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thereby worsening cerebral edema and resulting in deteriorating neurological condition with seizures&#44; coma&#44; increased intracranial pressure end eventually death&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1&#44;2&#44;4</span></a> An appropriate correction of hyponatremia was associated with increased survival&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In the recent years&#44; tolvaptan&#44; an orally active&#44; selective&#44; nonpeptide antagonist that blocks arginine vasopressin from binding to V2 receptors of the distal nephron inducing the excretion of electrolyte-free water &#40;the so-called &#8220;aquaretic effect&#8221;&#41; showed it effectiveness in the treatment of hyponatremia in randomized controlled trials&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a> but its use in neurocritically ill patients remains limited&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">2</span></a> Concerns with the potential risk of overcorrection and secondary osmotic demyelinating syndrome &#40;ODS&#41; arose&#44; although the incidence of overcorrection can be even higher when using the commonly accepted 3&#37; hypertonic saline&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">7</span></a> When tolvaptan is used&#44; initial doses of 7&#46;5 or 15<span class="elsevierStyleHsp" style=""></span>mg are recommended&#46;<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&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In this report&#44; we studied the effects of a single dose of tolvaptan in hyponatremic neurocritically ill patients&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The study was approved by our Hospital Research Committee&#46; The need of informed consent was waived due to the descriptive and retrospective nature of the study&#46;</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>&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><p id="par0030" class="elsevierStylePara elsevierViewall">Plasma sodium<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>135<span class="elsevierStyleHsp" style=""></span>mEq&#47;L</p></li><li class="elsevierStyleListItem" id="lsti0010"><p id="par0035" class="elsevierStylePara elsevierViewall">Plasma osmolality<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>280<span class="elsevierStyleHsp" style=""></span>mOsm&#47;kg of water</p></li><li class="elsevierStyleListItem" id="lsti0015"><p id="par0040" class="elsevierStylePara elsevierViewall">Urine osmolality<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mOsm&#47;kg of water</p></li><li class="elsevierStyleListItem" id="lsti0020"><p id="par0045" class="elsevierStylePara elsevierViewall">Urine sodium<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>40<span class="elsevierStyleHsp" style=""></span>mmol&#47;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 &#916; natremia was &#62;8 mEq&#47;L&#47;24<span class="elsevierStyleHsp" style=""></span>h&#46;<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&#46; Quantitative data were reported as median &#40;Interquartile Range &#40;IQR&#41; 25&#8211;75&#41; and categorical data as number and percentage&#46; Differences between natremia were compared using Mann&#8211;Whitney&#8211;Wilcoxon test and the association between 24<span class="elsevierStyleHsp" style=""></span>h fluid balance and <span class="elsevierStyleItalic">&#916;</span> natremia using linear regression&#46; A value of p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 was considered significant&#46; Statistical analysis was performed with SPSS<span class="elsevierStyleSup">&#174;</span> 20 &#40;IBM Corporation 2011&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Eight neurocritically ill patients admitted to our ICU fulfilled the above mentioned criteria of SIADH&#46; During their ICU stay&#44; all patients developed hyponatremia and were unsuccessfully treated with oral sodium chloride and 3&#37; hypertonic saline&#46; In such cases&#44; an initial dose of 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg tolvaptan was given in the morning shift &#40;in one patient 15<span class="elsevierStyleHsp" style=""></span>mg were administered&#41;&#46; Of note&#44; all patients increased their sodium levels and even in 3 patients &#40;37&#46;5&#37;&#41; no additional doses were deemed necessary&#46; Only one patient &#40;12&#46;5&#37;&#41; presented overcorrection requiring treatment with intravenous dextrose and parenteral desmopressin&#46; 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&#46; No clinical features of ODS were observed in the follow up&#46;</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 &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; A moderate association between <span class="elsevierStyleItalic">&#916;</span> Natremia and 24<span class="elsevierStyleHsp" style=""></span>h fluid balance was found &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<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&#46;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&#46; Some issues must be taking into consideration when evaluating our results&#58;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Tolvaptan resulted in an increase of sodium levels in all patients&#46; The effect of a single dose of tolvaptan was enough to solve the hyponatremia in some cases&#44; therefore minimizing the cost of the therapy&#46; Follow up doses were used in 5 patients&#44; when natremia decreased after the initial 48<span class="elsevierStyleHsp" style=""></span>h&#46; An initial increase lasting 48<span class="elsevierStyleHsp" style=""></span>h has been previously described&#46;<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&#44; our patients had limited access to water&#46; Unlimited access to water was deemed mandatory to avoid secondary hypovolemia&#46;<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&#44; such requirement should not be considered necessary&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Tolvaptan was safe at the 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg dose in all cases&#46; 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&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> Related factors include advanced liver disease&#44; malnourishment&#44; hypophosphatemia&#44; hypokalemia&#44; etc&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> We