thrombosis in patients undergoing percutaneous coronary intervention3. In contrast to abciximab, epitifibatide and tirofiban, orally available αII bβ3 antagonists lack efficacy and cause bleeding and have therefore failed at the preclinical or clinical trial stages. 4. Phosphodiesterase inhibitors The elevation of the levels of cyclic nucleotides cAMP and cGMP in the platelet cytosol stimulates signalling pathways that inhibit platelet activation. Indeed the inhibitory effects of endothelium-derived nitric oxide and PGI2 on platelet function are mediated through stimulation of cGMP- and cAMP-dependent signalling mechanisms, respectively. The inhibition of phosphodiesterase enzyme, which metabolize these second messengers, therefore suppresses platelet function. The phosphodiesterase inhibitors cilostazol and dipyridamole are licensed for the treatment of stroke and intermittent claudication, for which clinical trials have demonstrated modest but consistent benefit Novel antiplatelet agents 1. Ridogrel Ridogrel is a TxA2 inhibitor with additional prostaglandin endoperoxide receptor antagonist properties that further enhances its antiaggregatory effects by diverting endoperoxide intermediates into the prostacyclin production pathway. Despite positive results from initial pilot studies, the largest clinical study, The Ridogrel versus Aspirin Patency Trial (RAPT) failed to demonstrate any advantage with this agent over aspirin. 2. Other Thromboxane Inhibitors Additional thromboxane inhibitors currently under investigation include a NO-releasing aspirin, NCX4016, and a thromboxane receptor antagonist S18886.

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NCX-4016 has been demonstrated to have a beneficial effects in experimental models of restenosis and ex vivo studies of saphenous vein grafts of diabetic patients. Unlike aspirin or its derivatives, S18886 acts directly on the thromboxane receptor. Thus, it can inhibit not only TxA2 but also other eicosanoids not effected by aspirin, such as hydroxyeicosatetraenoic acids (HETEs) and isoprostanes. In a small study of aspirin-treated patients with CAD, a single dose of S18886 (10 mg) resulted in improved endothelial function as assessed by vasodilatory response to acetylcholine. 3. Other ADP Receptor Antagonist The ADP receptor antagonists currently being studied in phase II and III trials include the third oral thienopyridine prasugrel and 2 reversible non thienopyridine agents, AZD6140 and cangrelor. The results of the TRITON TIMI 284 have been recently published. In this trial which has randomised 13608 patients with acute coronary syndrome to receive prasugrel (a 60 mg loading dose and a 10 mg daily maintenance dose) and clopidogrel (300 mg loading dose and 75 mg daily maintenance dose) demonstrated a significant reduction in MI and stent thrombosis with a higher prevalence of bleeding complication, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. AZD6140 is a cyclopentyl triazolopyrimidine, and it offers potential therapeutic advantages when contrasted to the thienopyridine. AZD6140 is an orally active, direct-acting reversible inhibitor of the P2Y12 receptor that provides a more rapid and complete antiplatelet effect than clopidogrel because of its distinct pharmacodynamic and pharmacokinetic properties. In the DISPERSE5 (Dose Confirmation Study Assessing Anti-Platelet Effect of AZD6140 Versus Clopidogrel in NSTEMI) trial, a phase II study of patients with atherosclerosis, AZD6140 (100 and 200 mg BID) with concomitant aspirin therapy had peak inhibition of ADP-induced platelet aggregation within 3 hours as compared with only minimal inhibition seen with clopidogrel (with no loading dose) at 24 hours. Additionally, more potent inhibition of platelet aggregation was seen at days 14 and 28 in those receiving AZD6140 as compared with clopidogrel. Wheter more potent ex vivo platelet inhibition with AZD6140 will translate into the better clinical outcomes for patients is still to be determined. The DISPERSE-2 trial was a phase II study that evaluated the clinical safety of 90 mg BID and 180 mg BID of AZD6140 versus clopidogrel in patients presenting with non-ST elevation acute coronary syndromes and found similar rates of bleeding. The ongoing PLATO trial is a phase III study with an expected total enrollment of 18000 patients which is comparing the efficacy of AZD6140 against clopidogrel in patients with non-ST or ST elevation acute coronary syndromes.

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Cangrelor is an intravenous direct-acting reversible inhibitor of the P2Y12 purinoreceptor whose very short half-life offers a potential safety advantage over the currently available thienopyridines. Cangrelor has been shown to be well tolerated and safe in phase II studies performed in patients with ischaemic heart disease, acute coronary syndromes, and those undergoing PCI. The CHAMPION-PCI and CHAMPION-PLATFORM trials, both multicenter prospective randomized studies, will assessed the clinical effectiveness of cangrelor in comparison to clopidogrel in patients requiring PCI. 4. Protease-Activated Receptor Antagonist Thrombin, an essential component of the coagulation cascade, is also a potent stimulus for platelet activation. Its action are partly mediated through 2 specific protease-activated receptors (PARs), PAR1 and PAR4, both of which are G protein-coupled receptors. Two of the orally administrated PAR1 antagonist currently undergoing evaluation in phase II studies are E5555 and SCH530348. The TRANSCENDENCE PCI trial is a multicenter randomized study enrolling 1600 patients and is investigating the safety of various doses of SCH530348 when used in the nonemergent PCI setting; initial reports suggest excellent safety. 5. Platelet Adhesion Antagonists There is much interest in developing therapeutic modalities aimed at inhibiting the critical interaction between platelets and subendothelial components of the damaged vessel wall, thus preventing platelet adhesion altogether. One agent undergoing investigation is the collagen inhibitor, C1qTNF-related protein-1, which has been shown to inhibit the platelet aggregation by blocking the ability of vWF to bind collagen, thereby interrupting platelet adhesion and thrombogenesis. Similarly, the compound DZ-697b has been shown to selectively inhibit collagen- and vWF-induced platelet aggregation in human ex vivo studies. References 01. Antithrombotic Trialists’ Collaboration (2002). Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Bmj 324:71-86. 02. CAPRIE Steering Committee (1996). A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 348:1329-1339. 03. Popma JJ, Satler LF (1994). Early and late clinical outcome following coronary angioplasty performed with platelet glycoprotein IIb/IIIa receptor inhibition: the EPIC Trial results. J Invasive Cardiol 6 (Suppl A):19A-28A; discussion 45A-50A. 04. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20): 2001-15. 05. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol. 2007 Nov 6;50(19):1852-6.

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Anti-platelet therapy: evaluation of therapeutic efficacy G.F. Gensini, A.A. Conti, A.M. Gori, R. Marcucci Department of Medical and Surgical Critical Area, University of Florence, Department of Heart and Vessels, Azienda Ospedaliera Universitaria di Careggi, Florence, Italy

Platelets play an important role in the pathogenesis of arterial thrombosis and the inhibition of platelet function is one of the established therapeutic strategies in cardiovascular system. In patients with symptomatic coronary artery disease, percutaneous coronary intervention (PCI) with stenting is effective to prevent further ischemic events. However, recurrent coronary events, including stent thrombosis, remain a serious complication of this procedure and are associated with increased morbidity and mortality. The clinical effectiveness of addition of clopidogrel to aspirin(ASA) therapy to prevent cardiovascular events in patients with acute coronary syndromes and in those who undergo percutaneous coronary interventions (PCI). However, an interindividual variability in response to clopidogrel, as well as to acetylsalicylic acid, has been reported in patients with atherothrombotic disease, in particular among those with acute coronary syndromes. A growing body of evidence is demonstrating that the biological entity of residual platelet reactivity (RPR) on antiplatelet treatment, the so-called clopidogrel and/or aspirin nonresponsiveness, is associated with an increased risk of adverse cardiovascular events, such as stent thrombosis and cardiovascular death 1-4. Clopidogrel nonresponsiveness. – A recent meta-analysis 5 have evaluated whether patients that are biochemically labeled clopidogrel nonresponsive also exhibit “clinical non responsiveness” to clopidogrel, ie, a higher risk of stent thrombosis and other recurrent ischemic events. The meta-analysis identified 25 eligible studies and included a total of 3688 patients and in patients on clopidogrel treatment after PCI showed an overall prevalence of 21% of laboratory defined clopidogrel nonresponsiveness. Although the small sample size of the early prospective studies 1, 6-7 and the low number of cardiovascular events, the results of this meta-analysis indicate that patients ex vivo labeled clopidogrel resistant have an increased risk of adverse cardiovascular events and stent thrombosis (pooled odds ratio of cardiovascular outcomes was 8, 95% CI 3-19) 5. The relation of platelet reactivity and stent thrombosis has also been investigated with most studies reporting that high post-treatment platelet activity, determined by platelet aggregation induced by ADP, is associated with stent thrombosis 3, 6-7. In particular, our prospective study of 804 patients undergoing stenting 3, demonstrated that a clopidogrel nonresponsiveness measured by light transmittance aggregometry induced by 10 µMADP is an independent

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predictor of catastrophic and potentially fatal complications such as stent thrombosis. A number of platelet function assays are under laboratory and clinical evaluation. Among these, a flow cytometric vasodilator-stimulated phosphoprotein (VASP) phosphorilation assay has been evaluated in detecting a reduced response to clopidogrel: in patients undergoing PCI and a cutoff value of 50% in the VASP index was predictive of MACE at 6 months 8. In a prospective, randomized, multicenter study, patients with clopidogrel resistance, defined as a VASP index of more than 50%, undergoing coronary stenting, were randomized to a control group or to the VASP-guided group, in which patients received additional bolus clopidogrel to decrease the VASP index below 50%. Eight major adverse cardiac events (5%) were recorded during the 1-month follow-up, with a significantly lower rate in the VASP-guided group compared with the control group (0% vs. 10%; p <0.01), but no difference in the rate of major and minor bleeding (5% vs. 4%) was found. This is the first study which suggests that adjusting the clopidogrel loading dose according to platelet monitoring using the VASP index is safe and may significantly improve the clinical outcome after PCI in patients with clopidogrel resistance despite a first 600-mg loading dose 9. The effect of clopidogrel on platelet reactivity can be assessed with the VerifyNow P2Y12 assay, a whole blood based aggregometry assay. The results of this assay have been shown to be well correlated with ADP-induced platelet aggregation by LTA 10. A recent study performed on 380 patients undergoing PCI demonstrated that high post-treatment platelet reactivity measured with the point-of-care assay VerifyNow is associated with post-discharge events after PCI with DES, including stent thrombosis 4. Aspirin non responsiveness. – ASA clinical effectiveness for patients suffering from various vascular diseases has been well established in many clinical trials and in meta-analyses 11. However, in a proportion of patients with cardiovascular disease under ASA treatment, RPR, the so-called aspirin resistance, is detectable. Estimates of the prevalence of RPR in clinical trials vary enormously, ranging from 0% to over than 50% 12. Some clinical prospective studies reported a significant association between RPR and the occurrence of secondary cardiovascular events, and a recent meta-analysis by Snoep12 reported a significant role for the laboratory-defined aspirin resistance on the risk of clinical cardiovascular recurrences. Our meta-analysis 13 conducted in 11 prospective studies, with an overall population of 1952 CHD patients followed for a time ranging from 6 days to 4 years, showed a significant increased risk of clinical recurrences for patients who manifested RPR on ASA treatment. This association remained statistically significant even when subgroup analyses accor-

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ding to the duration of follow-up, ASA dosage, patients' characteristics, and laboratory method were performed. ASA resistance also might be associated with concomitant clopidogrel “resistance” 14. Patients identified as ASA- and clopidogrel-resistant have exhibited high platelet reactivity to collagen in addition to ADP and arachidonic acid stimulation, suggesting a generalized high-platelet-reactivity phenotype that might be associated with an increased risk for ischemic events. In 746 consecutive patients who had successful stent implantation and who were compliant to 6month dual antiplatelet treatment (ASA 325 mg and clopidogrel 75 mg daily) after a loading dose of 600 mg of clopidogrel, platelet function was assessed by light trasmittance aggregation induced by ADP, arachidonic acid and collagen. This prospective study shows that dual clopidogrel and aspirin nonresponsiveness increases the risk of thrombotic complications during a 6-month follow-up in comparison to clopidogrel and aspirin responsiveness, and to isolated clopidogrel or aspirin nonresponsiveness 14. In conclusion, different prospective studies demonstrate that an impaired and reduced inhibition of platelet function by antiplatelet treatment in the acute phase of the disease is associated with a subsequent worse clinical follow-up, underlying the importance of an optimal platelet inhibition in the acute phase of the disease. However, more prospective studies are needed to determine the independent prognostic importance of RPR during dual antiplatet therapy and the possible benefit of individually tailored anti-platelet treatment strategies in these cardiovascular disease patients.

on platelet reactivity in patients with stent thrombosis: results of the CREST study. J Am Coll Cardiol 2005; 46:1827-32. 08. Bonello L, Paganelli F, Arpin-Bornet M, et al. Vasodilatorstimulatedphosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 2007;5:1630-6. 09. Bonello L, Camoin-Jau L, Arques S, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol 2008;51:1404-11. 10. Paniccia R, Antonucci E, Gori AM, et al. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. J Thromb Haemost 2007;5:1839-47. 11. Antithrombotic Trialists’ Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86. 12. Snoep JD, Hovens MMC, Eikenboom JCJ, et al. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events. A systematic review and meta-analysis. Arch Intern Med 2007;167: 1593-9. 13. Sofi F, Marcucci R, Gori AM, Abbate R, Gensini GF. Residual platelet reactivity on aspirin therapy and recurrent cardiovascular events -A meta-analysis. Int J Cardiol 2008 (in press). 14. Lev EI, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006;47:27-33. 15. Gori AM, Marcucci R, Migliorini A, et al. Incidence and Clinical Impact of Dual Nonresponsiveness to Aspirin and Clopidogrel in Patients with Drug Eluting Stents. J Am Coll Cardiol 2008 (in press).

References 01. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171-5. 02. Geisler T, Langer H, Wydymus M, et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006;27: 2420-5. 03. Buonamici P, Marcucci R, Migliorini A, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007;49: 2312-7. 04. Price MJ, Endemann S, Gollapudi RR, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008;29:9921000. 05. Snoep JD, Hovens MC, Eikenboom, CJ et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: A systematic review and meta-analysis. Am Heart J 2007;154:221-31. 06. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POSTSTENTING study. J Am Coll Cardiol 2005;46:1820-6. 07. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect

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Antiplatelet therapy: side effects G. Lombardo, F. Prattichizzo, S. Betti Internal Medicine Unit, Department of Internal Medicine, St. Joseph Hospital, Empoli (FI), Italy

In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention and it may be termed a “side effect” when judged to be secondary to a main or therapeutic effect. The effects of platelet-active drugs in the prevention of arterial thrombosis, despite the proven lifesaving clinical benefits of inhibiting platelets, cannot be dissociated from the impairment of primary haemostasis, with an increased risk of bleeding (“reverse side of the coin”), which suggest a similar mechanism for both processes. The extent and the duration of platelet inhibition required to impair haemostasis may nevertheless differ from that required to prevent atherothrombosis: incomplete and transient blockage of platelet COX-1 by some NSAID (Non Steroidal Anti Inflammatory

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Drugs) is associated with an increased risk of bleeding without antithrombotic efficacy. The role of ADP and TXA2 in amplifying platelet activation in haemostasis is supported by the increase in the incidence of bleeding complications due to the use of low-dose of aspirin or thienopyridines. A multiple-dose study showed a comparable prolongation of bleeding time measurement (by 1.5 fold to 3.0 fold over controls) with clopidogrel (50-100 mg daily) and ticlopidine (500 mg daily) and the term “aspirin resistance” has been used to describe a number of different phenomena, including the inability of aspirin to cause a prolongation of bleeding time. In the matter of the platelet integrin glycoprotein IIb/IIIa, the clinical relevance of the main receptor for adhesion and aggregation is largely known from the associations between the use of pharmacological blockers of glycoproteins IIb/IIIa and bleeding complications, and from the study of Glanzmann’s Thrombasthenia. The risk of major bleeding was significantly increased during the treatment with abciximab in EPIC study (Evaluation of c7E3 Fab in the Prevention of Ischemic Complications), even subsequently was found that a reduction of heparin can greatly reduce the incidence. Beside haemorrhage due to glycoprotein IIb/IIIa inhibition, thrombocytopenia with a platelet count <50.000/l occurs in 1-2% of patients treated with abciximab, reversible by stopping the drug therapy. Severe thrombocytopenia has been reported in a small percentage of patient treated with Tirofiban and Eptifibatide. During the treatment with thienopyridine ticlopidine, beside haemorrhage due to decrease of platelet activation, similar thrombocytopenia may occur, sometimes associated to neutropenia (2.4% for neutrophil count <1.2×109/l) and/or aplastic anemia. Both ticlopidine and clopidogrel treatment were complicated by a very rare incidence of another life threatening condition: thrombotic thrombocytopenic purpura. Antiplatelet therapy has been the focus of extensive clinical investigations over the last two decades and, despite substantial differences in the reporting patterns of bleeding complications, low-dose ASA (daily dose <100 mg) “single-therapy” was associated with the lowest risk of bleeding. In the treatment of high risk patients, i.e. patient with acute coronary syndromes undergoing PCI (percutaneous coronary intervention), dual antiplatelet therapy is now a cornerstone but at the same time the risk of bleeding grows further on. The treatment with clopidogrel plus low-dose aspirin is independently associated to an increased risk of bleeding events: in the CHARISMA trial (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance), the rate of severe bleeding was 1.7% versus 1.3% (aspirin alone).

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The treatment with Prasugrel, a new thienopyridine that, like clopidogrel, prevents platelet activation linking permanently ADP receptor P2Y12, plus low dose aspirin was associated with an increased risk of major bleeding, including fatal bleeding. Inhibitors of cellular phosphodiesterase are associate with a low risk of bleeding. In the ESPS-2 study, bleeding of any site was doubled in the two aspirin arms but was indistinguishable from placebo in dipyridamole-treated patients: headache was the most common side effect of dipyridamole. Cilostazol, a quinolinone derivative that inhibits cellular phosphodiesterase (more specific for phosphodiesterase III), an oral antiplatelet agent with pleiotropic effects including inihibition of neointimal hyperplasia, has been successfully used to reduce the risk of restenosis after percutaneous coronary intervention (PCI), with no significant increase in the risk of bleeding. Persons who regularly take prolonged aspirin therapy have an increased risk of serious gastrointestinal complications, such as bleeding, perforation, or other adverse events resulting in hospitalization or death. These adverse effects, due to reduction of gastro protective prostaglandins levels (PGE2 and PGI2) as well as reduction of prostaglandin-dependent gastro protective functions are dose-dependent and among trials in which the daily dose of aspirin was 900 to 1300 mg, the incidence of stomach pain, heartburn and nausea was 40-60% higher than placebo. The frequency of gastrointestinal symptoms was instead comparably low in patients given 75 mg daily of aspirin or placebo during 12 to 50 months of therapy. Conclusions. – The literature and the clinical experience suggest that platelet-active drugs have proven life saving clinical benefit but are associated with a risk of bleeding as a consequence of impairment of haemostasis. Low-dose ASA is associated with the lowest risk, while during thienopyridines and platelet integrin glycoprotein IIb/IIIa inhibitors treatment the risk is higher. Dual antiplatelet therapy is a cornerstone in the treatment of high risk patients but at the same time the risk of bleeding grows further on. The choice can be optimized by individualising the treatment decision: patient initial risk and expected risk reduction, the incidence of side effects as well as the personal characteristics of patient are the hinges in the evaluation of the risk/benefit.

New antithrombotic agents I. Iori, A.M. Pizzini, M. Silingardi, D. Arioli Centro Emostasi e Trombosi-Stroke Unit, Department of Internal Medicine, Azienda Ospedaliera Santa Maria Nuova, Reggio Emilia, Italy

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Introduction. – Heparin and vitamin K antagonist (VKA) are the drugs of choice in primary and secondary prevention of venous and arterial thromboembolic disease. Heparin and low molecular weight heparin (LMWH) are given during acute phase in order to prevent thrombus extension and fatal pulmonary embolism (PE). VKA such as warfarin are administered during extended anticoagulation to prevent recurrent venous thromboembolism (VTE). These agents are highly effective but have several limitations: heparin and LMWH are parenteral drugs. On the other side, warfarin has a narrow therapeutic window, multiple drug-interactions, requires laboratory monitoring, dose adjustments and dietary restrictions. An “improved” oral anticoagulant would thus be highly desirable 1. New anticoagulant drugs target specific sites in the haemostatic network (Figure 1) 2. Direct thrombin inhibitors (DTIs) block thrombin interaction with its substrates, whereas factor Xa inhibitors (FXaI) block thrombin generation. DTIs. – Directly block thrombin by binding to three domains: the active site or catalytic site and two exosites. Bivalent DTIs block thrombin at both the active site and exosite 1, whereas univalent DTIs bind only to the active site. The group of bivalent

Figure 1. – Target of new antithrombotic agents 2.

DTIs includes hirudin and bivalirudin, whereas argatroban, melagatran (and its oral precursor, ximelagatran), and dabigatran are univalent DTIs (Table I) 3. Argatroban and lepirudin are approved for anticoagulation in patients with heparin-induced thrombocytopenia (HIT), and argatroban also for prophylaxis in patients with HIT. Bivalirudin is approved for patients with unstable angina, undergoing percutaneous transluminal coronary angioplasty (PTCA) and as an alternative treatment to heparin in patients with HIT requiring PTCA 1, 3. Melagatran and especially its oral prodrug ximelagatran, have been evaluated in several studies. Ximelagatran was found to be as effective as LMWH in VTE prevention after major orthopaedic surgery (METHRO III and EXPRESS studies) 4, 5, in DVT treatment (THRIVE II and III studies) 6, 7 and in stroke prevention in patients with atrial fibrillation (SPORTIF III, V) 8. Reports of an increase in liver enzymes were observed with ximelagatran in studies for treatment indications requiring prolonged administration (more than 35 days). However, this finding was not observed in studies on short-term (up to 11 days) prophylaxis of VTE after elective major orthopaedic surgery. The EXTEND study has evaluated the safety assessment of ximelagatran after prolonged administration (35 days) after elective hip replacement and hip fracture surgery 9. Ximelagatran administration is associated with an increased risk of liver toxicity and in some cases this side effect occurred after treatment withdrawal, making a laboratory surveillance policy inappropriate. For this reason in 2006 the drug was removed from the market. Dabigatran exetilate is an orally prodrug, which is rapidly absorbed and converted to the active form, dabigatran. Dabigatran have plasma half-life of 8 hours after single dose administration and up to 14 to 17 hours after multiple doses. Peak plasma concentration of dabigatran is reached approximately 2 hours after oral administration, with no accumulation of drug upon multiple dosing. Dabigatran is not metabolized by cytochrome P450 isoenzymes and the risk of drug-drug interactions is low. Since the absorption of dabigatran exilate in the stomach and

Table I. – Main properties and pharmacokinetic characteristics of DTIs 3. Characteristic

Recombinant hirudins

Bivalirudin

Argatroban

Ximelagatran and melagatran

Dabigatran

Route of administration

Intravenous, subcutaneous

Intravenous

Intravenous

Intravenous, subcutaneous and oral

Oral

Plasma half-life

Intravenous 60 min; subcutaneous 120 min

25 min

45 min

Intravenous and subcutaneous 2-3 hr; oral 3-5 hr

12 hr

Clearance

Kidney

Kidney, liver, other sites

Liver

Kidney

Kidney

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small intestine is dependent on an acid enviroment, drug absorption is reduced by 20% to 25% in patients treated with proton pump inhibitors 1, 2, 10. The efficacy and safety of dabigatran exetilate have been evaluated in phase II studies in patients undergoing total hip and knee replacement (RE-MOBILIZE, REMODEL) and in large phase III trials for prevention and treatment of VTE (RE-COVER and RE-MEDY) and for stroke prevention in atrial fibrillation (RELY) 1. The promising result from these trials suggest that dabigatran represent a significant improvement over existing therapies for the management of thromboembolic diseases. FXaI. â&#x20AC;&#x201C; Selective FXaI would effectively block coagulation since factor Xa is positioned at the start of the common pathway of the intrinsic and extrinsic coagulation system. Fondaparinux is a completely synthetic heparin-like molecule with selective anti factor Xa activity 1, 2. Its structure is based on the heparin sequence that interacts specifically with antithrombin III (ATIII), resulting in a conformational change that makes it effective in inhibiting factor Xa. However, its pentasaccharide chain is not long enough to interact with thrombin. Consequently, it has no thrombin inhibitory activity and it works by reducing thrombin generation. After subcutaneous administration, peak plasma levels are reached after 2 hours and the elimination half-life is 17 hours. Bioavailability is nearly complete after subcutaneous or intravenous administration. Fondaparinux activity can be assessed with anti-factor Xa assay; it has no effect on other coagulation test, including PT, PTT and thrombin time. Bleeding is the principal adverse effect: its frequency and severity have been quite similar to those observed with LMWH. Since the drug is excreted in the urine, elevated levels may be observed with renal insufficiency. Caution should be used in administering fondaprinux to patients with renal failure. Unlike heparins, fondaparinux does not bind to platelet factor 4 and consequently, its administration should not result in HIT 1. Although it has not yet been approved for the treatment of HIT, there are several reports of its efficacy in this condition. Four randomized controlled trials have showed that fondaparinux is more effective than LMWH in DVT prophylaxis in major orthopaedic surgery (EPHESUS, PENTATHLON 2000, PENTAMAKS, PENTHIFRA trial) 1, 2, 11. In two studies focusing acute-phase VTE treatment (MATISSE-DVT and MATISSE-PE trials) Fondaparinux was equally effective and safe as LMWH 12. Finally OASIS 5 trial in patients with acute coronary syndrome showed that fondaparinux is as effective as enoxaparin with a reduction in major bleeding at 9 days and mortality at 1 and 6 months 1. Idraparinux is a hypermethylated analogue of fondaparinux that binds to ATIII with very high affinity such that the half-life of the drug is prolonged to 80 hours. Idraparinux has been evaluated using once-weekly subcutaneous dose of 2.5 mg in the tre-

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atment of acute VTE (Van Gogh DVT and PE trial) 10. The discordant efficacy results in DVT and PE trials (idraparinux was less effective than conventional treatment in PE patients) highlights the importance of adequate levels of anticoagulation for initial treatment of PE, since the majority of the recurrences occurred early in idraparinux-treated patients. In the Van Gogh extension trial idraparinux causes excessive bleeding compared to placebo in the secondary prevention of VTE 10. In patients with non-valvular atrial fibrillation, long-term treatment with a 2.5 mg weekly dose of subcutaneously idraparinux was non inferior to VKA (AMADEUS trial) 13. However, there were significantly more clinically relevant episodes of bleeding with idraparinux than with VKA, which led to this trial being terminated early. Furthermore there is no specific antidote for idraparinux, but a biotinylated form (SSR 126517) which has an antidote, is currently under evaluation in clinical trials 10. The satisfactory results with fondaparinux have stimulated the development of a direct FXaI with an oral intake. The main oral direct FXaI involved in clinical trials include rivaroxaban (BAY 59-7939), apixaban (BMS), YM 150, LY 517717. Rivaroxaban is an orally active direct FXaI 1, 2. It has a rapid onset of action and half-life of 5-9 hours. Phase 2 studies showed that rivaroxaban was potentially safe and effective for thromboprophylaxis after major orthopaedic surgery across a wide range of dose (ODIXaKNEE and ODIXa-HIP) 1, 2. Total daily dose of 5 to 20 mg of rivaroxaban had efficacy and safety similar to those of enoxaparin after total hip and knee arthroplasty. A subsequent study indicated that rivaroxaban at a dose of 10 mg once daily had sufficient efficacy and safety for thromboprophylaxis after total hip replacement. Data from two Phase III clinical trials (RECORD 1 e 3) 14, 15 have been recently published and show that rivaroxaban, 10 mg once daily administered postoperatively for five weeks, is significantly more effective than enoxaparin in preventing symptomatic and asymptomatic VTE, in total hip and knee replacement surgery patients. The frequency of major bleeding and other safety outcomes, including on-treatment bleeding, hemorrhagic wound complications and hepatic enzyme elevations, was low and did not differ between the two treatment. Apixaban, a small molecule inhibitor of the active site of factor Xa, is a selective and reversible inhibitor of factor Xa, like rivaroxaban. The drug is absorbed from the gastrointestinal tract with a bioavailability more than 50% and peak plasma levels are achieved in about 3 hours. With repeated doses, the terminal half-life is between 9 and 14 hours. Apixaban is metabolized in the liver (via CYP3A4) and it is excreted by the kidneys. Apixaban prolongs the INR and the aPTT in a concentration-dependent fashion. Apixaban has been evaluated in phase II trials and these trials have showed a favourable effi-

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cacy and an acceptable bleeding safety profile at doses of 5-20 mg per day, in the prevention of VTE after knee replacement surgery. Several phase III trials are ongoing in different patient population including primary prevention of VTE, treatment of DVT and stroke prevention in atrial fibrillation 2. LY517717 is another orally active FXaI which as an half-life time of 25 hours in healthy subjects and primary route of elimination is the gastrointestinal tract. The safety and efficacy of LY517717 were evaluated in hip or knee replacement surgery and doses of 100150 mg of drug were as safe and efficacious as a standard enoxaparin regimen for the prophylaxis of VTE 2, 10. Conclusions. – The new oral agents, both DTIs and FXaI, share some characteristics of an “ideal” oral anticoagulant: high efficacy and safety index, predictable dose-response not requiring laboratory monitoring, rapid onset of action and minimal interaction with other drugs. However some concerns still remain about these drugs (no methods to assess compliance, no close clinical surveillance, liver toxicity, absence of antidote, dose adjustment in patients with renal dysfunction and in weight-extreme patients) and none of these at present could completely replace the conventional drugs in anticoagulant therapy. References 01. Bauer KA. New Anticoagulants. Hematology 2006;450456. 02. Haas S. New oral Xa and IIa inhibitors: updates on clinical trial results. J thromb Thrombolysis 2008;25:52-60. 03. Di Nisio M, Middeldorp S, Bller HR. Direct Thrombin Inhibitors. N Engl J Med 2005;353:1028-40. 04. Eriksson BI, Kälebo P, Bergqvisty D, Dahl OE, LindbrattS, Bylock A et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002;360:1441-7. 05. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Lassen MR, Mouret P et al. The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxapa-

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rin for the prevention of venous thromoembolism after total hip or knee replacement: the EXPRESS study. Thromb Haemost 2003;12:2490-6. 06. Francis CW, Berkowitz SD, Comp PC et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N E J Med 2003;349:1703-12. 07. Schulman S, Wahlander K, Lundstrom T, Clason SB, Eriksson H, THRIVE Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713-21. 08. Olsson SB, Executive Steering Committee on behalf of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003;362:1961-8. 09. Agnelli G, Eriksson BI, Cohen AT, Bergqvist D, Dahl OE, Lassen MR et al. Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran. Thromb Res 2008, doi: 10.1016/j.thromres.2008.02. 017 (in press). 10. Gross PL, Wiitz JI. New Anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol. 2008;28:380-386. 11. Turpie AG, Bauer KA, Eriksson BI et al. Fondaparinux versus enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery. A meta analysis of 4 randomized double-blind studies. Arch Intern Med 2002;162:1833-1840. 12. Bller HR, Davidson BL, Decousus H et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003;349:1695-1702. 13. The Amadeus Investigators. Comparison of idraparinux with K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, openlabel, non inferiority trial. Lancet 2008;371:315-21. 14. Eriksson BI, Borris LC, Friedman RJ, Hass S, Huisman M, Kakkar AK et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765-75. 15. Lassen M, Ageno W, Borris L, Lieberman JR, Rosencher N, Bandel TJ et al. Rivaroxaban versus Enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776-86.

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CHRONIC PAIN IN INTERNAL MEDICINE Assessment of pain in patients with cognitive impairment W. De Alfieri, L. Pasqui, T. Borgogni, F. Cellai, S. Petri, F. Riello, F. Nisticò Department for the Care of Frail Elderly and Chronicity, UO Geriatria – Az.USL 9, Grosseto, Italy

Introduction. – Assessment of pain provides information used to select interventions, monitor the effectiveness of treatment, and communicate care planning across health providers. Whereas self-report of pain is the gold standard for pain assessment, other approaches, such as observational report, are necessary in patients with advancing cognitive and/or verbal communication impairments. Pain tools have been developed for use in older adults with dementia, the most common cause of disabilities among the aging population. Ample evidences show that aging is associated with a high rate of painful conditions, irrespective of cognitive status 1, and have documented a high prevalence of pain in older patients with dementia 2; moreover no empirical studies have indicated persons with dementia experience significantly less pain sensation than individuals without a deficit in cognitive function and experimental ones revealed that pain thresholds (a sensory-discriminative aspect) is intact, whereas motivational-affective functions (as pain tolerance and autonomic reactivity) are affected in these patients. In people with dementia, neglected pain can cause additional health problems, as agitation, sleep disturbance, weight loss, depression, impaired functional abilities, social withdrawal, aggression, and increased health care utilization and costs. Despite the relevant prevalence and the burden of pain, undertreatment is a more frequent and frightening observation in severe dementia, as pain complaints decrease and sometimes take on less obvious or subtle forms. Pain assessment. – For the purposes of measuring pain in patients with cognitive impairment, the following operational definition can be used: pain is an unpleasant subjective experience that can be communicated to others either through self-report when possible or through a set of pain-related behaviours. In the clinical practice, the most commonly used pain assessment instruments are usually selected according to patient communicative capacity (Table I). In community-dwelling older persons with from mild to moderate cognitive impairment, pain rating scales are effective in discriminating levels of pain 3. Among residents in nursing home, persons with moderate-severe dementia, who can still com-

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municate about their pain, can report pain reliably at the moment or when prompted, even if pain recall and integration of pain experience over a period of time may be less reliable 4. The administered tools primary explore presence and intensity of pain, even if exploration of abstract thinking and of depressive symptoms is recommended to increase reliability of the assessment 5. For non-communicative persons, instead, pain is assessed by observation scales, which are applied to patients irrespective of their ability to communicate, and as they are particularly likely to reflect pain that needs treatment. Behavioural pain indicators, organized in a framework with six main types with specific examples, have been suggested to assess pain 6; categories are: a) Facial expressions, b) Verbalizations, vocalizations; c) Body movements; d) Changes in interpersonal interactions; e) Changes in activity patterns or routines; f) Mental status changes. On the other hand, clinical practice guidelines in long-term care setting provided useful sources to base decisions for pain management 7. The ability to use the tool, achieving high intrarater and interrater agreement in ratings during a standardized pain assessment protocol, is crucial to choose the instrument: it must be reliably and easily administered without staff burden. If used in elderly adults with moderate dementia, it must significantly be correlated with self-reported pain; on the contrary, there would be no significant correlation between selfreported and observed pain intensity in cognitively impaired individuals 1. Most of the behaviour scales only rate the presence of pain, but not the intensity. Generally, both physicians and nurses tend to underestimate the intensity of the patient’s pain, while family caregivers tend to overestimate it. Additional consideration should be given to evaluate instrument specificity and sensitivity to pain treatment; in fact, no many studies exist exploring the efficacy of pain control after using behaviour scale. A score requiring an intervention should not automatically start a measure to control pain: the behavioural items are not specific and could represent other important conditions such as delirium and adverse drug reaction. Moreover, signs selected by experience as indicative of pain aren’t exclusively representative of pain or related to painful condition (i.e., rigid posture in an extrapyramidal syndrome or gait changes in a vascular dementia): it should not be assumed that they represent pain until other relevant causes are considered. Whenever possible, behaviours should be observed during activity, such as transfers,

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Table I. – Pain assessment instruments in communicative and non-communicative patients. From Scherder E.(10), modified. Scale

Assessment

Aspect of pain Intensity Affect

Most frequently used self report pain rating scales for communicative patients Verbal Descriptor Scale

Seven adjectives: no pain to most intense pain

X

Revised Verbal Descriptor Scale

With some additional verbal descriptors and a visual pain thermometer

X

X X

Verbal Rating Scale

Five labels, such as “distressing”

X

Visual Analogue Scale

The worst imaginable pain to no pain (vertical)

X

Faces Pain Scale

Seven faces expressing no pain to most intense pain

X

11-Point Verbal Numeric Rating Scale

0-10 score (“what you rate your current pain?”)

X

Numeric Rating Scale

1-10 horizontal line

X

21-Point Box Scale

21 boxes: no pain to pain as bad as it could be

X

X

Selected available observation scales for pain assessment in non-communicative patients DS-DAT1

Nine indicators (such as frowning), scored for frequency, duration, and intensity

X

X

CNPI2

Six behavioural indicators (such as grimacing), scored both at rest and on movement

X

X

NOPPAIN3

Four main sections: pain observation during care conditions, pain behaviours (pain words, pain noises, pain faces, bracing, rubbing, and restlessness), pain intensity rating, pain thermometer (for global assessment of pain)

X

X

PACSLAC4

Four subscales and a total of 60 items, including facial expressions (such as pale X face, flushed, red face, teary eyed, sweating shaking/trembling, cold, and clammy), physical items (activity/body movements), physiological indicators (such as eating and sleeping changes, vocal behaviours), psychological items (social/personality/mood cues)

X

Doloplus2

Comprehensive tool. Three subscales: somatic -5 items -, psychomotor -2 items-, and psychosocial -3 items- reactions

X

X

NGS5

Based on the nursing staff members’ opinions about “how much pain?” (7 possible answers)

X

PPI6

Best word to describe physical pain (7 answers)

X

ADD7

Step by step, to be not just a scale but a total approach (“the tool is an intervention”)

X

FLACC8, modified by Odhner

For critically ill adults who are unable to verbalize; indicators: facial expression, activity, guarding, vital signs, and pain response; overall score: 0-10

X

PAINAD 9

Five pain behaviours (such as breathing)

X

X

PADE 10

Three parts: physical items (facial expression, breathing pattern, posture), global assessment (involving proxy evaluation of pain intensity), functional (including Activities of Daily Living, ADL)

X

X

Abbey

Score from six items (vocalization, facial expression, change in body language, plus behavioural, physiological, and physical changes)

X

X

1 2 3 4 5 6 7 8 9

10

12

X

Discomfort Scale-Dementia of Alzheimer Type. Developed for advanced Alzheimer patients Checklist of Non-Verbal Pain Indicators Non-communicative Patient’s Pain Assessment Instrument. Pain Assessment Checklist for Seniors with Limited Ability to Communicate. Nurse Global Scale of pain. It is based on global impression. Not reliable in persons with severe impairment or assuming pain medication. Present Pain Inventory. Based on nursing staff members’ perception of pain among residents. Difficulty in assessment, as well as NGS. Assessment of Discomfort in Dementia Behavioural Pain Assessment Scale. Studied for scoring postoperative pain in young children. Face, Legs, Activity, Cry, Comorbidity. Pain Assessment in Advanced Dementia. Specific behaviours in each domain are assigned a score from 0 to 2, based on their relationship to pain. Pain Assessment for the Dementing Elderly. Developed in advanced dementia.

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ambulation, and repositioning, since they can be misleading at rest. It should not be assumed that behaviour symptoms represent pain until other relevant causes are considered, based on a comprehensive evaluation. On the other hand, assessing people only with standardized tools may results in underrecognition of pain. As such, a comprehensive, hierarchical approach, that includes self-report, observations of pain behaviour, and proxy ratings, is recommended 8. Additional elements should include diagnoses of existing comorbidities and a complete medication history, assessment of psychosocial and functional status, and, if reasonable, patient expectations for pain relief. Apart from patients, actual barriers have been identified in organizations to achieve complete pain control: lack of commitment to pain issues, high turnover of direct care staff, lack of coordination of care team; moreover, the reported pain and the caregiver’s sensitivity to the signs of pain are weighted down with racial, ethnic, social, and gender biases and attitudes, while co-morbid conditions and multiple medication use may affect perception or interpretation of pain. Conclusions. – Although a standardized assessment tool is not yet available for widespread use, a comprehensive approach is recommended in older adults with cognitive impairment. Briefly, these issues are important 9: – Assume the presence of pain based on the underlying diagnoses or conditions causing or contributing to pain (disease, injury, procedure, or surgery). – Monitor for pain on a regular basis using a comprehensive list of behavioural indicators, at rest as well as during movements, suspecting pain in patients at risk. The evaluation of pain generally cannot wait for a formal procedure to be performed. – Typical nonverbal cues of pain and behavioural changes are well described. However, in older adults with dementia, they not help to confirm whether a symptom or finding means that the patients actually has the problem. Tools do not substitute for comprehensive bedside patients evaluation and discussion with the interdisciplinary team. – If the presence of pain is uncertain, an analgesic intervention may be warranted to evaluate presence of pain, preferring it to psychotropic drugs. Assessing pain accurately remains an extremely difficult daily challenge for clinicians and researchers. In the future, enhanced brain imaging techniques, sophisticated diagnostic options (electrophysiological and olfactory response), and monitoring of pain-related chemical substances may unfold for new possible indicators of pain. However, we must focus our attention on strategies to assist clinicians in recognizing pain with readily available methods and actual resources. Of utmost importance is raising awareness of pain presence in vulnerable persons, encouraging staff to anyhow assess and treat pain.

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References 01. Horgas AL, Nichols AL, Schapson CA., Vietes K. Assessing pain in persons with dementia: relationships among the non-communicative patient’s pain assessment instrument, self-report, and behavioral observations. Pain Manag Nurs 2007;8:77-85. 02. Herr K, Bjoro K, ,Decker S. Tools for assessment of pain in nonverbal older adults with dementia: a state-of-thescience review. J Pain and Symptom Manage 2006; 31:170-192. 03. Herr KA, Spratt K, Mobily PR, Richardson G. Pain Intensity assessment in older adults: use of experimental pain to compare properties and usability of selected pain scale with younger adults. Clin J Pain 2004;20:207-19. 04. Chu L, Schnelle JF, Cadogan MP, Simmons SF. Using the minimun data set to select nursing home residents for interview about pain. J Am Geriatr Soc. 2004; 54:2057-61. 05. Closs SJ, Barr B, Briggs M, Cash K, Seers K. A comparison of five pain assessment scales for nursing home residents with varying degrees of cognitive impairment. J Pain and Symptom Manage 2004; 27:196-205. 06. AGS Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. J Am Geriatr Soc 2002; 50: S205-S224. 07. American Medical Directors Association. The management of chronic pain in long term care settings. Columbia, MD: American Medical Directors Association, 2003. 08. Herr K, Coyne PJ, Key T, Manworren R, McCaffery M, Merkel S, Pelosi-Kelley J, Wild L, American Society for Pain Management Nursing. Pain assessment in the nonverbal patients: position statement with clinical practice recommendations. Pain Manag Nurs 2006; 7: 44-52. 09. Herr K, Decker S. Assessment of pain in older adults with severe cognitive impairment. Ann Long Term Care 2004;12:46--52. 10. Scherder E, Oosterman J, Swaab D, Herr K, Ooms M, Ribbe M, Sergeant J, Pickering G, Benedetti F. Recent developments of pain in dementia. BMJ 2005; 330: 461-4.

Chronic pain in internal medicine: what is new in pharmacological treatment A. Cecchin, A. Morettini, F. Corradi Department of Emergency and Internal Medicine Unit of Internal Medicine 1, AOU Careggi, Florence, Italy

The real change in chronic pain therapy is not the presence of new molecules, but the introduction of low-dose opioid, instead of classical titolation with morphine sulfate-immediate-release. Low-dose opioid is adeguate for chronic therapy of moderate chronic pain, even non-oncologic. This modality of treatment allows to move directly from the first to the third step of OMS scale. New research indicate also the efficacy of some opioids for the management of several pain, like neuropathic pain, for which morphine sulfate did not seem to determine an appropiate pain control. Results of several studies report the need of greater prudence and selection of patients for the use of transder-

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mic opioid, which remain however second choice after oral therapy (except in particular cases). In all patients, but especially in elderly patients with comorbidities, particular attention must be paid to collateral effects of analgesic drugs (opioids, NSAIDs, COXIB), and adjuvant analgesics in relation to singular molecules, to the tipology of pain or patient. Some changes concern some adjuvant analgesics, including anticonvulsants and antidepressant, particularly for their effects on neurophysiological mechanism. Do not underestimate the new laws that made some opioid prescription more simple. Conclusion. – Now it is time to review the drugs we dispose for chronic pain treatment and for a good practice.

Neuropathic pain in diabetes G. Seghieri Direttore UO Medicina 2 e Servizio Dietetico - Spedali Riuniti, Pistoia, Italy

Introduction. – From the historical Pirart’s paper, a huge array of epidemiological studies have recognized that at least one of four diabetic patients is affected by distal symmetric polyneuropathy (DSP). The distal symmetric sensory polyneuropathy affects, in fact, ∼30% of the hospital-based population and ∼25% of population-based samples of diabetic patients. The incidence of DSP is ∼2% per year. The most important etiological factors that have been associated with DSP are poor glycemic control, diabetes duration, as well as visceral obesity and height. Other factors which have been associated with DSP are arterial hypertension, age, smoking, and dyslipidemia. An important aspect of DSP is that it is responsible for substantial morbidity, increased mortality, and impaired quality of life. It is likewise known that this typical microvascular complication represents a major health problem, since people affected with it present typical symptoms of excruciating neuropathic pain. Pain represents an important subjective symptom, since it is often this complaint that drives patients to seek health care. The figures regarding these problems are really impressive since neuropathic pain is present in 16-26% of diabetic patients. It is obvious that pain associated with diabetic neuropathy substantially worsens the quality of life, in particular interfering with sleep and every day’s quality of life. The problem of neuropathic pain represents, however, a ‘grey area’ because despite its impact, 25 to 39% of the diabetic patients did not receive any treatment for pain. Etiopathogenesis. – According to experimental studies, as well as to therapeutic interventions aimed at reducing the symptoms, several mechanisms are

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thought to contribute to the pathogenesis of DSP and to pain: – The polyol pathway theory:according to which an increased flux through the polyol pathway leads to accumulation of sorbitol and fructose, this induces myo-inositol depletion, and consequently the reduction in Na+-K+-ATPase activity. As the result of these mechanisms the nerve action is impaired, leading a distorted progression of nerve action potentials. – A second mechanism is the disturbance in n-6 essential fatty acid and prostaglandin metabolism. All this leads to altered structure of nerve membrane, and consequently to impairment in morphological nerve structure. – A third hypothesis is the classical ‘vascular’ theory. According to this theory microvascular abnormalities lead to wide nervous ischemia and hypoxia. A more modern key to reading this ‘old’ theory, an important role in hypoxia is played by the oxidative stress which sets the transcription factor nuclear factor-κ in motion, increasing the activity of diacylglycerol (DAG)-protein kinase C β (PKCβ) pathways. – A non recent theory indicates the accumulation of nonenzymatic advanced glycation end products (AGEs) and the consequent damage of the proteic skeleton of nerves and microvessels, as the guilty of nervous damage. – An interesting theory postulates the epigenetic manifestations leading to a reduced expression and consequent depletion of neurotrophic factors such as nerve growth factor, insulin-like growth factor, or neurotrophin-3, which altogether lead to a disturbance in axonal transport properties. Finally there is the immunological damage induced by the production of autoantibodies to vagal nerve, sympathetic ganglia, and adrenal medulla. All this may induce nervous damage due to inflammatory changes. Clinical features. – The distal symmetric sensory, or DSP, is commonly associated with autonomic neuropathy. Often the onset is insidious. The fibers involved are the small-fiber unmyelinated (C) fibers and thinly myelinated (A) fibers as well as the largefiber myelinated (Aα Aβ) ones. Some studies suggest that the damage to small fiber neuropathy occurs early in the natural history of the disease. This kind of damage is responsible of pain firstly, and when large fibers are more deeply involved the typical deficit in nerve conduction occurs. In this latter case the motor deficits appear, at first in an insidious way and afterwards more and more evident either from a clinical or an instrumental detection way. DSP is an essential contributor to the pathogenesis of the foot ulcers and consequently of the lowerlimb amputation and consequently its precocious diagnosis if of paramount importance. Since this review is focused to pain any detail on the aspects of any single neuropathic clinical picture will be omitted. Pain is often excruciating and may persist over several years, leading to a progressive

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Table I. – Drugs active approaching the pathogenetic mechanisms (From Ziegler D. Diabetes Care,2008). Abnormality

Compound

Aim of tretment

Polpol pathway ↑

Aldose reductase inhibitors Sorbinil Tolrestat Ponalrestat Zopolrestat Zenarestat Lidorestat Fidarestat AS-3201 Epalrestat

Nerve sorbitol ↓

Myo-inositol ↓

Myo-inositol

Nerve myo-inositol ↑

Equivocal

Oxidative stress ↑

α-Lipoic acid

Oxygen free radicals ↓

Effective in RCTs, trials ongoing

Nerve hypoxia ↑

Vasodilatators ACE inhibitors Prostaglandin analogs phVEGF165 gene transfer

NBF ↑

Protein kinase C ↑

Status of RCTs

Withdrawn (AE) Withdrawn (AE) Ineffective Withdrawn (marginal effects) Withdrawn (AE) Withdrawn (AE) Effective in RCTs, trials ongoing Effective in RCTs, trials ongoing Marketed in Japan

Protein kinase C-β inhibitors (ruboxistaurin)

Angiogenesis ↑

Effective in one RCT Effective in one RCT RCTs ongoing

NBF ↑

RCTs

ongoing

C-peptide ↓

C-peptide

NBF ↑

Studies ongoing

Neurotrophism ↓

Nerve growth factor (NGF) BDNF

Nerve regeneration, growth ↑ Nerve regeneration, growth ↑

Ineffective Ineffective Ineffective

LCFA metabolism ↓

Acetil-L-carnitine

LCFA accumulation ↓

GLA synthesis ↓

γ-linolenic acid (GLA)

EFA matabolism ↑

Withdrawn

NEG ↑

Aminoguanidine

AGE accumulation ↓

Withdrawn

AE: adverse event; ACE: advanced glycation end product; BDNF: brain-derived neurotrophic factor; EFA: essential fatty acid; LCFA: long-chain fatty acid; NBF: nerve blood flow; NEG: nonenzymatic glycation; RCT: randomized clinical trial.

Table II. – Drugs for symptomatic therapy of pain in diabetic neuropathy. Drug class

Drug

Tricyclics

Amitriptyline Imipramine

SSRIs

Paroxetine Citalopram

Anticonvulsants

Gabapentin Pregabalin Carbamazepine Topiramate

Opioids

Tramadol Oxycodol

Daily dose (mg)

NNT

NNH

Side effects

25-150 25-150

2.4 (2.0-3.0) 2.4 (2.0-3.0)

2.7 (2.1-3.9) 2.7 (2.1-3.9)

++++ ++++

40 40

ND ND

ND ND

+++ +++

2.7 (2.2-3.4) 3.7 1.9 (1.4-2.8) 9.0

++ ++ +++ ++

7.8 ND

+++ +++

900-1,800 150-600 200-400 up to 400 50-400 10-60

3.7 3.3 3.3 3.0

(2.4-8.3) (2.3-5.9) (2.0-9.4) (2.3-4.5)

3.4 (2.3-6.4) ND

Data are medium (range) unless otherwise indicated. See refs. 2, 19, and 20. ND, not determined; NNH, number needed to treat to harm one patient; NNT, number needed to treat to achieve pain relief in one patient; SSRI, selective serotonin reuptable inhibitor.

deterioration in quality of life. Suddenly it may remit, without any plausible clinical explanation, often due to the complete atrophic change of the small unmyelinated fibers. Treatment. – In table 1 and table 2 there are the main treatment choices introduced according to the etiopahogenic theories. Intensive diabetes treatment in prevention of diabetic neuropathy. – In type 1 diabetes the role of intense and accurate control of the metabol-

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ic status is associated with a manifold reduction in the rate of the clinical symptoms of neuropathy, similarly with what happens for other microangiopathic complications such as retinopathy or nephropathy. It is interesting to note that the benefit of intensive therapy continues even after discontinuation of intensive therapy after the end of the trial data on type 2 diabetes are at variance since intensive therapy either had no effect or only partially slowed the progression of polyneuropathy.

