Drug utilization pattern in children and off-label use of medicines in a pediatric intensive care unit

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Grupos Anatomical, Therapeutic, Chemical classification system (grupos ATC). A: sistema digestivo y metabolismo; B: sangre y órganos hematopoyéticos; C: sistema cardiovascular; H: preparados hormonales sistémicos; J: antiinfecciosos de uso sistémico; M: sistema musculoesquelético; N: sistema nervioso; R: sistema respiratorio; S: órganos de los sentidos." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "E. Blanco-Reina, A.F. Medina-Claros, M.A. Vega-Jiménez, R. Ocaña-Riola, E.I. Márquez-Romero, Á. Ruiz-Extremera" "autores" => array:6 [ 0 => array:2 [ "nombre" => "E." "apellidos" => "Blanco-Reina" ] 1 => array:2 [ "nombre" => "A.F." "apellidos" => "Medina-Claros" ] 2 => array:2 [ "nombre" => "M.A." "apellidos" => "Vega-Jiménez" ] 3 => array:2 [ "nombre" => "R." "apellidos" => "Ocaña-Riola" ] 4 => array:2 [ "nombre" => "E.I." "apellidos" => "Márquez-Romero" ] 5 => array:2 [ "nombre" => "Á." 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Blanco-Reina, A.F. Medina-Claros, M.A. Vega-Jiménez, R. Ocaña-Riola, E.I. Márquez-Romero, Á. Ruiz-Extremera" "autores" => array:6 [ 0 => array:4 [ "nombre" => "E." "apellidos" => "Blanco-Reina" "email" => array:1 [ 0 => "eblanco@uma.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "A.F." "apellidos" => "Medina-Claros" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "M.A." "apellidos" => "Vega-Jiménez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "R." "apellidos" => "Ocaña-Riola" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "E.I." 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"apellidos" => "Ruiz-Extremera" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "f" "identificador" => "aff0030" ] 1 => array:2 [ "etiqueta" => "g" "identificador" => "aff0035" ] ] ] ] "afiliaciones" => array:7 [ 0 => array:3 [ "entidad" => "Departamento de Farmacología y Pediatría, Facultad de Medicina, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "UGC de Pediatría, Hospital Axarquía, Vélez-Málaga, Málaga, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Medicina de Familia, Centro de Salud La Victoria, Distrito Sanitario de Málaga, Málaga, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Departamento de Matemáticas, Escuela Andaluza de Salud Pública, Granada, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Dispositivo de Cuidados Críticos y Urgencias, Distrito Sanitario Málaga, Málaga, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Departamento de Pediatría, Universidad de Granada, Granada, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Unidad de Apoyo a la Investigación, Hospital Universitario San Cecilio, CIBERehd, Granada, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Utilización de fármacos en niños en cuidados intensivos: estudio de las prescripciones off-label" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 958 "Ancho" => 1560 "Tamanyo" => 62502 ] ] "descripcion" => array:1 [ "en" => "Distribution of medication use by ATC drug classes (values expressed as % of children receiving some drug within the class). Anatomical, therapeutic, chemical (ATC) classification system. A: digestive system and metabolism; B: blood and hematopoietic organs; C: cardiovascular system; H: systemic hormonal formulations; J: systemic antiinfectious agents; M: musculoskeletal system; N: nervous system; R: respiratory system; S: sensory organs." ] ] ] "textoCompleto" => "IntroductionIt has been estimated that less than 50% of the drugs used in children have been investigated in the pediatric population. Because of this, the treatment of such patients traditionally has been based on extrapolations referred to drugs that have been developed for adults. However, we know that the conduction of adequate clinical research is the best guarantee for safe, effective and quality treatment. The scarcity of clinical trials in children is due on one hand to the limited interest of the drug industry in this concrete patient population, and on the other to the difficulties inherent to pediatric research, which involves a number of fundamentally ethical and methodological barriers.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Accordingly, most therapeutic agents have not been studied in children, and the benefit–risk balance of their use is therefore often supported by only limited evidence. All this in many cases has caused quality information on pediatric recommendations to be scarce or inexistent.The Summary of Product Characteristics (SPC) approved by the Spanish Medicines Agency (Agencia Española del Medicamento y Productos Sanitarios [AEMPS]) is the official document reflecting the authorized conditions of use of the medication. Based on the findings of the clinical trials made, the SPC summarizes the essential scientific information addressed to health professionals. When the information on the use of a drug in children is limited or inexistent, its prescription is made outside the corresponding licensed or authorized terms–a situation internationally known as off-label (OL) and unlicensed (UL) drug use. Unlicensed prescription is generally understood as the prescription of drugs that have not been approved for the pediatric population, while off-label prescription involves the use of drugs that have been approved for children but which are used under conditions different from those authorized in the corresponding SPC, i.e., involving different indications, doses, age ranges or administration routes. The proportion of drugs prescribed outside the authorized terms has been studied in recent years, though the results have been highly varied.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Most studies have been conducted on an in-hospital basis, and those carried out in neonatal Intensive Care Units (ICUs) are particularly relevant in this respect. Among newborn infants, the number of patients that receive at least one OL or UL prescription is much higher than in any other medical or surgical pediatric ward–with percentages reaching 70–97% of the patients.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>The use of these OL or UL prescriptions is not necessarily incorrect: it simply means that the evidence and evaluations required by the health authorities (AEMPS and the European Medicines Agency [EMA]) are not available or are insufficient, and therefore cannot be reflected in the SPC. Nevertheless, it has been demonstrated that such drug use can be associated to certain safety problems.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> In fact, a number of studies have already shown that these prescriptions are a risk factor for the development of adverse drug reactions (ADRs), medication error and possible treatment failure.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> It has been estimated that OL or UL prescriptions are implicated in between 23% and 60% of all ADRs in children.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>An added problem is the lack of specific pediatric formulations, which favors the use of extemporaneous or magistral formulations aimed at adapting certain treatments to the oral route. These preparations are also related to possible medication error and involve uncertainty regarding the stability of the products used.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>Considering that intensive care is characterized by great and very diverse exposure to drugs, we were interested in knowing the frequency of prescriptions of this kind in this concrete area of practice. We were also particularly interested in exploring commonly used drugs such as dopamine, midazolam, fentanyl or furosemide–many of which have not been specifically investigated in the pediatric population, despite extensive experience with their use. On the other hand, most of the studies published to date have been carried out in the United Kingdom and in the Netherlands,<a class="elsevierStyleCrossRef" href="#bib0030">6</a> with very few data referred to the Spanish population. Indeed, the existing studies are limited to two areas unrelated to intensive care, namely gastroenterology<a class="elsevierStyleCrossRef" href="#bib0040">8</a> and out-hospital prescription practice.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> According to current European Union regulations referred to pediatric medications,<a class="elsevierStyleCrossRef" href="#bib0050">10</a> one of the necessary important tasks is to compile information on drug use in children in all the member states, with a view to evaluating the current situation and detecting those therapeutic areas where the need for additional pediatric studies is more pressing.The aim of the present study therefore was to determine the prescription profile and OL (outside SPC specifications) and UL (medicines not specifically authorized in children) uses in pediatric (PICUs) and neonatal Intensive Care Units (NICUs).Patients and methodsA cross-sectional observational study was conducted of all the prescriptions made in a cohort of children admitted to the ICU of a third-level public hospital in Granada (Andalusia, Spain). This ICU distributed the patients into neonatal (newborn infants up until one month of age) and pediatric patients (from the first month to 14 years of age).Based on consecutive recruiting over a 5-month period (July–November), we prospectively recorded the data on those patients in which at least one drug treatment was indicated. The information source was the case history and medical instructions. Information was collected referred to patient age, weight and reason for admission, as well as to drug treatment: indication, dose, frequency, dosing form and administration route. The drugs studied were grouped according to the Anatomical Therapeutic Chemical (ATC) classification index.All prescriptions were classified as OL or UL according to the information referred to pediatric use contained in the corresponding SPC. The criteria used were those published by Turner,<a class="elsevierStyleCrossRef" href="#bib0055">11</a> who classified OL as prescriptions involving doses, age ranges, administration routes or indications different from those reflected in the official drug authorization documentation. In turn, the definition of UL included drug substances still not authorized, drugs specifically contraindicated in children, the modification of formulations, and drugs for which no information at all is available referred to pediatric use.A descriptive analysis was made using the SPSS version 19.0 statistical package (Chicago, IL, USA). The comparison of means of quantitative variables between two groups of patients was based on the Student's t-test, while the chi-squared test was used for the comparison of proportions in the case of qualitative variables. Statistical significance was considered for p<0.05 in all cases. All personal information was anonymized, and the study was approved by the local Research Ethics Committee.ResultsThe study included a total of 81 patients, of which 59.3% (N=48) corresponded to the neonatal ICU (NICU) and 40.7% (N=33) to the pediatric ICU (PICU). The male gender was seen to predominate (59%), with no significant differences between the two Units. In the PICU the mean age was 4.4±4.7 years (range: 2 months–14 years), and among the newborn infants the mean gestational age was 34.5±4.2 weeks (range: 25–41 weeks), with a mean weight of 2335±949g (range: 780–4750g). One-third of the newborn infants weighed less than 2500g, though only 15% were very low weight.The most frequent reason for admission in the combined Units was prematurity-low weight (22.2%), followed by infections (21%), respiratory disease (17.2%) and neurological disorders (15%).The mean number of drugs prescribed per patient was 7.4±6 (range: 1–32; median 6). The neonates received more drugs than the pediatric patients, though the difference failed to reach statistical significance (8.3 vs 6.1 drugs; p=0.09). Overall, 601 prescriptions were made, involving 91 different drug substances. <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> shows the prescription profile according to therapeutic groups based on the ATC classification. Eighty percent of the children received at least one antibiotic–class J drugs (systemic antiinfectious agents) being the most frequently used, followed by classes N (nervous system) and C (cardiovascular). It was precisely in these three classes where differences were detected between the neonatal and pediatric patients–with significantly greater use among the neonates of antibiotics (92 vs 64%; p<0.001), nervous system drugs (58 vs 49%; p<0.05) and class C agents (62.5 vs 18.2%; p<0.001). The rest of the drug classes showed no differences in distribution. The 10 most frequently administered drug substances in the ICU were ampicillin (53% of the patients), gentamycin (52%), midazolam (44%), furosemide (34.5%), dopamine (33%), cefotaxime (31%), metamizol (29%), fentanyl (28%), vancomycin (25%) and methylprednisolone (22%).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>On analyzing the 601 prescriptions made, 52% were found to correspond to OL, while 5% were UL (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The number of OL and UL prescriptions per patient ranged from 0 to 8 (mean 2.39±1.7) and from 0 to 4 (mean 0.32±0.6), respectively. There was a slight tendency toward more OL prescriptions per patient among the neonates versus the pediatric patients (2.5 vs 1.8; p=0.06). A total of 22.3% of the children in the sample received at least one UL prescription, while 89% received at least one OL prescription. The few differences between neonatal and pediatric patients failed to reach statistical significance.