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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0020" class="elsevierStylePara elsevierViewall">Midazolam is a benzodiazepine still routinely used in Intensive Care Units &#40;ICUs&#41; for the sedation of ventilated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> As a short-acting and potent drug that causes less hemodynamic instability&#44; it could be the ideal sedative if it weren&#39;t for its significant cumulative power due to its pharmacokinetics&#46; This is due to its liposolubility and large volume of distribution&#44; which is exacerbated in obese patients with hepatic and&#47;or kidney failure&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Midazolam is hydroxylated by CYP3A4 into hydroxymidazolam&#44; which is pharmacologically less active than the original drug&#46; Between 50&#37; and 70&#37; of midazolam is excreted in the urine within the next 24&#8239;h as hydroxymidazolam&#46; Due to its hepatic metabolism&#44; liver failure also affects its metabolism&#46; Similarly&#44; in patients with kidney disease&#44; midazolam elevates the concentrations of hydroxymidazolam&#44; thus leading to an increased pharmacological activity&#46; Therefore&#44; it can cause oversedation during its use&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> takes longer to be eliminated&#44; and withdrawal symptoms are common&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Additionally&#44; there are times that we are not aware of the doses administered in continuous infusion&#46; For example&#44; a dose of midazolam at 10&#8239;mg per hour involves a daily dose of 240&#8239;mg&#44; 480&#8239;mg in 2 days&#44; or 1200&#8239;mg every 5 days&#44; which is equivalent to 80 vials of 15&#8239;mg or 240 vials of 5&#8239;mg&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Comparative studies between midazolam and other hypnotics&#44; such as propofol or isoflurane&#44; as well as studies comparing benzodiazepine and non-benzodiazepine sedation&#44; conclude that it is advisable to avoid benzodiazepines in critically ill patients because their use is associated with delayed awakening and extubation&#44; longer mean ICU and hospital lengths of stay&#44; a higher risk of delirium and cognitive dysfunction&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and increased mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> This has led to the latest international clinical practice guidelines to discourage the use of benzodiazepines and&#44; specifically&#44; midazolam infusions&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Despite the scientific evidence and recommendations published&#44; the use of midazolam in critically ill patients is still widespread&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The reasons for this are multiple&#58; lack of an internal working group leading the paradigm shift&#44; resistance to modifying year-long established routine clinical practices&#44; or the convenience of using a single midazolam infusion as a hypnotic&#46; Midazolam is also used to sedate hemodynamically compromised patients because it causes less hypotension&#44; and there is no solid evidence in specific populations of critically ill patients&#46; A retrospective study conducted by Sherer et al&#46; showed higher midazolam-related mortality rates compared to propofol in patients with cardiogenic shock&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Proper monitoring is essential to prevent oversedation&#44; especially in patients with deep sedation and neuromuscular blockers&#44; in whom continuous electroencephalographic devices should be used&#46; However&#44; despite proper monitoring&#44; the pharmacokinetic characteristics of midazolam&#44; with a longer half-life than propofol or isoflurane and greater cumulative power&#44; do not stop the patient from taking longer to awaken once sedation has been withdrawn&#46; In fact&#44; deep sedation with benzodiazepines has a higher risk of post-extubation delirium than sedation with other drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">There are cases&#44; and these are not exceptional cases&#44; where after days of midazolam infusion and an attempt to switch to shorter-acting drugs for dynamic sedation or awaken for invasive mechanical ventilation weaning&#44; these patients end up not waking up for days&#46; It becomes difficult to distinguish the effect of midazolam from acquired brain injury&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> These patients end up undergoing imaging modalities&#44; electroencephalograms&#44; and&#47;or flumazenil administration&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Currently&#44; regarding the established indications of moderate or deep sedation&#44; various alternatives have become available to benzodiazepine sedation&#44; such as propofol&#44; ketamine&#44; or inhalation sedation with isoflurane<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; These drugs allow for effective sedation without organ accumulation and a quick awakening time&#44; thus avoiding the drawbacks of midazolam sedation&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Benzodiazepines should be limited in our routine clinical practice in the management of critically ill patients&#46; Via enteral administration&#44; they can be indicated for alcohol withdrawal and alcoholic delirium tremens prevention&#46; Via IV bolus administration benzodiazepines can be indicated for procedural hypnosis&#44; acute control of epileptic status&#44; or emergency control of psychomotor agitation with risk to the patient or staff&#44; when pain is not the cause&#46; Via continuous IV infusion&#44; residual indications should be for end-of-life comfort provision and the management of intracranial hypertension when propofol&#44; ketamine&#44; or isoflurane are ill-advised&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Sedation at the ICU setting should not only be used to provide comfort to critically ill patients&#44; but also to prevent post-ICU stay syndrome&#44; while making sure that patients remain in their best possible clinical condition after ICU discharge&#44; avoiding additional safety problems such as delirium or oversedation&#46; This also allows for an efficient management of ICU beds&#44; thus facilitating the admission of other critically ill patients and humanizing clinical care by facilitating patient-family-health care provider interactions&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Several studies support that non-benzodiazepine sedation regimens are more cost-effective than benzodiazepine regimes&#44; despite the lower acquisition cost of the latter&#46; This overall cost reduction is likely due to a shorter duration of mechanical ventilatory support &#40;MVS&#41; and