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Treatment based on pathogenetic damage. – These drugs have (see Table I) been given with the aim of positively influencing the natural history of diabetic neuropathy designed to favourably influence the underlying neuropathic process rather than for symptomatic pain treatment. Among these drugs evidences exist on the possible positive action of or clinical use of α-lipoic acid, some aldose reductase inhibitors such as epalrestat and ranirestat. Not so promising seems the use of the protein kinase C β inhibitor ruboxistaurin. Finally C peptide infusion seems to give some advantages from the results of some studies. Symptomatic treatment of pain. – The symptomatic treatments are summarized in Table II. Any therapeutic scheme must take into consideration the clinical characteristics of the patient, remembering that these drugs are designed to ameliorate the pain, without influencing the clinical course of neuropathy. Antidepressants. – The use of antidepressant got estimators in the past, although no controlled trial has brought any clinical evidence of their usefulness in pain therapy. The problem is that they have a lot of adverse effects and that, eventually, only tricyclic antidepressant might have a role. However, their use is limited by relative high rates of adverse events and several contraindications. In this context, in fact, selective serotonin reuptake inhibitors have been found to be less effective than tricyclic antidepressants. Only recently dual selective inhibition of serotonin and norepinephrine such as duloxetine and venlafaxine have been found particularly effective in the therapy of diabetic neuropathy, at least in trials where they were compared with placebo. Other drugs. – Gabapentin, as well as other calcium channel or sodium channel blockers (among which some anticonvulsivants) have given alternate and non conclusive proofs of action in therapy of neuropathic pain. New perspectives. – The conclusion is that there is no entirely satisfactory pharmacotherapy of painful diabetic neuropathy, and therefore other non drugbased therapies have been attempted. Among these latter transcutaneous electrical nerve stimulation, or physical measures (e.g., cold water immersion) have been tried. The last news in this field come from high-frequency muscle stimulation or monochromatic infrared energy, both of which have significantly reduced neuropathic symptoms and signs in diabetic patients in uncontrolled Conclusions. – Our conclusions are that at the moment the therapy for diabetic neuropathy is in some way the ‘Cinderella’ of this disease. No active treatment has, indeed, been introduced with a ‘pathogenic’ approach, and therapy of pain is far from being completely satisfactory. Even with these shad-

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ows evidence has come that combination of drugs or the use of new drugs together with the older ones may lead to ameliorate the quality of life of these patients. References Shaw JE, Zimmet PZ, Gries FA, Ziegler D: Epidemiology of diabetic neuropathy. In Textbook of Diabetic Neuropathy. Gries FA, Cameron NE, Low PA, Ziegler D, Eds. Stuttgart, Thieme, 2003, p. 64-82. Daousi C, MacFarlane IA, Woodward A, Nurmikko TJ, Bundred PE, Benbow SJ: Chronic painful peripheral neuropathy in an urban community: a controlled comparison of people with and without diabetes Diabet Med 21:976-982, 2004. Galer BS, Gianas A, Jensen MP: Painful diabetic neuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Pract 47:123-128, 2000. Chan AW, MacFarlane IA, Bowsher DR, Wells JC, Bessex C, Griffiths K: Chronic pain in patients with diabetes mellitus: comparison with non-diabetic population. The Pain Clinic 3:147-159, 1990. Coppini DV, Bowtell PA, Weng C, Young PJ, Sönksen PH: Showing neuropathy is related to increased mortality in diabetic patients: a survival analysis using an accelerated failure time model J Clin Epidemiol 53:519-523, 2000. Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJM: Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care 21:1071-1075, 1998. Cameron NE, Eaton SE, Cotter MA, Tesfaye S: Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 44:1973-1988, 2001. Boulton AJM, Malik RA, Arezzo JC, Sosenko JM: Diabetic somatic neuropathies. Diabetes Care 27:1458-1486, 2004. Benbow SJ, Chan AW, Bowsher D, MacFarlane IA, Williams G: A prospective study of painful symptoms, small-fibre function and peripheral vascular disease in chronic painful diabetic neuropathy. Diabet Med. Martin CL, Albers J, Herman WH, Cleary P, Waberski B, Greene DA, Stevens MJ, Feldman EL, DCCT/EDIC Research Group: Neuropathy among the Diabetes Control and Complications Trial cohort 8 years after trial completion. Diabetes Care 29:340-344, 2006. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH: Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 118:289-305, 2005. Finnerup NB, Jensen TS: Mechanisms of disease: mechanism-based classification of neuropathic pain: a critical analysis. Nat Clin Pract Neurol 2:107-115, 2006. Jensen TS, Backonja MM, Hernandez Jimenez S, Tesfaye S, Valensi P, Ziegler D: New perspectives on the management of diabetic peripheral neuropathic pain. Diabetes Vasc Dis Res 3:108-19, 2006. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S: Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 116:109–118, 2005. Wernicke JF, Pritchett YL, D’Souza DN, Waninger A, Tran P, Iyengar S, Raskin J: A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 67:1411-1420, 2006. Ziegler D Treatment of diabetic neuropathy and neuropathic pain: how far have we come? Diabetes Care 31 Suppl 2:S255-61, 2008.

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Restless syndrome and Parkinson’s disease E. Unti, P. De Feo, R. Ceravolo Department of Neurology, University of Pisa, Pisa, Italy

Introduction. – Restless legs syndrome (RLS) is a very common disease, with a prevalence of 10% in all Caucasian populations. This pathology is clinically defined by the presence of (i) an urge to move the legs with or without an actual paraesthesia; (ii) a worsening of symptoms with inactivity; (iii) improvement with activity; and (iv) a worsening of symptoms in the evening and at night. Most people with RLS also have periodic limb movement during sleep, although this is not part of the clinical diagnostic criteria (Pankaj S. et al CNS Drugs 2008). RLS is a highly familial phenotype with heritability estimates between 40% and 60% depending on the method and population studied (Winkelmann J. Current Neurology and Neuroscience Reports 2008); five gene linkages have been identified to date, Deasautels et al (Desautels A. et al Am J Human Genet 2001) reported on the mapping of an RLS locus on the short arm of chromosome 12 in one family of French-speaking Canadians. A study of three-generation Italian family subsequently identified another locus on chromosome 14 (Bonati MT et al Brain 2003). However RLS can also be secondary to sisthemic conditions such as uremia, iron deficiency, pregnancy, and associated with a variety of medical conditions such as metabolic and hormonal alterations or neuropathy (Trenkwalder C. et al Lancet Neurol 2005). The pathophysiology of RLS is still not completely known; it has been suggested that central mechanisms are involved, hypothesis based on the action of drugs with CNS effects, such as dopaminergic agents, opioids and clonidine. Conversely, the use of dopamine D2 receptor antagonists that cross the blood-brain barrier exacerbates the symptoms of RLS, whereas exclusively peripherally-acting dopamine antagonists do not worsen symptoms (Pankaj S. et al CNS Drugs 2008). Functional magnetic resonance imaging investigations suggest activation of the brainstem and thalamus during RLS symptoms (Bucher SF. et al Ann Neurol 1997). Two recent studies have identified abnormalities in central somatosensory processing in patients with RLS (Schattschneider J. et al J neurol 2004; StiasnyKolster K. et al Brain 2004). In the first study, 16 patients with secondary RLS (72,5%) and 11 with primary RLS (55%) had pathological changes in temperature sensitivity, with sensory deficits likely linked to small-fibre neuropathy in secondary RLS and central process in primary RLS (Schattschneider J. et al J neurol 2004). In the second study, which examined pain sensitivity at baseline and after long-term treatment with levodopa in 11 patients with primary RLS,

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mechanical pain was increased in the arms (by a factor of 5.3) and legs (by a factor of 6.4) in RLS patients compared with controls (Stiasny-Kolster K. et al Brain 2004). This modulation of static mechanical hyperalgesia with long-term dopaminergic therapy suggests that RLS might be a disorder of pain modulation. Another possible mechanism may involve iron as suggested by the association of iron deficiency and RLS. Tarquini showed that iron levels exhibit circadian variations with reduced levels at night when the symptoms of RLS are more obvious (Tarquini B Chronobiologia 1978). An MRI study that measured regional brain iron levels revealed lower iron content in the substantia nigra of patients with RLS compared with healthy control subjects (Allen RP. et al Neurology 2001). Evidence from post-mortem studies has shown that tissue from RLS patients, compared with tissue from control, shows reductions in the substantia nigra in heavy-chain or H-ferritin (an indication of high iron utilization and low iron storage), an abnormal distribution of light-chain or L-ferritin (wich promotes cerebral iron storage) within the cells, and decreased transferrin receptor staining on cells containing neuromelanin (Connor JR. et al Neurology 2003). The exact interaction between CNS iron deficiency and dopaminergic dysfunction is not known but under investigation. Iron is necessary for the release of dopamine in the nerve synapse and can affect dopamine receptors (Zhao H. et al J Neurosci Res 2007). Diagnosis. – The diagnosis is based mainly on the patients’ history. Essential diagnostic criteria are urge to move the legs usually accompanied or caused by unpleasant sensation in legs that worsen during periods of rest or inactivity in particular at night and is partly or totally relieved by movement. Associated features may be: other family members affected, positive response to dopaminergic drugs, periodic limbs movement (referred by 85% of patients with RLS). Neurological examination, routine laboratory tests (including complete blood count, renal parameters, iron, ferritin and transferring levels) and electromiographic evaluation may be performed to rule out other causes for the symptoms and to identify signs of secondary RLS. Treatment. – The decision to initiate treatment is an individual one and is directed towards eliminate sleep disturbance, preventing fatigue or somnolence during the day trying to improve the ability of the patient to partecipate in work and leisure activity. In mild cases sometimes physical measures discovered by the patient such as moving legs or sensory stimuli could be sufficient in controlling the disturbance. Gold standard for moderate to severe RLS or cases of mild RLS not responding to non pharmacological measures are dopaminergic agents; first of all Levodopa per os assumed 1-2 hours before the onset

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of the symptoms. Dopamine receptor agonist in particular non ergot derivates such as ropinirole and pramipexole could be useful, best efficacy is reported when assumed 1-3 hours before the onset of symptoms. Possible adverse effects are similar for all dopaminergic drugs: nausea, diarrhoea, dyspepsia, orthostatic hypotension, muscle weakness, somnolence and headache. Other potential drugs are antiepilectics structurally related to GABA, such as gabapentin, which appear effective in patients with mild to moderate RLS symptoms who experience actual pain; benzodiazepines causing depression of CNS improve sleep and reduced arousal, useful in patients with mild or intermittent symptoms, in particular young individual. RLS and Parkinson’s disease: Sleep disturbance represent a common non motor complication of Parkinson’s disease (PD) and increase in frequency in advanced phases. The most common disturbances are those that involve nocturnal sleep and daytime manifestations such as excessive daytime sleepiness. Some sleep disorders, in particular REM sleep behaviour disorder (RBD) and excessive of daytime sleepiness (EDS) may present prior the motor signs. The correlation between restless legs syndrome and Parkinson’s disease is controversial and few studies revealed that the frequency of association of these two pathologies has been estimated as raging from 7.9 to 20.8 % (Ondo WG. et al Arch Neurol 2002). A study conducted by Esteban et al. (GòmezEsteban JC. Et al Mov Disord 2007) comprising 114 patients diagnosed with PD (59 men and 55 women) find out that 25 patients (21.9%) out of the total of patients diagnosed with PD met the RLS diagnostic criteria and only five out of these 25 patients reported a positive family history of RLS. Conclusion. – These findings, in agreement with those of Ondo et al, suggest an association between the two disorders. PD patients with or without RLS show differences in sleep quality evaluated with PDSS, but there is no increased incidence of diurnal hypersomnia. No clinical differences are registered between the two groups, except for the tendency to use more Levodopa in patients with PD and RLS. The diagnostic criteria actually used are not been established for PD patients, in fact some clinical features may be confounding for the presence of sleep

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disturbances in PD such as sleep fragmentation, akathisia, periodic limb movements, wearing off etc. On the basis of the association between the two pathologies we think that validated diagnostic criteria for RLS in the subgroup of PD should be developed. References Allen RP, Baker PB, Wehrl F, Song HK, Early CJ “MRI measurement of brain iron in patients with restless legs syndrome” Neurology 2001;56:263-5. Bonati MT, Ferini-Strambi L, Aridon P, Oldani A, Zucconi M, Casari G “ Autosomal dominant restless syndrome maps on chromosome 14q” Brain 2003;126:1485-92. Bucher SF, Seelas KC, Oertel WH, Reiser M, Trenkwalder C “Cerebral generators involved in the pathogenesis of restless syndrome” Ann Neurol 1997;41:639-45. Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RO, Ondo WG et al “Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome” Neurology 2004;62:1563-7. Desautels A, Turecki G, Montplaisir J, Sequeira A, Verner A, Ruoleau GA “Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q” Am J Human Genet 2001;57:1304-6. Gòmez-Esteban JC, Zarranz JJ, Tijero B, Velasco F, Barcena J, Rouco I et al “Restless legs syndrome in Parkinson’s disease” Mov Disord 2007;22:1912-1916. Ondo WG, Vuong KD, Jankovic J “Exploring the relationship between Parkinson disease and restless legs syndrome” Arch Neurol 2002;59:421-424. Pankaj S, Ondo WG “Restless legs syndrome: pathophysiology diagnosis and treatment” CNS Drugs 2008;22(6): 497-518. Schattschneider J, Bode A, Wasner G, Binder A, Deuschl A, Baron R “Idiopathic restless legs syndrome: abnormalities in central somatosensory processing” J Neurol 2004;251:977-82. Stasny-Kolster K, Magerl W, Oertel WH, Möller JC, Treede JC “Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome” Brain 2004;127:773-82. Tarquini B “Iron metabolism: clinical chronobiological aspects” Chronobiologia 1978;5:315-36. Trenkwalder C, Paulus W, Walters AS “The restless legs syndrome” Lancet Neurol 2005;4:465-475. Winkelmann J “Genetics of restless legs syndrome” Current Neurology and Neuroscience Reports 2008;8:211-216 Zhao H, Zhu W, Pan T, Xie A, Zhang A, Ondo WG et al “Spinal cord dopamine receptor expression and function in mice with 6-OHDA lesion of the A11 nucleus and dietary iron deprivation” J Neurosci Res 2007;85: 1065-76.

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BIOLOGIC DRUGS Use of biologic agents in rheumatoid arthritis L. Cantarini, F. Bellisai, M. Galeazzi Unit of Rheumatology, Department of Clinical Medicine and Immunologic Sciences, Policlinico Le Scotte, University of Siena, Siena, Italy

Rheumatoid arthritis (RA) is a systemic disease characterized by chronic inflammation of the synovial membrane joints damage and loss of the function. Substantial and irreversible joint damage already occurs within the first 2 years after disease onset. The current management of the disease includes the use of disease modifying anti-rheumatic drugs (DMARDs). Older DMARDs include methotrexate, sulphasalazine and hydroxychloroquine. Newer ones such as leflunomide and cyclosporine are also used. Progress in immunology has caused an increase in understanding the RA pathogenesis, resulting in new methods of treatment. Blocking of TNF-alpha, blocking interleukyn-1, or co-stimulation of CD28+ T-cells and depletion of CD20+ B-cells are all effective ways to diminish inflammation and joint damage. TNF-alpha antagonists interfere with the natural history of RA more effectively than traditional DMARD agents, including Methotrexate, and have a more rapid onset of action 1. The value of TNF-alpha antagonists in the management of RA is firmly established on experimental and clinical evidence. Inhibition of the inflammatory cytokine TNF is associated with significant improvement of signs and symptoms in most patient, and even with remission in some of them 2. TNF-alpha antagonists inhibit the further progression of radiological damage and significantly improve the quality of life, while preserving the functional status. Combining a TNF-alpha antagonist with methotrexate is today considered the gold standard in the treatment of RA 3; combining biologic therapies seems instead to increase risk without increasing benefits. Switching among TNF antagonists may solve problems of clinical failure or worsening response in many patients 4. The reduction in disability is long-term sustained 5. Anti TNF-alpha agents are immunogenic and can induce anti-drug antibodies production. The amount of anti-drug antibodies is higher for Infliximab and Adalimumab than for Etanercept and the antibodies to Etanercept do not affect its biological activity 6. Anakinra is an IL-1 receptor antagonist and it is administered as a daily subcutaneous injection; Ana-

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kinra has efficacy in treating RA when used alone or in combination with MTX 7. The TNF-alpha inhibitors have shown greater efficacy and they have a more convenient dosing regimen. However, it is a valuable drug in the treatment of some diseases such as adult Stillâ&#x20AC;&#x2122;s disease and systemic-onset juvenile idiopathic arthritis, where it works much better than the TNF-inhibitors 8, 9. Two new agents, with different mechanism of action, have been developed: Rituximab and Abatacept. They both have shown to be effective in patients who fail one or more TNF inhibitors. Rituximab is a monoclonal antibody directed against an antigen, CD20, on the surface of all B cells other than stem cells and pre-B lymphocytes. It does not affect plasma cells since they do not possess CD20 on their cell surface. Rituximab is a drug used for the treatment of lymphomas and it acts by binding to CD20 on B cells and causing cell lysis by both complement-dependent and antibody-dependent cell mediated cytotoxicity. Rituximab is associated with significant improvement of signs and symptoms in in RA patients who have failed conventional DMARDs and anti-TNF agents 10-11. Abatacept is a fusion protein linking the extracellular domain of human cytotoxic T-lymphocyteassociated antigen 4 (CTLA-4) to the Fc portion of human IgG1. It works by competing for the binding between CD28 on the T cell and CD80/86 on the antigenpresenting cell. This is an important co-stimulatory signal that is essential for T cell activation. Abatacept blocks T cell activation determining a reduction of the autoimmune process and a subsequent clinical improvement. The efficacy of abatacept has previously been demonstrated in patients with RA and an inadequate response to methotrexate (MTX) 12 and anti-tumor necrosis factor TNF agents 13. Regarding the safety profile, infections are serious potential side effects of any drug that modifies the immune response 4, however such infections only infrequently can be defined as serious and that happens mainly in patients who had received high cumulative doses of steroids or underwent joint surgery 15. For the anti-TNF agents, one particular infection that has to be looked for is tuberculosis (TB), and screening for TB before starting treatment is required. Anti-TNF agents also seems to increase the risk of lymphoma 16. The issue of whether treatment with anti-TNF agents poses a higher risk for solid malignancies remains unresolved.

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The early use of biologics has improved RA outcomes, but requires close monitoring of disease course and adverse events. References 01. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J M 2000;343:1586-93. 02. Weisman MH. Progress toward the cure of rheumatoid arthritis? The BeSt study. Arthritis Rheum 2005;52:3326-32. 03. Smolen JS, Van Der Heijde DM, St Clair EW, Emery P, Bathon JM, Keystone E et al. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum 2006;54:702-10. 04. Cohen G, Courvoisier N, Cohen JD, Zaltni S, Sany J, Combe B. The efficiency of switching from infliximab to etanercept and vice-versa in patients with rheumatoid arthritis. Clin Exp Rheumatol 2005;23:795-800. 05. Moreland LW, Weinblatt ME, Keystone EC, Kremer JM, Martin RW, Schiff MH et al. Etanercept treatment in adults with established rheumatoid arthritis: 7 years of clinical experience. J Rheumatol 2006;33:854-61. 06. de Vries MK, van der Horst-Bruinsma IE, Nurmohamed MT, Aarden LA, Stapel SO, Peters MJ et al. Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis (AS). Ann Rheum Dis 2008 [Epub ahead of print]. 07. Fleischmann RM, Schectman J, Bennett R, Handel ML, Burmester GR, Tesser J, et al. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra) in patients with rheumatoid arthritis: a large international, multicenter placebo-controlled trial. Arthritis Rheum 2003;48:927-34. 08. Fitzgerald AA, Leclerq SA, Yan A, Homik JE, Dinarello CA. Rapid responses to anakinra in patients with refractory adult-onset Still’s disease. Arthritis Rheum 2005;52: 1794-803. 09. Verbsky JW, White AJ. Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis. J Rheumatol 2004;31:2071-5. 10. Cohen SB, Greenwald M, Dougados MR, Emery P, Furie R, Shaw TM, et al. Efficacy and safety of rituximab in active RA patients who experienced an inadequate response to one or more anti-TNF alpha therapies. Arthritis Rheum 2005;52:1830. 11. Edwards JC, Szczepanski L, Szechinski J, FilipowiczSosnowska A, Emery P, Close DR, et al. Efficacy of Bcell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-81. 12. Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006;144:865-76. 13. Genovese M, Becker J-C, Schiff M, Luggen M, Sherrer Y, Kremer J, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005;353:1114-23. 14. Furst DE, Schiff MH, Fleishmann RM, Strand V, Birbara CA, Compagnone D, et al. Adalimumab, a fully human

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anti-tumour necrosis factor alpha-monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid arthritis). J Rheumatol 2003;30:2563-71. 15. Salliot C, Gossec L, Ruyssen-Witrand A, Luc M, Duclos M, Guignard S, Dougados M. Infections during tumour necrosis factor-alpha blocker therapy for rheumatic diseases in daily practice: a systematic retrospective study of 709 patients. Rheumatology 2007;46:327-34. 16. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295: 2275-85.

The role of immunological drugs in inflammatory bowel diseases G. Niccoli Gastroenerology Section, Second Internal Medicine, Spedali Riuniti, Livorno, Italy

Immunological drugs are generally used as a second step in the treatment of inflammatory intestinal diseases, when a more aggressive therapy is requested. Resistance and/or refractory to steroids is often a condition that leads to the shift of the therapy. In this area it is useful to distinguish these drugs in conventional and biologic agents. Conventional agent (Immunosuppressant). – Several studies show that azathioprine (AZA) and 6mercaptopurine (6-MP) are better than placebo for maintenance treatment. The main indications for the use of AZA in IBD are: 1) steroid sparing treatment; 2) maintenance of remission; 3) Crohn’s disease with fistulae and; 4) chronic active ulcerative colitis. The recommended dose for IBD is 1.5-2.5 mg/ kg/day for Azathioprine and 0.75-1.5 mg/kg/day for mercaptopurine. A low or absent activity of of the enzyme thiopurinemethyltranferase brings about hepatitis, bone marrow toxicity and pancreatitis, all reversible with drug suspension. This possibility needs a preliminary enzyme dosage and/or monitoring of blood tests. AZA and 6-MP are slow acting drugs and the optimum effect may only be expected after 12–17 weeks of treatment. Metotrexate (IM 25 mg weekly for up to 16 weeks followed by 15 mg weekly) has similar indications and is generally used in the forms of disease azathioprine/6-mercaptopurine resistant or in patients who can not tolerate thiopurines. Cyclosporine A is employed only as rescue therapy in refractory ulcerative colitis, as attempt to avoid surgery. Biologic agent. – In the latest years significant advances have been made in understanding the pathogenesis of inflammatory bowel diseases, particularly

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with the identification of the factors leading to the phlogosis. The advent of biologic drugs, through blockade some of these factors from monoclonal antibodies, has had a powerful impact on the approach to the management of these complex diseases. Biologic agents may have several targets: – proinflammatory cytochines (IL1 e TNF-alfa) – t cells activation – adhesion molecules – leukocytes recruitment Infliximab. – Infliximab is a murine chimeric monoclonal antibody against TNF-alpha. Given intravenously is capable to link to soluble and membranebound TNF-alfpha; induces in vitro complement activation. In Europe, infliximab is approved for: 1) induction and maintenance of remission in patients with moderate-to-severe Crohn’s disease unresponsive to conventional therapy; 2) inducing and maintaining Crohn’s fistula closure unresponsive to conventional therapy and drainage; 3) treatment of active ulcerative colitis from moderate to severe degree, in patients who are intolerant or have not responded adequately to conventional therapy, including corticosteroids and 6-MP and AZA. In adult patients with moderate-to-severe Crohn's disease unresponsive to conventional therapy, Infliximab (three infusions of 5 mg/kg at 0, 2, and 6 weeks) induces and maintains (infusion every 8 weeks) clinical response and remission, permits discontinuation of corticosteroids, and induces and maintains healing of the bowel. Treatment with IFX is relatively safe if used for appropriate indications. Infusion reactions are rare and respond to slowing the infusion rate or treatment with antihistamines, paracetamol, and sometimes corticosteroids. Active sepsis is an absolute contraindication, as this risks overwhelming septicaemia, while latent tuberculosis is a relative contraindication: to avoid reactivation of tuberculosis a specific pretreatment against mycobacterium is needed . IFX may exacerbate existing cardiac failure. The “top-down therapy” (infliximab is started prior to the initial dose of corticosteroids) is considered a new apporoch (not yet unanimously accepted) vs. the conventional “step-up therapy” (corticosteroids and immunomodulators are tried before infliximab). Only further experiences will answer to an important question: whether or not earlier and more aggressive therapy is going to be more effective. The use of Infliximab as a “bridge therapy” covers the latency in response to azathioprine. Since infliximab is a chimeric monoclonal antibody, immunogenicity (the development of “ATIs”, antibodies to infliximab) may occur, leading to loss of

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efficacy and acute and delayed infusion reactions that can limit treatment Adalimumab. – Adalimumab is a subcutaneously administered, recombinant, fully human, immunoglobulin G1 monoclonal antibody that binds with high affinity and specificity to human TNF. Is indicated for the treatment of severe Crohn's disease, with inadequate response to a complete therapeutic cycle based on corticosteroids and/or immunosuppressants, or in patients who are intolerant to such therapies or have medical contraindications to them. For induction therapy the dosage is 80-160 mg at week 0 and 80 mg after 2 weeks; then the dose of maintenance is 40 mg every second week. For induction treatment, Adalimumab should be administered in combination with corticosteroids. It can be given as monotherapy in case of intolerance to corticosteroids or where the treatment continued based on corticosteroids is inappropriate. As for Infliximab, Adalimumab is controindicated in sepsis and latent tuberculosis. Since it is a fully human antibody, Adalimumab may be less immunogenic in humans, with less development of antibody against the drug. Further studies are needed to fully evaluate the effectiveness of Adalimumab and its advantages over Infliximab. In the meantime many Groups use Adalimumab as a treatment for patients who were previously responsive to infliximab but after some time become refractory to or intolerant of it. Certolizumab Pegol. – Most recently, Certolizumab Pegol, a humanized anti-TNF Fab’ monoclonal antibody fragment linked to polyethylene glycol, has been introduced for the treatment of Crohn’s disease. Unlike other monoclonal antibodies, certolizumab does not contain an Fc fragment and therefore does not induce in vitro complement activation, antibodydependent cellular toxicity, or apoptosis. Certolizumab is indicated for reducing the signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy. Data from several trials should not be used to make direct comparisons with other anti-TNFalpha therapies, as they were designed to show efficacy over placebo and not other active therapies. However, Certolizumab appears to offer yet another therapeutic alternative in the ever-growing list of biologic agents for the treatment of Crohn’s disease. The recent American Gastroenterological Association (AGA) Institute Consensus Panel recommendations on the use of biologic therapy for the treatment of IBD1 suggested that the indications for Certolizumab therapy in Crohn's disease include: 1) induction of response and induction of remission in outpatient adults with moderate-to-severe Crohn's disease; 2) maintenance of response to certolizumab and maintenance of remission after certolizumab treatment; and 3) loss of response to infliximab.

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Natalizumab. – FDA has recently approved, after multiple sclerosis, a new indication for treating Crohn disease with natalizumab, alpha4 integrin-specific humanized monoclonal antibody. This is the first biologic drug not against TNF. Given by intravenous injection, is useful for inducing and maintaining clinical response and remission in adults with moderately to severely active Crohn’s disease (CD) with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and tumor necrosis factor-alpha (TNF-α) inhibitors. The clinical benefit of induction therapy with natalizumab in Crohn’s disease should be weighed against the potential risk of serious adverse events as PML (progressive multifocal leukoencephalopathy). Other biologic drugs: perspectives. – 1) CNTO 1275 (Ustekinumab): monoclonal antibody against interleukins IL-12 and IL-23. Good safety profile, useful in TNF antagonist resistence 2) Visulizumab: monoclonal antibody against CD3) CCX-282-B orally active inhibitor of chemokine receptor CCR9, which is expressed by mucosa-homing intestinal leukocytes. References 01. Clark M, Colombel JF, Feagan BC, et al. American Gastroenterological Association consensus development conference on the use of biologics in the treatment of inflammatory bowel disease. Gastroenterology. 2007;133: 312-339.

The Pisa center experience in DH: infusion reactions with biological drugs L. Bazzichi1, C. Giacomelli2, F. De Feo1, C. Ferrari1, A. Mammolo1, S. Bombardieri1 1Department

of Internal Medicine, Division of Rheumatology, University of Pisa, Italy; 2Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Pisa, Italy

Aim. – Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease usually characterized by the destruction of joints, functional disability, deterioration of the quality of life and shortened life expectancy. Tumor necrosis factor-alpha (TNF α) plays a key role in the pathogenesis of RA 1. The TNF-α antagonists now in clinical use are Etanercept (Wyeth Europe Ltd, Maidenhead, UK), Infliximab (Remicade, Centocor, Malvern, Pa, USA) and Adalimumab (Humira, Abbott, Abbott Park, Illinois, USA). These three compounds possess different biochemical characteristics and biological properties; they are different in terms of route and schedule of administration, half life, ability to fix complement and cytotoxicity. Etanercept is a fusion protein mimicking the TNF receptor p75, linked to the human IgG1 Fc. Infliximab and Adalimumab are monoclonal antibodies (chimeric the former, and fully human the latter) able to bind

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TNF α on the cell membrane as well as in the fluid phase 2. However the combination of anti TNF?? agent and MTX yields superior results for RA when compared with monotherapy, particularly with respect to excellent clinical responses (ACR 70, EULAR remission) and radiological outcomes 3-5. About 30% of patients with RA fail to achieve a marked clinical response to anti TNF α 6, furthermore these patients can be treated with two new biological agents: Rituximab and Abatacept. Rituximab, a chimeric monoclonal antibody, selectively depletes human CD20positive B cells 7. Rituximab depletes peripheral B cells, an action thought to reduce rheumatoid arthritis activity, and induces prolonged clinical improvement. Two 1000-mg infusions administered 2 weeks apart can result in a response that lasts for months. Most patients will require re-treatment, but the effect of repeated dosing on patient outcomes has not yet been determined 8. Combination therapy with MTX is recommended as this appears to achieve the best outcomes. Abatacept (Orencia, Bristol-Myers-Squibb, USA) is a humanized fusion protein composed of an immunoglobulin fused to the extracellular domain of CTLA-4, a molecule capable of binding B7, and is a selective costimulation modulator as it inhibits the costimulation of T cells. Sometimes Infliximab and Rituximab, chimeric molecules, provoke adverse events (AE) because they led to the formation of antibodies 9. For this reason Rituximab infusion are precede by a specific pre-medication, while the Infliximab infusion are precede by pre-medication only after physician’s decision. Grades of AE seriousness were as follows: mild, moderate, serious and life threatening. Mild reactions were defined as self-limiting and resolving after temporary stop/slowing of infusion. Moderate reactions were those that required closer attention, an extended observation period, and often the stop of the infusion. Serious reactions involved an infusion, respiratory symptoms/symptomatic blood pressure fall and need for close monitoring, often for a whole day and occasionally requiring ward referral. The aim of this work was to estimate the incidence of AE during the infusions and to evaluate the protocol for the treatment of infusion reactions. Methods. – We conducted a retrospective study on 368 consecutive patients treated with anti TNF α agents (138 patients were treated with Infliximab, 135 with Etanercept and 90 with Adalimumab), 21 treated with Rituximab and 5 with Abatacept, enrolled from 2002 to 2008 at the Division of Rheumatology, S. Chiara Hospital, Pisa. The above mentioned patients were affected by: 248 RA, 120 seronegative spondiloarthritis (SNSA). The adverse events and prophylaxis protocols were based on the type (i.e. acute or delayed) and severity of the reaction. The severity of the infusion reactions was assigned by the physician based on the patients’ signs and symptoms. However, the classification of the reaction severity was useful in terms of determining treatment. Intravenous (IV)

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access was established, and baseline vital signs were obtained before beginning the infusion, for the patients treated with Infliximab or Rituximab. The patients’ signs and symptoms were monitored every 30 min throughout the infusion. An emergency kit consisting of epinephrine, saline, oxygen, diphenhydramine, acetaminophen, methylprednisolone, and prednisone, an ambulatory bag and mask, and an emergency crash cart were made readily available. For mild acute reactions, the infusion rate was slowed, intramuscular (IM) chlorphenamine (10 mg) and per os (PO) acetaminophen (1000 mg) were administered, and vital signs were monitored every 10 min. After waiting for 20 min, the infusion rate was subsequently increased until tolerability levels. For initial moderate acute reactions, the infusion was stopped or slowed, IM chlorphenamine (10 mg) and PO acetaminophen (1000 mg), IV methylprednisolone 40-100 mg if the patient showed fine crackle were administered, and vital signs were monitored every 5 min. After 20 min, the infusion rate was restarted at a slow rate (10 ml/h) and subsequently increased as tolerated. For initial severe acute reactions, the infusion was stopped and normal saline infused. The airway was maintained and oxygen given, if available. Also, methylprednisolone 100 mg (if the patient showed fine crackle) (100 mg) or IV hydrocortisone (100 mg), followed by IM chlorphenamine (10 mg), and PO acetaminophen (1000 mg). Vital signs were monitored every 2 min. Epinephrine (0.1-0.5 ml, 1:1000) was given subcutaneously and could be repeated every 5 min for three doses. The prophylaxis protocol for the successive infusion for Infliximab consisted in pre-medication with IM chlorphenamine, methylprednisolone 20 mg or Hydrocortisone 100 mg IV and acetaminophen 1000 mg PO, 40 min before the infusion, and the administration rate was decreased. For Rituximab infusion all the patients received a specific pre-medication with chorphenamine 10 mg IM, methylprednisolne 100 mg IV and acetaminophen 1000 mg PO 30-40 min before the infusion. A delayed infusion reaction is defined as any adverse reaction that occurs from 24 h to 14 days after retreatment with Infliximab and Rituximab. Delayed infusion reactions, especially which Rituximab, generally present symptoms of arthralgia, myalgia, urticarial rash, fever, and malaise, are managed with corticosteroids (sickness syndrome). Results. – In 966 infusion/year with Infliximab in RA patients we observed 3.82 % infusion reaction, subdivided in 2.2% mild acute reaction, 1.23% moderate acute reaction and 0.4% severe acute reaction. In 720 infusion/year with Infliximab in SNSA patients we observed 1.85% infusion reaction, subdivided into 0.70% mild acute reaction, 0.93% moderate acute reaction and 0.21% severe acute reactions. 0.6% of RA

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patients and 0.98% of SNSA patients stopped the treatment with Infliximab because of infusion reactions. The adverse events usually occur after 6 infusions in RA and 8 in SNSA. In 21 RA patients treated with Rituximab, 13 were treated only one time, and 8 patients re-treated after 6-8 months. In 56 infusions with Rituximab we observed 1.8% moderate acute reaction and 1.8% delayed reaction. 9% of RA patients stopped the treatment with Rituximab because of infusion reactions. The adverse events usually occur after the first infusion. We performed only 12 infusions with Abatacept, and 8.33% RA patient showed a mild acute reaction (hypotension), so the therapy was not interrupted, and 1 patients interrupted the treatment because of worsening of RA symptoms. Conclusion. – Our results showed a low percentage of acute infusion reactions, especially the mild acute one. The pre-medication improve the percentage of acute infusion reaction. Moreover with a careful monitoring and a prompt assistance, especially performed by a trained nurse, all the acute infusion reactions can be controlled. References 01. Feldmann M, Maini RN: Anti-TNF therapy of rheumatoid arthritis: what have we learned? Ann Rev Immunol 2001; 19: 163-96. 02. Fiocco U, Bombardieri S: Differences in pharmacology of tumor necrosis factor (TNF) antagonists. Reumatismo 2005; 57 (Suppl. 1): 16-24. 03. Harriman G, Harper LK, Schaible TF: Summary of clinical trials in rheumatoid arthritis using Infliximab, an anti-TNF alpha treatment. Ann Rheum Dis 1999; 58 (Suppl. 1): I61-I64. 04. Klareskog L, Van Der HD, De Jager JP et al.: Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004; 363: 675-81. 05. Van De Putte LB, Atkins C, Malaise M et al.: Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis who have failed previous diseasemodifying antirheumatic drug therapy. Ann Rheum Dis 2004. 06. Criscione LG, St Clair EW. Tumor necrosis factor-alpha antagonists for the treatment of rheumatic diseases. Curr Opin Rheumatol 2002; 14: 204–11. 07. Shaw T, Quan J, Totoritis MC. B cell therapy for rheumatoid arthritis: the rituximab (anti-CD20) experience. Ann Rheum Dis 2003; 62 (Suppl 2): ii55–9. 08. Edwards JC, Szczepanski L, Szechinski J, FilipowiczSosnowska A, Emery P,Close DR, et al. Efficacy of Bcell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004; 350: 2572–81. 09. Cheifetz A, Smedley M, Martin S, Reiter M, Leone G, Mayer L, Plevy S. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol. 2003 Jun; 98 (6):1315-24.

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CARDIOVASCULAR DISEASE New issues in global cardiovascular protection C. Nozzoli, F. Pieralli Department of Emergency and Internal Medicine, Careggi General and University Hospital, Florence, Italy

The global cardiovascular risk concept. – In developed countries the progressive ageing of the population and the increasing possibilities of treatment of cardiovascular disease lead the global vascular burden on the rise. As more countries become developed and Westernized, deaths from infectious disease decline, certain vascular risk factors become more prevalent, and transitions to a greater preponderance of chronic vascular disease, such as hypertension, diabetes mellitus, coronary artery disease, peripheral vascular disease and stroke, become more apparent. We are facing a worldwide problem in terms of the future predicted global cardiovascular disease burden, and this is a major concern for public health with a big impact on social and economic resources. We now recognize that single vascular disorders (i.e.coronary artery disease, stroke, hypertension) have a variety of common links, including genetic predisposition and certain risk factors, and must be considered as a whole. The term “global cardiovascular risk” has a double significance: 1) “Global” because it implies a worldwide problem that encompasses multiple vascular outcomes; 2) “Global” because it implies a broad approach to cardiovascular disease management. One way of conceptualizing global vascular risk is through a pyramid (Figure 1). The top of the pyramid

Figure 1. – Determinants of global vascular risk.

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illustrates those who have clinically significant vascular disease, while the layers of vascular risk progress from the base upwards. At the base of the pyramid are those who are “at risk.” The wider base of the pyramid illustrates the greater global prevalence of those at risk, and as we progress upwards the risk of vascular disease increases. At the top, stroke, MI, peripheral arterial disease, and vascular death, which in 2002 accounted for 16.7 million deaths, are projected to account for 18.1 million deaths in 2010 in the world. At the base of the pyramid, we need to recognize the high global prevalence of vascular risk-inducing behaviors such as smoking, which is projected at 1.3 million, and physical inactivity at 60% to 85% of the population. As we move up a pyramid stage, hypertension is estimated to occur in 600 million, obesity in 300 million, and diabetes close to 150 million. Subclinical diseases, such as asymptomatic carotid stenosis, increased carotid intima-media thickness, silent cerebral infarcts are asymptomatic conditions before clinical disease becomes apparent that are often undetected by patients and physicians and pose a great opportunity for overt disease prevention 1. Another issue when we face with chronic disease in general and with cardiovascular disease in particular, is to consider the progression of disease over time to better understand the possibilities of disease care and prevention. As for all chronic diseases, the opportunities of treatment of cardiovascular diseases, reduce when the disease becomes clinically overt. Commonly used terms such as primordial, primary, secondary and tertiary prevention refer to different stages of potential, preclinical or clinically overt disease with different implication on disease management. Primordial prevention refers to a disease-free stage where prevention could be ideally accomplished with genetic investigation and modification and reducing the risk of developing a vascular risk factor modifying for example induction behaviours and promoting healthy lifestyle. Primary prevention deals with modification of risk factors to reduce the risk of clinically symptomatic disease. Unfortunately, clinicians more often intervene late in the progression of vascular disease when it is clinically overt and our efforts are addressed to reduce the risk of a recurrent event (secondary prevention) and to rehabilitation (tertiary prevention). At all stages, we need to be working on preventing the evolution or progression of disease, and shifting, as much as possible, our chronic disease curve to avoid the development of cardiovascular outcomes, such as MI, peripheral arterial disease, TIA, stroke, vascular cognitive impairment, and vascular death

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that represent different aspects of a same vascular disease process 2. The internal medicine specialists have a central role in the management of patients with established cardiovascular disease or at risk for, due to their “natural” imprinting to consider the patient as a whole with a global view to all disease processes. Old and new opportunities for global cardiovascular disease protection. – The pandemic of cardiometabolic disease raised new questions about prevention plans; there are global and selective approaches to prevent and treat cardiovascular diseases. From a public government standpoint, economic disincentive programs such as restrict smoking in public areas, as well as promote Mediterranean diet habits, increase physical activity programs, and educate the public about the benefits of a healthy lifestyle are potential mass approaches for global vascular risk prevention. From a clinician point of view, we usually get involved through the single patient risk approach. Our focus is on detecting those at the highest levels on the distribution of global vascular risk (middle and top of the pyramid), and trying to reduce risk through behaviour modifications and therapies. The contribution of medical societies is of great importance in promoting healthy styles of life, clinical trials and issuing guidelines and evidence-based recommendations for primary and secondary prevention of cardiovascular disease. Along with continuing medical education programs, these are tools for progressive learning and for spreading the best opportunities of cardiovascular disease treatment and prevention. As suggested earlier, the first step is to recommend a correct lifestyle to all patients with cardiometabolic disease in order to prevent and reduce vascular events and to reduce the need of drugs and strengthen the effects of pharmacological interventions. The beneficial effects of a healthy diet with low saturated fat intake, reach in vegetables and fruits are known since a long time. Physical activity has many beneficial effects on cardiovascular disease prevention as well as on coexisting comorbidities (i.e. osteoporosis, cognitive functional decline) in this elderly patients population 3-7. Recent advances have shown that an intensive pharmacological treatment for primary and secondary prevention, along with healthy lifestyle recommendations, determines particularly in high-risk patients a significant reduction in all major cardiovascular outcome measures. As well known, hypertension is a major risk factor for coronary artery disease, heart failure, stroke, and diabetes. Blood pressure goals have lowered over time and current guidelines recommend an individualized approach for the blood pressure goal, based on the global cardiovascular risk profile of the single patient. The various antihypertensive drug classes differ in their effects on cardiometabolic risk factors, with some being beneficial and others having neutral or even detrimental effects. Research has shown that suppression of the renin angiotensin

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system, with ACE-inhibitors and ARBs, can have clinical benefits beyond blood pressure lowering. Ancillary effects of the renin angiotensin system blockade with ACE inhibitors and ARBs are represented by the reduction of the incidence of new cases of diabetes, the renoprotective effects with reduction of proteinuria and preservation of renal function, as well as cardioprotective properties with preservation and amelioration of the ventricular function with reduction of the incidence of new cases of heart failure and atrial fibrillation 8-11. Renoprotective properties have been recently demonstrated with the use of a new antihypertensive class drug, the direct renin inhibitor aliskiren. Aliskiren in addition to standard therapy with losartan showed a superior efficacy in reducing proteinuria respect to losartan alone despite a similar reduction in blood pressure with both regimens in a population of hypertensive, type 2 diabetic individuals 12. Good news are coming from the use of rimonabant a Cannabinod1 receptor blocker on the persistent reduction of weight and improvement of the cardiovascular risk profile in obese diabetic and non diabetic patients, but more information is needed about the safety of this drug 13. The results of many trials on the efficacy of statin therapy have become milestones of the modern history of cardiovascular diseases. The effectiveness of statin therapy in the improvement of cardiovascular outcome beyond the amelioration of the lipid profile, has been fully demonstrated in a wide range of patient typologies in several clinical trials. Statins are a cornerstone therapy in the treatment of cardiometabolic diseases, and the intensity of treatment should be individualized on the single patient risk profile 14-15. Conclusions. – Many pharmacological and non pharmacological opportunities are now available to face the global cardiovascular protection mission. Patient management should now focus on global risk reduction rather than single risk factors control. The latest American and European guidelines on cardiovascular disease emphasize this treatment strategy. Health care professionals should promote a healthy style of life, with cardiovascular drug initiation, and choice of drug regimen individualized on the patient’s overall cardiovascular risk profile, internal medicine specialists should play a key role to accomplish this mission. References 01. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation. 2001;104:2746-2753. 02. Faxon DP, Fuster V, Libby P, et al. Atherosclerotic Vascular Disease Conference: Writing Group III: Pathophysiology. Circulation 2004;109:2617-2625. 03. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet. N Eng J Med 2001;344:3-10.

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04. GaedeP, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-393. 05. Schulze MB, Hoffmann K, Boeing H, et al. An accurate risk score based on anthropometric, dietary, and lifestyle factors to predict the development of type 2 diabetes. Diabetes Care 2007 Mar;30:510-5. 06. Knowler WC, Barret-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes mellitus with lifestyle intervention or metformin. N Eng J Med 2002;346:393403. 07. Mozaffarian D, Wilson PWF, Kannel WB. Beyond established and novel risk factors. Lifestyle risk factors for cardiovascular disease. Circulation 2008;117:3031-3038. 08. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients. N Eng J Med 2000; 342:145-153. 09. Yusuf S, Gerstein H, Hoogwerf B, et al. Ramipril and the development of diabetes. JAMA 2001;286:1882-1885. 10. Padwal R, Majumdar SR, Johnson JA, Varney J, McAlister FA. A systematic review of drug therapy to delay or prevent type 2 diabetes. Diabetes Care 2005;28:736-744. 11. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559. 12. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy. N Engl J Med 2008;358:2433-2446. 13. Christensen R, Bartels EM, Bliddal H et al. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 2007;370:1706-13. 14. MRC/BHF Heart Protection Study of cholesterol lowering, with simvastatin in 20,536 high-risk individuals: a randomised placebo controlled trial. Lancet 2002;360:722. 15. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. Stroke prevention by aggressive reduction in cholesterol levels (SPARCL) investigators. N Eng J Med 2006;355:549-559.

Hyperglycemia control in critically ill patient A. Lagi Dipartimento di Emergenza Urgenza – Ospedale S. Maria Nuova, Florence, Italy

Aim. – The acute diseases are frequently associated to increased glycaemia. Aim of the presentation was to introduce the argument and discuss the best way to control hyperglycaemia. Methods. – Study of literature. Results. – Hyperglicaemia is frequent, need to be treated to have a better outcome on mortality and morbidity Conclusion. – It is sure that hyperglicaemia over 180 mg/dl is related to outcome and that morbility and mortality are increased in patients. Any advantage has been demonstrated with early or very early control of hyperglycaemia so that there is not a critical cut-off time nor a time to treatment guideline.

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The acute diseases are frequently associated to increased glycaemia. The reports fix a different incidence according to the kind and grade of disease that the patient is suffering. Hyperglycaemia is present on 38% of emergency patients, on 36% of patients suffering from acute stroke and on 68% of patients staying in Intensive Care Unit (ICU) 1, 2. Hyperglycaemia is related to mortality at 30th and 180th day, to hospital and ICU stay, to number and severity of complications. Its pharmacological control and its reduction lower the complications of the principal disease, especially infective, the length and the cost of stay and, finally, hospital and extra hospital mortality. Patients recruited for interventional trials have different glycaemia: in Community Acquired Pneumonia (CAP) and in cardio - thoracic surgery 5% and 20% of patients respectively had glycaemia more than 200 mg/dl; in 75% of patients recovered in surgical ICU glycaemia was between 100 and 150 mg/dl. Some reports record glycaemia at arrival of patients in the hospital, some others regard glycaemia as mean value of a time period or as the higher value during the hospital stay. The conclusion is that we have not homogeneous data in the trials. We observed in the High Dependency unit (HDU) of Accident and Emergency Department of our Hospital, 182 consecutive cases of critically ill patients. Three glycemic intervals were evaluated: 100-140, 140180 and over 180 mg/dl: in these subjects hyperglycaemia was present at the arrival in 69% split in 30%, 18% and 21% respectively. The day after, at fast, the same subjects were revaluated: the percentage of distribution in the three intervals was 62%, 22% and 12% respectively. At the beginning of the studies on hyperglycaemia, it was related to worse outcome, mortality and complications. In the next year, from 1995 to 2003, different interventional trials demonstrated that the intensive therapy of hyperglycaemia changed the outcome at best. Intensive therapy was the infusion of insulin plus kalium per venam to have the target of glycaemia around 100 mg/dl. Conventional treatment was the subcutaneous supply of insulin to target around 140 mg/dl. The result of the trials was that patients on the intensive subgroup, suffering from Acute Myocardial Infarction (AMI) or recovering from surgical intervention, had reduction of mortality and infections. On these reports, it has been increased the idea that glycaemia itself, not only the metabolic profile of the patients, makes prognosis in short and long time. This makes the argument as appealing one. A concept has been imposed oneself, that hyperglicaemia itself is important to give the different outcome. This may be the consequence of intracellular derangement which hyperglicaemia causes. The control by insulin therapy is an advantage not only because insulin controls hyperglicaemia but by the metabolic input associated to insulin supply.

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Indeed, many significant data are now available which allow to tell that outcome is dependent from glycaemia control: the reports have been done in patients suffering from sepsis, AMI, AO Bypass and major surgical interventions. In 2004 American Association of Endocrinology made a statement which advices to have, as target, glycaemia between 80 and 110 mg/dl at fast and never over 180 mg/dl. Recently, in the years 2003-2008, many trials demonstrated the non-superiority of intensive vs standard treatment on target of mortality. There was difference on infections and length of hospital stay only 3, 4. Conclusion. – It is sure that hyperglicaemia over 180 mg/dl is related to outcome and that morbility and mortality are increased in patients suffering from stroke, coronary artery diseases and infections. Any advantage has been demonstrated with early or very early control of hyperglycaemia so that there is not a critical cut-off time nor a time to treatment guideline. The prudence ad the reason but not Evidence Based Medicine tells to begin treatment as soon as possible and to have target at value not over 140 mg/dl. The other side is that hypoglicaemia may be a dangerous effect. References 01. Kitabchi AE, Freire AX, Umpierrez GE. Evidence for strict inpatient blood glucose control: time to revise glycemic goals in hospitalized patients. Metabolism 2008. 02. Capes SE, Hunt D, Malmberg K et al. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001; 32(10):242632. 03. Van den Berghe G, Wilmer A, Hermans G, Meersseman W et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461. 04. The CREATE-ECLA Trial Group Investigators Effect of Glucose-Insulin-Potassium Infusion on Mortality in Patients With Acute ST-Segment Elevation Myocardial Infarction: The CREATE-ECLA Randomized Controlled Trial JAMA. 2005;293:437-446.

Anemia in chronic heart failure M. Cipriani, M. Alessandri, A. Montagnani, F. Rossi Unit of Internal Medicine, Misericordia Hospital, Local Health Unit 9, Grosseto, Italy

Epidemiology. – Anemia occurs commonly in patients with chronic heart failure (CHF). The prevalence of anemia in patients with low ejection fraction ranges widely from 4% to 61% (median 18%). Such a variability is partly attributable to use of inconsistent definitions of anemia in individual reports. Most studies indicate that the prevalence of anemia is increased in CHF populations with renal failure, advanced age, and more severe symptoms (30-61%) when compared with less symptomatic ambulatory population (4-23%).

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Patophisiology. – Anemia has convincingly been shown to be a powerful predictor of rehospitalization rates and survival in CHF. Most studies have shown a linear relationship between hematocrit (HCT) or hemoglobin (Hb) and survival. SOLVD 1 and PRAISE 2 trials reported an increase of death risk of 2.7% and 3% respectively as hematocrit decline of 1%. The clinical characteristics commonly associated with an increase of the risk of anemia in the population with CHF are: advanced age, female sex, chronic renal disease (CHD) (creatinin increase or the glomerular filtration rate reduction), low BMI, ACE-I use, increase of the central venous pressure, lower limbs edema , mellitus diabetes and arterial hypertension. The hemodinamic modifications associated with a severe anemia include increase of the pre-load, reduction of the peripheral vascular resistances and increase of the systolic range with a consequent increase of left ventricoular mass (LVM). Amond and his collegues 3, have found that an increase of 1 g/dl of Hb is associated to a reduction of the index of LVM of 4,1 g/m2 in a period of 24 weeks, whereas an increase of the LVM worst the prognosis of patients with CHF. The consequential observations from more studies suggest some separate mechanisms that can contribute to the anemia in patient with CHF. The CHD is a common comorbility in patients with CHF and many studies suggest it as a strong independent predictor factor of increased risk of anemia. The CHD is associated to a decreased production of eritropoietin (Epo) and to decrease of the Hb concentration with a linear relationship with reduction of the glomerular filtration rate. Although the anemia in patients with CHF is often classified as anemia associated to chronic disease, the martial deficit is present in less than 30% of the cases, therefore, it is mainly defined as normocitic anemia. Anemia is frequently associated to a BMI reduction and patients with cachexia are at high risk of development of anemia. A pro-inflammatory state has been observed both in patients with cachexia and with those with CHF. The Renina-Angiotnesina-Aldosterone system (RAAS system) plays a fundamental role in the normal regulation of the plasmatic and eritrocitary volume. The increase of the angiotnsina II expecially in the kidney alters the tension of O2, a regulatory factor of Epo secretion. The redoubt tension of O2 in the peritubular fibroblastis of the renal courtical is associated to an increase of the intracellular concentration of oxygen products, that increases the activation of the hypossia-induced factor-1 (HIF -1) and the expression of the eritropoietina gene expression. The Angiotesin II increase the secretion of Epo by the reducing renal blood flow and by increasing proximal tubular reabsorption; in addiction, the Angio-

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tensin II can directly stimulate the eritroid precursors in the bone marrow. On the other hand, the inhibition of renin-angiotnesin system (RAS) with ACE-I or with Angiotensin receptorial blockers (ARBs) is associated with a decrease of Epo synthesis and therefore of Hb concentration. More over ACE accelerates the catabolism of AcSDPK, a tetrapeptide inhibiting eritropoiesis. In the subjects with CHF anaemic treated with ACE-I the levels of Ac-SDKP are higher than in the CHF subject without anaema. In the clinical trials the pharmacological inhibition of the RAS causes a small but significant reduction of Hb levels. Anemia is frequently associated to clinical signs and symptoms of congestive CHF suggesting a process of emodiluition for an increase of the plasmatic volumes. This is an important issue since in such case the treatment with Epo could get worse the disease prognosis by increasing the total blood volume. A serious reduction of Hb (4-5 g/dl) is associated with retention of water and sodium, reduction of the blood renal flow and evidence of neuro-hormonal activation in absence of heart disease. The answer of the heart and kidney can be attributed to the effects of the severe anemia on the blood’s viscosity, tension of O2 on the microvascoular circulation and the availability of nitroxide. The lowest levels of anemia can contribute to the neuro-hormonal activation and to disease progression in patient with CHF. For instance in patient with beta talassemia the cardiac failure represents a frequent complication mediated by the emodinamic and neuro-hormonal effects of the severe and chronic anemia and by overload of iron due to frequent transfusions. An aggressive binding treatment reduces without eliminating the risk of CHF in these patients. The Hb is an important factor of transport of O2 to the skeletal muscles during the effort. Patient with CHF have a reduced reserves to compensate an eventual reduction of Hb levels and they can show a decrease of aerobic capacity in presence of moderate anemia. Many Authors reported the association between Hb reduction and increase of NYHA class. Many studies describes an inverse relationship between Hb or Htc decrease and left ventricoular hypertrophy in patient with CHD at last stages. In the studies that have assumed the Hb as a continuous variable, a diminution of 1 g/dl was independently associated to a significant increase of the risk of mortality. The clinical usefulness of hemotrasfusion in patient with CHF it is controversial. According with the guidelines of American College of Phisicians and of The American Society of Anesthesiology threshold of transfusion in subjects without risk factors known for cardiopathy is represented by a level of Hb ranges from 6 to 8 g/dl. However, on the basis of many studies, on the profiles of risk/benefit, the hemotrasfusion can be

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considered as an acute treatment for a severe anemia on an individual base, but it doesn't appear to be a practicable therapeutic strategy for the long term treatment of chronic anemia in CHF. Transfusion of blood is often associated to immunologic suppression with increase of the risk of infections, sensitization for HLA antigens, overloaded of iron. On the other hand the levels of Epo in patient with CHF are modestly raised, however in smaller way in comparison to those observable in the anaemic population. Accordingly the anemia of the sick of CHF can be responsive to the external administration of Epo. Therapy. – Actually 3 types of Epo, two type recombinant (rHuEpo) alpha and beta, and other the darbepoietina – alpha have been approved for anemia treatment. The first study reporting the use of the rHuEpo in patients with CHF in class NYHA III-IV and anemia (Hb <12 g/dl) was carried out by Silverberg and coll in the 2000 4. The Authors administered iron i.v. and Epo for 4-15 months. The Epo treatment allowed an increase of the Hb from 10,2 to 12,1 g/dl and was associated to an improvement of the functional class NYHA from 3.7 to 2.7 (p <0.05), to an increase of ejection fraction (28% to 35%, p <0.001) and to a reduction of furosemide titration. Successively they confirmed these data with a randomised trial with 8 months of follow-up. We should remember that the use of the eritropoietics agents is associated to an increase of the trombotic risk, even if in the various studies the thrombotics complications were not associated to an increase of the mortality. The chronic use of the rHuEpo can be associated to an increase of the levels of arterial pressure. Other rare collateral effects of HuEpo include epilepsy and marrow’s aplasia caused by antibody anti-Epo. The last guidelines about treatment of the CHF with anemia moderate-severe (Hb <11g/dl) and concomitant renal failure moderate - severe (glomerular filtration rate <60 mls/min) recommend the use of rHuEpo and supplement of oral iron up to obtaining the Hb target of 12 gs/dl. References 01. Konstam V, Salem D, Pouleur H, Kostis J, Gorkin L, Shumaker S et al. Baseline quality of life as a predictor of mortality and hospitalization in 5,025 patients with congestive heart failure. SOLVD Investigations. Studies of LeftVentricular Dysfunction Investigators. J Am Cardiol. 1996; 15:890-5. 2. Mozzafarian D, Nye R, Levy WC. Anemia predicts mortality in severe heart failure: the prospectiverandomized amlodipine survival evaluation. J Am Coll Cardiol. 2003;41: 1933-9. 3. Anand I, McMurray JJ, Whitmore J, Warren M, Pham A, McCamish MA et al. Anemia and its relationship to clinical outcome in heart failure. Circulation. 2004; 110:14954.

