Multidisciplinary consensus document on the management of massive haemorrhage. First update 2023 (document HEMOMAS-II) | Revista Española de Anestesiología y Reanimación (English Edition)

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(**) Articles cited in the recommendation rationale, without including citations in the introduction or methodology sections." ] ] ] "textoCompleto" => "IntroductionThe management of massive haemorrhage (MH) involves implementing several strategies to control bleeding, rapidly replenish blood loss, and minimise potentially life-threatening coagulopathy.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a>The recent creation and dissemination of multidisciplinary protocols and the publication of excellent guidelines<a class="elsevierStyleCrossRefs" href="#bib0015">3–5</a> has improved MH management, particularly in the early stages of haemorrhagic shock. However, uncontrolled traumatic bleeding remains the leading preventable cause of death.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>In 2015, a multidisciplinary group was formed to review the existing literature and prepare a document that would facilitate decision-making for all those involved in the treatment of MH.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> Endorsed by the Spanish scientific societies of Anaesthesiology and Resuscitation (SEDAR), Intensive and Critical Medicine and Coronary Units (SEMICYUC), and Thrombosis and Haemostasis (SETH), the group drafted 47 recommendations or suggestions for the management of MH.In 2021, given the time elapsed and the advances made in many aspects of MH management, the scientific societies decided it was time to update the existing guidelines using a special methodology that has allowed the expert panel to review and change, if needed, the existing recommendations.These guidelines address MH in multiple trauma patients, in the perioperative setting, and in intensive care; however, like the previous guidelines, obstetric haemorrhage, bleeding in paediatric patients, and intestinal bleeding have been excluded due to their particular characteristics and management strategies.Materials and methodsA group of 10 experts (the authors of this manuscript) met in May 2021 to establish the process for reviewing the original guidelines, and agreed to update the previous consensus recommendations on the basis of other clinical practice guidelines and a review of the latest literature. The methodology used was based on elements of the ADAPTE method that has been described in detail elsewhere,<a class="elsevierStyleCrossRef" href="#bib0040">8</a> and involves searching for and adapting other guidelines and published articles. For this project, the working group first identified the skills and resources needed prior to beginning the adaptation process. This was followed by the adaptation phase, in which the literature was searched for eligible guidelines, the recommendations sourced were uploaded to a matrix and, if appropriate, were adapted to the context of our guidelines. The topics to be covered in these guidelines were those included in the original document. The last phase of ADAPTE, where the opinion of decision-makers affected by the updated guide is obtained, was excluded.The group searched PubMed and EMBASE (January 2014–June 2021; see Supplementary material and <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) to identify clinical practice guidelines published in scientific journals and recommendations from scientific societies related to the management of MH.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>After protocolizing the strategy used to review the results of the bibliographic search and the recommendations of the original guideline (peer review), the results were shared so that the group could agree on the changes needed based on the latest evidence contained in other recommendations (see details of the review protocol in Supplementary material).ResultsOnly 1 of the 47 recommendations included in the original document was maintained without change. In all the remaining recommendations the group found it necessary to change the wording and/or the grade of recommendation and/or the level of evidence. Seven recommendations were eliminated, some were amalgamated into a single recommendations, and others were expanded based on the available evidence. The final updated guidelines contain 41 recommendations distributed in 14 sections with 61 statements (38 recommendations, 2 with level A evidence, and 23 suggestions). Tables 1MS and 2MS in the supplementary material compare the original and updated guidelines.Recommendations and rationaleDefinition and evaluationsRecommendation 1To evaluate the extent and/or severity of bleeding in surgical patients we recommend visually examining the surgical field to identify extensive microvascular bleeding, and in trauma patients we recommend evaluating the mechanism of injury, the anatomical pattern of injury, and the initial response to resuscitation. (1C)In patients at risk of MH, bleeding should be monitored by clinical examination and quantification.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> In trauma patients, the mechanism and anatomical pattern of injury, and the initial response to resuscitation should also be analysed. These measures can help predict the need to activate massive transfusion protocols (MTP).<a class="elsevierStyleCrossRefs" href="#bib0020">4,10</a>Recommendation 2We suggest using the Trauma Associated Severe Hemorrhage (TASH) score to promptly identify trauma patients who may benefit from the activation of a massive transfusion protocol (cut-off score 15), preferably in conjunction with a decrease in clot firmness shown by rotational thromboelastometry or TEG, if available. (2C)It is crucial to rapidly identify patients at risk of developing MH and requiring massive transfusion (MT) in order to immediately activate an MTP and improve prognosis.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>Several scales have been developed to assess multiple trauma patients, including the TASH score, which measures clinical (blood pressure and heart rate, among others) and analytical (haemoglobin, base excess) parameters and has been shown to correctly identify 88.8% of patients who will require MT.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>Viscoelastic tests (VET) can also help predict the need for MTP activation in trauma patients.<a class="elsevierStyleCrossRefs" href="#bib0060">12,13</a>Recommendation 3We suggest using the "resuscitation intensity" criterion, defined as the transfusion of at least 4 units of packed red blood cells in 1 hour, to promptly identify non-trauma patients that would benefit from activation of the massive transfusion protocol. (2C)In the prehospital setting, we suggest using a "Shock Index” score of 1 or higher to indicate the need to activate the massive transfusion protocol. (2C)In non-trauma patients, experts suggest using the resuscitation intensity criterion of 3−4 packed red blood cells (RBC) per hour as an indicator of bleeding severity.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>The shock index (SI) (heart rate divided by systolic blood pressure) is the only validated risk scale that exclusively uses clinical variables, and is considered very useful in the prehospital setting. An SI score of 1 higher predicts early mortality.<a class="elsevierStyleCrossRefs" href="#bib0020">4,14</a>Recommendation 4Hospitals should develop multidisciplinary massive transfusion protocols with evidence-based treatment algorithms that include activation and deactivation criteria and transfusion targets, and should consider transitioning to resuscitation guided by laboratory data or viscoelastic tests as soon as possible. We also recommend launching information campaigns, providing training for the teams involved, and periodically evaluating their effectiveness and compliance with the hospital’s quality and safety programs. (1B)The establishment and application of multidisciplinary MTPs has been shown to reduce the rate of blood transfusions and mortality in trauma patients.<a class="elsevierStyleCrossRefs" href="#bib0075">15,16</a> Experts recommend reviewing MTPs regularly in the context of quality and safety standards.<a class="elsevierStyleCrossRefs" href="#bib0020">4,17</a> Other MH scenarios involving refractory bleeding and suspected coagulopathy could also benefit from these protocols<a class="elsevierStyleCrossRef" href="#bib0090">18</a> by allowing clinicians to coordinate their efforts and effectively control MH.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>When developing MPTs, experts recommend transitioning from an algorithm based on fixed levels of blood components to another guided by laboratory data or VET results, which would reduce blood transfusions and patient morbidity and improve coagulopathy.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>Recommendation 5In patients presenting massive haemorrhage, we recommend basing the initial assessment on the clinical history and anamnesis (if possible), and start serial monitoring of blood pressure, heart rate, and serum lactate or base deficit in order to assess tissue perfusion and the degree of hypovolemic shock. (1C)Dynamic monitoring of tissue perfusion includes blood pressure, heart rate, oxygen saturation, and electrocardiography, in addition to clinical signs and symptoms.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Serial determination of serum lactate and base deficit is also recommended.