Volume 10 Supplement October 2015

Transcription

1 Volume 10 Supplement October 2015 E D I T O R-IN-CHIE F Domenico Pr isco PROCEEDINGS 116th National Congress of the Italian Society of Internal Medicine Rome, October 2015

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3 Internal and Emergency Medicine Official Journal of the Italian Society of Internal Medicine Volume 10 Supplement October 2015 SYMPOSIA Affordability of health care and aging New approach to geriatric patient Roberto Messina Edoardo Gnasso Claudio Taranto S1 Importance of comprehensive geriatric assessment in the evidence-based medicine era Graziano Onder Agnese Collamati S9 End-of-life care: a doctor s choice or a patient s choice? Giuseppe Remuzzi S15 Primary prevention and lifestyles Protective aspects of Mediterranean Diet Andrea Ghiselli S16 Primary prevention and lifestyles: physical exercise Giorgio Galanti Laura Stefani Cristian Petri Gabriele Mascherini S22 SELECTED PAPERS Pain in Internal Medicine The internist and pain in the hospital setting Maria Adele Giamberardino Giannapia Affaitati Francesco Cipollone Raffaele Costantini S31 Pharmacological treatment of pain in patients with multimorbidity and polipharmacy Silvia Benemei Pierangelo Geppetti S39 Metabolic syndrome and organ damage Metabolic syndrome and organ damage: NAFLD Silvia Fargion Giuseppina Pisano Anna Ludovica Fracanzani S45 LECTURE Gastroesophageal reflux disease (GERD) Patrizia Zentilin Edoardo Savarino Manuele Furnari Giorgia Bodini Elisa Marabotto Vincenzo Savarino S65 Acute heart failure: challenges in prognostic risk stratification and medical management Gianfranco Sinagra Davide Stolfo Enrico Fabris S74 WARD MEDICINE Arterial stiffness Maria Lorenza Muiesan Massimo Salvetti Anna Paini Claudia Agabiti-Rosei S82 Antibiotic therapy in critically ill patient Nicola Petrosillo Simone Topino Maria Adriana Cataldo S90 The new anti-platelet drugs: highlight on P2Y12 inhibitors Marco Cattaneo S94 Pulmonary arterial hypertension: new prognostic perspectives Nazzareno Galié S98 MEET THE EXPERT Primary aldosteronism: a brief update Gian Paolo Rossi Livia Lenzini Giuseppe Maiolino Teresa M. Seccia S99 New antihyperglycemic agents Paolo Cavallo Perin Cristina Amione Paolo Fornengo S104 Metabolic syndrome and cardiovascular organ damage Giuseppe Schillaci Francesca Battista Fabio Anastasio Mariano Crapa Yahya Alrashdi Giacomo Pucci S55

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5 Internal and Emergency Medicine Official Journal of the Italian Society of Internal Medicine Editor-in-Chief D. Prisco Department of Experimental and Clinical Medicine, University of Florence and Interdisciplinary Internal Medicine Unit AOU Careggi, Florence, Italy Co-Editor P. Rosen, Boston, USA Operative Group S. Del Pace, Florence, Italy R. Marcucci, Florence, Italy Advisory Board E. Agabiti Rosei, Brescia, Italy M. Alderman, New York, USA R. Barkin, Cambridge, MA, USA G. Berni, Florence, Italy J. Bousquet, Paris Cedex, France F. Caligaris Cappio, Milan, Italy N. Carulli, Modena, Italy G. Davì, Chieti, Italy M.M. d Elios, Florence, Italy G. Di Minno, Naples, Italy A.F. Dominiczack, Glasgow, UK L. Fabbri, Modena, Italy N. Gentiloni Silveri, Rome, Italy L. Gesualdo, Bari, Italy P.H.R. Green, New York, USA A.M. Heagerty, Manchester, UK A. Iorio, Hamilton, ON, Canada R.J. Johnson, Gainsville, FL, USA R. Landolfi, Rome, Italy R. Lauro, Rome, Italy G. Licata, Palermo, Italy G.D.O. Lowe, Glasgow, UK L. Luzzatto, Florence, Italy T. Macdonald, Dundee, UK G. Mancia, Milan, Italy N. Marchionni, Florence, Italy G. Masotti, Florence, Italy H. Meislin, Tucson, AZ, USA G. Palareti, Bologna, Italy P. Pignatelli, Rome, Italy E. Ritz, Heidelberg, Germany S. Romagnani, Florence, Italy B. Trimarco, Naples, Italy A. Tuttolomondo, Palermo, Italy A. Tyndall, Basel, Switzerland G. Valesini, Rome, Italy Editorial Board Chairman D. Prisco, Florence, Italy Editors W. Ageno, Varese, Italy G. Agnelli, Perugia, Italy A. Bartoloni, Florence, Italy S. Basili, Rome, Italy C. Borghi, Bologna, Italy M.D. Cappellini, Milan, Italy A. Carolei, L Aquila, Italy E.M. Clini, Modena, Italy G.R. Corazza, Pavia, Italy J. Douketis, Hamilton, ON, Canada P. Gresele, Perugia, Italy G. Laffi, Florence, Italy M. Levi, Amsterdam, Netherlands A. Licata, Palermo, Italy E. Maggi, Florence, Italy P.M. Mannucci, Milan, Italy E. Manzato, Padua, Italy P. Martelletti, Rome, Italy P.A. Modesti, Florence, Italy N. Montano, Milan, Italy M. Muscaritoli, Rome, Italy L. Pagliaro, Palermo, Italy V. Pengo, Padua, Italy F. Perticone, Catanzaro, Italy R. Pontremoli, Genoa, Italy P. Prandoni, Padua, Italy R. Polosa, Catania, Italy P. Sbraccia, Rome, Italy V. Toscano, Rome, Italy B. Vaira, Bologna, Italy A. Vannucchi, Florence, Italy F. Violi, Rome, Italy Emergency Medicine Chairman B. Adams, San Antonio, TX, USA Editors K.M. Ban, Cambridge, MA, USA W. Brady, Charlottesville, PA, USA D. Brown, Boston, MA, USA M. Cocci, Boston, MA, USA D. Coen, Milan, Italy S. di Somma, Rome, Italy M.W. Donnino, Boston, MA, USA J. Edlow, Boston, MA, USA C. Fischer, Boston, MA, USA F. Franceschi, Rome, Italy S. Grifoni, Florence, Italy M. Kennedy, Boston, MA, USA A.M. Landry, Boston, MA, USA D. Lauque, Toulouse, France G. Morabito, Rome, Italy J. Mosier, Tucson, AZ, USA R. Pini, Florence, Italy P. Rosen, Boston, MA, USA L. Sanchez, Boston, MA, USA R. Sbrojavacca, Udine, Italy B. Yersin, Lausanne, Switzerland K. Volz, Boston, MA, USA R.E. Wolfe, Boston, MA, USA Clinical Evidence and Health Technology Assessment Chairman G.F. Gensini, Florence, Italy Deputy Chairmen G. Costantino, Milan, Italy G. Casazza, Milan, Italy Editors S. Corrao, Palermo, Italy R. Grilli, Florence, Italy L. Moja, Milan, Italy S. Ricci, Perugia, Italy A. Squizzato, Varese, Italy L. Tagliabue, Milan, Italy G. Virgili, Florence, Italy Aims and Scope Internal and Emergency Medicine (IEM) is an independent, international, English-language, peer-reviewed journal designed for internists and emergency physicians. IEM publishes a variety of manuscript types including Original investigations, Review articles, Letters to the Editor, Medical Illustrations and Invited Editorials, Points of view and Commentaries. Occasionally IEM accepts unsolicited Reviews or Editorials. The journal is divided into three sections, i.e., Internal Medicine, Emergency Medicine and Clinical Evidence and Health Technology Assessment, with three separate editorial boards. In the Internal Medicine section, invited Case records and, occasionally, Physical examinations, devoted to underlining the role of a clinical approach in selected clinical cases, are also published. Occasionally, the Emergency Medicine section includes a Morbidity and Mortality Report and an Airway Forum concerning the management of difficult airway problems. Finally, in the Clinical Evidence and Health Technology Assessment section brief discussions of topics of evidence-based medicine (Cochrane s corner) and Research updates are published. IEM encourages letters of rebuttal and criticism of published articles whereas submission of case reports is not of interest for the journal. Topics of interest include all subjects that relate to the science and practice of Internal and Emergency Medicine. IEM is the official journal of the Italian Society of Internal Medicine and is published eight times per year starting with 2013.

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7 Intern Emerg Med (2015) 10 (Suppl):S1-S8 SYMPOSIUM Affordability of health care and aging New approach to geriatric patient Roberto Messina Edoardo Gnasso Claudio Taranto SIMI 2015 Abstract Italy, as all the social and economic advanced Countries, is experiencing a massive ageing process. According to Istat (GeoDemo), the Italian elderly population amounts to 13,014,942 individuals, representing 21.41% of the entire resident population (19% males, 24% females). Based on these evidences, has started a global discussion on how to properly face the ageing process. Neither the Italian welfare system, nor the social services system, were designed to satisfy this huge amount of incoming needs. The Italian context is even more complex from a demographic point of view. In fact Italy is facing an epic demographic turnaround, due to the baby boomers generation ageing process. This process will lead Italian ageing indicators to critical levels. In 2030 we will have to face an ageing index of (against in 2012) and an old age dependency ratio of 43% (32% in 2012). For these reasons and to satisfy the constant increasing of health services required, FederAnziani Senior Italia, the largest elderly Italian federation, presents in this paper a short summary of its last big project: the Mutual Aid Society (Senior Italia MAS). The concept behind this project is to promote the Mutual Aid Society as the milestone of a new National Health System (NHS) pattern, where the role and the activities of hospitals, general practitioners, specialists and all the main actors of Italian NHS are completely redefined, ensuring the geriatric patients a human and highly specialized approach to their needs by their general practitioners. Synthetically, MAS operations will be concretized in transfer a large number of diagnostic activities made by hospitals R. Messina ( ) President of FederAnziani Senior Italia. segreteria.presidenza@federanziani.it E. Gnasso C. Taranto Centre for Studies in Health Economics SIC Sanità In Cifre, Italy. towards general practitioner clinics, encouraging them to aggregate and cooperate into widely organized territorial structures in which several, complementary medical skills are guaranteed. These organizations would then be endowed of all the diagnostic tools necessary in order to provide citizens with a complete diagnostic service. The latter would thus result to be qualitatively better than the one that hospitals, overburdened by a series of other activities, were able to offer, obtaining a large cost saving too, through a redefinition in terms of role and operations of the very large number of hospitals displaced in Italy, reducing uneconomic duplications and wastefulness and gathering resources to provide a better health service. Moreover, this project will collect a large amount of resources through disease early detection and adherence enhancement, especially for geriatric patients. In this paper all of these aspects will be deeply analyzed. Riassunto L Italia, al pari di tutti i Paesi economicamente e socialmente avanzati, invecchia. Secondo i dati Istat (GeoDemo), al 1 gennaio 2014 gli anziani in Italia ammontavano a , pari al 21,41% della popolazione totale residente (19% maschi e 24% femmine) [1]. Da un po di tempo a questa parte si sta cominciando a pensare a come far fronte all inesorabile invecchiamento che aumenterà da qui ai prossimi anni. Né il nostro sistema di welfare, né i servizi socio-assistenziali sono, infatti, stati pensati per soddisfare quei bisogni che fino a qualche anno fa non erano presenti. Non solo, ma l invecchiamento della popolazione nata durante il baby boom degli anni 50 continuerà ad accrescere il peso della popolazione anziana in due modi: aumentando il cosiddetto indice di vecchiaia che passerà da un valore di 146,8 del 2012 a 207,1 nel 2030 e il tasso di dipendenza, che passerà dall odierno 32% al 43% nel 2030 [2]. Per questi motivi, e soprattutto per far fronte all incessante richiesta di servizi sanitari che tutto questo comporta, la più grande federazione di anziani italiana, FederAnziani Senior Italia, con questo documento presenta una sintesi del suo nuovo progetto: una Società di Mutuo Soccorso (Senior Italia SMS).

8 S2 Intern Emerg Med (2015) 10 (Suppl):S1-S8 La logica della SMS è proprio quella di puntare sul ruolo del medico di medicina generale (MMG) come fulcro attorno al quale far girare tutto il sistema salute, responsabilizzandolo con l ampliamento della propria attività, volta ad alleggerire quella degli ospedali, che molto spesso si trovano a dover effettuare esami diagnostico/strumentali che potrebbero essere svolti tranquillamente presso lo studio del MMG. Il valore aggiunto della SMS è proprio questo: garantire al paziente geriatrico un approccio umano da parte del proprio MMG. In sintesi, il funzionamento della SMS si traduce nel dotare le Unità Complesse di Cure Primarie (UCCP), costituite da medici convenzionati delle cure primarie e da altri operatori sanitari, di apparecchiature in grado di effettuare esami diagnostici semplici che consentirebbero di snellire le lunghe liste di attesa degli ospedali affinché possano meglio gestire la fase acuta della malattia. In questo modo si genererebbero dei risparmi economici grazie alla diagnosi in fase preventiva delle patologie e all aumento di aderenza alle terapie, soprattutto da parte dei pazienti anziani. Il presente elaborato entrerà nel merito del funzionamento della SMS. FederAnziani Senior Italia is an organization founded in 2006, with the aim to protect older people s rights and promote their quality of life. It operates nationally and, as its primary purpose, federates all those subjects who are concerned with the protection of social, health and economic integration of the elderly. It also promotes agreements with different Federations within the EU member countries. FederAnziani Senior Italia s network consists of roughly 3,500 Centri Anziani (Centres for the Elderly) counting over 3.5 million members around Italy. FederAnziani Senior Italia s commitment is to: protect the category of the elderly by any means and form; enhance and improve the role of the elderly people in the society; promote a culture that underlines the values of the elderly as an irreplaceable resource for the family and for the society; lead the public to consider the aging of the population as a positive achievement of our society; guide social policies for the elderly to develop programs oriented towards a positive view of the elderly and foster the promotion of well-being throughout life. FederAnziani Senior Italia achieves its goals through the following activities: promotion of meetings with Italian and foreign organizations which share the same purpose; organization of national and international symposia and seminars; promotion of proper forms of social representation, and comparisons of public and private organizations that operate at national and local level, as well as in the field of the social policies, taking into account health care issues, social services and leisure; collaboration with institutions and associations concerned with the problems linked to the protection of public health and human aging; promotion of healthy ageing and new lifestyle through all communication channels; training and updating caregivers, paramedical health and social care staff, in order to manage the daily problems of the elderly; promotion of the establishment of organizations (e.g. associations, cooperatives etc.). focused on the social welfare and the health of elderly and disabled people; support the centres for the elderly with social, cultural, physical and intellectual activities such as tourism, prevention, information in healthcare and computer usage training. Branches of FederAnziani Senior Italia People s Court of Justice for the Right to Health is the body of FederAnziani Senior Italia constantly working along with scientific/medical societies to defend, restore and improve the health rights of the elderly. The mission of the Court is to ensure the best care for everyone, apprising citizens on the newest and most cost-effective technological practices in any field and trying to find sustainable solutions for the inequalities of the whole health system. During the year, several meetings dealing with healthcare themes are organized, each of which is composed of different departments that gather together the main actors of the health sector. These meetings have different topics and their aim is to set up the symposium which takes part once a year and in which the best medical experts cooperate together trying to find any possible solution in order to solve any issues concerning the health system. The latest Congress took place from 21st to 23rd November 2014 in Rimini and it counted around 6,000 delegates, 4,000 physicians, health economists, experts in health law and institutions. The discussions that take place in the different departments start with the faults of the system and are meant to develop a document which, at the end of this stage, is endorsed by all members and finally presented to policy makers ( SIC - Sanità In Cifre ( Health In Figures ) is the Centre for Studies specialized in Health Economics, composed of health economists, experts in health law, physicians and

9 Intern Emerg Med (2015) 10 (Suppl):S1-S8 S3 pharmacologists, who work together with universities such as Catholic University of Rome, University of Tor Vergata in Rome, University of Messina and LUISS Business School in Rome. The Centre carries out researches on health economics matters and its main work consists in a summary of the most important national health system data collected into a compendium (SIC - Sanità In Cifre). From the next year, the book will be integrated with a full chapter with the main health European data. Senior Italia Foundation is the charity organization aiming to support older people through local and community-based projects. The Foundation is also in charge of national awareness campaigns carried out to promote active aging and to improve the role of the elderly in the Italian society ( FederAnziani Senior Italia is on the web with a wide network of information channels to communicate with an audience of all ages. The FederAnziani Senior Italia network on the web includes: the official website of the Federation ( the official website of the Popular Court of Justice for Health Rights ( the web TV Family TV ( and the official channel of FederAnziani Senior Italia on YouTube; the Facebook page Il Giornale del web and the FederAnziani Senior Italia official Facebook page; the Twitter account of the Senior Italia_FA and the Twitter account of the FederAnziani Senior Italia SIT - Senior International Tourism is a tour operator entirely specialized on the elderly. Travels are designed to offer wellness, relax, fun, assistance and entertainment. SIT offers its members the opportunity to access highly-qualified tourism services that are specifically designed to break down the barriers of age. Our tour operator also counts on the broad expertise of several collaborators around Europe ( turismosenzaeta.net/). International Co-operation Activities: FederAnziani Senior Italia works to support people in need, children or elders, in developing countries. The project started in Africa, where we brought help by building several wells for fresh water, a primary school, an orphanage, an arts and crafts school and more. Our mission is to ensure an adequate and sustainable National Health System (NHS) to its main consumers, elderly people. From this point of view, it is evident that the economical sustainability of NHS spending cannot only be analyzed as a matter of public expenditure, as well as the public budget constraint cannot only be complied through linear expenditure cuts. Unfortunately this is the reality we have been facing since recent years, characterized by the most severe economical crisis experienced in this century. As a result of this economical depression, Governments all over the world had to rescue financial institutions, through a massive usage of public resources with an obvious deterioration of public accounts. In such a situation, and especially considering the Italian context, our main concern was to define an adequate formula for the Italian government to follow in order to deal with the increasing complexity of providing a universal health assistance, both in terms of service quality and economical sustainability, avoiding to merely focus on one of the multiple dimensions of healthcare performance, i.e. costs. Recent history has showed the failure of this kind of NHS management approach. A continuous and constant reduction of resource allocation resulted in a less effective portfolio of health services for Italian patients, with a lower number of services provided and poorer quality. Yet this failed to bring about any significant enhancement of the Italian public accounts. After a long period of analysis and debate with representatives of all of the main actors operating in our NHS such as general practitioners, medical specialists, pharmacists, scientific societies and patient associations, it was clear that maintaining this kind of National Health System management could represent a concrete and serious risk. Such a trend could indeed jeopardize not only the qualitative level of the provided health services, but the very survival of a public health service system. Small reforms or marginal enhancements to the actual situation would not be enough. In order to increase both the quality of delivered healthcare and its economical sustainability a complete redesign of our NHS would be necessary. The most feasible proposal issued by our periodical meeting on this topic is to overcome the current conception of the Italian NHS altogether. Hospitals should no longer be conceived as places where terminal, not self-sufficient, chronic and inpatients are treated; instead, they have to be turned into excellence polyclinic centres for emergencies and scheduled inpatients. According to this new paradigm the Government could arrange a logistical and structural redesign of the whole system. By redefining role and operations of the very large number of hospitals displaced in Italy, uneconomical duplications and wastefulness would be reduced, and resources would be gathered so as to provide a better health service. For this to be possible, it is required to relieve hospitals of health screening and diagnostic activities, for this via redesigning the entire Italian NHS practicality. Our idea is to transfer these activities towards general practitioners clinics, encouraging them to aggregate and cooperate into widely organized territorial structures in which several, complementary medical skills are guaranteed. These organizations would then be endowed of all the diagnostic

10 S4 Intern Emerg Med (2015) 10 (Suppl):S1-S8 tools necessary in order to provide citizens with a complete diagnostic service. The latter would thus result to be qualitatively better than the one that hospitals, overburdened by a series of other activities, were able to offer, obtaining a large cost saving too. As far as the organizational side of this ambitious vision is concerned, FederAnziani Senior Italia proposed and shared its plan to set up a Mutual Aid Society (MAS): Senior Italia Società di Mutuo Soccorso. This body will be set up in collaboration with FIMMG (Federazione Italiana dei Medici di Medicina Generale Italian Federation of General Practitioners), UnipolSai and Unisalute. It would be in charge of combining, through relationships with policy makers, FederAnziani Senior Italia s adherents and citizens in general, FIMMG, Specialists and Scientific Societies, the legislative changes to the system, the agreement of the main actors of the NHS and the financial funds necessary to start, even in pilot form, this ambitious project. The basic condition for the implementation of this project is the creation of a two-way communication channel, both formal and informal, between general practitioners and medical specialists, which is to be based on modern telemedicine reporting system. Moreover it is crucial for the future of this idea to better regulate and train the professional figure of the general practitioners assistant, which is already implemented in our system within the National Contract for Employees of Professional Studies. According to this new vision of the NHS, this professional figure should play a completely different role, not to be limited to organizational assistance. It should indeed play a technical role in the actual running of the simplest diagnostic tests, in order to streamline the work of general practitioners, leaving the latter to the sole task of reading and interpreting clinical outcomes, the report of which would then be tele-transferred, exclusively in case of positivity, to specialists or hospital structures. The project is starting up, we have already developed studies and analyses on the necessary conditions to get off the ground the MAS s activities, setting goals, procedures for their achieving, instruments and resources required: specification and definition of the Individual Health Plan (IHP) as the way of managing elderly chronic patients in the shared therapeutic areas; define, for each pathology included into MAS s care program, type and the frequency of services provided to elderly patients; define the activities flow. MAS s target patients are all the self-sufficient elderly patients. We decided to consider only this category of patients because it is necessary for them to be able to reach GP s ambulatory, where the most common diagnostic exams will be provided. Considering the identified therapeutic areas in which the MAS will operate (Asthma/COPD, Atrial Fibrillation, Hypertension, Diabetes 2, Prostatomegaly, Dyslipidemia), useful for the society internal code redaction, is necessary to share the IHP between all the actors involved, in order to create a structured and complementary system to general practitioners, in terms of services provided to elderly chronic patients, frequency of diagnostic exams, for any pathology considered. The main actor in this plan represented by general practitioners, their role in elderly chronic patients management, the diagnostic activities provided to patients for a faster diagnosis and to maximize adherence to therapies, are the milestones of this project and all of these aspects will be the object of a specific agreement to be concluded between individual GPs and MAS [10]. Project s Actors: General practitioner (Gp): is the responsible for elderly chronic patient s took in charge, promotes early diagnosis through patient s education and awareness, has a role of initiative medicine performing in his clinic, or if needed sending patients to specialist, all the required diagnostic exams. Based on the exams results, carried out directly or not, makes or acquires the diagnosis for the specific pathology and automatically sets the IHP, basing its contents on the deep knowledge of patient s situation. After the diagnosis, GPs ensure patient s periodical execution of exams according to IHP content, following up patient s adherence to therapy. Pharmacist: in this context is the responsible for prevention (through the usage of questionnaires) giving information and awareness to patients, recommends a GP visit if necessary and monitors adherence to therapy. Specialist: at the specific GP s request, gives an expert advice to GP through telemedicine, manages inpatients cases. Mutual Aid Society: provides for, through its distribution chain, subscription of IHPs and payment of related fees, made by MAS members. The distribution network will be made up of qualified individuals, or may be part of the identified Insurance Provider. MAS may use, through a special agreement, the Insurance Provider s operations center (call center and computer system), which may work for the alignment of the service and the patient s behavior to the standards required, as well as the overall improvement of the service. MAS could even propose, in a indirect way, all of the insurance provider s health support services that could be useful for its members. FederAnziani Senior Italia: its role is to promote adherence culture between our participants. Facilitate MAS s quote of subscription for those participant whose GP has an agreement with MAS, explaining the MAS s operation and all the benefits related with this project.

11 Intern Emerg Med (2015) 10 (Suppl):S1-S8 S5 Any Actor can enjoy the fruits of this system: State and Regions: from our analysis, this project is extremely cost-efficient, with massive savings in managing elderly chronic patients and diagnostic expenditure. GPs, Specialists and Pharmacists: they will provide an integrative type of health care, which will help to better manage elderly chronic patients. They will develop new skills and competencies, having the possibility to handle diagnostic instruments. In this way the importance of their profession will be much more evaluate by community, especially from an economic point of view. Insurance Provider: this actor will have the chance to access to a big market, made, for at the end of the project, by 3.5 millions of elderly chronic patients, enjoying a better reputation and institutional exposure. FederAnziani Senior Italia and Elderly Patient: active contribution to its participants health promotion, simplifying and economizing the access to treatments. Effectively, the internal code of this society considers the main chronic disease in Italy: Asthma and COPD, Atrial Fibrillation, Hypertension, Diabetes 2, Prostatomegaly, Dyslipidemia [3-8]. The idea of this project born after several studies about non adherence costs related to these chronic pathologies (Figure 1). PIS ( Punto Insieme Sanità, a healthcare stock of the situation) Model FederAnziani Senior Italia proposes, during the year, several scientific symposia named PIS. PIS is a think tank in which different expertise are put together trying to redefine the Italian NHS, starting from the weak point of the system. During these meetings emerged a new pattern, for the Italian NHS, of patient s taking in charge, which could lead the entire health system to higher level of sustainability and performances: the PIS model. According to this paradigm, early diagnosis and adherence development can lead to 19 billion euro of saving [9-12] (Figure 2). The model starts from the initial check up of the patient, made by GPs in their clinics, thanks to diagnostic instruments provided by MAS (Prevention and Diagnosis Phase). From the results of the exams, GPs will set a Individual Health Plan (IHP) (Treatment Phase, only if necessary). The IHP identifies all the health performances provided by MAS through the entire organization (GPs, pharmacists, specialists and FederAnziani Senior Italia), is made for a single pathology (Asthma and COPD, Atrial Fibrillation, Hypertension, Diabetes 2, Prostatomegaly, Dyslipidemia) reporting the maximum frequency of diagnostic exams and performances provided by GPs, pharmacists and specialists. Italy: average grade of treated chronic patient (over 65) 38% Italy: average grade of adherence to treatment (chronic pathologies, over 65) 45% % % % 50.0% 67.5% 55.1% 62.1% 50.0% 30.0% 43.1% 36.5% % 0 Asthma/COPD Atrial fibrillation Hypertension Diabetes Prostatomegaly Dyslipidemia Treated Adherence to treatment Fig. 1 Italy: treated versus adherent chronic patients [3-9]. Elaborazione Centro Studi SIC. Abbreviation: COPD, chronic obstructive pulmonary disease.

12 S6 Intern Emerg Med (2015) 10 (Suppl):S1-S8 Prevention Diagnosis Treatment Follow-up Quick pathology emersion Better prevention Less therapy average cost per patient Hospital diagnostic expenditure reduction faster treatment beginning Less diagnostic services Shorter waiting time More efficiency of hospital s staff Increasing adherence Less adverse events Lower access to emergency department and hospitalization Less pharmaceutical expenditure 3.7 bil 3.8 bil 11.4 bil 18.9 bil Fig. 2 Adherence: cost saving plan. Finally, for patients who need treatments, GPs will follow-up the clinical evolution and patients adherence to therapy (Follow-up Phase). This is the paradigm that could lead us to a better NHS, for this to be realistically implemented is necessary to promote and share this vision to all the Italian GPs, motivating them in order to be the more incline to bear the brunt of a wide change in their professional life. It will be necessary, indeed, for GPs to intensify their relationship with patients, being an influential and trusted counselor, they even have to get a better specific comprehension and knowledge of the individual patient, in order to set a tailor made therapy based on patient s clinical and psychological history. Furthermore it is necessary to create, ex novo, some unavoidable conditions such as being the provider of a wide range of diagnostic and helpful performances, reorganizing the medical activity into large teams of GPs, in order to reduce bureaucracy wasted time. It is necessary for GPs to increase their relationship with specialists, involving them in telemedicine activities, as a second opinion of General Medicine. GPs have to improve their informatics skills, necessary to rule all of the telereporting processes, and share all of the lowdown about their patient, letting all the clinical team (other GPs, Pharmacist, Specialists) to be aware of patient conditions and peculiarities. Tools necessary for these activities are the electronic medical chart, the diagnostic instruments to provide to GPs, a telemedicine system and a bonus plan for GPs agreed upon. PIS Model: patient managing (for those who agreed upon the MAS) It is possible to resume the PIS Model (Figure 3) into three macro stages: 1. information and subscription of MAS, 2. took in charge of patient s clinical situation, 3. clinical evolution follow-up.

13 Intern Emerg Med (2015) 10 (Suppl):S1-S8 S7 Prevention Diagnosis Treatment Follow-up Information and education Citizens awareness to risk factors Execution/prescription of clinical and diagnostic exams based on shared guidelines Adress to specialist for specialistic exams Therapy setting for patients with mild symptoms Prescription appropriateness Took in charge of patient clinical situation Personal/individual health plan Monitoring exams and medical examinations Information and education Adress patients to GP Adherence services Monitoring of purchases regularity HOSPITAL Reporting of clinical and diagnostic exams and expert advices via telemedicine only if required by GP Expert advices via telemedicine only if required by GP Additional specialist exams if needed Manage of complications and inpatients MAS Partecipate to all the steps to set an easier patient s adherence to the service (reminding) and collecting useful feedbacks for a processes enhancement, even through the Insurance Provider Offer, for the distribution of indirect performances, Insurance Provider services Information and education of elderly citizens Raising patient awareness to chronic disease Raising patient awareness to adherence Fig. 3 In the first stage it is necessary to inform elderly patients through MAS s leaflets and informative materials, available into GPs waiting lounges and pharmacies, exposed and distributed into senior centers. There will even be scheduled symposia and meetings among senior centers involving elderly, GPs, MAS and pharmacists. After the information comes the awareness to the new model, made through direct information given to patients by GPs during examinations, to loyal customers by their pharmacists, by senior centers and a specific call center activity. All of this processing will lead to MAS s IHP subscription, directly during symposia and meetings among senior centers, or deferred subscription, made indirectly by Insurance Provider named to distribute MAS s IHP. The MAS collects, through the Insurance Provider s distributive channels and a specific call center, all the applications to IHP, and inform GPs about the subscription. The second stage of PIS Model starts with the initial check-up reservation, the first GP s examination, with the creation of an individual medical chart in which converge all the information available on the subject. A specific call center will contact the patient to remind the reservation, even listing the nearer agreed upon pharmacies to GP s clinic, or patient house (reminding and network pushing). GP s assistant will execute provided exams (spirometry, Holter, ECG, body mass index, blood and urine tests etc.), recording results into the individual electronic medical chart. GP consults the chart and, if a specialized support is not needed, examines the patient editing or updating the medical chart, otherwise, if a specialist examination is needed, plans a further reservation. Once the IHP is edited or updated, GP composes a tailor made follow-up plan, updating every single visit, and reserves the next follow-up visit, while the patient can take advantage buying all the needed drugs in one of the affiliated pharmacies. Pharmacists record all the purchases made by the MAS s members and proposes initiatives for adherence s awareness.

14 S8 Intern Emerg Med (2015) 10 (Suppl):S1-S8 1 General practitioner Patient with no Asthma/COPD diagnosis GP s examination Anamnesis and exams Specialist 1 At the first examination of patient with no Asthma/COPD diagnosis, GP makes an in-depth anamnesis: respiratory questionnaries and evaluation of symptoms smoke habit and working anamnesis In relation to COPD symptomatology: if missing check-up visit for other pathologies if present spirometry made by GP (with possible telemedicine reporting to specialist), BMI, ECG, oximeter Symptomatology Exams 2 If exams confirm diagnosis, GP performs bronchusdilatation test, staging and therapy If required by GP, prescription of possible specialist exams (chest X-ray, etc.) Simple spirometry, BMI, ECG, oximeter 2 GP s examination Diagnosis and staging Possible specialist exams for an in-depth analysis 3 GP manages patient s follow-up Bronchusdilatation test Therapy If required by GP, possible expert advise for diagnosis and IHP setting 3 GP s examination Follow-up Fig. 4 Individual Health Plan (IHP) for Asthma/COPD affected patients. Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; ECG, electrocardiogram; GP, general practitioner. MAS or the specific call center contact all the MAS s members for feedback on the provided services. The third and last stage of PIS Model deals with the follow-up activities [13]. In the Figure 4 is represented the PIS Model for Asthma/ COPD affected patients [5]. References 1. ISTAT - GeoDemo IRCCS-INRCA, Network Non Autosufficienza. L assistenza agli anziani non autosufficienti in Italia Degli Esposti L. Aderenza al trattamento, target terapeutico e sostenibilità economica nel paziente ipercolesterolemico 4. Degli Esposti L. Sostenibilità economica dell appropriatezza terapeutica, il caso statine e osteoporosi 5. SIMER - Società Italiana di Medicina Respiratoria. L aderenza in medicina respiratoria 6. FIMMG - Federazione Italiana dei Medici di Medicina Generale. Gestione integrata del paziente a rischio cardiovascolare 7. Brignoli O, Filippi A. Gestione a lungo termine dei pazienti con ipercolesterolemia 8. AIFA - Agenzia Italiana del Farmaco - OsMed Sokol MC. Impact of medication adherence 10. Corte di Giustizia Popolare per il Diritto alla Salute Strategic Advisory Board on Adherence Corte di Giustizia Popolare per il Diritto alla Salute Punto Insieme Sanità - Fare Aderenza Centro Studi SIC Sanità In Cifre - FederAnziani Senior Italia. Economical data and own calculations 13. Centro Studi SIC Sanità In Cifre - FederAnziani Senior Italia. Senior Italia SMS Project

15 Intern Emerg Med (2015) 10 (Suppl):S9-S14 SYMPOSIUM Affordability of health care and aging Importance of comprehensive geriatric assessment in the evidence-based medicine era Graziano Onder Agnese Collamati SIMI 2015 Abstract Health care systems are increasingly facing with a population getting older and older, characterized by several concomitant, overlapping clinical conditions and polypharmacy. The complexity of these patients translates into various degrees of functional and cognitive impairments, which increase their risk of developing geriatric syndromes like delirium, falls and incontinence, and ultimately impacts on quality of life. Appling the recommendation of clinical guidelines (CGL) derived from results of randomized clinical trial (RCT) to this complex population is not straightforward, as they have clear limitations including poor representativeness and clinical relevance of outcomes adopted in RCT. Indeed, in complex older patients, the care and the prescribing processes should be individualized and flexible. Changes in medications regimen over time are needed to adapt to the evolving health status, as treatments with proven efficacy at some point in middle or even late life, could become redundant and possibly dangerous in vulnerable older people. In this population a global assessment of patients characteristics, including multimorbidity, functional and cognitive status, presence of social problems and geriatric syndromes, life expectancy, may be necessary to individualize the process of care and to improve quality of prescribing. Comprehensive geriatric assessment (CGA) allows a complete and global assessment and management of the health care problems. CGA should be used to drive the care process and complete recommendation of CGL in older complex adults. G. Onder ( ) Centro Medicina dell Invecchiamento, Dipartimento di Scienze Gerontologiche, Geriatriche e Fisiatriche, Università Cattolica del Sacro Cuore, Largo F. Vito 1, Roma, Italy. graziano.onder@rm.unicatt.it A. Collamati Department of Gerontology, Neuroscience and Orthopedics, Università Cattolica del Sacro Cuore, Roma, Italy. Riassunto Secondo le proiezioni epidemiologiche, nel 2060 gli ultrasessantacinquenni rappresenteranno il 30% della popolazione totale europea e il numero degli ultraottantenni toccherà il 12,4% del totale. Questo aumento dell aspettativa di vita sta determinando la crescita esponenziale di una nuova categoria di pazienti caratterizzati dalla coesistenza di numerose patologie (multimorbilità), disabilità fisica e cognitiva e sindromi geriatriche (cadute, malnutrizione, incontinenza etc.). Tale paziente moderno presenta una complessità che pone in difficoltà gli schemi della medicina tradizionale, orientati sulla cura delle singole patologie. In particolare, il trattamento farmacologico delle malattie croniche, basato sull applicazione sistematica delle linee guida è ad oggi molto criticato e per molteplici ragioni ritenuto spesso non appropriato nell anziano complesso. Nel paziente con tali caratteristiche è importante individualizzare e rendere flessibile il processo di cura. I regimi farmacologici devono essere adattati alle caratteristiche del paziente e alle sue necessità. Al fine di migliorare la qualità della prescrizione medica e ridurre il rischio di eventi iatrogeni, è necessaria una valutazione globale del paziente anziano che consideri ogni aspetto della sua fragilità, le comorbidità, lo stato cognitivo e funzionale e le condizioni socio-economiche. La valutazione multidimensionale (VMD), tramite strumenti largamente validati che analizzano le principali aree critiche (Stato di salute fisica, Stato funzionale, Stato cognitivo, Umore e comportamento, Condizione economica, Situazione socio-ambientale) è in grado di identificare le priorità di cura del paziente creando un progetto efficace di trattamento e prevenzione della fragilità. La VMD si è dimostrata infatti efficace nel ridurre la mortalità, le re-ospedalizzazioni e nel migliorare le funzioni fisiche e cognitive in diversi setting assistenziali. Health care systems are increasingly facing with a population getting older and older. Life expectancy has dramatically increased in these last decades, due to the progress in health

16 S10 Intern Emerg Med (2015) 10 (Suppl):S9-S14 Heterogeneity of the older population determined by occurrence or absence of comorbidity, disability, poli-pharmacotherapy and geriatric syndromes, factors which can influence patients initial level of risk for a given outcome, responsiveness to treatment or vulnerability to adverse effect, is rarely addressed by RCT [12]. Trials primarily examine medical interventions; randomization (if successful) permits comparcare and demographic growth. As a consequence, a new kind of patient is becoming common in the actual population: the elderly. These modern patients are characterized by several concomitant, overlapping clinical conditions, usually receive multiple, frequently interacting, medications and treatments, and sometimes face with limited financial resources and inadequate social and family support in contrast with their increasing care needs. The complexity of these patients translates into various degrees of functional and cognitive impairments, which increase their risk of developing geriatric syndromes like delirium, falls and incontinence, and ultimately impacts on quality of life [1]. This degree of complexity surpasses the traditional understanding of medicine and its role. While health care systems have evolved to incorporate new technologies and clinical knowledge enabling them to deliver increasingly sophisticated acute care, the same systems are constantly challenged by complex geriatric patients with chronic and uncertain clinical status and with shifting medical, psychological and social needs. Indeed, traditional medicine has been modelled around the ideology of the disease model. This presumes a series of assumptions like: organ or system-based pathology causes disease, symptom and observation signs are caused by underlying disease, treatment is focused on eliminating the underlying pathology, health outcomes are determined by the disease and are the same for everyone. Also, functional impairment and quality of life, although of no primary interest, are improved by treating the causative disease. However, the disease model does not account for complexity of the modern patient and in particular non-disease specific complaints, multimorbidity and functional outcomes are rarely considered [2]. The Evidence Based Medicine approach in older adults This disease oriented model has informed the way we have developed and accrued knowledge. In the last fifteen years evidence based medicine (EBM) has been promoted as an answer to guarantee the best possible approach to single diseases. EBM rests on the data coming from randomized clinical trials and their meta-analyses and systematic reviews. However, there are several concerns with the type of evidence that RCT and meta-analyses provide [3-5]. Representativeness As mentioned as a result of the continuous rising in life expectancy, health care systems are progressively facing with a growing older population which is characterized by comorbidity, disability, poli-pharmacotherapy and geriatric syndromes. Unfortunately, such complex patients have been excluded from many evidence-generating RCT. Even when a trial is targeted to the elderly, the population enrolled is usually highly selected [6-8]. Older patients, and women especially, are strikingly under-represented in RCT, and patients with comorbidity, a common phenomenon at older ages, are generally excluded. For example, in a study assessing the percentage of women and individuals 75 years of age or older in 593 RCTs focusing on acute coronary syndromes, the percentage of patients who were at least 75 years of age was reported in only 268 RCTs. Overall, women represented less than 24% of the patients studied, and those at least 75 years of age were only 6.7% [9]. This lack of adequate data has produced criteria for appropriate drug use that are based on the limited and changing consensus of experts, rather than on outcome analysis. In addition, the RCTs on which the recommendations are based typically provide evidence of modest reductions in the relative risk of the disease-specific outcomes that are associated with the use of individual medications and, in very few cases, combinations of medications. In a recent paper, Dumbreck et al. selected three clinical guidelines produced by the National Institute for Health and Care Excellence (NICE) - type 2 diabetes, heart failure, and depression - and systematically looked for possible drug-disease and drug-drug interactions in relation to another 11 NICE guidelines for potentially comorbid chronic conditions [10, 11]. Drug-disease interactions were relatively uncommon and mostly occurred between the recommended drug and chronic kidney disease. But the authors identified many potentially serious drug-drug interactions, most of which were overlooked by the index guideline. In general, few disease-specific guidelines consider that target patients can also have other diseases, treated with other drugs. Recent guidelines for chronic illnesses such as chronic obstructive pulmonary disease (COPD), heart failure, and diabetes mellitus have attempted to account for likely comorbidities. Unfortunately, these guidelines consider only one comorbid disease at a time and provide few specific recommendations about how to manage people with multiple comorbidities. Heterogeneity

17 Intern Emerg Med (2015) 10 (Suppl):S9-S14 S11 isons of interventions not confounded by the individuality of patients. Here is the paradox of the trial: it is the best way to assess whether an intervention works, but it hardly can be considered the best way to evaluate who will benefit from it. This contradiction leaves a gap in the evidence available for clinicians. In seeking internal validity, RCTs show comparative efficacy of treatment for an average eligible and randomized patient (the tail in a gaussian distribution), not for pertinent subgroups characterized by such cogent clinical features as severity of symptoms, illness, comorbidity, and other clinical nuances. For this reason, in the last nearly 40 years, several concerns have been raised regarding the type of evidence trials provide and it has been questioned the possibility of extrapolating the evidence from such trials to subpopulations of elderly patients since the generalizability of the results remains unknown. Outcomes Outcomes in RCT tend to be disease-specific, for example, stroke prevention or exacerbation of chronic obstructive pulmonary disease. These outcomes can be used under ideal circumstances in a homogeneous population with a single disease. They make less sense, however, for comparing treatments in complex patients with multiple chronic conditions. Treatments that are effective for one disease may exacerbate other diseases, worsen cognitive or functional status, interact with geriatric syndromes or adversely affect overall health [13]. The likelihood of such mixed benefits and harms increases as the number of coexisting conditions mounts. Aggressive antihypertensive treatment, for example, may benefit relatively healthy hypertensive people at any age, but probably it is not effective or may cause harm in older adults with limited life expectancy and orthostatic hypotension already receiving multiple other medications. Disease-specific benefits may not be the highest priority for people who are simultaneously at risk for multiple important adverse outcomes. For this reason disease-specific outcomes may not adequately reflect treatment effects in complex older patients, but adoption of more universal outcomes (e.g., symptoms; physical functional status, including mobility; and social and role functions), which are measuring events that matter to patients, should be preferred. Complexity and clinical guidelines Appling the recommendation of clinical guidelines (CGL) derived from RCT results to complex elderly subjects is not straightforward, as they have clear limitations because of the above mentioned limitations. In addition, several character- istics of complex older patients can make the results of RCT difficult to apply. Social issues are seldom considered in RCT, on the contrary people with lack of social support or who find difficult to keep regular contact with medical centers are excluded from randomization or easily drop out from trial. In addition, the occurrence of several geriatric conditions which are rarely incorporated in clinical trials and treatment guidelines, may influence the efficacy and limit the use of medications prescribed to treat chronic conditions. In particular, presence of functional impairment, cognitive impairment, geriatric syndromes (i.e. falls) and limited life expectancy are common conditions occurring in older adults which may limit the efficacy of pharmacological treatments (as indicated by CGL) and question the appropriateness of treatment (Table 1). Limited life expectancy is an important parameter to estimate in order to understand if patients can benefit from a certain treatment [14, 15]. For example, in the case of diabetes, it is suspected that elderly patients should have at least 5 years of life expectancy in order to benefit from intensive lowering of glucose levels. On the contrary, when treating hypertension the use of ACE inhibitors may be recommended since the benefits of treatments have been accrued as early as 2-3 years in clinical trials [16]. Also presence of geriatric syndromes, defined as one symptom or a complex of symptoms with high prevalence in frail elderly patients, resulting from multiple diseases and multiple risk factors, may influence the effect of pharmacological treatment [17]. Geriatric syndromes, such as falls and polypharmacy, can have a devastating effect on quality of life of elderly patients and can have some direct implications for how intensely providers may actually manage chronic diseases. By the other hand, depression, orthostatic hypotension, urinary incontinence, and chronic pain are more common among elderly patients with chronic diseases and may influence potential benefits of pharmacological treatments. For example, orthostatic hypotension a relevant cause of fall-related injuries, which substantially limit patients quality of life and increase mortality, is directly related to antihypertensive medications, indicating the need of a less intensive treatment of hypertension in subjects suffering from this condition. Cognitive impairment is a common condition among older adults and it is associated with other common conditions such as hypertension, cardiovascular disease, diabetes, and osteoporosis. Several studies have emphasized the need to avoid drugs that may affect cognition or induce delirium, when treating patients with co-existing cognitive impairment. In addition, memory loss, decline in intellectual function, and impaired judgment and language, commonly seen in patients with cognitive impairment, have obvious effects on decision-making capacity, alter benefits and burdens, impact on

18 S12 Intern Emerg Med (2015) 10 (Suppl):S9-S14 Table 1 Factors influencing drug prescription in older adults. Condition/complexity Mechanism Consequence on drugs prescription Strategy Cognitive impairment Memory loss Decline in intellectual function Impaired judgment Impaired language Decreased decision making capacity Increased caregiver burden Patients excluded from clinical trial Reduced adherence Difficulties in titrating a drug Difficulties in reporting side effects Uncertainties about efficacy of treatments due to lack of studies Improve communication strategies Policy changes to include patients with cognitive impairment in clinical studies Simplify drug regimens Limited life expectancy Comorbidity Geriatric syndromes Orthostatic hypotension Urinary incontinence Falls Malnutrition Disability Lower chances of experiencing the benefit of therapy Increased risk of drug-drug interactions Increased risk of drug-disease interaction Reduced renal and liver function Reduced volume of distribution/ change in body composition Geriatric syndromes caused or worsened by prescribed drugs Impaired ability to manage pill containers Poor prognosis/shorter life expectancy Limited benefit from life prolonging drugs Altered risk benefit ratio from drugs used for prevention (i.e. antihypertensives) Exacerbated adverse event Exacerbated iatrogenic damages Raised severity of drug related illness Reduced benefit of drugs Altered risk benefit ratio from drugs used for prevention Reduced adherence with medication Limited benefit from life prolonging drugs Assess life expectancy and time needed to obtain benefits from drugs Simplify drug regimens and prefer use of drugs providing symptoms relief in patients with limited life expectancy Prioritize drug treatments based on clinical goals Check for drug-drug and drug-disease interaction before prescribing a new drug Assess renal and liver function before starting a new treatment and during follow up Gradually titrate drug Assess concentration of drugs with narrow therapeutic index (i.e. digoxin) Assess presence of geriatric syndromes Prioritize treatment based on presence of geriatric syndromes Assess life expectancy Simplify drug regimens Put in place strategies to improve adherence dom address the common problems encountered in geriatric care: comorbidity, polypharmacy, disability. With a few notable exceptions they do not provide indications for treatment in subjects with limited life expectancy and focus on reducing mortality rather than on quality of life issues. In general, a patient centered care is hardly addressed. Cognitive impairment is rarely discussed as possible modifiers of treatment plan, even though 1 in 5 of those over 80 years old will develop a clinically detectable form of dementia. Geriatric syndromes in general deserve little attention in CGL, notwithstanding the fact that any physician of any specialty will see every day patients suffering from these conditions, and it has been clearly demonstrated that drugs are frequently implicated in their pathogenesis [21]. If all existing CGL had to be followed strictly, in an old comorbid person this would result in a high number of drug prescriptions, with a high risk of adverse drug reactions from drug-drug and drug-disease interactions. Things are further complicated by problems in the health system (lack of coortreatment adherence and may cause communication difficulties including decreased ability to report adverse effects [18-20]. For example Brauner et al. have shown that, in presence of dementia, use of medications commonly indicated to treat osteoporosis can put the patient at great risk for developing serious iatrogenic illness [21]. Finally, presence of functional disability may limit the ability of patients to take medicines accurately. Functional deficits were related to a reduced ability to manage pill containers and therefore to reduced compliance with medication [16]. In addition, impaired physical function is a major determinants of life expectancy and this may in turn reduce benefits from a pharmacological treatment. Limitations in CGL mirror the complexity of the elderly population. Almost all of the major CGL released by medical societies include specific recommendation for the elderly. Anyway, their strength is usually low, given the poor evidence existing, so that they are usually general and vague. They sel-