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4. Silveberg DS, Wexler D, Blum M, Karen G, Sheps D, Leibovitch E et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markelly reduces hospitalizations. J Am Coll Cardiol. 2000; 35:1737-44.

Beta-bloockers in chronic heart failure G. Pettinà, E. Arcangeli, A. Armento, B. Crovetti, L. Morosi UOC Medicina Interna 1, Ospedale di Pistoia, Pistoia, Italy

Chronic heart failure (HF) is a common clinical syndrome resulting from coronary artery disease (CAD), hypertension (HTN), valvular heart disease and cardiomyopathy. Approximately 40% of patients with HF have preserved systolic function (HF-PSF), often associated with HTN, CAD and/or atrial fibrillation: such patients are older and more frequently female 1. The American College of Cardiology/American Heart Association in 2001 released guidelines that described the 4 stages of HF. Beta-blockers (BB) should be considered in stage A (patients at high risk of developing HF : post myocardial infarction, angina, HTN) and in stage B (all patients with systolic dysfunction, regardless of its aetiology) 1. In patients with symptoms of HF (stage C) there is now conclusive evidence that BB, when added to ACE inhibitors (ACEI) substantially reduce mortality, decrease sudden death and improve symptoms . Patients with HF – PSF should also receive a BB if they have HTN; CAD, atrial fibrillation 1. Despite the overwhelming evidence and guidelines that mandate the use of BB in patients with HF and without contraindication, in the real world out of trials, many patients do not receive this treatment. Clinicians are familiar with the symptoms of HF (tachycardia, cutaneous vasoconstriction, diaphoresis and reduced urinary output) caused by increased adrenergic activity. Almost 40 years ago Eugene Braunwald reported 2 that in patients with HF plasma norepinephrine concentration were elevated, whereas cardiac stores of the neurotransmitter are reduced. In the short term adrenergic overstimulation have a positive effect: increase cardiac output by increasing heart rate and inotropism and the induced vasoconstriction helps to maintain the perfusion to vital organs 3. In short term the use of a BB sometimes causes a life-threatening worsening of HF 3. Human cardiac myocytes have 3 adrenergic receptors: beta 1 (b1), beta 2 (b2) and alfa1. In normal functional heart b1 + b2 are about 70% of total adrenergic receptors and the rate b1/b2 is 70 to 30 4. In the decompensate heart the rate b1/b2/alfa is 2/1/1 because of a downregulation of b1 and a overe-

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spession of alfa. Data from model system in animals incontrovertibly indicate that chronic adrenergic signalling is a harmful compensatory mechanism in the failing heart and causes apoptosys, hypertrophy and arrhythmias. In the end-stage failing heart , 50% to 60% of the total signal transducing potential of adrenergic receptors is lost, but substantial signalling capacity remains 4. These and other data from model systems suggest that b-adrenergic receptors pathway desensitization changes present in the failing heart are adaptive and that a potentially effective therapeutic strategy would be to add to this endogenous antiadrenergic effect a drug inducing beta receptors block. The initial experience with BB in HF was reported in 1975 by a Swedish Group 5 but were not accepted in the clinical ground because the initial transient negative inotropic effect and the attendant risk of decompensation probably caused by used starting doses. More than 20 years later, the first multicenter randomized trial with mwtoprolol was published (1993) and in 1997, after the study “US-Carvedilol” 6, FDA first approved a BB for the treatment of HF. Extensive information from many randomized trials are now available. The use of BB in HF class II-IV in addition to ACEI reduce total mortality, cardiovascular mortality, sudden death and death caused by progression of cardiac failure. Furthermore BB reduces hospitalization, improves left ventricular ejection fraction and functional class. BB share a common class effect but some pharmacological and clinical difference exists. Bisoprolol and Metoprolol are b1 selective; Carvedilol blocks b1, b2 and alfa receptors inducing a peripheral vasodilatation. Differences regard intrinsic sympathomimetic activity and lipophilicity. In the clinical setting, nebivolol significantly reduced the composite outcome of death or cardiovascular hospitalization in elderly patients across reduced and preserved ejection fractions (SENIORS) 7. Carvedilol reduced all-cause mortality more than Metoprolol in the COMET study 8. European Society of Cardiology Guidelines (www. escardio.org) recommend the use of BB, unless contraindicated , in all patients (in NYHA class II-IV) with HF from different aetiology added to standard treatment (class of recommendation I, level of evidence A). Only bisoprolol, carvedilol, metoprolol and nebivolol can be recommended (Class I, level A). Contraindications to the use of BB are: bronchial asthma, severe bronchial disease, bradycardia (<50/min), hypotension (<85 mmHg). Because their use may predispose to sodium accumulation, BB should not initiate if patients are fluid-overloaded. As BB action may be biphasic, the initial dose should be small and increased slowly and progressively to the target dose used in the trials. Up-titration should be individual. Furthermore analysis of the dose response effects in the MERIT and CIBIS II trials also showed mortality reduction in the lower

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dose groups 9, 10. If during the treatment there is a worsening of HF, ESC guidelines suggest to increase the dose of diuretics or ACEI and temporarily the dose of BB if necessary. In the clinical setting of the real world, out of trials, the life-saving therapy with BB continue to be underutilized. Only 37% of the 11304 patients of Euro Heart Failure Survey were treated with BB vs 62% and 87% assuming ACEI and diuretics (12). The authors of TEMISTOCLE 11 study reported that 8.7% and 17.8% of patients with HF discharged respectively from Internal Medicine or from Cardiology Units of General Hospital in Italy were treated with BB in 2001. A more recent survey of patients with HF discharged from Internal Medicine Units in Italy reports that a BB was prescribed to 30% (CONFINE: in press). Target doses of BB are strongly recommended but in the clinical practice are achieved in a minority of patients. An international survey (IMPROVEMENT) 12 report that 60% of patients are treated with full doses of bisoprolol, 50% with carvedilol and 45% with metoprolol. BB use is a life-saving therapy for patients with HF: more effort is needed to improve knowledge about their effects and to support their use at the target dose in the clinical practice. References 01. Hunt SA, Baker DW, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure: executive summary. J Am Coll Cardiol 2001;38:2101-2113. 02. Chidsey CA; Harrison DC; Braunwald E. Augmentation of the plasma epinephrine response to exercise in patients with congestive heart failure. N Engl J Med 1962; 267:650-4 03. Braumwald E. Expanding indication for beta-blokers in heart failure. N Engl J Med 2001;344:1711-12. 04. Bristow MR. Beta-adrenergic receptor blockade in chronic heart failure. Circulation 2000;101:558-69. 05. Waagstein F, Hjalmarson A; Varnauskas E , et al. Effect of chronic beta-adrenergic blockade in congestive cardiomyopathy. Br Heart J. 1975;37:1022-36. 06. Packer M, Bristow MR, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. US Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349-55. 7. Flather MD, Shibata MC, Coats AJ et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly with heart failure (SENIORS). Eur Heart J 2005;26:215-22. 08. Poole-Wilson PA, Swedberg K, Cleland JG et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with CHF in the Carvedilol Or Metoprolol European Trial (COMET): a randomized controlled trial. Lancet 2003;362:7-13. 09. Wikstrand J, Hjialmarson A, Waagstein F et al. Dose of metoprolol CR/XL and clinical outcomes in patients with heart frailure: analysis of the experience in metoprolol randomized intervention trial in CHF (MERIT-HF). J Am Coll Cardiol 2002;40:491-98.

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10. Simon T, Mary-Krause M, Funck-Breantano C el al. Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in cardiac insufficiency bisoprolol study (CIBIS-II). Eur Heart J 2003; 24:552-59. 11. DiLenarda A, Scherillo M, Maggioni AP et al. Current presentation and management of heart failure in cardiology and internal medicine hospital units: a tale of two worldsthe TEMISTOCLE study. Am Heart J 2003 Oct; 146 (4):E12. 12. Cleland JGF, Cohen-Solal A, Cosin Aguilar J et al. Management of heart failure in primary care (the IMPROVEMENT of heart failure Programme): an international survey. The Lancet 2002;360:1631-39.

Direct renin inhibitor: focus on Aliskiren. Recent acquisitions and future perspectives G.M. Forteleoni1, M.Bardazzi2, M. Alessandri1, M. Cipriani1 1Unit of Internal Medicine, Misericordia Hospital, Local Health Unit 9, Grosseto; 2Medical Department, Novartis Farma, Italy

Background. – Since renin is the initial and ratelimiting substance of the RAAS, it’s been considered rational for a long time to interfere with it, but suitable agents with the required combination of high affinity for renin’s active site and sufficient bioavailability to permit chronic oral administration once daily, good tolerability and acceptable cost of production have been very hard to get. By producing more complete RAAS inhibition than with existing agents, direct renin inhibitors may afford greater protection from hypertensive complications on target organs (heart, kidney and others). Methods. – We review briefly the pharmacology, pharmacokinetics, efficacy, safety, and drug interactions of aliskiren for the treatment of mild-to-moderate hypertension and first evidences in end organ protection. Main pharmacological properties of Aliskiren. – Aliskiren is an orally-active, nonpeptidic, direct inhibitor of renin, the enzyme involved in the initial and rate-limiting step in the RAS cascade that results in angiotensin II production. Aliskiren reduces plasma renin activity (PRA), despite stimulating dose-dependent increases in plasma renin levels. In comparison, ACE inhibitors and angiotensin II receptor antagonists increase both PRA and renin levels. Following oral administration, aliskiren undergoes minimal metabolism and is mainly eliminated as unchanged (mostly unabsorbed) compound in the faeces Effects on blood pressure in monotherapy. – Aliskiren once daily provides persistent and smooth 24-hour BP reduction and demonstrates >24-hour blood pressure control, with a trough-to-peak ratio of 98% with the 300 mg dose 1. Aliskiren demonstrates antihypertensive efficacy in patients with obesity, dia-

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betes, impaired renal function and metabolic syndrome and regardless of age or gender Even during the early morning BP surge, aliskiren maintains sustained BP reductions. Aliskiren went through an extensive clinical evaluation in pivotal trials. A pooled analysis conducted on data from eight randomized, double-blind, multicentre trials with aliskiren monotherapy studies showed dose dependent efficacy versus placebo. The pooled studies included 8,481 patients with mild-to-moderate hypertension who received treatment with aliskiren monotherapy or placebo for 8-12 weeks. The effects of aliskiren 150 and 300 mg on mean sitting diastolic blood pressure (DBP) and mean sitting systolic BP (SBP) were compared with placebo for the overall pooled population. Once-daily treatment with aliskiren 150 and 300 mg provided dose-dependent reductions from baseline in DBP and SBP, which were significantly greater than the reductions provided by placebo. Aliskiren 150 mg is the recommended starting dose. Titration to 300 mg may provide additional benefit. Recently a double-blind, dose-titration study, in 842 patients with mild-to-moderate essential hypertension was published. Patients were randomized to receive aliskiren 150 mg once daily (od) or ramipril 5 mg od for 6 weeks after a 2-4-week placebo run-in period. Optional dose titration to aliskiren 300 mg or ramipril 10 mg was available at Week 6 if required for patients not achieving the goal BP of <140/90 mmHg. For those patients not achieving BP goal at Week 12, hydrochlorothiazide (HCTZ) was added for the remainder of the study at a starting dose 12.5 mg, with optional increase to 25 mg from Week 19 if required. After 6 weeks of treatment, aliskiren 150 mg provided significantly greater reductions in mean sitting systolic blood pressure (MSSBP) compared with ramipril 5 mg. Reductions in MSDBP were similar with aliskiren 150 mg and ramipril 5 mg at Week 6. At the Week 12 endpoint, reductions in both MSDBP and MSSBP were significantly greater with aliskiren monotherapy (150 or 300 mg) compared with ramipril monotherapy (5 or 10 mg). Another direct comparison was performed in a long-term, double-blind, randomized, active-controlled study comparing aliskiren with HCTZ in 1124 patients with mild-to-moderate hypertension. After a 2-4-week placebo run-in, patients were randomized to aliskiren 150 mg, HCTZ 12.5 mg or placebo. After 3 weeks, patients were force-titrated to aliskiren 300 mg or HCTZ 25 mg, and after a further 3 weeks patients in the placebo group were re-randomized to aliskiren 300 mg or HCTZ 25 mg. After a further 6 weeks, patients who had not achieved the BP target of <140/90 mmHg had amlodipine 5 mg added to their study treatment. If patients were not at BP target 6 weeks later, the dose of amlodipine was increased to 10 mg. Treatment continued for the remaining 34 weeks of the study (study duration 52 weeks in total).

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After 12 weeks of treatment, aliskiren 300 mg provided significantly greater BP reductions from baseline compared with HCTZ 25 mg (reduction in MSDBP: 17.4/12.2 mmHg with aliskiren vs 14.7/10.3 mmHg with HCTZ). Effects of aliskiren on blood pressure in combination therapy. – Study 2204: In this doubleblind factorial trial, hypertensive patients with DBP >95 mmHg and <110 mmHg were randomized to HCTZ 6.25-25 mg od or aliskiren 75-300 mg od, alone or in combination, for 8 weeks. The mean reduction in SBP with aliskiren 300 mg was -15.7 mmHg, and with placebo was -7.5 mmHg. Study 2307: In this double-blind trial, hypertensive patients (DBP>95 mmHg and <110 mmHg) with diabetes were randomized to ramipril 5 mg od, aliskiren 150 mg od, or ramipril 5 mg od + aliskiren 150 mg od. After 4 weeks, doses were doubled. Patients were treated for an additional 4 weeks. The mean reduction in SBP with aliskiren 300 mg was 14.7 mmHg. Study 2305: This was a non-responder, 6-week comparison of aliskiren 150 mg + amlodipine 5 mg vs amlodipine 10 mg in patients not controlled by amlodipine 5 mg. Study 2327: In this double-blind trial, hypertensive patients were randomized to placebo, aliskiren 150 mg od, valsartan 160 mg, or aliskiren/valsartan 150/160 mg for 4 weeks and then force-titrated to 300 mg, 320 mg, and 300/320 mg, respectively. End organ protection program: THE ASPIRE HIGHER PROGRAM. – It’s the largest ongoing clinical trials programme in the cardio-renal disease area, involving more than 35,000 patients across 14 randomized, double-blind trials. This programme is evaluating the potential organ protection and clinical outcomes benefits of direct renin inhibition with aliskiren beyond that provided by angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). We summarize the key findings of two studies from this programme recently published. Avoid study. – Published on june 5th, it evaluated the renoprotective effects of dual blockade of the RAAS by adding treatment with aliskiren, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. 599 patients were enrolled in this multinational, randomized, double-blind study 2. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months.

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Results. – The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo. A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower and diastolic, 1 mm Hg lower in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups. Conclusion. – Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. Aloft study. – This study evaluated the effects of adding aliskiren to an ACE-I in patients with heart failure. Patients with class II to IV heart failure, current or past history of hypertension, and plasma brain natriuretic peptide (BNP) concentration _100 pg/mL who had been treated with an ACE-I (or ARBs) were ran-

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domized to 3 months of treatment with placebo (n_146) or aliskiren 150 mg/d (n_156). The primary efficacy outcome was the between-treatment difference in N-terminal pro-BNP (NT-proBNP). Patients’ mean age was 68 years, mean ejection fraction was 31%, and mean SBP was 129_17.4 mm Hg. Sixty-two percent of the patients were in functional class II, and 33% were taking an aldosterone antagonist. Plasma NT-proBNP rose by 762_6123 pg/mL with placebo and fell by 244_2025 pg/mL with aliskiren. BNP and urinary (but not plasma) aldosterone were also reduced by aliskiren. Clinically important differences in blood pressure and biochemistry were not seen between aliskiren and placebo. In conclusions addition of aliskiren to an ACE-I (or ARBs) and Beta blocker had favorable neurohumoral effects in heart failure and appeared to be well tolerated. References 01. Frampton JE, Curran MP. Aliskiren: a review of its use in the management of hypertension. Drugs. 2007; 67: 1767-92. 02. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK; AVOID Study Investigators. Aliskirencombined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008; 358:2503-5.

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BONE METABOLISM The clinical risk in osteoporosis A. Montagnani1, S. Gonnelli2, M. Cipriani1, R. Nuti2 1Internal

Medicine, ASL 9, Grosseto, Italy; 2Department of Internal Medicine, Endocrine-Metabolic Science and Biochemistry, University of Siena, Siena, Italy

The increasing prevalence and awareness of osteoporosis, together with the development of treatments of proven efficacy, will increase the demand for the management of patients with osteoporosis. This in turn will require widespread facilities for the assessment of osteoporosis. The clinical risk in patients affected by osteoporosis is the fractures which are causes of important morbidity and mortality. For this reason attention has focussed on the identification of patients at high risk of fracture rather than the only identification of men and women with osteoporosis. Common sites for osteoporotic fracture are the spine, hip, distal forearm and proximal humerus. The remaining lifetime probability in women at the menopause of a fracture at any one of these sites exceeds that of breast cancer (approximately 12%), and the likelihood of a fracture at any of these sites is 40% or more in developed countries 1. Osteoporotic fractures also occur at many other sites including the pelvis, ribs, and distal femur and tibia. Collectively, all osteoporotic fractures account for 2.7 million fractures in men and women in Europe at a direct cost of 36 billion Euros 2. It is widely recognised that osteoporosis and the consequent fractures are associated with increased mortality, with the exception of forearm fractures 3. In the case of hip fracture, most deaths occur in the first 3-6 months following the event, of which 20-30% is causally related to the fracture event itself. Osteoporosis is defined according World Health Organization (WHO) criteria on the basis bone mineral density values 4. However, although bone mass is an important component of the risk of fracture, other abnormalities occur in the skeleton that contribute to fragility. Therefore, accurate assessment of fracture risk should ideally take into account other indices of fracture risk that add information to that provided by bone mineral density (BMD). Age, sex, body mass index (BMI), prior fracture or history of hip fracture, smoking, glucocorticoids use, alcohol consumption and secondary causes of osteoporosis are the most important factors which should be considered in clinical risk evaluation in osteoporotic patients. For any BMD, fracture risk is much higher in the elderly than in the young 5, in fact, age contributes to

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risk independently of BMD. A Swedish study reported that at the threshold for osteoporosis (T-score = -2.5 SD), the probability of hip fracture ranges from 1.4 to 10.5% in men and women, respectively 6. A low BMI is a significant risk factor for hip fracture. The risk is nearly two-fold increased comparing individuals with a BMI of 25 kg/m2 and 20 kg/m2. However, the value of BMI in predicting fractures is very much diminished when adjusted for BMD 7. Many studies indicate that a history of fragility fracture is an important risk factor for further fracture 8. Fracture risk is approximately doubled in the presence of a prior fracture. The increase in risk is even more marked for a vertebral fracture following a previous spine fracture. In general, adjustment for BMD decreases the relative risk by 10-20%. A family history of fragility fractures is a significant risk factor that is largely independent of BMD 9. In addition, the family history of hip fracture is a stronger risk factor than a family history of other osteoporotic fractures and is independent of BMD. Cigarette smoking is an other risk factor that is in part dependent on BMD 10. Glucocorticoids are an important cause of osteoporosis and fractures 11. The fracture risk conferred by the use of glucocorticoids is, however, only partly dependent on bone loss 12. The relationship between alcohol intake and fracture risk is dose-dependent. Intakes of 3 or more units daily are associated with a dose-dependent increase in risk 13. Finally, there are many secondary causes of osteoporosis associated with an increase in fracture risk (e.g. inflammatory bowel disease, endocrine disorders), but it is uncertain to what extent the high fracture risk is dependent on low BMD or other risk factors (e.g. the use of glucocorticoids). By contrast, rheumatoid arthritis causes a fracture risk independently of BMD and the use of glucocorticoids 12. To date, treatment of osteoporosis has largely been directed at women with clinical risk factors determined by BMD. The finding that the presence of clinical risk factors and age modulates risk, suggests that in order to be cost-effective the therapy threshold should be depends on fracture probability, rather than on a single BMD. The use of clinical risk factors in conjunction with BMD and age improves sensitivity of fracture prediction without adverse effects on specificity. Although the use of relative risks is feasible, the absolute risk of fracture seems to be more suitable for clinicians.

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Both International Osteoporosis Foundation (IOF) and the WHO recommend that risk of fracture should be expressed as a short-term absolute risk, namely, as the probability of fracture over a 10-year interval. On the basis of risk factors the patients should be stratified in low, high and intermediate risk patients. The first group will not need of any further investigation, the second group could be treated without BMD measurement if this does not influence the therapy management. Finally, the patients of the last group should undergo BMD exam in order to classify better the absolute risk. Another important issue in osteoporosis field is the identification of intervention threshold. To such purpose some parameters result fundamental. Quality adjusted life-years (QALYs) and similarly, disabilityadjusted life-years (DALYs) are the accepted units of measurement in health economic assessment of interventions using cost-utility analysis 14. Cost-effectiveness improved at any age with increasing fracture probability, because of the higher risk of fracture and thus the greater number of fractures avoided. A recent study showed that the treatment of osteoporosis in high risk population had a similar cost per QALY gained with respect to diuretic and statin therapy, two amongst the cheapest therapies of hypertension and hypercholesterolemia, respectively 15. However, the ability to assess fracture probability in individuals rather than in populations pose new challenge for the health economic evaluation of interventions remains the future challenge in osteoporosis research.

09. Kanis JA, Johansson H, Oden A, Johnell O, De Laet C, Eisman JA et al A family history of fracture and fracture risk: a meta-analysis. Bone 2004;35:1029-1037. 10. Kanis JA, Johnell O, Oden A, Johansson H, De Laet C, Eisman JA et al Smoking and fracture risk: a meta-analysis. Osteoporos Int 2006;16:155-162. 11. Van Staa TP, Leufkens HGM, Cooper C The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 2002;13:777-787. 12. Kanis JA, Johansson H, Oden A, Johnell O, de Laet C, Melton III LJ et al A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 2000;19:893–899 13. Kanis JA, Johansson H, Johnell O, Oden A, De Laet C, Eisman JA et al Alcohol intake as a risk factor for fracture. Osteoporos Int 2005;16:737-742. 14. Murray CJL, Lopez AP Global and regional descriptive epidemiology of disability. Incidence, prevalence, health expectancies and years lived with disability. In: Murray CJL, Lopez AD (eds) The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Cambridge University Press, Cambridge;1996. pp 201-246. 15. Zethraeus N, Ström O, Borgström F, Kanis JA, Jönsson B The cost-effectiveness of the treatment of osteoporosis, hypertension and hyperlipidaemia in Sweden. Osteoporos Int 2007;18:9-23.

References

Aim. – In humans, the bone remodelling process consists basically of two phases, reabsorption and “reparative” apposition of new bone tissue. These two processes have a greater intensity in humans than in other mammals and, differently than in other animals, their rate increases with advancing age. Every year 25% of trabecular bone and 3% of cortical bone is estimated to be renewed. This remodelling results by the action of a large series of systemic and local factors, with an important genetic and familial component. During the early decades of life the balance of the remodelling process is positive, and consequently bone mass increases; it follows a period of stable equilibrium between reabsorption and apposition and eventually their balance becomes physiologically negative with a loss of bone mass. Osteoporosis is an acceleration of this physiologic process, that independently of the origin, produces microstructural changes and increases bone fragility and fracture risk 1. Methods. – Several techniques are used to study bone tissue remodelling and to measure bone mass decrease (osteopenia/osteoporosis). These techniques are based on imaging procedures and on biochemical tests. The clinical diagnosis of osteoporosis is done

01. Consensus Development Conference Diagnosis, prophylaxis and treatment of osteoporosis. Am J Med 1993;94: 646-650. 02. Kanis JA, Johnell O, Oden A, Sembo I, Redlund-Johnell I, Dawson A et al Long-term risk of osteoporotic fracture in Malmo. Osteoporos Int 2000;11:669-674. 03. Kanis JA, Johnell O, on behalf of the Committee of Scientific Advisors of the International Osteoporosis Foundation Requirements for DXA for the management of osteoporosis in Europe. Osteoporos Int 2005;16:220-238. 04. Cooper C, Atkinson EJ, Jacobsen SJ, O’Fallon WM, Melton LJ A population based study of survival after osteoporotic fractures. Am J Epidemiol 1993;137:1001-1005. 05. Hui SL, Slemenda CW, Johnston CC (1988) Age and bone mass as predictors of fracture in a prospective study. J Clin Invest 81:1804–1809 06. Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jonsson B Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int 2001;12:989-995. 07. De Laet C, Kanis JA, Oden A, Johanson H, Johnell O, Delmas P et al Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int 2005;16:13301338. 08. Klotzbuecher CM, Ross PD, Landsman PB, Abbot TA, Berger M Patients with prior fractures have increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res 2000;15:721-727.

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In vivo and in vitro assessment of bone metabolism N. Mazzucai Nuclear Medicine Unit, Department of Medicina dei Servizi, Misericordia Hospital, ASL 9, Grosseto, Italy

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in an overt phase of the disease when bone fractures are manifest. Therefore diagnostic techniques able to diagnose the disease before the clinical symptom, are urgently needed to start with an adequate secondary prevention treatment. Several instrumental techniques are used to diagnose osteoporosis. 1) Histomorphometry is performed on bone specimens. This technique investigates disease pathogenesis and bone turnover rate. Unfortunately is site-specific and invasive. Therefore histomorphometry cannot be routinely used, and it is confined to research field, as it is also the case of calcium kinetics studies. 2) Radiology is not useful apart confirmation of bone fracture. 3) Bone densitometry (BD) is the most frequently used for its reliability in measuring bone mineral content and bone mass. BD affords an early preclinical diagnosis of osteoporosis and detects osteopenic subjects at risk for developing osteoporosis. Double Xray Absorption (DXA) is the BD method currently used. It is based on the use of a cathode-ray tube. Xray radiation dose to the patient is very low radioprotection care is not required 2. In spite of being DXA the gold standard for the diagnosis of osteoporosis, it has limitations of reliability, which must be considered in its clinical use. First, DXA measure of mineral bone content is expressed in surface units (mg/cm2) and not in volume units: as a consequence the thickness of the bone segment under examination participates in determining the final bone content value. A second important point is that DXA cannot distinguish between cortical and trabecular bone: in consequence different pathological processes of these two bone components cannot be distinguished with DXA examination. Recently quantitative ultrasonographic (QUS) densitometry techniques have been implemented. They make use of ultrasound waves to evaluate some bone parameters, like bone channels width, bone elasticity etc. QUS are heterogeneous techniques not yet fully standardized and validated 3, but their capability of evaluating the risk of femoral fracture has been already demonstrated and prospectively QUS may become a valid alternative to DXA. Another radiological technique to evaluate bone mineral content is Quantitative Computerized Tomography (QCT). It makes use of a X-ray tomograph with a dedicated software. This technique allows to differently evaluate trabecular and cortical bone given the 3D- view of the bone segment under examination and in consequence it affords a measure of real bone density (g/cm3). Anyway this technique is expensive, less accurate that DXA and involves a dosimetric exposition for the patient. In 1994 WHO defined that diagnosis and classification of osteopenia/osteoporosis are done measuring with DXA bone density of lumbar vertebrae, femoral and radial bones which are the skeletal segments most

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frequently and significantly involved by the disease. In particular, lumbar vertebrae are the sites electively affected by the disease in young patients for the rich trabecular component of vertebral bodies which is affected by a stronger remodelling process. Instead, after 65 years of age, DXA examination is preferentially performed on the femoral bone because at vertebral level the reliability of DXA measurement is affected by the presence of bone degenerative processes and soft tissue calcifications. The parameter used to diagnose the disease is the T-score that is the number of standard deviations (SDs) of patient’s BMD below the average BMD for a young adult at peak bone density (usually a 30 y old premenopausal woman). Briefly, T-score evaluates patients’ BMD in absolute terms, independently of an age compensation and with that the absolute risk of bone fracture. According to WHO, a subject is normal when its T-score is better than -1; the patient is osteopenic when his T-score is between -1 and -2.5; and he is osteoporotic when his T-score is below -2.5. Whenever a T-score value is below -2.5 and there are single or multiple fractures associated the patients is defined seriously osteoporotic. Z-score is another parameter currently used. Z-score is the number of SDs of patient’s BMD below the average BMD of a reference population of the same gender and age. Briefly Z-score informs about deviation of the patient from his expected BMD value. As regard biochemical analyses, the first level investigations performed usually after the instrumental detection of an osteoporosis are: – ESR (erythrocyte sedimentation rate), hemogram (complete blood count), alkaline phosphatase (ALP), serum protein electrophoresis, creatinine serum, calcium (better in the ionized form), calcium (24 hr urine) (the collection of an urine sample in the morning, in fasting state, after first voiding, is considered an accurate method to calculate calcium/creatinine ratio), inorganic phosphorus, liver panel. If the above parameters are in the normal value range, a secondary osteoporosis can be ruled out without second level diagnostic tests, which are instead mandatory whenever the primary level tests are abnormal or the patient is a male or a pre-menopausal woman and the Z-score is <-2SD. In these cases it is useful to perform the following second level tests: – calcium ionized (if lacked), parathyroid hormone, 25(OH)2-vitamin D3, autoantibodies anti-transglutaminase, cortisol (24 hr urine), thyroid panel, Testosterone/LH (in male), gonadotropins, prolactin, bone metabolism markers. Bone metabolism markers are specific biochemical markers that reflect bone osteoblastic/osteoclastic activity and give a reliable insight of the bone remodelling rate. These markers are predictive of the fracture risk and they begin to change 2-3 months after the onset of an effective treatment 4.

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Bone markers are generated in the remodelling process of the skeleton, especially of its trabecular component. Under the action of the circulating concentrations of PTH, T4, GH, estrogens and the production of growth factors (IL-1,IL-6,IGF-1) the osteoblasts of bone surface initiate the osteo-synthetic process. On the one hand, mature osteoblasts synthesize several bone-specific proteins (osteocalcina, fosfatasi alcalina-isoenzima osseo, collagene di tipo I) which can be detected in the blood stream and represent biochemical markers of bone remodelling (BRBM). On the other hand, activated osteoclasts produce proteases which metabolize the collagen substrate of bone mineral matrix. The end products of this process too can enter into the blood stream an can be used as BRBM. Osteoporosis is the final result of the uncoupling between bone oteoclastic and bone osteoblastic activities. All together, BRBMs afford a dynamic evaluation of the uncoupling and forecast future bone loss 5. To this aim BRBM are divided in: – Synthesis BRBM: BGP (osteocalcin), ALP, bonespecific alkaline phosphatase (BALP), propeptide of collagen type I (PICP). – Resorption BRBM: tartrate resistant acid phosphatase, hydroxyproline, pyridinoline and deoxypyridinoline, N-telopeptide (NTx) and C-telopeptide (CTx) of collagen type I. Currently most reliable BRBM are: BALP, osteocalcin, pyridinoline and deoxypyridinoline, NTx and CTx 6. Discussion. – MD value is a static parameter and it is not helpful to define the rate of bone remodelling and the short term (2-3 months) effect of pharmacological treatments; moreover instrumental diagnostic techniques are not useful to distinguish between primary and secondary osteoporosis. In fact, the secondary origin of an osteoporosis process can be suspected but not assessed only on the basis of a low Z-score. Differently, biochemical analyses are able to detect the origin of the osteoporosis and to distinguish a primary from a secondary process. Patients with primary osteoporosis have BRBM values in the normal range or slightly above it; BRBM values significantly above the normal range suggest a secondary origin of the disease or the co-existence of bone loss worsening factors. Other circulating factors can influence bone mineral metabolism. For instance, osteoporotic subjects have PTH values in the normal range, while calcitonin and D-vitamin (1,25-OH-D3) circulating concentrations are low. D-vitamin (25-OH-D3) low circulating level is specific of osteoporosis, because it is the form in which D-vitamin is deposited in the skeleton. 2-microglobulin concentration in the blood is useful to monitor bone response to pharmacological treatment. To this aim also the measure of several circulating cytokines (IL-1, IL-1 e IL-6) connected with bone remodelling might prove useful. Finally, in osteoporotic male subjects there is a strict relation

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between circulating levels of IGF-1 and disease severity, in particular very low IGF-1 levels have pathogenetic value 7. Recently, the important role of some micronutrients in the pathogenesis of osteoporosis has been shown. Among these, K-vitamin can be used in the diagnostic and in the therapeutic phase of the disease 8. K-vitamin is an important enzymatic cofactor which is implied in the activation of several enzymatic proteins of bone metabolism. Osteoporotic female patients have frequently low plasmatic levels of K-vitamin 9. Therefore, K-vitamin might be a reliable diagnostic marker to use in association with BRBMs in the diagnosis of osteoporosis and in monitoring treatment response of anti-reabsorption agents. References 01. Lata PF. et al. “Patient assessment in the diagnosis, prevention, and treatment of osteoporosis” Nutr Clin Pract. 2007 Jun;22(3):261-75. Review. 02. Rey P. et al. “Measurement of bone density in the wrist using X-ray absorptiometry: comparison with measurements of other sites” Rev Rhum Ed Fr. 1994 Oct;61(9):61926. 03. Sahota O. et al. “A comparison of the longitudinal changes in quantitative ultrasound with dual- energy X-ray absorptiometry: the four-year effects of hormone replacement therapy” Osteoporos Int. 2000;11(1):52-8. 04. Vasikaran SD.“Utility of biochemical markers of bone turnover and bone mineral density in management of osteoporosis” Crit Rev Clin Lab Sci. 2008;45(2):221-58. Review. 05. Ebeling PR. et al. “Bone turnover markers and bone density across the menopausal transition”. J Clin Endocrinol Metab. 1996 Sep;81(9):3366-71. 06. Garnero P. et al. “Assessment of bone resorption with a new marker of collagen degradation in patients with metabolic bone disease.” J Clin Endocrinol Metab. 1994 Sep;79(3):780-5. 07. Mc Cormick Rk.“Osteoporosis: integrating biomarkers and other diagnostic correlates into the management of bone fragility.” Altern Med Rev. 2007 Jun;12(2):113-45. Review. 08. Lanham et al “Importance of calcium, vitamin D and vitamin K for osteoporosis prevention and treatment.”Proc Nutr Soc. 2008 May;67(2):163-76. 09. Pearson DA. “Bone health and osteoporosis: the role of vitamin K and potential antagonism by anticoagulants”.Nutr Clin Pract. 2007 Oct;22(5):517-44. Review.

Osteoporosis and Inflammatory Rheumatic Diseases P. Cataleta, G. Palombi, C. Vitali Division of Internal Medicine and Section of Rheumatology, ‘Villamarina’ Hospital, Piombino, Italy

Introduction. – Osteoporosis (OP) is classically defined as a bone mass loss leading to both trabecular bone rarefaction and cortical bone narrowing. Generalised OP can be distinguished in a primary variant, which is mainly represented by the post-meno-

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pausal and senile forms, or can be defined as secondary when it develops during the course of different disorders, or after prolonged assumption of specific therapies. OP is often observed in different inflammatory rheumatic diseases, and therefore may be considered a common extra-articular feature of these disorders. Furthermore, in this kind of patients the presence of OP may cause frailty fractures and consequently increase the physical impairment and mortality risk. The pathogenesis of OP in inflammatory rheumatic diseases is multifactorial, although the activation of inflammatory mechanisms, the reduced mobility and sun exposure, and the concomitant corticosteroid therapy have been shown to play a crucial role. Epidemiology of OP in rheumatic diseases OP and rheumatoid arthritis. – Iuxta-articular osteoporosis is a classical feature of rheumatoid arthritis (RA) and, therefore, it has been included among the typical radiological signs, which are considered diagnostic for this disorder. Moreover, there is also large evidence that generalised OP is widely prevalent in this disorder, although the studies aimed at investigating this finding are not comparable to each other because of the different inclusion criteria and study methods which have been selectively applied. A large cross sectional multicentre study carried out in Italy 1 shows that a significant bone loss can be found (measured by DEXA) in 28.8 and 36.2% of patients with RA in the vertebral column and femoral neck, respectively. The lowest levels of bone mineral content are associated with the more severe degree of physical impairment (namely, in patients fulfilling Steinbroker class IV), and with the assumption of corticosteroid treatment. Furthermore, frailty fractures are observed in 15.2% of patients in this cohort. In the Oslo registry 2, significantly reduced bone density in femoral neck and vertebral bone has been observed in 14,7 and 16,8%, respectively. In a different series of the same registry 3, the frailty fractures have been estimated to be from 2 to 3 times more prevalent in patients with AR with respect to a comparable control population. Similar figures have been reported in studies which are limited to male patients with RA. Reduced bone density has in fact been observed both in femoral neck and in vertebral bodies (in 29 and 19%, respectively), and this finding was not related to plasma testosterone level 4. In the Oslo registry study 5, only femoral bone density appears to be significantly reduced in male patients with RA, and this is limited to those aged between 60 and 70 years. OP and systemic sclerosis 6. – Some studies have shown that the prevalence of OP in sustemic sclerosis (SSc) is similar to that observed in RA, although it seems to be more prevalent in the diffuse variant of the disease, and probably related to the early menopausal age of these patients. Other study, on the contrary, failed to demonstrate an increased prevalence of OP in patients with SSc.

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OP and systemic lupus erythematosus 7. – Several studies have supported the finding that bone density in patients with systemic lupus erythematosus (SLE) is reduced in comparison with matched controls, its prevalence varying from 13 to 24% and from 7 to 12% in vertebral column and femoral neck, respectively. Frailty fractures have also been found to be increased in patients with SLE (RR=4,5, CI 95% 3.8-5.8). OP and ankylosing spondylitis 8. – Although the presence of hyperostotic process at vertebral level in patients with ankylosing spondylitis (AS) may make the measurement of bone density unreliable in this site, bone density measurement in other sites has shown an increased prevalence of OP in patients with this disorder. Frailty fractures have also been found to be more frequent in patients with AS, even in early stages of the disease. Pathogenetic mechanisms inducing OP in rheumatic diseases. – Different cell types, as T- and B-lymphocytes, macrophages, fibroblasts, usually sustain the inflammatory process, which is active in many rheumatic diseases. This complex cellular machinery is able to produce a continuous self-activation throughout the release of a multitude of products, like cytokines, chemokynes, prostaglandins, metalloproteinases. Some of these substances can be considered as final effectors of the process, while others are also able to maintain the inflammation itself, by means of their autocrine, paracrine and endocrine functions. Generalised or local OP in many inflammatory conditions can be mainly ascribed to the activation of osteoclasts, or to an unbalanced activity regulation between osteoclasts, which physiologically are addressed to destroy the bone structure, and osteoblasts, which, on the contrary, are aimed at re-building newly formed bone. Osteoclasts are also the main cell type involved in the erosive changes, which can be observed in some rheumatic diseases, particularly in RA and AS 9). The RANK/RANKL/Osteoprotegerin system 10. – The Osteoprotegerin (OGP) is a soluble protein that blocks osteoclast formation and activation in vitro, and bone resorption in vivo. OPG is a secreted Tumor Necrosis Factor Receptor (TNFR) -related protein that regulates bone density and bone mass in animals. In some animal experimental models, its systemic administration can stop bone resorption. A TNF-related protein (named RANKL), able to interact with OPG, has been found on osteoblast membrane. It can be also isolated in its soluble form, once released by the osteoblast membrane by a specific enzymatic digestion. RANKL, in particular conditions, as synovial inflammation in RA, may also be expressed by other cell types, like T-lymphocytes and fibroblasts. RANKL has been shown to bind and activate another member of TNFR family, named RANK, present on osteoclast surface. Hormones and factors that stimulates bone resorption usually induce the expression of RANKL on osteogenic stromal cells. It has been demonstrated that RANKL

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over-expression can be triggered by PTH, calcitriol, prostaglandin E2, some interleukins, TNF· and corticosteroids. RANKL expression on osteoblasts coordinates bone remodelling by stimulating bone resorption by local osteoclasts, which in turn stimulate bone synthesis by closely adjacent osteoblasts. OPG therefore acts as a decoy receptor by blocking RANKL binding to its cellular receptor RANK. OPG is also produced by osteoblasts in response to anabolic agents, such as oestrogen and Trasforming Growth Factor-β (TGF-β). OPG over-expression blocks osteoclast production, which leads to osteopetrosis in mice, whilst OPG deletion or deficiency results in enhanced bone remodelling and consequent OP. RANKL-related RANK activation produces maturation, differentiation, and prolonged survival (by apoptosis inhibition) of osteoclasts. RANK signalling on osteoclast membrane produces the activation of a number of intracellular kinase pathway (NF-kB, TRAF, JNK, p38, ERK, etc), which transduce the message by activating osteoclast specific genes. The final results of all of these complex mechanisms is osteoclast hyperactivity with consequent loss of bone mass and density. Other pro-inflammatory cytokines. – TNFα appears to stimulate the differentiation, maturation and activity of osteoclasts both directly and by the RANKL/ RANK axis stimulation (11). The interleukins 1, 6, 7, 11, 17 (IL-1, -6, -7, -11,-17) have been demonstrated to play some role in inducing osteoclast activation in a number of inflammatory states. In some cases this effect is mediated by the action of TNFα (IL-1), or by a direct (IL-11) or indirect (IL-6) activation of RANKL/RANK system. Drug-induced OP. – Corticosteroids are often used to induce or maintain disease activity control in many inflammatory disorders, including rheumatic diseases. This drug belongs a lot of side effects and OP is probably the most important one in terms of health impact. The multiple action of corticosteroids on bone metabolism are summarised in Table I. The frailty fracture risk in patients taking long-term therapy with corticosteroids has been estimated to be around 20% with prednisone-equivalent doses equal or less than 5 mg, and around 60% with doses equal or above 20 mg per day. However, the effect of corticosteroids in inducing OP seems to be already present at a prednisone-equivalent dose of 2.5 per day. In addition, the bone loss is effective in the first three months after therapy introduction, with a fracture risk which increases up to 75%. The trabecular bone is that mainly interested and then bone density measurement at vertebral level is the best method to monitor the corticosteroid-induced OP 12. Other pathogenetic mechanisms. – Different degree of physical impairment is a common outcome of many rheumatic diseases. The consequent reduced mobility and sun exposure are certainly able to negatively influence the bone metabolisms, decreasing vitamin D

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Table I. – Main effects of glucocorticoids on bone metabolism. a. Endocrine effects • Reduced calcium absorption • Increased renal calcium loss • Secondary hyperparathyroidism • Hypogonadism • Reduced secretion of GH and IGF-1 b. Cell-mediated effects • Incresed expression of RANKL by osteoblasts and consequent osteoclast activation • Inhibition of osteoblast differentiation and mobilization from bone marrow precursors • Inhibition of osteoblast activity • Apoptosis induction of osteoblasts and osteocytes

absorption and activation, inducing a negative calcium metabolism balance, and finally a secondary hyperparathyroidism. Renal involvement, which is sometimes present in rheumatic diseases, and particularly in connective tissue disorders, can be per se associated with impaired activation of vitamin D and with a calcium negative balance. Finally, in SLE OP has also been ascribed to the lower levels of androgens described in this disorder. References 01. Sinigaglia L, Nervetti A, Mela Q, Bianchi G, Del Puente A, Di Munno O et al. A multicenter cross sectional study on bone mineral density in rheumatoid arthritis. Italian Study Group on Bone Mass in Rheumatoid Arthrtis. J Rheumology 2000; 27: 2582-9. 02. Haugeberg G, Uhlig T, Falch JA, Halse JI, Kvien TK. Bone mineral density and frequency Of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo County Rheumatoid Arthritis register. Arthritis Rheum 2000; 43:522-30 03. Ørstavik RE, Haugeberg G, Mowinckel P, Høiseth A, Uhlig T, Falch JA et al. Vertebral deformities in rheumatoid arthritis. A comparison with population-based controls. Arch Intern Med 2004; 164:420-5. 04. Stafford L, Bleasel J, Giles A, Handelsman D. Androgen deficiency and bone mineral density in men with rheumatoid arthritis. J Rheumatol. 2000 Dec; 27(12):2786-90. 05. Haugeberg G, Uhlig T, Falch JA, Halse JI, Kvien TK. Reduced bone mineral density in male rheumatoid arthritis patients: frequencies and associations with demographic and disease variables in ninety-four patients in the Oslo County Rheumatoid Arthritis Register. Arthritis Rheum 2000; 43:2776-84 06. Loucks J, Pope JE. Osteoporosis and sclerodermia. Semin Arthritis Rheum 2005; 34:687-2. 07. Di Munno O, Mazzantini M, Delle Sedie A, Mosca M, Bombardieri S. Risk factors for osteoporosis in female patients with systemic lupus erythematosus.Lupus 2004; 13:724-30. 08. Toussirot E, Michel F, Wendling D. Bone density, ultrasound measurements and body composition in early ankylosing spondylitis. Rheumatology (Oxford) 2001; 40:882-8.

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09. Walsh NC, Crotti TN, Goldring SR, Gravallese EM. Rheumatic disease: the effect of inflammationon bone. Immunological Reviews 2005, vol. 208: 228-251. 10. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003 May 15;423(6937): 33742. 11. Holstead Jones D, Kong Y-Y, Penninger JM. Role of RANKL and RANK in bone loss and arthritis; Annual Rheumatic Disease 2002; 61 (suppl II):ii32-ii39. 12. Di Munno O, Delle Sedie A. Osteoporosi da Glucorticoidi e Malattie Reumatiche. Reumatismo, 2006 58(1):11-21.

Treatment of osteoporosis R. Nuti, C. Caffarelli, S. Gonnelli Department of Internal Medicine, Endocrine-Metabolic Science and Biochemistry, University of Siena, Siena, Italy

Osteoporosis is defined in a National Institute of Health (NIH) Consensus Statement as ‘a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture’ 1. As the incidence of osteoporotic fractures continues to rise, it is important to identify the most effective therapies for reducing risk of fracture. Osteoporosis management should include the institution of the basic preventive strategies including adequate dietary intake of calcium and vitamin D, exercise, smoking cessation, and limited use of alcohol. These are the foundations of good bone health; however, in subjects at higher risk of osteoporosis, disease management may require the initiation of pharmacological intervention. Combined calcium and vitamin D supplementation is an essential component of the preventive management of osteoporosis, supported by a strong scientific rationale. A wealth of evidence has shown that calcium and vitamin D supplementation has a beneficial effect on the bone health and fracture risks specially when targeted to those who: 1) are receiving antiresorptive or anabolic osteoporosis therapy 2) are being treated with glucocorticoids 3) and are likely to be calcium or vitamin D insufficient. These benefits are most evident when 800-1000 IU day vitamin D is given with a dose of 1000-1200 mg day elemental calcium 2. Several pharmacological options are now available for the prevention and/or treatment of osteoporosis based on their ability to increase BMD and to reduce the risk of fracture. Estrogen Therapy. – Although hormone therapy increases bone mass and reduces the risk of fracture in low-risk postmenopausal women, increases in the risk of breast cancer, stroke, thrombotic events, and cardiovascular disease associated with the combined use of conjugated equine estrogens and medroxyprogesterone acetate outweigh its skeletal benefit. Neverthless the effects of estrogen on fracture risk in women with osteoporosis have not been evaluated. Moreover hormone therapy is not approved for the treatment of osteoporosis because the fracture data required by

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the US Food and Drug Administration (FDA) have never been submitted 3. Selective Estrogen Receptor Modulators (SERMs). – Raloxifene (60 mg once daily) is the only SERM currently approved for the prevention and treatment of osteoporosis. It acts as an estrogen agonist on bone and lipid metabolism and as an estrogen antagonist in the breast and endometrium. Raloxifene is effective in preventing postmenopausal bone loss and reducing the risk of vertebral fractures by 30% in patients with prevalent vertebral fractures, and 50% in patients without a prior vertebral fracture over 3 years. A reduction in nonvertebral and hip fractures by using SERMs has not been demonstrated. The nonskeletal effects of raloxifene include reductions in serum lipids and a 76% reduction in the risk of breast cancer in women with osteoporosis. Raloxifene increases the risk of deep vein thrombosis and pulmonary embolism to a similar extent as hormone therapy 4. New SERMs, such as bazedoxifene, arzoxifene, lasofoxifene and ospemifene, are currently being evaluated. Bisphosphonates (BPs). – At present BPs are the most widely prescribed treatment for osteoporosis. These drugs are stable analogues of pyrophosphate that have a strong affinity for bone apatite; these agents inhibit bone resorption by reducing the recruitment and activity of osteoclasts and increasing apoptosis. Bone formed while patients are receiving BPs treatment is histologically normal. Alendronate (A), risedronate (R), and ibandronate (I) are the BPs more extensively used for the prevention and the treatment of osteoporosis. In particularly A reduces vertebral and non-vertebral fractures by approximetely 50% in randomized controlled trials. The established dosage of A for the treatment of osteoporosis is 10 mg/day or 70 mg once weekly; a lower dosage (5mg/day or 35 mg once weekly) has been reported as being adequate for prevention 5. Also R reduced vertebral and non-vertebral fractures in randomized controlled trials. The dosage of R as treatment of established osteoporosis is 5 mg/day or 35 mg once weekly 6. Ibandronate reduced vertebral but not non-vertebral fractures approximately by 50% in randomized controlled trials carried out on postmenopausal women. The dosage recommended is 2.5 mg/day or 150 mg once monthly orally or 3 mg i.v. every 3 months 7. For several months a new phrmacological option has been used: that is a once-yearly infusion of 5 mg i.v. of zoledronic acid (Z). This use of Z was associated with a reduction in bone turnover marker and with a significant improvement in BMD. Moreover in patients treated with Z there was a reduction in vertebral fracture, clinical fracture and clinical vertebral fracture by 25%, 33%, and 77% respectively 8. BPs were relatively well tolerated, with gastrointestinal upset the most common complaint. Esophagitis is a potentially serious side effect in a small percentage of patients. The question of how long to prescribe a BP has not been

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fully clarified yet, because of concerns about ‘frozen bone’, with complete turning off of bone remodelling and also the development of osteonecrosis of the jaw (ONJ). However, the vast majority of reports of osteonecrosis refer to high-dose i.v. BPs used in the oncological setting, whereas very few cases have been reported in women using oral BPs for osteoporosis. Concerning ONJ at this stage clinical practice should not necessarily be altered, but dental review could be considered in women with significant dental disease. Strontium ranelate (SR). – Strontium is an alkaline earth element, like calcium, and is thus incorporated into the skeleton. Randomized controlled trials have shown a decreased risk of vertebral and hip fractures with SR. The approved dosage of SR is one 2 g sachet per day. Like BPs, SR is not advisable in women with fertility aspirations, since the effects on the fetal skeleton are unknown. SR causes a clinically significant overestimation of BMD because of the high attenuation of X-rays by strontium atoms in bone, as it has a higher atomic number than calcium (calcium 20, strontium 38). Therefore corrections are being studied to allow interpretation of BMD measurements in patients taking strontium ranelate 9. Parathyroid hormone peptides. – These were the first anabolic agents approved by the FDA for the treatment of postmenopausal osteoporosis. Unlike antiresorptive agents, parathyroid hormone peptides stimulate bone remodeling by increasing bone formation. Recombinant 1-34 parathyroid hormone, given as a 20 g s.c. daily injection, reduces vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. The full 1-84 parathyroid hormone peptide is given in the same way, in a daily dose of 100 Ìg and significatly reduce the risk of vertebral fractures. The reduction in hip fracture risk by using both 1-34 and 1-81 parathyroid hormones was not significant. Parathyroid hormone peptides were well tolerated, headache, nausea and asymptomatic hypercalcemia can occur but are rare (hypercalcemia being more evident with full 1-84 PTH). At present cost and the requirement of subcutaneous administration remain major limiting factors for parathyroid hormone peptides 10, 11. References 01. NIH Consensus Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785-795. 02. Boonen S, Vanderschueren D, Haentjens P & Lips P. Calcium and vitamin D in the prevention and treatment of osteoporosis – a clinical update J Intern Med 2006; 259:539-552. 03. Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ et al, for the Women’s Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 2003;290:1729-1738. 04. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, genant HK et al, for the Multiple Outcomes

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of Raloxifene Evaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:637-645. 05. Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E Musliner TA et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280:2077-2082. 06. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA 1999;282:1344-52. 07. Miller PD, McClung MR, Macovei L, Stakkestad JA, Luckey M, Bonvoisin B, et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res 2005 20:1315-1322. 08. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al. HORIZON Pivotal Fracture Trial Onceyearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-1822. 09. Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459-68. 10. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344:1434-41. 11. Greenspan SL, Bone HG, Ettinger MP, Hanley DA, Lindsay R, Zanchetta JR et al., Treatment of Osteoporosis with Parathyroid Hormone Study Group. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med 2007;146:326-39.