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The causes of UL prescriptions were equally distributed between modification of the formulations and contraindications in children. As examples of the former we have extemporaneous (magistral) formulations of nifedipine, folic acid, vitamin E, caffeine and vancomycin eyedrops. Contraindications and warnings due to non-established efficacy and safety in children in turn affected the use of drotrecogin, amiodarone and enoxaparin. On the other hand, in relation to the OL prescriptions, the main cause was the administration of doses different from those recommended in the SPC (79% of the OL cases), followed by different indications (13.5%), different patient age ranges (5%) and different administration routes (2.5%) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The indications not contemplated by the SPC were bronchopulmonary dysplasia in the case of dexamethasone, arginosuccinic aciduria in the case of dextromethorphan, irritability episodes in the case of alimemazine, hyperbaric lidocaine use as an antiarrhythmic agent, and aminophylline as respiratory center stimulant in apnea. Off-label use due to administration in patients with ages different from those contemplated in the SPC were mainly referred to the use of drugs in newborn infants and in general in patients under two years of age, for which the safety and efficacy profiles have not been established to date (e.g., budesonide and voriconazole in patients under two years of age). Some drugs were found to be prescribed under OL conditions due to more than one cause simultaneously, e.g., metamizol (dose, age and route different from the authorized specifications), alimemazine (dose, age and indication different from the authorized specifications), and dextromethorphan (indication and age different from the authorized specifications).DiscussionThe single-center nature of our study could limit its external validity. However, even accepting the variability between prescribers and centers, we consider that the results obtained may adequately reflect this often protocolized type of drug prescription practice in the intensive care setting. Furthermore, and from the perspective of a Spanish ICU, the data obtained may contribute to the assessment of current prescription practices requested by the European Medicines Agency.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>The publications on prescriptions of this kind offer very heterogeneous results, due to differences in the methodology, classification criteria and information sources used–a fact that complicates comparisons among the different studies. In the present study we chose the most widely employed classification of OL and UL prescription,<a class="elsevierStyleCrossRefs" href="#bib0060">12–17</a> originally described by Turner.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> In the same way as in most of the more recent studies, our main information source was the Summary of Product Characteristics (SPC) of the EMA. The SPC is regarded as the official document, since its data have been subjected to regulatory review, and it serves as a consulting tool for clinicians, offering guidance on the authorized conditions of prescription and administration of drugs. However, the need to update the SPCs should be considered, since in many cases they are outdated with respect to the generation of new uses based on quality studies. In effect, research and knowledge in certain areas modify clinical practice, though such changes are not reflected in the SPCs–particularly in those referred to old drugs or substances of little commercial interest for the drug industry.Drug exposure among the children of our ICU was highly variable and somewhat greater (mean of 7.4 and median of 6 drugs per patient) than in other studies (median of 3 drugs in the study corresponding to Turkey, 4 in Estonia, and 4.2 in Finland).<a class="elsevierStyleCrossRefs" href="#bib0015">3,18,19</a> Nevertheless, taking into account that our data are referred to the critical care setting, we feel that the figures are reasonable and similar to other published data in this same clinical setting.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> The prescription profile is coherent with the reasons for admission and with the predominance of neonates in the ICU. In this regard, antibiotics are typically the most commonly used drugs in such Units.<a class="elsevierStyleCrossRefs" href="#bib0015">3,12,18,21</a> On the other hand, the fact that 63% of the children received some drug belonging to class N is explained by the needs for sedation and analgesia–with midazolam and fentanyl ranking among the 10 most frequently prescribed drugs. In our sample there was a significantly greater proportion of antibiotic, nervous system and cardiovascular drug prescription in neonates than in pediatric patients–this being consistent with the most frequent clinical problems found in newborn infants. We also detected slight differences in profile: while the most commonly used antibiotics in neonates were ampicillin and gentamycin, the prescription of amoxicillin-clavulanate and cefotaxime predominated in the pediatric patients. This is logical, considering the microbiological spectrum to be covered in each case. Likewise, in relation to class N drugs, sedation was more frequent among newborn infants, while in the older children the use of this drug class more often involved analgesia and antifever prescription (e.g., paracetamol and metamizol).<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> reviews the main in-hospital studies found in the literature. In our case, a little over one-half of the prescriptions were OL–this figure being somewhat higher than those recorded in hospital pediatric wards<a class="elsevierStyleCrossRefs" href="#bib0040">8,12,16,19–25</a> (between 35% and 45%), closer to those recorded in NICUs,<a class="elsevierStyleCrossRefs" href="#bib0015">3,18,26–33</a> and perhaps a little higher than in other PICUs.<a class="elsevierStyleCrossRefs" href="#bib0170">34,35</a> This is logical, considering the important proportion of newborn infants in the present study. In this respect, it is not surprising that 89% of the admitted children received some prescription of this type. As is clearly seen in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>, the OL prescription rates differ greatly between countries and studies. Thus, in the case of NICUs, the proportions range from 22.7% in Italy<a class="elsevierStyleCrossRef" href="#bib0150">30</a> to 87% in Estonia.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> These very distinct results again reflect differences not only in the methodology and classifications used, but also in clinical practice as such. According to Palcevski, another possible source of variability is the type of hospital involved. In this regard, higher OL prescription rates would be expected in centers offering more sophisticated care, or in which the patients present more complicated disease processes.<a class="elsevierStyleCrossRef" href="#bib0100">20</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>The main type of OL prescription in our series was referred to the use of drug doses or administration frequencies different from those reflected in the SPC. This coincides with the observations of many other studies.<a class="elsevierStyleCrossRefs" href="#bib0060">12,14,15,20,21,23</a> Of note is the fact that the main drugs involving OL use due to doses different from those specified in the SPC are also among the most widely prescribed drug substances–particularly gentamycin, cefotaxime, vancomycin and midazolam. Regarding the non-authorized indications, it may be more interesting at this point to reflect upon the level of evidence supporting such use. Potentially controversial examples are the off-label use of alimemazine (authorized as an H1 antihistamine for the treatment of allergy) as a sedative, or the administration of aminophylline as an anti-apnea drug in premature infants. These clinical situations raise relevant research questions and should stimulate the conduction of independent studies to clarify the existing uncertainties.In our opinion, a notable observation in the present study was the scarce use of UL prescriptions, with an incidence of only 5% versus the usually reported range of 10–15% of all prescriptions in both the NICU setting<a class="elsevierStyleCrossRefs" href="#bib0130">26,27,29,30</a> and in pediatric wards.<a class="elsevierStyleCrossRefs" href="#bib0080">16,19,20</a> We consider that the extemporaneous formulation of drugs by the hospital pharmacy, or the modification of authorized products, may also be influenced by the pharmaceutical practices found in each individual country. In fact, in the Netherlands, for example, magistral formulation is a traditional practice–representing up to 48% of all prescriptions.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> Such formulations are also often prepared in Spanish hospital pharmacies, though there were few of them in our series. This might be explained by the critical condition of the patients admitted to our Unit, causing parenteral dosing to be the administration route of choice. After being moved to intermediate care or general wards, where the children are in a more stable condition, the need to modify or adapt oral solutions may be comparatively greater.It should be remembered that prescription outside the specifications of the SPC need not be inappropriate, and that such practice often represents the most rational and even the best option based on the current evidence and clinical practice guides.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> This is not always the case, however, and UL and OL prescription may be a risk factor for the appearance of adverse drug reactions (ADRs). It therefore must be guaranteed that children receive the safest and most effective drugs for each given disease condition. For this reason, European Directive 1901/2006 establishes as objective the increased development of pediatric medications, ensuring quality research and improving the available information on the use of drugs in children.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> In this regard, the EMA has launched initiatives such as the creation of a Pediatric Committee; Pediatric Investigation Plans (PIPs); the publication of a list of medications for which development for pediatric use is recommended; or the European Network of Pediatric Research. Independently of the implementation of these measures, we consider it reasonable to promote studies on drug utilization in children, divulgating the implications of OL and UL use and–in those cases where such prescription outside the specifications of the SPC or lacking authorization are not supported by clinical practice guides or quality studies–to propose prospective studies to collect information on efficacy and safety with a view to affording greater evidence and better elements of judgment in selecting drug products. We feel that studies of this kind are particularly interesting in critical care setting, due to the pharmacological profile involved in this setting.Lastly, a comment should be made on the legal aspects of drug use not contemplated in the SPC, for as has already been mentioned, the latter is an official document with a legally binding character. Drug use outside the specifications of the SPC has been contemplated since the year 2009 in the Spanish Royal Decree (RD) on the Availability of Medications in Special Situations,<a class="elsevierStyleCrossRef" href="#bib0180">36</a> which administratively facilitates such use when supported by the clinical practice guides or scientific evidence, and offers clarifications on the responsibilities in this respect. The mentioned Decree establishes that physicians can use medicines in a way different from the specifications contained in the SPC provided such use is justified, prescription is reflected in the patient case history, and at least verbal consent is obtained from the parents. This procedure has not yet been implemented in clinical practice, however, probably due to a lack of knowledge or because more time is needed. In this regard, the results of a recent national survey found 71.5% of the participating pediatricians to be aware of the meaning of the term “OL”; 61% claimed to prescribe drugs with indications not contemplated by the SPC; and 47% were aware that the indications should be reflected in the mentioned SPC. In contrast, a little under one-half of those interviewed claimed to inform the parents, and only 22% recorded such prescription practice in the patient case history.<a class="elsevierStyleCrossRef" href="#bib0185">37</a>Study sitePediatric ICU of San Cecilio University Hospital (Granada, Spain).Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres600886" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec615075" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres600885" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Metodología" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec615074" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Patients and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Study site" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-03-31" "fechaAceptado" => "2014-11-08" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec615075" "palabras" => array:5 [ 0 => "Intensive care" 1 => "Off-label use" 2 => "Unlicensed" 3 => "Children" 4 => "Neonates" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec615074" "palabras" => array:5 [ 0 => "Cuidados intensivos" 1 => "Usos off-label" 2 => "Fármacos no autorizados" 3 => "Niños" 4 => "Neonatos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectiveThis study aims to assess the prescription profile and license status of drugs used in a neonatal and pediatric intensive care unit (NPICU). MethodsA prospective observational study was conducted on a dynamic cohort of children admitted to an NPICU (N=81) in a tertiary hospital (Granada, Spain). All prescriptions were classified as off-label or unlicensed based on the Summary of Product Characteristics (SPC). ResultsOf a total of 601 prescriptions, the patients received a mean of 7.4±6 drugs each. The most commonly prescribed drugs corresponded to classes J (anti-infectious, systemic use) N (nervous system) and C (cardiovascular). A little over one-half of the prescriptions were off-label (52%), usually due to dosages differing from the SPC recommendations (79%), followed by different indications (13.5%), age (5%) and administration route (2.5%). In this NPICU, unlicensed usage represented only 5% of all prescriptions. ConclusionsThis study contributes data on prescription of this kind in a Spanish NPICU, revealing at least one off-label prescription in 89% of the children and at least one unlicensed use in 22.3%. These are high figures, but are to be expected given the inclusion of newborn infants and the critical care setting. Even though such usage follows clinical protocols, we underscore the dual need to base treatment on the best available evidence, and to upgrade the SPC accordingly." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivoEvaluar los usos off-label (fuera de ficha técnica [FT]) y unlicensed (medicamentos no autorizados específicamente para niños) en cuidados intensivos neonatales y pediátricos. MetodologíaSe realizó un estudio transversal en la UCINP (Unidad de Cuidados Intensivos Neonatales y Pediátricos) de un hospital público de tercer nivel de Granada, incluyéndose a todos los niños en los que se indicara al menos un tratamiento farmacológico, mediante reclutamiento consecutivo, y durante un periodo de 5 meses (N=81). Las variables recogidas fueron sociodemográficas, clínicas, y medicación. Todas las prescripciones fueron clasificadas a partir de la información contenida en FT sobre uso en niños. ResultadosHubo un total de 601 prescripciones, con una media de 7,4±6 medicamentos por niño. Los fármacos más empleados pertenecían a los grupos J (antiinfecciosos), N (sistema nervioso) y C (cardiovascular). Algo más de la mitad de las prescripciones fueron off-label (52%), fundamentalmente por emplear una dosificación distinta de la recomendada en FT (79%), seguida de diferente indicación (13,5%), edad (5%) y vía de administración (2,5%). El uso de medicamentos no específicamente autorizados en niños solo supuso el 5% de las prescripciones. ConclusionesEl presente estudio aporta datos sobre este tipo de prescripciones en una UCINP española. Pone de manifiesto que el 89% de los niños tiene al menos una prescripción fuera de FT y un 22,3% al menos un uso de fármaco no autorizado para niños. Cifras elevadas, pero justificables dentro del ámbito de unos cuidados intensivos que, además, incluyen neonatos. Pero aunque muchos de los tratamientos estén protocolizados, sería deseable mejorar la evidencia disponible, así como actualizar las FT." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Metodología" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Blanco-Reina E, Medina-Claros AF, Vega-Jiménez MA, Ocaña-Riola R, Márquez-Romero EI, Ruiz-Extremera Á. Utilización de fármacos en niños en cuidados intensivos: estudio de las prescripciones off-label. Med Intensiva. 2016;40:1–8." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 958 "Ancho" => 1560 "Tamanyo" => 62502 ] ] "descripcion" => array:1 [ "en" => "Distribution of medication use by ATC drug classes (values expressed as % of children receiving some drug within the class). Anatomical, therapeutic, chemical (ATC) classification system. A: digestive system and metabolism; B: blood and hematopoietic organs; C: cardiovascular system; H: systemic hormonal formulations; J: systemic antiinfectious agents; M: musculoskeletal system; N: nervous system; R: respiratory system; S: sensory organs." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "OL: off-label; UL: unlicensed." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of prescription \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentage (n) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drugs involved in each category \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">UL prescriptions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (30) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">UL category</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Modification of the formulation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 (15) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Vitamin E, folic acid, nifedipine, caffeine, vancomycin eyedrops \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Contraindicated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 (15) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Drotrecogin, amiodarone, enoxaparin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">OL prescriptions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52 (313) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">OL category</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Different dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">79 (247) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Gentamycin, amoxicillin-clavulanate, midazolam, cefotaxime, dexamethasone, vancomycin, metamizol, alimemazine, phenytoin, desmopressin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Different indication \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13.5 (42) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Aminophylline, dexamethasone, alimemazine, hyperbaric lidocaine, dextromethorphan \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Different age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (16) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Budesonide, voriconazole, alimemazine, metamizol, dextromethorphan \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Different route \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.5 (8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Metamizol \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab983076.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Prescription classification according to the conditions of authorization for children in the Summary of Product Characteristics (N=601 prescriptions)." ] ] 2 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "–: not indicated; OL: off-label; ICU: Intensive Care Unit; UL: unlicensed." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Country \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Year \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Location (unit) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No. patients (no. prescriptions) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OL prescription (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">UL prescription (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patients receiving≥1 OL/UL prescription (%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Conroy<a class="elsevierStyleCrossRef" href="#bib0130">26</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">United Kingdom \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1999 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neonatal ICU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">70 (455) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">54.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">90 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Conroy<a class="elsevierStyleCrossRef" href="#bib0110">22</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Europe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pediatric ward \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">624 (2262) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">67 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">‘T Jong<a class="elsevierStyleCrossRef" href="#bib0175">35</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Netherlands \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pediatric ICU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">238 (2139) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">92 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Avenel<a class="elsevierStyleCrossRef" href="#bib0135">27</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">France \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neonatal ICU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 (257) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">‘T Jong<a class="elsevierStyleCrossRef" href="#bib0140">28</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Netherlands \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neonatal ICU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">247 (2139) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">90 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Pandolfini<a class="elsevierStyleCrossRef" href="#bib0115">23</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Italy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2002 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pediatric ward \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1461 (4265) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">89 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Barr<a class="elsevierStyleCrossRef" href="#bib0145">29</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Israel \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2002 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neonatal ICU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">105 (525) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">93 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Bajcetic<a class="elsevierStyleCrossRef" href="#bib0120">24</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Serbia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2005 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cardiology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">544 (2130) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">76 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Dell’Aera<a class="elsevierStyleCrossRef" href="#bib0150">30</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Italy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neonatal ICU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">34 (176) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Hsein<a class="elsevierStyleCrossRef" href="#bib0105">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Germany \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2008 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pediatric ward \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">417 (1812) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">61 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Lindell-O<a class="elsevierStyleCrossRef" href="#bib0095">19</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Finland \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ward, neonatal ICU and surgery \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">141 (629) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">76 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Neubert<a class="elsevierStyleCrossRef" href="#bib0155">31</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Germany \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2010 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neonatal ICU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">183 (1978) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">70 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Khdour<a class="elsevierStyleCrossRef" href="#bib0060">12</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Palestine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2011 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pediatric ward \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">387 (917) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">35.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Van den Berg<a class="elsevierStyleCrossRef" href="#bib0080">16</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Netherlands \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2011 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oncology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39 (268) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">87 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Lass<a class="elsevierStyleCrossRef" href="#bib0015">3</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Estonia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2011 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neonatal ICU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">490 (1981) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Palcevski<a class="elsevierStyleCrossRef" href="#bib0100">20</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Croatia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pediatric ward \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">531 (1643) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Oguz<a class="elsevierStyleCrossRef" href="#bib0090">18</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Turkey \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neonatal ICU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">464 (1315) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Kimland<a class="elsevierStyleCrossRef" href="#bib0125">25</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sweden \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pediatric ward \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.947 (11,294) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Lee<a class="elsevierStyleCrossRef" href="#bib0170">34</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Malaysia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2013 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pediatric and Neonatal ICU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">194 (1295) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">34.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">92.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Kieran<a class="elsevierStyleCrossRef" href="#bib0160">32</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ireland \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neonatal ICU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">110 (900) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">79 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Laforgia<a class="elsevierStyleCrossRef" href="#bib0165">33</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Italy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neonatal ICU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">126 (483) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">37.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab983077.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Summary of the studies on OL/UL prescriptions in different hospital units." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => 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Drug utilization pattern in children and off-label use of medicines in a pediatric intensive care unit