19 Intern Emerg Med (2015) 10 (Suppl):S9-S14 S13 dination between different prescribers, hyper-specialization of practitioners, short time dedicated to patients), so that complex drug regimens are seldom reviewed and patients are left alone to manage their medication schedule. Comprehensive geriatric assessment In response to these limitations of the traditional medical approach, since about 30 years, a new technology has begun to growth, carried out by geriatricians: the comprehensive geriatric assessment (CGA). CGA does provide information on the various problematic areas of the elderly patient including his/her co-morbidities, syndromes, socio-economic problems, functional and cognitive deficits not covered by the traditional medical assessment and it allows a more specific and sensible care planning for that single patient [22]. Based on the utilization of several indicators, functional scales and objective measures, CGA emphasizes the identification of specific geriatric syndromes and of any functional impairment. On theoretical grounds, when adequately applied, CGA might: increase diagnostic accuracy, optimize medical treatment, improve prognosis, restore, maintain and maximize functional autonomy, compensate for the loss of autonomy with an appropriate support, improve quality of life, identify the appropriate care setting, reduce costs. An extensive literature has documented that applications of CGA have resulted in more detailed evaluation, improved care planning and overall better quality of care [23]. In addition, a global assessment of patients characteristics may be necessary to have a full assessment of iatrogenic illness and to improve quality of prescribing. The traditional approach to patients diseases and needs does not provide information on these problematic areas. CGA also allows a complete and global assessment and management of the health care problems, including evaluation of drugs with the goal of recognizing and preventing potential drug-related problems and improve quality of prescribing [17]. Noticeably a large study assessing the effect of CGA associated with a geriatric team approach, as compared with usual care on 834 frail older adults admitted to Veterans Hospitals in the US, showed a 35% reduction in the risk of a serious adverse drug reaction and a substantial reduction in unnecessary and inappropriate drug use and in the number of conditions with omitted drugs significantly associated with the intervention [24]. As compared with former approaches CGA is oriented on evaluation of drug treatment as part of a more global assessment of characteristics of older adults. Indeed, results of these studies confirm that in complex older adults, a full and global evaluation of the problems and needs obtained by CGA may be extremely helpful in simplifying drug prescription and prioritizing pharmacological and health care needs, resulting in an improvement in quality of prescribing and in a reduction in the risk of drug related illness [25]. Conclusion In conclusion, medical complexity of older adults may make drug prescribing a challenging task and may increase the risk of drug-related illness. For this reason, a complete and global examination of patient characteristics is mandatory in the drug prescribing process. Recommendations of clinical guidelines do not always address the level of complexity observed in older adults and for this reason they should applied with caution in this population. Indeed, in these type of patients, the prescribing process should be individualized and flexible. Changes in medications regimen over time are needed to adapt to the evolving health status, as medications with proven efficacy at some point in middle or even late life, could become redundant and possibly dangerous in vulnerable older people. References 1. Bergman H, Ferrucci L, Guralnik J et al (2007). Frailty: an emerging research and clinical paradigm: issues and controversies. J Gerontol A Biol Sci Med Sci 62: Tinetti ME, Fried T (2004). The end of the disease era. Am J Med 116(3): Sackett DL, Rosenberg WMC, Gray JAM et al (1996). Evidence based medicine: what it is and what it isn t. It s about integrating individual clinical expertise and the best external evidence. BMJ 312: Sibbald B, Roland M (1998). Understanding controlled trials. Why are randomised controlled trials important? BMJ 316: Evidence-Based Medicine Working Group (1992). Evidence-based medicine: a new approach to teaching the practice of medicine. JAMA 268: Avorn J (1997). Including elderly people in clinical trials. BMJ 315: Cherubini A, Oristrell J, Pla X et al (2011). The persistent exclusion of older patients from ongoing clinical trials regarding heart failure. Arch Intern Med 171(6): Crome P, Lally F, Cherubini A et al (2011). Exclusion of older people from clinical trials: professional views from nine European countries participating in the PREDICT study. Drugs Aging 28(8): Lee PY, Alexander KP, Hammill BG et al (2001). Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA 286(6):708-13

20 S14 Intern Emerg Med (2015) 10 (Suppl):S9-S Marengoni A, Onder G (2015). Guidelines, polypharmacy, and drugdrug interactions in patients with multimorbidity. BMJ 350:h Dumbreck S, Flynn A, Nairn M (2015). Drug-disease and drug-drug interactions: systematic examination of recommendations in 12 UK national clinical guidelines. BMJ 350:h Tinetti ME, Studenski SA (2011). Comparative effectiveness research and patients with multiple chronic conditions. N Engl J Med 364(26): Reuben DB, Tinetti ME (2012). Goal-oriented patient care--an alternative health outcomes paradigm. N Engl J Med 366(9): Holmes HM, Hayley DC, Alexander GC, Sachs GA (2006). Reconsidering medication appropriateness for patients late in life. Arch Intern Med 166(6): Onder G, Liperoti R, Foebel A et al (2013). Polypharmacy and mortality among nursing home residents with advanced cognitive impairment: results from the SHELTER Study. J Am Med Dir Assoc 14(6):450.e Onder G, Landi F, Fusco D et al (2014). Recommendations to prescribe in complex older adults: results of the CRIteria to assess appropriate Medication use among Elderly complex patients (CRIME) project. Drugs Aging 31(1): Onder G, Lattanzio F, Battaglia M et al (2011). The risk of adverse drug reactions in older patients: beyond drug metabolism. Curr Drug Metab 12(7): Tjia J, Briesacher BA, Peterson D et al (2014). Use of medications of questionable benefit in advanced dementia. JAMA Intern Med 174(11): Vetrano DL, Tosato M, Colloca G et al (2013). Polypharmacy in nursing home residents with severe cognitive impairment: results from the SHELTER Study. Alzheimers Dement 9(5): Colloca G, Tosato M, Vetrano DL et al (2012). Inappropriate drugs in elderly patients with severe cognitive impairment: results from the SHELTER Study. PLoS One 7(10):e Brauner DJ, Muir JC, Sachs GA (2000). Treating nondementia illnesses in patients with dementia. JAMA 283(24): Stuck AE, Siu AL, Wieland GD et al (1993). Comprehensive geriatric assessment: a meta-analysis of controlled trials. Lancet 342: Ellis G, Whitehead MA, Robinson D et al (2011). Comprehensive geriatric assessment for older adults admitted to hospital: meta-analysis of randomised controlled trials. BMJ 343:d Schmader KE, Hanlon JT, Pieper CF et al (2004). Effects of geriatric evaluation and management on adverse drug reactions and suboptimal prescribing in the frail elderly. Am J Med 116(6): Onder G, van der Cammen TJ, Petrovic M et al (2013). Strategies to reduce the risk of iatrogenic illness in complex older adults. Age Ageing 42(3): Conflict of interest: none.

21 Intern Emerg Med (2015) 10 (Suppl):S15 SYMPOSIUM Affordability of health care and aging End-of-life care: a doctor s choice or a patient s choice? Giuseppe Remuzzi TEXT NOT RECEIVED G. Remuzzi ( ) Milano oppure AO Papa Giovanni XXIII Bergamo???

22 Intern Emerg Med (2015) 10 (Suppl):S16-S21 SYMPOSIUM Primary prevention and lifestyles Protective aspects of Mediterranean Diet Andrea Ghiselli SIMI 2015 Abstract Unbalanced diet is related to an increased risk of several conditions and diseases such as overweight, obesity, diabetes, atherosclerosis and cancer. Mediterranean Diet is synonymous throughout the world of healthy and pleasant diet, however there is some confusion about how really Mediterranean Diet shoul be defined, because it is considered by the people, and unfortunately too often by professionals, such as a diet based on the tripod: bread, olive oil and wine. This geographical concept sharply clashes with the story (not all mediterranean people consume or consumed wheat, olive oil and wine), and with the lesson that we should take from the Seven Countries Study, the study by Ancel Keys from which the concept of the Mediterranean Diet arose. This diet was that of rural populations of the mediterranean basin. Energy intake, appropriate to the needs of hard-working farmers, came almost exclusively from plant food, and was complemented by very little amount of animal products that can fill deficiencies, without exposing to risk of overconsumption. Interpreting the model in this way we will realize that we will be able to include all the models that are now under investigation for prevention of diseases, and promotion of longevity, not called Mediterranean Diet because of this fundamental error. Calorie restriction (or intermittent fasting) a model widely studied in animal, but now extended to humans, is nothing but a Mediterranean Diet. Some time ago the hard manual labor was the precondition for being able to get some source of energy, while today, at least in the Western societies, humans free from the effort to get food, which is abundant everywhere, must resort to fasting to reach that caloric restriction, which was the natural of the Mediterranean Diet. Glycemic index and glycemic load of the Mediterranean Diet are quite low, although most of the energy comes from carbohydrates. A. Ghiselli ( ) CRA-NUT (Centro di Ricerca per gli Alimenti e la Nutrizione del CRA), Via Ardeatina 546, Roma, Italy. andrea.ghiselli@entecra.it However it came from whole grains, the fiber of which, together with those arising from the generous portions of legumes and vegetables, contributed to the reduction of glycemic index and load. The high intake of plant foods lowers the energy density of the diet and gives a large number of protective substances with antioxidant and anti-inflammatory capacity, which are thought responsible for the protection against oxidative stress, and subclinical inflammation, both phenomena linked to an increased risk of diseases and early mortality. These eating habits that characterized necessarily the diet of the mediterranean basin of the 60s, however, are changing because of the easy accessibility and availability of foods that modern society (thankfully) offers. So the Italian dietary habits are gradually moving away from the poor model characteristic of the first half of the last century and too abundant amount of animal products are consumed, outlining a model of great health, for its abundance of saturated fat (exceeding 10% of total calories), while fruits, vegetables, legumes and whole grains are poorly consumed, leading to a significant lack of fiber. Campaigns aimed at nutrition education must be carefully defined to redirect people to the Mediterranean Diet, which for the great variety of choices is a model palatable and easy to follow, able to prevent chronic diseases and allowing a healthy aging. Riassunto Una dieta inadeguata è correlata ad aumentati rischi per una serie di condizioni cliniche e patologie come sovrappeso, obesità, diabete, aterosclerosi e cancro. La Dieta Mediterranea è sinonimo in tutto il mondo di alimentazione salutare e allo stesso tempo gradevole e in grado di essere seguita con una certa facilità. Tuttavia c è molta confusione anche nella definizione di cosa sia la Dieta Mediterranea, che viene considerata sia dalla popolazione, ma spesso purtroppo anche dagli addetti ai lavori, come un alimentazione fondata sul tripode: pane, olio d oliva e vino. Questo concetto geografico stride nettamente con la storia (non tutti i popoli mediterranei consumano o consumavano grano, olio di oliva e vino) e soprattutto con l insegnamento che avremmo

23 Intern Emerg Med (2015) 10 (Suppl):S16-S21 S17 dovuto trarre dal Seven Countries Study, lo studio (o meglio la serie di studi) di Ancel Keys dai quali prese vita il concetto di Dieta Mediterranea. Tale dieta era l alimentazione seguita dalle popolazioni rurali dei popoli mediterranei che consisteva in una dieta la cui energia, commisurata al fabbisogno del duro lavoro contadino, veniva quasi esclusivamente da prodotti di origine vegetale, nobilitati da scarsissime quantità di prodotti animali idonei a integrare le carenze senza esporre a rischio di sovraconsumo. Se concepiamo così il modello, ci accorgeremo che esso comprende tutti i meccanismi ora al vaglio della moderna ricerca, che sembrano promettenti per la prevenzione delle patologie e per favorire la longevità, e che prendono nomi differenti dalla Dieta Mediterranea proprio per questo errore di fondo. La restrizione calorica (o il digiuno intermittente), modello che studiamo principalmente nell animale da esperimento, ma ora estendibile all uomo, altro non è che una Dieta Mediterranea. Tempo addietro la scarsità di energia e il duro lavoro dei campi erano condizioni imprescindibili, mentre oggi, in cui l uomo occidentale si è affrancato dalla fatica legata al procurarsi il cibo che trova in abbondanza ovunque, occorre imporsi fasi di digiuno per raggiungere quella restrizione calorica che era condizione naturale della Dieta Mediterranea. L indice e il carico glicemico della Dieta Mediterranea sono bassi, nonostante la gran parte dell energia provenga dai carboidrati. Proveniva però da cereali prevalentemente integrali, la cui fibra, insieme a quella derivante dalle generose porzioni di legumi e vegetali, contribuiva al mantenimento di un indice glicemico e di un carico glicemico estremamente ridotto a fronte di un lavoro muscolare importante. L alto apporto di alimenti di origine vegetale, oltre a comportare una densità energetica bassa, aveva come valore aggiunto tutta quella serie di sostanze protettive ad azione antiossidante e antinfiammatoria che si suppone siano alla base della protezione contro lo stress ossidativo e l infiammazione subclinica, fenomeni entrambi collegati a un aumentato rischio di mortalità precoce. Queste abitudini alimentari, che hanno caratterizzato obbligatoriamente la dieta del bacino mediterraneo degli anni 60, si vanno però perdendo a causa della facile accessibilità e disponibilità di alimenti che la moderna società (per fortuna) ci offre. Le scelte alimentari degli Italiani si vanno via via allontanando dal modello povero caratteristico della prima metà del secolo scorso e generose porzioni di prodotti animali appaiono con sempre maggiore frequenza sulla tavola, delineando un modello poco rassicurante dal punto di vista della protezione della salute in quanto ricco di grassi in genere e in particolare di grassi saturi che superano il 10% delle calorie complessive della dieta, mentre frutta, ortaggi, legumi e cereali integrali sono consumati così raramente da comportare una notevole carenza di fibra. Campagne mirate di educazione alimentare devono essere accuratamente definite per convincere la popolazione dell estrema versatilità del modello alimentare mediterraneo, che per la sua varietà di scelte rappresenta un modello facilmente perseguibile, gradevole al palato e in grado di prevenire le patologie croniche consentendo un invecchiamento sano. Protective aspect of Mediterranean Diet Poor diet is one of the major contributors to the leading causes of chronic disease and death in Western societies, including coronary heart disease, diabetes, cancer [1]. Mediterranean Diet is synonymous worldwide of a pleasant and healthy diet, able to maintain health, to prevent many diseases and to give a long life expectancy, satisfying at the same time the taste. Scientific literature reports thousands of papers, whose number steadily increased since 1960 (Figure 1), describing its preventing capability of almost all chronic diseases such as hypertension, diabetes, atherosclerosis, cancer as well as preclinical conditions such as insulin resistance and overweight. Its preventive capacity is so relevant that a recent Spanish multicenter, randomized, controlled trial [2], aimed at evaluating the effect of diet on primary prevention of cardiovascular disease in a population at high risk, has been early stopped for the obvious superiority demonstrated by the Mediterranean Diet. The concept of Mediterranean Diet was born in the 60s from an intuition of Ancel Keys, who identified blood cholesterol as the main responsible for the large differences in cardiovascular mortality between different population groups from different countries: the Seven Countries Study [3] (Figure 2). As the figure shows, mediterranean countries have a cardiovascular mortality rate lower than Northern European countries and USA, and lower blood cholesterol levels. It should also be noted that the country with the lowest blood Fig. 1 Number of scientific papers per year in PubMed using Mediterranean+diet as searching keywords.

24 S18 Intern Emerg Med (2015) 10 (Suppl):S16-S21 CHD death rates per 10, y = x R = Japan Japan Italy Italy Greece Italy Serbia Slovenia Serbia Dalmatia Greece Calories from saturated fats (%) Fig. 2 Main results of the Seven Countries Study: comparison between cardiovascular mortality and intake of saturated fats in different countries. Abbreviation: CHD, coronary heart disease. cholesterol levels and low cardiovascular mortality was the Japan. However, while the Mediterranean Diet has gained increasing success as a model of healthy diet, Japanese diet remained confined in some Sushi bar. To the greater fortune of the mediterranean way of eating has probably also contributed the long life of its creator, who has spent much of its life in a small village in Cilento, eating Italian food and demonstrating the protective qualities of the diet with its centenary life. This, however, has given territoriality to the Mediterranean Diet, a geographical basin of heritage, which really should not have, and has led several Authors [2, 4-6] to believe that Mediterranean Diet consisted in: high intake of plant food (cereals, fruit, vegetables, and pulses); olive oil as principal source of fat; low intake of saturated fat (from low consumption of meats and dairy); moderate intake of wine. USA Est Finland West Finland Nederland But olive oil and wine were consumed in some of the mediterranean countries, but not in all. The mediterranean coast of North Africa for example is characterized by the virtual absence of alcohol and the small quantities consumed are represented almost exclusively by beer; many mediterranean population did not use olive oil. Yet when the Mediterranean Diet in 2010 was included in the UNESCO list of intangible cultural heritage of humanity, all media, at least in Italy, have immediately materialized it with generous portions of steaming spaghetti, bread, olive oil, and wine. However Ancel Keys had just realized that people who had an active lifestyle and a diet low in calories but rich in nutrients, based on plant foods, had an extremely low cardiovascular mortality. This protection is evident regardless of the source of starch that can be wheat or rice (but probably also potatoes or corn), regardless of the seasoning fat, which may be olive oil or soybean oil (but probably also rapeseed, sunflower or peanut oils) regardless of the drink, which can be wine or tea (but probably also water or beer), and regardless of the surrounding sea, which can be the Mediterranean Sea or Pacific Ocean (but probably is the same for the Atlantic Ocean or the North Sea. In fact, an Italian steaming spaghetti dish, or a Spanish paella or a Greek pilaf will be not so different from (or more Mediterranean than), Cantonese rice, Japanese noodles, a Persian biryani, a Mexican taco, a North African couscous, or even a Peruvian tacu-tacu. We need to learn the lesson coming from the Seven Countries Study and we should understand that the so-called Mediterranean Diet is a way of eating, and not a menu composed by local food; it is a model in which all foods have their own space, but with different frequencies and amount of consumption. Can be defined as Mediterranean a Diet rich in plant food and very poor of animal food, can be defined as Mediterranean a Diet able to maintain a healthy body weight, and cannot be defined as Mediterranean the Diet followed by overweight people, irrespective of the food eaten. Mediterranean Diet is therefore defined as: energy supply sufficient to cover the energy needs; high intake of plant foods (cereals, fruit, vegetables, legumes, seeds and their products); low intake of animal products, required to fill up the specific nutrients particularly poorly represented in plants. Most of the total energy in a Mediterranean Diet came from carbohydrates (more than 60%), while a much smaller segment derived from fat (20-30%) and an even smaller segment from protein (about 10-15%). The Italian Recommendation for nutrients (LARN), in the attempt to identify the reference intervals suitable to allow the maintenance of health status, associated to a low risk for diseases, allowing in the same time a correct intake all the other micro- and macronutrients, proposed the values shown in Figure 3. The document also recommend to not exceed 15% of total energy from simple sugars (including those naturally present in fruits and milk), to consume less than 10% saturated fatty acids and to take 5-10% of total energy from polyunsaturated fatty acids. On this basis, therefore, it is clear that the food from which we take carbohydrates, proteins or fats is not important, provided they are mainly of plant origin. A similar model is able to explain the protective effects of Mediterranean Diet against chronic diseases and put together all the recently proposed

25 Intern Emerg Med (2015) 10 (Suppl):S16-S21 S19 Starches 20-35% 12-18% 45-60% Sugars Proteins Fats Fig. 3 Energy intake percentage from the different macronutrients. mechanisms involved in the protection against cardiovascular disease, cancer, hypertension, obesity and so on. Calorie restriction (and/or intermittent fasting) [7-9]. At least in experimental animals, calorie restriction and intermittent fasting improve several risk factors for coronary artery disease and cancer, through the expression SIRT1, including a reduction in blood pressure and increased insulin sensitivity. Scientific evidence, that calorie restriction and the several different models proposed for its realization (as intermittent fasting) are the basis for longevity, for healthy aging and for the prevention of chronic diseases, are becoming more and more solid. It is difficult to identify the exact mechanisms behind that, yet it is impossible to determine which combinations of foods are best for attaining a long and healthy life. For example, obesity is one of the conditions leading to an increased risk for cardiovascular disease and cancer through several mechanisms [10, 11]. Among the involved mechanisms there is the production of inflammatory cytokines and adhesion molecules from the adipose tissue [12]. A low-carbohydrates and high-protein diet, such as the Zone diet or other diets very fashionable for losing weight, gives in the short term better results than Mediterranean Diet in respect to low-protein and high-carbohydrates diet [13]. Yet high-protein (especially from animal sources) and low-carbohydrate diets are associated with increased production of pro-inflammatory molecules (IGF-1) and increased overall mortality and cancer risk [14]. At least in animal longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake [15]. Hence a mediterranean dietary pattern, characterized by frugality (inevitable in the past, desirable today), physical labor for food, lack of availability of animal protein as well as of high calorie products such as fat and sugar. Plant food, regardless of their content of vitamins and minerals, has for the most part a low caloric density (a lot of water, fiber, and volume). Mediterranean Diet gives a palatable satiety with a low calorie intake. Glycemic index/glicemic load [16, 17]. Despite the fact that more than 50% of total energy of a typical mediterranean dietary habit derived from carbohydrates, glycemic index and the glycemic load of this diet are low. This could be due in part to the traditional mediterranean habit of whole grain consumption [18], in part to the adequacy of energy intake (the first law of the Mediterranean Diet), in part to the frequent and abundant consumption of vegetables and legumes, able to contribute to the satiety [19] and modulate the second meal effect [20]. This consists in the effect that the first meal has on the blood sugar level after eating a second meal. If the glycemic load of the evening meal is low, the glycemic response of the later breakfast will be lower, and so on for subsequent meals [21]. The Mediterranean Diet was defined as the model followed by the rural population of southern Italy and Greece [4]. At those times these people, due to the hard work of farmers, had energy needs far superior to the current one, but a lower calorie intake. Antioxidants and oxidative stress It is widely recognized that oxidative stress could be the common mechanism underlying different diseases such as diabetes, cardiovascular disease and cancer [22, 23]. Oxidative stress occurs when the physiological balance between oxidant/oxidized compounds and antioxidant defenses is lost. Plant food contains large amounts of antioxidants and anti-inflammatory compounds, whose activities are still under investigation. On the other hand, although with some exceptions (free sugars, polyunsaturated fat, alcohol), plant foods do not involve risk of oxidative stress, provided that the intake is adequate to energy needs, as required by the Mediterranean Diet. One of the most convincing explanations for the protective effect of the Mediterranean Diet is the generous intake of antioxidant molecules: from resveratrol (erroneously attributed to red wine, but much more represented in strawberries and other wild berries), to lycopene from tomatoes, from anthocyanin of red oranges, quercetin from onions, tea catechins, vitamin E, vitamin C, to chlorogenic acid etc., an incredible vastness of antioxidant molecules was discovered and characterized the past 20 years. These molecules have received too much confidence for the primary and secondary prevention of chronic diseases and many intervention studies provided contrasting results.

26 S20 Intern Emerg Med (2015) 10 (Suppl):S16-S21 Table 1 Intakes of some nutrients and contribution of macronutrients to total energy intakes in Italian adult males and females, in comparison to recommendations (LARN). In bold values not matching LARN. Males years (n=1,068) LARN Females years (n=1,245) Nutrient Measure Mean SD Mean SD Energy kcal Protein % Fat % Saturated fatty acid % < Monounsaturated fatty acid % Polyunsaturated fatty acid % Available carbohydrate % Soluble carbohydrate % < Alcohol % Cholesterol mg < Fiber g Fiber g/1000 kcal Abbreviation: LARN, livelli di assunzione di riferimento di nutrienti ed energia; SD, standard deviation. Diet in fact is not the simple sum of components and nutrients, but a series of choices, each of which determines the other ones. The main consumption of whole grains, fruits and vegetables not only enriches the body of interesting and protective antioxidants and anti-inflammatory molecules, but also take the place of space of other foods with other molecules, with other methods of preservation, processing and treatment. DASH diet and hypertension The DASH diet (Dietary Approach to Stop Hypertension) is a food model developed by the National Institute of Health, USA, with the primary purpose of combat hypertension, but then aimed at preventing cardiovascular and weight loss. It is nothing more than the Anglo-Saxon translation of the Mediterranean Diet, with plenty of fruits and vegetables and a special attention to the presence of low-fat dairies [24]. The distribution of macronutrients is very similar to that showed in Figure 3: 55% carbohydrates, 27% fats and 18% proteins. The emphasis on plant food can achieve the dietary goals in terms of micronutrients such as potassium (4700 mg), fiber (30 g) and less than 2300 mg of sodium; the emphasis on lowfat dairy products aims to achieve the target of calcium (1250 mg/day) and cholesterol (150 mg/day). Conclusions The Mediterranean Diet appears therefore one of the best ways for the prevention of chronic diseases and for achieving a healthy aging. However, the present picture of food consumption in Italy is not very encouraging, because we are consuming half of the recommendations for fruit and vegetables, legumes and whole grains are almost unknown, while we take large quantities of fresh and processed meat, and cheeses [25]. As showed in Table 1, these habits are responsible for: caloric intake allegedly inadequate to energy expenditure, as an Italian out two is overweight; fiber intake well below the recommendations; high intake of total fats and saturated fats; low intake of polyunsaturated fats [26]. Well-designed campaigns of nutrition education could help people to correct some of these errors. By replacing only two servings of preserved meat per weak with the same number of servings of pulses, we could significantly increase fiber intake, while reducing the intake of saturated fat, salt and cholesterol. But we can hope to achieve nutritional goals only conceiving the Mediterranean Diet as a model and not as a menu made with mediterranean food. References 1. Willett WC, Koplan JP, Nugent R et al (2006). Prevention of chronic disease by means of diet and lifestyle changes. In: Jamison DT, Breman JG, Measham AR et al (eds): Disease control priorities in developing countries. 2nd edn., Washington (DC) 2. Estruch R, Ros E, Salas-Salvado J et al; Investigators PS (2013). Primary prevention of cardiovascular disease with a Mediterranean Diet. N Engl J Med 368(14): Coronary heart disease in seven countries. Summary (1970). Circulation 41(4 Suppl):I Ferro-Luzzi A, Sette S (1989). The Mediterranean Diet: an attempt

27 Intern Emerg Med (2015) 10 (Suppl):S16-S21 S21 to define its present and past composition. Eur J Clin Nutr 43(Suppl 2): Trichopoulou A, Costacou T, Bamia C, Trichopoulos D (2003). Adherence to a Mediterranean Diet and survival in a Greek population. N Engl J Med 348(26): Willett WC, Sacks F, Trichopoulou A et al (1995). Mediterranean Diet pyramid: a cultural model for healthy eating. Am J Clin Nutr 61(6 Suppl):1402S-6S 7. Faris MA, Kacimi S, Al-Kurd RA et al (2012). Intermittent fasting during Ramadan attenuates proinflammatory cytokines and immune cells in healthy subjects. Nutr Res 3(12): Longo VD, Fontana L (2010). Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci 31(2): Testa G, Biasi F, Poli G, Chiarpotto E (2014). Calorie restriction and dietary restriction mimetics: a strategy for improving healthy aging and longevity. Curr Pharm Des 20(18): Wilson PW, D Agostino RB, Sullivan L et al (2002). Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med 162(16): de Ferranti S, Mozaffarian D (2008). The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem 54(6): Fuentes E, Fuentes F, Vilahur G et al (2013). Mechanisms of chronic state of inflammation as mediators that link obese adipose tissue and metabolic syndrome. Mediators Inflamm 2013: Shai I, Schwarzfuchs D, Henkin Y et al for the Dietary Intervention Randomized Controlled Trial (DIRECT) Group (2008). Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med 359(3): Levine ME, Suarez JA, Brandhorst S et al (2014). Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab 19(3): Solon-Biet SM, McMahon AC, Ballard JW et al (2014). The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab 19(3): Jenkins DJ, Kendall CW, Augustin LS et al (2012). Effect of legumes as part of a low glycemic index diet on glycemic control and cardiovascular risk factors in type 2 diabetes mellitus: a randomized controlled trial. Arch Intern Med 172(21): Sacks FM, Carey VJ, Anderson CA et al (2014). Effects of high vs low glycemic index of dietary carbohydrate on cardiovascular disease risk factors and insulin sensitivity: the OmniCarb randomized clinical trial. JAMA 312(23): Widmer RJ, Flammer AJ, Lerman LO, Lerman A (2015). The Mediterranean Diet, its components, and cardiovascular disease. Am J Med 128(3): Haber GB, Heaton KW, Murphy D, Burroughs LF (1977). Depletion and disruption of dietary fibre. Effects on satiety, plasma-glucose, and serum-insulin. Lancet 2(8040): Mollard RC, Wong CL, Luhovyy BL, Anderson GH (2011). First and second meal effects of pulses on blood glucose, appetite, and food intake at a later meal. Appl Physiol Nutr Metab 36(5): Wolever TM, Jenkins DJ, Ocana AM et al (1988). Second-meal effect: low-glycemic-index foods eaten at dinner improve subsequent breakfast glycemic response. Am J Clin Nutr 48(4): Ross JS, Stagliano NE, Donovan MJ et al (2001). Atherosclerosis and cancer: common molecular pathways of disease development and progression. Ann N Y Acad Sci 947:271-92; discussion Ceriello A, Motz E (2004). Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol 24(5): Vogt TM, Appel LJ, Obarzanek E et al (1999). Dietary Approaches to Stop Hypertension: rationale, design, and methods. DASH Collaborative Research Group. J Am Diet Assoc 99(8 Suppl):S Leclercq C, Arcella D, Piccinelli R et al for the Group I-SS (2009). The Italian National Food Consumption Survey INRAN-SCAI : main results in terms of food consumption. Public Health Nutr 12(12): Sette S, Le Donne C, Piccinelli R et al for the Group I-SS (2011). The third Italian National Food Consumption Survey, INRAN-SCAI part 1: nutrient intakes in Italy. Nutr Metab Cardiovasc Dis 21(12):922-32

28 SYMPOSIUM Primary prevention and lifestyles Intern Emerg Med (2015) 10 (Suppl):S22-S30 Primary prevention and lifestyles: physical exercise Giorgio Galanti Laura Stefani Cristian Petri Gabriele Mascherini SIMI 2015 Abstract Physical activity is one of the most important determinants of public health. By definition, physical activity includes basic level of habitual physical activity, as well as exercise capacity to produce, by the contraction of skeletal muscles, an increase of energy expenditure. Several benefits of regular physical activity are now recognized in the literature, especially the reduction of many metabolic risk factors. It is also known that the physical inactivity and sedentary behavior are the main contributors to increase obesity. From this background, it is known an insufficient physical activity is frequently associated with an high risk of chronic diseases such as diabetes, hypertension, heart disease and various forms of cancer. Many of these aspects are often acquired and consolidated at an early age of the life. It is known that more than body mass index value, an increased abdominal circumference is often associated with an higher cardiovascular risk. In this context, it is therefore important to properly define and distinguish the various levels of spontaneous physical activity useful to increase the daily energy expenditure. Physical activity and correct nutrition work together in this address. It is essential that proper nutrition rounds of primary prevention and it should be regulated from the outset of adolescence, in order to reduce the possibility of acquiring improper eating and nutrition habits. Sport and exercise medicine is heavily involved in this role, especially since it is the first time of real assessment of the young population. G. Galanti ( ) Sports and Exercise Medicine Department, University of Florence, Via delle Oblate 5, Firenze, Italy. giorgio.galanti@unifi.it L. Stefani C. Petri G. Mascherini Sport and Exercise Medicine Department, AOU Careggi, University of Florence, Italy. Riassunto L attività fisica è uno dei più importanti determinanti della salute pubblica. Per definizione si definisce attività fisica il livello di base di attività fisica abituale, così come la capacità di esercizio di una persona e qualsiasi movimento corporeo prodotto dalla contrazione dei muscoli scheletrici che aumenta il dispendio energetico sopra il livello basale. Sono ormai riconosciuti in letteratura molteplici effetti benefici dell attività fisica regolare, soprattutto nella riduzione di molti fattori di rischio metabolici. È noto inoltre come sia l inattività fisica che il comportamento sedentario siano i principali fattori che contribuiscono alla diffusione della obesità. Una insufficiente attività fisica è infatti associata frequentemente ad un aumentato rischio di malattie come il diabete, l ipertensione, le malattie cardiache e varie forme di cancro. Ridotta attività fisica e sedentarietà rappresentano pertanto due componenti fortemente deleterie per lo stato di salute della popolazione generale e molti di questi aspetti che caratterizzano il comportamento generale vengono maturati e consolidati in età precoce. Infatti, nonostante un indice di massa corporea superiore alla norma o una condizione di obesità con aumento della circonferenza addominale sia spesso associato a un rischio cardiovascolare aumentato, è ben noto come soggetti fisicamente attivi, benché obesi o in sovrappeso, abbiano un rischio cardiovascolare inferiore rispetto ai soggetti sedentari. In questo contesto, è pertanto importante definire correttamente e distinguere i vari livelli di attività fisica spontanea utili ad aumentare il dispendio energetico giornaliero. Nondimeno è fondamentale una corretta alimentazione che completa il quadro della prevenzione primaria e che dovrebbe essere regolamentata fin dall età adolescenziale, allo scopo di ridurre la possibilità di acquisire scorrette abitudini alimentari e nutrizionali. La medicina dello sport e dell esercizio è fortemente coinvolta in questo ruolo, soprattutto perché rappresenta il primo momento di reale valutazione della popolazione giovane.

29 Intern Emerg Med (2015) 10 (Suppl):S22-S30 S23 Determinants of health Health determinants are factors whose presence changes in a positive or negative state of the health of citizens [1]. Accredited International Studies conducted a quantitative estimate of the impact of certain factors on the longevity of the community, used as an indirect indicator of the state of health: socio-economic factors and lifestyles contribute to 40-50%; the state and the conditions of the environment for 20-30%; genetic inheritance for a further 20-30%, and health services for 10-15% [2]. The World Health Organization has proposed a list of prerequisites for health, i.e. situations that must be present in the communities that capture the awareness and the decision to pursue the health of its members [3]. The determinants of health can be classified in different levels as follows: - at first level unmodifiable individual factors, e.g. age, sex, ethnicity, genetic features that however need to be taken into consideration when planning a population health profile; - at second level the identification of risk factors in individual lifestyles, e.g. smoking, sedentarism, alcohol abuse and drug consumption, modifiable through the application of appropriate policies and strategies of preventative intervention and health promotion; - at third level health care social networks are available for the community. If inadequate these can however represent a risk factor for the health and psychosocial well-being of the individual; on the contrary if well run they are a resource for the whole of the community; - at macro level we identify the structural factors that can be of their context, e.g. socio-economic and socio-cultural; or individual, e.g. level of education, professional status. The effect on health is not direct but mediated by factors contained in the lower levels, i.e. the proximal determinants of health. Stages of prevention The development of disease generally follows four stages during which measures for preventing further development can be adopted, with the aim of interrupting the condition and in any case to prevent it from worsening. Such measures include encouraging behavior and lifestyles that do not provide the terrain for diseases to develop in the first place, such as greatly lowering risk factors; they also include halting the progress of a diseases that have already set in and reducing any consequences. Stage 1. Early prevention This must begin as soon as possible, even before the insurgence itself of risk factors for the situation under examination. It includes such activities encouraging behavior and lifestyles that prevent any increase in the risk of diseases. Children that have grown up witnessing their parents drink heavily or smoke, or both, automatically think this is normal behavior and are more likely to follow suit in their own lives. Directly discouraging such habits would therefore be of primary importance. Stage 2. Primary prevention This means preventing the population from exposure to risk factors. Measures need to be adopted such as targeted strategies aimed at protecting the whole population, and especially strategies for groups at particularly high risk. Stage 3. Secondary prevention This includes many measures at our disposal, such as screening, x-rays, blood tests etc. that contribute to the early diagnosis of diseases, to their treatment and cure or to the prevention of their worsening. Stage 4. Tertiary prevention Also for this stage measures exist that can contribute to lowering the level of sufferance in chronic diseases or permanent disability and therefore ameliorating the quality of life in these patients. Primary prevention through exercise Historical overview Although Hippocrates and Galen recognized the benefits of physical activity, the beginning of exercise science occurred in the twentieth century. In the early 1920s, A. Krogh and A.V. Hill won separate Nobel Prizes in physiology and medicine for work related to physical activity. A study of London transport workers showed much lower rates of coronary occlusion and of death from heart attack among the physically active conductors than among the sedentary drivers. Based on these results some researchers formulated the hypothesis that vigorous physical activity helps protect against coronary heart disease (CHD) [4]. A study of the relationship of physical activity at work to CHD deaths among longshoremen provided further strong evidence of the benefits of physical activity [5]. Exposure assessment issues Self-reported questionnaires have provided valuable evidence of relationships between physical activity and disease outcomes. Nonetheless, some of them have led to a large amount of misclassification. Misclassification, in turn, has led to an underestimation of the observed effect. The objective assessment of physical activity levels, such as the use of accelerometers or specific fitness tests, is expected to provide stronger evidence of the effects of physical activity or inactivity on various health outcomes. Important changes concerning exercise intervention were

30 S24 Intern Emerg Med (2015) 10 (Suppl):S22-S30 confirmed with the 1989 recommendations of the US Preventive Services Task Force. The task force gave the same recommendation for counseling patients for physical inactivity as it gave for cigarette smoking and high blood pressure. Physical inactivity has long been recognized as a risk factor in coronary heart disease (CHD), but many physicians have felt it to be relatively unimportant compared with other risk factors such as cigarette smoking and elevated blood pressure. Recent studies have indicated that those who are not physically active have roughly the same risk of CHD developing as those with hypertension, hypercholesterolemia, or those who smoke. The strength of the association between physical inactivity and CHD is 1.9 compared with 2.1 for high systolic blood pressure, 2.4 for elevated serum cholesterol level, and 2.5 for smoking. Researchers have found that physical fitness is associated with lower rates of all causes of mortality as well as CHD and cancer mortality [6]. Further, the greatest reduction in relative risk occurred between the lowest level of fitness and the next lowest level. These data suggest that even modest improvements in fitness levels among the most unfit can result in substantial health benefits. Counseling of physically inactive patients should emphasize regular, mild-to-moderate activity, such as brisk walking. More strenuous exercise activities should be de-emphasized. In the past, exercise prescriptions typically suggested relatively intense activity, such as jogging, for 20 minutes at least three times per week. Now it is recommended that all patients should be counseled to engage in regular physical activity in a program tailored to their health status and life-style. Those new to exercise should start with a regular, low to moderate level. Their goal should be to engage in an activity like brisk walking at least three times per week for at least 30 minutes. Screening and intervention with physically inactive patients should specifically be included in periodic health examinations of all adults. A 1978 Harris survey found that most people reported they would be more likely to engage in health-promoting behavior if the recommendations came from their physician rather than from any other source. Inactive patients are most likely to comply with recommendations from their physicians for a regular pattern of exercise activity that can be maintained with minimal disruption of other aspects of their lives. Walking, when done briskly, is the ideal activity that meets these recommendations and can serve as a first step to more vigorous activities, if desired, in the future. Physical activity Physical activity in primary prevention should begin in the early school years and continue throughout an individual s lifetime. Schools must specifically designate physical education programs with aerobic activities for children at early ages. Programs should include recreational sports such as running, dancing, swimming, and selected types of resistance exercises using free weights and/or specific equipment. There also should be support for an active lifestyle for children at home. In the patient-visit setting, physicians and their staff should discuss physical activity and provide exercise prescriptions for patients and their families. In some instances, suggestions could be made about implementing physical activity recommendations at the worksite. Intensity, duration, and frequency as well as mode and progression should be considered in all types of physical activity programs. As children and adolescents become adults and discontinue the athletic endeavors of school and college, primary prevention must include a plan for a lifetime of appropriate physical activity. Ideally this activity should be done for at least 30 to 60 minutes four to six times weekly or 30 minutes on most days of the week. The frequency, duration, and intensity of the activity should be individualized to personal satisfaction as well as mode and progression. Subjects may use individual end points of exercise such as breathlessness and/or a fatigue level considered somewhat hard to hard on the Borg perceived exertion scale. Standardized charts that designate heart rates may help by providing heart rate end points that can be measured immediately after exercise, but these are not necessary [3]. Exercise should include aerobic activities such as bicycling (stationary or routine), walk-jog protocols, swimming, and other active recreational-leisure sports. Shoes and clothing appropriate for extremes of heat, cold, and humidity should be worn. Resistive exercises using free weights or standard equipment should be done two to three times weekly. These exercises should include 8 to 10 exercise sets consisting of 10 to 15 repetitions per set (arms, shoulders, chest, trunk, back, hips, legs) performed at a moderate intensity. If free weights are used, 15 to 30 pounds are adequate. Resistive exercises tend to complement aerobic exercise in that some training effect is realized. However, development of muscle tone is more important, as is strengthening of body musculature as adults age over time [3]. The long-term effect of any physical activity program is affected by compliance. In today s mobile society, an exercise plan must include activities for business trips and vacations. Exercise facilities may not be convenient in such settings, which may mean improvising. For example, a walk-jogger should bring walking or running shoes and find a safe place to walk or run at a pace that approximates his or her usual activity level. Many hotels or motels have an exercise facility with track or

31 Intern Emerg Med (2015) 10 (Suppl):S22-S30 S25 treadmill, exercise cycle, and weights, enabling travelers or others who are away from their usual routine to maintain an exercise program. Physical activity measured in total time or kilocalories per week is appropriate and may be achieved with various combinations of scheduling, such as 10 to 15 minutes in the morning and at noon and/or an afternoon/evening session. Many persons may schedule longer, less frequent periods of exercise. As intensity decreases, frequency and duration should increase and vice versa. The dosage or total calorie expenditure per week must be individualized. Persons with influenza syndromes or respiratory illnesses should decrease or stop exercise until they have recovered. If the recovery time is greater than 2 to 3 weeks, activity should be resumed at a lower level to compensate for the slight loss of training level. Various exercise testing measures of functional capacity are of interest but not necessary for primary prevention. Many athletically inclined persons like to have periodic oxygen consumption measurements to assess their level of training, but this is not routinely recommended. However, exercise testing should be done in those who are considered at high risk for cardiovascular disease (for example, those with hypertension or abnormal blood lipid levels). A lifestyle of physical activity from childhood throughout the adult years fosters health and longevity [7]. This improved state of health is enhanced by weight control, restricted intake of saturated fat and cholesterol, abstinence from cigarette smoking, and control of high blood pressure and glucose intolerance. All-cause mortality Physical activity has been associated with a decreased risk of death in various population groups. A prospective study of 17,265 men and 13,375 women ages years in Copenhagen found a substantial decrease in the risk of death among those who spent 3 hours per week commuting to work by bicycle compared to those who did not commute by bicycle [8]. Among the men and women ages 60 years and older, the multivariate-adjusted relative risk for all-cause mortality decreased substantially by fitness level. Among men, the death rate for those ages 80 years or older in the high fitness group was lower than that for the least fit men ages 60 to 69 years. Among men, the relative risk for all-cause and cardiovascular mortality are consistently lower for the fit when compared to the unfit across body fat categories. In other words, being moderately fit is associated with a substantially greater chance of survival even among those with 25 percent of their body weight as fat. Similarly, among men with metabolic syndrome, those in the moderate and high cardio-respiratory fitness groups have increasingly lower all-cause mortality than do the less fit men. Physical activity, fitness, and cancer The body of literature on physical activity and cancer is smaller than that discussed above, but it is growing. Three examples of relevant study results follow: women diagnosed with breast cancer had a lower multivariate-adjusted relative risk of death and of recurrence if they obtained at least 3 MET-hours of activity per week than if they had a lower exercise level. In a study of men with gastric cancer in Japan, the least fit quarter of the group (tested by cycle odometer) were much more likely to die of gastric cancer than were the fitter members of the group. Other researchers [9] report that the inverse association of cardio-respiratory fitness with cancer mortality remains after adjustment for the percentage of body fat. Personal experience: primary prevention and lifestyle Evaluation of physical activity and dietary behaviours in young athletes. Background Promoting healthy lifestyle in children and teenagers is especially important because health-related behaviour adopted during adolescence often succeeds into adulthood. Physical activity and dietary habits have been identified as key aspects of healthy lifestyle that may reduce the risk of non-communicable diseases including cardiovascular disease, depression, obesity and diabetes [10-12]. It has been demonstrated that participation in sports, or adequate physical activity, is helpful in maintaining a healthy life style [13]. It is therefore necessary to have healthy eating habits and adequate physical activity for proper growth. Aim To analyze lifestyle in young athletes, in order to evaluate physical activity and eating habits. Methods 922 young people that came to our Department for a sports eligibility examination [719 males (78.0%) and 203 females (22.0%)], aged between 8 and 18 years (mean age 13.7±2.7 yrs, weight 54.6±15.2 kg, height 163.3±15.5 cm) were asked to complete a questionnaire to assess their lifestyle and eating habits (I.N.R.A.N., Istituto Nazionale di Ricerca per gli Alimenti

32 S26 Intern Emerg Med (2015) 10 (Suppl):S22-S30 e Nutrizione, Italian national institute of research on food and nutrition). The study received approval from the Regional Ethics Committee. The parents of the young athletes signed the questionnaires for the treatment of personal data and informed consent. The study was carried out to comply with the ethical standards laid down in the 1975 declaration of Helsinki and was approved by the Local Ethics Committee. All the young athletes underwent a general clinical examination, which included taking and evaluating their history, a general clinical check-up, and a cardiological examination consisting of echocardiography and basic ECG at rest and under stress ECG. Weight and height were measured using a mechanical scale. Height was measured with the participants standing upright barefoot, heels together against the wall. The front of the feet were apart at an angle of about 60, and the whole body in upright posture. The measurements were performed by skilled technicians who were highly trained. Body mass index (BMI) was calculated as body mass divided by height squared (kg/m 2 ). In order to classify the participants as overweight, obese or normal, we decided to adopt the guidelines of Cole et al. [14], as recommended by the International Obesity Task Force (IOTF). The first part of the questionnaire includes questions indicating general information (weight, height, age, sex, and most widely used means for getting to school). The second part is related to physical activity and sports practiced: we assessed the frequency of the physical activity (<1 h, 1 h, >1 h a week) in addition to the type of sport practiced (months/years of activity and hours per week devoted to practice). The third part of the questionnaire assesses eating habits. Firstly, the data collected were about the meals consumed regularly throughout the day (breakfast, snack, lunch, snack and dinner), followed by a section on food allergies (self-reported) and possible adoption, frequency and type of dietary supplements. Finally, the last section is related to the frequency of weekly consumption of food groups. The food groups being: cereals and derivatives (such as pasta, rice, bread...), packaged cereals (cornflakes, biscuits, crackers...), fresh meat (chicken, turkey, beef, veal...), processed meats (ham, cold cuts, sausages...), fresh fish, milk or yogurt, cheese (fresh or aged), fresh fruit, dried fruit, vegetables (raw or cooked), legumes (white beans, chick peas, continental lentils...), eggs, desserts (ice cream, chocolate, homemade cakes...), sweetened beverages (cola, soda...) and alcohol (wine, beer, heavy alcohol...). Classification of sports involved was not only based on individual competitive sports but also on the two general types of exercise: dynamic and static. Each sport is classified by the level of intensity (low, medium, high) of dynamic or static exercise generally required to perform during competition. It also recognizes those sports with significant risk due to bodily collision, either because of the probability of heavy impact between competitors or between a competitor and an object in projectile motion or the ground, as well as the degree of risk for the athlete if a sudden syncopal event occurs [15, 16]. Thus, in terms of their dynamic and static demands, sports can be classified as IA (low static, low dynamic), IIA (moderate static, low dynamic), IIIA (high static, low dynamic); IB (low static, moderate dynamic), IIB (moderate static, moderate dynamic), IIIB (high static, moderate dynamic); IC (low static, high dynamic), IIC (moderate dynamic, high dynamic) IIIC (high static, high dynamic). Overweight (OW) or obese (OB) athletes were classified according to age and sex. International cut-off points for BMI identified the percentiles corresponding to BMIs of 25 (OW) and 30 (OB) kg/m 2 at age 18 [10]. The Mann-Whitney s U-test and Chi square test were used for comparisons of ordinal and categorical variables, respectively. All statistical analyses were performed using IBM- SPSS version 22.0 (IBM Corp., Armonk, NY, USA, 2013). A two-sided p-value <0.05 was considered significant. Results We divided BMI into the following classes (Table 1): - normal weight 86.3% (<12 yrs: 85.9%; 12-13: 84.0%; 14-15: 85.4%; >15: 89.0%) (87.3% of boys and 82.5% of girls); - overweight 12.4% (<12 yrs: 11.7%; 12-13: 14.0%; 14-15: 13.7%; >15: 10.6%) (11.5% of boys and 15.5% of girls); - obese 1.3% (<12 yrs: 2.4%; 12-13: 2.0%; 14-15: 0.9%; >15: 0.1%) (1.2% of boys and 2.0% of girls). Meal distributions: 2.2% reported not eating breakfast, 20.2% reported not having a mid-morning snack, all subjects have lunch, 15.3% have no mid-afternoon snack and all subjects have dinner. No statistical differences were found between normal-weight, overweight and obese athletes for the consumption of five meals a day or less. Times/quantities of weekly food consumption: cereals are consumed on average 10.8±5.5, packaged cereals 6.8±3.8, fresh meat 4.4±2.6, processed meats 3.4±2.6, fish 1.5±1.3, milk and yogurt 6.7±3.6, cheese 3.3±2.8, fresh fruit 8.5±5.8, dried fruit 0.8±1.7, vegetables 6.9±5.2, legumes 1.7±1.9, eggs 1.5±1.3, desserts 4.5±3.9, sweetened drinks 2.0±2.8 and alcohol 0.1±0.6. Overweight subjects eat less cereals (p=0.02), less dried fruit (p=0.029) and fewer desserts (p=0.025) per week (Table 1).

