Original Article
Neopterin levels and systemic inflammatory response syndrome in pediatric critically ill patients
Niveles de neopterina y síndrome de respuesta inflamatoria sistémica en pacientes críticos pediátricos
Raquel Gil-Gómeza, Javier Blasco-Alonsob,c,
, Pilar Sánchez-Yáñeza, Vanessa Rosa-Camachoa, Guillermo Milanoa,c
Corresponding author
a UGC de Cuidados Críticos y Urgencias Pediátricas, Hospital Regional Universitario de Málaga, Málaga, Spain
b Unidad de Gastroenterología, Hepatología y Nutrición Infantil, UGC de Pediatría, Hospital Regional Universitario de Málaga, Málaga, Spain
c Grupo IBIMA Multidisciplinar Pediátrico de Investigación, Spain
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"correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Niveles de neopterina y síndrome de respuesta inflamatoria sistémica en pacientes críticos pediátricos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 2611 "Ancho" => 3417 "Tamanyo" => 272167 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Correlation of basal neopterin and length of stay in PICU, hours of MV and VIS.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">During systemic inflammatory response syndrome (SIRS) situations, an increased activity in inducible NOS (iNOS) calcium independent has been demonstrated.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">1,2</span></a> In the last two decades, systematic studies have provided convincing evidence about several well-known markers of systemic inflammation<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3–6</span></a> such as C-reactive protein (CRP), amyloid A, interleukin-6, matrix metalloproteases and others, as markers of SIRS.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Activation of macrophages is a marker of chronic latent inflammation of the arterial wall, most likely as a result of the interaction between macrophages and oxidized lipoproteins. Activated macrophages are the principal source of proinflammatory cytokines such as IL-1 β and TNF-α, and they contribute to the progression and instability of atherosclerotic plaques. The activation of macrophages by interferon-γ released from activated T cells is accompanied by release of 2-amino-4-oxo-6 (<span class="elsevierStyleSmallCaps">d</span>-erythro-1′,2′,3′-trihydroxypropyl)-dihydropteridine (<span class="elsevierStyleSmallCaps">d</span>-erythro-neopterin).</p><p id="par0015" class="elsevierStylePara elsevierViewall">Therefore, neopterin production appears to be closely associated with activation of the cellular immune system.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">7</span></a> The biological function of neopterin is not completely clear: it is associated with nitric oxide synthesis and formation of reactive metabolites of oxygen, and it may be toxic to microorganisms.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">8</span></a> Increased concentrations are related to endothelial damage, neoplastic and inflammatory diseases and risk for septic complications.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Neopterin monitoring has been proven helpful in the follow-up of pathological conditions associated with the activation of cell-mediated immunity,<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">9</span></a> such as neoplasia, autoimmune diseases, organ transplantation (20–23), congenital immunodeficiencies and AIDS.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a> In some publications elevated levels have been linked to the existence of viral and bacterial infections. These studies mostly comprise a small number of individuals.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Neopterin is also considered a biomarker for atherosclerotic plaque instability both in coronary and carotid arteries.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a> This biological product released from activated macrophages acts as a pro-oxidant. Consequently, N is crucial in the inflammatory process and pathophysiology of the atheromatous process as well as in cellular death.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The aim of this study is to determine the correlation between plasma neopterin and biopterin levels and severity and degree of SIRS.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><p id="par0035" class="elsevierStylePara elsevierViewall">Single-center prospective observational study of patients admitted to PICU between November 2014 and February 2015 who met the inclusion criteria: age 7 days to 14 years, fulfillment of the SIRS criteria and signed informed consent. Exclusion criteria were intestinal resection, abdominal radiotherapy, intestinal inflammation or necrosis (enterocolitis, mucositis, …), development of pulmonary hypertension and age less than 7 days. Plasma neopterin and biopterin levels were measured at CEDEM Laboratory (Centro de Diagnóstico de Enfermedades Moleculares, Universidad Autónoma de Madrid), using as normal levels those from non-hospitalized healthy children with no known disease and with no active infection in the previous month, according to CEDEM's data.</p><p id="par0040" class="elsevierStylePara elsevierViewall">SIRS was considered if two or more of the following conditions<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">13</span></a> were met:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">Temperature >38<span class="elsevierStyleHsp" style=""></span>°C or <36<span class="elsevierStyleHsp" style=""></span>°C.