would recommend using the 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg dose for initiating tolvaptan in neurocritically ill patients&#46; As stated&#44; median <span class="elsevierStyleItalic">&#916;</span> Natremia was 5 &#40;4&#8211;8&#41;<span class="elsevierStyleHsp" style=""></span>mEq&#47;24<span class="elsevierStyleHsp" style=""></span>h in our sample&#46; Moreover&#44; we defined overcorrection as <span class="elsevierStyleItalic">&#916;</span> natremia<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; but some authors would even accept <span class="elsevierStyleItalic">&#916;</span> natremia 12<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#47;24<span class="elsevierStyleHsp" style=""></span>h safe in this setting&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The main limitation of this preliminary study is the retrospective and observational design&#46; In addition&#44; the limited number of patients generates weakness in the linear regression analysis due to extreme values and precludes more complex analysis&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In conclusion&#44; in neurocritically ill patients&#44; a low dose of 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg of tolvaptan was effective and safe in the treatment of hyponatremia due to SIADH&#46; Future studies will determine its exact role in the management of hyponatremia in the whole ICU population&#46; A prospective comparison with 3&#37; hypertonic saline is necessary&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">Dr&#46; Llompart-Pou declares having received honoraria from Otsuka for participating in a consensus document in the management of hyponatremia in critically ill patients&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Dr&#46; P&#233;rez-B&#225;rcena&#44; Novo and Raurich declare no financial disclosure&#46;</p></span></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Linear regression analysis of 24<span class="elsevierStyleHsp" style=""></span>h fluid balance and <span class="elsevierStyleItalic">&#916;</span> natremia after the first dose of tolvaptan&#46;</p>"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">ICH&#58;</span> intracerebral hemorrhage&#59; <span class="elsevierStyleItalic">TBI</span>&#58; traumatic brain injury&#59; <span class="elsevierStyleItalic">SAH&#58;</span> subarachnoid hemorrhage&#46;</p>"
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                  <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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Gender&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Natremia before tolvaptan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Natremia 24<span class="elsevierStyleHsp" style=""></span>h after tolvaptan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">&#916;</span> Natremia<br>24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Natremia 48<span class="elsevierStyleHsp" style=""></span>h after tolvaptan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">24<span class="elsevierStyleHsp" style=""></span>h fluid balance &#40;ml&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Follow up doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ICH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">132&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">135&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">135&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;1440&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&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">2<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="left" valign="top">ICH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">127&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">142&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">139&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;3425&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&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">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TBI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">131&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">138&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">137&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;1850&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&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">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SAH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">132&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">137&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">136&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;122&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&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">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SAH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">133&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">138&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">136&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;744&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&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">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cerebral abcess&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">132&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">140&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">140&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;4372&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&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">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SAH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">131&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">136&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">137&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;1726&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&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">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TBI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">134&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">136&nbsp;\t\t\t\t\t\t\n
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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
J.A. Llompart-Poua,b,
Autor para correspondencia
juanantonio.llompart@ssib.es

Corresponding author.