33 Intern Emerg Med (2015) 10 (Suppl):S22-S30 S27 Table 1 Weekly food consumption. BMI Sex C PC FM PM F MJ CH FF DF V L E CA SD A All Total 10.8± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.6 Males 11.0± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.6 Females 10.1± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.4 O Total 9.7±5.4* 6.8± ± ± ± ± ± ± ±0.1* 7.8± ± ± ±2.9** 1.8± ±0.4 Males 9.9± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.4 Females 9.1± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.2 Nw Total 10.9± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.6 Males 11.1± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.7 Females 10.3± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.4 Overweight + Obese versus Normal weight: *p<0.05; **p<0.01. Abbreviations: A, alcohol; BMI, body mass index; C, cereals; CA, cakes; CH, cheese; DF, dried fruit; E, eggs; F, fish; FF, fresh fruit; FM, fresh meat; L, legumes; MJ, milk and yogurt; Nw, normal weight; O, overweight + obese; PC, packaged cereals; PM, preserved meats; SD, sweetened drinks; V, vegetables. Regarding food allergies and intolerance: 1.1% reported gluten intolerance; subjects who practice physical activity seem more intolerant albeit not significantly (1.3%) in comparison to those who do not (0.9%); 4.7% reported other intolerances or food allergies. Additionally, subjects who practice physical activity proved to be more intolerant (5.7%), although not significantly, in comparison to those who do not practice physical activity (3.1%). No statistical differences between intolerance to gluten were found; other intolerances or food allergies appeared to be related to the adherence or non-adherence to physical activity. Regarding the question of taking supplements, 14.7% reported taking supplements and 13% of these habitually. The supplements taken most frequently were vitamins + minerals (Table 2). The older athletes tended to consume supplements (p<0.0001), which also meant they had participated in sports for the longest amount of time (p=0.001), for more times per week (p=0.001) and they consumed more processed meat (p=0.004), more eggs (p=0.025) and more alcohol (p<0.0001). Finally, 2.2% followed a diet (70.0% of normal-weight, 25.0% of overweight, and 5.0% obese). There was no association between sex, diet and BMI classes (Table 3). The main forms of transport used for getting to school were: car: 30%; public transport: 24.9%; motor bike 12.8% and only 3.4% cycled to school; 28.7% walked to school. These results do not show any association with BMI. The 61.4% reported doing physical activity in addition to sports (therefore 38.6% do not practice regular physical activity). The former have less BMI (p=0.001) and consumed fish several times a week (p=0.002) and eggs (p=0.019) in comparison to the latter. Normal-weight subjects begin to engage in sports around one year before (p<0.0001) and for about half an hour more per week, in comparison to overweight subjects (p=0.033). For each category of sports there was a greater adherence to those activities where the dynamic component prevails over the static component: the sports engaged in were soccer (50.7%), volleyball (9.5%), swimming (8.3%), basketball (6.4%), gymnastics (3.4%), rugby (3.1%), karate or judo (2.6%), dance (2.5%) and others (13.5%). When comparing static and dynamic sports, it was found that individuals who participated in static sport had a higher BMI in comparison to those who participated in dynamic sports. But no significant statistical differences were found. Conclusion Not only sports activity but also physical activity reduces the chances of being overweight and obese in children and ado-

34 S28 Intern Emerg Med (2015) 10 (Suppl):S22-S30 Table 2 Supplement intake. Physical activity No Vitamins Minerals Proteins Fibers Probiotics Vitamins + minerals Antioxidants Total No 295 (84.0%) 13 (3.7%) 14 (4.0%) 9 (2.6%) 1 (0.3%) 0 (0%) 19 (5.4%) 0 (0%) 351 (100.0%) Yes 479 (85.8%) 21 (3.8%) 10 (1.8%) 22 (3.9%) 0 (0%) 1 (0.2%) 24 (4.3%) 1 (0.2%) 558 (100.0%) Total 774 (85.1%) 34 (3.7%) 24 (2.6%) 31 (3.4%) 1 (0.1%) 1 (0.1%) 4 (4.7%) 1 (0.1%) Table 3 Descriptive characteristics of body composition in study sample. Normal weight (%) Overweight (%) Obese (%) Age (years) Total (n = 772) 86.3 (n = 111) 12.4 (n = 12) 1.3 < 12 (n = 177) 85.9 (n = 24) 11.7 (n = 5) (n = 168) 84.0 (n = 28) 14.0 (n = 4) (n = 193) 85.4 (n = 31) 13.7 (n = 2) 0.9 > 15 (n = 234) 89.0 (n = 28) 10.6 (n = 1) 0.1 Gender Male (n = 607) 87.3 (n = 80) 11.5 (n = 8) 1.2 Female (n = 165) 82.5 (n = 31) 15.5 (n = 4) 2.0 Physical activity Yes (n = 473) 87.8 (n = 61) 11.3 (n = 5) 0.9 No (n = 286) 83.6 (n = 49) 14.3 (n = 7) 2.0 Diet Yes (n = 14) 70.0 (n = 5) 25.0 (n = 1) 5.0 No (n = 757) 86.6 (n = 106) 12.1 (n = 11) 1.3 Five a meals day Yes (n = 541) 86.1 (n = 76) 12.1 (n = 11) 1.8 No (n = 230) 86.5 (n = 35) 13.2 (n = 1) 0.4 lescents. As a matter of fact the most effective programs are those combining sports and adequate physical activity. Researchers in this field agree that a diet based on an appropriate distribution of meals combined with regular physical activity, reinforce each other, and thus more effective results are obtained [17]. The examination of these young athletes showed a lower percentage of overweight children and especially of obese children, compared to the data collected for the whole of Tuscany. However, we observed that the majority of overweight and young obese people were aged between (16.0%). Moreover, regarding eating habits, even if some appear to be better, according to the data, compared to their peers who do not practice sports, the results are not very comforting. Cereal consumption is relatively low. We also found that participants consume little more than one daily serving of fruit and vegetables, way below the 5 recommended for a healthy diet. Little fish is consumed. Instead, it appears there is a high consumption of fresh and processed meats, and especially foods rich in simple sugars such as cakes and sweetened drinks are preferred. Another aspect is the consumption of supplements. Athletes can find 100% of their dietary needs from a well balanced nutrition plan that addresses performance, hydration, recovery, and health: only with certain medical conditions (e.g., iron, calcium, and vitamin D deficiency) or in those who usually eliminate some foods or food groups from their diet, in the event of illness, injury or hospitalization, supplementation may be beneficial [18]. No evidence supports the nutritional supplement-use for performance enhancement in adolescent athletes [19]. It is particularly important for young people to have healthy dietary habits rather than taking supplements. The taste preferences, food choices, and eating habits vary considerably according to age, on the basis of subjective and objective factors (sensory, emotional, psychological, environmental and social). Diet should meet the demands of all the nutrients and energy necessary to increase body mass, maintaining all physiological processes and adequate physical activity. Incorrect or poor eating habits not only determine the onset of chronic degenerative diseases in the long run, but they can also determine, in the short term, the lack of essential nutrients and compromise the development of necessary organisms in children. As far as the conduct of a constant physical activity is concerned, excluding sport, the results are not very encouraging: nearly 4 in 10 children do not carry out further physical activity in addition to sports. Among those who regularly practice physical activity, we have detected that 28% maintain a frequency of less than once a week.

35 Intern Emerg Med (2015) 10 (Suppl):S22-S30 S29 Regarding dynamic and static sports, it can be evaluated that with an increasing dynamic component, there is also a decreasing number of overweight and obese children. Most likely increased physical activity levels, as previously found in adults and children [20], would be necessary for a decrease in overweight and obesity in young people. As stated above, it is important to carry out constant and proper physical activity to maintain BMI in the correct range. In France, Italy and Denmark we find the lowest percentages of children who perform regular physical activity, with Italy showing the lowest frequencies, both males and females of all ages. Particularly alarming is that physical activity tends to have a further substantial fall in athletes aged between 11 and 15 in most European countries. Among other central causes a key role seems to be played by the poor amount of physical activity during leisure time, and the lack of possibility to get to school by bike or on foot in the few areas suitable for children and adolescents [21]. What is even more discouraging is the enormous increase in sedentary behavior, such as time spent watching television or sitting at a computer or playing video games. There now appears to be no more time for outdoor physical activities such as organized sports and games, or spontaneous play: this fact is now recognized as a true risk factor [22]. In addition, television and internet appear to have a devastating effect on the eating habits of children and adolescents and are associated with a greater consumption of sweetened beverages and with a major exposure to advertising of unhealthy foods [23]. Such a study highlights the opportunity to obtain more information, through a questionnaire, on several aspects of physical activity, eating habits and prevalence of risk factors. Accordingly, an initial picture of a given population can be obtained and interventions aimed at changing lifestyle habits can be planned and therefore monitored. Adequate and balanced nutrition is essential for young athletes in order to maintain health and performance. Higher education is necessary in order to promote a healthy lifestyle in terms of eating habits and physical activity. Not only young people, but also parents and coaches should be given nutrition education. Nutritional status should be monitored and evaluated by a team of specialists composed of nutritionists and physicians. Correct physical activity should be taught by athletic trainers. More information can be obtained also by using a specific questionnaire regarding physical activity, comparing young athletes with young people in general and evaluating the body composition in terms of fat mass, fat free mass and hydration status. Concluding remarks We have and are accumulating a very large amount of evidence on the effects of physical activity and fitness on a variety of health out-comes. For nearly every health outcome examined and in nearly every subgroup of the population, physical activity provides benefits. Adolescents and not exclusively adults, benefit of a correct lifestyle for primary prevention of those metabolic diseases strongly related to a higher cardiovascular risk factor. Regular physical exercise, more than sport, induces a progressive enhancement of all the anthropometrics parameters. Proper nutrition habits, combined with a physical activity, have a long term positive impact. References 1. Lloyd-Jones DM, Hong Y, Labarthe D et al (2010). Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association s strategic impact goal through 2020 and beyond. Circulation 121(4): Ford ES, Greenlund KJ, Hong Y (2012). Ideal cardiovascular health and mortality from all causes and diseases of the circulatory system among adults in the United States. Circulation 125(8): Suitor CW, Kraa VI (2007). Adequacy of evidence for physical activity guidelines development: Workshop Summary The National Academy Press 4. Lavie CJ, Randal JT, Squires RW et al (2009). Exercise training and cardiac rehabilitation in primary and secondary prevention of coronary heart disease. Mayo Clin Proc 84(4): Swift DL, Lavie CJ, Johannsen NM et al (2013). Physical activity, cardiorespiratory fitness, and exercise training in primary and secondary coronary prevention. Circ J 77(2): Ahmed HM, Blaha MJ, Nasir K et al (2013). Low-risk lifestyle, coronary calcium, cardiovascular events, and mortality: results from MESA. Am J Epidemiol 178: Trudeau F, Laurencelle L, Shephard RJ (2004). Tracking of physical activity from childhood to adulthood. Med Sci Sports Exerc 36: Gordon OM, Klügl M, Engebretsen L et al (2013). Prevention and management of non communicable disease: the IOC consensus statement, Lausanne. Br J Sports Med 47: Brown JC, Winters-Stone K, Lee A, Schmitz KH (2012). Cancer, physical activity, and exercise. Compr Physiol 2(4): Craigie AM, Lake AA, Kelly SA et al (2006). Tracking of obesity-related behaviours from childhood to adulthood: a systematic review. Maturitas 70: Rogol AD, Roemmich JN, Clark PA (2002). Growth at puberty. J Adolesc Health 31: Spear BA (2002). Adolescent growth and development. J Am Diet Assoc 102(Suppl3):S23-S Shelley EK, Machan EA, O Connor HT et al (2014). Continuous exercise but not high intensity interval training improves fat distribution in overweight adults. J Obes; Article ID , 12 pages 14. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH (2000). Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 320: Asmussen E (1981). Similarities and dissimilarities between static and dynamic exercise. Circ Res 48 Suppl 1:I3-10

36 S30 Intern Emerg Med (2015) 10 (Suppl):S22-S Jere HM, William H, Peter S, Steven PVC (2005). Task Force 8: Classification of Sports. JACC 45(8): Cordero AMJ, Ortegón Piñero A, Mur Villar N et al (2014). Revisión, programas de actividad física para reducir sobrepeso y obesidad en niños y adolescentes; revisión sistemática. Nutr Hosp 30(4): American College of Sports Medicine, American Academy of Family Physicians, American Academy of Orthopaedic Surgeons et al (2013). Selected issues for nutrition and the athlete: a team physicians consensus statement. Med Sci Sports Exerc 45(12): American College of Sports Medicine, American Academy of Family Physicians, American Academy of Orthopaedic Surgeons et al (2008). Selected issues for the adolescent and the team physicians: consensus statement. Med Sci Sports Exerc 40(11): Janssen I, Leblanc AG (2010). Systematic review of the health benefits of physical activity and fitness in school-aged children and youth. Int J Behav Nutr Phys Act 7: Aarts MJ, Mathijssen JJ, Van Oers JA, Schuit AJ (2013). Associations between environmental characteristics and active commuting to school among children: a cross-sectional study. Int J Behav Med 20(4): Thorp AA, Owen N, Neuhaus M, Dunstan DW (2011). Sedentary behaviors and subsequent health outcomes in adults: a systematic review of longitudinal studies, Am J Prev Med 41: Olafsdottir S, Berg C, Eiben G et al (2013). Young children s screen activities, sweet drink consumption and athropometry: results from a prospective European study. Eur J Clin Nutr 68:223-8

37 Intern Emerg Med (2015) 10 (Suppl):S31-S38 SELECTED PAPERS Pain in Internal Medicine The internist and pain in the hospital setting Maria Adele Giamberardino Giannapia Affaitati Francesco Cipollone Raffaele Costantini SIMI 2015 Abstract Pain is among the most frequent symptoms in medicine and one of the main reasons for patients seeking medical care. In the hospital setting, the internist mainly faces acute/recurrent pains, although various chronic pains also emerge in patients hospitalized for different symptoms. The most challenging acute/recurrent pains are of visceral origin and their correct identification is crucial for both diagnostic and therapeutic purposes. Collecting a detailed clinical history, targeted at the pain characteristics, and performing a specific physical examination of the painful area, including manoeuvers for hyperalgesia detection in somatic body wall tissues, represent the fundamental steps towards diagnosis, particularly to distinguish a visceral referred pain from a primary somatic pain. Special care should be taken in the evaluation of elderly, diabetic and hypertensive patients, in whom the pain threshold is raised and acute visceral pain, in particular, is hypo-expressed and/or tends to manifest atypically. As a general rule, pain symptoms should not be cancelled too early with analgesics as they represent a precious element to interpret the clinical picture. In contrast, a pain whose origin has already been identified and is no longer useful for diagnostic purposes should be relieved promptly and effectively, to avoid chronicization and long-term consequences such as a generalized state of pain hypersensitivity from central sensitization processes. M.A. Giamberardino ( ) Geriatrics Clinic, Department of Medicine and Science of Aging and Ce.S.I., G. D Annunzio University of Chieti, Via dei Vestini s.n., Chieti, Italy. mag@unich.it G. Affaitati F. Cipollone Geriatrics Clinic, Department of Medicine and Science of Aging and Ce.S.I., G. D Annunzio University of Chieti, Italy. R. Costantini Institute of Surgical Pathology, G. D Annunzio University of Chieti, Italy. Riassunto Il dolore è uno dei sintomi più frequenti in medicina e fra le ragioni principali di consultazione sanitaria da parte dei pazienti. L internista in corsia si trova ad affrontare prevalentemente situazioni di dolore acuto/ricorrente, anche se dolori cronici di vario tipo possono emergere in pazienti ospedalizzati in primis per altri sintomi. I dolori acuti/ricorrenti che pongono le maggiori problematiche di inquadramento sono soprattutto di origine viscerale e la loro corretta identificazione è cruciale ai fini diagnostici e conseguentemente terapeutici. Una anamnesi dettagliata di tutte le caratteristiche del sintomo dolore, combinata ad un esame obiettivo algologico specifico (comprensivo di manovre per il rilievo dell iperalgesia somatica nell area dolente) rappresentano gli steps fondamentali per indirizzare la diagnosi, soprattutto per distinguere il dolore viscerale riferito dal dolore somatico primitivo. Attenzione particolare va rivolta ai pazienti anziani, diabetici ed ipertesi, la cui soglia del dolore è innalzata e nei quali particolarmente il dolore viscerale acuto tende ad esprimersi in maniera atipica e sfumata. La cancellazione troppo precoce del sintomo dolore con terapia analgesica massiva andrebbe evitata per non incorrere in ritardi/errori diagnostici, mentre la terapia antalgica di un dolore già inquadrato sotto il profilo patogenetico va intrapresa in modo pieno e tempestivo per evitare conseguenze a lungo termine dello stimolo algogeno protratto, come l ipersensibilità generalizzata nei confronti degli stimoli dolorosi dovuta a fenomeni di sensibilizzazione centrale. Introduction Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage [1, 2]. It is among the most frequent primary complaints in the general population and one of the main reasons for patients seeking medical care, often in hospitals. Chest pain from ischemic heart disease or abdominal

38 S32 Intern Emerg Med (2015) 10 (Suppl):S31-S38 pain due to biliary or urinary colics from calculosis are just demonstrative examples [3, 4]. Pain is also additionally present in most patients who come to medical/hospital observation for other symptoms. In spite of its epidemiologic impact, however, pain has traditionally been scarcely assessed in hospital contexts other than specialized pain clinics. In Italy, its systematic recording has been introduced in medical records only in relatively recent times (after the approval of Law 38 in 2010), but it still regards evaluation of site and intensity only [5]. A thorough assessment of all characteristics of the pain is instead fundamental in every patient hospitalized in internal medicine units, for both diagnostic and therapeutic purposes. The following sections will focus on the steps the internist should follow to correctly assess pain symptoms in the ward. Pain assessment Medical evaluation of pain has the primary objective to determine whether the patient has acute or chronic pain [6]. Acute and/or recurrent pain (e.g., angina, biliary or urinary colics, pancreatitis pain) is the prevalent type of pain observed by the internist as a primary reason for patients hospitalization, although various chronic pains may emerge as secondary symptoms in patients hospitalized for other medical conditions [7]. Taking a detailed clinical history is the first fundamental step in the evaluation of the pain patient. A comprehensive history involves a precise account of the pain problem, in addition to the family history and a personal past and present general medical history. The clinical history must be obtained from the patient (or any relative or informed person if the patient is unable to provide correct information) soliciting, with appropriate questions, the most accurate description of the crucial aspects of the pain. Fundamental, amongst these, is the site where the pain is felt and the ability of the patient to discriminate it, i.e., to describe the location more or less precisely (circumscribed, diffuse, superficial, deep, scarcely, moderately or well localized). Information must also be acquired regarding: quality (e.g., pricking, burning, heavy, oppressive, tensive, constrictive, cramplike, lacerating, pulsating), intensity (from slight to intolerable), duration (seconds, minutes, hours, days), evolution in time (continuous, subcontinuous, ondulating, accessional), presence of neurovegetative signs (pallor, sweating, yawning, nausea, vomiting, diarrhea, frequent urination, bradycardia, hypotension up to collapse) or emotional reactions (anxiety, anguish, a sense of impending death). Detailed information should also be collected about the precise date of onset of the pain and the circumstances contributing to its causation (e.g., movement, effort). The type of onset: gradual or sudden, should be determined. Patients should be asked about the course of the pain in the period from its onset and the present medical observation: did the pain get better or worse with time? Did the location and spread change or remain the same? Were quality, severity and temporal characteristics of the pain and associated phenomena modified during the interval? Measurement of the actual spontaneous pain should then be performed. In internistic contexts, mainly dealing with acute pain, quantification of the symptom entails self-reports on a single dimension, usually intensity, using category scales, numeric rating scales or the visual analog scale (VAS). Numeric rating scales (0-10) and VAS are the most frequently employed. The VAS is a horizontal line, 100 mm in length, anchored by word descriptors at each end (no pain, the worst pain ever experienced). The patients mark on the line the point that they feel represents their perception of their current state. The VAS score is determined by measuring in millimetres from the left hand end of the line to the point that the patient marks. Pain as self-report on multiple dimensions is instead normally assessed in pain specialistic contexts, more centered on chronic pain [6, 8, 9]. Physical examination should follow the collection of the clinical history. In addition to the standard general physical examination (with particular attention to the neurologic examination), specific evaluation should be carried out of the painful region and, comparatively, of distant nonpainful areas. Examination of the painful region. It involves evaluation of all layers of the body wall in the affected area, i.e., skin, subcutis and muscle, particularly to detect sensory changes (e.g., allodynia, hyperalgesia) and trophic changes. Cutaneous examination in the painful area can reveal changes in skin color, teleangectasis, hypertrichosis, hyperhidrosis, cyanosis or flushing. Specific procedures should be applied to detect sensory changes. The brush test, consisting of lightly stroking the skin with a cotton wisp, may reveal allodynia (pain for nonpainful stimuli) if the patient reports pain at the manoeuver. The dermographic procedure and Head s technique (pin scratch test) are used to assess the presence of hyperalgesia (increased sensitivity to painful stimuli/ decreased pain threshold). For dermographism, longitudinal parallel lines (2 cm apart) are scratched onto the skin with the dorsal aspect of the thumbnail at a constant pressure. In normal skin, a vasodilatation reaction appears (red lines) while in a hyperalgesic area this reaction does not persist because the ischemic phase of dermographism takes prevalence (white lines). For Head s technique, concentric lines are scratched over the skin towards the area of altered dermographic reactivity with a needle tip at constant pressure and angle of

39 Intern Emerg Med (2015) 10 (Suppl):S31-S38 S33 inclination (25 ). The patient will show a painful reaction (wincing, groaning, or voluntary complaint) when the border of a hyperalgesic area is reached [6, 10]. Subcutis examination is carried out through pinch palpation, i.e., a fold of tissue is grasped and pressed between the thumb and index finger. The manoeuver provokes a painful reaction in hyperalgesia and is also useful to appreciate any local trophic change, such as the typical thickening and increased consistency in areas of persistent pain ( hard edema, on which firm pressure does not leave a fovea sign) [9]. Muscle examination involves appreciation, at inspection, of altered postures/attitudes of an antalgic/protective nature; of any contracture or altered trophism at both inspection and palpation; of painful reactions with palpatory procedures, which reveal hyperalgesia. Deep tenderness is best elicited by digital palpation using the middle finger to exert firm deep pressure on the painful site. The area of tenderness is mapped out and the neural segments involved are ascertained. Evocation of pain (and its location, irradiation or projection at a distance as in the case of myofascial trigger points) should be recorded during the manoeuver [7, 11]. More in general, in the whole painful area, factors or circumstances that reproduce, aggravate or relieve the pain need to be determined because they represent important and often conclusive evidence in making the diagnosis. One should particularly determine the effect of motion, application of heat and cold, but also of exercise, walking up steps, deep breathing, coughing, sneezing, straining, assumption of the prone, supine, and upright positions [6, 12]. Examination of distant nonpainful regions. A thorough appreciation of a pain condition in a patient needs necessarily also to involve evaluation of nonpainful control areas, where manoeuvres for assessment of deep and/or superficial hyperalgesia should be applied. A normal pain sensitivity in nonpainful areas, in fact, indicates the regional/peripheral origin of the pain condition of the patient, while hyperalgesia also extended to nonpainful zones points to a state of generalized sensitization indicative of the central origin of the pain, such as that typically characterizing fibromyalgia or arthritis in an advanced stage [13]. Examination of both painful and nonpainful sites could also be completed with the use of specific devices for measurement of pain thresholds, where available. The pressure algometer, for instance, is a portable device which can be used at bedside, it allows measurement of deep tenderness in tissues of the body wall in terms of minimal applied pressure (measured in kg-f) necessary to elicit a first sensation of pain. Hyperalgesia is revealed by lower than normal threshold values. Though not indispensable, instrumental measurement of sensory changes is a powerful tool to make the evaluation more objective and precisely control the effects of therapy in the pain patient [11, 14]. The correct interpretation of all the data collected at the clinical history and physical examination allows the internist to distinguish the different pain categories. Pain categories Pain can be either a symptom or a disease [6]. In the former case, it represents a precious sign for the clinician as it directs attention towards the injured/damaged structure and allows or facilitates the diagnosis: it is the signal of a potentially threatening stimulus somewhere in the body and has a protective role. Acute pain, most frequently faced by the internist in the hospital, is almost always a symptom. Every possible characteristic of the pain should be analyzed to try to identify the damaged structure and make the diagnosis. In this perspective the symptom should not be cancelled too early, or at least not before a reasonable orientation has been achieved about its origin, as an aggressive and early analgesic intervention may delay the diagnostic process and in some cases also expose the patient to a life-threatening situation [7, 9]. Pain as a disease is, instead, chronic. Leaving aside the particular case of chronic malignant pain, chronic benign pain can result from chronicization of an acute pain, persisting despite the healing of the primary generating event, due to central mechanisms of sensitization. This pain has therefore lost its protective function and is no longer useful for the diagnosis [6]. Pain as a disease, benign in nature, can also occur primarily as such, i.e., not apparently linked to any peripheral damage/ hyperstimulation of body structures from the very start. This is the typical case in syndromes of central sensitization, such as fibromyalgia or primary headaches with a high frequency of crises/chronic [13, 15, 16]. Pain as a disease is a source of constant suffering for the patient, and therefore needs to be relieved promptly and effectively. As already stated, it is less frequently encountered by the internist in the ward as it most typically arrives at the attention of specialistic pain centers. However, since incorrect diagnosis and treatment of acute/ recurrent forms of pain may lead to their chronicization, the internist may indirectly bear the responsibility of not preventing the development of several chronic pains if not able to handle acute pain properly. Pain as a symptom can be either nociceptive or neuropathic. The former originates from stimulation of nociceptors in peripheral tissues (superficial somatic, deep somatic, visceral). The latter originates directly from damage or dysfunction of peripheral and/or central nervous structures [6] (Figure 1).

40 S34 Intern Emerg Med (2015) 10 (Suppl):S31-S38 Nociceptive Nociceptive pain Superficial somatic Deep somatic Visceral Pain symptom Neuropathic Fig. 1 Pain from peripheral and/or central nervous structures is defined neuropathic; pain from every body structure, somatic or visceral is nociceptive pain. Every body structure, whether somatic or visceral, may, as a consequence of damaging or potentially damaging events, produce a pain which has specific characteristics but in clinical practice may pose complex diagnostic problems. A careful analysis of the symptoms does, however, allow a diagnostic orientation in most cases. Superficial somatic pain. This is pain at skin level. It does not usually involve interpretive problems, not only because the skin is easy to explore, but also because any individual has numerous previous experiences of this type of pain. Originating from a structure with a high density of innervation, skin pain is easily discriminated and its site very precisely described. It is pricking or burning, duration and intensity depend on the nature and duration of the stimulus. The evolution in time also varies in relation to the noxious event and is in general described as immediate, continuous or subcontinuous. There are usually no accompanying marked emotional reactions or neurovegetative signs. Additional stimuli exerted on the involved area increase the pain intensity. Deep somatic pain originates in the myofascial, ligamentous, osteoperostal and joint structures. Due to the less rich neurological substrate, it is perceived less precisely than skin pain and is typically diffused to the same neuromeric field as the primary involved structure. Described as piercing, cramplike, constrictive or oppressive, may be slight to maximal in intensity. Duration and evolution in time vary depending on the originating stimulus (continuous, subcontinuous, accessional). It is not generally accompanied by emotional signs, but in intense pain attacks, there may be minor neurovegetative signs such as pallor and sweating and, rarely, nausea. Additional stimuli, exerted on the painful area, increase the pain [9]. Visceral pain. Pain from internal organs is one of the most frequently encountered symptoms by the internist. The diagnostic approach to this type of pain needs to consider its typical temporal evolution. At its onset, true visceral pain typically appears at the midline of chest or abdomen, mainly in the lowest sternal region or epigastric region (but also posteriorly in the interscapular region) irrespective of the involved viscus. In this phase, in fact, pain from the heart, oesophagus, stomach, duodenum, gallbladder, kidney, pancreas, or other organs is always felt in this area. The symptom is vague, poorly defined, scarcely discriminated: the patient typically indicates the painful area with the entire palm of the hand, instead of using the finger. Pain intensity varies from slight to maximal and bears no relationship with the extent of the internal damage: a functional pain can be very intense, while a massively damaging internal process, such as a myocardial infarction, can produce a very mild sensation. It is thus particularly important for the internist to not rely on factor intensity to judge the severity of the medical condition. Emotional reactions typically accompany true visceral pain, consisting of anxiety, anguish, and sometimes a sense of impending death. Marked neurovegetative signs are moreover present, ranging from pallor and sweating to nausea, vomiting, bradycardia, frequent urination, alvus disturbances (diarrhea) and dysthermia. In some circumstances true visceral pain is not even a clear pain sensation and is expressed exclusively through a vegetative and emotional reaction accompanied by metaestesia, that is an intermediate sensation between pain and discomfort. A typical example is represented by myocardial infarction in which, at the onset, a sense of indigestion or heaviness is reported at gastric level. This may give rise to an incorrect diagnosis, especially as, with regard to the presence of vegetative signs, there may be nausea and vomiting. Another important characteristic of true visceral pain is that additional stimuli applied to the body wall structures within the painful area do not increase the pain. Pain can have a continuous, subcontinuous, ondulating or accessional progression and may last from a few minutes to a few hours. It is, however, limited in time, since it either ceases or becomes referred to somatic areas of the body wall (skin, subcutis and muscle) receiving the same sensory innervation as the involved viscus [7-9]. The first change in the transition of true visceral pain to referred pain is thus the site where the symptom is felt, which becomes specific for any involved viscus. Pain referral (i.e., pain felt in a region other than that in which the primary noxious insult takes place) is not exclusive of viscera: there may be, in fact, also referred pains from one deep

41 Intern Emerg Med (2015) 10 (Suppl):S31-S38 S35 somatic structure to another (from one muscle to another or from a joint to a muscle). However, it is a constant rule in visceral nociception. Referred pain from viscera can also arise as first manifestation of the visceral algogenic process and the phase of true visceral pain can be bypassed, or overlooked. When a patient presents to the internist with a pain which is felt in a specific somatic area, but whose visceral origin is suspected, the possible previous occurrence of true visceral pain should always been searched for with appropriate questions at the clinical history [4, 7-9]. In the phase of referred pain from viscera, the sensation becomes more similar to that originating directly from somatic structures, it is no longer accompanied by marked neurovegetative signs and emotional reactions and needs thus to be distinguished from a primary somatic pain. Two types of referred pain from viscera have been described: without and with hyperalgesia. Referred pain without hyperalgesia is felt in wide somatic zones within the neuromeric field of the involved viscus and may also extend to adjoining metameres. Additional stimuli exerted on the referred area, do not increase the symptom and the pain threshold is not decreased. Local anesthetic infiltration does not reduce the pain. Referred pain with hyperalgesia also appears in areas neuromerically connected with the affected viscus but its extent is limited. Additional stimuli onto the painful areas increase the symptom and the pain threshold is decreased (secondary hyperagesia). Local anesthetic infiltration in the referred area reduces the pain. Referred pain without hyperalgesia normally appears in the very first phases of the process of pain referral but is soon replaced by referred pain with hyperalgesia. Hyperalgesia first appears in the muscle layers, where it is often accompanied by a state of sustained contraction, but can then also extend upwards to involve the subcutis and the skin with the repetition of the visceral pain episodes or in the case of processes of long duration. Referred hyperalgesia from viscera is also usually accompanied by trophic tissue changes, i.e., increased thickness of the subcutis and decreased thickness/ section area of muscle, which can be documented clinically (pinch palpation, see above) and instrumentally, through measurement of tissue thickness via ultrasounds [3]. Referred pain without hyperalgesia is normally attributed to the phenomenon of convergence-projection, i.e., convergence of afferent sensory fibers from viscera and somatic structures on the same sensory neurons, which is the rule in visceral nociception. Stimuli arising from the internal organ would be interpreted by higher brain centers as if they came from the somatic area of pain referral because of mnemonic traces of previous experiences of somatic pain, in percentage much more numerous in life than those of visceral pain. Referred pain with hyperalgesia has been explained on the basis of both central and peripheral mechanisms. Central mechanisms involve phenomena of central sensitization i.e., hyperactivity and hyperexcitability of convergent viscero-somatic neurons, with consequent facilitation of the central effect of even slight stimuli applied onto the peripheral somatic area of pain referral. Reflex arcs would also be involved in the generation of the phenomenon. The afferent branch of the reflexes would be represented by sensory fibers from the viscus, while the efferent branch would be somatic towards the muscle and sympathetic towards superficial structures. The nociceptive input from the viscera would reflexely activate motoneurons to produce sustained contraction in muscles of the referred area; this contraction would in turn sensitize muscle nociceptors locally, contributing to the local hyperalgesia. The reflex arc would instead involve sympathetic efferent fibers towards the skin/subcutis, since it has been demonstrated that blockage of the sympathetic outflow towards the skin area of referral in patients with visceral referred pain is able to revert the local hyperalgesia [3, 6, 7]. When evaluating visceral pain, also other possible phenomena need to be explored, such as the presence of visceral hyperalgesia or viscero-visceral hyperalgesia (VVH). Visceral hyperalgesia is hypersensitivity of an internal organ due to inflammation and/or excess stimulation of the same organ (due to phenomena of both peripheral and central sensitization), as occurs in hypersensitivity to ingestion of food or liquids at gastric level in gastritis or pain/discomfort in the urinary bladder during cystitis. Exploring abnormal visceral sensitivity with appropriate questions to the patient is important to detect possible, even subclinical, inflammatory visceral conditions leading to visceral hyperalgesia. Viscero-visceral hyperalgesia is an enhancement of pain symptoms from two visceral districts when a patient is affected with two diseases in organs that share at least part of their central sensory projection (due to central sensitization of viscero-visceral convergent neurons): for example heart and gallbladder (C5), uterus and urinary tract (T10-L1), uterus and colon (T10-L1). It is the case of enhanced biliary pain and angina pain in ischemic heart disease concomitant with biliary calculosis, or of enhanced gastrointestinal pain and menstrual pain in women with concurrent irritable bowel syndrome and dysmenorrhea, or increased urinary pain and pelvic pain in women with concomitant urinary calculosis and endometriosis. In a patient presenting with a typical pain from one visceral district, which appears particularly intense and or longlasting in relation to the primary disease ascertained for that organ, it is always advisable to investigate also for the presence of any concurrent disease in a neuromerically connected organ, to exclude/confirm VVH especially as this has important repercussions on therapy (see section on therapeutic considerations) [4].

42 S36 Intern Emerg Med (2015) 10 (Suppl):S31-S38 Neuropathic pain This pain directly arises from peripheral and/or central nervous structures. The typical example is represented by neuralgias. It is usually perceived along the territory of distribution of the affected nerve, precisely discriminated, accessional, with short duration of single episodes (seconds/minutes), whose quality is described as lancinating, electric-shock like. It typically worsens at night and is normally accompanied by some neurovegetative signs and emotional reactions. Additional stimuli onto the painful area may be perceived as increased or decreased pain sensation [6]. Primary somatic versus visceral/referred pain The diagnostic algorithm Appreciation of the site of pain is the first element to consider when trying to distinguish primary somatic and visceral/ referred pain. A midline location can be suggestive of true visceral pain if local compression does not reveal hyperalgesia or indicate a primary somatic pain if hyperalgesia is present at the manoeuver. Pain in a somatic region other than the midline can be either primary somatic (e.g., a muscle pain from local injury/inflammation) or referred from a distant structure (either an internal organ or a distant different somatic area). Local compression of the painful area has then to be applied. If this manoeuver does not increase the pain and no hyperalgesia is revealed, the symptom can unequivocally be identified as a referred pain without hyperalgesia and thus its origin should be searched for at a distance, in a neuromerically connected area. If local compression increases the pain and local hyperalgesia is thus revealed, this pain can, again, be either primary somatic or referred with hyperalgesia and the diagnostic doubt persists. At this point only a thorough investigation (also possibly through specific instrumental examinations aimed at exploring both the local somatic and distant deep somatic or visceral structure) will allow a definite conclusion (Figure 2). Pain perception in particular groups of patients When evaluating pain in the ward, it is not only important to assess the characteristics of the symptom, but also carefully consider the specific profile of the patient. Gender and age are primary factors to be taken into account. Women tend, in fact, to have higher levels of pain perception (and lowered pain thresholds) for the same level of damage to affected structures, and also have more numerous conditions of functional pains with respect to men, such as irritable bowel syndrome or interstitial cystitis. In women, many forms of pain, for example chest pain, also tend to have an atypical presentation [4, 17, 18]. Age is a crucial factor [19]. In the past few decades, there has been an exponential rise in the average individual life expectancy, which has led to a significant percentage increase in the elderly population. Pain in the elderly has therefore become a topical subject, destined to play an increasingly important role in the field of pain diagnosis and management in the forthcoming years. Pain perception is altered by the aging process, although not similarly in the various structures. While superficial somatic pain (skin) tends to decrease, deep somatic pain, particularly at muscle level, and neuropathic pain increase. Acute visceral pain, instead, decreases, which may pose notable interpretive problems and should prompt the internist to devote great attention to even extremely mild symptoms suggestive of internal organ involvement in advanced age [6]. Comorbidities also modulate pain expression. The pres- Pain location Midline Does local compression reveal hypersensitivity? Any other somatic region Does local compression reveal hypersensitivity? Yes No Yes No Primary somatic pain True visceral pain Primary somatic pain Referred pain with hyperalgesia Referred pain without hyperalgesia Fig. 2 Primary somatic versus visceral/referred pain: flow chart for distinction.

43 Intern Emerg Med (2015) 10 (Suppl):S31-S38 S37 ence of hypertension or diabetes can decrease or even cancel pain perception of a number of specific algogenic entities, e.g., painless myocardial infarction, thus delaying their identification and treatment [4]. Careful assessment of all concomitant diseases in the pain patient should thus be performed. Considerations on pain therapy As already reported above, pain as a symptom, especially acute/chronic, is the most typical form encountered by the internist in the hospital setting. This type of pain represents a precious element to interpret the clinical picture in the patient and it should thus not be cancelled too early. Pain as a disease/chronic pain, instead, is no longer useful for diagnostic purposes and should be relieved promptly and effectively, having become a source of constant suffering for the patient, a situation which may per se complicate the general health status (chronic suffering impacts significantly on the function of all body systems and on the psychological asset) [6]. Unfortunately, in many contexts the medical attitude towards the relief of pain is exactly the opposite: a massive and early use of analgesics for pain symptoms at their onset, and a tendency to insufficient administration of antalgic therapy when pain has become a disease. The administration of drugs effective towards several forms of pain encountered in internistic hospital settings requires particular attention as regards the significant interactions that these compounds may have among them and with other drugs used in the patient for other medical reasons, such as anticoagulants or sedatives. Non steroidal anti-inflammatory drugs (NSAIDs), simple analgesics (such as paracetamol), combination analgesics (e.g., paracetamol plus codeine), weak and major opioids (tramadol or morphine), antiepileptics, as well as adjuvants [various antidepressants such as tricyclics, selective serotonin re-uptake inhibitors (SSRI), serotonin and noradrenalin reuptake inhibitors (SNRI), spasmolytics] or class compounds targeted at particular forms of pain (e.g., triptans for migraine) need to be selected with particular care not only in relation to the primary nature/origin of the pain (e.g., inflammatory, functional, neuropathic) but also considering the other patients comorbidities such as hepatic and renal failure, arterial hypertension or cardiac failure/arrhythmias [20]. A concurrent cardiovascular disease in a patient presenting a migraine attack, for example, may affect the therapeutic approach to the headache pain with voasoactive compounds, while the presence of cardiac conduction disturbances or arrhythmias in neuropathic pain patients can limit the use of first line drug treatments for this condition [21]. A diversified use of the different class compounds for pain treatment, based on an accurate diagnosis of the type of pain and general medical profile of the patient, is particularly important and should be encouraged. European statistics report, in fact, that the general approach to pain treatment in hospital internistic settings is prevalently based on the use/overuse of NSAIDs (with all the possible consequent significant side effects/adverse events at gastrointestinal, renal and cardiovascular level) while opioids are under-utilized even when these appear the most appropriate option ( opioidofobia ) [20, 22]. In addition to treatment of the pain, a pathophysiologic treatment of the disease causing the pain should always be undertaken, such as direct the patient to a surgical approach for specific conditions (e.g., gallbladder calculosis) or to an interventional approach for others [e.g., extracorporeal shockwave lithotripsy (ESWL) for urinary calculosis] [4, 23]. With this respect, it is worth noting that in viscero-visceral hyperalgesia effective treatment of one visceral condition also indirectly relieves pain from the other affected organ, for example cholecystectomy also relieves cardiac pain in patients with concomitant ischemic heart disease and gallbladder calculosis, or ESWL for urinary stones also relieves menstrual pain in women with concurrent urinary coclis and dysmenorrhea [4]. Conclusions In conclusion, the steps to follow by the internist in the ward when dealing with a pain patient are: detailed clinical history targeted at pain characteristics, physical examination including specific manoeuvres for detection of superficial and/or deep hyperalgesia, considering with particular attention gender and age of the patient as well as the presence of comorbidities whose impact onto pain perception is substantial [6]. Careful application and interpretation of this sequence of procedures allow a correct diagnostic orientation in most cases, and therefore the setting of an appropriate therapy, reducing the amount of specific instrumental diagnostic procedures to prescribe and consequently the costs to the healthcare system. References 1. Merskey H, Bogduk N (1994). Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. IASP Press, Seattle 2. Treede RD, Rief W, Barke A et al (2015). A classification of chronic pain for ICD-11. Pain Mar 14 [Epub ahead of print] 3. Giamberardino MA, Affaitati G, Lerza R et al (2005). Relationship between pain symptoms and referred sensory and trophic changes in patients with gallbladder pathology. Pain 114: Giamberardino MA, Costantini R, Affaitati G et al (2010). Viscero-visceral hyperalgesia: characterization in different clinical models. Pain 151: Fanelli G, Gensini G, Canonico PL et al (2012). Pain in Italy.

