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Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns
Comparação de dois esquemas posológicos de ibuprofeno para o fechamento do canal arterial em recém-nascidos pré-termo
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When symptomatic, it increases the need for ventilatory support, increases the risk of peri-intraventricular hemorrhage,<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">2</span></a> of bronchopulmonary dysplasia (BPD)<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">3,4</span></a> and necrotizing enterocolitis,<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">5</span></a> and reduces survival rates.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">6</span></a> However, there is no clear evidence of the long-term results of PDA treatment.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">7</span></a> Several randomized controlled trials have failed to show any benefit from treatment on survival and long-term outcomes.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">1,8,9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">A more conservative approach has been increasingly suggested, especially in patients with good clinical evolution. This is due to the high chance of spontaneous closure, more common in newborns weighing >800<span class="elsevierStyleHsp" style=""></span>g, without the need for mechanical ventilation and with no signs of heart failure or pulmonary congestion.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10,11</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In patients whose patent ductus arteriosus becomes clinically relevant and symptomatic, its constriction can be induced with cyclooxygenase inhibitors, such as indomethacin and ibuprofen, with permanent closure rates of around 60–80%.<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">12–14</span></a> Both have side effects, but ibuprofen seems to have fewer negative effects on the cerebral and renal blood flow and also possibly fewer gastrointestinal side effects.<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">15–17</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The recommended standard dose of intravenous ibuprofen for patent ductus arteriosus closure is 10<span class="elsevierStyleHsp" style=""></span>mg/kg/dose on the first day and 5<span class="elsevierStyleHsp" style=""></span>mg/kg/dose on the second and third days.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">18,19</span></a> However, Dani et al.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">16</span></a> demonstrated that the use of ibuprofen at high doses (20-10-10<span class="elsevierStyleHsp" style=""></span>mg/kg/day) is more effective than the standard regimen for PDA in preterm newborns with a gestational age <29 weeks, without increasing the rate of adverse effects.</p><p id="par0030" class="elsevierStylePara elsevierViewall">From the year 2012, aiming to achieve higher rates of PDA closure in preterm newborns, ibuprofen dose regimens were changed for the drug treatment of PDA in the Neonatal Intensive Care Unit of Hospital de Clínicas de Porto Alegre (HCPA). Higher doses of ibuprofen started to be utilized, rather than the previously used standard dose. Therefore, the doses changed to 20<span class="elsevierStyleHsp" style=""></span>mg/kg of ibuprofen for the first intravenous infusion on day 1, followed by 10<span class="elsevierStyleHsp" style=""></span>mg/kg on days 2 and 3, when newborns showed a hemodynamically significant ductus arteriosus confirmed by the echocardiography.</p><p id="par0035" class="elsevierStylePara elsevierViewall">This study aims to compare the therapeutic effectiveness and the impact of the two ibuprofen doses on PDA closure rates in preterm newborns, as well as other morbidities such as BPD, renal impairment, need for surgery for PDA closure, and death.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0040" class="elsevierStylePara elsevierViewall">A cohort study with historical control was performed. It included all preterm newborns who received intravenous ibuprofen in the period of January 2010 to December 2013 for the treatment of patent ductus arteriosus in the Neonatology Service of HCPA. The HCPA is a university tertiary referral hospital with the capacity to admit up to 50 newborns. It has 20 neonatal intensive care unit (NICU) beds, which encompass less complex cases to extremely preterm newborns and those with rare diseases. The study was approved by the ethics committee of the institution.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The population was divided into two groups, one receiving low-dose ibuprofen (10-5-5<span class="elsevierStyleHsp" style=""></span>mg/kg/day – single daily dose), treated before the change in dose regimens and those receiving high-dose ibuprofen (20-10-10<span class="elsevierStyleHsp" style=""></span>mg/kg/day – single daily dose) for three days, treated after the change in the care protocol.</p><p id="par0050" class="elsevierStylePara elsevierViewall">All patients underwent echocardiography for the diagnosis of PDA. Treatment was indicated for those with significant clinical signs and presence of respiratory symptoms, and with echocardiography findings showing left-right shunt through the ductus arteriosus with left atrium/aortic root ratio ≥1.5<span class="elsevierStyleHsp" style=""></span>mm.