Scientific Letter
Effect of single-dose of tolvaptan in neurocritical patients with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion
Efecto de una dosis única de tolvaptán en pacientes neurocríticos con hiponatremia debido a SIADH
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Llompart-Pou, J. Pérez-Bárcena, M. Novo, J.M. Raurich" "autores" => array:4 [ 0 => array:4 [ "nombre" => "J.A." "apellidos" => "Llompart-Pou" "email" => array:1 [ 0 => "juanantonio.llompart@ssib.es" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J." "apellidos" => "Pérez-Bárcena" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "M." "apellidos" => "Novo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "J.M." "apellidos" => "Raurich" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servei de Medicina Intensiva, Hospital Universitari Son Espases, Palma de Mallorca, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Efecto de una dosis única de tolvaptán en pacientes neurocríticos con hiponatremia debido a SIADH" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1141 "Ancho" => 2460 "Tamanyo" => 115582 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Linear regression analysis of 24<span class="elsevierStyleHsp" style=""></span>h fluid balance and <span class="elsevierStyleItalic">Δ</span> natremia after the first dose of tolvaptan.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Hyponatremia constitutes the most common electrolyte abnormality found in patients with acquired brain injury,<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1,2</span></a> being present in up to 20% of patients with traumatic brain injury (TBI) and 50% of patients with subarachnoid hemorrhage (SAH).<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In most cases, the underlying cause of euvolemic hyponatremia in brain injured patients is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">3</span></a> In this syndrome, an abnormal water/sodium handling is associated with an osmotic gradient that promotes the shift of water into brain cells, thereby worsening cerebral edema and resulting in deteriorating neurological condition with seizures, coma, increased intracranial pressure end eventually death.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1,2,4</span></a> An appropriate correction of hyponatremia was associated with increased survival.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In the recent years, tolvaptan, an orally active, selective, nonpeptide antagonist that blocks arginine vasopressin from binding to V2 receptors of the distal nephron inducing the excretion of electrolyte-free water (the so-called “aquaretic effect”) showed it effectiveness in the treatment of hyponatremia in randomized controlled trials,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a> but its use in neurocritically ill patients remains limited.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">2</span></a> Concerns with the potential risk of overcorrection and secondary osmotic demyelinating syndrome (ODS) arose, although the incidence of overcorrection can be even higher when using the commonly accepted 3% hypertonic saline.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">7</span></a> When tolvaptan is used, initial doses of 7.5 or 15<span class="elsevierStyleHsp" style=""></span>mg are recommended.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a> Some authors recommend its use as a treatment of SIADH induced hyponatremia when first line therapies including fluid restriction have failed.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In this report, we studied the effects of a single dose of tolvaptan in hyponatremic neurocritically ill patients.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The study was approved by our Hospital Research Committee. The need of informed consent was waived due to the descriptive and retrospective nature of the study.</p><p id="par0125" class="elsevierStylePara elsevierViewall">All patients fulfilled the following definition of SIADH<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">1</span></a>:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><p id="par0030" class="elsevierStylePara elsevierViewall">Plasma sodium<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>135<span class="elsevierStyleHsp" style=""></span>mEq/L</p></li><li class="elsevierStyleListItem" id="lsti0010"><p id="par0035" class="elsevierStylePara elsevierViewall">Plasma osmolality<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>280<span class="elsevierStyleHsp" style=""></span>mOsm/kg of water</p></li><li class="elsevierStyleListItem" id="lsti0015"><p id="par0040" class="elsevierStylePara elsevierViewall">Urine osmolality<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mOsm/kg of water</p></li><li class="elsevierStyleListItem" id="lsti0020"><p id="par0045" class="elsevierStylePara elsevierViewall">Urine sodium<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>40<span class="elsevierStyleHsp" style=""></span>mmol/L</p></li><li class="elsevierStyleListItem" id="lsti0025"><p id="par0050" class="elsevierStylePara elsevierViewall">Normal thyroid and adrenal function</p></li><li class="elsevierStyleListItem" id="lsti0030"><p id="par0055" class="elsevierStylePara elsevierViewall">Clinical euvolemia or hypervolemia</p></li><li class="elsevierStyleListItem" id="lsti0035"><p id="par0060" class="elsevierStylePara elsevierViewall">Absence of recent diuretics use</p></li></ul></p><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Overcorrection</span> was defined when the Δ natremia was >8 mEq/L/24<span class="elsevierStyleHsp" style=""></span>h.