ISSN: 2281-0692 – online edition
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J our nal of P e diat r ic and N eonat al I n dividualized Medicine Vol. 3 • N. 1 • April 2014
The Journal of Pediatric and Neonatal Individualized Medicine (www.jpnim.com) is a peerreviewed interdisciplinary journal which provides a forum on new perspectives in pediatric and neonatal medicine. The aim is to discuss and to bring readers up to date on the latest in research and clinical pediatrics and neonatology. Special emphasis is on the developmental origin of health and disease, perinatal programming and on the so-called ‘-omics’ sciences. Systems medicine blazes a revolutionary trail from reductionist to holistic medicine, from descriptive medicine to predictive medicine, from an epidemiological perspective to a personalized approach. The journal will be relevant to clinicians and researchers concerned with personalized care for newborns and children. Medical humanities will also be considered in a tailored way.
ISSN: 2281-0692 – online edition
www.jpnim.com Open Access
J our nal of P e diat r ic and N eonat al I n dividualize d Medicine Vol. 3 • N. 1 • April 2014
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Journal of Pediatric and Neonatal Individualized Medicine www.jpnim.com Open Access Official Journal UENPS (Union of European Neonatal and Perinatal Societies)
Editor-in-Chief Vassilios Fanos Cagliari, Italy
Associate Editors Jacob V. Aranda
Enrico Ferrazzi
Manuel Sanchez Luna
New York, USA
Milan, Italy
Madrid, Spain
Jaques Belik
Hercília Guimarães
Umberto Simeoni
Toronto, Canada
Porto, Portugal
Marseille, France
Giuseppe Buonocore
Amir Lahav
John N. van den Anker
Siena, Italy
Boston, USA
Washington, USA
Gavino Faa
Michele Mussap
Murat Yurdakök
Cagliari, Italy
Genoa, Italy
Ankara, Turkey
Editorial Board Rino Agostiniani
Memet Metin Özek
Pistoia, Italy
Carlo Virginio Agostoni Milan, Italy
Karel Allegaert Leuven, Belgium
Gamal Samy Aly Cairo, Egypt
Fani Anatolitou Athens, Greece
Roberto Antonucci San Gavino Monreale, Italy
Luigi Atzori Cagliari, Italy
Georgy Balla Debrecen, Hungary
Luigi Barberini Cagliari, Italy
Pier Paolo Bassareo Cagliari, Italy
Enrico Bertino Turin, Italy
Paolo Biban Verona, Italy
Dorret Irene Boomsma Amsterdam, The Netherlands
Luigi Cataldi Rome, Italy
Antonina I. Chubarova Moscow, Russia
Giovanni Corsello Palermo, Italy
Laura Cuzzolin Verona, Italy
Ernesto D’Aloja Cagliari, Italy
Olivier Danhaive San Francisco, USA
Carlo Dani Florence, Italy
Istanbul, Turkey
Antonio Del Vecchio Bari, Italy
Gian Paolo Donzelli Florence, Italy
Italo Farnetani Milan, Italy
Boris Filipovic-Grcic Zagreb, Croatia
Gabriele Finco Cagliari, Italy
Diego Gazzolo Alessandria, Italy
Mario HerreraMarschitz Santiago, Chile
Egbert Herting Lübeck, Germany
Nicoletta Iacovidou Athens, Greece
Neli Gueorgieva Jekova Sofia, Bulgaria
Georgios Konstantinidis Novi Sad, Serbia
Peter Krcho Košice, Slovakia
Gian Benedetto Melis Cagliari, Italy
Giovanni Montini Bologna, Italy
Corrado Moretti Rome, Italy
Fabio Mosca Milan, Italy
Giovanni Ottonello Cagliari, Italy
Eren Özek Istanbul, Turkey
Piermichele Paolillo Rome, Italy
Giovanna Perricone Palermo, Italy
Denis Pisano Cagliari, Italy
Melania Puddu Cagliari, Italy
Antonio Ragusa Milan, Italy
Francesco Raimondi Naples, Italy
Natella Rakhmanina Washington, USA
Mahmoud Rashad Al Baha, Saudi Arabia
Kosmas Sarafidis Thessaloniki, Greece
Mauro Stronati Pavia, Italy
Darinka Šumanović-Glamuzina Mostar, Bosnia and Herzegovina
Jerzy Szczapa Poznan, Poland
Rasa Tamelienė Kaunas, Lithuania
Meow-Keong Thong Kuala Lumpur, Malaysia
Bart Van Overmeire Bruxelles, Belgium
Heili Varendi Tartu, Estonia
Liliana S. Voto Buenos Aires, Argentina
Marco Zaffanello Verona, Italy
Massimiliano Zonza Cagliari, Italy
Official Journal UENPS (Union of European Neonatal and Perinatal Societies).
The Journal of Pediatric and Neonatal Individualized Medicine is a peer-reviewed interdisciplinary journal which provides a forum on new perspectives in pediatric and neonatal medicine. The aim is to discuss and to bring readers up to date on the latest in research and clinical pediatrics and neonatology. Special emphasis is on the developmental origin of health and disease, perinatal programming and on the so-called ‘-omics’ sciences. Systems medicine blazes a revolutionary trail from reductionist to holistic medicine, from descriptive medicine to predictive medicine, from an epidemiological perspective to a personalized approach. The journal will be relevant to clinicians and researcher concerned with personalized care for newborns and children. Medical humanities will also be considered in a tailored way. Journal Website: www.jpnim.com Journal Name: Journal of Pediatric and Neonatal Individualized Medicine Editor-in-Chief: Vassilios Fanos, Neonatal Intensive Care Unit, Puericulture Institute and Neonatal Section, AOU and University of Cagliari, Italy Serial Publication Number (ISSN online): 2281-0692 Publishing Frequency: six-monthly (2 issues/year) Publishing Mode: peer-reviewed, online and Open Access Publisher: Hygeia Press di Corridori Marinella, Quartu Sant’Elena (CA), Italy Authorization under Italian law: Aut. Trib. Cagliari n. 16/12 del 07/06/2012, iscrizione ROC n. 22729 del 10/07/2012
Journal of Pediatric and Neonatal Individualized Medicine Vol. 3 • N. 1 • April 2014 © 2014 Hygeia Press di Corridori Marinella Via Montecatini, 53 – Quartu Sant’Elena (Cagliari) – Italy www.hygeiapress.com
www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1) doi: 10.7363/0301
Contents
EDITORIALS e030111 David Barker: the revolution that anticipates existence Italo Farnetani, Vassilios Fanos
e030122 Variability in drug use among newborns admitted to NICUs: a proposal for a European multicentre study Laura Cuzzolin
OBITUARY e030121 Roberto Burgio: the scientist at the service of every new life born into the world [Article in English and Italian] • [Roberto Burgio: lo scienziato al servizio di ogni nuova vita nata al mondo] [Article in English and Italian] Italo Farnetani, Francesca Farnetani
REVIEWS e030123 Oxytocin and customization of assistance in labor
Antonio Ragusa, Alessandro Svelato
e030110 Considering ethical dilemmas related to brain death in newborns Ilias Chatziioannidis, Georgios Mitsiakos
e030116 Nutrition of preterm infants with bronchopulmonary dysplasia after hospital discharge – Part I Hercília Guimarães, Gustavo Rocha, M. Beatriz Guedes, Paula Guerra, Ana Isabel Silva, Susana Pissarra
e030117 Nutrition of preterm infants with bronchopulmonary dysplasia after hospital discharge – Part II Hercília Guimarães, Gustavo Rocha, M. Beatriz Guedes, Paula Guerra, Ana Isabel Silva, Susana Pissarra
e030120 Fluconazole therapy for treatment of invasive candidiasis in Intensive Care patients. Is it still valid from a pharmacological point of view? Mario Musu, Maurizio Evangelista, Paolo Mura, Andrea Cossu, Massimiliano Carta, Gian Nicola Aru, Gabriele Finco
ORIGINAL ARTICLES e030115 Respiratory infections in very low gestational age infants: a population-based cohort study in Estonia Liis Toome, Silvi Plado, Inge Ringmets, Mari-Anne Vals, Heili Varendi, Irja Lutsar
e030113 Perinatal management of gastroschisis
Vincenzo Insinga, Clelia Lo Verso, Vincenzo Antona, Marcello Cimador, Rita Ortolano, Maurizio Carta, Simona La Placa, Mario Giuffrè, Giovanni Corsello
e030109 Peripheral perfusion index-reference range in healthy Portuguese term newborns
Joana Jardim, Ruben Rocha, Gorett Silva, Hercília Guimarães
e030112 Caring for children with brain tumors in an oncology ward: a phenomenologichermeneutic study
Chiara Fioretti, Rosapia LauroGrotto, Debora Tringali, Eva M. Padilla-Muñoz, Massimo Papini
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Journal of Pediatric and Neonatal Individualized Medicine (JPNIM) • vol. 3 • n. 1 • 2014
e030108 Oral breathing: new early treatment protocol
Gloria Denotti, Selena Ventura, Ornella Arena, Arturo Fortini
CASE REPORTS e030101 Novel chromosomal translocation t(7;14) (q36.3;q11.2)dn in a female child with dysmorphic features
Jean-Pierre Antunes Gonçalves, Liliana Pinheiro, Maria João Magalhães, Arnaldo Cerqueira, Eduarda Abreu, Albina Silva, Carla Sá, Almerinda Pereira
e030114 Floppy Infant Syndrome: new approach to the study of neonatal hypotonia through the analysis of a rare case of X-Linked Myotubular Myopathy Massimiliano De Vivo, Silvana Rojo, Roberto Rosso, Giovanni Chello, Paolo Giliberti
e030107 A novel SRY nonsense mutation in a case of Swyer syndrome Clara Machado, Angela Pereira, José Matos Cruz, Alexandra Cadilhe, Albina Silva, Almerinda Pereira
QUESTION & ANSWER e030118 Polypoid lesion of nasal skin in a child: question
Clara Gerosa, Daniela Fanni, Luca Pilloni, Filippo Carta, Roberto Puxeddu, Gavino Faa
e030119 Rhabdomyomatous mesenchymal hamartoma presenting as a polypoid lesion of the nasal skin in a child: answer
ITALIAN SECTION REVIEWS e030102 [Use of oxygen during neonatal resuscitation] [Article in Italian] • Uso dell’ossigeno nella rianimazione del neonato
Roberto Antonucci, Annalisa Porcella, Luca Antonucci
e030103 [Neonatological emergencies in delivery room] [Article in Italian] • Il neonatologo ed alcune emergenze in sala parto Antonio Boldrini, Rosa Teresa Scaramuzzo
e030104 [Congenital toxoplasmosis: clinical manifestation, treatment and followup] [Article in Italian] • Il neonato con toxoplasmosi congenita: clinica, terapia e follow-up Lina Bollani, Mauro Stronati
e030105 [Group B streptococcal perinatal infection] [Article in Italian] • Infezione perinatale da Streptococco Gruppo B Giampiero Capobianco, Antonio Balata, Maria Chiara Mannazzu, Giorgio Olzai, Claudio Cherchi, Giuseppe Virdis, Francesco Dessole, Matteo Busacca, Erich Cosmi
e030106 [Acute pyelonephritis in the neonatal period] [Article in Italian] • Pielonefrite acuta in epoca neonatale
Giovanni Ottonello, Angelica Dessì, Danila Manus, Anna Paola Pinna, Fabiana Sau, Vassilios Fanos
Clara Gerosa, Daniela Fanni, Luca Pilloni, Filippo Carta, Roberto Puxeddu, Gavino Faa
Contents
www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030111 doi: 10.7363/030111 Advance publication: 2014 Jan 10
Editorial
David Barker: the revolution that anticipates existence Italo Farnetani1, Vassilios Fanos2 1
Department of Surgery and Interdisciplinary Medicine, University of Milano – Bicocca, Milan, Italy
2
Neonatal Intensive Care Unit, Puericulture Institute and Neonatal Section, AOU and University of
Cagliari, Italy
“The womb may be more important than the home” David Barker
Keywords
David Barker, Barker’s revolution, fetus, intrauterine life, perinatal programming. Corresponding author Italo Farnetani, Department of Surgery and Interdisciplinary Medicine, University of Milano – Bicocca, Milan, Italy; email: italo.farnetani@unimib.it.
How to cite Farnetani I, Fanos V. David Barker: the revolution that anticipates existence. J Pediatr Neonat Individual Med. 2014;3(1):e030111. doi: 10.7363/030111.
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Journal of Pediatric and Neonatal Individualized Medicine • vol. 3 • n. 1 • 2014
It was a shock to learn that on August 27, 2013, life abandoned David Barker, the man who “anticipated” the existence of babies by focusing attention on the importance of the fetus and what takes place during intrauterine life. Undoubtedly for him, Horatio’s phrase “Non omnis moriar”, was invaluable: Barker was one of the physicians who in the last decades brought about the greatest changes in medicine, changes so important as to represent a veritable revolution in medical thought. “Barker’s revolution” took place in 1995, when at the age of 57 (he was born on June 29th 1938), he published in the British Medical Journal an article so important that his thesis was defined as the “Barker hypothesis” [1]. At the beginning, as is the case with all great discoveries, Barker’s idea was controversial and hotly debated, but in the end it was accepted by the majority of physicians and scientists. It also modified the way of conducting research, prevention and clinical medicine. Barker studied 13,517 men and women born between 1924 and 1944 at the Helsinki University Hospital. The method he followed in the study was original. He had asked some historians for help in reconstructing the anamnesis of patients using available documents: clinical records, hospitalizations, drug prescriptions and causes of death. Barker’s conclusion was surprising, unexpected and innovative: the possibility of developing cardiovascular or metabolic diseases, such as diabetes, was related to conditions in the embryonic stage. The study reversed all the clinical and preventive acquisitions reached up to then and imposed preventive and therapeutic strategies starting from the beginning of pregnancy. To illustrate not only the scientific and ethical impact of Barker’s discovery, but also to understand his personality, we must describe medical thought and the socio-cultural context of the 1960s and 1970s, the years in which Barker published his first article in Nature (1961), and became a researcher in the department of social medicine at the University of Birmingham (1963), where he remained until 1979, when he became a professor of clinical epidemiology at the University of Southampton. According to Barker’s studies, the embryo obviously has a genetic complement coming from the mother and father, but from the very first stages of development it begins to undergo the influence of the outside environment, just as occurs for adults whose biological, psychological and pathological aspects are influenced by the environment to a not well-established percentage between genetic
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complement and epigenetics. Thus the embryo possesses within it all the genetic information coming from its family heritage, but from the time of conception it is influenced by the mother’s nutritional conditions, which are in turn determined by her socioeconomic context. Barker illustrated his research by comparing the embryo to the automobile which must be well put together to move in all environments, even damaged ones: the well-built models do not break down while the others may. If Barker’s discovery was revolutionary from the cultural standpoint, it was even more so from the strictly medical one. Not only was it necessary to change all the preventive strategies and focus more on the first period of life, but it was also necessary to reconsider the role of genetics to the advantage of the environment. Also debunked was the idea that to be in good health and live a long life it was necessary to choose the right parents: after Barker’s research we must add that it is not only best to choose the right parents, but also to find a favorable environment and good travelling companions. Genetics proposes, but epigenetics disposes. Genetics is written in ink and cannot be cancelled, while epigenetics is written in pencil and, if we so desire we can erase it and rewrite it: we cannot change our past but we can modify our future [2]. Barker’s research method was rigid from the methodological standpoint, but innovative and speculative in its working hypotheses, with a humanistic slant. Over the years, thanks to his brilliant intuitions, the concept of perinatal programming has become more and more accepted as: “The response by a developing organism to a specific challenge during a critical time window that alters the trajectory of development qualitatively and/or quantitatively with resulting persistent effects on phenotype” [3]. Much of our future lives as adults is decided in our mothers’ wombs. For example, alterations of the growth balance in the first three months of pregnancy, in the sense of hyponutrition, are associated in adult life with cardiovascular diseases, high blood pressure, dyslipidemia and obesity; alterations in the second three months may be associated with pulmonary and renal pathologies and, in the final three months diabetes, schizophrenia and personality disorders of the antisocial type. Thus not only is genetics important (to be able to) but also epigenetics (to be). Barker’s considerations concern not only the metabolic syndrome, but also the major neuropsychiatric disorders (depression, ADHD,
Farnetani • Fanos
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schizophrenia, autism) that may have their onset in the mother’s womb, as he himself underscored in an interview that appeared in Time in October of 2010 [4]. The changes that take place in the organism are far-reaching and oriented so as to lead the fetus to survival (I was born to be born, Pablo Neruda would say) but also to reproduce (I was born to reproduce myself). Imbalance in a critical window of development, for example in the second three months of pregnancy, may lead to cell hypodysplasia, a reduction of vascular arborization, reduction of ureteric bud arborization or that of the bronchial tree, which cannot be recovered, except partially, at a later time. In the same way, a noxa in the third three months of pregnancy causes an alteration of the cerebral connections. From this comes the possibility, at least potential, of transforming the critical window of vulnerability into one of opportunity to prevent cardiovascular diseases in the child and the adult. The objective is not only to reduce the noxae for the fetus, but also to learn how to increase the resilience of the fetus and the neonate. Barker’s thought was evolution and revolution together, altering medical thought in its entirety and forcing us to constantly pose important questions on the gestational age at which to apply neonatal reanimation or not. Barker’s idea has another practical corollary: it is evident that the role of obstetricians, perinatologists and neonatologists is more and more relevant in medicine and future prevention. In all likelihood,
Barker’s revolution
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future texts of internal medicine will deal less with traditional diseases (preventable or held to a minimum in the perinatal period) and more with clinical pictures not previously described (such as, for example, the metabolic syndrome itself). Unquestionably, besides the enormous merits of his clinical research, among the benefits that Barker has contributed there is that of having helped us to see things from new points of view. Not only is the neonate (and even more so the fetus) not an adult of reduced proportions, but perhaps the neonate is the “father” of the adult person [5]. We must, with great humility, reconsider all that we believed for decades in good faith; it is no accident that Eliot sums up his deep reflection in the following way: in my beginning is my end. References 1.
Barker DJ. Fetal origins of coronary heart disease. BMJ. 1995;311(6998):171-4.
2.
Fanos V. Pediatric and neonatal individualized Medicine: care and cure for each and everyone. J Pediatr Neonat Individual Med. 2012;1(1):7-10.
3.
Nijland MJ, Nathanielsz PW Developmental Programming of the Kidney. In: Newnham JP, Ross MG (Eds.). Early Life Origins of Human Health and Disease. Basel: Karger, 2009.
4.
Murphy Paul A. How the First Nine Months Shape the Rest of Your Life. Time. 2010, Sep. 22. Available at: http://content.time.com/time/ magazine/article/0,9171,2021065,00.html, last access: December 2013.
5.
Barker DJ. The fetal and infant origins of adult disease. BMJ. 1990 Nov 17;301(6761):1111.
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030122 doi: 10.7363/030122 Advance publication: 2014 Mar 25
Editorial
Variability in drug use among newborns admitted to NICUs: a proposal for a European multicentre study Laura Cuzzolin Department of Public Health & Community Medicine – Section of Pharmacology, University of Verona, Italy
“We cannot always make our patients better, but we can always make them worse” Bill Silverman
Keywords
Newborn, drug use, variability. Corresponding author Laura Cuzzolin, Department of Public Health & Community Medicine, Section of Pharmacology, University of Verona, Italy; tel.: +39 045 8027609; fax: +39 045 8027452; e-mail: laura.cuzzolin@univr.it.
How to cite Cuzzolin L. Variability in drug use among newborns admitted to NICUs: a proposal for a European multicentre study. J Pediatr Neonat Individual Med. 2014;3(1):e030122. doi: 10.7363/030122.
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The use of drugs in newborns admitted to Neonatal Intensive Care Units (NICUs) is characterized by a great variability in the management of the most common diseases and is a widespread phenomenon observed both within and between different countries. An interesting paper published some months ago [1] reported data on a preliminary part of the Treat Infections in Neonates (TINN) project set up under the 7th Framework Programme [2], describing the use of ciprofloxacin and fluconazole in 189 NICUs of 25 different European countries. These two drugs, respectively used to treat sepsis caused by multiple resistant organisms [3] and invasive candidiasis [4], are included in the EMA’s priority list of offpatent products with the highest need for studies in newborns [5] since there is insufficient data on their pharmacokinetics, efficacy and safety in neonates [6, 7]. From this paper emerged a heterogeneous situation as regards the treatment of bacterial and fungal neonatal sepsis within and between European countries. In detail, ciprofloxacin was used in 25% of NICUs in absence of guidelines about the use of ciprofloxacin for neonatal sepsis and mainly on the basis of a standard written protocol. This antibiotic was administered in dosages that varied enormously (ranging from < 10 mg/kg/day to > 30 mg/kg/day), with the most commonly used regimen being 20 mg/ kg/day. As regards fluconazole, considered by the IDSA guidelines a possible option for treatment of invasive candidiasis, 70% of NICUs administered this antifungine on the basis of a standard written protocol. The dosages used varied significantly (3-612-20 mg/kg) and only 16% of NICUs administered the recommended dose of 12 mg/kg/day reported by IDSA guidelines. Moreover, the interval between administrations also varied, following a 24-h (41% of NICUs), 48-h (24% of NICUs) or 72-h (19% of NICUs) interval. From the analysis of questionnaires emerged concerns expressed by respondents about antibiotic resistance and lack of safety data in neonates. This aspect of variability in drug use does not regard only the treatment of neonatal infections, but also other medicines commonly used in the neonate in the first period of life. In fact, the same scenario emerged as regards the treatment of PDA in preterm newborns. A questionnaire was sent to 24 European Societies of Neonatology and Perinatology and the analysis of data received from 45 NICUs of 19 European countries revealed a wide variation among countries as regards the use of NSAIDs to treat PDA, partly
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explained by the definition/diagnosis criteria of PDA. Intravenous indomethacin (mostly a 3060 min infusion) was used in 32 NICUs (71%), intravenous ibuprofen in 16 NICUs (36%) and oral ibuprofen, preferred for its low cost, in 13 NICUs (29%). 45% of NICUs applied two courses of treatment and 27% prescribed a third one (usually not indicated). Prolonged treatments were mentioned by 45% of wards, despite the greater incidence of enterocolitis and changes in renal function. Almost all NICUs treated hemodynamically significant PDA, while prophylactic treatments were applied in 2 NICUs [8]. To treat remains an unresolved issue, due to a lack of data that could clearly give a universal recommendation. In presence of a hemodynamically significant PDA, a consensus of the Iberian Society of Neonatology recommends to start the treatment between day 2 and 5 of life to increase the probability of success [9]. Undoubtedly, given the unique characteristics of the neonatal population, it could be justified in some situations to apply a treatment on individual basis. However, other factors could contribute to this variability in drug use. First of all, it is common the absence of evidence-based guidelines defining the better treatment for the most common diseases diagnosed in the newborn such as PDA and sepsis. Moreover, it is widespread the use of drugs in an offlabel manner, given the difficulty to perform clinical studies in the neonatal population. Some years ago, a review by Cuzzolin et al. [10] underlined the high number of newborns (> 80%) receiving an offlabel treatment. Despite an improvement in rational prescribing for pediatric population, including more than 500 labelling changes [11], off-label drug use remains an important health issue for neonates, as confirmed more recently by other authors [12-16]. This kind of use of medications makes the neonatal population highly vulnerable to adverse drug reactions (ADRs) [17] and medication errors [18]. In fact, the potential ADRs rate calculated in pediatric wards is 3 times higher compared to the other patient populations and even more significantly higher in NICUs, with most of ADRs involving uncorrected doses or unapproved formulations [17, 19, 20]. In a review published by Chedoe et al. [21], eleven studies were identified on the frequency of medication errors in NICUs: rates varied widely between studies (the highest rate was 5.5 medication errors per 100 prescriptions) and the majority of studies identified dose errors as the most common type of error. Differences in clinical practices between NICUs need to be addressed at a European level.
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Therefore, a multicentre study involving different NICUs of European countries could be useful to harmonize drug use in the neonate. The collection and recording of data regarding medicines given to newborns admitted to NICUs is an instrument of knowledge useful to evaluate the efficacy and safety of drugs used in this vulnerable patient population, with the purpose to give to all newborns identical health care opportunities [22].
10. Cuzzolin L, Atzei A, Fanos V. Off-label and unlicensed
Declaration of interest
12. Dessì A, Salemi C, Fanos V, Cuzzolin L. Drug treatments in a
JM, Rogido M, Zambosco G, Van Overmeire B. First SIBEN clinical consensus: diagnostic and therapeutic approach to patent ductus arteriosus in premature newborns. An Pediatr (Barc). 2008;69(5):454-81. prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety. Expert Opin Drug Saf. 2006;5(5):703-18. 11. American Academy of Pediatrics Committee on Drugs. Off-label use of drugs in children. Pediatrics. 2014;133(3):563-7.
The Author declares that there is no conflict of interest.
neonatal setting: focus on the off-label use in the first month of life. Pharm World Sci. 2010;32(2):120-4. 13. Nguyen KA, Claris O, Kassai B. Unlicensed and off-label drug use
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review of the current literature. Drug Saf. 2007;30(6):503-13. 22. Cuzzolin L, Zaccaron A, Fanos V. Unlicensed and off-label uses
Golombek SG, Sola A, Baquero H, Borbonet D, Cabañas F,
of drugs in paediatrics: a review of the literature. Fundam Clin
Fajardo C, Goldsmit G, Lemus L, Miura E, Pellicer A, Perez
Pharmacol. 2003;17(1):125-31.
Variability in drug use among newborns admitted to NICUs
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030121 doi: 10.7363/030121 Advance publication: 2014 Mar 31
Obituary
Roberto Burgio: the scientist at the service of every new life born into the world [Roberto Burgio: lo scienziato al servizio di ogni nuova vita nata al mondo] Italo Farnetani1, Francesca Farnetani2 1
University of Milano-Bicocca, Milan, Italy
2
Dermatology Clinic, University of Modena and Reggio Emilia, Italy
English text first, Italian follows
“Nobody is born of his own will and therefore we are all committed to ensuring that those who are born live good lives” [“Nessuno nasce per propria volontà e, quindi, siamo tutti impegnati a far vivere bene chi nasce”] Roberto Burgio
Keywords
Roberto Burgio, pediatrics, research, memory. Corresponding author Italo Farnetani, Department of Surgery and Interdisciplinary Medicine, University of Milano-Bicocca, Milan, Italy; email: italo.farnetani@unimib.it.
How to cite •
Farnetani I, Farnetani F. Roberto Burgio: the scientist at the service of every new life born into the world. [Article in English and Italian]. J Pediatr Neonat Individual Med. 2014;3(1):e030121. doi: 10.7363/030121.
•
Farnetani I, Farnetani F. Roberto Burgio: lo scienziato al servizio di ogni nuova vita nata al mondo. [Article in English and Italian]. J Pediatr Neonat Individual Med. 2014;3(1):e030121. doi: 10.7363/030121.
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English text
Pediatria essenziale is the text of pediatrics which, from its 1st edition in 1978 [1], has been a book studied and consulted by students, physicians and pediatricians and which guided Roberto Burgio’s thought up to the final edition in 2012 [2] to which he applied some five years of total commitment, with the involvement of 120 collaborators, a number so large that he defined it a “choral” work. He reviewed and verified every page in contact with the authors to whom he sent questions and requests for extensions. It was thus “his book”, the one to which he entrusted his thought, his knowledge, his being a man and physician. It is thus a work that will remain in the annals of pediatrics. By chance, which we do not want to consider fortuitous, Roberto Burgio concluded his life exactly one year after the presentation of the book in his Pavia at the Libreria Feltrinelli (Fig. 1). On that occasion he brought together his co-workers, colleagues, friends and also simple citizens. It was a tribute and homage to the master, but also to the man who had even become identified with his city: suffice it to say that he directed the pediatric clinic for twenty-four years starting from 1966, giving stability to a chair which in the previous half a century had been occupied by twelve different professors. He had brought Pavia to a level of international excellence and had refused the chairs in Florence and Rome.
Burgio was a descendent of the greatest Italian school of pediatrics, the Scuola di Rocco Jemma, of which he represented the third generation. He wrote: “School of pediatrics (Sicilian-Neapolitan) to which I have the honour of belonging and which historically finds in the name of Rocco Jemma its undisputed founder” [3]. To understand Burgio’s professional career, we must refer to certain dates. He received his degree on 8 July 1942 at the University of Palermo and immediately entered the pediatric clinic, where he studied under Michele Gerbasi (1900-1994) [4]. The period of his training coincided with the time at which the Allies landed in Sicily on 9 July 1943. They brought with them antibiotics and this made it possible for Gerbasi’s school, and thus also for Burgio, to shift his scientific and research priority from infectious diseases to food disorders, a subject that remained clearly present to Burgio in rereading the history of medicine in the immediate post-war period. In 1940, Michele Gerbasi described [5] “perniciosiform megaloblastic anaemia of breastfeeders” associated with manifestations of extrapyramidal “Parkinson-like” discomfort, the symptoms of which were hypomimia and slight undulatory tremors of limbs and head. He interpreted the disease as caused by feeding exclusively with the milk of wet nurses who, because of their poverty, ate vegetables only. Thus, there was a lack of animal proteins and a deficit of the Castle’s “extrinsic antiaenemic-pernicious factor” (then
Figure 1. Pavia, 8 March 2013, presentation of the treatise. Italo Farnetani (on the left) interviews Roberto Burgio. [Pavia, 8 marzo 2013, presentazione del trattato. Italo Farnetani (a sinistra) intervista Roberto Burgio].
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not better specified). Burgio demonstrated that the administration of one 1 gamma (microgram) per day of vitamin B12 (in the meantime identified as the aforementioned “extrinsic factor”) for 8 to 10 days restores the normal erythropoiesis with a strong “crysis of reticulocytes” on recovery. In the publication Le dimensioni dei granuloblasti e dei granulociti neutrofili nella ariboflavinosi [6], we can see the precision of Burgio’s scientific research based on in-depth work in the laboratory, but without ever losing sight of the child. The same outlook can be seen when he described a rare genetic malformation for the diagnosis of which research in the laboratory is essential, in fact from the description of the anamnesis we immediately see that the centre of his attention was focused on the child: “A sister born after 12 months is in normal conditions of growth, while our patient has grown with great difficulty (…) The fact is that at the age of 3 ½ years she was taller than our patient who at that time was 4 ½ years old…” [7]. In this period, under Gerbasi’s supervision, he translated the Trattato di pediatria by Fanconi and Wallgren [8]. In 1962 he won the chair of pediatrics in Perugia, where he remained until 1966, when he moved to Pavia where he spent the rest of his life. After the 1960s, at the time of great progress in the field of immunology and immunopathology, he worked in this sector, performing sophisticated studies. In particular, he devoted himself to transplantology, but even in this his main interest emerged as that of the child. The discovery he was proudest of and which he considered the best of his professional career was that of the “programmed sibling” when he advised the parents of a child who needed a marrow transplant to have another child when no compatible donor could be found. Besides the scientific explanation and reviewing the history of transplants, Burgio underscored two things: that it was a way of donating life to two persons (a sister was born and saved her elder brother’s life), and that now it was a happy family living in the province of Cremona. In conclusion, Burgio was a great master of pediatrics; he surely contributed to the progress of medicine and science in general. We wish to recall the concept he expressed during the presentation of his book in Pavia: “Nobody is born of his own will and therefore we are all committed to ensuring that those who are born live good lives. Parents first of all, but obviously pediatricians at their sides. This is
Remembering Italian pediatrician Roberto Burgio
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a maxim that I have placed on the back cover of the 5th edition of Pediatria Essenziale” [9]. Italian text
La Pediatria essenziale è il testo di pediatria che, dalla I edizione del 1978 [1], è stato un libro studiato e consultato da studenti, medici e pediatri e che ha veicolato il pensiero di Roberto Burgio, fino all’ultima edizione del 2012 [2] alla quale ha dedicato circa cinque anni di dedizione assoluta, coinvolgendo 120 collaboratori, tanto che la definì un’opera “corale”. Ha riguardato e verificato ogni pagina, confrontandosi con gli autori, ai quali ha spedito quesiti e richieste di ampliamento. È stato perciò il “suo libro” quello a cui ha affidato il suo pensiero, il suo sapere, il suo essere uomo e medico. È pertanto un’opera che resterà nella storia della pediatria. Per un caso, che non vogliamo considerare fortuito, Roberto Burgio ha concluso la sua esistenza terrena nello stesso giorno, a un anno di distanza, in cui il libro fu presentato nella sua Pavia alla Libreria Feltrinelli (Fig. 1). In questa occasione si riunirono collaboratori, colleghi, amici, ma anche semplici cittadini. Fu un tributo e un omaggio al maestro, ma anche a colui che si era identificato con la città, basti pensare che aveva diretto la Clinica pediatrica dal 1966 per ventiquattro anni, dando stabilità a una cattedra che invece nel mezzo secolo precedente al suo arrivo era stata occupata da dodici docenti. Aveva portato Pavia ad un livello di eccellenza internazionale, rifiutando le cattedre di Firenze e Roma. Burgio era un discendente della più grande scuola pediatrica italiana, la “Scuola di Rocco Jemma”, di cui lui rappresentava la terza generazione, come scrisse: “Scuola di pediatria (siculo-partenopea) alla quale mi onoro di appartenere e che storicamente trova il nome di Rocco Jemma quale incontrastato fondatore” [3]. Per capire il percorso professionale di Burgio, bisogna osservare alcune date. Si era laureato l’8 luglio 1942 presso l’Università di Palermo ed era subito entrato nella Clinica pediatrica, dove era divenuto allievo di Michele Gerbasi (1900-1994) [4]. Il periodo della formazione coincide proprio con il momento in cui gli Alleati, sbarcando nell’isola il 9 luglio 1943, portarono gli antibiotici, questo pertanto permise alla scuola del Gerbasi, e perciò anche a Burgio, di spostare la priorità scientifica e di ricerca dalle malattie infettive verso i disturbi della nutrizione, un argomento che resterà ben presente in
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Burgio nel rileggere, a livello storico, la storia della medicina nell’immediato dopoguerra. Michele Gerbasi descrisse nel 1940 [5] l’“anemia perniciosiforme megaloblastica del lattante”, associata a manifestazioni di sofferenza extrapiramidale simile al “parkinsonismo”; sintomi: ipomimia, tremori a piccole onde degli arti e del capo. Interpretò la malattia come dovuta ad alimentazione esclusiva con latte di nutrici che, per povertà, erano ad alimentazione vegetariana, pertanto con carenza in proteine animali, perciò con deficit del “fattore estrinseco antianemico-pernicioso” di Castle (allora ancora imprecisato). Burgio dimostrò che la somministrazione orale di 1 gamma (microgrammo) al giorno di vitamina B12 (nel frattempo identificata come il summenzionato “fattore estrinseco”) per 8-10 giorni ripristinava l’eritropoiesi normale con imponente “crisi reticolocitaria” della guarigione. Nella pubblicazione Le dimensioni dei granuloblasti e dei granulociti neutrofili nella ariboflavinosi [6], si nota l’accuratezza della ricerca scientifica di Burgio basata su approfondite ricerche di laboratorio, senza mai però perdere di vista il bambino. La stessa impostazione si nota quando descrive una rara malformazione genetica in cui la ricerca di laboratorio è essenziale per la diagnosi, infatti dalla descrizione dell’anamnesi si nota subito l’attenzione e la centralità del bambino: “Una sorellina nata dopo 12 mesi è in normali condizioni di accrescimento, mentre la nostra paziente si è accresciuta molto stentatamente (…) Sta di fatto che la sorella all’età di 3 ½ anni è apparsa più alta della nostra paziente allorchè questa aveva 4 ½ anni …” [7]. In questo periodo tradusse, con la supervisione di Gerbasi, il Trattato di pediatria di Fanconi e Wallgren [8]. Nel 1962 vinse la cattedra di pediatria di Perugia, ove restò fino al 1966, quando si trasferì a Pavia ove è restato per il resto della sua vita. Dagli anni Sessanta, in coincidenza con i notevoli sviluppi nel campo della immunologia e immunopatologia, si occupò di questo settore, compiendo raffinate ricerche, in particolare si dedicò alla trapiantologia, ma anche in questo ambito emerge il suo interesse e la centralità data al bambino. La scoperta a cui teneva di più e che riteneva essere la migliore della sua carriera professionale,
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era quella del “fratellino programmato”: consigliò a dei genitori che avevano un bambino da sottoporre a trapianto di midollo, per il quale non era stato trovato un donatore compatibile, di concepire un fratellino. Oltre alla spiegazione scientifica, nel ricostruire questa scelta nel percorso della storia dei trapianti Burgio sottolineava due cose, che era stato un modo di donare la vita a due persone (infatti nacque una sorellina che salvò la vita al fratello più grande) e che ora erano una famiglia felice che viveva in provincia di Cremona. In conclusione, Burgio è stato un grande maestro di pediatria, e sicuramente ha contribuito ai progressi della medicina e della scienza in generale. Vogliamo ricordare questo concetto che espresse proprio durante la presentazione del suo libro a Pavia: “Nessuno nasce per propria volontà e, quindi, siamo tutti impegnati a far vivere bene chi nasce. Genitori in primo luogo, ma pediatri ovviamente con essi. È una mia massima che ho riportato in IV di copertina di Pediatria Essenziale, V edizione” [9]. References 1.
Burgio GR, Perinotto G. Pediatria essenziale. Torino: UTET, 1978.
2.
Burgio GR, Martini A, Nespoli L, Notarangelo LD. Pediatria Essenziale. 5ª Ed. Milano: Edi-Ermes, 2012.
3.
Burgio GR. Caronia: lo scienziato-rettore visto da un maestro. In: Farnetani I (Ed.). Pediatri e medici alla Costituente. Un pezzo sconosciuto di storia della Repubblica. Cento (FE): Editeam, 2006, p. 24.
4.
Burgio GR. Michele Gerbasi: un caposcuola. Grand’Angolo di Edit-Symposia. Pediatria e Neonatologia. 2007;14:25-6.
5.
Gerbasi M. Anemia perniciosiforme osservata in bambini ad allattamento materno esclusivo e protratto. La Pediatria. 1940;48:505-26.
6.
Gerbasi M, Burgio GR, Le dimensioni dei granuloblasti e dei granulociti neutrofili nella ariboflavinosi. In: Scritti medici in onore di Giuseppe Caronia. Roma: Tip. Pliniana Ed. Faro, 1949, pp. 275-81.
7.
Burgio GR, Biscatti G, Tiepolo L, Scappaticci S. Studiando un caso di mosaico XO/XX, in Scritti in onore di Michele Gerbasi. Napoli: Stabilimento Tipografico G. Genovese, 1970, pp. 132-51.
8.
Fanconi G, Wallgren A. Trattato di pediatria. Milano: Casa Editrice Dr. Francesco Vallardi, 1960.
9.
Farnetani I. Intervista sul bambino e l’adolescente a Roberto Burgio. Pediatria Preventiva & Sociale. 2013;8:31-5.
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030123 doi: 10.7363/030123 Publication: 2014 Apr 09
Invited review
Oxytocin and customization of assistance in labor Antonio Ragusa, Alessandro Svelato Department of Obstetrics and Gynecology, Niguarda Hospital, Milan, Italy
Abstract
Synthetic oxytocin (synOT) is a commonly used drug in labor and it can be applied in all stages of labor. SynOT has been increasingly used over the years, and is currently one of the most common drugs employed in obstetrics. The goal of synOT administration is to cause the augmentation of labor; unfortunately, guidelines for the administration of this drug are often non-specific, although synOT is the drug most commonly associated with preventable adverse perinatal outcomes. Approximately half of all paid obstetric litigation claims in the United States involve allegations of injudicious use of oxytocin, and the association between oxytocin use, hyperstimulation, fetal distress and adverse neonatal outcome are well know. Furthermore, synOT and oxytocin have some extragenital effects that should be known by obstetricians. This review will present the viewpoint of the authors on this topic. Keywords
Synthetic oxytocin, labor, litigation, side effects, newborn, augmentation, dystocia. Corresponding author Antonio Ragusa, Department of Obstetrics and Gynecology, Niguarda Hospital, Milan, Italy; email: antonio.ragusa@gmail.com.
How to cite Ragusa A, Svelato A. Oxytocin and customization of assistance in labor. J Pediatr Neonat Individual Med. 2014;3(1):e030123. doi: 10.7363/030123.
Introduction
Oxytocin was isolated and synthesized for the first time in 1953 by Vincent du Vigneaud (1901-1978) who was awarded the Nobel Prize for Chemistry for this discovery two years later.
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Synthetic oxytocin (synOT) is a commonly used drug in labor and it can be applied in all stages of labor. SynOT has been increasingly used over the years, and is currently one of the most common drugs employed in obstetrics [1]. Its use in delivery rooms in the Western world has reached epidemic levels, with percentages of use of between 44.5-75% in nulliparous and between 25-40% in pluriparous [2-4]. SynOT is often used to treat dystocia, which is characterized by abnormal slow progress of labor, and is among the most common challenges in birth care, especially for primiparous women [5-7]. In a study of primiparas with spontaneous onset of labor at term, 37% were found to develop labor dystocia [8]. Swedish data has reported the use of synOT augmentation in some 70% of primiparas at term [9, 10]. The goal of synOT administration is to cause the augmentation of labor (that is, uterine activity sufficient to produce cervical change and fetal descent while avoiding uterine hyperstimulation and fetal compromise). A wide variety of synOT regimens may be used for labor augmentation provided that proper precautions are met, as clear guidelines and continuous cardiotocography (CTG). Unfortunately, guidelines for the administration of this drug are often non-specific [11], although synOT is the drug most commonly associated with preventable adverse perinatal outcomes [12]. Approximately half of all paid obstetric litigation claims in the United States involve allegations of injudicious use of oxytocin [13]. The association between oxytocin use, hyperstimulation, fetal distress and adverse neonatal outcome are well know [14-18]. Indeed, adverse perinatal outcome, related to fetal hypoxia due to impairment of gas exchange between contractions, may occur in the presence of uterine hyperactivity [18, 19]. Nevertheless, few obstetricians are also informed about the developmental consequences that synOT has on the fetus. It is known that, in addition to the classic endocrine functions in female animals during parturition and lactation, oxytocin acts as a potent modulator of social behavior in a diverse range of species from worms and voles to humans [20]. In particular, recent evidence shows that newborns’ neurobehavioral cues may be sensitive to intrapartum synOT [21]. In experiments on animals, the administration of oxytocin during labor was seen to have long term effects with regard to bonding, social
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behavior and on the hypothalamic-pituitaryadrenal axis, many of these effects show sexually dimorphic behavior [22]. Evidence coming from studies on humans show that the use of synOT in labor has effect on the maternal hormone balance. In a study [23], a significant negative correlation was noted in mothers who had received oxytocin infusion during labor: the higher the dose of synOT received during labor, the lower their endogenous oxytocin levels two days later. We know that the mothers’ plasma oxytocin in post partum is related to the amount of affectionate parenting behaviors, including “motherese” vocalizations, the expression of positive affect, and affectionate touch, whereas paternal plasma oxytocin is correlated with the degree of stimulatory parenting behavior, including proprioceptive contact, tactile stimulation, and object presentation [24]. In consideration of the above, it is very important to assess and analyze methods to manage dystocia that reduce the use and the amounts of synOT given during labor. Checklists and standardized protocols for the use of oxytocin have been tested and recommended by several authors in order to reduce adverse neonatal outcomes [11, 25]. In this paper, with the aim of clarifying the meaning of a new type of obstetric management, we briefly describe two particularly exemplary clinical cases. Case 1
Mrs. B.B., 28 years old, white Caucasian, Gravidity 1, Parity 0, at 38 weeks plus 3 days of gestation, uneventful pregnancy and normal fetal growth. At 08:00 am, the patient was admitted in active labor. Obstetrical examination reported an effaced, central cervix dilated: 4 cm, membranes intact. The presenting part was cephalic, station: -3, posterior left position. At 10:00 am, after two hours of regular active labor with four contractions in 10 minutes, position and cervical dilatation were unchanged. Fetal Heart Rate (FHR) was normal. The doctor on duty prescribed and performed amniotomy. After two hours, at 12:00 am, dilation was 5 cm and high-dosage oxytocin augmentation was administered. Two hours later, at 2:00 pm, dilation was 8 cm. Fetal position was right posterior and the head was still deflexed with a palpable presenting brow at the centre of the pelvic canal, station was -2, the contractions
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were six in 10 minutes, FHR showed atypical repetitive variable decelerations. An emergency caesarean section was performed. At 2:30 pm, a male fetus weighing 3,450 g was delivered surrounded by thick meconium, Apgar score was 1 and 5 at one and five minutes respectively. Umbilical artery pH was 7.04, base deficit -12. The overall duration of labor was 6 hours and 30 minutes. The newborn was discharged in good clinical health. Case 2
Mrs. C.H., 26 years old, Algerian, Gravidity 1, Parity 0, uneventful pregnancy and normal fetal growth. At 6:00 pm, the patient was admitted in active labor. Obstetrical examination recorded: posterior cervix, 75% shortened, dilation: 3 cm, intact amniotic sac, the presenting part was cephalic, station: -4, and no information was searched for head position. The contractions were two in 10 minutes. FHR was normal. At 7:54 pm, the cervix was posterior, 80% shortened, dilation: 4 cm, intact amniotic sac, the presenting part was cephalic, station: -4, unassessable head position. At 10:00 pm, cervical dilatation were unchanged, position of the fetal head was right anterior occiput markedly deflected with palpable brow at the centre of the pelvic cavity. This condition was explained to the patient. Pain control was achieved by epidural analgesia. Active postures were explained to the patient in order to favor fetal head rotation and flexion. FHR showed slight typical variable decelerations, which reduced in intensity and frequency. At 1:30 am position of the fetal head was right anterior occiput well flexed, without palpable brow, and dilation was complete. At 3:10 am, a female newborn of 3,680 g was delivered. Apgar score was 10 at one and five minutes, umbilical cord pH 7.22, and base deficit -2.9. The total duration of first stage of labor was 7 hours and 30 minutes, the active second stage lasted 1 hour and 40 minutes. Discussion
Commonly the cervimetric curve and the progression of the fetal presented part during second stage of labor have been used to diagnose labor dystocia. Using them as a screening test to looking for causes of dystocia together with a standardized protocol, which introduce the need
Oxytocin and customization of assistance in labor
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to specify indications, reduces the use of oxytocin for augmentation of labor, without changing the length of the same. Screening and, therefore, the presumptive diagnosis made before administration of synOT enabled to use the drug in patients who needed it most. This, together with the lower dosages used, led to speed reduction of labor in augmented patients while reducing, however, the number of uterine hyperstimulations. In short, excluding fetal malposition or problems regarding maternal tolerance to pain led to a reduced, more targeted and appropriate use of synOT. The analysis of the two above clinical cases is paradigmatic: in most delivery rooms in the Western world, these two cases would have been treated in the same way, with amniotomy and oxytocin, as for the first case with not so encouraging results. The association between oxytocin use and acidaemia at birth has not been thoroughly investigated. In prospective studies of induced or augmented labor in which high- versus low-dose protocols for oxytocin administration have been compared, no increased risk of acidaemia has been found [34-37]. Higher doses resulted in increased rates of hyperstimulation in some studies, although none demonstrated any significant difference in neonatal outcomes [35, 37, 38]. A recent systematic review [27] showed that the system of administration of high dosage of oxytocin was associated to a reduction in the number of caesarean sections and in the duration of labor compared to an increase in episodes of uterine hypertonus. We have written we were against this uncritical and depersonalized use of meta-analysis [39]. In studies, strict protocols limited the use of oxytocin, and discontinuation or decrease of the infusion were applied in situations of hyperstimulation, resulting in improvement of the fetal status [40]. Consequently, results in studies regarding the association between oxytocin use and acidaemia are conflicting. An explanation for this may be that if strict guidelines are followed for oxytocin administration, as for controlled clinical studies, with regard to supervision of contraction frequency and FHR patterns, the risk of fetal acidosis at birth could be avoided [40]. However, this focus is not always present in real-life daily clinical situations. There is a need of studies based on practical or pragmatic trials, which should register daily clinical practice, and provide answers to different types of questions compared to randomized controlled trials.
