Clinical Research
Experimental rat model of chronic cerebral hypoperfusion–reperfusion mimicking normal perfusion pressure breakthrough phenomenon
Modelo experimental en rata de hipoperfusión cerebral crónica – reperfusión remedando el síndrome de restablecimiento de la presión de perfusión cerebral normal
Juan Manuel Revueltaa, Álvaro Zamarrónb, José Fortesc, Gregorio Rodríguez-Botoa, Jesús Vaqueroa, Raquel Gutiérrez-Gonzáleza,c,
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a Department of Neurosurgery, Puerta de Hierro University Hospital, Manuel de Falla 1, 28222 Majadahonda-Madrid, Spain
b Department of Neurosurgery, La Paz University Hospital, P° Castellana 261, 28046 Madrid, Spain
c Health Research Institute–Fundación Jiménez Díaz (IIS-FJD), Avda Reyes Católicos 2, 28040 Madrid, Spain
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"identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Neurosurgery, Puerta de Hierro University Hospital, Manuel de Falla 1, 28222 Majadahonda-Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Neurosurgery, La Paz University Hospital, P° Castellana 261, 28046 Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Health Research Institute–Fundación Jiménez Díaz (IIS-FJD), Avda Reyes Católicos 2, 28040 Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Modelo experimental en rata de hipoperfusión cerebral crónica – reperfusión remedando el síndrome de restablecimiento de la presión de perfusión cerebral normal" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 651 "Ancho" => 1500 "Tamanyo" => 59499 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Intracranial pressure measurement. (A) Left burr hole posterior to the coronal suture. (B) Intraparenchymal sensor implanted through the burr hole to measure ICP.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Normal perfusion pressure breakthrough (NPPB) theory was first described almost 4 decades ago.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">1</span></a> The complementary concept of “occlusive hyperemia” is now more than 20 years old.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">2</span></a> Despite the anatomical and physiological differences with humans, and also considering the difficulties that investigating such complex and infrequent phenomenon entails, experimental research continues being the main tool to advance in a better understanding of these phenomena.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">3–11</span></a> Moreover, the unpredictable development of massive brain swelling and/or hemorrhage following complete obliteration of intracranial arteriovenous malformations (AVMs) still remains a crucial complication that limits the treatment of complex AVMs.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">12</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The aim of this study is to develop a reliable experimental animal model that enables the reproduction of the preliminary state of chronic cerebral hypoperfusion that happens in the tissue that surrounds the AVM nidus due to a vascular steal phenomenon. That chronic hypoperfusion precedes the hemodynamic phenomena and the increased permeability of the blood–brain barrier (BBB) that occur in the NPPB phenomenon presumably due to autoregulatory imbalance.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">11</span></a> Thus, the model may help not only to consolidate concepts but also to test different therapies for the prevention and/or treatment of the disease.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><p id="par0015" class="elsevierStylePara elsevierViewall">An experimental model was designed. The study was approved by the hospital Animal Care and Use Committee (CEBA016/2012). The care and handling of the animals were performed in accordance with European Directive and National Regulations and Guidelines for Animal Research. Twenty male Wistar rats weighing 250–350<span class="elsevierStyleHsp" style=""></span>g were randomly distributed into 2 groups with 10 animals each.</p><p id="par0020" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Study group</span>: was formed by 10 rats that on day 0 underwent general anesthesia by means of intramuscular injection of ketamine 75<span class="elsevierStyleHsp" style=""></span>mg/kg<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>xylazine 12<span class="elsevierStyleHsp" style=""></span>mg/kg, with rescue dose of 1/3 when needed in order to achieve adequate anesthetic depth. Heart rate, mean arterial pressure (MAP) and temperature were initially registered. Likewise, a burr hole posterior to the coronal suture on the left side was performed for intracranial pressure (ICP) measuring (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">A midline anterior cervical approach was then performed under microscopic view. An extracranial end-to-side arteriovenous fistula was created between the rostral end of the left external jugular vein (EJV) and the left common carotid artery (CCA) with simple interrupted 10/0 monofilament suture (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Draining veins to the EJV unrelated to intracranial circulation were occluded with monopolar cautery. Afterwards, both external carotid arteries (ECAs) were ligated with 6/0 monofilament suture and the cranial and cervical wounds were closed with simple interrupted 3/0 silk suture.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Control group</span>: was formed by 10 rats that on day 0 underwent general anesthesia by means of intramuscular injection of ketamine 75<span class="elsevierStyleHsp" style=""></span>mg/kg<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>xylazine 12<span class="elsevierStyleHsp" style=""></span>mg/kg, with rescue dose of 1/3 when needed in order to achieve adequate anesthetic depth. Similarly, heart rate, MAP and temperature were registered and a burr hole posterior to the coronal suture on the left side was performed for ICP recording. A midline anterior cervical approach was performed under microscopic view. Dissection of the left EJV and CCA was performed and both ECAs were ligated with 6/0 monofilament suture. Afterwards, cranial and cervical wounds were closed with simple interrupted 3/0 silk suture.