44 S38 Intern Emerg Med (2015) 10 (Suppl):S31-S38 Background examination. Operative proposals. Recenti Prog Med 103: Loeser JD (2001). Bonica s management of pain. Lippincott Williams & Wilkins, Philadelphia 7. Procacci P, Zoppi M, Maresca M (1986). Clinical approach to visceral sensation. In: Cervero F, Morrison JFB (eds). Visceral sensation, progress in brain research. Elsevier, Amsterdam, pp Vecchiet L, Giamberardino MA, Dragani L, Albe-Fessard D (1989). Pain from renal/ureteral calculosis: evaluation of sensory thresholds in the lumbar area. Pain 36: Vecchiet L, Vecchiet J, Giamberardino MA (1999). Referred muscle pain: clinical and pathophysiologic aspects. Curr Rev Pain 3: Jarrell J, Giamberardino MA, Robert M, Nasr-Esfahani M (2011). Bedside testing for chronic pelvic pain: discriminating visceral from somatic pain. Pain Res Treat 2011: Giamberardino MA, Affaitati G, Fabrizio A, Costantini R (2011). Myofascial pain syndromes and their evaluation. Best Pract Res Clin Rheumatol 25: Giamberardino MA, Tafuri E, Savini A et al (2007). Contribution of myofascial trigger points to migraine symptoms. J Pain 8: Affaitati G, Costantini R, Fabrizio A et al (2011). Effects of treatment of peripheral pain generators in fibromyalgia patients. Eur J Pain 15: Giamberardino MA, Tana C, Costantini R (2014). Pain thresholds in women with chronic pelvic pain. Curr Opin Obstet Gynecol 26: Tana C, Santilli F, Martelletti P et al (2014). Correlation between migraine severity and cholesterol levels. Pain Pract Tana C, Tafuri E, Tana M et al (2013). New insights into the cardiovascular risk of migraine and the role of white matter hyperintensities: is gold all that glitters? J Headache Pain 2013;14: Caldarella MP, Giamberardino MA, Sacco F et al (2006). Sensitivity disturbances in patients with irritable bowel syndrome and fibromyalgia. Am J Gastroenterol 101: Sato H, Droney J, Ross J et al (2013). Gender, variation in opioid receptor genes and sensitivity to experimental pain. Mol Pain 9: Molton IR, Terrill AL (2014). Overview of persistent pain in older adults. Am Psychol 69: Breivik H (2015). Treat the whole patient and be aware of drug interactions. J Pain Palliat Care Pharmacother 29: Giamberardino MA, Martelletti P (2015). Emerging drugs for migraine treatment. Expert Opin Emerg Drugs 20: Breivik H, Collett B, Ventafridda V et al (2006). Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 10: Costantini R, Affaitati G, Fabrizio A, Giamberardino MA (2011). Controlling pain in the post-operative setting. Int J Clin Pharmacol Ther 49:116-27

45 Intern Emerg Med (2015) 10 (Suppl):S39-S44 SELECTED PAPERS Pain in internal medicine Pharmacological treatment of pain in patients with multimorbidity and polipharmacy Silvia Benemei Pierangelo Geppetti SIMI 2015 Abstract Multimorbidity, the presence of two or more longterm disorders in an individual, and the consequent polypharmacy are common and troublesome conditions increasing with age. Pain often contributes to multimorbidity and, unfortunately, it cannot be treated in ease. All the evidence-based options, including non-pharmacological treatments, should be taken into consideration in order to appropriately manage pain in multimorbid patients. Age-related changes of pharmacokinetics and pharmacodynamics, some practical tips, and major analgesic classes of drugs are presented here, to raise physicians awareness of critical issues in therapeutic choices and to guide them in appropriate prescribing. Riassunto La polipatologia, definita come la contemporanea presenza di almeno due disturbi cronici, e la conseguente politerapia sono condizioni cliniche comuni e di difficile gestione, che aumentano progressivamente con l aumentare dell età. Le patologie dolorose spesso contribuiscono a comporre il quadro della polipatologia e, sfortunatamente, non sono di facile trattamento in tale contesto. Tutte le opzioni evidence-based, anche quelle non farmacologiche, devono essere prese in considerazione per poter trattare in maniera appropriata il dolore in pazienti con polipatologia. Le modificazioni farmacocinetiche e farmacodinamiche correlate all età, alcuni suggerimenti pratici e le maggiori classi di farmaci analgesici sono discussi, nella presente rassegna, per aumentare la consapevolezza del medico in merito ai passaggi critici della prescrizione e per favorire l appropriatezza prescrittiva. Introduction Multimorbidity, namely the presence of two or more longterm disorders in an individual, is a common and increasingly studied condition. Recent data corroborate the huge, even highest than predictable, personal and societal burden of this condition [1]. Multimorbidity is associated with an increased risk of loss of physical functioning, worsening quality of life, hospitalizations and, finally, premature death. It goes without saying that multimorbidity associated with polypharmacy. Polipharmacy in patients with multimorbidity is a troublesome question with a high impact in clinical practice. As a matter of fact, the current medical paradigm, from evidence-based medicine to healthcare systems, is tailored to patients with one single disorder and often acute episodes of illness [2]. Even clinical studies, with the a priori exclusion of multimorbid subjects, contribute to build this scenario. However, the presumption that, in order to treat patients with multimorbidity, to sum up drugs recommended for each individual condition is necessary and sufficient [2] is not supported by clinical data. Drugs effective and safe for those with one disorder are not necessarily effective and safe to treat the same condition in multimorbidity. For this reason, patients with multimorbidity not infrequently suffer from consequences of inappropriate treatments, such as drug-drug or drug-disease interactions and avoidable drug adverse reactions, with a resulting increased risk of double-dipping (i.e. addition of further drugs to treat drug-induced symptoms) [3]. P. Geppetti ( ) Clinical Pharmacology Unit, Department of Health Sciences, University of Florence, Viale Pieraccini 6, Firenze, Italy. pierangelo.geppetti@unifi.it S. Benemei Clinical Pharmacology Unit, Department of Health Sciences, University of Florence, Italy. Can we draw an identikit of the multimorbid patient prototype? According to most recent data, multimorbidity affects a large portion of the general population, as by age 65 years most people is multimorbid and age is a well-established determinant of multimorbidity [4].

46 S40 Intern Emerg Med (2015) 10 (Suppl):S39-S44 An outstanding cross-sectional study, including data from 1,751,841 people, shows that even if in absolute terms more people with multimorbidity were younger than 65 years, older people had more morbidities on average [5]. Between 70 and 75 years of age, for instance, a proportion of patients close to 30% suffers from at least 4 chronic conditions. Therefore, increasing age boosts the risk of multimorbidity and, consequently, of being treated with a higher number of drugs. Importantly, the number of drugs has been reported as the most important independent risk factor for the development of adverse drug reactions (ADRs) [6]. Accordingly, studies that used multivariate analysis report that the association between old age and ADRs results from the confounding association between age and polypharmacy, arguing that old age is just a marker for multimorbidity and the consequent polypharmacy [7]. On the other hand, increasing age per se can contribute to ADRs because of changes in pharmacokinetics and pharmacodynamics (see the section Age-related changes of pharmacokinetics and pharmacodynamics), and has been showed as an independent risk factor for severe ADRs [8]. To further complicate the picture, polypharmacy exposes multimorbid patients to drug-drug interactions and decreased adherence, which can in turn undermine the efficacy of prescribed treatments [9]. Taking into account the abovementioned evidence, the prototype of a multimorbid patient corresponds to an individual aged 65 years or older who is exposed to polypharmacy and has an increased risk to develop ADRs and poor adherence to prescribed treatments. Which is the burden of pain in multimorbid patients? Pain is one of the conditions that, independently from socioeconomic contributing factors, most frequently coexist with other diseases [5]. The Global Burden of Disease (GBD) estimates for 2010, for people aged 60-years or older, that the 4 th est most burdensome disorder is low back pain (19.1 million DALYs, disability-adjusted life years), placed in between diabetes (22.6 million) and cancer of the trachea, bronchus, or lung (18.6 million). In people over 65 years, the prevalence of painful condition as a whole, is reported to span between 50% and 86% [10, 11]. Therefore, pain treatment in >65 year-old patients, with multimorbidity and polypharmacy is a rather frequent condition in clinical practice. Age-related changes of pharmacokinetics and pharmacodynamics It has been long considered that age per se could be a determinant for clinically relevant changes in pharmacokinetics and pharmacodynamics. However, this assumption has been progressively challenged by clinical results in elderly healthy subjects. In addition, only few studies evaluated the clinical impact of adjusting doses according to pharmacokinetics-related changes. Many age-related physiologic changes, including increased gastric acidity or decreased albumin plasma levels, can alter pharmacokinetics. However, only some of them have been shown to affect dosing of different drugs. The increase in body fat and decline in total body water and lean body mass produce an increased apparent volume of distribution for lipophilic drugs and a smaller one for hydrophilic drugs. From a clinical point of view, it is worth to underline that changes in half-life parallel those of the volume of distribution. The reduction of first-pass hepatic metabolism is a well-established effect of aging. The extent of the phenomenon is quite variable among different classes of drugs, spanning from 30% to 50% for medicines cleared by Phase-I hepatic metabolism. The impairment of hepatic clearance is likely due to reduced hepatic blood flow and hepatic mass [6], rather than to changes in enzyme expression/function which are more under the control of genetic factors. Thus, oral bioavailability of drugs, which undergo extensive first pass metabolism, can be increased, and systemic clearance of drugs with a high hepatic extraction ratio can be decreased. Differently from what has been widely accepted for many years, older people do not show significant decrease in renal function, unless they are affected by cardiovascular diseases or in the presence of other risk factors [12]. It s noteworthy that interindividual variability more than age-related variability has been claimed to play a pivotal role in pharmacokinetic differences among individuals [6]. However, ageing-dependent progressive accumulation of random changes somehow contributes to the increase in interindividual variability [13]. The impact of interindividual variability is even more relevant in pharmacodynamics, for which generalizations have been rarely formulated. However, changes in the clinical response, due to age-related variations in the function of target effector systems, are now well-established for specific drugs, such as warfarin (i.e. increased anticoagulation), diazepam (i.e. increased sedation) and morphine (i.e. increased analgesic effect) [13].

47 Intern Emerg Med (2015) 10 (Suppl):S39-S44 S41 Basic principles and tools for the appropriate prescription of drugs in multimorbidity All the evidence-based options, including the non-pharmacological treatments, should be taken into consideration in order to appropriately manage coexisting conditions, including pain, in multimorbid patients. This general suggestion can be tailored to individual patients, according to practical tips: 1. Determine evidence about efficacy. Search the literature for clinical studies, even observational ones, including patients with multimorbidity or polypharmacy. Given the likelihood of dealing with patients aged 65 years or more, specific search for studies including geriatric population is recommended. 2. Determine the risk of ADRs. Taking into account comorbidities and age-related expected changes in pharmacokinetics and pharmacodynamics draw possible therapeutic scenarios and compare them according to their harm/benefit profile. 3. Choose optimal dosage regimen. According to the age and clinical status (i.e. hepatic and renal function) of the patients, choose the initial dosage. In the absence of any specific evidence, the general principle of start low, go slow should always be kept in mind. In order to foster patient s adherence, select the optimal available formulation. To this aim, consider: invasiveness, acceptability, and number of administrations needed. Always prefer the most simple dosage regimen. 4. Educate the patient. Discuss with the patient, according to her/his cognitive status, possible challenges related to drugs you would like to prescribe. Taking into consideration the patient autonomy will help you to understand if patient s goals and yours are the same. In addition, make the patient and/or caregivers aware about possible interactions of the drug with other drugs, even over-the counter drugs and herbal medicine, and foods. 5. Monitor drug effects and patient s adherence. Schedule visits to review the clinical condition of the patient. Ask patients and/or caregivers to carefully report any drugs and other substances, including food and herbal supplements, that he/she takes. The issue of inappropriate prescribing (misprescribing or underprescribing) has been long addressed in geriatric medicine, where a series of useful tools to guide prescription has been developed. Most experiences in this context have focused on choice of drug, dose, drug interactions, duration of therapy, duplication, and follow-up. The so-called drugto-avoid criteria, consisting of a list of drugs that should be avoided because their potential harms outweigh benefits, represents a cornerstone in the optimization of prescribing. Beers and colleagues developed a list in the US [14], while McLeod and others prepared a similar list in Canada [15]. According to their common structure, these lists indicate drugs that should always be avoided, doses that should not be exceeded, and drugs to avoid in patients with specific conditions. Major limitations attributed to these tools are the scarce transferability to other countries, failure to address many drug-drug and drug-disease interactions, and the lack of a user-friendly structure. New tools developed to overcome these major limitations have been recently validated [16]. STOPP (Screening Tool of Older Person s Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment) criteria are evidence-based rules of avoidance of commonly encountered instances of potentially inappropriate prescribing and potential prescribing omissions. In details, STOPP and START consist of 65 and 22 criteria, respectively. STOPP and START are organised according physiological systems in order to increase their usability. In addition, they do not refer to specific drugs but rather to drug classes, in order to increase their transferability to different countries. Recent evidence suggests that the abovementioned explicit criteria, should preferably be used together with implicit criteria, such as full clinical medication review by pharmacists, in order to identify drug-related problems [17]. Notwithstanding, both explicit and implicit criteria represent useful tools to optimize prescribing and, intuitively, the higher is the number taken by the patient, the better is the benefit deriving from their use. Which drugs can be used to treat pain in multimorbid patients? The analgesic therapy has a special place in the pharmacotherapy since the availability of a huge number of over the counter (OTC) medicines relevantly increases the risk of their inappropriate use. It has been shown that analgesics including non steroidal anti-inflammatory drugs (NSAIDs) are widely used and frequently taken inappropriately [18]. In addition, the OTC status is commonly associated to a decreased patients awareness about risks associated with a specific drug and, eventually, to its inappropriate use [18]. In addition, some analgesic drug classes, even if safe per se, have a relevant interacting potential with both diseases and other drugs. The interacting potential narrows the spectrum of therapeutic indications of such pharmaceutical classes, with the maximal narrowing in patients with multimorbidity and polypharmacy. In the following sections, the different classes of analgesic drugs will be presented accordingly to their interacting potential profile, starting from the less interacting ones.

48 S42 Intern Emerg Med (2015) 10 (Suppl):S39-S44 Paracetamol Paracetamol, a metabolite of phenacetin, also known as acetaminophen, is a non-acidic antipyretic and analgesic small molecule designed in Its use as analgesic spread worldwide after 1949, boosted by its efficacy as antipyretics and its low cost. Oral, rectal and intravenous formulations are available. The mechanism of action of paracetamol has long been uncertain, but quite recent evidence suggests a mechanism of action similar to that of NSAIDs. Paracetamol seems to poorly inhibit cyclooxygenase-1 (COX-1) and COX-2, with some selectivity for COX-2 [19]. However, paracetamol would inhibit the synthesis of prostaglandins and related factors only when low levels of arachidonic acid and peroxides are available with scarce activity at higher levels of arachidonic acid and peroxides. This dual activity would explain both the lack of suppression of the severe inflammation of rheumatoid arthritis and acute gout and the inhibition of the limited inflammation produced by tooth extraction The suggested COX-2 selectivity would be the cause of paracetamol poor anti-platelet activity and good gastrointestinal safety and tolerability. Similarly to NSAIDs and selective COX-2 inhibitors paracetamol displays both central and peripheral effects. Most recent evidence suggests additional analgesic mechanisms of paracetamol, including the ability to target and desensitize the emerging pain transducer, the transient receptor potential ankyrin 1 (TRPA1), a ion channel expressed by primary sensory neurones that has been shown to mediate both neuropathic and inflammatory pain [20, 21]. Paracetamol is somewhat less effective than NSAIDs and other analgesics in pain treatment with a much better safety profile than NSAIDs, in terms of cardiovascular and gastrointestinal safety [19]. In particular paracetamol, only slightly increases the risk of mortality, cardiovascular, and gastrointestinal haemorrhage [22]. While recently reported moderate gastrointestinal and cardiovascular toxicities may be less predictable, the overdose-dependent, sometime fatal, hepatoto/ renal toxicity can be controlled by appropriate dosing. The interacting potential of paracetamol is extremely low. The sole relevant reported interaction resides in the ability of paracetamol to increase the international normalized ratio (INR) in patients treated with coumarins, with a consequent increased risk of bleeding [19]. According to its safety profile, even if higher than currently perceived in the clinical community, and to the minimal risk of interactions with other drugs or diseases, paracetamol still deserves the first place among treatment for low-moderate pain. Opioids Opioids, and first morphine, still represent the quintessential analgesic drugs. During last decades many efforts have been spent to design the optimal opioid drug and regimen, devoid of the most common adverse effects, such as nausea and constipation, or more the threatening respiratory depression. In general, opioids act as analgesics by targeting G proteincoupled receptors, μ receptors (MOR), but likely also δ (DOR) and κ (KOR) receptors, which are involved in the control of pain circuits. Opioids are considered drugs of choice for severe pain. Opioids are commonly classified according to their potency in a continuum going from weak (e.g. tramadol), to strong (e.g. morphine). However, clinicians should avoid the identification of a higher potency with a more effective analgesia or higher abuse liability. From a therapeutic point of view, knowledge of both pharmacokinetics of different drugs and formulation features (e.g., extended vs. immediate release), is likely more helpful to an optimal analgesia. For instance, adverse effects of codeine and tramadol are more likely to occur in CYP2D6 ultra-rapid metabolisers. In addition, appropriate dosing titration that starts with an immediate-release formulation, around-the-clock dosing, and rotation practices further optimize the therapy with opioids. Detailed and updated recommendations for the responsible prescription of opioid for non-cancer pain have been recently published [23]. In patients with chronic non-cancer pain, the number needed to harm is 4.2 ( ), that is every four patients treated with opioids, more than one would have experienced an ADR with respect to placebo [24]. ADRs frequently occurring with opioid use are constipation (41%), nausea (32%), vomiting (15%), somnolence (29%), dizziness (20%), and itch (15%) [24]. All ADRs, but constipation, undergo a certain tolerance with chronic treatment. For this reason, under the first phases of treatment, antiemetics can be used together with laxatives while these latter should be used for the entire duration of therapy. The increased risk of falls and fractures is also a common ADR [25], which together with the doubling risk of delirium, should be considered particularly dangerous in elderly patients. The risk of severe respiratory depression and drug misuse is minimized by a careful selection of patients, with exclusion of those with predisposing conditions and history of substance abuse, respectively. In addition, to limit the risk of misuse, a strict monitoring programme, and avoidance of co-prescription with sedating agents and formulation hardly exploitable for misuse can be useful [25]. In principle, the potential of appropriately prescribed opioids to interact with other drugs is considered low. Some specific drugs, such as fentanyl or hydromorphone, can be preferred in case of decreased renal or hepatic function. Co-administration with other depressants of the central nervous system, such as antidepressants, sedative anti-histamines benzodiazepines and other hypnotics, and phenothiazines, increases the sedative ef-

49 Intern Emerg Med (2015) 10 (Suppl):S39-S44 S43 fect. The co-administration with monoaminooxidase (MAO) inhibitors should be avoided or, at least, a 2-week washing-out period should be adopted. In addition, fentanyl and buprenorphine should not be co-administered with CYP3A4 inhibitors (e.g. amiodarone, cimetidine, clarithromycin, diltiazem, erythromycin, itraconazole, ritonavir, verapamil). Nevertheless, opioids remain the mainstay for treatment of severe pain. Their effective and safe use is guaranteed by the strict selection of patients, careful drug choice and dose titration, and by continuous monitoring of patients. Non steroidal anti-inflammatory drugs (NSAIDs) The well-established recognition of NSAIDs as one of the most commonly used pharmaceutical classes worldwide clashes with their safety profile in long term regimens. The picture is even worsened when their interacting potential is taken into consideration. The first use of these active principles, originally salicilates contained the bark of willow tree, has been anecdotally referred to Hyppocrates and fellows. Notwithstanding their long-standing utilization, the awareness of potential harms linked to inappropriate utilization has only recently been increasing. Accordingly, medical societies, such as the American Geriatric Society or the American Gastroenterological Association, released guidelines and recommendations to support the appropriate prescription and utilization of these drugs [26]. As mentioned above, NSAIDs act as analgesic and antipyretics by inhibiting COX enzymes. Their unique ability to inhibit COX is also the basis of both their relevant anti-inflammatory effects and the antiplatelet action. Active principles are categorized according to their relative selectivity for the two COX isoforms. Similar concentrations of non-selective NSAIDs equally affect the enzymatic activity of both COX1, the ubiquitous housekeeping isoform, and COX2, the isoform induced by inflammation. On the other hand, at a given concentration, selective NSAIDs preferably inhibit one of the two isoforms. The extreme side of the selectivity is represented by COX2-inhibitors, for which the selectivity to COX2 is almost absolute. In addition, according to their chemical structure, NSAIDs can be classified in different families such as propionic acid derivatives or fenamates. The utilization of NSAIDs is associated with significant risks directly related to their mechanism of action. Most common side effects involve: the gastrointestinal tract, causing ulcers and consequential bleeding, perforation or obstruction, as prostaglandins exert a protective effect on the mucosa; kidney, with events spanning from renal dysfunction to renal failure, as prostaglandins are involved in the homeostatic autoregulation of renal arterioles; cardiovascular system, with both an increased risk of myocardial infarction, as the balance of COX-2 dependent endothelial vasodilating prostaglandins (i.e. prostacyclin) and COX-1 dependent platelet thromboxane parallels the balance among antithrombotic and protrombothic status, and a well-established risk of hypertension and cardiac failure; bleeding, with an increased risk especially if co-administered with anticoagulants or selective serotonin reuptake inhibitors (SSRIs). The cerebrovascular risk seems to be not altered by NSAIDs use, with the exception of diclofenac and aceclofenac. Upper gastrointestinal bleeding can be easily reduced by concomitant administration of proton pump inhibitors (PPIs), while no preventive therapy exists for the increased risk of bleeding from the lower gastrointestinal tract. Among the ADR unrelated to the mechanism of actions, anaphylaxis and rare hepatic toxicity are noteworthy. The interacting potential of NSAIDs with other drugs is extremely relevant, even from a quantitative point of view. In addition to the abovementioned drugs, NSAIDs may detrimentally interact with: angiotensin converting enzyme-inhibitors and sartans, with an additive effect on renal vasoregulation, especially in elderly with renal hypoperfusion or hypovolemia; b-blockers and diuretics, reducing their antihypertensive effects; quinolones, synergistically increasing the risk of convulsions, an observation that dictates special attention in epileptic patients; sulfonylureas, increasing the hypoglycemic risk. The statement the lowest dose for the shortest time is the most simple and efficacious advice on NSAIDs utilization. As a matter of fact, the well-established analgesic efficacy and even some recent evidence about positive impact on cancer prevention [27] cannot support a wide use of NSAIDs, which is commonly associated to avoidable and predictable ADRs, especially in elderly, and with many potential interactions in patients with multimorbidity and polypharmacy. Conclusions Pain in patients with multimorbidity and polypharmacy cannot be treated in ease. None of the analgesic drug classes is devoid of potential adverse reactions or interactions with diseases or drugs. However, accurate knowledge of patient medical and pharmacological history and available drugs together with confidence in tools for appropriate prescribing represent

50 S44 Intern Emerg Med (2015) 10 (Suppl):S39-S44 key elements to tailor the optimal treatment in such complicated and increasingly common patients. References 1. Smith SM, Soubhi H, Fortin M et al (2012). Managing patients with multimorbidity: systematic review of interventions in primary care and community settings. BMJ 345:e Banerjee S (2015). Multimorbidity--older adults need health care that can count past one. Lancet 385: Carlson JE (1996). Perils of polypharmacy: 10 steps to prudent prescribing. Geriatrics 51: Violan C, Foguet-Boreu Q, Flores-Mateo G et al (2014). Prevalence, determinants and patterns of multimorbidity in primary care: a systematic review of observational studies. PLoS One 9:e Barnett K, Mercer SW, Norbury M et al (2012). Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 380: Hilmer SN, McLachlan AJ, Le Couteur DG (2007). Clinical pharmacology in the geriatric patient. Fundam Clin Pharmacol 21: McLean AJ, Le Couteur DG (2004). Aging biology and geriatric clinical pharmacology. Pharmacol Rev 56: Onder G, Pedone C, Landi F et al (2002). Adverse drug reactions as cause of hospital admissions: results from the Italian Group of Pharmacoepidemiology in the Elderly (GIFA). J Am Geriatr Soc 50: Williams A, Manias E, Walker R (2008). Interventions to improve medication adherence in people with multiple chronic conditions: a systematic review. J Adv Nurs 63: Davis MP, Srivastava M (2003). Demographics, assessment and management of pain in the elderly. Drugs Aging 20: Hadjistavropoulos T, Herr K, Turk DC et al (2007). An interdisciplinary expert consensus statement on assessment of pain in older persons. Clin J Pain 23:S Shi S, Klotz U (2007). Age-related changes in pharmacokinetics. Curr Drug Metab 12: Mangoni AA, Jackson SH (2004). Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol 57: Beers MH, Ouslander JG, Rollingher I et al (1991). Explicit criteria for determining inappropriate medication use in nursing home residents. UCLA Division of Geriatric Medicine. Arch Intern Med 151: McLeod PJ, Huang AR, Tamblyn RM, DC Gayton (1997). Defining inappropriate practices in prescribing for elderly people: a national consensus panel. CMAJ 156: Gallagher P, Ryan C, Byrne S et al (2008). STOPP (Screening Tool of Older Person s Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation. Int J Clin Pharmacol Ther 46: Verdoorn S, Kwint HF, Faber A et al (2015). Majority of drug-related problems identified during medication review are not associated with STOPP/START criteria. Eur J Clin Pharmacol 2015:7 18. Wilcox CM, Cryer B, Triadafilopoulos G (2005). Patterns of use and public perception of over-the-counter pain relievers: focus on nonsteroidal antiinflammatory drugs. J Rheumatol 32: Graham GG, Davies MJ, Day RO et al (2013). The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology 21: Nassini R, Materazzi S, Andre E et al (2010). Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents. Faseb J 24: Andersson DA, Gentry C, Alenmyr L et al (2011). TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid delta(9)-tetrahydrocannabiorcol. Nat Commun 2: Roberts E, Delgado Nunes V, Buckner S et al (2015). Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis Mar 2. pii: annrheumdis Manchikanti L, Abdi S, Atluri S et al (2012). American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2--guidance. Pain Physician 15:S Kalso E, Edwards JE, Moore RA, McQuay HJ (2004). Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 112: Deyo RA, Von Korff M, Duhrkoop D (2015). Opioids for low back pain. BMJ 350:g Meara AS, Simon LS (2013). Advice from professional societies: appropriate use of NSAIDs. Pain Med 14 Suppl 1:S Friis S, Riis AH, Erichsen R et al (2015). Low-dose aspirin or nonsteroidal anti-inflammatory drug use and colorectal cancer risk: a population-based, case-control study. Ann Intern Med 163:347-55

51 Intern Emerg Med (2015) 10 (Suppl):S45-S54 SELECTED PAPERS Metabolic syndrome and organ damage Metabolic syndrome and organ damage: NAFLD Silvia Fargion Giuseppina Pisano Anna Ludovica Fracanzani SIMI 2015 Abstract Nonalcoholic fatty liver disease (NAFLD), considered the hepatic manifestation of the metabolic syndrome, represents an emerging public health problem worldwide, has reached epidemic proportions and is the most common chronic liver disease in western countries. The histological spectrum of NAFLD includes fatty liver without hepatocellular injury, steatohepatitis (NASH) with or without fibrosis, cirrhosis, and hepatocellular carcinoma. Population studies indicate that in western countries the prevalence of NAFLD is 25-30% and of NASH 5-8%. These values markedly increase in at risk populations such as obese and diabetic reaching prevalence of 90% for pure fatty liver and 35-40% for NASH. NAFLD has rapidly become the leading cause of chronic liver diseases also in children and as expected, is strictly associated to metabolic syndrome and cardiovascular disease. Accumulation of fat in the liver is the typical finding of steatosis and represents an ectopic deposition of fat. The primary underlying problems in NAFLD include an oversupply of free fatty acids, as a result of either too much lipolysis in adipose tissue or an excessive supply of carbohydrate promoting the de novo lipogenesis. Insulin resistance plays a central role in this process by allowing an excessive flow of fatty acids from adipose tissue and also by impairing peripheral glucose disposal. In addition, in insulin resistance states, mainly in expanded visceral adipose tissue, several cytokines, secreted S. Fargion ( ) Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, U.O.C. Medicina Interna ad Indirizzo Metabolico, Università degli Studi di Milano, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Via Francesco Sforza 35 (Padiglione Granelli), Milano, Italy. silvia.fargion@unimi.it G. Pisano A.L. Fracanzani Metabolic Internal Medicine, IRCCS Ca Granda Ospedale Maggiore Policlinico Foundation, Department of Transplants and Medical-Surgical Pathophysiology, University of Milan, Italy. by the adipocytes or by the inflammatory cells infiltrating the adipose tissue, promote the progression to steatohepatitis. Interestingly, recent data indicate that the gut liver axis plays a central role in the pathogenesis of obesity and NAFLD, mainly through the crosstalk of the intestinal microbiota with the host immune system modulating, inflammation, insulin resistance, and intestinal permeability. Usually fatty liver is diagnosed incidentally by ultrasonography, or for the alterations of liver enzymes, even if a large number of patients with NAFLD have normal ALT levels. In the presence of steatosis competing etiologies such as heavy alcohol assumption, medications such as tamoxifen and amiodarone, HCV chronic hepatitis, especially genotype 3, and Wilson s disease have to be ruled out. Once steatosis is diagnosed, a major problem is the identification of factors able to predict who is at risk of developing or already has NASH. Till now there is no certain test and/or variable able to foresee who will develop NASH and only liver biopsy is able to diagnose an already present NASH. Patients with simple steatosis are thought to have benign prognosis, whereas those with NASH may develop progressive liver disease. Non invasive diagnosis of liver fibrosis in NAFLD is one of the most rapidly evolving field in the last years given that the presence of fibrosis may change the prognosis of the patients and methods to noninvasively diagnose hepatic fibrosis have been developed including serum marker panels and mechanical measures of liver stiffness. In the last few years, data arising from genome-wide studies (GWAS) identified single nucleotide polymorphisms (SNPs) encoding for the I148M sequence variant of Patatin-like phospholipase domain-containing protein 3 (PNPLA3 or adiponutrin), to be strongly associated with NAFLD and its severity and with the risk of hepatocellular carcinoma (HCC). Over the last two decades there has been considerable growth in the literature evaluating the association between NASH, cryptogenic cirrhosis and HCC and it has been reported an incidence of HCC in NASH of 2.6%/year. The number

52 S46 Intern Emerg Med (2015) 10 (Suppl):S45-S54 of patients undergoing orthotopic liver transplantation for HCC secondary to NASH increased by nearly four-fold from 2002 to 2012, more than any other indication for orthotopic liver transplantation for HCC arising in patients with other etiologies. To date, there are no established treatment guidelines and no single approved therapy for NAFLD. The focus of NAFLD management is to ameliorate the NASH risk factors (i.e. insulin resistance and obesity), with the objective of preventing disease progression or regression of an already established fatty liver or NASH. The recommended first-line therapy is non-pharmacological with changes in lifestyle including weight reduction through diet, and physical exercise. Promising drugs are glitazones, which strongly improve adipose tissue insulin resistance, and PPAR-α e -δ receptor agonist and obeticholic acid, but results of the studies are still too preliminary. In conclusion, NAFLD represents an emerging public health problem worldwide. The identification of predictive factors associated with severe liver damage and of new therapeutic strategies will be the future goals of clinical and basic research. Riassunto La steatosi epatica non alcolica (NAFLD) rappresenta la più frequente epatopatia cronica nel mondo occidentale, ha raggiunto proporzioni epidemiche ed è considerata la manifestazione epatica della sindrome metabolica. La NAFLD è associata a un aumentata mortalità per patologie cardiovascolari, neoplastiche ed epatiche. La NAFLD comprende uno spettro di differenti quadri istologici, dalla semplice steatosi alla steatoepatite (NASH), con o senza fibrosi, che può evolvere a cirrosi ed epatocarcinoma. La prevalenza della NAFLD, valutata negli studi di popolazione mediante ultrasonografia, varia tra il 25-30% e raggiunge il 70% nei pazienti diabetici e il 91% negli obesi, mentre la prevalenza della NASH nella popolazione generale, diagnosticata mediante biopsia epatica, è del 5-8%. La NAFLD rappresenta un problema emergente anche nella popolazione pediatrica, essendo associata a obesità e sindrome metabolica e rappresentando la principale causa di epatopatia nei bambini e adolescenti dei Paesi occidentali. L insulino-resistenza svolge un ruolo chiave nell eziopatogenesi della NAFLD determinando un eccessivo flusso di acidi grassi liberi dal tessuto adiposo al fegato sia per elevata lipolisi che per de novo lipogenesi da aumentata disponibilità di carboidrati. La presenza di acidi grassi liberi e loro metaboliti causa danno epatico. Inoltre l iperglicemia e l iperinsulinemia determinano la disregolazione della secrezione di fattori di crescita tissutali (favorenti la fibrosi), di adipochine e citochine (promotori dell infiammazione), alla cui produzione partecipa anche il tessuto adiposo viscerale espanso. La steatosi epatica è di solito diagnosticata con ecografia o in seguito al riscontro dell incremento delle ALT, seppure un elevato numero di pazienti con NAFLD abbia le ALT nella norma. Ancora non risolta è l identificazione di fattori predittori di sviluppo di infiammazione e fibrosi che sono segno di evoluzione sfavorevole della steatosi, sebbene si ritenga che età, presenza di diabete/severa insulino-resistenza e manifestazioni multiple di sindrome metabolica siano fattori di rischio per NASH. Ad oggi la diagnosi di certezza di NASH è solo istologica. Negli ultimi anni i dati ottenuti dall analisi genetica genome-wide (GWAS) hanno permesso di identificare il polimorfismo I148M (sequence variant of Patatin-like phospholipase domain-containing protein 3) come il fattore genetico più fortemente associato alla steatosi. Questo polimorfismo si associa anche a una malattia epatica più severa e ad aumentato rischio di sviluppare tumore epatico, di cui fattori favorenti sono anche obesità e diabete. L epatocarcinoma, che rappresenta la seconda causa di decesso per tumore nel mondo, ha una prevalenza nella NAFLD inferiore rispetto all infezione da HBV e HCV, ma, data l elevata frequenza di steatosi epatica, diabete e sindrome metabolica nella popolazione generale, l impatto sulla sanità è enorme, documentato anche dall osservazione che l indicazione al trapianto di fegato per epatocarcinoma in NAFLD è quella che ha subìto il maggiore incremento negli ultimi anni. Sono stati segnalati anche diversi casi di epatocarcinoma insorti in pazienti con NAFLD in assenza di cirrosi. La prima linea di terapia della NAFLD, volta alla regressione della steatosi, è la modificazione dello stile di vita con presidi dietetici e attività fisica, oltre alla terapia delle complicanze extraepatiche, in quanto ad oggi non ci sono farmaci sicuramente efficaci. Recentemente sono stati proposti nuovi schemi terapeutici che prevedono l uso di glitazoni, agonisti del recettore PPAR-α e -δ, l acido obeticolico, agonista selettivo del farnesoid X receptor (FXR), che risulterebbero efficaci nella riduzione della fibrosi e dell infiammazione, ma dati conclusivi non sono ancora disponibili. In conclusione la NAFLD rappresenta un grosso problema di sanità pubblica data l elevata diffusione mondiale e il continuo aumento della sua prevalenza. L identificazione di fattori predittivi di danno epatico più severo (NASH e fibrosi) e di nuove molecole farmacologiche per il trattamento delle complicanze, rappresenteranno i futuri obiettivi della ricerca clinica e di base. Nonalcoholic fatty liver disease (NAFLD), considered the hepatic manifestation of the metabolic syndrome, represents an emerging public health problem worldwide, has reached epidemic proportions and, currently, is the most common chronic liver disease in western countries [1] being recognized as the most common cause of hepatic dysfunction in general population [2, 3]. The histological spectrum of NAFLD includes nonalcoholic fatty liver (NAFL; steatosis without hepatocellular injury), steatohepatitis [nonalcoholic steatohepatitis (NASH);

53 Intern Emerg Med (2015) 10 (Suppl):S45-S54 S47 Fig. 1 Cartoon depicting the progression from normal liver to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The possible role of the different components defining the metabolic syndrome responsible for insulin-resistance, lipotoxicity and oxidative stress is proposed. Abbreviations: FFA, free fatty acids; NAFL, nonalcoholic fatty liver; ROS, radical oxygen species. steatosis with inflammation and hepatocyte ballooning degeneration], fibrosis and ultimately cirrhosis. Patients who progress to cirrhosis, as patients with cirrhosis of other etiologies, are at risk of potentially life threatening liver-related complications such as portal hypertension, hepatic failure and hepatocellular carcinoma [4]. It is generally accepted that patients with pure steatosis without hepatocellular injury are at low risk of liver damage progression while patients with NASH are those who can develop cirrhosis and its complications (Figure 1). Thus it is evident how the identification of patients at risk of evolution to a more severe liver disease could be very useful but, unfortunately, till now the only tool to diagnose NASH is liver biopsy. Recently, data based on serial liver biopsies indicate that disease progression may also occur, even if more rarely, in patients with NAFL and 20% of patients progresses from a mild to more severe fibrosis during the course of the years [4]. Epidemiology Considering the continuous increase in the prevalence of obesity and diabetes in western countries it is not surprising that NAFLD affects about 25-30% of the general population with a prevalence of NASH of 5-8%. These values markedly increase in at risk populations such as obese and diabetic patients and in subjects who conduct a sedentary lifestyle, with a prevalence, for example, in obese subjects estimated to be for NAFLD of 91%, NASH of 37%, and unsuspected cirrhosis of 1.7% [5]. It is estimated that at least half of all patients with type 2 diabetes mellitus have NAFLD [6], and NAFLD diagnosed by ultrasound, or raised ALT or GGT, appears to be an independent risk factor for the development of type 2 diabetes mellitus. In addition, it is generally accepted that the presence of diabetes or a very severe insulin-resistance markedly increases the risk of having NASH and fibrosis [7]. Nevertheless still a large number of physicians who take care of diabetic patients do not submit their patients to blood liver function tests and liver ultrasonography. The problem of NAFLD is emerging also in pediatric populations. In fact NAFLD has rapidly become the leading cause of chronic liver diseases in children and as expected, is strictly associated to metabolic syndrome and cardiovascular disease. Given the difficulties in performing liver biopsies in children, the need for non-invasive tools to diagnose NASH is very strong. Adequate diagnostic and

54 S48 Intern Emerg Med (2015) 10 (Suppl):S45-S54 therapeutic management could prevent and counteract progression of pediatric NAFLD [8]. However, despite the knowledge and the awareness of NAFLD is increasing, still the disease is under recognized in a large portion of patients. In a recent analysis of subjects who had criteria for the diagnosis of NAFLD (presence of obesity, diabetes, increased lipids, hypertension, i.e. the different manifestations of the metabolic syndrome), the diagnosis of NAFLD was missed in 60% of the subjects and only ALT values higher than two-fold than upper normal values addressed to a correct diagnosis. Considering that many patients with NAFLD have normal ALT values [9] it is evident how the large majority of patients with NAFLD are not diagnosed in primary care settings [10]. The burden of NAFLD in public health care and in the different country economies is further documented by the evidence that liver transplantations for NAFLD is markedly increasing and the increment of liver transplantation for hepatocellular carcinoma (HCC) arising in NASH is markedly higher than that of transplantations due to HCC occurring in cirrhosis of other etiologies. Insulin-resistance and liver damage Accumulation of fat in the liver is the typical finding of steatosis representing an ectopic deposition of fat. The primary underlying problems in NAFLD include an oversupply of free fatty acids (FFAs), as a result of either too much lipolysis in adipose tissue sending fatty acids to the liver or an excessive supply of carbohydrate promoting the formation of new fatty acids in the liver via de novo lipogenesis (DNL) [11]. Insulin-resistance plays a central role in this process by allowing an excessive flow of fatty acids from adipose tissue and also by impairing peripheral glucose disposal. Supply processes include inappropriate lipolysis by insulin resistant adipocytes and increased carbohydrate precursors for DNL, secondary to peripheral and hepatic insulin-resistance. Metabolites of free fatty acids cause lipotoxic hepatocellular injury manifested as endoplasmic reticulum stress, inflammation, apoptosis, necrosis, and dysmorphic feature [12, 13]. Furthermore, hyperglycemia and hyperinsulinemia can cause an up-regulation of the connective tissue growth factor, thus promoting fibrogenesis. Other key players in the progression to steatohepatitis are the adipokines (adiponectin, leptin, and resistin) and several cytokines (such as TNF-a, IL-6 and IL-1) secreted by the adipocytes or by the inflammatory cells that infiltrate the adipose tissue in insulin-resistance states. Expanded visceral adipose tissue common in insulin-resistance states represents a preferential source of adipokines and cytokines potentially acting in the liver tissue [14]. Interestingly, recent data indicate that the gut-liver axis plays a central role in the pathogenesis of obesity and NAFLD, mainly through the crosstalk of the intestinal microbiota with the host immune system modulating, inflammation, insulin-resistance, and intestinal permeability [15]. Clues to the diagnosis of NAFLD The finding of elevated aminotransferase levels or an incidental discovery of liver steatosis during an ultrasonography performed for different reasons, are usually the first clues to suspect NAFLD. In the presence of steatosis competing etiologies such as heavy alcohol assumption, medications such as tamoxifen and amiodarone, viral hepatitis, especially genotype 3 and Wilson s disease have to be ruled out as well as the possible coexistence of other liver diseases has not to be ignored. As regarding ALT it is necessary to remember that the majority of patients with liver steatosis have ALT within normal values. A large study of Italian blood donors that excluded everyone with risk factors for the metabolic syndrome established that the upper reference range of ALT for women should be 19 IU/L and that for men should be 30 IU/L [16] in order to be able to rule out the presence of NAFLD. Given that NAFLD is the hepatic manifestation of metabolic syndrome, a simple way could be to suspect it in patients with the comorbidities typically defining the metabolic syndrome. Conditions that should be considered either to suspect NAFLD or, once diagnosed NAFLD, to prevent possible extrahepatic complications are overweight/obesity, type 2 diabetes, hypertension, dyslipidemia and other features of insulin-resistance such as polycystic ovary syndrome and obstructive sleep apnea. However worth noting is that overweight and obesity are not absolute prerequisites for the development of NAFLD including NASH since a small percentage of patients with a normal body mass index may develop the disease. Centripetal rather than peripheral obesity is the major risk factor, and some patients with a normal body mass index may actually be centripetally obese with increased visceral fat stores that predispose them to NASH and the other components of the metabolic syndrome. Thus, evaluation of visceral fat is necessary even in the presence of normal weight and the measure of waist circumference seems to be a better parameter than body mass index (BMI) and design a new category of apparently lean patients at risk of all complications of metabolic syndrome. In other words subjects with NAFLD are not all obese but all tend to have visceral fat accumulation and ectopic fat in other organs. Visceral and ectopic fat are increased in subjects with low expandability of subcutaneous fat and in those with large adipocytes that are not only hypertrophic, but also resistant to the anti lipolytic effect of insulin, resulting in

55 Intern Emerg Med (2015) 10 (Suppl):S45-S54 S49 fatty acid overflow, inflammatory processes and eventually, adipocyte necrosis. Once identified the presence of liver steatosis, a major problem is the identification of factors able to predict who is at risk of developing NASH or who already has NASH. Till now there is no certain test and/or variable able to foresee who will develop NASH and only liver biopsy is able to diagnose an already present NASH. Non-invasive diagnosis of NASH and fibrosis Patients with simple steatosis are thought to have benign prognosis, whereas those with NASH may develop progressive liver disease. For the diagnosis of steatosis, abdominal ultrasonography has been shown to have a sufficient degree of diagnostic accuracy. NASH can be differentiated from simple steatosis, as already mentioned, only by liver biopsy and is diagnosed when all of the following three criteria are met: 1. macrovesicular fatty change of hepatocytes, 2. inflammatory cell infiltration, 3. ballooning degeneration of hepatocytes [17]. However, liver biopsy is invasive, has drawbacks such as sampling error and cost and it is not possible to biopsy the huge number of patients with NAFLD. Various parameters of oxidative stress, inflammation, apoptosis, and fibrosis have been suggested to be useful for the non invasive diagnosis of NASH, one of the more promising is the cytokeratine 18 but conclusive data are still missing [18]. In recent years non invasive diagnosis of liver fibrosis in NAFLD is one of the most rapidly evolving field given that the presence of fibrosis may change the prognosis of the patients [19]. Methods to non invasively diagnose hepatic fibrosis have been developed including serum marker panels and mechanical measures of liver stiffness, both of which have been correlated with hepatic fibrosis. Among scores which quantify fibrosis, BARD (AST/ALT ratio 0.8; BMI 28; presence of diabetes), APRI [(AST (U/L)/upper normal limit of AST/platelet count ( 10 9 /L)) 100], NAFLD fibrosis score [ age (years) BMI (kg/m 2 ) IFG/diabetes (yes = 1, no = 0) AST/ ALT ratio platelet ( 10 9 /L) albumin (g/ dl)], FIB-4 [age (year) AST (IU/L)]/[platelet ( 10 9 /L) ALT (IU/L)] and Fibro Test (age, sex, bilirubin, GGT, apolipoprotein A1, haptoglobin, α2-macroglobulin), have been shown to predict liver-related and overall mortality in NAFLD [20-24]. Transient elastography (Fibroscan) is considered excellent at excluding advanced fibrosis and cirrhosis but its limitation is acquisition failure or unreliable readings related to obesity, which occurs in one quarter of patients with NAFLD. For the diagnosis of NASH despite different attempts to establish algorithms still those proposed need to be validated in large cohorts of patients including the NAFIC score [25], which comprises three variables, ferritin, fasting insulin, and type 4 collagen 7S. and at the moment is one of the more promising. Liver biopsies should be considered if NAFLD patients are suspected to have NASH or to be at risk of cirrhosis. The most accepted criteria to perform biopsy include abnormal ALT levels for more than 6 month in spite of undergoing diet change and exercise therapy, although it is impossible to rule out the presence of NASH in patients with ALT within normal values. Older age, obesity, severe insulin-resistance or diabetes, increased ferritin, present in about one third of the patients, and the presence of multiple manifestations of the metabolic syndrome are the main risk factors associated with NASH. The more accepted risk factors for the evolution from simple steatosis to NASH are shown in Table 1. Genetic predisposition to have steatosis and a progressive disease In the last few years, data arising from genome-wide (GWAS) identified single nucleotide polymorphisms (SNPs) encoding for the I148M sequence variant of Patatin-like phospholipase domain-containing protein 3 (PNPLA3 or adiponutrin), to be strongly associated with NAFLD and its severity. The 148M allele causes a critical aminoacidic substitution next to the catalytic domain, reducing the access of substrates and reducing the PNPLA3 enzymatic activity towards glycerolipids, favouring the development of macrovesicular steatosis, partly mediated by very low density lipoprotein retention. The rs CG SNP remains the most validated risk gene in this setting [26-28]. Several studies confirmed that the I148M polymorphism of PNPLA3 genotype is one of the strongest variables associated with NASH occurrence and progression to HCC in patients with NAFLD [29] in various populations throughout the world. Recently exome-wide association studies identified the rs C>T genetic variant of the transmembrane 6 superfamily member 2 (TM6SF2) gene, which encodes the E167K aminoacidic substitution, as a determinant of hepatic tryglicerides content, serum aminotransferases, and lower serum lipoproteins. A polymorphism of TMS6 which regulates lipid metabolism has been reported to be strongly associated with severity of liver damage in patients with steatosis and at the same time to protect from vascular damage [30]. Several other SNPs associated with NAFLD progression have been reported including neurocan, lysophospholipase-like 1, glucokinase regulatory protein, protein phosphatase 1 regulatory subunit 3b, and apolipoprotein C3.