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Newborns with congenital heart malformation, those without an echocardiogram to confirm the diagnosis, and those who did not complete the treatment due to clinical instability or death were excluded.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The collected demographic data included gestational age, birth weight, days of life at the beginning of treatment, need for other ibuprofen treatment cycles, need for surgical closure, death, and neonatal morbidities, such as bronchopulmonary dysplasia (defined as need for supplemental oxygen or ventilatory support at 28 days of life), necrotizing enterocolitis (presence of pneumatosis or intestinal perforation), need for ventilatory support (continuous positive airway pressure [CPAP], noninvasive mechanical ventilation [NIMV], mechanical ventilation [MV], and high-frequency ventilation [HFV]), presence of chorioamnionitis, sepsis with positive blood cultures, and peri-intraventricular hemorrhage grades III and IV. Serum creatinine and urea levels 48<span class="elsevierStyleHsp" style=""></span>h before and after completion of each treatment cycle were also recorded.</p><p id="par0065" class="elsevierStylePara elsevierViewall">The closure of the patent ductus arteriosus, the primary outcome, was defined as complete PDA closure observed on echocardiography.</p><p id="par0070" class="elsevierStylePara elsevierViewall">This study compared the clinical outcome of patients receiving higher doses of ibuprofen with those previously treated with lower doses.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Statistical analysis</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Sample size calculation</span><p id="par0075" class="elsevierStylePara elsevierViewall">To detect a difference of 30 percentage points (from 40% to 10% of ductus arteriosus closure failure), considering power of 80% and <span class="elsevierStyleItalic">α</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.05, 32 patients were necessary in each group.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical tests</span><p id="par0080" class="elsevierStylePara elsevierViewall">Data were stored in a database created with the software SPSS<span class="elsevierStyleSup">®</span> version 18.0 (SPSS Inc. Released 2009. PASW Statistics for Windows, Version 18.0 IL, USA), which was also used for statistical analyses. Categorical variables were described as absolute and relative frequencies, continuous variables with symmetrical distribution as mean and standard deviation, and the asymmetrical variables as median and interquartile range. Categorical variables were compared using Fisher's exact test, the quantitative variables with symmetrical distribution by Student's <span class="elsevierStyleItalic">t</span>-test, and those with asymmetrical distribution by the Mann–Whitney test. The significance level was set at 0.05.</p><p id="par0085" class="elsevierStylePara elsevierViewall">The study was approved by the institutional research committee, and all researchers signed a consent form in order to obtain access to patients’ medical records, in which they swore to maintain complete confidentiality.</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><p id="par0090" class="elsevierStylePara elsevierViewall">A total of 84 patients received ibuprofen for PDA closure in the abovementioned period; seven were excluded, three because they received five ibuprofen doses rather than one or two cycles of three doses, and four patients due to the incomplete treatment because of death or major clinical instability. There were no losses due to cardiac malformations or lack of diagnosis on echocardiography. The percentage of losses was 8.3%. The study population consisted of 77 patients, of whom 33 (42.8%) received high-dose and 44 (57.1%) low-dose ibuprofen.</p><p id="par0095" class="elsevierStylePara elsevierViewall">There was no significant difference between the two groups regarding birth weight (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.32), gestational age (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.49), days of life at the beginning of the treatment with ibuprofen (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.32), chorioamnionitis (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.62), need for mechanical ventilation (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.74), necrotizing enterocolitis (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.76), peri-intraventricular hemorrhage (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.99), hyaline membrane disease (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.06), and infection with a positive culture (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.71) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Among those who received low-dose treatment, 25 (56.8%) had PDA closure after the first cycle of ibuprofen and 17 (51.5%) after receiving high-dose treatment (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.99). A total of 22.7% of the patients in the low-dose group received a second cycle <span class="elsevierStyleItalic">vs</span>. 18.2% of patients in the high-dose group (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.63).