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Fistula permeability was corroborated on days 0, 7 and 60 of the experiment by doppler ultrasound exam (Mizuho 20<span class="elsevierStyleHsp" style=""></span>Hz surgical doppler system; Mizuho Medical Corporation, Tokyo, Japan).</p><p id="par0040" class="elsevierStylePara elsevierViewall">The replication of NPPB phenomenon was evaluated through hemodynamic, BBB integrity and histological assessment.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Hemodynamic measurement</span><p id="par0045" class="elsevierStylePara elsevierViewall">It was accomplished in all animals under general anesthesia by means of a non-invasive blood pressure measuring device (PanLab Harvard apparatus, Barcelona, Spain) and an intracranial catheter (Camino intraparenchymal sensor; Integra, New Jersey, USA – <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Measures were taken on day 0 (before and after fistula creation and/or ECAs ligation), day 7 and day 60. Cerebral perfusion pressure (CPP) was calculated from the difference between MAP and ICP. All parameters were compared between both cohorts.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Database information was processed and analyzed with statistical software Stata 15. Data were expressed as median (interquartile range). Mean arterial pressure, ICP and CPP values were analyzed using repeated-measures analysis of variance with general linear models routines. Considered level of significance was 5%.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">BBB permeability assessment</span><p id="par0055" class="elsevierStylePara elsevierViewall">The evaluation of the integrity of BBB was accomplished in 5 of the 10 rats from the study group and it was compared with the results obtained in 5 of the 10 rats from the control group. Qualitative evaluation of permeability to 10% sodium fluorescein was used for that purpose. Later, on day 60 of the experiment animals underwent general anesthesia with the protocol previously stated. Fistula occlusion was performed for 60<span class="elsevierStyleHsp" style=""></span>min in the study group. Then, all animals (both study and control groups) underwent transcarotid injection of 10% sodium fluorescein (0.6<span class="elsevierStyleHsp" style=""></span>ml/kg). Subsequently, a thoracotomy was performed to allow perfusion with saline solution through the left ventricle until complete clearance in the right ventricle was confirmed. Finally, euthanasia was held by decapitation and brain samples were obtained to assess extravasation of sodium fluorescein. Staining pattern was recorded by digital photography.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Histological assessment</span><p id="par0060" class="elsevierStylePara elsevierViewall">Light microscopy evaluation was accomplished in the remaining 5 rats from the study group and the results were compared with those obtained in the remaining 5 animals from the control group. Again, on day 60 of the experiment animals underwent general anesthesia. Rats from the study group underwent occlusion of the fistula for 60<span class="elsevierStyleHsp" style=""></span>min. All animals (both study and control groups) underwent transcardial perfusion with 4% paraformaldehyde solution in phosphate buffered saline and were euthanized. Brain samples were obtained and fixed in formalin, and finally they were paraffin-embedded for light microscopy evaluation. An independent observer analyzed the samples and described the pathological findings.</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><p id="par0065" class="elsevierStylePara elsevierViewall">A total of 31 animals were needed to achieve the experiment. Seven of them presented early mortality, 2 presented delayed mortality and 2 were excluded from the experiment when checking on day 7 that the fistula was not permeable. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> gathers the causes of mortality.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Both groups were homogeneous when comparing weight, temperature, heart rate, MAP, ICP and CPP before the beginning of the experiment (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Animals from the control group showed no neurological deficit. On the contrary, animals from the study group showed confusion and disorientation mainly in the first 24<span class="elsevierStyleHsp" style=""></span>h following the procedure. They also showed manifest difficulty for feeding and hydration issues, which was more pronounced during the first week and prevailed with less intensity during the 60 days that the experiment endured. Such difficulty was turned into a statistical significant loss of weight when compared with rats of the control group (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.004 at 60 days), but also when compared with their own weight at the beginning of the experiment (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.001 at 7 days).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">In addition to fistula permeability corroboration by Doppler ultrasound, surgical exploration on day 60 evidenced fistula patency in all cases, showing varicose, dilated and tortuous EJVs. Arterial hypoplasia was also observed in the CCA distal to the anastomosis (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Retrograde flow from the CCA to the anastomosed EJV was also confirmed.