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Tachycardia:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">•</span><p id="par0055" class="elsevierStylePara elsevierViewall">Children <5 years: FC >180/min.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">•</span><p id="par0060" class="elsevierStylePara elsevierViewall">Children >5 years: FC >150/min.</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0065" class="elsevierStylePara elsevierViewall">Tachypnea:<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">•</span><p id="par0070" class="elsevierStylePara elsevierViewall">Infants: respiratory rate (FR) >60/min.</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">•</span><p id="par0075" class="elsevierStylePara elsevierViewall">Children: FR >50/min.</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0080" class="elsevierStylePara elsevierViewall">PaCO<span class="elsevierStyleInf">2</span> <32<span class="elsevierStyleHsp" style=""></span>mm Hg.</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0085" class="elsevierStylePara elsevierViewall">WBC >12,000/cm<span class="elsevierStyleSup">3</span>, <4000/cm<span class="elsevierStyleSup">3</span> or >10% immature forms.</p></li></ul></p><p id="par0090" class="elsevierStylePara elsevierViewall">We reviewed clinical data [PICU length of stay, duration of mechanical ventilation (MV), vasoactive support measured by the vasopressor inotropic score (VIS)] and laboratory values (leucocytes, uric acid, C reactive protein (CRP), procalcitonin (PCT), albumin, lactate, neopterin and biopterin). Samples for neopterin and biopterin detection were collected on dry paper S&S 903 and analyzed by high-performance liquid chromatography (HPLC), all of them at the end of the collection, performing duplicate determinations for checking test variability. The blood samples on paper were stored frozen at −20<span class="elsevierStyleHsp" style=""></span>°C, keeping them dry and protected from light. Samples for other acute phase reactants were collected at admission and after 24<span class="elsevierStyleHsp" style=""></span>h and 3 days.</p><p id="par0095" class="elsevierStylePara elsevierViewall">The Pediatric Risk of Mortality (PRISM) is a prognostic scoring system that was developed to set the physiologic variables required for pediatric intensive-care unit (PICU) mortality risk assessment and to obtain an objective weighting of the variables analyzed. Results are adjusted for age (months) and expressed as percentage (risk of mortality). The severity of respiratory dysfunction was measured by PaO<span class="elsevierStyleInf">2</span>/FiO<span class="elsevierStyleInf">2</span> ratios. The time-dose for dopamine, dobutamine, epinephrine, norepinephrine, milrinone and vasopressin was recorded during the first 48<span class="elsevierStyleHsp" style=""></span>h. In our analysis, vasoactive inotropic score (VIS) was calculated as described by Gaies et al.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">VIS<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>dopamine (mcg/kg/min)<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>dobutamine (mcg/kg/min)<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>epinephrine (mcg/kg/min)<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>milrinone (mcg/kg/min)<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>10,000<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>vasopressin (U/kg/min)<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>norepinephrine (mcg/kg/min)</p><p id="par0105" class="elsevierStylePara elsevierViewall">We considered as neurological dysfunction if cerebral vascular injury (imaging test) was developed, or if regional cerebral tissue oxygen saturation decreased at least 20% from baseline for 15<span class="elsevierStyleHsp" style=""></span>s (cerebral desaturation). It was considered as a marker of morbidity to require at least 1 week stay in the intensive care unit. Pulmonary dysfunction was set when PaO<span class="elsevierStyleInf">2</span>/FiO<span class="elsevierStyleInf">2</span> was <300 and renal dysfunction when plasma creatinine was increased more than 20% when comparing with basal. Unfavorable evolution was defined when the patient suffered from pulmonary, renal, hemodynamic (need for two or more vasoactive drugs) or neurological dysfunction (epilepsy or cerebral vascular events) or if death finally occurred. Thus, we divided patients into two subgroups (favorable evolution; unfavorable evolution).</p><p id="par0110" class="elsevierStylePara elsevierViewall">Informed consent was obtained from all subjects’ parents. Ethical approval for this study was provided by the Ethical Committee “CEI de Centro Provincial de Málaga”. A descriptive analysis was performed, expressing continuous variables as median and interquartile range (IQ) and categorical variables as frequencies and percentages. Variables with a normal distribution and equal variances were compared between the groups with an independent sample <span class="elsevierStyleItalic">t</span> test. When a variable failed the normality or equal variance tests, the Mann–Whitney test was used for comparison. Comparison of means for favorable, unfavorable and control subjects was performed by means of an ANOVA test. An Spearman's <span class="elsevierStyleItalic">ρ</span> was used to correlate variables. Statistical significance was defined as a 2-tailed <span class="elsevierStyleItalic">p</span> 0.05.