Percutaneous vertebroplasty D. Gambacorta1, V. Lunghi1, U. Arrigucci1, M. Cirinei1, R. Gambacorta2, D. De Falco1, M. Zocchi1 1Department of Neuroradiology, Misericordia Hospital, Grosseto, Italy; 2Department of Resuscitation, Orbetello Hospital, Grosseto, Italy

Background. – Percutaneous vertebroplasty (VP) is a technique first described by Galibert and Deramond et al. for the treatment of vertebral angioma of C2 1. This technology has been borrowed from the orthopedic stabilisation surgery opencast bone destructive injuries 2. Since then much has been made. Currently the main indication is the treatment of pain resulting in osteoporotic vertebral fracture. Many other conditions can be treated with VP, thanks to improvements in materials and technology operations. In parallel, VP has spread widely in the United States but also in Europe and particularly in Italy. At time there is a substantial increase in percentage of procedures year after year 3. Crucial however is the qualitative and quantitative pain assessment. For this purpose are

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used scales of assessment which must be simple and one-dimensional, in order to be applied to all patients including those with expressive trouble 4. Among these the Visual Analogic Scale (VAS), the Digital Scale (NRS) and Verbal Scale (VRS) are particularly widespread and use. Methods. – The technique of carrying out the VP is relatively simple and safe. It must be executed by medical experts with radiological techniques. VP in fact is generally performed in the angiographic room, under radioscopic guide, sometimes associated with the TC, using AP and LL projections: anatomical references and radioscopic navigation become crucial. The procedure, preferably with biplane machine, however rarely available, allows you to view two orthogonal projections in real time. Particularly during the progression of needle and vertebral filling with acrylic resin. However, even with angiography monoplane the method can be performed safely and quickly. All vertebral level may be subject to VP: cervical, dorsal and lombar vertebra with trans or parapeduncolar, mono or bilateral access. The patient is placed in prone position on the angiographic table (Figure 1), with respiratory, pressure and electrocardiogram monitoring during the procedur (40-60 minutes in relation to the vertebrae treated). In situations of poor tissue opacity (the resolution contrast CT is higher than fluoscopic) and in proximity to vital organs (cervical vertebrae or main vessels), the TC control may be useful for monitoring the needle progression to its opti-

mal position. During Polimetilmetacrilato infusion (PMME: acrilic resina) the vision TC is unsafe. Leaks of polymer even in small amounts can cause direct and indirect damage (toxic and heat on nervous tissue and pulmonary embolism) potentially very serious. When this happens in space disc you create the conditions for new early fratture in the adjacent vertebral bodies. If the spread of PMME involves a venous channel, pulmonary embolism is possible. The most feared complication is the spread of cement within the vertebral canal, with direct damage on the nerves and spinal cord up to paraplegia (Figure 2). You may be use a needle of various diameters (11-15 G), preferably with beak of a flute points for its ease of bone penetration. It also recommends the use of a orthopedic hammer for advancement of the needle step by step, especially in bone sclerosis. When you reach the optimal position of the needle in the vertebra (1/3 front of the vertebral body in median position) inject the “cement” (PMME) previously prepared. The dust of polymer is homogenized with diluent liquid to obtain a consistency paste whitish-viscous fluid. Are then filled syringes polycarbonate from 1 cc, that are put into sterile water ice, that slows down the process of solidification, to obtain a working time sufficiently long. There are also dedicated syringes with screw mechanism. With just 2-4 cc of resin to get good vertebral filling. It is important to remember that the effectiveness of the result is not proportional to the amount of material injected and the vertebral filling.

Figure 1. – The patient is placed in prone position on the angiographic table.

Figure 2. – Spread of cement within the vertebral canal.

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Even small volumes of PMME are sufficient to achieve the disappearance or significant reduction of pain and its consequences in terms of posture, walking, compliance and respiratory autonomy and in other words in quality of life. Sometimes the cement is modified to improve its opacity (with the addition of barium sulfate) or mixed with antibiotics (Tobramicina). These procedures change the product and may affect his “suitability” in legal terms for use in VP. Does not exist at the time reports in the literature of harmful effects linked to the use of PMME modified during vertebroplasty procedures 5, with positive results in various applications. Results. – The pain persistent and resistant to medical treatment is main indication to VP. For resistance to medical treatment means mild or no pain reduction, despite the correct assumption of analgesic therapy or the appearance of side effects attributable to drugs (excessive sedation, constipation, mental confusion) after 4-6 months of treatment 6. The espansion of vertebral collapse with recovery of his height are a potential target. Vertebral osteoporotic collapse, metastatic colonization, multiple myeloma, emangioma aggressive, are all valid reasons to treatment with VP 7. In addition to pain, one or more crushed vertebrae can induce changes in abdominal (tension and digestive difficulties) and thoracic compliance (feeling fatigue and breathing difficulties) 8. The wedgeshaped front of vertebra is another indication to treatment. When reaches and exceeds 15° is considered instability by some authors. The articular processes spread can induce gradual stenosis of the spinal channel with spinal cord compression. Dublina AB et al. have documented that the wedge vertebral appears stabilized after a year of treatment with VP or Kyphoplasty 9. The correction on the kyphosis angle of spine is a important objective 10. This result, obtained with the VP or the Kyphoplasty, tends to run out new vertebral fractures. It is therefore very important to prevent small new fractur of adjacent vertebrae. Also in osteoporotic patients treated with VP, this remains a big problem 11. Conclusions. – In conclusion the VP is a valid therapy against vertebral fractures in nature osteoporo-

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tic painful, neoplastic and traumatic. It is a safe, effective, economic and little traumatic technique. Is likely the widespread use in the future. References 01. Galibert P, Deramond H, Rosat P, Le Gars D. “Preliminary note on the treatment of vertebral angioma y percutaneous acrili vertebroplasty”. Neurochirurgie. 1987; 33: 166-168. 02. Sundaresan N, Galicich JH, Lane JM, Bains MS, McCormack P: Treatment of neoplastic epidural cord compression by vertebral bodyresection and stabilization. J Neurosurg 63:676-684, 1985. 03. Nussbaum DA, MS, Gaillon P, MD, and Murphy K, MD. “A Review of Complications Associated with Vertebroplasty an Kyphoplasty as Reported to the Food and Drug Administration Medical Device Related Web Site”. J Vasc Interv Radiol. 2004, 15:1185-1192; 04. SIAARTI “Raccomandation for the treatment of postoperative paint”. Minerva Anestesiol. 2002 Oct; 68(10): 73550. 05. Mathis JM, Eckel TS, Belkoff SM, Deramond H. Percutaneous vertebroplasty: a therapeutic option for painassociated with vertebral compression fracture. J Back Musculoskel Rehabil 13:11-17, 1999. 06. McGraw JK, Cardella J, Barr JD, Mathis JM, Sanchez O, Schwartzberg MS, Swan TL, Sacks D: “Society of Interventional Radiology Quality Improvement Guidelines for Percutaneous Vertebroplasty”. J Vasc Interv Radiol. 2003; 14:S311-S315. 07. Gupta AK, Purkayastha S, Kapilamoorthy TR, Bodhey NK, Sarma SR. Management of painful neoplastic spinal lesions using percutaneous acriylic cement injection. J Neurorad 19: 236-244, 2006. 08. McKiernan F, Jensen R, Faciszewski T: The dinamic mobility of vertebral compression fractures. J Bone Min Res 18: 24-29, 2003. 09. Dublina AB, Hartmana J, Latchawa RE et al: The vertebral body fracture in osteoporosis: restoration of height using percutaneous vertebroplasty. Am J Neuroradiol 26: 489-492, 2005. 10. Teng MMH, Wei CJ, Wei LC et Al: Kiphosis correction and height restoration effect of percutaneous vertebroplasty. AJNR Am J Neuroradiol 24: 1893-1900, 2003. 11. Uppin AA, Hirsch Ja, Centenera LV et al: Occurrence of new vertebral body fracture after percutaneous vertebroplasty in patient with osteoporosis. Radiology 226: 119-124, 2003.

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EMERGING ISSUES IN INTERNAL MEDICINE Chronic obstructive pulmonary disease and comorbidities E. Santoro Medicine Unit, Department Medicine AUSL 8 Arezzo, Casentino Hospital, Bibbiena (Arezzo), Italy

Chronic obstructive pulmonary disease (COPD) is characterised by poorly reversible air flow limitation that is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, particularly cigarette smoke. Diagnosis and assessment of severity of COPD are based on the degree of air flow limitation at spirometry. Increasing evidence suggests that clinical features of COPD and airflow limitation are poorly correlated. A comprehensive approach, including imaging and assessment of exercise tolerance and body-mass index (BMI), is needed. Ageing is commonly characterised as a progressive impairment of function resulting in an increasing vulnerability to environmental challenge and a growing risk of disease. Ageing of the population increases the prevalence of chronic disease, which represent a huge proportion of human illness. They include cardiovascular disease (30% of projected total word wide death in 2005), cancer (13%), diabetes (2%) and chronic respiratory disease (7%), mainly COPD. COPD should be considered in any smoker aged >40 yrs with symptoms of cough, sputum production or dyspnoea, and spirometry should be used to evaluate the degree of airflow limitation. Cigarette smoking is the major risk factor of COPD and is also one the major risk factors of all chronic diseases and cancer . Cigarette smoke causes not only airway and lung inflammation but also systemic cellular and humoral inflammation, systemic oxidative stress, striking changes of vasomotor and endothelial function, and enhanced circulating concentrations of several pro coagulant factors. The systemic effects of smoking may contribute not only to respiratory abnormalities, symptoms and functional impairment associated with COPD but also to its chronic comorbidities 1. Cachexy 2, Skeletal muscle abnormalities 3, hypertension 4, diabetes mellitus, coronary artery disease 5, heart failure 6, pulmonary infectious, cancer and pulmonary vascular disease are the most common comorbidities responsible for the clinical manifestations and natural history of COPD 1. The other major risk factor for cardiovascular and other chronic comorbidities is obesity. Smoking and

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obesity may interact synergistically: the two risk factors are associated with insulin resistance, oxidative stress and increased concentrations of various cytokines and inflammatory markers, all off which ultimately lead to endothelial dysfunction and cardiovascular disease 7. COPD is associated with chronic heart failure (CHF) in â&#x2030;Ľ20% of patients 6. The impaired forced expiratory volume in one second is a powerful marker of morbidity and mortality and, particularly, of cardiovascular mortality. Increased arterial stiffness is also related to the severity of airflow obstruction and may be a factor in the excess risk for cardiovascular disease in COPD. Patients with severe COPD have elevated circulating levels of C-reactive protein (CRP). A working hypothesis to account for the high prevalence of left ventricular systolic dysfunction in patients with COPD is that low-grade systemic inflammation accelerates progression of coronary atherosclerosis, which ultimate results in ischemic cardiomiopathy 8. Patients with COPD often have one or more component of the metabolic syndrome. The metabolic syndrome recognised clinically by the findings of abdominal obesity, elevated triglycerides, atherogenic, dyslipidoemia, elevated blood pressure, high blood glucose and insulin resistance. Metabolic syndrome is also associated with a pro thrombotic state(with increases in plasminogen activator inhibitor and fibrinogen) and pro inflammatory state (with increases in acute-phase reactants, e.g. CRP) 9. Patients with COPD have osteoporosis (â&#x2030;¤70%) which are at last, in part, independent of treatment with steroid and decreased physical activity 10. Type 2 diabetes is independently associated with reduced lung function, which, together with obesity, may further worsen the severity of COPD. Low body mass index (BMI), age and low arterial oxygen tension are known to be significant independent predictor of mortality in COPD. BMI is the first of the four variables used in the BODE INDEX predicting the risk of death in COPD 7. Loss of fat-free mass (FFM) is detrimental to respiratory and peripheral muscle function, exercise capacity and health status, and is an important supplementary prognostic parameter. Bath weigh loss and loss of FFM are seen more commonly in emphysema and appear to be the result of a negative energy balance. Patients can certainly become so breathless with severe COPD that maintaining are adequate oral intake becomes difficult. However one physiologic response to starvation is a reduction in resting energy requirements. In contrast, many COPD patients have been noted to have increa-

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sed resting energy expenditure, associated with systemic inflammation. In addition, cachectic patients exhibit preferential loss off FFM, enhanced protein degradation and poor responsiveness to nutritional interventions . Moreover, altered protein, lipid and carbohydrate metabolism is seen in cachexia and is thought to be related to systemic inflammation 11. Muscle wasting in COPD therefore shows similarities to the cachexia seen in many other conditions including chronic heart failure, renal failure, cancer and acquired immunodeficiency syndrome. In the conditions, cachexia is not only associated with reduced survival, it is also related to poor functional status and health-related quality of life. In all these conditions, circulating levels of pro inflammatory molecules including TNF-α,IL-1,IL-6,IL-8, and γ-interferon (INF-γ) are increased with levels of anabolic hormones including insulin-like growth factors and testosterone are decreased 12. TNF-α has a key role in the muscle wasting and weigh loss seen in COPD. It has several direct effects ( anorexia, altered levels of circulating hormones and catabolic cytokines, and altered end organ sensitivities to them) that could promote muscle wasting 13. Vertebral fractures are present in up to 50% of steroid naïve males with COPD. Osteopenia has been confirmed to be a feature of COPD and associated with an increase in circulating TNF-α 14. L.M. Fabbri and K.F. Rabe suggested adding the term “chronic systemic inflammatory syndrome” to the diagnosis of COPD to reflect the complexity at the problem. The diagnosis and assessment of severity of COPD may be greatly affected by presence of a comorbid condition; therefore, lung function measurement, non invasive assessment of left ventricular function and/or glycaemia, such as CRP serum levels, should be performed in these patients. Several diseases are associated with similar inflammatory pathophysiology and coexist more commonly, suggesting that a common process is responsible for the clinical overlap. It is of course possible that the systemic inflammatory response to COPD precipitate disease processes at distant sites. Patients with COPD may present to other specialities because of the comorbidity and the diagnosis may be missed because of common symptoms in the overlapping conditions 15. References 01. Fabbri LM, Luppi F, Beghè B and Rabe KF Complex chronic comorbidities of COPD. Eur Respir J 2008;31:204-212 02. Morley JE, Thomas DR, Wilson MM Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr 2006;83: 735-743. 03. Balasubramamian VP, Varkey B, Chronic obstructive pulmonary disease: effects beyond the lungs. Curr Opin Pulm Med 2006; 12:106-11. 04. Blacher J, Safar ME. Large-artery stiffness, hypertension and cardiovascular risk in older patients. Nat Clin Cardiovasc Med 2005;2, 450-455. 05. Sidney S, Sorel M, Quesemberry CP Jr, De Luise C, Lanes

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S, Eisner MD: COPD and incident cardiovascular disease hospitalizations and mortality: Kaiser permanent. Medical Care Program. Chest 2005;128:2068-2075. 06. Rutten FH, Moons KG, Kramer MJ. Recognising heart failure in elderly patients with stable chronic obstructive pulmonary disease in primary care: cross sectional diagnostic study. BMI 2005;331:1379. 07. Poulain M, Doucet M, Major GC et al. The effect of obesity on chronic respiratory diseases: pathophysiology And therapeutic strategies. CMAJ 2006;174:1293-1299. 08. Le Jemtel TH, Padeletti, M, Jelic S. Diagnostic and Therapeutic challenges in patients with coexistent chronic obstructive pulmonary disease and chronic heart failure. J Am Coll Cardiol 2007;49:171-180. 09. Marquis K, Maltais F, Duguay V et al. The metabolic syndrome in patients with chronic obstructive pulmonary disease. J Cardiopulm Rehabil 2005; 25:226-232. 10. Jırgensen NR, SchwarzP, Holme I, Henriksen BM, Petersen LJ, Baker V. The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease: a cross sectional study. Resp Med 2007;101:177-185. 11. Tisdale MJ. Biology of cachexia. J Natl Cancer Inst 1997; 89:1763-1773. 12. Kotler DP. Cachexia. Ann Intern Med 2000;133: 622-634. 13. Stewart CE, Newcomb PV, Holly JM. Multifaceted roles of TNF-α in myoblast destruction: a multitude of signal transduction pathways. J Cell Physiol 2004;198:237-247. 14. Bolton CE, Ionescu AA, Shiels KM et al. Associated loss of fat-free mass and bone mineral density in chronic obstructive pulmonary disease. Am. J. Respir Crit Care Med 2004;170:1286-1293. 15. Fabbri LM, KF Rabe. From COPD to chronic systemic inflammatory syndrome? Lancet. 16. 2007;370:797-99.

Treatment of COPD: what’s new? G. Vagheggini, MD Weaning and Pulmonary Rehabilitation Unit, Auxilium Vitae Rehabilitation Center, Volterra, Italy

According to the ATS/ERS definition, “...chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease state characterised by airflow limitation...” 1. The airflow limitation is usually not fully reversible and progressive. Although COPD affects primarily the lungs with an abnormal inflammatory response to noxious particles or gases (e.g.: cigarette smoking), it also produces significant systemic consequences. In addition to inflammation, an imbalance of proteinases and antiproteinases in the lungs, and oxidative stress are also important in the pathogenesis of COPD 2. Effective medications for COPD are available and all patients who are symptomatic merit a trial of drug treatment. The medications for COPD currently available can reduce or abolish symptoms, increase exercise capacity, reduce the number and severity of exacerbations, and improve health status. At present, no treatment has modified the rate of decline in lung function. Bronchodilators in common clinical use (ß-agonists, anticholinergic drugs and methylxanthines), acts

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primarily by relaxing airway smooth muscle and improving lung emptying during tidal breathing. Although the increase in FEV1 may be relatively small, often is accompanied by larger changes in lung volumes 3. The delay of the onset of dynamic hyperinflation during exercise and a reduction of the residual volume may contribute to a reduction in perceived breathlessness 4. The effects of glucocorticoids in COPD are more modest as compared with bronchial asthma. However, in patients with severe COPD (usually classified as an FEV1 <50% pred.), there is evidence that the number of exacerbations per year and the rate of deterioration in health status can be reduced by inhaled corticosteroids 5. In hypoxaemic patients, survival, exercise, sleep and cognitive performance can be improved by supplemental longterm oxygen therapy (LTOT) 6-8. Pulmonary rehabilitation may improve dyspnoea, exercise ability, health status and healthcare utilisation through stabilizing or reversing systemic manifestations of the disease. Integrated into the individualized treatment of the COPD patient, pulmonary rehabilitation is an evidence-based, multidisciplinary, and comprehensive intervention for patients who are symptomatic and often have decreased daily life activities 9. Lower and upper extremity exercise training should be a mandatory component of a pulmonary rehabilitation program, in addition to an education program including information on collaborative self-management and prevention and treatment of exacerbations. Other components of a pulmonary rehabilitation programme are psychosocial/behavioural intervention, nutritional therapy, outcome assessment and promotion of long-term adherence to the rehabilitation recommendations. Irrespective of the degree of airflow limitation, weight loss and being underweight is associated with an increased mortality risk 10. In advanced stages of COPD, both energy balance and protein balance are disturbed, and in these patients weight loss and particularly muscle wasting contribute significantly to morbidity, disability and handicap 11. Surgical procedures as bullectomy, lung volume reduction surgery and lung transplantation may have a role in highly selected COPD patients, resulting in improved spirometry, lung volumes, exercise capacity, dyspnoea, health-related quality of life and possibly survival 12-14. The natural course of COPD is characterised by the occurrence of exacerbations: “events characterised by a change in the patient’s baseline dyspnoea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management” 1. The severity of the underlying disease, the presence of co-morbidities and the history of previous exacerbations must be considered when evaluating patients with exacerbations. Hospitalization of the patient is recommended in case of high-risk co-morbid conditions, severity and progression of symptoms, inadequate response to the outpatient treatment, inadequate home care. The need

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for admission to an intensive care unit (ICU) is related to the severity of respiratory dysfunction. The pharmacological treatment of patients with an exacerbation of COPD is based on the same medications utilised in the management of the stable patient; in addition, the evidence supports the use of systemic glucocorticosteroids 15. During a severe exacerbation, arterial blood gas analysis (ABGs) should be monitored for arterial oxygen (PaO2), arterial carbon dioxide tension (PaCO2) and pH and oxygen should be supplemented if hypoxemia occurs. The goal of the oxygen supplementation is to maintain PaO2≥60 mmHg, in order to prevent tissue hypoxia and preserve cellular oxygenation, and prevention of tissue hypoxia supercedes CO2 retention concerns. However, if CO2 retention and acidemia occurs, mechanical ventilation should be considered. Mechanical ventilation, either “invasive” or “noninvasive”, is a form of life support until the cause underlying the acute respiratory failure is reversed with medical therapy 15. The aim of ventilatory support is to ‘‘gain time’’ by unloading respiratory muscles, increasing ventilation, and improving arterial oxygenation and, eventually, hypercapnia and related respiratory acidosis 17. Noninvasive mechanical ventilation (NIV), while ensure a similar degree of efficacy, may avoid most of the complications related to the endotracheal intubation and to the loss of airway defence mechanisms 18. The use of NIV in adjunct to the standard treatment of acute-on-chronic respiratory failure due to acute exacerbations of COPD is supported by several randomized controlled trials, meta-analyses and guidelines 19. Because the improvement in overall survival, reduction of the endotracheal intubation, and shortening in the hospital and intensive care unit (ICU) length of stay, NIV has been proposed as the first-line ventilatory strategy in this condition with different timing and location according to the level of acute respiratory failure (ARF) severity 20-21. In patients with mild-to-moderate ARF, as indicated by pH levels 7.30-7.35, NIV was successfully administered in different settings, including on the ward, in order to prevent ETI 22. In more severely ill patients (pH ,7.25), the use of NIV as an alternative to ETI did not affect the mortality rate and the duration of ventilatory support, but the patients treated with NIV experienced a lower rate of complications. In this group of severe ARF patients, at high risk of failure, a NIV trial may be justified if ETI is not strictly required because of the need of protecting the airways and preventing loss of consciousness or gasping, provided that facilities for ETI are promptly available 23-24. Disease management of COPD is oriented to a systematic and integrated approach involving the patient, the primary care team and secondary care and rehabilitation services in order to integrate rehabilitative elements into a system of patient self-management and promotion of a healthy lifestyle. The following aspects are important: smoking cessation; early

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diagnosis and secondary prevention; education and self-management; pulmonary rehabilitation; monitoring and early recognition of exacerbation 1. References 01. ATS/ERS TASK FORCE. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23:932-946. 02. Repine JE, Bast A, Lankhorst I. Oxidative stress in chronic obstructive pulmonary disease. Oxidative Stress Study Group. Am J Respir Crit Care Med 1997;156:341-357. 03. Celli B, ZuWallack R, Wang S, Kesten S. Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Chest 2003; 124:1743-1748. 04. Belman MJ, Botnick WC, Shin JW. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;153:967-975. 05. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000; 320:1297-1303. 06. Report of the Medical Research Council Working Party. Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981;1:681-685. 07. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease. Ann Intern Med 1980;93:391-398. 08. Zielinski J, Tobiasz M, Hawrylkiewicz I, Sliwinksi P, Palasiewicz G Effects of long-term oxygen therapy on pulmonary hemodynamics in COPD patients: a 6-year prospective study. Chest 1998;113:65-70. 09. Joint ACCP/AACVPR Evidence-Based Clinical Practice Guidelines. Pulmonary Rehabilitation. CHEST 2007; 131: 4S-42S. 10. Schols AMWJ, Soeters PB, Dingemans AMC, Mostert R, Frantzen PJ, Wouters EF Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. Am Rev Respir Dis 1993;147:1151-1156. 11. Creutzberg EL, Wouters EFM, Mostert R, et al Efficacy of nutritional supplementation therapy in depleted patients with chronic obstructive pulmonary disease. Nutrition 2003; 19: 120-127. 12. Martinez FJ. Surgical therapy for chronic obstructive pulmonary disease: conventional bullectomy and lung volume reduction surgery in the absence of giant bullae. Semin Respir Crit Care Med 1999; 20: 351-364. 13. National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348:2059-2073. 14. American Thoracic Society. International guidelines for the selection of lung transplant candidates. Am J Respir Crit Care Med 1998;158:335-339. 15. Niewhoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med 1999;340: 1941-1947.

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16. BTS Guideline. Non invasive ventilation in acute respiratory failure British Thoracic Society Standards of Care Committee. Thorax 2002;57:192-211. 17. Laghi F, Tobin MJ. Indications for mechanical ventilation. In: Tobin MJ, ed. Principles & Practice of Mechanical Ventilation. 2nd Ed. McGraw-Hill, New York, 2006; pp. 129-162. 18. Hill NS. Noninvasive positive pressure ventilation. In: Tobin MJ, ed. Principles & Practice of Mechanical Ventilation. 2nd Ed. McGraw-Hill, New York, 2006; pp. 433-471. 19. Ambrosino N and Vagheggini G. Noninvasive positive pressure ventilation in the acute care setting: where are we? Eur Respir J 2008;31:1-13. 20. Nava S, Navalesi P, Conti G. Time of non-invasive ventilation. Intensive Care Med 2006;32:361-370. 21. Elliott MW. Non-invasive ventilation in acute exacerbations of chronic obstructive pulmonary disease: a new gold standard? Intensive Care Med 2002;28:1691-1694. 22. Plant PK, Owen JL, Elliott MW. Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomized controlled trial. Lancet 2000; 355: 1931-1935. 23. Conti G, Antonelli M, Navalesi P, et al. Noninvasive vs. conventional mechanical ventilation in patients with chronic obstructive pulmonary disease after failure of medical treatment in the ward: a randomized trial. Intensive Care Med 2002;28:1701-1707. 24. Lightowler JV, Wedzicha JA, Elliott MW, Ram FS. Noninvasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ 2003;326:185-189.

Ischaemic heart disease and selective If inhibitor V. Verdiani Department of Internal and Emergency Medicine, Careggi Hospital, Florence, Italy

Introduction. – The most prevalent cardiovascular disease in Western society is ischaemic heart disease. Stable angina pectoris is a common manifestation of cardiac ischaemia. Its prevalence increases with age in both genders. It is estimated that in countries with high ischaemic heart disease rates, the total number of persons with angina may be as high as 30-40 thousand per million of the total population. Angina occurs when insufficient oxygen is supplied to the heart muscle. Heart rate is a primary determinant of myocardial oxygen demand and may also affect myocardial perfusion. Heart rate and life expectancy. – Within the animal kingdom, the mammalians’ heart rate represents an inverse semi-logarithmic relation to life expectancy: small animals have a higher heart rate and shorter lifespan than do larger 1. The average number of heart beats per lifetime in mammalians is unexpectedly constant. This suggests that the life span is predetermined by the basic energetics of the living cells,

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and that the apparent inverse relation between life span and heart rate reveals the heart rate to serve as a marker of the metabolic rate. In humans, it was found that elevated resting heart rate (RHR) is also strongly associated with mortality. For instance, in the Framingham Study, in a cohort composed of 5070 subjects who were free from cardiovascular disease at the time of entry into the study, cardiovascular and coronary mortality increased progressively with RHR 2. Seccareccia et al. (MATISS) verified that in a low-risk Italian population, heart rate increment was associated with a relative risk increase from 1.52 (CI: 1.29-1.78) for all-cause mortality, 1.63 (CI: 1.26-2.10) for cardiovascular mortality, and 1.47 (CI:1.19-1.80) for non-cardiovascular mortality. Prognostic role of heart rate in cardiovascular disease. – In patients with coronary artery disease, the relationship between heart rate and mortality is even more established. In a large study 3 conducted in patients with established or suspected coronary atherosclerosis, heart rate at rest was an independent factor predicting survival. In this group, increased heart rate not only induces ischaemia but also predisposes to plaque rupture, and therefore, triggers acute coronary events, which are mostly responsible for mortality in patients with ischaemic heart disease. Heart rate acceleration can also increase the risk of an acute coronary syndrome. In a study involving patients with repeat coronary angiography, Heidland and Strauer 4 found an association between plaque disruption and heart rate >80 b.p.m. In another study 5 conducted in a large group of patients with stable angina, heart rate, together with increasing age and male gender, was an independent predictor of new coronary events. Current treatment of stable angina. – Revascularization offers effective relief of symptoms and in patients with extensive ischaemia, like those with left main or triple-vessel disease, it improves prognosis. However, medical treatment is still recommended as the first-line strategy to control symptoms. Beta-blockers, calcium-channel blocking agents, and nitrates have been the mainstay of medical therapy of chronic angina for a long time. Beta-blockers are most often recommended as primary therapy because, in addition to symptomatic relief, they have been found to reduce mortality and reinfarction, at least in post-infarction patients. In several patients, target doses of beta-blockers cannot be reached because of adverse effects: fatigue, lethargy, insomnia, worsening claudication, or erectile dysfunction in men. In addition, beta-blockers are contraindicated in some patients. Some calcium-channel blockers, such as verapamil or diltiazem, can also slow the heart rate, but their effect is difficult to predict, and the data on their clinical benefit are rather scanty. The selective If inhibition. – The pacemaker (If) current plays a central role in heart rate control 6. This makes it an interesting target for a pharmacological intervention. Inhibition of the If current results in heart

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rate reduction, with no other effects on the heart. This bradycardic effect has a clear potential to reduce ischaemia. Two drugs have entered late-phase clinical testing. The first was zatebradine 7, which exhibited promising pre-clinical findings but did not achieve angina prevention with the doses employed clinically, despite some heart rate reduction both at rest and during exercise, perhaps because the dose was limited by unacceptable ocular side effects. Ivabradine, first reported more than a decade ago 8, evidences unique specificity for the If current and manifests pharmacological properties that compare favourably with those of zatebradine. Pre-clinically, ivabradine causes dose-dependent heart rate slowing with no effect on myocardial contractility, peripheral vascular resistance, coronary vascular resistance, mean arterial pressure, and myocardial oxygen delivery to myocardial oxygen consumption ratio. Ivabradine: results of clinical trials. – A randomised, placebo-controlled, double-blind, multicentre, multinational study in 360 patients with stable angina for at least 3 months and documented coronary artery disease evaluated ivabradine in a short doseranging phase and in longer-term use 9. After 2 weeks of treatment, resting heart rate was significantly slower with ivabradine compared with placebo, and this reduction increased significantly with increasing dose (-4.5 and -9.5 bpm at 2.5 and 5.0 mg, respectively). The frequency of angina attacks and consumption of short-acting nitrates tended to fall with ivabradine use. The only reported adverse reactions were dosagerelated visual symptoms which were reported in less than 2% of patients with 5 mg orally twice daily. Such effects were generally transient, always reversible and very seldom severe enough to cause patients to voluntarily stop the drug. The results of the International Trial on the Treatment of angina with Ivabradine vs. Atenolol have been published 10. This randomised, double-blind study compared ivabradine with atenolol over 4 months in 939 patients with stable angina pectoris and documented coronary artery disease. Patients received either ivabradine 5 mg twice daily for 4 weeks increased to 7.5 mg twice daily for a further 3 months, or atenolol 50 mg once daily for 4 weeks increased to 100 mg once daily for a further 3 months. At trough drug activity, ivabradine 7.5 mg was non-inferior to atenolol for all primary and secondary analyses including time to limiting angina, time to angina onset and time to 1-mm ST-segment depression at month 4 (p <0.0001). Visual symptoms occurred at a similar rate to that seen in the first study. These results indicate that by lowering heart rate, ivabradine is at least as effective as atenolol in patients with stable angina pectoris. Extension of the analysis in patients aged over 65 years confirmed that the efficacy of ivabradine is maintained in older patients 11. In a double-blind trial involving 1195 patients 12, patients received either amlodipine or ivabradine for

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3 months. Ivabradine 7.5 mg bid significantly increased total exercise duration. In addition, ivabradine also improved both angina, as measured by time to limiting angina and time to angina onset, and ischaemia, as measured by time to 1-mm ST-segment depression. Formal statistical testing indicated that ivabradine was non-inferior to amlodipine in preventing angina (p <0.0001). In a 12-month, double-blind study, 386 patients receiving nitrates or calcium blockers for the treatment of angina were randomised to receive ivabradine 5.0 mg or 7.5 mg twice daily concomitant to their existing therapy 13. Ivabradine reduced heart rate by 10 and 12 bpm, respectively, for 5.0 and 7.5 mg doses. Moreover, the number of angina attacks was significantly reduced from baseline to month 12 in patients receiving ivabradine. Ivabradine reduces heart rate without any observed effects on myocardial contractility and does not alter the cardiac conduction system 14. Conclusion. – The prevalence of ischaemic heart disease is still high. Despite an important reduction in mortality, mainly as a result of improved primary and secondary prevention, there are still important unmet needs in the treatment of the disease. New pharmacological agents are needed to alleviate the symptoms, increase exercise tolerance, and improve quality of life. In this context, the novel selective and specific If inhibitor ivabradine appears to be an effective and safe treatment of stable angina through exclusive heart rate reduction. In guidelines on the management of stable angina pectoris of European Society of Cardiology (2006) Ivabradine is suitable as alternative agent in patients who do not tolerate beta-blockade. Other potential indications for its use are also being explored. References 01. Levine HJ. Rest heart rate and life expectancy. J Am Coll Cardiol 1997;30:1104-6. 02. Kannel WB, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J 1987;113:1489-94. 03. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 2005;26:967-74. 04. Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation 2001;104:1477-82. 05. Aronow WS, Ahn C, Mercando AD, Epstein S. Association of average heart rate on 24-hour ambulatory electrocardiograms with incidence of new coronary events at 48month follow-up in 1,311 patients (mean age 81 years) with heart disease and sinus rhythm. Am J Cardiol 1996; 78:1175-6. 06. Brown H, Difrancesco D. Voltage-clamp investigations of membrane currents underlying pace-maker activity in rabbit sino-atrial node. J Physiol 1980;308:331-51. 07. Goethals M, Raes A, van Bogaert PP. Use-dependent block of the pacemaker current I(f) in rabbit sinoatrial node

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cells by zatebradine (UL-FS 49). On the mode of action of sinus node inhibitors. Circulation 1993;88:2389-401. 08. Thollon C, Cambarrat C, Vian J, Prost JF, Peglion JL, Vilaine JP. Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49. Br J Pharmacol 1994;112:37-42. 09. Borer JS, Fox K, Jaillon P, Lerebours G; Ivabradine Investigators Group. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation 2003;107:817-23. 10. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K; INITIATIVE Investigators. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005;26:2529-36. 11. Fox KM, Tardif JC, Ford M. Anti-anginal and anti-ischemic efficacy of ivabradine – a selective and specific sinus node If current inhibitor – compared to atenolol in elderly patients with chronic stable angina. Heart 2005; 91(Suppl 1):A69. 12. Ruzyllo W, Ford I, Tendera M. Antianginal and antiischemic effects of the If current inhibitor ivabradine compared to amlodipine as monotherapy in patients with chronic stable angina: a 3-month randomized, controlled, double-blind, multicenter trial. Eur Heart J 2004;25: 878 (Abstract) 13. Lopes-Bescos L, Filipova S, Martos R. Long-term safety and antianginal efficacy of the If current inhibitor ivabradine in patients with chronic stable angina. A one-year randomized, double-blind, multicenter trial. Eur Heart J 2004;25:878 (Abstract). 14. Difrancesco D, Camm J. Heart rate lowering by specific and selective If current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs 2004;64:1757-65.

Role of the endocannabinoid system in the management of the cardiovascular risk M. Alessandri, L. Galassi, G.M. Forteleoni, A. Montagnani, M. Cipriani Centre for Study of Hypertension and Cardiovascular Risk, Unit of Internal Medicine, Misericordia Hospital, Local Health Unit 9, Grosseto, Italy

The endocannabinoid system. – Cannabis Sativa (marijuana) is the most widely consumed illegal drug in the world as of the 1960’s. Having been cultivated for over five thousand years for the fibres it provides for materials manufacturing process, Cannabis had been prescribed by the Chinese as from 2600 BC to treat cramps, rheumatic and menstrual pain. In 1964 ¢-9-tetrahydrocannabinol (THC) was isolated and identified as the active psychotropic constituent of Cannabis Sativa 1. In our days, a considerable number of Cannabis analogues have been prescribed as antiemetic and appetite stimulants to oncology patients on chemiotherapy. The first cannabinoid receptor was identified in 1988 2. In 1993 that receptor was called CB1, after the same

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year a second receptor had been characterized and named CB2 3. The CB1 receptors are primarily distributed to the brain in a complex network of interconnected circuits joining parts of the prefrontal cortex, amygdala and nucleus accumbens with other regions of the limbic system 4. Subsequent work has identified CB1 receptors peripherally throughout the body, most notably in adipose tissue and nerve tissue innervating the gastrointestinal tract 4. CB1 is also found in the adrenal gland, liver, muscle tissue, pituitary gland, testis and thyroid gland 4. The CB2 receptors are primarily in the lymphoid tissue and peripheral macrophages. There are two well-characterized endogenous cannabinoids (ECs) located in the brain and periphery. The first identified was anandamide (arachidonoylethanolamide, AEA), named from the Sanskrit word ananda, meaning “bliss”. The second was 2-arachidonoylglycerol (2-AG). AEA and 2-AG have similar binding affinity for CB1 and CB2 receptors. 2-AG has been shown to have higher efficacy at the CB2 receptor and acts as a full agonist at both the CB1 and CB2 receptors, whereas AEA is only a partial agonist 5. Most ECs act under demand or need, in response both to physiological and pathological stimuli. AEA is formed by hydrolysis of N-arachidonoyl ethanolamine by a phospholipase D, whereas 2-AG is formed following hydrolysis of phosphatidylinositol by phospholipase C and diacylglycerol lipase. Following synthesis, AEA and 2-AG are released, in the CNS, from postsynaptic neurones into the extracellular space and, travelling retrogradely, bind to presynaptic CB1 receptors. The overall effect is inhibition of the release of the resident neurotransmitter of the presynaptic neurone, whether excitatory (e.g. glutamate) or inhibitory (e.g. GABA). Both ECs are quickly metabolized and hydrolized by a fatty acid amide hydrolase (FAAH) and a monoacylglycerol lipase, respectively, in inactive compounds. Endocannabinoid activity. – Clinical and experimental studies have demonstrated that ECs and the concurrent activation of their CB1 receptors result in a plethora of effects, among them: 1) involvement in antinociceptivity, 2) movement control and short term memory inhibition, 3) ansyolitic effect through action on hypothalamus-hypophysis-adrenal axis, 4) food intake modulation 6. The results of studies in rodents suggest that the endocannabinoid system (ECS), acting in the CNS and at peripheral sites, such as in adipose and in muscle tissue, as well as in the liver and gastrointestinal tract, may play an essential role in integrating nutrient intake, lipid and glucose metabolism and fat storage 7. Studies conducted on the effects of THC have shown that this substance increases food intake and the body weight of experimental animals 7. Knockout mice lacking CB1 receptors show a lean phenotype, primarily as a result of spontaneously reduced caloric intake 7. Indeed, when such animals are fed a high-fat, obesity-promoting

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diet, they remain lean, and compared with wild-type animals, show low plasma insulin levels. In another experiment, levels of 2-AG and AEA were measured in the rat brain during fasting, feeding and after satiation. Levels of the ECs were very high in the mesolimbic area of the fasting, but lower in the feeding animals, suggesting this area is involved in motivational behavior to find and consume food 8. Stimulation of CB1 in adipose tissue induces lipoprotein lipase activity, while blockade causes up-regulation of the protein adiponectin which is able to increase free fatty acid oxidation and insulin sensitivity in skeletal muscle and liver. Moreover in skeletal muscle, CB1 stimulation reduces insulin-mediated glucose uptake, while, in the liver, leads to increases in de novo lipogenesis, and in the gastrointestinal tract food deprivation causes increase of AEA levels, suggesting a peripheral hunger signal. Effects of CB1 receptors selective blocking. – Multiple studies also indicate that the ECS is overactive in overweight and obese humans. Engeli et al. 9 demonstrated that obese women have elevated circulating levels of the ECs and reduced activity of FAAH. Sipe et al. 10 showed that overweight and obese individuals have an approximately two-fold increased frequency of an abnormal FAAH gene, resulting in decreased activity of this EC-inactivating enzyme. Multiple lines of evidence in both human and animal models suggest that over-activity of the ECS is intimately involved in management of weight, energy and metabolism. As such, interruption of ECS over-activity may provide an attractive therapeutic target for management of the increased cardiometabolic risk associated with overweight and obesity. Rimonabant, an orally available selective CB1 antagonist, has shown promise in both animals and humans in the treatment of cardiometabolic risk, especially in patients who are overweight, obese or have type 2 diabetes mellitus (T2DM) 11. The drug has been examined extensively in a series of clinical trials titled the “Rimonabant In Obesity (RIO) trials”. In these clinical trials the effect of treatment on cardiometabolic disorders associated with visceral adiposity and insuline resistence have been examined 12. The RIO-North America study and RIO-Europe study examined the effects of rimonabant on weightstable patients with a body mass index (BMI) greater than or equal to 30, or a BMI greater than 27 with treated or untreated dyslipidemia or hypertension. The RIO-Lipids study examined the effects of rimonabant on overweight or obese patients with dyslipidemia. The RIO-Diabetes study examined the effects of rimonabant on patients with T2DM. The treatment period lasted 1 year for all RIO trials except RIONorth America, at the conclusion of which there was an additional randomization for a second year of treatment. The results of RIO trials were highly consistent in terms of both efficacy and tolerability/safety outcomes. Treatment with rimonabant 20 mg/d

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resulted in marked and significant improvements compared with placebo in body weight and waist circumference, as well as HDL cholesterol, triglycerides, HbA1c, insuline resistence. Moreover, the cardiometabolic benefits achieved with rimonabant treatment were sustained for up to 2 years. The magnitude of these benefits has been greater than what would be expected from weight reduction alone, suggesting direct effects of the drug on cardiometabolic parameters. Thus, a therapy which consists of a CB1 receptor blockade as an adjunct to lifestyle modifications may significantly improve multiple cardiometabolic risk factors in overweight and obese patients in clinical practice 13. References 01. Gaoni Y, Mechoulan R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964;86:1646-7. 02. Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannbinoid receptor in rat brain. Mol Pharmacol 1988;34:605-13. 03. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61-5. 04. Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LI. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 2004; 47 (Suppl 1):345-58. 5. Sugiura T, Kondo S, Sugawara A, Nakane S, Shinoda A, Itoh K et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 1995;215:89-9. 06. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev 2006;8: 585-9. 07. Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert M. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 2003;112:423-31. 08. Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation by 2-arachidonoyl glycerol. Br J Pharmacol 2002; 136:550-7. 09. Engeli S, Böhnke J, Feldpausch M, Gorzelmak K, janke J, Bátkai S. Activation of the peripheral endocannabinoid system in human obesity. Diabetes 2005;54:2838-43. 10. Sipe JC, Waalen J, Gerber A, Beutler E. Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH). Int J Obes 2005;29: 755-9. 11. Bronander KA, Bloch MJ. Potential role of the endocannabinoid receptor antagonist rimonabant in the management of cardiometabolic risk: a narrative review of available data. Vasc Health Risk manag 2007;3:181-90. 12. Lillo JL. The endocannabinoid system as a novel approach for managing obesity. J Am osateopath Assoc 2007;107 (Suppl 2):512-20. 13. Jensen MD. What is the potential role of cannabinoid-1 receptor blockade in glucose and lipid management? Am J Med 2007;120(9A):S25-32.

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New drugs (DS) for chronic hepatitis B and C A. Pampana Fifth Unit of Internal Medicine, S.Chiara Hospital, Pisa, Italy

CHB. – Finite therapy (T) with interferons (IFNs) or nucleot(s)ide analogues (NUCs) (aim: off-T sustained virological response/SVR) or long term T with NUCs (aim: on-T virus suppression) are now proposed. IFNs have many side effects (AE). NUCs, orally taken hepatitis B virus (HBV) reverse transcriptase inhibitors, have few (often none) AE, but resistance (R) to NUCs may appear. R is related to A) high genetic variability of HBV; single mutation (mut) giving R to a d may be present before NUCs T, which selects it; B) HBV cccDNA (archive, not eradicated by T, of all the muts developed on T) in infected hepatocyte nucleus; C) potency of d (rate of viraemia fall and time to obtain the fall; the higher the potency the lower the risk of R); D) d genetic barrier (n of muts needed for R). 3 types of NUCs exist: Acyclic Nucleotides (Adefovir/ADV, Tenofovir/TDV, Alamifovir), D-Nucleosides (Entecavir/ETV), L-Nucleosides (Lamivudine/LAM, Emtricitabine/FTC, Telbivudine/LdT, Clevudine/LFMAU, Elvucitabine, Valtorcitabine).. NUCs may induce R to a d (even more potent) of the same or other type or to multiple NUCs. LAM can induce R to many other NUCs, included ETV. De novo combination T may prevent multi-d R. An increase of HBVDNA (1 log) and/or of ALT value on NUC T calls for a genotipic resistance test. R induces disease or existing cirrhosis progression and higher risk of death after liver transplantation (LT); LT needs negative HBV viraemia, so needs NUCs action. 5 years monoT R rate in naive patients/pts for marketed NUCs is: LAM 80%, ADV 29%, ETV (highest potency) 1,2%. ADV and ETV are used in LAM resistant pts. LdT. – Clinical trials: higher potency, lower rate of R than LAM or ADV 1, 2. 2 years monoT R rate: HBeAgpts 9%, HbeAg+ pts 22%. Once day dose (600 mg) to be adjusted with crcl <50 mL/min, not for hepatic impairment. AE: respiratory infections, fatigue, abdominal pain, headache, cough, myopathy, lactic acidosis+steatosis and death (as for other NUCs); CHB exacerbations after discontinuation. EMEA and Health Canada recently gave a new warning: risk of peripheral neuropathy (pn) (rare on LdT monoT) with LdT+PegIFN/α-2a. Pn (not known if reversible stopping T or if occurs using LdT+other IFNs) usually starts 3 months after initiation of T. TVD. – (Once day dose 300 mg; fixed-dose +FTC, once day dose). More potent than ADV: active against LAM resistant strains 3, well tolerated and more active than ADV in HBV compensated cirrhosis 4. MonoT does not induce significant viraemia fall in ADV resistant pts (fall with TDV+FTC) 5. AE: nausea, vomiting, diarrhea, asthenia, hepatotoxicity, abdominal pain, arf, Fanconi syndrome, proteinuria, tubular necrosis

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(accumulation in proximal tubule, more at high concentration). Bone disease and pathologic fractures, probably related to renal tubular and Ph/Ca metabolism alteration, are signalled in CHB treated pts. FTC. – ADV+FTC: HBVDNA significant fall over 96 weeks of T 6. In HBeAg- pts both FTC+LFMAU and FTC alone have a good antiviral response at week 24 (no R in FTC-naive, 7% R in FTC-experienced pts). LMFAU. – Once-daily (30 mg) d well tolerated and potent in previous studies. 24-week LFMAU T: sustained antiviral effect without R in HBeAg- pts. Longer T needed for durable remission 7. Italian guidelines for HBV T and prophylaxis in immunocompromised pts have been published 8. A strategy, from diagnosis of infection and disease to appropriate T, must be tailored for each CHB pt. Italian guidelines to clarify who, when and how treat, will be soon published 9. CHC. – P+Ribavirin (RBV) is the Standard T (ST), with different schedules and stopping rules according to hepatitis C virus (HCV) genotype (G) (SVR: all Gs 66%, G1 60%). To increase SVR, to treat nonresponders (nr) and relapser, to decrease AEs, are now proposed: 1) Response-Guided T (shorter or longer T); early predictors of response (RVR, Rapid Virologic Response = HCVRNA<50 IU/ml at week 4, EVR, Early Virologic Response=HCVRNA- or>2 log10 drop at week 12) are used; 2) maintaining RBV dose; 3) high induction P doses, high RBV doses; 4) comparative studies (P α-2a versus P α-2b); 5) new ds: a) specifically targeted antiviral T for CHC (STAT-C); b) new immunomodulatory ds (i.e. new IFNs); c) ds active on fibrosis. STAT-C ds: Protease inhibitors and no NUC Polimerase inhibitors, both G dependent, rapidly inducing R, are in advanced phase of study. MonoT induces R, that may be escaped combining 1) low genetic barrier ds+P+RBV or 2) non crossresistant ds with high genetic barrier. Protease inhibitors. Telapravir/TVR. – NS3/4A inhibitor. Phase Ib: +P α-2a greater viral load drop 10 than on monoT (750 mg tid). Phase II, PROVE 2 study: TVR+P α2a+RBV have greater, TVR+P α-2a lower efficacy than ST in naive G1 pts. Frequent AE: rash, more severe in TVR+P+RBV arm, and anemia. Breakthroughs in TVR arms are due to known muts (rate: TVR+P>TVR+ P+RBV); TVR R does not preclude response to ST 11. Boceprevir. – NS3 serine protease inhibitor. Phase I: monoT or +P α-2a in nr to ST. Ongoing Phase II: a) Boceprevir (100-800 mg tid)+P α-2b±RBV dose-finding study in nr to ST; b) Study in naive HCV pts: Boceprevir, 800 mg tid,+P α-2b+RBV have a high rate of EVR (79% HCVRNA- at week 12 versus 34% on ST alone). AE: fatigue, headache, nausea and anemia. Polimerase inhibitors. R1626. – Phase II: R1626+P α-2a±RBV show robust antiviral effect (81% HCVRNA- at week 4); R1626 dose limiting AE is neutropenia (12). It shows high genetic barrier 13.