</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Hemodynamic measurement</span><p id="par0080" class="elsevierStylePara elsevierViewall">Arteriovenous fistula creation resulted in an early and significant drop of MAP (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001), which lasted as long as the experiment endured. Intracranial pressure values showed an upward trend in all measurements (early postop, and days 7 and 60 of the experiment) in the study group when compared with the control one. However, such differences did not reach statistical significance. Finally, CPP also showed an early and statistical significant drop that kept on during the whole experiment (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001; <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> gathers all changes observed in both groups and in all measurements performed.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">BBB permeability assessment</span><p id="par0085" class="elsevierStylePara elsevierViewall">A marked and homogeneous fluorescein extravasation was observed in both hemispheres of the 5 rat brains composing the study group after the restoration of normal CPP through the arteriovenous fistula occlusion 60 days after its creation. No staining was observed in the 5 rats from the control group (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Histological assessment</span><p id="par0090" class="elsevierStylePara elsevierViewall">Light microscopy evaluation (hematoxylin and eosin staining) evidenced more pronounced presence of pyknotic neurons in the left hemisphere (ipsilateral to the arteriovenous fistula) of the rats from the study group. Such finding was observed neither in the contralateral hemisphere nor in the rat brains from the control group.</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">This study develops a new experimental model of chronic cerebral hypoperfusion–reperfusion in association with venous hyperemia that mimics the main hemodynamic and BBB permeability features that occur in the NPPB phenomenon. The model is based on the creation of an end-to-side anastomosis, similar to that described in previous studies.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">8–10</span></a> It also adds bilateral ligation of ECAs in order to improve arterial flow redistribution through the fistula. The main difference from the aforementioned models<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">8–10</span></a> lies in the avoidance of occlusion of the contralateral intracranial draining veins (posterior facial vein, draining vein of the transverse sinus). The decision was held in order to avoid increased mortality of the animals since the procedure would require extended surgical time (which means higher doses and longer exposure to anesthesia). In some cases, vein ligation should be performed in a different fashion (24<span class="elsevierStyleHsp" style=""></span>h later), which involves a new procedure.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">10</span></a> Control animals (sham-operated group) underwent dissection of EJV, CCA and ligation of bilateral ECAs to prevent differences related to cervical sympathetic nerves manipulation.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Even then, the number of rats excluded from the study due to early mortality was high at the beginning of the experiment. The most frequent cause was the difficulty to achieve correct feeding and hydration of study animals after the surgical procedure. Even though fistula formation did not involve explicit focal neurologic signs, it explains the presence of disorientation and/or confusion that was more pronounced during the first 24–48<span class="elsevierStyleHsp" style=""></span>h following the procedure and that hindered proper feeding of the rats despite close and exhaustive supervision of caregivers. Although disorientation almost completely disappeared one week after fistula formation, one rat died belatedly due to this same cause. Significant blood loss during the surgical procedure caused the death of 1 animal. Finally, 2 rats did not wake up from anesthesia in spite of keeping stable vital signs during the whole procedure. Intracranial pressure measurement on day 7 of the experiment entailed general anesthesia since intraparenchymal sensor placement in the conscious rat could cause non-experiment-related neurological damage or even the death of the rat. One animal did not wake up from anesthesia administered on day 7 for that purpose. Additionally, measurement of hemodynamic parameters in the anesthetized rat in every case (days 0, 7 and 60) homogenized baseline conditions of the animals and allowed more reliability when comparing results.</p><p id="par0105" class="elsevierStylePara elsevierViewall">Surgical exploration of the fistula prior to its occlusion on day 60 in the study rats showed varicose and dilated veins in every case (a finding that was expected when dealing with low resistance vessels with high flow). The increase in vein diameter has been also observed in different but comparable models.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">9,10</span></a> This change was accompanied by an evident reduced caliber of the CCA in its distal segment to the anastomosis, a finding that supports the attainment of the attempted cerebral hypoperfusion condition but that has not been described in other comparable rat models up to date.