</p><p id="par0105" class="elsevierStylePara elsevierViewall">Sixteen patients received a second ibuprofen cycle, but only 13 were submitted to an echocardiogram at the end of treatment; eight patients from the low-dose group and five from the high-dose group. Four patients (50%) had PDA closure after the low-dose and three (60%) after the high-dose treatment (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.99).</p><p id="par0110" class="elsevierStylePara elsevierViewall">Regarding the secondary outcomes, seven patients underwent surgery for PDA closure; 13.6% in the low-dose and 3% in the high-dose group (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.22). A total of 53 patients (68.8%) were assessed on the 28th day of life for bronchopulmonary dysplasia; 30 from the low-dose and 23 from the high-dose group. Twenty-two patients from the low-dose and 17 from the high-dose group developed BPD (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.99); 22 (50%) patients from the low-dose group died <span class="elsevierStyleItalic">vs.</span> 15 (45.5%) patients from the high-dose group (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.86). Urea and creatinine levels after the first cycle showed no statistically significant differences between the groups (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.62 for urea and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.29 for creatinine) and only one patient had oliguria, which was from the low-dose group (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discussion</span><p id="par0115" class="elsevierStylePara elsevierViewall">This study did not show greater efficiency of higher doses of intravenous ibuprofen over the standard dose for PDA closure in preterm newborns. In addition, no differences were found regarding the occurrence of short-term adverse effects or neonatal morbidities when the two regimens were compared.</p><p id="par0120" class="elsevierStylePara elsevierViewall">The optimal dose of ibuprofen for PDA treatment remains controversial. The standard regimen is based on limited and scarce pharmacokinetic data.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">19–21</span></a> Desfrere et al.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">22</span></a> suggested that a higher-dose regimen, with 20, 10, 10<span class="elsevierStyleHsp" style=""></span>mg/kg/day for three days, could attain higher PDA closure rates in newborns with less than 27 weeks of gestational age; however, the tolerability and safety should be carefully assessed in further studies before being routinely recommended.</p><p id="par0125" class="elsevierStylePara elsevierViewall">Meißner et al.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a> found a clear trend toward higher rates of PDA closure with higher doses with no increase in adverse effects, but without statistical significance.</p><p id="par0130" class="elsevierStylePara elsevierViewall">Hirt et al. demonstrated that, with the increase in postnatal age, plasma ibuprofen clearance also increased, resulting in a reduction of half-life (42.2<span class="elsevierStyleHsp" style=""></span>h at three days <span class="elsevierStyleItalic">vs</span>. 17.7<span class="elsevierStyleHsp" style=""></span>h at five days),<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">19</span></a> probably due to the maturation of cytochrome P450, which metabolizes ibuprofen.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">23</span></a> These authors concluded that the ibuprofen dose regimen should be prospectively tested.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Considering the hypothesis that the increase in ibuprofen doses for PDA closure would be more effective than the standard dose, with no increase in adverse events, Dani et al. designed a randomized controlled study, which assessed 70 newborns, of whom 35 received the standard dose, and 35, the double dose. The authors observed that the high-dose regimen was more effective for PDA closure in preterm newborns younger than 27 weeks of gestational age, with no increase of adverse events rates.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">16</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In disagreement with the results of the study by Dani et al.,<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">16</span></a> the use of high doses of ibuprofen in the present analysis showed no significant difference regarding the increase in PDA closure rates. Additionally, no difference regarding the effectiveness of the second cycle of treatment between the two groups was found. Although not statistically significant, the need for PDA surgical closure was higher in the group that received low doses of ibuprofen. However, the number of assessed patients was not sufficient to definitely analyze this outcome.</p><p id="par0145" class="elsevierStylePara elsevierViewall">This study showed no statistically significant differences regarding neonatal morbimortality, such as the presence of bronchopulmonary dysplasia, peri-intraventricular hemorrhage, necrotizing enterocolitis, and death between the groups that received different doses of ibuprofen.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Renal failure or oliguria has been reported in 5–7% of patients treated with ibuprofen for PDA closure, but it is reversible.