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> Although these parameters may not strictly correlate with the severity of bleeding, they do correlate with the degree of hypoperfusion and tissue hypoxia.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>Temperature managementRecommendation 6In patients presenting massive haemorrhage, we recommend routine temperature monitoring and rapid application of measures to prevent heat loss and hypothermia and to maintain core temperature above 35 °C. (1B)Measures to prevent hypothermia include removing wet clothing, covering the patient, increasing room temperature, using forced air blankets or circulating-water mattresses, and rapid infusion warmers for all fluids administered during mass transfusion. Extracorporeal warming systems can also be considered in patients with severe hypothermia and high risk of cardiac arrest. (2C)Maintaining normothermia reduces bleeding and transfusion requirements,<a class="elsevierStyleCrossRef" href="#bib0015">3</a> and should be a priority in patients with MH<a class="elsevierStyleCrossRef" href="#bib0020">4</a> due to the association between hypothermia (core temperature below 35 °C) and acidosis, hypotension, and coagulopathy. Systematic monitoring of core temperature will indicate the effectiveness of measures to combat hypothermia, such fluid warmers, forced air warming systems or circulating-water mattresses.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> It is also important to warm RBCs and other blood products before they are administered.Fluid therapyRecommendation 7We recommend the early administration of fluid therapy, preferably isotonic crystalloids, in patients with severe bleeding and hypotension. (1A)In patients with severe traumatic bleeding, balanced crystalloid solutions should be used instead of saline solutions. (1B)Administering fluids to replace volume is the first measure to be taken in MH,<a class="elsevierStyleCrossRef" href="#bib0100">20</a> as these patients are less tolerant of hypovolemia than anaemia.Crystalloids (Table 3MS, supplementary material) are the fluids of choice due to their clinical efficacy, moderate adverse effects, and low cost. There are insufficient data to suggest that the use of a colloid solution improves prognosis in patients with haemorrhagic shock,<a class="elsevierStyleCrossRef" href="#bib0095">19</a> and some authors have reported adverse effects such as allergic reactions (especially with gelatines), coagulation disorders, and kidney failure.Balanced solutions in multiple trauma patients have been associated with greater improvements in acid-base balance and hyperchloremia at 24 h than 0.9% saline solution,<a class="elsevierStyleCrossRef" href="#bib0105">21</a> and a better cost-benefit ratio.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> Although studies published after the literature review performed for this update suggest that both solutions could be effective in critically ill patients,<a class="elsevierStyleCrossRefs" href="#bib0115">23,24</a> we prefer balanced over saline solution in the management of MH in multiple trauma patients. If saline is used, no more than 1–1.5 l should be administered.<a class="elsevierStyleCrossRefs" href="#bib0020">4,19</a>Recommendation 8We recommend avoiding hypotonic crystalloid solutions such as lactated Ringer's in patients with severe traumatic brain injury. (1B)Hypotonic solutions, which are less expansive than isotonic and hypertonic solutions and increase the volume of free water, should be avoided in patients with severe traumatic brain injury (TBI) because they may increase mortality compared to 0.9% saline.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4,25,26</a>Recommendation 9We suggest avoiding hypertonic solutions for fluid resuscitation in patients with severe traumatic brain injury. (2C)Hypertonic saline is a first-line measure to temporarily reduce intracranial pressure, but it should not be used as the primary resuscitation fluid for haemorrhagic shock because it does not improve survival or cognitive outcomes.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>Recommendation 10Synthetic colloids should be used sparingly. (1C)The administration of synthetic colloids can aggravate coagulopathy due to their negative effect on haemostasis.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a>These colloids are thought to be more effective than crystalloids at restoring intravascular volume and reducing dosing requirements,<a class="elsevierStyleCrossRef" href="#bib0135">27</a> and are therefore suggested when the crystalloid-vasopressor combination fails to maintain basic tissue perfusion. However, they show no mortality benefit<a class="elsevierStyleCrossRef" href="#bib0140">28</a> and it remains unclear which solution should be first choice.Following the withdrawal of hydroxyethyl starches, the only synthetic colloids currently used are gelatines.Recommendation 11We recommend avoiding the routine use of albumin for volume replacement in patients with massive haemorrhage. (1C)There is no evidence that albumin is more effective than other solutes. It is also expensive and associated with potential risks, so it should not be the fluid of choice for volume resuscitation in MH.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> Although it has been suggested as a second-line fluid in septic patients after initial administration of large volumes of crystalloids,<a class="elsevierStyleCrossRef" href="#bib0145">29</a> this recommendation cannot be extrapolated to MH.A subgroup analysis of the SAFE study<a class="elsevierStyleCrossRef" href="#bib0150">30</a> suggested that the use of 4% albumin in TBI patients increased the risk of death, possibly due to its hypo-osmolarity.Some authors have recently suggested that albumin could preserve the endothelial glycocalyx and help maintain vascular permeability.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> Finally, albumin could be appropriate for fluid resuscitation in patients with cirrhosis or those undergoing liver<a class="elsevierStyleCrossRef" href="#bib0160">32</a> or cardiac surgery.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>Recommendation 12We recommend applying a restrictive volume replacement strategy to achieve target blood pressure until bleeding is controlled. (1B)It is reasonable to tolerate a certain degree of hypotension until bleeding has been controlled, taking into consideration the characteristics of each patient (advanced age, history of hypertension, and target tissue perfusion). Excessively high blood pressure can contribute to rebleeding.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>In liver surgery, a restrictive fluid strategy has been shown to reduce bleeding and transfusion requirement.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4,19</a>Fluid resuscitation in hypotensive patientsRecommendation 13We recommend setting target systolic blood pressure between 80 and 90 mmHg in bleeding, hypotensive, trauma patients without head injury. This should only be maintained until the source of the bleeding has been controlled, particularly in elderly or hypertensive patients. (1C)“Damage control resuscitation”, in other words, restrictive fluid replacement and permissive hypotension, has proven to be beneficial.<a class="elsevierStyleCrossRefs" href="#bib0020">4,19,34,35</a>However, the recommended mean blood pressure (50−60 mmHg) and systolic blood pressure (80−90 mmHg) values are arbitrary and may not be safe in all trauma patients, particularly those with blunt and penetrating trauma,<a class="elsevierStyleCrossRef" href="#bib0180">36</a> and should be carefully considered in elderly<a class="elsevierStyleCrossRef" href="#bib0185">37</a> and chronically hypertensive<a class="elsevierStyleCrossRef" href="#bib0190">38</a> patients.Recommendation 14In hypotensive patients with traumatic bleeding and TBI, we recommend setting a target systolic blood pressure of at least 110 mmHg until the source of bleeding has been controlled, particularly in certain patient groups, such as the elderly, hypertensive patients, etc. (1 C)Restrictive fluid replacement and permissive hypotension strategies are contraindicated in patients with severe TBI and acute spinal cord injury. In these cases, it is essential to maintain tissue perfusion pressure and cerebral autoregulation to ensure oxygenation.<a class="elsevierStyleCrossRefs" href="#bib0020">4,38</a>Recommendation 15If fluid therapy is not effective, we recommend considering early administration of norepinephrine to maintain blood pressure, ideally through a central venous line provided this does not delay the start of treatment. (1C)Vasopressors may be occasionally be necessary to maintain tissue perfusion, with norepinephrine being the agent of choice.A study comparing saline plus vasopressin versus saline alone found lower fluid requirements in the vasopressin group.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> Although early vasopressors have been shown to be beneficial,<a class="elsevierStyleCrossRef" href="#bib0200">40</a> observational studies have reported higher mortality among trauma patients receiving this therapy. For this reason, guidelines suggest using vasopressors in addition to fluids in patients with refractory hypotension.