</p><p id="par0110" class="elsevierStylePara elsevierViewall">Hemodynamic results showed a significant drop in MAP following fistula creation in the study group, which may turn into a drop in intracranial arterial pressure. In this model, ICP was directly measured by means of an intraparenchymal sensor. In our opinion, this method reflects in a more reliable fashion any pressure change that may occur in the brain of the rats. This is the first model that discards indirect venous pressure measurement (torcula, transverse sinus, jugular vein)<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">5,8,9</span></a> and replaces it by a real intraparenchymal value. Venous ectasia or hyperemia achieved by means of the diversion of arterial high flow through the anastomosis to the EJV would explain the increase in ICP value in the study rats following fistula creation. However, statistical analysis did not reached significance, a fact that may be explained by the small sample size, since we have confirmed significant increased ICP values in ulterior studies (unpublished data). However, it must be considered that other rat models achieve venous intracranial congestion (and therefore increased ICP) by ligating contralateral intracranial draining veins, as aforementioned.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">8,10</span></a> In any case, a significant drop in CPP was confirmed in the study rats, and it was maintained along the whole experiment, a distinctive feature that has not been described before in other models.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">8,10</span></a> Moreover, the descent was also significant when comparing study rats with themselves preoperatively, a fact that correlates with the attempted state of chronic cerebral hypoperfusion. This model is therefore able to recreate a hemodynamic condition of arterial hypoperfusion and congestive venous hyperemia that would mimic the so-called “vascular steal” phenomenon that AVMs provoke due to flow redistribution toward the nidus (and that implies a decrease in regional cerebral blood flow of the viable parenchyma surrounding the nidus).<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">11</span></a> This is the previous condition to simulate the NPPB phenomenon that occurs after fistula closure, which would resemble AVM excision. Further studies registering these hemodynamic parameters after fistula closure are needed.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Most rat models of chronic cerebral hypoperfusion have detailed hemodynamic changes but have not assessed BBB permeability. Only Hai et al. described BBB disruption after fistula occlusion, which was confirmed by dye extravasation and brain water content rise.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">8</span></a> The comparison of rat brains after transcarotid infusion (ipsilateral to the fistula) of sodium fluorescein in our model showed a homogeneous, bilateral and marked extravasation of the dye in the study animals that was absent in all control animals. Even though other authors have used other molecules to identify the rupture or increased permeability of BBB, such as Evans blue dye,<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">8,13</span></a> the usefulness of sodium fluorescein is also well-documented.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">14,15</span></a> We chose sodium fluorescein since its systemic distribution to peripheral organs (eyes, liver, skin) after injection allows easy identification of mistakes during administration technique, what prevents drawing wrong conclusions.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Finally, neither foci of edema nor hemorrhage were observed. Otherwise, the presence of pyknotic neurons in the ipsilateral brain hemisphere to the arteriovenous fistula was the main finding in histological exams. This may indicate ischemic damage, but further techniques are needed to confirm this point. Specific studies in a comparable model have shown an increased percentage of apoptotic cells in the rat brains (ipsilateral hemisphere) following occlusion of the fistula, which was only significant at 12–72<span class="elsevierStyleHsp" style=""></span>h after reperfusion (peaked at 24<span class="elsevierStyleHsp" style=""></span>h). Electron microscopy confirmed apoptosis and TUNEL staining was also positive during the same period following reperfusion in the same study.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">16</span></a> These findings would support neuronal damage due to reperfusion or ischemic injury after restoration of normal perfusion pressure in a chronic cerebral hypoperfusion model, and could mean the primary neurophysiological mechanism before edema and hemorrhage occur.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conclusion</span><p id="par0125" class="elsevierStylePara elsevierViewall">The formation of an arteriovenous fistula resulted in an immediate and significant decrease of MAP and CPP, which endured throughout the whole experiment. An increase in ICP was also observed. However, it did not reach statistical significance.</p><p id="par0130" class="elsevierStylePara elsevierViewall">The disturbance of BBB permeability was also verified in all cases after restoration of normal CPP through a marked and homogenous extravasation of sodium fluorescein in both hemispheres of rat brains.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Histological exam showed a clear increase in the number of pyknotic neurons in the left hemisphere. Even though this finding may denote ischemic damage, it is an unspecific fact itself and complementary techniques, such as TUNEL or electronic microscopy, are needed for a better evaluation.</p><p id="par0140" class="elsevierStylePara elsevierViewall">The results obtained from this study note a basic but useful experimental model that reproduces the essential features of AVMs in humans (chronic cerebral hypoperfusion and intracranial hypertension due to venous congestion). Moreover, they point that fistula occlusion is able to reproduce NPPB phenomenon. This model may result therefore useful to test different therapies for prevention and/or treatment of NPPB syndrome that complicates the treatment of complex intracranial AVMs in humans.