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">1</span></a> Among the patients in the present study, only one had oliguria and this patient belonged to the low-dose group. The administration of higher doses was well tolerated and patients showed no adverse effects. There was no significant difference related to serum levels of urea and creatinine after treatment with ibuprofen between the two groups. These findings are in agreement with the data previously published in the literature, which reported only mild adverse effects.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">22</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">To guarantee the safety and efficacy of different ibuprofen dose regimens, the authors emphasize the small number of assessed patients as a limitation of this study, in addition to its retrospective design. However, although it appears reasonable to consider higher doses when treatment is started after the 5th day of life, due to the drug pharmacokinetics, it was not possible to analyze this in the present study due to the small number of assessed patients. Randomized prospective studies could further elucidate this issue.</p><p id="par0160" class="elsevierStylePara elsevierViewall">This study showed no benefit in changing the ibuprofen dose regimen to double doses for the treatment of symptomatic PDA in preterm newborns. There was no significant difference when comparing the two treatment dose regimens.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicts of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres655719" "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" => "xpalclavsec665338" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres655718" "titulo" => "Resumo" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec665337" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methods" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Statistical analysis" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Sample size calculation" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical tests" ] ] ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Results" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-05-27" "fechaAceptado" => "2015-09-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec665338" "palabras" => array:3 [ 0 => "Patent ductus arteriosus" 1 => "Ibuprofen" 2 => "Preterm infant" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec665337" "palabras" => array:3 [ 0 => "Permeabilidade do canal arterial" 1 => "Ibuprofeno" 2 => "Recém-nascido prematuro" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To compare the efficacy of intravenous ibuprofen at high (20-10-10<span class="elsevierStyleHsp" style=""></span>mg/kg/dose) and low doses (10-5-5<span class="elsevierStyleHsp" style=""></span>mg/kg/dose) the closure of patent ductus arteriosus in preterm newborns.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8%) low-dose patients and in 17 (51.5%) high-dose patients (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.99). Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.99). Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.22). Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.99). Twenty-two (50%) low-dose patients died <span class="elsevierStyleItalic">vs.</span> 15 (45.5%) high-dose patients (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.86).</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens.</p></span>" "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" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Comparar a eficácia do ibuprofeno endovenoso em doses altas (20, 10 e 10<span class="elsevierStyleHsp" style=""></span>mg/kg/dose) e em doses baixas (10, 5 e 5<span class="elsevierStyleHsp" style=""></span>mg/kg/dose) para o fechamento do canal arterial em recém-nascidos pré-termo.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudo de coorte com controle histórico pesquisando recém-nascidos que receberam ibuprofeno endovenoso, no período de 2010 à 2013 na unidade de internação neonatal, em doses altas e baixas para o fechamento do canal arterial, documentado por ecocardiograma. Como desfechos secundários foram avaliados o número de ciclos de ibuprofeno realizados, a incidência de displasia broncopulmonar, enterocolite necrosante, alteração de função renal e óbito.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">77 pacientes receberam 3 doses de ibuprofeno para tratamento do canal arterial, sendo que 33 dose alta e 44 dose baixa. 25 (56.8%) dos que receberam dose baixa fecharam o canal após o 1° ciclo e 17 (51,5%) fecharam após receberem dose alta (p<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.99). 16 pacientes receberam o 2° ciclo, destes 50% fecharam o canal após uso de dose baixa e 60% após o uso de dose alta (p<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.99). 7 pacientes foram à cirurgia para fechamento do canal, sendo 13,6% do grupo que recebeu dose baixa e 3% dose alta (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.22). 39 pacientes desenvolveram displasia broncopulmonar, 50% do grupo de dose baixa e 51,5% do grupo de dose alta (p<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.99). 