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R7128. – Phase I: monoT, well tolerated, with significant, dose-dependent HCV suppression after 14 days. Phase II: R7128 (500 bid)+P α-2a+RBV show good potency and a safety profile similar to ST. Dose escalation (to 1500 mg bid)+P+RBV trial is ongoing 14. New IFNs Albuferon. – Albumin-conjugated IFN α-2b with 6 days half-life, in Phase II studies, given up to 1200 mg every 2 or 4 weeks+RBV, shows an efficacy/safety profile similar to that of ST in naive G1,2 or 3 pts. Phase III studies are ongoing. References 01. Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y et al. Telbivudine versus lamivudine in patients with chronic hepatitis B N Engl J Med 2007;357(25):2576-2588. 02. Chan HL, Heathcote EJ, Marcellin P, Lai CL, Cho M, Moon YM et al. Treatment of hepatitis B e antigen + chronic hepatitis with telbivudine or adefovir: a randomized trial Ann Intern Med 2007;47(11):745-754. 03. Manns M, Jeffers L, Dalekos G, Berg T, Trepo C, Roberts S et al. The antiviral response to Tenofovir Disoproxil (TDF) is comparable in Lamivudine (LAM)–naive and Lamivudineexperienced subiects treated for Chronic hepatitis B (CHB). 43rd annual meeting of the EASL. Milan, Italy. April 23-27, 2008. J Hepatol 2008;18(Suppl 2):S33. 04. M Buti, S Hadziyannis, P Mathurin, Urbanek P, Sherman M, Strasser S et al. Tenofovir disoproxil fumarate (TDF) is highly active for treatment of chronic hepatitis B in subjects with cirrhosis. 43rd annual meeting of the EASL Milan, Italy. April 23-27, 2008. J Hepatol 2008;18(Suppl 2):S33. 05. Berg T, Moller B, Trinh H, Chan S, Marcellin P, Suarez A et al. Tenofovir disoproxil fumarate (TDF) versus Emtrice plus TDF for treatment of chronic hepatitis B (CHB) in subjects with persistent viral replication receiving adefovir dipivoxil (ADV). 43rd annual meeting of the EASL. Milan, Italy. April 23-27, 2008. J Hepatol 2008;18(Suppl 2):S34. 06. Hui CK, Zhang HY, Bowden S, Locarnini S, Luk JM, leung KW et al. 96 weeks combination of adefovir dipivoxil plus emtricitabine vs. adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B J Hepatol 2008;48(5):714720. 07. Yoo BC, Kim JH, Koch KC, Um SH, Kim YS, Lee KS et al. Clevudine is highly efficacious in hepatitis B e ag egative chronic hepatitis B with durable off-therapy viral suppression Hepatology 2007;46(4):1041-1048. 08. Marzano A, Angelucci E, Andreone P, Brunetto M, Bruno R, Burra P et al. Prophylaxis and treatment of hepatitis B in immunocompromised patients Dig Liv Dis 2007;39(5): 397-408. 09. Carosi G, Rizzetto M Treatment of chronic hepatitis B: raccomendations from an italian workshop Dig Liv Dis 2008, in press. 10. Kieffer TL, Sarrazin C, Miller JS, Welker MW, Forestier N, Reesink HW et al. Telaprevir and pegylated interferonalpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication Hepatology 2007 Sep;46(3):631-639. 11. Dusheiko GM, Hezode C, Pol S, Goeser T, Bronowicki JP, Bourliere M et al. Treatment of chronic hepatitis C with Telapravir (TVR) in combination with peginterferon alfa 2a with or without Ribavirin: further interim analysis results of the PROVE 2 study. 43rd annual meeting of the EASL. Milan, Italy. April 23-27, 2008. J Hepatol 2008;18Suppl 2):S26.

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12. Pockros PJ, Nelson D, Godofsky E, Rocrigue-Torres M, Everson GT, Fried MW et al. Robust Synergistic Antiviral Effect of R1626 in Combination with Peginterferon alfa2a (40KD), with or without Ribavirin. Interim Analysis Results of Phase 2a Study (Presidential Plenary III). 58th Annual Meeting of the AASLD. Boston, MA. November 2-6, 2007. Abstract (oral) 167. Hepatology 2007;46(Suppl 1):311A. 13. Le Pogam S, Seshaadri A, Kang H, Kosaka A, Hu S, Symons J et al. Low level of resistance, low viral fitness and absence of resistance mutations in baseline quasispecies may con-

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tribute to high barrier to R1626 resistance in vivo. 43rd annual meeting of the EASL. Milan, Italy. April 23-27, 2008. J Hepatol 2008;18(Suppl 2):S10. 14. Reddy R, Rodriguez-Torres M, Gane E, Robson R, Lalezari J, Everson GT et al. Antiviral Activity, Pharmacokinetics, Safety, and Tolerability of R7128, a Novel Nucleoside HCV RNA Polymerase Inhibitor, Following Multiple, Ascending, Oral Doses in Patients with HCV Genotype 1 Infection Who have Failed Prior Interferon. 58th Annual Meeting of the AASLD. Boston, MA. November 2-6, 2007. LB Abstract 9. Hepatology 2007;46(Suppl 1):862A.

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FREE COMMUNICATIONS Ultrasound-guided cannulation of the common femoral vein in the Emergency Department V. Corsoni1, C. Zeloni2, E. Meucci1, A. Cartei1, G. Bandinelli1, A. Lagi1, S. Cencetti1 1Department of Emergency Medicine, Santa Maria Nuova Hospital, Florence, Italy; 2Department of Emergency Medicine, Misericordia e Dolce Hospital, Prato, Italy

Aim. – Patients admitted to the Emergency Department often require catheter insertion in a central vein, mainly for infusion of large amounts of fluid, for prolonged intravenous infusion of drugs and for lack of other peripheral venous access. When a venous access is required in critically ill patients, emergency physicians prefer to obtain it via the common femoral vein 1. Cannulation of the femoral vein has already been proved as a safe approach, though fewer and less severe complications seem to affect the subclavian approach but only when it is obtained by fellows of the Intensive Care Departments 2. Nonetheless, since several complications still affect the femoral approach 2-5, mainly due to anatomical variations in vessel diameters and relationships 6-10, a safer procedure looks necessary 11. Several studies stated that ultrasound-guided cannulation of the femoral vein represents a safer procedure in comparison to the traditional blind, external landmark-technique (12-14). In our Emergency Departments ultrasound-guided cannulation of the femoral vein was started 2 years ago by some skilled physicians. The purpose of the present study was to evaluate whether the ultrasoundguided technique could improve the safety of the procedure when compared to the traditional landmarkguided procedure, with a particular aim to evaluate the efficacy of the application of supplementary manoeuvres that have been demonstrated useful for improving femoral vein cannulation (e.g. Valsalva, decubitus change) 1, 10, 12. Methods. – We studied prospectively patients undergoing femoral vein cannulation in our Departments from April 2006 up to December 2007. The studied series did not include all the consecutive patients undergoing femoral vein cannulation in our Departments, but only included the consecutive patients undergoing this procedure when at least one of the Authors was present. The patients were not assigned to the ultrasound-guided or to the landmark-guided technique following blind randomized criteria, but simply depending upon the fact that the physicians who was performing the cannulation was skilled and well trained on ultrasound-guided technique or was

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not. When a femoral vein could not be cannulated with the landmark-guided technique, the case was considered as dropped-out from the study independently from the fact that the vascular access was then obtained via the ultrasound-guided technique or via the subclavian vein; when the ultrasound-guided approach did not allowed to obtain the vascular access, the case was as well considered as droppedout. The study included 87 patients (39 males and 48 females) aging 27-92 years (mean age 68.6 years): in 41 patients the ultrasound-guided technique was used, while the landmark-guided cannulation was attempted in the other 46 patients. A subset of patients was arbitrarily considered to be “difficult stick” for the insertion of the venous catheter when matching one the following criteria: obesity, burned skin, major trauma, shock. Table 1 displays the characteristics of both groups. The blind external landmark technique was as usual performed by manual localization of the femoral artery pulse in the femoral triangle inferior to the inguinal ligament, with needle insertion medial to the artery. The ultrasound-guided technique was performed in the same location with the aid of an ultrasound scanner (AU4, Esaote, Italy, and Logic 4000, General Electrics, USA), using the 7.5 Hz linear beam covered by a sterile sheath. The ultrasound scan produced a two-dimensional display image that allowed discriminating between femoral artery and vein by compressibility of the vein (B-mode imaging) and Doppler spectra (pulsed-Doppler examination); furthermore, the topographic relationship between artery and vein, as well as their abnormalities that could interfere with the venous access, could be identified at a first look by the ultrasound scan. Valsalva manoeuvre was not considered in this study, since it was rarely performed to facilitate vein cannulation because a large amount of the studied patients were not able to cooperate. Reverse Trendelenburg decubitus at 15 degrees was adopted both when the first venous puncture failed and when the ultrasound image revealed any anathomic variation that could worsen the result of the vein puncture (e.g. artery located anteriorly to the vein). The following parameters were evaluated for the study: a) number of femoral veins that were successfully cannulated, b) number of veins that were successfully cannulated at the first attempt, c) number of attempts (i.e. needle thrusts) that were necessary for a successful cannulation; d) number of cases in which the reverse Trendelenburg manoeuvre was performed, e) number of complications (i.e. femoral artery puncture, early formation of haematoma, femoral nerve irritation). We specify that femoral ner-

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ve irritation was recorded when a patient complained of acute pain down the ipsilateral lower limb while needle advancing. Other catheter-related complications, such as deep venous thrombosis, local infections, abscess formation, and sepsis were not recorded because most of the patients were soon moved from the Emergency Department to other Departments, thus far follow up was not possible. Furthermore, only referring to the group of the ultrasoundguided technique, the number of cases with femoral artery overlapping the femoral vein (from 50%to 100% of the estimated arterial lumen on B-mode imaging) was recorded. Data were statistically compared by means of two-tailed Student’s t test for independent measurements, Fisher’s exact test, or Mann-Whitney U test. Statistical significance was defined for p <0.05. Results. – Only one patient who was suffering from severe hemorrhagic shock could not be successfully cannulated with the ultrasound-guided technique and requested for subclavian insertion of the venous catheter (drop-out), while in 6 cases the landmark-guided technique did not allowed insertion of the catheter in the femoral vein (drop-out). Thus far, the rate of successful cannulation was 97.6% for the ultrasound-guided insertion versus 89.1% (p <0.01) with the landmark-guided technique. Cannulation of the common femoral vein resulted as successful at the first attempt in 31 cases with the ultrasound-guided insertion (75.6%) versus 60.9% (28 cases) of the patients undergoing landmark-guided insertion (p <0.05). Among the 18 cases of failure at the first attempt of venous catheter insertion at the first attempt, 12 cases were then positioned in reverse Trendelenburg decubitus at 15 degrees: the second needle insertion was able to cannulate the vein in 2 of the 6 cases who remained in the horizontal decubitus, and in 3 of the patients in the reverse Trendelenburg position, thus displaying no statistically significant benefit from this manoeuvre with the landmark-guided technique. In 11 patients, ultrasound B-mode imaging revealed the femoral artery being in the anterior position (differently from what commonly expected), thus overlapping the femoral vein: 6 patients were positioned in reverse Trendelenburg before needle insertion, with a rate of success at the first attempt corresponding to 4/5 cases in the horizontal decubitus, and 5/6 in the reverse Trendelenburg position, thus demonstrating no statistically significant benefit from this manoeuvre. Among the other 9 patients that were not successfully cannulated at the first attempt with the ultrasound-guided technique, 5 were then positioned in reverse Trendelenburg: the second attempt was successful for 2 patients of each position, with no statistically significant difference between the two positions. The average number of attempts (i.e. needle insertions) that were necessary when the first catheter failed was 3.2 ± 1.6 for the ultrasound-guided technique and 4.9 ± 2.4 for the landmark-guided technique (p <0.05). Femoral nerve irritation compli-

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Table I. – Demographic characteristics of the patient.

Age (years) Gender (M:F) “Difficult stick”

Ultrasound Guidance (n = 41)

Landmark Guidance (n = 46)

p

69.4 ± 29.2

67.8 ± 33.4

n.s.

18:22

21:25

n.s.

17

18

n.s.

cated 1 cannulation for each technique applied (p n.s.). Early haematoma formation occurred in 1 patient with the ultrasound guidance, and in 2 patients with the traditional technique (p n.s.). Arterial puncture occurred in 6 cases (14.6%) with the ultrasound-guided technique and in 11 (23.4%) with the landmark guidance (p <0.05). Conclusion. – Our data confirm that the ultrasound-guidance represents a useful aid for the insertion of femoral vein catheters, in comparison to the traditional blind external landmark-guided technique. This is in according to previous reports from the Emergency Department 13, 14 and Internal Medicine 12. Our series did no show any significant difference for the numbers of “difficult” cases undergoing one the two different techniques, therefore the presence of “difficult sticks” did not introduce any bias in comparing the results from the two groups (Table I). The total number of successful cannulations and cannulations performed at the first attempt, as well as the lower numbers of attempts and arterial punctures, stress the benefit of adopting ultrasound guidance for inserting a central catheter in the femoral vein. It must be remarked the our results in terms of successful cannulations, total punctures and complications were slightly worse than the data presented in previous studies 1-4, 10, 12-14. We do not have a definite answer for explaining this difference, but we think that it can be related to the older age of our series, that better represents the reality of the patients admitted to any Italian Emergency Department. It must be noted that accessories manoeuvres, such as the reverse Trendelenburg position, did not improve the results in our series: this is not in agreement with the previous reports 1,10,12, but both the reduced dimensions our sample and the difficulties in comparing patients and conditions from different study designs can reasonably account for this discrepancy. In conclusion, there are evident proofs for claiming the need of adopting ultrasound-guided technique for the femoral vein cannulation in every Emergency Department. References 01. Stone MB, Price DD, Anderson BS. Ultrasonographic investigation of the effect of reverse Trendelenburg on the cross-sectional area of the femoral vein. J Emerg Med 2006;30:211-3 02. Hamilton HC, Foxcroft DR. Central venous access sites for the prevention of venous thrombosis, stenosis and infec-

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tions in patients requiring long-term intravenous therapy. Cochrane Database Syst Rev 2007;18:CD004084 03. Purdue GF, Hunt JL. Vascular access through the femoral vessels: indications and complications. J Burn Care Rehabil 1986;7:498-500 04. Wlliams JF, Seneff MG, Friedman BC, NcGrath BJ, Gregg R, Sunner J, Zimmerman JE, et al. Use of femoral venous catheters in critically ill adults: prospective study. Crit Care Med 1991;19:550-3 05. Trottier SJ, Veremakis C, O’Brien J, Auer AI. Femoral deep vein thrombosis associated with central venous catheterization: results from a prospective, randomized trial. Crit Care Med 1995;23:52-9. 06. Macchi C, Corcos L, Cecchi F, Giannelli F, Repice F, Gheri G. Internal diameters of human femoral blood vessels in 50 healthy subjects using color Doppler ultrasonography. Ital J Anat Embryol 1996;101:107-14. 07. Baum PA, Matsumoto AH, Teitelbaum GP, Zuurbier RA, Barth KH. Anatomic relationship between the common femoral artery and vein: CT evaluation and clinical significance. Radiology 1989;173:775-7. 08. Hertzberg BS, Kliewer MA, DeLong DM, Lalouche KJ, Paulson EK, Frederick MJ, et al. Sonographic assessment of lower limb vein diameters: implications for the diagnosis and characterization of deep venous thrombosis. AJR 1997;168:1253-7. 09. Hughes P, Scott C, Bodenham A. Ultrasonography of the femoral vessels in groin: implications for vascular access. Anaesthesia 2000;55:1198-202. 10. Fronek A, Criqui MH, Denenberg J, Langer Rd. Common femoral vein dimensions and hemodynamics including Valsalva response as a function of sex, age, and ethnicity in a population study. J Vasc Surg 2001;33:1050-6. 11. Gadallah MF, White R, Vickers B, El-Shahawy M, Work J. Awareness of internal jugular, subclavian, superior vena cava and femoral venous anomalies may reduce morbidity of acute venous catheter procedures. Clin Nephrol 1996;44:345-8. 12. Kwon TH, Kim YL, Cho K. Ultrasound-guided cannulation of the femoral vein for acute hemodialysis access. Nephrol Dial Transplant 1997;12:1009-12. 13. Hilthy WM, Hudson Pa, Levitt MA, Hall JB. Real-time ultrasound-guided femoral vein catheterization during cardiopulmonary resuscitation. Ann Emerg Med 1997;29: 331-6. 14. Miller AH, Roth BA, Mills TJ, Woody JR, Longmoor CE, Foster B. Ultrasound guidance versus the landmark technique for the placement of central venous catheters in the emergency department. Acad Emerg Med 2002;9: 800-5.

Safety and efficacy of prolonged bivalirudin infusion after urgent and complex PCI B. Cortese1, A. Micheli1, A. Picchi1, S. Severi2, U. Limbruno1 1U.O. Emodinamica; 2U.O. Cardiologia; Dipartimento Cardiologico, Ospedale della Misericordia, Grosseto, Italy

Aim. – The addition of GP IIb/IIIa inhibitors (GPI) to unfractionated heparin (UFH) during percutaneous coronary intervention (PCI) has shown to improve

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both angiographic and clinical outcomes and is recommended by the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the treatment of patients (pts) with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) 3, 4. The direct thrombin inhibitor bivalirudin has also received a Class I recommendation in the ACC/ AHA and ESC guidelines for pts with NSTE-ACS undergoing an early invasive strategy 3, 4. Although the EMEA and FDA approved labeling for bivalirudin allows for lowdose prolonged post-procedure administration, this practice is not routine. Therefore, clinical trial data of bivalirudin do not reflect the impact of a longer postprocedural infusion 5. We theorized that a lack of post-procedure antithrombotic therapy, a timeframe of critical importance due to the thrombogenicity of the procedure, may contribute to increased rates of ischemic outcomes during the post-PCI timeframe. We hypothesized that a prolonged infusion of bivalirudin would be equivalent to UFH plus a GPI in protecting myocardium from thrombotic complications occurring just after PCI, expressed by CK-MB release. In the present analysis, we evaluated the incidence of procedural-related myocardial infarction (MI) and clinical outcomes in pts with ACS undergoing complex PCI with bivalirudin as a prolonged, postPCI infusion versus UFH plus a GPI. Methods Study population and procedures. – The study population consisted of 109 pts. From our database we retrospectively searched pts with ACS undergoing PCI with complex coronary lesions in year 2007 and compared two groups of pts, one treated with UFH + GPI in the catheterization laboratory (n=59), the other treated with bivalirudin during the procedure followed by a prolonged infusion post-PCI (n=50 pts). PCI lesion complexity was based upon the ACC/AHA classification of coronary lesions 6 and the length of stent used. On admission, all pts were treated with 250 mg aspirin, clopidogrel loading dose (unless the patient was on chronic therapy) and UFH (100 IU/kg bolus and 18 IU/kg/hour infusion). As per our common practice, UFH infusion was discontinued about 1/2 hour prior to coronary angiography. Per our institutional practice and the ACC/AHA guidelines, pts were considered to be adequately treated with clopidogrel if they were on chronic therapy or had been treated with a loading dose of 600 mg >2 hours or 300 mg >6 hours before PCI 4. Coronary angiography was performed by standard percutaneous techniques using the radial approach as the preferred route. CK-MB measurements were made between 8-12 hours and at 24 hours post-PCI. During PCI unfractionated heparin was administered as repetitive boluses in order to achieve an activated clotting time (ACT) between 200-250 seconds.

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We did not practice UFH infusion after PCI. Either eptifibatide or abciximab were administered as an intravenous (IV) bolus dose in the catheterization laboratory followed by a prolonged (12 hour) post-procedure infusion. Bivalirudin was initiated as an IV bolus of 0.75 mg/kg followed by a 1.75 mg/kg/h infusion for the duration of PCI, and a post-PCI infusion of 0.25 mg/kg/h for 4 hours. At the end of procedure all patients not correctly pre-treated with clopidogrel received a loading dose. Procedural success was defined as target lesion final stenosis <50% with TIMI grade 3 flow. Study endpoints. – The primary endpoint was procedural-related MI defined as 1) the development of new Q-waves on an ECG or, 2) a postprocedural CKMB elevation >3 times the upper limit of normal (for pts with normal pre-procedural values) or a value >150% of the last measurement prior to PCI (for pts with elevated pre-procedural CK-MB) 7. Secondary endpoints included 1) 30-day major adverse cardiac events (MACE), defined as death, Q-wave MI, or target vessel revascularization, and 2) 30-day non-CABGrelated major and minor bleeding. Non-CABG major bleeding was defined as intracranial, retroperitoneal, or intraocular bleeding, access site hemorrhage requiring intervention, ≥5 cm diameter hematoma, reduction in hemoglobin of ≥4 g/dL without or ≥3 g/dL with an overt bleeding source, reoperation for bleeding, or blood product transfusion. Minor bleeding included all other bleeding not meeting the criteria for major bleeding 8. Results Study population. – As shown in Table 1, there were no significant differences in the baseline clinical, procedural, and angiographic characteristics between the two groups. Approximately 50% of the overall population underwent PCI for non-ST-segment elevation MI; mean time from admission to angiography was approximately 20 hours in both groups (p=NS). Eptifibatide and abciximab were used in 57% and 43% of pts in the UFH + GPI group, respectively. In the bivalirudin group, GPIs were used in 10% of pts for procedural complications. Mean ACT values were significantly higher in the bivalirudin group, a finding consistent with previous results 9. Coronary anatomy reflected complex lesions in most pts, with almost 90% of the overall population having a type B2/C culprit lesion and mean stent lengths of 30 and 28 mm in the UFH + GPI and bivalirudin groups. Despite the lesion complexity, procedural success was achieved in 98% and 100% of pts in the UFH + GPI and bivalirudin groups, respectively. Clinical outcomes. – There was no significant difference in the rates of periprocedural MI among pts treated with UFH + GPI compared with bivalirudin (11.9% vs 8.0%, p=NS) (Table II). No significant differences between the two groups were observed in the rates of 30-day MACE (8.5 vs. 6.0%, p =NS) or its components. Numerically lower major bleeding was obser-

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Table I. – Baseline Clinical, Procedural, and Angiographic Characteristics. UFH + GPI Bivalirudin P-value (n=59) (n=50)

Age, y (mean ± SD) Male, % Diabetes, % Prior MI, % CrCl <40 mL/min, % Mean pre-procedural Hgb, g/dL Unstable angina, % Baseline CK-MB elevation, % TIMI risk score ≥4, % Mean left ventricular ejection fraction, % Correct clopidogrel loading dose, % Time to angiography, hr (mean ± SD) GPI use, % Complex coronary lesions, B2/C type, % Mean stent length, mm (mean ± SD) ≥2 vessel PCI, % Procedure duration, min (mean ± SD) Procedural ACT, sec (mean ± SD)

69 (±9.4) 70 (±9.5) 69 71 23 19 8 10 12 9

NS NS NS NS NS

12.1 55 21 59

11.5 49 27 62

NS NS NS NS

49

51

NS

47

58

NS

23 ± 18.4 19 ± 15.9 NS 100 10 <0.05 89

87

NS

30 ± 24.1 28 ± 18.4 47 49

NS NS

93 ± 28.4 89 ± 32.5

NS

221 ± 108 299 ± 142 <0.05

Table legend: UFH, unfractionated heparin; GPI: glycoprotein GP IIb-IIIa inhibitors; MI, myocardial infarction; CrCl, creatinine clearance; Hgb, haemoglobin; TIMI, Thrombolysis in Myocardial Infarction; PCI, percutaneous coronary intervention; ACT, activated clotting time.

ved in the bivalirudin group (4.0% vs. 8.4%, p=0.07), and minor bleeding events were significantly lower in with bivalirudin compared to UFH + GPI (4.0 vs. 21%, p=0.01) (Table II). We did not register any stent thrombosis in both groups. Conclusion. – Results of this study demonstrate that, compared with UFH + GPI, the use of intraprocedural bivalirudin followed by a prolonged, postprocedure infusion provides similar protection from ischemic events but with fewer bleeding complications in pts with ACS undergoing complex PCI, in a real-world setting. In previous studies comparing bivalirudin to GPIbased regimens, such as the REPLACE-2, ACUITY, and HORIZONS trials, the bivalirudin infusion was generally discontinued at the end of the procedure, while the GPI infusion was maintained for at least 12 hours per current guideline recommendations 8, 10, 11 (G.W. Stone, oral communication, TCT 2007, Washington D.C.).

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Table II. â&#x20AC;&#x201C; Clinical Outcomes. UFH + GPI Bivalirudin P-value (n=59) (n=50)

Periprocedural MI, % Final MBG 2 or 3, % 30-Day MACE, % Death Q-wave MI Target vessel revascularization 30-Day Major Bleeding, % 30-Day Minor Bleeding, % Stent Thrombosis, %

11.9 82.0 8.5 3.4 1.7 3.4 8.5 20.3 0

8.0 77.0 6.0 2.0 2.0 2.0 4.0 4.0 0

NS NS NS NS NS NS 0.07 0.01 NS

UFH, unfractionated heparin; GPI: glycoprotein GP IIb-IIIa inhibitors; MI, myocardial infarction; MBG, myocardial blush grade, MACE, major adverse cardiovascular events.

The Bivalirudin Angioplasty Trial was the first study to provide data on the safety and efficacy of a prolonged bivalirudin infusion 12. In this trial, 4312 pts with unstable or post-infarction angina were randomized to receive bivalirudin as a 1.0 mg/kg IV bolus dose followed by a 4-hour infusion of 2.5 mg/kg/h and a 14- to 20-hour infusion of 0.2 mg/kg/h or UFH as a 175 U/kg bolus followed by an 18- to 24-hour infusion of 15 U/kg/h. The primary composite endpoint of death, MI, or revascularization at 7 days occurred significantly less in the bivalirudin group compared to the UFH group (6.2% vs 7.9%, p=0.039). Differences persisted at 90 days (p=0.012) and 180 days (p=0.153). In addition to reduced adverse ischemic events, bivalirudin therapy was associated with significantly fewer bleeding complications (3.5% vs 9.3%, p<0.001). Porto and coworkers, using intravascular ultrasound and delayed-enhancement magnetic resonance imaging 13, have recently shown how during the first hours after successful PCI the risk of MI is higher in patients that experience small collateral vessel closure, stent thrombosis and distal plaque embolization. Several randomized clinical trials have shown the efficacy of GPI in terms of reduction of proceduralrelated MI 14, 15. In a recent pharmacodynamic investigation, the Clear Platelets study, at the top of clopidogrel administration given just after the procedure, a strategy of eptifibatide given during elective PCI showed a significantly lower occurrence of procedural-related MI compared to placebo 16. However, GPI use has often been associated to higher incidence of life-threatening, major and minor bleedings 8, 17. Moreover, in a double blind, randomized study, the Protect TIMI 30 trial, where bivalirudin was compared to eptifibatide in ACS patients undergoing PCI 9, among patients who were CK MB negative at baseline the bivalirudin group showed a significant increase in CK MB release after PCI, probably reflecting the lack of antithrombotic protection during the first hours after the procedure.

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The second point to underline derives from the preliminary results of the Horizons AMI trial, a direct comparison of bivalirudin and heparin + GPI during primary PCI; data showed a significantly lower incidence of cardiac death in the bivalirudin group, firstly ascribed to the fewer major, life-threatening haemorrages. Anyhow, in the bivalirudin group an increased incidence of acute stent thrombosis after primary PCI was found, even if rate of 1 month stent thrombosis was not different between the two groups (G.W. Stone, oral communication, TCT 2007, Washington D.C.). These results have fueled several discussions after which a strategy of prolonged, post PCI bivalirudin infusion has been advocated (http://www.theheart.org/article/822861.do). One more point to highlight is the percent of patients correctly pretreated with a thienopyridine. The pharmacological trial Albion investigated different clopidogrel loading doses and their effects on the extent and rate of platelet inhibition in patients undergoing PCI for an ACS 18; a 600 mg loading dose resulted superior to a 300 mg dose only after 4 hours, reflecting an insufficient effect of the drug at these dosages during the first 4 hours. In our study around 50% in both groups received a correct clopidogrel loading dose. This is a low percentage, if compared to the recommendations of current PCI guidelines, that suggest to give a 300 mg loading dose at least 6 hours and a 600 mg dose at least 2 hours before the procedure 10. However, our data reflect a common, real world issue about guidelines adherence; in the Crusade registry only 60% of patients undergoing PCI for an ACS in the USA received clopidogrel during the first 24 hours after PCI (19). Similarly, a retrospective study showed that in the USA >50% of patients undergoing urgent PCI do not receive a clopidogrel loading dose 4 hours prior to the procedure 20. One of the major criticisms raised by the interventionalist community about previous sperimentation of this drug derived from a subgroup analysis of the trial Acuity 8, that showed how patients that did not receive a thienopyridine before PCI and were treated with bivalirudin had a significant increase in 30-day ischemic complications compared to patients treated with heparin + GPI (10.3 vs. 7.5%, p=0.03). Results of the present analyses provide support for our hypothesis, as pts with ACS undergoing complex PCI with bivalirudin followed by a prolonged infusion had lower, though not statistically significant, rates of periprocedural MI, results that persisted at 30 days. Moreover, rates of non-CABG major and minor bleedings were significantly lower with bivalirudin compared to UFH + GPI. A last consideration should be made about the increased cost that this strategy would provide; with our post-procedural infusion rate we used a double amount of drug with a consequent double final cost compared to a peri-procedural only use; even if we did not observe any increase of bleeding complica-

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tions, more detailed cost-to-benefit analyses should be made in bigger populations; a direct comparison of two different bivalirudin strategies could also provide more informations. A final comment should be made about our preferred route of intervention, the transradial one. In expert centers it has been associated to fewer local bleedings and similar procedural success as compared to the transfemoral one 21-23; however the last approach is the most used in western countries, therefore our findings could underestimate the advantage of prolonged bivalirudin infusion on an heparin + GPI strategy in terms of reduced local bleedings. Our sperimentation has several limitations. It is a monocentric, observational study, despite similar groups were analyzed. A bigger population and a randomized trial could confirm our findings about the safety and efficacy of this treatment. We are conducting a multicenter randomized clinical trial of direct comparison between a peri-PCI bivalirudin treatment and its prolonged, 4-hour post PCI infusion, in terms of reduction of periprocedural MIs. Its results will give some more informations about this proposed strategy. Another major concern is about the current price of the drug; an extensive, prolonged infusion could raise treatment costs limiting its widespread use. Finally, we have used an arbitrary post-PCI infusion rate of bivalirudin: other sperimentations are needed to confirm its value. Conclusion. â&#x20AC;&#x201C; The post-PCI window is a critical time for patients treated with PCI in Europe and the US. A strategy of a prolonged antithrombotic infusion after PCI could serve to improve outcomes. Prolonged use of UFH after PCI has been abandoned due to an inability to reduce ischemic complications and associated higher rates of bleeding. In the present analysis, we have shown that a prolonged bivalirudin infusion is effective in protecting myocardium after PCI without increasing bleeding rates, and represents an attractive alternative in the setting of NSTE-ACS. References 01. Karvouni E, Katritsis DG, Ioannidis JP. Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions. J Am Coll Cardiol 2003;41:26-32. 02. Kong DF, Hasselblad V, Harrington RA, White HD, Tcheng JE, Kandzari DE, Topol EJ, Califf RM. Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions. Am J Cardiol 2003; 92:651-5. 03. Bassand JP, Hamm CW, Ardissino D, Boersma, E, Budaj A., Fernandez-Aviles, F, Fox, K.A, Hasdai D, Ohman, E.M, Wallentin L, Wijns, W. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1598-660. 04. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American

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Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-STElevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50:e1-e157. 05. Waksman R. ACUITY-PCI: one drug does not fit all. Lancet 2007;369:881-2. 06. Ryan TJ, Bauman WB, Kennedy JW, Kereiakes, DJ, King SB, 3rd, McCallister BD, Smith SC Jr., Ullyot DJ. Guidelines for percutaneous transluminal coronary angioplasty. A report of the American Heart Association/American College of Cardiology Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Committee on Percutaneous Transluminal Coronary Angioplasty). Circulation 1993;88:2987-3007. 07. Tricoci P, Peterson ED, Chen AY, Newby LK, Harrington, RA, Greenbaum AB, Cannon CP, Gibson CM, Hoekstra J W, Pollack CV Jr., Ohman EM, Gibler WB, Roe MT. Timing of glycoprotein IIb/IIIa inhibitor use and outcomes among patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (results from CRUSADE). Am J Cardiol 2007;99:1389-93. 08. Stone GW, White HD, Ohman EM, Bertrand ME, Lincoff, AM, McLaurin BT, Cox DA, Pocock SJ, Ware JH, Feit F, Colombo A, Manoukian SV, Lansky AJ, Mehran R, Moses, JW. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet 2007;369:907-19. 09. Gibson CM, Morrow DA, Murphy SA, Palabrica TM, Jennings LK, Stone PH, Lui HH, Bulle T, Lakkis N, Kovach R, Cohen DJ, Fish P, McCabe CH, Braunwald E. A randomized trial to evaluate the relative protection against postpercutaneous coronary intervention microvascular dysfunction, ischemia, and inflammation among antiplatelet and antithrombotic agents: the PROTECT-TIMI-30 trial. J Am Coll Cardiol 2006;47:2364-73. 10. King SB, 3rd, Smith SC, Jr., Hirshfeld JW, Jr., et al. 2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee. Circulation 2008;117:261-95. 11. Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, Keren G, Carr J, Cohen EA, Betriu A, Desmet W, Kereiakes DJ, Rutsch W, Wilcox RG, de Feyter PJ, Vahanian A, Topol EJ. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. Jama 2003;289:853-63. 12. Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: Final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142:952-9.

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13. Porto I, Selvanayagam JB, Van Gaal WJ, Prati F, Cheng A, Channon K, Neubauer S, Banning AP. Plaque volume and occurrence and location of periprocedural myocardial necrosis after percutaneous coronary intervention: insights from delayed-enhancement magnetic resonance imaging, thrombolysis in myocardial infarction myocardial perfusion grade analysis, and intravascular ultrasound. Circulation 2006;114:662-9. 14. Blankenship JC, Tasissa G, O’Shea JC, Iliadis EA, Bachour, FA, Cohen DJ, Lui HK, Mann T, 3rd, Cohen E, Tcheng J E. Effect of glycoprotein IIb/IIIa receptor inhibition on angiographic complications during percutaneous coronary intervention in the ESPRIT trial. J Am Coll Cardiol 2001;38:653-8. 15. Islam MA, Blankenship JC, Balog C, Iliadis EA, Lincoff AM, Tcheng JE, Califf RM, Topol EJ. Effect of abciximab on angiographic complications during percutaneous coronary stenting in the Evaluation of Platelet IIb/IIIa Inhibition in Stenting Trial (EPISTENT). Am J Cardiol 2002;90:916-21. 16. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation 2005;111: 1153-9. 17. Serebruany VL, Malinin AI, Eisert RM, Sane DC. Risk of bleeding complications with antiplatelet agents: metaanalysis of 338,191 patients enrolled in 50 randomized controlled trials. Am J Hematol 2004;75:40-7. 18. Montalescot G, Sideris G, Meuleman C, Bal-dit-Sollier, C., Lellouche, N., Steg, P. G., Slama, M., Milleron, O., Collet, J. P., Henry, P., Beygui, F., Drouet, L.. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006; 48:931-8. 19. Shah BR, Glickman SW, Liang L, Gibler WB, Ohman E M, Pollack CV Jr., Roe MT, Peterson ED. The impact of for-profit hospital status on the care and outcomes of patients with non-ST-segment elevation myocardial infarction: results from the CRUSADE Initiative. J Am Coll Cardiol 2007;50:1462-8. 20. Wang C, Kereiakes DJ, Bae JP, McCollam P, He J, Griffin B. Clopidogrel loading doses and outcomes of patients undergoing percutaneous coronary intervention for acute coronary syndromes. J Invasive Cardiol 2007;19:431-6. 21. Brasselet C, Tassan S, Nazeyrollas P, Hamon M, Metz D. Randomised comparison of femoral versus radial approach for percutaneous coronary intervention using abciximab in acute myocardial infarction: results of the FARMI trial. Heart 2007;93:1556-61. 22. Louvard Y, Benamer H, Garot P, Hildick-Smith D, Loubeyre C, Rigattieri S, Monchi M, Lefevre T, Hamon M. Comparison of transradial and transfemoral approaches for coronary angiography and angioplasty in octogenarians (the OCTOPLUS study). Am J Cardiol 2004;94:117780. 23. Philippe F, Larrazet F, Meziane T, Dibie A. Comparison of transradial vs. transfemoral approach in the treatment of acute myocardial infarction with primary angioplasty and abciximab. Catheter Cardiovasc Interv 2004;61:67-73.

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Meningeal metastases from malignant melanoma presenting with delirium, ataxia and visual hallucination P. Fabiani1, C. Baruffi1, C. Maddau2, M. Matucci2, L. Scarti1, G. Taccetti1, C. Cappelletti1 1Department

of Internal Medicine, Nuovo San Giovanni di Dio Hospital, Florence, Italy; 2Cytopathology Unit, Centre for Oncologic Study and Prevention, Florence, Italy

Introduction. – Neoplastic meningitis is clinically identified in 3% to 6% of patients with extraneural cancer 1, 2, but it remains noticeably under-diagnosed 3. The clinical pattern may be pleomorphic and often misleading 4. Magnetic Resonance Imaging (MRI) is reported to be a sensitive tool for detecting metastatic deposits along the central nervous system 5. However, microscopic metastases are below the resolution of MRI detection. Therefore, the standard diagnostic test for neoplastic meningitis remains the cytological identification of malignant cells in cerebrospinal fluid (CSF) 6. On the other hand, although CSF cytology is useful, malignant cells are not detected in as many as one third of patients who have compelling clinical or radiographic evidence of neoplastic meningitis. We report the case of a patient who was at first admitted in a psychiatric ward for depression and behavioural aberrancy and showing later multifocal neurological signs and symptoms, in which diagnostic value of cyto-oncology was crucial. Case report. – In March 1995, a 23-year-old man underwent surgical resection of a cutaneous malignant melanoma of the upper thigh. By April 1998, numerous subcutaneous metastatic lesions had been surgically resected. In September 2000 inguinal lymphnodal metastases were detected and a computed tomography (CT) scan showed enlarged lombo-aortic lymph nodes. A chemo-immunotherapy scheme based on dacarbazine, cis-platinum interleukin-2 was then administered. Six months later a left inguinal lymphadenomegaly recurred. After a new surgical treatment, he received for 1 year adjuvant high-dose interferon treatment, according to Kirkwood’s scheme 7. Subsequent clinical remission was observed and periodical total body proton emission tomography (PET) and chest and abdomen MRI resulted always negative. By June 2007, in absence of provoking factors, the patient began suffering from hyporexia, with progressive weight loss, insomnia, anhedonia and pollakiuria. No pathological findings were clinically evident from neurological point of view. Both CT scan and MRI of the head gave negative response by November 2007 and no hormonal abnormality was found. He underwent a psychiatric drug regimen with alprazolam, nortriptiline, flufenazine, sertraline with scarce results. Pollakiuria became more frequent by the end of March 2008 with psychiatric signs such as dysperception, detachment from reality, tremor, insomnia, restlessness, and visual hallucination.

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Based on diagnostic hypothesis of psychotic depression and the impracticality of home management, the patient was admitted in a psychiatric ward on 24 April 2008. Nevertheless no improvement of the clinical profile was obtained and the generalist consultant advised transferring him to the internal medicine ward after a new encephalic MRI on 2 May 2008 did not show any lesion. On 6 May 2008 the patient was admitted in internal medicine ward. No alteration of body temperature was observed. Vital parameters were found as follows: blood pressure ranged from 110/70 mmHg to 140/80 mmHg, heart rate around 100 beats per minute, diueresis variable from 1600 to 2000 ml/day. Blood gas analysis showed pH 7.55, pCO2 28 mmHg, pO2 122 mmHg, HCO3- 24.5 mmol/l, base excess 2.9 mmol/l; haemoglobin oxygen saturation was around 99%. There was weakness, ataxia, increased tendon reflex activity and normal Babinski reflex. Blood test showed normal haemoglobin level and total white cells count with relative neutrophylia, reduction of serum sodium around 125 mEq/L. Sodiuria was 35 mEq/L. This finding may be, at least

partly, due to a syndrome of inappropriate secretion of antidiuretic hormone (SIADH), many times reported to be secondary to intracranial pathology, sometimes linked to meningeal metastases of melanoma 8. Although hyponatremia was corrected, psychiatric and neurological syndrome was unaffected. As in mild encephalopathy associated with mild clouding of consciousness and confusion, EEG showed slowing of the posterior dominant rhythm, decreased from a higher to a lower alpha frequency and then into the theta frequency range 9. Chest and abdomen CT scan failed to show any significant alteration. It was thus planned to send some CNF specimens to the reference laboratory of Neuropathology of Bologna to rule out a possible bovine spongiform encephalopathy (BSE) but as soon as the specimen was drawn, physical characters of fluid oriented to a critical meningeal pathology. Despite a correct and atraumatic rachicentesis procedure performed on 12 June 2008, the CSF was in fact fairly xantochromic and turbid. Glucose level in CSF was extremely low (3 mg/dl) and proteins rather high (3103 mg/dl), chlorure was reduced (99 mEq/L); a full layer erythrocytes and 128 leucytes/mm3

A

B

C

D

Figure 1. â&#x20AC;&#x201C; Liquor. A-B: binucleated cell without pigment from malignant metastatic melanoma (Papanicolau staining, 400X); C-D: positive immunostaining for S-100 (400X).

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were found. Such CSF pattern led to some diagnostic options as tubercular meningitis, other infective meningitis, neoplastic meningitis. On the contrary, GuillainBarré-Stroll syndrome and multiple sclerosis could be ruled out for the presence of pleocytosis. In any case oligoclonal bands as well as anti-ganglioside autoantibodies were absent. Even though Mantoux delayed hypersensivity reaction was negative, microscopic exam and polymerase chain reaction (PCR) for Koch’s bacillus (BK) were performed and turned out to be negative. Microbiologic cultural test for BK was in course at the time of diagnosis. Serology for spirochetae, viruses, including human immunodeficiency virus (HIV), turned out to be negative, too. The probability of neoplastic meningo-encephalitis was high at this point and one specimen of CSF consequently underwent cytological examination. The prompt answer of pathologist cleared away any doubts about benignity/malignancy. Plenty of severely atipic, clearly malign elements were identified in cellular sediment, but we had to wait for the final response empowered by immonohistochemical techniques, since no melanin pigment was detected in tumoral cells. Immunostaining for S-100 beta protein, a tumour marker in malignant melanoma 10, was found to be positive in atipic cells from CSF (Fig. 1). Radiotherapy is a well-recognized and favourable treatment for cases of neoplastic meningitis with large tumour volume including parenchymal brain metastasis, sites of symptomatic disease, or CSF flow block. Because neoplastic meningitis affects the entire central nervous system, chemotherapy treatment can involve intra-CSF fluid or systemic therapy. Most patients with neoplastic meningitis have progressive systemic disease and therefore treatment is palliative and tumour response is of limited durability 11. Furthermore, as there is no convincing evidence of a prolonged survival with aggressive treatment, new trials need be designed to assess the effect of treatment on quality of life and influence on neurological symptoms 12. In our case parents refused any aggressive therapy due to the advanced stage of disease and uncertainty of significant advantage. In spite of transitory ameliorative affect of corticosteroid therapy, progressive deterioration led to coma and death on 19 May 2008. Autopsy was not performed. Microbiologic test for BK turned out negative after a sixty days culture. References 01. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. New TNM melanoma staging system: linking biology and natural history to clinical outcomes. Semin Surg Oncol 2003;21:43-52. 02. Chamberlain MC. Neoplastic meningitis. Curr Neurol Neurosci Rep. 2008;8:249-58. 03. Jaeckle KA. Neoplastic meningitis from systemic malignancies: diagnosis, prognosis and treatment. Semin Oncol. 2006;33:312-23. 04. Levidou G, Korkolopoulou P, Papetta A, Patsouris E, Agapitos E. Leptomeningeal melanoma of unknown pri-

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mary site: two cases with an atypical presentation of acute meningitis. Clin Neuropathol. 2007;26:299-305. 05. Fogarty GB, Tartaguia C. The utility of magnetic resonance imaging in the detection of brain metastases in the staging of cutaneous melanoma. Clin Oncol (R Coll Radiol). 2006;18(4):360-2. 06. Glantz MJ, Cole BF, Glantz LK, et al.: Cerebrospinal fluid cytology in patients with cancer: how to minimize false negative results. Cancer 1998, 82:733-739. 07. Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, Rao U; Eastern Cooperative Oncology Group. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004;10:1670-7. 08. Sanghera P, El-Modir A. Malignant melanoma and SIADH. Clin Oncol (R Coll Radiol). 2005;17:199-200. 09. Markand ON. Pearls, perils, and pitfalls in the use of the electroencephalogram. Semin Neurol. 2003;23:7-46. 10. Radfar A, Stefanato CM, Ghosn S, Bhawan J. NGFR-positive desmoplastic melanomas with focal or absent S-100 staining: Further evidence supporting the use of both NGFR and S-100 as a primary immunohistochemical panel for the diagnosis of desmoplastic melanomas. Am J Dermatopathol. 2006;28:162-7. 11. Balm M, Hammack J. Leptomeningeal carcinomatosis: presenting features and prognostic factors. Arch Neurol 1996;53: 626-32. 12. Chamberlain MC, Tsao-Wei D, Groshen S. Neoplastic meningitis-related encephalopathy: prognostic significance. Neurology. 2004;63:2159-61

Osteoporosis with costal and vertebral fractures: initial presentation of systemic mastocytosis P. Fabiani1, M. Benucci2, C. Bettazzi3, S. Bracci1, L. Monsacchi1, M. Manfredi4, S. Ciolli5, C. Cappelletti1 1Department

of Internal Medicine, Nuovo San Giovanni di Dio Hospital, Florence, Italy; 2Section of Rheumatology, Department of Internal Medicine, Nuovo San Giovanni di Dio Hospital, Florence, Italy; 3Day Hospital and Day Service, Department of Internal Medicine, Nuovo San Giovanni di Dio Hospital, Florence, Italy; 4Laboratory of Immunology and Allergology Unit, Nuovo San Giovanni di Dio Hospital, Florence, Italy; 5Unit of Haematology Careggi Hospital, Florence, Italy

Introduction. – Systemic mastocytosis (SM) is an uncommon disorder characterised by an abnormal proliferation of mastocytes which can infiltrate numerous organs and tissues, such as the skin, bone marrow, spleen, lymph nodes, liver and the gastrointestinal tract 1. The symptoms of the illness vary and reflect the involvement of tissues. It is possible to observe fatigue, weight loss, sweats, abdominal pain and diarrhoea, pruritus and urticaria, wheezing, tachycardia, hypotension or hypertension, arthralgia and bone pain 2. The involvement of the skin in SM causes urticaria pigmentosa which is sometimes the only manifestation of the illness. The main site of involvement of SM, however, is the skeleton with an involvement evaluated by radiography and bone

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scintigraphy in about 70% of affected individuals 2-3. In many cases, bone involvement is the only manifestation of the illness 4, both from the initial stage and during its progress. Because of the possibility of aggressive progress with haematological involvement, characterised by myelophthisis, association with lymphoproliferative or myeloproliferative diseases, coagulation disorders or mastocytic leukaemia 5, the recognition of aspects of bone involvement in its early stages is of fundamental importance to the management of the illness. We describe a case report of a 57year-old woman with SM presenting with steoporosis with costal and vertebral fractures. Case report. – By February 2006 a 57-year-old woman came to our attention for persistent low fever for 3 months, begun after a pathologic fracture of the first lumbar vertebra (L1). The patient’s anamnesis presented a history of osteoporosis whose secondary causes were ruled out in Endocrinology unit 5 years before; a hyperthyroidism was diagnosed in 2005 with a swollen throat, weight loss and thyreotossicosis, being treated with Metimazole 5 mg per day. Four episodes of spontaneous costal fracture were reported from the age of 45. Her risk factors for osteoporosis included, besides thyreotoxicosis, menopause at 46 years old and cigarette-smoking (20 per day). Her general practitioner’s treatment included a combination of calcium 1g and vitamin D 800 UI per day. Bone densitometry carried out in December 2003 showed bone moderate loss of mineral density getting worse during the hospital stay. The standard X-ray of lumbar rachis on 18 January 2006 showed a typical compression fracture due to osteoporosis. To better characterize the bone tissue a magnetic resonance imaging (MRI) of the rachis and pelvis carried out on 27 January 2006 showed the presence in all the vertebrae of multiple roundish areas from a few mm up to about 1 cm, hyperintense in the STIR sequences and with an aspect partially confluent with soma of D10-D11-D12 bodies (Fig. 1). Somatic hollows were observed also on D5D6-D7 bodies. The 99mTc bone scintigraphy performed on 1 February 2006 showed pathologic hyperactivity on L1, compatible fracture induced bone rebuilding. No other abnormal element was found. To rule out a metastatic bone disease, the patient underwent a series of tests: mammography, oesophago-gastroduodenoscopy, recto-colonoscopy, thoracic abdominal Tc, all of which had negative results. All the blood tests were within the normal range, including total proteins and protein fraction, electrophoresis, immuno-electrophoresis, Bence Jones protein and urine light chains. The pathological data obtained were the following: bone alkaline phosphatase 93 UI/L (normal values: 10-22 UI/L), OHPr/creatinine 0,069 (normal values: <0.020), D-pyr/creatinine 12.3 (normal values <7), NTX/creatinine 63.7 (normal values <47). The

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Figure 1. – Rachis MRI (see text). tryptase tests repeated on two different samples evidenced values of 24.2 and 29.8 micrograms/L (normal values <13.5 micrograms/L). The patient underwent a bone marrow biopsy which showed on histological examination the presence in the perisinusoidal and paratrabecular area of T and B lymphocyte aggregates and round and fused cell elements with the presence of cytoplasmic granules in aggregates of 15 or more mastocytes (MCT+ CD117+) with an involvement of 20% of the medullary cells compatible with the diagnosis of systemic mastocytosis (Fig. 2.1, 2.2). An important datum in mastocyte/ osteoclast interaction explaining mastocytosis osteoporosis is represented by the production by mastocytes of cytokines such as IL-1, IL-3, IL-6 and TGF-‚ which promote the activation of osteoclasts in many models 6. High levels of IL-6 correlate with osteoporosis and with bone pain in patients with SM 7. The D816V-mutated variant of KIT, a thyrosin-kinase growth factor receptor, triggers multiple signaling pathways and is considered essential for malignant transformation in mast cell neoplasma. The accumulation of mastocytes is the result of activation of the KIT which, following mutation, produces different clinical manifestations 8. Even though the relationship between mastocytes and osteoclasts is not completely clear, the receptor KIT and the response to its binding have been observed on osteoclasts too 9. On 10 October 2006, the patient was reffered to the

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A

B

Figure 2. – A-B: bone marrow biopsy. haematologist and molecular biology investigations were conducted on bone marrow cells by polymerase chain reaction (PCR)-based DNA sequencing according to standard method of the EAC program 10. A c-KIT D816V mutation was detected. The TK inhibitor imatinib (Gleevec®) has recently been found to counteract growth of neoplastic MCs exhibiting wild-type KIT or the rarely occurring F522C-mutated variant of KIT 11,12. Since SM harbouring a c-KIT D816V mutation is not responsive to imatinib 13 and others primising tyrosine kinase inhibitors under clinical investigations at the moment are not available, the patient began therapy with Pamidronate 60 mg/ month for six months and intererferon-α2B with a dosage of 1 million U twice a week. No more fracture were reported in clinical hystory from then on. References 01. Webb TA, Li CY, Yam LT. Systemic mast cell disease: a clinical and hematopathological study of 26 cases. Cancer 1982;49:927-38. 02. Travis WD, Li CY, Bergstralh EJ, Yam LT, Swee RG. Systemic mast cell disease: analysis of 58 cases and literature review. Medicine 1988;67:345-68. 03. Poppel MH, Gruber WF, Silber R, Holder AK, Christman RO. The roentgen manifestations of urticaria pigmentosa(mastocytosis). AJR 1959;82:239-48. 04. Tharp MD. Southwestern Internal Medicine Conference: the spectrum of mastocytosis. Am J Med Sci 1985;289: 119-32.

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05. Parker RI. Hematologic aspects of systemic mastocytosis. Hematol Oncol Clin North Am 2000;3:557-68. 06. Theoharides TC, Boucher W, Spear K. Serum interleukin6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol. 2002;128:34450. 07. Fitzpatrick LA, Buzas E, Gagne TJ, Nagy A, Horvath C, Ferencz V, et al. Targeted deletion of histidine decarboxylase gene in mice increases bone formation and protects against ovariectomy-induced bone loss. Proc Natl Acad Sci USA. 2003;100:6027-32. 08. Tharp MD, Chan IJ. Mastocytosis. Adv Dermatol. 2003; 19:207-36. 09. Gay S, Jones RE Jr, Huang GQ, Gay RE. Immunohistologic demonstration of platelet-derived growth factor (PDGF) and sis-oncogene expression in scleroderma. J Invest Dermatol. 1989;92:301-3. 10. Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N, et al. Standardzation and quality control studies of “real-time” quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – a Europe Against Cancer program. Leukemia 2003;17:2318-57. 11. Akin C, Brockow K, D’Ambrosio C, et al. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated forms of c-KIT. Exp Hematol. 2003;31:686-692. 12. Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD. A novel form of mastocytosis as-sociated with a transmembrane c-KIT mutation and response to imatinib. Blood. 2004;103:3222-3225. 13. Lim KH, Pardanani A, Tefferi A. KIT and Mastocytosis. Acta Haematol. 2008;119:194-198.

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Community-acquired pneumonia and comorbidities A. Lagi, R. Cersosimo Internal Medicine Department, S. Maria Nuova Hospital, Florence, Italy

Aim. – This study analysed the influence of different kinds of antimicrobial therapies in patients with Community-Acquired Pneumonia (CAP). Any study has been designed to establish relationship between co-morbidities and death with different therapeutic schedules. The primary outcome of this study was to assess differences in hospital mortality, 30-day mortality related to different age, pharmacological regimens, risk class and/or co-morbidities. Methods. – The charts of 256 patients hospitalised for CAP were analysed. Two groups of patients were compared, those receiving Guideline - concordant and non concordant antibiotic therapies. Five variables were evaluated: age, risk class, comorbidities, recent antibiotic therapy, pharmacological regimens and related to 30-day mortality Results. – The mean age of patients was 76 years. The Guidelines-concordant antimicrobial therapies cases were 150), the Guidelines-nonconcordant cases were 106. Total mortality (inpatient and 30-day) numbered 48 (18.7%), of which 31 cases (20.6%) were from the Guidelines-concordant group and 17 cases (16%) from the nonconcordant group. The difference between the groups was not significant. Thirty-day post-discharge mortality was 7.7% (n=17), calculated as a percentage of the patients living after discharge (n=225). No difference was observed among the different therapy regimens on primary outcome. The most important determinant on 30-day mortality was the presence of comorbidities and age. Aim. – Pneumonia is the most common infective cause of mortality in Italy. While the CAP mortality rate is less than 1% in outpatients, it averages between 12% and 14% among hospitalised patients 1-4. Any study has been designed to establish relationship between co-morbidities and death with different therapeutic schedules. The primary outcome of this study was to assess differences in hospital mortality and 30-day mortality, risk class and/or co-morbidities related to different regimens. Methods Study Sample. – The charts of patients included in the study were selected from consecutive cases from 1 January to 31 December, 2006. The schedules were identified using the International Classification of Diseases, Ninth Revision (ICD 9) based on a discharge diagnosis of CAP as the primary diagnosis of pneumonia (480.0-483.99 and 485-487.0) or a primary diagnosis of respiratory failure (518.81) with secondary diagnosis of pneumonia.