Utilización de fármacos en niños en cuidados intensivos: estudio de las prescripciones off-label

E. Blanco-Reinaa,

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eblanco@uma.es

Corresponding author.

, A.F. Medina-Clarosb, M.A. Vega-Jiménezc, R. Ocaña-Riolad, E.I. Márquez-Romeroa,e, Á. Ruiz-Extremeraf,g

a Departamento de Farmacología y Pediatría, Facultad de Medicina, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain

b UGC de Pediatría, Hospital Axarquía, Vélez-Málaga, Málaga, Spain

c Medicina de Familia, Centro de Salud La Victoria, Distrito Sanitario de Málaga, Málaga, Spain

d Departamento de Matemáticas, Escuela Andaluza de Salud Pública, Granada, Spain

e Dispositivo de Cuidados Críticos y Urgencias, Distrito Sanitario Málaga, Málaga, Spain

f Departamento de Pediatría, Universidad de Granada, Granada, Spain

g Unidad de Apoyo a la Investigación, Hospital Universitario San Cecilio, CIBERehd, Granada, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">It has been estimated that less than 50&#37; of the drugs used in children have been investigated in the pediatric population&#46; Because of this&#44; the treatment of such patients traditionally has been based on extrapolations referred to drugs that have been developed for adults&#46; However&#44; we know that the conduction of adequate clinical research is the best guarantee for safe&#44; effective and quality treatment&#46; The scarcity of clinical trials in children is due on one hand to the limited interest of the drug industry in this concrete patient population&#44; and on the other to the difficulties inherent to pediatric research&#44; which involves a number of fundamentally ethical and methodological barriers&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Accordingly&#44; most therapeutic agents have not been studied in children&#44; and the benefit&#8211;risk balance of their use is therefore often supported by only limited evidence&#46; All this in many cases has caused quality information on pediatric recommendations to be scarce or inexistent&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The Summary of Product Characteristics &#40;SPC&#41; approved by the Spanish Medicines Agency &#40;<span class="elsevierStyleItalic">Agencia Espa&#241;ola del Medicamento y Productos Sanitarios</span> &#91;AEMPS&#93;&#41; is the official document reflecting the authorized conditions of use of the medication&#46; Based on the findings of the clinical trials made&#44; the SPC summarizes the essential scientific information addressed to health professionals&#46; When the information on the use of a drug in children is limited or inexistent&#44; its prescription is made outside the corresponding licensed or authorized terms&#8211;a situation internationally known as off-label &#40;OL&#41; and unlicensed &#40;UL&#41; drug use&#46; Unlicensed prescription is generally understood as the prescription of drugs that have not been approved for the pediatric population&#44; while off-label prescription involves the use of drugs that have been approved for children but which are used under conditions different from those authorized in the corresponding SPC&#44; i&#46;e&#46;&#44; involving different indications&#44; doses&#44; age ranges or administration routes&#46; The proportion of drugs prescribed outside the authorized terms has been studied in recent years&#44; though the results have been highly varied&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Most studies have been conducted on an in-hospital basis&#44; and those carried out in neonatal Intensive Care Units &#40;ICUs&#41; are particularly relevant in this respect&#46; Among newborn infants&#44; the number of patients that receive at least one OL or UL prescription is much higher than in any other medical or surgical pediatric ward&#8211;with percentages reaching 70&#8211;97&#37; of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The use of these OL or UL prescriptions is not necessarily incorrect&#58; it simply means that the evidence and evaluations required by the health authorities &#40;AEMPS and the European Medicines Agency &#91;EMA&#93;&#41; are not available or are insufficient&#44; and therefore cannot be reflected in the SPC&#46; Nevertheless&#44; it has been demonstrated that such drug use can be associated to certain safety problems&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In fact&#44; a number of studies have already shown that these prescriptions are a risk factor for the development of adverse drug reactions &#40;ADRs&#41;&#44; medication error and possible treatment failure&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> It has been estimated that OL or UL prescriptions are implicated in between 23&#37; and 60&#37; of all ADRs in children&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">An added problem is the lack of specific pediatric formulations&#44; which favors the use of extemporaneous or magistral formulations aimed at adapting certain treatments to the oral route&#46; These preparations are also related to possible medication error and involve uncertainty regarding the stability of the products used&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Considering that intensive care is characterized by great and very diverse exposure to drugs&#44; we were interested in knowing the frequency of prescriptions of this kind in this concrete area of practice&#46; We were also particularly interested in exploring commonly used drugs such as dopamine&#44; midazolam&#44; fentanyl or furosemide&#8211;many of which have not been specifically investigated in the pediatric population&#44; despite extensive experience with their use&#46; On the other hand&#44; most of the studies published to date have been carried out in the United Kingdom and in the Netherlands&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> with very few data referred to the Spanish population&#46; Indeed&#44; the existing studies are limited to two areas unrelated to intensive care&#44; namely gastroenterology<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and out-hospital prescription practice&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> According to current European Union regulations referred to pediatric medications&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> one of the necessary important tasks is to compile information on drug use in children in all the member states&#44; with a view to evaluating the current situation and detecting those therapeutic areas where the need for additional pediatric studies is more pressing&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The aim of the present study therefore was to determine the prescription profile and OL &#40;outside SPC specifications&#41; and UL &#40;medicines not specifically authorized in children&#41; uses in pediatric &#40;PICUs&#41; and neonatal Intensive Care Units &#40;NICUs&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><p id="par0035" class="elsevierStylePara elsevierViewall">A cross-sectional observational study was conducted of all the prescriptions made in a cohort of children admitted to the ICU of a third-level public hospital in Granada &#40;Andalusia&#44; Spain&#41;&#46; This ICU distributed the patients into neonatal &#40;newborn infants up until one month of age&#41; and pediatric patients &#40;from the first month to 14 years of age&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Based on consecutive recruiting over a 5-month period &#40;July&#8211;November&#41;&#44; we prospectively recorded the data on those patients in which at least one drug treatment was indicated&#46; The information source was the case history and medical instructions&#46; Information was collected referred to patient age&#44; weight and reason for admission&#44; as well as to drug treatment&#58; indication&#44; dose&#44; frequency&#44; dosing form and administration route&#46; The drugs studied were grouped according to the Anatomical Therapeutic Chemical &#40;ATC&#41; classification index&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">All prescriptions were classified as OL or UL according to the information referred to pediatric use contained in the corresponding SPC&#46; The criteria used were those published by Turner&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> who classified OL as prescriptions involving doses&#44; age ranges&#44; administration routes or indications different from those reflected in the official drug authorization documentation&#46; In turn&#44; the definition of UL included drug substances still not authorized&#44; drugs specifically contraindicated in children&#44; the modification of formulations&#44; and drugs for which no information at all is available referred to pediatric use&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">A descriptive analysis was made using the SPSS version 19&#46;0 statistical package &#40;Chicago&#44; IL&#44; USA&#41;&#46; The comparison of means of quantitative variables between two groups of patients was based on the Student&#39;s <span class="elsevierStyleItalic">t</span>-test&#44; while the chi-squared test was used for the comparison of proportions in the case of qualitative variables&#46; Statistical significance was considered for <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 in all cases&#46; All personal information was anonymized&#44; and the study was approved by the local Research Ethics Committee&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0055" class="elsevierStylePara elsevierViewall">The study included a total of 81 patients&#44; of which 59&#46;3&#37; &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>48&#41; corresponded to the neonatal ICU &#40;NICU&#41; and 40&#46;7&#37; &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>33&#41; to the pediatric ICU &#40;PICU&#41;&#46; The male gender was seen to predominate &#40;59&#37;&#41;&#44; with no significant differences between the two Units&#46; In the PICU the mean age was 4&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;7 years &#40;range&#58; 2 months&#8211;14 years&#41;&#44; and among the newborn infants the mean gestational age was 34&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;2 weeks &#40;range&#58; 25&#8211;41 weeks&#41;&#44; with a mean weight of 2335<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>949<span class="elsevierStyleHsp" style=""></span>g &#40;range&#58; 780&#8211;4750<span class="elsevierStyleHsp" style=""></span>g&#41;&#46; One-third of the newborn infants weighed less than 2500<span class="elsevierStyleHsp" style=""></span>g&#44; though only 15&#37; were very low weight&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The most frequent reason for admission in the combined Units was prematurity-low weight &#40;22&#46;2&#37;&#41;&#44; followed by infections &#40;21&#37;&#41;&#44; respiratory disease &#40;17&#46;2&#37;&#41; and neurological disorders &#40;15&#37;&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The mean number of drugs prescribed per patient was 7&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6 &#40;range&#58; 1&#8211;32&#59; median 6&#41;&#46; The neonates received more drugs than the pediatric patients&#44; though the difference failed to reach statistical significance &#40;8&#46;3 vs 6&#46;1 drugs&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;09&#41;&#46; Overall&#44; 601 prescriptions were made&#44; involving 91 different drug substances&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> shows the prescription profile according to therapeutic groups based on the ATC classification&#46; Eighty percent of the children received at least one antibiotic&#8211;class J drugs &#40;systemic antiinfectious agents&#41; being the most frequently used&#44; followed by classes N &#40;nervous system&#41; and C &#40;cardiovascular&#41;&#46; It was precisely in these three classes where differences were detected between the neonatal and pediatric patients&#8211;with significantly greater use among the neonates of antibiotics &#40;92 vs 64&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; nervous system drugs &#40;58 vs 49&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; and class C agents &#40;62&#46;5 vs 18&#46;2&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; The rest of the drug classes showed no differences in distribution&#46; The 10 most frequently administered drug substances in the ICU were ampicillin &#40;53&#37; of the patients&#41;&#44; gentamycin &#40;52&#37;&#41;&#44; midazolam &#40;44&#37;&#41;&#44; furosemide &#40;34&#46;5&#37;&#41;&#44; dopamine &#40;33&#37;&#41;&#44; cefotaxime &#40;31&#37;&#41;&#44; metamizol &#40;29&#37;&#41;&#44; fentanyl &#40;28&#37;&#41;&#44; vancomycin &#40;25&#37;&#41; and methylprednisolone &#40;22&#37;&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">On analyzing the 601 prescriptions made&#44; 52&#37; were found to correspond to OL&#44; while 5&#37; were UL &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The number of OL and UL prescriptions per patient ranged from 0 to 8 &#40;mean 2&#46;39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;7&#41; and from 0 to 4 &#40;mean 0&#46;32<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6&#41;&#44; respectively&#46; There was a slight tendency toward more OL prescriptions per patient among the neonates versus the pediatric patients &#40;2&#46;5 vs 1&#46;8&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;06&#41;&#46; A total of 22&#46;3&#37; of the children in the sample received at least one UL prescription&#44; while 89&#37; received at least one OL prescription&#46; The few differences between neonatal and pediatric patients failed to reach statistical significance&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">The causes of UL prescriptions were equally distributed between modification of the formulations and contraindications in children&#46; As examples of the former we have extemporaneous &#40;magistral&#41; formulations of nifedipine&#44; folic acid&#44; vitamin E&#44; caffeine and vancomycin eyedrops&#46; Contraindications and warnings due to non-established efficacy and safety in children in turn affected the use of drotrecogin&#44; amiodarone and enoxaparin&#46; On the other hand&#44; in relation to the OL prescriptions&#44; the main cause was the administration of doses different from those recommended in the SPC &#40;79&#37; of the OL cases&#41;&#44; followed by different indications &#40;13&#46;5&#37;&#41;&#44; different patient age ranges &#40;5&#37;&#41; and different administration routes &#40;2&#46;5&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The indications not contemplated by the SPC were bronchopulmonary dysplasia in the case of dexamethasone&#44; arginosuccinic aciduria in the case of dextromethorphan&#44; irritability episodes in the case of alimemazine&#44; hyperbaric lidocaine use as an antiarrhythmic agent&#44; and aminophylline as respiratory center stimulant in apnea&#46; Off-label use due to administration in patients with ages different from those contemplated in the SPC were mainly referred to the use of drugs in newborn infants and in general in patients under two years of age&#44; for which the safety and efficacy profiles have not been established to date &#40;e&#46;g&#46;&#44; budesonide and voriconazole in patients under two years of age&#41;&#46; Some drugs were found to be prescribed under OL conditions due to more than one cause simultaneously&#44; e&#46;g&#46;&#44; metamizol &#40;dose&#44; age and route different from the authorized specifications&#41;&#44; alimemazine &#40;dose&#44; age and indication different from the authorized specifications&#41;&#44; and dextromethorphan &#40;indication and age different from the authorized specifications&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">The single-center nature of our study could limit its external validity&#46; However&#44; even accepting the variability between prescribers and centers&#44; we consider that the results obtained may adequately reflect this often protocolized type of drug prescription practice in the intensive care setting&#46; Furthermore&#44; and from the perspective of a Spanish ICU&#44; the data obtained may contribute to the assessment of current prescription practices requested by the European Medicines Agency&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The publications on prescriptions of this kind offer very heterogeneous results&#44; due to differences in the methodology&#44; classification criteria and information sources used&#8211;a fact that complicates comparisons among the different studies&#46; In the present study we chose the most widely employed classification of OL and UL prescription&#44;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#8211;17</span></a> originally described by Turner&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> In the same way as in most of the more recent studies&#44; our main information source was the Summary of Product Characteristics &#40;SPC&#41; of the EMA&#46; The SPC is regarded as the official document&#44; since its data have been subjected to regulatory review&#44; and it serves as a consulting tool for clinicians&#44; offering guidance on the authorized conditions of prescription and administration of drugs&#46; However&#44; the need to update the SPCs should be considered&#44; since in many cases they are outdated with respect to the generation of new uses based on quality studies&#46; In effect&#44; research and knowledge in certain areas modify clinical practice&#44; though such changes are not reflected in the SPCs&#8211;particularly in those referred to old drugs or substances of little commercial interest for the drug industry&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Drug exposure among the children of our ICU was highly variable and somewhat greater &#40;mean of 7&#46;4 and median of 6 drugs per patient&#41; than in other studies &#40;median of 3 drugs in the study corresponding to Turkey&#44; 4 in Estonia&#44; and 4&#46;2 in Finland&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;18&#44;19</span></a> Nevertheless&#44; taking into account that our data are referred to the critical care setting&#44; we feel that the figures are reasonable and similar to other published data in this same clinical setting&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> The prescription profile is coherent with the reasons for admission and with the predominance of neonates in the ICU&#46; In this regard&#44; antibiotics are typically the most commonly used drugs in such Units&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;12&#44;18&#44;21</span></a> On the other hand&#44; the fact that 63&#37; of the children received some drug belonging to class N is explained by the needs for sedation and analgesia&#8211;with midazolam and fentanyl ranking among the 10 most frequently prescribed drugs&#46; In our sample there was a significantly greater proportion of antibiotic&#44; nervous system and cardiovascular drug prescription in neonates than in pediatric patients&#8211;this being consistent with the most frequent clinical problems found in newborn infants&#46; We also detected slight differences in profile&#58; while the most commonly used antibiotics in neonates were ampicillin and gentamycin&#44; the prescription of amoxicillin-clavulanate and cefotaxime predominated in the pediatric patients&#46; This is logical&#44; considering the microbiological spectrum to be covered in each case&#46; Likewise&#44; in relation to class N drugs&#44; sedation was more frequent among newborn infants&#44; while in the older children the use of this drug class more often involved analgesia and antifever prescription &#40;e&#46;g&#46;&#44; paracetamol and metamizol&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> reviews the main in-hospital studies found in the literature&#46; In our case&#44; a little over one-half of the prescriptions were OL&#8211;this figure being somewhat higher than those recorded in hospital pediatric wards<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;12&#44;16&#44;19&#8211;25</span></a> &#40;between 35&#37; and 45&#37;&#41;&#44; closer to those recorded in NICUs&#44;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;18&#44;26&#8211;33</span></a> and perhaps a little higher than in other PICUs&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;35</span></a> This is logical&#44; considering the important proportion of newborn infants in the present study&#46; In this respect&#44; it is not surprising that 89&#37; of the admitted children received some prescription of this type&#46; As is clearly seen in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#44; the OL prescription rates differ greatly between countries and studies&#46; Thus&#44; in the case of NICUs&#44; the proportions range from 22&#46;7&#37; in Italy<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> to 87&#37; in Estonia&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> These very distinct results again reflect differences not only in the methodology and classifications used&#44; but also in clinical practice as such&#46; According to Palcevski&#44; another possible source of variability is the type of hospital involved&#46; In this regard&#44; higher OL prescription rates would be expected in centers offering more sophisticated care&#44; or in which the patients present more complicated disease processes&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">The main type of OL prescription in our series was referred to the use of drug doses or administration frequencies different from those reflected in the SPC&#46; This coincides with the observations of many other studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;14&#44;15&#44;20&#44;21&#44;23</span></a> Of note is the fact that the main drugs involving OL use due to doses