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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The Clinical Practice Guidelines for the Prevention and Management of Pain&#44; Agitation&#47;Sedation&#44; Delirium&#44; Immobility&#44; and Sleep Disruption in Adult Patients in the ICU &#40;PADIS Guidelines&#41; suggest a protocol-based&#44; stepwise approach for pain and sedation management that promotes treating pain over initiating a sedative agent &#40;conditional recommendation&#44; moderate quality of evidence&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Opioid analgesics remain the most utilized agents to achieve this endpoint despite well-established adverse effects including but not limited to respiratory depression&#44; constipation&#44; delirium&#44; and immunosuppression&#46; Although there is substantial variation in the method of administration and agent selected&#44; available data indicates that opioids are utilized in nearly 85&#37; of mechanically ventilated patient-days&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In 2016&#44; guidelines published by the Centers for Disease Control &#40;CDC&#41; noted that long-term opioid use often begins when opioids are prescribed for acute pain&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Since this time&#44; the majority of every clinical practice guideline with recommendations related to pain management advocates for the use of opioid-sparing interventions in conjunction with non-pharmacologic approaches when available&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#8211;9</span></a> In critically ill patient populations&#44; the PADIS Guidelines suggest use of acetaminophen as an adjunct to opioids in critically ill patients and conditionally suggest use of ketamine for post-surgical pain and gabapentinoids for neuropathic pain to reduce opioid requirements and improve pain control&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Nefopam is also recommended as an adjunct or alternatives to opioids but it is not commercially available in the United States or Canada&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The efficacy and safety of nonopioid analgesics for patients in an intensive care unit &#40;ICU&#41; setting was evaluated in a review of studies published up to October 1&#44; 2019 by Wheeler et al&#46; <a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The investigators found that the use of any adjunct agent compared to opioids alone was associated with decreased opioid use&#46; However&#44; the decrease in oral morphine equivalents over 24&#8239;hours was small &#40;mean difference&#44; 25&#46;89&#8239;mg less&#59; 95&#37; CI&#44; 19&#46;97&#8211;31&#46;81&#8239;mg&#41; and of low certainty&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Debate exists regarding what defines a substantial opioid-sparing effect&#44; whether a reduction in opioids translates to improved patient outcomes&#44; and what defines an acceptable benefit-to-risk ratio in critically ill patient populations at risk for adverse drug events&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In recent years&#44; various groups and organizations including the Food and Drug Administration &#40;FDA&#41; have drafted guidance documents that address future research design for studies evaluating opioid-sparing medications and outcomes that would be considered clinically meaningful&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> The purpose of this scoping review is to provide an update to the review by Wheeler et al&#46; and discuss if medications commonly recommended as opioid-sparing agents have evidence of an acceptable benefit-to-risk profile as elucidated in guidance documents to justify their use in heterogeneous populations of critically ill patients in ICU settings&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Patients and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Protocol and registration</span><p id="par0025" class="elsevierStylePara elsevierViewall">The Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews &#40;PRISMA-ScR&#41; was utilized for drafting and revision of the protocol by the research team&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Eligibility criteria</span><p id="par0030" class="elsevierStylePara elsevierViewall">Inclusion criteria consisted of randomized controlled trials evaluating adjunctive analgesic use in adult patients &#40;aged 18 years or older&#41; in an ICU setting from October 1&#44; 2019&#44; to June 1&#44; 2023&#46; Studies were excluded if interventions were initiated outside of the ICU &#40;e&#46;g&#46;&#44; emergency department&#44; operative room&#44; post-anesthesia care units&#41;&#44; if interventions were peri-procedural such as line insertions or dressing changes&#44; if they were regional in nature &#40;e&#46;g&#46;&#44; peripheral nerve blocks&#44; epidural or intrathecal catheters&#41;&#44; or if single-doses were studied&#46; Other exclusion criteria included studies without an English-language translation and studies done in mixed populations of ICU and floor patients&#46; The criteria were selected to mirror that of the previous systematic review by Wheeler et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Human subjects</span><p id="par0035" class="elsevierStylePara elsevierViewall">This review did not involve human subjects and thus approval from the institutional review board was not necessary&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Information resources</span><p id="par0040" class="elsevierStylePara elsevierViewall">Two bibliographic databases were searched to identify relevant literature