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Right from the beginning of the infusion we observed initially mild hypernatremias &#40;151<span class="elsevierStyleHsp" style=""></span>mEq&#47;L 6<span class="elsevierStyleHsp" style=""></span>h after starting the infusion&#41; that progressed upward up to 164<span class="elsevierStyleHsp" style=""></span>mEq&#47;L that were inconsistent with the values shown by the gasometer even though the levels of IV sodium supplied had been reduced&#44; but without presence of polyuria or other criteria of diabetes insipidus &#40;DI&#41;&#46; The initial dose was 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;h&#44; but it was titrated upward to a maximum of 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;h&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">After withdrawing the drug&#44; the levels of natremia went back to normal&#44; and we were able to conduct one retrospective study based on a review of the clinical histories of all children who received sodium thiopental from 2009 to 2015&#44; in order to analyze all possible inconsistencies between the natremia found in our core lab &#40;Na<span class="elsevierStyleInf">B</span>&#41;&#8212;Dimension Vista 1500&#44; Siemens Healthcare Diagnostics&#44; Newark&#44; USA&#8212;and the natremia found in the gasometer &#40;Na<span class="elsevierStyleInf">G</span>&#41;&#8212;ABL800 Flex&#44; Radiometer GmbH&#44; Copenhagen&#44; Denmark&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Several sociodemographic variables were considered together with characteristics from the episodes reported&#44; the doses of thiopental&#44; the sodium supplied during the infusion&#44; and the levels of natremia 48<span class="elsevierStyleHsp" style=""></span>h after the administration obtained by the analyzer &#40;Na<span class="elsevierStyleInf">B</span>&#41; and the gasometer &#40;Na<span class="elsevierStyleInf">G</span>&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Since the samples analyzed through these two methods were not obtained simultaneously&#44; and in an attempt to avoid the influence of IV sodium supply&#44; the pairs of values obtained with time intervals<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>12<span class="elsevierStyleHsp" style=""></span>h were selected as long as the same infusion and clinical situation was maintained&#44; and with time intervals<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>h whenever any of these parameters had changed&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The quantitative variables are expressed as mean and standard deviation &#40;normal distribution&#41;&#44; or mean and interquartile range &#40;IQR&#41; &#40;for the rest&#41;&#46; For the comparison of the levels of natremia obtained through both of the aforementioned methods&#44; the Student&#39;s <span class="elsevierStyleItalic">t</span> test and the Mann&#8211;Whitney&#39;s <span class="elsevierStyleItalic">U</span> test were used when appropriate&#46; The steady-state interclass correlation coefficient was estimated&#44; and the Bland&#8211;Altman diagram was built&#46; The <span class="elsevierStyleItalic">p</span> value was established in 0&#46;05&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The study was assessed and approved by the corresponding Ethics Committee from the Provincial Research&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Fourteen &#40;14&#41; patients received thiopental in the period analyzed&#59; nine &#40;9&#41; of them due to intracranial hypertension&#59; four &#40;4&#41; due seizures&#59; and one &#40;1&#41; case due to difficult sedation&#46; Thirty-five &#40;35&#41; pairs of measurements were analyzed 28&#47;35 during the infusion&#46; The Na<span class="elsevierStyleInf">G</span> average was 148&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;65<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#44; and the Na<span class="elsevierStyleInf">B</span> average 154&#46;78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;04<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; The difference mean during the infusion was 5&#46;5<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#40;1&#46;5&#8211;8&#46;75&#41;&#44; and before the infusion&#44; 1<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#40;&#8722;3 to 2&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;017&#46; The interclass correlation coefficient was 0&#46;77 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; when we looked at the pairs of values during the infusion&#46; The concordance limits in the Bland&#8211;Altman diagram &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; were &#8722;6&#46;26&#44; 18&#46;26&#46; In fifty &#40;50&#41; per cent of the pairs of measurements&#44; the difference was<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#40;17&#46;9 per cent between 5 and 7&#46;5<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#59; 14&#46;3 per cent between 7&#46;5 and 10<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#59; 17&#46;9 per cent<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#41;&#44; with a maximum difference of 25<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#46; The mean dose of thiopental was 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;h &#40;2&#8211;5&#41;&#46; The differences between both methods were more significant when doses<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;h were used &#40;7<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#91;2&#8211;11&#93; <span class="elsevierStyleItalic">versus</span> 5<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#91;1&#8211;7&#93;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;12&#41;&#46; In all patients the IV sodium supplies were reduced as a consequence of hipernatremia&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">In the patients who received osmolar therapy after the withdrawal of thiopental&#44; the goal was to maintain the levels of natremia in blood between 145 and 150<span class="elsevierStyleHsp" style=""></span>mEq&#47;L as part of the management of the underlying condition&#46; This is why it makes sense that after the withdrawal of thiopental&#44; the state of normonatremia was not reached in these patient&#46; However&#44; in the four &#40;4&#41; patients who did not receive osmolar therapy after the withdrawal of thiopental&#44; the hipernatremia disappeared&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In