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0115" class="elsevierStylePara elsevierViewall">The initial recruitment yielded 108 patients; 37 were removed due to non meeting inclusion criteria leaving a total of 71, with 28 patients finally included (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">A total of 28 patients were finally included: 78.9% were males, 25% less than one year-old, median age 5.04 months (IQ 1.47–10.26). The pediatric risk of mortality score (PRISM II) in the first 24<span class="elsevierStyleHsp" style=""></span>h of admission was 2.0% (IQ 1.1–5.0) with an average length of stay in intensive care unit of 5.0 days (IQ 2.7–18.7) and 10 patients stayed for more than 6 days. Mechanical ventilation was used in 90.2% of patients admitted, with median duration 6.0<span class="elsevierStyleHsp" style=""></span>h (IQ 3.7–102.0), only 9 patients (32%) longer than 24<span class="elsevierStyleHsp" style=""></span>h; vasoactive drugs employed in 33.3%, with maximum VIS score mean 7.33<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>11.5 (median 0 (IQ 0–14)). Main causes of admission were cardiac surgery (39%), neurosurgery (18%), respiratory insufficiency (14%), sepsis (4%) and miscellany (25%). There were 6 patients who suffered from complications. Hemodynamic instability was the main complication (21%), followed by respiratory distress (18%), renal dysfunction (11%) and neurological impairment (3.5%). Two patients died during follow-up.</p><p id="par0125" class="elsevierStylePara elsevierViewall">When analyzing CRP in 0<span class="elsevierStyleHsp" style=""></span>h, 24<span class="elsevierStyleHsp" style=""></span>h, 3rd day samples (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), there is a statistically significative progressive increase in CRP during the first three days. Concerning procalcitonin, the increase reaches a maximum at 24<span class="elsevierStyleHsp" style=""></span>h. Results from lactic acid and uric acid are shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>, demonstrating no significantly difference between samples.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">Neopterin (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>) in the early hours of admission is 2.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.2<span class="elsevierStyleHsp" style=""></span>nmol/L and 2.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.4<span class="elsevierStyleHsp" style=""></span>nmol/L at 24<span class="elsevierStyleHsp" style=""></span>h, both of them within the normal laboratory range (0.7–3.8<span class="elsevierStyleHsp" style=""></span>nmol/L). The basal biopterin is 1.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.5<span class="elsevierStyleHsp" style=""></span>nmol/L and 1.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.4<span class="elsevierStyleHsp" style=""></span>nmol/L at 24<span class="elsevierStyleHsp" style=""></span>h (normal range 0.6–1.5<span class="elsevierStyleHsp" style=""></span>nmol/L).</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">Neopterin is significantly higher in patients with length of stay >6 days (<span class="elsevierStyleItalic">p</span> 0.02), with mechanical ventilation (MV) for more than 24<span class="elsevierStyleHsp" style=""></span>h (<span class="elsevierStyleItalic">p</span> 0.023) and who suffered from complications (<span class="elsevierStyleItalic">p</span> 0.05). Neopterin correlates directly (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>) with the duration of MV (Rho 0.6, <span class="elsevierStyleItalic">p</span> 0.011), length of stay in PICU (Rho 0.75, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001) and maximum VIS (Rho 0.73, <span class="elsevierStyleItalic">p</span> 0.001). Additionally, biopterin directly correlates with the PRISM score (Rho 0.61, <span class="elsevierStyleItalic">p</span> 0.008) and the leukocyte count (Rho 0.88, <span class="elsevierStyleItalic">p</span> 0.002). No correlation with CRP, procalcitonin, lactic or uric acid seen.</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">When comparing patients with favorable and unfavorable evolution, basal neopterin levels were similar (2.21<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.22 vs 2.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.25) but its levels at 24<span class="elsevierStyleHsp" style=""></span>h were significantly different (2.0<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.98 vs 3.83<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.77, <span class="elsevierStyleItalic">p</span> 0.049).</p><p id="par0145" class="elsevierStylePara elsevierViewall">There is a clear difference between those children postoperative of cardiovascular surgery (higher neopterin and biopterin both basal and at 24<span class="elsevierStyleHsp" style=""></span>h) and the rest of admissions (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">With a basal neopterin of 2.3<span class="elsevierStyleHsp" style=""></span>nmol/L the ODDS ratio for prolonged stay is 13.3 (1.05–26.6); with a basal neopterin of 2.8<span class="elsevierStyleHsp" style=""></span>nmol/L the ODDS ratio for complications is 8 (2.1–23.2) and with a neopterin at 24<span class="elsevierStyleHsp" style=""></span>h of 2.35<span class="elsevierStyleHsp" style=""></span>nmol/L is 13 (1.9–28.7).