56 S50 Intern Emerg Med (2015) 10 (Suppl):S45-S54 Table 1 Risk factors for evolution of nonalcoholic fatty liver disease (NAFLD). Risk factors Age Metabolic syndrome Gender Ethnicity Diet Obstructive sleep apnoea Indices Waist circumference: 94 cm for men and 80 cm for women (ethnicity specific measurements) Fasting glucose >100 mg/dl or on treatment Tryglicerides >150 mg/dl or on treatment HDL cholesterol <40 mg/dl for men and <50 mg/dl for women or on treatment Blood pressure >135/85 mmhg or on treatment High cholesterol and saturated fats High fructose intake Moderate/low quantity of alcohol consumption Berlin questionnaire (BQ) Sleepness Epworth Scale (ESS) Apnoea/hypopnea index (AHI) by polysomnography Increased risk with age Independent predictors for fibrosis Women are at risk of advanced fibrosis High risk in Hispanic Increased risk of fibrosis Increased risk of hepatic fibrosis Genetic factors PNPLA3 I148M polymorphism Associated with more severe liver disease and risk of hepatocellular carcinoma Hepatocellular carcinoma (HCC) Liver cancer represents a major health problem, being the second leading-cause of cancer death worldwide [31]. The predominant risk factor for HCC is cirrhosis, regardless of the underlying liver disease. Despite the burden of HCC due to hepatitis B virus (HBV), hepatitis C virus (HCV) and alcoholic cirrhosis, over the last two decades there has been considerable growth in the literature evaluating the association between NAFLD, NASH or cryptogenic cirrhosis and HCC [32]. In a French retrospective analysis, HCC was detected in 27% of obese patients with cryptogenic cirrhosis versus 21% in cirrhotic patients with viral hepatitis C [33]. The incidence of HCC was estimated at 3-8%/year and 3-5%/year for hepatitis B and hepatitis C cirrhosis, respectively, and that of NASH at about 2.6%/year [34]. HCC associated with NAFLD accounted for 35% of cases in an English referral liver unit in 2010, representing a >10 fold increase from 2000 [35]. The number of patients undergoing orthotopic liver transplantation for HCC secondary to NASH increased by nearly four-fold from 2002 to 2012, more than any other indication for orthotopic liver transplantation for HCC arising in patients with other etiologies [36]. Risk factors for HCC in NAFLD/NASH It is known that obesity [37] and type 2 diabetes mellitus are both risk factors for HCC, thus given their association with NAFLD it is not surprising the high risk of HCC development in these patients. The risk of HCC development resulted increased not only in obese but also in overweight subjects [38] and there are several reports on the association between HCC and type 2 diabetes mellitus, including evidence from population-based studies and meta-analyses. The hazard ratio for HCC development in diabetics ranges from 2 to 3, and type 2 diabetes mellitus caused a 1.73-fold enhancement in HCC development in HCV related cirrhosis with the highest risk in poor compensated subjects [39]. In addition, type 2 diabetes mellitus has been found associated with the presence of metastasis spread at HCC diagnosis [40]. An association between metabolic syndrome and HCC has been documented in case series, and longitudinal studies [41] and more recently in U.S. general population [42]. Another factor which has been hypothesized to increase the risk of developing HCC is the presence of excess hepatic iron. Sorrentino et al. in a retrospective study reported iron deposition as a risk factor for HCC development in patients with NASH-related cirrhosis but confirmatory data are missing [43]. Interestingly, even small entity of alcohol intake has been reported among the factors contributing to the development of HCC in NASH [34]. Pathophysiology of HCC in NASH The exact mechanism behind the development of HCC in NASH remains unclear, although the pathophysiologic mechanisms include insulin-resistance and the subsequent inflammatory cascade which likely contributes to the carcinogenic potential of NASH. Studies in mice and humans have shown that obesity induces alterations in the intestinal microbiota that lead to production of deoxycholic acid, a bacterial metabolite that

57 Intern Emerg Med (2015) 10 (Suppl):S45-S54 S51 causes DNA damage and can promote development of HCC, by inducing a senescence-associated secretory phenotype in stellate cells. This could represent a link between overweight/ obesity, NAFLD and HCC. Also the peroxisome proliferation-activated receptors (PPARs) have been implicated in the pathogenesis of NAFLD/NASH-HCC [44]. Familial, epidemiologic and twin studies suggest that heritability plays a major role in the susceptibility towards NA- FLD and progressive forms of liver diseases associated with steatosis with possible evolution to HCC. As earlier mentioned, since 2008, when a variant in the PNPLA3 gene was found to be strongly associated with NAFLD, several studies showed that this variant was not only associated with NASH but also with an increased risk of HCC. The role of this polymorphism in HCC occurrence was confirmed not only in several cohorts of NAFLD patients but also in HCV-related cirrhosis [29, 45, 46]. Rare loss-of-function mutations in apolipoprotein B resulting in very low density lipoproteins hepatic retention and in telomerase reverse transcriptase influencing senescence have been linked to HCC in NAFLD [47]. Clinical features, prognosis and curative treatment of HCC in NASH Different reports suggest that patients with NAFLD-HCC tend to be older, with tumors diagnosed at more advanced stages, but these assumptions are not supported by strong data. In addition several data indicate that NASH patients less likely have hepatic bridging fibrosis or cirrhosis than patients with HCC occurring in other chronic liver diseases [48]. In a recent study of cohort patients with HCC, up to 13% of patients with HCC do not have underlying cirrhosis. HCC patients with NAFLD or metabolic syndrome had more than a five-fold risk of having HCC in the absence of cirrhosis compared to patients with HCV related HCC [49]. In a U.S. national cohort of 1,500 patients who developed HCC from Veterans Administration hospitals, cirrhosis was less common in NAFLD-related cases compared with alcoholic liver disease or HCV-related HCC [50]. Patients with NASH seem to have longer overall survival in agreement with other studies indicating that NAFLD/ NASH tumors are less aggressive compared with hepatitis-related HCC, but these data are still debated. HCC in NAFLD: implications for management and therapeutic options The incidence of HCC in NASH cirrhosis ranges between 2-2.6%/year [1], value above the cut-off of 1.5% suggested for the implementation of surveillance [51]. However, a significantly higher percentage of patients with NAFLD-related HCC did not receive HCC surveillance before their HCC diagnosis, compared with alcohol- or HCV-associated HCC patients. Furthermore, 62% of NAFLD-related HCC patients received HCC-specific treatment in comparison with 78% (p<0.01) of HCV-related HCC patients [50]. The fact that fewer patients with NAFLD-related HCC are enrolled in a surveillance program might be explained by the fact that: 1. many of these patients do not have cirrhosis, the stage which sets the implementation of surveillance, 2. ultrasonography, the more used screening test to detect HCC, can be difficult in overweight/obese patients NAFLD, 3. discovery of HCC may not be a priority because of co-morbidities or advanced age. Thus, since many patients with NAFLD develop HCC before reaching a cirrhotic stage, it is necessary to be able to identify patients at risk but at the moment defined risk factors for HCC have not been defined, except the PNPLA3 polymorphisms. The therapeutic options for patients with HCC in NAFLD are the same as those for patients with other underlying liver disease [52] as no evidence suggests that they should be treated differently. However resection could be more frequently considered since these patients are often not cirrhotic. Comorbidities have to be taken into account, particularly cardiovascular disease (CVD), and it has also to be considered that the presence of steatosis negatively impacts liver regeneration. In terms of prevention, several studies have suggested that metformin lowers the risk of HCC in patients with type 2 diabetes [53]. A nation-wide, case-control Taiwanese study including almost 300,000 individuals found a dose-dependent reduction in HCC risk in diabetics assuming metformin. In addition, it has to be remembered that the presence of NAFLD/NASH interacts with other etiologic factors of different liver diseases to increase the risk of HCC. Also statins have been reported to significantly decrease the risk of HCC in diabetic patients, possibly due to their anti-inflammatory properties [54]. Therapy To date, there are no established treatment guidelines and no single approved therapy for NAFLD. The different drugs proposed are listed in Table 2. The focus of NAFLD management is to ameliorate the NASH risk factors (i.e., insulin-resistance and obesity), with the objective of preventing disease progression or regression of an already established fatty liver or NASH. The recommended first-line therapy is non-pharmacological with changes in lifestyle including weight reduction

58 S52 Intern Emerg Med (2015) 10 (Suppl):S45-S54 Table 2 Drugs proposed for therapy of nonalcoholic steatohepatitis (NASH). Benefit Agent Action Primary therapy: life style modification (weight reduction and physical activity) Potential benefit Pioglitazone Vitamin E Ameliorates insulin-resistance and promotes fatty acid uptake peripherally Prevention of the non enzymatic oxidation of cell constituents by free radicals No clear benefit Ongoing trial Metformin Statin UDCA PUFAs Angiotensin receptor blockers Pentoxyfylline GS-9450 GFT-505 Obeticholic acid Cenicriviroc Liraglutide Sitagliptin GS-6624 (simtuzumab) Reduces insulin-resistance Treats dyslipidemia Prevents apoptosis and down regulates inflammatory pathways Reduce liver fat content Promote survival of hepatic myofibroblasts, with improvements in necroinflammation Reduces production of oxygen-free radicals Prevents apoptosis by caspase inhibition Dual PPAR-α/-δ agonist (improves hepatic glucose utilization, anti-inflammatory effects) FXR agonist (promotes insulin-sensitivity) CCR2/CCR5 antagonist (interferes with recruitment of monocyte macrophages) GLP-1 agonist (induces insulin secretion) DPP-IV inhibitor (prevents degradation GLP-1) Anti-LOXL-2 antibody (interferes with extracellular matrix) Abbreviations: CCR, chemokine receptors; DPP-IV, dipeptidyl peptidase-iv; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; LOXL-2, lysyl oxidase-like 2; PPAR, peroxisome proliferator-activated receptor; PUFAs, polyunsaturated fatty acids; UDCA, ursodeoxycholate. through diet, physical exercise and limiting sedentarity. Interestingly, evidence has been reported that physical exercise leads not only to reduction of hepatic and visceral fat but also to improvement of liver histology [55]. Worth noting that among the diet factors recognized to be highly toxic for the liver is the use of drinks rich in fructose. Additionally, concurrent metabolic disorders such as type 2 diabetes mellitus, hyperlipidemia, or arterial hypertension, when present, should be well controlled. In patients who failed these measures or in those with advanced disease (NASH with significant fibrosis), pharmacological treatments specifically directed at improving hepatic inflammation, fibrosis and/or clearing steatohepatitis might be necessary [56]. Since contradictory results have often been obtained with the same drug, there is an urgent need for well-conducted, randomized controlled trials [57]. Given that the main source of free fatty acids reaching the liver is an uncontrolled release from insulin-resistant adipose tissue, correction of IR, in particular at adipose level, is a relevant aim and most therapeutic trials have focused on insulin sensitizers. An ideal candidate to improve insulin sensitivity in NAFLD is metformin but only small studies are available with inconsistent results. Promising drugs are glitazones which strongly improve adipose tissue insulin-resistance followed by reduction in steatosis and necroinflammation. However, the long-term safety and benefit is unknown and it should be used with caution in patients with impaired cardiac function, given that these drugs have as side effects weight gain and water retention [58]. Among new drugs obeticholic acid, a bile acid with selective farnesoid X receptor (FXR) agonist capacity, able to modulate triglyceride, glucose and cholesterol homeostasis has demonstrated encouraging histological results. Fibrosis score regressed by one stage or more in 35% of patients treated with obeticholic acid versus 19% with placebo [59]. However these data need confirmation in larger trials. The most concerning side effects were pruritus and an increase in LDL cholesterol. An ongoing study, the GFT505, utilizes the dual PPAR-α and -δ agonist. PPAR-δ activation results in an increase in hepatic fatty acid β-oxidation, inhibition of hepatic lipogenesis, reduction of hepatic glucose production and improvement in hepatic inflammation. The dual PPAR-α and -δ agonist GFT505 improves hepatic and peripheral insulin sensitivity, dyslipidemia, inflammatory markers and liver function tests in abdominally obese, insulin resistant patients [60]. In a few months results of the GFT505 trial should be disclosed. A different approach to the therapy of NASH is the use of Vitamin E which is an antioxidant and has been demonstrated to have beneficial effects on liver histology in non-diabetic patients with NAFLD but there are some concerns on its use because it has been reported to increase the risk of hemorrhagic stroke and prostate cancer. At the moment the use of Vitamin E should be restricted to patients who have not responded to lifestyle modifications and have a precirrhotic stage of NASH [61]. Also iron depletion, which possibly acts as antioxidant, has been proposed in patients with NAFLD, with evidence of reduction of insulin-resistance and improvement of liver histology. However confirmatory data in large cohorts of patients are needed [62]. It has been reported that ursodeoxycholate (UDCA), a hydrophilic bile acid, improves liver enzymes and decreases

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61 Intern Emerg Med (2015) 10 (Suppl):S55-S64 SELECTED PAPERS Metabolic syndrome and organ damage Metabolic syndrome and cardiovascular organ damage Giuseppe Schillaci Francesca Battista Fabio Anastasio Mariano Crapa Yahya Alrashdi Giacomo Pucci SIMI 2015 Abstract The metabolic syndrome (MetS), a cluster of cardiovascular risk factors closely linked to insulin resistance whose prevalence is high and rapidly rising in the western population, has been recognized as a predictor of diabetes and future cardiovascular disease in the general population, as well as in various clinical settings. There is evidence that the MetS increases cardiovascular risk, independently from the concomitant effect of several traditional cardiovascular risk factors. Emerging data suggest that MetS might also be a risk factor for chronic kidney disease, although its effects on chronic kidney disease emergence or progression beyond the contribution of dysglycemia and high blood pressure are far from being established with certainty. The concept of the MetS has been a topic of lively discussion, given its controversial pathogenesis and clinical usefulness, and several important conceptual and practical drawbacks in its definition questions its utility as a risk stratification tool. Nevertheless, the definition of MetS has gained wide popularity in the clinical arena as a simple, practical tool for identifying those subjects in whom the presence of multiple metabolic risk factors associated with insulin resistance imparts an increased cardiovascular risk which is not adequately considered by the traditional cardiovascular risk factors. Identification of the MetS may help clinicians to move away from a strategy based on single risk factors to one that focuses on multiple risk factors and may increase G. Schillaci ( ) Dipartimento di Medicina, Università degli Studi di Perugia, Struttura Complessa di Medicina Interna, Azienda Ospedaliero-Universitaria di Terni, Piazzale Tristano di Joannuccio 1, Terni, Italy. giuseppe.schillaci@unipg.it F. Battista F. Anastasio M. Crapa Y. Alrashdi G. Pucci Department of Internal Medicine, University of Perugia, Unit of Internal Medicine, Azienda Ospedaliero-Universitaria of Terni, Italy. the awareness of both physicians and patients regarding the cardiovascular importance of targeting metabolic risk factors through weight reduction and exercise. Riassunto Alcuni fattori di rischio cardiovascolare lipidici e non lipidici tendono ad associarsi nello stesso paziente con una frequenza maggiore rispetto a quella attesa sulla base dei dati epidemiologici. Numerose definizioni sono state proposte per questa costellazione di fattori, e tra essi il termine sindrome metabolica è quello che ha riscontrato il maggiore successo presso la comunità scientifica. Nonostante numerose ed autorevoli voci scettiche circa la consistenza, l omogeneità e la stessa esistenza di una sindrome metabolica, il raggruppare in un unica definizione i fattori di rischio metabolici aggiuntivi rispetto a quelli già noti ha guadagnato grande favore in medicina clinica. Secondo i criteri del National Cholesterol Education Program nell Adult Treatment Panel III (ATP III), rivisti dall American Heart Association, la sindrome metabolica è definita dalla presenza di 3 o più di questi criteri: 1) livelli sierici di trigliceridi >150 mg/dl (o trattamento ipotrigliceridemizzante); 2) livelli sierici di colesterolo HDL <40 mg/ dl nei maschi e <50 mg/dl nelle femmine (o trattamento per basso colesterolo HDL); 3) glicemia a digiuno >100 mg/dl (o trattamento farmacologico); 4) circonferenza vita >102 cm nei maschi, >88 cm nelle femmine; 5) pressione arteriosa 130/85 mmhg (o trattamento antipertensivo). La sindrome metabolica è un predittore indipendente di diabete mellito e di morbilità e mortalità cardiovascolare. È stato osservato che questo dato è in parte atteso, visto che nella definizione della sindrome metabolica sono inclusi fattori di rischio cardiovascolare ben noti, quali l ipertensione arteriosa, i bassi valori di colesterolo HDL e in parte il diabete mellito stesso. Tuttavia, la sindrome metabolica costituisce un fattore di rischio cardiovascolare indipendente sia dopo aver escluso i pazienti con diabete mellito, sia in studi condotti in popolazioni composte interamente da pazienti ipertesi. Non è ancora chiarito con certezza quanto il rischio car-

62 S56 Intern Emerg Med (2015) 10 (Suppl):S55-S64 diovascolare conferito dalla sindrome metabolica sia spiegato dalle sue componenti o fino a che punto vi sia un rischio aggiuntivo conferito proprio dall associazione dei fattori di rischio. La maggioranza dei dati suggerisce che la sindrome metabolica non sia in grado di predire il rischio di mortalità e di malattie cardiovascolari meglio di quanto non facciano le sue singole componenti. Una parte del significato prognostico cardiovascolare sfavorevole della sindrome metabolica è legato al fatto che la sindrome si accompagna a una più elevata prevalenza di una serie di indicatori di danno d organo cardiovascolare preclinico la cui presenza condiziona il rischio di morbilità e mortalità vascolare: ipertrofia ventricolare sinistra, aterosclerosi carotidea, rigidità delle grandi arterie. L iperglicemia e la produzione da parte del tessuto adiposo viscerale di una serie di peptidi biologicamente attivi che hanno un influenza sulle proprietà elastiche della parete arteriosa possono costituire plausibili meccanismi di tali associazioni. Introduction The term metabolic syndrome (MetS) is commonly referred to the cluster of central obesity, dyslipidemia, impaired glucose metabolism and elevated blood pressure. The fact that all these conditions are characterized by the presence of insulin resistance has generated the hypothesis that this metabolic defect is responsible for the tendency of these elements to segregate both at the individual and at the population level. Furthermore, insulin resistance and the associated compensatory hyperinsulinemia have been shown to be also associated to a host of other abnormalities (Table 1) and are largely considered to be the major driving force for the development of the syndrome and its consequences. The MetS is supposed to have clinical relevance in that it confers an additional risk not only to develop diabetes but also, and more importantly, atherosclerotic cardiovascular diseases (CVD). Recently the MetS has also been suggested to be a powerful predictor of chronic kidney disease (CKD). The importance of MetS from the public health perspective is underlined by a recent analysis of the United States general population which shows that in the first decade of this century, despite a reduction in the prevalence of hypertension and hypertriglyceridemia due to increases in anti-hypertensive and lipid-modifying drugs, respectively, the prevalence of hyperglycemia and central obesity substantially increased, particularly in women, thus highlighting the urgency of addressing abdominal obesity as a healthcare priority [1]. In this review we will briefly discuss the mechanisms that underlie the cluster, the problems inherent to the MetS definitions and its clinical relevance as a predictor of cardiovascular organ damage. Table 1 Abnormalities associated with insulin resistance/hyperinsulinemia. Abnormal glucose metabolism Impaired fasting glucose Impaired glucose tolerance Abnormal uric acid metabolism Plasma uric acid concentration Renal uric acid clearance Dyslipidemia Triglycerides HDL cholesterol LDL particle diameter Postprandial lipemia Hemodynamic Sympathetic nervous system activity Renal sodium retention Blood pressure (about 50% of patients with hypertension are insulin resistant) Hemostatic Plasminogen activator inhibitor-1 Fibrinogen Vascular dysfunction Endothelial dysfunction Microalbuminuria Insulin resistance and the metabolic syndrome MetS is largely the consequence of an unhealthy lifestyle, although there are also specific disease conditions and drugs that predispose to its development. Quantitative and qualitative errors in food intake, bi-directionally related to both sedentary lifestyle and stress, all contribute to cause abnormal stress hormones, substrates and kinins release as well as profound tissue changes that, in interaction with the individual genetic background, cause hemodynamic and metabolic derangements which may eventually pass the thresholds for the clinical diagnosis of diabetes, hypertension and dyslipidemia [2]. Thus, insulin resistance might be regarded, rather than as a primary cause, as a sort of final common pathway for a number of negative environmental factors and participates to the development of the MetS in combination with obesity and stress hormones. In an analysis of the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study [3], insulin resistance, hyperinsulinemia and central obesity were found to be the predominant factors for the development of the syndrome, and their overall effect will result from their specific combination in any given individual. To this regard, particularly interesting is the finding that a murine model of extreme hepatic insulin resistance and hyperinsulinemia developed an abnormal lipid profile characterized by low HDL cholesterol and a high VLDL cholesterol, and also developed early and extensive atherosclerosis [4]. However, serum triglycerides were lower than in the wild type animal, and plasma glucose was similar confirming that the MetS phenotype is the result of multiple factors acting on specific targets.

63 Intern Emerg Med (2015) 10 (Suppl):S55-S64 S57 The definition of metabolic syndrome An effort has been done by major scientific bodies to generate a set of diagnostic criteria in order to uniform the definition of the syndrome. The discussion has focused both on the diagnostic thresholds and on more essential aspects such as whether insulin resistance should be included, whether obesity is a necessary element, and how many elements of the syndrome should be included and with what priority (Table 2) [5-9]. Although the debate is still open, two definitions have somewhat prevailed over the others: the one proposed by the National Cholesterol Education Program Adult Treatment Panel III (ATP III) [7, 8], and the one forwarded by the International Diabetes Federation (IDF) [6]. While there is consensus with respect to the diagnostic levels for blood pressure, for triglycerides, HDL cholesterol and glucose, the thresholds for waist are lower in the IDF definition. The waist circumference thresholds of the two most used definitions are indeed 8 cm different and this is responsible for prevalence rates according to IDF usually 150% that of ATP III. Moreover, for the IDF definition the presence of central obesity is mandatory (condicio sine qua non) while no hierarchy is present for the ATP III definition among the 5 criteria. Of note, plasma glucose threshold has been lowered by the ATP III in its 2005 release [9] (Table 3), and is now equal to that proposed by the IDF; both have adopted the 2003 American Diabetes Association definition of impaired fasting glucose [10]. Although apparently minor, this 10 mg/dl shift from the previous 110 mg/ dl has a major impact on the prevalence of the MetS since it increases by 3 to 5 fold the prevalence of dysglycemia into the adult population [11]. Finally, both definitions clearly (and unfortunately) do not adopt upper limit in the thresholds including the disease conditions (e.g. diabetes and overt hypertension), and require a minimum of 3 abnormalities. If on one hand these definitions have the quality of simplicity, on the other there are major objections that can be raised [12]. The major is inherent to the fact that there is an Table 2 Different proposed definitions of the metabolic syndrome. Required condition World Health Organization, 1998 Type 2 diabetes, impaired glucose tolerance, or insulin resistance* International Diabetes Federation, 2005 Waist 94 cm (European men), 80 cm (European women) National Cholesterol Education Program (NCEP) ATP III, 2001 NCEP ATP III modified according to AHA/NHLBI, 2005 No. of conditions + 2 of the following: + 2 of the following: 3 of the following: 3 of the following: Glucose 100 mg/dl 110 mg/dl 100 mg/dl, or drug treatment Lipids HDL cholesterol <35 mg/dl (men), <39 mg/dl (women), and/or triglycerides 150 mg/dl <40 mg/dl (men), <50 mg/dl (women) <40 mg/dl (men), <50 mg/dl (women) <40 mg/dl (men), <50 mg/dl (women), or drug treatment 150 mg/dl 150 mg/dl 150 mg/dl, or drug treatment Obesity Waist/hip >0.90 (men), >0.85 (women), or BMI 30 kg/m 2 Waist 102 cm (men), 88 cm (women) Waist 102 cm (men), 88 cm (women) Blood pressure 140/90 mmhg 130/85 mmhg 130/85 mmhg 130/85 mmhg, or drug treatment Other Microalbuminuria Reference [5] [6] [7, 8] [9] * Under hyperinsulinemic euglycemic conditions, glucose uptake below lowest quartile for background population under investigation. Abbreviation: AHA/NHLBI, American Heart Association/National Heart, Lung, and Blood Institute; BMI, body mass index. Table 3 Definition of the metabolic syndrome according to the National Cholesterol Education Program (NCEP) ATP III, modified according to American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) (2005) [8]. Measure (any 3 of 5 constitute diagnosis Categorical cutpoints of metabolic syndrome) Elevated waist circumference* 102 cm in men, 88 cm in women Elevated triglycerides 150 mg/dl or on drug treatment for elevated triglycerides Reduced HDL cholesterol <40 mg/dl in men, <50 mg/dl in women or on drug treatment for reduced HDL cholesterol Elevated blood pressure 130/85 mmhg or on antihypertensive drug treatment Elevated fasting glucose 100 mg/dl or on drug treatment for elevated glucose * To measure waist circumference, locate top of right iliac crest. Place a measuring tape in a horizontal plane around abdomen at level of iliac crest. Before reading tape measure, ensure that tape is snug but does not compress the skin and is parallel to floor. Measurement is made at the end of a normal expiration.

64 S58 Intern Emerg Med (2015) 10 (Suppl):S55-S64 uncontrolled overlap between disease states and metabolic syndrome. Therefore, a diabetic with severe hypertension and hypoalphalipoproteinemia is equal to a prehypertensive subjects with impaired fasting glucose and a waist of 103 cm. This is of particular relevance if we are dealing with cardiovascular disease prevention. In this respect, given the well established relevance of diabetes and hypertension and also their large prevalence in the population, at least these two conditions should be excluded from the MetS or at least used in a different manner. The impact of the MetS, thus, should be evaluated in homogeneous groups of individuals with respect to the presence of diabetes and/or hypertension. Alternatively, the MetS should not be treated only as a dummy variable (present or absent) but graduated in order to convey also the information related to how much its elements are deviated from normality. This concept has been formally addressed [13] and a MetS score can easily be generated by using simple tables based on the result of principal component analysis. Metabolic syndrome and cardiovascular disease MetS is a predictor of the future occurrence of CVD. A meta-analysis of the impact of the MetS on CVD risk has provided an odds ratio of about 1.7 but with a significant (p<0.001) heterogeneity (with values ranging from 1.1 to 4.0) [14]. A source of this variability is related to the presence of diabetes. In fact, when diabetics are carefully excluded, the estimates are reduced by approximately 50% becoming of borderline significance and, depending on the different end points, single elements (HDL for coronary heart disease, hypertension for cardiovascular disease and glucose for all cause mortality) show the same predictive power of full-blown MetS [15]. It has also been suggested that the greater prevalence of MetS in the United States may significantly contribute to the explanation of excess CVD mortality in the United States compared with Japan [16]. The studies that have formally verified whether the MetS, or any combination of three MetS elements, confers a risk greater than what is carried by the sum of the elements have failed [17]. It is still possible that in some specific and more homogeneous populations the MetS might result an independent risk factor. Such a suggestion emerges from a recent study where the MetS resulted a significant CVD predictor only in subjects at lower cardiovascular risk [18]. It has also been suggested that MetS could be a stronger predictor of cardiovascular disease and death among women, who are generally at lower cardiovascular risk than in men [19]. In contrast, in a large prospective study on type 2 diabetics [20], the MetS did not result a significant risk factor for events essentially because the presence of any one element of the MetS was already associated with a higher CV death incidence (with respect to having none) and by adding up other elements no further increase in the risk was observed. An explanation of the poor performance of the MetS in diabetics, and more in general in high risk populations, is related to the fact that atherosclerosis is a slow process that starts early and eventually manifests itself with events that in turn are promoted by factors (e.g. blood pressure gradients, platelet function, LDL cholesterol, cigarette smoking, matrix degradation) not necessarily linked to plaque growth. Interestingly, when atherosclerosis is estimated through surrogate indices (electrocardiography, echocardiography, carotid ultrasound, ankle-brachial blood pressure, and urinary albumin excretion) its prevalence in subjects with the MetS (but not diabetics) results intermediate between healthy subjects and diabetics [21]. We conclude that in type 2 diabetes (and probably in other high risk population) the presence of MetS have little relevance and any effort should be directed at controlling traditional CV risk factors. Type 1 diabetes does not take exception, also in this special population, in fact, MetS does not represent a more powerful tool than its single components. Microalbuminuria, dyslipidemia and blood pressure were, in this order, the elements that provided and entirely justified the predictive power of the various MetS definitions (World Health Organization, ATP III, IDF) [22]. Another critique to the studies showing an excess cardiovascular risk in MetS is that the syndrome includes in its definition high blood pressure, which is per se a strong risk factor and could thus explain in part the MetS-related cardiovascular risk. In a consecutive series of 1742 patients with essential hypertension [23], we observed that the rate of cardiovascular events during follow-up was almost double in patients with MetS (3.23 per 100 patient-years) than in the hypertensive patients without the syndrome (1.76 per 100 patient-years, p<0.001; Figure 1, left panel), and the event rate increased progressively according to the number of features of the MetS (Figure 1, right panel). After adjustment for age, sex, total cholesterol, smoking, 24-hour systolic blood pressure, serum creatinine, and left ventricular hypertrophy, the risk was still higher in patients with MetS (hazard ratio 1.73, 95% confidence interval ). MetS was an independent predictor of both cardiac and cerebrovascular events (hazard ratios 1.48 and 2.11, respectively). The adverse prognostic value of MetS was attenuated but still significant among the 1637 patients without diabetes (hazard ratio 1.43, 95% confidence interval ). These data show that MetS amplifies the hypertension-associated cardiovascular risk, independently from the effect of several traditional cardiovascular risk factors. The adverse prognostic significance of the metabolic syndrome in hypertensive subjects has been later confirmed by Pierdomenico et al. [24], and by Andreadis et al. in a Greek

65 Intern Emerg Med (2015) 10 (Suppl):S55-S64 S59 Cardiovascular event-free survival No metabolic syndrome Metabolic syndrome Log-rank = 45.4 p< Follow-up (years) # at risk Cardiovascular events / 100 patient-years Number of metabolic risck factors Fig. 1 Left, cardiovascular event-free survival curves in 1742 hypertensive patients with (black line) or without (grey line) the metabolic syndrome. Right, cardiovascular event rate among hypertensive patients grouped by number of characteristics of the metabolic syndrome [23]. hypertensive cohort [25]. This is particularly relevant if considering that the prevalence of MetS is about double among hypertensive subjects than in the general population due to the clustering of high blood pressure with other features of the MetS at the population level. In our series [23], we found that 34% fulfilled the definition of MetS according to the ATP III [7, 8], while the prevalence of MetS in the Italian adult population is about 15-18% [26, 27]. It has been argued that MetS is not a single disorder because its traditional features do not represent one entity. In an attempt to identify a MetS model that optimally predicts type 2 diabetes and CVD while still representing a single entity, the predictive ability for type 2 diabetes and CVD of several one-factor MetS models was tested using confirmatory factor analysis [28]. The standard model, representing the current MetS definition, had an acceptable model fit, and the model extended with high-sensitivity C-reactive protein predicted type 2 diabetes and CVD slightly better than did the standard model. The Author conclude that it seems appropriate to represent the traditional MetS components by a single entity, and that extension of this entity with C-reactive protein may slightly improve predictive ability for type 2 diabetes and CVD. A different approach to address the issue of the prognostic value of the MetS is offered by Gami et al. [14]. In their meta-analysis, the Authors included all prospective studies that simultaneously adjusted for MetS and other major cardiovascular risk factors, including some of the MetS components. As shown in Figure 2, an increased risk of cardiovascular disease or death was found in patients with MetS, even after controlling for its components (relative risk 1.54, 95% confidence interval ). There is also limited evidence that the prognostic impact of the MetS is partly independent from overall cardiovascular risk as expressed by the Framingham Risk Score. In a post-hoc analysis of two large trials of hypolipidemic treatment, patients with the MetS showed increased risk of major cardiovascular events irrespective of their Framingham-calculated 10-year risk score category (>20% vs 20%) [29]. Taken together, these data suggest that in patients with essential hypertension the MetS is associated with an excess (+50%) cardiovascular risk that is not entirely accounted for by traditional risk factors. Metabolic syndrome and subclinical cardiovascular organ damage In 1993, Richard B. Devereux and Michael H. Alderman developed the concept of pre-clinical CVD [30]. They suggested that CVD typically develops through two stages: the development of asymptomatic or pre-clinical anatomic and functional CVD (such as left ventricular hypertrophy, carotid atherosclerosis, arterial stiffness, and renal dysfunction) in response to risk factors and other variables, and the precipitation of morbid events by progression of preclinical disease or by the action of additional triggering mechanisms in the presence of pre-clinical disease. The concept has gained wide acceptance because most measures of pre-clinical organ damage have a closer relation than risk factors with the subsequent risk of complications, thus indicating that their detec-

66 S60 Intern Emerg Med (2015) 10 (Suppl):S55-S64 Study McNeill (ARIC) 1.62 ( ) RR (95% CI) Covariates in risk model MS Age Sex BP Lipids Glu Other X X X X X Sattar (WOSCOPS) 1.41 ( ) X X X X X X X Schillaci (PIUMA) 1.73 ( ) X X X X X X Summary 1.54 ( ) Fig. 2 Meta-analysis of the relative risk (RR) and 95% confidence intervals (CI) for metabolic syndrome and incident cardiovascular events and death. Only studies that simultaneously included into multivariable models of metabolic syndrome and some of its components were considered [14]. Abbreviations: BP, blood pressure; Glu, glucose; MS, metabolic syndrome. tion may be warranted to improve clinical risk stratification. The earlier and more extensive development of pre-clinical CV organ damage might be one of the mechanisms through which MetS might increase cardiovascular risk in hypertension. Among the markers of organ damage, left ventricular hypertrophy has a special place, not only given to its established predictive value for incident CVD [31], but also to the clear-cut evidence that treatment-induced reduction has favourable effects on cardiovascular morbidity and mortality [32]. It has been demonstrated that, compared with hypertensive subjects without the MetS, hypertensive subjects with the syndrome have a greater degree of left ventricular hypertrophy [33, 34]. In 618 nondiabetic, untreated hypertensive subjects, echocardiographically-detected left ventricular mass was significantly greater in subjects with MetS. In that study, the effect of MetS was more pronounced in women, and was partly independent from the effect of several hemodynamic and non-hemodynamic determinants of left ventricular mass, including age, body mass index, and 24-hour systolic blood pressure [34]. MetS has also been associated to subclinical atherosclerosis, identified as increased carotid intima-media thickness [35] and maladaptive carotid remodeling [36]. However, in a study carried out in patients attending a lipid clinic, MetS did not correlate with carotid intima-media thickness to a greater extent than what is expected from its component parts [37]. In a prospective analysis of 370 subjects over 60 years of age without evidence of early carotid atherosclerosis who were followed for 2 years, MetS at baseline was a significant independent predictor of newly developed carotid plaques [38], suggesting that metabolic syndrome plays an important role in initiating the atherosclerotic process. The link between the metabolic syndrome and arterial stiffness, one of the key parameters of early vascular aging, has received wide attention in the last decade. In a hypertensive population, an independent link has been established between the MetS and increased aortic stiffness [39], a major predictor of cardiovascular morbidity and mortality in hypertension [40]. These findings have been later replicated, both in hypertensive [41] and normotensive [42] individuals, and in the general population [43]. A greater impact of the MetS on arterial stiffness in the female gender has been reported in some studies [44, 45], but not in all [46]. Interestingly, MetS might be a key mediator of increased arterial stiffness in non-cardiovascular disease which have recently associated with an increased cardiovascular risk, such as systemic lupus erythematosus [47] and HIV infection [48, 49]. Several potential mechanisms can explain the association between metabolic syndrome and arterial stiffness in hypertension. The putative pathways leading from the MetS to increased large-artery stiffness are displayed in Figure 3. Metabolic syndrome and chronic kidney disease A link between MetS and CKD has been suggested in a cross-sectional analysis of the National Health and Nutrition Examination Survey III database, a sample of population representative of the whole U.S. population, in which Chen et al. [50] showed that MetS was associated with a 2.60 (95% confidence interval ) risk of chronic kidney disease as defined by an MDRD-estimated GFR less than 60 ml/min per 1.73 m 2. As expected they also observed that each and all MetS elements were significant risk factors and concluded that MetS might be an important factor in the cause of chronic kidney disease. Since the more powerful predictor of CKD

67 Intern Emerg Med (2015) 10 (Suppl):S55-S64 S61 Ageing Insulin resistance Adiposity Pro-inflammatory state Oxidative stress Leptin Insulin MMPs TIMP ET, ANG II, Nitric oxide SNS α-adrenergic tone Arterial wall remodeling Collagen Cross-linking AGEs Elastin Fragmentation Density VSMC hypertrophy Growth factors VSMC tone Arterial stiffness Fig. 3 Putative pathways leading from the metabolic syndrome and its components to the arterial structural and functional changes underlying large-artery stiffness. Abbreviations: AGEs, advanced glycation end-products; ANG II, angiotensin II; ET, endothelin; MMPs, matrix metalloproteases; SNS, sympathetic nervous system; TIMP, tissue inhibitor of MMPs; VSMC, vascular smooth muscle cells. was high blood pressure, it is not surprising that when MetS was defined as presence of 3 or more elements other than blood pressure the odds ratios almost halved (odds ratio 1.99, 95% confidence interval ). However, cross-sectional studies cannot establish cause-effect relationships, and it is possible (and also plausible) that the cause-effect relationship is opposite with CKD favoring the emergence of the MetS (at least of higher blood pressure, dysglycemia and dyslipidemia). The MetS as a risk factor for the future development of CKD has been investigated in several prospective population-based studies. Rashidi et al. [51] have reported on the Tehran Lipid and Glucose Study, in which 4607 non-diabetic adult subjects without CKD at baseline were followed for an average of 3 years. While individuals with MetS had an increased risk of developing CKD during follow-up (3.4% vs 2.0%, odds ratio 1.88, 95% confidence interval ), the risk was no longer significant when hypertensive subjects were excluded from the analysis, thus underlying the overwhelming contribution of high blood pressure to CKD risk. In a population of nondiabetic American Indians with a high prevalence of MetS (38%), MetS was associated to an increased risk for incident CKD, but again no adjustment for hypertension status was allowed in that study [52]. Interestingly, the relationship between metabolic syndrome and incident CKD was stronger in those who developed diabetes during follow-up [52], thus suggesting that a likely mechanism for MetS-associated CKD risk might be the development of diabetes during follow-up. At partial variance with these results are the conclusions from the Atherosclerosis Risk in Communities study, a large, population-based survey of over 10,000 adult nondiabetic American subjects who were followed for 9 years [53]. In this large study with a longer follow-up, the multivariable adjusted odds ratio of developing CKD in participants with MetS was 1.43 (95% confidence interval ). After adjusting for the subsequent development of diabetes and hypertension during follow-up, the excess risk of incident CKD among participants with MetS was about halved, but indeed it was still significantly increased (odds ratio 1.24, 95% confidence interval ) [53]. In a meta-analysis of 11 studies (n=30,146), MetS was significantly associated with the development of egfr <60 ml/min per 1.73 m 2 (odds ratio 1.55, 95% confidence interval ) [54]. In a prospective study carried out in 6430 healthy Taiwanese people [55], MetS was related to the incidence of CVD independent of insulin resistance, and combined effect of metabolic syndrome and insulin resistance contributed to the risk of CVD. More than the MetS as a whole, some studies suggest the possibility that obesity and dyslipidemia play a role in the development of CKD independent of hypertension and dysglycemia. The support emerges mainly from experimental studies while clinical trials are lacking. Preliminary evidence is in favor for an independent role of hypertriglyceridemia in

68 S62 Intern Emerg Med (2015) 10 (Suppl):S55-S64 the progression towards CKD [56], while with regard to CKD progression the independent role of overweight and/or obesity remains to be conclusively proven [57, 58]. Data from the Diabetes Control and Complications Trial (DCCT/EDIC) have shown that in type 1 diabetes waist circumference predicts the subsequent development of microalbuminuria but not the decline in creatinine clearance [59]. Until MetS is demonstrated to be a risk factor for CKD emergence or progression beyond the contribution of dysglycemia and high blood pressure in prospective studies, there is little novel information that can be gained by introducing this diagnosis into the clinical management of the patient with, or at risk of, CKD. Conclusions The concept of the MetS has been a topic of lively discussion, given its controversial pathogenesis and clinical usefulness, and still no consensus has been reached concerning diagnostic criteria. Although an agreed-on benefit elicited by the definition of the MetS is to emphasize the importance of the cluster of cardiovascular disease risk factors associated with insulin resistance, several important conceptual and practical drawbacks in the definition of the MetS question its utility as a risk stratification tool [12, 60]. It should also not be ignored that unwarranted consideration of MetS as a new disease entity may divert attention away from the major modifiable risk factors. Nevertheless, the definition of MetS has gained wide popularity in the clinical arena as a simple, practical tool for identifying those subjects in whom the presence of multiple metabolic risk factors imparts an increased cardiovascular risk which is not adequately considered by the traditional cardiovascular risk factors. Indeed, of the 5 features of the MetS according to the ATP III, abdominal obesity, high triglycerides, and modest elevations of blood glucose were not part of the original Framingham risk factor score. This could have some relevance also from the perspective of prevention of advanced CKD, given that it is well demonstrated that early identification and treatment of high-risk patients prevent and delay progression to dialysis. Identification of the MetS helps clinicians to move away from a strategy based on single risk factors to one that focuses on multiple risk factors and gives insight into the mechanisms by which the adipose tissue affects both insulin target tissues and vasculature, thus improving our understanding of the link between obesity and cardiovascular disease. 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70 S64 Intern Emerg Med (2015) 10 (Suppl):S55-S64 the risk for chronic kidney disease among nondiabetic adults. J Am Soc Nephrol 16: Thomas G, Sehgal AR, Kashyap SR et al (2011). Metabolic syndrome and kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 6: Yun JE, Won S, Sung J, Jee SH (2012). Impact of metabolic syndrome independent of insulin resistance on the development of cardiovascular disease. Circ J 76: Muntner P, Coresh J, Smith JC et al (2000). Plasma lipids and risk of developing renal dysfunction: the atherosclerosis risk in communities study. Kidney Int 58: Kwan BC, Murtaugh MA, Beddhu S (2007). Associations of body size with metabolic syndrome and mortality in moderate chronic kidney disease. Clin J Am Soc Nephrol 2: Reynolds K, Gu D, Muntner P et al (2007). Body mass index and risk of ESRD in China. Am J Kidney Dis 50: de Boer IH, Sibley SD, Kestenbaum B et al (2007). Central obesity, incident microalbuminuria, and change in creatinine clearance in the epidemiology of diabetes interventions and complications study. J Am Soc Nephrol 18: Reaven G (2005). Just being alive is not good enough. Clin Chem 8: Conflicts of interest: none. Sources of funding: the position of Giacomo Pucci as an Adjunct Assistant Professor at the University of Perugia was funded by a grant from the Fondazione Cassa di Risparmio di Terni e Narni.