from October 1&#44; 2019&#44; to June 1&#44; 2023&#44; which included PubMed &#40;National Library of Medicine&#44; 2019&#8211;2023&#41; and Cochrane Library &#40;Wiley&#44; 2019&#8211;2023&#41;&#46; To limit the possibility of missed studies&#44; the search was performed with the assistance of a medical librarian using different databases and reviewing reference lists of included trials to help identify any missing articles&#46; An initial search was completed in December of 2022&#46; An updated search was performed in February and May of 2023&#46; The final search&#44; done prior to completion of the manuscript to capture any studies recently published&#44; was completed utilizing PubMed on June 1<span class="elsevierStyleSup">st</span>&#44; 2023&#46; Keyword concepts for the search included the following terms&#58; &#8220;intensive care unit&#44;&#8221; &#8220;opioid&#44;&#8221; and &#8220;analgesia&#46;&#8221; The full search strategy can be found in Appendix A&#46; Duplicate articles were identified and removed&#44; and the database reviews were supplemented by reviewing references of key reviewed articles&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Selection of sources of evidence</span><p id="par0045" class="elsevierStylePara elsevierViewall">To provide consistency in data extraction&#44; a single reviewer screened articles for the review&#46; Two other reviewers then reviewed the included articles to form a final consensus&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Screenings were conducted in two sequential stages with the first comprising an initial assessment of the title&#47;abstract&#44; if no exclusion criteria were noted the next stage was a full review of the article&#46; Reasons for exclusion were recorded at each stage&#46; To reduce clinical heterogeneity&#44; studies evaluating regional anesthesia interventions and interventions initiated in non-ICU settings were excluded&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Data charting process</span><p id="par0055" class="elsevierStylePara elsevierViewall">The data charting process was completed in accordance with previous scoping review protocols&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Key study characteristics and detailed information on all metrics to determine opioid sparing effects were made jointly by the reviewers&#46; One reviewer independently charted the data&#46; Discussions&#44; with all reviewers&#44; were held to resolve disagreements on criteria&#46; The variables of interest included year of publication&#44; country&#44; study design and setting&#44; number of subjects&#44; patient population&#44; types of interventions provided and their relationship to opioid usage&#44; and clinically important endpoints such as ICU length of stay&#44; duration of mechanical ventilation&#44; and incidence&#47;duration of delirium&#46; A data extraction table was developed prior to data extraction to provide a format for documenting key study characteristics&#46; The article PMID and titles were charted in excel and duplicates were removed throughout the data extraction process&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Critical appraisal of individual sources of evidence</span><p id="par0060" class="elsevierStylePara elsevierViewall">Scoping reviews&#44; unlike systematic reviews&#44; examine literature where it is uncertain what questions may be posed&#46; Thus&#44; critical appraisals are not pertinent for this scoping review&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Data analysis and synthesis of results</span><p id="par0065" class="elsevierStylePara elsevierViewall">Full text articles were assessed for eligibility after the initial screening process&#46; For a depiction of the process used in synthesizing the data for this scoping review see the PRISMA flow diagram &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Risk of bias assessment</span><p id="par0070" class="elsevierStylePara elsevierViewall">Risk of bias assessment was not necessary for this scoping review&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Results</span><p id="par0075" class="elsevierStylePara elsevierViewall">The PRISMA diagram for the scoping review is outlined in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46; A total of six randomized controlled trials were included for analysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;20</span></a> The patient populations evaluated in the trials included mixed medical&#47;surgical ICU patients &#40;n&#8239;&#61;&#8239;2&#41;&#44; cardiothoracic ICU patients undergoing elective coronary artery bypass graft &#40;CABG&#41; surgery &#40;n&#8239;&#61;&#8239;2&#41;&#44; oral and maxillofacial surgical patients &#40;n&#8239;&#61;&#8239;1&#41;&#44; and neuroscience ICU patients &#40;n&#8239;&#61;&#8239;1&#41;&#46; One-half of the studies were completed in patients admitted to the ICU post-operatively&#46; Two of the studies compared a non-opioid agent &#40;ketamine in one study&#44; gabapentin in the other study&#41; to a control group&#44; one study compared gabapentin to placebo&#44; two studies compared dexmedetomidine to other agents &#40;clonidine in one study&#44; midazolam in the other study&#41;&#44; and one study compared ketorolac to paracetamol&#46; Full characteristics of the included trials are described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Of the trials published since 2019&#44; the opioid-sparing effects of the intervention groups were commonly secondary endpoints with the majority demonstrating modest reductions in opioid use&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16&#44;19&#44;20</span></a> Primary