ICU length of stay thanks to the use of non-benzodiazepine sedatives&#44; including inhalation sedation&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In conclusion&#44; shorter ICU stays&#44; more bed availability&#44; improved patient function after ICU discharge&#44; and lower overall costs per patient make the choice of sedatives for our patients a fundamental aspect of their management&#46; And midazolam infusion during MVS does not favor any of these premises&#46;</p></span>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Isoflurane&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Receptor it binds to&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GABA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GABA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NMDA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GABA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bioavailability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;90&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;90&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80 &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Protein binding&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">95&#37;&#44; albumin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97&#37;&#44; albumin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Half-life&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;8&#8722;3&#8239;h&#46; Extended up to 3 times in the elderly and up to 6&#8239;h in continuous infusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0005" class="elsevierStylePara elsevierViewall">2&#8211;4&#8239;min &#40;fast distribution half-life&#41;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0010" class="elsevierStylePara elsevierViewall">30 to 60&#8239;min &#40;slow distribution half-life&#41;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0015" class="elsevierStylePara elsevierViewall">4 to 7&#8239;h &#40;terminal half-life&#41;</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;10 min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15 min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Active metabolites&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hydroxymidazolam&#44; pharmacologically active&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Norketamine&#44; it hydrolizes and conjugates to pass to inactive status&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Metabolization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatic in 40&#37;&#8211;50&#37; due to CYP3A4 cytochrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatic due to glucuronidation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatic due to demethylation by cytochrome P450&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;2&#37; of fluorine turns into fluoride and trifluoroacetic acid of renal elimination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elimination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#37;&#8211;80&#37; is cleared as hydroxymidazolam alfa glucuronide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Urinary within 24 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Renal &#40;95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pulmonary &#40;95&#37;&#41; of unaltered form&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "imagenFichero" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Pharmacokinetics and pharmacodynamics of hypnotics used for moderate and deep sedation at the ICU setting&#46;</p>"
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      "titulo" => "References"
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                            0 => "G&#46;L&#46; Fraser"
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Lee"
                            1 => "S&#46; Choi"
                            2 => "E&#46;J&#46; Jang"
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                  ]
                  "host" => array:1 [
                    0 => array:1 [
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            5 => array:3 [
              "identificador" => "bib0030"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Celis-Rodr&#237;guez"
                            1 => "J&#46;C&#46; D&#237;az Cort&#233;s"
                            2 => "Y&#46;R&#46; C&#225;rdenas Bol&#237;var"
                            3 => "J&#46;A&#46; Carrizosa Gonz&#225;lez"
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                            5 => "L&#46;E&#46; Ferrer Z&#225;ccaro"
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                    0 => array:2 [
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            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Scherer"
                            1 => "J&#46; Kleeberger"
                            2 => "A&#46; Kellnar"
                            3 => "L&#46; Binzenh&#246;fer"
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                  ]
                  "host" => array:1 [
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                      "doi" => "10.1016/j.jcrc.2022.154051"
                      "Revista" => array:5 [
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            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differential Effects of Gamma-Aminobutyric Acidergic Sedatives on Risk of Post-Extubation Delirium in the ICU&#58; A Retrospective Cohort Study from a New England Health Care Network"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "O&#46; Azimaraghi"
                            1 => "K&#46; Wongtangman"
                            2 => "L&#46;J&#46; Wachtendorf"
                            3 => "P&#46; Santer"
                            4 => "S&#46; Rumyantsev"
                            5 => "C&#46; Ahn"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/CCM.0000000000005425"
                      "Revista" => array:6 [
                        "tituloSerie" => "Crit Care Med"
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                        "volumen" => "50"
                        "paginaInicial" => "E434"
                        "paginaFinal" => "44"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34982739"
                            "web" => "Medline"
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                      ]
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                ]
              ]
            ]
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In favour-against debate in intensive care medicine
Current role of midazolam in the sedation of the ventilated critically ill patient: against
Papel actual del midazolam en la sedación del paciente crítico ventilado: en contra
Jesus Caballeroa,
Corresponding author
jecablo@gmail.com

Corresponding author.