different from those specified in the SPC are also among the most widely prescribed drug substances&#8211;particularly gentamycin&#44; cefotaxime&#44; vancomycin and midazolam&#46; Regarding the non-authorized indications&#44; it may be more interesting at this point to reflect upon the level of evidence supporting such use&#46; Potentially controversial examples are the off-label use of alimemazine &#40;authorized as an H1 antihistamine for the treatment of allergy&#41; as a sedative&#44; or the administration of aminophylline as an anti-apnea drug in premature infants&#46; These clinical situations raise relevant research questions and should stimulate the conduction of independent studies to clarify the existing uncertainties&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">In our opinion&#44; a notable observation in the present study was the scarce use of UL prescriptions&#44; with an incidence of only 5&#37; versus the usually reported range of 10&#8211;15&#37; of all prescriptions in both the NICU setting<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27&#44;29&#44;30</span></a> and in pediatric wards&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;19&#44;20</span></a> We consider that the extemporaneous formulation of drugs by the hospital pharmacy&#44; or the modification of authorized products&#44; may also be influenced by the pharmaceutical practices found in each individual country&#46; In fact&#44; in the Netherlands&#44; for example&#44; magistral formulation is a traditional practice&#8211;representing up to 48&#37; of all prescriptions&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Such formulations are also often prepared in Spanish hospital pharmacies&#44; though there were few of them in our series&#46; This might be explained by the critical condition of the patients admitted to our Unit&#44; causing parenteral dosing to be the administration route of choice&#46; After being moved to intermediate care or general wards&#44; where the children are in a more stable condition&#44; the need to modify or adapt oral solutions may be comparatively greater&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">It should be remembered that prescription outside the specifications of the SPC need not be inappropriate&#44; and that such practice often represents the most rational and even the best option based on the current evidence and clinical practice guides&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> This is not always the case&#44; however&#44; and UL and OL prescription may be a risk factor for the appearance of adverse drug reactions &#40;ADRs&#41;&#46; It therefore must be guaranteed that children receive the safest and most effective drugs for each given disease condition&#46; For this reason&#44; European Directive 1901&#47;2006 establishes as objective the increased development of pediatric medications&#44; ensuring quality research and improving the available information on the use of drugs in children&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> In this regard&#44; the EMA has launched initiatives such as the creation of a Pediatric Committee&#59; Pediatric Investigation Plans &#40;PIPs&#41;&#59; the publication of a list of medications for which development for pediatric use is recommended&#59; or the European Network of Pediatric Research&#46; Independently of the implementation of these measures&#44; we consider it reasonable to promote studies on drug utilization in children&#44; divulgating the implications of OL and UL use and&#8211;in those cases where such prescription outside the specifications of the SPC or lacking authorization are not supported by clinical practice guides or quality studies&#8211;to propose prospective studies to collect information on efficacy and safety with a view to affording greater evidence and better elements of judgment in selecting drug products&#46; We feel that studies of this kind are particularly interesting in critical care setting&#44; due to the pharmacological profile involved in this setting&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Lastly&#44; a comment should be made on the legal aspects of drug use not contemplated in the SPC&#44; for as has already been mentioned&#44; the latter is an official document with a legally binding character&#46; Drug use outside the specifications of the SPC has been contemplated since the year 2009 in the Spanish Royal Decree &#40;RD&#41; on the Availability of Medications in Special Situations&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> which administratively facilitates such use when supported by the clinical practice guides or scientific evidence&#44; and offers clarifications on the responsibilities in this respect&#46; The mentioned Decree establishes that physicians can use medicines in a way different from the specifications contained in the SPC provided such use is justified&#44; prescription is reflected in the patient case history&#44; and at least verbal consent is obtained from the parents&#46; This procedure has not yet been implemented in clinical practice&#44; however&#44; probably due to a lack of knowledge or because more time is needed&#46; In this regard&#44; the results of a recent national survey found 71&#46;5&#37; of the participating pediatricians to be aware of the meaning of the term &#8220;OL&#8221;&#59; 61&#37; claimed to prescribe drugs with indications not contemplated by the SPC&#59; and 47&#37; were aware that the indications should be reflected in the mentioned SPC&#46; In contrast&#44; a little under one-half of those interviewed claimed to inform the parents&#44; and only 22&#37; recorded such prescription practice in the patient case history&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Study site</span><p id="par0120" class="elsevierStylePara elsevierViewall">Pediatric ICU of San Cecilio University Hospital &#40;Granada&#44; Spain&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">This study aims to assess the prescription profile and license status of drugs used in a neonatal and pediatric intensive care unit &#40;NPICU&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A prospective observational study was conducted on a dynamic cohort of children admitted to an NPICU &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>81&#41; in a tertiary hospital &#40;Granada&#44; Spain&#41;&#46; All prescriptions were classified as <span class="elsevierStyleItalic">off-label</span> or <span class="elsevierStyleItalic">unlicensed</span> based on the Summary of Product Characteristics &#40;SPC&#41;&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Of a total of 601 prescriptions&#44; the patients received a mean of 7&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6 drugs each&#46; The most commonly prescribed drugs corresponded to classes J &#40;anti-infectious&#44; systemic use&#41; N &#40;nervous system&#41; and C &#40;cardiovascular&#41;&#46; A little over one-half of the prescriptions were <span class="elsevierStyleItalic">off-label</span> &#40;52&#37;&#41;&#44; usually due to dosages differing from the SPC recommendations &#40;79&#37;&#41;&#44; followed by different indications &#40;13&#46;5&#37;&#41;&#44; age &#40;5&#37;&#41; and administration route &#40;2&#46;5&#37;&#41;&#46; In this NPICU&#44; <span class="elsevierStyleItalic">unlicensed</span> usage represented only 5&#37; of all prescriptions&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This study contributes data on prescription of this kind in a Spanish NPICU&#44; revealing at least one <span class="elsevierStyleItalic">off-label</span> prescription in 89&#37; of the children and at least one <span class="elsevierStyleItalic">unlicensed</span> use in 22&#46;3&#37;&#46; These are high figures&#44; but are to be expected given the inclusion of newborn infants and the critical care setting&#46; Even though such usage follows clinical protocols&#44; we underscore the dual need to base treatment on the best available evidence&#44; and to upgrade the SPC accordingly&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Evaluar los usos <span class="elsevierStyleItalic">off-label</span> &#40;fuera de ficha t&#233;cnica &#91;FT&#93;&#41; y <span class="elsevierStyleItalic">unlicensed</span> &#40;medicamentos no autorizados espec&#237;ficamente para ni&#241;os&#41; en cuidados intensivos neonatales y pedi&#225;tricos&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Metodolog&#237;a</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se realiz&#243; un estudio transversal en la UCINP &#40;Unidad de Cuidados Intensivos Neonatales y Pedi&#225;tricos&#41; de un hospital p&#250;blico de tercer nivel de Granada&#44; incluy&#233;ndose a todos los ni&#241;os en los que se indicara al menos un tratamiento farmacol&#243;gico&#44; mediante reclutamiento consecutivo&#44; y durante un periodo de 5 meses &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>81&#41;&#46; Las variables recogidas fueron sociodemogr&#225;ficas&#44; cl&#237;nicas&#44; y medicaci&#243;n&#46; Todas las prescripciones fueron clasificadas a partir de la informaci&#243;n contenida en FT sobre uso en ni&#241;os&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Hubo un total de 601 prescripciones&#44; con una media de 7&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6 medicamentos por ni&#241;o&#46; Los f&#225;rmacos m&#225;s empleados pertenec&#237;an a los grupos J &#40;antiinfecciosos&#41;&#44; N &#40;sistema nervioso&#41; y C &#40;cardiovascular&#41;&#46; Algo m&#225;s de la mitad de las prescripciones fueron <span class="elsevierStyleItalic">off-label</span> &#40;52&#37;&#41;&#44; fundamentalmente por emplear una dosificaci&#243;n distinta de la recomendada en FT &#40;79&#37;&#41;&#44; seguida de diferente indicaci&#243;n &#40;13&#44;5&#37;&#41;&#44; edad &#40;5&#37;&#41; y v&#237;a de administraci&#243;n &#40;2&#44;5&#37;&#41;&#46; El uso de medicamentos no espec&#237;ficamente autorizados en ni&#241;os solo supuso el 5&#37; de las prescripciones&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El presente estudio aporta datos sobre este tipo de prescripciones en una UCINP espa&#241;ola&#46; Pone de manifiesto que el 89&#37; de los ni&#241;os tiene al menos una prescripci&#243;n fuera de FT y un 22&#44;3&#37; al menos un uso de f&#225;rmaco no autorizado para ni&#241;os&#46; Cifras elevadas&#44; pero justificables dentro del &#225;mbito de unos cuidados intensivos que&#44; adem&#225;s&#44; incluyen neonatos&#46; Pero aunque muchos de los tratamientos est&#233;n protocolizados&#44; ser&#237;a deseable mejorar la evidencia disponible&#44; as&#237; como actualizar las FT&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Blanco-Reina E&#44; Medina-Claros AF&#44; Vega-Jim&#233;nez MA&#44; Oca&#241;a-Riola R&#44; M&#225;rquez-Romero EI&#44; Ruiz-Extremera &#193;&#46; Utilizaci&#243;n de f&#225;rmacos en ni&#241;os en cuidados intensivos&#58; estudio de las prescripciones <span