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Fluid therapy and traumatic brain injury: A narrative review
Fluidoterapia y daño cerebral traumático: una revisión narrativa
Eduardo Esteban-Zuberoa,
Corresponding author
eezubero@gmail.com

Corresponding author.
, Cristina García-Murob, Moisés Alejandro Alatorre-Jiménezc
a Emergency Department, Hospital San Pedro, Logroño, Spain
b Department of Pediatrics, Hospital San Pedro, Logroño, Spain
c Department of Pediatric Gastroenterology, Children's Mercy Hospital, Kansas City, USA
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Traumatic brain injury &#40;TBI&#41; is a major public health problem and a significant cause of death and disability&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> The damage may be divided into two phases&#58; &#40;a&#41; a primary acute injury because of the traumatic event&#59; and &#40;b&#41; a secondary injury due to the hypotension and hypoxia generated by the previous lesion&#44; which leads to ischemia and necrosis of neural cells&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In middle-aged patients&#44; trauma is the leading cause of death&#44; with TBI responsible for most of these&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> In the United States&#44; this pathology causes 275&#44;000 hospitalizations and 52&#44;000 deaths per year as a related factor in more than 30&#37; of all injury-related deaths&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">3</span></a> The relevance of this pathology is also related to the sequelae&#44; generating an economic impact of over &#36;80 billion in the United States&#46; This data is also associated with the clinical stratification of TBI&#44; beginning from 10&#37; &#40;mild TBI&#41;&#44; 60&#37; &#40;moderate TBI&#41;&#44; and 100&#37; &#40;severe TBI&#41;&#44; according to Glasgow Coma Scale Score &#40;GCS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">According to the literature&#44; TBI studies are mainly categorized based on physical examination instead of the underlying cause&#46; This way of stratification catalogs TBI as a neurological condition without a relationship with a pathology&#46; This association is the key to understanding why several clinical trials have not achieved significant results&#46; This situation is not observed in general guidelines&#44; such as &#8220;chest pain&#8221;&#46; This symptomatology results from different pathologies with well-known management guidelines&#44; such as myocardial infarction&#44; pneumonia&#44; and aortic dissection&#46; Attending to TBI&#44; the underlying pathology may be unclear&#44; without a clear treatment &#40;diffuse swelling&#44; ischemia&#44; blossoming contusion&#44; etc&#46;&#41;&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Therefore&#44; the patient evaluation and management of TBI in the Emergency Department and Urgent Cares is critical&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">5</span></a> The first approach&#39;s main goal should be to avoid secondary brain injury&#46; It has been observed that secondary insults such as systolic blood pressure lower<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>90<span class="elsevierStyleHsp" style=""></span>mmHg or SpO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>92&#37; in moderate and severe TBI patients increase mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> Due to the relevance of maintaining correct brain oxygenation&#44; some authors discuss the benefits of delayed patient transfer to a hospital due to complicated intubation&#46; In this line&#44; a study observed that prehospital rapid sequence intubation performed by paramedics in head-injured patients with GCS<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>9 was associated with an increase in mortality&#46; This result may be related to the transient hypoxia during the prehospital procedures&#44; excessive over-ventilation causing hypocapnia&#44; vasoconstriction&#44; impaired cerebral blood flow &#40;CBF&#41;&#44; and longer scene times&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">7</span></a> This study concludes that rapid transfer and more basic airway strategies to maintain oxygenation in head-injured patients improve the results&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Fluid therapy &#40;FT&#41; also plays an essential role in the early management of TBI&#46; This therapy is required to &#40;a&#41; Normal maintenance&#59; &#40;b&#41; Blood or fluid loss due to wounds&#44; drains&#44; induced diuresis&#44; etc&#46;&#59; &#40;c&#41; Third space losses called fluid sequestration in tissue edema or ileus&#59; and &#40;d&#41; Increased systemic requirements resulting from fever and hypermetabolic state&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a> Consequently&#44; rapid infusion as quickly as possible of large volumes of crystalloids is performed in daily practice&#44; usually an empirical approach due to the lack of studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">A search for studies on fluid therapy and traumatic brain injury up to October 2022 was performed in the databases PubMed &#40;MEDLINE&#44; Cochrane Library&#41;&#44; Web of Science &#40;WoS&#41;&#44; and Scopus&#46; A combination of Medical Subjects Headings &#40;MeSH&#41; and free-text terms were used as a search strategy for each database&#46; The searched terms were&#58; &#40;&#8220;fluid therapy&#8221; &#91;MeSH Terms&#93; AND &#8220;traumatic&#8221; &#91;MeSH Terms&#93;&#41; AND &#40;&#8220;brain injury&#8221; &#91;MeSH Terms&#93;&#41;&#46; The inclusion criteria were studies