, J. Pérez-Bárcenaa,b, M. Novoa, J.M. Rauricha
a Servei de Medicina Intensiva, Hospital Universitari Son Espases, Palma de Mallorca, Spain
b Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Hyponatremia constitutes the most common electrolyte abnormality found in patients with acquired brain injury&#44;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1&#44;2</span></a> being present in up to 20&#37; of patients with traumatic brain injury &#40;TBI&#41; and 50&#37; of patients with subarachnoid hemorrhage &#40;SAH&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In most cases&#44; the underlying cause of euvolemic hyponatremia in brain injured patients is the syndrome of inappropriate secretion of antidiuretic hormone &#40;SIADH&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">3</span></a> In this syndrome&#44; an abnormal water&#47;sodium handling is associated with an osmotic gradient that promotes the shift of water into brain cells&#44; thereby worsening cerebral edema and resulting in deteriorating neurological condition with seizures&#44; coma&#44; increased intracranial pressure end eventually death&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1&#44;2&#44;4</span></a> An appropriate correction of hyponatremia was associated with increased survival&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In the recent years&#44; tolvaptan&#44; an orally active&#44; selective&#44; nonpeptide antagonist that blocks arginine vasopressin from binding to V2 receptors of the distal nephron inducing the excretion of electrolyte-free water &#40;the so-called &#8220;aquaretic effect&#8221;&#41; showed it effectiveness in the treatment of hyponatremia in randomized controlled trials&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a> but its use in neurocritically ill patients remains limited&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">2</span></a> Concerns with the potential risk of overcorrection and secondary osmotic demyelinating syndrome &#40;ODS&#41; arose&#44; although the incidence of overcorrection can be even higher when using the commonly accepted 3&#37; hypertonic saline&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">7</span></a> When tolvaptan is used&#44; initial doses of 7&#46;5 or 15<span class="elsevierStyleHsp" style=""></span>mg are recommended&#46;<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&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In this report&#44; we studied the effects of a single dose of tolvaptan in hyponatremic neurocritically ill patients&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The study was approved by our Hospital Research Committee&#46; The need of informed consent was waived due to the descriptive and retrospective nature of the study&#46;</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>&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><p id="par0030" class="elsevierStylePara elsevierViewall">Plasma sodium<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>135<span class="elsevierStyleHsp" style=""></span>mEq&#47;L</p></li><li class="elsevierStyleListItem" id="lsti0010"><p id="par0035" class="elsevierStylePara elsevierViewall">Plasma osmolality<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>280<span class="elsevierStyleHsp" style=""></span>mOsm&#47;kg of water</p></li><li class="elsevierStyleListItem" id="lsti0015"><p id="par0040" class="elsevierStylePara elsevierViewall">Urine osmolality<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mOsm&#47;kg of water</p></li><li class="elsevierStyleListItem" id="lsti0020"><p id="par0045" class="elsevierStylePara elsevierViewall">Urine sodium<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>40<span class="elsevierStyleHsp" style=""></span>mmol&#47;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 &#916; natremia was &#62;8 mEq&#47;L&#47;24<span class="elsevierStyleHsp" style=""></span>h&#46;<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&#46; Quantitative data were reported as median &#40;Interquartile Range &#40;IQR&#41; 25&#8211;75&#41; and categorical data as number and percentage&#46; Differences between natremia were compared using Mann&#8211;Whitney&#8211;Wilcoxon test and the association between 24<span class="elsevierStyleHsp" style=""></span>h fluid balance and <span class="elsevierStyleItalic">&#916;</span> natremia using linear regression&#46; A value of p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 was considered significant&#46; Statistical analysis was performed with SPSS<span class="elsevierStyleSup">&#174;</span> 20 &#40;IBM Corporation 2011&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Eight neurocritically ill patients admitted to our ICU fulfilled the above mentioned criteria of SIADH&#46; During their ICU stay&#44; all patients developed hyponatremia and were unsuccessfully treated with oral sodium chloride and 3&#37; hypertonic saline&#46; In such cases&#44; an initial dose of 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg tolvaptan was given in the morning shift &#40;in one patient 15<span class="elsevierStyleHsp" style=""></span>mg were administered&#41;&#46; Of note&#44; all patients increased their sodium levels and even in 3 patients &#40;37&#46;5&#37;&#41; no additional doses were deemed necessary&#46; Only one patient &#40;12&#46;5&#37;&#41; presented overcorrection requiring treatment with intravenous dextrose and parenteral desmopressin&#46; 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&#46; No clinical features of ODS were observed in the follow up&#46;</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 &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; A moderate association between <span class="elsevierStyleItalic">&#916;</span> Natremia and 24<span class="elsevierStyleHsp" style=""></span>h fluid balance was found &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<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&#46;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&#46; Some issues must be taking into consideration when evaluating our results&#58;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Tolvaptan resulted in an increase of sodium levels in all patients&#46; The effect of a single dose of tolvaptan was enough to solve the hyponatremia in some cases&#44; therefore minimizing the cost of the therapy&#46; Follow up doses were used in 5 patients&#44; when natremia decreased after the initial 48<span class="elsevierStyleHsp" style=""></span>h&#46; An initial increase lasting 48<span class="elsevierStyleHsp" style=""></span>h has been previously described&#46;<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&#44; our patients had limited access to water&#46; Unlimited access to water was deemed mandatory to avoid secondary hypovolemia&#46;<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&#44; such requirement should not be considered necessary&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Tolvaptan was safe at the 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg dose in all cases&#46; 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&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> Related factors include advanced liver disease&#44; malnourishment&#44; hypophosphatemia&#44; hypokalemia&#44; etc&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> We would recommend using the 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg dose for initiating tolvaptan in neurocritically ill patients&#46; As stated&#44; median <span class="elsevierStyleItalic">&#916;</span> Natremia was 5 &#40;4&#8211;8&#41;<span class="elsevierStyleHsp" style=""></span>mEq&#47;24<span class="elsevierStyleHsp" style=""></span>h in our sample&#46; Moreover&#44; we defined overcorrection as <span class="elsevierStyleItalic">&#916;</span> natremia<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; but some authors would even accept <span class="elsevierStyleItalic">&#916;</span> natremia 12<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#47;24<span class="elsevierStyleHsp" style=""></span>h safe in this