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">1</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">We retrospectively analyzed the effect on the sodium levels and fluid balance in the first 24<span class="elsevierStyleHsp" style=""></span>h after tolvaptan was given. Quantitative data were reported as median (Interquartile Range (IQR) 25–75) and categorical data as number and percentage. Differences between natremia were compared using Mann–Whitney–Wilcoxon test and the association between 24<span class="elsevierStyleHsp" style=""></span>h fluid balance and <span class="elsevierStyleItalic">Δ</span> natremia using linear regression. A value of p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05 was considered significant. Statistical analysis was performed with SPSS<span class="elsevierStyleSup">®</span> 20 (IBM Corporation 2011).</p><p id="par0075" class="elsevierStylePara elsevierViewall">Eight neurocritically ill patients admitted to our ICU fulfilled the above mentioned criteria of SIADH. During their ICU stay, all patients developed hyponatremia and were unsuccessfully treated with oral sodium chloride and 3% hypertonic saline. In such cases, an initial dose of 7.5<span class="elsevierStyleHsp" style=""></span>mg tolvaptan was given in the morning shift (in one patient 15<span class="elsevierStyleHsp" style=""></span>mg were administered). Of note, all patients increased their sodium levels and even in 3 patients (37.5%) no additional doses were deemed necessary. Only one patient (12.5%) presented overcorrection requiring treatment with intravenous dextrose and parenteral desmopressin. This patient received a 15<span class="elsevierStyleHsp" style=""></span>mg initial dose and had risk factors for ODS such as advanced liver disease and alcoholism. No clinical features of ODS were observed in the follow up.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Baseline and clinical data in response to the administration of tolvaptan in the eight patients analyzed are shown (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). A moderate association between <span class="elsevierStyleItalic">Δ</span> Natremia and 24<span class="elsevierStyleHsp" style=""></span>h fluid balance was found (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.05) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<span class="elsevierStyleVsp" style="height:0.5px"></span></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">Our results showed that a single 7.5<span class="elsevierStyleHsp" style=""></span>mg dose of tolvaptan was effective and safe in the treatment of hyponatremia due to SIADH in neurocritically ill patients. Some issues must be taking into consideration when evaluating our results:</p><p id="par0090" class="elsevierStylePara elsevierViewall">Tolvaptan resulted in an increase of sodium levels in all patients. The effect of a single dose of tolvaptan was enough to solve the hyponatremia in some cases, therefore minimizing the cost of the therapy. Follow up doses were used in 5 patients, when natremia decreased after the initial 48<span class="elsevierStyleHsp" style=""></span>h. An initial increase lasting 48<span class="elsevierStyleHsp" style=""></span>h has been previously described.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">2</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Due to the etiology of severe injury, our patients had limited access to water. Unlimited access to water was deemed mandatory to avoid secondary hypovolemia.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">10</span></a> We believe that in the ICU setting and with close monitoring of fluid balance and sodium levels, such requirement should not be considered necessary.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Tolvaptan was safe at the 7.5<span class="elsevierStyleHsp" style=""></span>mg dose in all cases. The only episode of overcorrection occurred with a 15<span class="elsevierStyleHsp" style=""></span>mg dose in a patient with additional risk factors for overcorrection and ODS.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> Related factors include advanced liver disease, malnourishment, hypophosphatemia, hypokalemia, etc.