<a class="elsevierStyleCrossRefs" href="#bib0020">4,19</a>Norepinephrine is usually administered via a central venous line due to the risk of subcutaneous diffusion and necrosis, but peripheral venous administration is both feasible and effective.Damage controlRecommendation 16We recommend applying "damage control surgery" in trauma patients who require prolonged surgery and/or present acidosis and/or hypothermia and who also present complex or inaccessible anatomical lesions causing refractory bleeding. (1B)The aim of “damage control resuscitation” is to rapidly control bleeding and restore intravascular volume. The strategy includes minimising blood loss, hypotensive resuscitation, balanced haemostatic treatment with a high red blood cell:plasma:platelet ratio (1:1:1, according to the original concept),<a class="elsevierStyleCrossRef" href="#bib0205">41</a> the application of an MTP, restricted crystalloid infusion, and possibly haemostatic supplements.<a class="elsevierStyleCrossRefs" href="#bib0020">4,42,43</a>Damage control surgery is one of the basic resuscitation strategies in specific patients, and consists of abbreviated laparotomy and retroperitoneal packing to compress bleeding that is hard to control, followed by restoration of local blood flow where necessary and control of contamination from abdominal viscera.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> This preliminary measure is followed at least 48 h later by a second intervention to remove the "packing", leaving the definitive abdominal repair for a third intervention, if necessary.The concept of “orthopaedic damage control”.<a class="elsevierStyleCrossRef" href="#bib0220">44</a> consisting of initial stabilization of fractures and leaving definitive osteosynthesis for a second intervention, has been described in multiple trauma patients with severe bone fractures.MonitoringRecommendation 17We recommend using dynamic variables such as stroke volume variation (SVV) and pulse pressure variation (PPV) instead of static variables such as central venous pressure (CVP) or pulmonary artery occluded pressure (PAOP) to guide fluid administration in patients in sinus rhythm with severe bleeding who are receiving controlled mechanical ventilation and do not respond to initial fluid therapy. (1B)Dynamic rather than static parameters should be used because they can measure preload and guide the response to fluids in patients with controlled mechanical ventilation and sinus heart rhythm. Commonly used dynamic variables with a high predictive value are stroke volume variation (SVV) and pulse pressure variation (PPV),<a class="elsevierStyleCrossRef" href="#bib0015">3</a> although dynamic variables of volume status (SVV and PPV), CO2 gap, and central venous oxygen saturation can also be used.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Recommendation 18We recommend performing early, serial determinations of lactate and base deficit to estimate and monitor the severity of bleeding, the degree of hypoperfusion, tissue hypoxia, and shock. (1B)Serial determination of early changes in serum lactate and base deficit are among the most useful laboratory data to estimate and monitor the extent of hypoperfusion and tissue hypoxia, and are a good indicator of prognosis in patients with MH.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4,19</a>Recommendation 19In patients with severe bleeding, we recommend early monitoring of haemostasis in order to optimize the administration of blood products and prohaemostatic drugs. Treatment should be individualised using algorithms based, ideally, on the results of viscoelastic tests (1B), or failing that, on conventional clotting test results. (1C)The most widely used viscoelastic tests (VET) for monitoring coagulation are Rotem® (Instrumentation Laboratory, Bedford, MA, USA) and TEG® (Haemonetics Corporation, Boston, MA, USA). Conventional clotting tests should include prothrombin time (PT), activated partial thromboplastin time (aPTT), the Clauss fibrinogen assay, and platelet count. There is insufficient evidence to show the superiority of one method over another,<a class="elsevierStyleCrossRefs" href="#bib0210">42,45</a> but VETs provide rapid results and additional information on hyperfibrinolysis, clot firmness, and hypofibrinogenemia.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>In specific scenarios, such as cardiac surgery and liver transplantation, VETs have proven useful in reducing bleeding and transfusion needs (1B in cardiac surgery.<a class="elsevierStyleCrossRefs" href="#bib0020">4,46</a> The International Society of Thrombosis and Haemostasis (ISTH) suggests using VETs during liver transplantation<a class="elsevierStyleCrossRef" href="#bib0235">47</a> and the British Society of Haematology suggests using VETs to guide transfusion in obstetric haemorrhage, liver disease, cardiac surgery, and traumatic bleeding.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>Recommendation 20We recommend basing the indication for RBC transfusion on the result of serial haemoglobin determinations, taking into account both clinical and laboratory parameters. (1C)The decision to administer blood should be based not only on clinical and laboratory parameters, such as blood pressure, heart rate, SI, plasma lactate levels, and base deficit, but also on the patient's clinical situation, i.e., multiple trauma (type of fracture or injury), surgery, or other scenarios.<a class="elsevierStyleCrossRefs" href="#bib0240">48,49</a>Blood transfusionRecommendation 21In patients presenting massive haemorrhage, we recommend considering early, restrictive transfusion of RBCs. (1B)We suggest using leukodepleted blood components. (2B)Transfusion of RBCs is generally necessary when blood loss is between 30% and 40%. Taking the patient’s specific situation into consideration, in addition to clinical and analytical parameters, will avoid performing transfusion based on isolated haemoglobin determinations. A restrictive strategy reduces the need for RBC transfusion, but does not have a greater impact on morbidity and mortality than a liberal strategy.<a class="elsevierStyleCrossRef" href="#bib0250">50</a>The use of leukodepleted blood reduces the immune-related complications associated with allogeneic blood transfusion.Recommendation 22We recommend administering RBCs to achieve a target Hb of between 7 and 9 g/dL. (1B)We suggest considering a transfusion target of 9−10 g/dL in high-risk patients with comorbidities, such as chronic cardiovascular disease, acute coronary syndrome, stroke, thrombocytopaenia, and cancer. (2C)The restrictive transfusion threshold is usually 7−8 g/dL haemoglobin, and therefore should be avoided in most patients with haemoglobin above that range. In certain patient subgroups and clinical contexts, experts suggest achieving a plasma haemoglobin level of over 9 g/dL (chronic cardiovascular disease, acute coronary syndrome, stroke, or low-weight and elderly patients), although there is insufficient evidence to establish recommendations on the optimal transfusion strategy in these subgroups.<a class="elsevierStyleCrossRefs" href="#bib0250">50,51</a>Recommendation 23We recommend basing initial empirical management of massive haemorrhage on the concept of haemostatic resuscitation with a high fresh plasma-to-packed red blood cell ratio (at least 1:2) in patients with massive haemorrhage secondary to severe trauma. There is insufficient evidence to make specific recommendations in non-trauma patient. (1C)Some authors suggest that transfusion strategies with fixed, high plasma/RBC ratios, are beneficial, particularly in multiple trauma patients, although it has not been possible to show that the 1:1:1 ratio has a better risk-benefit profile than the 1:1:2.<a class="elsevierStyleCrossRefs" href="#bib0010">2,52–54</a>Plasma transfusionRecommendation 24In massive haemorrhage follow-up, we recommend administering fresh plasma using a goal-directed strategy based on clinical signs (microvascular bleeding, bleeding control) and laboratory tests (evidence of prolonged CT or R in viscoelastic tests, or a high prothrombin time (PT) ratio and/or activated partial thromboplastin time (aPTT) in conventional tests). (1C)Plasma transfusion is still the gold standard for preventing and treating coagulopathy in MH, despite its known drawbacks and the slow turnaround of laboratory tests.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>According to studies, transfusion based on a pre-established higher blood product ratio provides a higher volume of plasma and platelets compared with a goal-directed strategy.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>Platelet transfusionRecommendation 25We recommend administering platelet concentrates to maintain platelets above 50 × 109/L in all patients with active bleeding. (1C)We suggest performing platelet transfusion to maintain platelets above 100 × 109/L in patients with massive haemorrhage and brain injury or eye injury, or in patients scheduled for neurosurgery or interventions involving the posterior pole of the eye, or in patients with platelets above 50 × 109/L and active, refractory bleeding. (2C)We suggest considering platelet concentrate transfusion to maintain a count of 50 × 109/L in patients requiring a major invasive procedure or in multiple trauma patients, even in the absence of bleeding. (2C)Despite the lack of solid scientific evidence, there is widespread agreement that a platelet count of at least 50 × 109/L should be maintained in patients with acute bleeding.<a class="elsevierStyleCrossRefs" href="#bib0020">4,7,19,55–57</a>In patients with TBI or eye bleeding, we recommend maintaining platelets above 100 × 109/L.