class="elsevierStyleItalic">off-label</span>&#46; Med Intensiva&#46; 2016&#59;40&#58;1&#8211;8&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Distribution of medication use by ATC drug classes &#40;values expressed as &#37; of children receiving some drug within the class&#41;&#46; Anatomical&#44; therapeutic&#44; chemical &#40;ATC&#41; classification system&#46; A&#58; digestive system and metabolism&#59; B&#58; blood and hematopoietic organs&#59; C&#58; cardiovascular system&#59; H&#58; systemic hormonal formulations&#59; J&#58; systemic antiinfectious agents&#59; M&#58; musculoskeletal system&#59; N&#58; nervous system&#59; R&#58; respiratory system&#59; S&#58; sensory organs&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">OL&#58; off-label&#59; UL&#58; unlicensed&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of prescription&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentage &#40;n&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drugs involved in each category&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">UL prescriptions</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">UL category</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Modification of the formulation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50 &#40;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Vitamin E&#44; folic acid&#44; nifedipine&#44; caffeine&#44; vancomycin eyedrops&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Contraindicated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50 &#40;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Drotrecogin&#44; amiodarone&#44; enoxaparin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">OL prescriptions</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52 &#40;313&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">OL category</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Different dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">79 &#40;247&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gentamycin&#44; amoxicillin-clavulanate&#44; midazolam&#44; cefotaxime&#44; dexamethasone&#44; vancomycin&#44; metamizol&#44; alimemazine&#44; phenytoin&#44; desmopressin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Different indication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&#46;5 &#40;42&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Aminophylline&#44; dexamethasone&#44; alimemazine&#44; hyperbaric lidocaine&#44; dextromethorphan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Different age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Budesonide&#44; voriconazole&#44; alimemazine&#44; metamizol&#44; dextromethorphan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Different route&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;5 &#40;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Metamizol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab983076.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Prescription classification according to the conditions of authorization for children in the Summary of Product Characteristics &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>601 prescriptions&#41;&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">&#8211;&#58; not indicated&#59; OL&#58; off-label&#59; ICU&#58; Intensive Care Unit&#59; UL&#58; unlicensed&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Country&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Location &#40;unit&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46; patients &#40;no&#46; prescriptions&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OL prescription &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">UL prescription &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patients receiving<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>1 OL&#47;UL prescription &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Conroy<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">United Kingdom&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1999&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neonatal ICU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">70 &#40;455&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Conroy<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Europe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pediatric ward&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">624 &#40;2262&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">&#8216;T Jong<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Netherlands&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pediatric ICU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">238 &#40;2139&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Avenel<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">France&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neonatal ICU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40 &#40;257&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">&#8216;T Jong<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Netherlands&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neonatal ICU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">247 &#40;2139&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Pandolfini<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Italy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pediatric ward&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1461 &#40;4265&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">89&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Barr<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Israel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neonatal ICU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">105 &#40;525&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Bajcetic<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Serbia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2005&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cardiology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">544 &#40;2130&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Dell&#8217;Aera<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Italy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neonatal ICU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">34 &#40;176&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Hsein<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germany&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pediatric ward&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">417 &#40;1812&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Lindell-O<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Finland&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2009&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ward&#44; neonatal ICU and surgery&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">141 &#40;629&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Neubert<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germany&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2010&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neonatal ICU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">183 &#40;1978&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Khdour<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Palestine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pediatric ward&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">387 &#40;917&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">35&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">49&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Van den Berg<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Netherlands&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oncology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39 &#40;268&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Lass<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Estonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neonatal ICU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">490 &#40;1981&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Palcevski<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Croatia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pediatric ward&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">531 &#40;1643&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Oguz<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Turkey&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neonatal ICU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">464 &#40;1315&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Kimland<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sweden&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pediatric ward&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;947 &#40;11&#44;294&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Lee<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Malaysia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pediatric and Neonatal ICU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">194 &#40;1295&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">34&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">92&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Kieran<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ireland&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neonatal ICU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">110 &#40;900&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Laforgia<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Italy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neonatal ICU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">126 &#40;483&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">37&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Summary of the studies on OL&#47;UL prescriptions in different hospital units&#46;</p>"
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                        0 => array:2 [
                          "etal" => false
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                          "etal" => false
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Adverse drug reactions in newborns&#44; infants and toddlers&#58; pediatric pharmacovigilance between present and future"
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                      "titulo" => "The impact of unlicensed and off-label drug use on adverse drug reactions in paediatric patients"
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                      "titulo" => "Off-label and unlicensed prescribing for newborns and children in different settings&#58; a review of the literature and a consideration about drug safety"
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                          "etal" => false
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Article information