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> We would recommend using the 7.5<span class="elsevierStyleHsp" style=""></span>mg dose for initiating tolvaptan in neurocritically ill patients. As stated, median <span class="elsevierStyleItalic">Δ</span> Natremia was 5 (4–8)<span class="elsevierStyleHsp" style=""></span>mEq/24<span class="elsevierStyleHsp" style=""></span>h in our sample. Moreover, we defined overcorrection as <span class="elsevierStyleItalic">Δ</span> natremia<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>mEq/L/24<span class="elsevierStyleHsp" style=""></span>h, but some authors would even accept <span class="elsevierStyleItalic">Δ</span> natremia 12<span class="elsevierStyleHsp" style=""></span>mEq/L/24<span class="elsevierStyleHsp" style=""></span>h safe in this setting.</p><p id="par0105" class="elsevierStylePara elsevierViewall">The main limitation of this preliminary study is the retrospective and observational design. In addition, the limited number of patients generates weakness in the linear regression analysis due to extreme values and precludes more complex analysis.</p><p id="par0110" class="elsevierStylePara elsevierViewall">In conclusion, in neurocritically ill patients, a low dose of 7.5<span class="elsevierStyleHsp" style=""></span>mg of tolvaptan was effective and safe in the treatment of hyponatremia due to SIADH. Future studies will determine its exact role in the management of hyponatremia in the whole ICU population. A prospective comparison with 3% hypertonic saline is necessary.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">Dr. Llompart-Pou declares having received honoraria from Otsuka for participating in a consensus document in the management of hyponatremia in critically ill patients.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Dr. Pérez-Bárcena, Novo and Raurich declare no financial disclosure.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1141 "Ancho" => 2460 "Tamanyo" => 115582 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Linear regression analysis of 24<span class="elsevierStyleHsp" style=""></span>h fluid balance and <span class="elsevierStyleItalic">Δ</span> natremia after the first dose of tolvaptan.</p>" ] ] 1 => 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:3 [ "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">ICH:</span> intracerebral hemorrhage; <span class="elsevierStyleItalic">TBI</span>: traumatic brain injury; <span class="elsevierStyleItalic">SAH:</span> subarachnoid hemorrhage.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patient number \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">Diagnosis \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">Gender \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">Age (years) \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">Day \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">Natremia before tolvaptan \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">Natremia 24<span class="elsevierStyleHsp" style=""></span>h after tolvaptan \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">Δ</span> Natremia<br>24<span class="elsevierStyleHsp" style=""></span>h \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">Natremia 48<span class="elsevierStyleHsp" style=""></span>h after tolvaptan \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">24<span class="elsevierStyleHsp" style=""></span>h fluid balance (ml) \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">Follow up doses \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">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ICH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">132 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">135 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">135 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−1440 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \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">2<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">*</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ICH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">127 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">142 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">139 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−3425 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \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">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TBI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">131 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">138 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">137 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−1850 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \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">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SAH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">132 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">137 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">136 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−122 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \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">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SAH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">133 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">138 