<a class="elsevierStyleCrossRefs" href="#bib0020">4,19,56</a> This threshold has been extended to include patients with persistent bleeding.<a class="elsevierStyleCrossRefs" href="#bib0020">4,19,56,57</a> There are no strong recommendations regarding platelet transfusion to control bleeding in patients with platelet dysfunction.<a class="elsevierStyleCrossRef" href="#bib0285">57</a>Some experts suggest administering prophylactic platelet transfusion in patients requiring major surgery or in multiple trauma patients when platelets are below 50 × 109/L.<a class="elsevierStyleCrossRefs" href="#bib0020">4,19,58,59</a>Recommendation 26We suggest avoiding platelet transfusion in patients taking antiplatelet therapy before intracerebral haemorrhage (spontaneous or traumatic), unless they will require neurosurgery. (2C)This recommendation is derived from the PATCH study<a class="elsevierStyleCrossRef" href="#bib0300">60</a> in which clinical outcomes and 3-month mortality were worse in transfused patients (see recommendation 41).Recommendation 27We suggest administering an initial dose of 4–8 platelet concentrates (or the equivalent: 1–2 units pooled), or 1 apheresis unit, adjusting the rate of administration to bleeding persistence, the platelet count achieved with the initial dose, the response to other measures to control bleeding, and the results of viscoelastic tests, if available. (2C)The platelet transfusion dose was already suggested in the previous version of this guide. If donors are available, 1 apheresis unit (equivalent to 4−6 platelet concentrates) increases the count by 30−50 × 109/L and reduces exposure to multiple donors.<a class="elsevierStyleCrossRefs" href="#bib0020">4,58,59</a>Prothrombin complex concentrateRecommendation 28In the context of massive haemorrhage, we recommend administering prothrombin complex concentrate and vitamin K to rapidly reverse the effect of antivitamin K oral anticoagulants in patients treated with these drugs. (1B)In this context, administration of prothrombin complex concentrate (PCC), preferably four-factor prothrombin complex concentrate,<a class="elsevierStyleCrossRefs" href="#bib0025">5,19,61–64</a> should be the first choice for urgent reversal of the anticoagulant effect of antivitamin-K drugs<a class="elsevierStyleCrossRefs" href="#bib0015">3,5,9,17</a> (Tables 4MS and 5MS, supplementary material). Although the optimal dosing strategy remains unclear, experts recommend adjusting the dose to the patient’s weight and INR values.<a class="elsevierStyleCrossRef" href="#bib0305">61</a>Recommendation 29We do not recommend prothrombin complex concentrate as first choice haemostatic in patients with massive haemorrhage who have not received antivitamin K oral anticoagulants, although it may be used in certain patients based on the urgency of the treatment and the availability of fresh plasma. (1C)There is insufficient evidence to recommend the use of PCC as first choice haemostatic in MH.In specific scenarios, however, such as refractory bleeding, cardiac surgery,<a class="elsevierStyleCrossRefs" href="#bib0315">63,64</a> liver surgery, and multiple trauma,<a class="elsevierStyleCrossRef" href="#bib0325">65</a> some experts suggest the off-label use of PCC in the context of multimodal management of MH, in accordance with the established legal framework.<a class="elsevierStyleCrossRefs" href="#bib0015">3–5,9,17</a>Recommendation 30We suggest restricting the use of activated prothrombin complex concentrate or rFVIIa to haemophiliac patients with inhibitors who present massive haemorrhage. (2C)Activated PCC (FEIBA) and rFVIIa are specifically indicated in congenital haemophilia with inhibitor and acquired haemophilia.<a class="elsevierStyleCrossRefs" href="#bib0330">66,67</a>Recommendation 31We suggest using prothrombin complex concentrates with caution in high thrombotic risk patients who present massive life-threatening bleeding or require surgery that cannot be delayed. (2C)Although PCCs are considered safe, thrombotic complications have been reported in 2%–4% of patients treated for MH. Therefore, the risk/benefit balance must be individualised in patients with bleeding and high risk for thrombosis.FibrinogenRecommendation 32We recommend using the Clauss fibrinogen method, FIBTEM in ROTEM® or Functional Fibrinogen in TEG® to determine fibrinogen for diagnosis or clinical management decisions in patients with massive haemorrhage (1C)This recommendation, included in the previous version of the guide,<a class="elsevierStyleCrossRef" href="#bib0035">7</a> remains valid.<a class="elsevierStyleCrossRefs" href="#bib0020">4,9,13,68</a>,<a class="elsevierStyleCrossRef" href="#bib0345">69</a> Fibrinogen should be quantified using the Clauss method.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>Recommendation 33In patients with active bleeding, we recommend administering fibrinogen concentrate if plasma levels (Clauss functional assay) are below 1.5–2.0 g/L, or A5 FIBTEM is below 7–9 mm or, by equivalence, the maximum amplitude on the citrated functional fibrinogen assay is less than 10 mm. (1C)We recommend administering fibrinogen concentrate together with RBCs in the initial phase of massive, particularly trauma-related, bleeding as an alternative to haemostatic resuscitation, even if VET or clotting results are unavailable (1C)The threshold for fibrinogen administration is controversial. Plasma levels should not be lower than 1.5 g/L,<a class="elsevierStyleCrossRefs" href="#bib0015">3,4,13,19</a>,<a class="elsevierStyleCrossRefs" href="#bib0225">45,68–70</a> which corresponds to A5 FIBTEM < 7 mm, although a threshold of 8−9 mm has been proposed in some clinical scenarios.<a class="elsevierStyleCrossRef" href="#bib0350">70</a> The equivalent threshold in TEG® is a maximum amplitude (MACFF) of 10 mm.Recommendation 34We suggest administering an initial dose of 25−50 mg/kg of fibrinogen concentrate if the recommended plasma threshold is not achieved. Repeat doses, if required, should be guided by VET. (2C)In adult traumatic bleeding patients, we suggest administering a minimum loading dose of 3−4 grams. (2C)We do not recommend plasma as the first choice source of fibrinogen; however, it can be used if fibrinogen concentrate or cryoprecipitate is not available. (1C)Although we recommend administering a loading dose of 3−4 g in patients with multiple trauma and then continuing with VET-guided administration,<a class="elsevierStyleCrossRefs" href="#bib0020">4,19</a> the dose should ideally be weight-adjusted<a class="elsevierStyleCrossRefs" href="#bib0015">3,4,19,68</a> (Table 6MS).Alternatively, 4−6 ml/kg cryoprecipitate could be used (approximately 1U/5−10 kg).<a class="elsevierStyleCrossRefs" href="#bib0015">3,4,9,71</a>Factor VIIaRecommendation 35Factor VIIa should not be first-line therapy in massive haemorrhage. (1B)We suggest considering factor VIIa only in patients refractory to conventional haemostatic measures. (2B)Factor VIIa is not indicated for the treatment of MH. The few studies investigating factor VIIa in massive haemorrhage have reported equivocal results and a high incidence of thrombotic events, particularly arterial.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4,9,17</a>,<a class="elsevierStyleCrossRefs" href="#bib0095">19,72</a>We suggest using factor VIIa only if all other haemostasis measures have been ineffective and fibrinogen, platelet count, pH, and temperature have been optimized<a class="elsevierStyleCrossRefs" href="#bib0020">4,68,72</a> (Table 7MS).AntifibrinolyticsRecommendation 36We recommend administering tranexamic acid (TXA) within 3 hours of the onset of massive traumatic haemorrhage and in patients with TBI. (1A)We suggest treating severe perioperative bleeding with tranexamic acid, ideally under VET guidance. (2B)The recommendation to use TXA in multiple trauma and TBI patients is based on the CRASH-2<a class="elsevierStyleCrossRef" href="#bib0365">73</a> and CRASH-3 studies, respectively. However, it is important to bear in mind that late administration does not provide benefits and increases complications.<a class="elsevierStyleCrossRef" href="#bib0370">74</a> The recommended loading dose is 1 g over 10 min, followed by infusion of 1 g over 8 h.In the perioperative context, some authors suggest administering TXA to treat active bleeding, although this is not supported by evidence from randomised trials. TXA should be administered when hyperfibrinolysis has been confirmed, except in cardiac surgery, where there is a high level of evidence (1A) to recommend it as a prophylactic.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>Other measuresRecommendation 37We suggest evaluating the administration of desmopressin (0.3 μg/kg) in bleeding patients with von Willebrand disease. (2C)We suggest evaluating the administration of desmopressin (0.3 μg/kg) in uraemic bleeding patients treated with aspirin or patients with critical bleeding and known platelet dysfunction. (2C)Desmopressin (DDAVP) is effective in the treatment and prevention of mild to moderate bleeding in patients with congenital or acquired disorders of primary haemostasis.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4,9</a>Recommendation 38We recommend using topical haemostatics in combination with conventional surgery-specific measures in patients presenting massive haemorrhage. (1B)Topical haemostatics are effective when the source of bleeding can be accessed directly.