with traumatic brain injury patients&#44; with any date or publication language&#46; The exclusion criteria were&#58; &#40;a&#41; articles with a relevant risk of bias&#44; &#40;b&#41; articles without clinical data&#44; and &#40;c&#41; studies with non-usable data&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Pathophysiology of traumatic brain injury</span><p id="par0035" class="elsevierStylePara elsevierViewall">Brain parenchyma &#40;80&#37;&#41;&#44; cerebrospinal fluid &#40;CSF&#41; &#40;10&#37;&#41;&#44; and cerebral blood volume &#40;CBV&#41; compose the three compartments of the cranium&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> The main characteristic is the equilibrium among them&#44; regulating the intracranial pressure &#40;ICP&#41; in adults &#40;10<span class="elsevierStyleHsp" style=""></span>mmHg&#41; and children &#40;7<span class="elsevierStyleHsp" style=""></span>mmHg&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">As we commented previously&#44; the pathophysiology of TBI involves a complex cascade of events that could be divided into two different phases&#46; The first one is a primary acute injury because of the traumatic event&#46; Secondary damage occurs after the first lesion when alterations in CBF&#44; cerebral oxygen delivery&#44; inflammation&#44; and cellular metabolism lead to ischemia and necrosis of neural cells&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> An inflammatory response is generated after the acute injury&#46; However&#44; if this situation is maintained&#44; it develops cerebral edema&#44; leak of oxygen delivery&#44; ischemia&#44; and necrosis of cells&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> Therefore&#44; cerebral edema is a marker of evolving injury in TBI and is the consequence of disrupting the blood-brain barrier &#40;BBB&#41; and lymphatic drainage disruption&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Cytotoxic and vasogenic edema are the main types of edema observed in TBI&#46; The first one promotes the accumulation of intracellular water in cerebral cells&#44; hypoxia&#44; and ischemia&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">12</span></a> On the other hand&#44; vasogenic edema results from cerebral blood vessels disruption&#44; causing a breakdown of the BBB and increasing leakage into the extravascular interstitial space&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">10&#44;12</span></a> As a response to cerebral edema&#44; intracranial volume increases&#46; However&#44; ICP suffers minimal variations due to vasoconstriction and the shunting of CSF &#40;compensatory phase&#41;&#46; If edema persists&#44; these regulatory mechanisms fail&#44; promoting intracranial hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">13</span></a> This state results from a reduction in CBF of oxygen&#44; glucose&#44; and essential substrates&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">14</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">TBI is not only defined as the increase of intracranial pressure&#46; In severe TBI&#44; other pathophysiologic states could be observed&#44; including hypovolemia and hypotension&#46; Therefore&#44; it is essential to measure the blood flow gradient&#44; defined as cerebral perfusion pressure &#40;CPP&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a> CPP is defined as the difference between mean arterial pressure &#40;MAP&#41; and ICP &#40;CPP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>MAP<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>ICP&#41;&#46; It could be concluded that systemic hypotension implies a decrease of CPP value&#8212;hemorrhage&#44; third-space fluid losses&#44; and vasoplegia that can develop hypotension&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">16</span></a> It is recommended to maintain CPP values<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>70<span class="elsevierStyleHsp" style=""></span>mmHg in adult patients&#46; In contrast&#44; in the pediatric age group&#44; due to the broad age range&#44; it is recommended to aim CPP<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>40&#8211;65<span class="elsevierStyleHsp" style=""></span>mmHg as an age-related continuum for the optimal treatment threshold&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">17</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Support treatment in TBI aims to enhance CPP&#44; improve cerebral perfusion&#44; and reduce the degree of brain injury&#46; To achieve these results&#44; non-invasive techniques could be performed&#44; including the elevation of the head of the bed with the head in midline position and maintenance of normothermia&#46; If this treatment fails&#44; pain and sedation medications&#44; mechanical ventilation&#44; neuromuscular blockade&#44; and controlled hyperventilation should be initiated&#46; Instead of this&#44; euvolemia is the goal during resuscitation of TBI&#44; being necessary to administrate FT and inotropic medications&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Fluid therapy and traumatic brain injury</span><p id="par0060" class="elsevierStylePara elsevierViewall">The Brain Trauma Foundation &#40;BTF&#41; and the Lund Concept are the primary organisms that develop guidelines recommendations for TBI treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> Both documents have in common the lack of a strong recommendation about which FT is recommended to use in TBI&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">20</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Prior to the review of the