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">136 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−744 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \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">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cerebral abcess \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">132 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">140 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">140 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−4372 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \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">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SAH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">131 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">136 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">137 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−1726 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \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">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TBI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">134 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">136 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">136 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−456 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \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">Median (IQR) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">46 (33–54) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17 (11–24) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">132 (131–133) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">138 (136–140) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (4–8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">136 (136–138) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−1600 (−3000 to −500) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1577197.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Means that this patient received a single 15<span class="elsevierStyleHsp" style=""></span>mg-dose.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Baseline and clinical data of the eight patients studied.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:11 [ 0 => array:3 [ "identificador" => "bib0060" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hyponatremia in neurotrauma: the role of vasopressin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 2 | 9 | 11 |
| 2024 October | 79 | 52 | 131 |
| 2024 September | 70 | 38 | 108 |
| 2024 August | 96 | 45 | 141 |
| 2024 July | 91 | 36 | 127 |
| 2024 June | 65 | 47 | 112 |
| 2024 May | 53 | 29 | 82 |
| 2024 April | 62 | 44 | 106 |
| 2024 March | 70 | 35 | 105 |
| 2024 February | 74 | 41 | 115 |
| 2024 January | 65 | 39 | 104 |
| 2023 December | 74 | 42 | 116 |
| 2023 November | 62 | 43 | 105 |
| 2023 October | 93 | 27 | 120 |
| 2023 September | 53 | 39 | 92 |
| 2023 August | 48 | 24 | 72 |
| 2023 July | 51 | 28 | 79 |
| 2023 June | 37 | 16 | 53 |
| 2023 May | 68 | 36 | 104 |
| 2023 April | 46 | 22 | 68 |
| 2023 March | 88 | 38 | 126 |
| 2023 February | 64 | 24 | 88 |
| 2023 January | 64 | 26 | 90 |
| 2022 December | 88 | 36 | 124 |
| 2022 November | 74 | 47 | 121 |
| 2022 October | 75 | 59 | 134 |
| 2022 September | 46 | 34 | 80 |
| 2022 August | 50 | 56 | 106 |
| 2022 July | 55 | 47 | 102 |
| 2022 June | 66 | 34 | 100 |
| 2022 May | 85 | 42 | 127 |
| 2022 April | 143 | 49 | 192 |
| 2022 March | 121 | 57 | 178 |
| 2022 February | 127 | 46 | 173 |
| 2022 January | 98 | 36 | 134 |
| 2021 December | 90 | 43 | 133 |
| 2021 November | 106 | 47 | 153 |
| 2021 October | 76 | 77 | 153 |
| 2021 September | 48 | 53 | 101 |
| 2021 August | 35 | 47 | 82 |
| 2021 July | 40 | 44 | 84 |
| 2021 June | 53 | 50 | 103 |
| 2021 May | 70 | 48 | 118 |
| 2021 April | 197 | 98 | 295 |
| 2021 March | 106 | 34 | 140 |
| 2021 February | 85 | 40 | 125 |
| 2021 January | 74 | 33 | 107 |
| 2020 December | 53 | 31 | 84 |
| 2020 November | 63 | 16 | 79 |
| 2020 October | 61 | 28 | 89 |
| 2020 September | 57 | 22 | 79 |
| 2020 August | 51 | 22 | 73 |
| 2020 July | 54 | 19 | 73 |
| 2020 June | 58 | 16 | 74 |
| 2020 May | 75 | 13 | 88 |
| 2020 April | 63 | 10 | 73 |
| 2020 March | 53 | 13 | 66 |
| 2020 February | 105 | 63 | 168 |
| 2020 January | 62 | 23 | 85 |
| 2019 December | 62 | 15 | 77 |
| 2019 November | 44 | 23 | 67 |
| 2019 October | 44 | 18 | 62 |
| 2019 September | 49 | 35 | 84 |
| 2019 August | 28 | 26 | 54 |
| 2019 July | 30 | 31 | 61 |
| 2019 June | 30 | 11 | 41 |
| 2019 May | 34 | 38 | 72 |
| 2019 April | 15 | 17 | 32 |
| 2019 March | 22 | 18 | 40 |
| 2019 February | 27 | 26 | 53 |
| 2019 January | 20 | 33 | 53 |
| 2018 December | 18 | 36 | 54 |
| 2018 November | 66 | 34 | 100 |
| 2018 October | 107 | 19 | 126 |
| 2018 September | 27 | 9 | 36 |
| 2018 August | 16 | 11 | 27 |
| 2018 July | 37 | 10 | 47 |
| 2018 June | 31 | 10 | 41 |
| 2018 May | 17 | 6 | 23 |
| 2018 April | 25 | 11 | 36 |
| 2018 March | 17 | 4 | 21 |
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