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Perspectives on perfusion monitoring in septic shock after the ANDROMEDA-SHOCK trial
Perspectivas sobre la monitorización de la perfusión en el choque séptico tras el ensayo ANDROMEDA-SHOCK
a Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
b Department of Pulmonology and Critical Care, Columbia University Medical Center, New York, USA
c Department of Pulmonology and Critical Care, NYU Medical Center, Bellevue Hospital, New York, USA
d Erasmus MC University Medical Center, Rotterdam, The Netherlands
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Hernández, J. Bakker" "autores" => array:2 [ 0 => array:4 [ "nombre" => "G." "apellidos" => "Hernández" "email" => array:1 [ 0 => "glennguru@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J." "apellidos" => "Bakker" "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Pulmonology and Critical Care, Columbia University Medical Center, New York, USA" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Pulmonology and Critical Care, NYU Medical Center, Bellevue Hospital, New York, USA" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Erasmus MC University Medical Center, Rotterdam, The Netherlands" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Perspectivas sobre la monitorización de la perfusión en el choque séptico tras el ensayo ANDROMEDA-SHOCK" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2075 "Ancho" => 2917 "Tamanyo" => 277531 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Concept of hemodynamic coherence in septic shock.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Septic shock is a highly lethal condition where several pathogenic factors are involved in progressive tissue hypoperfusion.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">1</span></a> Fluid resuscitation is a first-line therapy to reverse hypoperfusion. However, this may induce fluid overload, particularly when administered to fluid-unresponsive patients or when inappropriate resuscitation goals are pursued. Unfortunately, despite extensive research, many uncertainties remain on the best perfusion monitoring and resuscitation target.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">The complexities of persistent hyperlactatemia</span><p id="par0010" class="elsevierStylePara elsevierViewall">Recent guidelines recommend lactate normalization as a resuscitation target. However, the rationale of lactate-guided therapy has been challenged as it may expose patients to the risk of over-resuscitation considering that the decrease in lactate levels over time is relatively slow even in survivors.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">2,3</span></a> In addition, lactate is a non-specific marker of hypoperfusion and several pathogenic mechanisms besides hypoperfusion may be involved. Adrenergic-driven muscle glycolysis and impaired hepatic lactate clearance are important confounding mechanisms in septic shock.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1,2</span></a> Recognizing a clinical pattern of hypoperfusion-related hyperlactatemia is important since optimizing systemic blood flow in that context could improve prognosis. In contrast, pursuing additional resuscitation in non-hypoperfusion-related cases might lead to the toxicity of over-resuscitation.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Multimodal perfusion monitoring including flow-sensitive parameters such as central venous O<span class="elsevierStyleInf">2</span> saturation (ScvO<span class="elsevierStyleInf">2</span>), central venous-arterial pCO<span class="elsevierStyleInf">2</span> gradient (Pcv-aCO<span class="elsevierStyleInf">2</span>), and peripheral perfusion, may disclose the presence of hypoperfusion-related hyperlactatemia when any of these variables is abnormal.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1,2,4</span></a> Persistent hyperlactatemia without a hypoperfusion context is associated with a better prognosis,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">4</span></a> and eventually this condition could be managed more conservatively.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">The role of capillary refill time (CRT) assessment</span><p id="par0020" class="elsevierStylePara elsevierViewall">CRT emerges as a rational alternative to guide septic shock resuscitation.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a> The skin territory lacks auto-regulatory flow control, and therefore, sympathetic activation impairs skin perfusion during circulatory dysfunction, a phenomenon that can be evaluated by peripheral perfusion assessment. Several studies confirm that abnormal peripheral perfusion after initial<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a> or advanced<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">7</span></a> resuscitation is associated with increased morbidity and mortality.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">6,7</span></a> The improved prognosis associated with CRT normalization, its rapid-response time to fluid loading, its relative simplicity, its availability in resource-limited settings, and its capacity to change in parallel with perfusion of physiologically relevant territories such as the hepatosplanchnic region,<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a> constitute strong reasons to consider CRT as target for initial septic shock resuscitation.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">The ANDROMEDA-SHOCK trial</span><p id="par0025" class="elsevierStylePara elsevierViewall">ANDROMEDA-SHOCK was a multicenter, randomized controlled trial comparing CRT- versus lactate-targeted resuscitation in patients with early septic shock.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a> The hypothesis was that targeting CRT assessed with a standardized method, would lead to decreased mortality and organ dysfunction. The protocol mandated sequential steps starting with fluid challenges, followed by vasoactive-related interventions if necessary, until the target was reached. CRT-targeted resuscitation was associated with lower mortality (34.9% vs. 43.4%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.06), beneficial effects on organ dysfunction, and less treatment intensity. The worldwide impact and immediate application of CRT-guided resuscitation makes additional research an urgent task (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">The concept of hemodynamic coherence in septic shock</span><p id="par0030" class="elsevierStylePara elsevierViewall">Hemodynamic coherence is a condition in which resuscitation of systemic macrohemodynamic variables results in concurrent improvement in regional and microcirculatory blood flow.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">9–11</span></a>. Impaired vascular tone with decreased venous return and arterial hypotension are key pathogenic mechanisms in early septic shock. At this stage, fluid resuscitation (in fluid-responsive patients) and mean arterial pressure (MAP) optimization may improve macrocirculatory, regional, and microcirculatory blood flow, which is consistent with preserved hemodynamic coherence and associated with better prognosis (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">At more advanced stages, when excessive adrenergic tone and microvascular/endothelial inflammation predominate, regional flow distribution and microcirculatory dysfunction may not respond to systemic blood flow optimization. Thus, hemodynamic coherence is lost, and efforts to further increase stroke volume or MAP by fluids or vasoactive agents might lead to fluid overload or catecholamine toxicity. This could result in worsening tissue perfusion by promoting interstitial edema, or by further deteriorating regional perfusion. How to treat patients at this stage is uncertain and a matter of future research, including the potential role of early immunomodulating therapies.