</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0155" class="elsevierStylePara elsevierViewall">In the present study, CRP and procalcitonin concentrations change during first three days after admission. However, concentrations started to rise in the first 6<span class="elsevierStyleHsp" style=""></span>h postoperatively, reaching a peak at 24<span class="elsevierStyleHsp" style=""></span>h for procalcitonin (PCT) and at 3 days for CRP, similar to that described in other studies.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">5,6,15</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">The present study was focused on the effective role played by neopterin in SIRS in pediatric patients. Unlike in other studies, ours results showed similar blood concentrations of this marker compared to the normal levels given by the laboratory<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">11,16</span></a>; however, levels were higher in patients with a longer stay in PICU, with more prolonged mechanical ventilation and a higher need for vasoactive inotropic drugs. These results must be considered useful in highlighting the activated process of macrophage cells involved in PICU pediatric patients.</p><p id="par0165" class="elsevierStylePara elsevierViewall">We found highly significant differences between cardiovascular and non cardiovascular patients for each of the evaluated days of the observation period, similar to other data published.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">17</span></a> This result may be associated with increased oxidative stress caused by chronic low blood perfusion.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a> On the contrary, patients with the same clinical presentation at baseline, but with low neopterin levels measured at the same time-point, did have a lower VIS. In addition to a sustained increase, patients with worse outcome showed a significantly higher level of neopterin at 24<span class="elsevierStyleHsp" style=""></span>h. It has been known for several years that CPB is associated with a generalized inflammatory response. The exposure of blood cells and plasma to artificial membranes and the activation of several cell types in the setting of ischemia and reperfusion are believed to play an important role in the development of this generalized inflammatory reaction.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a> Soluble adhesion molecules released into the circulation are believed to be markers of cellular activation and reflect the extent of inflammation and endothelial damage.</p><p id="par0170" class="elsevierStylePara elsevierViewall">We were unable to establish connection with the defining parameters of SIRS: PCR, procalcitonin, uric or lactic acid. Induction of these parameters is also multifactorial; infection, severe systemic inflammation, organ dysfunction, tissue trauma, and many other aetiologies cause their induction. In certain studies, both PCT and CRP showed limited diagnostic value in critical patients in terms of identifying infectious origins.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">18</span></a> Several published data indicate that PCT and CRP indeed are parameters that, in particular, are more strongly induced in patients in whom the systemic inflammatory response is complicated by infection, or vice versa. CRP concentrations are high already during the less severe stages of organ dysfunction and systemic inflammation, but values are not much further increased during the more severe stages of disease.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">19,20</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">In the relatively recent point of view that ascribes to inflammation an important role in the pathophysiology of multiorgan dysfunction after cardiovascular surgery, it is intriguing to consider for neopterin an active role in the mechanisms responsible of SIRS.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">11,15,17</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">These results represent another way to demonstrate the inflammatory response in critically ill patients and the potential usefulness of neopterin as prognostic marker.</p><p id="par0185" class="elsevierStylePara elsevierViewall">We propose that a link exists between high neopterin levels and worse SIRS profile, suggesting a potential clinical use of neopterin as a marker for disease activity in subject with cardiovascular disease. This could help in identifying patients who are at a higher risk of developing cardiovascular adverse events who might benefit from urgent preventive strategies exploitation or extensive diagnostic work-up, as well as actual therapy, depending from their co-morbidities.</p><p id="par0190" class="elsevierStylePara elsevierViewall">Although there is much remains to be done, our work generates important findings in the field of immune mediated response to critical illness. Having acknowledged the limitations of data processing, we can nevertheless confirm that there are some limitations of this study. Although the present study has yielded some preliminary findings, its design is not without flaws. The main limitations of our study were the small sample and the high number of losses derived from blood sample collection/processing.