, Manuela García-Sánchezb, Carola Giménez-Esparza Vichc
a Servicio de Medicina Intensiva, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica IRBLleida, Lleida, Spain
b Servicio de Medicina Intensiva, Hospital Universitario Virgen Macarena de Sevilla, Sevilla, Spain
c Servicio de Medicina Intensiva, Hospital de la Vega Baja, Alicante, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0020" class="elsevierStylePara elsevierViewall">Midazolam is a benzodiazepine still routinely used in Intensive Care Units &#40;ICUs&#41; for the sedation of ventilated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> As a short-acting and potent drug that causes less hemodynamic instability&#44; it could be the ideal sedative if it weren&#39;t for its significant cumulative power due to its pharmacokinetics&#46; This is due to its liposolubility and large volume of distribution&#44; which is exacerbated in obese patients with hepatic and&#47;or kidney failure&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Midazolam is hydroxylated by CYP3A4 into hydroxymidazolam&#44; which is pharmacologically less active than the original drug&#46; Between 50&#37; and 70&#37; of midazolam is excreted in the urine within the next 24&#8239;h as hydroxymidazolam&#46; Due to its hepatic metabolism&#44; liver failure also affects its metabolism&#46; Similarly&#44; in patients with kidney disease&#44; midazolam elevates the concentrations of hydroxymidazolam&#44; thus leading to an increased pharmacological activity&#46; Therefore&#44; it can cause oversedation during its use&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> takes longer to be eliminated&#44; and withdrawal symptoms are common&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Additionally&#44; there are times that we are not aware of the doses administered in continuous infusion&#46; For example&#44; a dose of midazolam at 10&#8239;mg per hour involves a daily dose of 240&#8239;mg&#44; 480&#8239;mg in 2 days&#44; or 1200&#8239;mg every 5 days&#44; which is equivalent to 80 vials of 15&#8239;mg or 240 vials of 5&#8239;mg&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Comparative studies between midazolam and other hypnotics&#44; such as propofol or isoflurane&#44; as well as studies comparing benzodiazepine and non-benzodiazepine sedation&#44; conclude that it is advisable to avoid benzodiazepines in critically ill patients because their use is associated with delayed awakening and extubation&#44; longer mean ICU and hospital lengths of stay&#44; a higher risk of delirium and cognitive dysfunction&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and increased mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> This has led to the latest international clinical practice guidelines to discourage the use of benzodiazepines and&#44; specifically&#44; midazolam infusions&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Despite the scientific evidence and recommendations published&#44; the use of midazolam in critically ill patients is still widespread&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The reasons for this are multiple&#58; lack of an internal working group leading the paradigm shift&#44; resistance to modifying year-long established routine clinical practices&#44; or the convenience of using a single midazolam infusion as a hypnotic&#46; Midazolam is also used to sedate hemodynamically compromised patients because it causes less hypotension&#44; and there is no solid evidence in specific populations of critically ill patients&#46; A retrospective study conducted by Sherer et al&#46; showed higher midazolam-related mortality rates compared to propofol in patients with cardiogenic shock&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Proper monitoring is essential to prevent oversedation&#44; especially in patients with deep sedation and neuromuscular blockers&#44; in whom continuous electroencephalographic devices should be used&#46; However&#44; despite proper monitoring&#44; the pharmacokinetic characteristics of midazolam&#44; with a longer half-life than propofol or isoflurane and greater cumulative power&#44; do not stop the patient from taking longer to awaken once sedation has been withdrawn&#46; In fact&#44; deep sedation with benzodiazepines has a higher risk of post-extubation delirium than sedation with other drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">There are cases&#44; and these are not exceptional cases&#44; where after days of midazolam infusion and an attempt to switch to shorter-acting drugs for dynamic sedation or awaken for invasive mechanical ventilation weaning&#44; these patients end up not waking up for days&#46; It becomes difficult to distinguish the effect of midazolam from acquired brain injury&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> These patients end up undergoing imaging modalities&#44; electroencephalograms&#44; and&#47;or flumazenil administration&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Currently&#44; regarding the established indications of moderate or deep sedation&#44; various alternatives have become available to benzodiazepine sedation&#44; such as propofol&#44; ketamine&#44; or inhalation sedation with isoflurane<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; These drugs allow for effective sedation without organ accumulation and a quick awakening time&#44; thus avoiding the drawbacks of midazolam sedation&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Benzodiazepines should be limited in our routine clinical practice in the management of critically ill patients&#46; Via enteral administration&#44; they can be indicated for alcohol withdrawal and alcoholic delirium tremens prevention&#46; Via IV bolus administration benzodiazepines can be indicated for procedural hypnosis&#44; acute control of epileptic status&#44; or emergency control of psychomotor agitation with risk to the patient or staff&#44; when pain is not the cause&#46; Via continuous IV infusion&#44; residual indications should be for end-of-life comfort provision and the management of intracranial hypertension when propofol&#44; ketamine&#44; or isoflurane are ill-advised&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Sedation at the ICU setting should not only be used to provide comfort to critically ill patients&#44; but also to prevent post-ICU stay syndrome&#44; while making sure that patients remain in their best possible clinical condition after ICU discharge&#44; avoiding additional safety problems such as delirium or oversedation&#46; This also allows for an efficient management of ICU beds&#44; thus facilitating the admission of other critically ill patients and humanizing clinical care by facilitating patient-family-health care provider interactions&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Several studies support that non-benzodiazepine sedation regimens are more cost-effective than benzodiazepine regimes&#44; despite the lower acquisition cost of the latter&#46; This overall cost reduction is likely due to a shorter duration of mechanical ventilatory support &#40;MVS&#41; and ICU length of stay thanks to the use of non-benzodiazepine sedatives&#44; including inhalation sedation&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In conclusion&#44; shorter ICU stays&#44; more bed availability&#44; improved patient function after ICU discharge&#44; and lower overall costs per patient make the choice of sedatives for our patients a fundamental aspect of their management&#46; And midazolam infusion during MVS does not favor any of these premises&#46;</p></span>"