order to assess the measurement differences between both methods&#8212;gasometry an core lab analyzer&#44; we analyzed thirty &#40;30&#41; pairs of values in patients who did not receive thiopental and obtained a difference of 1&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;75<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;71&#41;&#44; and a Pearson correlation coefficient of 0&#46;87&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">One of the main limitations of this study is its retrospective nature&#44; which is why the pairs of compared values were not collected simultaneously&#46; This is why we picked the analytics based on the time interval elapsed between both pairs&#46; Most patients received isotonic serum as a neuroprotective strategy&#44; or hypertonic serum for the management of brain swelling&#44; and intracranial hypertension&#46; For this reason&#44; the levels of natremia that were slightly high can be considered consistent with the therapy received and not lead to any initial changes of serum therapy&#59; however&#44; as we extend the infusion&#44; the false hypernatremia becomes more evident&#44; leading to the reduction of the IV sodium supply&#46; The complications derived from the use of hypotonic serum in this type of patients are well known&#44; and they favour the development of secondary brain swelling&#44; and brain hypertension&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The only study published so far is the one conducted by Feyen et al&#46; who have been investigating the same adverse event associated to Siemens Dimension Vista analyzer from an index case that we have been investigating&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a> These authors have been testing this discrepancy <span class="elsevierStyleItalic">in vitro</span> and have confirmed that the mechanism responsible for such a discrepancy is based on the interaction between the thiopental molecule and the polymeric membrane&#44; which in turn alters its polarity and&#44; consequently&#44; the reading of the results based on different electric powers&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a> Also there are two &#40;2&#41; cases of adult patients that have been presented in different congresses&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">This finding was brought to the attention of the Unit of Clinical Analyses and the manufacturer of the analyzer&#44; since we are talking about an important error that may be detrimental to the security of the patients&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The false hypernatremia due to the interference between thiopental and the Siemens Dimension Vista analyzer is an important factor that may influence the therapeutic decisions made in neurocritical patients&#44; and hence&#44; lead to the administration of hypotonic fluids that may have deleterious effects such as brain swelling&#44; and intracranial pressure&#46;</p></span>"
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-10-03"
    "fechaAceptado" => "2017-01-21"
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Garc&#237;a-Soler P&#44; Amores-Torres M&#44; Sanchiz-C&#225;rdenas S&#44; Gonz&#225;lez-G&#243;mez JM&#44; Dayaldasani A&#44; Milano-Manso G&#46; Tiopental y falsa hipernatremia&#58; compruebe su analizador&#46; Med Intensiva&#46; 2017&#59;41&#58;573&#8211;574&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Bland&#8211;Altman diagram&#46; SD&#58; standard deviation&#59; Na<span class="elsevierStyleInf">B</span>&#58; natremia obtained using the core lab analyzer&#59; Na<span class="elsevierStyleInf">G</span>&#58; natremia obtained using the gasometer&#46;</p>"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The qualitative variables are expressed as absolute frequency &#40;relative&#41;&#46; The results from the numerical variables are expressed as mean &#40;interquartile range&#41;&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sex Male</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10 &#40;71&#46;43&#41;&nbsp;\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"><span class="elsevierStyleItalic">Age &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;65 &#40;2&#8211;10&#46;22&#41;&nbsp;\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"><span class="elsevierStyleItalic">Weight &#40;kg&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16 &#40;12&#8211;32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Underlying conditions</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CET&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;35&#46;71&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Encephalitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;21&#46;43&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;21&#46;43&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Hypoxic&#8211;ischaemic encephalopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;7&#46;14&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Pulmonary disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;7&#46;14&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Posterior fossa tumour&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;7&#46;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Reason for the thiopental</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Intracranial hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;62&#46;28&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Status&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;28&#46;57&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Sedation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;7&#46;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Initial dose &#40;mg&#47;kg&#47;h&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \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"><span class="elsevierStyleItalic">Maximum dose &#40;mg&#47;kg&#47;h&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11 &#40;78&#46;57&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">200 &#40;160&#8211;255&#41;&nbsp;\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"><span class="elsevierStyleItalic">IV sodium supply at the end of the infusion &#40;mEq&#47;L&#41;</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">100 &#40;60&#8211;150&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005"><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 &#40;Student&#39;s <span class="elsevierStyleItalic">t</span> test&#41;&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Sociodemographic characteristics of patients and episodes recorded&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:6 [