71 Intern Emerg Med (2015) 10 (Suppl):S65-S73 LECTURE Gastroesophageal reflux disease (GERD) Patrizia Zentilin Edoardo Savarino Manuele Furnari Giorgia Bodini Elisa Marabotto Vincenzo Savarino SIMI 2015 Abstract Gastroesophageal reflux disease (GERD) is highly prevalent in western countries, with a rate of up to 20% in the general population, and has a relevant impact on quality of life and health costs. In agreement with the Montreal classification, GERD occurs when the reflux of gastric content into the esophagus causes troublesome symptoms and/or complications. The causes of GERD are unknown, but there are several pathogenetic mechanisms that can favor the disease. The main factor is represented by the transient inappropriate relaxations of the lower esophageal sphincter (LES), which are induced in a reflex way by postprandial gastric distension and are stimulated by unvoluntary secondary peristalsis in the distal two thirds of esophageal body, where smooth muscles are present. Additional mechanisms are an impaired clearing ability of the esophagus in about 50% of cases, a delayed gastric emptying in 30-40% of patients and several environmental factors, such as obesity, some alimentary elements and drugs reducing the LES competence. A gastric acid hypersecretion is lacking. Hiatal hernia can be a condition favoring GERD, but this depends on its length and the grade of disruption of esophagogastric junction. In the last decade we have realized that, apart from the presence of esophageal mucosal lesions (erosions, intestinal metaplasia) in less than 30% of cases, the majority of GERD patients (about 70%) have typical symptoms of reflux (heartburn and regurgitation) without any mucosal alteration visible V. Savarino ( ) Department of Internal Medicine, University of Genova, Viale Benedetto XV 6, Genova, Italy. vsavarin@unige.it P. Zentilin M. Furnari G. Bodini E. Marabotto Department of Internal Medicine, University of Genova, Italy. E. Savarino Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Italy. at endoscopy and this form has been defined as non-erosive reflux disease (NERD). Accordingly, the diagnosis of GERD can be made exclusively on the basis of the presence of typical symptoms. However, many recent studies have stressed that NERD includes an heterogeneous group of patients with remarkable pathophysiological and clinical differences, that should be better classified using a technique able to characterize the chemical nature of gastric refluxate, because their management and therapeutic response change in relation to the various mechanisms originating symptoms. The traditional esophageal ph-metry was considered a valid tool to identify GERD patients, because it measured the total esophageal exposure time, the number of acid reflux episodes and the association between symptoms and acid refluxes. However, the crescent awareness that factors/stimuli different from acid are implicated in the induction of symptoms in GERD has stimulated the research for innovative diagnostic methodologies. Moreover, the more frequent need of evaluation of patients refractory to proton pump inhibitors (PPIs) has created further interest in this direction. Finally, we have witnessed a rising request of studying patients with extra-esophageal symptoms, such as laryngeal and respiratory disturbancies, suggestive for GERD, which represent a real challenge in clinical practice due to the difficulty to establish the causal relationship between symptoms and reflux events. In this scenario, the advent of new esophageal functional tests, such as high resolution manometry and impedance-ph-metry, has allowed us to enhance the knowledge of the pathophysiological mechanisms inducing GERD and, then, to improve its diagnosis and management. On the contrary, the diagnostic role of upper gastrointestinal endoscopy is greatly reduced and this technique is limited to the study of PPI-refractory patients or to the search for the most important complication of GERD, that is Barrett esophagus, which is a potentially dangerous condition, even though its transformation into neoplasia occurs much more rarely than reported in the past. The first choice medical therapy is represented by PPIs,

72 S66 Intern Emerg Med (2015) 10 (Suppl):S65-S73 which are the most powerful antisecretory agents today available. They are very effective in healing erosive esophagitis and in relieving symptoms of non-erosive forms, if acid plays the most relevant pathogenetic role. In patients with non-acid reflux, surgery can be a useful therapy, while pain modulators are indicated in patients with hypersensitive esophagus or functional heartburn, because their symptoms are not due to acid, but seem to be linked to a status of visceral hypersensitivity. Riassunto La malattia da reflusso gastroesofageo (MRGE) è un disturbo altamente prevalente nei Paesi occidentali, in quanto colpisce fino al 20% della popolazione generale con un impatto rilevante sulla qualità di vita e sui costi della salute. In accordo con la classificazione di Montreal, la MRGE si sviluppa quando il reflusso di contenuto gastrico causa sintomi invalidanti e/o complicanze. Le cause della patologia non si conoscono, ma esistono numerosi meccanismi patogenetici che possono favorirla. Il principale fattore è rappresentato dai rilasciamenti transitori inappropriati dello sfintere esofageo inferiore, che avvengono per via riflessa su stimolazione della peristalsi secondaria, a partenza dalla muscolatura liscia dell esofago. Ad essi si aggiungono un frequente disturbo della capacità di clearing dell esofago, un ritardato svuotamento gastrico nel 30-40% dei casi ed altri fattori, quali obesità, elementi dietetici e farmaci, che riducono la tenuta dello sfintere suddetto. Una ipersecrezione acida gastrica non è presente. L ernia iatale può essere una condizione favorente soprattutto in relazione alla sua lunghezza e al grado di alterazione della giunzione esofago-gastrica. Nell ultimo decennio abbiamo constatato che, a parte la presenza di lesioni mucose esofagee (erosioni, metaplasia intestinale) in meno del 30% dei casi, la maggioranza dei pazienti con MRGE (circa il 70%) ha sintomi tipici da reflusso (bruciore retrosternale e rigurgito) senza alcuna lesione mucosa endoscopicamente visibile, condizione che viene definita come malattia da reflusso non-erosiva (NERD). In accordo con tale definizione, la diagnosi di MRGE può essere posta sulla sola base della presenza di sintomi tipici. Tuttavia, alcuni studi recenti hanno sottolineato che la NERD comprende un gruppo eterogeneo di pazienti, con alcune differenze fisiopatologiche e cliniche, che dovrebbero essere meglio classificati usando una tecnica appropriata per la caratterizzazione chimica del refluito gastrico, perché la loro gestione e la risposta terapeutica cambiano a seconda dei vari meccanismi che sono alla base della produzione dei sintomi. La tradizionale ph-metria esofagea era considerata un utile strumento per identificare i pazienti con MRGE, poiché misurava il tempo di esposizione acida dell esofago distale, il numero degli episodi di reflusso acido e l associazione tra sintomi e reflussi acidi. Tuttavia, la crescente consapevolezza che fattori/stimoli differenti dall acido sono implicati nell induzione di sintomi nella MRGE ha stimolato la ricerca di mezzi diagnostici innovativi. Inoltre, la più frequente richiesta di valutazione di pazienti refrattari alla terapia acidosoppressiva con PPI ha creato ulteriore interesse in questa direzione. Infine, è rilevante considerare l invio crescente ai nostri ambulatori di pazienti con disturbi extra-esofagei, quali sintomi laringei e respiratori, suggestivi di MRGE, che rappresentano una vera sfida nella pratica clinica per le difficoltà di stabilire la relazione potenziale tra questi sintomi e il reflusso. In questo contesto, l avvento di nuovi test di funzione esofagea, quali la manometria ad alta risoluzione e la ph-impedenzometria, ha permesso rilevanti progressi nel comprendere i meccanismi fisiopatologici che contribuiscono allo sviluppo della MRGE e, quindi, la sua diagnosi e gestione. Al contrario, il ruolo diagnostico dell endoscopia del tratto digestivo superiore si è andato progressivamente riducendo ai casi refrattari alla terapia antisecretiva e alla ricerca della complicanza più temibile della MRGE, cioè l esofago di Barrett, che è una condizione potenzialmente precancerosa, anche se la sua degenerazione in neoplasia avviene molto più raramente di quanto si ritenesse in passato. La terapia medica di prima scelta è rappresentata dai farmaci inibitori di pompa protonica, che sono i più potenti antisecretivi noti. Essi funzionano molto bene nel cicatrizzare le esofagiti erosive e nei casi non-erosivi, in cui l acido è elemento patogenetico fondamentale. Nei casi in cui predomina il reflusso non-acido, la chirurgia antireflusso può essere utile, mentre i farmaci modulatori del dolore viscerale sono indicati nei pazienti con esofago ipersensibile e con pirosi funzionale, in cui i sintomi non sono più legati all acido ma originati da stimoli che richiamano la presenza di una ipersensibilità viscerale. Introduction Gastroesophageal reflux disease (GERD) is defined as a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications. Typical esophageal GERD symptoms include heartburm and regurgitation. Additional esophageal symptoms are chest pain and, more rarely, dysphagia. Extraesophageal or atypical symptoms with an established association with GERD on the basis of population-based studies are chronic cough, asthma and hoarseness. However, these symptoms have potential etiologies other than GERD and, in the absence of a concomitant esophageal GERD syndrome, the causal role of reflux in them remains controversial. GERD complications are mainly attributable to mucosal injury, the most common being reflux esophagitis. Peptic stricture, Barrett s metaplasia and esophageal adenocarcinoma may also complicate GERD. According to the Montreal classification of reflux disease [1], we have a group of syndromes that mirror the different mani-

73 Intern Emerg Med (2015) 10 (Suppl):S65-S73 S67 festations of reflux disease. These are conveniently divided into esophageal and extraesophageal syndromes. There are two symptomatic reflux syndromes, as shown in: Typical reflux syndrome. It is defined by the presence of troublesome heartburn and/or regurgitation. The former is a burning sensation in the retrosternal area (behind the breastbone) and the latter is the perception of flow of refluxed gastric content into the mouth or hypo-pharynx. Reflux chest pain syndrome. Gastroesophageal reflux can cause episodes of chest pain that resemble coronary ischemia. The chest pain can be indistinguishable from ischemic cardiac pain and may not be accompanied by heartburn or regurgitation. Syndromes with esophageal injury: reflux esophagitis Reflux esophagitis is the most frequent form of esophageal injury and is defined endoscopically by visible breaks of the distal esophageal mucosa. In clinical practice, endoscopic evidence of esophagitis is seen in about 30% of patients with typical GERD symptoms. Syndromes with esophageal injury: Barrett s esophagus and esophageal adenocarcinoma Barrett s esophagus is defined as the replacement of the distal squamous epithelium of the esophagus with columnar epithelium, which is represented by intestinal-type metaplasia in bioptic material. This intestinal metaplasia remains unchanged lifelong in the majority of patients, whereas it can evolve to dysplasia and adenocarcinoma in some cases. Thus, Barrett s esophagus is considered the most serious complications of GERD. Extraesophageal syndromes They are subdivided into those with established association with gastroesophageal reflux (chronic cough, laryngitis, asthma and dental erosions) and the ones with only proposed, but not proven, association with reflux (pharyngitis, sinusitis, idiopathic pulmonary fibrosis and recurrent otitis media). The Montreal Consensus group recognized that these disorders are usually multifactorial processes and gastroesophageal reflux may be a simple co-factor rather than a cause. Epidemiology of GERD Studies of the epidemiology of GERD have been limited by the lack of consensus as to when symptoms of heartburn or regurgitation become troublesome enough to constitute a disease. However, population based studies suggest that when symptoms of moderate intensity occur twice a week, quality of life drops and than they become troublesome. Taking into account the above aspects, the prevalence of GERD in Usa (13-20%) is similar to that in Europe (9,8-18%), while it is lower in Asia (2,5-4,8%). Obesity, increasing age, a family history of reflux disease, and chronic consumption of certain drugs (nitrates, calcium antagonists, benzodiazepines etc.) are significant risk factors. The disease may occur also in children, although its incidence decreases from the age of 1 year to the age of 12 years. There is higher prevalence of reflux symptoms in Hispanic subjects compared to the Caucasian ones [2]. The epidemiology of extraesophageal syndromes and their relationship with reflux disease are more difficult to assess, but they are not very frequent and remain confined to about 10-15% of the entire spectrum of reflux symptoms. GERD is a chronic disease with phases of recurrence and remission overtime, but it can be considered as a benign disorder from a prognostic point of view. Pathophysiology of GERD Many factors are presently seen as important in the physiology of GERD, which is due to multiple mechanisms. The antireflux barrier is thought to consist of the intrinsic pressure of the lower esophageal sphincter (LES), the extrinsic compression of the LES by crural diaphragm and the flap valve constituted by an acute angle of His. The LES is a 3-4 cm segment of tonically contracted smooth muscle at the esophago-gastric junction (EGJ). Normally, the EGJ is surrounded by the crural diaphragm. Resting LES tone varies among normal individuals from 15 to 30 mmhg relative to intragastric pressure. Especially during inspiration, the crural diaphragm contributes to the maintenance of EGJ competence. For this reason, the crural diaphragm is often referred to as an extrinsic sphincter, the smooth muscle of the LES being the intrinsic sphincter. A third component of the antireflux barrier at the EGJ is represented by the so-called flap valve, formed by a musculo-mucosal fold created by the entry of the esophagus into the stomach along the lesser curvature. With this anatomical arrangement, increased intra-abdominal or intragastric pressure compresses the subdiaphragmatic portion of the esophagus. This is supposed to prevent EGJ opening and reflux during periods of abdominal straining. Mechanisms of reflux Current thinking is that there are three dominant reflux mechanisms: transient LES relaxations (TLESRs), LES hypotension and anatomical disruption of the EGJ, that is hiatus hernia. TLESRs constitute the most important reflux mechanism in

74 S68 Intern Emerg Med (2015) 10 (Suppl):S65-S73 healthy subjects and in a very large part of GERD patients. They are common and occur mainly during swallows to allow the passage of a bolus from the esophagus into the stomach. TLESRs are considered the physiological mechanism which enables venting of gas from the stomach, also known as belching. Since the discovery of TLESRs in the early 1980s, it has become increasingly clear that most reflux episodes occur during them [3]. A TLESR is currently defined as an abrupt decline in pressure at the position of LES, which is not induced by swallowing. The primary stimulus which triggers a TLESR is gastric distension, often resulting from accumulation of gastric air or consumption of a meal. This explains why TLESRs are mainly a post-prandial phenomenon. Several studies suggest that tension receptors in the stomach appear to be more relevant than pressure receptors as the stimulus for TLESRs. Relaxation of the EGJ during a TLESR is stimulated from secondary peristalsis, which is not swallow-induced and starts from mid esophagus as the result of a vago-vagal reflex commencing with activation of gastric receptors primarily in subcardiac region (Figure 1). Although the majority of studies show a similar rate of TLESRs in healthy subjects and in GERD patients, there is a higher percentage of TLESRs which not only vent air but are also associated with greater gastroesophageal reflux in the latter ones. A second mechanism is represented by LES hypotension, which occurs when the LES pressure is lower than 10 mmhg measured by manometry. Episodes of free reflux are observed only when the LES pressure is lower than 5 mmhg. Shortlived increases in intra-abdominal pressure caused by straining are often the precipitating factor of the reflux. This mechanism is particularly frequent in patients with scleroderma. The presence of hiatus hernia favors gastroesophageal reflux in that it increases the severity of esophageal acid exposure. It alters the position of the LES with respect to the crural diaphragm because these two important factors of the anti-reflux barrier are no more coupled. Fig. 1 The physiologic record of a spontaneous transient relaxation of the lower esophageal sphincter. Abbreviation: DEMG, diaphragmatic electromyographic activity. Impaired esophageal clearance Esophageal ph combined with manometric studies show that primary peristalsis (swallow-induced) is the main clearance event after acid reflux in upright position. The contribution of secondary peristalsis (distension-induced) to clear a reflux event is a less important phenomenon. Nevertheless, secondary peristalsis is especially relevant at night because it is the initial event in more than 80% of the reflux episodes probably attributable to the inhibition of the swallowing reflex. Esophageal motility disorders are present in around 30% of the patients with GERD, being ineffective esophageal motility the most prevalent alteration. In addition, chemical clearance due to the bicarbonates contained in saliva is decreased in GERD and this contributes to prolong the contact of acid reflux with esophageal mucosa. Gastric factors A delayed gastric emptiyng has been demonstrated in about 40% of GERD patients and this can favor the backflow of material contained in the stomach. There is no evidence of gastric acid hypersecretion in GERD patients, but acid represents the most aggressive factor in determining mucosal damage or the occurrence of symptoms.

75 Intern Emerg Med (2015) 10 (Suppl):S65-S73 S69 In summary, the alteration of the anti-reflux barrier associated with an inadequate clearing of refluxate and a delayed gastric emptying together with dietetic factors, drugs able to reduce the competence of LES and obesity induce the reflux of too much acid into the wrong place, that is the esophagus, the mucosa of which is very sensitive to this aggressive element (Figure 2). Abnormal oesophageal clearing TOO MUCH ACID IN THE WRONG PLACE Insufficient antireflux barrier Phenotypic presentations of GERD Altered gastric emptying Diet, drugs, overweight etc. In the past decade it has been realized that erosive reflux disease represents the minority of patients with GERD (~30%), whereas the majority of them (~70%) are included in the non-erosive reflux disease (NERD) phenotype, in that they have typical reflux symptoms without any esophageal mucosal lesion visible at endoscopy [2]. Epidemiological studies performed in two Swedish municipalities and two Italian villages on large samples of patients with reflux symptoms undergoing upper endoscopy have shown that the rate of endoscopy-negative cases can even be as high as 75% [4]. Our knowledge about the natural history of GERD is controversial; some studies have shown that progression to erosive reflux disease is frequent, whereas others deny this evolution. A systematic review of the literature in this field seems to confirm that the majority of patients with NERD remain as such overtime and only a small proportion (ranging from 0-30%) progresses to erosive reflux disease each year, and very few patients with NERD develop Barrett s esophagus. Although the diagnosis of NERD has been made in the past exclusively on the basis of the presence of symptoms (heartburn and regurgitation) and the absence of mucosal lesions at endoscopy, modern pathophysiological studies carried out with 24 h esophageal impedance ph testing have demonstrated that this population of patients with typical reflux symptoms is markedly heterogeneous and can be subdivided into several well defined subgroups with specific functional patterns [5]. About 40% of NERD patients has an excess of acid in the esophagus (true NERD), while the remaining part (60%) has a normal esophageal acid exposure. Among the latter, there are several distinct subgroups: patients with hypersensitive esophagus to acid (~20%), patients with hypersensitive esophagus to non-acid (~15%) and patients with functional heartburn (~25%) (Figure 3). Patients with hypersensitive esophagus to both acid and non-acid have negative endoscopy, normal esophageal acid exposure, and positive association between symptoms and episodes of reflux. The main proposed mechanism for symptom generation in these patients is the presence of dilated intercellular spaces (DIS) in the mucosa of the distal part of the esophagus, as this histological alteration enables acid to reach and activate Fig. 2 Primary factors of gastroesophageal reflux disease (GERD). 5% Complicated GERD 30% Erosive reflux disease 25% Functional heartburn 40% True NERD 20% Acid hypersensitive 15% oesophagus Non-acid hypersensitive oesophagus 65% Endoscopy-negative Fig. 3 Endoscopic + impedance-ph categorization in patients with typical symptoms of gastroesophageal reflux disease (GERD). Abbreviations: GERD, gastroesophageal reflux disease; NERD, non-erosive reflux disease. esophageal chemosensitive receptors [6]. DIS can be caused by many components of refluxate, including not only acid but also weakly acidic reflux, which explains why both chemical types of reflux are able to produce the same typical reflux symptoms, such as heartburn, regurgitation and acidic taste. Functional heartburn, in contrast, is a condition characterized by the symptom of heartburn not related to any gastroesophageal reflux, as diagnosed by means of 24-h impedance ph testing. In other words, there is no excess of acid and no association between the symptom heartburn and episodes of reflux. Nowadays, this subgroup of patients cannot anymore be considered within the realm of GERD and must be included among the large population of patients with functional gastrointestinal disorders. In fact, they do not respond usually to PPI therapy, but must be treated with pain modulators, because their symptoms are probably generated by both peripheral and central hypersensitivity frequently associated with psychopathology [7].

76 S70 Intern Emerg Med (2015) 10 (Suppl):S65-S73 Diagnosis of GERD Diagnostic testing for GERD include the assessment of symptoms (e.g. patient history or GERD questionnaires), the response to a trial of acid suppression (generally with a proton pump inhibitor, PPI), evaluation for acid-related damage to the esophageal mucosa (endoscopy), or determination of pathological reflux on prolonged ambulatory monitoring with ph or impedance ph. In clinical practice, a diagnosis of GERD is often made based upon symptom presentation along with a good response to a trial of PPI therapy. Beyond taking a careful history for typical symptoms of GERD, a number of validated questionnaires are available including specific symptom scales and GERD-related quality of life scales. Upper endoscopy is indicated when the clinical presentation includes alarm features such as dysphagia, bleeding or weight loss. Endoscopy provides a robust diagnosis of GERD when erosive esophagitis is present, but this is only found in approximately 30% of untreated patients and even a smaller proportion of patients after treatment with a PPI. Random biopsies to look for evidence of GERD in those with normal endoscopy are not recommended, because conventional histology has poor performance for a diagnosis of GERD. Direct measurement of gastroesophageal reflux through ph or impedance ph monitoring can establish whether there is a pathological amount of acid reflux and if there is an association between symptoms and reflux episodes. Impedance ph monitoring, in particular, enables measurement of both acid and non-acid reflux (Figures 4 and 5). Figure 4 shows that there is a fall in impedance values which move in retrograde direction (from the bottom to the top) and a concomitant drop in ph values below 4.0 units detected by the ph electrode and this identifies the occurrence of an acid reflux, while Figure 5 shows that the fall in retrograde impedance values is not accompanied by a drop of ph below 4.0 and then this is called a non-acid reflux episode. The distinction between acid and non-acid reflux can be obtained only by this modern technique, in that the traditional ph-metry alone is able to measure only acid refluxes [8]. Non-acid reflux episodes may be clinically important in patients with persistent symptoms despite acid-suppressive therapy. Evaluation should always begin with a careful history. A PPI trial is a reasonable action for diagnosing GERD in patients with typical symptoms. GERD cannot be diagnosed by barium esophagogram or esophageal manometry and then these examinations must not be prescribed. Endoscopy should be performed when alarm features are present or to assess the presence or not of Barrett s esophagus in risky patients, because the diagnosis of Fig. 4 Acid gastroesophageal reflux (GER) episode.

77 Intern Emerg Med (2015) 10 (Suppl):S65-S73 S71 Fig. 5 Non-acid gastroesophageal reflux (GER) episode. this complication must be made on the basis of the histological demonstration of intestinal metaplasia in the distal part of the organ. Objective documentation of GERD by endoscopy or reflux monitoring is mandatory before antireflux surgery. Endoscopy is scarcely useful in patients with extraesophageal symptoms, because less than 30% of them has erosive esophagitis. On the contrary, impedance ph monitoring is more remunerative in these patients, although the cause-effect relationship between atypical symptoms and reflux episodes must be validated by a trial with good response to proton pump inhibitors (PPIs). It is important to note that in some patients the reported symptoms may be due to causes other than GERD, including functional heartburn; in these cases, endoscopy and reflux monitoring can be valuable tools to exclude GERD. Complications of GERD The most frequent and relevant complications of GERD are peptic strictures and Barrett s esophagus. Peptic structures. An esophageal peptic stricture is usually a short, focal, and straight narrowing of the esophageal lumen located near the gastroesophageal junction and occurs as a consequence of long-standing GERD. Approximately 4-10% of patients with GERD undergoing endoscopy are found to have peptic stricture, but with the current widespread use of PPIs, the prevalence of peptic strictures has greatly decreased. The most common symptom of peptic stricture is dysphagia. Patients frequently first experience solid food dysphagia which may progress to liquid dysphagia and possible food impaction, if acid control is not obtained. As stricture formation is most commonly associated with long-standing GERD, patients will have a long history of chronic heartburn or acid regurgitation. The initial diagnostic test should be endoscopy as it enables visual inspection and localization of the injury. This test may also provide the opportunity for treatment through balloon or bougie dilation, which may be repeated if an optimal diameter and symptomatic relief are not achieved after a single dilation. Barrett s esophagus. The most serious complication of GERD is represented by Barrett s esophagus. This is an acquired condition resulting from severe esophageal injury. It remains unclear why some patients with GERD develop Barrett s esophagus whereas others do not. The diagnosis of Barrett s esophagus is established if the squamo-columnar junction is displaced proximal to the gastro-esophageal junction and intestinal metaplasia is detected by biopsy. Barrett s

78 S72 Intern Emerg Med (2015) 10 (Suppl):S65-S73 esophagus would be of little importance if not for its well-recognized association with adenocarcinoma of the esophagus. Fortunately, the overall disease burden of esophageal cancer remains low and cancer risk for a given patient with Barrett s esophagus may now be lower than previously estimated. The most recent studies have shown that only 1 patient every cases of Barrett s metaplasia will evolve to esophageal adenocarcinoma, depending on the country where the epidemiological study is performed. Patients with Barrett s esophagus are difficult to distinguish clinically from patients with GERD uncomplicated by a columnar-lined esophagus. They have generally a long history of reflux disease, are male and of white race, and a subset of them may have an inherited predisposition, as studies have reported on families with multiple affected relatives over successive generations and recent work has found several germ-line mutations associated with Barrett s esophagus and esophageal carcinoma. Identification of Barrett s esophagus patients may be hampered by the paradox that, despite this condition is the most severe complication of GERD, these patients have an impaired sensitivity to esophageal acid perfusion compared to patients with uncomplicated GERD, which may be related to the fact that many of them are elderly, and there may be an age-related decrease in acid sensitivity. Endoscopically, Barrett s esophagus is characterized by displacement of the squamo-columnar junction proximal to the gastro-esophageal junction defined by the proximal margin of gastric folds. The new Prague classification provides the most reliable way to describe a Barrett segment greater that 1 cm length, as it describes the circumferential extent (C value) and maximum extent (M value) of columnar mucosa above the proximal margin of the gastric folds [9]. If the squamo-columnar junction is above the level of the esophago-gastric junction, biopsies should be obtained for the diagnosis of Barrett s esophagus, which is characterized by the presence of intestinal metaplasia.the optimal yield for intestinal metaplasia comes with taking at least four biopsies, whereas taking more than eight biopsies does not seem to enhance the assessment of intestinal metaplasia further. As we have already said, the overall burden of esophageal adenocarcinoma remains relatively low. Thus, most patients with Barrett s esophagus die of other causes, the most common being cardiovascular disease. Furthermore, the survival of patients with Barrett s esophagus is similar to that of the general population. Current guidelines recommend endoscopic screening for GERD individuals with evident risk factors, such as age greater or equal to 50 years, male gender, Caucasian race, chronic GERD symptoms (> 5 yrs), elevated body mass index (BMI) and male-pattern abdominal obesity. The suggested algorithm for endoscopic surveillance suggests to repeat the examination at 3-5 year intervals after two consecutive findings of no dysplasia in the first year. If there is low or high-grade dysplasia, intervals must be shortened (6 or 3 months). Medical therapy is useful in these patients and it has been shown in both retrospective and prospective trials that PPIs are able to prevent the evolution of metaplasia to dysplasia when they are taken continuously even at standard dosages. At present, patients with high-grade dysplasia or early adenocarcinoma should be treated with endoscopic mucosal resection in case of nodularity on the esophageal mucosa or the use of radiofrequency ablation to destroy tissues with penetration depth of 0.5 mm. The results are good, but patients treated with both modalities need to be continuously controlled overtime after the procedures because of the risk of buried islands of metaplastic tissue under the new squamous epithelium and they can also evolve to dysplasia and neoplasia. Overview of GERD treatments Targeting individual elements of GERD pathophysiology is the basis of GERD treatments. Paradoxically, although gastric acid secretion is usually normal in GERD patients, the lethal effect of gastric juice to esophageal epithelial cells is a key event in the pathogenesis of esophagitis and symptom occurrence. Consequently, the dominant medical GERD treatments focus on inhibiting acid secretion [10]. Firstly, there are many recommendations regarding lifestyle modifications as GERD therapy, although evidence supporting them is weak. They consist in avoiding food that may reduce the competence of LES (fatty foods, chocolate), may precipitate heartburn by a direct irritative effect on the esophageal mucosa (citrus, carbonated drinks, spicy foods), may reduce the process of acid clearance (weight loss, raising the head of bed and avoiding recumbent position for 2-3 h after meals). Obesity and weight control merits special attention because accumulating evidence suggests this is one of the root causes of the GERD epidemic of the past two decades. Acid neutralization with antacid, the use of a mechanic barrier with alginate or pharmacologically inhibiting gastric acid secretion are cornerstones of GERD therapy. The most potent drugs are the PPIs, which block the final common pathway for acid secretion. Histamine-2 receptor antagonists (H2Ra) competitively block histamine-stimulated acid secretion, making them less potent than PPIs and giving them a shorter duration of action. PPIs treat GERD in an indirect fashion and therefore do not cure definitely reflux disease. In erosive esophagitis they facilitate mucosal healing with close to 100% effectiveness and also the symptom heartburn is controlled in the majority of cases. However, there is a 20% difference in

79 Intern Emerg Med (2015) 10 (Suppl):S65-S73 S73 therapeutic gain for heartburn dependent on whether or not it occurs in the context of erosive esophagitis or non-erosive reflux disease. This is due to the fact that all trials performed in the past enrolled patients with NERD, which was diagnosed on the simple basis of a negative endoscopy. Accordingly, this unique population was not distinguished into the various subgroups we have above mentioned and therefore it was contaminated with patients with hypersensitive esophagus to non-acid and functional heartburn, two conditions which do not respond to PPI therapy because acid does not represent any pathogenetic role in them. If it is true that the specificity of heartburn as an acid-induced symptom is less in the absence of esophagitis, it is noteworthy to emphasize that also the response of the other typical GERD symptom, that is regurgitation, is lower than that of heartburn by a factor of about 20%. The efficacy of antisecretory agents in extra-esophageal manifestations of GERD, on the contrary, is very poor and limited to a small group of patients, who present atypical together with typical symptoms. Reflux inhibitors, such as baclofen and other GABA agonists, which enable us to control TLESRs that are the dominant mechanism of reflux in most GERD patients, failed to show significant improvement in heartburn and regurgitation and so their development has been stopped. Also prokinetic drugs, which would increase esophageal clearance of refluxate by enhancing peristalsis, did not show relevant benefits in GERD treatment, both alone and added to PPIs. There are also no high-quality data supporting the use of compounds able to decrease esophageal mucosal permeability to luminal contents, thus reducing the toxic effect of gastric refluxate on esophageal mucosa. Whatever the presentation of GERD, maintenance therapy is usually required for continued symptom control. This can be made either continuously or on demand, depending on the frequency and severity of relapses. Continuous therapy is needed in patients with frequent recurrences, severe erosive esophagitis, the few cases with extraesophageal symptoms responding to PPI therapy and those with Barrett s esophagus. As to the last group of reflux patients, a recent prospective study has shown that the continuous administration of PPIs allows to reduce significantly the rate of transformation of intestinal metaplasia to dysplasia, which is the first step for the evolution to adenocarcinoma. Patients with hypersensitive esophagus or with functional heartburn can be treated with low-dose tryciclic antidepressants or selective serotonin reuptake inhibitors (SSRIs). However, thus far there are no large studies that evaluated these drugs in reflux patients with visceral hypersensitivity. Antireflux surgery by Nissen fundoplication can be an effective alternative to medical therapy and several large and long-lasting trials have shown that both treatments are similar in controlling heartburn and acid regurgitation. However, high-quality evidence on the efficacy of surgical treatment of reflux exists only for esophagitis and/or excessive distal acid exposure. Some small uncontrolled clinical trials have also shown that anti-reflux surgery can be useful in patients not responding to PPI therapy because of the objective demonstration by impedance-ph monitoring of weakly acidic reflux as responsible of refractory symptoms. Endoscopic reflux treatments have demonstrated minimal efficacy and an unacceptable incidence of adverse events, leading to the rapid withdrawal of most of them from the market. References 1. Vakil N, van Zanten SV, Karhilas P et al; Global Consensus Group (2006). The Montreal definition and classification of gastroesophageal reflux disease; a global evidence-based consensus. Am J Gastroenterol 101: Dent J, El-Serag HB, Wallander MA, Johansson S (2005). Epidemiology of oesophageal reflux disease: a systematic review. Gut 54: Dent J, Dodds WJ, Friedman RH et al (1980). Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 65: Savarino E, Zentilin P, Savarino V (2013). NERD: an umbrella term including heterogeneous subpopulations. Nat Rev Gastroenterol Hepatol 10: Savarino E, Zentilin P, Tutuian R et al (2008). The role of non-acid reflux in NERD : lessons learned from impedance-ph monitoring in 150 patients off therapy. Am J Gastroenterol 103: Zentilin P, Savarino V, Mastracci L et al (2005). Reassessment of the diagnostic value of histology in patiewnts with GERD, using multiple biopsy sites and an appropriate control group. Am J Gastroenterol 100: Galmiche JP, Clouse RE, Bàlint A et al (2006). Functional esophageal disorders. Gastroenterology 130: Sifrim D, Castell D, Dent J, Kahrilas P (2004). Gastroesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 53: Sharma P, Dent J, Armstrong D et al (2006). The development and validation of an endoscopic grading system for Barrett s esophagus; the Prague C and M criteria. Gastroenterology 131: Savarino V, Di Mario F, Scarpignato C (2009). Proton pump inhibitors in GORD. An overview of their pharmacology, efficacy and safety. Pharmacol Res 59:135-53

80 Intern Emerg Med (2015) 10 (Suppl):S74-S81 LECTURE Acute heart failure: challenges in prognostic risk stratification and medical management Gianfranco Sinagra Davide Stolfo Enrico Fabris SIMI 2015 Abstract Heart failure constitutes a major public health concern and is one of the leading causes of mortality and hospitalization. The ability to discriminate patients with acute heart failure (AHF) syndromes at increased risk for adverse outcomes after discharge is critical to guide therapeutic decision-making. The main treatment goals in the hospitalized patient with AHF are to restore euvolemia and to minimize adverse events. Common in-hospital treatments include intravenous diuretics, vasodilators, and inotropic agents. This review will discuss the initial clinical assessment of AHF patients, including the main clinical, hemodynamic and biochemical markers related to the post-discharge outcomes. Finally, the contemporary medical management of patients with AHF has been briefly summarized. G. Sinagra ( ) Cardiovascular Department, Ospedali Riuniti and Postgraduate School of Cardiology, University of Trieste, Via Valdoni 1, Trieste, Italy. gianfranco.sinagra@aots.sanita.fvg.it D. Stolfo E. Fabris Cardiovascular Department, Ospedali Riuniti and Postgraduate School of Cardiology, University of Trieste, Italy. Riassunto Lo scompenso cardiaco costituisce un problema sanitario di estrema rilevanza ed è una delle principali cause di morte e riospedalizzazione. La capacità di individuare i pazienti ricoverati con scompenso cardiaco acuto a più elevato rischio di outcome sfavorevole dopo la dimissione è importante per guidare le scelte cliniche e terapeutiche. I principali target durante l ospedalizzazione sono la risoluzione della congestione e la gestione delle complicanze. I trattamenti medici di più ampio utilizzo rimangono i diuretici, i vasodilatatori e gli inotropi. Questa revisione si pone l obiettivo di discutere l assessment iniziale dei pazienti con scompenso cardiaco acuto, includendo una rivalutazione dei fattori prognostici correlati alla prognosi, sia clinici che emodinamici, nonché i biomarcatori. Infine, le attuali strategie farmacologiche verranno brevemente riassunte. Definition Heart failure (HF) can be defined as an abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues, despite normal filling pressures (or only at the expense of increased filling pressures) [1]. Acute HF (AHF) is the term used to describe the rapid onset of, or change in, symptoms and signs of HF. Because AHF is a life-threatening condition that requires immediate medical attention usually leads to urgent admission to hospital. In most cases, AHF arises as a result of deterioration in patients with a previous diagnosis of HF. In patients with pre-existing HF there is often a clear precipitant or trigger (e.g. an arrhythmia or discontinuation of diuretic therapy and volume overload or severe hypertension). AHF however may also be the first presentation and it is called de novo AHF. Clinical classification A clinically relevant and wildly used system for classifying AHF was developed by Stevenson et al. [2]. It classifies patients on the basis of the clinical presence or absence of hypoperfusion (cold vs warm) and of congestion at rest (wet vs dry). In contrast, system focused more on the cause of HF than on the severity of disease at presentation has been proposed [1]: 1. acute decompensated heart failure in which symptoms of

81 Intern Emerg Med (2015) 10 (Suppl):S74-S81 S75 AHF are mild and do not fulfil criteria for cardiogenic shock, pulmonary oedema or hypertensive crisis; 2. hypertensive AHF: signs and symptoms of HF are accompanied by high blood pressure (BP) and relatively preserved left ventricular function; 3. pulmonary oedema accompanied by severe respiratory distress; 4. cardiogenic shock: defined as evidence of tissue hypoperfusion induced by HF after correction of pre-load; 5. high output failure, characterized by high cardiac output, usually with high heart rate and warm peripheries, pulmonary congestion, and sometimes with low BP; 6. right HF, characterized by low output syndrome with increased jugular venous pressure, increased liver size and hypotension. The current European Society of Cardiology guidelines [3] focused on the distinction of heart failure with reduced ejection fraction (EF) (HF-REF), or systolic HF (usually considered with EF 35%) and patients with preserved EF (HF-PEF) that describes patients with an EF in the range of 35 50%. Finally special populations are considered: patients with a concomitant acute coronary syndrome, isolated right ventricular failure, AHF with cardiorenal syndrome, perioperative AHF. Patients with a PEF-HF represent a grey area and frequently present mild systolic dysfunction. The diagnosis of HF-PEF is largely one of exclusion, i.e. potential non-cardiac causes of the patient s symptoms (such as anaemia or chronic lung disease) must first be discounted. Current approach to diagnosis Patients present with signs and symptoms, not diagnoses. Although dyspnea is the most common symptom in AHF, it has a large list of differential diagnoses. Efficient diagnosis is critical, because delays in the delivery of care for AHF are associated with increases in mortality, hospital length of stay, and treatment costs [4-6]. History and physical examination Multiple studies suggest that there is no historical or physical examination finding that achieves sensitivity and specificity >70% for the diagnosis of AHF. The S3 gallop is very specific and carries prognostic implications, but with a low sensibility. Dyspnea on exertion is the most typical symptom, widely sensitive but not specific. Clinical judgment alone is sometimes misleading, and needs to be supported by instrumental diagnostic techniques. Chest radiography Chest radiography demonstrating pulmonary venous congestion, cardiomegaly, and interstitial edema are considered specific test findings for AHF. However, their absence cannot rule out AHF, because up to 20% of patients with AHF shows no congestion on chest radiography, particularly in late-stage HF [7]. Electrocardiography Electrocardiography may suggest a specific cause or precipitant of AHF, such as myocardial ischemia, acute myocardial infarction, or supraventricular arrhythmias. Electrocardiography may also offer clues as to the underlying cause of chronic HF. Biomarkers The natriuretic peptides (NPs) B-type NP (BNP) and its precursor N-terminal pro-bnp are the most established AHF diagnostic biomarkers. They are particularly useful in the setting of undifferentiated dyspnea by adding diagnostic accuracy for AHF [8]. BNP testing is a class 1 guideline recommendation by both the European and American Heart Failure Societies and may be particularly useful when the etiology of dyspnea is unclear. The role of newer markers, such as MRproANP, ST2 and galectin-3, in the diagnostic algorithm is instead less clear. Several factors can affect NP levels, such as age, sex, weight, and renal function and clinicians should be aware of the potential limitations of NPs in the diagnostic assessment of patients admitted to the emergency department [9]. Biological variability also influences the interpretation of NPs levels. Despite these limitations and a substantial grey zone when interpreting results, NP testing remains useful and is additive to physician assessment for diagnosis of AHF. Echocardiography and lung ultrasonography Echocardiography is the most common and readily available non-invasive test with which to evaluate the structural function of the heart and its role is well established. In people presenting with suspected AHF, a complete transthoracic Doppler 2D echocardiography should be performed within 48 hours since admission to guide early specialist management and to identify the underlying cardiac disease [10]. However, an earlier approach can be helpful in particular conditions, as patients presenting with hemodynamic instability or at highrisk for mechanical complications where making specific diagnoses (e.g. pericardial tamponade, myocarditis, endocardi-

82 S76 Intern Emerg Med (2015) 10 (Suppl):S74-S81 tis, acute valve disease) will guide immediate management. It can also be considered to support the differential diagnostic process in the most uncertain situations. Lung ultrasonography is an emerging technique that demonstrated to be helpful in the emergency department setting to detect volume overload and AHF, increasing the diagnostic accuracy when coupled with examination and NP measurement [11]. Adding lung ultrasonography to conventional echocardiography allows an integrated cardiopulmonary ultrasound examination, and this is an important opportunity for the cardiologist. Lung ultrasonography adds important information in the clinical evaluation of patients presenting with dyspnea, and hopefully it will be considered in the future guideline as a useful tool for the diagnostic work-up of patients with suspected AHF. Prognostic risk stratification The accurate identification of patients at highest risk of adverse outcomes who would be the most likely to benefit from intensive medical therapy and the prognostic stratification of patients with AHF following discharge is challenging in the management of AHF. Several clinical, hemodynamic, biochemical, and echocardiographic parameters have been found to be associated with increased risk of post-discharge adverse prognosis (Table 1) and many attempt have been performed to develop multivariable models aiming to improve the prognostic discrimination [12-14]. Age Older age has been widely demonstrated to negatively affect the long-term survival [13, 15]. In the OPTIMIZE-HF registry the 60 to 90-day mortality increased by 22% for every 10-year increase in age [13]. Comorbid conditions In a study of more than 30,000 patients, comorbid conditions were found to be significant predictors of short-term and 1-year mortality in AHF patients [15]. Heart rate In a trial among patients hospitalized with AHF, resting heart rate at time of admission was associated with a worst prognosis, independent of the underlying rhythm (sinus or atrial fibrillation) [16]. Furthermore, heart rate emerged as an independent prognostic factor also in multiple multivariable models assessing short-term prognosis in AHF [17, 18]. Table 1 Markers of poor prognosis following acute heart failure hospitalization. Clinical Age Body mass index Multiple comorbidities Admission serum biomarkers BNP / NT-proBNP Cardiac troponin Serum sodium Serum creatinine Blood urea nitrogen C-reactive protein Novel biomarkers Galectin-3 Soluble ST2 NGAL Hemodynamic markers Heart rate Systolic blood pressure Persistent congestion at discharge Hemoconcentration Medication changes Inotropes Withdrawal of beta-blocker therapy Diuretic dose Prescription of ACEi at discharge Abbreviations: ACEi, angiotensin converting enzyme inhibitor; BNP, B-type natriuretic peptide; NGAL, neutrophil gelatinase-associated lipocalin; ST2, stimulation expressed gene 2. Systolic blood pressure Hypotension and evidence of organ hypoperfusion is associated with increased in-hospital and post-discharge mortality in AHF patients. Improved survival associated with higher admission systolic blood pressure is consistent across published studies [19, 2, 14]. Hemoconcentration It is known that the hemoconcentration during hospitalization for AHF is the expression of sustained reduction in volume overload and, thus, has also been associated with a better outcome [20]. Additionally, hemoconcentration achieved later during hospitalization has been associated with improved survival emphasizing the importance of sustained decongestion during the treatment of AHF [21]. Beta-blocker therapy Retrospective analyses of the OPTIME-CHF, COMET, and ESCAPE trials demonstrate that AHF patients in whom beta-blocker therapy was discontinued had worse outcomes compared to those who remained on beta-blocker therapy

83 Intern Emerg Med (2015) 10 (Suppl):S74-S81 S77 [22-24]. In a propensity-adjusted analysis, the continuation of beta-blocker therapy during the index hospitalization was associated with a significantly lower risk of post-discharge death [25]. This must be reviewed with caution, as patients in whom beta-blockers were withdrawn likely represented a sicker cohort. Diuretic therapy In the ESCAPE trial, higher diuretic dose was strongly associated with increased 6-month mortality [26]. Similarly, data from the ADHERE registry reveal that patients who received <160 mg/day of furosemide had a lower risk of in-hospital mortality and intensive care unit (ICU) stay [27]. The prognostic effect of cardiorenal syndrome and diuretic resistance have been previously demonstrated [28]. In the DOSE trial no differences in symptoms and renal function were observed according to diuretic strategies (low vs high dose and continuous vs bolus administration) [29]. Serum biomarkers Natriuretic peptides Both the biologically active BNP and biologically inert NT-proBNP have emerged as useful clinical tools in risk prediction after discharge [30]. In the REDHOT multicenter study, BNP levels at admission strongly predicted 90-days outcomes [31]. Later studies demonstrated the optimal performance of NPs estimation at discharge, both as absolute value or relative change from admission. It carries indeed the additional information concerning the effectiveness of the treatment adopted during hospitalization [32]. Serum creatinine The utilization of serum creatinine (scr) or scr changes during AHF as a prognostic marker is definitively challenging, given the high prevalence of chronic kidney disease in HF patients, as well as the complex hemodynamic and neurohormonal interactions between cardiac and renal disease. Baseline renal impairment has been confirmed to be associated with unfavourable outcomes in both chronic and acute HF patients [28]. On the other hand, the influence of in-hospital worsening renal function (WRF) on prognosis is more controversial. In a recent metanalysis including over 45,000 patients, the higher risk of adverse prognosis associated with WRF was observed even in the AHF subgroup [28]. Conversely, previous studies concluded for either neutral or positive effects of a transient decrease in renal filtration in AHF setting [20, 29]. Actually, the reason for these discrepancies might be probably explained by the cause of WRF. A decline in renal function can be merely the result of an aggressive diuretic treatment if the loss in plasma volume exceeds the fluid replacement in intravascular space [21]. Serum blood urea nitrogen (BUN) It is known that, in patients with HF, BUN in addition to being a marker of renal function, provides information related to the grade of functional neurohormonal activation. The prognostic impact of BUN in AHF has been demonstrated in recent studies, attesting its significance in predicting the detrimental effects of a failing circulation on the kidneys [33]. Accordingly, BUN is one of the strongest, independent predictors of in-hospital mortality identified in the ADHERE registry [14]. Novel biomarkers A number of novel markers have been proposed for diagnosis and prognostication of AHF patients. The soluble ST2 receptor is a member of the interleukin family, and it is up-regulated in response to myocardial stretch. ST2 levels correlate with NYHA functional class and predict 1-year mortality in patients with AHF [34]. Neutrophil gelatinase-associated lipocalin (NGAL) is a marker of acute kidney injury. When investigated in AHF, higher levels strongly predicted all-cause death or hospital readmission at 30 days [35], although some data indicated that NGAL more accurately reflects underlying renal function rather than cardiac disease [36]. Galectin-3 promotes collagen synthesis and cardiac fibrosis. The majority of evidence with galectin-3 relates to chronic heart failure, although galectin-3 was also elevated in patients with AHF, and higher levels predicted short- and long-term mortality [37]. Therapeutic management The syndrome of AHF comprises activation of multiple systems/pathways (neuro-hormonal, immune, inflammatory) in multiple organs (heart, kidney, liver, gastrointestinal tract and endothelium) that make the management complex. Fluid overload, increased vascular stiffness and resistance play often a central role in the pathophysiology of AHF and proper management generally requires a combination of diuretics, vasodilators, and occasionally inotropic support, to achieve the goal of an euvolemic and adequately perfused patient. Diuretics and ultrafiltration Diuretic therapy is widely used to treat the symptoms and signs of fluid overload and pulmonary and systemic congestion, and loop diuretics are the most commonly used. Clear evidences regarding the best therapy in terms of doses, ways and methods of administration are not available.

84 S78 Intern Emerg Med (2015) 10 (Suppl):S74-S81 Performed studies usually proved the accuracy of pharmacokinetic assumptions on intravenous continuous infusion compared to bolus injection, but proved not to be conclusive as regards clinical and efficacy outcomes. The Diuretic Optimization Strategies Evaluation (DOSE-HF) trial [29] was conducted to prospectively compare administration in 308 patients of intravenous diuretic therapy via bolus dosing or continuous infusion. Each group was further stratified to either a low-dose or high-dose regimen. Neither mode (bolus vs infusion) nor dosing (low-dose vs high-dose) of furosemide were associated with improvement in the composite endpoint of death, rehospitalization or emergency department visit at 60 days of follow-up. Ultrafiltration is an alternative method of sodium and water removal. Ultrafiltration functions by removing isotonic plasma water across a semipermeable membrane with the assistance of a transmembrane pressure gradient. The UNLOAD study [38], randomized 200 patients with AHF to ultrafiltration or intravenous diuretics and showed a reduction of weight compared with diuretics at 48 hours and improved readmission rate at 90 days. The advantages of this technique, compared with diuretic therapy, are a more rapid fluid removal, a higher sodium clearance, a decreased risk of electrolyte imbalances and lack of neurohormonal activation. However, catheter-related complications, hypotension, and haemorrhage due to systemic anticoagulation are limits to its widespread use. Recently, ultrafiltration strategy was tested in patients with AHF and worsened renal function in the CARRESS-HF study, demonstrating a lower efficacy in preserving renal function with similar decongestion effects and higher rate of adverse events [39]. Therefore, at present, it is reasonable to use ultrafiltration for selected patients with refractory congestion not responsive to conventional medical therapy. Vasodilators After diuretics, intravenous vasodilators are probably the most useful medications for the management of AHF. Intravenous nitroglycerin (NTG) acts primarily through venodilation, lowers preload, and may help to rapidly reduce pulmonary congestion. According to guideline [3] intravenous infusion of a nitrate should be considered in patients with pulmonary congestion/oedema and a systolic blood pressure >110 mmhg, who do not have severe mitral or aortic stenosis, to reduce pulmonary capillary wedge pressure and systemic vascular resistance. Symptoms and blood pressure should be monitored frequently during administration. Sodium nitroprusside (SNP) is a balanced preload-reducing venodilator and afterload-reducing arteriodilator that also dilates the pulmonary vasculature. According to clinical guidelines, SNP can be used in situations similar to NTG but caution is recommended in patients with acute myocardial infarction. Nesiritide is a human BNP that acts mainly as a vasodilator reduces LV filling pressure but has variable effects on cardiac output, urinary output, and sodium excretion. Overall, presently there are no data that suggest that intravenous vasodilators improve outcomes in the patient hospitalized with HF. However, intravenous vasodilators are commonly used to the relief of dyspnea in the hospitalized HF patient with intact blood pressure. Inotropes Administration of inotropes or vasopressors should be limited to patients presenting with low cardiac output, low systolic blood pressure (<85-90 mmhg) despite adequate volume status, and/ or clear evidence of shock or organ hypoperfusion [3, 40]. The use of positive inotropic drugs has been related to increased morbidity and mortality in the larger part of the main studies on AHF. Problems include increased arrhythmias, induced myocardial ischemia, and in some cases hypotension. The largest database demonstrating increased mortality with inotropes is the ADHERE registry, where short-term inotropic therapy was associated with increased in- hospital mortality [41]. As mentioned above, the evidence that inotropic therapy increases mortality is further confirmed by the fact that this adverse relationship was not affected by the variables associated with the worst condition typically characterizing patients that need inotropic support [42]. Conventional inotropic agents and vasopressors Dopamine Dopamine, at low doses (<3 mcg/kg/min) activates dopaminergic receptors that induce vasodilation in various vascular beds, including the coronary and renal arteries. Despite the early observation demonstrating increased renal blood flow, the Renal Optimization Strategies Evaluation in Acute Heart Failure trial (ROSE AHF) recently found that neither nesiritide nor low dose dopamine were better than placebo when added to standard care [43]. Intermediate doses of dopamine (3-10 mcg/kg/min) activate β-adrenergic receptors causing increased inotropy and heart rate. At higher infusion rates (10-20 mcg/kg/min), dopamine acts primarily as an α-adrenergic agonist resulting in peripheral vasoconstriction. The recent trial by De Backer et al. showed that a drug with a strong inotropic effect (dopamine) at higher doses could be deleterious compared to a potent vasopressor with a weak inotropic activity (norepinephrine), particularly in the treatment of cardiogenic shock [44].