endpoints evaluated were commonly those that might be considered clinically important in critically ill patient populations &#40;e&#46;g&#46;&#44; incidence and duration of delirium&#44; duration of mechanical ventilation&#41;&#44; but with no intent to relate them to opioid-sparing effects&#46; Additionally&#44; benefits with respect to the incidence of delirium and duration of mechanical ventilation are potentially confounded in the two studies that utilized benzodiazepines in the control group&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;20</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The trials included in this scoping review demonstrated variable results with respect to opioid-sparing effects&#44; with four trials<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;17&#44;20</span></a> revealing statistically significant reductions in opioid requirements and two trials<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;19</span></a> reporting no differences in opioid requirements&#46; Wang et al&#46; reported a mean reduction in intravenous hydromorphone of 1&#46;82&#8239;mg in mechanically ventilated patients undergoing maxillofacial surgery using a sedation regimen consisting of dexmedetomidine compared to midazolam&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Another study by Shokri et al&#46; reported a mean intravenous morphine reduction of 4&#46;13&#8239;mg over 72&#8239;hours in mechanically ventilated patients undergoing CABG surgery that received dexmedetomidine compared to clonidine for sedation&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Javaherforooshzadeh et al&#46; evaluated morphine requirements with adjunctive paracetamol compared to ketorolac in postoperative CABG patients and reported a mean reduction 1&#46;42&#8239;mg at 24&#8239;hours with paracetamol&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Finally&#44; Salarian et al&#46; reported a mean difference in fentanyl infusion rate of 2&#46;3&#8239;mcg&#47;kg&#47;hour in a mixed population of critically ill patients receiving mechanical ventilation with gabapentin added to standard care&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The incidence and duration of delirium were evaluated in four out of six trials included in this scoping review&#46; Two studies reported reductions in the incidence and duration of delirium with dexmedetomidine compared to midazolam or clonidine infusions for sedation&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> In one trial by Salarian et al&#46; that compared the addition of gabapentin to a sedation regimen consisting of fentanyl and midazolam to a control group that received the same sedation regimen without gabapentin&#44; the incidence of delirium was evaluated as a secondary endpoint&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Patients that received gabapentin had lower rates of delirium compared to control &#40;43&#37; vs 17&#46;3&#37;&#44; p&#8239;&#61;&#8239;0&#46;03&#41;&#46; Finally&#44; a study using adjunctive ketamine reported no differences in the incidence of delirium compared to a protocolized&#44; nurse-driven sedation regimen with daily spontaneous awakening trials and spontaneous breathing trials&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Four out of the six randomized controlled trials compared duration of mechanical ventilation as either a primary or secondary outcome&#46; Two of the trials reported reductions in duration of mechanical ventilation&#44; both of which included dexmedetomidine in the intervention group&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> However&#44; the absolute reductions in the duration of mechanical ventilation were small &#40;6&#46;3&#8239;minutes and 1&#46;8&#8239;hours&#41;&#46; The other two studies evaluating adjunctive ketamine and gabapentin reported no differences in the duration of mechanical ventilation&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Of the trials included in this scoping review&#44; none evaluated the impact of the intervention on opioid prescriptions at ICU transitions of care&#44; hospital discharge&#44; or long-term opioid utilization&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">The results of this scoping review indicate that there have been a limited number of randomized controlled trials evaluating opioid-sparing agents in critically ill patient populations since a review by Wheeler et al&#46; involving studies up to 2019&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Additionally&#44; there remains no consistent definition with respect to what absolute or percentage reduction in opioid requirements defines a clinically meaningful opioid-sparing agent&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> The review by Wheeler et al&#46; concluded that opioid adjunctive medications in addition to opioids as compared to an opioids alone led to reductions in patient-reported pain scores at 24&#8239;hours &#40;standard mean difference&#44; &#8211;0&#46;88&#59; 95&#37; CI&#44; &#8211;1&#46;29 to &#8211;0&#46;47&#41; and decreased opioid consumption &#40;in oral morphine equivalents over 24&#8239;hour&#59; mean difference&#44; 25&#46;89&#8239;mg less&#59; 95&#37; CI&#44; 19&#46;97&#8211;31&#46;81&#8239;mg less&#41;&#44; but both findings were of low certainty&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">A recently published consensus document formulated by participants from universities&#44; government agencies&#44; industry&#44; and patient advocacy organizations suggested that an opioid-sparing intervention must include the following elements without causing