different FT types&#44; it is important to remark the relevance of vigorous resuscitation to achieve the goal of systolic blood pressure between 90 and 110<span class="elsevierStyleHsp" style=""></span>mmHg&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> The dose-dependent relation between hypotension and irreversible brain damage has been observed&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> It is known that TBI is usually related to hemorrhage&#44; usually observed after a delay in bleeding control after normotensive resuscitation was not successful&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">22</span></a> The authors conclude that hypotension is not recommended in TBI patients&#46; However&#44; hemorrhage control usually does not provide the patient&#39;s survival&#44; being necessary to explore this field to improve the outcomes&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Crystalloids</span><p id="par0070" class="elsevierStylePara elsevierViewall">This type of FT contains small water-soluble molecules&#44; being easier to cross the semi-permeable membranes&#46; The osmolarity is similar to plasma&#44; and its sodium levels affect the distribution among the body compartments&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">23</span></a> The extracellular fluid compartment &#40;ECF&#41; contains 75&#37; of interstitial fluid&#46; It implies that 3&#8211;4<span class="elsevierStyleHsp" style=""></span>l of crystalloids are required to replace 1<span class="elsevierStyleHsp" style=""></span>l of blood loss&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">24</span></a> These values are affected by the patient&#39;s status &#40;normovolemic or hypovolaemic&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Frequently used in prehospital admission&#44; no benefits in survival outcomes have been observed&#44; including aggressive resuscitation in hemorrhagic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">26</span></a> As a result&#44; recent studies suggested that transfusion of red blood cells&#44; plasma&#44; and platelets &#40;ratio 1&#58;1&#58;1&#41; is better than crystalloids due to the diminished risk of hemodilution&#44; brain edema&#44; and inflammation secondary to a large volume of fluids&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">27</span></a> Ko et al&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">28</span></a> agree with observing an increase in mortality in patients that received &#8805;2<span class="elsevierStyleHsp" style=""></span>L during resuscitation compared to those who received less&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The osmolarity of crystalloids is possible to divide this solution into isotonic&#44; hypotonic&#44; and hypertonic&#46; Isotonic solutions include normal saline&#44; Ringer&#39;s solution&#44; or plasmalyte&#46; These three types of fluids do not affect the brain water content&#44; being distributed easier in the ECF and intracellular fluid compartment &#40;ICF&#41;&#46; However&#44; the most frequently used solution &#40;Ringer&#41; has a lower osmolarity &#40;254<span class="elsevierStyleHsp" style=""></span>mOsm&#47;L compared to 300<span class="elsevierStyleHsp" style=""></span>mOsm&#47;L of the gold standard isotonic solution&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> This difference explains why large volumes of Ringer could generate brain edema due to increased ICP&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a> Consequently&#44; the use of hypotonic solutions does not have sense and must be avoided&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">A different type of crystalloid fluid is hypertonic saline &#40;HTS&#41;&#46; This treatment is primarily used in patients with elevated ICP due to TBI due to its effect in a small volume during resuscitation&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">30&#44;31</span></a> It has been suggested that the beneficial effects of HTS are due to its capability to modulate the innate immune response&#44; especially the neutrophil burst activity&#46; Therefore&#44; an improvement in cardiovascular output and cerebral oxygenation is observed&#44; reducing cerebral edema&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a> However&#44; in clinical practice&#44; these theories are not entirely supported in patients affected by TBI or hemorrhagic shock&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">33</span></a> One of the largest clinical trials evaluating the neurological outcomes after six months of TBI and mortality rate after 28 days of the event did not observe any benefits&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">33</span></a> These results agree with a later study of the same group&#44; being necessary to stop the study due to an increase of mortality in a subgroup of patients treated with HTS but not blood transfusion in the first 24<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a> However&#44; in the literature are also observed positive results using hypertonic saline-dextran solution &#40;HSD&#41; in patients presented with hypotension&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a> These authors observed an increase in survival compared to regular treatment&#46; Rockswold et al&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">36</span></a> also agree with these results&#44; monitoring a decrease of ICP and increase of CPP and brain oxygenation in patients affected by severe TBI&#44; especially those affected with higher baseline ICP and lower CPP levels&#46; In conclusion&#44; HTS is recommended in TBI