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding</span><p id="par0145" class="elsevierStylePara elsevierViewall">This work was supported by the <span class="elsevierStyleGrantSponsor" id="gs1">Spanish Ministries of Economy and Competitiveness in collaboration with the European Regional Development Fund (FEDER)</span> [grant number <span class="elsevierStyleGrantNumber" refid="gs1">PI 12/02901</span>].</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflict of interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">None.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1378470" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1266312" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec1266310" "titulo" => "Abbreviations" ] 3 => array:3 [ "identificador" => "xres1378469" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec1266311" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Hemodynamic measurement" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "BBB permeability assessment" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Histological assessment" ] ] ] 7 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Hemodynamic measurement" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "BBB permeability assessment" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Histological assessment" ] ] ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusion" ] 10 => array:2 [ "identificador" => "sec0060" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of interest" ] 12 => array:2 [ "identificador" => "xack479021" "titulo" => "Acknowledgements" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-09-28" "fechaAceptado" => "2019-11-13" "PalabrasClave" => array:2 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1266312" "palabras" => array:5 [ 0 => "Arteriovenous malformation" 1 => "Experimental" 2 => "Model" 3 => "Normal perfusion pressure breakthrough" 4 => "Research" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1266310" "palabras" => array:9 [ 0 => "NPPB" 1 => "AVM" 2 => "BBB" 3 => "MAP" 4 => "ICP" 5 => "EJV" 6 => "CCA" 7 => "ECA" 8 => "CPP" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1266311" "palabras" => array:5 [ 0 => "Experimental" 1 => "Investigación" 2 => "Malformación arteriovenosa" 3 => "Modelo" 4 => "Presión de perfusión cerebral" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Normal perfusion pressure breakthrough (NPPB) phenomenon is a major life-threatening complication that restricts the treatment of complex intracranial arteriovenous malformations. The aim of the study it to develop a rat model mimicking NPPB phenomenon that enables the evaluation of any therapy to prevent such complication.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Twenty Wistar male rats were randomly assigned to either a study or a control group. Study animals underwent an end-to-side left external jugular vein-common carotid artery anastomosis and ligation of bilateral external carotid arteries. Control animals only underwent ligation of bilateral external carotid arteries. All animals were sacrificed sixty days after the procedure. Hemodynamic parameters [mean arterial pressure (MAP), intracranial pressure (ICP) and cerebral perfusion pressure (CPP)], blood–brain barrier (BBB) permeability (measured by fluorescein staining) and histological features were then compared between both groups.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A significant decrease in MAP and CPP was confirmed in the study group. An increase in ICP was also observed. A significant decrease in MAP and CPP was also present in the study group when comparing preoperative values with those recorded on days 0 (postoperative), 7 and 60. Fluorescein staining findings were consistent with signs of BBB disruption in study animals. Histological analysis demonstrated an increased number of pyknotic neurons in the ipsilateral hemisphere of rat brains included in the study group.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">These results confirm that this model mimics a vascular steal state with chronic cerebral hypoperfusion comparable to patients with AVMs behavior and disruption of the BBB after fistula closure comparable to NPPB phenomenon disorders.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El síndrome de restablecimiento de la presión de perfusión cerebral (PPC) normal es una complicación grave, que supone un riesgo vital y limita el tratamiento de malformaciones arteriovenosas complejas. El objetivo de este estudio es desarrollar un modelo animal remedando dicho síndrome que permita evaluar terapias para su prevención.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Veinte ratas macho Wistar fueron asignadas aleatoriamente a un grupo estudio o control. Los animales de estudio se sometieron a una anastomosis término-lateral entre la vena yugular externa y la arteria carótida común izquierdas y ligadura bilateral de las arterias carótidas externas. Los animales control se sometieron a la ligadura bilateral de las arterias carótidas externas. Todos los animales se sacrificaron 60 días después. Se compararon parámetros hemodinámicos (presión arterial media [PAM], presión intracraneal [PIC] y PPC), permeabilidad de la barrera hemato-encefálica (BHE) y características histológicas entre ambos grupos.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El grupo estudio mostró un descenso significativo de la PAM y la PPC, así como un aumento de la PIC respecto al grupo control. Al comparar los valores preoperatorios con aquéllos registrados los días 0 (postoperatorio), 7 y 60 en el grupo estudio, también se confirmó un descenso significativo de la PAM y la PPC. La disrupción de la BHE fue constatada únicamente en el grupo estudio mediante la extravasación de fluoresceína sódica. El análisis histológico demostró mayor número de neuronas picnóticas en el hemisferio ipsilateral a la anastomosis de los animales estudio.