<a class="elsevierStyleCrossRefs" href="#bib0020">4,7,9</a>Recommendation 39We recommend considering mechanical control measures, such as angioembolization. (1B)We suggest using endovascular procedures (e.g., REBOA) to treat massive haemorrhage in certain patients, if available. (2C)Angioembolization is an effective alternative to early open surgery<a class="elsevierStyleCrossRef" href="#bib0015">3</a> in certain patients (nonvariceal or lower upper gastrointestinal bleeding, or pancreatitis-induced arterial bleeding), and in patients with pelvic fracture.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>The use of aortic balloon occlusion can be considered under extreme circumstances in multiple trauma patients to gain time until bleeding can be controlled,<a class="elsevierStyleCrossRef" href="#bib0020">4</a> in patients with a ruptured abdominal aortic aneurysm, and in those with severe gastrointestinal or peripartum haemorrhage.<a class="elsevierStyleCrossRef" href="#bib0205">41</a>Recommendation 40We recommend monitoring plasma calcium levels in bleeding patients (1C), particularly if massive transfusion is required. (1B)We recommend maintaining plasma calcium levels in the normal range and administering calcium in case of hypocalcaemia (ionic Ca <3.6 mg/dl, or corrected serum calcium <7.5 mg/dl). (1B)It is important to control calcium whenever large volumes of blood components are administered.<a class="elsevierStyleCrossRefs" href="#bib0375">75–77</a>Recommendation 41In cases of severe or massive haemorrhage, we recommend ascertaining whether the patient is under treatment with antiplatelet drugs or anticoagulants. If so, reversal agents should be administered, provided an individual analysis has shown that the benefit outweighs the risk of thrombosis. (1B)We recommend administering prothrombin complex concentrate plus vitamin-k in patients treated with vitamin K-dependent oral anticoagulants. (1B)We suggest performing early platelet transfusion in patients with bleeding clearly associated with antiplatelet drugs, ideally after monitoring platelet function. (2C)In patients treated with dabigatran, we suggest administering idarucizumab instead of non-specific haemostatic agents such as prothrombin complex concentrates. (2A)We suggest administering andexanet alpha or prothrombin complex concentrate in patients receiving oral factor-Xa inhibitors (“xabans”) who present life-threatening or uncontrolled bleeding. (2C)Platelets may be the best option in patients with bleeding clearly associated with antiplatelet drugs.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> The effectiveness of this treatment will depend on certain factors, such as the antiplatelet drug involved, the time since the last dose, the mechanism and site of bleeding, and the criteria of efficacy.<a class="elsevierStyleCrossRef" href="#bib0390">78</a> Dosage is equally uncertain, with some authors suggesting 0.7 × 1011/10 kg (equivalent to approximately one unit of platelet concentrate per 10 kg, or 2 pools in a 70−80 kg patient) in bleeding associated with aspirin use, up to double when associated with clopidogrel, or even more in the case of prasugrel.<a class="elsevierStyleCrossRefs" href="#bib0015">3,78</a>A systematic review of platelet transfusion in patients with brain haemorrhage was inconclusive due to methodological limitations of the studies reviewed.<a class="elsevierStyleCrossRefs" href="#bib0290">58,79,80</a>Specific reversal agents are recommended in patients treated with anticoagulant drugs<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> (Table 8MS). The use of idarucizumab to reverse dabigatran anticoagulation does not appear to be associated with a clear reduction in mortality.<a class="elsevierStyleCrossRef" href="#bib0405">81</a> The recommended doses are 5 g in 2 intravenous doses of 2.5 g over 15 min. Andexanet-alpha has been approved to reverse anticoagulation in patients treated with apixaban and rivaroxaban.DiscussionManagement of MH is extremely complex, and patient survival can be improved by using the multiple tools and strategies included in clinical guidelines, consensus documents, and massive transfusion protocols.This multidisciplinary document, endorsed by SEDAR, SEMICYUC and SETH, updates the recommendations of the original HEMOMAS document.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> This version, like the previous edition, omits specific scenarios such as obstetrics, paediatrics, and gastrointestinal bleeding, because the specific measures required deviate from the purpose of this update.We used a methodology based on a review of relevant articles published since the previous edition — a strategy that allowed us to update the previous recommendations without amending the fundamental structure of the original document.The number of recommendations has been reduced to 41 – fewer than the 2016 edition – containing a total of 61 statements, of which 38 are recommendations and 23 suggestions. The only recommendations with the highest level of evidence refer to the early use of isotonic crystalloids and tranexamic acid in patients with traumatic MH. During the update process, we found it necessary to change the grade of recommendation or level of evidence and wording of certain statements. Table 2MS lists all these modifications.The document highlights the importance of damage control surgery, transfusion of blood products based on appropriate RBC/plasma/platelet ratios, guiding haemostatic therapy by VET or conventional coagulation tests that give a better picture of coagulopathy and allow clinicians to individualize treatment, and specific measures required in patients treated with antiplatelets and anticoagulants.ConclusionsMH is associated with a high rate of mortality. It is vital to regularly update recommendations for the multidisciplinary management of MH in order to allow clinicians to promptly diagnose patients with MH and at risk of MH, implement strategies to control bleeding, replace lost blood volume, and avoid the associated coagulopathy.Financial supportThe present study has been funded by an unrestricted grant from CSL-Behring.AcknowledgementsThe authors wish to thank Fernando Rico-Vilademoros for methodological support, Isabel San Andrés for the literature search, and Ampersand Consulting for logistics in preparing the manuscript. In the years since publication of the first document, some of the original authors have retired from their professional practice. Their generosity in giving way to other colleagues who have joined the panel of experts of the present document must be acknowledged. This new version would not have been possible without the publication of the first HEMOMAS document.Author contributionsJVL: general coordination, review of the recommendations, writing of the manuscript, review and approval of the manuscript. CA, EG, PM, PMN, PP. JAP, MQ, FJRM, AS: review of the recommendations, writing of the manuscript, review and approval of the manuscript." 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] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-05-12" "fechaAceptado" => "2023-05-16" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1692684" "palabras" => array:6 [ 0 => "Massive haemorrhage" 1 => "Transfusion" 2 => "Red blood cells" 3 => "Fresh plasma" 4 => "Fibrinogen" 5 => "Viscoelastic assay" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1692685" "palabras" => array:6 [ 0 => "Hemorragia masiva" 1 => "Transfusión" 2 => "Concentrado de hematíes" 3 => "Plasma fresco" 4 => "Fibrinógeno" 5 => "Test viscoelásticos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "This document is an update of the multidisciplinary document HEMOMAS, published in 2016 with the endorsement of the Spanish Scientific Societies of Anaesthesiology (SEDAR), Intensive Care (SEMICYUC) and Thrombosis and Haemostasis (SETH).The aim of this document was to review and update existing recommendations on the management of massive haemorrhage. The methodology of the update was based on several elements of the ADAPTE method by searching and adapting guidelines published in the specific field of massive bleeding since 2014, plus a literature search performed in PubMed and EMBASE from January 2014 to June 2021.Based on the review of 9 guidelines and 207 selected articles, the 47 recommendations in the original article were reviewed, maintaining, deleting, or modifying each of them and the accompanying grades of recommendation and evidence. Following a consensus process, the final wording of the article and the resulting 41 recommendations were approved by all authors." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El presente documento supone una puesta al día del documento multidisciplinar HEMOMAS, publicado en el año 2016 con el aval de las Sociedades de Anestesiología y Reanimación (SEDAR), Medicina Intensiva, Crítica y Unidades Coronarias (SEMICYUC) y de Trombosis y Hemostasia (SETH).El objetivo de este documento fue revisar y actualizar las recomendaciones existentes sobre el manejo de la hemorragia masiva. Se siguió una metodología basada en elementos del método ADAPTE (búsqueda y adaptación de guías publicadas en el ámbito específico de la hemorragia masiva desde 2014, más búsqueda bibliográfica en PubMed y EMBASE desde enero-2014 hasta junio-2021). Tras la revisión de 9 guías y 207 artículos seleccionados, se actualizaron las 47 recomendaciones existentes en el artículo original, manteniendo, suprimiendo o modificando cada una de ellas y sus grados de recomendación y evidencia. 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Multidisciplinary consensus document on the management of massive haemorrhage. First update 2023 (document HEMOMAS-II)