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusions</span><p id="par0195" class="elsevierStylePara elsevierViewall">In conclusion, neopterin can be considered as a representation of the macrophage activation process and, based on our findings, we hypothesize that plasma level of neopterin is useful to elicit the involvement of the activated macrophage, which, in turn, is able to promote oxidative stress. The plasma level of neopterin may also be considered a new and diverse target for medical and interventional procedures in PICU patients. Therefore, new and original medical protocols are required to address this issue in order to protect against the inflammatory process, with N serving as a novel marker to monitor its efficacy.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Authors’ contribution</span><p id="par0200" class="elsevierStylePara elsevierViewall">R. Gil-Gómez had primary responsibility for protocol development, patients’ enrolment, outcome assessment, preliminary data analysis and writing the manuscript.</p><p id="par0205" class="elsevierStylePara elsevierViewall">J. Blasco-Alonso participated in the development of the protocol and analytical framework for the study, was responsible for patient's enrolment and contributed to the writing of the manuscript.</p><p id="par0210" class="elsevierStylePara elsevierViewall">P. Sánchez and V. Rosa were responsible for an analytical framework and writing of the manuscript.</p><p id="par0215" class="elsevierStylePara elsevierViewall">G. Milano supervised the design and execution of the study and contributed to the reviewing of the manuscript.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflict of interest</span><p id="par0220" class="elsevierStylePara elsevierViewall">The authors declare that there is no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres947373" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Discussion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec919840" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres947374" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Discusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec919841" "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" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Authors’ contribution" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-09-19" "fechaAceptado" => "2016-11-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec919840" "palabras" => array:4 [ 0 => "Neopterine" 1 => "Systemic inflammatory response syndrome" 2 => "Pediatrics" 3 => "Critical illness" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec919841" "palabras" => array:4 [ 0 => "Neopterina" 1 => "Síndrome de respuesta inflamatoria sistémica" 2 => "Enfermedad crítica" 3 => "Pediatría" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Neopterin and biopterin are subproducts of redox reactions, which act as cofactor of enzymes responsible for nitric oxide production. We hypothesized that plasma neopterin suffers different evolution during the first days of a critically ill child.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Single-center prospective observational study in patients 7 days to 14 years admitted to our PICU and that met SIRS criteria. Neopterin and biopterin levels as well as other acute phase reactants were collected at admission and at 24<span class="elsevierStyleHsp" style=""></span>h.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 28 patients were included, 78.9% male, median age 5.04 years (interquartile range [IQR] 1.47–10.26), PRISM II 2.0% (IQR 1.1–5.0). Mechanical ventilation (MV) in 90% of patients, median duration of 6.0<span class="elsevierStyleHsp" style=""></span>h (IQR 3.7–102.0); median PICU length of stay 5.0 days (IQR 2.7–18.7), maximum VIS through 0 (IQR 0–14). Baseline neopterin level 2.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.2<span class="elsevierStyleHsp" style=""></span>nmol/l and at 24<span class="elsevierStyleHsp" style=""></span>h 2.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.4<span class="elsevierStyleHsp" style=""></span>nmol/l. Baseline biopterin is 1.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.5<span class="elsevierStyleHsp" style=""></span>nmol/l and 1.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.4<span class="elsevierStyleHsp" style=""></span>nmol/l at 24<span class="elsevierStyleHsp" style=""></span>h. Neopterin levels significantly higher in patients with PICU length of stay >6 days (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">.</span>02), patients who needed MV >24<span class="elsevierStyleHsp" style=""></span>h (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">=</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">.</span>023) and those who developed complications (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">=</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">.</span>05). Neopterin correlates directly and statistically significant with the duration of MV (rho<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">=</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">.</span>6, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">=</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">.