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Data Collection. – Co-morbidities evaluated at the beginning of the enrolment was: Heart Failure (HF), Diabetes (DIA), Chronic Obstructive Pulmonary Disease (COPD), Chronic Renal Failure (RF) and recent antibiotic therapy ( on month before the beginning of the pneumonia which has brought patient to hospital admission). Inpatient and 30-day mortalities were noted. To that end, information from the Florentine Health Service Community Register database was utilized. Antimicrobial Therapy. – The class of antibiotic therapy, time started and schedules were recorded. Each patient - therapy was classified according to single molecules or their combination and considered GL- concordant if it agreed with the guidelines put forth by either the Infectious Diseases Society in 2003 or the American Thoracic Society in 2001 1, 2. Further information about the hospitalised patients was collected including the presence of fever, alteration in white blood cell count (WBC), results from urinary antigen studies (Pneumococcus and Legionella), serologic tests, blood cultures, sputum cultures, and bronchoscopy to obtain bronchoalveolar lavage to account for a specific antimicrobial therapy. Cases in which antibiotic therapy was initiated more than 8 hours following diagnosis of pneumonia were considered “late therapy” and excluded (late therapy group). In the β-lactam group, we included intravenous ampicillin or amoxicillin in combination with sulbactam or clavulanate; and non-pseudomonal 2nd or 3rd generation cephalosporins. The macrolide group included intravenous clarithromycin and azithromycin. The “other” group included carbapenem, monobactam, piperacillin/tazobactam, clindamycin, teicoplanin, metronidazole, and glycopeptide and aminoglycoside antibiotics. Risk Assessment. – The severity of illness at presentation was scored using the Pneumonia Severity Index (PSI) 5. Patients were classified into risk classes I through V. Statistical analysis. – Five variables were involved in the analysis: age, comorbidity (HF, COPD, RF, DIA, recent antibiotic therapy), risk-class (defined according to PSI), therapy regimens (defined as GL - concordant and discordant) and patient outcome (in-hospital death, 30-day mortality after discharge). Univariate statistics were used to compare sociodemographic and clinical characteristics and their association with mortality. The effect of the different classes of antibiotic therapies, GL-concordant or nonconcordant, on inpatient and 30-day mortality was assessed. Categorical variables were analysed using the chi-square test and continuous variables were analysed using the Student’s t-test. Multivariate logistic regression models (forward method with p<0.10 for entrance into and p>0.15 for removal from the model) were fitted to assess the prognostic effect on in-hospital and 30-day mortality of the following

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covariates: Pneumonia Severity Index, history of Chronic Obstructive Pulmonary Disease, Heart Failure, Chronic Renal Failure, Diabetes. All analyses were performed using Stata 8 (Stata Corporation, College Station. Texas).We considered a P value ≤0.05 as significant. Results. – 322 charts were examined, of which 34 were excluded owing to a diagnosis not included in this study. Analysis was performed on the remaining 288 cases. Incidents of pneumonia that began three or more days following hospital admission were considered hospital-acquired pneumonia and excluded. The remaining cases were subdivided into therapy guideline-concordant and nonconcordant groups. The mean age (years) of the 256 patients was 76 ±16. The GL-concordant cases (n=150) had a mean age of 74 ±18 and included 70 males and 80 females. The GL-nonconcordant cases (n=106) had a mean age of 77 ±14 and included 66 males and 46 females. The two groups of patients were similar upon every variable. Although the incidence of COPD was different in the two groups, the incidence of all the five variables together does not differ between the two groups of patients (p = 0,13). The number of inpatient deaths was not significantly different. Of the total starting population (n=256), total mortality (inpatient and 30-day) numbered 48 (18.7%), of which 31 cases (20.6%) were from the GL-concordant group and 17 cases (16%) from the nonconcordant group. The difference between the groups was not significant. Thirty-day post-discharge mortality was 7.7% (n=17), calculated as a percentage of the patients living after discharge (n=225). These were divided into GL-concordant ( 13 patients) and nonconcordant ( 4 patients). The most common GL concordant empiric antimicrobial regimens used included the use of ‚-lactam plus fluoroquinolone (n=54), betalactam plus macrolide (n=46) and fluoroquinolone alone (n=45). Patients treated with macrolide alone were few in number (n=5). The most common GL- nonconcordant antimicrobial regimens were β-lactam alone (n=44) and a combination of fluoroquinolone and macrolide (n=14). The remaining patients (n=48), designated “other”, were treated with different and serial combinations of antimicrobial drugs and were difficult to categorize into clearly defined groups. No significant difference was found in inpatient mortality when comparing different antimicrobial regimens. Only the difference in the length of the hospital stay between the “other” group and the GL concordant groups or the β-lactam group was significant (P<0.05). No significant association was found between fever (duration and level), WBC, risk class and outcome. The outcomes produced allowed interpreting the covariance matrix in terms of path coefficients. In particular, the patient outcome seems to be dependent mainly on comorbidity (1.05). Age (0.17), therapy

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(0.01) and risk class (0.01) do not influence the patient outcome. On the other side, both the risk class and the comorbidity appear to be dependent on age (respectively 0.86 and 0.37). The risk class is weakly dependent on comorbidity (0.28). Conclusion. – Our first observation is that inpatient and 30-day mortalities in the two subgroups were not significantly different, neither when considering the higher-risk classes, IV and V, nor the different specific therapeutic regimens. The mortality rate in non-severe CAP (risk classes I-III) is in accordance with recent reports 3 that indicate no difference in the antimicrobial regimen and equivalence between β-lactam treatment alone and those including macrolides, ketolides, or quinolones. This is consistent with the concept that the routine addition of macrolide or monotherapy or quinolones is not a necessary standard treatment for patients admitted to hospital with CAP 6. These data seem to conflict with many statements in the literature that combination therapy (‚-lactam plus macrolide or 4th generation quinolone) provides a survival benefit or a shortened hospital stay in patients with moderate to severe CAP (risk class IV and V), compared to monotherapy such as 3rd generation cephalosporin 7. Thus, in the literature, the differences that favour of one therapy over other can be partially explained by selection bias, that is, prescription on the basis of severity of the illness at first presentation, the pneumococcal resistance pattern or the presence of a combination of infections. In this study, differences in age, therapy and risk class do not influence the patients’ mortality or length of stay. It is striking as different medications, GLconcordant or discordant, have the same impact on mortality. The length of the hospital stay, which reflects complexity of the patients and their therapeutic response, is similar in the two subgroups but not within the various therapeutic regimens provided. Data must be interpreted. Some patients in GL- discordant group had overtreatment because adjunctive therapies have been done or guided by specific laboratory examinations. Particular attention must be paid to the “other” group. These patients experienced longer hospital stays than the other clearly-defined groups (18 vs. 10-13 days, macrolide regimen excluded). The antimicrobial regimen chosen for use in the “other” group is the consequence of first treatment failure, the need to resort to specific drugs for specific bacteria, and finally a particularly challenging case. In other words, patients in this group were reassessed and treated with specific or more efficient antimicrobial therapies when they showed signs of deterioration or failure to improve. Inpatient mortality in this group was the same as the other groups. In accordance with the literature, we did not find any regimen to be superior to another, especially whether combination therapy is used.

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Comorbidities have been demonstrated to have a significant effect on 30-day mortality. Age is determinative variable influencing risk class and comorbility. The risk class does not affect mortality. We therefore conclude that risk class, recent antibiotic therapy are not as important predictors of mortality in the study population as comorbilities all together. The age is a variable able to influence risk class and the comorbilities, in such a way that it may represent an indirect predictor of mortality. References 01. Lionel A, Mandell LA, Bartlett JG, Dowe SF, File TM Jr., Musher DM, Whitney C. Update of Practice.- Guidelines for the Management of Community-Acquired Pneumonia in Immunocompetent Adults. Clin Infect Dis 2003;37:140533. 02. Niederman MS, Mandell LA, Anzueto A, et al, American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001;163:1730-1754. 03. Mills GD, Oehley MR, Arrol B. Effectiveness of β - lactam antibiotics compared with antibiotics active against atypical pathogens in non-severe community acquired pneumonia: meta-analysis. BMJ 2005; 330:456-458. 04. Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. JAMA. 1995;274:134-141. 05. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336:243-250. 06. Oosterheert JJ, Bonten MJM, Hak E, et al. How good is the evidence for the recommended empirical antimicrobial treatment of patients hospitalised because of communityacquired pneumonia? A systematic review. J Antimicrob Chemother 2003;52:555-563. 07. Houck PM, MacLehose RF, Niederman MS et al. Empiric antibiotic therapy and mortality among medicare pneumonia inpatients into western states Chest 2001;119:14201426.

Supine hypertension and orthostatic hypotension: is it a causal or casual association? A. Lagi, S. Cencetti Medicina d’Urgenza e Unità per lo studio della sincope e della ipotensione, Ospedale di Santa Maria Nuova, Florence, Italy

Aim. – It is opinion that patients with supine hypertension, more than 140/90 mmHg, and orthostatic hypotension suffering from autonomic failure. The orthostatic hypotension is defined as reduction of arterial pressure more than 20/10 mmHg on standing. Some patients suffering from Multiple-System Atrophy (MSA), Parkinson disease (PD) or Progressive Autonomic Failure (PAF) have this kind of arterial pressure 1-4. Some other diseases may be collected in this set, as dysautonomia associated with diabetes or amyloidosis. Association of supine hypertension and orthostatic

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hypotension (Hyp-Hyp) is bizzarre because the two signs are opposite. It is a supposition that causal mechanisms of hypertension are not able to get high the arterial pressure when the patient is standing or instead, if the patient is normotensive, that he is not able to control the increase of arterial pressure on laying. The physiological and clinical features suggest that the increase of circulating pool (hypervolemia) and the baroreflex gain 5, 6 bring about hypertension and that reduction of peripheral resistences is the cause of orthostatic hypotension. Sympathetic failure is the source of peripheral failure 3. Hypervolemia and increase of stroke volume have never demonstrated in patients suffering from dyasautonomia, so that the pathophysiology of supine hypertension has not proved to be true 7, 8. Many reports gave a detailed account of the different clinical features in patients suffering from the same disease. The conclusion is that 26% of PD- patients and 56% of MSA-patients suffer from supine hypertension 1,4. Supine hypertension, which certainly is sign of dysautonomia, may be found in many diseases so that it can not be indicative of only one disease 1; in the same way the patients with Hyp-Hyp phenomena can not be fully included into dysautonomic diseases because they are different for dropping off the arterial pressure, change of heart rate, symptoms on standing and association with target organ damage (left ventricular hypertrophia, vascular brain disease, syncope) 9. These concepts allow to think the patients with HypHyp as heterogeneous population and that they are clustered by the same symptoms (hypertension and hypotension) in presence of different hemodinamic and pathophysiolic pattern. The aim of the study was to demonstrate this hypothesis. Which is the hemodinamic pattern, the kind of disease and the level of dysautonomia marking the HypHyp patients. Methods. – During nine months, from april to december 2007, we recruited the subjects who were hypertensive, consecutive out-patients. Arterial pressure and heart rate were measured two times, supine and after three minutes of standing. The arm position and the cuff, when measuring blood pressure, was parallel supine and standing 10. Supine blood pressure high more than 140/90 mmHg, which decreased more than 20/10 mmHg on standing 11 was inclusion criteria and defined Hyp-Hyp pattern The stroke volume (SV) was calculated by echocardiographic method in supine position and after three minutes on standing, according to the relationship between the systolic output and aortic valvular orifice. The SV was calculated per body surface (SV/m2). The hemodinamic pattern of 49 patients included in the study are reported in Table I. Autonomic activity is represented in Table II. Brain-MR was fulfilled in 28 patients and Spect scanning con 123I –MIBG in 18. The conclusive diagnosis in the two subgroups are represented in Table III.

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Table I. – Hemodinamic parameters in patients. Age (years)

SAP/DAP supine

SAP/DAP orthostatic

¢ Heart rate

Supine Resistences mmHg/ml

Orthostatic Resistences mmHg/ml

Cardiac Output ml/min/m2 supine

Hyp-Hyp 1 (31 pts, 24 males)

77 (8)

175/93 (26/8)++

128/72 (18/8)

11 (8)

3.48 (1.03)++

2.74 (1.14) 2,863(674)§ 3,121 (611)

Hyp-Hyp 2 (18 Pts, 12 males)

68 (12)*

165/95 (21/9) (NS) ++

116/80 (16/8) (NS)

12 (12) (NS)

3.16 (0.3) (NS)++

5.15 (0.7) **

2,474 (32) (NS)++

Cardiac Output ml/min/m2 standing

2059 (70)*

Differences intergroups: NS: =non significant differences; *p< 0.05; ** p<0.01 Hyp-Hyp 1 vs 2 Differences intragroup: § = non significant differences; + p< 0.05; ++ p<0.01 supine vs orthostatic

Table II. – Autonomic parameters in patients. Hyp-Hyp 1 Hyp-Hyp 2

BRS ms/mmHg

NA clino (pg/ml)

NA orto (pg/ml)

A clino pg/ml

A orto pg/ml

5.1 (2.4) 6 (4.4) (NS)

178 (73) § 224 (119) (NS) ++

253 (111) 479 (112)*

29 (9) § 34 (11) (NS) §

41 (22) 94 (22) (**)

Differences intergroups: NS: =non significant differences; * p< 0.05; ** p<0.01 Hyp-Hyp 1 vs 2. Differences intragroup: § = non significant differences; + p< 0.05; ++ p<0.01 layining vs standing.

Table III. – Different diagnosis in patients. MSA

Parkinson disease with OH

PAF

Diabetes

Hypertension

Paraneoplastic

Pheocromocitoma

Others

Hyp-Hyp 1

8

12

4

6

0

1

0

0

Hyp-Hyp 2

1

2

0

3

6*

2

1

3**

* treated with drugs. ** renal failure 2 cases, renal artery stenosis 1 case.

The others hemodinamic parameters were calculated: – Cardiac output = SV* heart rate (HR) – Mean Arterial Pressure (MAP) = Systolic Arterial Pressure/3 + Diastolic arterial pressure – Peripheral resistences = MAP/SVm2 Patients were split in two subgroups by the different values of the peripheral resistences and output (HypHyp 1 e 2). Heart rate was calculated as orthostaticsupine difference (Δ ortho – supine). Sympathetic activity and was evaluated by supine and orthostatic cathecolamine dosage, by baroreflex gain during the phase IV of Valsalva maneuver on sitting. Antecubital venous blood was drawn through an indwelling catheter after at least 15 minutes of supine rest. Plasma level of cathecols were assayed by high pressure liquid chromatography with electrochemical detection. Furthermore each patients was diagnosed by clinical approach (anamnesis, physical examination, blood tests). Specific tests were done to link Hyp-Hyp pattern with the related disease (brain-MRI, Spet scanning 123IMIBG). Results were evaluated by Student t-test for paired data and difference <0.05 was chosen as significant Results. – The evaluated population were 736 consecutive hypertensive (mean age 71 ± 12 y.o., 394

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males); 49 patients affected from Hyp-Hyp pattern were recruited for the study; they were 6,1% of the evaluated patients. The mean age was 77 ± 8 y.o. Males were 30 and M:F ratio was 1:1.5. Conclusion. – The results of the study are in accordance with the hypothesis of the work. The Hyp-Hyp pattern is a symptom present in different diseases as it would be a syndrome. In the study population dysautonomic diseases are 73% of the cases (37/49) but 12 can not be included in this class. Patients with Hyp-Hyp, suffering from dysautonomic disease, have a trait pattern of arteriolar peripheral resistences which are diminished on standing. Arteriolar resistences differentiate the two subgroups (Hyp-Hyp 1 e 2) on contrary of orthostatic-supine change of arterial pressure or heart rate (Tab I). Cardiac output does not change from supine to orthostatic position in Hyp-Hyp 1 (Tab I); it does change in Hyp-Hyp 2 patients indeed. These last data are perfectly in accordance with the change of peripheral resistences and have a confirmation value because they are collected with different parameters. The diagnosis of the autonomic diseases is difficult, time-consuming, needs to use dedicated skills and laboratory and it can not be done bedside. The scanning and imaging which have been done in the patients are

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not performed in each hospital, are expensive and timeconsuming. The calculation of arteriolar resistences in supine and standing is easy, cheap and it does not need specific skill, it may be done in each hospital and bedside. This test may be considered as the first diagnostic line in patients with Hyp – Hyp pattern. References 01. Pathak A, Senard JM. Blood pressure disorders during Parkinson's disease: epidemiology, pathophysiology and management. Expert Rev Neurother. 2006; 6(8):1173-80. 02. Goldstein DS, Holmes CS, Dendi R, Bruce SR, Li ST. Orthostatic hypotension from sympathetic denervation in Parkinson’s disease Neurology 2002; 58(8):1247-55. 03. Biaggioni I, Robertson RM Hypertension in orthostatic hypotension and autonomic dysfunction. Cardiol Clin. 2002;20(2):291-301. 04. Goldstein DS, Pechnik S, Holmes C, Eldadah B, Sharabi Y. Association between supine hypertension and orthostatic hypotension in autonomic failure. Hypertension. 2003; 42: 136-142. 05. Robertson D, Hollister AS, Biaggioni I et al. Thediagnosis and treatment of baroreflex failure New Engl J Med 1993;329:1449-1455. 06. Goldstein DS, Holmes C, Sharabi Y, Brentzel S, Eisenhofer G. Plasma level of catechols and metanephrines in neurogenic orthostatic hypotension. Nweurology 2003;60:1327: 1332. 07. Wilcox CS, Puritz R, Lightman SL; Bannister R, Aminoff MJ. Plasma volume regulation in patients with progressive autonomic failure during changes in salt intake and posture. J Lab Clin Med 1984;104:331-339. 08. Shannon J, Jordan J, Costa F, Robertson D, Biaggioni I. The hypertension of autonomic failure and its treatment Hypertension 1997; 30(5):1062-1067. 09. Lagi A, Rossi A, Comelli A et al. Postural hypotension in hypertensive patients Blood Press. 2003;12(5-6):340-344. 10. Guss DA, Abdelnur D, Hemingway TJ. The impact of arm position on the measurement of orthostatic blood pressure. J Emerg Med 2008, 34:377-382. 11. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology 1966;46:1470-1481.

What happens before syncope? Study of the time-frame preceding vaso-vagal syncope A. Lagi, S. Cencetti, A. Cartei Medicina d’urgenza, Unità per lo studio della sincope e della ipotensione, Ospedale Santa Maria Nuova, Florence, Italy

Aim. – The sequence of the events characterizing the very last part of the vaso-vagal crisis it has not been determined. We hypothesized that the changes in respiratory frequency and Tidal volume could precede the cardiovascular signals and have influence on them. Therefore the aim of the present study was to analyze the variations in respiratory pattern preceding the vaso-vagal syncope full blown and the relationship between cardiovascular functions, heart rate and sys-

68

tolic arterial pressure in order to assess the temporal sequence. Methods. – Eleven consecutive patients of mean age 29 years old were studied. Heart rate, arterial pressure, respiratory frequency, Tidal volume, carbon dioxide and oxygen saturation in time domain and frequency domain from supine and standing recordings were analyzed. Results. – Increase in respiratory frequency and Tidal Volume precedes the variation of cardiovascular parameters without having influence on them in the last period before syncope. Conclusion. – The novel view these data achieve is that respiratory activity is different in the time-frame preceding syncope, both in VT and breathing rate, and that the increase of the lung ventilation does not influence the baroreflex control during the presyncopal period but may be cause of the baroreflex failure during the full-blown of syncope. Aim. – The sequence of the events characterizing the last part of the vaso-vagal crisis preceding the full blown vaso-vagal syncope (VVS) has not been determined. Previous studies underlined that the full expression of the vaso-vagal reaction is preceded by changes in the respiratory pattern, i.e. hyperventilation, hypocapnia and cerebral vasoconstriction, in the last three minutes preceding bradycardia and hypotension 1-3. Reciprocal and complex influences exist between cardiovascular and respiratory activity 4, 5. We studied baroreflex control by assessing relationship between RR interval and Systolic Arterial Pressure (SAP) before syncope and whether the changes in Respiratory Frequency (RF) and Tidal volume (VT) preceded the cardiovascular signals and also influenced them. Therefore the aim of the present study was to analyze the respiratory variations preceding the full blown - VVS and the relationship between the cardiovascular functions, Heart Rate (HR) and SAP, in order to determine their temporal sequence. Methods. – Eleven consecutive patients (7 females) of mean age 29 years (range 21-32 y.o.) were studied. Each subject suffered from frequent VVS in the last year. None of them was taking any drug, neither had smoking habits and they were free from any other known disease. Baseline recordings were performed in the supine position. Afterwards the tilt table was turned up and the recording was started at 80° and maintained for 45 minutes or prematurely interrupted if hypotension and bradycardia occurred. Data acquisition and analysis. – The following signals were recorded: ECG, respiratory signal frequency, VT, respiratory gas (CO2 end Tidal, O2 Saturation percentage) and non-invasive arterial blood pressure (Finapres). Data obtained in supine position (Supine) were analyzed separately from those in standing. Heart Rate, SAP, VT and Respiratory Frequency were calculated.

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The standing recording was therefore divided in two segments of 100 seconds each, the first one representing the Early Orthostatic Phase, indicated as Orthostatic Period, – i.e. 280-160 seconds before syncope - and the second one representing the Late Orthostatic Phase, which precedes the syncope, indicated as Presyncopal Period - i.e. 100 seconds before syncope. A baseline supine recording of 100 seconds duration was analyzed. The parameters in time and frequency domain were calculated in the three recorded segments. Results were expressed comparing the Supine position with the Orthostatic Period and between this last and the Presyncopal Period. Time domain analysis. – Mean values and total variability were calculated for each one of the studied variables (RR interval, SAP, VT and Respiratory Frequency) in the three periods. Respiratory gas were recordered breath-by-breath. Furthermore each one of the three periods was split in five time-frames of 20 seconds each and the mean values were then compared. This analysis allowed to follow the time course of the events in each variable measured (RR, SAP, Respiratory Frequency and VT, CO2 and O2 Sat%). Frequency domain analysis. – Power spectral analysis (PSA) was calculated for HR, SAP and Respiratory Frequency using an autoregressive model (12), during each period (Supine, Orthostatic Period, Presyncopal Period). Power Spectral Analysis results were expressed as Total Power (TP), Low (0.03-0.15 Hz) and High (0.15-0.35 Hz) Frequency (LF and HF respectively) powers. LF and HF components of RR interval were calculated in normalized units, and therefore were expressed as a percentage of total variability after subtracting the power below the low LF limit <0.03 Hz. Analysis of arterial baroreflex. – Analysis of arterial baroreflex was undertaken on the data obtained by cross-spectral analysis. The gain of arterial baroreflex was estimated by dividing the fluctuations of the RR interval by fluctuations of SAP at the same frequency. Calculation of the baroreflex gain, was expressed as α index 6. Statistics. – Comparisons of the three analyzed phases were made by means of two-tails paired t test. Significance was set for p value <0.05. Results Time domain. – The changes of cardiovascular parameters, Respiratory Frequency and VT are represented in fig. 1 as mean of beat-by-beat resumed in segment of 20”: – Heart rate significantly increased from Supine to Orthostatic Period (from 66 to 76 beats per minute). – SAP had not significant differences in Supine vs. Orthostatic Period. – VT had significant difference in Presyncopal Period vs. Orthostatic Period and Supine. The mean value of VT was 142% vs. 105% and 100%, respectively. – Respiratory Frequency increased in Presyncopal

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Period vs. Supine and Orthostatic Period (19 vs. 13 and 16 breaths per minutes, respectively). – pCO2 significantly decreased in Orthostatic Period vs. Supine (35 vs. 38 mmHg) and in Presyncopal Period vs. Orthostatic Period (32 vs. 35 mmHg). – O2 saturation did not change. Power Spectral analysis RR interval – From Supine to Orthostatic Period the Total Power dropped (from 16,360 to 252 msec2), LF power increased (from 18.7 to 61.1 msec2) and HF power decreased (from 84 to 50 msec2). – From Orthostatic Period to Presyncopal Period no differences were found. Systolic Arterial Pressure – From Supine to Orthostatic Period the Total Power (from 4.83 to 31 mmHg2), LF power (from 2.92 to 24 mmHg2) and HF power (from 1.9 to 7 mmHg2) increased (Fig. 2). – No significant difference was observed from Orthostatic Period to Presyncopal Period. Respiratory Frequency – Significant increase was found in each component: Total Power (from 4.4 to 11.8 msec2), LF (from 2 to 6.1 msec2) and HF (from 4.2 to 9.1 msec2) increased from Supine to Orthostatic Period. – From Orthostatic Period to Presyncopal Period Total Power (from 11.8 to 18.6 msec2) and HF component (from 9.14 to 11 msec2) significantly increased Peak of Frequency The peak of frequency of the different oscillations are shown in tab 1. – No changes were observed in the frequency of SAP in the three different periods (Supine, Orthostatic Period and Presyncopal Period. – HF-main frequency progressively increased from Supine through Orthostatic Period and Presyncopal Period both in RR interval (0.25, 0.27 and 0.28 Hz/s) and in Respiratory Frequency (0.25, 0.26 and 0.31 Hz/s) reaching significant difference between Presyncopal Period vs. Supine. – The LF component was not significantly different in the three periods. Baroreflex The α index is reported in tab I. The α index decreased from Supine to Orthostatic Period while no further changes were found between Orthostatic Period and Presyncopal Period. Discussion. – The main feature of the study was the characterization of the different patterns in cardiovascular and respiratory signals in the period preceding the full blown VVS. Significant differences for VT (fig 1), for Respiratory Frequency and pCO2 (fig 1, tab 1) allowed to distinguish the Presyncopal Period vs. the Orthostatic Period and Supine. Significant differences were found for Heart Rate (Fig. 1) and PSA (fig 2) in the Orthostatic Period vs. Supine. We studied Arterial Blood Pressure, Heart Rate and Respiratory Frequency variability in order to investigate

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Figure 1. – Mean of Heart Rate, Systolic Arterial Pressure, Tidal Volume and Respiratory Frequency in different study phases. Table I. – Peak frequencies of RR intervals, Systolic Arterial Pressure and Respiratory Frequency in the three phases of the study. Supine

OP

PP

LF

HF

LF

HF

LF

HF

RR

0.093 (.006)

0.255 (.041)

0.094 (.006)

0.276 (.049)

0.092 (.005)

0.281^ (.031)

SAP

0.098 (.012)

0.318 (.02)

0.096 (.003)

0.321 (.006)

0.098 (.005)

0.31 (.007)

RF

0.09 (.02)

0.29 (.02)

0.07 (.02)

0.318 (.03)

0.06+^ (.03)

0.35 ^ (.04)

RR-SAP α index

15.5 (8.7)

54.8 (68)

5.1 (2.2)°

5.4 (1.8)§

6.4 (3.9)

7 (4.9)

+ range 0.04-0.10; ^ significant difference (p<0.01) Presyncopal Period vs. Supine; ° significant difference (p<0.02) in OP vs. Supine; § significant difference (p<0.05) in OP vs. Supine SAP, systolic arterial pressure; RF, respiratory; OP, early orthostatic phase; PP, Presyncopal Period,; LF Low Frequency power; HF, High Frequency power.

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two events: the first one concerning the relationship between the respiratory activity, i.e. Respiratory Frequency and VT, and the other cardiovascular parameters, the second one in relation to the baroreflex function whether it was disabled before hypotension begun. The results of PSA, represented in fig 2, show the physiological changes from Supine to Standing: in RR we

Figure 2. – Mean of spectral cardiovascular parameters in the three phases.

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observed the reduction of Total Power, the increase of LF and the reduction of HF, while in SAP an increase of Total Power, LF and HF was found. As far as the two phases in which the Standing was divided, Orthostatic Period and Presyncopal Period, are equivalent. Analysis of respiration. – Changing position from Supine to Standing significantly modify Respiratory Activity. Respiratory Frequency (from 0.25 Hz to 0.26 Hz, i.e. from 14 to 16 breaths per minute), and VT were increased (fig 1 and tab. I) while pCO2 (from 38 to 35 mmHg) decreased. Respiratory Activity shows a further change in Presyncopal Period, represented by the increase of Respiratory Frequency (from 0.26 to 0.31 Hz, i.e. from 16 to 19 breaths per minute, tab. I) and VT (42% increase from the baseline value) and by the decrease of pCO2 (from 35 to 31 mmHg) (Fig. 1). These overall results seem to suggest the following conclusions: a) there is a change in Respiratory Activity during the three different periods of the study; b) the increase of lung ventilation, expressed by the values of Respiratory Frequency and VT, characterizes the last period before syncope (i.e. Presyncopal Period); c) pCO2 is reduced as effect of increased lung ventilation. Normally respiration is coupled to heart rate and this phenomenon causes the respiratory sinus arrhythmia. The increase in VT would modify spectral parameters by increasing respiratory arrhythmia. We did not find increase of spectral power in RR and SAP frequency domains for Presyncopal Period vs. Orthostatic Period. On the other hand the increase of Total Power and HF was observed in Respiratory Frequency domain (Fig. 2). This finding demonstrates that the respiration pattern in Presyncopal Period, characterized by increasing of Respiratory Frequency and VT, has not influence on RR and SAP rhythms. Baroreflex function. – The presence of hypotension and bradycardia in the full-blown phase of syncope is index of baroreflex failure meaning the failure to support the normal cardiovascular function. The baroreflex function, explored by the α index, has normal and physiological pattern in all phases preceding the full blow of syncope (tab I). This is unmodified in presence of increased Respiratory Frequency and VT: in other words their increase is not able to modify baroreflex function in any periods, particulary in Presyncopal Period. Hyperventilation in Presyncopal Period, whose objective is the increase of blood venous return to heart to maintain an adequate SAP and cerebral perfusion, precedes the blunted baroreflex gain Is hyperventilation a compensator factor in the phase preceding syncope? – The physiological significance of the Respiratory Activity before the full blown of VVS and the best way to typify remains to be understood. It is possible that the increase of VT had a finalistic function, i.e. increasing the venous blood afflux to

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thorax during the preparatory phase in which the pooling of blood in the subdiaphragmatic vessels network reaches its maximum level. The dissociation between Respiratory Activity and cardiovascular signals may be explained as the effect of the increase of VT on different control systems such as pulmonary receptors, sympathetic activity or cerebral vascular resistance 3. A conclusive hypothesis is that the venous return is able to stimulate the low pressure baroreceptors found in atria and in the pulmonary vessels. Sympathetic activity and increase of ventilation are the main components sustaining the venous return by the effect of the thoracic pump. The higher VT, the greater the increase of the venous return, meaning that an inverse correlation between breathing rate and pressure fall exists. This may suggest that the increase in ventilation is more efficient in maintaining blood pressure if the breathing rate is slower 7. The impor-

tance of breathing in the time-frame preceding syncope has been highlighted 2, 3: the appearance of high Respiratory Activity is an index of inefficient compensatory action and comes before syncope. During Presyncopal Period, the increased Respiratory Frequency associated to the increase of pulmonary ventilation, triggers the subsequent events represented by hyperventilation-induced hypocapnia leading to cerebral vasoconstriction 3 also in the chemoreflex areas 2. This respiratory pattern is an index of increased chemoreflex gain that, through reciprocal influences 4, 5, 8 leads to baroreflex failure in the full expression of VVS. In Presyncopal Period, the stimulation of high-threshold lung stretch receptors takes place, thus causing the following events (i.e. hypotension, bradycardia and apnea), through their capability to inhibit sympathetic efferent activity 9. It remains to define the reciprocal influence between chemoreflex activity and baroreflex failure.

Figure 3. â&#x20AC;&#x201C; Hypothetical steps of Baroreflex Failure in Syncope

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The conclusion is that between the two orthostatic periods, particularly in the one preceding syncope, baroreflex function does not play an important role in the development of syncope. This affirmation is not original because other observations came to this conclusion even though any case-study has not been carried out yet. The novel view these data achieve is that the Respiratory Activity is different in the time-frame preceding syncope, both in VT and breathing rate. The increase of the Respiratory Activity not related to heart rate and systolic pressure, sign of chemoreflex hyperfunction, may be cause of the baroreflex failure during the full-blown of syncope. References 01. Grubb BP, Gerard G, Roush K et al. Cerebral vasoconstriction during head-upright tilt-induced vasovagal syncope. A paradoxical and unexpected response. Circulation. 1991;84:1157-1164. 02. Lipsitz LA, Hayano J, Sakata S. et al. Complex demodulation of cardiorespiratory dynamics preceding vasovagal syncope. Circulation 1998;98:977-983. 03. Lagi A, Cencetti S, Corsoni V et al. Cerebral vasoconstriction in vasovagal syncope: any link with symptoms? Circulation 2001;104:2694-2698. 04. Somers VK, Mark AL, Zavaa DC et al. Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans J Appl Physiol 1989;67:20962100. 05. Somers VK, Mark AL, Zavaa DC et al. Contrasting effects of hypoxia and hypercapnia on ventilation and sympathetic activity in humans J Appl Physiol 1989;67:2101-2106. 06. Pagani M, Somers VK, Furlan R, et al. Changes in autonomic regulation induced by physical training in mild hypertension. Hypertension; 1988; 12:600-610. 07. Bernardi L; Passino C. Porta C et al. Widespread cardiovascular autonomic dysfunction in primary amyloidosis: does spontaneous hyperventilation have a compensatory role against postural hypotension? Heart 2002;88:615-621. 08. Somers VK, Mark AL, Abboud FM. Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans J Clin Invest 1991;87:1953-1975. 09. Ponikowski P, ChuaTP, Piepoli M et al. Augmented peripheral chemosensitivity as a potential input to baroreflex impairment and autonomic imbalance in chronic heart failure. Circulation 1997;96:2586-2594.

Outcome of patients with elevated cardiac troponin I level after mild trauma E. Meucci1, A. Lagi1, S. Cencetti1 1Emergency and Accident Unit, Emergency Department, Santa Maria Nuova Hospital, Florence, Italy

Aim. – Cardiac troponin I is a specific marker of acute cardiac damage that is used in the diagnosis of acute myocardial infarction (AMI) and acute coronary syndrome (ACS). Occasional reports have noted an increase in cardiac troponin I levels after rhabdomy-

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olysis and have related it to creatine kinase (CK) and creatinine concentrations 1-3. Cardiac I Troponin I levels may be elevated in critically ill patients (stroke, major surgery, sepsis, rabdomyolysis) without evident acute cardiac involvement and it has been correlated with poor prognostic outcome 4-11. The hypothesis of this study was that abnormal values of cardiac troponin I might have prognostic significance also in minimally traumatized subjects and that might be a preclinic marker of cardiac disease. Methods. – Between June and July 2007, 164 consecutive patients with mild trauma were enrolled and followed for survival and cardiac diseases as cause of death or hospital readmission. The severity of trauma was scored for each patient using a score system based upon the number of body segments involved. Subjects with evident acute cardiac disease were excluded (AMI or ASC, sustained ventricular or atrial arrhythmias, evidence of cardiac failure or diabetes, and cardiac pulmonary resuscitation/defibrillation before or as the cause of admission). Patient histories and electrocardiographic examination (ECG) were evaluated to rule out coronary disease (CAD) or other significant cardiac alterations. Values of CK, cardiac troponin I, and creatinine were taken at several times and matched; cTnI and Ck were also matched with the different classes of trauma derived from the score applied. They were also matched with the severity of trauma and with the presence of signs or symptoms of cardiac disease (i.e. alteration on ECG or pre-existing cardiologic history. Telephone interview was used to evaluate events during the 6 months after discharge: death and/or morbidity for cardiac causes. 37 patients were escluded because of incomplete datas. For patient classification and statistical analysis, we considered variation crescendo-decrescendo and the highest level of each recorded parameter. The 2 test was used to compare paired data, and a P value of less than 0.5 was considered significant. Results. – The severity of trauma, ck and creatinine values did not correlate with cardiac troponin I alterations. Patients with cardiac troponin I levels only slightly above normal values experienced significantly more events such as death, ACS, cardiac syncope, PCI, aortocoronary bypass, and PM and ICD implantation. Table I shows the number of events for cardiac troponin I-normal and cardiac troponin I-elevated patients with abnormal ECG and/or CAD history versus those with normal ECG and no CAD history. No statistical significance emerges from the comparison (P = 0.4, abnormal vs normal ECG and/or CAD history in cardiac troponin I-normal patients; P= 0.2, abnormal vs normal ECG and/or CAD history in cardiac troponin I–elevated patients) but appears a trend of troponin towards a more accurate prognostic value.

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Table I. – Patients distribution according to cardiac troponin I values, events at follow-up, and ECG/CAD history. Normal

Events cardiac troponin I

Elevated

Events cardiac troponin I

Abnormal ECG and/or CAD history

37

2*

11

6**

Normal ECG and negative CAD history

70

1

9

4

* P = 0.4 abnormal vs normal ECG and/or CAD history in cardiac troponin I-normal patients. ** P= 0.2 abnormal vs normal ECG and/or CAD history in cardiac troponin I-elevated patients

Table II. – Types of events during follow-up. Normal cardiac troponin I

Elevated cardiac troponin I

Abnomal ECG and/or CAD hystory

Normal ECG and negative CAD hystory

107

20

48

79

IMA o SCA

1

2

1

2

PTA o bypass

2

0

2

0

Sincope cardiogena

0

2

1

1

PM/ICD

0

1

1

0

Pazienti

Morte cardiaca Totale eventi

1

4

3

2

4 (3.7%)*

9 (45%)

8 (16.6%)**

5 (6.3%)

* P <0.01 cardiac troponin I–normal vs cardiac troponin I–elevated patients. ** P = 0 .7, abnormal ECG and/or CAD history vs normal ECG and negative CAD history.

Table II shows the types of events that occurred according to the cardiac troponin I values and ECG/clinical history. During the 6-month follow-up, 8 events occurred for the cardiac troponin I-elevated patients (n = 17), affecting 47% of the subgroup, whereas there were only 3 events in the cardiac troponin I-normal patients, affecting 3.4% of the subgroup. Although there were few overall events, the difference between cardiac troponin I-elevated and cardiac troponin I-normal patients was statistically significant (P <0.01). On the other hand there was no significant differences between patients with normal and abnormal ECG (P = 0.7). Conclusion. – An increase in cardiac troponin I levels is one of the defined diagnostic criteria for AMI and ACS 12-14. Literature is in accordance that cardiac troponin I levels are not affected by rhabdomyolysis and that cardiac troponin I is in fact highly specific for myocardial damage. In fact cardiac troponin I appears to have negative prognostic value after mild trauma in noncritically ill patients, thus identifying a group of subjects that are at higher risk to develop adverse cardiac outcome in a short follow-up. Moreover cardiac troponin I’s preclinical value is stronger than alteration of ECG or pre-existing cardiac history. These results are particularly relevant in those patients otherwise considered at lowrisk and could permit an ealy evaluation in order to discover a preclinical cardiac disease.

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References 01. Lavoinne A, Hue G. Serum cardiac troponins I and T in early post traumatic rhabdomyolysis. Clin Chem 1998;44: 667-8. 121. 02. Benoist J, Cossen C, Mimoz O, Edmund A. Serum cardiac troponin I, creatine kinase (CK) and CK-MB in early posttraumatic rhabdomyolysis. (Letter)Clin Chem 1997;43:416-7. 124. 03. Simpson AJ, Labugger R, Hesketh GG, et al. Differential detection of skeletal troponin I isoforms in serum of a patient with rhabdomyolysis: marker of muscle injury? Clin Chem 2002;48:1112-4. 127. 04. LimW, Cook DJ, Griffith LE, et al. Elevated cardiac troponin levels in critically ill patients: prevalence, incidence, and outcomes. Am J Crit Care 2006;15(3):280-8. 05. Brobbey A, Ravakhah K. Elevated serum cardiac troponin I level in a patient after a grand mal seizure and with no evidence of cardiac disease. Am J Med Sci 2004;328(3):189. 06. Punukollu G, Gowda RM, Khan IA, et al. Elevated serum cardiac troponin I in rhabdomyolysis. Int J Cardiol 2004; 96(1):35-40. 07. Fernandes Jr CJ, Akamine N, Knobel E. Cardiac troponin: a new serum marker of myocardial injury in sepsis. Intensive Care Med 1999;25(10):1165-8. 08. Di Angelantonio E, Fiorelli M, Toni D, et al. Prognostic significance of admission levels of troponin I in patients with acute ischaemic stroke. J Neurol Neurosurg Psychiatry 2005;76(1):76-81. 09. Wu TT, Yuan A, Chen CY, et al. Cardiac troponin I levels are a risk factor for mortality and multiple organ failure in noncardiac critically ill patients and have an

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additive effect to the APACHE II score in outcome prediction. Shock 2004;22(2):95-101. 10. Finsterer J, Stollberger C. Where does troponin I derive from in rhabdomyolysis? Am J Emerg Med 2006;24:509-10. 11. Melli G, Chaudhry V, Cornbiath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine 2005;84: 377-85. 12. Labugger R, Organ L, Collier C, et al. Extensive troponin I and T modification detected in serum from

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patients with acute myocardial infarction. Circulation 2000;102: 1221-6. 13. Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined: a consensus document. J Am Coll Cardiol 2000;36:954-69. 14. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. J Am Coll Cardiol 2000;36:970-1062.

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A Campylobacter jejuni enteritis associated with tetany and rabdomyolisis

Heyde syndrome: a case report L. Abate1, S. Zacchei1, P. Biagi1, C. Mellone2 1U.O.

Medicina; 2Sezione Aggregata di Endoscopia digestiva SL – 7 Siena - Ospedali Riuniti della Val di Chiana senese, Montepulciano (SI), Italy

L. Abate, S. Zacchei, P. Biagi U.O. Medicina ASL – 7 Siena, Ospedali Riuniti della Val di Chiana senese, Montepulciano (SI), Italy

Introduction. – Campylobacter jejuni (CJ), is a recognised cause of acute enteritis transmitted by orofecal route both by interhuman spread and by water or contaminated foods. Flies can act as a vector. This curved bacillus produces a toxin which effects are similar to the cholera toxin. After an incubation of 1-7 days watery diarrhea appears, sometime bloody, with fever, abdominal pains, headache, dizziness, muscle pain, general discomfort, rarely vomit. The intestinal mucosa, above all of the terminal ileum, show corroded areas. The duration of illness ranges between 2 and 7 days. The clinical picture may be self limiting or, rarely, may induce a fulminant form; it has been recently recognized an assonal polineuropathy, related to the serotypes Or-2 and Or-10, the Miller-Fisher syndrome, a variant of the Guillain-Barré syndrome. Antibiotic treatment (particularly fluorchinolones and macrolids) shorten the spread phase and reduce relapses. We describe a CJ enteritis characterized by a peculiar severity caused by lifethreatened dysionia. Case report. – 49 year-old woman, smoker, barkeeper with a negative previous history. She was admitted to our observation after 5 days of watery diarrhea, for intense tetanic spasms from two days and for upper paraparesis. Actually at the clinical examination Cvosteck and Trousseau signs were positive and paraparesis was really a marked asymmetric hypostenia prevailing on left side. ECG showed sinus rhythm, U wave, and Qtc markedly lengthened (+ 0,07’’). Laboratory findings revealed K+= 1,9 mEq/ls, Ca++= 5,6 mg/dl; Mg++= 1,1 mg/dl, CK 7340 UI/l, LDH 1004 U/l and myoglobin 2516 g/ml. She underwent corrective therapy (cristalloids, electrolytes), and after having been isolated from the feces CJ colonies, was planned treatment with Ciprofloxacin to 500 mg b.i.d. She refused colonscopy to define the patologic derangement of intestinal mucosa. Her clinical conditions soon improved to reach in three days normal cenestesis. Despite an accurate investigation we have not found the epidemic mechanism that has allowed her but not her relatives, to contract the infection.

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Introduction. – Heyde syndrome is the association between aortic stenosis and gastrointestinal bleeding, and it was first described in 1958. Although a causal relationship has been suspected, little is known about the precise relationship between these two phenomena. A decreased level of the high molecular weight von Willebrand factor multimers in most cases of aortic stenosis by enhanced proteolysis and the stopping of recurrent bleeding from gastrointestinal angiodysplasias following aortic valve replacement support, this hypothesis. We present a report of a patient with degenerative aortic valve stenosis, who suffered from repetitive massive gastrointestinal bleeding, Case report. – 76 year-old woman with negative hystory, with recent onset of dyspnea associated with faintness. She was admitted in a Cardiologic Unit where was diagnosed atrial fibrillation (AF) (mean 80 beats/min) and moderate-severe aortic stenosis (AoS) by echocardiography. For it was judged that conversion to sinusal rythm would fail for left atrium diameter (46 mm) and the unknown onset of AF she was treated with coumadin and beta blockers and prescribed six months echocardiografic follow up. Routine blood examinations in that setting were normal. After a month she had a presyncope while playing with her little nephew; she went to the Emergency room of our hospital where was noticed she was very pale. Her blood examination revealed anemia (Hb = 7,5 g/dL), INR = 2,4, PLT = 240.000. At the rectal exploration the finger was withdrawn stained with red blood amidst with feaces. She was admitted in Internal Medicine Department. Both EGDS and colonscopy in urgency were negative, ileoscopy of the last 50 cm of the ileum showed the presence of red blood but was not able to define the hemorragic source. The following day was registered a further decrease of Hb (0,5 g/dL), with more rectal blood loss. TAO was cut off, vitamin K and somatostatine infusion started with 3 units of RBC. About 12 hours later she had massive enterorrhagia which needed 4 RBC units more. The following evening, another massive torrential enterorrhagia (Hb dropped to <6 g/dL) which needed 4 + 3 RBC transfusion. A second EGDS revealed in duodenum (third portion) angiodysplastic spots with signs of recent bleeding. They were locally infiltrated with adrenaline. She was transferred to the Surgical Department of Siena University Hospital for further examination and therapy.

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To date we have notice that a selective superior mesenteric artery arteriography showed no active bleeding, an enteroscopy revealed multiple angiodysplastic spots in the ileum, and video capsule confirmed these findings. The patient continues to bleed, and still needs multiple emotransfusional supports. It is possible that she may need ileal resection and/or the aortic valve substitution.

Thrombophilic genetic hereditary pulmonary thromboembolism L. Abate, S. Zacchei, S. Pacini, P. Biagi U.O. Medicina ASL – 7 Siena, Ospedali Riuniti della Val di Chiana senese, Montepulciano (SI), Italy

Introduction. – Pulmonary thromboembolism (PET) in young subjects is frequently caused by genetic thrombophilia: we describes two cases, in which an occasional event was the primer of the illness. Clinical series Case 1. – 33 year-old man. After 20 days of immobilization owing to minimal astragalic infraction during which he had regularly subcutaneous low molecular weight eparin (LMWE), 3 days after the removal of the chalk and suspension of the EBPM, he had repeated episodes of sudden dyspnea. A new more intense attack, associated to sharp pain at the basal right thorax, needed hospitalization. At the admission edema was seen in the right leg, D-dimer was > to 1600 and EGA revealed respiratory alcalosis with hypossiemia and hypocapnia. A lung spiral TC showed thrombi in the inferior branches of the pulmonary arteries, venous limbs echocolor doppler showed a thrombotic obstruction of right popliteal vein. Thrombophilic genetic factors revealed: • Mutation C677T of the gene that codifies for the enzyme MTHFR; • Mutation 844ins68 of the gene that codifies for the enzyme Cistationina B-sintase; • Mutation of the gene that codifies for glycoprotein IIb/IIIa receptor; • The polimorfism of the 5G/4G gene promoter's of the PAI-1. The investigation among his family has found that the patient’s daughter, his father and a brother were asymptomatic carriers of the same genetic anomalies. Case 2. – 30 year-old man. Three days before the admission had to witness to a ceremony standing uninterruptedly for 6 hours and after, in the same day, he had to remain to the desk for many hours to study for an university examination. The day after he felt a sense of weight in the left inferior limb, dyspnea on effort and low grade fever. After three days in he went to the emergency room and was admitted to our Department. At the clinical examina-

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tion aching of the left calf, crackles at the right pulmonary base were registered. The D-dimer test was increased, echocardiographic findings were coherent with acute, moderate degree pulmonary hypertension, and the presence of multiple and bilateral emboli (more on the right) were revealed at the lung spiral TC. The search of thrombophilic genetic factors was positive for: • Mutation G1691A of the gene of the factor V of the coagulation (FV Leyden); • Mutation A1298C of the gene that codifies for the enzyme MTHFR; • The polimorfism of the 5G/4G gene promoter's of the PAI-1. The investigation among his relatives has underlined that his father is an asymptomatic carrier of the same genetic defects.

Focus on rheumatoid arthritis F. Atzeni Unità di Reumatologia, Azienda Ospedaliera Polo Universitario L. Sacco, Milan, Italy

Rheumatoid arthritis (RA) is a systemic disease characterized by chronic inflammation of the synovial joints damage and loss of the function. The ultimate goal in managing RA is to prevent joint damage and to maintain functional ability. Consequently, early diagnosis and treatment is important, but predictive markers for RA are still confined to autoantibodies and also magnetic resonance imaging (MRI) and sonography do not appear to sufficiently distinguish between early RA and non RA. Evidence shows that substantial and irreversible joint damage already occurs within the first 2 years after disease onset. This “window of opportunity” hypothesis for therapeutic intervention in RA is based on the existence of a time frame within which there is a potential for a greater response to therapy, resulting in sustained benefits or, perhaps most important, a chance of cure. There is increasing evidence for beneficial effects of early DMARDs (disease-modifying anti-rheumatic drugs) therapy over delayed treatment in patients who present with arthritis of recent onset. However, no universal consensus exists concerning the choice of initial drug or whether single drug or combination should be given as initial treatments. Most studies demonstrated superiority of aggressive over conventional approaches. Because the tumor necrosis factor (TNF)-alpha inhibitors have proved to stop joint damage progression in severe progressive RA, the achievement of these agents in early RA are currently of great interest. Rheumatoid arthritis (RA) is a systemic disease characterized by chronic inflammation of the synovial joints damage and loss of the function. Sub-

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stantial and irreversible joint damage already occurs within the first 2 years after disease onset. The current management of the disease includes the use of disease modifying anti-rheumatic drugs (DMARDs). Older DMARDs include methotrexate, sulphasalazine and hydroxychloroquine. Newer ones such as leflunomide and cyclosporine are also used. Progress in immunology has caused an increase in understanding the RA pathogenesis, resulting in new methods of treatment. Blocking of TNF-alpha, co-stimulation of CD28+ T-cells and depletion of CD20+ B-cells are all effective ways to diminish inflammation and joint damage. Early use of biologics has improved outcomes but requires close monitoring of disease course and adverse events.

The San Giuseppe hospital relocation M. Biagini1, G. Lombardo2, I. Fiorini, S. Regoli3 1Department Director Area Medical ASL 11 Empoli; 2Area Medical Director ASL 11 Empoli; 3Nurse Coordinator

The new Empoli’s Hospital complex born to respond to the need to qualify the health care of nearly 230000 residents in the Ausl 11’s territory, and in particular to concentrate technology, today an essential factor for medical practice and integrate the professionals skills. With its 44000 square meters divided into 4 buildings the new St. Joseph hospital hosts the wards and equipment necessary to treat acute phase of illness, in fact for this reason approximately 400 beds equipped with the latest technology not only in diagnostics field but also in the clinical documentation and comfort hotel. The opening of a new hospital represents a defining and unique moment in the life of a company that, along with the improvement of services, opportunities for professional and technological development, may introduce problems and their possible negative effects that nobody is able to predict with certainty, this fact has imposed a strategy to the company in response to the complicated technical-logistical and organisational problems associated with the transfer of activities and relating on its service, oriented towards: 1) the identification of responsibility levels; 2) activation of progressive measures; 3) monitoring the action taken; 4) verification of the results reached; 5) a continuous upgrade; The first department transferred, dated 03/04/2008, was the U.O.C. internal and emergency medicine of the Empoli’s presidium hospital, the event was lived with great enthusiasm and excitement from all staff who has worked and took care of the planning transfer to the smallest details so

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that everything could play ensuring the best conditions security and comfort for their patients. In a very short time, about 3 weeks, planning what was needed, who had to do and expected time has seen the succession of a series of steps each one was indispensable for the successful outcome. Step n. 1 – Guided tour: all staff divided into groups, was accompanied in the new structure and was able to inspect the location of hospital space, premises, the use of these, furnishings present and how these could be used. Step n. 2 – Requested material: has been evaluated carefully type material to request, quantity and delivery times to build 2 settings for a total of 48 beds. Step n. 3 – Organization working groups: in turn all staff has worked in the old headquarters to prepare the material to transfer and the new one to fix it and inspect its new location. Step n. 4 – Distribution of operating instruction and business processes: has been done over a fire prevention course and show ways of using the new equipment and electrical devices to all staff. Step n. 5 – Activities of hospitalisation: modulation of admissions in the last week to get to April 3 with a maximum of 40 patients to transfer. Step n. 6 – Transfer Mode: Identifying the degree of instability clinical users to transfer assessed with MEWS(modified early warning score), blood tests and ECG. Communication to 118 central control which has prepared the appropriate means for each user and identified the time interval between a means transport to another. Step n. 7 – Preventive activities: set out ways of patients to transfer, identification and planning of when, how many and what electrical appliances to move. Collaboration with law enforcement and civil protection to optimize the safety transport. Comunication of way to follow with specific signs. Step n. 8 – Information to users: distributed a brochure to patients and their families with instruction to transfer ways. Step n. 9 – Chek-out and chek-in activities: Before the transfer each user has subject further medicalnursing evaluation, prepared documentation, maximum comfort guaranteed. The same assessment was repeated by staff on duty in the new structure upon arrival users. Step n. 10 – Methods of care: for the first 3 days was planned one additional nursing units during the night. All this occurred in close collaboration with the nursing and health directorate, that have set up a crisis unit ready to intervene if necessary. END POINT: The attention and commitment of all staff was rewarded with great satisfaction: in less than 3 hours were transferred 38 patients without any criticality.