            0 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Manual de prescripci&#243;n pedi&#225;trica"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "C&#46;K&#46; Taketomo"
                            1 => "J&#46;H&#46; Hodding"
                            2 => "D&#46;M&#46; Kraus"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:4 [
                        "edicion" => "18&#46;<span class="elsevierStyleSup">a</span> ed&#46;"
                        "fecha" => "2014"
                        "editorial" => "Lexi-Comp"
                        "editorialLocalizacion" => "Madrid"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0040"
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              "referencia" => array:1 [
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                        0 => array:2 [
                          "etal" => false
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                            1 => "P&#46;R&#46; Krishnan"
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                          ]
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            2 => array:3 [
              "identificador" => "bib0045"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "New aspects in the pathogenesis&#44; prevention&#44; and treatment of hyponatremic encephalopathy in children"
                      "autores" => array:1 [
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                          "etal" => false
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                            0 => "M&#46;L&#46; Moritz"
                            1 => "J&#46;C&#46; Ayus"
                          ]
                        ]
                      ]
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                  ]
                  "host" => array:1 [
                    0 => array:1 [
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            3 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fluid management of the neurological patient&#58; a concise review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M&#46; Van der Jagt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13054-016-1309-2"
                      "Revista" => array:5 [
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                        "fecha" => "2016"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27240859"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Falsely elevated sodium levels during thiopental treatment in the ICU&#58; technical interference on a laboratory device with important clinical relevance"
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Scientific Letter
Thiopental and false hypernatremia: Check your analyzer
Tiopental y falsa hipernatremia: compruebe su analizador
P. García-Solera,
Corresponding author
pagarsol79@gmail.com

Corresponding author.
, M. Amores-Torresa, S. Sanchiz-Cárdenasa, J.M. González-Gómeza, A. Dayaldasanib, G. Milano-Mansoa
a Unidad de Cuidados Intensivos Pediátricos, Hospital Regional Universitario de Málaga, Málaga, Spain
b Unidad de Análisis Clínicos, Hospital Regional Universitario de Málaga, Málaga, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Thiopental is a barbituric anaesthetic drug used in the management of refractory epileptic seizures and intracranial high blood pressure&#46; It has multiple adverse events such as low blood pressure&#59; myocardial depression&#59; immunodepession&#59; an extended depression of consciousness due to accumulations after the infusion&#59; and ischaemia&#44; among others&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">1&#44;2</span></a> However&#44; the altered concentration of sodium is not an adverse effect reported in the technical label&#46; We wish to inform on the finding of false thiopental-induced hypernatremia due to the interaction of this drug with our core laboratory analyzer&#46; Thus&#44; the goal of our study is to analyze the concordance and correlation between the natremia obtained in two &#40;2&#41; different analyzers in patients treated with sodium thiopental from an index case&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The index case of our observation was a two-year-old child hospitalized in our unit with clinical manifestations of refractory seizures who required the initiation of one continuous perfusion of sodium thiopental&#46; Right from the beginning of the infusion we observed initially mild hypernatremias &#40;151<span class="elsevierStyleHsp" style=""></span>mEq&#47;L 6<span class="elsevierStyleHsp" style=""></span>h after starting the infusion&#41; that progressed upward up to 164<span class="elsevierStyleHsp" style=""></span>mEq&#47;L that were inconsistent with the values shown by the gasometer even though the levels of IV sodium supplied had been reduced&#44; but without presence of polyuria or other criteria of diabetes insipidus &#40;DI&#41;&#46; The initial dose was 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;h&#44; but it was titrated upward to a maximum of 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;h&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">After withdrawing the drug&#44; the levels of natremia went back to normal&#44; and we were able to conduct one retrospective study based on a review of the clinical histories of all children who received sodium thiopental from 2009 to 2015&#44; in order to analyze all possible inconsistencies between the natremia found in our core lab &#40;Na<span class="elsevierStyleInf">B</span>&#41;&#8212;Dimension Vista 1500&#44; Siemens Healthcare Diagnostics&#44; Newark&#44; USA&#8212;and the natremia found in the gasometer &#40;Na<span class="elsevierStyleInf">G</span>&#41;&#8212;ABL800 Flex&#44; Radiometer GmbH&#44; Copenhagen&#44; Denmark&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Several sociodemographic variables were considered together with characteristics from the episodes reported&#44; the doses of thiopental&#44; the sodium supplied during the infusion&#44; and the levels of natremia 48<span class="elsevierStyleHsp" style=""></span>h after the administration obtained by the analyzer &#40;Na<span class="elsevierStyleInf">B</span>&#41; and the gasometer &#40;Na<span