</span>011), PICU length of stay (rho<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">=</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">.</span>75, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.0001) and VIS (rho<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">=</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">.</span>73, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">=</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">.</span>001). Additionally, biopterin directly correlates with the PRISM (rho<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">=</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">.</span>61, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">=</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">.</span>008).</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">There is a higher neopterin level when longer PICU stay, higher VIS score, longer MV and occurrence of complications, pointing at the involvement of an activation of the cellular immune system.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Discussion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La neopterina y biopterina, subproductos de reacciones redox, son cofactores en la producción de óxido nítrico. <span class="elsevierStyleItalic">Hipótesis:</span> La neopterina y biopterina plasmáticas sufren evolución diferente durante los primeros días de una enfermedad crítica en pediatría.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio prospectivo observacional monocéntrico en pacientes de 7 días-14 años ingresados en UCIP con criterios de SRIS. Se recogieron, al ingreso y a las 24<span class="elsevierStyleHsp" style=""></span>h, los niveles de neopterina y biopterina, otros reactantes de fase aguda y datos clínicos.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se analizó a 28 pacientes, el 78,9% varones, de 5,04 años (RIQ 1,47–10,26), con PRISM II 2,0% (RIQ 1,1–5,0), ventilación mecánica (VM) en 90% (36,8% >24<span class="elsevierStyleHsp" style=""></span>h), duración de VM de 6,0<span class="elsevierStyleHsp" style=""></span>h (RIQ 3,7–102,0), ingreso en UCIP de 5,0 días (RIQ 2,7–18,7), media de VIS máximo de 0 (RIQ 0–14). La neopterina inicial fue de 2,3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1,2<span class="elsevierStyleHsp" style=""></span>nmol/l y a las 24<span class="elsevierStyleHsp" style=""></span>h de 2,3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1,4<span class="elsevierStyleHsp" style=""></span>nmol/l. La biopterina basal fue 1,3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0,5<span class="elsevierStyleHsp" style=""></span>nmol/l y a las 24<span class="elsevierStyleHsp" style=""></span>h 1,4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0,4<span class="elsevierStyleHsp" style=""></span>nmol/l. La neopterina fue significativamente mayor en estancia >6 días (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,02), VM<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>24<span class="elsevierStyleHsp" style=""></span>h (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,023) y con complicaciones (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,05). La neopterina se correlaciona de forma directa con la duración de VM (rho<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,6; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,011), la estancia en UCIP (rho<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,75; p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0,0001) y el VIS (rho<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,73; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,001). Adicionalmente, la biopterina se correlaciona directamente con el PRISM (rho<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,61; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,008) y la cifra de leucocitos (rho<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,88; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,002).</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Discusión</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Existe un ascenso de neopterina con mayor estancia, mayor VIS, VM más duradera y aparición de complicaciones, lo que refleja una activación del sistema inmune celular en los más graves.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Discusión" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Gil-Gómez R, Blasco-Alonso J, Sánchez-Yáñez P, Rosa-Camacho V, Milano G. Niveles de neopterina y síndrome de respuesta inflamatoria sistémica en pacientes críticos pediátricos. An Pediatr (Barc). 2017;87:343–349.</p>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1547 "Ancho" => 1633 "Tamanyo" => 110337 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flow chart diagram of selection process.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1749 "Ancho" => 3417 "Tamanyo" => 210089 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Plasma CRP and procalcitonin kinetics.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1325 "Ancho" => 3417 "Tamanyo" => 137654 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Plasma lactic acid and uric acid kinetics.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1304 "Ancho" => 3397 "Tamanyo" => 140110 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Neopterin and biopterin kinetics (nmol/L).