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    "fechaRecibido" => "2023-07-23"
    "fechaAceptado" => "2023-10-10"
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        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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            "identificador" => "at0005"
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                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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Midazolam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Propofol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Ketamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Isoflurane&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Receptor it binds to&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GABA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GABA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NMDA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GABA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bioavailability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;90&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;90&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80 &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Protein binding&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">95&#37;&#44; albumin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97&#37;&#44; albumin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Half-life&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;8&#8722;3&#8239;h&#46; Extended up to 3 times in the elderly and up to 6&#8239;h in continuous infusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0005" class="elsevierStylePara elsevierViewall">2&#8211;4&#8239;min &#40;fast distribution half-life&#41;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0010" class="elsevierStylePara elsevierViewall">30 to 60&#8239;min &#40;slow distribution half-life&#41;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0015" class="elsevierStylePara elsevierViewall">4 to 7&#8239;h &#40;terminal half-life&#41;</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;10 min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15 min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Active metabolites&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hydroxymidazolam&#44; pharmacologically active&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Norketamine&#44; it hydrolizes and conjugates to pass to inactive status&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Metabolization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatic in 40&#37;&#8211;50&#37; due to CYP3A4 cytochrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatic due to glucuronidation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatic due to demethylation by cytochrome P450&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;2&#37; of fluorine turns into fluoride and trifluoroacetic acid of renal elimination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elimination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#37;&#8211;80&#37; is cleared as hydroxymidazolam alfa glucuronide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Urinary within 24 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Renal &#40;95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pulmonary &#40;95&#37;&#41; of unaltered form&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Pharmacokinetics and pharmacodynamics of hypnotics used for moderate and deep sedation at the ICU setting&#46;</p>"
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                      "autores" => array:1 [
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                          "etal" => true
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                            0 => "M&#46; Garc&#237;a-S&#225;nchez"
                            1 => "J&#46; Caballero-L&#243;pez"
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                            4 => "M&#46;A&#46; Romera-Ortega"
                            5 => "C&#46; Pardo-Rey"
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                    0 => array:2 [
                      "doi" => "10.1016/j.medin.2018.12.003"
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                        "link" => array:1 [
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                      "titulo" => "The pharmacology of oversedation in mechanically ventilated adults"
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                        0 => array:2 [
                          "etal" => false
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                            0 => "J&#46;W&#46; Devlin"
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                  "contribucion" => array:1 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "K&#46;F&#46; Rengel"
                            1 => "C&#46;J&#46; Hayhurst"
                            2 => "P&#46;P&#46; Pandharipande"
                            3 => "C&#46;G&#46; Hughes"
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                    0 => array:2 [
                      "doi" => "10.1213/ANE.0000000000004066"
                      "Revista" => array:6 [
                        "tituloSerie" => "Anesth Analg &#91;Internet&#93;"
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                        "volumen" => "128"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Benzodiazepine versus nonbenzodiazepine-based sedation for mechanically ventilated&#44; critically ill adults&#58; A systematic review and meta-analysis of randomized trials"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46;L&#46; Fraser"
                            1 => "J&#46;W&#46; Devlin"
                            2 => "C&#46;P&#46; Worby"
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ISSN: 21735727
Original language: English
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