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The need to integrate these two types of knowledge in evidence-based medicine has been recently stigmatized; fundamentally, there is no clear line that separates efficacy studies from those which assess effectiveness [41]. It is well known that there is a linear relationship between the amount of synOT administered during labor and acid base equilibrium at birth, and that hyperactive uterine contraction pattern and synOT use are the most important risk factors for acidaemia at birth [40]. Moreover, increased uterine contractility is a risk factor for hypoxic/ischemic encephalopathy in full-term newborns [42]. In addition, various studies show that the shortterm behavior of human newborns is influenced by the use of synOT during labor. Fewer prefeeding cues were observed in infants exposed to synOT versus those unexposed and differences were significant for brief and sustained hand to mouth cues [21]. In a pilot study of 20 healthy newborns exposed to intrapartum synOT and epidural, less sucking activity was observed in newborns exposed to higher versus lower intrapartum synOT dosage (p = 0.03) [43]. Additionally, three months after birth, there was less exclusive breastfeeding in women exposed to higher versus lower intrapartum synOT dosage [43]. An epidemiology study found that immediate postpartum administration of synOT significantly related to a 6-8% reduction in breastfeeding at 48 h postpartum [44]. In another study [21], 44% of exposed infants demonstrated a low level of prefeeding organization, compared to none from the unexposed group. In contrast, 25% of exposed versus 64% of unexposed infants demonstrated high pre-feeding organization. After adjusting for covariates, exposed infants had 11.5 times (95% CI: 1.8-73.3) the odds of demonstrating low/medium versus high levels of pre-feeding organization compared to unexposed infants [21]. SynOT was recently added to the list of medication designated as high-alert by the USA Institute for Safe Medication [45]. High-alert medications are drugs that bear a heightened risk of causing significant patient harm when they are used in error. The common mistakes regarding synOT use in clinical practice need to be emphasized, not least in view of the fact that the use of synOT is liberal, widespread and is on the increase. The role of synOT is a frequent issue in malpractice cases regarding labor and has been estimated to cause harm in 20-30% of such cases [46]. Violation of
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guidelines regarding use of synOT is probably one reason for adverse neonatal outcomes [46]. It is unlikely that there is a lack of awareness of their existence and their contents. A possible reason is that non-adherence only uncommonly results in an adverse neonatal outcome experienced by the individual midwife or physician, since many fetuses have the ability to tolerate hyperstimulation without becoming seriously affected [46], with the consequence that staff members lose their awareness of adverse side effects, such as hyperstimulation of contractions [43]. This mechanism, really important in obstetrics and in all contexts with low prevalence of side effects, is known as the normalization of deviance [12]. In our opinion, the epidemic level of use that synOT has reached in Western countries is in part due to the fact that, in delivery rooms, a diagnosis is not usually carried out, and we tend to observe events that take place and to give them a name (slow down of cervimetric curve, secondary arrest of dilation, prolonged latent phase, arrest of progression of the presenting part, etc.). These names do not correspond to the search for an etiology and, therefore, etiological therapies are not applied. As already said, synOT is often used to treat dystocia, but one of the real problem is that there is no universal consensus on the definition of dystocia. One way to define labor abnormalities is to divide them into protraction disorder (slower than normal) and arrest disorder (complete cessation of progress). To diagnose either of these disorders, the woman must be in the active phase of labor. The World Health Organization defines protraction disorder as less than 1 cm/h in cervical dilatation for a minimum of 4 hours [47]. The term “cervical dystocia” is just the description of a biological phenomenon, during which the uterine cervix dilates slowly or the part presented does not progress correctly into the pelvic cavity, which is a biological warning sign and can be used as a clinical screening test. The cause of this abnormality might be searched both in maternal and fetal conditions. Causes of dystocia can be cephalo-pelvic disproportion, deflection attitude, occiput posterior position and inefficient uterine contractions [48]. If we look for a causal diagnosis regarding labor arrest, we can discover that the incorrect position of the fetus is the cause in 60% of cases [49]. Other aspects may also be taken into consideration when discussing causes of dystocia, such as psychological factor, and risk factors
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such as high maternal age, high body mass index, infertility, epidurals use and stress during labor [50, 51]. It should therefore be clear that therapy for dystocia cannot be the same and monotonic for all these causes. The ACOG (American College of Obstetricians and Gynecologists) bulletin on dystocia correctly claims that: “Abnormal labor or dystocia in the first or second stage of labor can be associated with one or more abnormalities of the cervix, uterus, maternal pelvis, or fetus. In addition, advanced maternal age, nulliparity, maternal anxiety, multiple gestation, and intrauterine infections have been reported to be associated with longer active labors.” The ACOG committee of experts, however, do not draw the natural consequences from the assumptions, even though correct, as they do not make any further mention of these causative agents and, on the other hand, continues saying: “Dystocia is defined as abnormal labor (...) A more practical classification is to categorize labor abnormalities as slower-than-normal (protraction disorders) or complete cessation of progress (arrest disorders)”; the bulletin therefore concludes that: “Oxytocin administration should be considered when a patient has a protraction or arrest disorder” [5]. Once labor has been diagnosed [52, 53], we must understand the correct speed with which to proceed, considering that any cervimetric curve that we choose from the many suggested by literature is, once again, the macroscopic description of a biological phenomenon, and not the absolute benchmark for that particular woman, at that particular time of her labor [54]. In other word the speed at which cervical dilation continues during labor for each woman is characteristic for that particular woman and not for others as demonstrated by the elegant work of Incerti et al. [55]. Obstetricians and midwives must know and respect the individuality of each woman; deviation for the percentage is not a diagnosis, but only an alarm signal that needs a diagnosis. Unfortunately, soon after their introduction, cervical dilatation curves were named “labor curves” as a result of an uncensored “clinical rhotacism”: the cervix became the totality of labor and a normal labor had to be forced into a normal dilating cervix. This is the result of what we could define as a minimalistic approach to the management of labor where cervical dilatation becomes a diagnostic test on top of which medical action is taken in a cascade of interventions, amniotomy, oxytocin infusion and caesarean section, without any attempt to understand the reason of this type of delay in dilatation (Fig. 1).
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A more open approach should be applied during labor towards the different causes of dystocia, not confusing the causes of the dystocia, both maternal and fetal, with the consequences of the same, that are lack of progress in dilation and descent of the presenting part. We call this approach “comprehensive management” of dystocia (Fig. 2). In our experience, we utilized the same paradigm of Western medicine to human labor that is applied to any deviation from normal physiology: diagnosis before therapy. We have known, for some time now, that the therapeutic use of change of maternal posture [30, 56] or digital rotation from occipito-posterior to occipito-anterior decreases the need for caesarean sections [32, 57, 58]. There are many open questions that need to be studied further. In addition to fetal position and behavior, there are further important questions that the therapist must consider when faced with an arrest disorder in labor, such as the psychological state of the woman or the type of relationship the woman has with those assisting her during labor and birth or with her partner. The psychological state of the mother is closely connected to the duration of labor [59, 60]. In effect, taking into consideration and diagnosing the psychological state of the parturient in the case of dystocia, we can also carry out a diagnosis that includes not only the therapeutic possibility of augmentation, but also alternative possibilities such as, for example, the presence of a midwife specifically trained or the use of pain control techniques [61]. Of course, if the problem that causes the dystocia is the mother’s character, the cure cannot be only or exclusively the speeding up of labor using amniotomy or oxytocin [62]. A further aspect not well studied regarding labor is the quality of the relationship that the mother has with those assisting her during labor and birth; which is closely connected with the perception of pain [63]. The relationship with the midwife can and must therefore be therapeutic [64, 65]. Some interesting explanations have been given about relationship between length of labor and stress [66]. When we prescribe synOT we must remember that oxytocin has been called “the Great Facilitator of Life” [67], it interferes with numerous human homeostatic systems (Fig. 3); administering it means that we must be reasonably sure that the benefits of the medication outweigh the costs. In a study [68] – in which the authors compare, one month postpartum, the childbirth experiences of primiparous women with slow labor progress who
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Figure 1. The vicious circle of the minimalistic approach to the management of labor. Cervical dilatation becomes a diagnostic test on top of which medical action is taken in a cascade of interventions: amniotomy, oxytocin administration and caesarean section, without any attempt to understand and treat the reason of delay in dilatation.
Figure 2. Comprehensive management of cervical dystocia during human labor.
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Figure 3. The spheres of life illustrate numerous areas at which oxytocin may affect behavior and physiology to facilitate the propagation of the species in different periods of life. Modified from Lee et al., 2009 [67].
had received early versus postponed oxytocin augmentation – early oxytocin augmentation for slow labor progress does not appear to be more beneficial than expectant management regarding women’s perceptions of childbirth one month postpartum. The authors conclude saying: “Given the risks for the fetus associated with oxytocin treatment, prudent expectant management seems to be a safe and viable alternative” [68]. We must change our clinical habits and behavior, motivating them with therapeutic actions supported by etiological diagnosis. The administration of oxytocin must be reserved for the category of parturients who have, objectively, a reduction in the effectiveness and frequency of uterine contractility, after the exclusion of all other possible causes. In our department, simply using the cervimetric curve as a screening tool and not as a diagnostic tool, in two years we have reduced the use of synOT from 40% to 5% on all labor and delivery. Amniotomy was reduced from 22% to 2.6%. These changes have led to a significant reduction in
Oxytocin and customization of assistance in labor
iatrogenic interventions on childbirth. The overall result has been the reduction in the number of caesarean sections, especially in the first four out of ten Robson’s groups [26], In particular, in group one of Robson the proportion of caesarean sections was reduced from 25.6% to 6% [personal data]. Personalized labor
It is crucial to consider labor as a unique process involving not only the length of cervical dilatation and descent of the fetal presented part but also and primarily the woman with her obstetric and personal history, her feelings and behaviors. Adopting a customized approach that we name “comprehensive management” versus minimalistic management of dystocia in laboring patients belonging to the first four out of ten Robson’s groups reduces the use of oxytocin and amniotomy for augmentation of labor, leading to a reduction in the number of caesarean sections performed during labor.
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In probability theory, the normal (or Gaussian) distribution is a continuous probability distribution, defined by the formula:
Gaussian distribution is said to be normally distributed and is called a normal deviate. If μ = 0 and σ = 1, the distribution is called the standard normal distribution or the unit normal distribution, and a random variable with that distribution is a standard normal deviate. Since its introduction, the normal distribution has been known by many different names: the law of error, the law of facility of errors, Laplace’s second law, Gaussian law, etc. However, by the end of the 19th century some authors had started using the name normal distribution, where the word “normal” was used as an adjective – the term now being seen as a reflection of the fact that this distribution was seen as typical, common – and thus “normal”. However, as early as 1920, Person wrote: “Many years ago I called the Laplace-Gaussian curve the normal curve, which name, while it avoids an international question of priority, has the disadvantage of leading people to believe that all other distributions of frequency are in one sense or another abnormal...” [69]. In conclusion, the mean and median (indicators of central tendency) are abstract measures that are not suitable for each single case, they describe a biological phenomenon but do not, alone, enable us to carry out a diagnosis. Normality and cervimetric curves must be used as a guide to highlight the need to carry out a diagnosis and not be used as the diagnosis itself. Personalized medicine must take the place of percentile medicine in traditional clinical approach (diagnosis and treatment). Personalized medicine uses percentile curves to give a prognosis or carry out a diagnosis and consequent treatment using a “patient-centric” approach in which the individual profile of each single person is assessed and, on the basis of this, a specific therapeutic strategy is applied. This guarantees the patient more opportunities to be informed about the individual probabilities of becoming ill or to suffer from certain complications, also iatrogenic, and, in short, means limiting to the utmost the “toxic cost” of the diagnosis/treatment, without paying a price in terms of reduction in effectiveness.
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The impact of this approach is evident not only on the quality of life of the patient, but also on the optimization of the management of health care resources. In fact, we are already questioning the sustainability of Healthcare Systems (using diagnostic/treatment methods that enable to save by carrying out specific diagnosis, which also enable to give more precise prognosis and, last but not least, use types of therapy really efficient for each individual patient, resulting in savings that are not only economical, but social too). In the Western world, more than half the women who give birth are administered oxytocin during labor [33]. From an evolutionary or phylogenetic point of view, it is unlikely that this is really needed, and is therefore a biological need. The fact that more than half of Western women need pharmaceutical help to give birth is unreasonable and, in fact, the reasons behind the widespread and strong administration of oxytocin in the Western world are not only biological, but also cultural. Nevertheless, it can be easily seen that reducing the use of oxytocin and amniotomy enables to respect longer augmented labor times and probable lead an improvement in all the other index of maternal and newborn outcomes (spontaneous or operative labor, caesarean delivery, rate of episiotomy, acid-base balance at birth). Nevertheless, we trust that personalized therapy will improve patient outcomes, finally entering in the era of personalized medicine. Declaration of interest The Authors declare that there is no conflict of interest.
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030110 doi: 10.7363/030110 Received: 2013 Oct 06; revised: 2013 Nov 18; accepted: 2013 Nov 21; advance publication: 2014 Jan 10
Review
Considering ethical dilemmas related to brain death in newborns Ilias Chatziioannidis, Georgios Mitsiakos Neonatal Intensive Care Unit A.U.T, GPN “Papageorgiou”, Thessaloniki, Greece
Abstract
Brain death (BD), as the irreversible and permanent loss of cerebral and brainstem function, is relatively uncommon among newborns who need life support. It is considered the result of an acute and irreversible central nervous system insult. Asphyxia, severe intracranial hemorrhage and infection are the most common causes of BD in children. BD diagnosis is usually based on clinical criteria. Dilemmas about life prolonging treatment for severely compromised infants – as brain dead infants are – has become challenging since neonatal intensive care unit (NICU) care has developed, quality of life and resource issues are nowadays continuously underlined. Caring for premature babies is expensive and costs have risen especially since an increased number of infants with handicaps survives. Intensivists’ main duty is first to save lives and then to interrupt treatment in certain conditions like detrimental brain damage. The objective of this article is to present ethical decisions regarding brain dead newborns in order to balance between organ donation necessities and withholding/withdrawing treatment, with respect to the important role of infants’ parents in the process. Keywords
Ethics, brain death, newborn. Corresponding author Ilias Chatziioannidis, 3B Ag. Triados Str., 57010 Pefka, Greece; tel. +0030 2310-910401, +0030 6977 244542; e-mail: drilias@windowslive.com.
How to cite Chatziioannidis I, Mitsiakos G. Considering ethical dilemmas related to brain death in newborns. J Pediatr Neonat Individual Med. 2014;3(1):e030110. doi: 10.7363/030110.
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Introduction
Brain death (BD) is the permanent and irreversible loss of brainstem and cortical function [1]. Terms like brainstem, neocortical and whole brain death are not identical [2]. Loss of brain function arises medical, ethical and philosophical issues [3]. Loss of brain function is also loss of human life, even though heart and spinal cord may still operate [4-5]. Development of cardio respiratory support in neonatal intensive care units (NICU’s) rises the need to define BD criteria in newborns [6]. BD criteria in adults can be implemented for children, infants, full-term newborns (except for premature newborns < 37 weeks gestational age [GA] because of insufficient data) despite differences in brain function assessment, resistance to hypoxia and aetiology of BD [7-9]. Guidelines from task forces emphasized the importance of medical history/clinical examination in determining the aetiology and irreversibility of coma, specifying age-related observational periods and ancillary neurodiagnostic testing. Determination of BD in newborns is based mainly on clinically accepted neurological criteria [10]. Age-related observational periods and neurodiagnostic tests are still needed to be evaluated for BD diagnosis in children under 1 year of age [8]. 1987’s BD guidelines for children younger than 1 year of age in United States, were recently revised in 2011 by Nakagawa et al. [7]. These guidelines are based on the definition of coma cause, irreversible cessation of higher brain function in addition to brainstem, exclusion of reversible causes, clinical neurological examination criteria, neurodiagnostic tests and suggestion of specific observational periods according to age. BD diagnosis in newborns > 37 wks GA to 30 days of age is mainly established on neurological examination and ancillary testing. Combination of neurological examination (unresponsive infant in coma with loss of brainstem function), electro cerebral silence (ECS) and/or no flow on cerebral blood flow (CBF) study for a 24 hours observational period is confirmatory of BD [7]. Lack of knowledge, consistency to BD diagnosis guidelines, inability to adequately assess brainstem function and level of consciousness in premature infants of gestational age < 37 wks make BD diagnosis in newborns invaluable [11, 12]. Definition of BD is necessary for two main reasons: 1. to permit withholding/withdrawing treatment; interruption of curative treatment;
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2. to provide vital organs for the purposes of transplantation; from cadaveric or live related donors. In UK organ donation is not implemented for children under 2 yrs of age, whereas in other western commonwealth countries donation and transplantation procedures in this age group are customary [13]. In the following paper, we present a moral and medical framework within which guidelines should be followed regarding quality for end of life care for detrimental CNS damage in newborns as in BD. Organ donation decisions are out of the scope of this article. Moral duty in the NICU environment
Despite the fact that neonatal intensive medicine has considerably evolved over the last three decades, neonatologists are confronted with some important and complex ethical dilemmas/questions. During this period, treatment has significantly progressed and nowadays it is possible for many more infants to be safely discharged home. Decisions for prolonging life or interrupting treatment in severely compromised newborns reflect the opposite sites of intensivists’ medical and ethical duty, in this highly controversial and debatable issue [14]. Doctors’ moral duty is fulfilled by a number of principals: First, the doctor must always take under consideration the newborn’s perceived/best interests. Second, every newborn, regardless of his birth weight, gestational age or clinical situation has the right to his preservation for survival and on the other hand the right to die with dignity. Third, patient’s right to control his own destiny should be respected. Regarding newborns, their parents decide on behalf of their child [15, 16]. Ethical dilemmas decisions are a really difficult task, while medical paternalism, doctor’s character (compassion, humbleness, courage) or beliefs, parent’s character, relations and ignorance of the NICU environment are all mixed together under a very painful and stressful feeling due to their beloved child’s seriously deteriorated health status [17]. However, it is worth pointing that doctors and nurses should not act as technical managers and, when it is required to use end-of-life treatments for severely compromised newborns, consequences for the newborn itself and its family should always be considered. Additionally, medical staff should always have in mind that available human and financial resources are limited while demands are not.
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Recognizing that national, cultural and religious differences do exist, for end of life decisions significant questions must be answered. In what clinical situations are such decisions appropriate? How is ‘quality of life’ being determined for the neonatologist? Who should be responsible for such decisions? When should the prolonging life question be erased? What are the appropriate measures for BD newborns? Clinical situations for end of life treatment
Infants with severe congenital malformations (i.e. anencephaly), extreme prematurity with major CNS complications, serious CNS damage (i.e. by infection, hemorrhage, hypoxic-ischemic encephalopathy) and BD are considered candidates for end of life decision making process [18]. ‘Quality of life’ judgments
Severe abnormalities or catastrophic brain damage may have disastrous effects on newborn’s quality of life, which is of great importance for any treatment decision to withhold/withdraw treatment [12]. Quality of life means capacity for future health, development and well-being, potential ability to communicate (to act and interact, to have meaningful relationships with others) and at least substantial intellectual function. It does not have to do with probable physical handicap and generally the conception of considering the infant as a burden (as a human being or on financial terms) for the society is misleading. Responsibility for decision making
Ethics committees’ role for end of life decisions remains advisory in most European countries as is often the common practice in USA. End of life treatment decisions and support to the family becomes a responsibility of the intensive care team. Doctors and parents must be viewed as partners in the decision-making process with a measure of prudence considerating that legislation for BD diagnosis and handling these infants in most countries remains unclear. It is important to remember that in situations like BD there is no moral difference between a decision not to commence/continue treatment and to withhold/ withdraw treatment when the outcome will be death any way.
Brain death in newborns and ethical dilemmas
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When should the prolonging life question be erased?
The key question here is at what point, if the prognosis is so poor, prolonging life should be morally justified? Additionally if an infant has a detrimental CNS damage for whom possessing/ achieving self awareness is impossible, should this impair the doctors’ decision of non-treatment? Doctor’s clinical wisdom is proved when he balances infant’s benefits/interests with burdens/ costs of treatment. Since there are no benefits for the infant with BD and death is beyond doubt, interpreting BD diagnosis with extreme accuracy is vital for parents and medical staff to help them decide if a newborn should be supported further or not. In this case of a brain dead newborn the prospect of a ‘demonstrably awful life’ is sufficient for selective nontreatment to be appropriate. It seems morally justified to withdraw treatment in circumstances where diagnosis and prognosis of recovery without detrimental consequences is not possible beyond doubt, and where doctors and family agree that continued survival cannot be in the patient’s best interests [19]. Clearly, when it is determined that prognosis is so poor and the burden of treatment appears to outweigh the benefits, like in brain dead newborns, it is considered ethically appropriate to discontinue aggressive life support and employ comfort measures. Non-treatment and comfort measures for brain death infants
Once decision of non prolonging infants’ life has been taken, the medical team’s main obligation is to ‘treat for dying’ by providing comfort measures. There is a need to be consistent in relation to selective non-treatment. Thus the infant must be made comfortable with sufficient analgesia, appropriate hydration and nursing care. Once the decision is that sustaining life is against the neonate’s best interests, all life prolonging treatments should be withheld. Consequently administration antibiotics, resuscitation and even, on occasion, artificial nutrition should be withheld [20]. Gradually, in countries where there is a tendency to wait for a virtually certain prognosis of impending death, it is becoming evident that, with the ongoing discussion of the ethical issues relating not to prolong life, there has been a swing towards a more deliberated approach to decision-making in intensive care units. We should also remind that
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date and time of decisions to withhold/withdraw life sustaining treatment, along with the clinical documentation and parental confirmation must always be entered into newborn’s medical notes.
2.
Parker BL, Frewen TC, Levin SD, Ramsay DA, Young GB, Reid RH, Singh NC, Gillett JM. Declaring pediatric brain death: current practice in a Canadian pediatric critical care unit. CMAJ. 1995;153:909-16.
3.
Machado C. Diagnosis of brain death. Neurol Int. 2010;2(1):e2.
Conclusions
4.
Korein J, Machado C. Brain death – Updating a valid concept for
BD criteria for newborns and adults have a common basis despite different central nervous system pathology (immaturity of reflexes, open sutures/fontanels and intracranial pressure changes). BD should be based mainly on neurological clinical examination and ancillary testing. Combination of neurologic examination, ECS and no flow on CBF study in a preterm or term newborn for 24 hours observational period is confirmatory of BD. Physicians are not familiar with the diagnosis of BD, although is extremely crucial for parents and medical staff to realize this ‘end of life’ condition. Judgments about non-treatment (to withhold or to withdraw treatment) of BD newborns, should only be taken by clinical in charge consultant neonatologists. It is essential for physicians to develop a greater understanding for BD certification in newborns and also to be familiar with end-of-life care methods. Neonatologists acting in the BD newborns’ perceived/best interests and taking under consideration ‘quality of life’ judgments should use and not misuse their moral right to withdraw supportive measures. Parental support and decisionmaking progress should be handled sensibly and scientifically based, respectively. The goal should always be to provide a broad implementation of the ethical and medical principles for end of life decision making, achieving the desired balance between benefits in favor of patients’ best interests and burdens of treatment.
5.
2004. Adv Exp Med Biol. 2004;550:1-14. Wijdicks EF. The neurologist and Harvard criteria for brain death. Neurology 2003;61:970-6. 6.
Morenski J, Oro J, Tobias J, Singh A. Determination of death by neurological criteria. J Intensive Care Med. 2003;18:211-21.
7.
Nakagawa TA, Ashwal S, Mathur M, Mysore M; Society of Critical Care Medicine, Section on Critical Care and Section on Neurology of American Academy of Pediatrics; Child Neurology Society. Clinical Report-Guidelines for the Determination of Brain Death in Infants and Children: An Update of the 1987 Task Force Recommendations Nakagawa 2011. Pediatrics. 2011;128(3):e720-40.
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Ashwal S, Serna-Fonseca T. Brain death in infants and children. Critical Care Nurse. 2006;26:117-28.
9.
Machado C. Determination of death. Acta Anaesthesiol Scand. 2005;49:592-3.
10. Banasiak KJ, Lister G. Brain death in children. Curr Opin Pediatr. 2003;15(3):288-93. 11. Mejia RE, Pollack MM. Variability in brain death determination practices in children. JAMA. 1995;274:550-3. 12. Woodrum DE, McCormick TR. Misguided good intentions. J Perinatol. 2002;22(1):72-4. 13. Brierley J. Neonatal organ donation: has the time come? Arch Dis Child Fetal Neonatal Ed. 2011;96(2):80-3. 14. Doyal L. Needs, rights and the moral duties of clinicians. In: Gillon R (Ed.). Principles of health care ethics. London: Wiley, 1993. 15. Doyal L, Wilsher D. Towards guidelines for withholding and withdrawal of life prolonging treatment in neonatal medicine. Arch Dis Child Fetal Neonatal Ed. 1994;70(1):66-70. 16. Brazier M. Medicine, patients and the law. London: Penguin Books, 1992: 90-1. 17. Dunn PM. Appropriate care of the newborn: ethical dilemmas. J Med Ethics. 1993;19(2):82-4.
Declaration of interest
18. Campbell AG, McHaffie HE. Prolonging life and allowing death:
The Authors declare that there is no conflict of interest.
19. McHaffie HE, Cuttini M, Brölz-Voit G, Randag L, Mousty
infants. J Med Ethics. 1995;21(6):339-344. R, Duguet AM, Wennergren B, Benciolini P. Withholding/
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withdrawing treatment from neonates: legislation and official guidelines across Europe. J Med Ethics. 1999;25(6):440-6.
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Wang M, Wallace P, Grueb JP. Brain death documentation: analysis and issues. Neurosurgery. 2002;51:731-6.
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20. Catlin A, Carter B. Creation of a neonatal end-of-life palliative care protocol. J Perinatol. 2002;22:184-95.
Chatziioannidis • Mitsiakos
www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030116 doi: 10.7363/030116 Received: 2014 Jan 22; revised: 2014 Feb 09; accepted: 2014 Mar 10; advance publication: 2014 Mar 29
Review
Nutrition of preterm infants with bronchopulmonary dysplasia after hospital discharge – Part I Hercília Guimarães1,4, Gustavo Rocha1,4, M. Beatriz Guedes1, Paula Guerra2, Ana Isabel Silva3, Susana Pissarra1,4 1
NICU, 2Pediatric Division, 3Physical and Rehabilitation Medicine Department Pediatric, Integrated
Pediatric Hospital, São João Hospital, 4Faculty of Medicine of Porto University, Porto, Portugal
Abstract
Bronchopulmonary dysplasia (BPD) remains the most common severe complication of preterm birth. In addition to well known risk factors, nutrition plays an important role in normal lung development and maturation. Nutrition has a direct effect on the developing lung because it can modulate lung structure. Lung growth and maturation continue after hospital discharge and BPD patient’s nutritional requirements and feeding problems will need a specialized multidisciplinary approach during follow-up. Our aim is to review the scientific literature on the most relevant aspects of nutrition of BPD patients after hospital discharge. Keywords
Preterm infants, bronchopulmonary dysplasia, hospital discharge, nutrition, human milk, formula feeding, undernutrition. Corresponding author Hercília Guimarães, NICU, Integrated Pediatric Hospital, São João Hospital, Faculty of Medicine of Porto University, Porto, Portugal; email: herciliaguimaraes@gmail.com.
How to cite Guimarães H, Rocha G, Guedes M, Guerra P, Silva AI, Pissarra S. Nutrition of preterm infants with bronchopulmonary dysplasia after hospital discharge – Part I. J Pediatr Neonat Individual Med. 2014;3(1):e030116. doi: 10.7363/030116.
Introduction
Bronchopulmonary dysplasia (BPD) is a chronic pulmonary disease that affects mainly preterm infants and remains the most common severe complication of preterm birth. In the past, BPD was mainly caused by ventilator injury and affected about 30% of preterm infants with birth
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weights below 1,000 grams [1]. The increasing survival of extremely low gestational age (ELGA) infants associated to gentler ventilation techniques, antenatal steroids and surfactant treatment changed the picture of BPD: the so called “new BPD” is a lung development problem with impairment of alveolarisation which results in pulmonary and vascular hypoplasia with less interstitial cellularity and fibrosis [2-4]. Several factors are considered responsible for altering lung development and may subsequently support the development of BPD. In addition to well known risk factors, nutrition plays an important role in normal lung development and maturation [58]. Nutrition has a direct effect on the developing lung because it can modulate lung structure. In rats, caloric restriction reduces the alveolar number by 55% and the alveolar surface area by 25% [9]. However, 72 hours after re-feeding rat lungs are remodeled with normal alveolar numbers and surface areas [10]. A sufficient amount of protein and calories is necessary for organ growth; thus, a low protein or caloric intake will impair lung development, resulting in BPD. However, there is an ongoing debate concerning the required amount of nutrients to prevent the postnatal growth retardation or postnatal growth failure also called extrauterine growth restriction (EUGR) of very preterm infants with BPD [11, 12]. Lung growth and maturation continue after hospital discharge and BPD patient’s nutritional requirements and feeding problems will need a specialized multidisciplinary approach during follow-up. Our aim is to review the scientific literature on the most relevant aspects of nutrition of BPD patients after hospital discharge. Undernutrition, growth failure and nutritional needs in BPD patients
About 50% infants with severe BPD develop postnatal growth failure, defined as weight < 10th percentile for postmenstrual age (PMA) at NICU discharge [13]. Growth failure is common in infants with BPD, with reported rates of 30% to 67% in infants with BPD and has an impact on growth, persisting in 53% of cases to 4-8 years of age [14-17]. Malnutrition is associated with prematurity and is aggravated by BPD although the actual impact of these two factors is difficult to quantify [18].
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During NICU hospitalization preterm infants receive enteral and parenteral nutrition, according to usual recommendations [19]. However, due to the clinical status of high risk newborns, in some severe situations babies receive fewer nutrients that they really need. It has been shown that preterm with BPD received less enteral feeding in the first two weeks of life than those without BPD, suggesting that a minimal amount of enteral nutrition is necessary to prevent BPD [20]. Patients with moderate and severe BPD who already have breathing problems may aggravate their respiratory function during feeding, showing oxygen desaturation that is verified in 6-40% of VLBW infants. This post discharge feeding desaturation also has a negative association with growth outcome in BPD patients [21]. Anorexia often seen in these patients can further aggravate and difficult the oral intake. The mechanisms of anorexia are probably multiple: exhaustion associated with dyspnoea and respiratory failure (increased effort during breast feeding or bottle feeding), eating disorders (prolonged hospitalizations, divestment in the oropharyngeal sphere, oral painful stimuli) as well as the anorectic effect of pro-inflammatory cytokines. Anorexia may be responsible for oral feeding failure and precipitate the beginning of supplemental enteral nutrition (EN) through a nasogastric tube or gastrostomy. The behavioural problems can also contribute to an inadequate oral intake (e.g. oral motor dysfunction). Early intervention programs may be helpful in addressing these issues by providing developmental stimulation and physical and occupational therapy as indicated. Referral to a developmental behavioural paediatrician or behavioural psychologist may be helpful for such children. The inability to meet increased metabolic demands through oral nutrition can be aggravated by the frequent malnutrition and the need for catch up growth. Denne et al. estimated the energy needs of infants with BPD to be 15% to 25% higher than healthy controls [22, 23]. The European Society of Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) has recently suggested that a reasonable energy range for healthy growing preterm infants is 110-135 kcal/kg/day, therefore it seems also reasonable to agree that BPD infants may need an even higher caloric intake [19]. Thus, an energy intake of 140 kcal/kg/day can be required during active periods of disease. However
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the energy needs can differ from infant to infant and change depending on the patient’s respiratory status, clinical condition and level of activity. Different kinds of oral/enteral feeds are available for preterm babies after hospital discharge: multinutrient fortification of human milk, nutrient enriched formula for preterm infants, postdischarge formula or standard formula for healthy term infants. Assuming that inferior growth is undesirable we can improve nutrient intake of a human fed preterm infant in two ways: 1) Fortifying expressed breast milk or 2) Replacing some breast feeds with nutrientenriched formula feeds (formula for preterm infants or postdischarge formulae). In this case the effects of the substitution of one third, half, two thirds of daily energy intake in breast-fed infants by formula for preterm infants or postdischarge formula has been studied [24]. Fortified expressed breast milk
Although human milk (HM) is the recommended nutritional source for newborn infants for at least the first six months of life, unfortified HM may not meet the recommended nutritional needs of the growing preterm [25, 26]. Fortification is an alternative approach to increase nutrient intake in human milk-fed infants. It must be started when enteral feed is about 80 ml/kg/day, if the amount of human milk is more than 50% of total enteral feeding. The available human milk fortifiers contain varying amounts of protein, carbohydrate, calcium, phosphate, electrolytes, vitamins and other minerals (zinc, manganese, copper and magnesium) [25]. There are two different forms of fortification of HM: standard and individualized. The standard fortification consists in adding fixed concentrations of fortifier to maternal milk, not always corresponding to the nutritional requirements of individual infants. This method is commonly used in most NICUs but the results obtained in terms of growth are not always satisfactory. Standard fortification improved short-term growth, increased nitrogen retention, had no long term advantages in terms of either growth or development, had no clear effect on bone mineral content and was not associated with adverse effects [27]. The individualized fortification is now believed to be the best solution to prevent the protein undernutrition of preterm infants. Two methods have been proposed for individualization: targeted fortification, depending on milk analyses, and adjustable fortification, depending on the metabolic
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response of each infant. Using targeted fortification the amount of fortifier is given according to the weekly determinations of milk protein content. It depends on the availability of the milk analyses [28]. In the adjustable fortification the protein intake is adjusted on the basis of blood urea nitrogen. This method is effective in delivering an adequate protein intake, and growth approximates the one in uterus [29]. For human milk fed infants, either human milk fortification or replacement of some of the feeds (1/3 to 2/3) by preterm or nutrient enriched formulae are, as previously discussed, reasonable alternatives. In this setting, protein, minerals and trace elements are all increased. The strategy to fortify human milk is considerably more laborious and difficult and dispute exists as to which should be the human milk fortifier (formula for term infants, formula for preterm infants or human milk fortifiers used in hospitals). There is some evidence pointing towards a positive relationship between duration of human milk feeding and the later Bayley Mental Index, particularly in infants with chronic lung disease. In a study by O’Connor and co-workers infants with chronic lung disease fed > 50% human milk until term corrected age showed a mean Bayley Motor Index about 11 points higher at 12 months corrected age [30]. There are some concerns regarding safety of fortifying human milk with human milk fortifiers after hospital discharge since the content of some minerals and vitamins may well be excessive, posing these infants at increased risk of trace elements deficiency (copper) and hypervitaminosis (vitamin A and D) [24]. Formula feeding
Postdischarge formulae are specifically designed for preterm infants after discharge from hospital. These are energy (about 72 to 74 kcal/100 ml) and protein (about 1.8 to 1.9 g/100 ml) enriched, and variably enriched with minerals, vitamins, and trace elements compared to standard term formula. Expert bodies and authorities recommend these formulae for preterm infants for three to twelve months post-discharge [31]. Some experts state that current recommendations to prescribe postdischarge formula for preterm infants following hospital discharge are not supported by enough available evidence. However, they agree that some limited evidence exist that feeding preterm infants following hospital discharge with formula for preterm infants (energy enriched [to about 80
Nutrition of preterm infants with BPD after hospital discharge – Part I
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kcal/100 ml], protein enriched [2.0 to 2.4 g/100 ml], and variably enriched with minerals, vitamins, and trace elements to support intra-uterine nutrient accretion rates) may increase growth rates up to 18 months corrected age [32]. Healthy preterm babies can up-regulat their feed volume in such away that energy intake is identical no matter the type of milk ingested (human milk, standard, preterm or postdischarge formula) [33]. However same upregulating pattern is difficult for the sick preterm infant with BPD due to the high nutritional needs. It is difficult to provide an adequate caloric intake keeping the amount of fluid in the 130-150 ml/kg/ day range. Infant formulae, designed to be similar to human milk, are typically lower in caloric density, calcium, and phosphorus. Infant formulae (67 kcal/100 ml) and even postdischarge formulae (72-74 kcal/100 ml) would need to be ingested in large volumes of 180-200 ml/kg/day at standard concentrations, if they were intended to meet the energy needs of BPD infants. These difficult infants with BPD usually need concentrated postdischarge formulae (up to 80 kcal/100 ml) or formulae for preterm infants (80 kcal/100 ml) to ensure adequate energy, protein, and mineral intake to promote catch-up weight gain. We need to be aware that increasing the caloric density of commercial infant formula through concentration or the addition of modular nutrients like glucose polymers and medium chain triglycerides increases the osmolality of the formula, which can cause diarrhoea or malabsorption [34, 35]. For this reason, formulae usually are not concentrated beyond 80 kcal/100 ml unless severe fluid restriction is needed [36]. Additional increases in the caloric density of formulae should be made gradually (e.g. in increments of 3 kcal/30 ml) with modular supplements (glucose polymers, medium chain triglycerides) to a maximum of 100 kcal/ 100 ml. In this setting, the prescriber should be certain that individual nutrients are not provided in excessive amounts. The addition of carbohydrate or fat to infant formulae alters the nutrient ratio of the formula by providing no protein calories [37, 38]. Care should be taken to avoid providing more than 60 percent of energy from fat, which may induce ketosis. In a study performed by Brunton and co-workers, 60 preterm infants with BPD were randomly assigned to receive, as postdischarge feeding, term or postdischarge formula. The authors reported that BPD infants fed postdischarge formula had higher nitrogen, mineral and zinc retention and, at 3
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months corrected age, attained significantly greater length, bone mineral content and lean mass [38]. Fewtrell and co-workers, however, compared high caloric density formula with standard term formula in infants with BPD and found no difference in growth parameters between groups [39]. If the baby has already introduced complementary food, the most caloric solid foods need to be chosen, like soups and dishes enriched with fat and carbohydrates. How to feed BPD infants to provide nutritional needs in difficult patients?
If despite the optimization of oral intake the child is unable to meet nutritional requirements by mouth in order to achieve adequate catchup growth, supplementation of oral feedings with daytime or nighttime enteric feedings must quickly be considered [37]. Enteral nutrition allows increasing caloric intake, reducing the gastric distension that impairs ventilation and ensures better digestion and intestinal absorption of nutrients. Nasal or orogastric access can be used for infants and children who are predicted to have only short-term need for enteral feeds (e.g. less than two or three months). In addition, they are often used as an interim measure to feed and assess tolerance of enteral feedings before placement of an ostomy for long-term enteral feeding. A soft, flexible feeding tube (e.g. made from polyurethane or silicone) should be used if possible. Tube sizes of 4 French should be used for neonates and infants. Potential disadvantages with this route are interference with oral intake, easy dislodgement, irritation in the nasal/oral area, infection. A gastrostomy tube should be rapidly programmed in the more severe cases or if longterm enteral feeding is required. They are usually easily placed laparoscopically or endoscopically. The gastrostomy can be fitted with a device that is easy to cover with clothes and transient and easily removed without sequelae when no longer needed. Disadvantages of gastrostomy placement include local irritation/infection, leaking, allergic reaction, and possible dislodgement. The appropriated formula for enteral feeding could be the human breast milk or preterm formula or postdischarge formula, eventually concentrated and/or enriched until 1 kcal/ml. Bolus intragastric feedings are generally preferred over continuous feeds if they can be tolerated, since they provide a more normal pattern of eating and can deliver larger volumes
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over a shorter period of time (generally 10 to 30 minutes per bolus). If the patient can tolerate a bolus by gravity infusion, a pump is not necessary. Bolus feeds may also reduce the risk of aspiration because they are typically administered while the infant or child is awake and upright. On the other hand, the bolus feeding method might also increase the risk of pulmonary aspiration if large volumes are given. If a bolus feed is given while the child is asleep, the head of the bed should be elevated at least to a 45 degree angle to help reduce aspiration risk [40]. All patients undergoing a nutritional program of oral/enteral feeding should be strictly monitored and energy intake must be adjusted as required. They need to be periodically reassessed by plotting serial heights and weights, and the volume, concentration and type of feeds should be adjusted to achieve optimal growth. In conclusion, successful management of difficult infants with BPD and failure to thrive (undernutrition) would benefit from comprehensive postdischarge nutrition that should require a plan to address contributing medical, nutritional, developmental/behavioural, and psychosocial factors. That includes the use of nutrient-enriched preterm/postdischarge formulae, eventually concentrated and enriched into 1 kcal/ml and also the use of enteral nutrition and feeding therapy, ensuring adequate energy intake, parental support and education. Vitamins and mineral supplementation
Whilst a considerable attention has been focused on preterm macronutrient needs after discharge, less attention has been placed on micronutrients, in particular minerals, trace elements and vitamins. Calcium and phosphorus are of major concern in preterm babies since these elements are accreted primarily in the third trimester of pregnancy and it is very difficult to ensure an adequate dietary supply of these minerals during the first few weeks of life, particularly in the smallest and sickest of these babies, conditioning the occurrence of undermineralized bones. Infants with BPD are at increased risk of calcium and phosphorus deficiency due to their low enteral intakes associated with fluid restriction and the common need for diuretic therapy [14, 41]. The Nutrition Committee of the ESPGHAN recommends an intake of 120-140 mg/ kg/day of highly bioavailable calcium salts and 60-90 mg/kg/day of phosphate [19]. It is likely that when a mineral rich postdischarge or preterm
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formula or fortified human milk is used, no extra mineral supplementation, namely of calcium and phosphorus, is needed [42, 43]. Iron supplementation need depends on feeding regimen (human milk versus nutrient enriched or preterm formula) and history of previous multiple transfusions of packed red blood cells. Different scientific societies agree on the need for iron supplementation of preterm infants with 2 mg/kg/ day until 12 months, amount already provided by fortified formulae. Patients submitted to multiple packed red blood cell transfusions probably don’t need iron supplementation [19]. Vitamin D, glucocorticoid and retinoid are involved in the alveolarization. Knowing that BPD is characterized by arrested alveolarization, a complex integration of their effects on gene expression in postnatal lungs seems to contribute to the improvement of alveolarization [44]. There is no evidence that preterm infants after discharge should receive greater doses of vitamin D than term infants. However, the Nutrition Committee of the ESPGHAN suggests an intake of 800-1,000 IU/day of vitamin D [19]. The administration of vitamin A, necessary for proper development and healing of lungs, has been reported on BPD prevention, but there are no studies about its effect on BPD discharged patients [45]. Declaration of interest The Authors declare that there is no conflict of interest.
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Nutrition of preterm infants with BPD after hospital discharge – Part I
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030117 doi: 10.7363/030117 Received: 2014 Jan 22; revised: 2014 Feb 09; accepted: 2014 Mar 10; advance publication: 2014 Mar 29
Review
Nutrition of preterm infants with bronchopulmonary dysplasia after hospital discharge – Part II Hercília Guimarães1,4, Gustavo Rocha1,4, M. Beatriz Guedes1, Paula Guerra2, Ana Isabel Silva3, Susana Pissarra1,4 1
NICU, 2Pediatric Division, 3Physical and Rehabilitation Medicine Department Pediatric, Integrated
Pediatric Hospital, São João Hospital, 4Faculty of Medicine of Porto University, Porto, Portugal
Abstract
Preterm infants with bronchopulmonary dysplasia often present with severe growth failure at discharge from the neonatal intensive care unit. Catch-up growth accelerates after hospital discharge, nevertheless, feeding problems may need a specialized approach. Following the revision of the scientific literature on the most relevant aspects on nutrition of patients with bronchopulmonary dysplasia after hospital discharge in Part I, in this article the Authors present and discuss important issues such as catch up growth, swallow dysfunction, gastroesophageal reflux, and how to improve feeding competences. Keywords
Bronchopulmonary dysplasia, catch up growth, gastroesophageal reflux, swallow dysfunction, very low birth weight preterm infant. Corresponding author Hercília Guimarães, NICU, Integrated Pediatric Hospital, São João Hospital, Faculty of Medicine of Porto University, Porto, Portugal; email: herciliaguimaraes@gmail.com.
How to cite Guimarães H, Rocha G, Guedes MB, Guerra P, Silva AI, Pissarra S. Nutrition of preterm infants with bronchopulmonary dysplasia after hospital discharge – Part II. J Pediatr Neonat Individual Med. 2014;3(1):e030117. doi: 10.7363/030117.
Introduction
Lung growth and maturation continue after hospital discharge and bronchopulmonary dysplasia (BPD) patient’s nutritional requirements and feeding problems will need a specialized multidisciplinary approach during follow-up.
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Following the revision of the scientific literature on the most relevant aspects on nutrition of BPD patients after hospital discharge in Part I, in this article we are discussing such issues as: • Common problems (catch up growth, swallow dysfunction, gastroesophageal reflux). • How to improve feeding competences? Catch-up growth
Preterm infants accrue significant nutrient deficits during hospitalization, and at the time of discharge most very low birth weight preterm infants have moderate to severe growth failure [1]. Infants with significant morbidities and infants with extremely low birth weight have more severe growth failure since they regain birth weight at a later age, and they gain weight more slowly. Catchup growth accelerates after hospital discharge. The follow-up and treatment of BPD patients after hospital discharge is better performed in a specialized multidisciplinary setting, both because the child is most often an extreme preterm, and because he or she may need respiratory support and respiratory medications. Tracheostomy and ventilatory support may be needed in some patients, and a significant number will need oxygen at home for a variable period, along with bronchodilator therapy, inhaled steroids, fluid management, nutritional support, respiratory physiotherapy, infection preventive measures including vaccination against influenza and pneumococcus, and prophylaxis of respiratory syncytial virus infection with monoclonal antibody Palivizumab [2]. BPD and long term oxygen use have not been consistently found as predictors of poor growth [3]. This is in contrast to the observation of BPD as a contributing factor in poor growth of the hospitalized very low birth weight preterm infant prior to initial discharge [4, 5]. Different studies on BPD patients showed delayed catch-up growth for weight, height and head circumference at different moments of evaluation [6-11]. Two studies published during the eighties showed that by two years of age 2035% of BPD patients presented a height that was below -4SD (standard deviation), 66% presented a weight below -4SD, and 28% presented a head circumference below -4SD [9, 10]. A different study, in 1995, including 406 patients, revealed that BPD patients aged between eight and ten years presented lower Z scores than no BPD patients, -0.4
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(± 1.3) for height, -0.5 for weight (± 1.3), and -1.4 (± 1.3) for head circumference [6]. However, after controlling for possible confounders (using analysis of covariance), no significant differences were demonstrated between the two groups.The authors concluded that significant differences were noted between children with and without BPD for weight and head circumference but not height, and when possible confounders were taken into account, the differences were no longer appreciated. Thus, the previously reported poor growth in children with BPD may have been related to other factors and not necessarily to BPD. Even if the majority of the studies show an inconsistent catch-up growth among BPD patients, the prevalence and degree of malnutrition are difficult to evaluate in this population of patients [11]. From one study to another, the results are not consistent, highlighting the difficulty in finding the best criteria for the assessment of malnutrition for these children [11]. Some studies use centiles for the expression of height, weight and head circumference, other studies use Z scores of height, weight and head circumference, or even Z score of weight/height. The disparity among studies also results from their antiquity, the definitions used for BPD, and the fact that the populations of preterm were different [11]. Poor growth may be the result of a complex interaction of a number of factors, including inadequate nutrition, morbidities affecting energy requirements, endocrine abnormalities, central nervous system insults, medications that may affect protein and energy metabolism, and others. While inadequate nutrition itself may impact brain maturation and growth during a vulnerable period, it may also more broadly affect health by compromising other organs maturation, impairing immune function, and diminishing reserves for recovery from chronic or intercurrent illness or surgery. More recent published literature refers that, in preterm neonates, catch-up and pulmonary alveolar growth occur during the first two years of life; 10% to 25% of preterm infants with BPD are undernourished after two years of age, and 30% to 60% of them also suffer from persistent airway obstruction, hyperinflation and bronchial hyperreactivity [12]. Nutritional status at the age of two years in children who had BPD in infancy influences nutritional and pulmonary outcomes in childhood [13]. Growth retardation, delayed bone mass accretion and delayed catch-up growth in infants who develop BPD have been reported in some studies [14-17].
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The etiology of this delayed growth performance is multifactorial including the limited nutrient intake because of restricted fluid intake, feeding intolerance and/or extended parenteral nutrition, extremely prematurity, and the interference with growth processes by exogenous steroids, when prescribed to enhance pulmonary function [18, 19]. Dexamethasone, commonly used in extreme premature infants as a therapy to promote earlier weaning from the ventilator, has the negative effects of a potent steroid on growth and mineral and bone metabolism [20]. Ward et al. verified that dexamethasone was associated with abrupt growth restriction without recovery by term age [19]. Although the infants included in the study were born appropriate for gestational age (birth weight: 782 ± 185 g, gestational age: 25 ± 1 wk), length fell to < 5% percentile during dexamethasone treatment with only 1/17 infants demonstrating significant catch-up (> 5% percentile) by term age. Weight fell to < 5% percentile in 13/17 infants during dexamethasone and only 2/13 infants crossed above the 5% percentile by term age [21]. Postnatal steroids induce abnormalities in bone metabolism by interfering with one or more aspects of the growth hormone-insulin-like growth factor (GH-IGF-1) axis [19]. Bone cell activity is suppressed during steroid therapy, as indicated by reduced circulating osteocalcin (a bone-formation marker) and N-telopeptide (a bone resorption marker), although both markers rose by 10 days after the completion of dexamethasone therapy [19]. Even tapered dosing regimens of dexamethasone are associated with restriction in weight, length and head circumference growth and abnormalities in biochemical markers of bone turnover [18, 20]. The steroid-induced abnormalities observed in extreme premature babies were reproduced in the early weaned piglet model, thus proving that the restrictions in growth and bone are a result of the steroid drug and not only a result of the lung disease or extreme prematurity [21-23]. Preterm infants, especially those with BPD, have a multitude of feeding problems and it is reasonable that the restricted growth could result from inadequate nutrient delivery rather than a direct effect of the steroid drug. Two prospective descriptive studies demonstrated that nutrient intake of dexamethasone-treated infants was not different either during or after dexamethasone or when compared to no treated infants matched for size and gestation [18, 19]. Thus, the catabolic effects of dexamethasone on protein metabolism
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and its interference with the GH-IGF-1 axis are the more likely explanations for the immediate influence of the drug on normal development [24, 25]. Administration of GH with or without IGF1 only partially attenuated the steroid-induced abnormalities in growth and bone metabolism [21]. The role of nutrition in attenuating the negative effects of steroid drugs on growth processes during drug administration or as rehabilitation after the completion of drug treatment needs to be investigated. Swallow dysfunction
Infants with BPD can experience significant feeding difficulty, possibly secondary to tachypnea interfering with coordination of sucking. This is especially problematic as these infants often have increased metabolic demands and caloric requirements imposed by chronic hypoxia [26]. Indeed, feeding difficulties, decreased nutrient intake, decreased fluid tolerance secondary to BPD, and increased metabolic needs in infants with BPD often result in long-term reduced rates of growth [9, 27]. Palatal grooves caused by prolonged intubation may also make it difficult to achieve a proper seal between the tongue and palate [28]. Successful feeding in infants with BPD is further compromised by acute oxygen desaturation during feedings [29, 30]. Craig et al. have noted that the breathing patterns during feeding in infants with BPD did not demonstrate the striking regularity seen in control term infants [31] Gewolb and co-workers analyzed the rhythmic differences during feeding in infants with BPD and post menstrual age matched control group without BPD, from initiation of bottle feeding until discharge, with simultaneous digital recordings of pharyngeal and nipple (teat) pressure [32]. Unlike the control group, there was no significant correlation between post menstrual age and stability of suckle rhythm, aggregation of suckles or swallows into runs, or length of suckle runs. Comparing those infants > 35 weeks’ post menstrual age, the group with BPD had significantly decreased stability of suckle rhythm, decreased aggregation into suckle runs, and decreased length of suckle runs. Percentage of swallows in runs was also decreased in the cohort with BPD, as was length of swallow run. Thus, in infants with BPD, anticipated maturational patterns of suckle and swallow rhythms that normally occur in preterm infants did not occur. Delay in attainment of stable suckle and swallow rhythms
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in preterm infants, especially after 35 weeks’ post menstrual age, may predict subsequent feeding and neurological problems [32]. Infants with BPD do not follow predicted maturational patterns of suck-swallow rhythmic integration [33]. Individual rhythms of suck, swallow, and respiration are disrupted in preterm infants with BPD. Integration of respiration into suck-swallow efforts is critical for establishing coordinated suckle feeding. One study quantitatively assessed the coordination of respiration and swallow in infants with and without BPD [34]. Participants were studied at postmenstrual age of 32 to 40 weeks and postnatal age of 2 to 12 weeks using digital recordings of pharyngeal pressure, nasal thermistor flow, and thoraco-abdominal plethysmography. Apnoeic swallows were significantly increased after 35 weeks in infants with BPD compared with non-BDP infants, as were swallow-breath phase relationships involving apnoea. The BPD cohort also had significantly higher swallowbreath coefficients of variation and breath-breath coefficients of variation than non-BPD infants, indicating less rhythmic coordination of swallowing and respiration during feeding. Results emphasize the need for frequent rests and closer monitoring when feeding infants with respiratory compromise. Quantitative assessment of the underlying rhythms involved in feeding may be predictive of longerterm feeding and neurological problems [34]. Cervical accelerometer with digital signal processing can identify signals that are consistently associated with swallowing during feeding of infants. It is shown that these signals, called initial discrete sounds, become more uniform with advancing postmenstrual age in healthy preterm infants. In a study by Reynolds and co-workers there was no significant correlation between variance index and postmenstrual age for the BPD cohort [35]. The variance index of infants with BPD was significantly different from that of infants without BPD. While the variance index for the healthy control group decreased with advancing postmenstrual age, the variance index of the BPD group increased with advancing postmenstrual age. Oral feeding has been reported to compromise breathing among preterm infants with BPD during hospitalization or shortly after discharge. However, limited information is available concerning whether preterm infants with BPD remain vulnerable to feeding and growth insufficiency after a longer term of follow-up. The study performed by Li-Ying and co-workers examined the effect of severity of BPD
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on pulse oxygen saturation (SpO2) during feeding and growth in very low birth weight preterm infants during infancy, at 2, 4, and 6 months of corrected age [36]. Infants with severe BPD showed significantly lower mean levels of SpO2 during feeding at 2-6 months corrected age. Those with severe BPD further exhibited higher rates of growth delay (weight < 10th percentile) throughout the study period. Among VLBW infants, severe BPD had an adverse relation with subsequent weight measures after adjustment for medical and demographic confounding variables. Gastroesophageal reflux
Premature infants have an increased risk of developing gastroesophageal reflux. Having an infant or child with gastroesophageal reflux can be extremely overwhelming for parents and families. Reflux may be painful, causing infants to cry constantly, refuse to eat, spit up frequently, and sleep poorly. The daily routine of giving medication, dealing with the constant vomiting and special feedings, and the frequent doctor visits can be exhausting. If gastroesophageal reflux is left untreated, long-term complications such as feeding disorders, inadequate weight gain, narrowing of the oesophagus, and damage to the tissue in the oesophagus (called Barrett’s syndrome) can develop. For non-complicated reflux, no intervention is required for most infants. Effective parental reassurance and education regarding regurgitation and lifestyle changes are usually sufficient to manage infant reflux. Sandifer syndrome, apnea and apparent life-threatening events are the extraesophageal manifestations of gastroesophageal reflux in infants. Pharmacotherapeutic agents used to treat gastroesophageal reflux encompass antisecretory agents, antacids, surface barrier agents and prokinetics. Currently, North American Society for Pediatric Gasroenterology, Hepatology and Nutrition (NASPGHAN) and European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) practice guidelines concluded that there is insufficient evidence to justify the routine use of prokinetic agents. Omeprazole may be used for short-term treatment of gastroesophageal reflux with erosive esophagitis in infants aged from 1 to 12 months. Although Nissen fundoplication is now well established as a treatment option in selected cases in children, its role in neonates and young infants is unclear and is only reserved for selective infants who did not
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respond to medical therapy and have life-threatening complications of gastroesophageal reflux [37, 38]. Infants with BPD have a higher incidence of gastroesophageal reflux [39]. Infants with gastroesophageal reflux may suffer from frequent aspiration, pneumonia, apnoea, and failure to thrive [40]. Pulmonary deterioration, failure to growth, and refusal to eat may herald gastroesophageal reflux in preterm neonates [37]. Prolonged gastric tube use and feeding intolerance increase the risk for gastroesophageal reflux in low birth weight infants with BPD [40]. In preterm infants with BPD, transient lower oesophageal sphincter relaxations are the predominant mechanism underlying gastroesophageal reflux, and oesophageal clearance mechanisms are fully functional, which is similar to that seen in healthy preterm infants [41]. Fundoplication and gastrostomy is effective in facilitating growth and feeding in addition to decreasing oxygen requirements in infants with severe BPD and gastroesophageal reflux [42]. Randal Giuffre et al. analysed the effect of fundoplication and gastrostomy in patients with BPD and gastroesophageal reflux [42]. The postsurgical respiratory response was observed to be a rapid decrease in oxygen requirements and an absence of further aspiration episodes. A mean decrease of 0.14 in fractional inspired oxygen concentration was noted by 30 days postoperatively, and by 180 days the decrease in fractional inspired oxygen concentration was 0.22. All infants were fed by gastrostomy by postoperative day 4, with no evidence of clinical reflux. The nutritional response was noted to be an increase in growth velocity with increasing age (i.e., catch-up growth) and ease of feeding. At both 30 and 180 days postoperatively, the mean growth velocity was more than double the preoperative growth velocity. In addition, ease of postoperative feeding reduced the nursing care requirements and allowed earlier discharge from hospital. Nissen fundoplication is a feasible, effective and safe operation in severe gastroesophageal reflux, and may be used when medical treatment fails [43]. How to improve competences?