class="elsevierStyleInf">G</span>&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Since the samples analyzed through these two methods were not obtained simultaneously&#44; and in an attempt to avoid the influence of IV sodium supply&#44; the pairs of values obtained with time intervals<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>12<span class="elsevierStyleHsp" style=""></span>h were selected as long as the same infusion and clinical situation was maintained&#44; and with time intervals<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>h whenever any of these parameters had changed&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The quantitative variables are expressed as mean and standard deviation &#40;normal distribution&#41;&#44; or mean and interquartile range &#40;IQR&#41; &#40;for the rest&#41;&#46; For the comparison of the levels of natremia obtained through both of the aforementioned methods&#44; the Student&#39;s <span class="elsevierStyleItalic">t</span> test and the Mann&#8211;Whitney&#39;s <span class="elsevierStyleItalic">U</span> test were used when appropriate&#46; The steady-state interclass correlation coefficient was estimated&#44; and the Bland&#8211;Altman diagram was built&#46; The <span class="elsevierStyleItalic">p</span> value was established in 0&#46;05&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The study was assessed and approved by the corresponding Ethics Committee from the Provincial Research&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Fourteen &#40;14&#41; patients received thiopental in the period analyzed&#59; nine &#40;9&#41; of them due to intracranial hypertension&#59; four &#40;4&#41; due seizures&#59; and one &#40;1&#41; case due to difficult sedation&#46; Thirty-five &#40;35&#41; pairs of measurements were analyzed 28&#47;35 during the infusion&#46; The Na<span class="elsevierStyleInf">G</span> average was 148&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;65<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#44; and the Na<span class="elsevierStyleInf">B</span> average 154&#46;78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;04<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; The difference mean during the infusion was 5&#46;5<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#40;1&#46;5&#8211;8&#46;75&#41;&#44; and before the infusion&#44; 1<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#40;&#8722;3 to 2&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;017&#46; The interclass correlation coefficient was 0&#46;77 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; when we looked at the pairs of values during the infusion&#46; The concordance limits in the Bland&#8211;Altman diagram &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; were &#8722;6&#46;26&#44; 18&#46;26&#46; In fifty &#40;50&#41; per cent of the pairs of measurements&#44; the difference was<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#40;17&#46;9 per cent between 5 and 7&#46;5<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#59; 14&#46;3 per cent between 7&#46;5 and 10<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#59; 17&#46;9 per cent<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#41;&#44; with a maximum difference of 25<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#46; The mean dose of thiopental was 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;h &#40;2&#8211;5&#41;&#46; The differences between both methods were more significant when doses<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;h were used &#40;7<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#91;2&#8211;11&#93; <span class="elsevierStyleItalic">versus</span> 5<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#91;1&#8211;7&#93;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;12&#41;&#46; In all patients the IV sodium supplies were reduced as a consequence of hipernatremia&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">In the patients who received osmolar therapy after the withdrawal of thiopental&#44; the goal was to maintain the levels of natremia in blood between 145 and 150<span class="elsevierStyleHsp" style=""></span>mEq&#47;L as part of the management of the underlying condition&#46; This is why it makes sense that after the withdrawal of thiopental&#44; the state of normonatremia was not reached in these patient&#46; However&#44; in the four &#40;4&#41; patients who did not receive osmolar therapy after the withdrawal of thiopental&#44; the hipernatremia disappeared&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In order to assess the measurement differences between both methods&#8212;gasometry an core lab analyzer&#44; we analyzed thirty &#40;30&#41; pairs of values in patients who did not receive thiopental and obtained a difference of 1&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;75<span class="elsevierStyleHsp" style=""></span>mEq&#47;L &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;71&#41;&#44; and a Pearson correlation coefficient of 0&#46;87&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">One of the main limitations of this study is its retrospective nature&#44; which is why the pairs of compared values were not collected simultaneously&#46; This is why we picked the analytics based on the time interval elapsed between both pairs&#46; Most patients received isotonic serum as a neuroprotective strategy&#44; or hypertonic serum for the management of brain swelling&#44; and intracranial hypertension&#46; For this reason&#44; the levels of natremia that were slightly high can be considered consistent with the therapy received and not lead to any initial changes of serum therapy&#59; however&#44; as we extend the infusion&#44; the false hypernatremia becomes more evident&#44; leading to the reduction of the IV sodium supply&#46; The complications derived from the use of hypotonic serum in this type of patients are well known&#44; and they favour the development of secondary brain swelling&#44; and brain hypertension&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The only study published so far is the one conducted by Feyen et al&#46; who have been investigating the same adverse event associated to Siemens Dimension Vista analyzer from an index case that we have been investigating&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a> These authors have been testing this discrepancy <span class="elsevierStyleItalic">in vitro</span> and have confirmed that the mechanism