an unacceptable increase in pain&#58; &#40;1&#41; prevents opioids from being started&#44; &#40;2&#41; decreases opioid treatment duration&#44; &#40;3&#41; decreases the cumulative opioid dose&#44; or &#40;4&#41; reduces opioid-related adverse outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> In addition&#44; the Food and Drug Administration &#40;FDA&#41; published a draft guidance document to address challenges of developing non-opioid medications to manage pain in light of the opioid crisis which questioned whether the term &#8220;opioid-sparing&#8221; was sufficient to justify labeling regarding reduced opioid requirements&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> While these guidance documents do not specifically address critically ill patient populations&#44; the basic tenets generally remain applicable&#46; Of the six included studies in this scoping review&#44; none prevented an opioid from being started&#44; none decreased opioid treatment duration&#44; four trials showed a modest reduction in cumulative opioid dose&#44; and four studies addressed delirium and mechanical ventilation as described below&#46; None of the trials addressed all elements recommended in guidance documents&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Preventing opioid initiation in postoperative&#47;trauma-related pain or in mechanically ventilated patients using the protocol-based&#44; stepwise approach for pain and sedation management suggested in the PADIS guidelines might be desirable but is challenging with currently available non-opioid therapeutic options in patients with more severe pain states&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> However&#44; minimizing duration in critically ill patients&#44; particularly with respect to discontinuation of therapy at transitions of care out of the ICU or prior to discharge would likely represent a clinically important outcome&#46; Several studies involving critically ill patient populations opioid-na&#239;ve prior to ICU admission and that received opioids as part of an analgosedation or analgesia-first regimen were ultimately discharged from the hospital with a prescription rates for an opioid varying between 20&#37; to 47&#46;1&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#8211;24</span></a> In addition&#44; persistent opioid use among opioid-na&#239;ve ICU survivors measured at various time points between 3 and 12 months after ICU discharge ranged from 2&#46;6&#37; to 23&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;24&#8211;26</span></a> Given concerns related to adverse effects of opioids in general and long-term opioid use disorder in ICU survivors&#44; opioid-sparing agents that reduce duration of opioid use are warranted&#46; A useful discussion of opioid-sparing options for managing analgesia&#44; sedation&#44; and delirium in critically ill adult patients is provided in clinical practice guidelines compiled by the Pan-American and Iberian Federation of Societies of Critical Medicine and Intensive Therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> These guidelines recommend decreasing sedation levels with the use of multimodal pain management strategies while recognizing the need for more research on alternatives to opioids&#46; Agents such as dexmedetomidine&#44; remifentanil&#44; and ketamine are discussed in the guidelines&#46; Of note&#44; the terminology regarding sedation has implications for patient management&#46; For example&#44; analgesia-first sedation in which an analgesic is used before a sedative is different from analgesia-based sedation in which an analgesic is used instead of a sedative to manage agitation or facilitate mechanical ventilation&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Potential risks of opioid sparing strategies include inappropriate pain control which may lead to prolonged duration of mechanical ventilation&#44; ventilator dyssynchrony&#44; increased ICU length of stay&#44; and post-traumatic stress disorder&#46; Additionally&#44; interpretation of any opioid-sparing effects and reductions in duration of mechanical ventilation or delirium is often complicated by confounding variables &#40;e&#46;g&#46;&#44; use of benzodiazepines&#41; in published studies&#46; Regardless&#44; there is appeal to the use of agents such as dexmedetomidine that may reduce the duration of mechanical ventilation and delirium while providing sedation to critically ill patients&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> A useful paper for clinicians wishing to minimize the problems associated with oversedation was compiled by the Zero Oversedation Project of the Sedation&#44; Analgesia and Delirium Working Group of the Spanish Society of Intensive and Critical Care Medicine and Coronary Units&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> The paper contains practical information with tools to help ensure optimal patient management including minimizing the risk of excessive sedation&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The study by Salarian et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> which suggested that the addition of gabapentin to a sedation regimen led to a reduced rate of delirium&#44; is not corroborated by the results of a recent study that demonstrated that perioperative gabapentin use was associated with increased risk of delirium among older patients after major surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Furthermore&#44; prescription use of gabapentin has increased more than five-fold between 2006 and 2018 with a coexisting increase in gabapentin-related overdose death exacerbated by