setting&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The main limitation of this preliminary study is the retrospective and observational design&#46; In addition&#44; the limited number of patients generates weakness in the linear regression analysis due to extreme values and precludes more complex analysis&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In conclusion&#44; in neurocritically ill patients&#44; a low dose of 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg of tolvaptan was effective and safe in the treatment of hyponatremia due to SIADH&#46; Future studies will determine its exact role in the management of hyponatremia in the whole ICU population&#46; A prospective comparison with 3&#37; hypertonic saline is necessary&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">Dr&#46; Llompart-Pou declares having received honoraria from Otsuka for participating in a consensus document in the management of hyponatremia in critically ill patients&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Dr&#46; P&#233;rez-B&#225;rcena&#44; Novo and Raurich declare no financial disclosure&#46;</p></span></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Linear regression analysis of 24<span class="elsevierStyleHsp" style=""></span>h fluid balance and <span class="elsevierStyleItalic">&#916;</span> natremia after the first dose of tolvaptan&#46;</p>"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">ICH&#58;</span> intracerebral hemorrhage&#59; <span class="elsevierStyleItalic">TBI</span>&#58; traumatic brain injury&#59; <span class="elsevierStyleItalic">SAH&#58;</span> subarachnoid hemorrhage&#46;</p>"
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                  <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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnosis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Day&nbsp;\t\t\t\t\t\t\n
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                  \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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">&#916;</span> Natremia<br>24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Natremia 48<span class="elsevierStyleHsp" style=""></span>h after tolvaptan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">24<span class="elsevierStyleHsp" style=""></span>h fluid balance &#40;ml&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Follow up doses&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">132&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">135&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">135&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;1440&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&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">2<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="left" valign="top">ICH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">127&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">142&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">139&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;3425&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&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">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TBI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">131&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">138&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">137&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;1850&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&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">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SAH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">132&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">137&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">136&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;122&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&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">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SAH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">133&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">138&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">136&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;744&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&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">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cerebral abcess&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">132&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">140&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">140&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;4372&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&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">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SAH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">131&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">136&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">137&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;1726&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&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">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TBI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">134&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">136&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">136&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;456&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&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">Median &#40;IQR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">46 &#40;33&#8211;54&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17 &#40;11&#8211;24&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">132 &#40;131&#8211;133&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">138 &#40;136&#8211;140&#41;&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;4&#8211;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">136 &#40;136&#8211;138&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;1600 &#40;&#8722;3000 to &#8722;500&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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            0 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hyponatremia in neurotrauma&#58; the role of vasopressin"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46; Kleindienst"
                            1 => "M&#46;J&#46; Hannon"
                            2 => "M&#46; Buchfelder"
                            3 => "J&#46;G&#46; Verbalis"
                          ]
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                    0 => array:2 [
                      "doi" => "10.1089/neu.2015.3981"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neurotrauma"
                        "fecha" => "2016"
                        "volumen" => "33"
                        "paginaInicial" => "615"
                        "paginaFinal" => "624"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26472056"
                            "web" => "Medline"
                          ]
                        ]
                      ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Use of oral vasopressin V2 receptor antagonist for hyponatremia in acute brain injury"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;B&#46; Jeon"
                            1 => "H&#46;A&#46; Choi"
                            2 => "C&#46; Lesch"
                            3 => "M&#46;C&#46; Kim"
                            4 => "N&#46; Badjatia"
                            5 => "J&#46; Claassen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000350844"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Neurol"
                        "fecha" => "2013"
                        "volumen" => "70"
                        "paginaInicial" => "142"
                        "paginaFinal" => "148"
                        "link" => array:1 [
                          0 => array:2 [
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