85 Intern Emerg Med (2015) 10 (Suppl):S74-S81 S79 Dobutamine Dobutamine has a direct agonist effect on β1 and β2-adrenergic receptors with minimal vasoconstrictor properties and less tachycardia [45]. Dobutamine might have an advantage over dopamine, avoiding peripheral constriction and incresed afterload. Conversely, it can reduce blood pressure in some patients due to the peripheral vasodilatory properties. Vasodilation could preserve the microcirculation, improve organ and coronary perfusion, decreasing left ventricular afterload and oxygen consumption. Tachycardia, myocardial ischemia and arrhythmias can occur during dobutamine infusions, especially at higher doses. Tolerance to the effect starts infusion with lasting >72 hours. Short-term infusion can be beneficial for patients with low-cardiac output and signs of organ hypoperfusion. However, longer treatment were related with higher 6-month mortality [46]. Norepinephrine Norepinephrine has potent α- and β-adrenergic receptor agonist properties including increased chronotropy, heightened inotropy, and increased peripheral vasoconstriction. Typically, it is infused at 0.2 to 1 mcg/kg/min and can be associated with tachycardia, myocardial ischemia, and arrhythmias. Despite similar results in the overall population of patients presenting with various types of shock in a comparator randomized study between norepinephrine and dopamine, the subset of patients with cardiogenic shock derived more survival benefit from norepinephrine [44]. Non-adrenergic inotropic agents Milrinone Milrinone is a phosphodiesterase inhibitor, positive inotropic agent with peripheral vasodilator effects. Milrinone also has lusitropic properties which are manifested by improvement in diastolic function. It minimally raises heart rate [47]. Based on the lack of head-to-head trials, there is no preference for milrinone versus dobutamine in the majority of patients. However, milrinone may be preferred in patients receiving β-adrenergic blocking drugs and in some patients with markedly elevated pulmonary artery pressure or right ventricular failure. As milrinone enhances camp, it may reduce pulmonary artery pressure via a vasodilator mechanism, and therefore may improve right ventricular function [47]. Milrinone exerts a greater hypotensive effect than dobutamine and has a longer plasma elimination half-life. In randomized controlled studies, milrinone failed to demonstrate a superior effect compared to placebo [48]. Levosimendan Levosimendan is a calcium sensitizing drug widely used in Europe, but not approved in the United States. The drug appears to enhance troponin C sensitivity to intracellular calcium, thereby enhancing cardiac inotropy and lusitropy [49]. Levosimendan also has vasodilating effects by opening smooth muscle ATP-dependent potassium channels. Calcium sensitizing agents have the theoretical advantage of driving contractile state without increasing camp or calcium itself, both of which have adverse effects. It appears that levosimendan s ability to enhance calcium responsiveness of myofilaments potentiates contractility and enhances relaxation, with slight o no increase in oxygen demand. The drug has been tested in the cardiac surgery settings apparently with promising outcome effects [50]. In addition, repetitive levosimendan dosing in patients suffering from advanced chronic HF have shown beneficial effects on haemodynamics, neurohormone levels and symptoms [51]. Two different randomized studies assessed the effect of levosimendan in AHF patients. The REVIVE-II study indicated no difference in mortality at 90 days, although survival was not a primary end-point, and levosimendan was associated with more adverse effects [52]. In the SURVIVE levosimendan was compared with dobutamine in a randomized, controlled trial involving 1327 patients. Levosimendan did not significantly reduce all-cause mortality at 180 days, and did not affect any secondary clinical outcomes. Subgroup analyses indicate nevertheless that levosimendan might outperform dobutamine in beta-blocked patients and in patients with acute decompensation of chronic HF [53]. Conclusions AHF remains a complex and difficult to manage clinical entity with few recent advances. This review focused on prognostic risk stratification of patient presenting with AHF and on common in-hospital medical treatments. The increasing prevalence of HF in the population and the consequent higher economic and human burden posed by the disease require the development of new treatments. Although some new therapies seem beneficial from a physiologic standpoint, clinical studies have yet to show solid improvements in outcome. Moreover the methods used to investigate their safety and efficacy can be challenging. Nevertheless, future clinical trials must be conducted in order to improve the evidence base and drive optimal therapy for AHF. References 1. Dickstein K, Cohen-Solal A, Filippatos G et al (2008). ESC guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology developed in collaboration with the Heart Failure Association of

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87 Intern Emerg Med (2015) 10 (Suppl):S74-S81 S81 NaTriuretic Peptide in acutely decompensated heart failure (GAL- LANT) trial. Eur J Heart Fail 13(8): Shrestha K, Borowski AG, Troughton RW et al (2011). Renal dysfunction is a stronger determinant of systemic neutrophil gelatinase-associated lipocalin levels than myocardial dysfunction in systolic heart failure. J Card Fail 17(6): Shah RV, Chen-Tournoux AA, Picard MH et al (2010). Galectin-3, cardiac structure and function, and long-term mortality in patients with acutely decompensated heart failure. Eur J Heart Fail 12(8): Costanzo MR, Guglin ME, Saltzberg MT et al (2007). Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 49(6): Bart BA, Goldsmith SR, Lee KL et al (2012). Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 367(24): Yancy CW, Jessup M, Bozkurt B et al (2013) ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 128(16):e Abraham WT, Adams KF, Fonarow GC et al (2005). In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 46(1): Mebazaa A, Parissis J, Porcher R et al (2011). Short-term survival by treatment among patients hospitalized with acute heart failure: the global ALARM-HF registry using propensity scoring methods. Intensive Care Med 37(2): Chen HH, Anstrom KJ, Givertz MM et al (2013). Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 310(23): De Backer D, Biston P, Devriendt J et al (2010). Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 362(9): Sonnenblick EH, Frishman WH, LeJemtel TH (1979). Dobutamine: a new synthetic cardioactive sympathetic amine. N Engl J Med 300(1): O Connor CM, Gattis WA, Uretsky BF et al (1999). Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J 138(1 Pt 1): Francis GS, Bartos JA, Adatya S (2014). Inotropes. J Am Coll Cardiol 63(20): Cuffe MS, Califf RM, Adams KF et al (2002). Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 287(12): Givertz MM, Andreou C, Conrad CH, Colucci WS (2007). Direct myocardial effects of levosimendan in humans with left ventricular dysfunction: alteration of force-frequency and relaxation-frequency relationships. Circulation 115(10): Toller W, Heringlake M, Guarracino F et al (2015). Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion. Int J Cardiol 184: Altenberger J, Parissis JT, Ulmer H, Poelzl G (2010). Rationale and design of the multicentre randomized trial investigating the efficacy and safety of pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep study). Eur J Heart Fail 12(2): Packer M, Colucci W, Fisher L et al (2013). Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail 1(2): Mebazaa A, Nieminen MS, Filippatos GS et al (2009). Levosimendan vs. dobutamine: outcomes for acute heart failure patients on beta-blockers in SURVIVE. Eur J Heart Fail 11(3): Conflicts of interests: none declared.

88 Intern Emerg Med (2015) 10 (Suppl):S82-S89 WARD MEDICINE Arterial stiffness Maria Lorenza Muiesan Massimo Salvetti Anna Paini Claudia Agabiti-Rosei SIMI 2015 Abstract Aortic pulse wave velocity (PWV) represents a well known index of aortic stiffness and may be easily measured in humans, by the use of noninvasive ultrasound methods of high reproducibility. Several epidemiologic studies have demonstrated that aortic PWV is a predictor of cardiovascular events in populations of hypertensive subjects, independently of confounding factors such as age, gender, body mass index, brachial blood pressure and metabolic abnormalities. For this reason, 2013 European guidelines have proposed the use of PWV measurement for risk stratification of hypertensive patients, confirming the importance of carotid-femoral PWV (cfpwv) as a sub-clinical organ damage. Several methods have been proposed to analyze the structure and function of large arteries. Among all, the measurement of PWV seems to be the most simple, accurate and reproducible method and ideal for the application in clinical practice. The Reference Value for Arterial Stiffness Collaboration provided normal and reference values for cfpwv, measured using a standardized methodology in a large European population, in subjects or patients with different cardiovascular risk factors, and according to different age and blood pressure (BP) categories. European guidelines have indicated a threshold greater than 10 m/sec as an index of large artery stiffening. M.L. Muiesan ( ) Department of Clinical and Experimental Sciences, University of Brescia and Department of Medicine Azienda Spedali Civili di Brescia, Piazzale Spedali Civili Brescia 1, Brescia, Italy. marialorenza.muiesan@unibs.it M. Salvetti Department of Clinical and Experimental Sciences, University of Brescia and Department of Medicine, Azienda Spedali Civili di Brescia, Italy. A. Paini C. Agabiti-Rosei Department of Medicine, Azienda Spedali Civili di Brescia, Italy. Future research will establish the additional BP independent effect of different pharmacological interventions as well as the prognostic value of aortic stiffness changes. Riassunto La valutazione del danno d organo rappresenta un aspetto assai importante della stratificazione del rischio cardiovascolare nei pazienti con ipertensione arteriosa. Infatti il riscontro di un danno d organo iniziale rappresenta una condizione di malattia preclinica in cui il paziente è esposto ad un maggiore rischio cardiovascolare. Recentemente è stata sottolineata la possibilità di valutare il precoce invecchiamento arterioso, ovvero le alterazioni strutturali e funzionali che si instaurano con l età, ma che sono accelerate dalla presenza di diversi fattori di rischio cardiovascolare. Dal 2007 le Linee Guida della Società Europea della Ipertensione Arteriosa e di Cardiologia (ESH/ESC) avevano incluso la rigidità arteriosa fra le forme di danno d organo suggerite per l identificazione di pazienti a rischio cardiovascolare, proponendo che, quale indice di rigidità arteriosa, venga privilegiato l uso della valutazione della velocità dell onda di polso carotideo-femorale ( pulse wave velocity, o PWV). La misurazione della PWV si è infatti affermata nel corso degli anni come metodica di riferimento per la valutazione della rigidità arteriosa. Questo tipo di approccio si è dimostrato semplice, non invasivo e riproducibile. La tecnica prevede la rilevazione della morfologia dell onda sfigmica mediante l utilizzo di trasduttori cutanei posizionati a livello carotideo e femorale. La misurazione del ritardo temporale fra i due piedi delle onde pulsatorie ( transit time, Δt) e della distanza fra i due siti di rilevazione (ΔL) consente di calcolare con accuratezza la velocità dell onda di polso, secondo la formula PWV = ΔL/ Δt. È opportuno sottolineare che la rigidità arteriosa può essere analizzata mediante altri approcci, quali lo studio della distensibilità arteriosa locale o anche attraverso parametri derivati, mediante tonometria d appianamento, dall analisi della morfologia dell onda di polso: l augmentation index, che esprime l aumento di pressione generato dalla riflessione

89 Intern Emerg Med (2015) 10 (Suppl):S82-S89 S83 dell onda dalla periferia, può essere ritenuto un indice indiretto di rigidità arteriosa. L utilizzo di queste ultime metodiche è al momento attuale prevalentemente legato a protocolli di ricerca e, come già sottolineato, le Linee Guida suggeriscono l impiego della PWV quale indicatore di aumento della rigidità arteriosa, proponendo un cut-off di 10 m/sec. Recentemente sono stati definiti i valori normali di riferimento per la PWV in soggetti senza fattori di rischio cardiovascolare e in pazienti con progressivo aumento dei valori pressori. L inclusione della PWV quale indicatore di danno d organo preclinico poggia su solide basi scientifiche. Infatti numerosi studi trasversali hanno dimostrato che la rigidità arteriosa e fattori di rischio cardiovascolare come l invecchiamento, l ipertensione arteriosa, l ipercolesterolemia, il diabete mellito di tipo 2 o l intolleranza glucidica, la sindrome metabolica e la presenza di elevazione degli indici di infiammazione sono correlati fra loro, suggerendo che la rigidità arteriosa possa essere considerata alla stregua di un marker di rischio cardiovascolare. Inoltre nei soggetti con aumento della PWV vi è una maggior prevalenza di altre forme di danno d organo, sia a livello renale, che cardiaco, che vascolare. Ma è ancor più importante sottolineare che la PWV carotideo-femorale ha un significato prognostico indipendente per mortalità per tutte le cause, per mortalità cardiovascolare, per eventi coronarici mortali e non mortali e per ictus cerebrale in differenti gruppi di pazienti, ovvero in pazienti con ipertensione arteriosa essenziale, in pazienti con diabete mellito tipo 2, con insufficienza renale terminale, negli anziani e nella popolazione generale. Ad ulteriore conferma dei risultati dei singoli studi, una recente metanalisi di 17 studi longitudinali, nei quali sono stati inclusi più di pazienti, con un follow-up medio di 8 anni, ha ulteriormente confermato che l aumento della PWV è fattore predittivo indipendente per eventi cardiovascolari e per mortalità per tutte le cause, indipendentemente dagli altri fattori di rischio cardiovascolare. È importante sottolineare che, mentre il significato prognostico della rigidità arteriosa è ampiamente dimostrato, rimane da chiarire il valore prognostico delle modificazioni nel tempo della PWV durante terapia e tuttora i dati a tale riguardo sono limitati a pazienti ad alto rischio cardiovascolare, in pazienti affetti da insufficienza renale terminale. Guerin e collaboratori hanno osservato che la mancata riduzione della PWV durante trattamento antipertensivo identifica pazienti nei quali vi è una aumentata mortalità nel follow-up, indipendentemente dai valori di pressione arteriosa. Altri studi dovranno meglio chiarire il significato prognostico delle modificazioni nel tempo della PWV in gruppi di pazienti a rischio cardiovascolare meno elevato. Il riscontro di un aumento della PWV può dunque modificare in maniera significativa la stratificazione del rischio cardiovascolare e avere ripercussioni importanti sulle scelte terapeutiche. Infatti il riscontro di danno d organo in pazienti che, dopo una valutazione iniziale dei fattori di rischio cardiovascolare e del danno d organo potrebbero essere definiti a rischio cardiovascolare basso o medio, la presenza di danno d organo comporta il passaggio ad una categoria di rischio elevato, con conseguente indicazione, in base alle attuali Linee Guida, ad un inizio del trattamento farmacologico. L analisi della PWV costituisce uno strumento assai efficace per una accurata valutazione del danno d organo nei pazienti ipertesi, in grado di consentire una più precisa stima del rischio cardiovascolare globale e di favorire l ottimizzazione delle strategie di trattamento. Introduction In more recent years it has become possible to evaluate the vascular aging process by the measurement with non-invasive technique [1]. European guidelines have included aortic stiffness among the subclinical target organ damages that might be assessed in a hypertensive patient, for a more accurate and precise cardiovascular (CV) risk stratification [2]. In fact several studies have documented a correlation between arterial stiffness measures (in particular aortic pulse wave velocity, PWV) and CV risk factors, such as aging, arterial hypertension, diabetes mellitus, metabolic syndrome, hypercolesterolemia as well as markers of chronic inflammation processes [3] and more importantly, an increase of aortic stiffness has been shown to predict the occurrence of CV events above and independently of traditional risk factors [4]. Alterations of segmental and local arterial mechanics The major vessel of interest when determining arterial stiffness is the aorta, since the buffering of ventricular systolic energy occurs at the level of the thoracic and abdominal aorta [5-7]. With aging the proximal conduit arteries lose their elastic properties and the capacity to dampen the pulsatility of ventricular ejection in systole and to transform a pulsatile pressure and flow at the aorta in a continuous pressure and flow at the site of arterioles. This phenomenon has been clearly described in humans, examining the pressure/volume curves of aorta segments obtained from patients dead at different ages, and thereafter confirmed by non-invasive techniques [5, 6, 8]. The main pathophysiological consequences of arterial stiffness are (a) the increase in systolic blood pressure (BP), because of the impaired reservoir function of elastic conduit arteries; (b) the decrease in diastolic BP because of the lack of elastic energy consequent to elastic recoil of stretched vessel walls. The progressive reduction in compliance associated with aging is responsible for the parallel increase in pulse

90 S84 Intern Emerg Med (2015) 10 (Suppl):S82-S89 pressure (PP), and this phenomenon is independent by any change in mean BP. The pulsatile component of hemodynamic is also fundamental in order to guarantee a continuous and not intermittent flow and perfusion to peripheral small vessels and organs, and plays a main role in both the development and progression of aging, CV disease and its clinical sequelae. The higher the arterial stiffness, the higher the speed of travel of forward and retrograde waves. In 1922, Bramwell and Hill [9] described for the first time a significant correlation between the pulse wave velocity (PWV) and age. Several other epidemiological studies, conducted in different groups of patients have demonstrated and confirmed that PWV increases with the aging process, both in men and women [7]. The increase in PWV with age has been observed also in patients with a low prevalence of atherosclerotic lesions, indicating that the progressive loss of arterial compliance may develop independently of atherosclerotic damage, at least in part. In the presence of atherosclerotic vascular process, starting with endothelial dysfunction, a vicious circle develops: vessel s mechanical properties may influence endothelial dysfunction [10] and atherosclerotic damage that on the other side may exert an unfavorable effect of vascular stiffness. With aging, the increase in aorta walls stiffness may contribute to the alteration of the pulse pressure amplification, a physiological phenomenon that may be observed in young healthy subjects when analyzing the different pressure waves measured at the level of the aorta and of a peripheral artery (brachial or radial); on the opposite, in elderly subjects a progressive reduction of the difference between central and peripheral PP develops. In fact pressure waveform morphology is influenced by the dynamic interaction between the forward wave, generated by ventricular systole, and the backward wave, travelling from the peripheral sites towards the central aorta. The increase in aortic stiffness, and possibly functional and morphological changes in aortic branches and microvasculature, cause an earlier arrival of the reflected wave in the central aorta and augment pressure in late systole, increasing PP. This augmentation can be expressed as aortic augmentation index (AIx), i.e. the percentage value of the increment pressure of aortic PP caused by the reflected wave [3]. Few studies have prospectively investigated the longitudinal and temporal relationships among aortic stiffness and central hemodynamics and peripheral BP showing that an increase in carotid-femoral PWV (cfpwv) or brachial-ankle PWV (bapwv) may predict the incidence of hypertension in normotensive subjects [11-14]. Arterial stiffness and pulsatile hemodynamic parameters (central systolic and pulse pressure, AIx and pressure) are associated with target organ damage (left ventricular hypertrophy [15], microalbuminuria, carotid intima-media thickening, endothelial dysfunction and microvascular alterations [16]) and with clinical events and therefore are often used interchangeably as indexes of arterial stiffness. However, determinants of central pressure, AIx and regional or local PWV are different. In particular, central systolic and pulse pressure and AIx are influenced by wave velocity, the amplitude of reflected wave, the reflectance sites, and the duration and pattern of ventricular ejection, and therefore by changes in heart rate and ventricular contractility [17, 18]; aortic PWV represents the speed of wave travel and is dependent of the intrinsic alteration in arterial stiffness [9]. In addition central BP and AIx may change in different pathophysiological conditions and under the effect of drugs, without any change in PWV, thus suggesting a greater effect on reflected waves, heart rate or ventricular ejection rather than on intrinsic wall stiffness[19]; the effect of heart rate changes is more prominent on AIx than on cfpwv [20]. Aging and BP are the main determinants of vascular stiffness, inducing a reduced synthesis and an increased degradation of elastin, in association with an increased synthesis and reduced degradation of type 1 and type 3 collagen [21]; calcification of the vessel wall may also occur, as frequently observed in elderly subjects and in hypertensive patients. According to a proposed model of vessel wall structure, muscular fibers are organized in series in respect to collagen fibers and both are in parallel to elastic fibers [22]. Wall stress is directed to collagen elements during muscular contraction (stiffer wall) and to elastic lamina during muscular relaxation (more compliant wall) [10]. With aging the contractile component contribution to vessel wall stiffness is progressively reduced [23], while the extracellular matrix changes, including an increase of collagen fibers density in the media layer [21, 24, 25] have a relevant role. The elastin/collagen ratio, which has a key role in determining the viscoelastic properties of the vessel wall, is progressively reduced with advancing age [25-28]. The observed changes in vessel wall material spatial organization, characterized by a greater number of vascular muscle cells and internal lamina elastica connections and a decrease of fenestrations dimensions, should improve the pressure load to elastic material [10]. In addition non enzymatic glycation end products may further influence functional vessels properties, by the cross-linking with cellular matrix proteins, leading to collagen increased proteolysis resistance and reduced solubility [27, 29-32]. More recently the calpain-1 induced activation of metalloproteinases-2 (MMP2) has been suggested to contribute to the extracellular matrix remodeling [33]. Other mechanisms of aging-related arterial stiffening and hypertension include metabolic syndrome [34], inflammation [35], and neurohormonal dysfunction. According to O Rourke, the repeated cyclic stress imposed to vessels walls could represent the mechanism responsible

91 Intern Emerg Med (2015) 10 (Suppl):S82-S89 S85 for the vascular degenerative process induced by age, with fragmentation and loss of elastic fibers organization in the vessel wall [36]. Carotid and other conduit arteries may undergo a 10% circumferential stress for every heartbeat, and it has been calculated that fibers fracture may occur after 800 millions cycles at a heart rate of 70 beats /minute, i.e. after 25 years of life. Peripheral muscular arteries undergo a minor stretch (<5%), corresponding to fibers fracture after 100 years of age; according to this hypothesis the elastin fibers fragmentation would start in early age in central conduit arteries, but not in peripheral muscular vessels; in the presence of hypertension vessel walls stress increases, because of more pronounced pressure fluctuations, accelerating the degenerative process of arterial stiffening. No changes in peripheral muscular arteries (such as the radial artery) compliance have been observed in hypertensive patients as compared to normotensive subjects [22, 37-39]. Laurent et al [40] did not observe an increase in carotid local stiffness, as confirmed by other authors in humans [41] and animal models [38, 42]; on the opposite Stewart et al have shown that carotid PWV was 24% higher and carotid compliance was 48% lower in hypertensive patients, despite normal BP values [43]. A large number of publications and several reviews have reported the various pathophysiological conditions associated with increased arterial stiffness and wave reflections, including arterial hypertension [44-50] and in particular isolated systolic hypertension [32, 51-55]. Arterial stiffness measurement Arterial stiffness may be measured at systemic and local levels. Systemic arterial stiffness can be estimated from models of the circulation and should not be confounded with blood velocity. Regional and local arterial stiffness can be measured directly, noninvasively, at various sites along the arterial tree and they are based on direct measurements of parameters strongly linked to wall stiffness. The measurement of PWV is generally accepted as the most robust method to determine arterial stiffness [3]. CfPWV is a direct measurement, and it corresponds to the widely accepted propagative model of the arterial system [3]. This approach has been shown to be simple, non-invasive and reproducible. The technique for PWV measurement is usually performed recording transcutaneously by mechano-transducers or applanation tonometers two different waveforms at the right common carotid artery and the right femoral artery (i.e., carotid-femoral PWV) using the foot-to-foot velocity method and the time delay (Δt, or transit time) measured between the feet of the two waveforms [56]. The foot of the wave is defined at the end of diastole, when the steep rise of the wave front begins. The transit time is the time of travel of the foot of the wave over a known distance (travel distance). Pressure waveforms can be recorded simultaneously to provide automated measurement of PWV (Complior System, Colson, Les Lilas, France) or can be recorded sequentially from different sites by a single high-fidelity applanation tonometer, and transit time calculated using registration with a simultaneously recorded ECG (SphygmoCor system, AtCor, Sydney, Australia) or other devices. BaPWV has been suggested as a simpler alternative to cf- PWV since the aortic PWV was the main independent correlate of bapwv, followed by leg PWV [57]. The wave travel distance is usually derived from the surface distance between the two recording sites, i.e. the common carotid artery and the common femoral artery. PWV is calculated as follows: PWV = D (m)/δt (s). The accuracy of the travel distance is crucial, since small differences in travel distance may have a substantial influence on absolute values of PWV. According to the most recent consensus paper it is possible to calculate the subtracted distance or preferably to measure the direct distance and apply a 0.8 coefficient, to take into account the different pathways of the pressure wave already described [58]. The technique implies some possible practical limitations, such as the difficulty to obtain accurate recording of the femoral pressure waveform in patients with metabolic syndrome, obesity, diabetes, and peripheral artery disease [59]. A stenosis of aortic, iliac, or proximal femoral arteries may attenuate or delay the pressure wave. In 2010 the Reference Value for Arterial Stiffness Collaboration provided normal and reference values for cfpwv, measured using a standardized methodology in a large European population, including 16,867 individuals and patients from 13 different centers across 8 European countries [60]. Normal values were derived from individuals showing optimal BP values and no CV risk factors. Reference values were calculated in subjects or patients with different CV risk factors, and according to different age and BP categories. The 2013 ESH/ESC guidelines have confirmed the importance of cfpwv as a sub-clinical organ damage and have indicated a threshold greater than 10 m/sec as an index of large artery stiffening [2]. A variety of different waveforms can be used including pressure [56], distension [61], and Doppler [62].The distension waves obtained at a short time interval at two arterial sites (common carotid and femoral artery, for instance) by high-resolution echo-tracking devices can be also used to calculate PWV, using the R-wave of the ECG for calculating the time delay [3, 63, 64]. Echo-tracking systems offer some

92 S86 Intern Emerg Med (2015) 10 (Suppl):S82-S89 additional advantages, allowing the calculation of Young s elastic modulus (using a radiofrequency accurate measure of intima-media thickness), and the determination of arterial stiffness for any given BP from the arterial/diameter curves, (assuming that the cross section of an artery is circular); these parameters require the simultaneous measurement of local pressure, which is usually obtained by applanation tonometry and calibration of the waveform to brachial mean and diastolic pressures obtained by integration of the brachial or radial waveform, or automatic calculation using transfer function processing. For the calculation of wall properties, it is assumed that the cross section of an artery is circular. Arterial distensibility, determined from the systolic-diastolic variations in arterial cross-sectional area and local PP, allows the evaluation of arterial elastic properties, while the elastic properties of the arterial wall material are estimated by the Young s incremental elastic modulus (Einc), which takes into account the thickness of the intima-media thickness [3, 58]. In addition nuclear magnetic resonance may be the most appropriate method for the evaluation of less superficial vessels [3, 58]. Arterial stiffness and clinical outcome Since 1812 a fundamental role for arterial stiffness in the development of CV events was suggested by Warren et al [65]. The earlier reflection of backward pulse waves [66] in late systole in the presence of increased arterial stiffness negatively affects the pressure load to the left ventricle, and the coronary perfusion during diastole favoring the development of left ventricular hypertrophy, systolic and diastolic dysfunction, and myocardial ischemia [15, 67, 68]. In recent years numerous studies have reported an association between alterations of arterial stiffness and of pulsatile hemodynamic parameters and the occurrence of CV events [4]. The increase in cfpwv has been shown to predict all-cause mortality, CV mortality, fatal and non-fatal coronary artery events, fatal stroke in different groups of patients, with arterial hypertension [69-71], with diabetes mellitus [72], with end-stage renal disease [73, 74], in elderly patients [75, 76] and in the general population [77-79]. Most importantly the prognostic significance of PWV is independent of brachial BP values, of major CV risk factors, and of the Framingham risk score [69], indicating that aortic stiffness has a better predictive value than each of the classical risk factors [80]. A possible explanation for the additional prognostic significance and more accurate CV risk re-stratification of cfpwv [81, 82] is that aortic stiffness reflects the damage of CV risk factors on the aortic wall over a long period of time, while the values of BP, glycemia, and lipids, measured at the time of risk assessment, may widely fluctuate over time. Data about prognostic significance of arterial stiffness measured at other arterial sites are less consistent. Carotid stiffness was predictive of CV events in a small number of patients with end-stage renal disease [83] or following renal transplantation [84] and in a large prospective cohort with a high prevalence of insulin resistance [85], while no predictive value was demonstrated in a larger number of patients with manifest arterial disease [86]. In contrast to cfpwv, CV event free survival was not associated to either brachial PWV or femoro-tibial PWV in end-stage renal disease patients [83] suggesting that upper and lower limb territories may not reflect aortic, cerebral, and coronary artery damage. Central AIx and PP are both independent predictors of allcause mortality in end-stage renal disease patients [87], in patients undergoing percutaneous coronary intervention [68, 88, 89], in the hypertensive patients of the CAFE study [90] and in general population sample [67], while in older female hypertensives, participating into the Second Australian National BP (ANBP2) study the use of carotid applanation tonometry (AIx or total arterial compliance) show no benefit over brachial cuff pressure in prognosis [91]. Data on changes in PWV and occurrence of CV events are still limited. Guerin et al [92] have demonstrated that in end-stage renal disease patients the persistence of elevated cfpwv was associated with a worse survival as compared to patients with a decrease of cfpwv, independently of brachial BP changes. It remains to be demonstrated in hypertensive patients at lower CV risk that a reduction or a normalization of arterial stiffness is effective in reducing CV events beyond brachial BP reduction. Effect of treatment Exercise training, weight loss, low to moderate sodium diet, moderate alcohol consumption, but also dietary supplements may have a beneficial effect on changes in arterial stiffness. The reduction of BP per se may induce a decrease of cfpwv [93]. Among antihypertensive classes of drugs, diuretics, beta-blockers, ACE inhibitors, angiotensin II type 1 receptor blocker (AT1 blockers), and calcium channel antagonists are able to reduce arterial stiffness [3, 94]. Some studies have also shown that a non-dihydropiridinic calcium-antagonist (acute administration) or an ACE-inhibitor [95, 96] or an angiotensin II receptor blocker [97] are able to reduce arterial stiffness and/or wave reflections independently of the reduction in brachial BP.

93 Intern Emerg Med (2015) 10 (Suppl):S82-S89 S87 In addition a decrease in arterial stiffness has been determined by ACE inhibitors, nitrates, and aldosterone antagonists in congestive heart failure patients, as well as statins, and antidiabetic drugs. The additional BP independent effect of different pharmacological interventions remains to be further evaluated. References 1. Nilsson PM, Boutouyrie P, Cunha P et al (2013). Early vascular ageing in translation: from laboratory investigations to clinical applications in cardiovascular prevention. J Hypertens 31: Mancia G, Fagard R, Narkiewicz K et al (2013) ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 31: Laurent S, Cockcroft J, Van Bortel L et al (2006). Expert consensus document on arterial stiffness: methodological issues and clinical applications. 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95 Intern Emerg Med (2015) 10 (Suppl):S82-S89 S Muiesan ML, Salvetti M, Paini A et al (2010). Pulse wave velocity and cardiovascular risk stratification in a general population: the Vobarno study. J Hypertens 28: Sehestedt T, Jeppesen J, Hansen TW et al (2010). Risk prediction is improved by adding markers of subclinical organ damage to SCORE. Eur Heart J 31: Pannier B, Guerin AP, Marchais SJ et al (2005). Stiffness of capacitive and conduit arteries: prognostic significance for end-stage renal disease patients. Hypertension 45: Barenbrock M, Kosch M, Joster E et al (2002). Reduced arterial distensibility is a predictor of cardiovascular disease in patients after renal transplantation. J Hypertens 20: van Sloten TT, Schram MT, van den Hurk K et al (2014). Local stiffness of the carotid and femoral artery is associated with incident cardiovascular events and all-cause mortality: the Hoorn study. J Am Coll Cardiol 63: Dijk JM, Algra A, van der Graaf Y et al (2005). Carotid stiffness and the risk of new vascular events in patients with manifest cardiovascular disease. The SMART study. Eur Heart J 26: London GM, Blacher J, Pannier B et al (2001). Arterial wave reflections and survival in end-stage renal failure. Hypertension 38: Weber T, Auer J, O Rourke MF et al (2005). Increased arterial wave reflections predict severe cardiovascular events in patients undergoing percutaneous coronary interventions. Eur Heart J 26: Jankowski P, Kawecka-Jaszcz K, Czarnecka D et al (2008). Pulsatile but not steady component of blood pressure predicts cardiovascular events in coronary patients. Hypertension 51: Williams B, Lacy PS, Thom SM et al (2006). Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 113: Dart AM, Gatzka CD, Kingwell BA et al (2006). Brachial blood pressure but not carotid arterial waveforms predict cardiovascular events in elderly female hypertensives. Hypertension 47: Guerin AP, Blacher J, Pannier B et al (2001). Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation 103: Ong KT, Delerme S, Pannier B et al (2011). Aortic stiffness is reduced beyond blood pressure lowering by short-term and long-term antihypertensive treatment: a meta-analysis of individual data in 294 patients. J Hypertens 29: Ghiadoni L, Bruno RM, Stea F et al (2009). Central blood pressure, arterial stiffness, and wave reflection: new targets of treatment in essential hypertension. Curr Hypertens Rep 11: Tropeano AI, Boutouyrie P, Pannier B et al (2006). Brachial pressure-independent reduction in carotid stiffness after long-term angiotensin-converting enzyme inhibition in diabetic hypertensives. Hypertension 48: Asmar RG, London GM, O Rourke ME et al (2001). Amelioration of arterial properties with a perindopril-indapamide very-low-dose combination. J Hypertens Suppl 19:S15-S Laurent S, Boutouyrie P (2014). Dose-dependent arterial destiffening and inward remodeling after olmesartan in hypertensives with metabolic syndrome. Hypertension 64:709-16

96 Intern Emerg Med (2015) 10 (Suppl):S90-S93 WARD MEDICINE Antibiotic therapy in critically ill patient Nicola Petrosillo Simone Topino Maria Adriana Cataldo SIMI 2015 Abstract Critically ill patients (CIP) with infection need to be promptly treated with appropriate antimicrobials. However, antibiotic treatment for these patients is challenging due to typical alteration in the pharmacokinetic/pharmacodynamic (PK/PD) profile of antimicrobials, to the frequent renal and hepatic impairment, and to the higher risk of antibiotic resistant bacteria etiology. In CIP with infection empirical antibiotic therapy should be chosen according to the suspected site of infection (to both predict the etiology and to prescribe the antibiotic according to its capability of penetration into the infection site), the setting in which the infection developed (i.e., home, nursing home, or hospital), the medical history, the local microbial-susceptibility patterns, and the PK/PD considerations. Regarding the PD properties of antibiotics, it should be emphasised that the bactericidal activity is of extreme importance for clinical cure in some infections. Endocarditis, meningitis and cerebral abscesses need to be treated with bactericidal antibiotics and it is generally recommended not to use bacteriostatic antibiotics also in patients with septic shock. Finally, special attention should be paid to patient s risk factors for harboring multidrug-resistant (MDR) bacteria since resistance to multiple antibiotics poses a further threat to CIP due to the probability of inappropriate antimicrobial therapy. When relevant microbiological data are available, the antibiotic treatment should be re-assessed and, if possible, narrow spectrum antibiotic should be administered in order to minimize the risk of selecting MDR-bacteria. M.A. Cataldo ( ) National Institute for Infectious Diseases L. Spallanzani, Via Portuense 292, Roma, Italy. adriana.cataldo@inmi.it N. Petrosillo S. Topino UOC Infezioni Sistemiche e dell Immunodepresso, National Institute for Infectious Diseases L. Spallanzani, Roma, Italy. Riassunto La scelta della terapia antibiotica empirica nel paziente critico con infezione deve essere effettuata valutando diversi fattori fra cui il verosimile sito di infezione, la storia clinica del paziente (in particolar modo le co-morbidità e la presenza di fattori di rischio per batteri resistenti a multipli antibiotici), l epidemiologia batterica locale e, infine, le caratteristiche farmacocinetiche e farmacodinamiche (PK/PD) dei farmaci. Numerosi studi hanno dimostrato che la tempestività e l appropriatezza della terapia antibiotica influenzano fortemente l outcome del paziente critico con infezione. L appropriatezza della terapia antimicrobica è correlata non solo al pattern di sensibilità antibiotica dell agente eziologico, ma anche al dosaggio del farmaco e al sito di infezione. Gli antibiotici devono essere scelti fra quelli con la maggiore capacità di penetrazione nel sito di infezione e con la maggior efficacia nei confronti dei microorganismi più frequentemente isolati in tali siti. È inoltre indispensabile valutare, sia nel paziente con infezione diagnosticata al momento del ricovero ospedaliero sia in quello con infezione nosocomiale, la presenza di fattori associati al rischio di infezione causata da batteri resistenti a multipli antibiotici. Una conoscenza dell epidemiologia locale è anche essenziale nella scelta della terapia antibiotica empirica. Infine, è necessario valutare le caratteristiche PK/PD degli antibiotici. Nel paziente critico vi sono tipicamente delle modifiche nell entità dell irrorazione sanguigna dei tessuti, un aumento del volume di distribuzione, alterazioni della capacità di legare le proteine e della clearance renale e/o epatica che possono influenzare notevolmente le caratteristiche PK/ PD degli antibiotici. È importante sottolineare che nel paziente critico il rischio di ottenere concentrazioni sub-ottimali di antibiotici con conseguente fallimento terapeutico è maggiore rispetto a quello di determinare effetti avversi causati da un eventuale sovradosaggio. Dal punto di vista della farmacodinamica è importante scegliere antibiotici con attività battericida, in particolare per la terapia di meningiti, endocarditi, ascessi cerebrali e, preferibilmente, anche nello shock settico.

97 Intern Emerg Med (2015) 10 (Suppl):S90-S93 S91 La terapia antibiotica scelta empiricamente deve poi essere rivalutata una volta acquisiti i risultati delle colture microbiologiche e il pattern di sensibilità antibiotica. Introduction Critical illness is any disease process which causes physiological instability that, in the absence of medical intervention, may produce a clinical progression to respiratory, cardiovascular and neurologic impairment [1]. Infections are among the causes of critical illness or may be a complication of critical illness [2]. Critically ill patients (CIP) with infection need to be promptly treated with appropriate antimicrobials. However, antibiotic treatment for these patients is challenging due to typical alteration in drug pharmacokinetics (PK), to the frequent renal and hepatic impairment and to the higher risk of antibiotic resistant bacteria etiology. In this article we will present relevant literature data on principles guiding the antimicrobial choice in CIP with infection diagnosed in general medical wards. Choice of empiric antibiotic therapy Numerous papers have demonstrated that the more timely and appropriate is the administration of an antibiotic in CIP with infection the better is the outcome. Kumar et al. [3] retrospectively studied 2,154 patients with septic shock and found that time to initiation of appropriate antibiotic therapy was the strongest predictor of survival with a survival rate of 80% in patients starting an effective antibiotic within the first hour of documented hypotension. Moreover each 1-hour delay of starting antimicrobial therapy over the next 6 hours after the diagnosis of septic shock, decreased average survival rates by 7.6% [3]. Several studies have demonstrated that outcome is significantly improved when the initial choice of antibiotic is appropriate. Appropriateness of antimicrobial therapy is related not only to the causative agent of the infection but also to the dosing and to the site of infection. As a consequence, special efforts should be made in order to predict the source of infection, the likely etiology and the antimicrobial susceptibility pattern of the causative agent. Source of sepsis First of all the source of infection needs to be assessed in order to both predict the etiology and to prescribe the antibiotic according to its capability of penetration into the infection site. The Table shows the most frequent microorganisms isolated according to the infection site. Because the delivery of drugs to the local site of infection can not be directly measured, in vitro parameters have been established to predict the probability of success of antimicrobial therapy. Antibiotic susceptibility testing are used for this scope determining the minimum inhibitory concentration (MIC). The antibiotic concentration in the infectious site must exceed the MIC for the best cure rates. Antibiotic failure may occur if the administered antibiotic, even if chosen according to the MIC, does not achieve a satisfactory concentration at the target site. On the contrary, antibiotics considered partially or not effective according to MIC, may be clinically effective if they are able to achieve a high concentration at the infection site [4]. For example, aminoglycosides might be used for urosepsis even if the organism has a high MIC value, on the contrary they are not recommended for pulmonary infections, irrespective of the MIC value. In addition local factors such as the vascularity index of a site should be evaluated when deciding the best antibiotic. Usually good drug levels Table 1 Most frequent bacteria according to the infection site. Infection site Pathogens Urinary tract Enterobacteriaceae, Pseudomonas aeruginosa, Enterococcus spp., Staphylococcus spp. Cardiovascular Staphylococcus spp., Streptococcus spp., Enterococcus spp., HACEK, Gram negative bacteria, fungi Abdomen Enterobacteriaceae, Pseudomonas aeruginosa, Enterococcus spp., anaerobes, Candida spp. CA, HCA and HA pneumonia Streptococcus pneumoniae, Staphylococcus aureus, Legionella pneumophila, Mycoplasma pneumoniae, Haemophilus influenzae, Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus VA pneumonia Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, anaerobes, Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii Intravascular device Staphylococcus spp., Enterobacteriaceae, Pseudomonas aeruginosa, Candida spp. SSTI Streptococcus spp., Staphylococcus spp., anaerobes CNS Streptococcus pneumoniae, Listeria monocytogenes, Neisseria meningitidis, Haemophilus influenzae, Escherichia coli, fungi Abbreviations: CA, community acquired; CNS, central nervous sistem; HA, hospital acquired; HACEK, Haemophilus parainfluenzae, Aggregatibacter spp., Cardiobacterium hominis, Eikinella corrodens, Kingella spp.; HCA, health care associated; SSTI, skin and soft tissue infections; VA, ventilator associated.

98 S92 Intern Emerg Med (2015) 10 (Suppl):S90-S93 are achieved in joint, pleural and peritoneal space infections due to the high vascularity index of these sites [4]. Importantly, antibiotics cannot be effectively delivered into abscesses or other necrotic tissue and into foreign body infections. In these cases an urgent source control is required. Examples of infections that require a surgical intervention include intra-abdominal abscesses, necrotizing pancreatitis with infection, mediastinitis, bacterial empyema, gangrenous cholecystitis, obstructive uropathy, necrotizing soft tissue infections, purulent foreign body infections [4]. Pharmacokinetic and pharmacodynamic (PK/PD) considerations When deciding the correct antibiotic dose, drug PK and pathophysiological changes typical of CIP that can affect PK/ PD properties of the drugs should be carefully taken into account. The PK/PD profile of antimicrobials is expected to be altered in the CIP due to several factors including modifications in tissue blood flow, increase in volume of distribution (Vd), alterations in protein binding, alteration in the ability of liver to clear drug, enhanced or impaired renal clearance. As a consequence of these physiological changes, PK of antimicrobials is affected to a different extent in the CIP according to their chemical-physical properties, that is being hydrophilic or lipophilic in nature [5]. In regards to lipophilic antimicrobials, the physiological changes occurring with critical illness are in general less relevant in altering the PK profile. Similar concentration-time profiles are observed for lipophilic agents in critically ill as well as non-cip. PK of hydrophilic antimicrobials may be especially affected in septic patients [6]. This is related to the limited tissue distribution of hydrophilic antibiotics which is normally restricted to the extracellular space. In patients with severe sepsis and/or with septic shock, the Vd of hydrophilic agents may be temporarily increased due to the capillary leakage in organs. Larger loading dosages of aminoglycosides are needed to achieve desirable target concentrations [7]. Since hydrophilic antimicrobials are cleared by the renal route, fluctuations of renal function that usually occur in CIP, may increase or decrease the drug clearance. When treating CIP severe infection using hydrophilic antimicrobials, therapy must always be started with a full loading dose, irrespective of the patient s renal function. This will allow prompt achievement of therapeutically effective concentrations in tissues. However, in the subsequent days, maintenance dosages have to be adjusted according to renal function. This is especially relevant for aminoglycosides and glycopeptides to avoid drug overexposure that may cause toxic effects. Regarding the relationship between hepatic dysfunction and drug clearance, the only antimicrobials for which dosage reduction is recommended for patients with Child-Pugh class C are metronidazole, tigecycline and caspofungin [8-11]. In conclusion, for CIP with infection it should be emphasised that overall the risk of suboptimal concentrations is higher than the risk of adverse effects due to overdosing, especially for hydrophilic antimicrobials. Regarding the PD properties of antibiotics, the bactericidal activity is of extreme importance for clinical cure in some infections. Endocarditis, meningitis and cerebral abscesses need to be treated with bactericidal antibiotics. It is generally recommended not to use bacteriostatic antibiotics also in patients with septic shock, although this necessity is not widely accepted. Risk of infection due to multidrug-resistant (MDR) bacteria The initial assessment of the risk factors for infection with MDR pathogens is a prerequisite for proper empirical antibiotic therapy. Resistance to multiple antibiotics poses a further threat to CIP due to the probability of inappropriate antimicrobial therapy. Important MDR-pathogens involved in nosocomial infections are methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci and multidrug-resistant Gram-negative bacteria (MDR-GN), including MDR-Pseudomonas aeruginosa, MDR-Acinetobacter baumannii, extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and carbapenemase-producing Klebsiella pneumoniae (KPC). In the last years MDR bacteria have been reported with increased frequency also at hospital admission. Factors most frequently reported to be associated with the risk of harbouring MDR bacteria at hospital admission are previous exposure to antibiotics, hospitalizations in the previous 6 months, repeated hospitalization, residency in long-term care facilities, contact with health-care setting (e.g. hemodialysis, urinary catheter, home dressing of wounds and/or skin ulcers), previous infection or colonization by MDR-bacteria. All these factors need to be evaluated in any CIP with infection in order to assess his risk of harboring MDR-bacteria and to consequently choose the best empirical antimicrobial therapy. Actually the frequency of antibiotic-resistant pathogens at hospital admission widely varies in published studies. The heterogeneity of findings might be due to different local microbiology and individual risk factors, such as functional status or prior antibiotic exposure. Several scores elaborated to predict the probability of harboring MDR bacteria at hospital admission have been proposed. The various scores published in scientific literature may help in a better identification of patients at risk for MDR-bacte-

99 Intern Emerg Med (2015) 10 (Suppl):S90-S93 S93 ria infections needing a broader antibiotic coverage. However an important limitation of the scores is represented by the limited generalisability to hospital settings with different patients case mix and different local microbiological patterns. As a consequence, therapy for infection in CIP has to be decided caseby-case considering the local ecology, the specific risk factors for antibiotic-resistant infection and for unusual etiology, and the functional status of every single patient. Regarding the empiric therapy of nosocomial infections in the CIP, the antibiotic choice must be guided by the local bacterial epidemiology of each hospital and/or ward and by the patient risk factors for harboring MDR-bacteria. Importantly, since it has been demonstrated that colonized patients have a high risk of developing infection due to the same colonizing strain, empirical antibiotic treatment active against the colonizing strain should be taken into consideration for patients known to be colonized by MDR-bacteria. Reassessment of empirical therapy: de-escalation When relevant microbiological data are available, the antibiotic treatment should be re-assessed. If possible narrow spectrum antibiotic should be administered in order to minimize the risk of selecting MDR-bacteria. At this time it also possible to choose the antibiotic with the best PK/PD characteristics for each patient and each infection. Moreover if relevant microbiological cultures are negative and if evidence points away from the presence of bacterial infection, antibiotic therapy should be discontinued. Importantly it has been demonstrated that de-escalation strategy can be safely applied in the setting of intensive care unit (ICU) acquired pneumonia [12] and of sepsis or severe sepsis [13]. Interestingly, a significant higher rate of recurrent infections was reported in the non de-escalated group [13]. Conclusion In CIP with infection an appropriate and timely empirical antibiotic therapy should be chosen according to the suspected site of infection, the setting in which the infection developed (i.e., home, nursing home, or hospital), the medical history (with attention to co-morbidities and risk factors for MDR-bacteria), the local microbial-susceptibility patterns, and the PK/PD considerations. This is the only way to reduce unnecessary usage of broad spectrum antibiotics, with related adverse events, and to improve the clinical outcome. References 1. Frost P, Wise MP (2007). Recognition and early management of the critically ill ward patient. Br J Hosp Med 68:M Blot S (2008). Limiting the attributable mortality of nosocomial infection and multidrug resistance in intensive care units. Clin Microbiol Infect 14: Kumar A, Roberts D, Wood KE et al (2006). Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34: Kumar A (2011). Optimizing antimicrobial therapy in sepsis and septic shock. Crit Care Nurs Clin North Am 23: Blot SI, Pea F, Lipman J (2014). The effect of pathophysiology on pharmacokinetics in the critically ill patient-concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev 77: Gous A, Lipman J, Scribante J et al (2005). Fluid shifts have no influence on ciprofloxacin pharmacokinetics in intensive care patients with intra-abdominal sepsis. Int J Antimicrob Agents 26: Niemiec Jr PW, Allo MD, Miller CF (1987). Effect of altered volume of distribution on aminoglycoside levels in patients in surgical intensive care. Arch Surg 122: Perianez-Parraga L, Martinez-Lopez I, Ventayol-Bosch P et al (2012). Drug dosage recommendations in patients with chronic liver disease. Rev Esp Enferm Dig 104: Korth-Bradley JM, Baird-Bellaire SJ, Patat AA et al (2011). Pharmacokinetics and safety of a single intravenous dose of the antibiotic tigecycline in patients with cirrhosis. J Clin Pharmacol 51: Blot S, Vandewoude K (2004). Management of invasive candidiasis in critically ill patients. Drugs 64: McCormack PL, Perry CM (2005). Caspofungin: a review of its use in the treatment of fungal infections. Drugs 65: Joung MK, Lee JA, Moon SY et al (2011). Impact of de-escalation therapy on clinical outcomes for intensive care unit-acquired pneumonia. Crit Care 15:R Morel J, Casoetto J, Jospé R et al (2010). De-escalation as part of a global strategy of empiric antibiotherapy management. A retrospective study in a medical-surgical intensive care unit. Crit Care 14:R225-31