Feeding problems depend on the severity of BPD. Safe and successful oral feeding requires appropriate maturation and coordination of sucking, swallowing and respiration. Infants with BPD often have difficulty achieving coordinated
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suckle feeding, possibly secondary to tachypnea interfering with suck coordination, which limits the use of bottle or breast feeding initially [32, 44, 45]. These children have low sucking pressure and sucking frequency, short sucking burst duration, high respiratory rate, greater decrease in oxygen saturation, long deglutition apnea and low feeding efficiency [44, 46]. Optimal oral feeding should occur when a regular rhythmic relation exists between suck, swallow and respiration; however, infants with BPD do not seem to follow predicted maturational patterns of suck-swallow rhythmic integration [32]. A multidisciplinary approach is essential for therapeutic success. If aspiration is suspected or risk of aspiration is a factor, instrumental assessments of swallowing, such as video fluoroscopic swallowing assessment or fiber-optic endoscopic evaluation of swallowing may be necessary following the clinical evaluation [47]. Sensory feedback is essential. Nonnutritive sucking, for example with a pacifier or a finger, provides benefits to the ability of oral feeding skills. This therapy improve feeding tolerance, accelerates the transition from tube to oral feed, increase weight gain, improve breastfeeding scores and increase gastric motility [44]. Concomitant stimulation of oral-motor skills should occur in all tube-fed patients to prepare them for eventual feeding by mouth when there is no longer a risk of aspiration and swallowing functions have matured [45]. At this stage, gustatory stimuli (with a little of milk or other sugary flavors) may be used for the child to come into contact with the taste, smell and texture [46]. As respiratory status improves bolus feedings may be initiated [45]. After the introduction of solid foods, it is important to progress in consistencies and textures [48]. The delay in the introduction of solid foods can result in food refusal and occasionally the development of food aversions. Infants with anatomical or physiologic abnormalities present a higher risk of having difficulty establishing and maintaining oral feeding due to inability to initiate oral feedings within deadlines appropriate to the age [47]. There are many therapeutic techniques that can be used depending on each clinical case. Strategies such as postural techniques intended to improve safety and efficiency while allowing for oral feeding [47, 49]. Some children show significantly improved oral skills and timing of swallowing with posture and position changes [47, 50]. The environment should be quiet without unnecessary stimulation because these children
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are already easily overwhelmed by tactile, visual, auditory and kinesthetic stimuli. Sleep cycles should be respected whenever possible [45]. Other strategies include diet modifications (variations in texture, tastes and temperature of food), changes in feeding routine or changes in presentation of food. Oral sensorimotor intervention is a method whose benefits are still inconclusive but promising that involves techniques that are directed toward improving a child’s ability to accept, manipulate and swallow foods successfully. This may include techniques like facial massage, vibration, tapping of oral musculature, stroking the face, the use of a brush or other kinds of stimulation in order to desensitizing and improving function [47, 48]. Oral-motor dysfunction during feeding should be recognized as soon as possible. The parents/ caregivers should be informed about maneuvers to improve neuromuscular coordination during feeding such as thickened feeds [45]. It is essential that the treatment sessions also involve parent and caregiver education in every meeting, as well as offer home programs and suggestions for how to work with children at home on a daily basis [47].
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Declaration of interest
in infants with bronchopulmonary dysplasia up to 3 months corrected age: a randomized trial of a high-energy nutrient-enriched formula fed after hospital discharge. J Pediatr. 1998;133:340-5.
The Authors declare that there is no conflict of interest.
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030120 doi: 10.7363/030120 Received: 2014 Jan 28 ; revised: 2014 Mar 18; accepted: 2014 Mar 20; advance publication: 2014 Mar 26
Review
Fluconazole therapy for treatment of invasive candidiasis in Intensive Care patients. Is it still valid from a pharmacological point of view? Mario Musu1, Maurizio Evangelista2, Paolo Mura1, Andrea Cossu1, Massimiliano Carta1, Gian Nicola Aru1, Gabriele Finco1 1
Department of Medical Sciences “M. Aresu”, University of Cagliari, Cagliari, Italy
2
Department of Emergency, Catholic University of the Sacred Heart, Rome, Italy
Abstract
Fluconazole – antimycotic belonging to the first generation azoles – is widely used as treatment for invasive candidiasis and candidemia in numerous clinical settings as Neonatal Intensive Care Unit (NICU) and adult Intensive Care Unit (ICU), as well as oncology, onco-hematology and solid organ transplantation. More recently use of antimycotics has spread to medical divisions, where fungal infections represent an emerging problem due to population’s ageing, malnourishment and important comorbidities. Fluconazole is effective against numerous Candida species, particularly against albicans, tropicalis and parapsilosis strains. On the other hand, C. krusei is intrinsically resistant to fluconazole and C. glabrata can be sensitive or resistant in a dose dependent fashion. Epidemiological variability is noteworthy and depends on the geographical location of the institution, the clinical setting, and the frequency and intensity of fluconazole employment for invasive candidiasis. In many ICUs fluconazole sensitive C. albicans is cultured in 50% of positive samples, while the remaining 50% show growth of variably sensitive fungal species, often resistant to fluconazole. Due to increasingly frequent emergence of resistant strains of Candida spp., American guidelines (IDSA) in 2009, and European ones (ESCMID) in 2012, recommended substitution of fluconazole with echinocandines as first line therapy in patients with severe disease, as defined by an APACHE II score greater than 15. Thus fluconazole must be limited to low risk cases, treatment of sensitive strains and de-escalation from echinocandin therapy, after microbiological diagnosis and drug resistance profile characterization. Keywords
Fluconazole, invasive candidiasis, ICU, APACHE II score, sensitivity, resistance.
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Corresponding author
pH nor content [6, 7]. It is hydrophilic, with low protein bounded fraction (11-13%) and a volume of distribution (DV) equal to total body water [6]. An important feature of the drug is its capacity to concentrate in cerebrospinal fluid, as much as 50-60% of plasmatic concentration: this makes it useful in treatment of Candida spp. infections of the central nervous system [7]. When administered at its standard dosages of 200-400 mg/die, 11% of fluconazole undergoes hepatic metabolism, while 80% is excreted unmodified with urine [8]. Drug’s plasmatic half-life ranges from 30 hours in patients with normal renal function to 90 or more hours in patients with creatinine clearance lower than 20 ml/min. It is therefore easy to understand that its posology has to be opportunely reduced in patients affected by renal failure. Generally, in patients with creatinine clearance from 20 to 60 ml/ min, a 50% dose reduction – obtained halving the dose or doubling administration intervals – is to be considered adequate. Moderate inhibition of CYP 3A4, CYP 2C8/9 and CYP 2C19 must be taken into account, especially in patients assuming complex therapies (as ICU patients generally are), which could interfere. Clinical efficacy correlates tightly with area under the curve (AUC) of concentration over a 24 hour time span, divided by minimal inhibiting concentration (MIC) for fluconazole. Animal studies enlightened that with azoles, an AUC/MIC ratio of 25 is necessary to obtain 50% of maximal efficacy. An AUC/MIC ratio from 25 to 50 is required to obtain a mean drug concentration equal to twice the MIC [9]. Azoles have a narrow therapeutic range, thus overlooking their pharmacokinetics most likely makes the eventuality of plasmatic levels either below the range of efficacy or oppositely too elevated (possible toxic adverse reactions). Fluconazole posology for an adult with normal renal function, requires a loading dose of 12
Paolo Mura MD, Department of Medical Sciences “M. Aresu”, University of Cagliari, SS.554, Bivio per Sestu, 09042 Monserrato (CA), Italy; tel. +39 070 51096543; email: mura_paolo@hotmail.com.
How to cite Musu M, Evangelista M, Mura P, Cossu A, Carta M, Aru GN, Finco G. Fluconazole therapy for treatment of invasive candidiasis in Intensive Care patients. Is it still valid from a pharmacological point of view? J Pediatr Neonat Individual Med. 2014;3(1):e030120. doi: 10.7363/030120.
Pharmacological profile of Fluconazole
Due to its efficacy and safety for prolonged use – even at high dosages – fluconazole has been extensively used as first line drug in prophylaxis and treatment of invasive candidiasis [1, 2]. It’s a fungistatic agent that acts inhibiting selectively fungal cytochrome P450 (CYP)-dependent enzyme lanosterol 14α-demethylase, causing depletion of cell membrane ergosterol, an essential component of fungal cell wall. Inhibition of ergosterol synthesis impairs membrane fluidity, and leads to accumulation of toxic 14α-methylated sterols, resulting in growth arrest and eventual fungal cell death [3, 4]. It is active against 90% of Candida species. Nevertheless, increasing drug resistance has been witnessed, especially towards less common species (Tab. 1). Among strains most frequently isolated in ICU, C. krusei appears to be intrinsically resistant to fluconazole, while C. glabrata can be resistant or sensitive in a dose related fashion. Fluconazole exists both in oral and intravenous formulations and shows – as its azoles congeners – an excellent oral availability, linear pharmacokinetics unaffected by gastric
Table 1. Candida species sensitivity to antifungal drugs. Modified from Pappas et al., 2009 [5]. Candida species
Fluconazole
Voriconazole
Anphotericine B
Echinocandin
Candida albicans
S
S
S
S
Candida glabrata
From S-DD to R
From S-DD to R
From S to I
S
Candida tropicalis
S
S
S
S
Candida parapsilosis
S
S
S
From S to R
Candida krusei
R
S
From S to I
R
Candida lusitaniae
S
S
From S to R
S
Candida guillermondii
From S to R
From S to R
From S to R
From I to R
S: sensitive; DD: dose dependant; R: resistant; I: intermediate.
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mg/kg followed by a daily dose of 6 mg/kg. The dose is halved when creatinine clearance is less than 60 ml/min. Monitoring plasma concentration is usually unnecessary and can be done occasionally when considered useful to improve the therapeutic effect [10]. The empiric use of fluconazole (before microbiological identification of the specific strain and its drug sensitivity is available) is becoming increasingly risky, given the frequent finding of non albicans strains in ICU patients biological samples [11, 12]. Invasive candidiasis epidemiology in ICU
Candidemia is the fourth cause of blood stream infection in ICU patients in North America [13]. Similar data are found in Europe. A recent French study observed that 33% of ICU patients presents candidemia, invasive candidiasis or both [14]. A multicenter prospective, observational study conducted in 38 Italian ICUs between 2006-2008 showed a median rate of candidemia of 10.08 per 1,000 admissions, 40% of them were sustained by non albicans species [15]. Candida species diffusion can be differently distributed among various institutions, as well as their characteristic sensitivity and resistance to fluconazole. In the last two decades many institutions witnessed the progressive reduction in incidence of C. albicans, paralleled by the increment of non albicans species, which in some ICU represent the 50% of isolated specimens. More frequently isolated non albicans species are C. parapsilosis, C. glabrata, C. tropicalis and C. krusei [14]. Less frequently C. lusitaniae, C. guillermondii e C. rugosa are the isolated species. C. glabrata and tropicalis are rare in NICU, while C. parapsilosis accounts for as much as 30% in this setting [16, 17]. Numerous studies have been carried out to justify the reasons why there has been a shift in the prevalence from C. albicans to non albicans species in ICU environment. Extensive fluconazole use is one of the possible causes, for the increased resistance to the drug as well as for the progressive substitution of albicans species with non albicans drug resistant strains as principal etiologic agent of infection. Furthermore wide use of intravascular devices and parenteral hypernutrition are possible causes for infection by emerging non albicans species [18, 19]. Though any hospitalized patient can suffer from Candida spp. infection, subjects affected by cancer, hematologic disease or immunodeficiency are more prone to it. Usually infection is endogenous,
Invasive candidiasis and fluconazole therapy in ICUs
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moving from skin or mucous membranes into the bloodstream then disseminating throughout the organism [20]. Another cause of proliferation and diffusion of fungi in non neutropenic patients, is the wide use of broad-spectrum antibacterial therapy. In ICU patients many risk factors have been identified, such as trauma, parenteral nutrition, intravascular catheters, immunosuppressive drugs and corticosteroids, skin or intestinal barrier damage. The last two in particular, are extremely relevant (Tab. 2). Candidemia diagnosis is based on repeated hematic cultures. Culture sensitivity is not optimal and time span to obtain a diagnosis is often prolonged in many institutions. Among new proposed exams, only b-D-glucan is cited as a diagnostic tool for candidemia in IDSA guidelines [5]. Though considered promising, till now no controlled studies have been carried out on its efficacy and elevated costs and false positive rates among ICU patients may limit its utility.
Table 2. Risk factors for candida infection in ICU. Modified from Bassetti et al., 2010 [21]. Patient population
Risk factors
All patients
Abdominal surgery, intravascular catheters, total parenteral nutrition, broad spectrum antibiotics, immunosuppression and corticosteroids, acute kidney injury, diabetes, solid organ trasplantation, hemodialysis, acute pancreatitis
ICU patients
Prolonged stay (> 96 h), candida colonization (expecially if multifocal), high APACHE II score, low birth weight (neonatal intensive care unit)
Therapy of candidiasis
As it takes a long time to have a certain diagnosis, strategies to begin appropriate therapy as soon as possible in patients at high risk for Candida spp. infections or probably infected have been developed. These are represented by antimycotic drug prophylaxis in patients at risk for infection, and empiric and preemptive therapy. Antimycotic prophylaxis is well documented in settings such as oncology, oncohematology and neonatology, while guidelines do not recommend it for candidosis and candidemia prevention in ICU [5], although studies reporting a reduction in fungal infections in patients under prophylaxis can be found in literature. No
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clear mortality reduction has been proven by these studies. Disadvantages of fluconazole prophylaxis include toxicity from prolonged use, environmental selective pressure on local flora and emergence of resistant strains [22]. Fluconazole prophylaxis is only recommended in specific ICUs, with a rate of infection superior to 1-2% and in patients at high risk for infection [5]. Empiric therapy, defined as administration of antimycotics in presence of persistent fever refractory to therapy, has been proposed in order to anticipate treatment and reduce mortality in neutropenic and non neutropenic patients [5]. This approach can cause a significant and not always necessary increment in the number of treated cases. So preemptive therapy appears till now more promising. It is defined as the introduction of antifungal therapy when specific risk factors are identified: ICU stay > 96 h, broad-spectrum antibiotic therapy, severe sepsis, gastrointestinal surgery, total parenteral nutrition, clinical evidence for multifocal Candida spp. colonization or positive b-D-glucan assay. This strategy is meant to permit an early treatment in high risk cases while avoiding many unnecessary treatments [21]. Nevertheless, though promising, its efficacy still needs to be proven by clinically and statistically adequate prospective studies. In cases documented by positive cultures – if an antimycogram is available – treatment is easier. The drug of choice is the one characterized by the highest sensitivity, lowest adverse reaction rate and severity and lowest cost. Unfortunately, even when bloodstream invasion has been documented, exact Candida spp. characterization and sensitivity are not always available in short time. For these reasons and according to epidemiological data documenting a constant increase in the incidence rate of non albicans species and fluconazole resistant strains, 2009 ISDA and 2012 ESCMID guidelines [23] extend to high risk non neutropenic patients the recommendation of echinocandins as first line drugs for treatment of invasive candidiasis and candidemia. In patients characterized by moderate-severe disease, high APACHE II score, hemodynamic instability and likely cardiac involvement, echinocandins are recommended due to their high fungicidal activity on Candida spp. strains. Therapy can be modified later, according to sensitivity demonstrated by cultural exams, shifting to fluconazole in stable sensitive to treatment patients [5, 24, 25]. Echinocandins are contraindicated in C. parapsilosis infections, as resistance by this strain has been reported [26]. It is important to remember that after cultures become negative and important
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clinical improvement is obtained, oral antifungal therapy is recommended for the next 14 days, with single most suitable drug for Candida single species (step down therapy). Two more issues must be kept in mind when dealing with treatment of a mycotic infection. Though a clinical trial conducted on 842 adult patients failed to demonstrate any benefit from early removal of intravascular catheters [27], guidelines and expert opinions judge necessary and wise removal of intravascular devices when blood cultures are positive for Candida spp. The second problem is represented by the fact that many Candida species produce biofilm, significantly contributing to their virulence and persistence of infection [28]. Biofilm producing strains show higher resistance to fluconazole therapy and respond better to treatment with amphotericine B than echinocandins [29]. Conclusions
Candida infections are increasing worldwide and are becoming a frequent cause of disease not only in ICU or oncohematologic settings, but even in medical divisions, among the elder malnourished population and in patients affected by chronic obstructive pulmonary disease. Mycotic infection epidemiology is evolving and non albicans fluconazole-resistant strains are emerging. Fluconazole is still useful in treatment of many Candida spp. strains and can be used in low risk patients and in institutions where resistant strains have not emerged. In moderate-severe risk patients, or in hospitals where resistant strains are frequently isolated, echinocandins must be considered as first line treatment, and eventually substituted only after patient stabilization and isolation and characterization of the responsible fungus. Oral therapy with fluconazole or other appropriate azoles (step-down) – if active against isolated strain – can be considered when blood cultures become negative. There is still not complete agreement on optimal management for ICU patients with suspect candidemia. Prophylaxis is not recommended, as it exposes to risk of unnecessary treatment and is a likely cause of emergence of resistant strains. Empiric therapy based on local epidemiology and severity of illness is a widely used approach, but implies as well a high number of unnecessary treatments. Preemptive treatment seems to be promising, as it minimizes the risk of late treatment and reduces the number of patients treated unnecessarily. Low sensibility of blood cultures and the long time they require to be performed make
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Journal of Pediatric and Neonatal Individualized Medicine • vol. 3 • n. 1 • 2014
desirable the development of biomarkers of fungal infections. B-D-glucan is promising but no studies have clearly demonstrated its potentialities.
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11. Mayr A, Lass-Flörl C. Epidemiology and antifungal resistance in invasive Aspergillosis according to primary disease: review of the literature. Eur J Med Res. 2011;16:153-7. 12. Binder U, Lass-Flörl C. Epidemiology of invasive fungal
Aknowledgement The Authors wish to thank Toby Schwartzbarth for the language revision of the manuscript.
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030115 doi: 10.7363/030115 Received: 2014 Feb 09; revised: 2014 Mar 13; accepted: 2014 Mar 24; advance publication: 2014 Mar 31
Original article
Respiratory infections in very low gestational age infants: a population-based cohort study in Estonia Liis Toome1,2, Silvi Plado2, Inge Ringmets3, Mari-Anne Vals1,4, Heili Varendi1,4, Irja Lutsar5 1
Department of Paediatrics, University of Tartu, Tartu, Estonia
2
Clinic of Paediatrics, Tallinn Children’s Hospital, Tallinn, Estonia
3
Department of Public Health, University of Tartu, Tartu, Estonia
4
Children’s Clinic, Tartu University Hospital, Tartu, Estonia
5
Department of Microbiology, University of Tartu, Tartu, Estonia
Abstract
Background: There is little comparative information available on the occurrence of respiratory infections (RI) in infants with different degrees of maturity at birth. We aimed to determine the rate and characteristics of RI during the first two years of life in very low gestational age (VLGA) infants compared with the control cohort of full-term (FT) infants and to identify the risk factors for unfavourable outcomes of RI. Methods: The study was a part of a population-based prospective cohort study of VLGA infants born at 22-31 gestational weeks in 2007 in Estonia. At the corrected age of 2 years, surviving 155 VLGA infants were compared with their individually matched FT controls. Perinatal variables were recorded prospectively whereas episodes and characteristics of RI were assessed retrospectively by parental interviews. A logistic regression model was used to test risk factors for unfavourable outcomes (wheezing, recurrent wheezing, and hospitalisation) of RI. Results: The frequency of RI was similar in VLGA and FT infants. However, wheezing as well as recurrent wheezing due to RI was more frequent in VLGA than in FT infants, 34% vs. 21% (OR: 1.9; 95% CI: 1.1-3.2) and 14% vs. 5% (OR: 3.3; 95% CI: 1.4-7.1), respectively. During RI, VLGA infants also needed more hospitalisations (33% vs. 18%; OR: 2.3; 95% CI: 1.3-3.9). There was no significant difference between VLGA infants without bronchopulmonary dysplasia (BPD) compared with FT infants in wheezing and recurrent wheezing. BPD was the main risk factor for all unfavourable outcomes of RI. Conclusions: The frequency of RI in VLGA and FT infants is similar but BPD is more likely than prematurity in itself to predispose VLGA infants to a more severe clinical course of RI. Keywords
Bronchopulmonary dysplasia, hospitalisation, population-based study, respiratory infections, very low gestational age infants, wheezing.
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Corresponding author
2014;3(1):e030115. doi: 10.7363/030115.
gestational age (VLGA) infants born before 32 gestational weeks (GW) has improved dramatically due to improvements in perinatal care. Depending on GA, 51% and 93% of those born at 22-25 and 26-31 GW, respectively, survived in 2007 [15]. To evaluate the effect of recent changes in perinatal care on respiratory morbidity we conducted a populationbased study with the primary aims to determine the rate and the characteristics of RI during the first two years of life in VLGA infants compared with their FT controls and to identify risk factors associated with unfavourable outcomes of RI.
Introduction
Methods
Acute respiratory infections (RI) are one of the most frequent health problems in young children. It has been shown that during the first years of life a normal child may present up to five to eight annual diseases due to RI [1, 2]. Several social and environmental factors, such as attendance of day care, family size, air pollution, parental smoking, and home dampness have been suggested to predispose to recurrent RI [3]. Wheezing commonly accompanies RI during the first years of life [4, 5]. Recurrent or serious RI, especially with wheezing episodes, during the critical period of lung development in the first years of life, may lead to an increased risk of asthma later in life [6]. Although many RI are not severe, they contribute to a poorer health-related quality of life for children, to absenteeism from work for parents, and to increased costs for society [7, 8]. While acute respiratory morbidity in full-term (FT) infants is relatively well studied, data on preterm infants during the post-surfactant era and among different gestational age (GA) groups are scarce. Previous studies have shown that compared with FT infants, premature infants are more susceptible to acute RI having more wheezing episodes and hospital readmissions due to respiratory problems in the first two years of life [9, 10]. Moreover, they are more likely to die from acute lower respiratory tract infections than other infants [11]. Although some data are available comparing acute respiratory morbidity in premature and FT infants from the same recruitment area and time period [12, 13], to our knowledge, no nationwide population-based studies have been published. In Estonia, a Baltic country with a population of 1.3 million and health care expenditure (in terms of purchasing power parity per capita) three times lower than in countries that were members of the European Union before 2004 [14], the survival of very low
Study design
Liis Toome, Clinic of Paediatrics, Tallinn Children’s Hospital, Tervise 28, 13419 Tallinn, Estonia; phone: +372 6977155; e-mail: liis.toome@lastehaigla.ee.
How to cite Toome L, Plado S, Ringmets I, Vals M-A, Varendi H, Lutsar I. Respiratory infections in very low gestational age infants: a population-based cohort study. J Pediatr Neonat Individual Med.
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The present study was seeded into the nationwide cohort study of VLGA infants born from 1 January 2007 to 31 December 2007 in Estonia. The details of that study are presented elsewhere [16]. Patients and controls Altogether 187 VLGA (22 + 0 to 31 + 6 GW) infants were born alive and 158 (84.5%) survived until hospital discharge. Two children died before 2 years of age (one as a consequence of severe bronchopulmonary dysplasia [BPD], and the other as a consequence of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency) and one had moved abroad. The remaining 155 infants underwent an assessment at the corrected age of 2 years. For each surviving VLGA infant, two matched FT (≥ 37 GW) infants were identified from maternity ward databases using the following inclusion criteria: 1) no requirement for medical interference during the first week of life; 2) born in the same geographical area; 3) having the same gender and nationality; and 4) born as the first or the second infant after the expected date of birth of the VLGA infant. As a rule, for each VLGA infant the first FT control infant was selected. However, if the parents of the first FT control infant were not accessible, the second control was approached. In two cases, both families of identified control FT infants refused to participate in the follow-up. A total of 153 FT infants were enrolled in the study. Monitoring of patients and data collection Perinatal data of VLGA infants were collected prospectively. At the corrected age of 24 (± 1)
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months, the families of VLGA and FT infants were invited to a study centre for physical and developmental assessment. Structured parental interviews were performed and socio-demographic and environmental exposures (parental age and education, family structure and income, number of siblings in the same household, duration of breastfeeding, and age at day care attendance) as well as the presence of respiratory illnesses during the first two years of life were recorded. The parents or legal guardians were specifically asked about the infant’s acute respiratory morbidity, wheezing episodes during RI, overall hospitalisations and hospitalisations due to RI, and the number of antibiotic courses prescribed in total and for RI. All RI cases treated at home were identified only by parental report whereas parental reports of hospitalisations were checked against the hospital databases to capture all admissions and their reasons. Definitions Infants whose birth weight was below the 10th percentile for their GA according to the Fenton Intrauterine Growth Curves [17] were considered small for GA. BPD was diagnosed if there was oxygen dependency at 36 weeks’ postmenstrual age [18]. All RI cases were identified by parental reports using the following criteria: 1) episodes of illness characterised by nasal congestion, rhinorrhea, cough, sore throat, fever, and/or wheeze; or 2) physiciandiagnosed upper or lower (bronchitis, bronchiolitis, pneumonia) respiratory tract infections or acute otitis media. RI with gastrointestinal symptoms were included whereas gastroenteritis (e.g. rotavirus, norovirus) not accompanying RI were excluded. Recurrent RI were defined as the presence of a higher number of RI episodes than the population’s mean value. Wheezing was defined as an episodic wheeze due to RI whereas recurrent wheezing (RW) was defined as three or more episodes of wheezing due to RI during the study period. Wheezing, RW, and hospitalisation due to RI were considered to be unfavourable outcomes of RI. Socioeconomic status of the parents included: 1) educational level, categorised as low (no formal education or primary education), middle (secondary education), or high (higher professional education or university degree); and 2) monthly income per family member, categorised as low (< 2,000 Estonian crowns / < 128 EUR), medium (2,000-10,000 Estonian crowns / 128-641 EUR), or high (> 10,000 Estonian crowns / > 641 EUR).
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Age at day care attendance was defined as chronological age at the first entry into day care centre. Breastfeeding included both exclusive and/ or partial breastfeeding regardless of the amount. Neurodevelopmental impairment and growth restriction at the infants’ corrected age of 2 years are detailed elsewhere [16]. Statistical analysis Statistical analysis was performed using the statistical package Stata 12 (StataCorp. 2011. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP). Associations between the characteristics of RI and maturity at birth were assessed by Poisson regression and presented as incidence rate ratios (IRR) with 95% confidence intervals (CI) or by conditional logistic regression and odds ratios (OR) depending on the type of variables. The distributions of the reasons for hospitalisations were compared by Fisher exact test. Uni- and multivariate logistic regression analyses were used in risk factor analysis for unfavourable outcomes of RI as follows: selected risk factors were first added in the univariate model and only statistically significant variables (p < 0.05) were then included in the multivariate model. The following risk factors were tested: maternal age and education, family income and size, infant gender, GA, birth weight < 10th percentile, multiple birth, BPD, duration of breastfeeding, age at day care attendance, as well as weight < 10th percentile and neurodevelopmental impairment at the corrected age of 2 years. The analysis described above was carried out in both study cohorts as a whole as well as only for VLGA infants whereas the same selected risk factors were used. Ethics The study was approved by the Ethics Review Committee on Human Research of the University of Tartu and parent(s) or legal guardian(s) signed informed consent prior to inclusion. Results
Patients’ demographics The background characteristics of VLGA infants and their FT controls are summarised in Tab. 1 and Tab. 2. Three VLGA infants had a congenital anomaly or a syndrome of clinical significance (Tetralogy of Fallot, congenital laryngeal stenosis,
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Table 1. Perinatal variables and morbidity of very low gestational age (VLGA; 22 + 0 to 31 + 6 gestational weeks) and full-term (FT; 37 + 0 to 41 + 6 gestational weeks) infants. VLGA infants (n = 155)
OR (95% CI) or P-value for comparing means
FT infants (n = 153)
Perinatal variables Antenatal steroids, n (%)
128 (83)
0
NA
Multiple births, n (%)
38 (25)
2 (1)
24.5 (5.8-103.7)
Gestational age, mean (95% CI), weeks
28.8 (28.4-29.1)
39.6 (39.4-39.7)
< 0.001
Birth weight, mean (95% CI), g
1,314 (1,252-1,377)
3,611 (3,536-3,685)
< 0.001
Small for gestational age (SGA) at birth, n (%)
10 (6)
7 (5)
1.4 (0.5-3.9)
Male gender, n (%)
88 (57)
87 (57)
1.0 (0.6-1.6)
Surfactant, n (%)
88 (57)
0
NA
Mechanical ventilation, n (%)
91 (59)
0
NA
Postnatal steroids, n (%)
8 (5)
0
NA
Bronchopulmonary dysplasia (BPD), n (%)
29 (19)
0
NA
Weight < 10 percentile at discharge, n (%)
85 (55)
NA
NA
Neurodevelopmental impairment (NDI) at 2 years of CA, n (%)
19 (12)
4 (3)
5.2 (0.7-15.7)
Weight < 10 percentile at 2 years of CA, n (%)
48 (31)
21 (14)
2.8 (1.6-5.0)
Morbidity th
th
CA: corrected age; NA: not applicable. SGA is defined as weight below the 10th percentile for the gestational age according to the Fenton Intrauterine Growth Curves; BPD is defined as oxygen dependency at 36 weeks’ postmenstrual age; NDI is defined as cerebral palsy with the Gross Motor Function Classification System level 2-5, Cognitive and/or Language Composite Scores by Bayley-III -2 SD to -3 SD, and/or moderate or severe hearing and/or visual impairment; weight < 10th percentile at 2 years of CA is defined as weight below the 10th percentile according to the Estonian age- and gender-specific growth standards.
Table 2. Demographic variables of very low gestational age (VLGA; 22 + 0 to 31 + 6 gestational weeks) and full-term (FT; 37 + 0 to 41 + 6 gestational weeks) infants. VLGA infants (155 infants, 134 mothers)
FT infants (153 infants, 152 mothers)
OR (95% CI) or P-value for comparing means
Maternal age, mean (95% CI), years
31.4 (30.3-32.5)
30.5 (29.7-31.3)
0.194
Maternal higher education, n (%)
36 (27)
76 (50)
0.4 (0.2-0.6)
Paternal age, mean (95% CI), years
34.4 (33.2-35.7)
34.4 (32.2-36.7)
0.210
Paternal higher education, n (%)
20/124 (16)
51/151 (34)
0.4 (0.2-0.7)
Low income of the family, n (%)
31 (23)
18 (12)
2.4 (1.2-4.5)
Number of children in the family, mean (95% CI)
2.2 (2.2-2.4)
1.7 (1.6-1.8)
< 0.001
Age at day care attendance, mean (95% CI), months
22.7 (21.8-23.7)
20.4 (19.6-21.1)
< 0.001
Duration of breastfeeding, mean (95% CI), days
147 (119-175)
308 (273-342)
< 0.001
Higher education is defined as higher professional education or university degree; low income of the family is defined as family’s monthly income per one family member < 2,000 Estonian crowns / < 128 EUR.
and Hallermann-Streiff syndrome) and two FT infants had a congenital disease (toxoplasmosis and hypothyreosis) diagnosed after the first week of life. BPD was diagnosed in 29 (19%) of VLGA infants; in 19 (49%) and 10 (9%) of infants born at 22-27 and 28-31 GW, respectively. VLGA infants were more likely to be from low-income families
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than FT infants and their parents were less likely to have higher education. During the first year of life 12 (8%) and during the second year 7 (5%) VLGA infants were given a monthly injection of respiratory syncytial virus monoclonal antibody during peak respiratory syncytial virus season. The mean duration of breastfeeding in VLGA infants was significantly
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shorter than in FT infants. Most infants were cared for at home in both groups. Only one infant in each group went to day care before the age of 12 months. At the age of 18 months, 5% of VLGA and 14% of FT infants attended some form of organised day care.
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The mean annual number of RI was 1.5 during the first and 1.9 during the second year of life in VLGA as well as in FT group. If, however, the VLGA group was divided into those born at 22-27 GW and those at 28-31 GW, significant differences during the first year of life were observed. Namely the mean number of RI episodes per child favoured babies with higher GA (Tab. 3). The frequency of annual RI divided into none, 1-3, and > 3 episodes was similar between VLGA and FT group during the first as well as the second year of life. In the multivariate analysis, no associations were found between any of the investigated risk factors and the occurrence of recurrent RI.
those born at 22-27 GW had more RW than those born at 28-31 GW (Tab. 3). The presence of BPD was a significant risk factor for wheezing among VLGA infants. VLGA infants with BPD as compared to those without BPD experienced more frequently wheezing (55% vs. 29%; OR: 3.08; 95% CI: 1.347.04) as well as RW (28% vs. 10%; OR: 3.31; 95% CI: 1.22-8.97) whereas there was no significant difference between VLGA infants without BPD compared with FT infants in wheezing and RW (29% vs. 21%; OR: 1.51; 95% CI: 0.87-2.62; and 10% vs. 5%; OR: 2.40; 95% CI: 0.93-6.21, respectively). In multivariate analysis in the whole study population, maternal higher education was protective against wheezing and male gender as well as the presence of BPD promoted wheezing whereas only BPD was associated with RW (Tab. 4). In multivariate analysis of the VLGA group, GA (as a continuous variable) was not associated with wheezing or RW, whereas BPD was a significant risk factor for wheezing (OR: 3.17; 95% CI: 1.36-7.41) as well as for RW (OR: 4.96; 95% CI: 1.46-16.83).
Wheezing
Hospitalisation
Compared with FT, VLGA infants had more wheezing episodes including RW. Furthermore,
During the study there were altogether 149 hospital admissions in VLGA and 69 in FT group.
Respiratory infections
Table 3. Respiratory infections (RI) in very low gestational age (VLGA) and full-term (FT) infants during the first two years of life. VLGA infants 22-27 GW (n = 39)
28-31 GW (n = 116)
OR or IRR* (95% CI)
VLGA infants
FT infants
22-31 GW (n = 155)
37-41 GW (n = 153)
OR or IRR* (95% CI)
Frequency of RI Mean number of RI (min-max) per child
3.8 (0-12)
3.2 (0-12)
1.08 (0.95-1.23)*
3.4 (0-12)
3.4 (0-16)
1.00 (0.92-1.08)*
• 1st year of life
2.0 (0-8)
1.3 (0-8)
1.23 (1.00-1.51)*
1.5 (0-8)
1.5 (0-8)
1.01 (0.88-1.15)*
• 2 year of life
1.8 (0-7)
1.9 (0-7)
0.98 (0.80-1.22)*
1.9 (0-7)
1.9 (0-8)
0.99 (0.88-1.13)*
Recurrent RI, n (%) of infants
19 (49)
47 (41)
1.39 (0.67-2.89)
66 (43)
62 (41)
1.09 (0.69-1.71)
• 1st year of life
13 (33)
41 (35)
0.91 (0.42-1.97)
60 (39)
55 (36)
1.13 (0.71-1.79)
• 2 year of life
15 (38)
58 (50)
0.63 (0.30-1.31)
73 (47)
70 (46)
1.06 (0.67-1.65)
Mean number of wheezing episodes (min-max) per child
1.2 (0-4)
0.6 (0-4)
1.35 (1.04-1.75)*
0.8 (0-4)
0.4 (0-4)
1.42 (1.13-1.78)*
Wheezing, n (%) of infants
18 (46)
34 (29)
2.07 (0.98-4.36)
52 (34)
32 (21)
1.91 (1.14-3.19)
Recurrent wheezing, n (%) of infants
10 (26)
11 (9)
3.29 (1.27-8.51)
21 (14)
7 (5)
3.27 (1.35-7.14)
nd
nd
Wheezing
*Associations are presented as incidence rate ratios (IRR). GW: gestational weeks. Recurrent RI is defined as the presence of a higher number of RI episodes than the population’s mean value; recurrent wheezing is defined as ≥ 3 wheezing episodes during the study period.
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The overall hospitalisation rate and that due to RI was significantly greater in VLGA than FT infants (Tab. 5). However, the proportion of hospital admissions due to RI among all hospitalisations was similar in both groups (53% vs. 57%). Of all RI episodes, 15% in VLGA and 8% in FT infants (p < 0.001) were admitted to hospital. The reasons for hospitalisation due to RI differed between VLGA and FT infants with higher frequency
of bronchitis or bronchiolitis in VLGA infants (Tab. 5). No differences between those born at 22-27 GW and 28-31 GW were observed. Among VLGA infants, hospitalisation rate was greater in those with BPD compared to those without BPD (55% vs. 28%; OR: 3.20; 95% CI: 1.40-7.33) whereas hospitalisation rate was also greater in VLGA infants without BPD compared with FT infants (28% vs. 18%; OR: 1.79; 95% CI: 1.02-3.17).
Table 4. Results of the uni- and multivariate analyses of significant risk factors associated with wheezing and hospitalisation during acute respiratory infections during the first two years of life in the whole study cohort of very low gestational age and full-term infants. Recurrent wheezing (≥ 3 episodes)
At least 1 wheezing episode
OR (95% CI) (Univariate analysis)
Hospitalisation
OR (95% CI) (Univariate analysis)
OR (95% CI) (Multivariate analysis)
OR (95% CI) (Multivariate analysis)
OR (95% CI) (Univariate analysis)
OR (95% CI) (Multivariate analysis)
Maternal higher education
0.45 (0.26-0.78)
0.49 (0.28-0.87)
NS
NS
NS
NS
Male gender
1.90 (1.12-3.21)
1.84 (1.07-3.18)
NS
NS
1.88 (1.10-3.23)
1.82 (1.04-3.18)
Prematurity
1.91 (1.14-3.19)
1.37 (0.78-2.41)
3.27 (1.35-7.94)
2.40 (0.93-6.21)
2.29 (1.34-3.90)
2.99 (1.29-6.92)
Bronchopulmonary dysplasia
3.82 (1.75-8.34)
2.90 (1.24-6.75)
4.93 (1.94-12.54)
3.31 (1.22-8.97)
4.31 (1.97-9.44)
1.84 (1.04-3.27)
NS: not significant. Higher education is defined as higher professional education or university degree; bronchopulmonary dysplasia is defined as oxygen dependency at 36 weeks’ postmenstrual age.
Table 5. Hospitalisation and antibiotic consumption in very low gestational age (VLGA) and full-term (FT) infants during the first two years of life. VLGA infants 22-27 GW (n = 39)
28-31 GW (n = 116)
OR (95% CI) or P-value for comparing means
VLGA infants
FT infants
22-31 GW (n = 155)
37-41 GW (n = 153)
OR (95% CI) or P-value for comparing means
Hospitalisation All hospitalisations, n (%) of infants
23 (59)
62 (53)
1.25 (0.60-2.61)
85 (55)
47 (31)
2.74 (1.72-4.37)
Hospitalisations due to RI, n (%) of infants
15 (38)
36 (31)
1.39 (0.65-2.96)
51 (33)
27 (18)
2.29 (1.34-3.90)
• URTI, n (%) of hospitalisations
4 (17)
18 (33)
22 (28)
18 (46)
• Bronchitis/bronchiolitis, n (%) of hospitalisations
16 (67)
25 (45)
41 (52)
11 (28)
• Pneumonia, n (%) of hospitalisations
1 (4)
8 (15)
9 (11)
3 (8)
• Otitis, n (%) of hospitalisations
3 (13)
4 (7)
7 (9)
7 (18)
Antibiotic consumption during RI, n (%) of infants with RI
29/37 (78)
70/99 (71)
1.50 (0.61-3.67)
99/136 (73)
75/134 (56)
2.10 (1.27-3.50)
• 1st year of life
17/30 (57)
32/68 (47)
1.47 (0.62-3.49)
49/98 (50)
39/104 (38)
1.67 (0.95-2.92)
• 2nd year of life
25/32 (78)
55/86 (64)
2.01 (0.78-5.19)
80/118 (68)
64/119 (54)
1.81 (1.07-3.07)
Reason of hospitalisation due to RI 0.176
0.040
Antibiotics
GW: gestational weeks; RI: respiratory infections; URTI: upper respiratory tract infections.
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Male gender, prematurity, and BPD were independent risk factors for hospitalisation in the multivariate analysis in the whole study population (Tab. 4). In multivariate analysis of the VLGA group, GA (as a continuous variable) was not associated with hospitalisations due to RI whereas BPD appeared to be a significant risk factor (OR: 3.20; 95% CI: 1.40-7.33). Antibiotic consumption The odds of receiving antibiotics due to RI were 2.1 times greater for VLGA as compared with FT infants (Tab. 5). Again, VLGA infants with BPD received antibiotics more often than those without BPD (83% vs. 60%; OR: 3.26; 95% CI: 1.179.12) whereas there was no significant difference in VLGA infants without BPD compared with FT infants (60% vs. 49%; OR: 1.53; 95% CI: 0.95-2.46). Discussion
In the present population-based study covering the entire annual birth cohort of Estonia we observed a similar frequency of RI among VLGA and FT infants during the first two years of life. On closer examination, however, a greater frequency of RI among those born at 22-27 GW as compared with the other GA categories was observed in the first year of life. Despite the similar rate of RI in both groups, VLGA infants experienced more wheezing and RW episodes, especially those born before 28 GW. Moreover, VLGA infants also required hospitalisations and received antibiotics due to RI more frequently. However, there was no significant difference between VLGA infants without BPD compared with FT infants in wheezing and RW. In multivariate analyses it was not prematurity in itself but the presence of BPD that appeared to be the most important independent risk factor for unfavourable outcomes of RI. The main strengths of this nationwide cohort study are the inclusion of the entire annual cohort of very preterm births in Estonia and having an age, gender, and geographic location matched control group of FT infants. The use of GA instead of birth weight as an inclusion criterion reduced the proportion of infants who were small for their GA at birth. The attainment of very high follow-up rates close to 100% should also be noted. In the present study, we describe a lower mean annual number of RI for VLGA infants as well as for FT infants than reported in Germany (1.5 vs. 3.1
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RI episodes in the first and 1.9 vs. 3.2 episodes in the second year of life, respectively) and in the United States (5.1 episodes per child-year during the first three years of life) [1, 2]. Late day care attendance due to 18 months of fully paid parental leave in Estonia is one of the most obvious contributing factors. Attendance of day care has been identified as a significant risk factor for RI in several studies regardless of the day care setting, size of the day care group, or the number of hours spent in day care [1, 19]. In our study the mean age of day care entry was 22.7 months in VLGA and 20.4 months in FT infants and only one child in both groups attended day care at the age of 12 months. In a study performed in the Netherlands, 66% of 12-monthold children attended day care [20]. Another factor in the low rate of RI that should be noted is the retrospective design of parental interviews which potentially may miss some mild cases of RI and thus lead to the under-reporting of RI. Depending on the country, study design, and year, at least one episode of wheezing has been described in 15-39% of children [13, 21] during the first years of life with the occurrence of RW in 12-36% of children [21]. In addition, wheezing and RW are more common in premature as compared with FT infants, occurring in up to 40-68% and 13-25%, respectively [12, 22, 23]. Similarly, higher prevalence of wheeze and RW was observed in our study among VLGA infants as compared with FT infants (34% vs. 21% and 14% vs. 5%, respectively). However, we should emphasize that the prevalence of both was in the lower end of the previously reported data in other countries [12, 13, 21-23]. We suggest that a relatively low rate of RI could be just one reason. Although important gaps remain in the current knowledge regarding the role of viral RI in infancy in the inception of asthma [24], wheezing and prematurity have been associated with respiratory morbidity in future life [25]. Whether a relatively low frequency of RI and wheezing episodes in our study cohort might predict better long-term respiratory health, it needs further long term studies. Despite the similar frequencies of RI, the hospitalisation rates were significantly higher in VLGA, suggesting at least in part a more severe disease in VLGA than FT infants. Significant country-wide differences reported in hospitalisation rates might reflect variations in patient management with different thresholds for hospitalisation. In terms of VLGA infants, our hospitalisation rates were well in line with those in other countries. In the first two years of life 33% of VLGA, 55% of the ones with BPD and 28% of the ones without,
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and 18% of FT infants were admitted to hospital due to RI at least once in Estonia. In a French study of infants born prior to 29 weeks of gestation, 47% were readmitted at least once within the first 9 months of life and the re-hospitalisation rate was twice as high for children who had had chronic lung disease [26]. Similarly, in a US study [27] in the cohort of infants born before 33 GW, 49% of infants with BPD were re-hospitalised in the first year of life, more than twice the rate of re-hospitalisation of the non-BPD population, which was 23%. However, much lower rates of hospitalisations have been reported for preterm as well as for FT infants in Switzerland: 25% of preterm infants with median GA of 28.7 weeks and only 1.5% of infants born at term had to be hospitalised for respiratory problems in their first year of life [12, 13]. Routine antibiotic use for viral RI is not recommended in evidence-based clinical practice guidelines [28]. Nevertheless, despite the rarity of serious bacterial infections, antibiotics are frequently used in children younger than 24 months [29]. In the present study we noted that antibiotic consumption during RI was relatively high, especially in VLGA infants. These findings likely reflect the cautious approach of paediatricians and family doctors in treating RI during the first years of life. On the other hand, diagnostic limitations and lack of rapid tests for distinguishing between bacterial and viral RI may also play a role, at least in the initiation of empiric therapy. A vast number of risk factors (e.g. abnormal early lung function including BPD, day care attendance, male gender, parental smoking, family size, exposure to home dampness and mould, and prematurity) have been associated with recurrent RI, wheezing, and hospitalisations due to RI in the first years of life [1, 3, 12, 13, 20-22, 30]. Although the protective role of breastfeeding and maternal university education against recurrent RI and infant wheezing is well known in developing countries, the effect in more developed countries is less clear [3, 21]. In the present study four risk factors – low maternal education, male gender, prematurity, and the presence of BPD – were found to be significant for unfavourable outcomes of RI (wheezing, RW, and hospitalisation) whereas BPD was the only one for all of them. The present study was carried out in a relatively unique socio-demographic setting characterised by late day care attendance and small family size. Nevertheless, from a clinical point of view our results suggest a tailored approach when planning hospital discharge of VLGA infants. Special
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attention should be targeted to the parents of infants born before 28 GW or with BPD in counselling to limit the exposure of their children to respiratory viruses and environmental risk factors. Additionally, national immunisation programmes for preterm babies should be adapted accordingly, particularly in the countries with limited resources. The retrospective design of parental interviews should be noted as a main limitation of the study. While all RI cases treated at home were identified only by parental reports, there exists a possibility of a memory bias which we believe is similar in parents of VLGA and FT infants. Still it may lead to underreporting of mild RIs. Secondly, data about relevant childhood immunisations and common environmental risk factors, like parental smoking and presence of pets at home, were not collected. According to the national statistics by the age of 2 years up to 95% of children in Estonia have received all immunisations recommended by the national programme [31]. Thus we believe that abovementioned limitations did not preclude us from drawing adequate conclusions. Conclusions
The frequency of RI in general was similar among VLGA and FT infants, except for those born at 22 to 27 GW. Nevertheless, VLGA infants had more wheezing episodes and hospitalisations due to RI than their FT counterparts. However, there was no significant difference between VLGA infants without BPD compared with FT infants in wheezing and RW. BPD was the main risk factor for all unfavourable outcomes of RI among VLGA infants. These data suggest that still in the era of modern perinatal care BPD is more likely than prematurity in itself to predispose VLGA infants to a more severe clinical course of RI. Consequently, the study emphasizes the need to allocate resources for prevention of RI, first of all, to VLGA infants with BPD and to those born before 28 GW. Overall, efforts to reduce BPD and a better knowledge of the peri- and postnatal factors that affect immature lungs should be a key priority for health care while striving to decrease long-term respiratory sequelae and the costs of acute respiratory morbidity of VLGA infants. Acknowledgements The Authors are grateful to all the children and their families who participated in the study and acknowledge the dedicated efforts of the
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Journal of Pediatric and Neonatal Individualized Medicine • vol. 3 • n. 1 • 2014
national neonatal register and follow-up team (Pille Andresson, MariLiis Ilmoja, Kati Korjus, Lea Maipuu, Pille Saik, Anneli Kolk, Mairi
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infants: burden of disease in the first year of life. Eur J Med Res. 2011;16(5):223-30.