concomitant opioid use&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> Given the widespread use of opioids in critically ill patients and concerns about safety&#44; adoption of gabapentin use as an opioid-sparing agent in this patient population requires additional study&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Reduced duration of mechanical ventilation represents another potential clinically important outcome of opioid-sparing agents assuming pain assessments are routinely employed&#46; As noted by Garc&#237;a S&#225;nchez and Alc&#225;ntara Carmona&#44; 70&#37; of patients receiving mechanical ventilation in Spanish ICUs receive opioids but only 52&#37; of ICUs use routine pain assessment scales&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> The studies in our scoping review demonstrating that dexmedetomidine but not ketamine reduced the duration of mechanical ventilation are consistent with a previously published meta-analysis&#44; which reported a reduction in the duration of mechanical ventilation with dexmedetomidine &#40;low certainty of evidence&#41; and no reduction in duration of mechanical ventilation with ketamine &#40;moderate certainty of evidence&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The cause and effect of the potential opioid-sparing effects of dexmedetomidine on duration of mechanical ventilation requires additional study&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Future directions for research should include a focus on the effectiveness and safety of non-opioid medications in critically ill patients and not rely on extrapolations from studies conducted in other patient populations&#46; Critically ill patients are at increased risk for a number of organ dysfunctions that might preclude the administration of medications commonly administered in other patient settings&#46; For example&#44; critically ill patients are at risk for acute kidney injury and gastrointestinal bleeding&#44; conditions that would necessitate the avoidance of nonsteroidal anti-inflammatory drugs &#40;NSAIDs&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Future investigations also need to evaluate outcomes beyond opioid sparing effects&#46; A medication&#8217;s benefit in terms of an opioid-sparing effect must outweigh safety-related concerns &#40;i&#46;e&#46;&#44; benefit exceeding risks&#41;&#44; which becomes complex in critically ill patients at substantial risk for complications such as bleeding&#44; acute kidney injury &#40;AKI&#41;&#44; and respiratory failure&#46; Potential clinically important endpoints that could be evaluated with opioid-sparing regimens include duration of mechanical ventilation &#40;or ventilator-free days&#41;&#44; incidence and duration of delirium&#44; reduction in post-operative ileus&#44; and incidence of respiratory failure leading to mechanical ventilation&#46; Ideally&#44; any improvements in these clinical outcomes would not be outweighed by adverse outcomes such as alterations in hemodynamics&#44; AKI&#44; bleeding complications&#44; among others&#46; Clinically meaningful outcomes related specifically to opioid sparing that should be investigated might include avoidance of opioid use&#44; decreased duration or cumulative doses of opioid administration&#44; or reductions in opioid-related adverse effects&#46; Finally&#44; there is a need for more research to identify novel analgesic agents that can either serve to eliminate the use of opioids or serve as adjunctive therapies&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conclusion</span><p id="par0145" class="elsevierStylePara elsevierViewall">Utilization of adjunct agents to limit opioid exposure is a widespread practice amongst clinicians in the ICU setting&#44; though it comes with difficulties and barriers&#46; However&#44; few studies have shown benefits &#40;beyond decreased opioid consumption&#41; of utilizing non-opioid medications in patients who are critically ill and requiring analgesics&#46; Further studies are needed to determine the implications of opioid sparing amongst critically ill patients admitted to the ICU&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Author contributions</span><p id="par0150" class="elsevierStylePara elsevierViewall">All authors contributed to conception and design&#44; acquisition&#44; analysis&#44; or interpretation of data&#44; drafted&#44; and critically revised the manuscript&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Funding</span><p id="par0155" class="elsevierStylePara elsevierViewall">No funding was used for this manuscript&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Conflict of interest</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Data availability statement</span><p id="par0165" class="elsevierStylePara elsevierViewall">There is no shared data&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The purpose of this scoping review was to evaluate literature involving opioid-sparing medications in critically ill patients with a focus on clinically meaningful outcomes&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Design</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Scoping review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Setting</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Intensive care unit&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Patients or participants</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Adult patients in an intensive care unit setting&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Interventions</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">None&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Main