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Flugelman Index for the evaluation of delayed discharge C. Bozzano1, E. Mei1, I. Lancini1, N. Zuccone1, D. Vanni2, C. Pedace1 1 Department of Internal and Geriatric Medicine, San Donato Hospital, Arezzo, Italy; 2Department of Internal Medicine, San Donato Hospital, Arezzo, Italy

Aim. – Identify patients with difficult discharge, describe their clinical and social features and follow their pathway outside the hospital, to evaluate the post-discharge prognosis. Methods. – From September 1st to October 31st 2007, were collected clinical data of all patients admitted in the medical wards of the District General Hospital of Arezzo. We evaluated 317 patients, performing multidimensional assessment. Related data refer to the recruitment phase, as the 6 and 12 months follow-up period is still in progress. Results. – The average patient’s age was 81 years (SD:13) and the average period of hospital staying was 10 days (SD:7). 34% of patients showed a Flugelman Index 17: they was 84 yr old (SD:8) and they had a comorbidity Index III. 49% of this group had an adequate support by the family (52% with caregiver), 19% came from RSA, and for 32% the family needed help for the care of the patient. 87% showed loss of autonomy at the admission (according to Barthel Index), while the 8% lost it just before acute deterioration. 90% had a severe cognitive impairment. 27% of the patients with a Flugelman Index 17 died during hospitalization, and the average hospital staying of the discharged was 13 days (SD:9). Conclusion. – Flugelman Index could be helpful to identify more critical patients and to detect factors affecting the hospitalization, in order to establish an adequate program of discharge it. Thanks to Clinical Research Technology-Salerno for co-operation.

Carotid dolichoartheriopathies and cerebral hemodynamics A. Cartei1, C. Zeloni2, M.T. Passaleva1, Rossi A.1, V. Corsoni1, S. Cencetti1 1 Department of Emergency Medicine, Santa Maria Nuova Hospital, Firenze, Italy; 2Department of Emergency Medicine, Misericordia e Dolce Hospital, Prato, Italy

Aim. – Carotid dolichoartheriopathies (CD) (kinking, coiling, looping, tortuosity) are reported between 4 and 25% in patients undergoing ultrasound scanning of the carotid artheries (J. B Thomas, L .Antiga et al. Stroke 2005). Often CD are recognized in asymptomatic patients undergoing ultrasound investigations for screening of the cardiovascular risk (N. Mumoli, M. Cei. Circ J 2008). Surgical correction of

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CD has been proposed for symptomatic patients (E. Ballotta, G. Thiene et al. J Vasc Surg 2005), but it still remain under debate wether the sole finding of CD requests for surgical correction (L. Del Corso, D. Moruzzo et al. Angiology 1998). Therefore, we aimed to test the presence of eventual effects of CD on cerebral hemodynamics as a potential risk for cerebrovascular ischemia. Methods. – Among 107 consecutive patients who showed unilateral CD on carotid ultrasounds in our departments, 78 subjects (43 females and 35 males; mean age 64.9 ± 13,4 years) subsequently underwent noninvasive cerebral hemodynamics investigations by means of continuous-wave Doppler ophthalmic test (8-MHz beam) and pulsed-wave Transcranial Doppler (2 MHz beam). Patients with previous stroke and with carotid stenosis >60%, independently from the side, were excluded from the study. Recordings of basal mean flow velocity on the middle cerebral arteries were achieved though the transtemporal sonographic windows, and vasomotor reactivity was estimated as velocity increase in response to carbon dioxide increase at the end of maximal breath-holding test: all measurements were performed at basal rest in the supine dorsal decubitus and after neck rotations on both sides. Data from the two sides (with and without CD) were compared by means of paired Student’s T-Test; statistical significance was set for p value <0.05. Results. – No patient demonstrated positive ophthalmic test, both in the basal dorsal supine decubitus and at neck rotations on the two sides. Asymmetry on the middle cerebral arteries was not significant both for the basal measurements and during neck rotations: the maximum asymmetry was 7,8% on the side with CD versus the controlateral. Also the reactivity to carbon dioxide increase during maximal breath-holding was within the normal range on both sides, with no significant difference; neck rotation did not introduce significant interhemispheric difference. Conclusion. – Our data demonstrate that CD are common morphological findings that can not account for any abnormanility of cerebral hemodynamics

A prospective randomised trial to evaluate the safety and efficacy of a prolonged bivalirudin infusion after PCI B. Cortese1, A. Genovesi-Ebert3, A. Micheli1, A. Picchi1, S. Severi2, U. Limbruno1 1

U.O. Emodinamica, Dipartimento Cardiologico, Ospedale della Misericordia, Grosseto (GR), Italy; 2U.O. Cardiologia, Dipartimento Cardiologico, Ospedale della Misericordia, Grosseto (GR), Italy; 3Servizio di Emodinamica, Unità Operativa di Cardiologia, Ospedale Civile, Livorno, Italy

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Aim. – Modern anti-thrombotic strategies for patients undergoing percutaneous coronary interventions (PCI) must take into account the risk of both ischaemic and haemorrhagic complications. Among the recently extensively tested antithrombotic drugs, bivalirudin has shown to reduce the risk of haemorrhagic complications following PCI, without increasing the risk of thrombotic complications; however there remain some concern about its efficacy in minimizing ischaemic complications in special subset of patients, such as those not correctly pretreated with a thyenopiridine or after complex procedures. Procedural related myocardial infarction after both urgent or elective procedures is currently a main concern after PCI and has been correlated to impared survival. We studied the safety and efficacy of a prolonged post-PCI bivalirudin infusion versus a standard procedural only bivalirudin dosing strategy in patients with stable ur unstable angina. Methods. – Patients (n=178) undergoing elective/ urgent PCI were randomised in two primary care centers to treatment with bivalirudin using i) bolus and peri-PCI infusion only (n=90) or ii) bolus with peri- and 4 hour post-PCI infusions (n=88). The primary endpoint of the study was the incidence of peri-procedural myocardial infarction defined as a CK-MB increase ?3 times above the upper limit of normal at 24 hrs. Secondary endpoints were 30 day major adverse cardiovascular events (death, myocardial infarction, unplanned revascularisation) and 30 day major and minor bleeding based on the ACUITY definition. Results. – The two groups did not differ significantly over baseline and procedural characteristics. 38% and 43% of patients had unstable angina, the remaing patients had stable angina (p=NS for both). Complex coronary lesions, B2/C type as for the ACC/AHA classification was observed respectively in 77.1% and 83.3% of patients (p=NS). The group treated with a prolonged post-PCI bivalirudin infusion showed a significantly reduced incidence of the peri-procedural myocardial infarction (6.8 vs. 14.9%, p=0.04); we did not register significant differences in the incidence of 30 day major adverse cardiovascular events; 20 day major (1.1 vs. 1.1, p=NS) or minor (3.4 vs. 3.3, p=NS) bleedings were also similar in the two groups. Conclusion. – In patients undergoing elective or urgent PCI, a prolonged post-PCI bivalirudin infusion when compared to a standard bivalirudin strategy, significantly reduced the incidence of peri-procedural myocardial infarction at 24 hours without increasing the risk of bleeding.

Aim. – Bivalirudin, a direct thrombin inhibitor, has shown to warrant similar clinical outcomes at the expense of fewer bleedings when compared to an heparin + glycoprotein IIb/IIIa inhibitor (GPI) strategy during percutaneous coronary interventions (PCI), mostly for acute coronary syndromes. In fact, modern anti-thrombotic strategies for patients undergoing PCI must take into account the risk of both ischaemic and haemorrhagic complications. Otherwise, some concerns have recently been raised about bivalirudin’s efficacy after PCI in protecting myocardium from both plaque derived ischemia and procedural related complications. We studied the safety and the efficacy of a prolonged, post-PCI bivalirudin infusion and compared it to a standard therapy in such a kind of patients with heparin + GPI. Methods. – From our database we retrospectively compared two groups of patients affected by acute coronary syndromes without ST segment elevation at surface ECG, and undergone urgent and complex PCI. The first one had been treated with heparin + GPI (59 patients), the second one with bivalirudin during the PCI and with a 4 hours post-PCI infusion (50 patients). Primary endpoint was peri-procedural myocardial infarction; secondary endpoints were 30-day major adverse cardiovascular events and 30-day major and minor bleedings. Results. – The two groups were not different for baseline and procedural data. Most patients had complex coronary lesions in both groups (ACC/AHA type B2/C lesions: 89% and 87% respectively, P=NS). Mean age was 69 and 71 years in the two groups, and 29% and 30% of patients respectively suffered diabetes (P=NS). A TIMI risk score ?4 was detected respectively in 59 and 62% of patients (P=NS). Such data reflected a high risk population. We observed comparable incidence of procedural related myocardial infarctions (11.9 vs. 8%, P=NS), primary endpoint of the study, and 30-day major adverse cardiovascular events (8.5 vs. 6%, P=NS), with a trend towards fewer major bleedings (8.5 vs. 4%, P=0.07) and significantly fewer minor bleedings in the bivalirudin’s group (20.3 vs. 4.0%, P<0.05). Conclusion. – A prolonged bivalirudin infusion following urgent and complex PCI seems effective in protecting myocardium without increasing bleeding rates if compared to the gold standard therapy in this subset of patients constituted by heparin + GPI, and represents an attractive alternative to standard pharmacological treatment in the catheterization laboratory, especially in patients at high risk of haemorragic complications.

A prolonged bivalirudin infusion after urgent and complex PCI seems safe and effective

No reflow - a new chance to tret this disorder?

B. Cortese1, A. Micheli1, A. Picchi1, S. Severi2, U. Limbruno1

B. Cortese1, A. Micheli1, A. Picchi1, S. Severi3, U. Limbruno1

1

1 U.O. Emodinamica; 2U.O. Cardiologia; Dipartimento Cardiologico, Ospedale della Misericordia, Grosseto, Italy

U.O. Emodinamica; 2U.O. Cardiologia; Dipartimento Cardiologico, Ospedale della Misericordia, Grosseto, Italy

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Introduction. – No reflow, defined as failure to restore normal myocardial blood flow despite removal of coronary obstruction, is a not rare complication of ST-elevation acute myocardial infarction (STEMI), and is associated with impared survival1. Its incidence is higher in critically ill patients. Several systemic and intracoronary (i.c.) drugs have shown to warrant no reflow reversal only in some patients, with variable efficacy on angiographic and clinical outcome2,3. To our knowledge, i.c. use of bivalirudin has not yet been described. Case report. – An 81 year old diabetic patient affected by chronic renal failure was admitted to our intensive care unit for sudden dyspnea and faint; an inferior STEMI with right ventricular involvement was diagnosed. Echocardiographic examination showed akinesia of the free wall of the right ventricle and hypokinesia of the postero-lateral left ventricular wall. Laboratory examinations showed a modest anemia (haemoglobin 10.9 g/dl) with a platelet count of 205.000/uL and a creatinine clearance of 40 ml/min (calculated with the Cockcroft Gault formula). Due to the high clinical risk the patient was initially treated conservatively with plasma expanders, betablockers, aspirin and unfractionated heparin (UFH), in order to achieve an aPTT of 50-70 seconds, delaying clopidogrel use; we also attempted thrombolysis with partial success (ST recovery <50% with improvement of symptoms). On day 3 we observed lower levels of haemoglobin (8,1 g/dl) and a lower platelet count (125.000/uL); moreover, a 2:1 atrial flutter resistant to electrical cardioversion (150 and 200 J) determined worsening of the already impaired haemodinamic balance (mean arterial pressure 70 mmHg). We started dopamine infusion, but observed further worsening of haemodinamics with the development of cardiogenic shock; moreover, platelet count drop to 69.000/uL, raising the suspect of heparin-induced thrombocytopenia (HIT). We then decided to perform emergent coronary angiography via the radial route, and observed a normal left coronary artery. The right coronary artery presented a ruptured thrombotic plaque in its second segment, with both postero-lateral and posterior interventricular artery sub-occluded by thrombi that had probably embolized. We attempted thrombus aspiration with Export® catheter without success, rather obtaining no reflow of the coronary artery, possibly related to distal microembolization of thrombus due to mechanical friction of the catheter. The patient suddenly experienced marked hypotension with mean arterial pressure <50 mmHg. We decided not to perform intra-aortic counterpulsation because of the coagulatory imbalance and extreme tortuosity of femoral and iliac arteries. Excluded GP IIb/IIIa inhibitors or nitroprusside use by reason of the coagulatory and haemodynamic impairment, we started bivalirudin infusion at 12.5 ml/h (half infusion rate due to renal impairment) after 5 mg systemic and 5 mg i.c. boluses. The drug, who-

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se pH is described to be between 5-64, was empirically tamponed with 5 ml of patient blood in order to near a physiological pH. Following angiography showed resolution of coronary thrombus with a remaining subcritical stenosis, that we decided not to stent. We observed a final TIMI 3 flow and myocardial blush grade 2. The following day surface ECG showed sinus rhythm, and a mean blood pressure of 75 mmHg was recorded; echocardiography showed improvement of free-wall motion of the right ventricle, with hypokinesia of the postero-lateral wall, and a left ventricular ejection fraction of 50%. After 6 days the patient was discharged without ischaemic or haemorragic complications and with a normal platelet count. At one-month clinical visit the patient was asymptomatic. Discussion. – This case highlights intriguing clinical and technical issues. High coronary thrombus burden is a risk factor for the development of no reflow probably because of distal microembolization1. After unsuccesful thrombus aspiration it seemed reasonable to us to use an i.c. drug. Because of haemodinamic and coagulatory impairment we did not feel safe with the i.c. drugs commonly used to treat this complication (e.g., adenosine, sodium nitroprusside, GP IIb/IIIa inhibitors, calcium channel blockers). Bivalirudin, a short-acting anticoagulant that directly inhibits both free and clotbound thrombin, even if not yet tested to treat this complication, showed to be safe and effective in determining no reflow reversal. It was in our opinion the peri-PCI anticoagulant of choice because of the high risk of haemorragic complications due to platelet count drop caused by HIT5. Moreover, for this reason and due to the worsening anemia we found not safe to use an adjunctive GP IIb/IIIa inhibitor. Conclusion. – We showed how bivalirudin, a drug diffusely used in the catheterization laboratory, can be safely used via the i.c. route to treat no reflow phenomenon due to distal microembolization. References 01. Reffelmann T, Kloner RA. The no-reflow phenomenon: A basic mechanism of myocardial ischemia and reperfusion. Basic Res Cardiol. 2006;101(5):359. 02. Parikh KH, Chag MC, Shah KJ, Shah UG, Baxi HA, Chandarana AH et al. Intracoronary boluses of adenosine and sodium nitroprusside in combination reverses slow/no-reflow during angioplasty: a clinical scenario of ischemic preconditioning. Can J Physiol Pharmacol. 2007 Mar-Apr;85(3-4):476-82. 03. Harding SA. The role of vasodilators in the prevention and treatment of no-reflow following percutaneous coronary intervention. Heart. 2006 Sep;92(9):1191-3. Epub 2006 Apr 10. 04. http://www.angiomax.com/AboutAngiomax/dosingAdmin.aspx 05. Lewis BE, Hursting MJ. Direct thrombin inhibition during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Expert Rev Cardiovasc Ther. 2007 Jan;5(1):57-68.

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A new strategy to treat large coronary thrombus burden: combined, superselective pharmacological management B. Cortese1, A. Micheli1, A. Picchi1, S. Severi2, U. Limbruno1 1U.O. Emodinamica; 2U.O. Cardiologia; Dipartimento Cardiologico, Ospedale della Misericordia, Grosseto, Italy

Aim. – Percutaneous coronary intervention (PCI) in patients with high thrombus burden is a demanding clinical situation, associated with both early and long term impaired clinical outcome. Mechanical management of coronary extensive thrombosis has been shown to effectively remove a variable fraction of intracoronary thrombus. Anyhow, a large interpatient variability is often observed and large randomized trials failed to demonstrate any clear benefit of such mechanical strategies on clinical outcome. Pharmachological management of this condition may be attempted through intravenous and/or intracoronary administration of glycoprotein IIb/IIIa inhibitors, as well as through the intracoronary administration of fibrinolytic agents. Otherwise, the simultaneous use of both types of drug might lead to improved thrombus resolution but it is usually avoided due to the expected sharp increase in bleeding risk. Methods and Results. – In 12 patients undergoing urgent and emergent PCI and with high coronary thrombus burden we experimented an intracoronary, super-selective infusion of urokinase (100.000 U) followed by abciximab (5 mg) via a 2.9 French microcatheter with multiple sideholes in 20 minutes (about 30% of the standard bolus dose of abciximab and about 10% of the standard dose of urokinase). All procedures were performed via the radial route. We observed a significantly reduced final thrombus area: from 52,5 (±21.6) to 33.2 (±14.9) after urokinase, and 22.3 (±14.0) after abciximab (p<0.05 vs. basal and vs. post-urokinase); we also observed an acceptable tissue perfusion (mean final TIMI flow 2.8, mean final myocardial blush grade 1.9); moreover, this strategy allowed us to abstain from stent implantation in 7 out of 12 patients, because subsequent atherosclerotic lesion was considered subcritical. The procedure and subsequent hospital stay were uneventful for all patients. At 30-days clinical follow up we did not register any cardiovascular adverse event or bleeding complication. Conclusion. – In our study, a strategy of intracoronary, intra-clot, prolonged infusion of urokinase followed by abciximab significantly reduced the thrombotic burden with respect to baseline. In our opinion, the local, intra-clot route of delivery of the two drugs may allow for the creation of a “high-concentration” local micro-environment and, at the same time, a “low-concentration” systemic environment which may be expected not to impact on bleeding risk.

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Such conspicuous reduction allowed us to abstain from stent implantation or to perform it without inducing angiographically visible distal embolization or residual slow-flow. Finally, this treatment strategy did not increase the risk of bleeding due to low concentration of drug used. These promising preliminary results warrant a larger, prospective, randomized study comparing safety and efficacy of this pharmacological strategy with standard intravenous glycoprotein IIb/IIIa inhibitor treatment plus adjunctive use of embolic protection mechanical devices.

Education of self measurement of blood pressure in Grottaglie S. Lenti1, P. Corradini2, C. Frigerio1, C. Pedace1 1USL

8 Arezzo, 2USL9 Casteldelpiano (GR), Italy

Aim. – The ED.A.P.A. Project (Education of selfmeasurement of blood pressure) was conceived to train hypertensive patients in self blood pressure monitoring (SBPM) and to survey their feedback, including patient’ assessment, by recording their related cardiovascular diseases (CVD risks factors) and lifestyle habits. Methods. – The project was conducted during the year 2006. Initially we met Grottaglie’s citizens and illustrated to participants the importance of SBPM at home in the overall management of hypertension, that might lead to a better control of BP and cardiovascular outcomes. After explaining the correct technique for SBPM, we distributed semiautomatic devices (OMRON M6) and asked the participants to fill in the Hypertension Questionnaire Form and record their own blood pressure values in a diary. Results. – Among almost 3000 citizens interviewed, 370 (198 M, 172 F; mean age: 60 years) agreed to take part in our study. They were hypertensive for almost 10 years, but waited 3 years before beginning therapy. They measure BP 4 times a month and, in the same sitting, 66% of them carried out only 1 measurement, 29% of them 2 measurements and only 2.5% carried out 3 measurements. Taking as reference BP value of 135/85 mmHg, we registered 28% of the population as normotensive and the remaining 72% as hypertensive. Among the hypertensives, 30% showed a good control, 55% showed a bad one and the remaining 15% was not aware of being hypertensive. Adding non-treated hypertensives to those treated but not controlled, we noticed that 70% of the participants was not properly controlled. Regarding risk factors, almost 64% showed hypercholesterolemia; 18% were smokers; 35% of males and 28% of females showed hyperglicemia and 63% of the latter had a waist line > 88 cms; 32% used to consume alcohol (46% males and 15% females); 26% had a metabolic syndrome; 13% was affected by vascular brain injuries, 30% by peripheral artheriopaty, 35%

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had heart diseases, 10% was nephropatics and 13% was diabetic. Conclusion. – By this project we evidenced that, with simple devices and low costs, it is possible to make people understand the importance of self-measurement for a more practical management of the illness, for the follow-up of the BP values and to verify the efficiency of the treatment. A more active and direct role of hypertensive patients in their own medical care could reasonably bring a reduction of expenses in long-term management of the disease, a reduction of inappropriate shifts of therapy and, as seen, an increased reliability of the self-measured pressure values.

Cardiometabolic prevention project in a Tuscany population S. Lenti1, L. Ghiadoni2, A. Montagnani3, G. Landini4, S. Taddei 2, C. Nozzoli 4 on behalf PRECAM Study Group (FADOI and SIIA Tuscany Regional sections) 1Arezzo; 2Pisa; 3Grosseto; 4Florence,

Italy

Aim. – Hypertension (HT) often clusters with other cardiovascular (CV) risk factors, particularly with metabolic abnormalities. Clinical trials demonstrated the benefit of Blood Pressure (BP) reduction in preventing CV events. However, currently BP control (<140/90 mmHg) in HT patients is insufficient (5-30%). In the PRECAM (PREvention CArdioMetabolic) study we evaluates the prevalence and control of HT and CV risk factors in an Italian population. Methods. – The study was performed as joint venture between FADOI (Federazione delle Associazioni dei Dirigenti Ospedalieri Internisti) and SIIA (Società Italiana dell’Ipertensione Arteriosa) with support of CRI (Croce Rossa Italiana) and ANIMO (Associazione Nazionale Infermieri Medicina Ospedaleria). The study was conducted in 14 places of Tuscan cities, enrolling 2579 subjects. In all a clinical questionnaires oriented to metabolic diseases, waist circumference (WC) and BP measurements (2 measurements, UA787, A&D Medical) were obtained. Metabolic syndrome (MS) was defined in according to ATPIII criteria (BP>130/85 mmHg), abdominal obesity, low HDL cholesterol, high triglycerides (TG), diabetes mellitus (DM). Results. – Mean age was 60±16 years; 46% were women (72% postmenopausal). Abdominal obesity was detected in 48% of the population. Self reported HT was present in 34% of subjects whereas DM in 9%, low cholesterol HDL in 9%, and high TG in the 16% of the subjects. Accordingly, MS was detected in 15% of the population, and metabolic risk factors had 30% higher prevalence in HT patients than the overall population. Moreover, 3% of the subjects had a history of stroke, 6% of myocardial infarction, 11% of peripheral artery disease, 2% of renal insufficien-

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cy. Smoking habit was present in 22% and sedentary lifestyle in 39%. Mean BP values in the population were 139.4±23/81±12.0 mmHg with 53% of the subjects showing BP <140/90 mmHg. Among self reporting normotensives 36% had BP >140/90 mmHg. Among HT patients 90% (93% in men, 88% in women) were on pharmacologic treatment. BP control was detectable in 36%, with lower control of systolic BP (27% of patient: 25% in men, 30% in women) than diastolic BP in 66% (67% in men, 65% in women). Conclusion. – Although the study suffers of important bias, namely in data collection protocol, the PRECAM study seems to confirm the frequent association of HT with other metabolic CV risk factors and the poor BP control in the general population, strengthening the importance of population strategies aimed at improving lifestyle changes and antihypertensive treatments.

Self evalutation project of the osteoporosis risk in Grottaglie S. Lenti1, C. Nucci2, A. Donati3, F. Tropeano3, F. Capponi2, T. Rissante4 1USL8

Arezzo; 2University of Siena; 3University of Florence; Club of Grottaglie, Italy

4Soroptimist

Aim. – Osteoporosis determines a bone fragility with an higher risk of fracture. In order to identify the subjects at risk the QU.A.D.R.O. project (QUestionario Autovalutazione Del Rischio di Osteoporosi) has been created, thanks to the Committee “Medici per San Ciro” and thanks to the Soroptimist Club of Grottaglie with the aid of the health ministery. The aim of this study has been to effectuate a sanitary education about the osteoporosis risk addressed to the Grottaglie citizens. Methods. – In Autumn 2007 since 15 days have been given 10000 anonymus questionaries of self evalutation about the osteoporosis risk containig 7 questions: citizens calculated themselves the risk and they had advices based on the score. Results. – 3990 citizens (M.1184, F 2806) have taken part of: 7,3% of men of the general group and 16,7% of women, age 50 and 70 years, 31% of women and 5% of men. Men less than 50 years old show an higher risk compared to the next class (51-55 years old) and this risk is higher compared to women with less than 50 years; moreover in the men the weight reduction and the risk increasing rate has a more linear behaviour rispect to the women. Women in the menopause phase since more than 5 year shows a very hight risk (about 25%) and double (50%) if years are more than 10. While for the smoke the dates seen interpretable only for the extreme risk levels: that is to say the important difference exists only amoung those who

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smoke and those who smoke more than 20 cigarettes a day; even if women smoke less they present an higher risk more than the 40%. The maternal femoral fractures’ datas are significant of a very hight risk and they affect on a percentage of more than 50%. Amoung the personal fractures we can notice how the femoral ones are the most frequent and this makes the risk increase highly: this is another important data because usually the first fracture often gives the way to a long series of relapses (dominoes effect) with the risk and the mortality increase. For this purpose the 47% shall correct the risk factors, while the 34% shall execute a D.E.X.A. (Dual Energy X-ray Absorptiometry) and the 19% shall begin as soon as possible a proper therapy for the osteporosis. Conclusion. – The indication that arise, if projected to the national reality are far enought from the ones given by the last ISTAT survay and they are almost similar to the ESOPO (Epidemiological Study On the Prevalence Osteoporosis), according to which the 33% of women and the 14% of men have an hight osteoporosis risk. The prevention has an important roule in precocius age. The project has showed that they are correctable risk factors (smoke and weight) through life habit, that anagrafical factors (age and menopause phase) can’t be corrected but foreseeable. We should take in to consideraction precociusly, that family factors can’t be corrected but which should increase the problem sensibility and finally previous fracture inteded as adapt factors of steep in secondary prevention. It should be hoped than these projects are necessary to underline the connection between research, clinical practis and sanitary planning.

Intraductal papillary mucinous neoplasm. Definition, diagnosis and treatment of a precancerous lesion of the pancreas C.F. Vagheggini, C. Benvenuti, A .Giuello, A. Amendola, V. Santillo, E. Capritti, V. De Crescenzo, F. Iovine, M. Manini U.O Medicina Interna, Ospedale di Pitigliano, Italy

Introduction. – Cystic lesions of the pancreas may be divided pathologically into retention cysts, pseudocysts, cystic neoplasms. Four types of cystic neoplasms of the pancreas have been described: Mucinous cystadenoma/cystadenocarcinoma, Mucinous duct ectasia (intraductal papillary mucinous neoplasm), Serous cystadenoma, Papillary cystic neoplasm. Intraductal papillary mucinous neoplasm (IPMN) was first described in 1982. In 1996, the World Health Organization (WHO) classified cystic mucin-producing pancreatic neoplasms into two distinct entities,

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i.e., intraductal papillary mucinous tumor and mucinous cystic tumor. In the revised WHO classification in 2000, the two neoplasms were renamed as intraductal papillary mucinous neoplasm and mucinous cystic neoplasm, respectively. Classification: IPMNs have been classified as main duct IPMN (MDT-IPMN) or branch duct IPMN (BDTIPMN). MDT-IPMN: dilation of the main pancreatic duct >1 cm. BDT-IPMN: presence of a pancreatic mucinous cyst communicating with the pancreatic duct without main duct dilation. Etiology and pathogenesis: There does not appear to be genetic or familial predisposition. Similarly, tobacco and alcohol consumption do not conclusively increase the risk of developing IPMN. Clinical presentation: IPMN has most commonly been described in people between the ages of 60 to 70 years, having the following characteristic: a longstanding history of recurrent acute pancreatitis. Diagnosis: The differential diagnosis of IPMN includes chronic obstructive pancreatitis, mucinous cystic tumors of the pancreas, pancreatic ductal adenocarcinoma. Treatment and prognosis: The overall prognosis of patients with early-stage IPMN containing a cancer who have undergone surgical resection is favorable with up to 60 to 80 percent three-year survival. In contrast, only one-fifth of patients with invasive cancer and positive margins survive at three years .The current recommendation is to resect all main duct IPMNs as long as the patient is a good surgical candidate. The lower prevalence of malignancy in branch duct IPMNs and the reassurance from the studies that the likelihood of invasive cancer is very low in small cysts raise the possibility of management with careful observation in asymptomatic patients. Case report. – A 87 years old woman admitted to our ward for abdominal pain, in the right upper quadrant. Anamnesis: heart failure, anemia due to peptic ulcer disease, osteoporosis, TIA. Laboratory evaluation: elevation in serum aminotransferases, hyperbilirubinemia (direct >50%), alkaline phosphatase, white blood cell, LDH. Ultrasonography: presence of stones and sludge in the gallbladder. Gallbladder wall thickening. Magnetic resonance cholangiography (MRCP): Presence of stones in the gallbladder and in the cystic duct. Presence of a subcentimetric cyst in the head of the pancreas. Diagnosis: cholestatic hepatitis in patient with gallstones and cyctic lesion of the pancreas. Conclusion. – Non-inflammatory cystic lesions of the pancreas are more common than previously recognized. At the moment they represent the 10 percent of pancreatic cysts and the 1 percent of pancreatic cancers.

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IPMN is a precancerous lesion with a well described adenoma carcinoma sequence, many patients have no symptoms and the neoplasm is detected incidentally at imaging studies performed for unrelated indications. None of the imaging modalities is conclusive. Often there is a delay in diagnosis of up to several months, due to the insidious nature of this disease and the lack of awareness of this entity among physicians. Considering the age of our patient, we have chosen for a follow-up program. However, management decisions should be based upon the confidence in the diagnosis, the presence of symptoms, and a discussion with the patient regarding the possible risk of subsequent malignancy.

An internistic gynecomastia A. Marcocci, P. Biagi, L. Abate, S. Pacini, S. Zacchei U.O. Medicina ASL – 7 Siena, Ospedali Riuniti della Val di Chiana senese, Montepulciano (SI) Italy

Introduction. – Gynecomastia, is the development of abnormally large mammary glands in males resulting in breast enlargement, owing to non neoplastic proliferation of mammals ducti and increased periductal stroma; breast prominence due solely to infiltration of subcutaneous tissue by inflammation or tumor is termed pseudogynecomastia. The causes of common adult gynecomastia are mutiple: medications including hormones, increased serum estrogen, decreased testosterone production, androgen receptor defects, chronic kidney disease, chronic liver disease, HIV treatment, lung and testicular tumors and other chronic illness. In some case the cause remain uncertain, although it has generally been attributed to an imbalance of sex hormones or the tissue responsiveness to them. Case report. – Man, 49 y.o. admitted in hospital owing to hematuria. In the past hystory: oesophagectomy with colonic transposition, postoperative pulmonary embolism. In 2005 hemopericardium during TAO treatment. From 2005 for dyspepsia he was added with levosulpiride (25 mg t.i.d.) and protonic pump inhibitors. His clinical examination was negative apart from increased volume and tender right mammary gland with echo resulting in ductal ectasia. Negative were testes examination and echo, chest X rays, CT of the abdomen. Routine laboratory was normal, TSH, FSH, LH, GH were normal, Prolactin 63,9 ng/ml (normal) with macroprolactin and testosterone 2,8 ng/ml (normal). A brain NMR showed a left lobe of hypophysis increased (2 mm in diameter) coherent with hyperplasia/microadenoma. Conclusion. – Taking into account that gynecomastia may hidden some more serious problem, we must remember that medications cause 10-20% of post-adolescent adults cases. In this patient many causes may explain the sign: levosulpiride blocking the

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actions of dopamine (prolactin-inhibiting factor/PIF) on the lactotrope cell groups in the anterior pituitary may have induced gynecomastia; also warfarin is reported to give brest enlargement but the mechanism remain unknown. The hypophysis hyperplasia/ microadenoma may be the consequence of chronic gland stimulation by levosulpiride. We stopped levosulpiride and warfarin and right mammary gland dimension and tenderness reduced, and after the patient’s brest turned normal, Prolactin levels had fallen to 4,3 ng/ml.

Observational study on prevalence of pain and use of analgesic therapy in patients admitted to Internal Medicine wards M. Bimbi, D. Bartoli, C. Caviglioli, A. Cecchin, N. Vannucci, A. Morettini Department of Internal Medicine 1 Azienda Ospedaliera Universitaria Careggi, Florence, Italy

To evaluate the prevalence of pain as a symptom at the moment of admission, as well as its duration and typology, we carried out an observational study in 4 Internal Medicine wards of AOU-Careggi from 1st April to 30th May 2008. In the form patients were also asked to declare whether they had taken an analgesic therapy, and then which drugs had they made use of, for how long, and how did they judge the efficacy of the treatment, referring to commonly used monodimensional scales. Preliminary data show that at the moment of admission the prevalence of symptom “pain” is 33,8%; 57% of these patients suffer from chronic pain (lasting at least 3 months), but too often they take medications only when they already have pain, receiving strong oppiates seldom (14,6%), inappropriately to intensity and duration of the symptom. A satysfactory control over pain is reached in approximately 50% of treated patients. These data, although not definitive, show the need of a stronger concern to reach a better knowledge and implementation of monitoring and of a correct treatment of pain.

Budd Chiari syndrome: a case report M. Paci1, S. Meini1, F. Vizzuti2, M. Rosselli2, A. Piluso1, N. Scopetani1, U. Arena2, M. Zipoli2, G. Laffi2, A. Tafi1 1UOC Medicina Interna, Ospedale di Volterra, A.S.L. 11, Pisa, Italy; 2SOD Malattie Intestinali ed Epatologia, Dipartimento di Specialità Medico-Chirurgiche, A. O. U. Careggi, Florence, Italy

Aim. – Budd-Chiari syndrome (BCS) is caused by obstruction of the hepatic venous outflow which may occur anywhere from the small hepatic veins to the

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right atrium. This condition presents with characteristic manifestations regardless of the cause. Methods. – MD, 31-year-old male. Patient’s history: Hodgkin lymphoma (nodular sclerosis type) at the age of 17 treated by splenectomy, chemo- and radiotherapy; hypothyroidism treated by hormonal substitute therapy; depression syndrome. In February 2008, he was admitted to the Hospital of Volterra with abdominal pain, hepatomegaly, and minimal ascites. Blood tests showed increased cholestasis, slight hypertransaminasemia and hyper-ammonemia without liver failure. Abdominal US revealed a dishomogeneous liver with reduced portal flow and contrast CT and MRI confirmed hepatomegaly with nodular margins, dishomogeneous parenchyma, and thin-walled, convoluted sovrahepatic veins. Etiologic studies revealed negative hepatitis markers, CMV, monotest, toxoplasma, and autoantibodies (ANA, ASMA, anti-LKM), and unaltered iron/copper metabolism. Oncologic re-evaluation excluded recurrence of lymphoma (normal hemochrome, LDH, and ‚2-microglobulin). No use of hepatotoxic drugs (the patient was taking levothyroxine and paroxetine which was gradually discontinued without improvement in liver disease). During hospitalization, the patient was treated with diuretics and antibiotics but blood tests showed progressive elevation of transaminase and cholestasis values. The clinical picture and abnormal intrahepatic flow led to the hypothesis of BCS. The patient was transferred to the Department of Intestinal and Hepatic Disease of Careggi Hospital to undergo sovrahepatic vein catheterization, measurement of portal pressure, and transjugular hepatic biopsy. The procedure revealed obstruction of the right and middle hepatic veins, drainage into the left hepatic vein, and a spiderweb-like parenchyma, which were consistent with BCS. Left hepatic vein ostial stenosis was also identified and treated with angioplasty which reduced the trans-stenostic gradient from 26 mmHg to 8,5 mmHg. Low molecular weight heparin therapy (anticoagulant and betablocker doses) was commenced. Results. – Etiologic study of BCS excluded the presence of blood disorders (liver biopsy was negative for tumor cell proliferation, amyloid, and iron; jak2 and CD34 studies are underway) but demonstrated the presence of Leiden V Factor (homozygosis for G1691A polymorphism). US findings are almost normal, showing a decrease in the liver volume after 1 month. Conclusion. – BCS is a vascular disorder of the liver that, although quite rare, must be taken into account in the differential diagnosis of acute and chronic hepatic disease. A thorough search for risk factors – both hereditary and acquired – is mandatory due to the frequent co-existence of different etiologic factors and prevalence of multiple risk factors in up to 25% of patients. Leiden V Factor is responsible for approximately 25% of BCS cases, with a relative risk of disease of about 10 in patients presenting with this type of alteration.

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A Candida Glabrata pneumonia in Internal Medicine department S. Pacini, L. Abate, P. Biagi U.O. Medicina, ASL – 7 Siena, Ospedali Riuniti della Val di Chiana senese, Montepulciano (SI), Italy

Introduction. – Candida spp have emerged as the 4th most common cause of nosocomial bloodstream infection, Candida Glabrata (CG) is the 2th most common cause of candidemia in US hospitals. It is defined by the National Institutes of Health as a “rare disease” and is associated with high attributable mortality rate. CG is an opportunistic pathogen, able to cause both local and systemic infections (septicaemia, pyelonefritis, pneumonia, endocarditis) above all in immunodepressed patients or in hospital long staying patients and generally the interval between the admission and the infection ranges from 18 to 22 days. Detailed reports of primary community acquired CG pneumonia (CAP) have not been described. We present a case of CG CAP characterized by a peculiar severity in a not compromised host. Case report. – 79 year-old woman was admitted to our observation after 7 days of fever and cough with mucopurulent sputum. Her previous clinical history was negative. She didn’t take any drug. At the admission chest X rays showed a segmentary dense infiltrate of the left lower lobe but no rales on clinical examination; blood gas analysis showed marked hypoxiemia (PaO2= 44 mmHg); WBC= 26500 (neutrophils 85%). Hemocultures were negative. She was emipirically treated with (piperacillin, levofloxacine) and with O2 Ventimask support. Her clinical conditions did not improve in the following days so a lung CT was performed. It showed no change in the segmentary pneumonia of the left inferior lobe. A bronchoscopic examination showed a marked mucopurulent inflammation of the bronchial tree with the left inferior bronchus occluded by dense secretions; bronchial toilette was performed with consequent complete bronchial patency. Bronchial brush showed neutrophils and limphocytes; BAL gave result of no common bacteria nor micobacteria but revealed that CG colonies were present and widely represented. According to the antibiogram results we have treated the patient with amfotericin B. A new chest X rays, ten days after showed improvement of the pulmonary infiltrate. The patient was discharged healed. This case is peculiar in that a CG was acquired in a patient not hospitalized, nor immune compromised and without predisponing long antibiotic therapy before.

A relapse of Clostridium difficile induced Pseudomembranous Colitis batterico “Cutisorb Sorbact” S. Pacini, L. Abate, P. Biagi U.O. Medicina, ASL – 7 Siena, Ospedali Riuniti della Val di Chiana senese, Montepulciano (SI), Italy

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Introduction. – Clostridium difficile (CD), an anaerobic, spore-forming, gram-negative rod, causes 15%25% of all cases of antibiotic-associated diarrhea, the severity of which ranges from mild forms to fulminant pseudomembranous colitis (PC). The CD does not invade the colonic mucosa and it does not cause disease if no toxin A and B are produced. The CD toxin-A induces disruption of epithelial integrity, loss of polarity of colonocytes, impaired cell migration, cell death, histological inflammatory damage. Diagnostic assays include tests for the detection of CD products or genes and culture methods for isolation of a toxin-producing bacterium. The cell cytotoxicity assay was considered as the gold standard. However enzyme immunoassay test that detects toxins A and B is the most employed method in clinical setting. Case report. – 67 year-old woman was admitted to our observation for anemia and acute respiratory insufficiency in pulmonary embolism and deep vein thrombosis (DVT). At the admission mild self limiting diarrhea was present. One month before she had a streptococcal angina for she was treated with amoxicillin-clavulanate antibiotic by mouth after which a diarrhea ensued. In that occasion CD could be demonstrated and she was treated treated with metronidazole (500 mg t.i.d.) with clinical remission. Apart from routine laboratory, colture tests of the feces were negative, toxin A test for CD was negative, Ca 19-9 was moderately increased. A colonscopy showed a mucosal pattern coherent with PC and a NMR showed wider than normal intestinal wall. Hystologic findings showed exudative inflammation with pseudomembranes on mucous ulcers. The patient was treated again with metronidazole with clinical remission. This case underlines that: – relapse of CD are frequent: about 20-25% of patients have recurrent infection. Up to 5 percent of patients have more than six recurrences. Recurrence seldom is caused by treatment-resistant strains; usually, it is due to the germination of persistent C. difficile spores in the colon after treatment or to reinfection because of reingestion of the pathogen; – the sensitivity of the immunoassay (specificity of 93 to 100 percent, sensitivity is 63 to 99) may miss some case; – most relapses respond to another course of the same antibiotics given in standard dosages.

Transient global amnesia in antiphospholipidic sindrome: a case report and review S. Pacini, L. Abate, P. Biagi U.O. Medicina, ASL – 7 Siena, Ospedali Riuniti della Val di Chiana senese, Montepulciano (SI), Italy

Introduction. – Transient global amnesia (TGA) is an isolated amnesic syndrome with normal neuro-

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logical examination where patients remain alert and communicative with no loss of personal identity; however, they experience striking loss of memory for recent events and an impaired ability to retain new information. Precipitant factors of TGA include physical exertion and Valsalva-like manoeuvres. The episode must have resolved within 24 h. TGA usually affects patients between the ages of 40 and 80. It is an infrequent neurological disturbance whose precise pathophysiology is not known. Many cases of TGA seem to be associated with factors of increased risk of cerebral venous thrombosis, such as polycythemia, antiphospholipid antibodies, venous hypertension and female sex. TGA is not related to cerebral arterial ischemia. Most cases of TGA may be due to small thrombi in the deep cerebral venous system. Small venous thrombi may be difficult to visualize even when using modern imaging technology. Cerebrovascular disease is one of the most common conditions associated with antiphospholipids syndrome (APS). Its is an autoimmune disorder in which the body produces antibodies to its phospholipids or plasma proteins: anticardiolipin antibodies (ACA) and lupus anticoagulant (LA). These antibodies interfere with the assembly of phospholipids complexes and therefore inhibit coagulation, inducing a hypercoagulability state. APS is associated with a clinical syndrome of vascular thrombosis, thrombocytopenia, recurrent fetal loss and livedo reticularis, whether or not a clinical diagnosis of systemic lupus erythematosus (SLE) coexists. Many neurologic disorders have been described in patients with ACA including stroke, seizures, dementia, migraine, ocular ischemia, chorea, transverse myelopathy, cerebral phlebitis. We describe a clinical case of TGA in APS without SLE. Case report. – A 64 years-old woman was admitted to our observation unit for TGA while she was working at home. She referred several similar episodes in the past. Her story revealed x spontaneous aborption of the first thrimester, intrauterine fetal death e several deep vein thrombosis. The physical examinatio was unrevealing. Head TC, EEG, echocolordoppler of sovraortic arteries were normal. The chemical blood panel showed an increase in PTT (74,3 sec), presence of ACA (150,8) and of LA (173,7). ANA (negative). The patient underwent oral anticoagulant therapy.

Cytomegalovirus pneumonia in a non insulin dependent diabetes mellitus patient R. Bassu, A. Alessandrì, M. Checchi, L. Teghini, L. Tonarelli, I. Lucchesi, G. Panigada Internal Medicine, Ospedale SS Cosma e Damiano Pescia, Azienda USL 3, Pistoia, Italy

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Cytomegalovirus (CMV) pneumonia is a life-threatening disease in immunocompromised patients, such as transplant recipients, patients treated with immunosuppressive therapy and AIDS patients. In immunocompetent patients acute cytomegalovirus infection is common, but most often asymptomatic; or inducing an acute prolonged febrile syndrome, associated with lymphadenitis and arthralgia and occasionally mild organ involvment (pneumonia, myocarditis, pericarditis, colitis, and haemolytic anemia). We describe a cytomegalovirus (CMV) infection case complicated by severe bilateral pneumonia and respiratory distress in a patient without any cause of immunologic deficiency but diabetes. On March 2008 a 76 years old male was admitted to our unit because of herpetic corneal endothelitis and pneumonia. His medical history encountered non insulin dependent diabetes mellitus (NIDDM), uncomplicated diverticular disease of the colon and chronic elevation of neoplastic marker CA 19.9, without any strumental evidence of neoplastic proliferation. He recovered with antibiotical therapy and discharged. On April 2008 the patient developed soleal deep venous thrombosys, complicated by pulmonary embolism. The treatment with low molecular weight heparin (LMWH) was successful. On May 2008 fever and worsening respiratory performance appeared. In the first part of hospitalisation the patient showed intermittent fever, respiratory fatigue and a CT scan with several, bilateral pulmonary nodules and mediastinic lymphadenopathy. A second CT scan revealed a interstitial evolution of lung disease. Any microbiological marker was negative, including Quantiferon TB gold, blood colture, HIV Antibodies and CMV serology (antibodies and antigenemia) No autoimmunity marker was positive. Bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies was performed. Typical herpetic inclusion bearing cells was identified in BAL and CMV polymerase chain reaction was highly positive. Ganciclovir intravenous therapy started and we observed progressive improvement of general and respiratory condition. By now the patient is normothermic and eupneic. This case suggests the following consideration: – Symptomatic disease by CMV is more common than previously believed in immunocompetent people. Sometimes it induces severe and life - threatening organ involvement. – In this patient clinical manifestations linked to this viral infection was pleiomorfic (ocular involvement, vascular damage, lung interstitial disease) and distribuited in a wide temporal period. Any clinical, laboratory and strumental effort must be done to

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screen this differential diagnosis in order to avoid dangerous therapeutic delay or mistakes. – Often serological analysis is not sufficient to reach CMV infection diagnosis and bronchoscopy with bronchoalveolar lavage is a very useful support.

Stratification of thromboembolic risk in atrial fibrillation R. Bassu, R. Giovannetti, M. Straniti, L. Tonarelli, A. Alessandrì, I. Lucchesi, G. Panigada Internal Medicine, Hospital of Pescia (PT), Italy

Aim. – Atrial fibrillation is the most common heart rhythm disorder. Non valvular atrial fibrillation is an independent risk factor for ischemic stroke. The risk is five times greater than in the general population. Warfarin is more effective than aspirin (ASA) at reducing thromboembolic risk in patients with non-valvular atrial fibrillation, but whether this benefict outweight the increased risk of bleeding, particulary in elderly patients is unknow. In patients at low-risk, an antiplatelet agent should suffice because the bleeding risk of oral anticoagulation neutralizes the benefict of thromboembolism prevention in these patients. The risk of stroke in atrial fibrillation is not homogeneous and clinical factors associated with atrial fibrillation contribuite to this risk. International guidelines show high –risk factors: previous thromboembolism, advances age(>75 years), diabetes mellitus, hypertension, heart failure and structural heart disease or presence of moderate-severe LV systolic dysfunction on two-dimensional echocardiography. The assessment of bleeding risk is part of the clinical assessment of patients with atrial fibrillation. Often we tend to undertreat patients with oral anticoagulation because of risk of major bleeding. The goal of the present study was to assess the adherence to guidelines in our department. Methods. – We calculated the risk profile in 69 consecutive patients with non-valvular atrial fibrillation hospitalized in our department of Internal Medicine during two months of 2007. Risk stratification was made considering age >5 years, sex, previous embolic events, previous stroke or transient ischemic attack, associated co-morbidities (i.e. arterial hypertension, diabetes mellitus, heart failure, diseases at high risk of major bleeding), impaired left ventricular systolic function and causes of hospitalization. Results. – 69 patients with non-valvular atrial fibrillation (31 men; 38 women) were enrolled. Average age was 79.6 years, patients with more than 75 years were 88.4% (25 men; 36 women), patients with previous stroke or transient ischemic attack were 13%, patients with arterial hypertension were 43.4%, patients with diabetes mellitus were 30.4%, patients with heart failure were 42%, with impaired left ven-

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tricular systolic function were 14.4%, with previous systemic embolism were 2.9%. Five patients (7.25%) were hospitalized for cerebral ischemia, one patient (1.45%) for peripheral embolism, one patient (1.45%) for l hemorrhagic stroke and 21 patients (30.4%) for heart failure. 60 patients were classified as “high risk” patients but only 58.3% of them had oral anticoagulation at discharge (9 patients of these had contraindications to warfarin). Conclusion. – In our department antithrombotic treatment was in agreement with the guideline in only 60% of patients with non-valvular atrial fibrillation, at high thromboembolic risk: so therefore appears necessary to improved guidelines-adherence.

An unusual case of ischemic stroke G. Brunelleschi1, M. Straniti1, R. Giovannetti1, A. Birindelli1, R. Bassu1, P. Montalto2, A. Natali2, G. Panigada1 Medicine, 2Gastroenterology, Ospedale SS. Cosma e Damiano, Pescia, Italy

normal. Transesophageal ecochardiography (TEE) showed a floating (IV Type) atheromatous plaque (4 mm × 3 mm) sited in the aortic arch. The Patient was treated with aspirin and LMWH with progressive stabilization of clinical condition during the hospital phase. SIRS was treated with daily prednisone therapy. A reducational program was scheduled for persisting left hemiplegia. No signs of SIRS at patient discharge. Conclusion. – 1. Systemic inflammatory response without infection is a well-known phenomenon in various types of acute cerebral injury. 2. Atherosclerotic disease of the aortic arch is an important risk factor for ischemic stroke and a possible source of cerebral emboli 3. TEE is a valuable tool in the evaluation of ischemic stroke; it is able to find lesions not detected at TTE and so to determine a change of the patient management. Thus it may be recommended in the evaluation of patients with acute ischemic stroke.

1Internal

Case report. – A 46 years old english patient was admitted to our Hospital because of the onset of vomiting and diarrhoea with fever, tachypnoea/tachycardia and confusion during a period of holidays in Italy. He had a previous history of peptic ulcer disease, and was treated for acute diverticulitis some weeks before his travel to Italy. He underwent vasectomy some years before. His wife described an episode of transient left facial paralisis with rapid complete resolution some months before. During the observational period in emergency department he developed left hemiplegia. Cerebral computed tomography (CT) scan showed parenchymal hypodensity of the right hemisphere with brain swelling, and the hyperdense right middle cerebral artery sign. Epiaortic vessel Doppler Ultrasonography showed steno-occlusive disease of the right internal carotid artery (reverse-flow). Blood tests excluded a thrombophilic disorder. White Blood Cell Count was 18000. Blood and urine colture tests were negative. Systemic inflammatory response syndrome (SIRS) was diagnosed according to the current definition (presence of >/=2 of the following: temperature of <36 degrees C or >38 degrees C, heart rate of >90 bpm, respiratory rate of >20 breaths/min, and white blood cell count of <4000/mm3 or >12000/mm3). Cerebral Magnetic Resonance Imaging (MRI) with vascular study confirmed right emisphere ischemia and the presence of medial intracranial haemorrhage recently occurred. There was evidence of a reduced blood flow in middle cerebral artery and carotid siphon, and a right internal carotid artery occlusion. Transthoracal echocardiography (TTE) showed either no valvular heart disease, or intracavitary thrombi or vegetations. Global left ventricular function was

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Serious adverse event due to a therapy with monoclonal antiangiogenetic antibodies, in a patient suffering from adenocarcinoma of the colon brought to evidence by the Trousseau syndrome G. Parca, S. Stanganini, A. Tufi, N. Lazzerini, M.P. Rosito, E. Santoro Internal Medicine, Ospedale del Casentino, Azienda USL 8 Arezzo, Italy

Introduction. – Description of a clinical case showing two points of particular interest: on the one hand it recalled the close association between venous thrombo-embolism and tumour, whereas on the other it enabled to highlight some difficulties in the management of new therapies relying on antiblastic and antiangiogenetic drugs. Case report. – Mrs A.M. 54, was affected by hydiopathic phlebothrombosis to her right leg, and for treatment we have applied an anti-coagulating therapy. Anamnesys, objective data, chest X rays, abdomen scan, and blood tests with neoplasy markers, showed that all was within the norm. Six months later, Mrs A.M. returns under our inspection (November 2007) displaying symptoms like vomit and acute abdominal pain: an X ray examination to the abdomen showed a blockage of the bowels. The patient was subjected to urgent surgical intervention involving emicolectomy. Hystological exams enabled us to discover an intestinal adenocarcinoma, affecting the perivisceral sierosa. Regional lymphonodes resulted affected by metastasis (stage T3 N2 G3).