Männamaa, Svetlana Müürsepp, Marileen Olenko, Haide Põder, Triinu
13. Latzin P, Frey U, Roiha HL, Baldwin DN, Regamey N, Strippoli
Tänavsuu, and Tiina Valvas) for their practical help with collecting
MP, Zwahlen M, Kuehni CE; Swiss Paediatric Respiratory
data for this study. We thank Tuuli Metsvaht for a thoughtful review
Research Group. Prospectively assessed incidence, severity, and
of the manuscript.
determinants of respiratory symptoms in the first year of life.
Declaration of interest and source of funding
Pediatr Pulmonol. 2007;42(1):41-50. 14. WHO Regional Office for Europe (2007). European Health for All database (HFA-DB). Copenhagen: WHO Regional Office for
The study was supported by Estonian Science Foundation (grant GARLA 7094, TARMB 2726) and in part by Abbott Laboratories Estonia through Estonian Perinatal Society. The Authors have no other funding or conflicts of interest to disclose.
Europe. Available at: http://www.euro.who.int/hfadb, last access: March 2010. 15. Toome L, Ringmets I, Andresson P, Ilmoja ML, Saik P, Varendi H. Changes in care and short-term outcome for very preterm infants in Estonia. Acta Paediatr. 2012;101(4):390-6.
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Toome • Plado • Ringmets • Vals • Varendi • Lutsar
www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030113 doi: 10.7363/030113 Received: 2014 Jan 14; revised: 2014 Mar 19; accepted: 2014 Mar 26; advance publication: 2014 Mar 31
Original article
Perinatal management of gastroschisis Vincenzo Insinga, Clelia Lo Verso, Vincenzo Antona, Marcello Cimador, Rita Ortolano, Maurizio Carta, Simona La Placa, Mario Giuffrè, Giovanni Corsello Department of Sciences for Health Promotion and Mother and Child Care “Giuseppe D’Alessandro”, University of Palermo, Italy
Abstract
Gastroschisis is an abdominal wall defect, typically located to the right of the umbilical cord, requiring an early surgical treatment shortly after birth. Affected patients can be identified during intrauterine life with US and should be delivered in referral hospitals where a multisciplinary approach can be provided, involving neonatologists, clinical geneticists, surgeons and other specialists. These patients require a complex management in Neonatal Intensive Care Unit (NICU) and a long term follow-up after discharge. Exceed the acute neonatal condition, gastroschisis has a good prognosis, if there are no overlapping complications, and it should be differentiated from omphalocele, burdened with worse prognosis, and other conditions in the wide spectrum of abdominal wall defects. Keywords
Abdominal wall defect, prenatal diagnosis, newborn, malformation, intensive care, surgical treatment. Corresponding author Mario Giuffrè, Department of Sciences for Health Promotion and Mother and Child Care “Giuseppe D’Alessandro”, Università degli Studi di Palermo, Via Alfonso Giordano 3, 90127 Palermo, Italy; tel./fax +39 091 6555452; mobile +39 328 0410496; email: mario.giuffre@unipa.it.
How to cite Insinga V, Lo Verso C, Antona V, Cimador M, Ortolano R, Carta M, La Placa S, Giuffrè M, Corsello. G. Perinatal management of gastroschisis. J Pediatr Neonat Individual Med. 2014;3(1):e030113. doi: 10.7363/030113.
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Introduction
Gastroschisis (or laparoschisis) is an abdominal wall defect typically located to the right, rarely left, of the umbilical cord in which intestines, and occasionally other abdominal contents, herniate through the wound without lining membranes. Another rare form of gastroschisis described in the literature is the vanishing one (or closed). Gastroschisis has been also classified into simple and complex forms. The latter correspond to the cases where there are intestinal atresia, perforation, ischemia or necrosis, or loss of bowel occurred in utero. In the wide spectrum of abdominal wall defects, gastroschisis should be distinguished from omphalocele. A first difference relates to the anatomy of the malformation: the first is a paraumbilical cleft, usually to the right of the umbilicus, while the second is a defect in the midline, with protrusion of part of the intestine into the base of the umbilical cord. In the omphalocele the herniated portion does not occur covered by skin, muscle or fascia, but only by a thin membrane consisting of amnion externally and peritoneum internally, with mesenchymal connective tissue between them. In gastroschisis, instead, the viscera displaced have no coating. Gastroschisis probably derives from a vascular defect, unlike omphalocele in wich there is the persistence of the umbilical cord, in the region normally occupied by somatopleure. Recent hypotheses have focused on a vascular aberration of umbilical and omphalomesenteric veins, interfering with the development of the somatopleure at the junction with the body stalk or a solution of continuity that is formed later than the development of the abdominal wall. Alternatively, the cause of gastroschisis may be an early vascular accident involving the omphalomesenteric arteries [1, 2]. Gastroschisis has a better prognosis, with less perinatal mortality, compared to omphalocele (given its frequent association with karyotype abnormalities and genetic syndromes). However in infants with gastroschisis the herniated organs may present signs of compression, that carries an increased risk of obstruction, stenosis, perforation, meconium peritonitis, polyhydramnios and ischemic events. Epidemiological studies published in the last two decades, reveal an average prevalence of 1.76:10,000 born (0.4 to 3.01) [3-6]. The etiology of gastroschisis is not known, but is thought to be the result of a combination of genetic and non-genetic factors. Various hypotheses have been formulated. Support for a vascular mechanism
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comes from the association with various vasoactive pharmacological compounds, such as a report of gastroschisis in dizygotic twins following excessive maternal alcohol ingestion in the first trimester (OR: 2.4) [7, 8]. Cigarette smoking (ORs: 1.2-2.1) and recreational drug abuse, known to cross the placenta and affect the umbilical circulation, have also been linked to gastroschisis and both induce vasoconstriction and have deleterious effects on the fetoplacental circulation [9-11]. Among the non genetic risk factors, drugs taken during pregnancy – such as aspirin, ibuprofen and acetaminophen (OR: 2.2) [12-16] – deserve attention. Another risk factor is represented by maternal genitourinary infections, before or during the first trimester of pregnancy [17]. The role of young maternal age is described in most studies: women aged between 14 and 19 have a higher risk of pregnancies with offspring affected by gastroschisis (OR: 7.2), compared to women aged 25-29 years [18]. In addition, combining maternal age and ethnicity, the data show a greater risk for white women between 20 and 24 years of age, especially of Hispanic nationality (OR: 1.5), as well as recent data from some British records indicate an higher incidence in England, with 2-3 cases for 10,000 births in total. The risk of recurrence is low (3-5%). Some studies attribute a role to father’s age, indicating an increased risk among fathers aged between 20 and 24 years compared to those aged 25-29 years [19]. Regarding the genetic risk factors, there are only few cases in which chromosomal abnormalities have been detected. Materials and methods
This retrospective study examined infants with gastroschisis born in the last decade at Palermo University Hospital. We collected anamnestic data, relating to the couple and the course of pregnancy, perinatal and neonatal features, paying attention to the pre- and post-surgical management. The history has focused on the method of conception, the course of pregnancy and the presence of any risk factors. The family history has been directed toward search of previous cases of gastroschisis or hereditary diseases. It was investigated a correlation with the age of the parents and maternal intake of alcohol or smoking during pregnancy, as well as any maternal diseases or infections arising during pregnancy. Among the perinatal and neonatal parameters, moreover, it has been paid more attention to sex and karyotype, the mode of delivery, gestational age and birth weight.
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The congenital defects have been described in the size of the breach, differentiating the herniated viscera, represented only by the intestine or also by stomach and bladder. In association with gastroschisis, in some infants there were other defects, some determining complications that influenced the clinical course. It has been assessed the timing and mode of surgery, distinguishing between cases with immediate closure and those with packaging of a silo. In addition we explored pre- and postoperative ventilatory support and nutrition, in terms of method and timing, which have influenced the average length of hospitalization. Results
In the study period we assisted 5 infants with gastroschisis (pictures of patients 3 and 4 are shown in Figures 1-3). Prenatal ultrasounds allowed to identify, three patients with gastroschisis during intrauterine life, between the 18th and the 31st week of gestation. First of all, we evaluated the risk factors identified over the years by various authors. Parental age was on average 26 and 29 years, respectively in mothers and fathers, values that differ from those in the literature that report an increased risk of gastroschisis in women who conceive between 14 and 19 years (OR: 7.2) and for fathers aged between 20 and 24 years [18-19]. Regarding the possible association of the disease with smoking cigarettes, this habit was present only in one of the mothers of our patients. An important role is attributed to genitourinary infections, before or during the first trimester of pregnancy (OR: 5.0) [17], and we demonstrated a seroconversion for T. gondii in the first trimester in one pregnancy. There was a predominance of females, with a ratio F:M of 1.5:1. At birth, we studied the karyotype of each newborn and there were no chromosomal abnormalities. All neonates except one were born by caesarean section and in two cases there was meconiumstained amniotic fluid. The choice of timing was mainly based on the condition of the fetus, assessed by ultrasound examination. At term birth is associated, in general, with a better neonatal outcome because of the possibility of earlier closure of the defect and less amount of time for the transition to oral feeding. Unfavorable prognostic signs at prenatal ultrasonography, which may represent an indication for preterm delivery (34-36 weeks of gestation) are: reduced
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Figure 1. Patient 3 at birth. Massive herniation of the entire small bowel, stomac, bladder and spleen. Intense inflammatory component, with significant dilatation of the bowel loops, intensely erythematous and covered with fibrinous exudate. Chemical peritonitis has already led to the formation of adhesions between the loops.
Figure 2. Patient 4 at birth. Herniation of the small intestine. Bowel loops covered with fibrinous exudate and adherence, without significant dilatation.
Figure 3. Patient 3 in second day of life with a silo performed for gradual reduction of herniated viscera.
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intestinal peristalsis, increase of thickening of the abdominal wall, reduced intestinal vasculature, oligohydramnios. Our patients presented a mean gestational age of 36 weeks (range: 34.3-37.6) and an average birth weight of 2,200 g (range: 1,900-2,900). In all cases the wall defect was right located, confirming the extreme rarity of left locations [20] or even vanishing forms [21]. More than an infant presented at birth malformations associated with gastroschisis: intestinal malrotation (1/5), umbilical hernia (1/5), patent ductus arteriosus (1/5); intestinal aganglia (1/5). It has been shown that fetuses with abdominal wall defect are at risk of congenital heart disease and especially of persistent pulmonary hypertension, therefore echocardiography is indicated in prenatal and postnatal follow-up [22]. Among the complications arising in patients with gastroschisis, the most frequent were: intestinal obstruction (2/5), biliary regurgitation (2/5), respiratory distress (2/5), acute renal failure (2/5), short bowel syndrome (1/5). In addition, a newborn developed an infection with coagulase-negative Staphylococcus (Tab. 1). At birth, all patients showed a good adaptation to extrauterine life. All infants underwent the surgical correction of gastroschisis in the first 24-48 hours of life. Only in one newborn it was carried out the packaging of a silo (Fig. 3) and the delayed repair of the defect. Following surgery, the mean duration of total parenteral nutrition was 25 days (range: 10-52), while on average these infants were ventilated through an endotracheal tube for 12 days and required an average hospital stay of 62 days
(range: 24-98); the timing of nutritional support and ventilation were reduced to a minimum, taking into account the associated iatrogenic (infective, metabolic, …) risks. Two patients died, for the other three surgery and neonatal intensive care were resolutive with a survival of 60%, while in the literature appears a survival of 90%. Management of infants with gastroschisis
Gastroschisis is a rare malformation which requires timely surgical correction and neonatal intensive care. The medical team should be prepared before the birth of an infant with gastroschisis, therefore a prenatal diagnosis is very important for neonatal outcome. The possibility of a twin pregnancy increases the complexity of the perinatal management [23]. The diagnosis of gastroschisis can be made between the 18th and 20th week of gestation, suggested by the presence of irregularities of abdominal wall, hyperechoic loops, devoid of echogenic coating, protruding in lateral position respect to the normally inserted umbilical cord. Ultrasound examination can also detect IUGR and possible complications. At birth, our first approach to the infant with gastroschisis is aimed at preventing heat and fluid loss, onset of infection, ischemic or traumatic injury to the intestine. Over the years there have been proposed various prognostic factors detectable at birth, which guide the post-natal care. The presence of respiratory failure seems to increase mortality. Our initial attitude in these cases is conservative
Table 1. Characteristics of gastroschisis and correlated diseases in five patients. Herniated viscera EI
I
S
B
Associated malformations
Complications
Patient 1
-
+
-
-
-
infection by coagulase-negative Staphylococcus
Patient 2
+
-
-
-
aganglia
intestinal obstruction, acute renal failure, short bowel syndrome
Patient 3
+
-
+
+
-
biliary gastric regurgitation, intestinal obstruction, respiratory distress
Patient 4
-
+
-
-
intestinal malrotation, umbilical hernia
biliary gastric regurgitation
Patient 5
+
-
-
-
patent ductus arteriosus
renal failure, respiratory distress
EI: entire small intestine; I: some intestinal loops; S: stomach; B: bladder.
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and, after obtaining an improvement in the clinical condition of the patient, we proceed with the surgery. The aim of surgical treatment of gastroschisis is to restore the integrity of the anterior abdominal wall, reducing the herniated viscera within the abdominal cavity. The surgeon can proceed with the primary fascial closure of the defect or the allocation of the loops eviscerated in a container (silo) and reduction of the content over time. Schuster first described [24] the creation of a silo for patients in whom there was a lack of domain for the viscera (visceral abdominal disproportion), allowing a gradual return of the viscera in the abdomen and a natural dilatation of the abdominal wall in one or two days, without respiratory and hemodynamic instability usually determined by primary closure. It is important to monitor the intra-abdominal pressure already during surgery. The high intraabdominal pressures may be responsible also for hemodynamic alterations, as in the case in which cause a compression of the inferior vena cava with a reduction in venous return to the right heart and heart failure [25]. After repair of congenital defects of the abdominal wall is often necessary to resort to the reconstruction of the umbilicus reaching results aesthetically pleasing. The follow-up in the immediate postoperative involves cardiovascular and respiratory functions. Characteristic of newborns with gastroschisis is the “bell” aspect of the chest, due to the protrusion of the abdominal organs outside the abdominal cavity during pregnancy. Furthermore the difficulty in breathing or alteration between the abdominal muscle and diaphragmatic dynamic, makes it difficult to supply the patient, that requires a support of parenteral nutrition. Another characteristic of infants with gastroschisis is the intestinal failure, usually multifactorial, derived from motility disorders, associated intestinal anomalies and loss of intestinal length due to necrosis or surgical resection. It is now recognized an important role in the early enteral feeding, as well as reducing the times of total parenteral nutrition, and therefore the associated risks, has a trophic action by stimulating the mucosa and promoting growth in length of the intestine. Therefore, early enteral feeding should be the common goal, especially among those neonates undergoing extended surgical resection that predisposes them to short bowel syndrome. Other complications are those related to ventilation and nutrition. These can be the cause of infectious episodes, where endotracheal tubes
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or catheters may be the site of entrance and proliferation of pathogens, bacteria or fungi [2630]. Both treatments, if protracted, may also lead to organ dysfunction. In particular, prolonged mechanical ventilation can be responsible for the onset of bronchopulmonary dysplasia and oxygen dependence, and long-term parenteral nutrition can frequently cause liver failure and cholestasis. The management of an infant with gastroschisis involves the cooperation of several specialists such as obstetrician, midwife, neonatologist, geneticist, sonographer, pediatric surgeon, and pediatric nurses. The abilities of integration and cooperation of these caregivers influence the clinical evolution and prognosis of the patient. The neonatologist assumes the role of patient care manager, dealing with various aspects of care in the neonatal intensive care unit, both in the preoperative and in the long and complex post-surgical hospital stay. In particular, the neonatologist manages assisted ventilation, total parenteral nutrition, prevention of infections and identifies and treats any associated diseases [31-34]. The management of patients with gastroschisis therefore requires a highly specialized hospital with a multispecialist team to address the different and complex problems of these young patients. An accurate long-term follow-up is needed to prevent frequent complications. Therefore the centralization of the patients to a referral hospital is crucial to increase and optimize clinical expertise. Declaration of interest The Authors declare that there is no conflict of interest.
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030109 doi: 10.7363/030109 Received: 2013 Nov 21; revised: 2014 Jan 30; accepted: 2014 Feb 07; advance publication: 2014 Mar 20
Original article
Peripheral perfusion index-reference range in healthy Portuguese term newborns Joana Jardim, Ruben Rocha, Gorett Silva, Hercília Guimarães Neonatal Intensive Care Unit, Centro Hospitalar São João, Oporto, Portugal
Abstract
Introduction: Peripheral perfusion index (PPI) is a non-invasive numerical value of peripheral perfusion derived from a pulse oximeter signal. It has been suggested that PPI may be a valuable adjunct diagnostic tool to detect early clinically significant hemodynamic embarrassment. The aim of this paper was to determine normal PPI in healthy newborns, in order to establish cut-off values that can be use in different pathologic settings. Material and Methods: Prospective observational study performed with term newborns, born in a tertiary level care hospital between January 1st to December 31st 2012. Demographic data such as gender, gestational age, birth weight and Apgar score were collected. PPI, heart rate (HR) and arterial blood oxygen saturation (SpO2) were evaluated simultaneous on the right hand (preductal) and on the left foot (postductal) of the newborn, before discharge from the hospital. Results: 2,032 newborns, 52% male, with a mean birth weight of 3,237 ± 432 g and median gestational age of 39 weeks, were evaluated. PPI values obtained were: preductal median of 1.6 with interquartile range of 1.2-2.3, postductal median of 1.4 with interquartile range of 1-2 (p < 0.001). Conclusions: PPI is an easily applicable non invasive method to monitor peripheral perfusion changes. We established normal PPI values in healthy Portuguese newborns. PPI was higher on the upper limb (preductal) when compared to the lower limb (postductal).This finding has important implications, in the time of choosing a single probe placement, and in the interpretation of the results. Keywords
Newborn, peripheral perfusion index, pulse oximeter, preductal, postductal, peripheral flow. Corresponding author Joana Jardim, Neonatal Intensive Care Unit, Centro Hospitalar São João, Oporto, Portugal; email: joanajardim@sapo.pt.
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How to cite Jardim J, Rocha R, Silva G, Guimarães H. Peripheral perfusion indexreference range in healthy Portuguese term newborns. J Pediatr Neonat Individual Med. 2014;3(1):e030109. doi: 10.7363/030109.
Introduction
An important aim of hemodynamic monitoring is the early detection of inadequate tissue perfusion and oxygenation, in order to institute early therapy and guide resuscitation [1]. During circulatory disturbance, redistribution of blood flow, caused by increased vasoconstriction, results in decreased perfusion of the skin. As peripheral tissues are sensitive to alterations in perfusion, monitoring of the peripheral circulation could be an early marker of tissue hypoperfusion. Poor peripheral perfusion can be assessed from clinical signs such as cold, pale, clammy and mottled skin associated with an increase in capillary refill time, central-to-toe temperature difference, laser doppler and capillary microscopy [1-3]. Recently, pulse oximetry signal has been suggested, as well, to reflect changes in peripheral perfusion. Peripheral perfusion index (PPI) is a noninvasive measure that reflects the real time changes in peripheral flow [4-6]. It is an assessment of the pulsatile strength at a specific monitoring site (e.g. the hand, finger or foot) and is calculated from the ratio between the pulsatile component (arterial component) and the nonpulsatile component of the light (skin, other tissues), reaching the pulse oximeter detector [1, 2, 6]. When peripheral hypoperfusion exists, the pulsatile component decreases, and because the nonpulsatile component does not change, the ratio drops [2]. PPI is therefore primarily influenced by the amount of blood at the site of measurement and not by the oxygen saturation [4, 6]. Recent studies have been demonstrating the potential use of PPI in the neonatal setting. PPI was found to be correlated significantly with other indirect estimates of cutaneous blood flood, i.e. cardiac activity and central-to-peripheral temperature gradients in low birth weight infants [6]. Low PPI values have been showed to be a predictor for high illness severity in newborns [7]; PPI monitoring could help in the early detection of perinatal inflammatory disease such as subclinical chorioamnionitis [8]. In newborns with critical congenital heart disease, with duct dependent systemic circulation,
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PPI may increase the rate of detection, since some left heart obstructive diseases are undetected using only pulse oximetry screening [6]. There are few publication studies for the reference values of PPI in neonatal period and none in our country. Thus, the aim of this study was to assess the reference PPI values in term healthy newborns, in Portuguese population. Methods
This prospective observational study was performed with term newborns (gestational age > 37 weeks) that were born in a tertiary level care hospital (Centro Hospitalar São João, Porto, Portugal) in the last year (January 1st to December 31st 2012). Newborns were evaluated for PPI, heart rate (HR) and arterial blood oxygen saturation (SpO2) in a single and simultaneous determination. This took place in the regular nursery, incorporated in ordinary nursing routines, at the bedside of the mother, after the first 24 hours of life, before discharge from the hospital. The monitoring sites were the right hand and the left foot of the newborn. PPI values were assessed using the new generation Masimo SET® Radical pulse oximeter, during at least 30 seconds or until the establishment of a valid signal (variance < 2% of SpO2 and < 0.3 of PPI) (Fig. 1). The determinations took place when the babies were asleep or quietly awake and normothermic. Newborn’s hour of life, at the time of the measurement, was also registered. The exclusion criteria were: i) preterm newborns, ii) newborns admitted in the neonatal intensive care unit, iii) neonates with major malformations (including congenital heart diseases), iv) clinically ill newborns (including infections). It was also established that none of the newborns selected was readmitted, subsequently, with congenital heart disease after discharge (6 months follow-up). Regarding demographic data, gestational age (GA), gender, birth weight and Apgar score were collected from the clinical records of the selected newborns. This study was authorized by the São João Hospital Ethical Committee. Statistical analysis, including analysis of distributions, was carried out on commercial software SPSS. Data are expressed as mean and medians with the 5th to 95th percentiles. Differences between groups were assessed by using the MannWhitney test for nonparametric data. A p value less than 0.05 was considered statistically significant.
Jardim • Rocha • Silva • Guimarães
Journal of Pediatric and Neonatal Individualized Medicine • vol. 3 • n. 1 • 2014
A.
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Table 1. Demographic data of the study population. Study sample characteristics
B.
Male Gender
52%
Gestational age (weeks) Min-Max Median
37-41 39
Weight (g) Min-Max Mean ± SD
1,940-4,990 3,237 ± 432
Apgar score at 1 minute Median
9
Apgar score at 5 minutes Median
10
Table 2. Median values for age at measurement, PPI, HR and SpO2. Preductal Hour of life at the measurement (hours) Median (range)
Figure 1. New generation Masimo SET® Radical pulse oximeter.
Results
This study included 2,032 newborns. Demographic and clinic data are summarized in Tab. 1. All the newborns presented a normal clinical examination or physiologic jaundice, but without otherwise physical examination alterations. None was discharged home with less than 48 hours of life. The median PPI, HR and SpO2 values were evaluated (Tab. 2). Preductal PPI was measured on the right hand and postductal PPI on the left foot of the newborn. The measurements obtained were significantly higher on the right hand comparing with the left foot (preductal median = 1.6, postductal median = 1.4; p < 0.001). The cut-off values for PPI between the 5th and 95th percentile were: 0.77 and 3.9 preductally; 0.64 and 3.4 postductally. (Tab. 3). The mean difference between pre and postductal PPI was 0.25. Discussion
Peripheral vasoconstriction is an early warning sign of circulatory embarrassment, as blood flow
Peripheral perfusion index in healthy newborns
Postductal
35 (24-94)
PPI Median
1.6
1.4
HR (beats/min) Median
126
126
SpO2 (%) Median
100
100
HR: heart rate; PPI: peripheral perfusion index; SpO2: arterial blood oxygen saturation.
Table 3. Preductal and postductal percentiles. Percentile 5
25
50
75
95
Preductal PPI
0.77
1.2
1.6
2.3
3.9
Postductal PPI
0.64
1
1.4
2
3.4
P Value*
< 0.001
*Mann-Whitney Test.
is diverted from the less important tissues to vital organs [1-3]. Noninvasive monitoring of peripheral perfusion can be a complementary approach that allows early and prompt intervention avoiding organ damage. Because the pulse oximeter is used extensively in intensive care units, the PPI can be easily obtained. Low PPI suggests peripheral vasoconstriction (or severe hypovolemia) and high PPI suggests vasodilation. There are several works in adult population regarding application of PPI in clinical practice, but few in neonatal age. Zaramella et al. correlated PPI in 43 term newborns (GA 39.1 ± 1.4 weeks, age at evaluation 2.6 ± 0.9 days) with calf muscle perfusion. They
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have obtained a mean PPI of 1.2 ± 0.3 and have showed a positive correlation between PPI and both calf blood flow and oxygen delivery [10]. De Felice et al. evaluated 101 newborns (gestational age 34.7 ± 4.0 weeks) during the first 24 hours of life, and have obtained a mean PPI of 1.54 ± 0.8 [7]. In both studies a single place measurement was used, the lower limbs. Our results, corresponding to a large sample, are similar (mean foot PPI 1.6 ± 0.9) despite De Felice study included pre and term newborns. Granelli et al. published the largest study of PPI in healthy newborns (n = 10,000), between 1 and 120 hours of age, and compared with those with left duct dependent heart disease. PPI values obtained in the healthy group were preductal median = 1.68 with interquartile range 1.18-2.4 and postductal median = 1.71 with interquartile range of 1.20-2.5; mean difference of -0.02 (nonsignificant) [6]. In contrast to these results, we found preductal PPI significantly higher than postductal PPI (mean difference 0.25 ± 1); a finding that was also noted by Kinoshita et al. but in preterm newborns (< 32 weeks) during the first 48 hours [9]. This knowledge has implications at the time of choosing the site of measurement, since a low postductal value compared to preductal PPI must be carefully interpreted before assuming lower limb hypoperfusion. Granelli also reported that PPI < 0.7 in at least one limb gave an odds ratio for left heart obstructive disease (LHOD) of 23.75 [6]; in our study we have obtained a PPI < 0.7 either pre or postductally in 8% of the newborns, in which no cardiac disease was diagnosed. Our experience in conducting this study revealed that PPI is easy, relatively low-cost, free of subjective interpretation and low time consuming; as such the determinations were integrated into the regular nursing routines. It can be a useful tool in estimating peripheral perfusion non-invasively and continuously. This study has some limitations. We did not evaluate other haemodynamic parameters such as skin temperature and blood pressure at the time of PPI measurements. Photoplethysmographic analysis is relatively sensitive to newborn movement and other several factors such as stress (pain) and anxiety. At last, the within individual PPI variability in the first days of life was not studied.
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Our results established the normal preductal and postductal PPI in healthy Portuguese term newborns. This work contributes to enhance the knowledge of PPI in this age group, in order to create standardized reference values. Normal values have to be defined, before using this additional tool in different clinical settings. Contributors and supporting agencies Masimo® provided the equipment used in this study – namely the Masimo SET® Radical pulse oximeter.
Declaration of interest The Authors declare that there is no conflict of interest.
References 1.
Lima A, Bakker J. Noninvasive monitoring of peripheral perfusion. Intensive Care Med. 2005;31:1316-26.
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Lima AP, Beelen P, Bakker J. Use of a peripheral perfusion index derived from the pulse oximetry signal as a noninvasive indicator of perfusion. Crit Care Med. 2002;30:1210-3.
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van Genderen M, van Bommell J, Lima A. Monitoring peripheral perfusion in critically ill patients at the bedside. Curr Opin Crit Care. 2012;18(3):273-9.
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Sahni R, Schulze KF, Ohira-Kist K, Kashyap S, Myers MM, Fifer WP. Interactions among peripheral perfusion, cardiac activity, oxygen saturation, thermal profile and body position in growing low birth weight infants. Acta Paediatr. 2010;99:135-9.
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Cresi F, Pelle E, Calabrese R, Costa L, Farinasso D, Silvestro L. Perfusion index variations in clinically and hemodynamically stable preterm newborns in the first week of life. Ital J Pediatr. 2010;36:6.
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Granelli Ad, Ostman-Smith I. Noninvasive peripheral perfusion index as a possible tool for screening for critical left heart obstruction. Acta Paediatr. 2007;96:1455-9.
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De Felice C, Latini G, Vacca P, Kopotic RJ. The pulse oximeter perfusion index as a predictor for high illness severity in neonates. Eur J Pediatr. 2002;161:561-2.
8.
De Felice C, Del Vecchio A, Criscuolo M, Lozupone A, Parrini S, Latini G. Early postnatal changes in the perfusion index in term newborns with subclinical chorioamnionitis. Arch Dis Child Fetal Neonatal Ed. 2005;90:F411-4.
9.
Kinoshita M, Hawkes CP, Ryan CA, Dempsey EM. Perfusion index in the very preterm infant. Acta Paediatr. 2013;102(9):e398-401.
10. Zaramella P, Freato F, Quaresima V, Ferrari M, Vianello A, Giongo D, Conte L, Chiandetti L. Foot pulse oximeter perfusion index correlates with calf muscle perfusion measured by near-infrared spectroscopy in healthy neonates. J Perinatol. 2005;25(6):417-22.
Jardim • Rocha • Silva • Guimarães
www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030112 doi: 10.7363/030112 Received: 2013 Dec 10; revised: 2014 Feb 11; accepted: 2014 Feb 12; publication: 2014 Apr 01
Original article
Caring for children with brain tumors in an oncology ward: a phenomenologic-hermeneutic study Chiara Fioretti1, Rosapia Lauro-Grotto2, Debora Tringali3, Eva M. Padilla-Muñoz4, Massimo Papini3 1
Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Italy
2
Department of Health Sciences, University of Florence, Italy
3
Lapo Association, Florence, Italy
4
Department of Personality, Evaluation and Psychological Treatment, University of Seville, Spain
Abstract
Brain tumors are the most common form of solid tumors in childhood and are characterized by an uncertain prognosis, often meaning tumor invasive surgical procedures in the first steps of the patient’s treatment. In a Pediatric Oncology Ward, children with brain tumors are considered a challenge for health professionals, due to the nature of the relationship between the child, the parents, and the health care providers in the initial phase of the patient’s illness. Here we present a phenomenologic-hermeneutic study, developed in the Oncology Ward of a Hospital in Southern Spain. All the caregivers of the Ward underwent interviews concerning their experience in caring for children with brain tumors. Interviews were recorded and transcribed with the consent of the participants and were analyzed by content themes. In the present paper, we focus on the experiences concerning the first meeting of the professionals with the children and their families and the principal critical issues related to the communication of the diagnosis. Keywords
Brain tumors, staff, pediatric triangle, pediatric psycho-oncology, communication of the diagnostis, group dynamics. Corresponding author Rosapia Lauro-Grotto, Department of Health Sciences, University of Florence, Italy; email: rosapia.laurogrotto@unifi.it.
How to cite Fioretti C, Lauro-Grotto R, Tringali D, Padilla-Muñoz EM, Papini M. Caring for children with brain tumors in an oncology ward: a phenomenologic-hermeneutic study. J Pediatr Neonat Individual Med. 2014;3(1):e030112. doi: 10.7363/030112.
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Introduction
Brain tumors in childhood are characterized by several peculiarities, both from the point of view of their care and of the psychological and emotional implications. When compared to the case of the disease’s onset in adulthood, in the case of any pediatric patient, the care pathway unfolds through the vicissitudes of the so called “pediatric triangle” [1] including at its vertices the health care staff, the child or adolescent and the parents. This complexity factor is especially relevant in the case of chronic or severe illness, such as a tumor. As shown in the last two decades [2-4], the coping strategies that the family puts in place to deal with the disease and its internal dynamics within the pediatric triangle are fundamental for the patient’s psychological balance and for the achievement of the therapeutic goals [1]. The complexity of the dynamics within the pediatric triangle is well known in pediatric psycho-oncology [5-9]. A patient who contacts the institution has a variety of needs that relate to his illness, which the institution responds to with professionals, each one with his technical skills. Everyone is implicitly and inevitably accepting to pose and return partial questions and partial answers [1]. The theme of the communication of the diagnosis in pediatric oncology has been treated extensively in relation to its consequences on the psycho-emotional balance of the patient and his family [10]. In the case of a serious illness, the communication of the diagnosis must be carried out by the medical staff by taking into account some important variables: primarily, the degree of awareness of the parents about previously communicated information and what they really want to know about the disease [11]. The pediatrician is essential in the process of communication as he’s the one who will lay the foundation of the therapeutic alliance by managing the information, by accepting the outpouring of the parents and by structuring together with them the therapeutic plan [12, 13]. Additionally Buckman [11] suggests that in the “ideal” mode of communication of the diagnosis, the parents can dissolve their doubts and find the most appropriate way to communicate the news to the child as well while being followed and supported by the pediatrician. There is nowadays growing consensus that the child with cancer requires effective communication with respect to his health condition [14]. It has also been observed that, especially in the initial phase of hospitalization, pediatric patients express
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a strong need to be involved in care planning and in the treatments [5, 7]. However less attention has been paid to the starting phase of the therapeutic relationship within the pediatric triangle. If we consider the relevance of the experience that the child and the family develop in the contact with the hospital environment and the expert system, it is necessary to analyze the emotional dynamics and the practices that are adopted in this phase and their implications in the course of treatment [15, 14]. Brain tumor deserves a deeper focus, as this is a particular form of childhood cancer that involves additional problems in the initial phase of the therapeutic relationship. It is a kind of limit-case and therefore some of the dynamics that characterize the initial phase of the therapeutic process can be observed in this context with greater vividness and clarity. Infant tumors of the central nervous system are the most common form of solid tumors in childhood and the second most diffused malignant form after leukemia in the pediatric age, with a mean incidence on 3.3 cases over 100,000 children [16]. The concept of degree of malignancy of these forms is peculiar, as tumors that appear to be less aggressive can be placed in brain areas that are crucial for life support or can prevent normal development. The prognosis is also very uncertain, ranging from 20% to 70% survival 5 years post onset according to the istochemical characterization of the disease. These pathologies are extremely heterogeneous, a fact that, taken together with the paucity of the evidence in the literature, implies in the professional awareness that “every case is a single case (...) Diseases are all different, all children are different, parents are all different... So you can imagine the situation... a mystery from beginning to end!” to say it in the words of one of our interviewed pediatricians [14]. The uncertain prognosis and the variability of this type of cancer are even more difficult to manage, in practical and emotional terms, at the time of communication of the diagnosis and in the initial phase of the therapeutic relationship. Brain tumors are often characterized by an acute episode at onset and the symptoms at diagnosis are generally connected to the raise of intracranial pressure, with headaches, vomiting and nausea [17]. We must therefore assume that in most cases in the run of 24 to 48 hours the parents of children who look absolutely normal are forced to face the diagnosis of a pathology that deeply threatens the psycho-physical development of the child, if not also his survival. The child could be obliged to
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Journal of Pediatric and Neonatal Individualized Medicine • vol. 3 • n. 1 • 2014
undergo a surgical intervention that may last from 6 to 10 hours with an indeterminable outcome, and from which the child might emerge in a state of deep emotional alteration. What is required from the parents, at this point and in the space of a few moments, is to trust and rely on the medical team upon which the survival of their children and the preservation of their future depends. In other cases, the onset of the disease can be slow and insidious, thus exposing the family members to a long phase of uncertainty, during which the often reassuring response of the health care professionals can lead to episodes of dramatic underestimation of the symptoms – often subtle and difficult to read – on which parents try to convey, with increasing anxiety, for medical attention. The diagnosis, already dramatic in itself, is accepted with extra rage and suffering, coming from the experience of being not believed, and with the anguish of having lost time and possibly valuable chances of care. In assuming the care of these cases, the health professional staff exposes itself to very strong emotional drifts that are often to be faced in the context of a strict contiguity between children, parents, and staff members, under the pressure of heavy organizational demands and in the need of assuming responsibility for very difficult decision making processes. The present study
The present study, designed according to the phenomenologic-hermeneutic approach [18, 19], intends to explore the interpersonal and relational dimensions in the process of taking care of a child affected by a brain tumor, taking into account both the texture of human relationships which build the therapeutic activity of the staff by promoting or hindering it, and the development of the personal dimension in the context of the professional bond with the patient and his family members [20-23]. We focus on the perceptions of the professionals about the incoming patients and their families, we analyze the practices that are instantiated in this initial phase of the therapeutic process and we enlighten the emotional reactions of the various staff members facing these very complex medical and relational situations. Between February and July 2010 a research plan was developed and implemented in collaboration with the staff of the pediatric Oncology Ward of the Virgen del Rocío Universitary Hospital, Sevilla (Spain). The study focuses on the experience of the first contact between the patient and his family members and the
Caring for children with brain tumors in an oncology ward
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health care professionals in the Ward. The actionresearch was designed in the context of a previously established collaboration between the Department of Health Sciences of the University of Florence and the “Departamento de Personalidad, Evaluación y Tratamiento Psicológicos” of Seville. Methods
Design The research was designed according to a phenomenologic-hermeneutic approach. Foundationally, hermeneutic phenomenology explores the individual’s context to capture the essence or the underlying meaning of lived experiences as they are brought to light through the experiences of individuals. The experience needs to be described as well as interpreted to fully understand the meaning of the lived experience [24, 25]. The qualitative methodology, mainly the phenomenologicalhermeneutic method, is a preferred tool to approach and understand the needs of children with cancer and their families [6, 23, 26, 27]. Setting and participants The Head of the Department of Pediatric Oncology assigned to the research team a set of health care professionals who usually took part in the therapy of children affected by brain tumors, according to their different specialities. They were contacted individually by the research team and all agreed to participate in the study. Overall 19 staff members of the Virgen del Rocío Hospital, Seville, were interviewed: 12 from the Oncology Ward (2 oncologists, 1 psychologist, 1 radiotherapist, and 8 nurses), 4 from the Surgery Ward (3 nurses and 1 neurosurgeon), 1 psychiatrist, 1 physiatrist, and 1 intensivist from the Intensive Care Unit. In this paper, we consider only the interviews with the staff members of the Oncology Ward, due to the fact that, as we could note during the study, the multiple perspectives that emerge by comparing the points of view of staff members belonging to different specialities and Wards deserve a dedicated analysis. Procedure The methodology of the intervention was divided into 4 phases. In the first explorative phase, as a result of nonformal contacts with the Head of the Oncology Ward
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of Virgen del Rocio Hospital and preliminarily to the development of the analytical questionnaire, the research team interviewed the parents of children affected by a brain tumor in order to examine, from an external point of view, the Ward procedures and interpersonal dynamics. In the second phase, involving data collection, interviews were conducted by trained researchers in an adequate context that was provided by the staff inside the Hospital. To present the project to the participants, in March 2010 a meeting was held at which clarifications on the objectives, intervention, and procedures were explained. At this time, consent to participate was also requested and obtained from all professionals. In this phase the individual testimonies of the operators were collected with the aid of a semi-structured questionnaire. This one can be divided into five thematic blocks, each of which includes several questions presented to the respondents, ranging over the subsequent contents: resources and difficulties of the professional role, the first contact with a child suffering a brain tumor and with his parents, the way for communicating the diagnosis, the feelings that are experienced by the staff members during the various phases of the therapeutic process, the relationship between the respondent and the rest of his/her colleagues from the Oncology Ward, but also with the staff of the other Units involved in the treatment of brain tumors and finally the most relevant personal episodes connected to the care of a child suffering from brain tumors. The interviews were conducted during working hours in a contest made available by the staff and suitable for listening, without preset time limits. The interviews lasted from 35 to 50 minutes. The past research experience has shown that a relationship with a caring person is a framework that facilitates the expression of personal feelings and views and can support the initial elaboration of the emotional contents of the experiences. “This methodology allows to create a space where the operator can find a way to re-evaluate his experiences and a suitable context in order to express feelings and problems that might otherwise remain a source of anxiety in front of which the operator is helpless” [28]. With the consensus of the participants, interviews were recorded and transcribed. In the third phase, the analysis phase, the research group discussed single interviews over several meetings. An Interpretative Phenomenologic Analysis [29, 30] allowed for the reorganization of the material into themes and phenomenologic categories. The researchers reduced the complexity
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of data experience through rigorous and systematic analysis [31, 32]. This type of analysis is based on the process of giving meaning to the world and to the experiences of the participants and seeks to maintain a certain level of attention on what is different, but also to balance this expounding exercise with the commonalities that is shared across the different testimonies. In the fourth phase, the feedback phase, the phenomenological categories emerged from the analysis were presented to the participants in a feedback group meeting held in June 2011, thus promoting an in-depth discussion of the results. The purpose of restitution to the Ward was to create a common space for the universal and individual emotional events and issues that had emerged in order to improve the responsiveness of families with children affected by cancer of the central nervous system. Findings
A complex picture of personal, professional, organizational, and institutional demands emerges from the data. Here we focus on themes concerning emotional and pratical resources and difficulties about the communication of the diagnosis to the children and their families, all themes included in the second block of the interview questionnaire. The dimension of urgency It is evident in the data that relating to a child with brain tumor is considered to be a very difficult task for the hospital professionals. A crucial difficulty arises if the first meeting with the ill child occurs only after he has undergone neurosurgery, which can have a tremendous impact on the mental and psychological functioning of the patient. In this case the staff is forced to start the relationship without knowing how the child was “before.” Many operators declared that they would prefer to see the child before the diagnosis. An oncologist told us: “It would be ideal that it (the first contact) happened during the diagnosis. In that way you are allowed to know the child before the surgery. To meet him, to see him, to know how the problem started, and then to see him again after the surgery and then begin the treatment. However there are times when the first contact happens when the children have already been operated on, which is negative because we want to meet them early on, when the diagnosis is made” (oncologist 3).
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Nurses, too, feel the difficulties in meeting the children after the interventions: “They come already operated on and you did not meet them before...” (nurse 3).
Moreover, the words reported by nurse 3 seems to speak about the perception of a child who is so different after surgery, that the ‘true’ child appear to be lost. Often the professionals experience the dramatic change of the children after the intervention. A nurse recalls an episode in which she had a conversation with a child before neurosurgery and just the day after she was not able to recognise him. She expresses her disconcertion when meeting a patient she knew who came back from surgery in a deeply impaired state: “Personally I was talking with the child that had come here the day before the surgery: ‘How are you?’ ‘Well! I’m well!’ And the day after he was operated on, then he went to intensive therapy for a little bit of time, and when he returned here was a low child... with a lot of needs... and then little by little they begin to talk... It is different from one child to the next” (nurse 7).
The need to communicate the diagnosis to the patient and family members in the Department of Oncology before the neurosurgery acquires a crucial importance not only from an emotional point of view, but also in terms of organization of the therapeutic plan. To define the goals of patient care, in the eyes of the professionals it is essential to know the child’s condition prior to the physical and cognitive impairment associated with neurosurgical intervention. An oncologist of the staff said in this regard: “When we go and see the child who is already in neurosurgery, this is because we were not told that he was there, then we go and he has already been operated there and we meet the family and the child, it is often in the Intensive Care Unit... and our difficulty is to know how he was before and the extent to which we can make the child return as he was before, when you do not know” (oncologist 1).
The dimension of acceptance Professionals also report that after the first meeting with the parents of children with brain tumors, they are often in a state of shock after the communication of the diagnosis. Commenting about their reaction, a nurse told us:
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“I can tell you my personal experience: when you see them entering for the first time and you see their faces you understand that you can’t do anything because in that moment the world has turned against them” (nurse 2).
In this situation it is very difficult to create a good relationship with the parents. In particular, nurses try to establish a relationship that is based on the parents’ needs. In the words of the interviewees the first contact with the child and family must be characterized by acceptance and consideration of the needs. The nursing staff is available to answer questions and face the doubts expressed by the parents; sometimes, however, a temporary attitude of rebellion must be accepted as well: “However in the first contact it is very difficult to talk with them. Because, maybe, the parents and also the child are there pent up... You must begin to contact them in a different way. Let’s say that they rebell against the system: all that you do, they quarrel and discuss with you... Nothing seems good to them, you go there with a positive approach, you try to help them, but they don’t accept your help, and therefore it becomes very difficult. Many times after the first contact we comment on the etiquette that we gave them, an etiquette that says e.g. ‘This father is hostile, problematic,’ and you are not aware of the fact that he is not that way. Maybe you are not able to talk with them, but after a week you already see that you can talk with them, and maybe they laugh. It is a normal evolution! So at the beginning it is complicated, but after a while they open up” (nurse 2).
The experience of profound shock of the family members and the initial rebellion against the disease can be accepted by the nursing staff thanks to the activation of peculiar resources. Among these, the nurses underline the importance of the warm, affectionate, and open attitude that they try to communicate during the first contact. In fact, when the child and family arrive at the unit, staff receives them with an empathic attitude and emotional availability, to meet their needs of comfort and encouragement. In this regard, nurse 1 tells an episode she experienced during a night shift: “I saw that those parents could not sleep, and I took advantage of the situation for a moment, I brought the parents out of the room, took them to the office, and spent two hours talking to them. Of course you just cannot help... but you’re talking with them. And they see in you a kind of peace of mind, that you’re explaining things, that you’re giving them hope... then the parents with whom I
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did this... they were positively impressed throughout the disease. They saw a good person, say, who helped them in the most difficult moment” (nurse 1).
The first contact with the young patients is invested by a strong emotional charge where acceptance assumes again a central role. Some professionals prefer to contact children with a playful attitude, as illustrated by nurse 5: “I make jokes... I ask if they have brothers or sisters... One thing that really works well is asking about their favourite football team! I start making jokes on that, right? What I try to do in the first contact with the children is to try to show them a serene face, a pleasant one, so that they know you are there trying to help them” (nurse 5).
Collaboration between the professionals The words of the professionals show that there are two faces in the communication of the diagnosis: on one side, the doctor is always the professional who communicates the diagnosis to the children and the families. Doctors and nurses affirm this practice: “In the case of brain tumors, normally the neurosurgeon or the oncologist communicates the diagnosis. They are the ones who stay there” (oncologist 2).
Another professional tells us: “The doctor gives the diagnosis, here actually the oncologist does it. I believe that the group of oncologists or of doctors in general do it fairly well. They perform a series of tests to get to the diagnosis and from there they talk with the parents... Maybe even the neurosurgeon..., but at times it happens that the child is in neurosurgery when a quick surgery is planned, so first thing, they go in the operating room and the parents cannot really access the information until the neurosurgeons operate on the child. So it can also happen that the neurosurgeon leaves the operating room and says, ‘This child has a tumor, called such, that is located in this place’ and he gives the prognosis. And in this occasion, the neurosurgeons give the news... the bad news. But it is always the doctor. The neurosurgeon or the oncologist” (nurse 8).
However, on the other side, we can say that there is a shared form of communication involving all the types of professionals who participate in
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the care. From the words of the professionals, it is clear that the communication of the diagnosis does not happen in a single session with the family and the patient, but develops over time through a real form of multidisciplinary collaboration among professionals. In fact, the doctor is the one who has the burden of bringing the bad news initially, but the nurses and the psychologist are deeply concerned with the promotion of a fair processing of the received information, as they provide answers to the questions posed by both the family and the children and reassure them with respect to the therapeutic procedures. In this sense, the participation of all the stakeholders in the communication of diagnosis, although at different times and with different roles, not only favors the creation of a relationship of trust and an open dialogue between family members and staff, but also reduces the probability that any misunderstanding or confusion from the patient or the family could remain unnoticed. An oncologist comments on this collaboration: “It is a form of shared communication because everyone explains something to them. The neurosurgeon explains to them what I said before, that the child has a little ball in the head. We explain the treament because they understand it as such, for example, when you do an intraveneous treament you have to explain to them that they must come to the hospital, that you have to put in a cannula to administer the medicine. And for example, the nurses generally come on the topic of the operating room, they bring the masks so the children are familiar with these, they bring all the tools so the children can see that those are the instruments” (oncologist 3).
For sure, nurses have an important role in the family’s processing of the news of the diagnosis. All nurses express the awareness that they are the professionals who welcome the parents and their doubts and fears after the communication of the diagnosis: “They leave the office still blind, they have not yet internalized, maybe they can’t believe it, and with all the doubts that they hide, they always come to us nurses! Because normally the doctor is there in the morning, he gives them the news, and when the parents become aware it is already afternoon or night. Like I said before, the nurses are those who stay the closest to the family” (nurse 5).
In any case, even in this shared way of communication, each professional appears to
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protect the therapeutic relationship built with the patient and family by his colleagues. When providing clarification for a colleague’s information to the family, the cornerstone of the intervention is to safeguard the privacy of the exchange that parents have with the oncologist. In this way, by re-learning the news directly from the words of the family, it is possible to assess the degree of understanding that the family and the child have about the clinical situation, and where appropriate, to signal any problem to the colleagues for clarification: “When they see me for the first time, they blow off, they cry... and they take it for granted that I know the diagnosis, but I tell them that the doctor told me that there is a sick child, that, approximately, I understand what it is, but I need that they do explain to me what the doctor said. I do so because I don’t want them starting to think that the doctor spreads around pieces of confidential information. I prefer that they tell me what they know, in order to understand the level of awareness that have about what’s going on. Normally they are aware of the facts, as I see them explaining them very well, but if I see that they say something that I think is not correct, or that is dissonant with what I know about this type of cancer, then I alert the doctor, I say that it is better if he talks with the family once more” (psychologist 2).