variables of interest</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">PubMed and Cochrane Library were searched from October 1&#44; 2019 to June 1&#44; 2023&#46; Inclusion criteria consisted of randomized controlled trials evaluating adjunctive analgesic use in adult patients in an intensive care unit setting&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Results</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">There were 343 citations and titles identified in the initial search&#44; with 328 remaining after removal of duplicates&#44; 294 excluded at title and abstract screening&#44; 34 available for full text review&#44; and six included in the scoping review&#46; Most studies reported modest reductions in opioid use as a secondary endpoint&#46; Improvement in clinical outcomes such as reduction in duration of mechanical ventilation or delirium were reported in two trials with dexmedetomidine&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conclusions</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">In recently published trials of adjunctive agents in critically ill patients&#44; opioid-sparing effects were small&#46; Data to support improvements in clinical outcomes remains limited&#46;</p></span>"
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            "identificador" => "abst0025"
            "titulo" => "Interventions"
          ]
          5 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Main variables of interest"
          ]
          6 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Results"
          ]
          7 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusions"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Objectivo</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">El prop&#243;sito de esta revisi&#243;n de alcance fue evaluar la literatura sobre medicamentos ahorradores de opioides en pacientes cr&#237;ticos con un enfoque en resultados cl&#237;nicamente significativos&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Dise&#241;o</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Revisi&#243;n de alcance utilizando los elementos de informes preferidos para revisiones sistem&#225;ticas y la extensi&#243;n de metan&#225;lisis para revisiones de alcance&#46;</p></span> <span id="abst0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">&#193;mbito</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Unidad de Cuidados Intensivos&#46;</p></span> <span id="abst0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Pacientes o participantes</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Pacientes adultos en una unidad de cuidados intensivos&#46;</p></span> <span id="abst0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Intervenciones</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Ninguno&#46;</p></span> <span id="abst0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Variables de inter&#233;s principales</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Se realizaron b&#250;squedas en PubMed y Cochrane Library desde el 1 de octubre de 2019 hasta el 1 de junio de 2023&#46; Los criterios de inclusi&#243;n consistieron en ensayos controlados aleatorios que evaluaron el uso de analg&#233;sicos complementarios en pacientes adultos en una unidad de cuidados intensivos&#46;</p></span> <span id="abst0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Resultados</span><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Se identificaron 343 citas y t&#237;tulos en la b&#250;squeda inicial&#44; 328 restantes despu&#233;s de la eliminaci&#243;n de duplicados&#44; 294 excluidas en la selecci&#243;n de t&#237;tulos y res&#250;menes&#44; 34 disponibles para revisi&#243;n del texto completo y seis incluidas en la revisi&#243;n de alcance&#46; La mayor&#237;a de los estudios informaron reducciones modestas en el uso de opioides como criterio de valoraci&#243;n secundario&#46; En dos ensayos con dexmedetomidina se informaron mejoras en los resultados cl&#237;nicos&#44; como la reducci&#243;n de la duraci&#243;n de la ventilaci&#243;n mec&#225;nica o el delirio&#46;</p></span> <span id="abst0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclusiones</span><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">En ensayos publicados recientemente sobre agentes complementarios en pacientes cr&#237;ticamente enfermos&#44; los efectos ahorradores de opioides fueron peque&#241;os&#46; Los datos que respaldan las mejoras en los resultados cl&#237;nicos siguen siendo limitados&#46;</p></span>"
        "secciones" => array:8 [
          0 => array:2 [
            "identificador" => "abst0045"
            "titulo" => "Objectivo"
          ]
          1 => array:2 [
            "identificador" => "abst0050"
            "titulo" => "Dise&#241;o"
          ]
          2 => array:2 [
            "identificador" => "abst0055"
            "titulo" => "&#193;mbito"
          ]
          3 => array:2 [
            "identificador" => "abst0060"
            "titulo" => "Pacientes o participantes"
          ]
          4 => array:2 [
            "identificador" => "abst0065"
            "titulo" => "Intervenciones"
          ]
          5 => array:2 [
            "identificador" => "abst0070"
            "titulo" => "Variables de inter&#233;s principales"
          ]
          6 => array:2 [
            "identificador" => "abst0075"
            "titulo" => "Resultados"
          ]
          7 => array:2 [