patients without conferring a survival benefit in a general manner&#46; However&#44; in patients with intracranial hypertension&#44; its benefits are higher than isotonic crystalloid solutions&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Synthetic colloids</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Gelatins</span><p id="par0090" class="elsevierStylePara elsevierViewall">This semi-synthetic colloid is not used in daily practice since it has a high risk of anaphylactic reactions&#44; especially in rapid infusions&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">25&#44;37</span></a> Gelatin preparations have a low molecular mass range and a mean molecular weight of 30&#8211;35<span class="elsevierStyleHsp" style=""></span>kDa&#46; One of their most important characteristics is their rapid renal excretion &#40;80&#37; molecules<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>kDa&#41;&#44; increasing the risk of dehydration if the adequate crystalloid infusion is not administered&#46; In addition&#44; their intravascular persistence is short &#40;2&#8211;3<span class="elsevierStyleHsp" style=""></span>h&#41;&#44; especially in the urea-linked gelatins&#46; Due to the negative charges contained in their molecules&#44; chloride concentrations are lower compared to other colloids&#46; Consequently&#44; intracellular edema could be increased if large amounts of fluids are provided due to its hyposmolality&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Dextranes</span><p id="par0095" class="elsevierStylePara elsevierViewall">Derived from the action of the bacterium Leuconostoc mesenteroides and mediate via the dextran sucrose enzyme&#44; they are neutral&#44; high-molecular-weight glucopolysaccharides based on glucose monomers&#46; Its excretion is mainly via the kidneys &#40;70&#37;&#41;&#46; Different molecules are produced in the hydrolysis grade&#44; being the main characteristic of its capacity as a plasma expander&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> Blood flow improvement results from a reduction in blood viscosity&#46; In addition&#44; dextrans inhibit platelet adhesiveness&#44; enhances fibrinolysis and reduces factor VIII activity&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Modern solutions do not affect blood crossmatching or cause rouleaux formation as previously&#46; However&#44; they may generate renal dysfunction via tubular obstruction&#44; especially in renal insufficiency and hypovolaemia patients&#46; As gelatins&#44; severe anaphylactic reactions like immune complex type III can result from prior cross-immunization against bacterial antigens forming dextran reactive antibodies&#46; However&#44; the incidence is low&#44; especially if monovalent hapten pre-treatment is administered &#40;injection of 3<span class="elsevierStyleHsp" style=""></span>g dextran 1&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Hydroxyethyl-starch &#40;HES&#41;</span><p id="par0105" class="elsevierStylePara elsevierViewall">HES is a semi-synthetic colloid prepared from amylopectin&#44; a glucose polymer derivative&#46; Its viscosity is lower than dextran or gelatin but does not reach the low viscosity of albumin&#46; The mean molecular weight of the different HES preparations ranges from 70 and 670<span class="elsevierStyleHsp" style=""></span>kDa&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">The kinetics of this degradation is determined by the molar substitution and the C2&#47;C6 ratio representing the quotient of the numbers of glucose residues hydroxyethylated at positions 2 and 6&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> Consequently&#44; its intravascular half-life is observed if a high molar substitution and a high C2&#47;C6 ratio are generated&#44; making the HES molecule less susceptible to plasma amylase&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">HES activity is also characterized by its capacity to decrease plug capillary induced by sepsis and major trauma and restore macrophage function after hemorrhagic shock&#46; Compared with 20&#37; albumin in these patients&#44; 10&#37; HES significantly improves hemodynamic parameters in the systemic and microcirculation&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">38</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Like previously commented synthetic colloids&#44; the main problem of HES is its increased risk of acute kidney injury&#46; In the literature are few studies of its benefits in TBI&#46; In a single-center retrospective cohort study of 171 people with severe TBI&#44; 78&#37; of patients received 6&#37; HES 200&#47;0&#46;5 during hospitalization&#46; There was no association with mortality&#44; change in serum creatinine&#44; or establishment of renal injury&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">39</span></a> Another study performed in 7000 patients admitted in the Intensive Care Unit revealed no significant difference in 90-day mortality between patients resuscitated with 6&#37; HES &#40;130&#47;0&#46;4&#41; or saline&#46; However&#44; an increased risk of renal-replacement therapy was observed in patients who received HES treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">40</span></a></p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Natural colloids</span><p id="par0125" class="elsevierStylePara elsevierViewall">The main characteristic of colloids is their difficulty crossing semi-permeable membranes due to their larger and more insoluble molecules&#46; The molecular weight&#44; shape&#44; ionic charge&#44; and capillary permeability determine their movement out of the