The communication to the underage patient Coming to the issue of the communication of the diagnosis to the underage patient, the interviewees took two different positions. In a medical perspective, the oncologists reaffirm that the child should always be informed about the diagnosis, in a way that is suitable for his level of comprehension. “So... Pediatrics!... Here there are children aged a few months, up to 14-15 years... then depending on the age of the child, we sit down with him and explain in his own words what’s going on... We simply say: ‘look... you had pain in the head? Well... this head pain and vomiting you had, this is because we have found that you have a ball in the head and this ball... we’ll try to remove it... So maybe you will have to undergo surgery in order to take the ball away, and after we’ll see if there will be other treatments to be done.’ And we explain it to him according to the child’s ability to understand us and according to his age... but always, in one or another way we tell them. Of course, it is different if he’s 16 years old or 4, but even if he is very young we always give him a few hints to understand why he is in hospital” (oncologist 1).
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Some professionals, however, underline how difficult it might be to communicate the diagnosis to a child whose comprehension abilities might be reduced due to neurosurgery. Once again, the theme of the physical and neurological consequences of the interventions is central in the collected data. The state of unconsciousness that sometimes follows surgery can limit the possibility to communicate directly to the child about his clinical status. In this regard, a nurse says: “Telling the child? The point is that normally the children, when they arrive here, have already been operated on. So... in fact the children are in a kind of comatose state. Maybe before diagnosis children feel symptoms... maybe because their head hurts then they know something... but I do not think that the children are given a lot of information” (nurse 5).
The professional’s feelings: healthy positive coping When the parents are in a state of shock, they require the opportunity to express their feelings in front of the staff members that are there to support them. On this topic, an oncologist told us: “Logically it is a piece of news that... is like an emotional bomb for them. Here in this office many parent have cried... and that’s it. I let them cry and after that I always try to give them hope that we can help them” (oncologist 1).
Nevertheless, professionals have to take care of the families and the patients, but they also have to manage a severe emotional shock for themselves: “Then at times you are there in the room and the doctor comes in with the M.R.I. scans and says: ‘This here is a tumor...’ and maybe it is a tumor as big as an orange in the center of the child’s head... And it cannot be removed! It seems impossible” (nurse 4).
There are a lot of different feelings which the professionals have about the first meeting with children affected by brain cancer and their families: hope, compassion, senses of struggle and rebellion, among others. A nurse told us that the first feeling in her experience is the toughest, as it is the one that reminds her that here is “still another child, one more suffering” (nurse 3). “My feelings? “Still another!” Still another... yes... because, well, there is no difference if he is young or not,
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but they all are children, so I think: “So young... and already he starts having all this.” Because he comes here and remains for one year at the minimum. So young and already in this routine? All that he will have to suffer, all that will happen to him...” (nurse 3).
Faced with this complexity of mixed emotions, some professionals reported an attempt to create a defensive barrier in order to avoid becoming too involved by work experience. This form of protection, as effectively explained in the words oncologist 3, does not always seem to work, but instead clashes with the need to establish a therapeutic practice on the relationship with the patient, even if this means becoming more involved with him: “I really live it in such a way that... I try not to be so involved as not to be able to provide any help... but the truth is that after, I become fond of each patient! Each bit of news... every time there is a new child... I do not know how to explain it... they tell me ‘Come, you who are more used to it.’ Well, I’m used to the work, not to the suffering... Is it that bad?... You live with each of them (...) We need to start from scratch to help them... and become attached” (oncologist 3).
Anyway, it is very difficult for the professionals to manage emotions and to disconnect with the work experience when they live their private life. Some nurses and oncologists report that they always think about job when they are at home: “… At your home you cry. You start crying. It is always the same. Either from a song that they are playing on the radio or for whatever other reason. At my children’s school party for Christmas, I saw all these children singing, so healthy, so happy, all so right, and I started crying and I was not able to stop. They were all looking at me and saying: “But what is she doing, that one, is she crazy?” All the world happy and I was crying! And it’s just like that, I start crying, and it happens that way. I was there crying for two hours and after that it went off” (nurse 4).
Discussion
The importance of including the perspective of the child suffering from cancer to improve the quality of their care is a topic considered by different studies, and is designed by a qualitative methodology [5-7, 24, 26]. However, considering the triangle comprising child, family and professional staff
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that provides care in the field of pediatric psychooncology, perhaps this latter group has received less attention from the phenomenological-hermeneutic method. As we wrote in the introduction of this article, our working group has tried to deepen the point of view of health care professionals involved in the treatment process of children with brain cancer (specifically, oncologists, surgeons, nurses, etc.) [14, 25, 33], in particular their perceptions about the patients and their families in the very critical phase of the initial contact with the staff and along the diagnostic process. The therapeutic approach to brain cancer is among the more complex protocols in oncology as many specialists coming from different disciplines are involved in the therapy from the very beginning. A child with brain tumor therefore might be addressed to the Oncology Ward or to the Neurosurgery Unit first, according to his clinical conditions and to the urgency to plan neurosurgery. This is not usually the case for patients presenting with other oncological pathologies. Most of the members of the Oncology Ward staff signaled that a supplementary source of difficulties arises with these patients when it is not possible for them to meet the patient before he undergoes neurosurgery. Many health care providers affirmed that it is not at easy to get in touch with a child who is in a state of profound emotional distress and suffers from severe cognitive limitations due to the drawbacks of the intervention. According to the interviews, the problem cannot be limited to the issue of establishing the therapeutic relationship as the fact of not knowing the patient in his standard way of functioning and behaving can be a relevant limitation even when defining the specific goals of the therapeutic plan, especially those related to quality of life issues. In a concrete plan, these kinds of problems enlighten the complexity implied by the intrinsic multidisciplinary characterization of the process of caring for a child with brain tumors, one that is often set in place under the absolute urge of a lifesaving intervention. If we consider the participants’ words from a psychodynamic perspective, the opportunity to get in contact with the child before surgery, when he is still looking like a healthy child, suggests the need to remain in contact with a kind of an image of a “good and whole object”. Recovery is often seen as a kind of restitutio ad integrum, and the possibility to keep in mind a concrete image of this integrum (the child as an intact, unbroken object) could provide support to the healing faculties of the staff members in a deep
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psychological sense. According to a psychodynamic point of view we would say that when the child gets worse and his physical conditions deteriorates, an inner image of the child remains, who says: “Well! I’m well!,” as nurse 7 reported, as a good and lively object that preserves and protects the therapeutic bond [34]. From a different theoretical and methodological perspective, the study Jackson and colleagues [35] conducted in a pediatric hospital in Melbourne also discusses the feelings of parents in the early days after diagnosis, thus, the need to establish effective communication between staff members and parents to provide the best possible care to children diagnosed with brain tumor. Nurses express their discomfort in facing families just after the communication of diagnosis, when they can feel how shocked they are and that is not possible to do anything for them, “because in that moment the world revolves around them” (nurse 2). Testimonies show that is important to create a gradual relationship, based on the parents’ needs, allowing them to digest the difficult information over time and to experience a complex range of emotional states: anger, rebellion, despair, but also, in the end, confidence in the professionals. Although health care providers report a certain degree of personal and professional satisfaction with respect to the relationship with patients and their families, they appear to be aware that the construction of a positive therapeutic alliance is the result of an extended process that often begins with the rebellion of the families against accepting of their present situation. This difficulty in the first contact hinders the possibility of developing a family-centered care, which is a highly relevant approach in pediatric oncology, chiefly for nurses. Thus, MacKay and Gregory [36], utilizing personcentered interviews to collect data, interviewed 20 nurses of the Oncology Ward of a pediatric hospital in West Canada. The purpose of this study was to identify how pediatric oncology nurses implemented family-centered care (FCC) into their practice, what facilitated and enabled pediatric oncology nurses to implement FCC, and which barriers and challenges were present in their settings when implementing FCC. Hill and colleagues [37] also developed a qualitative methodology that focuses on how fathers view and understand their roles in families with a child with acute lymphoblastic leukemia: specific training of professionals, not only of nurses, in implementing FCC, could alleviate some of the difficulties highlighted in the interviews.
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In order to cope with the experience of these families, the healthcare staff has developed a way of communicating that is shared by all professionals with the intent to meet the fears and doubts that arise in parents and children through full availability to answer questions and review the information as it is understood by the parents about the diagnosis over time in different occasions. By engaging in these practices, parents are supported in their reworking through information provided by the doctor and other health care providers. In this way, all professionals will demonstrate their availability to be seen as a constant presence that can be supportive and trustworthy in the hard times that follow the diagnosis. In the study by Clarke and Fletcher [12], the main problems of communication between professionals and parents were analyzed, especially in the early days about diagnosis . Parents usually began their narratives of the defining moments in the months, weeks, or days prior to the diagnosis. The authors reported on parents’ views about one of the defining moments in the stories. Communication with the parents This level, called by us “communication issues,” includes the parents’ issues with how the communication was made at diagnosis, contradictions and confusion, feeling whether they are getting the “right” amount of information, if they received good or poor communication, if they feel listened to, and errors in medical information. With respect to the theme of the communication of diagnosis, staff members expressed discordant opinions to Clarke and Fletcher [12] about who communicates the diagnosis and about which two aspects of the communications emerged. All professionals agree that it is always a doctor who informs the children and the parents about the clinical situation. In some respects, in the view of almost all the members of the staff of care, the physician receives the family in his office and explains to them the problem that has emerged by explaining the nature of the illness and the type of the treatments required. However, some health care providers believe that, in practice, there is a shared form of communication between different type of professionals (oncologists, neurosurgeons, nurses, or psychologists) who contribute to explaining the diagnosis to the child and parents, thus vastly enriching the communication [38]. Nurses recognize their role as important in this phase of the disease. Being the professionals
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who spend more time in the care of the patient and his family, it is often the nurse, as well as the psychologist, who can help the parents to really become aware of the diagnosis already received. In this form of multidisciplinary communication, however, professionals respect the protection of privacy of the patient-physician relationship in order to preserve the trust that is a crucial point of the therapeutic alliance. The psychologist in the Pediatric Oncology Ward at the Southern Spain hospital, for example, usually requires to be informed directly by the family about the patient’s clinical conditions, in order to avoid any suspicion that the doctor could spread around confidential information. This suggests that the communication between the family and the team takes place along two different temporal levels. The first, a synchronous one, is characterized by the bad news that the physician brings to the parents and the child, which is recognized by all professionals as the official communication of the diagnosis. A second plan, however, unfolds in a diachronic way through several communications that are developed more continuously over time, with each designed to provide more detailed information and clarification of various aspects from the different professional figures. It is at this second level of communication that the family has time to digest the bad news of the disease, gradually adding information and clarifying those that are not yet fully internalized. In the latter case, every member of staff has his specific role: the doctor explains the dynamics of therapies and their possible consequences; the nurse takes care of the patient and clarifies the doubts day by day thus strengthening the efficacy of the communication; the psychologist watches over the correct understanding of the information and the holding of therapeutic alliance. Communication with the child Coming to the issue of the communication of diagnosis to the child, once again it clearly emerges that the staff worries about the relational difficulties due to the condition of temporary cognitive disability that the child can be forced to face. On the one hand, the position taken by the staff of care is to acquaint the patient of his disease while consistently adopting the terms and conditions that are most appropriate to his age and to his understanding of the situation. From another point of view that position is not always pursued because sometimes the children are in a comatose-like state.
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With regard to the emotions experienced by the health care providers in this first phase of the treatment, professionals express the need to take care of the families, but also to take care of themselves when they are confronted with such hard experiences in their daily life. Some professionals try to protect themselves from the most painful experiences implied by their working practice by “getting a shield” or by maintaining a certain degree of emotional detachment from the children with brain tumors. However, professionals, who are well aware of the importance of the relational aspects in their work, tend to avoid this illusory protective barriers and get deeply involved at an emotional level. Conclusions
The aims of a phenomenologic-hermeneutic study is to stimulate a reflection about practice in those who are involved in such complex relational and professional issues, and possibly to facilitate the exploration of the links between self-reflection and good practice. By analysing the life experiences of health care professionals who demonstrate such a deep involvement in their professional goals and such a delicate attention to the personal implications for themselves, the families and the patients, it is therefore possible to enlighten some points that could deserve deeper attention in clinical practice. First of all, we would like to stress the relevance of providing enough space and care, both in mental and organizational terms, for the multidisciplinary team to elaborate the emotional implications of the clinical situations that are faced day to day when coming in touch with such dramatic circumstances as those implied by a diagnosis of brain cancer in a pediatric patient. We would like to describe this need by a methaphor that emerged during one of the last group meetings we had with the participants in the last phase of the study: each painful experience, each piece of bad news, each loss, each therapeutic failure is destined to be preserved not only in the memory but as a kind of ‘open wound’ in the psychic body of the staff members, both at the individual as well as at the group level. Now it is evident that bandages and protections must be provided in order to allow the professionals to continue in their therapeutic efforts, so that the ‘open wound’ will not be kept in full sight all time long; and yet these psychic wounds deserve attention and care in some moments at least, in order to avoid complications and further, unjustified suffering for the staff.
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The second point we would like to stress is the complexity that emerges when the communication of the diagnosis is seen as a psychological process and not only as a mere interpersonal act: the family in fact has to be introduced to a new reality, the one of being a family with a child suffering from a brain cancer. It is not a matter of ‘knowing’, it is a matter of facing the ‘meaning’ of this condition, its implications both in practical and in psychological terms, its sense. It is of course true that the physician who is in charge of a given patient and family is the one who has the responsibility for the communication. Nevertheless, from the data we can see how each one of the staff members who gets in touch with the family and the child is implicitly or explicitly required to support the parents’ inquire for meaning and implications. The nurse who is providing details on the rules that govern routinary events in the ward, as well as the sanitary operator who is showing to a mother how to clean the hair of the child after surgery, the neurosurgeon who is explaining the possible long term consequences of the surgery, all these are indeed deeply involved in the process of explaing to the parents what it is like to have a child with a brain cancer. In this perspective, the effort to share the same view on what is going on among the staff members, despite the differences that constantly emerge due to the professional role and to the personal preferences and believes, becomes indispensable and a valuable working tool for the multidisciplinary team. The family sees itself in the professionals’ eyes, and therefore the degree of integration in the team is a foundamental protection for the psychological integrity of the parents facing such traumatic events, and by their interposition for the patient himself. We suggest that responsibility for such a sharing process should be considered as a mandatory aspect of an effective leadership in these contexts. Declaration of interest
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The Authors declare that there is no conflict of interest.
16. Sinzig M, Gasser J, Jauk B, Hausegger KA. [Brain tumors in
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20. Bleger J. Psicohigiene y psicología institucional. Buenos Aires: Paidós, 1966. [It. transl.: Psicoigiene e psicologia istituzionale. Loreto: Libreria Editrice Lauretana]. 21. Carli R, Paniccia MR. Analisi della domanda. Bologna: Il Mulino, 2003. 22. Correale A. Area traumatica e campo istituzionale. Rome: Edizioni Borla, 2006. 23. Dixon-Woods M, Young B, Heney D. Rethinking experiences of childhood cancer: a multidisciplinary approach to chronic childhood illness. London: Open University Press, 2005. 24. Woodgate R. Feeling states: a new approach to understanding how children and adolescents with cancer experience symptoms. Cancer Nurs. 2008;31(3):229-38.
30. Mantovani G, Spagnolli A. Metodi qualitativi in psicologia. Bologna: Il Mulino, 2003. 31. Smith JA. Beyond the divide between cognition and discourse: Using interpretative phenomenological analysis in health psychology. Psychol Health. 1996;11(2):261-271. 32. Smith JA, Osborn M. Interpretative phenomenological analysis. In: Smith JA (Ed.). Qualitative psychology: a practical guide to research methods. London: Sage, 2003. 33. Lauro-Grotto R, Tringali D, Papini M. Close encounters with caregivers: the case of pediatric brain tumors. Psychooncology. 2007;16(9):264-65. 34. Klein M. Notes on some schizoid mechanisms. Int J Psychoanal. 1946;27(Pt 3-4):99-110.
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Fioretti • Lauro-Grotto • Tringali • Padilla-Muñoz • Papini
www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030108 doi: 10.7363/030108 Received: 2013 Oct 03; revised: 2013 Nov 15; accepted: 2013 Nov 17; advance publication: 2014 Jan 10
Original article
Oral breathing: new early treatment protocol Gloria Denotti1,2,3,4, Selena Ventura2,3,4, Ornella Arena2,3,4, Arturo Fortini2,3,4 1
Pediatric Dentistry, School of Dentistry, Cagliari University, Sardinia, Italy
2
Post-graduate School in Orthodontics, Cagliari University, Sardinia, Italy
3
Department of Pediatric Dentistry, Cagliari University, Sardinia, Italy
4
Department of Orthodontics, Cagliari University, Sardinia, Italy
Abstract
Oral breathing is a respiratory dysfunction that affects approximately 10-15% of child population. It is responsable of local effects and systemic effects, both immediate and long-term. They affect the growth of the subject and his physical health in many ways: pediatric, psycho-behavioral and cognitive. The etiology is multifactorial. It’s important the establishment of a vicious circle involving more areas and it is essential to stop it as soon as possible. In order to correct this anomaly, the pediatric dentist must be able to make a correct diagnosis to treat early the disfunction and to avoid the onset of cascade mechanisms. Who plays a central role is the pediatrician who first and frequently come into contact with little patients. He can identify the anomalies, and therefore collaborate with other specialists, including the dentist. The key aspect that guides us in the diagnosis, and allows us to identify the oral respirator, is the “adenoid facies”. The purpose of the study is to highlight the importance and benefits of an early and multidisciplinary intervention (pediatric, orthopedic-orthodontic-functional). A sample of 20 patients was selected with the following inclusion criteria: mouth breathing, transverse discrepancy > 4 mm, early mixed dentition, central and lateral permenent incisors, overjet increased, lip and nasal incompetence, snoring and/or sleep apnea episodes. The protocol of intervention includes the use of the following devices and procedures: a maxillary rapid expander (to correct the transverse discrepancy, to increase the amplitude of the upper respiratory airway and to reduce nasal resistances tract) in association with myo-functional devices (nasal stimulator and oral obturator). They allow the reconstruction of a physiological balance between the perioral musculature and tongue, the acquisition of nasal and lips competence and the reduction of overjet. This protocol speeds up and stabilizes the results. The control of the muscles during the growth phase is important: muscular forces influence the direction of facial growth.
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Keywords
Oral breathing, systemic effects, “tools” for pediatric interception, rapid palatal expansion, neuromuscular re-education. Corresponding author Gloria Denotti, Associate Professor of Pediatric Dentistry, School
then a negative influence on psycho-social life of the subject are all aspects related to a poor oxygenation [2-5]. A multidisciplinary intervention is needed to solve the problem where the specialist that has a key role is the pediatrician. Since there is a close correlation between oral breathing and dento-facial inharmonies, the pediatrician should involve the pediatric dentist after an early identification of an oral breathing in a child.
of Dentistry and Post-graduate School in Orthodontics, Cagliari University, Sardinia, Italy; Department Chair of Pediatric Dentistry, Cagliari University, Sardinia, Italy; email: gloriadenotti@gmail.com.
Table 1. Anamnesis and physical examination [10, 11]. Family anamnesis
Physical examination
Tiredness
Dark Circles
Epistaxis
Nasal Septum
Difficult sleeping
Verbal articulation
Snoring
Posture
Apnea
Breathing
Introduction
Swallowing saliva wets the pillow
Deglutition
Difficult chewing
Adenoids
Oral breathing, in children, is a very common problem. This dysfunction affects approximately 10-15% of child population. It results in a wide spectrum of consequences both immediately and at long-term. These consequences involve different districts of the body (mouth, craniofacial development, upper and lower airway) [1]. They influence the growth of the subject and his physical health in many ways, pediatric, orthodontic, orthopedic, behavioral, metabolic, cardiovascular, psycho-behavioral, cognitive and phonatory [2-5]. Oral breathing, in fact, can be considered as the most obvious manifestation of a syndromic pattern that has an impact not only on the physical sphere, but also on a social and psycho-cognitive level [3, 6]. The pathogenesis is complex and multifactorial. Causes can be both local and systemic, related to malformations, bad habits, airway disease, etc. [7, 8]. However, what must be emphasized, is that these problems intersect each other forming a vicious circle that keep itself [2, 9]. An early diagnosis (Tab. 1), in collaboration with the pediatrician, and the interceptive treatment, which interrupts the circuit as soon as possible, are important steps. In this way is possible to avoid several conditions: frequent infections, pathological masticatory pattern, the development of a malocclusion, incorrect deglutition and phonation, abnormalities of body posture (Fig. 1A). Short attention span, decreased memory, poor school performance, changes in sleep-wake cycle, day irritability and
Keep open mouth
Tonsils
How to cite Denotti G, Ventura S, Arena O, Fortini A. Oral breathing: new early treatment protocol. J Pediatr Neonat Individual Med. 2014;3(1):e030108. doi: 10.7363/030108.
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Encoding nasal Lingual frenulum Lips Skeletal analysis
a.
b.
Figure 1A. Postural characteristics of patients affected by oral breathing: Cephalic Posture (a), Body Posture (b).
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Journal of Pediatric and Neonatal Individualized Medicine • vol. 3 • n. 1 • 2014
There are numerous studies that confirm the influence of a wrong respiratory pattern on the dento-facial development [12-15]. Oral breather develops some specific characteristics [16]. The easiest aspect to identify is the “adenoid facies” (Fig. 1B), characterized by long face, dark circles marked, postural attitude with open mouth, flattened cheekbones, short and incompetent upper lip (Tab. 2), nostrils small and hypotonic, low-lingual posture, posterior mandible rotated, open bite tendency, hyperextension of the head [5], extrusion of the posterior teeth, transverse discrepancy, crossbite, “V”shape maxilla [25], arched palate, lingual version in the posterior elements [26]. There is a diagnostic scheme (Tab. 2) which allows a first evaluation of the patient and the classification of certain functions (type of breathing, the presence of bad habits, the presence of problems of phonation, etc.) to adapt the treatment to the severity of the dysfunction of the patient.
a.
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b.
d. c.
Figure 1B. Clinical characteristics of an oral breather: adenoid facies (a); V-shape Maxilla (b); lip incompetence (c); nasal incompetence (d) [3-6, 9, 16-24].
Table 2. The different effects of oral breathing.
a b
Lips: Lip incompetence; short upper lip; chapped lips, bulky or flabby.
Oral-facial muscles: Facial muscles hypotonia; lingual posture low; atypical swallowing.
Tongue: low lingual posture; possible short lingual frenulum.
Maxilla: hypoplasia of transverse and sagittal planes; arched palate, high palate; vertical soft palate; rotation of the bispinale planea; flattened and/or absent cheekbones.
Mandible: increase in lower facial height; growth in posterolateral rotation; distal position or antero position (skeletal Class II or III)b.
Posture: extension of the head; inversion of cervical lordosis; low posture of the mandible; lowering of the hyoid bone; scapular winging.
Nose and sinuses: adeno-tonsillar hypertrophy; underdevelopment of the nasal cavity and paranasal sinuses; nose broad-based and small; nostrils facing the high.
Dentature: buccal version of maxillary incisors; back inclination of the mandibular incisors; dento-alveolar crowding; unilateral or bilateral crossbite; anterior open bite; modification of the bacterial flora and increased susceptibility to caries.
Other: fonesi and timbre of the voice are altered (especially the issuance of certain phonemes such as M, N, NG), since the nasal cavity does not carry out its functions as a sounding board; may tend to obesity or extreme thinness.
Bispinale the plane is the plane passing through the anterior nasal spine and posterior nasal spine. If the jaw is more shifted forward with respect to the maxilla it’s class III. If the jaw is positioned back than the norm it’s class II.
Aim of the study
The aim of the study is to highlight the benefits of early treatment and combined orthodontic-orthopedic-functional. Materials and methods
It was selected a sample of 20 patients aged between 6 and 10 years (9 M, 11 F) who had the following inclusion criteria: deciduous dentition,
Oral breathing: new early treatment protocol
or at least a first mixed dentition (with the eruption of central and lateral permanent incisors and first permanent molars), mouth breathing, transverse discrepancy greater than 4 mm, with or without crossbite, increased overjet (OVJ, i.e. the distance between the margins of the upper and lower incisors in the horizontal plane), nose incompetence, lip incompetence, snoring and/or sleep apnea. We have adopted the following exclusion criteria: previously orthodontic treatment, patients with muscle diseases that could affect the neuromuscular re-education,
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patients with cleft or other malformations. The protocol “Early treatment” includes a rapid palatal expander (screw A.621 Leone® Italy) bonded on the decidous molars [26-28] (Fig. 2a), in association with the use of silicone myofunctional devices such as the nasal stimulator (Fig. 2b) and the oral obturator (Fig. 2c), that speeds and increases the effectiveness and stability of treatment [11]. These appliances also allow the reconstitution of a physiological balance between the perioral musculature and tongue, the improvement of the overjet and the acquisition of lips and nose competences [11]. It’s fundamental the control of the muscles during the growth phase: muscular forces influence the direction of facial growth as they form the functional matrix of the jaw bones [2, 6, 9]. Different parameters were evaluated for all 20 patients at time T1 (before treatment) and at the end a.
b.
c.
Figure 2. Rapid maxillary expansor screw A-621 Leone® (a); nasal stimulator (b); oral obturator (c).
of early interceptive treatment that lasts an average of one year (T2). The parameters that we examined were: overjet (measured in millimeters), transverse discrepancy between the arches (detected through measurement in millimeters with a digital caliber of the diameters between the central of the first upper molars and the cusps of distobuccal first lower molars), labial and nose competence (measured with the use of clinical parameters present in Tab. 3A and Tab. 3B). The protocol involves the use, in succession, of an oral obturator permeable, semi-permeable, and impermeable (for a period of about 4 months, each), so we can lead gradually the patient to a nasal breathing, also facilitated by the association with a nasal device [11]. After 6 months from the beginning of myofunctional therapy, a rapid palatal expander bonded on decidous molars is positioned. The active phase of the palatal expander is in the range 15-21 days. It depends on the extent of the discrepancy. The stabilization phase of the suture is about 6 months. The used expander is the one the new micro-screw A-0621 Leone® Italy. It has an orthopedic action with the minimum space in the mouth of children that are very small. So the discomfort of the child is avoided and the collaboration is improved [21, 22, 28]. Two activations per day during the first week, and a daily activation from the second week, if the suture is opened, should be performed. The most obvious clinical sign of the disjunction of the palatal suture is the opening of the interincisal diastema and 4-6 month to stabilise the expansion of maxillary sutures are needed.
Table 3. Parameters used to evaluate the nasal and lip competences [11].
A.
Relationship between the lips A normal relationship of the upper lip is ranged from 1/3 to 2/3 more forward than the lower lip. We also consider: • upper lip incompetent at rest (not touching the lower lip); • dry or chapped lips. For its codification we will give a grade 0 to the normal relationship of the lips, a degree 1 with respect to the upper incompetent lips at rest, a grade 2 for dry or chapped lips.
B.
Codification of the nostrils Degree of collapse nasal codified by dr. Duran. It encodes 5 degrees (plus a degree 0 of total absence of the problem) in function of the motility of the nostrils during forced inspiration: 0 = bilateral dilation of the nostrils during inspiration; 1 = no dilatation nor collapse of the nostrils during inspiration; 2 = partial unilateral collapse; 3 = partial bilateral (3-a) or total unilateral (3-b) collapse; 4 = total one-sided and partial collapse of the opposite side; 5 = total bilateral collapse.
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Results
The use of nasal device allows the stimulation of the insertions of perinasal muscles, and the remodeling of cartilage. Thus, the patient acquired the perception of his nose (in patients with alteration of 4th and 5th grade the use of the device was prolonged). The oral obturator exercised and strengthened the perioral musculature, allowed the patient to acquire lips competence and a gradual transition from oral to nasal breathing. This device has also the advantage of improving and sometimes solving the OVJ as can be noted in Fig. 3. Other results are presented in Fig. 4 and Fig. 5. An example of Cone Beam Computed Tomography (CBCT) is presented in Fig. 6. Conclusions
The correlation between oral breathing and dento-facial inharmonies was confirmed in numerous contributions in the literature [13, 29, 30]. The rapid palatal expander is a valid appliance to solve malocclusion and oral breathing. It improves the morphology and function of the masticatory system and the upper part of the airway. Thanks to the connections between oral cavity, nasopharynx and auditory tube, the expander can also improve
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ear disease and/or dysfunction of the acoustic type [12, 13, 30, 31]. The maxilla constitutes the upper wall of the oral cavity and the floor of the nasal cavity [19].
a.
b.
c.
Figure 4. Lip incompetence before treatment (a), lips stimulation during treament (b), lip competence after treament (c). a.
b.
a. Figure 5. Adenoid facies before treatment (a), after treatment (b). The expansion, however, allows the correction of the discrepancy of transverse crossbite, the improvement of the palate morphology and the increase of airway patency by expanding the nasal cavity (such result has anatomical bases; in fact, the maxilla constitutes the roof of the oral cavity and the floor of the nasal cavity).
b.
Figure 3. Overjet before (a) and after (b) treatment with Maxillofacial Surgery (MFS) oral obturator.
Oral breathing: new early treatment protocol
Figure 6. The airflow in the upper airways in Cone Beam Computed Tomography (CBCT).
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Table 4A. Values obtained at T1. Patient
Overjet (OVJ) (mm)
Discrepancy transversal (mm)
Lip competence
Nasal competence
Snoring and/or sleep apnea
1
3.5
1
Grade 0
Grade 2
no
2
4
0
Grade 1
Grade 0
no
3
3.2
3
Grade 0
Grade 0
no
4
2.9
2
Grade 0
Grade 2
no
5
3.5
1
Grade 1
Grade 3
yes
6
3
0
Grade 0
Grade 0
no
7
3.7
1
Grade 0
Grade 0
no
8
4.1
4
Grado 0
Grade 3
no
9
2.7
2
Grade 1
Grade 1
no
10
4.8
0
Grade 0
Grade 1
yes
11
4.3
-1
Grade 1
Grade 1
no
12
2.0
0
Grade 0
Grade 0
no
13
3
1
Grade 1
Grade 2
no
14
5.5
-1
Grade 1
Grade 1
no
15
3.3
-2
Grade 0
Grade 0
no
16
3.8
0
Grade 0
Grade 0
no
17
3.5
0
Grade 0
Grade 1
no
18
2.5
1
Grade 0
Grade 0
no
19
3.5
-1
Grade 0
Grade 1
no
20
2
1
Grade 0
Grade 1
yes
Table 4B. Values obtained at T2. Patient
Overjet (OVJ) (mm)
Discrepancy transversal (mm)
Lip competence
Nasal competence
Snoring and/or sleep apnea
1
5
7
Grade 2
Grade 3
yes
2
6
4
Grade 2
Grade 2
no
3
4.7
6
Grade 1
Grade 1
no
4
3.4
8
Grade 2
Grade 4
yes
5
3.7
7
Grade 1
Grade 4
yes
6
3
5
Grade 0
Grade 1
no
7
4.8
4
Grade 1
Grade 3
no
8
6
10
Grade 1
Grade 5
yes
9
4.1
9
Grade 1
Grade 2
no
10
5.3
6
Grade 2
Grade 3
yes
11
5.5
5
Grade 1
Grade 4
no
12
2.9
7
Grade 0
Grade 3
no
13
3
5
Grade 2
Grade 3
yes
14
6.4
6
Grade 2
Grade 2
no
15
4.4
5
Grade 0
Grade 2
no
16
5.1
6
Grade 1
Grade 1
yes
17
3.5
7
Grade 1
Grade 1
no
18
3.9
8
Grade 0
Grade 2
yes
19
4.5
4
Grade 1
Grade 3
no
20
5
5
Grade 1
Grade 4
yes
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A general conclusion that may be drawn from the results is that an early and interceptive treatment of functional alterations corrects bad habits, unphysiological growth directions and posture. In this way we can avoid drastic future choices such as dental extractions and orthodontic-surgical solutions to the end of growth, but, more generally, we can reduce systemic future problems. Based on the analysis of several clinical parameters and medical anamnesis (such as improvement of adenoid facies, lips and nose competence acquisition, reduction of overjet, correction of crossbite, improved palatal morphology, improvement in attention span and concentration, improvement in school performance, etc.), we can conclude that the use of the new multidisciplinary (orthopedic-orthodonticfunctional) protocol “early treatment” is effective in the resolution of oral breathing with stable and long-lasting results.
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assessment of the stomatognatic system. Int J Orofacial Myology. 2012;38:15-26. 11. Durán von Arx J. Mecánica fija “MFS”. Barcelona: Nexus Medica, 2004. 12. Lime M. Orthognathic and orthodontic consequences of mouth breathing. Acta Otorhinolaryngol Belg. 1993;47(2):145-55. 13. Linder-Aronson S. Adenoids. Their effect on mode of breathing and nasal airflow and their relationship to characteristics of the facial skeleton and the denition. A biometric, rhino-manometric and cephalometro-radiographic study on children with and without adenoids. Acta Otolaryngol Suppl. 1970;265:1-132. 14. Ricketts RM. Respiratory obstructions and their relation to tongue posture. Cleft Palate Bull. l958;8:3-6. 15. Subtelny JD. The significance of adenoid tissue in orthodontia. Angle Orthod. 24:59,1954. 16. Limme M. Orthodontic consequences of mouth breathing. Rev Belge Med Dent (1984). 1991;46(4):39-50. 17. Baldissera. Fisiologia e biofisica medica. Milan: Poletto Editore, 1996. 18. Kosky K. Variability of the craniofacial skeleton. Am J Orthod.
Declaration of interest
1973;64,188. 19. Lloyd Du Brul E. Anatomia orale di Sicher (ed. it. a cura di Miani A,
The Authors declare that there is no conflict of interest.
Ferrario VF). Milan: Edi.Ermes, 1982. 20. Lopatiene K, Babarskas A. Malocclusion and upper air way
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030101 doi: 10.7363/030101 Received: 2013 Sept 28; revised: 2013 Nov 03; accepted: 2013 Nov 07; advance publication: 2014 Jan 10
Case report
Novel chromosomal translocation t(7;14)(q36.3;q11.2)dn in a female child with dysmorphic features Jean-Pierre Antunes Gonçalves1,2, Liliana Pinheiro3, Maria João Magalhães1, Arnaldo Cerqueira1, Eduarda Abreu3, Albina Silva3, Carla Sá3, Almerinda Pereira3 1
Pediatric Department, Braga Hospital, Braga, Portugal
2
Community Health, School of Health Sciences, University of Minho, Portugal
3
Neonatology, Braga Hospital, Braga, Portugal
Abstract
When evaluating a newborn with peculiar phenotype it is mandatory to perform chromosomal studies. In this case report, the genetic study revealed a novel de novo translocation involving chromosome 7 and 14, thus establishing the following karyotype: as 45,XX,der (7)t(7;14) (q36.3;q11.2),-14dn.ish 7q36.3(VIJyRM2185 enh).mpla 7qsubtel(P036E1,P070-B2)x3,14q11.2(P036-E1,P070-B2)x1. Keywords
Phenotype, translocation, karyotype. Corresponding author Jean-Pierre Antunes Gonçalves; Hospital, Sete Fontes – S.Victor, 4710-243 Braga, Portugal; tel. +351253027000; fax +351253027999 (Hospital); email: pierre_3.14r@hotmail.com.
How to cite Gonçalves J-P, Pinheiro L, Magalhães M, Cerqueira A, Abreu E, Silva A, Sá C, Pereira A. Novel chromosomal translocation t(7;14)(q36.3;q11.2)dn in a female child with dysmorphic features. J Pediatr Neonat Individual Med. 2014;3(1):e030101. doi: 10.7363/030101.
Introduction
There are almost 1.550 genes on chromosome 7 [1] and 1.200 genes on chromosome 14 [2] that code for hundreds of different proteins with different functions. In most unbalanced translocation it is not possible to predict what phenotypes or abnormalities to expect and how severe the last may be. Besides the scarce information about translocation involving chromosomes 7 and 14, it has been described that deletions on chromosome 7 are associated with a range of phenotypes including craniofacial malformations
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(frontal prominent, craniosynostosis, microcephaly, malformed ears, changes in the eyes and eyelids), congenital heart problems, distal limbs and genitalia malformations and moderate to severe retardation of psychomotor development [3-5]. In this report the authors present a child with a de novo translocation involving chromosome 7 and 14:45,XX,der(7)t(7;14)(q36.3;q11.2),-14dn. Figure 1. Patient phenotype diagram showing a low implantation of ears, and hypertelorism.
Clinical report
The patient is a female newborn referred for evaluation of dysmorphic features and little spontaneous movement in the neonatal period. Prenatal ultrasound studies revealed a single umbilical artery. She was born at 38 weeks by caesarean delivery to a 35-year-old healthy gravida 2 para 2 mother. The family history is negative for birth defects, mental retardation, infant deaths or metabolic disorders. Pregnancy, labour and delivery were uncomplicated. Her weight, height and head circumference were adequate for gestational age. Apgar scores were 8 at 1 and 5 minutes and 10 at 10 minutes after birth. Shortly after birth she presented with transient tachypnea of the newborn and was admitted in neonatal intensive care unit. Physical examination showed low implantation of ears, hypertelorism (Fig. 1), short neck, mild axial hypotonia and little spontaneous movement. Blood and cerebrospinal fluid cultures, thyroid function, metabolic studies and transfontanelar and abdominal ultrasounds were normal. Echocardiography showed patent foramen ovale and a small apical muscular interventricular communication with left-to-right shunting (Fig. 2). Classical karyotyping using conventional high resolution GTG banding (where GTG is G-banding with trypsin-Giemsa) [6] was performed on metaphases obtained from PHA-stimulated lymphocytes from the patient and her parents, according to standard procedures. CTG-banded chromosomes (where CTG is C-banding with trypsin-Giemsa) obtained from the lymphocytes of the proband revealed 45,XX chromosomes with a translocation involving the long arms of chromosomes 7 and 14. There is only one normal chromosome 14. This chromosome analysis revealed the breakpoint at 7q36.3 and 14q11.2. The proband’s karyotype was designated 45,XX,der(7)t(7;14)(q36.3;q11.2),-14. To detect duplications and deletions a multiplexligation probe amplification (MLPA) analysis [7]
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A.
B.
Figure 2. Echocardiography showed patent foramen ovale (A) and interventricular communication (B).
was performed using a human subtelomeric probeset for all chromosomes. The SALSA – multiplex ligation-dependent probe amplification kits (P036 and P070) were developed and manufactured by MRC-Holland. The preparation and sequences of the probes have been described elsewhere [8]. Fluorescence in situ hybridisation (FISH) was performed to assist in identifying a possible subtelomeric duplication of chromosome 7 long
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arm. A subtelomeric probe of chromosome 7 was used (VIJyRM2185). A microdeletion in the long arm of chromosome 14 (band 14q11.2) and a subtelomeric tandem duplication of chromosome 7 (band 7q36.3) were detected in MLPA and FISH analyses, respectively. Therefore, the genetic studies revealed a de novo translocation involving chromosome 7 and 14: 45,XX,der (7)t(7;14)(q36.3;q11.2),-14dn.ish 7q36.3(VIJyRM2185 enh).mpla 7qsubtel(P036E1,P070-B2)x3,14q11.2(P036-E1,P070-B2)x1 (Fig. 3 and Fig. 4). Since the phenotypically normal parents showed normal karyotype, this abnormality was considered de novo. She was discharged for outpatient consultation at age of 13 days.
Figure 3. Partial karyotype of the proband, showing normal chromosomes 7 and 14 and der(7)t(7;14) after GTG banding GTG banding (where GTG is G-banding with trypsin-Giemsa).
Figure 4. Multiplex-ligation probe amplification (MLPA) results showing a 14q deletion and a 7q duplication.
Novel chromosomal translocation t(7;14)(q36.3;q11.2)dn
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Currently (4-month-old), she is feeding normally. Her weight is 5.830 g (25th centile), length is 64.5 cm (75th to 90th centiles) and head circumference is 43 cm (75th to 90th centiles). She is alert, visually tracks and has a social smile. She has normal head and trunk control and the neurologic examination is normal. Discussion
As far as we have investigated, this is the first report of a new cytogenetics imbalance: a tandem dup7q36.8 and a 14q11.2 microdeletion. Since the phenotypically normal parents showed normal karyotype, this abnormality is considered de novo. Here, we used multiplex ligation-dependant probe amplification combined with FISH and cytogenetic studies, which allows us to find this translocation. MLPA facilitates the amplification and detection of multiple targets with a single primer pair. In a standard multiplex PCR reaction, each fragment needs a unique amplifying primer pair. These primers being present in a large quantity result in various problems such as dimerization and false priming. With MLPA, amplification of probes can be achieved. Thus, many sequences (up to 40) can be amplified and quantified using just a single primer pair. MLPA reaction is fast, inexpensive and very simple to perform. Various techniques including DGGE (denaturing gradient gel electrophoresis), DHPLC (denaturing high performance liquid chromatography), and SSCA (single strand conformation analysis) effectively identify SNPs (single nucleotide polymorphisms) and small insertions and deletions. MLPA, however, is one of the accurate, timeefficient techniques to detect genomic deletions and insertions. MLPA can successfully and easily determine the relative copy number of all exons within a gene simultaneously with high sensitivity. Alternatively, array comparative genomic hybridization (aCGH) can be used in order to complement the cytogenetic findings, and define accurately the deletion breakpoints and the extent of the deletion. For technical and financial limitations we are not able to provide these analyses. Consequently, it is not possible to establish a precise genotype-phenotype correlation. This case report suggests that molecular cytogenetic techniques should be used to investigate unpublished translocations, especially when they seems to be associated with dysmorphic features, mild hypotonia in neonatal period and cardiac abnormalities.
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Genetic analysis in this case was of significant benefit to the patient’s family because it provided a possible explanation for the child’s problems. Knowledge about clinical anomalies associated with translocation involving chromosomes 7 and 14 are still scarce and so we hope this case report could represent an improvement to better characterize this genetic disorder.
2.
Heilig R, Eckenberg R, Petit JL, Fonknechten N, Da Silva C, Cattolico L, Levy M, Barbe V, de Berardinis V, Ureta-Vidal A, Pelletier E, Vico V, Anthouard V, Rowen L, Madan A, Qin S, Sun H, Du H, Pepin K, Artiguenave F, Robert C, Cruaud C, Brüls T, Jaillon O, Friedlander L, Samson G, Brottier P, Cure S, Ségurens B, Anière F, Samain S, Crespeau H, Abbasi N, Aiach N, Boscus D, Dickhoff R, Dors M, Dubois I, Friedman C, Gouyvenoux M, James R, Madan A, MaireyEstrada B, Mangenot S, Martins N, Ménard M, Oztas S,
Acknowledgements
Ratcliffe A, Shaffer T, Trask B, Vacherie B, Bellemere C,
We would like to thank N. Oliva-Teles, M.C. Ribeiro, M. Mota-Freitas
Briez-Silla S, Combette S, Dufossé-Laurent V, Ferron C,
for their assistance with the cytogenetics analyses.
Lechaplais C, Louesse C, Muselet D, Magdelenat G, Pateau
Belser C, Besnard-Gonnet M, Bartol-Mavel D, Boutard M,
E, Petit E, Sirvain-Trukniewicz P, Trybou A, Vega-Czarny N,
Declaration of interest
Bataille E, Bluet E, Bordelais I, Dubois M, Dumont C, Guérin
The Authors declare that they don’t have any financial interests or
Wunderle E, Gauguet G, Roy A, Sainte-Marthe L, Verdier J,
affiliations with institutions, organizations, or companies that are
Verdier-Discala C, Hillier L, Fulton L, McPherson J, Matsuda
mentioned in the manuscript or whose products or services are discussed.
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T, Haffray S, Hammadi R, Muanga J, Pellouin V, Robert D,
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Gonçalves • Pinheiro • Magalhães • Cerqueira • Abreu • Silva • Sá • Pereira
www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030114 doi: 10.7363/030114 Received: 2013 Dec 13; revised: 2014 Feb 02; accepted: 2014 Feb 03; advance publication: 2014 Feb 20
Case report
Floppy Infant Syndrome: new approach to the study of neonatal hypotonia through the analysis of a rare case of X-Linked Myotubular Myopathy Massimiliano De Vivo, Silvana Rojo, Roberto Rosso, Giovanni Chello, Paolo Giliberti Neonatal Intensive Care Unit, “V. Monaldi” Hospital (A.O. dei Colli), Naples, Italy
Abstract
The Floppy Infant Syndrome includes a variety of signs and symptoms: decrease in muscle tone (hypotonia), in muscle power (weakness) and ligamentous laxity and increased range of joint mobility. Strictly speaking, the term “floppy” should be used to describe a form of hypotonia. In our case the clinical and molecular study of a rare form (1:50.000) of X-Linked Myotubular Myopathy (X-Linked MM), with an early onset of peripheral hypotonia, led us to develop a general protocol for the differential diagnosis of neonatal hypotonia. Keywords
Floppy infant, weakness, neonatal hypotonia, myotubular myopathy, newborn onset, central and peripheral hypotonia. Corresponding author Massimiliano De Vivo, Neonatal Intensive Care Unit, “V. Monaldi” Hospital (A.O. dei Colli), Naples, Italy; email: drdevivo.m@tin.it.
How to cite De Vivo M, Rojo S, Rosso R, Chello G, Giliberti P. Floppy Infant Syndrome: new approach to the study of neonatal hypotonia through the analysis of a rare case of X-Linked Myotubular Myopathy. J Pediatr Neonat Individual Med. 2014;3(1):e030114. doi: 10.7363/030114.
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Introduction
The term “Floppy Infant” is used to describe a newborn with poor muscle tone and power (weakness) with increased joint mobility [1]. This clinical diagnosis has numerous etiologies and a specific diagnosis is not always easy to establish except in more common and widely recognized conditions, such as chromosomal disorders [2]. The underlying pathology of infantile hypotonia can be divided into four broad categories: the central nervous system, the peripheral nerves, the muscle and the neuromuscular junction [3, 4]. Based on clinical criteria hypotonia can be classified in two major groups: central hypotonia and peripheral hypotonia. Central origin accounts for about 66% to 88% of cases, with peripheral origins or unknown causes accounting for the balance. In addition several congenital disorders that are characterized by hypotonia have both central and peripheral symptoms, such as metabolic and genetic disorders [2]. A detailed family, pregnancy and birth history should be conducted first [5, 6]. Family history should include any other family member with hypotonia, muscle diseases or genetic disorders. Prenatal history should include the mother’s description of fetal movements, polyhydramnios or oligohydramnios, any maternal illness, maternal exposure to infectious agents and maternal drugs and alcohol use [7, 8]. Moreover perinatal history should include abnormal fetal presentation, Apgar scores, feeding difficulties, abnormal postures and seizures [5, 8]. The initial clinical approach to the hypotonic neonate is to determine if the problem is central or peripheral. This is of crucial importance when planning diagnostic investigations [9], that must include neurological assessment and an evaluation of weakness [9, 10]. In fact paralytic hypotonia with significant weakness and without cognitive delay suggests a peripheral neuromuscular problem, whereas non-paralytic hypotonia without significant weakness points can be attributed to a central cause which may be neurological, genetic or metabolic [9]. The prevalence of specific signs or symptoms can help to perform a differential diagnosis between central and peripheral hypotonia. The presence of mixed clinical features can help to orient towards a mixed and more complex hypotonia due to syndromic conditions [2]. We describe a newborn with a rapid and severe onset of peripheral hypotonia since the first hours of life, with a rare form of X-Linked Myotubular Myopathy (X-Linked MM), diagnosed via a diagnostic work-
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up oriented toward the early identification of clinical symptoms. This underlines the importance of a correctly conducted differential diagnosis, in order to allow a rapid clinical assessment, thus allowing better management of such infants. Case report
A 1-day old newborn, male sex, was admitted to our hospital for respiratory failure and hypotonia. He was born at term (37.4 weeks of gestational age) by elective cesarean delivery and he was adequate for gestational age (AGA, weight 2.850 kg). Apgar score was 7/8. Pregnancy history was normal. The mother, was 35-years-old, G2P0, had a first pregnancy that ended in a cesarean delivery at the 38th week of gestation for dystocic presentation. The maternal clinical phenotype was normal and familiar history was unremarkable. At the birth the neonate revealed an early onset of severe hypotonia with necessity of early intubation and mechanical ventilation. The clinical examination, at a few hours of life, detected the presence of marked hypotonia with an absence of active movements, severe respiratory failure, reducing glare and bilateral cryptorchidism. Laboratory evaluations were performed, including: markers of infections, blood culture, asphyxia indices (CK-MB, troponine), muscle enzymes (CK, LDH) and ammonia. All tests were negative and also the brain ultrasound, performed in the first day of life, was normal. The clinical picture and results of laboratory tests confirmed an early-onset form of peripheral neonatal hypotonia. Therefore, we started a differential diagnosis among the most frequents forms of neonatal hypotonia: Steinert’s syndrome, Prader-Willi’s syndrome and Spinal Muscle Atrophy type I (SMA I). Specifically, in our case, Steinert’s syndrome was excluded for the absence of familiarity, myotonia and other typical changes, such as cataract and hypothyroidism. Prader-Willi’s syndrome, initially evaluated for the presence of hypotonia and cryptorchidism, was later excluded for the absence of typical clinical signs (such as high prominent forehead, narrow bifrontal diameter, downturned corners of the mouth, micrognathia, dysplastic ears and small hands and feet) and for the presence of severe form of hypotonia with rapid appearance of respiratory failure. The SMA I was also excluded, being characterized by later onset of symptoms and by the absence of cryptorchidism. Conversely the combination of hypotonia, muscle weakness, male gender, bilateral cryptorchidism and severe respiratory failure was compatible with
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a form of Myotubular Myopathy (MM). Therefore, a muscle biopsy was performed, considering the extreme severity of the general conditions of the infant and the rapid progression of clinical symptoms. The muscle microscopic examination showed centronuclear myopathy with numerous central nuclei compatible with a form of MM. The negative family history and the severity of the clinical picture excluded the presence of an autosomal MM; therefore, a molecular analysis of the MTM1 gene was performed. MTM1 gene is located on chromosome Xq28 and is involved in the pathogenesis of X-Linked MM. The molecular analysis, performed by direct sequencing, confirmed the presence of the mutation c.85 C>T (p.R29X) on the exon 3 of the MTM1 gene in the mother and in the newborn (Fig. 1). Discussion
The X-Linked MM is a rare form of peripheral hypotonia (1:50.000), which affects only male infants, characterized by congenital hypotonia with weakness, severe respiratory failure at birth, difficulty in nutrition, specific dysmorphisms (ptosis eyelid, head and body elongated, slender hands and
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feet), cryptorchidism and other signs wich are less frequents and include anemia, hepatic cysts, cardiac problems and cognitive delay. The disease is caused by mutations of the myotubularin gene (MTM1), located on chromosome Xq28. The molecular analysis in affected patients and in female carriers confirms the presence of a mutation in the MTM1 gene. The prognosis is unfortunately unfavorable [11, 12]. The critical analysis of this case study allowed us to revise our constructive approach to differential diagnosis of neonatal hypotonia, through the development of a shared internal protocol for diagnosis and clinical management. The diagnostic protocol classifies neonatal hypotonia into three different forms (central, peripheral and mixed) according to the onset of the symptoms. These symptoms must be assessed by a careful maternal and familiar history and a proper neurological and clinical examination, such as the evaluation of the active and passive tone, the presence of sensory impairment, weakness, archaic and tendon reflex and stability of respiratory function. In fact, the peripheral forms are characterized by hypotonia in the presence of weakness, hypo- or areflexia, respiratory failure, crying faint and weak suck. Instead, the central forms are characterized by
Figure 1. Family tree. No family history of muscular disorders. In the newborn the muscle biopsy shows a centronuclear myopathy. The MTM1 gene mutation on Xq28 region (c.85C>T) is present in mother (Carrier Female) and newborn (Myotubular Myopathy).