22 (50%) dos pacientes do grupo dose baixa evoluiu a óbito <span class="elsevierStyleItalic">versus</span> 15 (45,5%) dos pacientes do grupo de dose alta (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.86).</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusão</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Não encontramos diferença em relação ao fechamento do canal arterial, assim como ocorrência de efeitos adversos, quando comparamos os dois esquemas posológicos.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Please cite this article as: Dornelles LV, Corso AL, Silveira RC, Procianoy RS. Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns. J Pediatr (Rio J). 2016;92:314–8.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0035">The study is associated with the Neonatology Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">GA, gestational age; BW, birth weight; DL, days of life; RDS, respiratory distress syndrome; sepsis, presence of positive blood culture; NEC, necrotizing enterocolitis; PIVH, peri-intraventricular hemorrhage.</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="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Low dose group \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">High dose group \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col"><span class="elsevierStyleItalic">p</span> \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">(<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>44) \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">(<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>33) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GA (weeks)<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27.9 (±3.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27.4 (±2.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.49 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BW (grams)<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1002 (±428) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">913 (±321) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.32 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Start of treatment (DL)<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (2–4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (2–4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.32 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RDS<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42 (95.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27 (81.8%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.06 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chorioamnionitis<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (22.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (30.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.62 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sepsis<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 (43.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 (36.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.71 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ventilatory support<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">43 (97.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32 (97%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.74 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">NEC<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (15.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (21.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.76 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PIVH<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (20.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (21.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">>0.99 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1077225.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Student's <span class="elsevierStyleItalic">t</span>-test (mean and standard deviation).</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Mann–Whitney test (median and interquartile range).</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Fisher's exact test (frequency and percentage).</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Characteristics of the studied patients.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia.</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="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Low-dose group \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">High-dose group \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col"><span class="elsevierStyleItalic">p</span> \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">(<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>44) \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">(<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>33) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PDA closed after 1st cycle<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 (56.8%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17 (51.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">>0.99 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Received 2nd cycle<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (22.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (18.