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After acknowledgment of the disorder, adjuvant chemiotherapeutical treatment begun (scheme FOLFOX). In May 2008, after a Scan and TC to the chest – abdomen, we discovered a recrudescence of the disorder with secondary lesions to the lymphonodes and to the right adrenal gland. Due to the presence of extended metastasis, we discontinued the adjuvant chemotherapeutical treatment and started a 1st line cancerous metastasis treatment, with an association of chemotherapeutical drugs and monoclonal antibodies inhibitors of the VEGF (bevacizumab), a drug which has shown in various random studies of phase 3 to significantly increase, according to statistics, general survival, a disease-free survival, and an all around rate of positive results. During the first chemotherapy cycle, the patient complained of cardiopalm sensation and chest pressuring pain. ECG showed atrial fibrillation and high FVM with ST elevation. Having taken note of her miocardial ischimia condition, the patient was subjected to electrical cardioversion, which led to the restoration of the synusal rhythm and the normalization of the ST tract. At this stage the patient should have been submitted to a coronarography test, but the recent administration of the antiangiogenetic drug has advised not to proceed with it. Having taken note of the adverse results of the first drug treatment, this was discontinued and only chemiothrapeutic treatments were carried on. The connection between venous thromboembolism (TEV) and tumour, well known from the earliest studies of Trousseau (1865), bears a great importance in the clinical area. In fact TEV may represent the earliest manifestation of a still subclinic neoplasy, and the correlation acquires an even more interesting connotation when we think of a tumor diagnose – such as in this case – which may even be distanced from the insurgence of the thrombosis event. As to the bevacizumab, it is a humanized monoclonal antibody which inhibits the activity of human VEGF and that has shown to be associated with an increased risk of angina, and myocardial heart attack, as well as of severe thromboembolic events (even cerebrovascular ones). Furthermore such drug increases the risk of hemorrhage and of gastro-intestinal perforations. The occurrence of the above described events, obviously advises us not to proceed with this therapy.

Churg Strauss syndrome: a case report C. Prugnola, M. Cercignani, G. Meucci U.O. Medicina Interna P.O. Orbetello ASL9, Grosseto, Italy

Introduction. – Churg strauss syndrome (CSS) is a systemic vasculitis characterized by the presen-

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ce of asthma, hypereosinofilia and sinusitis with necrotazing vasculitis and extravascular eosinophil gnanulomas. The American College of Rheumatology has proposed 6 criteria for CSS classification, four being needed for CSS diagnosed with 85% sensitivity and 99.7% specificity: asthma, eosinophilia >10%, paranasal sinusitis, pulmunary infiltrates, histologic proof of vasculitis and mononeuritis multiplex. CSS has been divided into three distinct phases, wich may or may not be sequential. The prodromal phase is characterized by asthma with or without allergic rhinitis. The second phase is marked by pheripheral blood eosinophilia, cronic eosinophilic pneumonia or eosinophilic gastroenteritis. The third, vasculitis fase, may involve any organ: lung, heart, periperal nervous system, kidney, lymphonodes, muscle and skin. Skin involvement occurs in more than two third of patients. Conditions in the differential diagnosis of CSS include Wegener's granulomatosis, drug reactions, bronchocentric granulomatosis, eosinophilic granuloma, fungal and parassitic infection and malignancy. Case report. – R.S., women, 54 years old, (already known as asmathic patient) affected by asthma by many years and treated with Formoterol and Fluticason. She suffered by ischemic ictus 2 years before. Since a month presented a progressive respiratory problems with dispnea and cough. In last 3 days the respiratory symptoms became so serius that the patient went to Emergency Department. At physical examination the findings suggested massive pleural effusion witch was confirmed by chest radiography and successively by CT scan. After the stabilization of respiratory emergency the patient was admitted to Internal Medicine Unit. In the same day the patient underwent to standard blood exams and pleuric fluid analysis. Blood examinations showed marked improvement of eosoniphils count (7000 mmc), as well as in pleuric fluid. Analysis of respiratory capacity evidenced a severe obstruction airways state. Considering the possibility of Churg-Strauss Syndrome, we performed: – Ct scan of the skull, showing the presence of pansinusitis. – EMG, with presence of periferic neuropathy. – Biopsy of skin lesion, which relevaed the presence of granulomatosis lesion associates to necrotizing angioitis, characteristic of Churg-Strauss Syndrome. After the beginning of steroid therapy by i.v. (methylprednisolone at a dose of 40 mg), dyspnea, count cell in the blood, fluid effusion in the pleurisy, improved coming quickly back to normal. Actually the patient needs to be treated with ciclosporin and bolus of steroids monthly, obtaining a good control of the disease lesions and symptoms.

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Retroperitoneal bleeding during enoxaparin treatment in patient with bilateral deep vein thrombosis: difficulties in management F. Ristori, C. Scerra, M. Falciani, C. Seravalle, A. Montigiani, GC. Landini U.O. Medicina Interna, ASL 10, Ospedale di S. Maria Nuova, Florence, Italy

Introduction. – Venous thromboembolism is a common clinical event in medical patients, especially in those with multiple risk factors. Low molecular weight heparin (LMWH) treatment has been demonstrated to be as safe and effective as intravenous treatment with non fractionated heparin in these patients. Despite a weight adjusted treatment, major bleeding can occur causing difficulties in the management. Case report. – An 75-year-old woman with a history of psicosis, Parkinson disease, obesity and renal insufficiency presents with bilateral leg swelling. Duplex venous ultrasonography demonstrated bilateral deep thrombosis of the iliac, femoral and popliteal veins. Treatment with enoxaparin 8000 UI subcutaneously every 12 hours was initiated. On the seventh 7 day she developed acute hemorrhagic shock due to a large retroperitoneal hematoma requiring intensive care. Pulmonary embolism protection was achieved by percutaneous insertion of inferior vena cava filter maintaining low dose of LMWH treatment. There is a growing number of cases in which enoxaparin has been associated with severe bleeding. On average, a retroperitoneal hematoma occurs within 5 days of therapy with enoxaparin. It appears that patients at highest risk are of advanced age, have renal impairment and receive concomitant medications that can affect hemostasis. Enoxaparin is eliminated predominantly by the kidneys but no guidelines for dose adjusting in renal insufficiency have been developed. In high risk patients and especially in renal impairment with serum creatinine greater than 2.0 mg/dl orcreatinine clearance less than 30 ml/minuteenoxaparin activity should be carefully monitored by measuring anti-factor Xa-activity.

Stroke care pathway in medicine departments in Florence, Italy S. Spolveri1, S. Bacalli2, A. Righi3, S. Tatini4, G. Tavernese5, C. Cappelletti1 1 Stroke Unit and Department of Internal Medicine N. San Giovanni di Dio Hospital, Florence, Italy; 2Department of Internal Medicine, S. Maria Nuova Hospital, Florence, Italy; 3Department of Internal Medicine, N. Mugello Hospital, Borgo San Lorenzo (FI), Italy; 4Department of Internal Medicine, S. Maria Annunziata Hospital, Antella (FI), Italy; 5Department of Internal Medicine, Serristori Hospital, Figline (FI), Italy

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Aim. – Clinical pathways or integrated care pathways are quality improvement tools that guide health providers in the coordination and management of care of patients with a specific clinical problem 1. Clinical pathway are intended to support, not replace clinical judgment and differ from practice guidelines, protocols and algorithms as they are utilized by a multidisciplinary and multi-professional team, translating best evidences of medicine into local action. Care within a Stroke Unit reduces death or dependency after stroke 2, 3. However, studies have found significant variation in clinical practice, access to stroke unit care, organization of patient care and clinical outcome 4, 5. Stroke care pathways have been introduced as a method to promote organized and efficient patient care that is based on best evidence and guidelines 6, 7, 8. In Florence, Italy, there are two main hospital areas: Careggi University with a Neurological Stroke Unit and Florentine Health Area with five General Hospitals (Nuovo San Giovanni di Dio Hospital, Santa Maria Nuova Hospital, Mugello Hospital, Santa Maria Annunziata Hospital and Serristori Hospital) where overall stroke patients (about 1100 patients/year) are admitted in the medical departments. Two Stroke Units with dedicated multidisciplinary team (medical, nursing, therapy, dietary and social work staff) are allocated in NSGD hospital and SMA hospital; in the others the stroke patients are hospitalized in general wards. Methods. – To provide explicit and well-defined standard of care, decrease unwanted practice variation and also optimize the management of resources we developed a Stroke Care Pathway, with staff meetings between professionals of the five hospitals. We identified the national guidelines, SPREAD 2007 9 and reviewed our actions involving local staff from all disciplines that provide stroke care: so we focused the best practice which was feasible to achieve locally. As a model, we used the Calgary Regional Health Authority clinical pathways 10, available on Internet and suitable for our needs. Results. – The Stroke Clinical Pathway developed in Health Florentine Area has four main components: a timeline, with flow sheets for first 24 hours of care, days 2 to 6, pre discharge and discharge days (predetermined length of stay: 8 days); the categories of care or activities (assessment/monitoring, interventions, diagnostic, mobility, nutrition, consults, discharge planning, patient/family education, pathway check); the provider signs and the variation record to allow deviations to be documented and analyzed (see Table 1 and 2). The urgent evaluation and treatment of acute stroke patients who presents to Emergency Department are referred to other pathways, so we did not consider the thrombolytic therapy. The clinical pathway is to remain part of the patient’s health record; is an interdisciplinary tool to be used and recorded on by the appropriate discipline involved in the stroke care and treatment. Documentation

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Table I. – First 24 hours of care. Date.

Table II. – Discharge day. Date

Care Categories Initials, Variance, Action

Care Categories Initials, Variance, Action

Assessment/ monitoring

Assessment/ monitoring

BP, HR, Sat O2, breath rate, temperature q6h. Capillary blood glucose (if <60 mg/dL or >200 mg/dL call physician) NIH Stroke Scale q6h Skin integrity risk (Braden Scale) Nutritional status Bowel and bladder function Pain status (VAS) Swallowing screen (flow-chart) Fall risk (Conley Scale) Before stroke modified Rankin Scale

Interventions IV saline or Ringer; avoid IV glucose Aspirin 300 mg if CT scan shows no blood; wait 24 h if thrombolytic therapy. DVT prophylaxis O2 if SatO2>92% Avoid excessive lowering of blood pressure Avoid sublingual drugs Treat hyperglycemia with IV or SC insulin Treat hyperthermia if >37°C Assess urine flow. Flow-chart bladder catheter Mouth care q2h Diagnostic

CT scan without contrast (if not yet done) Carotid Doppler, as soon as possible Chest x-ray if not already done Repeat 12 lead ECG, if not monitored Ask for echocardiogram TT Ask for CT or MRI scan after 24 hours Ask for EEG or monitor EEG if suspect epilepsy Consider echocardiogram TE if possible cardioaortic stroke mechanism. Consider vasculitic or coagulopathy screen if undetermined causes stroke mechanism

Mobility and ADL

Activity as tolerated Sitting up in chair Reposition for immobile patients q2h

Nutrition

NPO pending swallowing screen Monitor first oral intake Re-screen in 24 hrs

Consults

Consult neurologist if suspect epilepsy Consult vascular surgeon if carotid stenosis >50% Consult neurosurgeon if cerebral hematoma (see SPREAD guidelines)

Discharge planning

Consider if problematic discharge Ask for social worker assessment Ask for therapist assessment Ask for dietary assessment

Patients/ family education

Patient/family understand provisional diagnosis, planned investigations and provisional treatment plan. Ask for informed consent if invasive diagnostic screening Initiate stroke care education package

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BP, HR, Sat O2, breath rate, temperature NIH Stroke Scale FIM or modified Rankin Scale Re-assess skin integrity Bowel and bladder function

Interventions Discharge summaries to receiving provider Prescriptions written Establish follow up controls Remove IV catheter Assess urine flow Arrange for transfer to rehabilitation setting, or home Patients/ family education

Information on severity and impact of neurological deficit and prognosis Discussion of limits/benefits of rehabilitation

of the clinical pathway is not intended to be duplicated: initials beside care categories indicates item has been completed during the date specified on the pathways and reduces the need to write a statement in relation on the patient’s record. The next step will be the application of the stroke care pathway in the computerized medical record, which will assess performance indicators, the compliance of the recommendations and identification of critical points with the analysis of variance. Conclusion. – The routine implementation of care pathways for acute stroke management may be associated with positive effect on the process of care and clinical outcome also in patients treated outside organized stroke care unit. References 01. Campbell H, Hotchkiss R, Bradshaw N, Porteous N. Integrated care pathways. BMJ 1998; 316:133-137. 02. Stroke Unit Trialists’ Collaboration. Organized patient (stroke unit) care for stroke. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD000197. 03 Candelise L, Gattinoni M, Bersano A, Micieli G, Sterzi R, .Morabito A on behalf of the PROSIT Study Group. Stroke unit care for acute stroke patients: an observational study. Lancet 2007; 369: 299-305. 04. McKewitt C, Coshall C, Tilling K, Wolfe C. Are there inequalities in the provision of stroke care? Analysis of a inner-city stroke register. Stroke 2005; 36(2):315-320. 05. Mold F, Wolfe C, McKevitt C. Falling through the net of stroke care. Health Soc Care Community 2006;14(4):349356. 06. Kwan J, Hand P, Dennis M, Sandercock P. Effect of introducing an integrated care pathway in an acute stroke unit. Age Ageing 2004; 33(4):362-367. 07. Esteve M, Serra-Prat M, Zaldivar C, Verdaguer A, Berenguer J. Impact of a clinical pathway for stroke patients. Gac Sanit 2004; 18(3):197-204. 08. Wolff AM, Taylor SA, McCabe JF. Using checklists and reminders in clinical pathways to improve hospital inpatiens care. Med J Aust 2004; 181(8):428-431.

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09. SPREAD Stroke Prevention And Educational Awareness Diffusion. V Edizione 2007. 10. Stroke Care Pahway. http://www.calgaryhealthregion.ca/ clin/cme/cpg/strokepath.pdf

Thrombolytic therapy in acute stroke patients: the experience of a Stroke Unit in Florence, Italy S. Spolveri1, S. Bracci1, F. Baccetti1, L. Monsacchi1, C. Cappelletti1, L. Bagnoli2

(modified Rankin Scale 0-2) is 51,8% vs 53,4% of Italian series; four patients died (12,9% vs 13%). Conclusion. – Our series is representative of a population with older medium age; we use thrombolytic therapy more frequently in cardio-embolic and lacunar subgroups with severity interim; treatment is safe and the short-term and at 3 months prognosis are good. It must be improved the time delay between diagnostic and treatment. We think that thrombolytic therapy is feasible and acute stroke treatment could be more effective in many other hospitals in Tuscany.

1

Stroke Unit, Department of Internal Medicine, N. San Giovanni di Dio Hospital, Florence, Italy; 2Emergency Medicine Department, N. San Giovanni di Dio Hospital, Florence, Italy

Aim. – The Stroke Unit of S. Giovanni di Dio Hospital in Florence, Italy, is a primary stroke centre, as defined by European Stroke Organization. It is a part of the Internal Medicine Department, with a dedicated staff to provide appropriate diagnosis and treatment for acute stroke patients. In Tuscany most of stroke patients are admitted in Internal Medicine Departments, but only nine centres are using the thrombolytic therapy and five of these are neurologic unit. We want to show that thrombolytic therapy in acute stroke patients can be feasible, effective and safe in hospitals with similar characteristics to our. Results. – Since ’04 April we treated 31 patients with rt-PA e.v., (19 males and 12 females, 2% of overall stroke patients) according to SITS-MOST protocol. Mean age was 72 (F 74,7 years: M 71,8 years), higher than other Italian centres (67 years); 3 cases were treated off-protocol ( after 3 hours from onset of symptoms). The prevalence of risk factors is slight different than Italian series, in agreement with the age difference: there are more patients with atrial fibrillation (29% vs. 23%), hyperlipidaemia (45% vs 25%) and heart failure (16% vs. 6%), while we didn’t treat any recurrent stroke (0% vs 9%); the subgroups are large vessel disease (37%), cardio-embolic (33%), lacunars (15%), multiple causes (15%). Medium NIH baseline score is 11, i.e. we had treated less severe cases than other Italian centres (medium NIHSS = 13). The time delay between onset of symptoms and early treatment is 141 minutes (faster than Italian series: 155 minutes): “door to needle time” is 77 minutes, about a quarter of hour more than the standards required by the Guidelines ACLS. The door-CT scan time is 25’ in line with the required standards. NIH Scale had an average reduction of 5 points in the first 24 hours, with a significant early improvement in 61% patients compared to 56% of other centres; the Global Outcome at 7 days is much better in 12/31 pts (12%), better in 9/31 pts (13%), worse in 3/31 pts (10%). Symptomatic intracranial cerebral hemorrhage did not occur in any patient (according to SITS-MOST definition). At 3 months the proportion of independence patients

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DC shock and spontaneous rupture of a normal spleen R. Laureano, M.P. Briganti, C. Mugnaini, F. Piani, S. Tatini Department of Internal Medicine, Santa Maria Annunziata Hospital, Florence, Italy

Introduction. – Traumatic rupture of the normal spleen and pathologic spleen rupture is quite common event. However, rupture of the spleen in the absence of either trauma or disease, so-called spontaneous rupture, can also occur 1. This event has been observed after vomiting 3, coughing 3 and colonscopy 4: our case was observed after DC shock. The pathologic and clinical features of spontaneous rupture of the normal spleen are the same of traumatic disruption. Spontaneous splenic rupture must fulfill the following criteria: no history of trauma or of unusual effort which could injure the spleen; no evidence of disease in organs other than the spleen which is known to affect the spleen and could cause it to rupture; no evidence of perisplenic adhesions that suggests that it had been traumatized or had ruptured previously; the spleen should be normal on gross and histologic examination other than findings of hemorrhage and rupture; clotting studies are usually normal 5; no any significant rise in viral antibody titers suggestive of recent infection with splenic involvement (Epstein-Barr 1virus, cytomegalovirus, and hepatitis viruses 6). Case report. – A 80 -year-old man with a history of coronary artery disease, hypertension and atrial fibrillation, was admitted to the emergency department with a new episode of arythmia. Chest examination was unsignificant and abdomen was soft with normal bowel sounds. Blood pressure (BP) was 200/100 mm Hg, initial hemoglobin concentration was 14.2 g/dL, with a normochromic normocytic picture, WBC count 10.0 mcl, platelet count 308/µL, and electrolytes, BUN, creatinine, 1liver 1function tests, clotting studies, D-dimer, 1and cardiac markers were within normal limits. Atrial fibrillation result in the ECG. After dalteparin 200 u.i /kg i.v, chemical cardioversion failed to restore sinus rythm and then DC shock was performed. Few minuts later the patient became hemodynamically unstable with a drop in his BP to 90/60

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mmHg. Repeat hemoglobin level was 11.4 g/dL. The CT scan of the abdomen and pelvis showed a large hematoma of the spleen and free fluid in the peritoneum. Urgent laparotomy revealed the presence of fresh blood and clots in the peritoneal cavity. The spleen, without pathologic pictures, was ruptured and a splenectomy was performed. Further examination of the viscera revealed no other abnormality. The patient and his family could not remeber history of significant trauma, either recent or in the remote past. However the new episode of atrial fibrillation could be related to sympatetic activation after bleeding in the spleen for an unnoticed abdominal trauma. References 01. Lieberman ME. Levitt MA. Spontaneous rupture of the spleen: a case report and literature review. American Journal of Emergency Medicine. 7(1):28-31, 1989. 02. Lennard, TW, Burgess, P Vomiting and “spontaneous” rupture of the spleen. Br J Clin Pract 1985;39,407-410 03. Nagib T. Toubia, MD; Maroun M. Tawk, MD, FCCP; Robyn M. Potts, MD and Gary T. Kinasewitz, MD: Cough and Spontaneous Rupture of a Normal Spleen Chest 2005;128:1884-1886. 04. Ahmed A, Eller PM, Schiffman FJ. Splenic rupture: an unusual complication of colonoscopy. Am J Gastroenterol. 92: 1201-4, 1997. 05. Orloff, MJ. Peskin, GW. Spontaneous rupture of the normal spleen-a surgical enigma. International Abstracts of Surgery. 106:1-11 1958. 06. Crate ID. Payne MJ. Is the diagnosis of spontaneous rupture of a normal spleen valid? Journal of the Royal Army Medical Corps. 137:50-1, 1991.

Wandering spleen and pelvic left kidney S. Tatini, M.P. Briganti, C. Lusini, G. Regoli, R. Laureano Department of Internal Medicine, Santa Maria Annunziata Hospital, Florence, Italy

Introduction. – The spleen is anchored in left subfrenic position by the gastrosplenic ligament, and the splenorenal ligament. Failure of development of these ligaments results in a long splenic mesentery and an abnormally mobile spleen, with an increased risk for axial torsion and infarction. The reported incidence in series of splenectomies is less than 0.5% 1, 2. It is associated with pancreatitis of the tail, portal veins thrombosis and abdominal trauma 3, 4, 5. The symptoms are variable from a chronic abdominal discomfort to acute abdomen. The most specific sonographic finding for wandering spleen is low position of the spleen 6. CT scan show a displaced spleen and partial o total failure of the spleen to enhance with i.v. contrast medium, indicating infarction 7. The splenectomy, now it is performed for vessel thrombosis with severe infarction also by videolaparoscopic techniques. The preferred treatment is splenopexy especially in children

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(8). We report a case of infarction of a wandering spleen in association with pelvic left kidney. Case report. – A 40 years old woman was admitted for fever and pain in the left upper side of the abdomen and in hypogastrium, like left renal colic. She refers an history of abdominal pain and of pelvic left kidney. The CT scan showed a large congested spleen; the ultrasound confirmed the displaced spleen, but no structural damage. An high white blood cell count (18.280/micron) was the only hematological alteration. Laparotomy shows a large ischemic spleen with a vascular pedicle, twisted of 360 degrees, in the pelvis, near to left kidney and lack of the omentum, of the lienorenal, and gastrolienal ligaments. The left kidney received blood by an artery originated from left common iliac artery: splenectomy was performed. To our knowledge the present case is the first report of wandering spleen associated to a pelvic left kidney. The ectopic kidney is a quite widespread inborn imperfection (1/900 births) and sonografy findings allow to know morfological and functional damage of wandering spleen. References 01. Desai DC, Hebra A, Davidoff AM, Schnaufer L: Wandering spleen: a challenging diagnosis. South Med J 1997 Apr; 90 (4): 439-43. 02. Maxwell-Armstrong CA, Clarke ED, Tsang TM and Stewart RJ: The wandering spleen. Archives of Disease in Childhood, Vol 74, 247-248, Copyright 1996. 03. Sheflin JJ, Lee CM, Kretchmar K. Torsion of wandering spleen and distal pancreas. Am J Radiol 1984;142:100. 04. Yilmaz C, Esen OS, Colak A, Yildirim M, Utebay B, and Erkan N: Torsion of a Wandering Spleen Associated With Portal Vein Thrombosis J. Ultrasound Med., March 1, 2005; 24(3): 379 - 382. 05. Walcher F. MD, Schneider G. MD, Marzi I. MD, Kriener G. MD, Kramann B. MD, PhD, Mutschler W. PhD: Torsion of a Wandering Spleen after Abdominal Trauma. The J Trauma vol 43 (6): 983-984.December 1997. 06. Karmazyn B, Steinberg R, Gayer G, Grzowski S, Freud E, Kornreich L.: Wandering spleen-the challenge of ultrasound diagnosis: report of 7 cases. J. Clin Ultrasound 2005 Dec;33(9):433-8. 07. Ben EA, Zissin R, Copel L, Vasserman M, Herts M, Gottlied P, Gayer G: The wandering spleen: CT findings and possible pitfalls in diagnosis. Clin Radiol 2006 Nov;61(11): 954-8. 08. Cavazos S, Ratzer ER, Fenoglio ME: Laparoscopic management of the wandering spleen. Laparoendosc Adv. Surg Tech.A. 2004 Aug;14(4):227-9.

Screening for TPO autoantibodies in pregnancy: is it worthwhile? C. Nassi1, G. Ozzola2, S. Marcantoni3, C. Sommella4, C. Vezzosi3, M. Paggini5, D. Vanni6 1Medicina Interna, Dipartimento di Medicina Interna, PO Sansepolcro (AR), USL 8, Arezzo, Italy; 2Sezione Laboratorio Analisi, Dipartimento di Patologia Clinica, Ospedale del Casentino, Bibbiena (AR), USL 8, Arezzo, Italy; 3Sezione di

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Endocrinologia, Dipartimento di Medicina Interna, PO San Donato, USL 8, Arezzo, Italy; 4UO Ostetricia e Ginecologia, Dipartimento Materno Infantile, Ospedale del Casentino, Bibbiena (AR), USL 8, Arezzo, Italy; 5UO Biochimica Clinica, Dipartimento di Patologia Clinica, PO San Donato, USL 8, Arezzo, Italy; 6Medicina Interna, Dipertimento di Medicina Interna, PO San Donato, USL 8, Arezzo, Italy

Aim. – Maternal subclinical hypothyroidism during early pregnancy has been shown to be associated with impaired neuropsychological development of children and several other adverse outcomes including premature birth, preeclampsia, breech delivery, and increased fetal mortality 1. These findings have triggered a debate about whether all pregnant women should be screened for hypothyroidism. Prevalence of suclinical hypothyroidism in pregnant women is estimated to be 2-5% 2-4, that of overt hypothyroidism 0,2-0,3% 2-5. Screening for TSH in pregnancy could be even more justified in moderate iodine deficient areas such as Appeninnic valleys. Thyroid autoantibodies (Atb) are found in 5-15% of woman in childbearing age and chronic autoimmune thyroiditis is the main cause of hypothyroidism during pregnancy 6, 7. The aim of our study was to determine the prevalence of TPO Atb in pregnant women in Casentino, an Appenninic valley in Eastern Tuscany defining relationship with TSH values, to evidence if routinary assay of TPO Atb in pregnancy is useful in the evaluation of thyroid function impairment. Methods. – In a group of 107 unselected pregnant women aged 31,5 ±4,2 yrs having been living in Casentino for at least three months, TSH, fT4 and TPO thyroid Atb were assayed during the first trimester of pregnancy. TSH and fT4 were measured by Advia Centaur Siemens Direct Immunochemiluninescence. TPO Atb by Immulite Siemens Immunoenzymatic Assay with luminogenic substrate. The manufacturer’s reference values for TSH are 0,35-5,5 mUI/l, for fT4 are 11,5-22,7 pmol/l, normal reference values for TPO is <35 kU/l. Results. – Prevalence of positive TPO Atb in pregnancy was of 7,4%. No correlation was observed between TPO Atb positivity and women age. Women with TPO positivity showed a higher medium TSH (3,1±1,7 mUI/l vs 1,7±0,8 mUI/l), difference however not statistically significative. Subclinical hypothyroidism, using as reference range that of the general population, was found in only one woman aged 28, with highly positive TPO Atb. A TSH value above 3 mUI/l was found in 10 women (9,3%) and among them 4 had positive TPO Atb (40%). Conclusion. – In our study, conducted in a group of unselected women, without asking for personal or family history of thyroid disease, the prevalence of

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TPO Atb is of 7,4% according to what previously reported in literature. Since we found no correlation between TSH value and TPO Atb positivity, the only assay of TSH as a first screening of thyroid function in pregnancy seems reasonable. Many studies call for the use of trimester- and assayspecific reference ranges for thyroid function tests in pregnancy 9, 10. In our study, using an upper normal value of TSH of 3 mUI/l, 9,3% of women would have subclinical hypothyroidism and among them only 40% had positive TPO Atb. The utility of specific reference values of thyroid function test during pregnancy is still matter of debate. These data support the validity of a screening for TSH in pregnancy, unselected screening for TPO Atb seems useless. These preliminary data should be further evaluated with data on pregnancy outcome. References 01. Allan WC et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 2000;7:27-130. 02. Klein RZ et al. Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol (Oxf) 1991;35:41-46. 03. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526-534. 04. Glinoer D. The systematic screening and management of hypothyroidism and hyperthyroidism during pregancy. Trends Endocrinol Metab 1998; 9:403-411. 05. Casey BM et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2006; 107:337-341. 06. World Health Organisation, Technical consultation of experts in Geneva in January 2005. The prevention and control of iodine deficiency in pregnant and lactating women and in children under two years: recommendations of a WHO Technical Consultation. Public Health Nutr 2007 Dec; 10(12A):1606-11. 07. Davis LE, Leveno KJ, Cunningham FG. Hypothyroidism complicating pregnancy. Obstet Gynecol 1998;72:108-112 08. Abalovic et al. Management of thyroid disfunction during pregnancy and postpartum: An Endocrine Society Clinical Practice Guideline 2007; J Clin Endocrinol Metab Aug; 92(8 Suppl):S1-47. 09. Baloch Z et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003;13:3-126. 10. Mandel SJ, Spencer CA, Hollowell JG. Are detection and treatment of thyroid insufficiency in pregnancy feasible? Thyroid 2005;15:44-53.

A fever with a not itching erytema S. Zacchei, L. Abate, P. Biagi U.O. Medicina, ASL – 7 Siena, Ospedali Riuniti della Val di Chiana senese, Montepulciano (SI), Italy

Introduction. – The toxic shock syndrome (TSS) it is a serious multisystemic acute disease characterized by high fever, hypotension, vomit, abdominal pain, diar-

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rhea, muscle pain, headache and maculo papular erytema induced by an infection of esotoxin producing Staphylococcus strain (most of all S. aureus). TSS is characterized by anemia (not hemolitic), leucocitosis, thrombocitopenia followed by thrombocitosis, high prothrombin time, high partial thromboplastin time, hepatocellular dysfunction, and skeletal muscle damage. In the most serious cases acute respiratory distress syndrome may ensue. Case report. – 83 year-old man, with immobilization syndrome as a results of cerebral hemorrhage, and hypertension was admitted owing to high grade fever from some days associated with purplish red lesions of the lumbar region and the thighs. Chest X Rays were negative, blood analysis revealed marked increase of inflammation signs (ESR, CRP), pathologic coagulation (INR = 1,80, Quick time = 41%, aPTT = 37,7 sec, Fibrinogen mg 606%, Thrombin time 15,0 sec) and increased liver enzymes (ALT, AST, Alk P, gamma GT). The clinical picture was dominated by high grade fever (39,5°C), marked hypotension, headache and by not itching erytematous wide spots at the thighs, buttocks and lumbar region; particularly at the left thigh it was present a reddened area like a burn. In the sacral region a little II degree pressure lesion was present. Its culture gave positive results for: Pseudomonas Aeruginosa, Staphylococcus Haemolyticus, Escherichia Coli, Citrobacter Koseri. It was undertaken therapy with levofloxacin and amikacin according to the antibiogram results with gradual improvement, the patient was discharged healed. Conclusion. – The coagulase negative staphylococci are normally present on the skin, to determine a TSS they need to overcome the skin barriers to penetrate deeply; bedsores may represent the entry door. Currently the percentage of penicillins resistant bacteria is increased so, waiting for the tests of sensibility in vitro, fluoroquinolones are the recommended empirical therapy.

Any link between carotid dolichoartheriopathies and cardiovascular risk factors? C. Zeloni1, V. Corsoni2, M. T. Passaleva2, F. Prosperi Iovi2, A. Cartei2, S. Cencetti2 1 Department of Emergency Medicine, Misericordia e Dolce Hospital, Prato, Italy; 2Department of Emergency Medicine, Santa Maria Nuova Hospital, Florence, Italy

Aim. – Several previous studies already reported Carotid Dolichoartheriopathies (CD) (kinking, coiling, looping, tortuosity) as occurring in 2-25% of patients undergoing ultrasound scanning of the carotid artheries (J.B. Thomas et al. Stroke 2005). Reciprocal relationship between arterial geometry and atherosclerosis have already been hypothesized (T.J. Leipzig et al. Surg Neurol 1986, L Del Corso et al. Angiology 1998). Nonetheless the results of other studies gave contrasting results regar-

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ding the causal links between CD and vascular risk factors (G. Prencipe et al Minerva Cardionagologica 1998; C. Togay-Isikay Acta Neurol Belg 2005). We retrospectively evaluated our personal experience on patients with CD in order to assess the eventual relationships between the major cardiovascular risk factors and CD. Methods. – Criteria for exclusion from the study were: previous or acute stroke or coronary artery syndromes, comatose patients on admittance, heart failure II-IV NYHA grade, atrial fibrillation. Among 107 consecutive patients fulfilling the criteria for inclusion who displayed CD on echocolordoppler investigations performed in our departments in the period September 2006 – May 2007, we could apply this study protocol on 89 subjects. We sought for arterial hypertension (i.e. systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg), diabetes mellitus, hypercholesterolemia, cigarette smoking, age (<65 years, between 65 and 75 years, >85 years), and gender both in patients’ clinical histories and in clinical and laboratoristic findings on admittance. We sought for eventual relationship between any of the major cardiovascular risk factors evaluated and the presence of CD. Multivariate analysis was performed by means of SPSS statistical package, we set significance level for p value <0.05. Results. – Females represented 69,2% of the examined subjects. Patients aging < 65 years represented 17,7% of the sample, patients in the age range between 65 and 75 years accounted for 38,6% of the subjects, while 43,7 % of the patients were older than 75 years. Arterial hypertension was present in 19,7% of the patients. Hypercholesterolemia was found in 11,9% of the patients with CD. Diabetes mellitus was affecting 4, 3% of the patients. Regular cigarette smokers were 18,8% of the patients. Statistically significance relationship was found only for gender and age (p <0.05 and 0.01 respectively). Conclusion. – Among the major cardiovascular risk factors that had been selected for this study protocol, only advanced age and feminine gender displayed a significant association with CD. A bias could be introduced by selecting the patients presenting to the Emergency Room for acute pathologies, who represent indeed an older population than the one that could be studied as instance from the database of the cardiovascular and cardiomethabolic ambulatories.

Catheterization via caudal puncture of the epidural space with a 5F angiography catheter and a coaxial steerable 0.038’’ guidewire to perform mecanichal adhesiolysis D. Gambacorta1, V. Lunghi1, U. Arrigucci1, M. Cirinei1, R. Buontempo2, M.Zocchi1 1Unit of Neuroradiology, Department of Imaging Misericordia Hospital, Grosseto, Italy; 2Unit of anaesthesia, Misericordia Hospital, Grosseto, Italy

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Introduction. – To descibe a technique for epidural medication delivery with angiographic catheters and guidewires inserted via caudal pncture and andvanced cephalad under fluoroscopic guidance in the treatment of painful spinal deseases. Case report. – Low back pain (LBP) may be supported by the presence of fibrotic tissue and/or adhesions. The causes can be many including hernias disc, stenosis of the channel and the well-known “failed back surgery syndrome” (FBSS). These conditions can determinate epidural scarring, which can physically prevent direct application of drugs to nerves and other spinal tissues and to treat chronic back pain. Epidural fibrosisi is not well diagnosed by current imaging techniques and makes difficult or impossible correct delivering of drugs in the tru sites pain’s origin. Epidural catheterization allows to perform an epidurography and detect source of pain, to deliver specific drugs in the affected site, and to make mechanical adhesiolysis which provides adequate routes to venus and interstitial run-off, via the neuroforamen and the periradicular spaces (physiological efflux pathways), aiming to mainteinance long-termk result. In these situations, the insertion at the sacral hiatus of a specific catheter (catheter Racz) under fluoroscopic guidence, allows achieving root concerned and selective injection of a mixture of drugs again edema ed inflammation: this tecnique is called adhesiolysis. The classic Racz’s protocol provides for infusion for three consecutive days. After careful analysis about the effectiveness and possible complications related to stay in situ of the catheter adhesiolysis is today performed in many centres in day surgery. In our tecnique we used an angiographic 5 French hockey-stick tip catheter and a coaxial 0.038’’ steerable guidewire inserted at the sacral hiatus and advanced cephalad under fluoroscopic guidance; adhesiolysis deal with the direct cannulation of a specific lesion area ( before identified by epidurography as a filling defect, topographically related with the patient sintomatology), leading the catheter within the lesion, above it and laterally across the neuroforamen, producing a subsequent run-off of the injected contrast-medium (mechanical adhesiolysis) and, hopefully, adequate paths for inflammation resorption. Furthermore it is possible to administer steroids and anaesthetic. By this tecnique we perform physical action without the use of chemicals for lysis adhesions. In a period of 11 month a total of 18 patients with LBP underwent adhesiolysis in our institute; we evaluated the efficacy of the the procedure in the long (6 months), medium (3 months) and brief (1 monts) term. The procedure was completely successful in long term for six patients, in medium term for five patients and in brief term for three patints.

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A case of cerebral hemorrhage related to bone marrow aplasia likely induced by clopidogrel P. Randisi, F. Rossi, M. Alessandri, M. Cipriani Unit of Internal Medicine, Misericordia Hospital, Local Health Unit 9, Grosseto, Italy

Introduction. – Clopidogrel bisulfate, a thienopyrinidine derivate, was approved for the reduction of ischemic events in patients with recent myocardial infarction (MI), stroke, and peripheral arterial disease. It has been introduced into clinical practice for efficient platelet (PLT) inhibition by inhibiting binding of ADP to its receptor and subsequent ADP-mediated activation of GP IIb/IIIa complex with fewer side effects than ticlopidine or ASA. However, there were several reports concerning the potentially fatal types of hematologic dyscrasia associated with clopidogrel therapy, such as aplastic anemia, neutropenia, pancytopenia, thrombocytopenia and trombocytopenic purpura. We experienced a side effect pancytopenia in a woman treated with clopidogrel and ASA after MI, occurred on May 2007, where percutaneous transluminal angioplasty (PTCA) and stenting were performed. Case report. – A 72-year-old caucasian female who had a history of MI (PTCA and stenting on May 2007), peripheral and cerebral vascular disease, hypertension, dyslipidemia, hypothyroidism, chronic renal failure. At home the patient was treated with ASA 100 mg, clopidogrel 75 mg, levothyroxine 50 µg, furosemide 25 mg, simvastatin 20 mg, bisoprolol 5 mg, allopurinol 300 mg, lansoprazole 30 mg. Admitted in date 19/07/2007 to the Internal Medicine Unit of Misericordia Hospital for anemia, after 3 months of treatment with ASA and clopidogrel, hematologic findings disclosed important anemia (5.5 g/dl), normal white blood cell (WBC) counts (5.35 × 103/µl) and PLT counts (271 × 103/µl). Clinical examination of the patient did not reveal pathologic findings. We made dosage of sideremia (increased, 242 µg/dl), ferritin (increased, 309 ng/ml), Vit B 12 and folic acid (both normal 445 pg/ml and 7,3 ng/ml respectivelly). A gastroscopy revealed only atrophic aspect of stomach walls. The dosage of erythropoietin revealed increased value (>306 mu/ml). After one month from the first admission in Hospital, hematologic findings disclosed pancytopenia (WBC = 3.25 × 103/µl; Hb= 7.5 g/dl; PLT = 14 × 103/µl). So we pro-ceeded with bone marrow biopsy which revealed hypocellular marrow lowly representing the erythroid line, presence of lymphatic nodule with morphological and immunophenotipical characteristics of benignity. During the patient’s hospital stay the clinical condition evolved with fever, gastric hemorragic disease and IM. The patient’s blood exames revealed a severe thrombocytopenia (PLT = 6 × 103/µl). In date 1/09/07 we transferred the patient to the Intensive Care Unit because of an hemorragic stroke; she died in the same day.

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characteristics of headache that signal a potential significant organic problem in order to improve the management of this patient group.

Headache in the emergency room: an observational study M. Alessandri1, F. Rossi1, A.M. Romagnoli1, G.M. Forteleoni1, O. Panichi1, M. Breggia2, M. Cipriani1 1Headache Centre, Unit of Internal Medicine, Misericordia Hospital, Local Health Unit 9, Grosseto, Italy; 2Unit of Emergency Medicine and Surgery, Department of Emergency, Local HealthUnit 9, Grosseto, Italy

Aim. – Patients presenting to the Emergency Room (ER) with a chief compliant of headache represent 2% or more of all ER visits. Most commonly the headache is without serious underlying cause, but occasionally can be related to diseases requiring prompt diagnosis and immediate treatment. The objective of our study was to assess history, examination, final diagnosis and treatment of acute headache presenting to the ER during a one-year period. Methods. – A retrospective study was performed in the ER of the Misericordia Hospital of Grosseto, including patients with headache who have attended the ER between 1 January and 31 December 2004. For each patient a data collection was performed, recording demographic and clinical information, as well as final diagnosis at discharge. Results. – Four hundred and ten patients with headache accounted for 1.25% of all patients (32,869) attending ER of Misericordia Hospital in 2004. The media age was 45 years and sex ratio (m/f) was 1.5/1. Computed tomography of the head was performed in 178 patients. Twenty patients underwent radiography of the skull, 13 electroencephalographic examination and 1 patient lumbar puncture. In 95 patients headache was treated by administering non steroidal antiinflammatory drugs of which the most used were ketorolac and indomethacin. At discharge 152 patients were diagnosed as having a headache, 31 as having headache associated with other symptoms and 38 as post-traumatic headache. Thirty-five (8.5%) patients were found to have a serious underlying cause of their headache, the most common being cerebral hemorrhage (4.6%). Cerebral ischemia represented 3.4% of all cases and only 2 cases (0.5%) of cerebral neoplasm were identified. Fifty-one (2.5 %) patients remained without a diagnosis. Seventy-six (18.5%) patients were admitted to Hospital, mainly in Internal medicine and neurology Units. Conclusion. – Our study confirm the small proportion of patients with acute headache attending the ER. In fact, although a common symptom, headache rarely requires urgent attention. It must be assumed that something out of the ordinary has happened for patients to present to Hospital and so, until proved otherwise, headache must be considered a reflection of an underlying severe pathological process. In our study 8.5% of patients presenting with headache suffered from an intracranial potentially fatal condition. Therefore, the ER physician must recognize symptoms and

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Outcome of elderly patients from a setting for low-intensity care: the Registry of the Internal Medicine Department of Santa Chiara Hospital in Firenze, Italy C. Mugelli1, V. Ciambrone1, I. Bruni1, L. Gargani1, V. Scarpelli1, F. Sequi1, D. Bartoli1, S. Cencetti2, A. Lagi2 1 Department of Internal Medicine, Santa Chiara Hospital, Firenze, Italy; 2Department of Emergency Medicine, Santa Maria Nuova Hospital, Firenze, Italy

Aim. – The setting for low-intensity care is a relatively clearly defined concept for pathologies affecting adults and young adults, but it still remains affected by unclear criteria when applied to the elderly patients that are carrying a large amount of confounding factors like comorbidities, fragility and inadequate social and/or familiar environment. Our Department is deputed to direct admittance from the Emergency Department of the Santa Maria Nuova Hospital in Florence, with the restriction to represent a setting of low-intensity of care for elderly patients. Because of the complexity of the elderlies, the widely accepted criteria of the MEWS score is inadequate to screen the patients for the low-intensity care setting in the elderly population, therefore we examined our registry in order to look for stronger predictors for screening and outcome. Methods. – We retrospectively examined data from the first four months of the current year, comprehending 229 consecutive patients. The outcome was arbitrarily assigned to group 0, 1, and 2 basing on the following criteria: discharge from hospital with return to home (group 0), return to home with a program of domiciliary assistance already planned by the hospital (group 1), and unfavourable outcome (transferred to the Emergency Department, to long-lasting rehabilitation setting, or in-hospital dead) for group 2. The following parameters were considered: MEWS score, BADL score, IADL score, EXTON score, presence of inadequate nutritional state, inadequate Mini Mental State, inadequate control of deglutition, urinary incontinence, plagues, and principal diagnosis. Statistical analysis was performed by non parametrical tests for mean comparisons among groups, and with squaredï adjusted by r x c tables, for frequency comparison among groups. Results. – Mean age was significantly (p<.05) higher in group 1:86.6 ± 7.0 years versus 74.5 ± 4.9 in group 0 and 78.5 ± 8.9 in group 2. MEWS score was inadequate for low- intensity care setting in 31% of group 0, 33% of group 1, and 36% of group 2, with no significant differences. Cardiovascular and urinary

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diseases were equally represented in all groups, whereas cerebral diseases affected more frequently groups 1 and 2 (p<.01), gastrointestinal diseases group 1 (p<.05), and respiratory diseases group 2 (p<.01). The best BADL and IADL scores at income were best in group 0 (p<.01); group 1 showed better scores than group 2 (p<.05); EXTON scores did not differ among groups. Frequency of plagues at income did not differ among groups, whereas Mini Mental State, inadequate control of deglutition, inadequate nutritional state, and urinary incontinence were significantly best (p<.01) in group 0. Conclusion. – Unfavourable outcome is not expected from patients assigned to a low-intensity setting. Our data demonstrate that the complex computing of the widely used scores can not represent a reliable predictor of outcome in elderly patients. Elementary clinical variables and the main underlying disease, mainly the cerebral diseases, are stronger predictors of outcome in the elderly patients.

Radiometabolic treatment of secondary bone lesions: retrospective evaluation of bone metabolism markers variations L. Lelli, M. Dalla Porta, M. Tosti Balducci, M. Pellegri, N. Mazzuca Nuclear Medicin Unit, ASL 9 Grosseto, Italy

Aim. – The radiometabolic therapy with Samarium (SM-EDTMP) or Strontium (SR-CLORURO), actually rapresents only a palliative treatment aimed at improving the quality of life. This treatment can influence the values of hematic and urinary indices of bone metabolism. The possible use of the markers of bone metabolism to evaluate the success of therapy, assumes great relief in the perspective of a combined chemotherapy and bone-targeted radiotherapy treatment to slow down the progression of disease and to obtain a prolonged survival. Methods. – Levels of the urinary bone resorption marker deossipiridinoline (Dpyd) and the serum bone formation markers bone-specific alkaline phosphatase (BALP), telopeptide C-terminal and N-terminal (sICPT, s-INPT) were assessed in patients with bone metastasis.

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Dpyd rapresent a potential biochemical index of bone metastases in follow-up of the single patient and its hematic levels are higher in subjects with bone lesione lesion; s-ICPT and in particular s-INPT level were more consintent prognostic indicator than BALP and seems to be able to monitor the answer to the radiometabolic treatment; Bone-specific Alkaline Phosphatase is the must used marker progression index of the bone desease in advanced prostate cancer. The aim of the study was to estabilish evidence of inorder to evaluate the correlations between the variation of bone markers and the progression of disease; We have retrospectively evaluated the clinical records of 15 patients with advanced prostatic and breast cancer treated with radiometabolic therapy in our unit. Before treatment all the fifteen patients with multiple documented metastases, carried out a basal bone scintigrafic examination and an assessment of bone markers. Approximately 24 hours after the administration of the radiometabolic treatment a total-body scintigraphy was done in order to visualize the effective distribution of the radiotracer in bone metastases. The blood test have been done again approximately a month after the initial treatment. Results. – The most majority of patients (13/15) had a decrement of the values of urinary Dpyd, and hematic ICPT and INPT, while slight modifications have been observed in BALP’s values. The patient that experienced a greater benefit from treatment where the ones who had a highter improvement of same markers. Toghether with some markers monitored the levels of CT and PTH that showed little variation after the treatment probably due to change in blood calcium values. Conclusion. – According to literature, our study seems to demonstrate that changes in bone metabolic markers effectively represent the efficacy of radiometabolic treatment in patients with bone metastasis due to prostate and breast cancer. In the particularly, Dpyd has the higher specificity compared with BALP and PSA, which being influenced also by visceral metastasis is not considerable a marker of bone progression disease. Further studies arroling a higher number of patient are necessary to confirm these preliminary data in which Dpyd seems to be a sensitive and specific indicator of responce to radiometabolic treatment with osteotropic radionuclides in patient affected with bone metastasis disease.

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AUTHORS’ INDEX

Authors’ Index F Fabiani P., 59, 61 Falciani M., 94 C Ferrari C., 22 Caffarelli C., 39 Fiorini I., 81 Cantarini L., 19 Forteleoni G.M., 30, 48, Cappelletti C., 59, 61, 94, 101 96 Frigerio C., 85 Capponi F., 86 Capritti E., 87 G Cartei A., 53, 68, 82, 99 Galassi L., 48 Cataleta P., 36 Galeazzi M., 19 Caviglioli C., 88 Gambacorta D., 40, 99 Cecchin A., 13, 88 Gambacorta R., 40 Cellai F., 11 Gargani L., 101 Cencetti S., 53, 66, 68, 73, B Genovesi-Ebert A., 82 82, 99, 101 Bacalli S., 94 Gensini G.F., 5 Ceravolo R., 17 Baccetti F., 96 Ghiadoni L., 86 Cercignani M., 93 Bagnoli L., 96 Cersosimo R., 64 Giacomelli C., 22 Bandinelli G., 53 Checchi M., 90 Giovannetti R., 91, 92 Bardazzi M., 30 Ciambrone V., 101 Giuello A., 87 Bartoli D., 88, 101 Ciolli S., 61 Gonnelli S., 33, 39 Baruffi C., 59 Cipriani M., 27, 30, 33, 48, Gori AM., 5 Bassu R., 90, 91, 92 100, 101 Bazzichi L., 22 Cirinei M., 40, 99 I Bellisai F., 19 Conti A.A., 5 Iori I., 7 Benucci M., 61 Cordisco A., 3 Iovine F., 87 Benvenuti C., 87 Corradi F., 13 Bettazzi C., 61 Corradini P., 85 L Betti S., 6 Corsoni V., 53, 82, 99 Biagi P., 79, 80, 88, 89, 90, Cortese B., 55, 82, 83, 83, Laffi G., 88 98 Lagi A., 26, 53, 64, 66, 68, 85 73, 101 Biagini M., 81 Crovetti B., 29 Bimbi M., 88 Lancini I., 82 Birindelli A., 92 Landini G., 86 D Bombardieri S., 22 Landini G.C., 94 Dalla Porta M., 102 Borgogni T., 11 Laureano R., 96, 97 De Alfieri W., 11 Bozzano C., 82 De Crescenzo V., 87 Lazzerini N., 92 Bracci S., 61, 96 De Falco D., 40 Lelli L., 102 Breggia M., 101 De Feo F., 22 Lenti S., 85, 86 Briganti M.P., 96, 97 De Feo P., 17 Limbruno U., 55, 82, 83, 83, 85 Donati A., 86 Brunelleschi G., 92 A Abate L., 79, 80, 88, 89, 90, 98 Abbate R., 3 Alessandrì A, 90, 91 Alessandri M., 27, 30, 48, 100, 101 Amendola A., 87 Arcangeli E., 29 Arena U., 88 Arioli D., 7 Armento A., 29 Arrigucci U., 40 , 99 Atzeni F., 80

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Bruni I., 101 Buontempo R., 99

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Lombardo G., 6, 81 Lucchesi I., 90, 91 Lunghi V., 40, 99 Lusini C., 97 M Maddau C., 59 Mammolo A., 22 Manfredi M., 61 Manini M., 87 Marcantoni S., 97 Marcocci A., 88 Marcucci R., 3, 5 Matucci M., 59 Mazzuca N., 102 Mazzucai N., 34 Mei E., 82 Meini S., 88 Mellone C., 79 Meucci E., 53, 73 Meucci G., 93 Micheli A., 55, 82, 83, 85 Monsacchi L., 61, 96 Montagnani A., 27, 33, 48, 86 Montalto P., 92 Montigiani A., 94 Morettini A., 13, 88 Morosi L., 29 Mugelli C., 101 Mugnain C., 96 N Nassi C., 97 Natali A., 92 Niccoli G., 20 Nisticò F., 11 Nozzoli C., 24, 86 Nucci C., 86 Nuti R., 33, 39

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AUTHORSâ&#x20AC;&#x2122; INDEX

O Ozzola G., 97 P Paci M., 88 Pacini S., 80, 88, 89, 90 Paggini M., 97 Palombi G., 36 Pampana A., 50 Panichi O., 101 Panigada G., 90, 91, 92 Parca G., 92 Pasqui L., 11 Passaleva M.T., 82, 99 Pedace C., 82, 85 Pellegri M., 102 Petri S., 11 PettinĂ  G., 29 Piani F., 96 Picchi A., 55, 82, 83, 85 Pieralli F., 24 Piluso A., 88

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Pizzini A.M., 7 Prattichizzo F., 6 Prosperi Iovi F., 99 Prugnola C., 93 R Randisi P., 100 Regoli G., 97 Regoli S., 81 Riello F., 11 Righi A., 94 Rissante T., 86 Ristori F., 94 Romagnoli A.M., 101 Rosito MP., 92 Rosselli M., 88 Rossi A., 82 Rossi F., 27, 100, 101 S Santillo V., 87 Santoro E., 43, 92

Scarpelli V., 101 Scarti L., 59 Scerra C., 94 Scopetani N., 88 Seghieri G., 14 Sequi F., 101 Seravalle C., 94 Severi S., 55, 82, 83, 85 Silingardi M., 7 Sommella C., 97 Spolveri S., 94, 96 Stanganini S., 92 Straniti M., 91, 92 T Taccetti G., 59 Taddei S., 86 Tafi A., 88 Tatini S., 94, 96, 97 Tavernese G., 94 Teghini L., 90 Tonarelli L., 90, 91 Tosti Balducci M., 102

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Tropeano F., 86 Tufi A., 92 U Unti E., 17 V Vagheggini C.F., 87 Vagheggini G., 44 Vanni D., 82, 97 Vannucci N., 88 Verdiani V., 46 Vezzosi C., 97 Vitali C., 36 Vizzuti F., 88 Z Zacchei S., 79, 79, 80, 88, 98 Zeloni C., 53, 82, 99 Zipoli M., 88 Zocchi M., 40, 99 Zuccone N., 82

October 2008


VII CONGRESSO NAZIONALE FAOI TOSCANA  

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