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hypotonia with sensory impairment, seizures and hypo- or hyperreflexia; finally, in mixed forms there is an overlap of symptoms between peripheral and central forms. This initial clinical assessment helps to plan a specific diagnostic approach that allows a more rapid and less laborious diagnosis using targeted laboratory and instrumental examinations, either of first or second level. For diagnosing central hypotonia the first level (I level) examinations require the tests for the infections (blood culture, infection markers) and metabolic diseases (ammonia in the first) and the evaluation of cerebral function (EEG and/or aEEG); subsequently the second level (II level) analysis requires neuroimaging (Cerebral Ultrasonography, head CT and/or MRI). In peripheral forms the I level investigations are the muscle enzymes (CK, LDH) and the II level analysis includes the neuromuscular functionality tests (EMG, muscle biopsy), with molecular biology if indicated for confirmation. Lastly, in mixed forms, only a multidisciplinary approach (genetic, neurological, metabolic) may facilitate a rapid and direct diagnosis (Tab. 1). In conclusion, diagnosis of congenital hypotonia remains elusive in many cases, despite the advent of sophisticated laboratory and neuroimaging tests. However, our case highlights the importance of first clinical
approach for its crucial role in contribution of an early diagnosis and in differentiating disorders of central versus peripheral origin by performing a careful history of the infant, mother and family and conducing non-invasive clinical and developmental assessments. The primary objective of the diagnosis is to enable, where possible, an early identification of the problem to start an effective supportive therapy. A precise etiological diagnosis also allows formulating a more accurate prognosis. Last but not least, the identification of forms of neonatal hypotonia with familial transmission is crucial for the formulation of a genetic counseling for future pregnancies. Ideally, these assessment and diagnostic strategies are best accomplished by an interdisciplinary team of developmental specialists (pediatricians, obstetrics, medical geneticists and child neurologists). However, a linear protocol is an easy way to help the clinician to establish a rapid diagnosis and initiate an early treatment. Acknowledgments The Authors are grateful to Prof. Lucio Santoro (Department of Neurology, University Federico II, Naples) for muscle analysis and to Prof. Enrico Bertini (Department of Neuroscience and Neurorehabilitation, Bambino Gesù Hospital, Rome) for gene analysis.
Table 1. Protocol for differential diagnosis of Congenital Hypotonia. This protocol puts neonatal hypotonia into three different forms (central, peripheral and mixed) according to the onset of the symptoms, maternal and familiar history and neurological and clinical examination. The laboratoristic and instrumental investigations are established according to the initial orientation. Signs and symptoms
Type
I Level
II Level
Diagnosis
Hypotonia, weakness, hypo-areflexia, respiratory failure, crying faint, weak suck, maternal and familial history suggestive
Peripheral Hypotonia
Muscle enzyme (CK, LDH)
EMG, muscolar biopsy
If suggestive, search for mutations = Ereditary neuropathies (SMA I), congenital muscolar dystrophies (Steinert), congenital myopathies (myotubular, nemaline...)
Hypotonia, sensory impairment, seizures, hypo-hyperreflexia, personal and pregnancy history suggestive
Central Hypotonia
Screening for sepsis (blood culture, infection’s indices), ammonia, EEG and/or aEEG
Neuroimaging (cerebral ultrasonography, head CT and/or MRI)
= Congenital trauma, HIE, HIC, infections, brain malformations
Mixed symptoms
Mixed Hypotonia
Multidisciplinary approach (Geneticists, Neurologists, experts on metabolism)
Karyotype, molecular analysis, FISH
= Chromosomal rearrangements, trisomy: 13, 18, 21 = Subtelomeric deletions (+ tests of methylations) = Prader-Willi’s syndrome (+ dysmorphism, abnormal odors, multiorgan disorders: cataracts, hepatomegaly, etc.) = metabolic and storage diseases
CK: serum Creatine Kinase; LDH: Lactate Dehydrogenase; EMG: Electromyography; EEG: Electroencephalography; aEEG: amplitude-integrated Electroencephalography; CT: Computed Tomography; MRI: Magnetic Resonance Imaging; FISH: Fluorescence In Situ Hybridization; SMA: Spinal Muscolar Atrophy; HIE: Hypoxic Ischemic Encephalopathy; HIC: Intracranial Hemorrhage.
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Declaration of interest
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The Authors have no conflicts of interest to declare.
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030107 doi: 10.7363/030107 Received: 2013 Oct 27; revised: 2013 Dec 26; accepted: 2014 Jan 02; advance publication: 2014 Jan 16
Case report
A novel SRY nonsense mutation in a case of Swyer syndrome Clara Machado1, Angela Pereira1, José Matos Cruz2, Alexandra Cadilhe2, Albina Silva1, Almerinda Pereira1 1
Pediatrics Department, Braga Hospital, Portugal
2
Fetal Medicine Unit, Obstetrics Department, Braga Hospital, Portugal
Abstract
Swyer syndrome is a condition in which individuals with one X chromosome and one Y chromosome in each cell have a female appearance. They generally have female external genitalia, a normal uterus and Fallopian tubes, but no functional gonads. Its prevalence is about 1 in 30,000 births. Mutations in the SRY gene have been identified in 15-20% of the cases. The authors present the clinical case of a female fetus, who was the first child of young, healthy, unrelated parents, with increased nuchal translucency in first trimester ultrasonography and combined risk for Down syndrome of 1/20. Prenatal karyotype was 46,XY. Delivery occured at 37 weeks gestation by cesarean section. Uneventful neonatal period. At birth she had adequate weight and height and presented complete female external genitalia with no other abnormalities. Pelvic ultrasound showed normal morphology of the uterus, ovaries were not visualized. Hormonal study was normal. Repeated postnatal karyotype confirmed 46,XY. Follow-up on Neonatology Consultation as outpatient. Abdomino-pelvic MRI (3 months old) showed presence of uterus with normal dimensions and appearance and ovaries not clearly defined. The molecular genetic testing revealed the Q 114X (c.340 C>T) mutation of the SRY gene, a nonsense mutation that as not been described. Early diagnosis of Swyer syndrome in childhood is only possible if a karyotype is carried out for other reasons, such as for example as part of prenatal diagnosis (as it happened with our patient). This prompt diagnosis is important for early institution of hormone replacement therapy and close monitoring, because of the risk of gonadal malignancy. Clinical and imaging surveillance is mandatory in order to program early gonadectomy if necessary. In our patient, the novel mutation detected in the SRY gene may be an aetiopathogenic factor in clinically defined 46,XY complete gonadal dysgenesis. Keywords
Female, gonads, karyotype, mutation, syndrome, Swyer.
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Corresponding author Clara Machado, Pediatrics Department, Braga Hospital, Portugal; email: clara.machado@gmail.com.
How to cite Machado C, Pereira A, Matos Cruz J, Cadilhe A, Silva A, Pereira A. A novel SRY nonsense mutation in a case of Swyer syndrome. J Pediatr Neonat Individual Med. 2014;3(1):e030107. doi: 10.7363/030107.
Introduction
Swyer syndrome was first recognized in 1955 when Gim Swyer described two cases of sex reversal that differed from the known forms of what was then termed “male pseudohermaphroditism”. The two women had a 46,XY karyotype and had primary amenorrhoea, tall stature, female external genitalia (although one had an enlarged clitoris) and normal – albeit hypoestrogenised – vagina and cervix [1]. This condition was later linked to dysgenetic gonads and is also known as complete gonadal dysgenesis (CGD) [2]. 46,XY CGD is characterized by a 46,XY karyotype, normal female external genitalia, completely undeveloped (“streak”) gonads, no sperm production, hypergonadotropic hypogonadism (secondary to gonadal failure) and presence of normal Mullerian structures (uterus, fallopian tubes and vagina) [3]. These individuals are typically raised as females and have a female gender identity [4]. Swyer syndrome has been estimated to occur in approximately in 1 in 30,000 people [4]. The diagnosis relies on clinical findings, gonadal history, chromosome analysis, and testing to detect changes in one of the following genes: SRY, NR5A1, DHH, NR0B1 or WNT4 [3]. Mutations in the SRY gene have been identified in between 15-20% of individuals with this condition. These mutations prevent production of the sex-determining region Y protein or result in the production of a nonfunctioning protein. A fetus whose cells do not produce functional sex-determining region Y protein will develop as a female, despite having a Y chromosome. In the remaining 80-90% of cases, the SRY gene is normal and mutations in other genes are probably implicated [4]. Swyer syndrome can be inherited in an autosomal dominant (NR5A1 mutations, heterozygous mutations in DHH, WNT4
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duplications), autosomal recessive (homozygous [or compound heterozygous] mutations in DHH), X-linked (NR0B1 duplications) or Y-linked (SRY mutations) manner depending on the gene involved [3]. Most cases of SRY-related Swyer syndrome result from new mutations and occur in people with no history of the disorder in their family. The condition usually first becomes apparent in adolescence with delayed puberty and primary amenorrhoea due to the fact that the gonads have no hormonal or reproductive potential [2]. Affected individuals usually begin hormone replacement therapy during adolescence to induce menstruation and development of female secondary sex characteristics such as breast enlargement and body hair. This therapy also helps prevent reduced bone density (osteopenia). Women with this disorder do not produce eggs, but may be able to become pregnant with a donated egg or embryo [4]. A high incidence of gonadoblastoma and germ cell malignancies has been reported, and therefore, the current practice is to proceed to a gonadectomy once the diagnosis is made [2]. If the patient is not able to undergo surgery of if she refuses it, a careful follow up is necessary. If gonads are removed early in life to prevent gonadal tumors, life span is not reduced. The cumulative risk of developing gonadoblastoma is 30% by age 40 years [3]. Presentation of the case
The authors describe the case of a healthy 33-years old pregnant (first pregnancy) with increased nuchal translucency in first trimester ultrasonography and combined risk for Down syndrome of 1/20. For this reason amniocentesis was performed and fetal karyotype was 46,XY. In the second trimester ultrasonography, nuchal fold was increased and normal female genitalia were found, despite fetal karyotype. Fetal echocardiogram was normal. The pregnancy was uneventful, and the delivery occurred at 37 weeks gestation by cesarean section, due to breech presentation of the fetus. Apgar scored 1’:10/5’:10. At birth, the newborn had adequate weight and length (weight: 2,930 g, length: 47 cm, head circumference: 35 cm), and presented complete female external genitalia with no other abnormalities or dismorphic characteristics (Fig. 1). Her parents were young, healthy and unrelated and there are no cases of genetic syndromes in the family.
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Pelvic ultrasound showed normal morphology of the uterus but ovaries were not visualized (Fig. 2). The karyotype performed postnatally confirmed 46,XY. Hormonal study in the neonatal period was normal. Neonatal period was uneventful. Pelvic magnetic resonance imaging (MRI) was made at 3 months of life and revealed the presence of uterus with normal dimensions and appearance, but ovaries not clearly defined (Fig. 3).
Figure 1. Complete female external genitalia at birth.
Figure 2. Pelvic ultrasound.
Figure 3. Abdomino-pelvic MRI (3 months old).
Swyer syndrome and a novel SRY nonsense mutation
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The molecular genetic testing was accomplished, with sequencing of the gene coding of the SRY gene, and revealed the Q 114X (c.340 C>T) mutation of the SRY gene, a nonsense mutation that as not been described. She maintains follow-up on Neonatology and Pediatric Endocrinology consultation. Discussion
In utero, sexual differentiation follows a sequential pattern. After fertilization there is establishment of the genotype of the embryo and under the influence of the single gene determinant (testes determining factor) on the short arm of the Y chromosome, there is differentiation of the primordial gonads into the testes. The ovaries develop by default, in the absence or nonfunctioning of the Y chromosome. This differentiation of the primordial gonads into the testes or ovary will lead to an alteration of the hormonal milieu of the fetus, which in turn results in the corresponding differentiation of the internal and external genitalia [5]. In complete gonadal dysgenesis patients, immature bi-potential gonads fail to differentiate along the male pathway, during early embryonic development [7]. Pivotal to this process is the SRY gene. Most SRY mutations are de novo events affecting one family member, and 11 familial mutations have been described [13]. All lies in the DNA-binding high-mobility group (HMG) box. Six of the changes are missense mutations, three are nonsense mutations and two deletions causing frameshifts [8]. Our patient presented a SRY mutation consisting in the variant Q 114X (c.340 C>T) which we report for the first time in the literature. Affected individuals are raised as females and usually are not diagnosed until puberty, when primary amenorrhea is evident because of the lack of estrogen and progesterone production by the streak gonads [3]. Early diagnosis of Swyer syndrome in childhood is only possible if a karyotype is carried out for other reasons, such as for example as part of prenatal or as part of family screening following the diagnosis of a sibling with the condition [2]. In the presented case, the results of nuchal translucency and fetal ultrasound induced to perform amniocentesis as a further examination which led to the diagnosis. The prompt diagnosis has a crucial importance for several reasons like the early institution of hormone replacement therapy (for induction of
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puberty, fertility and prevention of osteopenia) and close monitoring, because of the risk of gonadal malignancy [6], as the overall survival rate is 90100% in cases diagnosed in the early stages but decreases to 54% in those diagnosed in the advanced stages [9]. The major risk is the development of gonadoblastoma which can be avoided with early diagnosis and surgical removal of streak gonads [3]. In this patient ovaries were not visualized in pelvic MRI and so we were not able to confirm the presence of streak gonads. Therefore clinical and imaging surveillance is mandatory in order to program early gonadectomy. In conclusion, early diagnosis of Swyer syndrome is crucial in view of the high risk of malignancies that can develop at an early age. Although increased awareness has probably improved the management of these women, it is important that they continue to be followed up in tertiary centers by multidisciplinary teams. In fact, they are able to provide the multifaceted care that is required in terms of induction of puberty, prevention of osteopenia and fertility. It is also important for these centers to form larger databases to acquire a better understanding of the condition and improve their management.
2.
Michala L, Goswami D, Creighton S, Conway G. Swyer syndrome: presentation and outcomes. BJOG. 2008;115:737-41.
3.
Ostrer H. 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K (Eds.). GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.
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books/NBK1547/; initial posting: May 2008; last revision: September 2009. 4.
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Panicker R, Srinivas S. Swyer’s Syndrome: An Uncommon Cause of Primary Amenorrhoea. MJAFI. 2009;65:186-7.
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Temime RB, Chechia A, Attia L, Ghodbane I, Boudaya F, Makhlouf T, Koubaa A. Syndrome de Swyer : à propos de cinq cas. J Gynecol Obstet Biol Reprod (Paris). 2009;38:220-5.
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Battaglia F, Plotti F, Angelucci M, Aloisi A, Angioli R. Novel mutation of the sex-determining region on the Y chromosome in a 46,XY female patient with monolateral dysgerminoma: A case report. J Obstet Gynaecol Res. 2013;39(1):442-5.
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Ross Hawkins J. Mutational analysis of SRY in females. Hum Mutat. 1993;2:347-50.
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Ayhan A, Bildirici I, Günalp S, Yuce Kl. Pure dysgerminoma of the ovary: A review of 45 well staged cases. Eur J Gynaecol Oncol. 2000;21:98-101.
10. Behtash N, Karimi Z M. Dysgerminoma in three patients with Swyer syndrome. World J Surg Oncol. 2007;5:71-2. 11. Hughes IA, Houk C, Ahmed SF, Lee PA; LWPE/ESPE
Declaration of interest The Authors declare that there is no conflict of interest.
Consensus Group. Consensus statement on management of intersex disorders. Arch Dis Child. 2006;91:554-63. 12. Biason-Lauber A, Konrad D, Meyer M, deBeaufort C. Ovaries and Female Phenotype in a Girl with 46,XY Karyotype and
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Mutations in the CBX2 Gene. Am J Hum Genet. 2009;84:658-63. 13. Ságodi L, Ladányi E, Kiss Á, Tar A, Lukács V, Minik K, Vámosi
Swyer GI. Male pseudohermaphroditism: a hitherto undescribed
I. [Pure 46,XY gonadal dysgenesis]. [Article in Hungarian]. Orv
form. Br Med J. 1955;2:709-12.
Hetil. 2010;151(48):1991-5.
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Question
Polypoid lesion of nasal skin in a child: question Clara Gerosa1, Daniela Fanni1, Luca Pilloni1, Filippo Carta2, Roberto Puxeddu2, Gavino Faa1 1
Division of Pathology, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
2
Department of Otorhinolaryngology, University of Cagliari, Cagliari, Italy
Keywords
Quiz, skin, polyp, nose, child, newborn. Corresponding author Clara Gerosa, Division of Pathology, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy; email: clarge@tiscali.it.
How to cite Gerosa C, Fanni D, Pilloni L, Carta F, Puxeddu R, Faa G. Polypoid lesion of nasal skin in a child: question. J Pediatr Neonat Individual Med. 2014;3(1):e030118. doi: 10.7363/030118.
Case summary
A 2-year-old male presented with a congenital polypoid mass on the nasal skin; no recent growth. The infant was born at term without other congenital anomalies. There was no family history of similar skin lesions. The polypoid lesion was surgically removed. At macroscopy, the polyp sample measured 6x3x3 mm, it was elastic and skin covered. At the microscopic examination, the sections showed a lesion covered by a normal epidermis; dermis was composed of skeletal muscle fibers, mature adipose tissue and fibrous connettive fibres (Fig. 1A); the skeletal muscle fibers were aligned perpendicular to the surface epithelium (Fig. 1B).
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Questions
1. What is your morphological diagnosis? 2. Which complementary investigation do you suggest? 3. Which is your differential diagnosis? Declaration of interest The Authors declare that there is no conflict of interest.
Figure 1A. Skeletal muscle fibers, mature adipose tissue and fibrous connettive fibres in the dermis.
Figure 1B. The skeletal muscle fibers were aligned perpendicular to the surface epithelium.
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Answer
Rhabdomyomatous mesenchymal hamartoma presenting as a polypoid lesion of the nasal skin in a child: answer Clara Gerosa1, Daniela Fanni1, Luca Pilloni1, Filippo Carta2, Roberto Puxeddu2, Gavino Faa1 1
Division of Pathology, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
2
Department of Otorhinolaryngology, University of Cagliari, Cagliari, Italy
Keywords
Hamartoma, skin, nose, genetic defects, striated muscle fibers. Corresponding author Clara Gerosa, Division of Pathology, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy; email: clarge@tiscali.it.
How to cite Gerosa C, Fanni D, Pilloni L, Carta F, Puxeddu R, Faa G. Rhabdomyomatous mesenchymal hamartoma presenting as a polypoid lesion of the nasal skin in a child: answer. J Pediatr Neonat Individual Med. 2014;3(1):e030119. doi: 10.7363/030119.
Answers
1. The histological picture is characterized by the presence of skeletal muscle fibers and adipose tissue are suggestive for hamartoma. 2. Actin muscle specific immunohistochemical stain, to confirm the presence of skeletal muscle fibers. 3. Differential diagnosis with rhabdomyoma.
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Introduction
Rhabdomyomatous mesenchymal hamartoma (RMH) is a rare congenital lesion of the dermis and soft tissue [1], first described in 1986 as a striated muscle hamartoma [2]. It has been reported under various names: striated muscle hamartoma, congenital midline hamartoma, hamartoma of cutaneous adnexa and mesenchyme [3]. Etiology of this lesion is unknown; it has been hypothesized that be due to an abnormal migration of mesodermal stem cells during embryiogenesis or to right genetic defects [3, 4]. Patients with RMH occasionally have other congenital defects [5]. RMH usually presents as a polypoid or papular cutaneous lesion that ranges in size from a few millimeters to 1-2 cm and occurs in areas where there is a superficial striated muscle, as the nose, chin, periorbital and anterior neck areas [6]. Here we report a case of RMH in a 2-year-old child presenting with a congenital polypoid mass on the nasal skin.
hamartoma of infancy, neuromuscular choristoma and cutaneous embryonal rhabdomyosarcoma [13] Complete excision is curative [13].
Pathological findings
Declaration of interest
Histologically the lesion was covered by a normal squamous epithelium. Mature striated muscle fibers was found within the dermis extending into the subcutaneous tissue. The fibers were admixed with fibrous connettive tissue, mature adipose tissue, adnexal structures. The striated fibers arranged perpendicular to the surface of the skin. There was no evidence of malignity [7-9].
The Authors declare that there is no conflict of interest.
Figure 1. Actin muscle specific himmunoistochemical showed striated muscle fibers aligned perpendicular to the surface epithelium, surrounded by connective tissue and adipose tissue.
References 1.
Uribe MA, Uribe CJ. [Rhabdomyomatous mesenchymal hamartoma]. [Article in Spanish]. Actas Dermosifiliogr. 2008;99(6):474-6. 2.
1986;3:153-7. 3.
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Hendrick SJ, Sanchez RL, Blackwell SJ, Raimer SS. Striated muscle hamartoma: description of two cases. Pediatr Dermatol.
Discussion
RMH is a rare benign lesion of the deep dermis and subcutaneous fat in the region of the head and neck [1, 10, 11]. The etiology of this condition is unknown. Cases of RMH have been reported to be associated with other genetic defect such as amniotic band syndrome, Delleman syndrome and the Goldenhar syndrome [4, 10, 12]. Distinctive characteristics of these lesions are striated muscle fibers aligned perpendicular to the surface epithelium, surrounded by connective tissue and adipose tissue. Actin muscle specific immunohistochemical stain must be performed to confirm the presence of fiber skeletal muscle (Fig. 1) [13]. The differential diagnosis includes rhabdomyoma, nevus lipomatosis superficialis, fibrous
Díaz-Pérez JA, García-Ramírez CA, García-Vera JA, Melo-
Rosenberg AS, Kirk J, Morgan MB. Rhabdomyomatous mesenchymal hamartoma: un unusual dermal entity with a report of two cases and rewiew of the literature. J Cutan Pathol. 2002;29:238-43.
4.
Weedon D, Williamson RM, Patterson JW. Smooth and skeletal muscle tumours. In: Chapter 5 – Soft Tissue Tumours. In: LeBoit PE, Burg G, Weedon D, Sarasin A (Eds.). World Health Organization Classification of Tumours. Pathology and Genetics of Skin Tumors. Lyon: IARC Press, 2006, pp. 252-3.
5.
Hayes M, van der Westhuizen N. Congenital rhabdomyomatous mesenchymal hamartoma. Am J Dermatopathol. 1992;14:64-5.
6.
Solis-Coria A, Vargas-González R, Sotelo-Avila C. Rabdomyomatous mesenchymal hamartoma presenting as a skin tag in the sternoclavicular area. Pathol Oncol Res. 2007;13(4): 375-8.
7.
Ashfaq R, Timmons CF. Rhabdomyomatous mesenchymal hamartoma of skin. Pedriatr Pathol. 1992;12(5):731-5.
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8. 9.
White
G.
Congenital
rhabdomyomatous
mesenchymal
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11. Ortak T, Orbay H, Unlu E, Uysal C, Uraloglu M, Sensoz OM.
hamartoma.Am J Dermatopathol. 1990;12(5):539-40.
Rhabdomyomatous mesenchymal hamartoma. J Craniofac
Katsumata M, Keong CH, Satoh H. Rhabdomyomatous
Surg. 2005;16:1135-7.
mesenchymal hamartoma of skin. J Dermatol. 1990;17(6): 384-7.
12. Farris
P,
Manning
S,
Wuitch
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Rhabdomyomatous
mesenchymal hamartoma. Am J Dermatol. 1994;16:73-5.
10. Weil Lara B, Sanz Trellez A, Leon Fradejas M, Prieto Ramirez
13. Weiss SW, Goldblum JR. Chapter 20 – Rhabdomyoma. In:
E, Gomez Valcarcel JJ, Martinez de la Torre V. Hamartoma
Weiss SW, Goldblum JR. Enzinger and Weiss’s Soft Tissue
mesenquimal rabdomiomatoso. Rev Esp Patol. 2004;37:
tumors. Fifth edition. Maryland Heights, MO: Mosby Elsevier,
429-32.
2008, pp. 591-2.
Rhabdomyomatous mesenchymal hamartoma: answer
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030102 doi: 10.7363/030102 Received: 2013 Aug 08; revised: 2013 Sept 16; accepted: 2013 Sept 16; advance publication: 2014 Jan 10
Review
Uso dell’ossigeno nella rianimazione del neonato Roberto Antonucci1, Annalisa Porcella1, Luca Antonucci2 Unità Operativa Complessa di Nido, Neonatologia e Pediatria, Ospedale “Nostra Signora di Bonaria”, San
1
Gavino Monreale Università di Cagliari
2
Proceedings Articoli Selezionati del “3° Convegno Pediatrico del Medio Campidano” · Guspini · 25 Maggio 2013 Guest Editor: Roberto Antonucci
Abstract
Immediately after birth, the newly born infant undergoes physiological changes including lung aeration, decrease of pulmonary vascular resistance and initiation of pulmonary gas exchange. Under particular circumstances, this transition process is not adequately accomplished, thus resulting in perinatal asphyxia. In the past decade, remarkable changes have occurred in attitudes towards the use of oxygen in the delivery room. Although oxygen is a lifesaving therapy in neonatal resuscitation, high oxygen concentrations may be harmful to term infants, and especially to preterm infants. In fact, the use of high concentrations of oxygen in the first minutes after birth can lead to an excessive release of free oxygen radicals and to subsequent oxidative stress, with potential damage to multiple organs including the brain, lungs, eyes, and gastrointestinal tract. In 2010, the American Heart Association published revised guidelines for neonatal resuscitation including the recommendations on the measurement and monitoring of oxygenation status and on oxygen supplementation in the delivery room. Some key points of these recommendations are the following: (1) the clinical assessment of skin color is a poor indicator of oxygenation immediately after birth; (2) pulse oximetry provides rapid, continuous and accurate measurement of both oxygenation and heart rate during delivery room resuscitation; (3) the provision of blended oxygen during neonatal resuscitation should be aimed at maintaining oxygen saturations similar to those of uncompromised babies born at term. This paper reviews the available evidence on the management of supplemental oxygen during neonatal resuscitation at birth, and also highlights knowledge gaps. Keywords
Oxygen supplementation, neonatal resuscitation, delivery room, newborn.
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Corresponding author
Ossigeno e radicali liberi in età neonatale
Roberto Antonucci, MD, Chief, Division of Neonatology and Pediatrics,
Pur essendo un elemento fondamentale per la vita degli organismi eucarioti, l’ossigeno può svolgere paradossalmente effetti tossici derivanti dalla sua capacità di generare radicali liberi. Questi ultimi sono molecole instabili e altamente reattive a causa della presenza di elettroni spaiati sull’orbitale esterno. Tali molecole si generano normalmente in qualsiasi cellula vivente, essendo coinvolte nelle reazioni di ossidoriduzione utili alla sua sopravvivenza, ma assumono il ruolo di importanti mediatori di danno cellulare e tissutale quando prodotte in quantità eccessive. I radicali liberi dell’ossigeno esplicano anche un’azione protettiva sull’organismo, essendo prodotti dai fagociti attivati durante i processi di killing (batterico) ossidativo [5], e svolgono un ruolo nella regolazione di letti vascolari come il circolo polmonare ed il dotto arterioso [6]. I radicali liberi dell’ossigeno, insieme ad alcuni agenti ossidanti che vengono facilmente trasformati in radicali, vengono indicati con il termine collettivo di reactive oxygen species (ROS) [7]. Gli organismi aerobi hanno sviluppato, nel corso dell’evoluzione, efficienti sistemi antiossidanti per rimuovere i radicali liberi. Tali sistemi di difesa sono costituiti da enzimi antiossidanti, quali la superossido dismutasi, la catalasi e la glutatione perossidasi, nonché da composti antiossidanti a basso peso molecolare, quali il glutatione, il beta carotene e le vitamine A, E e C. Lo squilibrio tra fattori pro-ossidanti e quelli antiossidanti può portare ad un accumulo di ROS ed al cosiddetto stress ossidativo, con potenziale danno cellulare e tissutale [7]. Infatti, le condizioni in cui si realizza un danno dell’apparato mitocondriale (ad esempio iperossia, ischemia/riperfusione), così come qualunque condizione che riduca la difesa antiossidante (ad esempio la prematurità), possono causare un accumulo di ROS. Questi ultimi determineranno poi un danno cellulare attraverso l’ossidazione di lipidi, proteine e polisaccaridi, nonché un danno diretto a carico del DNA (Tab. 1). Tali effetti dannosi possono esitare nella morte cellulare sia per apoptosi che per necrosi [8, 9]. Il neonato risulta particolarmente vulnerabile al danno ossidativo, sia a causa della maggiore produzione postnatale di ROS, che per l’incapacità dei sistemi di difesa di limitare le reazioni indotte dagli stessi ROS. Inoltre, l’encefalo del neonato contiene una più alta concentrazione di ferro libero nonché di acidi grassi polinsaturi, localizzati
“Nostra Signora di Bonaria” Hospital, San Gavino Monreale, Italy; e-mail: roant@tiscali.it.
How to cite •
Antonucci R, Porcella A, Antonucci L. Uso dell’ossigeno nella rianimazione del neonato. J Pediatr Neonat Individual Med. 2014;3(1):e030102. doi: 10.7363/030102.
•
Antonucci R, Porcella A, Antonucci L. [Use of oxygen during neonatal resuscitation]. [Article in Italian]. J Pediatr Neonat Individual Med. 2014;3(1):e030102. doi: 10.7363/030102.
Introduzione
Alla nascita, il neonato va incontro ad una complessa serie di modificazioni fisiologiche che sono alla base del processo di transizione dalla vita intrauterina a quella extrauterina. I dati della letteratura indicano che circa il 10% dei neonati richiede assistenza alla nascita per iniziare a respirare, mentre meno dell’1% dei neonati necessita di misure di rianimazione intensiva [1]. La condizione che più frequentemente richiede la rianimazione del neonato alla nascita è rappresentata dall’asfissia. Su 130 milioni di nati/anno nel mondo, circa 4-5 milioni presentano asfissia alla nascita, la quale è anche una delle cause più frequenti di morte neonatale. Approssimativamente un quarto dei nati asfittici va incontro a decesso, mentre un quarto esita in sequele neurologiche quali paralisi cerebrale, ritardo mentale ed epilessia [2, 3]. La rianimazione del neonato alla nascita ha quindi il duplice scopo di prevenire la morte e di ridurre le sequele neurologiche a lungo termine associate all’asfissia. La rianimazione neonatale con l’impiego di ossigeno, attuata per la prima volta nel 1777 da François Chaussier [4], è stata tradizionalmente praticata utilizzando ossigeno allo stato puro. Tale pratica terapeutica non si fondava su alcuna base scientifica ma, semplicemente, sull’assunto che la concentrazione di ossigeno del 100% fosse quella ottimale per rianimare un neonato. In seguito al riconoscimento dei rischi connessi allo stato di iperossiemia, è stata avviata una serie di studi, sperimentali e clinici, diretti a valutare quali fossero le modalità più adeguate per la somministrazione di ossigeno nella rianimazione del neonato, in termini sia di efficacia che di sicurezza.
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Tabella 1. Meccanismi di danno cellulare dei ROS. 1. Perossidazione lipidica • Membrana cellulare: perdita dell’equilibrio osmotico con ingresso di liquidi e ioni e fuoriuscita di metaboliti fondamentali per la ricostituzione dell’ATP • Membrana dei mitocondri: incapacità di produrre ATP e liberazione di proteine proapoptotiche • Membrana dei lisosomi: liberazione di enzimi lisosomiali che innescano l’autodigestione della cellula 2. Ossidazione delle proteine • Ossidazione delle catene laterali con formazione di legami crociati (ponti disolfuro) • Ossidazione della catena proteica Conseguenze: modificazione del sito attivo (enzimi); modificazione della conformazione (proteine strutturali) 3. Danno del DNA • Rottura di un singolo filamento • Rottura del doppio filamento • Formazione di legami crociati e conseguente costituzione di “addotti”
specialmente nelle membrane cellulari, e ciò lo espone maggiormente all’azione dannosa dei ROS che hanno come target proprio tali sostanze [7]. Il neonato pretermine è più vulnerabile del neonato a termine sotto tale profilo, a causa dell’immaturità dei suoi sistemi antiossidanti, i quali maturano fisiologicamente con l’avanzare della gravidanza. La somministrazione di steroidi prenatali incrementa l’attività degli enzimi antiossidanti, ma non sembra in grado di neutralizzare completamente lo stress ossidativo, in particolar modo nel nato prematuro [10, 11]. Inoltre, la formazione di ROS derivante dalla rianimazione con alte concentrazioni di ossigeno può superare la capacità dei naturali sistemi antiossidanti (quali la superossido dismutasi, la catalasi e la glutatione perossidasi), di per sé ridotta nel nato pretermine. Questo squilibrio tra sostanze ossidanti e antiossidanti gioca un ruolo importante nello sviluppo di alcune condizioni morbose tipiche della prematurità, quali la retinopatia del prematuro, la displasia broncopolmonare e l’enterocolite necrotizzante [12, 13]. Inoltre, nei neonati pretermine, l’iperossia può causare una riduzione del flusso ematico cerebrale, con conseguente danno ischemico [14]. Ipossia ed iperossia nel neonato
Il neonato che necessita di rianimazione alla nascita presenta quasi sempre un certo grado di ipossia. Negli anni più recenti, è stato dimostrato che la valutazione clinica del colorito cutaneo è un
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indicatore impreciso e scarsamente accurato dello stato di ossigenazione nell’immediato periodo postnatale. Lo studio di O’Donnell et al. [15] documentò che i Clinici avevano spesso giudizi discordanti circa il fatto che un neonato presentasse un colorito roseo o meno. Fu evidenziato inoltre che, nei casi in cui i Clinici dichiaravano che i neonati erano rosei, i valori di SpO2 misurati col pulsossimetro potevano variare tra il 10% ed il 100% [15]. D’altro canto, l’assenza di cianosi si è dimostrata un indicatore assai scadente dello stato di ossigenazione di un neonato [1]. Alla luce di tali riscontri, il colorito cutaneo non viene più considerato un indicatore affidabile di ossigenazione o di efficacia della rianimazione [16]. D’altro canto, si è rivelato particolarmente utile, anche nelle fasi iniziali della rianimazione neonatale, l’impiego del pulsossimetro, di cui esistono varie tipologie con caratteristiche differenti [17]. I pulsossimetri di nuova generazione sono in grado di rilevare in modo continuo, tramite apposite sonde neonatali, valori affidabili di saturazione di ossigeno e di frequenza cardiaca già 1-2 minuti dopo la nascita. Tali apparecchiature sono attualmente considerate lo strumento ottimale per il monitoraggio della saturazione di ossigeno in sala parto [4], e ne viene raccomandato l’uso in caso di cianosi persistente, di somministrazione di ossigeno supplementare, o di ventilazione a pressione positiva da prolungare per più di qualche atto ventilatorio [1]. Durante la rianimazione del neonato, viene raccomandato specificamente il monitoraggio della SpO2 preduttale, per cui la sonda del pulsossimetro deve essere posizionata a livello del polso destro o del palmo della mano destra. Inoltre, al fine di ottenere una più rapida acquisizione del segnale, è utile collegare la sonda prima al paziente e successivamente al pulsossimetro [1]. Nel neonato “fisiologico”, i valori di ossigenazione considerati normali nella vita postnatale non vengono raggiunti prima di circa 10 minuti dalla nascita. I valori di saturazione di ossigeno possono mantenersi normalmente tra il 70 e l’80% per alcuni minuti dopo la nascita, causando una cianosi apparente durante tale periodo di tempo [1]. Mariani et al. [18] hanno recentemente dimostrato che i neonati sani a termine nati al livello del mare presentano una saturazione di ossigeno del 60% circa durante il parto, e che essa raggiunge e supera il 90% a circa 10 minuti di vita. Altri studi hanno evidenziato che i nati da taglio cesareo presentano valori di saturazione più bassi rispetto a quelli riscontrati nei nati da parto vaginale [19], e che i neonati prematuri
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Journal of Pediatric and Neonatal Individualized Medicine • vol. 3 • n. 1 • 2014
impiegano più tempo per raggiungere valori di saturazione superiori al 90% [20]. Se è vero che l’ipossia non trattata può determinare un danno multiorgano, sono sempre maggiori le evidenze che indicano come l’esposizione, anche per brevi periodi, ad un eccesso di ossigeno durante e dopo la rianimazione può esitare in esiti avversi. Pertanto, la somministrazione di ossigeno deve porsi il duplice obiettivo di evitare l’ipossia da un lato e l’iperossia dall’altro, specie nei nati prematuri che sono maggiormente suscettibili agli effetti tossici dell’ossigeno. Tuttavia, allo stato attuale delle conoscenze, non è stato identificato ancora un valore di SpO2 al di sotto del quale la somministrazione di ossigeno abbia più vantaggi che svantaggi, né è noto un valore di SpO2 massimo che possa essere considerato sicuro e non dannoso [4]. Le linee guida emanate nel 2010 dall’American Heart Association (AHA) indicano dei ranges “target” di saturazione di ossigeno pre-duttale riferiti ai primi 10 minuti di vita, da utilizzare durante la rianimazione del neonato a prescindere dalla sua età gestazionale [1]. Come segnalato da Saugstad et al. [21], numerosi dati clinici dimostrano che la rianimazione del neonato con ossigeno al 100%, piuttosto che con aria ambiente, è gravata da un aumentato stress ossidativo a 4 settimane di vita, da un aumentato danno miocardico e renale, da un Apgar score e da una frequenza cardiaca più bassi a 5 minuti di vita, da un ritardo nel primo respiro, e dalla necessità di una rianimazione più prolungata [21]. L’iperossia si è dimostrata responsabile, inoltre, della riduzione del flusso ematico cerebrale nei nati a termine e pretermine. L’ossigeno gioca peraltro un ruolo fondamentale nella transizione dalla circolazione fetale a quella post-natale, riducendo le resistenze vascolari polmonari. Studi condotti sull’animale asfittico documentarono ecograficamente che gli animali rianimati con aria presentavano una normalizzazione della (elevata) pressione vascolare polmonare che era sovrapponibile a quella degli animali trattati con ossigeno al 100% [22, 23]. Lakshminrusimha et al. [24] dimostrarono che anche una breve esposizione all’ossigeno al 100% era sufficiente per incrementare in modo significativo, a livello delle arterie polmonari di quinta generazione, la contrazione indotta da agenti vasocostrittori quali norepinefrina e KCl, mentre la rianimazione con aria non influenzava tale contrattilità. Su una popolazione di neonati a termine con grave asfissia, rianimati con aria versus ossigeno puro, Vento et al. [25] studiarono prospetticamente il danno cardiaco e renale causato dalla riossigenazione. Nei neonati
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rianimati con ossigeno al 100%, rispetto a quelli rianimati in aria ambiente, fu documentato un aumento della troponina plasmatica e dell’ N-acetilglucosaminidasi urinaria, indici di danno a carico delle cellule del miocardio e del tubulo prossimale renale, rispettivamente. Fu rilevata inoltre una concentrazione di glutatione ossidato minore nei neonati rianimati in aria ambiente rispetto a quella riscontrata nei neonati rianimati con ossigeno al 100%, ad indicare un minore stress ossidativo nel primo gruppo di neonati. Le conclusioni dello studio furono che l’uso di aria ambiente nella rianimazione del neonato con asfissia grave, se confrontato con l’uso di ossigeno al 100%, è altrettanto efficace e riduce il danno acuto che si determina a carico del miocardio e del rene durante le fasi di ischemia e riperfusione [25]. Uso dell’ossigeno nella rianimazione neonato alla nascita: evidenze cliniche
del
Sin dagli anni ’60, uno studio sperimentale aveva dimostrato che, in conigli neonati rianimati con aria ambiente, l’outcome era sovrapponibile a quello osservato in conigli neonati rianimati con ossigeno al 100% [26]. Alla fine degli anni ’90, Saugstad et al. [27] condussero uno studio multicentrico su neonati di peso superiore a 999 g, allo scopo di dimostrare che la rianimazione neonatale in aria era efficace quanto quella condotta con ossigeno al 100%, come indicato da precedenti studi pilota. Tale studio documentò che i tempi del primo respiro e del primo vagito erano significativamente più brevi nei neonati rianimati con aria rispetto a quelli rianimati con ossigeno puro, e che l’indice di Apgar al primo minuto era più alto nel primo gruppo. Gli Autori ipotizzarono che la rianimazione con ossigeno puro potesse indurre atelettasia polmonare o depressione della funzione ventilatoria, o entrambe, spiegando così i risultati ottenuti [27]. Nel 2003, uno studio indiano mise a confronto l’uso di aria ambiente versus l’uso di ossigeno al 100% nella rianimazione del neonato asfittico con peso alla nascita superiore a 1.000 g. In tale studio, l’outcome dei neonati rianimati in aria fu simile a quello dei neonati rianimati con O2 al 100% e non furono riscontrate differenze tra i due gruppi nel miglioramento della frequenza cardiaca a 1, 5 e 10 minuti e nell’indice di Apgar a 5 e 10 minuti. Inoltre, il tempo necessario per emettere il primo vagito e la durata della rianimazione furono significativamente più brevi nel gruppo rianimato con aria rispetto
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al gruppo di controllo rianimato con O2 al 100%. Non si registrarono invece differenze significative tra i due gruppi di neonati riguardo alla mortalità complessiva e a quella correlata all’asfissia [2]. Una successiva metanalisi, condotta su 1.737 neonati, evidenziò una riduzione significativa della mortalità neonatale, pari al 5%, nei neonati rianimati alla nascita con aria ambiente rispetto a quelli rianimati con O2 al 100%. Tale differenza fu documentata sia nei nati a termine che nei pretermine. Inoltre, nei neonati rianimati in aria, il punteggio di Apgar a 5 minuti e la frequenza cardiaca a 90 secondi furono significativamente maggiori, e l’inizio dell’attività respiratoria spontanea significativamente più precoce, rispetto a quelli osservati nei neonati rianimati con ossigeno al 100%. All’età di 1822 mesi, l’accrescimento somatico, lo sviluppo psicomotorio, il numero di paralisi cerebrali e/o di ritardo mentale furono sovrapponibili nei due gruppi studiati [3]. Nello studio di Bajaj et al. [28], condotto su neonati di peso superiore a 1.000 g, la rianimazione con aria ambiente non offrì alcun beneficio in termini di riduzione della mortalità o di incidenza di encefalopatia ipossicoischemica rispetto alla rianimazione con ossigeno al 100%, né risultò gravata da un’aumentata incidenza di esiti avversi. Tali Autori conclusero, quindi, che l’utilizzo di aria nella rianimazione poteva essere raccomandato laddove l’ossigeno non fosse disponibile. Successivamente, una review sistematica con metanalisi evidenziò che la rianimazione neonatale in aria ambiente era gravata da una mortalità inferiore rispetto a quella con ossigeno al 100%, sia nella prima settimana di vita che a 1 mese e oltre, mentre l’incidenza di severa encefalopatia ipossico-ischemica (stadi II-III) era sovrapponibile nei due gruppi di pazienti [29]. Altri studi hanno valutato la risposta alla rianimazione con differenti concentrazioni di ossigeno, in distinte popolazioni di neonati. Neonati pretermine Nel 2008, uno studio prospettico randomizzato valutò l’uso di aria versus ossigeno al 100% nella rianimazione del neonato pretermine di età gestazionale inferiore a 32 settimane. La rianimazione con aria ambiente dei neonati studiati non consentì di raggiungere la saturazione di ossigeno target del 70% a 3 minuti e dell’80% a 5 minuti di vita, e tutti i neonati necessitarono di ossigeno supplementare. I ricercatori postularono che i valori saturimetrici persistentemente bassi, osservati nei nati molto
Uso dell’ossigeno nella rianimazione del neonato
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prematuri durante la rianimazione in aria ambiente, potevano derivare dal mancato adattamento alla nascita dei vasi polmonari in assenza di ossigeno supplementare. In particolare, fu ipotizzata una persistente vasocostrizione polmonare, con shunt destro-sinistro a livello del dotto arterioso e del foramen ovale, che poteva derivare da una diversa sensibilità all’ossigeno della circolazione polmonare nel nato pretermine rispetto al nato a termine. La raccomandazione degli Autori, pertanto, fu quella di non utilizzare aria ambiente nella rianimazione iniziale dei nati prematuri, ma optare invece per concentrazioni di ossigeno tra il 30% e il 40%, regolando successivamente la frazione inspirata di ossigeno allo scopo di far incrementare lentamente la saturazione fino a valori dell’85% a 7-10 minuti di vita [13]. Dawson et al. [30] osservarono che, nei nati prematuri di età gestazionale inferiore a 30 settimane, l’utilizzo di aria ambiente nelle fasi iniziali della rianimazione rendeva necessario poi l’impiego di ossigeno supplementare per raggiungere valori accettabili di SpO2. Escrig et al. [31] studiarono un campione di neonati estremamente prematuri (≤ 28 settimane di gestazione), sottoposti a rianimazione alla nascita, per stabilire se l’impiego iniziale di una bassa FiO2 (30%) fosse altrettanto efficace di quello di un’alta FiO2 (90%) ai fini del raggiungimento di una SpO2 target dell’85%, a 10 minuti di vita. Essi documentarono che le condizioni cliniche e i valori di SpO2 e di frequenza cardiaca dei neonati trattati con alte concentrazioni di ossigeno erano sovrapponibili a quelli dei neonati che ricevevano basse concentrazioni di ossigeno durante la rianimazione. D’altro canto, i neonati inizialmente ventilati con alte concentrazioni di ossigeno ricevevano una maggiore quantità totale di ossigeno e presumibilmente avevano un maggior rischio di danno da radicali liberi, senza alcun vantaggio in termini di mortalità neonatale precoce o di tassi di mortalità neonatale. Un successivo studio evidenziò che la rianimazione con ossigeno al 30% di neonati prematuri di età gestazionale compresa tra 24 e 28 settimane causava minori stress ossidativo, flogosi e necessità di ossigeno, e riduceva il rischio di displasia broncopolmonare [32]. Infine, nei neonati di età gestazionale inferiore a 37 settimane, fu documentata una sopravvivenza maggiore se venivano rianimati inizialmente con aria piuttosto che con ossigeno al 100% [3, 33, 29]. Nonostante non sia nota con esattezza la concentrazione ottimale di ossigeno da somministrare ai prematuri durante la rianimazione, una percentuale iniziale di ossigeno
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tra il 25% ed il 30% sembra in grado di favorire una regolare transizione alla vita extrauterina, ridurre il carico di ossigeno e diminuire il rischio di danno e flogosi causati dall’ossigeno [4]. Non sono attualmente disponibili in letteratura sufficienti evidenze per definire un’appropriata strategia di somministrazione dell’ossigeno durante la rianimazione, nei neonati pretermine di età gestazionale tra 32 e 37 settimane [16]. Neonati a termine Nello studio di Vento et al. [34], l’outcome finale dei nati a termine asfittici rianimati in aria risultò sovrapponibile a quello riscontrato nei neonati rianimati con ossigeno allo stato puro. Inoltre, il gruppo di neonati rianimati in aria richiese un tempo inferiore di ventilazione a pressione positiva per raggiungere un pattern di respirazione spontanea, mentre il gruppo rianimato con ossigeno puro sviluppò iperossiemia, documentata anche da un aumento della concentrazione di glutatione ossidato. Nel 2004, una review sistematica con una metanalisi di trials mise a confronto la rianimazione con aria e quella con ossigeno al 100%. Le conclusioni dello studio furono che l’aria ambiente rappresentava la prima scelta nella rianimazione iniziale in sala parto per il neonato a termine o presso il termine, e che l’utilizzo dell’ossigeno andava riservato ai casi in cui tale modalità rianimatoria iniziale avesse fallito [33]. Neonati con grave compromissione alla nascita Un’attenzione speciale meritano i neonati con grave asfissia alla nascita, quelli in arresto cardiaco, o che presentano una frequenza cardiaca inferiore a 60 battiti per minuto (bpm). Tali neonati, infatti, avendo una compromissione dell’attività circolatoria, possono presentare valori di saturazione di ossigeno non attendibili, per cui la somministrazione di ossigeno a concentrazioni maggiori dovrebbe essere guidata dalla frequenza cardiaca piuttosto che dalla saturazione di ossigeno [4]. In un recente lavoro è stato suggerito che, se l’indice di Apgar al primo minuto è inferiore a 1, la risposta della frequenza cardiaca alle prime ventilazioni dovrebbe guidare l’utilizzo dell’ossigeno, ancor prima di poter misurare dei valori saturimetrici attendibili. In particolare, se la frequenza cardiaca non aumenta nonostante l’esecuzione di adeguate ventilazioni, la concentrazione di ossigeno dovrebbe essere rapidamente aumentata, anche fino al 100%, per ottenere un rapido ripristino del circolo [35].