intravascular space and their duration of action&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a> Due to its higher osmolality&#44; colloids increase plasma volume in a higher ratio than the volume infused&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">38</span></a></p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Albumin</span><p id="par0130" class="elsevierStylePara elsevierViewall">Albumin is one of the most used colloids&#44; being an effective volume expander without allergic-type reactions and no intrinsic effects on clotting&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">42</span></a> The literature reveals contradictory results comparing albumin with different fluid therapies&#46; A study compared 4&#37; albumin with 0&#46;9&#37; sodium chloride for resuscitation in patients affected by hemorrhagic shock&#46; In the subpopulation of TBI patients&#44; higher mortality was observed in patients treated with albumin&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">18</span></a> This result can be supported by the increased risk of brain edema&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">43</span></a> However&#44; these results do not agree with a previous study performed by Tomita et al&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">44</span></a> Compared to synthetic colloids&#44; increased survival has not been observed&#44; dismissing its use in clinical practice due to its higher costs&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">45</span></a> The Lund Concept recommendations continue to support the use of 4&#37; albumin<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">20</span></a> in spite of the evidence of harm&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">42&#44;43</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Plasma products</span><p id="par0135" class="elsevierStylePara elsevierViewall">It is observed that high ratios of fresh frozen plasma &#40;FFP&#41; added to packed red blood cells results in an increased ratio of survival compared to massive transfusion&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">46</span></a> It could be due to the complications associated with the large volume of crystalloid required during resuscitation and its protective effect on the endothelium and endothelial glycocalyx layer and BBB&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">47</span></a> In the literature&#44; there are few studies about the empirical use of FFP in patients affected by severe TBI&#46; However&#44; their results revealed an increased risk of delayed traumatic intracerebral hematoma formation than 0&#46;9&#37; sodium chloride&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">48&#44;49</span></a> Regarding mortality&#44; Zhang et al&#46; did not observe significant differences&#44; observing an increased rate in blood transfusions and coagulopathy in patients treated with FFP&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">49</span></a> However&#44; the study performed by Etemadrezaie et al&#46; revealed contradictory results&#44; observing a decreased ratio of surveillance without differences in coagulopathy in patients treated with FFP&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">48</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">The administration of plasma has also been studied in a ratio of 1&#58;1&#58;1 &#40;FFP&#58; packed red blood cells&#58; platelet&#41; compared to non-ratio&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">50</span></a> Patients treated with a ratio-based resuscitation had significantly lower mortality than those who did not&#44; and crystalloid administration was associated with increased odds of death&#46; In addition&#44; it was not observed an increased risk of neurosurgical intervention and intracranial hemorrhage&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Chang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">51</span></a> evaluated the benefits of early plasma transfusion during resuscitation in patients affected by TBI without polytrauma or intracranial hemorrhage&#46; The authors observed that early plasma transfusion increased survival in patients affected by multifocal intracranial hemorrhage&#46; However&#44; this study divided the patients into different subgroups attending the brain lesion&#44; observing significant differences between them&#44; making it difficult to achieve a conclusion&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">The benefits of FFP added to standard care have also been observed in patients affected by TBI and transferred by air from the accident scene to the Emergency Department&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a> Their results revealed an improvement of 30-day survival in patients treated with FFP&#46; In addition&#44; these patients received less crystalloid fluid&#44; vasopressors&#44; and packed red blood cells in the first 24<span class="elsevierStyleHsp" style=""></span>h&#44; had lower international normalized ratios&#44; lower 24<span class="elsevierStyleHsp" style=""></span>h mortality&#44; and lower 30-day mortality&#46; These benefits were mainly observed in severe patients&#46; In addition&#44; these results were also increased if the treatment was initiated early&#44; suggesting that minimizing the time from injury to administration may be necessary&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Hyperosmolar fluids</span><p id="par0155" class="elsevierStylePara elsevierViewall">The use of hyperosmolar fluids is not discussed in clinical guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">20</span></a> This