responsible for such a discrepancy is based on the interaction between the thiopental molecule and the polymeric membrane&#44; which in turn alters its polarity and&#44; consequently&#44; the reading of the results based on different electric powers&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a> Also there are two &#40;2&#41; cases of adult patients that have been presented in different congresses&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">This finding was brought to the attention of the Unit of Clinical Analyses and the manufacturer of the analyzer&#44; since we are talking about an important error that may be detrimental to the security of the patients&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The false hypernatremia due to the interference between thiopental and the Siemens Dimension Vista analyzer is an important factor that may influence the therapeutic decisions made in neurocritical patients&#44; and hence&#44; lead to the administration of hypotonic fluids that may have deleterious effects such as brain swelling&#44; and intracranial pressure&#46;</p></span>"
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-10-03"
    "fechaAceptado" => "2017-01-21"
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Garc&#237;a-Soler P&#44; Amores-Torres M&#44; Sanchiz-C&#225;rdenas S&#44; Gonz&#225;lez-G&#243;mez JM&#44; Dayaldasani A&#44; Milano-Manso G&#46; Tiopental y falsa hipernatremia&#58; compruebe su analizador&#46; Med Intensiva&#46; 2017&#59;41&#58;573&#8211;574&#46;</p>"
      ]
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        "etiqueta" => "Figure 1"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Bland&#8211;Altman diagram&#46; SD&#58; standard deviation&#59; Na<span class="elsevierStyleInf">B</span>&#58; natremia obtained using the core lab analyzer&#59; Na<span class="elsevierStyleInf">G</span>&#58; natremia obtained using the gasometer&#46;</p>"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The qualitative variables are expressed as absolute frequency &#40;relative&#41;&#46; The results from the numerical variables are expressed as mean &#40;interquartile range&#41;&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sex Male</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10 &#40;71&#46;43&#41;&nbsp;\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"><span class="elsevierStyleItalic">Age &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;65 &#40;2&#8211;10&#46;22&#41;&nbsp;\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"><span class="elsevierStyleItalic">Weight &#40;kg&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16 &#40;12&#8211;32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Underlying conditions</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CET&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;35&#46;71&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Encephalitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;21&#46;43&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;21&#46;43&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Hypoxic&#8211;ischaemic encephalopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;7&#46;14&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Pulmonary disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;7&#46;14&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Posterior fossa tumour&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;7&#46;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Reason for the thiopental</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Intracranial hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;62&#46;28&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Status&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;28&#46;57&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Sedation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;7&#46;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Initial dose &#40;mg&#47;kg&#47;h&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;2&#8211;4&#46;5&#41;&nbsp;\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"><span class="elsevierStyleItalic">Maximum dose &#40;mg&#47;kg&#47;h&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;25 &#40;4&#8211;5&#41;&nbsp;\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"><span class="elsevierStyleItalic">Duration of the infusion &#40;hours&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">62 &#40;29&#46;5&#8211;101&#46;75&#41;&nbsp;\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"><span class="elsevierStyleItalic">Enteral nutrition during the infusion</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11 &#40;78&#46;57&#41;&nbsp;\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"><span class="elsevierStyleItalic">IV sodium supply at the beginning of the infusion &#40;mEq&#47;L&#41;</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">200 &#40;160&#8211;255&#41;&nbsp;\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"><span class="elsevierStyleItalic">IV sodium supply at the end of the infusion &#40;mEq&#47;L&#41;</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">100 &#40;60&#8211;150&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005"><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 &#40;Student&#39;s <span class="elsevierStyleItalic">t</span> test&#41;&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Sociodemographic characteristics of patients and episodes recorded&#46;</p>"
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    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:6 [
            0 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Manual de prescripci&#243;n pedi&#225;trica"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "C&#46;K&#46; Taketomo"
                            1 => "J&#46;H&#46; Hodding"
                            2 => "D&#46;M&#46; Kraus"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:1 [
                      "Libro" => array:4 [
                        "edicion" => "18&#46;<span class="elsevierStyleSup">a</span> ed&#46;"
                        "fecha" => "2014"
                        "editorial" => "Lexi-Comp"
                        "editorialLocalizacion" => "Madrid"
                      ]
                    ]
                  ]
                ]
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ISSN: 21735727
Original language: English
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