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.63 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PDA closed after 2nd cycle<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (50%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (60%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">>0.99 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Urea<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">84.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>40.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">77.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>48.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.62 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Creatinine<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.86<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.74<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.29 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oliguria<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (2.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">>0.99 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Surgery<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (13.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BPD<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22 (50%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17 (51.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">>0.99 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Death<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22 (50%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 (45.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.86 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1077224.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Fisher's exact test (frequency and percentage).</p>" ] 1 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Student's <span class="elsevierStyleItalic">t</span>-test (mean and standard deviation).</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Treatment outcomes.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:23 [ 0 => array:3 [ "identificador" => "bib0120" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Patent ductus arteriosus of the preterm infant" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "S.E. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 4 | 8 |
| 2024 October | 20 | 22 | 42 |
| 2024 September | 14 | 28 | 42 |
| 2024 August | 26 | 28 | 54 |
| 2024 July | 36 | 35 | 71 |
| 2024 June | 21 | 14 | 35 |
| 2024 May | 16 | 18 | 34 |
| 2024 April | 40 | 22 | 62 |
| 2024 March | 17 | 12 | 29 |
| 2024 February | 15 | 23 | 38 |
| 2024 January | 15 | 19 | 34 |
| 2023 December | 11 | 26 | 37 |
| 2023 November | 18 | 27 | 45 |
| 2023 October | 24 | 28 | 52 |
| 2023 September | 28 | 40 | 68 |
| 2023 August | 17 | 17 | 34 |
| 2023 July | 13 | 12 | 25 |
| 2023 June | 14 | 8 | 22 |
| 2023 May | 16 | 17 | 33 |
| 2023 April | 24 | 4 | 28 |
| 2023 March | 33 | 14 | 47 |
| 2023 February | 22 | 13 | 35 |
| 2023 January | 29 | 14 | 43 |
| 2022 December | 33 | 17 | 50 |
| 2022 November | 42 | 24 | 66 |
| 2022 October | 29 | 25 | 54 |
| 2022 September | 23 | 26 | 49 |
| 2022 August | 24 | 27 | 51 |
| 2022 July | 14 | 20 | 34 |
| 2022 June | 17 | 25 | 42 |
| 2022 May | 19 | 42 | 61 |
| 2022 April | 38 | 30 | 68 |
| 2022 March | 17 | 22 | 39 |
| 2022 February | 11 | 36 | 47 |
| 2022 January | 9 | 15 | 24 |
| 2021 December | 11 | 31 | 42 |
| 2021 November | 6 | 15 | 21 |
| 2021 October | 10 | 13 | 23 |
| 2021 September | 4 | 6 | 10 |
| 2021 August | 9 | 9 | 18 |
| 2021 July | 1 | 7 | 8 |
| 2021 June | 6 | 9 | 15 |
| 2021 May | 7 | 10 | 17 |
| 2021 April | 5 | 9 | 14 |
| 2021 March | 4 | 8 | 12 |
| 2021 February | 6 | 6 | 12 |
| 2021 January | 6 | 9 | 15 |
| 2020 December | 6 | 8 | 14 |
| 2020 November | 8 | 11 | 19 |
| 2020 October | 7 | 5 | 12 |
| 2020 September | 10 | 12 | 22 |
| 2020 August | 7 | 1 | 8 |
| 2020 July | 6 | 4 | 10 |
| 2020 June | 10 | 4 | 14 |
| 2020 May | 12 | 4 | 16 |
| 2020 April | 16 | 12 | 28 |
| 2020 March | 12 | 6 | 18 |
| 2020 February | 14 | 9 | 23 |
| 2020 January | 19 | 15 | 34 |
| 2019 December | 10 | 6 | 16 |
| 2019 November | 7 | 6 | 13 |
| 2019 October | 15 | 10 | 25 |
| 2019 September | 16 | 6 | 22 |
| 2019 August | 10 | 12 | 22 |
| 2019 July | 15 | 10 | 25 |
| 2019 June | 14 | 21 | 35 |
| 2019 May | 11 | 7 | 18 |
| 2019 April | 19 | 10 | 29 |
| 2019 March | 12 | 9 | 21 |
| 2019 February | 4 | 2 | 6 |
| 2019 January | 13 | 7 | 20 |
| 2018 December | 13 | 8 | 21 |
| 2018 November | 6 | 7 | 13 |
| 2018 October | 14 | 11 | 25 |
| 2018 September | 11 | 15 | 26 |
| 2018 August | 3 | 54 | 57 |
| 2018 July | 11 | 12 | 23 |
| 2018 June | 4 | 5 | 9 |
| 2018 May | 5 | 7 | 12 |
| 2018 April | 6 | 0 | 6 |
| 2018 March | 10 | 3 | 13 |
| 2018 February | 1 | 2 | 3 |
| 2018 January | 6 | 1 | 7 |
| 2017 December | 2 | 1 | 3 |
| 2017 November | 10 | 5 | 15 |
| 2017 October | 8 | 4 | 12 |
| 2017 September | 4 | 3 | 7 |
| 2017 August | 3 | 0 | 3 |
| 2017 July | 1 | 0 | 1 |
| 2017 June | 8 | 13 | 21 |
| 2017 May | 4 | 0 | 4 |
| 2017 April | 10 | 7 | 17 |
| 2017 March | 3 | 1 | 4 |
| 2017 February | 4 | 2 | 6 |
| 2017 January | 9 | 7 | 16 |
| 2016 December | 12 | 9 | 21 |
| 2016 November | 13 | 3 | 16 |
| 2016 October | 15 | 13 | 28 |
| 2016 September | 18 | 15 | 33 |
| 2016 August | 16 | 11 | 27 |
| 2016 July | 44 | 19 | 63 |
| 2016 June | 43 | 19 | 62 |
| 2016 May | 17 | 13 | 30 |
| 2016 April | 9 | 9 | 18 |
| 2016 March | 7 | 6 | 13 |
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