fluids group contains agents such as HTS &#40;a crystalloid solution&#41; and mannitol&#44; used in patients affected by TBI with cerebral edema and raised ICP&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">33</span></a> Its benefits are mainly based on its activity after administering a small fluid volume during resuscitation&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a> One of the main characteristics of HTS is its capacity to improve cardiovascular output and cerebral oxygenation while reducing cerebral edema&#46; In addition&#44; innate immune-cell functions seem to be modulated by hypertonicity&#44; specifically neutrophil burst activity&#44; probably beneficial for modulation of the inflammatory response to trauma&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">HTS and&#47;or mannitol could play an essential role in mitigating the pathophysiological consequences observed in the secondary injury of the brain&#46; In the brain&#44; injured areas promote leukocytes congregation&#44; causing vasodilation and peroxidase&#47;protease-mediated cell death&#46; In addition&#44; cell-mediated immunity could be altered&#44; being moderated by HTS&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">53</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Hypoxemia results in the depletion of ATP&#44; cellular membrane ion pump dysfunction&#44; increased intracellular sodium levels&#44; and endothelial cell swelling&#46; These disturbs promote narrowing of the vascular lumen&#44; hindering the red blood cells passing through vessels&#44; leading to premature apoptosis of neuronal cells&#46; In addition&#44; a decrease of extracellular sodium reversing the direction of the Na-glutamate cotransporter could be observed due to neuronal depolarization induced by brain injury&#46; As a consequence&#44; an increase in extracellular glutamate is observed&#44; increasing the neurotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a> The potential benefits of HTS during resuscitation are based due to its capacity to improve alveolar gas exchange by reducing extravascular lung volume&#44; reversing endothelial and red blood cell swelling&#44; improving blood flow and oxygen delivery and restores extracellular sodium and cellular action potential&#44; moderating glutamate toxicity in the brain&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">55</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">During reperfusion of hypoxemic tissue&#44; the production of radical oxygen species can propagate tissue injury&#46; On the other hand&#44; mannitol may limit the secondary oxidative damage in the brain due to its activity as a scavenger of radical oxygen species&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">56</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Despite these arguments&#44; the literature did not conclude the role of HTS in patients affected by TBI&#46; Cooper et al&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">57</span></a> did not observe statistical differences in survival outcomes comparing HTS and saline solution&#46; Bulger et al&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">36</span></a> compared HTS&#44; HTS&#47;dextran&#44; and normal saline in patients affected by TBI&#44; evaluating the neurological outcome at six months after TBI&#46; The study was finished early due to futility&#44; as the interim analysis could not prove neurological status improvement or mortality at six months&#46; However&#44; in patients with increased ICP&#44; HTS and mannitol effectively decreased it&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">56</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">The literature also compared the beneficial effects of HTS and mannitol&#46; Mangat et al&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a> observed that HTS bolus therapy appears to be superior to mannitol in reducing the combined burden of intracranial hypertension and associated hypoperfusion in severe TBI patients&#46; These results agree with two recent meta-analysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">59&#44;60</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">On the other hand&#44; Wade et al&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a> observed that hypertonic saline-dextran solution &#40;HSD&#41; in patients who presented with hypotension increased survival outcomes compared to standard care&#46; Rockswold et al&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">36</span></a> also agree with these results&#44; observing a decrease of ICP and the increase of CPP and brain oxygenation in patients affected by severe TBI&#44; especially those with higher baseline ICP and lower CPP levels&#46; In conclusion&#44; HTS is recommended in TBI patients without conferring a survival benefit in a general manner&#46; However&#44; in patients with intracranial hypertension&#44; its benefits are higher than isotonic crystalloid solutions&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusions</span><p id="par0190" class="elsevierStylePara elsevierViewall">The literature does not observe a &#8220;gold standard&#8221; of fluid therapy on TBI treatment&#46; In addition&#44; the presence of acute hemorrhage or hemorrhagic shock difficult for the outcomes is frequently observed in these patients&#46; Crystalloids and hyperosmolar fluids &#40;especially in patients with increased ICP&#41; could be the most beneficial treatments&#44; being Ringer less desirable than other isotonic crystalloids&#46; In addition&#44; the use of plasma products during resuscitation