            "identificador" => "abst0080"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#8902;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Gambadoro G&#44; Kopp BJ&#44; Erstad BL&#46; Implicaciones de los medicamentos ahorradores de opioides en pacientes cr&#237;ticos&#58; una revisi&#243;n exploratoria&#46; Med Intensiva&#46; 2024&#46; <span class="elsevierStyleInterRef" id="intr0005" href="https://doi.org/10.1016/j.medin.2024.06.001">https&#58;&#47;&#47;doi&#46;org&#47;10&#46;1016&#47;j&#46;medin&#46;2024&#46;06&#46;001</span>&#46;</p>"
      ]
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="par0180" class="elsevierStylePara elsevierViewall">The following is Supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0100"
          ]
        ]
      ]
    ]
    "multimedia" => array:3 [
      0 => array:8 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 2713
            "Ancho" => 2083
            "Tamanyo" => 231715
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0005"
            "detalle" => "Figure "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Preferred Reporting Items for Systematic Reviews and Meta-Analysis &#40;PRISMA&#41; diagram&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0010"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\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">Study&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">Standard Care and Opioids Utilized&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">Comparison Groups&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">Duration of intervention&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">Patient subgroup and number of patients&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">Mean age &#40;yr&#41;&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">&#37; Female patients&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">Outcome&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">Wang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&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">Continuous infusion hydromorphone &#40;4&#8211;8&#8239;mcg&#47;kg&#47;hour&#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">IV Midazolam &#40;MID&#41; &#40;0&#46;04&#8211;0&#46;2&#8239;mcg&#47;kg&#47;hour&#41;orIV Dexmedetomidine &#40;DEX&#41; &#40;1 mcg&#47;kg over 10&#8239;minutes and then continuous infusion 0&#46;2&#8211;0&#46;7&#8239;mcg&#47;kg&#47;hour&#59; maximum 1 mcg&#47;kg&#47;hour&#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">12 hours&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">Oral and maxillofacial surgical patients&#44; mechanically ventilatedDEX n&#8239;&#61;&#8239;20&#59; MID n&#8239;&#61;&#8239;20&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">MID&#8239;&#61;&#8239;60&#46;5DEX&#8239;&#61;&#8239;60&#46;05&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">27&#46;5&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">Lower mean hydromorphone requirements in DEX group vs MID &#40;3&#46;87&#8239;&#177;&#8239;1&#46;13&#8239;mg vs 5&#46;69&#8239;&#177;&#8239;0&#46;77&#8239;mg&#59; p&#8239;&#61;&#8239;0&#46;001&#41; &nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\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">Shokri et al&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&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">Morphine 1&#8211;2&#8239;mg rescue doses allowed in both groups&#46;Midazolam 15&#8239;mcg&#47;kg permitted in DEX group when maximum dose inadequate&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">IV DEX &#40;0&#46;7&#8211;1&#46;2&#8239;mcg&#47;kg&#47;hour&#59; maximum 1&#46;4&#8239;mcg&#47;kg&#47;hour&#41;orClonidine &#40;0&#46;5&#8239;mcg&#47;kg over 10&#8211;15&#8239;minutes followed by continuous infusion at 1&#8211;2&#8239;mcg&#47;kg&#47;hour&#59; maximum 2&#8239;mcg&#47;kg&#47;hour&#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">24&#8239;hours or until ICU discharge up to 72&#8239;hours&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">Adults between 60&#8211;70 years of age undergoing coronary artery bypass graft &#40;CABG&#41; surgery&#44; mechanically ventilatedDEX n&#8239;&#61;&#8239;144&#59; Clonidine n&#8239;&#61;&#8239;142&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">DEX&#8239;&#61;&#8239;63&#46;75 Clonidine&#8239;&#61;&#8239;64&#46;38&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">51&#46;4&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">Lower mean post-operative morphine consumption over 3 days in DEX group vs clonidine &#40;18&#46;24&#8239;&#177;&#8239;8&#46;62&#8239;mg vs 22&#46;37&#8239;&#177;&#8239;10&#46;73&#8239;mg&#59; p&#8239;&#60;&#8239;0&#46;001&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\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">Javaherforooshzadeh et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&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">Standard protocol for sedation after surgery consisting of propofol 0&#46;5&#8239;mg&#47;kg&#47;hour and morphine 0&#46;1&#8239;mg&#47;kg&#47;hourPCA morphine after extubation&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">IV Ketorolac 0&#46;5&#8239;mg&#47;kg every 6&#8239;hours orIV Paracetamol 10&#8239;mg&#47;kg every 6&#8239;hours&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">Study drug was continued for 24&#8239;hoursMorphine consumption was collected for 48&#8239;hours&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">Adults between 30&#8211;70 years of age&#44; elective on-pump CABG&#59; ejection fraction &#8805; 30&#37;&#59; CTICUKetorolac n&#8239;&#61;&#8239;30&#59; Paracetamol&#8239;&#61;&#8239;30&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">Ketorolac&#8239;&#61;&#8239;61&#46;83Paracetamol&#8239;&#61;&#8239;58&#46;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">38&#46;3&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">Lower