ISSN: 21735727
Original language: English

DOI:10.1016/j.medine.2014.11.007

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2024 November	8	15	23
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2024 August	60	52	112
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2024 June	48	64	112
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2024 March	60	33	93
2024 February	68	47	115
2024 January	49	34	83
2023 December	34	43	77
2023 November	47	33	80
2023 October	35	32	67
2023 September	54	38	92
2023 August	45	25	70
2023 July	34	26	60
2023 June	37	19	56
2023 May	51	33	84
2023 April	34	23	57
2023 March	63	32	95
2023 February	49	44	93
2023 January	41	29	70
2022 December	75	34	109
2022 November	68	48	116
2022 October	75	26	101
2022 September	46	60	106
2022 August	84	39	123
2022 July	70	32	102
2022 June	42	36	78
2022 May	38	38	76
2022 April	47	45	92
2022 March	52	54	106
2022 February	34	38	72
2022 January	52	54	106
2021 December	53	52	105
2021 November	47	56	103
2021 October	75	99	174
2021 September	42	47	89
2021 August	35	43	78
2021 July	36	45	81
2021 June	46	25	71
2021 May	51	51	102
2021 April	103	77	180
2021 March	62	35	97
2021 February	94	32	126
2021 January	78	22	100
2020 December	55	26	81
2020 November	49	40	89
2020 October	68	35	103
2020 September	49	21	70
2020 August	42	24	66
2020 July	42	29	71
2020 June	97	20	117
2020 May	138	21	159
2020 April	88	8	96
2020 March	53	94	147
2020 February	120	102	222
2020 January	87	70	157
2019 December	88	64	152
2019 November	122	110	232
2019 October	167	40	207
2019 September	67	27	94
2019 August	74	27	101
2019 July	100	49	149
2019 June	86	35	121
2019 May	102	39	141
2019 April	57	35	92
2019 March	66	40	106
2019 February	71	35	106
2019 January	457	38	495
2018 December	108	77	185
2018 November	171	84	255
2018 October	257	32	289
2018 September	90	20	110
2018 August	40	15	55
2018 July	59	12	71
2018 June	67	22	89
2018 May	75	10	85
2018 April	116	12	128
2018 March	219	7	226
2018 February	162	12	174
2018 January	104	11	115
2017 December	152	11	163
2017 November	36	20	56
2017 October	32	17	49
2017 September	25	12	37
2017 August	17	8	25
2017 July	18	15	33
2017 June	24	10	34
2017 May	33	10	43
2017 April	21	10	31
2017 March	13	15	28
2017 February	9	6	15
2017 January	10	6	16
2016 December	38	18	56
2016 November	55	19	74
2016 October	56	24	80
2016 September	55	14	69
2016 August	38	6	44
2016 July	45	16	61

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