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Uso dell’ossigeno nella rianimazione del neonato alla nascita: cenni sulle più recenti linee guida
Le linee guida sulla rianimazione neonatale, emanate nel 2010 dallo European Resuscitation Council, raccomandano che, nel neonato a termine, la rianimazione venga iniziata somministrando aria piuttosto che ossigeno al 100%. L’uso di ossigeno a concentrazioni maggiori viene raccomandato solamente nei casi in cui, nonostante un’adeguata ventilazione, la frequenza cardiaca non aumenti o l’ossigenazione (rilevata possibilmente con un pulsossimetro) si mantenga su livelli non accettabili. Riguardo ai neonati pretermine di età gestazionale inferiore a 32 settimane, le medesime linee guida segnalano che, nella gran parte dei casi, la rianimazione in aria non consente di raggiungere il target di saturazione di ossigeno desiderato, con conseguente ipossiemia, mentre l’utilizzo di ossigeno al 100% è più frequentemente gravato dal rischio di iperossia. In tali neonati, le suddette linee guida raccomandano di utilizzare una miscela aria-ossigeno la cui concentrazione sia regolata in base alla misurazione della SpO2 col pulsossimetro, prevedendo la possibilità di iniziare la rianimazione in aria solamente nel caso in cui non sia disponibile il miscelatore aria-ossigeno [36]. Nel 2010, l’American Heart Association ha pubblicato le proprie linee guida revisionate, nelle quali viene raccomandato di iniziare la rianimazione con aria o con miscela aria-ossigeno, sia nel neonato a termine che nel pretermine, per poi regolare la concentrazione di ossigeno sotto guida pulsossimetrica con l’obiettivo di raggiungere valori di SpO2 preduttale nel range “target”. Le suddette linee guida includono a tale scopo una tabella in cui sono riportati i range interquartili delle SpO2 preduttali misurate in neonati a termine sani dopo parto vaginale a livello del mare. Nel caso in cui non si abbia a disposizione il miscelatore aria-ossigeno, viene raccomandato di iniziare la rianimazione in aria. Qualora il neonato sia gravemente bradicardico (frequenza cardiaca < 60 bpm) dopo 90 secondi di rianimazione con basse concentrazioni di O2, queste ultime devono essere aumentate (sino a raggiungere il 100%) per il tempo necessario a riportare la frequenza cardiaca a valori normali [1]. Nel 2012, la World Health Organization (WHO) ha pubblicato le proprie linee guida sulla rianimazione di base del neonato, dirette in special modo a coloro che prestano la loro assistenza in ambienti dove è scarsa la disponibilità di risorse
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umane e/o tecnologiche durante il parto. Riguardo all’uso dell’ossigeno nella rianimazione del neonato, tali linee guida forniscono raccomandazioni differenziate in funzione dell’età gestazionale. Secondo tali raccomandazioni, la ventilazione dovrebbe essere iniziata con aria nei neonati di età gestazionale maggiore di 32 settimane mentre, nei neonati pretermine di età gestazionale uguale o inferiore a 32 settimane, è preferibile iniziare la ventilazione con ossigeno al 30%. Viene inoltre raccomandato l’uso del pulsossimetro per decidere circa il bisogno di ossigeno supplementare e per monitorizzare la concentrazione di ossigeno necessaria [37]. Il Gruppo di Studio sulla Rianimazione Neonatale della Società Italiana di Neonatologia ha recentemente pubblicato le raccomandazioni sulla somministrazione di ossigeno in sala parto [4]. L’approccio iniziale che esse prevedono è sostanzialmente simile a quello raccomandato nelle linee guida della WHO. Uso dell’ossigeno nella rianimazione del neonato alla nascita: possibili soluzioni pratiche alternative
Le più recenti linee guida internazionali per la rianimazione neonatale raccomandano di iniziare la rianimazione con aria piuttosto che con il 100% di ossigeno in neonati a termine e con una FiO2 tra il 30% ed il 90% nei neonati pretermine con età gestazionale < 32 settimane. La somministrazione di ossigeno supplementare dovrebbe essere regolata attraverso la miscelazione di ossigeno e aria, e la concentrazione di ossigeno somministrata dovrebbe essere guidata dalla pulsossimetria. I pulsossimetri sono apparecchiature portatili, relativamente poco costose, ed ampiamente disponibili anche in contesti con risorse limitate. L’aria compressa e i miscelatori, viceversa, non sono disponibili in molti contesti dove viene attuata la rianimazione neonatale, sia nei paesi sviluppati che in quelli a limitate risorse. La conseguente limitata capacità di controllare la FiO2 può condurre, sulla base delle più recenti raccomandazioni, a una cura non ottimale del neonato, specialmente quando si renda necessaria una bassa FiO2. Il pallone auto-insufflante (PAI), ancora ampiamente diffuso nei centri nascita dei paesi sviluppati e non, non richiede una sorgente di gas compresso per il proprio funzionamento. Se si collega un PAI a una sorgente di ossigeno puro, la FiO2 a livello della maschera dipende dall’entità
Uso dell’ossigeno nella rianimazione del neonato
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della miscelazione tra flusso di ossigeno in entrata e aria ambiente aspirata nella sacca. Le caratteristiche tecniche del PAI consentono di regolare la FiO2 a livello della maschera semplicemente regolando il flusso di ossigeno in entrata, senza richiedere un miscelatore separato e una fonte di aria compressa. Quando si utilizza un PAI con reservoir, alimentato con un flusso di ossigeno di 5-10 L/min, la FiO2 erogata ai pazienti è di circa il 90-100%. D’altro canto, la concentrazione di ossigeno erogata quando si utilizza un PAI senza reservoir si ritiene essere di circa il 40%, anche se studi recenti hanno dimostrato che, ai range di pressione raccomandati dalle linee guida internazionali, le concentrazioni di ossigeno sono maggiori. Da un punto di vista pratico, nelle situazioni in cui non siano disponibili aria compressa e miscelatori e si impieghi invece un PAI, la possibilità di utilizzare una relazione ben definita tra flusso di ossigeno e FiO2 erogata può diventare uno strumento essenziale per gli operatori addetti all’assistenza del neonato. In un recentissimo studio, Trevisanuto et al. [38] hanno valutato la relazione tra flusso di ossigeno e FiO2 erogata durante la ventilazione a pressione positiva (PPV) eseguita su un manichino con un PAI neonatale dotato di reservoir. I dati da essi ottenuti mostrano che la FiO2 erogata dipende da 3 fattori: entità del flusso di ossigeno, pressione di picco inspiratorio (PIP) e tempo trascorso. Da tali dati può essere sviluppato uno schema che mette in correlazione il flusso di ossigeno e la corrispondente FiO2 erogata. L’operatore può modulare la FiO2 efficace in un range compreso tra il 21% e l’85-95% utilizzando un flussometro, regolando semplicemente il flusso di ossigeno in modo progressivo da 0 L/min a 5 L/ min in base alla pulsossimetria. Questo schema può rappresentare uno strumento utile e poco costoso per la rianimazione del neonato, nei casi in cui non siano disponibili una sorgente di aria compressa e un miscelatore. Conclusioni
Numerosi studi clinici sembrano ormai dimostrare che la rianimazione alla nascita del neonato a termine debba iniziare con aria ambiente, e che la somministrazione di ossigeno vada riservata ai casi di persistenza di una bradicardia importante. Nel nato pretermine di bassa età gestazionale (< 32 settimane), invece, la somministrazione di una miscela aria-ossigeno al 30% sembra essere la strategia iniziale più idonea, considerato che la rianimazione in aria di tale tipo di neonato esita
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facilmente in ipossia e che, d’altro canto, egli è particolarmente suscettibile ai danni da radicali liberi dell’ossigeno in caso di iperossia. La valutazione clinica del colorito cutaneo non viene più raccomandata come indicatore attendibile dello stato di ossigenazione durante la rianimazione del neonato, mentre l’impiego del pulsossimetro consente una misurazione accurata e continua dell’ossigenazione e della frequenza cardiaca. Allo stato attuale delle conoscenze, restano ancora aperti alcuni problemi relativi all’impiego dell’ossigeno nella rianimazione del neonato alla nascita (Tab. 2). In futuro, un corretto uso dell’ossigeno nella rianimazione del neonato dovrà certamente basarsi sulle migliori e più recenti evidenze scientifiche disponibili, ma anche orientarsi verso un approccio “individualizzato”, ossia ottimizzato in funzione delle caratteristiche del singolo paziente e della sua risposta all’ossigenoterapia.
2.
Ramji S, Rasaily R, Mishra PK, Narang A, Jayam S, Kapoor AN, Kambo I, Mathur A, Saxena NC, Saxena BN. Resuscitation of asphyxiated newborns with room air or 100% oxygen at birth: a multicentric clinical trial. Indian Pediatrics. 2003;40:510-7.
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van der Walt J. Oxygen – elixir of life or Trojan horse? Part 1: oxygen and neonatal resuscitation. Paediatr Anaesth. 2006;16(11):1107-11.
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Saugstad OD, Sanderud J. Circulatory effects of oxygen radicals. Biomed Biochim Acta. 1989;48(2-3):S20-4.
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Perrone S, Negro S, Tataranno ML, Buonocore G. Oxidative stress and antioxidant strategies in newborns. J Matern Fetal
Tabella 2. Uso dell’ossigeno nella rianimazione del neonato alla nascita: problemi aperti. • Qual è la migliore strategia e quali le indicazioni per l’impiego dell’ossigeno nella rianimazione dei neonati pretermine di età gestazionale tra 32 e 37 settimane? • Quale concentrazione di ossigeno è meglio utilizzare nei casi di bradicardia persistente che non risponde rapidamente a una corretta ventilazione? • Qual è l’effetto della rianimazione con aria versus quella con ossigeno supplementare sul ripristino del flusso cerebrale e sul successivo danno cerebrale, durante l’arresto circolatorio? • Qual è l’SpO2 target ottimale per intraprendere e quale quella per sospendere la somministrazione di ossigeno supplementare nel neonato compromesso sottoposto a rianimazione alla nascita? • L’SpO2 target per i neonati pretermine dovrebbe essere differente da quella per i neonati a termine? • Qual è l’outcome a lungo termine (mortalità e sviluppo neuromotorio) dei neonati rianimati applicando su larga scala le recenti linee guida?
Neonatal Med. 2010;23(S3):63-5. 8.
O’Donovan DJ, Fernandes CJ. Mitochondrial glutathione and oxidative stress: implications for pulmonary oxygen toxicity in premature infants. Mol Genet Metab. 2000;71:352-8.
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Wallace KB, Eells JT, Madeira VM, Cortopassi G, Jones DP. Mitochondria-mediated cell injury. Symposium overview. Fundam Appl Toxicol. 1997;38(1):23-37.
10. Chen Y, Martinez MA, Frank L. Prenatal dexamethasone administration to premature rats exposed to prolonged hyperoxia: a new rat model of pulmonary fibrosis (bronchopulmonary dysplasia). J Pediatr. 1997;130(3):409-16. 11. Vento M, Escrig R, Saenz P, Sastre J, Izquierdo I. Prenatal corticosteroids enhance the antioxidant defence system in extremely premature infants. Presented at the 2006 Pediatric Academic Societies’ annual meeting: April 29 to May 2, 2006; San Francisco, CA. 12. Tan A, Schulze A, O’Donnell CP, Davis PG. Air versus oxygen for resuscitation of infants at birth. Cochrane Database Syst Rev. 2005;(2):CD002273. 13. Wang CL, Anderson C, Leone TA, Rich W, Govindaswami B,
Declaration of interest
Finer NN. Resuscitation of preterm neonates by using room air or 100% oxygen. Pediatrics. 2008;121:1083-9.
The Authors declare that they have nothing to disclose in relation with this article.
14. Lundstrom KE, Pryds O, Greisen G. Oxygen at birth and prolonged cerebral vasoconstriction in preterm infants. Arch Dis Child Fetal Neonatal Ed. 1995;73:F81-6.
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030103 doi: 10.7363/030103 Received: 2013 May 06; revised: 2013 Jun 19; accepted: 2013 Jun 24; advance publication: 2014 Jan 10
Review
Il neonatologo ed alcune emergenze in sala parto Antonio Boldrini1,2, Rosa Teresa Scaramuzzo1,3 1
U.O. Neonatologia, Azienda Ospedaliera Universitaria Pisana, Pisa
2
Università di Pisa, Pisa
3
Istituto di Scienze della Vita, Scuola Superiore Sant’Anna, Pisa
Proceedings Articoli Selezionati del “3° Convegno Pediatrico del Medio Campidano” · Guspini · 25 Maggio 2013 Guest Editor: Roberto Antonucci
Abstract
Introduction: In the delivery room the neonatologist may deal with emergencies, not always predictable by pre-natal diagnosis. Among these dangerous situations, we include: i) extremely preterm birth of a newborn very/extremely low birth weight and ii) shoulder dystocia in term newborns. We will discuss in details these two clinical scenarios. Methods: We reviewed the main recent papers about resuscitation of very/ extremely low birth weight preterm newborns and about dystocia of shoulder reported in PubMed database. After that, we compared reported results with practice in our Unit and discussed the topics considering strategies to optimize the results and minimizing possible errors. Discussion and conclusions: In our opinion the optimization of clinical practice in Neonatology should be based on: i) national or international recommendations drawn up by commissions or study groups of experts, on the basis of scientific evidence, ii) local department protocols, in order to standardize staff interventions within the same unit; iii) ongoing training of doctors, nurses and midwives, through simulation sessions and CRM (Crisis Resources Management). As regards shoulder dystocia, The Tuscan Group for Clinical Risk Management drawn a poster to be showed in every delivery room, in order to allow the staff to rapidly remember the correct clinical interventions. On the other hand, as regards ventilatory preterm newborns strategies, the Centro di Formazione e Simulazione NINA is working on a project of a mechatronich simulator for staff training (MERESSINA). Keywords
Preterm newborn, Delivery Room Intensive Care Unit (DRICU), alveolar recruitment, functional residual capacity (FRC), shoulder dystocia, simulation.
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Corresponding author Prof. Antonio Boldrini, U.O. Neonatologia, Azienda Ospedaliera Universitaria Pisana, Via Roma, 67 – 56126 Pisa, Italy; tel./fax +39 050 992029; e-mail: antonio.boldrini@med.unipi.it.
How to cite •
Boldrini A, Scaramuzzo RT. Il neonatologo ed alcune emergenze in sala parto. J Pediatr Neonat Individual Med. 2014;3(1):e030103. doi: 10.7363/030103.
•
Boldrini A, Scaramuzzo RT. [Neonatological emergencies in delivery room]. [Article in Italian]. J Pediatr Neonat Individual Med. 2014;3(1):e030103. doi: 10.7363/030103.
Introduzione
L’assistenza in sala parto comporta, per il neonatologo, l’evenienza di dover fronteggiare situazioni di emergenza. Alcune problematiche possono essere anticipate dalla diagnosi prenatale, per esempio l’idrope fetale, alcune cardiopatie complesse e una certa percentuale di casi di ernia diaframmatica. Altre condizioni di emergenza, invece, non sono previste o del tutto prevedibili: patologie chirurgiche come l’onfalocele o la gastroschisi, patologie metaboliche, etc. L’individuazione in utero di una malformazione fetale concede all’équipe di sala parto il tempo necessario per pianificare una strategia di assistenza e intervento, ma anche in questi casi non sempre e non tutto è esattamente prevedibile. Al contrario, il neonatologo è il professionista che per primo e più direttamente si trova ad affrontare l’urgenza quando non è stata posta alcuna diagnosi prima della nascita, perché il difetto in sé non è precocemente diagnosticabile o perché la gestante ha mancato di sottoporsi ai dovuti controlli. Quest’ultima evenienza è in costante aumento, anche per il crescente numero di immigrati, che restano relegati alle fasce sociali meno abbienti e con limitato accesso ai servizi sanitari, anche per fattori culturali. In quest’ottica, abbiamo inteso approfondire la trattazione di due tra le condizioni di emergenza che il neonatologo può essere chiamato a gestire in sala parto: la nascita di un neonato pretermine, di peso molto o estremamente basso, e la nascita di un neonato, generalmente a termine, con distocia di spalla. Metodi
Per la trattazione dei due argomenti prescelti abbiamo effettuato un’attenta revisione della
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Letteratura più recente, selezionando attraverso il database PubMed pubblicazioni peer-reviewed (edite dall’anno 2000 e fino al mese di aprile 2013). In particolare, per approfondire la gestione del neonato pretermine di alto grado, di peso molto o estremamente basso, in sala parto, abbiamo revisionato i lavori relativi alla rianimazione cardiorespiratoria e al controllo della temperatura: la ricerca nel database è stata condotta inserendo come parole chiave “delivery room intensive care unit/temperature/resuscitation AND very low birth weight”. Per entrambi gli argomenti, poi, nella seconda parte del nostro lavoro abbiamo confrontato i risultati della Letteratura con la nostra esperienza specifica, includendo nell’analisi le indicazioni della Società Italiana di Neonatologia, della sezione di Gestione del Rischio Clinico della Regione Toscana e, infine, i protocolli della nostra Unità Operativa (U.O.). Sulla base di un’attività ormai quadriennale, abbiamo infine ampliato la discussione con risultati e considerazioni derivate dall’originale esperienza del Centro di Formazione e Simulazione Neonatale NINA, afferente alla nostra U.O. [1]. Emergenza del neonato prematuro: la nascita VLBW/ELBW
L’Organizzazione Mondiale della Sanità riporta che nel 2005 la nascita pretermine ha avuto un’incidenza globale pari a 9,6%, equivalente a un numero di circa 12,9 milioni di neonati. La maggior parte delle nascite pretermine, circa l’85% ovvero 10,9 milioni di casi, avviene in Africa e Asia. In Europa il numero di neonati pretermine è di circa 0,5 milioni l’anno, 0,9 milioni in Nord America e altrettanti in America Latina e Caraibi. L’Europa, dunque, ha il tasso di natalità pretermine più basso, circa il 6,2% [2]. Tuttavia, in termini assoluti, lo 0,3% dei neonati nasce molto prima del termine, a un’età gestazionale inferiore alle 28 settimane (i cosiddetti ELGANs, Extremely Low Gestational Age Neonates). Anche per questo, la nascita pretermine è una delle maggiori cause di mortalità perinatale (27%) e di sequele a distanza [3], senza alcuna significativa riduzione dei tassi di morbidità negli ultimi 10 anni [4]. Le evidenze scientifiche riportate nella Letteratura degli ultimi anni enfatizzano l’importanza degli interventi di stabilizzazione del neonato pretermine di alto grado, di peso molto o estremamente basso (Very Low Birth Weight, VLBW o Extremely Low Birth Weight, ELBW), in sala parto, ancor
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prima dell’ingresso in Terapia Intensiva Neonatale (TIN): le cure della prima ora di vita, the golden hour, possono influenzare ampiamente gli esiti a distanza in questa popolazione di neonati estremamente vulnerabili [4-6]. Mutuato dai settings di assistenza ai pazienti politraumatizzati, il concetto di golden hour per il neonato pretermine include la rianimazione cardiorespiratoria, la termoregolazione, l’antibioticoterapia precoce, la nutrizione parenterale per la prevenzione o la gestione dell’ipoglicemia (Fig. 1). È, dunque, un intervallo di tempo in cui l’équipe medicoinfermieristica applica efficacemente protocolli mirati (team-oriented task-driven protocols) [7]. Tra gli esiti della prematurità, importanza particolare ha la patologia polmonare cronica, il cui quadro esemplificativo è la displasia broncopolmonare (BPD), associata a protratte manovre di rianimazione cardiopolmonare in sala parto, così come lo sono una più alta mortalità e incidenza di sequele neurologiche [8]. Nell’ottica della golden hour, le linee guida della rianimazione edite nel 2010 dall’International Liaison Committee on Resuscitation (ILCOR), dallo European Resuscitation Council (ERC), dall’American Heart Association (AHA) e dall’American Academy of Pediatrics (AAP) enfatizzano la necessità di un approccio cosiddetto gentle, ovvero minimamente invasivo, già dalla sala parto [9, 10]. Pressione e volume dei gas erogati durante la rianimazione cardiopolmonare dovrebbero essere i minimi necessari per ottenere la stabilizzazione, senza causare volu-barotrauma alle vie aeree e ai polmoni immaturi. La FiO2 erogata dovrebbe essere inizialmente compresa tra 21% e 30%, Figura 1. Schematizzazione degli interventi essenziali nella “golden hour” del neonato estremamente pretermine VLBW/ELBW.
Il neonatologo ed alcune emergenze in sala parto
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per evitare un eccessivo stress ossidativo. Particolare attenzione dovrebbe essere prestata al mantenimento di un’adeguata volemia, per evitare brusche variazioni pressorie che pongono l’encefalo a rischio di sanguinamenti. Infine, viene sottolineata l’utilità dei più moderni dispositivi tecnologici, presidi per la ventilazione ma anche per il monitoraggio dei parametri vitali, che devono essere applicati già in sala parto, ancor prima del trasporto in TIN [6, 9, 11]. Alla nascita è necessario espandere il polmone che non ha mai respirato e stabilizzare rapidamente un’effettiva capacità funzionale residua (CFR). Il ritardare l’instaurarsi di una efficace ventilazione espone il polmone al rischio di edema polmonare e al ritardo del riassorbimento del liquido fetale intrapolmonare. Superato ormai l’approccio dell’intubazione elettiva, è attualmente condiviso l’utilizzo della CPAP per l’applicazione di una pressione di fine espirazione (PEEP), che sostenga il respiro spontaneo del neonato pretermine, quando presente ed efficace [9]. Analogamente, la somministrazione di surfactante estrattivo endotracheale, eventualmente con modalità INSURE, è scelta terapeutica rescue e non profilattica [12]. Tuttavia, allo scopo di minimizzare il volu-barotrauma di cui si diceva precedentemente, è necessario erogare PEEP e volumi tidalici controllati, soprattutto in considerazione della particolare anatomia del polmone del neonato ELGAN, costituito prevalentemente o pressochè esclusivamente da sacculi, con uno scarso sviluppo della rete microvascolare e della matrice connettivale, e privo di surfactante endogeno [13]. Il dispositivo ottimale per l’erogazione di PEEP e PIP (pressione di picco) controllate durante la ventilazione a pressione positiva intermittente in sala parto è il T-piece, al cui uso tutti gli operatori dovrebbero essere addestrati [14]. Quando necessaria, la ventilazione meccanica dovrebbe essere erogata per il più breve tempo possibile e con modalità minimamente aggressive (ad esempio ventilazione sincronizzata). I volumi tidalici ottimali sono schematizzati nella Tab. 1: ai valori indicati, per peso corporeo, è necessario sommare la quota di spazio morto aggiuntivo dovuta al tubo endotracheale. L’applicazione di una PIP di + 25 cm H2O continuativa per 15 secondi con T-piece potrebbe consentire un efficace reclutamento alveolare in sala parto, favorendo la clearance del liquido endoalveolare e la successiva areazione degli spazi
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Tabella 1. Valori di volume corrente (50° percentile) per peso corporeo. Peso corporeo (g)
Volume corrente (ml/kg) 50° percentile
500-1.000
5,4
1.000-2.500
5,7
2.500-5.000
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polmonari [15, 16]. Infatti, molto più che i canali del Na+ e lo stimolo adrenergico sulle cellule epiteliali (che hanno comunque capacità di riassorbimento inversamente proporzionali all’età gestazionale), è la differenza di pressione a determinare un gradiente di flusso verso i capillari polmonari, i vasi pleurici e i linfatici. Nel modello animale di coniglio, la manovra della sustained inflation, seguita dall’applicazione di PEEP controllata, consente che si stabilisca una migliore capacità funzionale residua [17]. Durante la stabilizzazione in sala parto, i neonati VLBW/ELBW hanno la spiccata tendenza alla perdita di calore: precedentemente immersi in un fluido caldo, dopo la nascita essi si trovano in un ambiente a temperatura più bassa, con stimoli abrasivi su una cute estremamente delicata, ancora priva delle fisiologiche protezioni. Secondo il Vermont Oxford Network, oltre il 60% di questi neonati arriva in TIN con una temperatura corporea < 36,5°C: lo stress da freddo o una franca ipotermia sono fattori di rischio indipendenti per mortalità precoce [18, 19]. Pertanto, mantenere un adeguato controllo della temperatura, anche limitando le perdite insensibili di liquidi attraverso la cute, è cruciale: presidio adeguato sono, a questo scopo, i sacchetti di polietilene [20]. Come si evince da questa trattazione, seppur parziale e sintetica, allo scopo di assistere adeguatamente i neonati più vulnerabili (gli ELGANs innanzitutto), è necessario che la sala parto sia attrezzata con tutti i presidi utili per la rianimazione, la stabilizzazione e il monitoraggio, al pari di una postazione di TIN: da qui l’acronimo, ormai comunemente in uso, di DRICU (Delivery Room Intensive Care Unit) [4]. Emergenza del neonato a termine: la distocia di spalla
La distocia di spalla ha un’incidenza complessiva di 0,2-1,6% e in genere basso rischio di ricorrenza (9,8%-16,7%). I principali fattori di rischio, che tuttavia rendono ragione solo di circa la metà dei
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casi, includono l’obesità materna associata o no a diabete gestazionale, la macrosomia fetale, un travaglio di parto prolungato [21]. Pur trattandosi di un evento spesso imprevisto, esso è potenzialmente associato a conseguenze gravi per madre e neonato. Infatti, fino al 40% delle paralisi ostetriche del plesso brachiale si associa a distocia di spalla; più frequentemente si osserva frattura di clavicola senza lesione nervosa mentre, in casi più rari, la distocia di spalla si inscrive in un’asfissia perinatale, di gravità variabile fino allo sviluppo di una paralisi cerebrale infantile [22, 23]. La frattura di clavicola è in genere “a legno verde”, ma può talora essere completa. Se non si verifica un danno del plesso, il neonato generalmente mantiene l’arto addotto e con il gomito esteso; i movimenti passivi e la palpazione causano dolore, il riflesso di Moro è asimmetrico. Tali segni clinici sono transitori: la lesione ossea consolida sempre spontaneamente, quindi non necessita di trattamento, ma è utile consigliare facilitazioni per le manovre di accudimento. La paralisi del plesso brachiale è la causa di morbidità più frequentemente associata alla distocia di spalla, ma circa il 50% dei neonati con questa lesione nervosa non ha avuto distocia di spalla [21]. Storicamente, infatti, si riteneva che la paralisi fosse conseguenza diretta della compressione della spalla fetale contro la sinfisi pubica materna o di un’eccessiva trazione laterale e rotazione forzata della testa del nascituro con deviazione dall’asse del tronco, dato che in genere la distocia di spalla richiede l’applicazione di una forza maggiore da parte dell’ostetrico per il disimpegno delle spalle durante il parto. Tuttavia, sappiamo oggi che un numero significativo di paralisi si verifica per eventi in utero, e questo rende ragione dei casi non associati a distocia di spalla: le cause possibili includono anomalie dell’organo materno (utero bicorne, utero setto), fibromi uterini, il malposizionamento intrauterino del feto, l’ipercinesia uterina durante il travaglio, la mancata rotazione delle spalle o l’impatto della spalla posteriore del feto contro il promontorio sacrale. Le lesioni del plesso brachiale, infine, si possono osservare anche dopo taglio cesareo (4% circa) [22]. La lesione nervosa può essere limitata a uno stato di edema importante, compressivo (neuroprassia), con guarigione in genere entro un mese; può consistere invece nell’interruzione dell’assone a guaina integra (axonotmesi), con recupero entro un paio d’anni, o può, nei casi più gravi, essere caratterizzata da rottura sia dell’assone che
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della guaina, e in questo caso la prognosi quoad valetudinem dell’arto è severa. La percentuale di lesioni che esitano in danni permanenti è variabile, nelle casistiche riportate in Letteratura, dal 5 al 22% [21]. Nel caso in cui la lesione interessi le radici C5-C6 (paralisi superiore o di Erb-Duchenne), è compromessa l’innervazione dei muscoli deltoide, bicipite, brachiale anteriore e brachio-radiale: l’arto è ipomobile, addotto, intraruotato con l’avambraccio pronato; la prensione può essere normale. Se, invece, la lesione interessa le radici C7-C8-T1 (paralisi inferiore o di Klumpe), è compromessa l’innervazione dei muscoli flesso-estensori del polso e delle dita, quindi mano e polso sono paralizzati. Il braccio è in posizione cosiddetta da schermitore se la paralisi è completa e in genere si associa interessamento delle fibre simpatiche, con conseguente ptosi palpebrale, miosi ed enoftalmo. Discussione e conclusioni
Obiettivo della buona pratica clinica è gestire gli eventi avversi non prevenibili, come possono essere alcune delle situazioni di emergenza a cui abbiamo accennato in questo lavoro, ed eliminare invece quelli prevenibili, cioè dovuti ad errori, che pongono a rischio la salute del neonato e/o della madre ma costituiscono anche un rischio per il medico e per l’azienda. Nella Letteratura più recente di ambito neonatologico l’errore medico è un argomento di crescente interesse, con larga eco anche nei mezzi di comunicazione di massa e sulla stampa non specialistica per le valenze sociali, etiche ed emotive estremamente rilevanti che riguardano la donna, la maternità, il neonato. In Italia un ampio studio osservazionale della durata di 6 anni ha concluso che il numero di procedimenti legali è ancora relativamente basso, se confrontato al versante ginecologico-ostetrico o chirurgico: circa il 39% delle denunce riguarda avvenimenti di sala parto, il 38% fatti accaduti nella nursery, il 22% circa in TIN e solo poco più dell’1% durante il trasporto in ambulanza [24]. La gestione del rischio clinico, all’interno delle aziende ospedaliere, anche nel settore maternoinfantile, è quindi condizione imprescindibile per il miglioramento della qualità delle cure e della sicurezza del paziente. Nel Regno Unito il Clinical Negligence Scheme for Trust (CNST) (2005) ha sviluppato uno schema per la sicurezza delle strutture di ostetricia basato sui seguenti
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standard: organizzazione, capacità di imparare dall’esperienza (segnalazione volontaria di eventi avversi o incident reporting, clinical audit), comunicazione, presa in carico del paziente, corretta compilazione delle cartelle cliniche, formazione e competenze specifiche (sul parto), implementazione della gestione del rischio clinico, livelli di staffing (ovvero ottimizzazione della capacità di lavorare in gruppo). A nostro parere, l’ottimizzazione della pratica clinica in ambito neonatologico dovrebbe poggiare su tre pilastri: i) la stesura di raccomandazioni nazionali o internazionali, elaborate da commissioni o gruppi di studio di esperti, sulla scorta delle evidenze scientifiche; ii) protocolli di reparto, perché nell’ambito di ciascuna U.O. sia garantita uniformità di intervento; iii) formazione continua di medici, infermieri e ostetrici, anche attraverso sessioni di simulazione e di CRM (Crisis Resources Management). In Toscana è stato costituito un Laboratorio Regionale per la Gestione del Rischio Clinico in Ostetricia e Ginecologia, composto da un gruppo di professionisti delle aziende delle tre aree vaste, allo scopo di identificare e analizzare alcune delle maggiori aree di criticità nei processi di cura del percorso materno infantile e proporre soluzioni attuabili. Nello specifico, ad esempio, è stato redatto un poster che, affisso in tutte le sale travaglio-parto, fornisca uno strumento di impatto visivo immediato in caso di distocia di spalla, per ricordare in modo sintetico le manovre da effettuare (con relativa illustrazione) in successione corretta. Un poster è stato redatto anche per la rianimazione neonatale in sala parto, tuttavia senza particolare specifico riferimento ai neonati ELGAN: quanto alla gestione cardiorespiratoria di questa categoria di neonati particolarmente vulnerabili, sarebbe auspicabile che ciascun centro di cure intensive (3° livello assistenziale) formulasse, al proprio interno, un protocollo di gestione in sala parto. Come suggerito anche da altri Autori, uno schema del genere dovrebbe comprendere le modalità di approccio ventilatorio, i criteri di utilizzo dei supporti ventilatori non invasivi, i criteri per l’intubazione e per la somministrazione di surfactante; a seguire, per le cure in TIN, i criteri per l’estubazione e il divezzamento dalla ventilazione meccanica o dal supporto respiratorio [25]. Gli eventi avversi sono più frequentemente dovuti alla combinazione infausta di fattori umani come scarsa qualità del lavoro di squadra e scarsa comunicazione, piuttosto che a singoli errori. La
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formazione in simulazione, per training e re-training in CRM, mutuato dall’aeronautica, è un approccio a nostro parere estremamente efficace per ridurre gli errori e migliorare la sicurezza del paziente. L’obiettivo è convertire un “team di esperti” in un “team esperto”, attraverso strategie personalizzate e un approccio ad alta fedeltà, che aiuti anche a modulare, all’interno del gruppo di lavoro, i fattori emotivi oltre che integrare e armonizzare le competenze professionali [26]. In quest’ottica, il Centro di Formazione e Simulazione Neonatale NINA sta implementando molteplici strategie di approccio: i) erogazione di corsi a media e alta fedeltà a gruppi di professionisti, pediatri, neonatologi, anestesisti, medici dell’emergenza, infermieri, ostetrici, operanti sia all’interno dell’Azienda Ospedaliero-Universitaria Pisana che al di fuori, nell’Area Vasta Nord-Ovest della Toscana e su tutto il territorio nazionale; ii) debriefing dell’operato dei professionisti all’interno della U.O., grazie ai dispositivi tecnologici con i quali sono cablate tutte le sale parto e che consentono di videoregistrare gli eventi e riguardarli a distanza, come suggerito in Letteratura, per corroborare l’apprendimento e correggere i propri errori [27]; iii) laboratorio di ricerca, per soluzioni innovative nell’ambito della simulazione, ad esempio la progettazione di un simulatore di apparato respiratorio neonatale, il cui obiettivo è proprio ottimizzare la gestione anche del neonato VLBW/ELBW [28]. Infine, avendo parlato di situazioni di emergenza come la nascita di un neonato VLBW/ELBW e la distocia di spalla, per fortuna relativamente poco frequenti, non possiamo esimerci da un’ultima considerazione. Per assicurare un’alta percentuale di successi è determinante il volume di casistica raggiunto realmente, oltre che in simulazione, in una particolare procedura: questo dato dovrebbe indicare il grado di esperienza raggiunto da una U.O. nel gestire quel particolare tipo di intervento e dovrebbe quindi correlare con la qualità dei risultati.
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Annibale DJ, Bissinger RL. The golden hour. Adv Neonatal Care. 2010;10(5):221-3.
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Shah PS. Extensive cardiopulmonary resuscitation for VLBW and ELBW infants: a systematic review and meta-analyses. J Perinatol. 2009;29(10):655-61.
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Declaration of interest
best? J Pediatr Child Health. 2011;47(10):698-703. 15. Lista G, Castoldi F, Cavigioli F, Bianchi S, Fontana P. Alveolar
The Authors declare that there is no conflict of interest.
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24. Fanos V, Tagliabue P, Greco L, Agostiniani R, Carbone MT, D’Agostino P, Correra A. Neonatal malpractice claims in Italy: how big is the problem and which are the causes? J Matern Fetal Neonatal Med. 2012;25(5):493-7. 25. Sant’Anna GM, Keszler M. Developing a neonatal unit ventilation protocol for the preterm baby. Early Hum Dev. 2012;88(12): 925-9. 26. Eppich WJ, Brannen M, Hunt EA. Team training. Implications for emergency and critical care pediatrics. Curr Opin Pediatr. 2008;20(3):255-60. 27. Finer N, Rich W. Neonatal resuscitation for the preterm infant: evidence versus practice. J Perinatol. 2010;30(Suppl):S57-66. 28. Scaramuzzo RT, Ciantelli M, Baldoli I, Bellanti L, Gentile M, Cecchi F, Sigali E, Tognarelli S, Ghirri P, Mazzoleni S, Menciassi A, Cuttano A, Boldrini A, Laschi C, Dario P. MEchatronic
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030104 doi: 10.7363/030104 Received: 2013 May 19; revised: 2013 Jul 15; accepted: 2013 Jul 20; advance publication: 2014 Jan 10
Review
Il neonato con toxoplasmosi congenita: clinica, terapia e follow-up Lina Bollani, Mauro Stronati Dipartimento Materno Infantile, S.C. di Neonatologia, Patologia Neonatale e Terapia Intensiva, Fondazione IRCCS Policlinico San Matteo, Pavia
Proceedings Articoli Selezionati del “3° Convegno Pediatrico del Medio Campidano” · Guspini · 25 Maggio 2013 Guest Editor: Roberto Antonucci
Abstract
Toxoplamosis is a parasitic zoonosis which occurs worldwide, but is prevalent in Europe, South America and Africa. When infection occurs for the first time during pregnancy, mother to child transmission of the parasite can cause congenital toxoplasmosis. Rate of congenital infection ranges from less than 0.1 to approximately 1 per 1,000 live births. The risk of transmission depends on the gestational age at the time of maternal infection. A diagnosis of congenital toxoplasmosis is usually considered in infants who present: hydrocephalus, chorioretinitis, and intracranial calcifications, but this triade is very rare. Approximately 85% of the infants with congenital toxoplasmosis are clinically normal at birth; however, sequelae of infection may become apparent only months or even years later. Chorioretinitis is the main complication of congenital toxoplasmosis, late onset retinal lesions and relapse can appear many years after birth, but the overall ocular prognosis is satisfactory when infection is identified and treated accordingly. Fortunately, serious neonatal forms and severe neurological impairment have become rare, but prompt treatment of children with convulsions, abnormal muscle tone, hydrocephalus, may improve the prognosis and result in almost normal outcome. For infants who have congenital toxoplasmosis, treatment soon after birth for 1 year with pyrimetamine, sulfadiazine and leukoverin led to remarkable resolution of serious, active disease. A long follow-up is necessary to assess the long-term outcome of children and young adults with congenital toxoplasmosis, that is favourable for the majority of cases. Epidemiological surveillance needs to be improved in order to determine the effectiveness of prevention programs. Keywords
Newborn, congenital toxoplasmosis, retinochoroiditis, risk factors, follow-up.
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Corresponding author Lina Bollani, Dirigente medico I livello, Dipartimento Materno Infantile, S.C. di Neonatologia, Patologia Neonatale e Terapia Intensiva, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; tel.: +390382502518; e-mail: l.bollani@smatteo.pv.it.
How to cite •
Bollani L, Stronati M. Il neonato con toxoplasmosi congenita: clinica, terapia e follow-up. J Pediatr Neonat Individual Med. 2014;3(1):e030104. doi: 10.7363/030104.
•
Bollani L, Stronati M. [Congenital toxoplasmosis: clinical manifestation, treatment and follow-up]. [Article in Italian]. J Pediatr Neonat Individual Med. 2014;3(1):e030104. doi: 10.7363/030104.
Introduzione
La toxoplasmosi è la più importante malattia parassitaria in Europa e la forma congenita ne è l’espressione più grave. La toxoplasmosi congenita si verifica dopo un’infezione primaria, spesso asintomatica, contratta da una gravida recettiva. L’incidenza stimata dell’infezione toxoplasmica acquisita in donne gravide è di circa 1-6/1.000 gravidanze, mentre l’incidenza della toxoplasmosi congenita in Europa si aggira intorno a 0,5-3/1.000 nati vivi, mentre negli USA è intorno a 0,1-1/1.000. Secondo il SYROCOT (Systemic Review on Congenital Toxoplasmosis study group) una gravida infetta darà alla luce un neonato con toxoplasmosi congenita nel 29% dei casi [1]. Il rischio che il toxoplasma superi la barriera placentare, e possa quindi infettare il feto, dipende dall’epoca di gravidanza in cui si verifica la sieroconversione materna. Dai dati più recenti la probabilità di trasmissione è stimata essere il 15% a 13 settimane, il 44% a 26 settimane e il 71% a 36 settimane, per raggiungere il 90% nelle ultime settimane di gestazione [1]. La gravità del danno embrio-fetale è invece inversamente correlata all’epoca gestazionale della sieroconversione materna: i nati da madre con infezione nel primo trimestre di gravidanza più frequentemente mostrano segni di una toxoplasmosi grave; al contrario, la maggior parte di quelli la cui madre ha contratto l’infezione nell’ultimo trimestre (e acquisita dal feto oltre la 30a settimana) ha un’infezione subclinica, confermata dagli accertamenti sierologici specifici eseguiti nel corso del primo anno di vita.
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Nella metanalisi condotta dal SYROCOT, su un gruppo di neonati europei infetti, il 19% presenta almeno un tipo di manifestazione clinica nel primo anno di vita, in particolare il 14% ha lesioni oculari e il 9% lesioni intracraniche diagnosticate mediante l’ecografia cerebrale [1]. Lo stesso studio rileva che, con il progredire dell’età gestazionale al momento della sieroconversione materna, si riduce il rischio di lesioni intracraniche dal 20,6%, per un’infezione del primo trimestre, allo 0,6%, per quelle dell’ultimo trimestre; il declino della probabilità di avere lesioni oculari risulta invece meno significativo [1]. Esistono in natura tre differenti ceppi virulenti designati come tipo I, II e III, che differiscono in virulenza e pattern epidemiologici di occorrenza. Il genotipo II è quello maggiormente frequente in Europa, mentre i genotipi I/III sono per lo più isolati negli animali e nel Sud America. Anche la gravità clinica della forma acquisita è variabile nelle diverse realtà geografiche, sia per la dose infettante, che per differenze di virulenza nei 3 ceppi (tipo I, II e III) geneticamente individuati di T. gondii. In Africa e America Centrale sono inoltre stati isolati ceppi cosidetti atipici (ricombinanti), che presentano generalmente virulenza maggiore [2]. Manifestazioni cliniche
La toxoplasmosi congenita, che in epoca neonatale è del tutto asintomatica nell’85% dei casi, può manifestarsi alla nascita o nei primi mesi di vita, con sintomi che variano notevolmente per gravità ed interessamento d’organo, o divenire evidente nell’infanzia o nell’adolescenza attraverso deficit visivi o sequele tardive a carico del sistema nervoso centrale. La classica triade (idrocefalia, calcificazioni intracraniche e corioretinite), è divenuta molto rara, ma comunque 2/3 delle manifestazioni cliniche coinvolgono il sistema nervoso centrale e l’occhio. Le manifestazioni neonatali, variamente presenti, comprendono: idrocefalia, microcefalia, calcificazioni endocraniche, corioretinite, cataratta, convulsioni, nistagmo, ittero, petecchie, anemia, prematurità e basso peso; nessuno dei sintomi è patognomonico per toxoplasmosi, ma tutti possono essere riconducibili ad altre infezioni congenite (CMV, Herpes simplex, rosolia, sifilide) o ad una infezione generalizzata [3]. Ne deriva che, in assenza di diagnosi prenatale, il sospetto di toxoplasmosi congenita, nei casi
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asintomatici, nasce eccezionalmente sulla base dell’esame obiettivo, ma quasi sempre sulla base dell’anamnesi sierologica specifica della madre in gravidanza. Il neonato con infezione subclinica è un neonato asintomatico in cui gli esami sierologici e/o parassitologici pre- o post-natali abbiano documentato l’infezione. Le conseguenze oftalmologiche sono al primo posto tra le manifestazioni di una toxoplasmosi congenita, in particolare la corioretinite è quella più frequentemente descritta, con incidenza variabile dal 9% al 31% [4]. Dal punto di vista patogenetico, la corioretinite è un processo infiammatorio che inizia negli strati profondi della retina e secondariamente interessa la coroide. La reazione infiammatoria (con edema e infiltrazione dei polimorfonucleati, leucociti, linfociti e plasmacellule) esita in distruzione e disorganizzazione degli strati retinici. In oftalmoscopia indiretta, il reperto tipico della corioretinite toxoplasmica mostra un’evidente lesione focale biancastra, descritta come “faro nella nebbia” dovuta alla lesione attiva a livello retinico, circondata da una intensa reazione infiammatoria vitreale; le lesioni ricorrenti sono in genere descritte ai bordi di cicatrici corioretiniche. Pochi autori hanno preso in considerazione le altre possibili patologie oftalmologiche descritte nella toxoplasmosi congenita e che possono contribuire al danno della funzione visiva: strabismo, microftalmia, cataratta, distacco retinico, atrofia del nervo ottico, iridociclite, nistagmo, glaucoma. Alcune di queste manifestazioni si sviluppano più di frequente come conseguenza di un focolaio corioretinico, e in particolare rappresentano un marker indiretto della gravità della toxoplasmosi oculare, soprattutto quando vi siano lesioni che interessano la macula. Molti casi di strabismo (esoexotropia), attribuiti a miopia, nell’86% dei casi erano dovuti ad interessamento maculare [5]. Tra gli accertamenti diagnostici utili in epoca neonatale e nei primi mesi di vita, l’ecografia cerebrale riveste un ruolo importante per mettere in evidenza calcificazioni cerebrali, dilatazione ventricolare, poroencefalia. Le calcificazioni derivano dal deposito di calcio entro aree di necrosi che fanno seguito a fenomeni di vasculite riguardanti soprattutto la regione periacqueduttale e periventricolare. In linea di massima sono descritti due tipi di calcificazioni: multiple sparse nella materia bianca e nell’area periventricolare delle regioni occipito-parietali e
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temporali, o strie curvilineari nei gangli della base e nella testa del nucleo caudato [6]. Tra le più gravi manifestazioni cliniche di interessamento del SNC, l’idrocefalia deriva o da ostruzione dei ventricoli da parte di tessuto necrotico a seguito di una encefalite grave che porta a distruzione della normale architettura cerebrale, o da distruzione del tessuto cerebrale periventricolare. L’idrocefalo da ostruzione dell’acquedotto del Silvio con dilatazione dei ventricoli laterali può talvolta essere l’unica manifestazione di una toxoplasmosi congenita. Le lesioni ampiamente distruttive possono anche dare un quadro gravissimo di poroencefalia. Un quadro completo delle manifestazioni cliniche della toxoplasmosi congenita e della loro frequenza, viene riportato nella Tab. 1. Terapia
Il trattamento di elezione nella toxoplasmosi congenita rimane l’associazione pirimetamina
Tabella 1. Segni e sintomi in 210 soggetti con infezione congenita certa da T. gondii [6, trad. e mod.]. Segni clinici
Neonati esaminati
Prematurità Peso alla nascita < 2.500 g Peso alla nascita ≥ 2.500-3.000 g
210
IUGR
N° positivi (%) 8 (3.8) 5 (7.1) 13 (6.2)
Postmaturità
108
9 (8.3)
Ittero
201
20 (10)
Epatosplenomegalia
210
9 (4.2)
Porpora trombocitopenia
102
3 (1.4)
Anomalie emocromo (anemia, eosinofilia)
210
9 (4.4)
Microcefalia
210
11 (5.2)
Idrocefalia
210
8 (3.8)
Convulsioni
210
2 (5.7)
Ritardo psicomotorio
210
8 (3.8)
Calcificazioni endocraniche (Rx)
210
11 (5.2)
Anomalie ecografiche
49
24 (11.4)
Anomalie TAC cerebrale
13
5 (10)
Anomalie EEG
191
11 (84)
Anomalie del liquor
163
16 (8.3)
Microftalmia
210
56 (34.2)
Strabismo
210
6 (2.8)
Corioretinite
210
11(5.2)
Unilaterale
34 (16.1)
Bilaterale
12 (5.7)
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e sulfamidico. Entrambi i farmaci sono efficaci sulla forma attiva del ciclo vitale del parassita (tachizoita), il razionale della terapia durante l’infezione acuta è appunto quello di distruggere i tachizoiti e prevenirne la trasformazione in nuove cisti, su cui questi farmaci non sono attivi. [7] Definita la diagnosi, la terapia con pirimetamina e sulfadiazina dovrebbe essere intrapresa con lo scopo di prevenire la notevole incidenza di sequele tardive segnalate nei bambini che ricevono inadeguato o nessun trattamento. La pirimetamina, scoperta nel 1950 da una serie di ricerche impostate allo scopo di migliorare l’attività antimalarica di alcune sostanze, fu dapprima utilizzata su animali infettati in via sperimentale con T. gondii e quindi nell’uomo. Somministrata per via orale, la pirimetamina è assorbita lentamente, ma completamente, a livello del tubo gastroenterico, presenta un’emivita sierica nel neonato di circa 60 ore, rimane a lungo nell’organismo e raggiunge nel liquor una concentrazione di circa il 10-20% dei concomitanti livelli sierici. La pirimetamina è utilizzata in associazione ad un sulfamidico, grazie all’effetto sinergico contro il T. gondii; l’attività combinata dei due farmaci è di otto volte superiore a quella ottenibile con la somma dei singoli effetti. Grazie a questa azione sinergica sulla via di sintesi dei folati, è possibile ridurre il dosaggio della pirimetamina e quindi moderarne gli effetti ematotossici. In particolare, la pirimetamina come meccanismo d’azione inibisce la diidrofolato reduttasi, importante nella sintesi delle basi pirimidiniche; ne deriva pertanto una possibile, ma reversibile, depressione del midollo osseo. La neutropenia, comunque reversibile, è l’effetto tossico più frequente benché si possa verificare anche riduzione delle piastrine ed anemia [8]. Meno frequentemente possono aversi disturbi gastrointestinali e vomito; l’intossicazione acuta da sovradosaggio accidentale, nei neonati, dà inappetenza, vomito, ma soprattutto ipereccitabilità e convulsioni [8, 9]. Il dosaggio della pirimetamina è di 1 mg/kg/die ogni 12 ore per i primi 2 giorni di terapia, quindi è di 1 mg/kg/die in unica somministrazione per 2-6 mesi; oltre questo periodo si prosegue con la stessa dose per tre giorni alla settimana (lunedì, mercoledì, venerdì) fino all’anno [6]. Nel nostro reparto viene riservato il trattamento quotidiano di pirimetamina per i primi sei mesi ai neonati con sintomatologia clinica, mentre i neonati con infezione subclinica, dopo i primi due
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mesi di trattamento, proseguono con tre giorni alla settimana fino all’anno. I sulfamidici, in base alle loro caratteristiche chimiche, sono in grado di inibire la diidrofolatosintetasi necessaria per la sintesi dell’acido folico nella moltiplicazione dei batteri. Nella terapia della toxoplasmosi, la sulfadiazina sembra essere il sulfamidico più attivo, somministrata per via orale è rapidamente e completamente assorbita dal canale gastroenterico, l’emivita plasmatica di 1219 ore la rende preferibile ad altri sulfamidici, la sua concentrazione nel liquor raggiunge il 50% di quella plasmatica; escreta per via renale, se ne deve considerare l’effetto nei pazienti con insufficienza renale e nei soggetti con deficit di G6PD. La sulfadiazina si somministra al dosaggio di 100 mg/kg/die in 2 somministrazioni giornaliere per 12 mesi di terapia [6]. La tollerabilità di entrambi i farmaci è stata giudicata buona e non sono segnalati effetti di tossicità, né discrasie ematologiche o patologie maligne a insorgenza tardiva, nei neonati che siano stati trattati a lungo con pirimetamina e sulfadiazina [8]. Per prevenire la depressione midollare, si deve sempre associare l’acido folinico al dosaggio di 1020 mg tre volte alla settimana [6]; altri preferiscono 50 mg in dose unica settimanale. Qualora compaia una transitoria neutropenia in corso di terapia, può essere necessario aumentare la prescrizione dell’acido folinico e/o effettuare una temporanea sospensione della pirimetamina. Sono comunque necessari controlli programmati della crasi ematica, ogni 7-15 giorni secondo alcuni autori, ogni 15-30 giorni secondo altri; inoltre è anche opportuno effettuare periodicamente un esame urine per evidenziare un’eventuale cristalluria dovuta alla scarsa solubilità della sulfadiazina. Questo inconveniente può essere tuttavia evitato con una buona idratazione del paziente. In Francia, è routinario l’impiego del Fansidar®, in cui la pirimetamina è in combinazione con la sulfadossina, avente emivita di 120-195 ore e legame plasmatico del 90%. Questa associazione offre il vantaggio di ridurre il numero delle somministrazioni ad un’unica dose ogni 10-14 giorni e di migliorarne la compliance, ma sono state descritte rare manifestazioni cutanee anche gravi, da intolleranza del sulfamidico long acting, quali rash, epidermolisi, sindrome di Lyell, che hanno imposto la sospensione della terapia [7]. Sono ancora insufficienti i dati di farmacocinetica sia dell’azitromicina, che sembra avere
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buona concentrazione tessutale ed intracellulare oltre ad attività in vivo contro il T. gondii, sia dell’atovaquone, che sembra essere attivo sulle forme cistiche, ma il cui uso non è ancora consentito nella gravida e nel neonato. Entrambi questi farmaci sono comunque stati utilizzati in seconda battuta, in soggetti immunocompromessi che avevano manifestato reazioni avverse alla pirimetamina e sulfamidici [7, 10]. Ad oggi, non vi è consensus circa la durata ottimale della terapia; in Danimarca è prescritta per tre mesi, secondo le raccomandazioni dell’Organizzazione Mondiale della Sanità, sostenuta dal razionale che la durata della parassitemia può persistere fino a quattro settimane; in alcuni centri della Francia e in Svizzera è proseguita fino a 12-24 mesi [7]. In Francia è attualmente in corso uno studio (TOSCANE) randomizzato controllato con l’obiettivo principale di valutare l’efficacia di due strategie differenti nella prevenzione della corioretinite nelle forme non severe di toxoplasmosi congenita. La terapia iniziale, con l’associazione pirimetamina e sulfamidico, è effettuata in entrambi i gruppi per tre mesi; in seguito un gruppo prosegue fino a nove mesi di età con l’associazione pirimetamina e sulfadossina (Fansidar®), mentre nell’altro la terapia viene sospesa. La durata complessiva dello studio è di due anni, durante i quali si mantiene uno stretto follow-up clinico ed oftalmologico dei neonati reclutati [11]. Se il neonato, oltre ai segni clinici dell’infezione, dovesse presentare processi infiammatori (corioretinite attiva, iperproteinorrachia, ecc.) sarà opportuno associare un corticosteroide (prednisone: 1 mg/kg/die in due dosi per os) che andrà gradualmente sospeso dopo la risoluzione dei segni infiammatori [6]. Follow-up
Il follow-up del neonato con infezione congenita riguarda in particolare l’aspetto oftalmologico, ecografico, neurologico, uditivo e sierologico. Wallon e collaboratori per primi si preoccuparono di valutare dal punto di vista prognostico la possibilità della comparsa tardiva di nuove lesioni oculari o della ricorrenza di lesioni già note attraverso un follow-up proseguito fino all’età di 14 anni in bambini con infezione congenita adeguatamente trattati. Il 24% dei soggetti reclutati sviluppava almeno una lesione oculare nel corso del follow-up della durata media di sei anni e il tempo
Il neonato con toxoplasmosi congenita
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intercorso tra la prima e la seconda lesione oculare variava da 1,5 a 10 anni [4]. In uno studio di Faucher e collaboratori, l’incidenza della lesione retinica interessava il 18,9% degli infetti e la prima lesione retinica compariva, in un caso, 12 anni dopo la nascita [12]. Dal momento che le patologie oculari associate alla corioretinite possono comparire più tardivamente nella vita, e talvolta rimanere imprevedibili, è importante proseguire un follow-up a lungo termine, soprattutto nei bambini con lesioni della macula. I genitori debbono essere consapevoli, non solo del rischio della corioretinite, ma anche delle patologie associate e delle loro conseguenze. Allo scopo di individuare fattori di rischio predittivi per lo sviluppo di corioretinite, è stato condotto uno studio retrospettivo su 300 neonati con toxoplasmosi congenita trattata con pirimetamina e sulfadiazina per un anno. In un’analisi sia univariata che multivariata, è risultato che la presenza di calcificazioni cerebrali nell’ecografia cerebrale eseguita alla nascita accresceva il rischio di sviluppare una corioretinite prima dei due anni di vita [13]. In uno studio prospettico condotto in 6 centri europei, la presenza di anomalie endocraniche all’ecografia fetale e di manifestazioni cliniche neurologiche o sistemiche, entro i quattro mesi di vita, erano le principali condizioni predittive di una corioretinite entro i quattro anni di vita. L’implicazione pratica di questi risultati dovrebbe essere che si richiede una sorveglianza oftalmologica maggiore nei soggetti che alla nascita presentano calcificazioni endocraniche [14]. C’è uniformità tra i vari centri nel programmare un follow-up che preveda un controllo del fondo oculare, eseguito in oftalmoscopia indiretta, ogni tre mesi nel primo anno di vita, ogni sei mesi nel secondo e almeno una volta all’anno successivamente, senza limiti di età, tenuto conto che la compliance migliora considerevolmente con gli anni. L’effetto delle lesioni sulla capacità visiva dipende dalla loro relazione topografica rispetto alla macula e al nervo ottico; l’acuità visiva non è danneggiata dalle lesioni periferiche, e quelle che interessano la macula in genere sono monolaterali. Peyron e collaboratori, mediante lo Psychological General Well-Being Index e attraverso un questionario Visual Functioning (VF14), hanno indagato la qualità di vita (ansia, depressione, self control, vitalità) di adulti noti per avere contratto la toxoplasmosi congenita. Il questionario riguardava le difficoltà correlate al deficit visivo
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nell’adempimento dei compiti routinari della vita quotidiana. Gli Autori concludono che, nella maggior parte dei casi, la toxoplasmosi congenita non compromette la qualità di vita a lungo termine, o limita le performance visive dei pazienti affetti; inoltre non sembra esservi evidenza di limitazioni nelle funzioni cognitive poiché il livello scolastico è persino più alto di quello della popolazione generale [15]. A fronte di numerosi studi, per lo più focalizzati sulla patologia retinica della toxoplasmosi congenita, si ha poca documentazione sulle valutazioni sistematiche e prospettiche circa l’aspetto neurologico, cognitivo e motorio di questi bambini; soprattutto per la difficoltà di condurre un follow-up neurologico a lungo termine. Nelle pubblicazioni degli anni ’60, si distinguevano sequele neurologiche maggiori (idrocefalia, microcefalia, convulsioni, grave ritardo psicomotorio) e minori (disfunzione cerebellare lieve e ritardo transitorio dello sviluppo psicomotorio). I primi studi hanno dimostrato che i neonati con toxoplasmosi congenita non trattati con anomalie sistemiche e neurologiche alla nascita sviluppavano quasi costantemente ritardo mentale, convulsioni e spasticità. Autori come Eichenwald (1960), Wilson (1980), Koppe (1986), segnalavano infatti che i neonati con manifestazioni neurologiche alla nascita, se non trattati, a quattro anni di età avevano oltre l’85% di probabilità di avere ritardo mentale, l’81% di manifestare convulsioni, il 60% di perdere la vista, il 33% di idro/microcefalia e dal 14% fino al 26% di sordità [16-18]. Attualmente, gravi anomalie neurologiche sono divenute rare, anche perché, qualora lo screening ultrasonografico fetale mostri importanti lesioni intracraniche, in diversi centri è proposta l’interruzione di gravidanza [19]. Anomalie neurologiche sono comunque possibili e i fattori predisponenti sembrano essere l’infezione materna del primo trimestre di gravidanza, la mancanza di terapia prenatale, la presenza di corioretinite e segni clinici alla nascita. Una tempestiva terapia dei neonati con segni neurologici (idrocefalia, convulsioni, anomalie del tono muscolare) può decisamente migliorare la prognosi e l’outcome neurologico [20, 21]. Roizen afferma che gli esiti neurologici e di sviluppo sono stati significativamente migliori per la maggior parte dei bambini trattati rispetto ai non trattati o trattati per un solo mese. Benché il livello delle funzioni cognitive di quelli molto
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compromessi fosse inferiore a quello dei fratelli non infettati, non si è osservato un deterioramento significativo della funzione neurologica e cognitiva dei bambini posti in terapia [22]. Una sistematica review sulla prevalenza della sordità neurosensoriale nell’infezione toxoplasmica congenita è molto rassicurante, infatti questa risulta essere nulla nei neonati trattati per 12 mesi con terapia specifica iniziata precocemente [23]. Questo dato è confermato anche dal National Collaborative Chicago-based, Congenital Toxoplasmosis Study, che segnala nessun caso di perdita dell’udito tra neonati con sintomatologia neurologica moderata o severa trattati alla nascita [21]. Conclusioni
Sforzi ulteriori sono necessari per attuare più efficaci misure di prevenzione dell’infezione in gravidanza, sia attraverso una capillare informazione ed educazione sanitaria, sia, soprattutto, con uno screening mensile nelle gravide, al fine di intraprendere al più presto una terapia specifica [24]. Rima McLeod, in una pubblicazione che ripercorre la storia della toxoplasmosi congenita, conclude in discussione con questa osservazione: “Attualmente i dati della letteratura disponibili suggeriscono che le strategie terapeutiche correntemente utilizzate si sono dimostrate, in trials clinici controllati, efficaci e sicure; pertanto siamo obbligati al trattamento di questa malattia con farmaci di dimostrata efficacia contro il parassita. Questo perché in assenza del trattamento si possono sviluppare lesioni oculari e cerebrali che durano tutta la vita” [25]. Declaration of interest The Authors declare that there is no conflict of interest.