100 Intern Emerg Med (2015) 10 (Suppl):S94-S97 WARD MEDICINE The new anti-platelet drugs: highlight on P2Y 12 inhibitors Marco Cattaneo SIMI 2015 Abstract P2Y 12 is a platelet receptor for ADP, which is the target of efficacious antithrombotic drugs. About 1/3 of patients treated with clopidogrel, the most widely used P2Y 12 inhibitor, displays poor inhibition of platelet function and is not protected from cardiovascular events. Recently developed drugs, such as prasugrel and ticagrelor, proved more effective than clopidogrel in inhibiting platelet function and in reducing the incidence of major cardiovascular events in patients at risk. Riassunto Il P2Y 12, un recettore piastrinico per l ADP, è il bersaglio farmacologico di farmaci antitrombotici efficaci. Il clopidogrel, l inibitore del P2Y 12 più spesso utilizzato nella pratica clinica, in combinazione con l aspirina riduce l incidenza di eventi cardiovascolari in pazienti con sindrome coronarica acuta (SCA). Purtroppo, il farmaco non inibisce adeguatamente la funzione piastrinica in circa 1/3 dei pazienti, che pertanto non sono adeguatamente protetti. L adeguamento del trattamento in base ai risultati del test di funzione piastrinica non risolve il problema. Nuovi farmaci, quali il prasugrel e il ticagrelor, inibiscono la funzione piastrinica nella grande maggioranza dei pazienti e riducono più efficacemente del clopidogrel l incidenza di eventi cardiovascolari. Entrambi i farmaci aumentano l incidenza di complicanze emorragiche, ma il beneficio clinico netto è nettamente a loro favore. Il ticagrelor, in combinazione con aspirina, è più efficace dell aspirina da sola nel ridurre gli eventi cardiovascolari in pazienti che hanno avuto un infarto miocardico da almeno un anno. Il cangrelor è un efficace inibitore parenterale di P2Y 12, che può essere utile nel trattamento di pazienti con SCA e nella preparazione a interventi chirurgici di pazienti in terapia con inibitori orali di P2Y 12. M. Cattaneo ( ) Unità di Medicina III, Ospedale San Paolo, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via Antonio di Rudinì 8, Milano, Italy. marco.cattaneo@unimi.it Introduction Adenosine diphosphate (ADP), by interacting with its platelet receptors P2Y 1 and P2Y 12 promotes the formation of platelet aggregates, which play an important role in the formation of arterial trhombi [1]. Drugs that inhibit P2Y 12 are efficacious antithrombotic drugs. Ticlopidine and clopidogrel belong to the thienopyridine family of P2Y 12 inhibitors: they are pro-drugs that need to be converted in vivo by the hepatic cytochrome P-450 (CYP) enzymatic pathway to active metabolites, which covalently bind to P2Y 12, thereby irreversibily inhibiting the receptor [1, 2]. Due to its toxicity (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in the clinical practice. Despite its proven antithrombotic efficacy, clopidogrel has some drawbacks, the main one being that it induces a widely variable degree of inhibition of platelet function, which is attributable to several factors, including inter-individual differences in the extent of metabolism of the pro-drug [1, 2]. About 1/3 of treated patients does not display inhibition of P2Y 12 -dependent platelet function, and, as a consequence, is not adequately protected from major adverse cardiac events (MACE) [1, 2]. Laboratory monitoring is not the solution for the high inter-individual variability of response to clopidogrel Several authors proposed to tailor clopidogrel treatment based on results of platelet function tests: patients with poor response to clopidogrel should be treated with higher doses of the drug or with alternative treatments [3]. However, the efficacy of this strategy has not been confirmed by the results of two large randomized clinical trials (RCT) [4, 5] and a large intervention, non randomized study, which enrolled about 2000 patients with acute coronary syndromes (ACS) [6]. Many authors raised criticisms to the designs of RCT in-

101 Intern Emerg Med (2015) 10 (Suppl):S94-S97 S95 stead of accepting that their negative results should be taken as proof of the ineffectiveness of laboratory monitoring of clopidogrel therapy. 1. The patients enrolled in RCT had low risk of MACE, being mostly affected by stable coronary disease. However, the percentage of ACS patients (39.8% and 27%) enrolled in RCT mirrors the percentage of ACS patients (35%) enrolled in the observational studies that laid the groundwork for RCT [7]. 2. The studies were underpowered to show the advantage of monitoring. This would imply that RCT showed a trend of reduced risk of MACE in the monitoring arm, which was not statistically significant due to insufficient statistical power. Actually, RCT showed a non-statistically significant trend of higher incidence of MACE in the laboratory monitoring arm. 3. The laboratory test used was not adequate. Patients were tested by the point-of-care VerifyNow, which has been the most commonly used test in observational studies [7]. 4. The cut-off values were not correct. RCT adopted the same or very similar cut-off values as observational studies [7]. 5. The endpoints were not correct. This criticism refers to the ARCTIC study, which included peri-procedural myocardial infarction, diagnosed based on the increase in the serum levels of troponin, possibly caused by the procedure of coronary revascularization rather than by coronary thrombosis [5]. Although this criticism is shareable, it must be noted that also other end-points (including stent thrombosis and death) tended to be more frequent in the monitoring arm [5]. 6. Patients should have been treated with more effective P2Y 12 antagonists, such as prasugrel and ticagrelor, than with high doses of clopidogrel, which may be still be ineffective in many patients. Although it must be noted that a proportion of poor responders enrolled in the ARCTIC study was treated also with prasugrel and GPIIb/IIIa antagonists [5], this is a shareable criticism. However, it could be argued that prasugrel or ticagrelor be used on a first basis in all patients, without bothering to monitor platelet function, because they proved to have a more advantageous risk-to-benefit ratio, compared to clopidogrel. Prasugrel Prasugrel is a new thienopyridine, with more rapid and consistent inhibitory effects on platelet aggregation than clopidogrel, due to its peculiar chemical structure, which permits conversion to its active metabolite with less dependence on CYP enzymes than clopidogrel [2]. Consequences of the different metabolism of prasugrel, compared to that of clopidogrel, are faster appearance of its active metabolite in circulating blood, higher mean area under the concentration-time curve of its active metabolite, faster and greater mean inhibition of P2Y 12 -dependent platelet function, no influence of the CYP genotype on its pharmacokinetics and pharmacodynamics, much lower inter-individual variability in inhibition of P2Y 12 -dependent platelet responses [2]. The more favourable pharmacokinetics and pharmacodynamics of prasugrel compared to clopidogrel result in greater clinical benefit, as shown by the results of the phase III trial TRITON-TIMI 38, which evaluated 13,608 high-risk patients with ACS who required percutaneous coronary intervention (PCI) [8]. Prasugrel was associated with fewer ischemic events, but higher incidence of major and fatal bleeding complications. In a post-hoc analysis, three subgroups appeared to have less net clinical benefit and/or greater harm: patients with previous cerebrovascular accidents, patients 75 years of age or older and patients weighing less than 60 kg. Other analyses showed that prasugrel was a more effective antithrombotic drug than clopidogrel in patients with diabetes, ST-elevation myocardial infarction (STEMI), coronary stents or recurrent cardiovascular events on treatment [1, 2]. The benefit-to-risk ratio appeared particularly favourable in patients with diabetes, also because the incidence of TIMI major bleeding complications did not differ between the 2 treatments groups [9]. Among patients treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had a higher rate of MACE than did noncarriers, while, among those treated with prasugrel, the CYP2C19 genotype did not affect the incidence of MACE. The TRILOGY ACS trial showed that prasugrel is not superior to clopidogrel in non-st segment elevation ACS patients initially intended for non-invasive management: therefore, the trial did not change the guidelines recommending prasugrel only for ACS patients scheduled for PCI [10]. Given the previous findings from TRITON-TIMI 38, prasugrel dose was reduced to 5 mg in patients 75 years of age and older or below 60 kg. No differences in terms of incidence of bleeding complications were found between prasugrel- and clopidogrel-treated patients [10]. The ACCOAST assessed the efficacy and safety of preloading with prasugrel at the time of diagnosis rather than after coronary angiography in patients with non-st-elevation ACS [11]. Enrollment was stopped shortly before trial completion because of an increased rate of major bleeding in the pretreatment arm in the absence of a benefit in terms of ischemic events. In the pharmacodynamic substudy, there was a greater platelet inhibition in the pretreatment group than in the control group at the time of PCI [11]. Ticagrelor Ticagrelor belongs to the new chemical class cyclopentyl-triazolo-pyrimidines: it does not require conversion to an active metabolite and has a half-life of about hours [2]. After

102 S96 Intern Emerg Med (2015) 10 (Suppl):S94-S97 oral administration, it rapidly and reversibly inhibits P2Y 12. Ticagrelor has an additional mechanism of action, mediated by the inhibition of cellular re-uptake of adenosine: as a consequence, ticagrelor-treated patients display higher circulating concentrations of adenosine, which has important physiological effects that can contribute to antithrombotic activity of the drug [12, 13]. The incidence of unexplained dyspnea was significantly higher in ticagrelor-treated patients, compared to clopidogrel-treated patients: this is likely due to the reversible mechanism of action of the drug [14]. Ventricular pauses were also more frequent in ticagrelor-treated patients. The results of PLATO trial, in which ticagrelor was compared to clopidogrel for prevention of MACE in patients with non-st or ST elevation acute coronary syndromes (2/3 of them underwent PCI) showed that ticagrelor decreases the incidence of MACE and mortality [15].There was a higher incidence of TIMI major non-cabg-related bleedings in patients who received ticagrelor, compared with those treated with clopidogrel. Therefore, similarly to the TRITON-TIMI 38 trial, the PLATO trial showed that a more consistent, adequate inhibition of P2Y 12 -dependent platelet function than that achieved with standard doses of clopidogrel is associated with greater antithrombotic efficacy and higher risk of non-cabg-related major bleedings. The ATLANTIC study randomized 1862 patients with STelevation MI going for coronary angiography to either prehospital (in the ambulance) or in-hospital (in the catheterization laboratory) ticagrelor administration [14]. Randomization occurred at the time of diagnosis and the median time from randomization to angiography was 48 minutes with a median time difference of 31 minutes between the two treatment strategies. The coprimary endpoints were: 1) proportion of patients who did not have a 70% or greater resolution of ST-segment elevation before PCI, and 2) the proportion of patients who did not have Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography. There was no difference between groups in either the two coprimary endpoints or major bleeds, but the rates of definite stent thrombosis were lower in the prehospital treatment both within 24 hours of index PCI as well as at 30 days [16]. The PEGASUS trial showed that in patients with a myocardial infarction more than 1 year previously, treatment with ticagrelor plus aspirin significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased the risk of major bleeding, compared to treatment with aspirin alone [17]. Cangrelor Cangrelor is a potent inhibitor of ADP-induced aggregation, does not require conversion to an active metabolite and is immediately active after intravenous infusion, with a half-life of 3 to 6 minutes. Two trials, which compared cangrelor to clopidogrel in patients requiring PCI, were prematurely terminated due to insufficient evidence of superiority of cangrelor [2]. In a more recent double-blind, placebo-controlled trial, cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding, in 11,145 patients who were undergoing either urgent or elective PCI [18]. Finally, the BRIDGE trial showed that cangrelor could useful as bridging therapy in patients on treatment with oral P2Y 12 antagonists who need to undergo surgery [19]. Conclusion The pharmacopeia of drugs inhibiting the platelet P2Y 12 receptor for ADP is rapidly expanding. Compared to clopidogrel, the new thienopyridine prasugrel and the direct P2Y 12 antagonist ticagrelor are characterized by faster onset of action and more consistent inhibition of platelet function in treated subjects. The more advantageous risk-to-benefit profile that emerged in randomized clinical trials and the failure of studies addressing the issue of inter-individual variability of response to clopidogrel suggest that the new inhibitors should be preferred to clopidogrel. Two caveats oppose this proposed approach: 1. prasugrel and ticagrelor increase the risk of major bleeding compared to clopidogrel. However, this is the price to pay for obtaining a good inhibition of platelet function in the vast majority of treated patients, which is exactly the goal that laboratory monitoring of antiplatelet therapy aims to achieve. Not surprisingly, good responders to clopidogrel bleed more than poor responders. In addition, it must be emphasized that the net clinical benefit is in favour of prasugrel and ticagrelor; 2. prasugrel and ticagrelor are more expensive than clopidogrel, which is now a generic drug. However, the costs of their use should be compared to the costs of monitoring, which include the cost of the new drugs to be given to poor responders (about 35% of patients), and the cost of laboratory tests, which could be rather high, especially if, as suggested by some, more than one test should be used and repeated testing is necessary. References 1. Cattaneo M (2010). New P2Y(12) inhibitors. Circulation 121: Cattaneo M (2011). The platelet P2Y 12 receptor for adenosine diphosphate: congenital and drug-induced defects. Blood 117: Cattaneo M (2012). Response variability to clopidogrel: is tailored treatment, based on laboratory testing, the right solution? J Thromb Haemost 10:327-36

103 Intern Emerg Med (2015) 10 (Suppl):S94-S97 S97 4. Price MJ, Murray SS, Angiolillo DJ (2011). Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study. J Am Coll Cardiol 59: Collet JP, Cuisset T, Rangé G (2012). Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 367(22): Parodi G, Marcucci R, Valenti R (2011). High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA 306: Norgard NB, Mathews KD, Wall GC (2009). Drug-drug interaction between clopidogrel and the proton pump inhibitors. Ann Pharmacother 43: Wiviott SD, Braunwald E, McCabe CH et al (2007). Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357: Wiviott SD, Braunwald E, Angiolillo DJ et al (2008). Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in Myocardial Infarction 38. Circulation 118: Roe MT, Armstrong PW, Fox KA (2012). Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 367: Montalescot G, Bolognese L, Dudek D (2013). Pretreatment with prasugrel in non-st-segment elevation acute coronary syndromes. N Engl J Med 369(11): Cattaneo M, Schulz R, Nylander S (2014). Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance. J Am Coll Cardiol 63: Nylander S, Femia EA, Scavone M et al (2013). Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism. J Thromb Haemost 11: Cattaneo M, Faioni EM (2012) Why does ticagrelor induce dyspnea? Thromb Haemost 108: Wallentin L, Becker RC, Budaj A (2009). Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361: Montalescot G, van t Hof AW, Lapostolle F (2014). Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 371: Bonaca MP, Bhatt DL, Cohen M et al (2015). Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 372: Bhatt DL, Stone GW, Mahaffey KW (2013). Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 368: Angiolillo DJ, Firstenberg MS, Price MJ (2012). Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA 307:265-74

104 Intern Emerg Med (2015) 10 (Suppl):S98 WARD MEDICINE Pulmonary arterial hypertension: new prognostic perspectives Nazzareno Galié SIMI 2015 TEXT NOT RECEIVED N. Galié ( ) Università di Bologna

105 Intern Emerg Med (2015) 10 (Suppl):S99-S103 MEET THE EXPERT Primary aldosteronism: a brief update Gian Paolo Rossi Livia Lenzini Giuseppe Maiolino Teresa M. Seccia SIMI 2015 Abstract Primary aldosteronism (PA), the most common form of endocrine hypertension, is usually caused by an aldosterone-producing adenoma or adrenal hyperplasia, albeit it can also be due to rare genetics causes. Early identification and diagnostic subtyping of PA is key to avoid harmful consequences to the cardiovascular system, such as atrial fibrillation, ischemic and haemorrhagic stroke, flash pulmonary oedema, myocardial infarction and heart failure. The screening for PA is mandatory for patients with resistant hypertension, hypokalemia, early onset hypertension, and incidentally discovered adrenal masses. It entails the measurement of renin and aldosterone and the calculation of the aldosterone renin ratio (ARR), followed by subtype differentiation through adrenal vein sampling (AVS). After the demonstration of excess lateralized aldosterone secretion, laparoscopic adrenalectomy can cure or markedly improve hypertension in 82% of cases. Riassunto L iperaldosteronismo primario (PA), la forma più comune di ipertensione endocrina, è causato da un adenoma producente aldosterone o da iperplasia surrenalica o da rare cause genetiche. L identificazione precoce e la diagnosi di sottotipo di PA sono fondamentali per evitare conseguenze dannose per il sistema cardiovascolare, come fibrillazione atriale, ictus ischemico ed emorragico, edema polmonare flash, infarto del miocardio e scompenso cardiaco. Lo screening per il PA è obbligatorio per i pazienti con ipertensione resistente, ipokaliemia, ipertensione a esordio precoce, e in presenza di incidentalomi surrenalici. Lo screening prevede la misurazione di renina e aldosterone, e quindi il G.P. Rossi ( ) Department of Medicine DIMED, Clinica dell Ipertensione Arteriosa University Hospital, Via Giustiniani 2, Padova, Italy. gianpaolo.rossi@unipd.it L. Lenzini G. Maiolino T.M. Seccia Department of Medicine DIMED, Clinica dell Ipertensione Arteriosa University Hospital, Padova, Italy. calcolo del rapporto aldosterone renina (ARR), seguita dalla differenziazione del sottotipo mediante adrenal vein sampling (AVS). Dopo la dimostrazione di una lateralizzazione dell eccesso di secrezione di aldosterone, la surrenectomia laparoscopica guarisce o migliora notevolmente l ipertensione nell 82% dei casi. Introduction An excess section of the mineralocorticoid hormone aldosterone by an adrenocortical adenoma, currently defined as primary aldosteronism (PA), represents the paradigm of mineralocorticoid hypertension. A low or undetectable plasma renin is the hallmark of PA, which can be due to rare causes, but more commonly is caused by an autonomous production of aldosterone by an aldosterone-producing adenoma or adrenal hyperplasia (Table 1). Even though in PA the suppression of renin due to volume expansion should blunt aldosterone se- Table 1 Subtypes of primary aldosteronism. Surgically not curable Bilateral adrenal hyperplasia Unilateral aldosterone-producing adenoma with bilateral adrenal hyperplasia Familial type I hyperaldosteronism (also known as glucocorticoid-remediable aldosteronism) Surgically curable Aldosterone-producing adenoma (aldosteronoma) unilateral bilateral Primary unilateral adrenal hyperplasia Multinodular unilateral adrenocortical hyperplasia Ovary aldosterone-secreting tumor Familial type II hyperaldosteronism Familial type III hyperaldosteronism (KCNJ5 K + channels germline mutations) Aldosterone-producing adenoma or bilateral adrenal hyperplasia with concomitant pheochromocytoma Aldosterone-producing carcinoma

106 S100 Intern Emerg Med (2015) 10 (Suppl):S99-S103 cretion, the excess aldosterone secretion persists and leads to an excess activation of the mineralocorticoid receptor (MR). Along with the high BP, the latter damages the cardiovascular system, ultimately leading to atrial fibrillation, ischemic and haemorrhagic stroke, flash pulmonary oedema, myocardial infarction and heart failure [1-3]. Early identification of PA, followed by diagnosis of its subtypes and institution of specific treatment [2], is therefore of paramount importance to avoid these harmful consequences. Prevalence The largest prospective survey designed to provide solid data on the prevalence of PA in consecutive patients referred to hypertension centres showed a prevalence of PA of 11.2%, about half of the cases being due to a surgically curable subtype (Table 1) [4]. Thus, PA is the most common curable endocrine form of hypertension in referred patients. Of note, most cases of PA were found in normokalemic patients, which implies that hypokalemia is not a condicio sine qua non of the disease. Hence, a search strategy for PA limited to the hypokalemic hypertensive patients can lead to deny the diagnosis to many patients, thus explaining the under diagnosis of PA [5]. Clinical features and screening According to the Endocrine Society guidelines, screening for PA is mandatory in some categories of patients, who have an increased pre-test probability of PA, including those with resistant hypertension, grade 2 or 3 hypertension, spontaneous or diuretic-induced hypokalemia, incidentally discovered apparently non functioning adrenal mass (incidentaloma) and early onset (juvenile) hypertension and/or stroke (<50 years) [6]. Other experts favour however a wide screening strategy for PA in all newly presenting patients with hypertension, because of the high prevalence of PA, and of the beneficial effects of an early diagnosis followed by specific treatment. The first step for diagnosing PA requires the demonstration of a plasma renin (measured as activity PRA, or direct active renin concentration, DRC) that is disproportionately low in relation to sodium intake. The second step is to measure plasma aldosterone concentration (PAC) to differentiate PA, from apparent mineralocorticoid excess and Liddle s syndrome. For practical reasons these two steps are usually performed together. The PAC and renin values are then used to calculate the aldosterone renin ratio (ARR) [5], whose proper use requires consideration of a several key issues (Table 2): the ARR value depends on PAC and on levels of renin. This means that very different PAC and renin values can produce the same ARR and, moreover, that a suppressed renin value will increase the ARR even when PAC is normal. To avoid diagnosing as normo-aldosteronemic many PA cases, which instead have low-renin essential hypertension (as in the elderly and people of African origin), the lowest renin value to be used in the calculation of the ARR should be fixed at a minimum (which is 0.2 ng/ml per h for PRA and 0.36 ng/ml for DRC) [5]. Some important points must be made concerning the renin measurement. For a detailed discussion of the pros and cons of the PRA and DRC assay, the reader is referred elsewhere [7]. In addition to fix the minimum level of renin in the correlation of the ARR we recommend use of the combination of an increased ARR and a PAC >15 ng/dl, rather than ARR alone, to detect patients with PA. Multivariate discriminant analysis strategies, which use the absolute values instead of the ratio of multiple variables, avoid these problems and achieve an accurate identification of PA [8]. These strategies, which can Table 2 Suggestions for the correct use of the aldosterone renin ratio (ARR) as a screening test. Factors affecting ARR Suggestion Serum levels of potassium Correct hypokalemia, if present, before performing the test Plasma aldosterone concentration (PAC) High PAC might originate from low salt intake or use of diuretics. Thus, prepare patient with adequate salt intake and measure 24h urinary sodium excretion. Withdraw diuretics at least 3-4 weeks (and mineralocorticoid receptor antagonists at least 6 weeks) before testing Renin assay Because of low precision of the PRA or DRA assay for low renin values, fix the lowest level of renin to be used in the ARR Patient position and blood sampling Standardize the position of the patient and sampling conditions at your centre Handling of the samples Handling and storage of plasma samples differ for PRA and DRA assays Drugs a 1 -receptor blocker doxazosin and long-acting calcium channel blockers are allowed ARR accuracy The cut-off value that provides the best combination of sensitivity and specificity should be identified at each centre by ROC curves Abbreviations: ARR, aldosterone renin ratio; DRA, direct active renin; PAC, plasma aldosterone concentration; PRA, plasma renin activity; ROC, receiver operating characteristic.

107 Intern Emerg Med (2015) 10 (Suppl):S99-S103 S101 Table 3 Effects of drugs and conditions on aldosterone renin ratio (ARR). Factor PAC Renin ARR False positive rate False negative rate Medications b-blockers Central α-2 agonists NSAIDs K + losing diuretics K + sparing diuretics Angiotensin-converting enzyme inhibitors Angiotensin II receptor blockers Long-acting calcium channel blockers Renin inhibitors Potassium status Hypokalemia Potassium loading Sodium status Sodium depletion Sodium loading Aging Abbreviations: NSAID, non steroidal anti-inflammatory drug; PAC, plasma aldosterone concentration. be implemented for use in available worksheets and adapted for clinical decision making, have the additional advantage of providing an estimate of the individual patient s probability of developing PA, which enables clinicians to decide on an individual basis whether to proceed with further testing [8]. It is important, however, to remember that the ARR carries quantitative information: values markedly high, for example greater than 100, are a strong indication that the patient has PA. ARR values that are less rose, e.g. between 26 and 100, should be regarded as a clue of the presence of PA [5], but must be confirmed at retesting. Most antihypertensive drugs affect PAC, renin values, or both, and thereby the ARR. Therefore, the key step in screening for PA is a careful preparation of the patient both in terms of drugs and of conditions for the testing (Table 3). Before measuring aldosterone and renin levels, treatment must be properly modified. In patients in whom interrupting the antihypertensive treatment could be harmful the α 1 -receptor blocker doxazosin and the long-acting, calcium channel blockers, can be used alone or in combination to control blood pressure during screening. These drugs have negligible effects on the ARR. When the patient needs a stronger treatment than these agents, knowledge of the effects of the different drugs on the ARR and its components can enable a clinician to confirm or exclude the diagnosis of PA. As regards the conditions for testing, the patients should be investigated in the morning after they have being resting supine, or sitting quietly, for 1 hour. Hypokalemia that, if present, reduces aldosterone secretion and can lead to false negative results, must be excluded with measurement of the serum levels of potassium. An assessment of sodium intake, which is essential for a correct interpretation of renin and aldosterone values, is recommended. This can be accurately be achieved by measuring 24h urinary sodium excretion. Exclusion of primary aldosteronism The ARR often gives false positive results that must be identified and excluded before selecting the patient for adrenal vein sampling (AVS). The guidelines recommend performing a confirmatory test [6] to identify such false positive cases. The most commonly used tests include the oral sodium-loading test, the saline infusion test, the captopril challenge test, and the fludrocortisone + salt loading test. Purpose of these tests is to show the autonomy of excess secretion of aldosterone from the renin-angiotensin system, but unfortunately aldosterone secretion depends on angiotensin II in many PA patients. Accordingly, relying on these tests can lead to miss diagnosis in several patients with PA. Imaging and subtype differentiation by AVS A high resolution CT scan with 2-3 mm cuts is the best available technique for identifying adrenal nodules. However, an

108 S102 Intern Emerg Med (2015) 10 (Suppl):S99-S103 imaging-guided strategy for subtype differentiation of PA is inadequate to achieve discrimination between surgically curable and not curable subtypes of PA because aldosterone-producing adenomas (APAs) are often quite small and because of several other considerations [5]. Hence, imaging results alone can be misleading and might lead to useless and/or inappropriate adrenalectomy, and to exclude from adrenalectomy many potentially curable with this procedure [9]. All guidelines therefore agree that AVS is the best test to differentiate unilateral from bilateral causes of PA and it should be offered to all patients before adrenalectomy [6]. As an indication for adrenalectomy, AVS should only be used in patients with unequivocal biochemical evidence of PA who are candidates for general anaesthesia and surgery, and who are willing to achieve long-term cure of PA with adrenalectomy [5]. The performance and interpretation of AVS undoubtedly require considerable expertise; therefore, this test should only be performed in experienced tertiary referral centres. For an in-depth discussion of the issues surrounding the use of AVS the readers are referred elsewhere to a recent expert consensus statement [10]. An alternative approach to the demonstration of excess lateralized aldosterone could be the C 11 methomidate positron emission tomography, but this technique requires a cyclotron facility for the preparation of the tracer and, therefore, could only be developed at large tertiary referral centres. Management The Endocrine Society Guidelines [6] state that a lateralized aldosterone secretion should be demonstrated before undertaking surgery in patients who are candidates for general anaesthesia and wish to achieve long-term cure. Laparoscopic adrenalectomy, which implies a short hospital stay and a very low operative risk, is currently the best available treatment [5]. When performed after demonstration of lateralized aldosterone, excess adrenalectomy cured all patients from the hyperaldosteronism and cured or markedly improved hypertension in ~82% of the patients. A long duration of hypertension and the presence of vascular remodelling, both of which are caused by a delayed diagnosis, predict a blunted blood pressure fall [11]. Even when antihypertensive treatment cannot be withdrawn after adrenalectomy, resistant hypertension is usually resolved at long-term [11], and a considerable improvement in quality of life occurs [5]. Therefore, overall available evidence supports the concept that the sooner the diagnosis is made and adrenalectomy performed, the better the outcome [12]. Failure to cure PA can be the result of an inaccurate diagnosis or more frequently derives from the concurrence of essential hypertension. A treatment based on MR antagonists, such as spironolactone, canrenone, potassium canrenoate and eplerenone (which is more selective, but also more expensive, weaker and shorter acting than the other antagonists and is not generally available), is a reasonable alternative to adrenalectomy for patients who are not candidates for surgery or do not show lateralized aldosterone excess. The occurrence of gynecomastia and impotence, the more annoying side effects of the MR antagonists, is dose-dependent, which suggests the use of reduced doses in combination, if necessary, with other agents, such as long-acting calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can be particularly useful to control the counter-regulatory stimulation of the renin angiotensin system triggered by the diuretic action of the MR antagonists. Recent discoveries of mutations in ion channels in APA [13] and at the germline level might ultimately change our understanding and diagnostic and therapeutic approach to PA. For the time being, following a few simple rules and a streamlined approach, physicians can successfully and cost-effectively identify and treat many patients with socalled essential hypertension whose high blood pressure is caused by hyperaldosteronism. Acknowledgments The work herein reviewed was supported by research grants from FORICA (The Foundation for advanced Research in Hypertension and Cardiovascular diseases), the FP7-funded COST ADMIRE network (BM1301), the Società Italiana dell Ipertensione Arteriosa, the Ministry of University and Scientific Research (MIUR) and the University of Padova. References 1. Rossi GP, Sacchetto A, Pavan E et al (1997). Remodeling of the left ventricle in primary aldosteronism due to Conn s adenoma. Circulation 95: Rossi GP, Sechi LA, Giacchetti G et al (2008). Primary aldosteronism: cardiovascular, renal and metabolic implications. Trends Endocrinol Metab 19: Milliez P, Girerd X, Plouin PF et al (2005). Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 45: Rossi GP, Bernini G, Caliumi C et al (2006). A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 48: Rossi GP (2011). A comprehensive review of the clinical aspects of primary aldosteronism. Nat Rev Endocrinol 7: Funder JW, Carey RM, Fardella C et al (2008). Case detection, diagnosis, and treatment of patients with primary aldosteronism: an

109 Intern Emerg Med (2015) 10 (Suppl):S99-S103 S103 endocrine society clinical practice guideline. J Clin Endocrinol Metab 93: Rossi GP, Barisa M, Belfiore A et al (2010). The aldosterone-renin ratio based on the plasma renin activity and the direct renin assay for diagnosing aldosterone-producing adenoma. J Hypertens 28: Rossi GP, Rossi E, Pavan E et al (1998). Screening for primary aldosteronism with a logistic multivariate discriminant analysis. Clin Endocrinol (Oxf) 49: Kempers MJ, Lenders JW, van Outheusden L et al (2009). Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Ann Intern Med 151: Rossi GP, Auchus RJ, Brown M et al (2014). An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension 63: Rossi GP, Bolognesi M, Rizzoni D et al (2008). Vascular remodeling and duration of hypertension predict outcome of adrenalectomy in primary aldosteronism patients. Hypertension 51: Rossi GP, Barisa M, Allolio B et al (2012). The Adrenal Vein Sampling International Study (AVIS) for identifying the major subtypes of primary aldosteronism. J Clin Endocrinol Metab 97: Choi M, Scholl UI, Yue P et al (2011). K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331: Conflict of interest and financial disclosure to be disclosed: none.

110 Intern Emerg Med (2015) 10 (Suppl):S104-S107 MEET THE EXPERT New antihyperglycemic agents Paolo Cavallo Perin Cristina Amione Paolo Fornengo SIMI 2015 Abstract Novel drugs for treatment of Type 2 Diabetes (T2DM) [DPP-IV inhibitors or gliptines, SGLT2 inhibitors or glifozines, GLP-1 receptor agonists] show a slide anti-hyperglycemic efficacy (HbA1c reduction between 0.6 and 1.5%), a new mechanism of action and a good safety profile, with a negligible risk of hypoglycemia. All of them can be used as monotherapy or as an add-on option with every pre-existent drug and at every step of T2DM, also in association with insulin. New insights for the GLP1-receptor agonists are represented by the weekly administration, leading to a better tolerability profile, a higher HbA1c reduction and an increased patient s compliance. Glifozins show a new antihyperglycemic mechanism working as inhibitors of the proximal tubule glucose reabsorption leading to increased renal glucose excretion (glycosuria) with resulting plasma glucose reduction. All these novel therapeutic options seem to have a good cardiovascular profile, but we are still waiting for the confirmation data coming from the ongoing studies. Riassunto I nuovi farmaci anti-iperglicemici per il trattamento del diabete tipo 2 (inibitori del DPP4 o gliptine, inibitori del SGLT2 o glifozine, agonisti del recettore del GLP-1) sono caratterizzati da una variabile potenza anti-iperglicemica (riduzione HbA1c di 0,6-1,5%), un nuovo meccanismo d azione e una buona sicurezza, soprattutto per quanto riguarda un trascurabile rischio di ipoglicemia. Questi farmaci possono essere usati in monoterapia o in associazione con altri farmaci anti-iperglicemici in tutte le fasi del diabete tipo P. Cavallo Perin ( ) Department of Medical Sciences, School of Medicine, University of Torino, Corso Dogliotti 14, Torino, Italy. paolo.cavalloperin@unito.it C. Amione P. Fornengo Department of Medical Sciences, School of Medicine, University of Torino, Italy. 2. La novità degli agonisti del recettore del GLP-1 riguarda le molecole di più recente introduzione a somministrazione settimanale, alcune delle quali presentano una miglior tollerabilità (più rapida scomparsa degli effetti gastrointestinali, scarsa reazione nel sito di iniezione) e una miglior accettazione da parte del paziente. Le glifozine presentano invece un meccanismo del tutto innovativo: inibiscono il riassorbimento tubulare di glucosio aumentando l escrezione renale di glucosio (glicosuria) con effetto decrescente al diminuire dell iperglicemia. Sebbene i nuovi farmaci abbiano un effetto favorevole sui fattori di rischio cardiovascolare, è necessario disporre dei risultati degli studi ancora in corso per definire la loro efficacia protettiva sugli eventi cardiovascolari. Introduction The increasing prevalence of type 2 diabetes has stimulated development of many new approaches to safely treat hyperglycaemia. The aim of these therapies is to reduce and maintain glycemia as close to normal for as long as possible after diagnosis and prevent development of complications, with a low risk of hypoglycemia. Here we focused on the most recent antidiabetic agents appeared in clinical practice. Gliptines Dipeptidyl peptidase-4 inhibitors (DPP4-i) or gliptines are relatively new oral antihyperglycemic agents. The current clinical guidelines [1] for type 2 diabetes suggest adding a DPP4-i instead of sulfonylurea as second line treatment to metformin if there is a considerable risk of hypoglycemia or if sulfonylurea is contraindicated. In our country many DPP4-i are available: sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin. They show a similar antihyperglycemic effica-

111 Intern Emerg Med (2015) 10 (Suppl):S104-S107 S105 cy, a favourable effect on body weight, are associated with a negligible incidence of hypoglycemia and a low incidence of adverse events [2]. They are weight neutral (or even induce modest weight loss), lower blood pressure, improve postprandial lipemia and endothelial function, reduce inflammatory markers, diminish oxidative stress [3], and show a lower risk of major cardiovascular events compared with other classes of antidiabetic agents [4]. A meta-analysis of randomized clinical trials involving more than 55,000 patients showed that when DPP4-i were compared against all comparators (placebo and active treatment) there was no difference in all cause mortality, cardiovascular mortality, acute coronary syndromes, but there was a significant reduction when DPP4-i were compared with active comparators (RR=0.63, 95% CI , p=0.03) [5]. Indeed, the two main outcome trials contributing to analysis of these outcomes (SAVOR-TIMI 53 with saxagliptin [6] and EXAMINE with alogliptin [7]) both reported stand-alone neutral outcomes. The significant excess of heart failure hospitalizations with the DPP4-i versus placebo or other hypoglycemic agents was mainly driven by the SAVOR-TIMI 53 [6] where it was a formal adjudicated secondary endpoint, as well as the EXAMINE study [7]. However, significance was lost with sensitivity analysis looking only at trials at low risk of bias, and there are no specific mechanistic reasons to explain this finding. In fact, these DPP4-i increase circulating levels of glucagon-like peptide-1, which has been shown to improve cardiac contractile function [8]. Use of DPP4-i is associated with small increases in resting heart rate when used in association with ACE inhibitors [9]. Further ongoing large-scale cardiovascular outcome studies should help address this issue. Glifozins A new approach to reduce plasma glucose concentrations in patients with T2DM is to inhibit glucose reabsorption by the kidney [10]. Recently, several members of a new class of drugs, sodium-glucose co-transporter 2 inhibitors (SGLT2-i) or glifozins, that act via this mechanism, have been approved for type 2 diabetes also in Italy. The kidney contributes to the glucose homeostasis, in first line, by glucose reabsorption to the circulation of the glucose filtered. Glucose reabsorption is mediated by specific glucose transport proteins, in particular sodium-glucose co-transporter 2 (SGLT2) [11]. In patients with type 2 diabetes, the renal capacity to reabsorb glucose and the threshold at which renal excretion of glucose occurs are increased contributing to hyperglycemia, as a result of an upregulation of SGLT2 expression in the proximal tubule [12]. Therefore, inhibition of glucose reabsorption and augmentation of renal excretion of glucose represent a new mechanism to reduce hyperglycemia. SGLT2 inhibitor-induced glucose excretion is proportional to the amount of glucose filtered by the kidneys, which is a function of the glomerular filtration rate (GFR) and plasma glucose concentration. Hyperglycemia leads to increased glucose filtration and may lead to a greater excretion of glucose with SGLT2 inhibition. Since the antihyperglycemic action of SGLT2-i is independent of the secretion or action of insulin and diminishes as hyperglycemia decreases, the intrinsic risk of hypoglycemia with this drug class is low. Glucose excretion as a consequence of SGLT2 inhibition results in a loss of calories that leads to a decrease in body weight and fat mass [13]. Thereafter SGLT2-i also have a mild diuretic effect with modest lowering of blood pressure (BP) [14]. SGLT2-i are new insulin-independent agents that, given adequate renal function, improve glycemic control in patients with type 2 diabetes not adequately controlled by diet and exercise or by other antidiabetic agents. Canaglifozin The recommended starting dose is 100 mg once daily, which can be increased to 300 mg once daily in patients with an estimated GFR (egfr) 60 ml/min/1.73 m 2. A maximum dose of 100 mg is recommended for patients with an egfr ml/ min/1.73 m 2 ; canaglifozin should not be used in patients with an egfr <45 ml/min/1.73 m 2 [15]. Canaglifozin at 100 mg/ day and 300 mg/day significantly reduced HbA1c by 0.37% to 1.16%, and fasting plasma glucose (FPG) by 25 to 43 mg/ dl compared with placebo when used as monotherapy or as add-on therapy. Canaglifozin also decreases post-prandial glycemia (PPG) and reduces body weight by 1.9 to 3.3 kg [14]. Canaglifozin is well tolerated: genital infections were more frequent versus placebo, especially in women, and osmotic diuresis-related adverse events (AEs; e.g. pollakiuria and polyuria) were also increased [15]. Canaglifozin may cause hyperkalemia, especially in patients with moderate renal impairment (egfr 45 to <60 ml/min/1.73 m 2 ) and in patients taking drugs that affect potassium excretion. Small, acute decreases in the egfr with canaglifozin have been reported in patients with T2DM and normal renal function and in those with CKD [16]. Incidence of hypoglycemia was negligible. Regarding the lipid profile canaglifozin increased low-density lipoprotein cholesterol (LDL-C) by 2% to 12% compared with placebo or comparator [15]. Dapaglifozin The recommended starting dose is 5 mg once daily, which can be increased to 10 mg once daily. Kidney function should

112 S106 Intern Emerg Med (2015) 10 (Suppl):S104-S107 be assessed before initiating dapaglifozin, which should not be used (or discontinued) in patients with an egfr <60 ml/ min/1.73 m 2 [17]. In the registration trials dapaglifozin reduced mean HbA1c between 0.54 and 0.68%, reduced FPG by 15 to 28 mg/dl and reduced body weight by 2.0 kg compared with placebo [18]. Dapaglifozin may have a reduced efficacy in patients with moderate (GFR ml/min) to severe (<30 ml/min) renal impairment, and is contraindicated in patients with an egfr <30 ml/min/1.73 m 2 [19]. Adverse events reported with dapaglifozin were mild to moderate and, except for infections of the genital tract and urinary tract, were reported at a similar frequency as with placebo. The acute and reversible reductions in egfr reported with dapaglifozin may reflect reversible hemodynamic effects rather than permanent changes in renal function [19]. Hypoglycemia occurred at a similar rate of placebo in the dapaglifozin monotherapy study, add-on to metformin studies, addon to pioglitazone study, and add-on to sitagliptin study. The proportion of patients reporting hypoglycemic episodes was higher when dapaglifozin was added to a sulfonylurea or insulin. Dapaglifozin should not be used in patients with active bladder cancer, and should be used with caution in those with a history of bladder cancer [17]. Empaglifozin The recommended starting dose is 10 mg/d, which can be increased to 25 mg/day. Empaglifozin should not be used in patients with an egfr <45 ml/min/1.73 m 2, and renal function should be monitored more frequently in patients with an egfr <60 ml/min/1.73 m 2 [20]. Mean changes from baseline in HbA1c for empaglifozin 10 and 25 mg/day were 0.74% to 0.85% in monotherapy, and 0.38% to 0.64% if used as add-on therapy. Empaglifozin also significantly reduced FPG ( 12 to 36 mg/dl) and 2-h PPG after a mixed-meal test ( 33 to 52 mg/dl) [21]. Reduction in body weight was from 1.6 to 2.5 kg. Genital infections were increased with empaglifozin versus placebo. Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1 RAs) The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) effectively reduces HbA1c and body weight while having a low risk of hypoglycemia; they are all administered by subcutaneous injections. Currently the GLP-1 RAs approved between US and Europe are: exenatide twice daily, liraglutide once daily, exenatide once weekly, albiglutide once weekly, lixisenatide once daily and dulaglutide once weekly. The interest is now mainly related to the GLP-1 RAs administered once weekly. The GLP-1 RAs represent an heterogeneous class showing a similar antihyperglycemic effect (HbA1c reduction from 0.8% to 1.5%) and variable gastrointestinal and injection-site related side effects. Albiglutide once weekly was less efficacious at both lowering HbA1c and lowering body weight compared with liraglutide, but had less gastro-intestinal side effects [22]. Dulaglutide once weekly was more efficacious at lowering HbA1c compared with exenatide twice daily and was non-inferior to liraglutide at lowering HbA1c. Weight loss was similar for dulaglutide and exenatide twice daily, but was greater with liraglutide compared to dulaglutide. In the dulaglutide head-to-head comparisons with exenatide twice daily and liraglutide, gastrointestinal side effects disappeared earlier with dulaglutide [23, 24]. Quality of life data indicate that once weekly injections result in higher patient satisfaction compared with twice daily injections. The risk of hypoglycemia is low with GLP-1 RAs and rates were similar across all GLP-1 RA treatment groups in the headto-head clinical studies. Additional studies with different active comparators will further highlight the differences in efficacy and tolerability within this class of agents. Although GLP-1 RAs show a beneficial effect on cardiovascular risk factors, more data from large-scale studies are required to evaluate their effects on cardiovascular events and assess their long-term safety. Incoming drugs Many other agents (FFAR1/GPR40, GPR 119, glucokinase activators, betatrophin(s), FOXO1, glucagon-receptor antagonists, oxyntomodulin, HGP modulators, AMPkinase modulators, IL-1 receptor antagonists, 11-beta-HSD1 inhibitors, glucagon and GLP-1 co-agonist) are now studied and developed, involving different pathophysiological mechanisms discovered in type 2 diabetes and they represent the incoming therapy of the future [25]. References 1. Inzucchi SE, Bergenstal RM, Buse JB et al (2015). Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 58: Karagiannis T, Paschos P, Paletas K et al (2012). Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 344:e Scheen AJ (2013). Cardiovascular effects of gliptins. Nat Rev Cardiol 10: White WB, Pratley R, Fleck P et al (2013). Cardiovascular safety of the dipeptidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab 15:668-73

113 Intern Emerg Med (2015) 10 (Suppl):S104-S107 S Wu S, Hopper I, Skiba M, Krum H (2014). Dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes: meta-analysis of randomized clinical trials with 55,141 participants. Cardiovasc Ther 32: Scirica BM, Bhatt DL, Braunwald E et al (2013). Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369: White WB, Cannon CP, Heller SR et al (2013). Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 369: Khan M, Deaton C, Rutter M et al (2013). Incretins as a novel therapeutic strategy in patients with diabetes and heart failure. Heart Fail Rev 18: Marney A, Kunchakarra S, Byrne L, Brown NJ (2010). Interactive hemodynamic effects of dipeptidyl peptidase-iv inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension 56: Pfister M, Whaley JM, Zhang L, List JF (2011). Inhibition of SGLT2: a novel strategy for treatment of type 2 diabetes mellitus. Clin Pharmacol Ther 89: Mather A, Pollok C (2011). Glucose handling by the kidney. Kidney Int 79(suppl 120):S1-S6 12. DeFronzo RA, Hompesch M, Kasichayanula S et al (2013). Characterization of renal glucose reabsorption in response to dapaglifozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care 36: Bolinder J, Ljunggren O, Kullberg J et al (2012). Effects of dapaglifozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab 97: Lambers Heerspink HJ, de Zeeuw D, Wie L et al (2013). Dapaglifozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 15: Lavalle-Gonzalez FJ, Januszewicz A, Davidson J et al (2013). Efficacy and safety of canaglifozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomized trial. Diabetologia 56: Weir MR, Kline I, Xie J et al (2014). Effect of canaglifozin on serum electrolytes in patients with type 2 diabetes in relation to estimated glomerular filtration rate (egfr). Curr Med Res Opin 30: Komoroski B, Vachharajani N, Boulton D et al (2009). Dapaglifozin, a novel SGLT2 inhibitor, induces dose-dependent glicosuria in healthy subjects. Clin Pharmacol Ther 85: Bailey CJ, Gross JL, Hennicken D et al (2013). Dapaglifozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med 11: Kohan DE, Fioretto P, Tang W, List JF (2014). Long term study of patients with type 2 diabetes and moderate renal impairment shows that dapaglifozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 85: Heise T, Seman L, Macha S et al (2013). Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple rising doses of empaglifozin in patients with type 2 diabetes mellitus. Diabetes Ther 4: Rosenstock J, Jelaska A, Frappin G et al (2014). Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empaglifozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol 2: Pratley R, Nauck, M, Barnett, A et al (2014). Once weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol 2: Tujilo JM, Nuffer W, Ellis SL (2015). GLP-1 receptor agonists: a review of head-to-head clinical studies. Ther Adv Endocrinol Metab 6: Kuritzky L, Umpierrez G, Ekoé M et al (2014). Safety and efficacy of dulaglutide, a once weekly GLP-1 receptor agonist, for the management of type 2 diabetes. Postgrad Med 126: Kahn SE, Cooper ME, Del Prato S (2014). Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet 383:

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116 116 CONGRESSO NAZIONALE Società Italiana di Medicina Interna E T N IE RO Z A IL P CENT AL Roma, 10 /12 Ottobre 2015 Congress Center Rome Cavalieri