</p>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 2611 "Ancho" => 3417 "Tamanyo" => 272167 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Correlation of basal neopterin and length of stay in PICU, hours of MV and VIS.</p>" ] ] 5 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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" 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">Non cardiovascular<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>17 \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">Cardiovascular<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11 \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">p</span> \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">Neopterin basal (nmol/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><span class="elsevierStyleBold">1.69</span><span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><span class="elsevierStyleBold">3.25</span><span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleBold">0.022</span> \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">Neopterin 24<span class="elsevierStyleHsp" style=""></span>h (nmol/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><span class="elsevierStyleBold">1.67</span><span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><span class="elsevierStyleBold">3.30</span><span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.93 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleBold">0.024</span> \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">Biopterin basal (nmol/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><span class="elsevierStyleBold">1.09</span><span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><span class="elsevierStyleBold">1.65</span><span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleBold">0.043</span> \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">Biopterin 24<span class="elsevierStyleHsp" style=""></span>h (nmol/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.31<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.65<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1604462.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Neopterin and biopterin according to reason for admission.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0105" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sepsis and the global burden of disease in children" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "N. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 13 | 20 |
| 2024 October | 46 | 41 | 87 |
| 2024 September | 75 | 52 | 127 |
| 2024 August | 62 | 52 | 114 |
| 2024 July | 48 | 27 | 75 |
| 2024 June | 59 | 26 | 85 |
| 2024 May | 49 | 42 | 91 |
| 2024 April | 55 | 30 | 85 |
| 2024 March | 53 | 27 | 80 |
| 2024 February | 49 | 30 | 79 |
| 2024 January | 44 | 25 | 69 |
| 2023 December | 53 | 13 | 66 |
| 2023 November | 43 | 24 | 67 |
| 2023 October | 52 | 21 | 73 |
| 2023 September | 17 | 19 | 36 |
| 2023 August | 26 | 28 | 54 |
| 2023 July | 43 | 25 | 68 |
| 2023 June | 27 | 20 | 47 |
| 2023 May | 46 | 13 | 59 |
| 2023 April | 48 | 28 | 76 |
| 2023 March | 59 | 24 | 83 |
| 2023 February | 48 | 17 | 65 |
| 2023 January | 21 | 21 | 42 |
| 2022 December | 56 | 40 | 96 |
| 2022 November | 88 | 24 | 112 |
| 2022 October | 59 | 40 | 99 |
| 2022 September | 41 | 32 | 73 |
| 2022 August | 40 | 77 | 117 |
| 2022 July | 30 | 65 | 95 |
| 2022 June | 50 | 48 | 98 |
| 2022 May | 44 | 39 | 83 |
| 2022 April | 29 | 43 | 72 |
| 2022 March | 66 | 65 | 131 |
| 2022 February | 38 | 52 | 90 |
| 2022 January | 49 | 54 | 103 |
| 2021 December | 58 | 44 | 102 |
| 2021 November | 32 | 51 | 83 |
| 2021 October | 60 | 65 | 125 |
| 2021 September | 35 | 43 | 78 |
| 2021 August | 36 | 54 | 90 |
| 2021 July | 41 | 36 | 77 |
| 2021 June | 28 | 38 | 66 |
| 2021 May | 60 | 41 | 101 |
| 2021 April | 105 | 46 | 151 |
| 2021 March | 70 | 29 | 99 |
| 2021 February | 50 | 16 | 66 |
| 2021 January | 66 | 28 | 94 |
| 2020 December | 39 | 15 | 54 |
| 2020 November | 38 | 19 | 57 |
| 2020 October | 38 | 18 | 56 |
| 2020 September | 39 | 25 | 64 |
| 2020 August | 57 | 11 | 68 |
| 2020 July | 57 | 19 | 76 |
| 2020 June | 42 | 17 | 59 |
| 2020 May | 70 | 18 | 88 |
| 2020 April | 22 | 18 | 40 |
| 2020 March | 37 | 18 | 55 |
| 2020 February | 48 | 21 | 69 |
| 2020 January | 65 | 22 | 87 |
| 2019 December | 65 | 24 | 89 |
| 2019 November | 63 | 14 | 77 |
| 2019 October | 71 | 21 | 92 |
| 2019 September | 76 | 15 | 91 |
| 2019 August | 33 | 27 | 60 |
| 2019 July | 36 | 18 | 54 |
| 2019 June | 30 | 22 | 52 |
| 2019 May | 88 | 20 | 108 |
| 2019 April | 75 | 28 | 103 |
| 2019 March | 48 | 19 | 67 |
| 2019 February | 47 | 14 | 61 |
| 2019 January | 40 | 29 | 69 |
| 2018 December | 41 | 31 | 72 |
| 2018 November | 86 | 22 | 108 |
| 2018 October | 172 | 17 | 189 |
| 2018 September | 66 | 39 | 105 |
| 2018 August | 5 | 0 | 5 |
| 2018 July | 4 | 0 | 4 |
| 2018 June | 3 | 0 | 3 |
| 2018 May | 9 | 0 | 9 |
| 2018 April | 77 | 0 | 77 |
| 2018 March | 34 | 0 | 34 |
| 2018 February | 25 | 0 | 25 |
| 2018 January | 37 | 0 | 37 |
| 2017 November | 0 | 9 | 9 |
| 2017 October | 0 | 6 | 6 |
| 2017 September | 0 | 14 | 14 |
| 2017 August | 0 | 10 | 10 |
| 2017 July | 0 | 7 | 7 |
| 2017 June | 0 | 14 | 14 |
| 2017 May | 0 | 31 | 31 |
| 2017 April | 0 | 113 | 113 |
| 2017 March | 0 | 9 | 9 |
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