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030105 doi: 10.7363/030105 Received: 2013 May 09; revised: 2013 Aug 23; accepted: 2013 Aug 23; advance publication: 2014 Jan 10
Review
Infezione perinatale da Streptococco Gruppo B Giampiero Capobianco1, Antonio Balata2, Maria Chiara Mannazzu3, Giorgio Olzai3, Claudio Cherchi3, Giuseppe Virdis1, Francesco Dessole1, Matteo Busacca1, Erich Cosmi4 1
Clinica Ostetrica e Ginecologica, Dipartimento di Scienze Chirurgiche, Microchirurgiche e Mediche,
Università degli Studi di Sassari 2
Unità Operativa Complessa di Pediatria e Neonatologia, ASL Olbia
3
Neonatologia e TIN, AOU Sassari
4
Clinica Ostetrica e Ginecologica, Università di Padova
Proceedings Articoli Selezionati del “3° Convegno Pediatrico del Medio Campidano” · Guspini · 25 Maggio 2013 Guest Editor: Roberto Antonucci
Abstract
The bacterium group B Streptococcus (GBS) is the leading cause of neonatal bacterial infection in developed countries. GBS is a Gram positive bacterium located primarly in the gastrointestinal tract and genitourinary system. The presentation of GBS neonatal disease includes pneumonia, respiratory distress and meningitis. The newborn is colonized during passage through the birth canal. The mother, when colonized, is usually asymptomatic. GBS is present in the vagina of about 10-15% of women towards the end of pregnancy. During the first 7 days of life (early onset infection) about 3% of the colonized children develop the infection, especially meningitis, that may be fatal or leave sequelae; this infection predominantly results from vertical transmission of GBS from colonized mothers during the intrapartum period. Infection of GBS from one week to 90 days of age (late onset infection) results from transmission after birth. In Italy, according to national guidelines of pregnancy 2011, a culture-based screening approach is performed: all patients are screened for vaginal and rectal GBS between 36 and 37 weeks of gestation and if found positive are then treated with prophylactic antibiotics during labor. Intravenous intrapartum antibiotic prophylaxis (IAP) in women who carry GBS, from the onset of labour until delivery (given ≥ 4 hours before delivery), reduces the risk of early onset neonatal GBS infection from 4.7% to 0.4%. Penicillin G is the antibiotic of choice. In case of penicillin allergy, erythromicin or clindamycin are generally active against GBS and carry no particular risks for the infant.
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Keywords
Group B Streptococcus (GBS), neonatal early onset infection, intrapartum antibiotic prophylaxis, Penicillin G, screening, neonatal sepsis. Corresponding author Giampiero Capobianco, MD, Ph.D, Gynecologic and Obstetric Clinic, Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Viale San Pietro 12, 07100, Sassari, Italy; tel.: +39079228482; fax: +39079228265; e-mail: capobia@uniss.it.
How to cite •
Capobianco G, Balata A, Mannazzu MC, Olzai G, Cherchi C, Virdis G, Dessole F, Busacca M, Cosmi E. Infezione perinatale da Streptococco Gruppo B. J Pediatr Neonat Individual Med.
dio precoce), caratterizzata principalmente da polmonite, meningite, sepsi che può essere fatale o può indurre gravi sequele. L’infezione da GBS late onset (dopo 7 giorni di vita) non sembra essere collegata alla colonizzazione intrapartum ma piuttosto ad un’infezione nel post partum [2]. In Emilia-Romagna, uno studio di popolazione ha rilevato, in neonati di età inferiore a 3 mesi (periodo 2003-2005), un’incidenza di malattia da GBS pari a 0,5 per 1.000 nati vivi [3]. Il rischio di infezione early onset aumenta in caso di parto prematuro, febbre materna durante il parto e rottura prematura della membrane amniocoriali da più di 18 ore prima del parto. Questi fattori di rischio si osservano nel 50-75% dei casi di infezione early onset [2]. Prevenzione dell’infezione da GBS
2014;3(1):e030105. doi: 10.7363/030105. •
Capobianco G, Balata A, Mannazzu MC, Olzai G, Cherchi C, Virdis G, Dessole F, Busacca M, Cosmi E. [Group B streptococcal perinatal infection]. [Article in Italian]. J Pediatr Neonat Individual Med. 2014;3(1):e030105. doi: 10.7363/030105.
Introduzione
Lo Streptococco di gruppo B (Streptococcus agalactiae, GBS) è la principale causa di infezione neonatale grave nei Paesi sviluppati. Il neonato è colonizzato durante il passaggio nel canale del parto. Il GBS può essere presente nel tratto gastrointestinale o genitale della donna. L’infezione vaginale nella paziente in gravidanza è, di solito, asintomatica [1-4]. Al contrario, nel neonato l’infezione da GBS può produrre quadri clinici di estrema gravità; nelle forme ad esordio precoce (early onset disease) si può avere un quadro di sepsi, di polmonite e, meno frequentemente, di meningite [4]; nelle forme ad esordio tardivo (late onset disease), le principali manifestazioni cliniche sono rappresentate dall’osteomielite, dall’artrite settica, dalla cellulite o da altre infezioni localizzate. Dati epidemiologici
In Italia, uno studio recente eseguito in una popolazione di donne gravide del Nord-Italia ha stimato una prevalenza di colonizzazione vaginale del 17,9% [1]. Circa un terzo dei neonati di donne portatrici è colonizzato al momento del parto. Durante i primi 7 giorni di vita, circa il 3% dei neonati colonizzati può sviluppare un’infezione early onset (ad esor-
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Nel 1996 il Centers for Disease Control and Prevention (CDC) americano ha pubblicato le prime linee guida per la prevenzione della malattia da GBS, che sono state aggiornate nel 2002 e nel 2010 [4-10]. La Tab. 1 mostra il sistema di punteggio basato sulle prove di evidenza per determinare la forza delle raccomandazioni [4, 11]. Secondo queste linee guida si possono utilizzare due approcci per identificare le pazienti che dovrebbero essere trattate con profilassi antibiotica intrapartum; il primo approccio è basato sul trattamento antibiotico solo sulla base di fattori di rischio, quali prolungata rottura prematura delle membrane amniocoriali (> 18 ore), febbre materna intrapartum (≥ 38°C) (A II), parto prematuro (< 37 settimane), precedente figlio con infezione neonatale, batteriuria durante la gravidanza (A III); il secondo approccio, adottato in Italia in base alle Linee Guida sulla Gravidanza Fisiologica, ISS, SNLG, aggiornamento 2011 [8] (Tab. 2), è quello basato sullo screening universale vagino-rettale tra 35 e 37 settimane di gestazione con trattamento antibiotico intrapartum solo delle donne risultate positive (A II). Infatti, la colonizzazione da GBS può essere intermittente o transitoria, perciò il valore predittivo positivo di un esame colturale eseguito a più di 5 settimane dal parto è basso e risulta di scarsa utilità clinica. Un confronto tra questi 2 approcci in uno studio americano pubblicato sul New England Journal of Medicine nel 2002 ha dimostrato una maggiore efficacia dello screening colturale universale rispetto a quello basato sui soli fattori di rischio (RR: 0,46; IC 95%: 0,36-0,60) [9].
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Tabella 1. Sistema di punteggio basato sulle prove di evidenza per determinare la forza delle raccomandazioni [4, 5, 11]. Categoria
Definizione
Raccomandazione
Forza delle raccomandazioni A
Forte evidenza di efficacia e reali benefici clinici
Fortemente raccomandata
B
Forte o moderata evidenza di efficacia ma solo limitati benefici clinici
Generalmente raccomandata
C
Insufficiente evidenza di efficacia o efficacia che non eccede i possibili effetti avversi
Opzionale
D
Moderata evidenza di inefficacia o di effetti avversi
Generalmente non raccomandata
E
Forte evidenza di inefficacia o di effetti avversi
Mai raccomandata
Qualità dell’evidenza a supporto della raccomandazione I
Evidenza derivante almeno da uno studio controllato appropriatamente randomizzato o da uno studio sperimentale di laboratorio rigorosamente disegnato replicato da un ricercatore indipendente
II
Evidenza derivante almeno da uno studio controllato non randomizzato, studi analitici di coorte o caso-controllo (preferibilmente da più di un centro), studi di serie temporali multiple, risultati inattesi da studi non controllati, o una certa evidenza da esperimenti di laboratorio
III
Evidenza da opinioni di autorità riconosciute basate su esperienza clinica o di laboratorio, studi descrittivi o rapporti di commissioni di esperti
Tabella 2. Raccomandazioni Italiane [8]. • Tutte le pazienti in gravidanza alle 36-37 settimane devono eseguire screening dell’infezione da GBS mediante tampone vaginale e rettale. • Le donne con tampone positivo devono ricevere un trattamento antibiotico intrapartum. • Tale approccio consente di ridurre il numero delle infezioni neonatali da GBS early onset. • Prima delle 37 settimane compiute vi è l’indicazione alla profilassi antibiotica intrapartum indipendentemente dal risultato del test. GBS: Streptocco di gruppo B (Streptococcus agalactiae).
Un esame urine positivo per la presenza di GBS è considerato un segno di importante colonizzazione materna e di aumentato rischio di infezione neonatale, pertanto un’indicazione al trattamento antibiotico [8]. Diversi studi clinici randomizzati hanno dimostrato che la profilassi antibiotica endovena intrapartum nelle donne portatrici di GBS, da iniziare dall’inizio del travaglio fino al momento del parto, consente la riduzione del rischio di infezione early onset dal 4,7% allo 0,4% (p = 0,02) [2]. La penicillina G (benzylpenicillina) è l’antibiotico di scelta mentre la penicillina A (ampicillina: 2 g e.v. all’inizio del travaglio e 1 g ogni 4 ore fino al momento del parto) è una valida alternativa (A I) [2, 8]. Infatti, un trial su 352 donne, che ha confrontato ampicillina e penicillina intrapartum, non ha dimostrato differenze significative negli esiti neonatali o materni [10]. L’antibioticoprofilassi intrapartum è considerata adeguata se è iniziata almeno 4 ore prima del parto (C III). In caso di allergia alle penicilline, cefazolina
Infezione perinatale da Streptococco Gruppo B
(B II) (2 g e.v., seguiti da 1 g ogni 8 ore) o eritromicina (500 mg e.v. ogni 6 ore) o clindamicina (900 mg e.v. ogni 8 ore) sono generalmente attivi contro il GBS (C III). Il maggior rischio associato con l’assunzione della penicillina, soprattutto per le forme iniettabili, è la reazione anafilattica che può avere serie conseguenze per la partoriente e per il feto e la cui frequenza stimata è di 5 casi ogni 10.000 trattamenti. Il rischio di reazione anafilattica può essere ridotto se, al momento della profilassi, viene eseguita un’accurata anamnesi allergologica e si usa un antibiotico alternativo in caso di pregressa storia di anafilassi. Management ostetrico italiano: prima del parto
Screening prenatale con tampone vaginale e rettale in tutte le donne gravide tra 36 e 37 settimane di gravidanza (A II) [8]. La gravida che risulta positiva allo screening non va trattata durante la gravidanza, salvo in presenza di batteriuria (segno di colonizzazione intensa) che deve essere invece trattata sia in gravidanza che al parto [12]. Non devono eseguire lo screening [12]: • gestanti che hanno già avuto un neonato con sepsi da GBS; • gestanti che hanno presentato batteriuria da GBS in qualunque fase della gravidanza attuale, poiché esse dovranno essere comunque obbligatoriamente profilassate. La batteriuria è significativa solo se GBS presente in concentrazioni > 100.000 ufc/ml.
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Non è necessaria la profilassi nelle gravide con tampone vaginale e rettale positivo per GBS alle quali viene effettuato un taglio cesareo fuori travaglio a membrane integre (es. taglio cesareo programmato) indipendentemente dall’età gestazionale (C III) [12]. Le donne candidate a taglio cesareo programmato dovrebbero, comunque, essere sottoposte a screening vaginale e rettale routinario per la ricerca del GBS a 36-37 settimane di gestazione perché l’esordio del travaglio o la rottura delle membrane può capitare prima del taglio cesareo programmato e, in queste circostanze, le donne con colonizzazione da GBS devono ricevere la profilassi antibiotica intrapartum (A II). In caso di tampone vaginale e rettale non noto o non eseguito sono comunque da profilassare le donne che presentano fattori di rischio (per trasmissione verticale) quali febbre intrapartum (≥ 38°C, sospetta corionamnionite), rottura prematura della membrane amniocoriali da oltre 18 ore, età gestazionale < 37 settimane, precedente figlio con infezione neonatale e batteriuria durante la gravidanza. In tale situazione bisogna eseguire il prima possibile il tampone vaginale e rettale e programmare l’osservazione del neonato fino a disporre del risultato del tampone [12]. Il personale ostetrico/ginecologico è tenuto a scrivere in cartella se la profilassi è stata eseguita, il farmaco usato, il dosaggio, l’ora di somministrazione e deve comunicare questi dati al neonatologo. Management neonatologico: prevenzione nei neonati secondo le linee guida CDC, 2010
Per individuare il più precocemente possibile i casi di probabile sepsi neonatale è necessario utilizzare l’algoritmo presentato nella Fig. 1 [4, 5]. Il neonato con segni di sepsi (alterazioni della temperatura, segni di distress respiratorio, crisi di apnea, colorito pallido grigiastro, cianosi, torpore, letargia, difficoltà nell’alimentazione) dovrebbe essere sottoposto ad un valutazione diagnostica completa comprendente emocoltura, esame emocromocitometrico completo (CBC) con formula leucocitaria e conta piastrinica, proteina C reattiva (PCR), procalcitonina (PCT), radiografia del torace (se presente un qualsiasi segno di patologia respiratoria), e la rachicentesi (se il paziente è abbastanza stabile da tollerare la procedura) (A II). In questi casi è sempre indicato il trattamento antibiotico empirico ad ampio spettro. Viene solitamente utilizzata l’associazione ampicillina-aminoglicoside con posologie graduate
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in base all’età gestazionale e all’intervallo dalla nascita. Gli aminoglicosidi dovrebbero essere somministrati monitorando la concentrazione ematica del farmaco. I neonati in buone condizioni cliniche, nelle cui madri era stata sospettata una corionamnionite, dovrebbero essere sottoposti a una valutazione laboratoristica limitata e ricevere la terapia antibiotica in attesa dei risultati colturali (A II). La valutazione dovrebbe comprendere emocoltura ed emocromo con conta differenziale dei leucociti e delle piastrine, senza radiografia del torace o rachicentesi. La consultazione con il personale ostetrico, per valutare se è stata sospettata una corioamnionite, è importante per decidere la gestione del neonato (C III). I neonati che appaiono in buone condizioni cliniche, le cui madri non hanno presentato una corionamnionite e per le quali non era indicata la profilassi contro lo GBS, dovrebbero ricevere cure di routine (C III). I neonati in buone condizioni cliniche, indipendentemente dall’età gestazionale, le cui madri hanno ricevuto adeguata profilassi intrapartum contro lo GBS (penicillina, ampicillina o cefazolina ≥ 4 ore prima del parto), devono essere osservati per almeno 48 ore, e non devono essere sottoposti a nessun esame diagnostico di routine (B III). Questi neonati possono essere dimessi già nelle prime 24 ore dopo il parto, se gli altri criteri di dimissione sono stati rispettati, se esiste la possibilità di un immediato accesso alle cure mediche, e se è presente una persona in grado di rispettare pienamente le istruzioni per l’osservazione a casa (C III). I neonati che appaiono in buone condizioni cliniche, le cui madri non hanno ricevuto profilassi contro lo GBS nonostante vi fosse un’indicazione per la profilassi contro lo GBS o nelle quali è stata praticata una profilassi inadeguata, se sono in buone condizioni, hanno un’età gestazionale ≥ 37 settimane e la durata della rottura delle membrane prima della nascita era < 18 ore, devono essere osservati per un periodo di almeno 48 ore, e non è raccomandato nessun test diagnostico di routine (B III). Se il neonato è in buone condizioni ed ha un’età gestazionale < 37 settimane o la rottura delle membrane è avvenuta 18 o più ore prima della nascita, deve essere sottoposto ad una valutazione laboratoristica limitata e ad una osservazione per almeno 48 ore (B III). Le principali modifiche introdotte da queste linee guida del 2010 CDC (rispetto a quelle del 2002) sono riportate nella Tab. 3 [4, 5].
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Figura 1. Algoritmo per la prevenzione nei neonati secondo le linee guida CDC, 2010 [4, 5].
Segni di sepsi neonatale?
SÌ
Valutazione diagnostica completa * Terapia antibiotica †
NO
Corioamnionite materna? §
SÌ
Terapia antibiotica †
NO Profilassi per GBS indicata per la madre?
Valutazione diagnostica limitata ¶
NO
Assistenza clinica di routine † †
SÌ
Osservazione ≥ 48 ore ††§§
SÌ Madre che ha ricevuto penicillina, ampicillina o cefazolina per ≥ 4 ore prima del parto? NO E.G. ≥ 37 settimane o durata della rottura delle membrane < 18 ore?
SÌ
GBS: Streptocco di gruppo B (Streptococcus agalactiae); E.G.: età gestazionale. * La valutazione diagnostica completa comprende emocoltura, un esame emocromocitometrico completo (CBC) con formula leucocitaria e conta piastrinica, radiografia del torace (se sono presenti anomalie respiratorie), e la puntura lombare (se il paziente è stabile abbastanza da tollerare la procedura e si sospetta una sepsi). † La terapia antibiotica dovrebbe essere orientata verso le più comuni cause di infezione neonatale, includendo l’ampicillina per via endovenosa per GBS e la copertura per gli altri organismi (tra cui l’E. coli e altri patogeni Gram-negativi) e dovrebbe tener conto dei modelli locali di resistenza agli antibiotici. § La consultazione con gli ostetrici è importante per determinare il livello di sospetto clinico per corionamnionite. La corionamnionite viene diagnosticata clinicamente e alcuni segni sono aspecifici. ¶ La valutazione limitata comprende emocoltura (alla nascita) e CBC con formula leucocitaria e piastrine (alla nascita e/o a 6-12 ore di vita). † † Se i segni di infezione si sviluppano deve essere condotta una completa valutazione diagnostica e iniziata la terapia antibiotica. § § Se ≥ 37 settimane di gestazione, l’osservazione si può effettuare a casa dopo 24 ore se gli altri criteri di dimissione sono stati rispettati, l’accesso all’assistenza medica è prontamente disponibile, ed è presente una persona in grado di rispettare pienamente le istruzioni per l’osservazione a casa. Se una di queste condizioni non è soddisfatta, il bambino deve essere osservato in ospedale per almeno 48 ore e fino a quando i criteri di dimissibilità non sono realizzati. ¶ ¶ Alcuni esperti consigliano un emocromo con formula leucocitaria e piastrine all’età postnatale di 6-12 ore.
Osservazione ≥ 48 ore ††¶¶
NO E.G. < 37 settimane o durata della rottura delle membrane ≥ 18 ore?
SÌ
Valutazione diagnostica limitata ¶ Osservazione ≥ 48 ore ††
Tabella 3. Le principali modifiche introdotte dalle linee guida CDC del 2010 rispetto a quelle del 2002 [4, 5]. • L’algoritmo si applica ora a tutti i neonati. • Si è chiarito che si definisce profilassi antibiotica intrapartum adeguata la somministrazione da almeno 4 ore di penicillina, ampicillina o cefazolina e.v. prima del parto (A II) [13]. Tutti gli altri farmaci o regimi terapeutici sono considerati inadeguati ai fini della gestione neonatale. • I neonati che appaiono in buone condizioni, le cui madri avevano un’indicazione per la profilassi contro lo GBS ma non l’hanno ricevuta (antibiotici intrapartum) o hanno ricevuto terapia intrapartum inadeguata, possono essere gestiti con l’osservazione per un periodo di almeno 48 ore, a meno che il neonato non abbia meno di 37 settimane di età gestazionale o le membrane si siano rotte oltre 18 ore prima del parto, nel qual caso si effettuerà una valutazione limitata con osservazione per un periodo di almeno 48 ore (B III). • I neonati che appaiono in buone condizioni con età gestazionale di 35-36 settimane, le cui madri hanno ricevuto adeguata profilassi antibiotica intrapartum, non richiedono valutazione diagnostica di routine (C III). GBS: Streptocco di gruppo B (Streptococcus agalactiae).
Infezione perinatale da Streptococco Gruppo B
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Casi particolari neonatologici
Conclusioni
Nella Tab. 4 sono riportati alcuni casi particolari neonatologici [12].
I take-home messages di questo articolo sono riportati nella Tab. 5.
Tabella 4. Casi particolari neonatologici [12]. Caso
Definizione
Comportamento da seguire
Neonato asintomatico “a rischio”
Neonato con IAP completa (iniziata da ≥ 4 ore):
• Osservazione di 48 ore
Se età gestazionale ≥ 37 settimane e PROM <18 ore:
• PCR a 24-48 ore • osservazione di 48 ore
Se età gestazionale ≤ 37 settimane o PROM > 18 ore:
• Emocoltura alla nascita • Emocromo con formula leucocitaria e piastrine alla nascita e a 6-12 ore + PCR (ed eventuale PCT) a 24-48 ore • Osservazione di 48 ore
Neonato con IAP materna assente o incompleta pur essendo questa necessaria
Neonato con età gestazionale < 35 settimane (indipendentemente dalla IAP materna)
• Emocromo con formula leucocitaria e piastrine + emocoltura alla nascita • Emocromo con formula leucocitaria e piastrine + PCR (ed eventuale PCT) a 24-48 ore • Osservazione di 48 ore
Neonato nato da madre con corioamnionite sospetta* o certa (febbre intrapartum + 2 tra i seguenti segni: leucocitosi al parto, tachicardia materna o fetale, perdite vaginali maleodoranti)
• Emocoltura alla nascita • Emocromo con formula leucocitaria e piastrine alla nascita e a 6-12 ore + PCR (ed eventuale PCT) a 24-48 ore • Terapia antibiotica doppia fino all’esclusione dell’infezione del neonato con gli esami colturali
Note
Se PCR / GB / PCT sono patologici, si deve eseguire la terapia antibiotica doppia (ampicillina + gentamicina) almeno fino all’arrivo della risposta degli esami colturali
*Poichè la diagnosi di corioamnionite sospetta è clinica e si basa su segni talora aspecifici, la gestione del neonato dovrebbe essere eseguita dopo aver consultato il Ginecologo che ha in carico la madre per valutare il livello di sospetto clinico della corioamnionite
IAP: profilassi antibiotica intrapartum; PROM :Premature Rupture of Membranes; PCR: proteina C reattiva; PCT: procalcitonina; GB: Globuli Bianchi.
Tabella 5. Take-home messages. • L’introduzione dello screening universale a tutte le donne gravide a 36-37 settimane di gravidanza ha permesso di ridurre il tasso di infezione neonatale da GBS da 0,47/1.000 nati nel periodo 1999-2001 a 0,34/1.000 nati nel 2004 [14]. • La profilassi antiobiotica intrapartum con ampicillina, da iniziare almeno 4 ore prima del parto [11], e un’adeguata assistenza al neonato hanno consentito di ridurre l’incidenza di infezione neonatale early onset da GBS dell’80% ma, ancora nel 2010, l’infezione da GBS rappresenta la principale causa di sepsi neonatale ad esordio precoce [14]. • L’intervallo di tempo 36-37 settimane è stato scelto in quanto l’infezione/colonizzazione può essere transitoria ed è importante sapere lo stato nel periodo che precede il parto. Infatti, uno studio ha dimostrato che la colonizzazione da GBS può essere intermittente o transitoria, perciò il valore predittivo positivo di un esame colturale eseguito a più di 5 settimane dal parto è basso e risulta di scarsa utilità clinica [15]. • La prevenzione neonatale dell’infezione da GBS ad esordio precoce ha compiuto importanti progressi, ma l’evidenza scientifica è ancora incompleta in alcuni aspetti importanti quali: strategie di prevenzione della malattia da GBS nei neonati pretermine; efficacia della IAP per le donne allergiche alla penicillina ad alto rischio di anafilassi; fattori che inducono la malattia da GBS ad esordio precoce anche tra i nati da pazienti con tampone prenatale negativo per GBS [11]. • Lo sviluppo di test di laboratorio rapidi per idendificare il GBS intrapartum, per essere realmente utili, dovrebbero avere un tempo di risposta inferiore ai 30 minuti ed avere un’altissima sensibilità diagnostica e, a tutt’oggi, non sono ancora disponibili, con queste peculiarità, nella pratica clinica. • Lo screening universale e la profilassi antibiotica intrapartum non hanno avuto un impatto misurabile sulla malattia da GBS ad esordio tardivo o sulla malattia da GBS tra gli adulti non in gravidanza. GBS: Streptocco di gruppo B (Streptococcus agalactiae); IAP: profilassi antibiotica intrapartum.
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Journal of Pediatric and Neonatal Individualized Medicine • vol. 3 • n. 1 • 2014
Declaration of interest
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine 2014;3(1):e030106 doi: 10.7363/030106 Received: 2013 Jul 27; revised: 2013 Aug 31; accepted: 2013 Oct 01; advance publication: 2014 Jan 10
Review
Pielonefrite acuta in epoca neonatale Giovanni Ottonello1, Angelica Dessì1, Danila Manus1, Anna Paola Pinna1, Fabiana Sau1, Vassilios Fanos1,2 1
Terapia Intensiva Neonatale, Puericultura e Nido, Azienda Ospedaliero Universitaria di Cagliari
2
Dipartimento di Scienze Chirurgiche, Università degli Studi di Cagliari
Proceedings Articoli Selezionati del “3° Convegno Pediatrico del Medio Campidano” · Guspini · 25 Maggio 2013 Guest Editor: Roberto Antonucci
Abstract
Urinary tract infections (UTIs) represent one of the most common pathological conditions in children. It is estimated that even in the countries with the most advanced health care programmes, such as the United States and Europe, UTIs represent the most common serious infections in pediatrics. In the earliest stages of life, UTIs represent the most common febrile illness, although the non specific clinical presentation often leads to diagnostic underestimation. Neonatal UTIs surely represent a special case among pediatric UTIs and need specific considerations and separate treatment with respect to later age: it is no coincidence that the main national and international guidelines for the diagnosis and treatment of UTIs, such as those issued by the American Academy of Pediatrics (AAP) and by the Working Group of the Italian Society of Pediatric Nephrology, exclude from their indications the newborn and the infant under two months of age. Low gestational age, low birth weight, association with malformative uropathies are considered specific risk factors. Breastfeeding has a protective effect. E. coli is the major responsible of UTI in term newborns and infants, followed by K. pneumoniae, Proteus spp., E. cloacae. Finally, Candida spp. is very important in hospitalized children. Treatment includes the combination of ampicillin plus an aminoglycoside (frequently gentamicin). The article shows the main aspects of the urinary tract infections in the neonatal period and a review of the most recent literature on the subject. Keywords
Newborn, acute pyelonephritis, vesicoureteral reflux, antibacterial therapy.
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Corresponding author
vafanos@tiscali.it, vafanos@tin.it.
e il trattamento delle IVU, quali quelle emanate dall’American Academy of Pediatrics (AAP) e dal Gruppo di Lavoro della Società Italiana di Nefrologia Pediatrica (SINP), escludono dalle loro indicazioni i neonati e i lattanti di età minore di 2 mesi di vita [3-5].
How to cite
Epidemiologia
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Nei primi 6-12 mesi di vita vi è una maggiore incidenza di IVU nel sesso maschile (rapporto maschi/femmine pari a 1,6:1) [6], in particolare nei soggetti non circoncisi. La circoncisone viene considerata da alcuni autori come parte della terapia delle IVU [7]. Tuttavia, una recente revisione sistematica di trial randomizzati e studi clinici che ha valutato il rapporto costi-benefici della circoncisione, trova che vi sia un effetto clinico positivo solo per quei bambini che hanno un elevato rischio di IVU, in particolare IVU ricorrenti e alto grado di reflusso vescico-ureterale (RVU) [8]. Trattando in maniera specifica il periodo neonatale, è da riportare che la bassa età gestazionale, il basso peso alla nascita, l’associazione con eventuali uropatie malformative e le procedure invasive a cui questo gruppo di bambini viene sottoposto, rappresentano peculiari fattori di rischio che, sinergicamente, possono spiegare l’elevata incidenza di IVU. Da segnalare il ruolo protettivo del latte materno: i neonati allattati al seno avrebbero una minore suscettibilità alle IVU rispetto a quelli allattati artificialmente. L’azione protettiva sarebbe particolarmente evidente alla nascita, per diminuire fino ai sette mesi di vita, dopo i quali non sono dimostrati effetti benefici [9]. Nei nati pretermine allattati al seno vi è una riduzione delle IVU di oltre 3 volte rispetto a quelli non allattati al seno [10].
Vassilios Fanos, MD, Professor of Pediatrics, Chief Neonatal Intensive Care Unit, Puericultura Institute and Neonatal Section, University of Cagliari, Italy; tel.: +3907051093403; email addresses:
Ottonello G, Dessì A, Manus D, Pinna AP, Sau F, Fanos V. Pielonefrite acuta in epoca neonatale. J Pediatr Neonat Individual Med. 2014;3(1):e030106. doi: 10.7363/030106.
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Ottonello G, Dessì A, Manus D, Pinna AP, Sau F, Fanos V. [Acute pyelonephritis in the neonatal period]. [Article in Italian]. J Pediatr Neonat Individual Med. 2014;3(1):e030106. doi: 10.7363/030106.
Introduzione
A seguito del significativo decremento delle infezioni sostenute dallo S. pneumoniae e dall’H. influenzae, ottenuto grazie ai più recenti programmi vaccinali nei paesi del mondo economicamente più avanzati, le infezioni delle vie urinarie (IVU) rappresentano le infezioni gravi più comuni nei lattanti e nei bambini [1]. In particolare, nella fascia di età neonatale e nel piccolo lattante, le IVU rappresentano la patologia di più frequente riscontro in corso di febbre, nonostante sia possibile una sottostima diagnostica dovuta ad una presentazione clinica talora aspecifica. Le IVU che determinano un interessamento renale per pielonefrite acuta (PNA), se non precocemente riconosciute e correttamente trattate, possono dare origine a un danno parenchimale renale permanente (scar). Si stima che circa il 15-41% dei bambini con PNA sviluppi scars [2-3], considerate una delle principali cause di danno renale acquisito in età pediatrica in grado di evolvere (in alcuni casi) in ipertensione arteriosa e insufficienza renale cronica [4]. Attualmente i dati relativi all’incidenza di queste complicanze sono oggetto di revisione, in quanto in passato venivano inclusi in questo gruppo un grande numero di bambini che presentavano un danno renale displasico congenito piuttosto che acquisito. Le IVU che insorgono nel periodo neonatale e nel piccolo lattante presentano una serie di caratteristiche del tutto peculiari che limitano l’applicazione delle evidenze derivate da studi condotti su bambini di età compresa tra i 2 e i 24 mesi di vita. Per tali ragioni le principali linee guida internazionali e nazionali per la diagnosi
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Etiologia
L’E.coli è il principale responsabile di PNA (90%) nel neonato a termine e nel lattante febbrile [11], seguito da K. pneumoniae, Proteus spp., E. cloacae. Tuttavia è importante segnalare come, nel neonato pretermine ricoverato, i microrganismi maggiormente coinvolti nelle IVU sembrano identificarsi con i patogeni responsabili delle infezioni nosocomiali delle singole unità di Terapia Intensiva Neonatale (TIN). Una ricerca condotta alcuni anni fa ha messo in evidenza come l’E. coli fosse il microrganismo più frequentemente isolato (80%) in corso di IVU nel bambino, ma non nel neonato ricoverato in TIN, in cui veniva riscontrata
Ottonello • Dessì • Manus • Pinna • Sau • Fanos
Journal of Pediatric and Neonatal Individualized Medicine • vol. 3 • n. 1 • 2014
un’elevata incidenza di Gram-positivi. Tutti questi dati sottolineano l’esigenza di tracciare specifiche mappe delle popolazioni microbiche patogene nei singoli reparti, al fine di ottimizzare il più possibile le strategie preventive e terapeutiche [12]. Infine va segnalata l’importanza, per i neonati ospedalizzati, della Candida spp. ritenuta (con frequenze che arrivano al 40%) il principale patogeno delle IVU nosocomiali presso le TIN, sia nei neonati a termine con anomalie congenite sia nei prematuri. In oltre la metà dei casi di infezioni primarie renali sostenute da Candida spp. si riscontra diffusione ematogena [13], con tassi di mortalità che arrivano al 30% [14]. Clinica
Nei neonati e lattanti le manifestazioni cliniche di IVU possono essere estremamente variabili: in taluni casi i sintomi sono pochi, aspecifici e variamente associati tra loro, come un minimo rialzo termico, difficoltà ad alimentarsi, insorgenza di rigurgiti e vomiti, diarrea, ittero e irritabilità [15]. Altre volte la presentazione è quanto mai acuta e grave, con severa ipertermia, scadimento delle condizioni generali, compromissione circolatoria e alterazione del sensorio, tutti sintomi tipici di un vero e proprio stato di urosepsi. Una complicanza clinica di particolare rilevanza delle PNA (che ne condiziona il trattamento terapeutico) è la diffusione dell’infezione dal rene per via ematogena. Tra PNA e sepsi esiste una correlazione bidirezionale: una PNA può rappresentare una localizzazione secondaria di una sepsi e, viceversa, una sepsi può conseguire alla generalizzazione di una PNA primitiva. In letteratura vengono riportate incidenze di urosepsi variabili, che oscillano tra 5% e il 38% con maggiori frequenze relativamente al periodo neonatale e nei nati pretermine [16-17]. Diagnosi
Secondo le più recenti linee guida per la diagnosi e il trattamento delle IVU pubblicate dall’AAP, la diagnosi di IVU viene fatta in base alla contemporanea presenza di piuria nel sedimento urinario e l’isolamento di un numero di almeno 50.000 colonie (CFUs) per ml di un singolo organismo uropatogenetico in campioni di urine appropriatamente raccolti [5]. La riduzione della soglia di positività delle colture urinarie, da 100.000 CFUs (come indicato nelle precedenti linee guida AAP) a 50.000 CFUs,
Pielonefrite acuta in epoca neonatale
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potrebbe in apparenza determinare un incremento della sensibilità e un decremento della specificità dell’esame, rispettivamente. Viceversa, rientrando nei più recenti criteri di definizione di IVU la contemporanea presenza di piuria, quelle situazioni in cui vi sia una coltura positiva per contaminazione o le batteriurie asintomatiche non potranno essere considerate come IVU [5]. Un argomento ancora molto discusso è quello relativo alla tecnica di raccolta dei campioni urinari: nonostante l’AAP consideri valida esclusivamente la tecnica di prelievo attraverso la puntura sovrapubica (meglio se eco-guidata) e la cateterizzazione uretrale, queste procedure vengono ritenute nei paesi anglosassoni e in Italia eccessivamente invasive, e viene ammessa (con i dovuti accorgimenti igienici) la raccolta tramite sacchetto sterile [3]. Nelle linee guida di riferimento e nella letteratura più recente, l’esecuzione di esami ematici quali la Proteina C Reattiva (PCR) e la conta dei Globuli Bianchi non viene consigliata per distinguere tra IVU alta o bassa, perché i due test sono poco correlati con la sede dell’infezione [3-18]. Sebbene con risultati non sempre del tutto attendibili, in particolare in pediatria e neonatologia nei bambini di peso molto basso, un’indice di infezione particolarmente utilizzato nella pratica clinica in corso di PNA è la procalcitonina (PCT). La PCT sierica, marker di infezione batterica, non solo presenta un’alta sensibilità e specificità per la PNA, ma appare correlata con la severità della malattia (PNA e sepsi) così da poter essere utilizzata come marker prognostico [19]. È stato inoltre suggerito che la concentrazione serica della PCT al momento del ricovero in neonati e bambini affetti da PNA possa essere predittiva per una successiva evoluzione in scars renali [20]. Risultati incoraggianti, quali markers di PNA, anche se di difficile applicazione nella pratica clinica quotidiana, si sono avuti col dosaggio sierico e urinario di diverse citochine infiammatorie, quali la IL-1, la IL-6 e la IL-8. Tali mediatori giocano un importante ruolo nella risposta dell’organismo alle infezioni batteriche e diversi studi hanno documentato che possano rappresentare promettenti e non invasivi (urine) marker di localizzazione infettiva renale e di rischio di evoluzione in scars [21-22]. Sebbene la scintigrafia con Tc-99m DMSA continui a rappresentare il gold standard dello studio per immagini della PNA, tale metodica non trova un utilizzo pratico soprattutto nel periodo neonatale. Le ultime linee guida dell’AAP specificano come lo
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studio scintigrafico raramente abbia delle ricadute pratiche nel trattamento della fase pielonefritica acuta ed andrebbe riservato, con fini di ricerca nel follow-up, soprattutto alla valutazione di eventuali esiti renali a distanza [5]. Tra le metodiche diagnostiche per immagini, l’ecografia (B-mode, completata col power-Doppler), grazie alla rapidità d’esecuzione, all’innocuità e alla ripetibilità d’esame, è la tecnica d’indagine più utilizzata in corso di PNA soprattutto nel periodo neonatale [23]. Il suo ruolo, oltre che nell’individuazione di eventuali segni di interessamento infettivo parenchimale renale, è importante per la diagnosi di eventuali patologie malformative associate [24]. L’esecuzione della cistouretrografia minzionale (CUM) non trova utilizzo nella fase acuta di una PNA, ma trova indicazione qualora ecograficamente si documenti la presenza di idronefrosi, di cicatrici renali o altri segni suggestivi per la presenza di reflusso vescico-ureterale o uropatia ostruttiva ed ancora qualora vi sia stato un decorso clinico di UTI atipico o complesso o in caso di UTI ricorrenti [5]. Terapia
Il trattamento della PNA nel periodo neonatale (anche per la possibile concomitanza di una batteriemia) prevede l’utilizzo empirico di antibiotici per via parenterale, che vanno iniziati prima ancora di avere disponibilità del risultato dell’urinocoltura e dell’emocoltura. Particolarmente importante è l’applicazione di tutti quei presidi di supporto generale che tendono a garantire il mantenimento dell’equilibrio idrico-elettrolitico, acido-base e della funzionalità renale, che spesso sono alterati negli stati di urosepsi. In genere viene utilizzata un’associazione tra ampicillina protetta (in relazione alle sempre maggiori segnalazioni di resistenze antibiotiche dell’E. coli) [25-26] e un aminoglicoside [27]. Appare ormai assodato l’uso in monosomministrazione giornaliera dell’aminoglicoside, che garantisce analoghi effetti terapeutici e minori effetti collaterali (nefrotossici, ototossici) rispetto alla plurisomministrazione giornaliera [3]. Relativamente alla durata totale della terapia viene consigliato un trattamento non inferiore ai 7 giorni, in un range compreso tra i 7 e i 14 giorni, in quanto non esistono in letteratura studi specifici che mettano a diretto confronto questi diversi periodi di terapia e che indichino la durata ottimale [5]. Nell’ottica di personalizzare sempre più la cura della PNA (terapia sartoriale), appaiono di particolare importanza recenti studi tesi a valutare
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la base genetica individuale di suscettibilità alle UTI (geni HSPA1B, CXCR1, CXCR2, TLR2, TLR4, TGF-beta1) [28] e la risposta immunitaria del singolo paziente (interleukine, difensine) [29]. Un possibile scenario futuro per un approccio personalizzato terapeutico (uso/non uso di antibiotico-terapia) è stato recentemente ipotizzato da Godaly et al. proprio in base alle caratteristiche di virulenza del germe e alla singola risposta immunitaria dell’ospite [30]. Follow-up
I bambini che presentano una PNA nel periodo neonatale, devono essere mantenuti in regime di profilassi antibiotica in presenza di RVU ≥ 3° (già diagnosticato) o di IVU recidivanti o ricorrenti specie se febbrili. Alla dimissione è bene programmare, in accordo con l’urologo-pediatra, l’eventuale esecuzione di una CUM (radioisotopica, radiologica o cistosonografica) e di una Scinti-DMSA per la ricerca di RVU e cicatrici renali o considerare lo studio, attraverso metodiche scintigrafiche dinamiche (MAG 3), dei tempi di transito urinario. Appare opportuno, nell’attesa dell’esecuzione dei suddetti accertamenti strumentali, mantenere il paziente in profilassi antibiotica. Dopo la dimissione il neonato va tenuto in stretto controllo clinico, ai genitori va insegnato a riconoscere i primi sintomi di insorgenza di IVU e come utilizzare a domicilio di sticks per il rilevamento di globuli bianchi e nitriti urinari. Nei maschi va valutata la presenza di fimosi e considerato un suo eventuale trattamento. Conclusioni
Le PNA nel neonato presentano degli aspetti del tutto peculiari e differenti rispetto alle età successive, tali da limitare l’applicazione delle evidenze derivate da studi condotti su bambini di età superiore e da non permettere di tracciare specifiche linee guida al di sotto dei due mesi di vita. Colpiscono prevalentemente il sesso maschile, presentano un’elevata incidenza di infezioni “non E. coli”, esordiscono a volte con una sintomatologia aspecifica, ma spesso con un quadro di urosepsi, complicanza che si verifica con maggiore frequenza rispetto al bambino più grande. Sarà importante promuovere ulteriori studi e acquisire un maggior numero di dati al fine di stabilire anche per questo specifico periodo di vita dei percorsi diagnostico-terapeutici e delle condotte comportamentali il più possibile condivise.
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Declaration of interest
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