may convey an improved outcome&#44; especially in the out-of-hospital environment&#46; Future clinical studies should focus on the effect of specific fluid prescriptions and osmotic agents on short- and long-term outcomes&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Funding</span><p id="par0195" class="elsevierStylePara elsevierViewall">No external funding sources&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflict of interests</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare&#46; The authors declared that this study has received no financial support&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Traumatic brain injury &#40;TBI&#41; is an important health and social problem&#46; The mechanism of damage of this entity could be divided into two phases&#58; &#40;1&#41; a primary acute injury because of the traumatic event&#59; and &#40;2&#41; a secondary injury due to the hypotension and hypoxia generated by the previous lesion&#44; which leads to ischemia and necrosis of neural cells&#46; Cerebral edema is one of the most important prognosis markers observed in TBI&#46; In the early stages of TBI&#44; the cerebrospinal fluid compensates the cerebral edema&#46; However&#44; if edema increases&#44; this mechanism fails&#44; increasing intracranial pressure&#46; To avoid this chain effect&#44; several treatments are applied in the clinical practice&#44; including elevation of the head of the bed&#44; maintenance of normothermia&#44; pain and sedation drugs&#44; mechanical ventilation&#44; neuromuscular blockade&#44; controlled hyperventilation&#44; and fluid therapy &#40;FT&#41;&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The goal of FT is to improve the circulatory system to avoid the lack of oxygen to organs&#46; Therefore&#44; rapid and early infusion of large volumes of crystalloids is performed in clinical practice to restore blood volume and blood pressure&#46; Despite the relevance of FT in the early management of TBI&#44; there are few clinical trials regarding which solution is better to apply&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The aim of this study is to provide a narrative review about the role of the different types of FT used in the daily clinical practice on the management of TBI&#46; To achieve this objective&#44; a physiopathological approach to this entity will be also performed&#44; summarizing why the different types of FT are used&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">El traumatismo craneoencef&#225;lico &#40;TCE&#41; es un importante problema sanitario y social&#46; El mecanismo de da&#241;o de esta entidad se podr&#237;a dividir en dos fases&#58; 1&#41; una lesi&#243;n aguda primaria a causa del evento traum&#225;tico&#44; y 2&#41; una lesi&#243;n secundaria por la hipotensi&#243;n e hipoxia generada por la lesi&#243;n anterior&#44; que conduce a la isquemia y necrosis de las c&#233;lulas neurales&#46; El edema cerebral es uno de los marcadores pron&#243;sticos m&#225;s importantes observados en el TCE&#46; En las primeras etapas de TCE&#44; el l&#237;quido cefalorraqu&#237;deo compensa el edema cerebral&#46; Sin embargo&#44; si aumenta el edema&#44; este mecanismo falla&#44; aumentando la presi&#243;n intracraneal&#46; Para evitar este efecto en cadena&#44; en la pr&#225;ctica cl&#237;nica se aplican varios tratamientos&#44; entre ellos la elevaci&#243;n de la cabecera de la cama&#44; el mantenimiento de la normotermia&#44; los f&#225;rmacos para el dolor y la sedaci&#243;n&#44; la ventilaci&#243;n mec&#225;nica&#44; el bloqueo neuromuscular&#44; la hiperventilaci&#243;n controlada y la fluidoterapia &#40;FT&#41;&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El objetivo de la FT es mejorar el sistema circulatorio para evitar la falta de ox&#237;geno a los &#243;rganos&#46; Por lo tanto&#44; en la pr&#225;ctica cl&#237;nica se realiza una infusi&#243;n r&#225;pida y temprana de grandes vol&#250;menes de cristaloides para restablecer el volumen sangu&#237;neo y la presi&#243;n arterial&#46; A pesar de la relevancia de la FT en el manejo temprano del TCE&#44; existen pocos ensayos cl&#237;nicos sobre qu&#233; soluci&#243;n es mejor aplicar&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">El objetivo de este estudio es proporcionar una revisi&#243;n narrativa sobre el papel de los diferentes tipos de FT utilizados en la pr&#225;ctica cl&#237;nica diaria en el manejo del TCE&#46; Para lograr este objetivo&#44; tambi&#233;n se realizar&#225; un abordaje fisiopatol&#243;gico de esta entidad&#44; resumiendo por qu&#233; se utilizan los diferentes tipos de FT&#46;</p></span>"
      ]
    ]
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                        0 => array:2 [
                          "etal" => true
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                          "etal" => false
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                        ]
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                  ]
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "A&#46;R&#46; Changa"
                            1 => "B&#46;M&#46; Czeisler"
                            2 => "A&#46;S&#46; Lord"
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                  ]
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                    0 => array:2 [
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                        "fecha" => "2019"
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              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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