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusión</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los resultados descritos apuntan a un modelo que remeda el estado de robo vascular con hipoperfusión cerebral crónica comparable al que sufren los pacientes con malformaciones arteriovenosas, así como la disrupción de la BHE tras el cierre de la anastomosis, comparable al acontecido en el síndrome de restablecimiento de la PPC normal tras la exclusión de la malformación.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 651 "Ancho" => 1500 "Tamanyo" => 59499 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Intracranial pressure measurement. (A) Left burr hole posterior to the coronal suture. (B) Intraparenchymal sensor implanted through the burr hole to measure ICP.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1298 "Ancho" => 1500 "Tamanyo" => 218960 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Arteriovenous fistula. (A) Rostral end of the left EJV anastomoses laterally to the left CCA. (B) End-to-side anastomosis before vascular clips removal. (C) Early postoperative view of the arteriovenous fistula and ipsilateral ECA ligation. (D) Delayed postoperative view of the fistula on day 60, prior to its occlusion. The vein is varicose and tortuous, and CCA is hypoplastic in its distal segment to the anastomosis (arrow).</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 832 "Ancho" => 3167 "Tamanyo" => 240002 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Comparison of hemodynamic measurements. (A) Comparison of MAP between study and control groups (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.009). (B) Comparison of ICP between study and control groups (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.343). (C) Comparison of CPP between study and control groups (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.004).</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 914 "Ancho" => 750 "Tamanyo" => 79757 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Blood–brain barrier disruption. (A) Rat brain from the study group. Sodium fluorescein staining is evidenced. (B) Rat brain from the control group. No staining is evidenced following fluorescein perfusion.</p>" ] ] 4 => 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: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">Cause of death \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Early (<48<span class="elsevierStyleHsp" style=""></span>h) \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Delayed (7–30 days) \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">Anesthesia \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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">Intraoperative loss of blood volume \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \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">Severe loss of weight \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2367042.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Causes of mortality.</p>" ] ] 5 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Values expressed as median (IQR).</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study group \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Control group \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span> value \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" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Day 0, preop.</span></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>Weight (g) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">320 (295–330) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">327.5 (310–335) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.413 \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>Temperature (°C) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35.05 (34.4–35.5) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34.4 (34–35.7) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.633 \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>Heart rate (bpm) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">403.5 (372–414) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">387.5 (342–402) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.105 \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>MAP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">114 (106–123) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">124 (113–130) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.436 \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>ICP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (11–15) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.5 (10–15) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.465 \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>CPP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">101 (93–113) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">110 (100–112) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.444 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Day 0, postop.</span></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>Temperature (°C) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32.8 (32.2–33) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33.1 (32.3–33.9) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.338 \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>Heart rate (bpm) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">376 (324–410) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">378 (343–421) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.132 \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>MAP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">91 (76–108) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">117 (108–134) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.001</span><a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \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>ICP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 (13–16) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (11–15) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.343 \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>CPP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77 (63–88) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">106 (97–119) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold"><0.001</span><a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Day 7</span></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>Weight (g) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">292.5 (285–300) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">315 (305–335) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.083<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \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>Temperature (°C) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35.35 (35–35.8) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35.15 (34.9–35.7) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.824 \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>Heart rate (bpm) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">364 (312–388) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">406 (344–427) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.008</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>MAP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">85 (82–97) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">112.5 (107–117) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.028</span><a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \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>ICP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.5 (12–14) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 (9–12) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.416 \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>CPP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">74 (70–82) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">103.5 (95–108) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.015</span><a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Day 60</span></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>Weight (g) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">307.5 (290–325) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">452.5 (430–480) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><<span class="elsevierStyleBold">0.001</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>Temperature (°C) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35 (34.3–35.3) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34.75 (34.6–35.1) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.858 \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>Heart rate (bpm) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">380 (366–397) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">366 (360–401) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.121 \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>MAP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">87.5 (85–93) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">113.5 (109–119) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.009</span><a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \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>ICP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.5 (11–13) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9.5 (8–11) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.343 \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>CPP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">76.5 (72–82) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">102 (97–111) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.004</span><a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2367043.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "<p class="elsevierStyleNotepara" id="npar0005"><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>0.001, comparing day<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>postoperatively in the study group with regard to day 0 preoperatively in the same group.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Comparison between study and control groups. Hemodynamic parameters.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0085" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Normal perfusion pressure breakthrough theory" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R.F. Spetzler" 1 => "C.B. Wilson" 2 => "P. Weinstein" 3 => "M. Mehdorn" 4 => "J. Townsend" 5 => "D. 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Baines" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3171/jns.1987.66.4.0563" "Revista" => array:6 [ "tituloSerie" => "J Neurosurg" "fecha" => "1987" "volumen" => "66" "paginaInicial" => "563" "paginaFinal" => "567" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3559722" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0100" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A model of the pathophysiology of cerebral arteriovenous malformations by a carotid jugular fistula in the rat" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.K. Morgan" 1 => "R.E. Anderson" 2 => "T.M. Sundt" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0006-8993(89)91071-8" "Revista" => array:6 [ "tituloSerie" => "Brain Res" "fecha" => "1989" "volumen" => "496" "paginaInicial" => "241" "paginaFinal" => "250" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2804633" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0105" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intracranial venous hypertension and the effects of venous outflow obstruction in a rat model of arteriovenous fistula" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J.B. Bederson" 1 => "O.D. Wiestler" 2 => "O. Bruestle" 3 => "P. Roth" 4 => "R. Frick" 5 => "M.G. 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