mean morphine consumption at 24&#8239;hours in the paracetamol group vs the ketorolac group &#40;0&#46;29&#8239;&#177;&#8239;0&#46;41&#8239;mg vs 1&#46;71&#8239;&#177;&#8239;0&#46;53&#8239;mg&#59; p&#8239;&#61;&#8239;0&#46;027&#41; and at 48&#8239;hours &#40;0&#46;22&#8239;&#177;&#8239;0&#46;15&#8239;mg vs 2&#46;18&#8239;&#177;&#8239;0&#46;52&#8239;mg&#59; p&#8239;&#61;&#8239;0&#46;007&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\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">Dhakal et al&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&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">Protocolized opioid regimen consisting of fentanyl 25&#8211;50&#8239;mcg every hour as needed with conversion to oxycodone 5&#8211;10&#8239;mg every 4&#8239;hours as needed if pain inadequately relieved with fentanyl Opioid dose converted to morphine equivalents &#40;unclear if IV or oral morphine equivalents&#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">Gabapentin &#40;100&#8239;mg three times daily&#59; titrated every 24&#8239;hours up to a maximum dose of 900&#8239;mg three times daily&#41;orPlacebo&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">7 days&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">Patients 18 years of age and older with aneurysmal SAH in neuro ICUGabapentin n&#8239;&#61;&#8239;8&#59; Placebo n&#8239;&#61;&#8239;8&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">Gabapentin&#8239;&#61;&#8239;52&#46;7Placebo&#8239;&#61;&#8239;49&#46;8&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">75&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 significant difference in mean morphine equivalent requirements at day 7 in the gabapentin group vs placebo group &#40;19&#46;4&#8239;&#177;&#8239;14&#46;8&#8239;mg vs 20&#46;2&#8239;&#177;&#8239;13&#46;5&#8239;mg&#59; p&#8239;&#61;&#8239;0&#46;79&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\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">Amer et al<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&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">Standard ICU analgesia&#47;sedation protocol used at study institution&#46; Opioid regimen consisted of fentanyl&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">Ketamine &#40;1&#8211;2&#8239;mcg&#47;kg&#47;min&#41;orControl group receiving standard of care&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">Treatment duration up to 48&#8239;hours&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
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                  \t\t\t\t">Admission to medical&#44; surgical&#44; or transplant ICU&#44; mechanical ventilation anticipated for at least 24&#8239;hours after enrollment&#40;N&#8239;&#61;&#8239;83&#44; ketamine n&#8239;&#61;&#8239;40&#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">Median ketamine&#8239;&#61;&#8239;59Median control group &#61; 61&nbsp;\t\t\t\t\t\t\n
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                  \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">38&#46;6&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 significant difference in median cumulative weight-based dose of fentanyl &#40;69&#46;6&#8239;mcg&#47;kg in ketamine group vs 63&#46;5 mcg&#47;kg in control group&#59; p&#8239;&#61;&#8239;0&#46;69&#41; or non-weight-based dose of fentanyl &#40;4400&#8239;mcg in ketamine group vs &#8239;cg in control group&#44; p&#8239;&#61;&#8239;0&#46;67&#41;at 48&#8239;hours&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">Salarian et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&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">Fentanyl &#40;1&#8211;2&#8239;mcg&#47;kg&#47;hour&#41;andmidazolam &#40;0&#46;06&#8211;0&#46;2&#8239;mg&#47;kg&#47;hour&#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">Gabapentin &#40;300&#8239;mg every 8&#8239;hours&#41;OrControl group&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">Not reported&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">Mixed medical and surgical&#47;trauma patients between the ages of 18&#8211;70 receiving mechanical ventilation for more than 3 daysGabapentin n&#8239;&#61;&#8239;23Control n&#8239;&#61;&#8239;20&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">Gabapentin&#8239;&#61;&#8239;57&#46;7Control group&#8239;&#61;&#8239;52&#46;4&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">53&#46;5&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">Significant reductions in mean fentanyl dose in the gabapentin group vs control &#40;1&#46;8&#8239;&#177;&#8239;0&#46;1&#8239;mcg&#47;kg&#47;hour vs 4&#46;1&#8239;&#177;&#8239;1&#46;5 mcg&#47;kg&#47;hour&#59; p&#8239;&#60;&#8239;0&#46;01&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Original article
Available online 12 July 2024
Implications of opioid-sparing medications in critically ill patients: A scoping review
Implicaciones de los medicamentos ahorradores de opioides en pacientes críticos: una revisión exploratoria
Gabriella Gambadoroa, Brian J. Koppb, Brian L. Erstadc,
Corresponding author
erstad@pharmacy.arizona.edu

Corresponding author.
a Critical Care Pharmacist, Banner – University Medical Center, 1625 N. Campbell Avenue, Tucson, AZ, 85719, USA
b Clinical Pharmacy Specialist, Surgical-Trauma ICU, Banner – University Medical Center, 1625 N. Campbell Avenue, Tucson, AZ, 85719, USA
c Department of Pharmacy Practice & Science, University of Arizona R. Ken Coit College of Pharmacy, Tucson, AZ, 85721, USA

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