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">CRT: the link between macrocirculation and the microcirculation?</span><p id="par0040" class="elsevierStylePara elsevierViewall">Capillary refill time (CRT) appears as a physiologically sound target and its improvement after stroke volume optimization is a signal of tissue reperfusion in patients with septic shock. Some observations support the potential role of CRT in revealing the status of hemodynamic coherence. First, three recent studies show that patients with normal vs. abnormal CRT after fluid resuscitation exhibit a highly significant difference in mortality (ranging from 9 to 23% vs. 45 to 55%).<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">5–7</span></a> This remarkable and consistent difference suggests, although does not prove, a preserved hemodynamic coherence in CRT normalizers (responders). Second, improvement in CRT after fluid resuscitation is associated with a parallel increase in hepatosplanchnic blood flow.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a> Third, CRT showed the fastest kinetics of recovery in septic shock survivors as compared with other commonly used perfusion parameters.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">3</span></a> Fourth, normalization of CRT in the ANDROMEDA-shock study was associated with less organ dysfunction.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">On the other hand, an abnormal CRT not responding to increments in systemic flow might be explained by several mechanisms including a more advanced stage of septic shock with uncoupling or loss of hemodynamic coherence; an excessive adrenergic tone with regional hypoperfusion; or a more severe systemic inflammatory state with endothelial/coagulation activation/dysfunction which could lead to impairment and heterogeneity of microcirculatory flow.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> None of these mechanisms may respond to systemic flow optimization at this stage.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Based on the preceding considerations, we could propose that CRT response to a rapid flow increasing maneuver may be used as a novel “hemodynamic coherence test.” A parallel improvement in regional blood flow, microcirculation and hypoperfusion-related parameters should be expected in patients that normalize CRT, as reflection of preserved hemodynamic coherence.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusions</span><p id="par0055" class="elsevierStylePara elsevierViewall">Multimodal perfusion monitoring might be useful to determine a hypoperfusion-context in persistent hyperlactatemia, thus promoting a physiologically-oriented septic shock resuscitation. CRT-guided septic shock resuscitation is associated with decreased mortality and organ dysfunction. CRT changes after rapid flow increasing maneuvers may identify the status of hemodynamic coherence, helping clinicians to decide on the most appropriate strategy for each stage. Further research is required to test these hypotheses.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflict of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "The complexities of persistent hyperlactatemia" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "The role of capillary refill time (CRT) assessment" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "The ANDROMEDA-SHOCK trial" ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "The concept of hemodynamic coherence in septic shock" ] 5 => array:2 [ "identificador" => "sec0030" "titulo" => "CRT: the link between macrocirculation and the microcirculation?" ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-08-30" "fechaAceptado" => "2019-09-08" "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2075 "Ancho" => 2917 "Tamanyo" => 277531 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Concept of hemodynamic coherence in septic shock.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">CRT, capillary refill time.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><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"><span class="elsevierStyleItalic">Main findings of the ANDROMEDA-SHOCK study favoring CRT-targeted septic shock resuscitation</span> \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"><span class="elsevierStyleHsp" style=""></span>Lower mortality (34.9% vs. 43.4%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.06) \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"><span class="elsevierStyleHsp" style=""></span>Less organ dysfunctions at 72<span class="elsevierStyleHsp" style=""></span>h (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.045) \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"><span class="elsevierStyleHsp" style=""></span>Lower mortality in the predefined subgroup of patients with less organ dysfunctions at baseline (20.4% vs. 39.3%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.03) \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"><span class="elsevierStyleHsp" style=""></span>Faster improvement in organ dysfunctions during the first 72<span class="elsevierStyleHsp" style=""></span>h (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001) \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"><span class="elsevierStyleHsp" style=""></span>Less resuscitation fluids (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.01) \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"><span class="elsevierStyleHsp" style=""></span>Less vasopressor testing (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.02) \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"><span class="elsevierStyleVsp" style="height:0.5px"></span> \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"><span class="elsevierStyleItalic">Some unsolved issues and challenges for a CRT-focused research agenda</span> \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"><span class="elsevierStyleHsp" style=""></span>Mechanisms of the beneficial effect of CRT-targeted resuscitation in the ANDROMEDA-SHOCK study \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"><span class="elsevierStyleHsp" style=""></span>Pathophysiologic determinants of an abnormal CRT \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"><span class="elsevierStyleHsp" style=""></span>Does CRT accurately represent skin blood flow? \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"><span class="elsevierStyleHsp" style=""></span>Is CRT an equivalent of a vascular occlusion test to detect abnormal microvascular reactivity? \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"><span class="elsevierStyleHsp" style=""></span>Is there a relationship between an abnormal CRT and adrenergic tone? \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"><span class="elsevierStyleHsp" style=""></span>Does CRT respond in real-time to increments in systemic blood flow? \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"><span class="elsevierStyleHsp" style=""></span>What is the impact of vasoactive agents on CRT? \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"><span class="elsevierStyleHsp" style=""></span>Does normalization of CRT after a fluid challenge predict the status of hemodynamic coherence between macrocirculation and regional/microcirculatory blood flow? \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2170274.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Main findings of the ANDROMEDA-SHOCK study and research agenda for CRT.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:11 [ 0 => array:3 [ "identificador" => "bib0060" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The holistic view on perfusion monitoring in septic shock" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G. 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