Documento multidisciplinar de consenso sobre el manejo de la hemorragia masiva. Primera actualización 2023 (documento HEMOMAS-II)

Juan V. Llaua,

Corresponding author

juanvllau@gmail.com

Corresponding author.

, César Aldecoab, Emilia Guaschc, Pascual Marcod, Pilar Marcos-Neirae, Pilar Paniaguaf, José A. Páramog, Manuel Quintanah, F. Javier Rodríguez-Martorelli, Ainhoa Serranoj

a Anestesiología y Reanimación, Hospital Universitario Doctor Peset, València, Spain

b Anestesiología y Reanimación, Hospital Universitario Río Hortega, Valladolid, Spain

c Anestesiología y Reanimación, Hospital Universitario La Paz, Madrid, Spain

d Hemoterapia y Hematología, Hospital General Universitario Dr. Balmis, Alicante, Spain

e Medicina Intensiva, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain

f Anestesiología y Reanimación, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

g Hematología y Hemoterapia, Clínica Universidad de Navarra, Pamplona, Spain

h Medicina Intensiva, Hospital Universitario La Paz, Madrid, Spain

i UGC Hematología y Hemoterapia, Hospital Universitario Virgen del Rocío, Sevilla, Spain

j Medicina Intensiva, Hospital Clínico Universitario, València, Spain

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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Flowchart of bibliographic search&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">&#40;&#42;&#41; Manual search&#58; identification of eligible article after reviewing the references included in selected articles and guidelines&#46; &#40;&#42;&#42;&#41; Articles cited in the recommendation rationale&#44; without including citations in the introduction or methodology sections&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The management of massive haemorrhage &#40;MH&#41; involves implementing several strategies to control bleeding&#44; rapidly replenish blood loss&#44; and minimise potentially life-threatening coagulopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The recent creation and dissemination of multidisciplinary protocols and the publication of excellent guidelines<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;5</span></a> has improved MH management&#44; particularly in the early stages of haemorrhagic shock&#46; However&#44; uncontrolled traumatic bleeding remains the leading preventable cause of death&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In 2015&#44; a multidisciplinary group was formed to review the existing literature and prepare a document that would facilitate decision-making for all those involved in the treatment of MH&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Endorsed by the Spanish scientific societies of Anaesthesiology and Resuscitation &#40;SEDAR&#41;&#44; Intensive and Critical Medicine and Coronary Units &#40;SEMICYUC&#41;&#44; and Thrombosis and Haemostasis &#40;SETH&#41;&#44; the group drafted 47 recommendations or suggestions for the management of MH&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In 2021&#44; given the time elapsed and the advances made in many aspects of MH management&#44; the scientific societies decided it was time to update the existing guidelines using a special methodology that has allowed the expert panel to review and change&#44; if needed&#44; the existing recommendations&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">These guidelines address MH in multiple trauma patients&#44; in the perioperative setting&#44; and in intensive care&#59; however&#44; like the previous guidelines&#44; obstetric haemorrhage&#44; bleeding in paediatric patients&#44; and intestinal bleeding have been excluded due to their particular characteristics and management strategies&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Materials and methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">A group of 10 experts &#40;the authors of this manuscript&#41; met in May 2021 to establish the process for reviewing the original guidelines&#44; and agreed to update the previous consensus recommendations on the basis of other clinical practice guidelines and a review of the latest literature&#46; The methodology used was based on elements of the ADAPTE method that has been described in detail elsewhere&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and involves searching for and adapting other guidelines and published articles&#46; For this project&#44; the working group first identified the skills and resources needed prior to beginning the adaptation process&#46; This was followed by the adaptation phase&#44; in which the literature was searched for eligible guidelines&#44; the recommendations sourced were uploaded to a matrix and&#44; if appropriate&#44; were adapted to the context of our guidelines&#46; The topics to be covered in these guidelines were those included in the original document&#46; The last phase of ADAPTE&#44; where the opinion of decision-makers affected by the updated guide is obtained&#44; was excluded&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The group searched PubMed and EMBASE &#40;January 2014&#8211;June 2021&#59; see Supplementary material and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; to identify clinical practice guidelines published in scientific journals and recommendations from scientific societies related to the management of MH&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">After protocolizing the strategy used to review the results of the bibliographic search and the recommendations of the original guideline &#40;peer review&#41;&#44; the results were shared so that the group could agree on the changes needed based on the latest evidence contained in other recommendations &#40;see details of the review protocol in Supplementary material&#41;&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Results</span><p id="par0045" class="elsevierStylePara elsevierViewall">Only 1 of the 47 recommendations included in the original document was maintained without change&#46; In all the remaining recommendations the group found it necessary to change the wording and&#47;or the grade of recommendation and&#47;or the level of evidence&#46; Seven recommendations were eliminated&#44; some were amalgamated into a single recommendations&#44; and others were expanded based on the available evidence&#46; The final updated guidelines contain 41 recommendations distributed in 14 sections with 61 statements &#40;38 recommendations&#44; 2 with level A evidence&#44; and 23 suggestions&#41;&#46; Tables 1MS and 2MS in the supplementary material compare the original and updated guidelines&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Recommendations and rationale</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Definition and evaluations</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Recommendation 1</span><p id="par0050" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">To evaluate the extent and&#47;or severity of bleeding in surgical patients we recommend visually examining the surgical field to identify extensive microvascular bleeding&#44; and in trauma patients we recommend evaluating the mechanism of injury&#44; the anatomical pattern of injury&#44; and the initial response to resuscitation&#46; &#40;1C&#41;</span></p><p id="par0055" class="elsevierStylePara elsevierViewall">In patients at risk of MH&#44; bleeding should be monitored by clinical examination and quantification&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> In trauma patients&#44; the mechanism and anatomical pattern of injury&#44; and the initial response to resuscitation should also be analysed&#46; These measures can help predict the need to activate massive transfusion protocols &#40;MTP&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;10</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Recommendation 2</span><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest using the Trauma Associated Severe Hemorrhage &#40;TASH&#41; score to promptly identify trauma patients who may benefit from the activation of a massive transfusion protocol &#40;cut-off score 15&#41;&#44; preferably in conjunction with a decrease in clot firmness shown by rotational thromboelastometry or TEG&#44; if available&#46; &#40;2C&#41;</span></p><p id="par0065" class="elsevierStylePara elsevierViewall">It is crucial to rapidly identify patients at risk of developing MH and requiring massive transfusion &#40;MT&#41; in order to immediately activate an MTP and improve prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Several scales have been developed to assess multiple trauma patients&#44; including the TASH score&#44; which measures clinical &#40;blood pressure and heart rate&#44; among others&#41; and analytical &#40;haemoglobin&#44; base excess&#41; parameters and has been shown to correctly identify 88&#46;8&#37; of patients who will require MT&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Viscoelastic tests &#40;VET&#41; can also help predict the need for MTP activation in trauma patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Recommendation 3</span><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest using the &#34;resuscitation intensity&#34; criterion&#44; defined as the transfusion of at least 4 units of packed red blood cells in 1&#8239;hour&#44; to promptly identify non-trauma patients that would benefit from activation of the massive transfusion protocol&#46; &#40;2C&#41;</span></p><p id="par0085" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In the prehospital setting&#44; we suggest using a &#34;Shock Index&#8221; score of 1 or higher to indicate the need to activate the massive transfusion protocol&#46; &#40;2C&#41;</span></p><p id="par0090" class="elsevierStylePara elsevierViewall">In non-trauma patients&#44; experts suggest using the <span class="elsevierStyleItalic">resuscitation intensity</span> criterion of 3&#8722;4 packed red blood cells &#40;RBC&#41; per hour as an indicator of bleeding severity&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">The shock index &#40;SI&#41; &#40;heart rate divided by systolic blood pressure&#41; is the only validated risk scale that exclusively uses clinical variables&#44; and is considered very useful in the prehospital setting&#46; An SI score of 1 higher predicts early mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;14</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Recommendation 4</span><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Hospitals should develop multidisciplinary massive transfusion protocols with evidence-based treatment algorithms that include activation and deactivation criteria and transfusion targets&#44; and should consider transitioning to resuscitation guided by laboratory data or viscoelastic tests as soon as possible&#46; We also recommend launching information campaigns&#44; providing training for the teams involved&#44; and periodically evaluating their effectiveness and compliance with the hospital&#8217;s quality and safety programs&#46; &#40;1B&#41;</span></p><p id="par0105" class="elsevierStylePara elsevierViewall">The establishment and application of multidisciplinary MTPs has been shown to reduce the rate of blood transfusions and mortality in trauma patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> Experts recommend reviewing MTPs regularly in the context of quality and safety standards&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;17</span></a> Other MH scenarios involving refractory bleeding and suspected coagulopathy could also benefit from these protocols<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> by allowing clinicians to coordinate their efforts and effectively control MH&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">When developing MPTs&#44; experts recommend transitioning from an algorithm based on fixed levels of blood components to another guided by laboratory data or VET results&#44; which would reduce blood transfusions and patient morbidity and improve coagulopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Recommendation 5</span><p id="par0115" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In patients presenting massive haemorrhage&#44; we recommend basing the initial assessment on the clinical history and anamnesis &#40;if possible&#41;&#44; and start serial monitoring of blood pressure&#44; heart rate&#44; and serum lactate or base deficit in order to assess tissue perfusion and the degree of hypovolemic shock&#46; &#40;1C&#41;</span></p><p id="par0120" class="elsevierStylePara elsevierViewall">Dynamic monitoring of tissue perfusion includes blood pressure&#44; heart rate&#44; oxygen saturation&#44; and electrocardiography&#44; in addition to clinical signs and symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Serial determination of serum lactate and base deficit is also recommended&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> Although these parameters may not strictly correlate with the severity of bleeding&#44; they do correlate with the degree of hypoperfusion and tissue hypoxia&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Temperature management</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Recommendation 6</span><p id="par0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In patients presenting massive haemorrhage&#44; we recommend routine temperature monitoring and rapid application of measures to prevent heat loss and hypothermia and to maintain core temperature above 35&#8239;&#176;C&#46; &#40;1B&#41;</span></p><p id="par0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Measures to prevent hypothermia include removing wet clothing&#44; covering the patient&#44; increasing room temperature&#44; using forced air blankets or circulating-water mattresses&#44; and rapid infusion warmers for all fluids administered during mass transfusion&#46; Extracorporeal warming systems can also be considered in patients with severe hypothermia and high risk of cardiac arrest&#46; &#40;2C&#41;</span></p><p id="par0135" class="elsevierStylePara elsevierViewall">Maintaining normothermia reduces bleeding and transfusion requirements&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and should be a priority in patients with MH<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> due to the association between hypothermia &#40;core temperature below 35&#8239;&#176;C&#41; and acidosis&#44; hypotension&#44; and coagulopathy&#46; Systematic monitoring of core temperature will indicate the effectiveness of measures to combat hypothermia&#44; such fluid warmers&#44; forced air warming systems or circulating-water mattresses&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> It is also important to warm RBCs and other blood products before they are administered&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Fluid therapy</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Recommendation 7</span><p id="par0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend the early administration of fluid therapy&#44; preferably isotonic crystalloids&#44; in patients with severe bleeding and hypotension&#46; &#40;1A&#41;</span></p><p id="par0145" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In patients with severe traumatic bleeding&#44; balanced crystalloid solutions should be used instead of saline solutions&#46; &#40;1B&#41;</span></p><p id="par0150" class="elsevierStylePara elsevierViewall">Administering fluids to replace volume is the first measure to be taken in MH&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> as these patients are less tolerant of hypovolemia than anaemia&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Crystalloids &#40;Table 3MS&#44; supplementary material&#41; are the fluids of choice due to their clinical efficacy&#44; moderate adverse effects&#44; and low cost&#46; There are insufficient data to suggest that the use of a colloid solution improves prognosis in patients with haemorrhagic shock&#44;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> and some authors have reported adverse effects such as allergic reactions &#40;especially with gelatines&#41;&#44; coagulation disorders&#44; and kidney failure&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Balanced solutions in multiple trauma patients have been associated with greater improvements in acid-base balance and hyperchloremia at 24&#8239;h than 0&#46;9&#37; saline solution&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and a better cost-benefit ratio&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Although studies published after the literature review performed for this update suggest that both solutions could be effective in critically ill patients&#44;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a> we prefer balanced over saline solution in the management of MH in multiple trauma patients&#46; If saline is used&#44; no more than 1&#8211;1&#46;5&#8239;l should be administered&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;19</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Recommendation 8</span><p id="par0165" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend avoiding hypotonic crystalloid solutions such as lactated Ringer&#39;s in patients with severe traumatic brain injury&#46; &#40;1B&#41;</span></p><p id="par0170" class="elsevierStylePara elsevierViewall">Hypotonic solutions&#44; which are less expansive than isotonic and hypertonic solutions and increase the volume of free water&#44; should be avoided in patients with severe traumatic brain injury &#40;TBI&#41; because they may increase mortality compared to 0&#46;9&#37; saline&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;25&#44;26</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Recommendation 9</span><p id="par0175" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest avoiding hypertonic solutions for fluid resuscitation in patients with severe traumatic brain injury&#46; &#40;2C&#41;</span></p><p id="par0180" class="elsevierStylePara elsevierViewall">Hypertonic saline is a first-line measure to temporarily reduce intracranial pressure&#44; but it should not be used as the primary resuscitation fluid for haemorrhagic shock because it does not improve survival or cognitive outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Recommendation 10</span><p id="par0185" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Synthetic colloids should be used sparingly&#46; &#40;1C&#41;</span></p><p id="par0190" class="elsevierStylePara elsevierViewall">The administration of synthetic colloids can aggravate coagulopathy due to their negative effect on haemostasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">These colloids are thought to be more effective than crystalloids at restoring intravascular volume and reducing dosing requirements&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> and are therefore suggested when the crystalloid-vasopressor combination fails to maintain basic tissue perfusion&#46; However&#44; they show no mortality benefit<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> and it remains unclear which solution should be first choice&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Following the withdrawal of hydroxyethyl starches&#44; the only synthetic colloids currently used are gelatines&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Recommendation 11</span><p id="par0205" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend avoiding the routine use of albumin for volume replacement in patients with massive haemorrhage&#46; &#40;1C&#41;</span></p><p id="par0210" class="elsevierStylePara elsevierViewall">There is no evidence that albumin is more effective than other solutes&#46; It is also expensive and associated with potential risks&#44; so it should not be the fluid of choice for volume resuscitation in MH&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Although it has been suggested as a second-line fluid in septic patients after initial administration of large volumes of crystalloids&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> this recommendation cannot be extrapolated to MH&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">A subgroup analysis of the SAFE study<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> suggested that the use of 4&#37; albumin in TBI patients increased the risk of death&#44; possibly due to its hypo-osmolarity&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Some authors have recently suggested that albumin could preserve the endothelial glycocalyx and help maintain vascular permeability&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Finally&#44; albumin could be appropriate for fluid resuscitation in patients with cirrhosis or those undergoing liver<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> or cardiac surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Recommendation 12</span><p id="par0225" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend applying a restrictive volume replacement strategy to achieve target blood pressure until bleeding is controlled&#46; &#40;1B&#41;</span></p><p id="par0230" class="elsevierStylePara elsevierViewall">It is reasonable to tolerate a certain degree of hypotension until bleeding has been controlled&#44; taking into consideration the characteristics of each patient &#40;advanced age&#44; history of hypertension&#44; and target tissue perfusion&#41;&#46; Excessively high blood pressure can contribute to rebleeding&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">In liver surgery&#44; a restrictive fluid strategy has been shown to reduce bleeding and transfusion requirement&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;19</span></a></p></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Fluid resuscitation in hypotensive patients</span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Recommendation 13</span><p id="par0240" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend setting target systolic blood pressure between 80 and 90&#8239;mmHg in bleeding&#44; hypotensive&#44; trauma patients without head injury&#46; This should only be maintained until the source of the bleeding has been controlled&#44; particularly in elderly or hypertensive patients&#46; &#40;1C&#41;</span></p><p id="par0245" class="elsevierStylePara elsevierViewall">&#8220;Damage control resuscitation&#8221;&#44; in other words&#44; restrictive fluid replacement and permissive hypotension&#44; has proven to be beneficial&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;19&#44;34&#44;35</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">However&#44; the recommended mean blood pressure &#40;50&#8722;60&#8239;mmHg&#41; and systolic blood pressure &#40;80&#8722;90&#8239;mmHg&#41; values are arbitrary and may not be safe in all trauma patients&#44; particularly those with blunt and penetrating trauma&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> and should be carefully considered in elderly<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> and chronically hypertensive<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> patients&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Recommendation 14</span><p id="par0255" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In hypotensive patients with traumatic bleeding and TBI&#44; we recommend setting a target systolic blood pressure of at least 110&#8239;mmHg until the source of bleeding has been controlled&#44; particularly in certain patient groups&#44; such as the elderly&#44; hypertensive patients&#44; etc&#46; &#40;1 C&#41;</span></p><p id="par0260" class="elsevierStylePara elsevierViewall">Restrictive fluid replacement and permissive hypotension strategies are contraindicated in patients with severe TBI and acute spinal cord injury&#46; In these cases&#44; it is essential to maintain tissue perfusion pressure and cerebral autoregulation to ensure oxygenation&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;38</span></a></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Recommendation 15</span><p id="par0265" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">If fluid therapy is not effective&#44; we recommend considering early administration of norepinephrine to maintain blood pressure&#44; ideally through a central venous line provided this does not delay the start of treatment&#46; &#40;1C&#41;</span></p><p id="par0270" class="elsevierStylePara elsevierViewall">Vasopressors may be occasionally be necessary to maintain tissue perfusion&#44; with norepinephrine being the agent of choice&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">A study comparing saline plus vasopressin versus saline alone found lower fluid requirements in the vasopressin group&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Although early vasopressors have been shown to be beneficial&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> observational studies have reported higher mortality among trauma patients receiving this therapy&#46; For this reason&#44; guidelines suggest using vasopressors in addition to fluids in patients with refractory hypotension&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;19</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">Norepinephrine is usually administered via a central venous line due to the risk of subcutaneous diffusion and necrosis&#44; but peripheral venous administration is both feasible and effective&#46;</p></span></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Damage control</span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Recommendation 16</span><p id="par0285" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend applying &#34;damage control surgery&#34; in trauma patients who require prolonged surgery and&#47;or present acidosis and&#47;or hypothermia and who also present complex or inaccessible anatomical lesions causing refractory bleeding&#46; &#40;1B&#41;</span></p><p id="par0290" class="elsevierStylePara elsevierViewall">The aim of &#8220;damage control resuscitation&#8221; is to rapidly control bleeding and restore intravascular volume&#46; The strategy includes minimising blood loss&#44; hypotensive resuscitation&#44; balanced haemostatic treatment with a high red blood cell&#58;plasma&#58;platelet ratio &#40;1&#58;1&#58;1&#44; according to the original concept&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> the application of an MTP&#44; restricted crystalloid infusion&#44; and possibly haemostatic supplements&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;42&#44;43</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall">Damage control surgery is one of the basic resuscitation strategies in specific patients&#44; and consists of abbreviated laparotomy and retroperitoneal packing to compress bleeding that is hard to control&#44; followed by restoration of local blood flow where necessary and control of contamination from abdominal viscera&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> This preliminary measure is followed at least 48&#8239;h later by a second intervention to remove the &#34;packing&#34;&#44; leaving the definitive abdominal repair for a third intervention&#44; if necessary&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">The concept of &#8220;orthopaedic damage control&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> consisting of initial stabilization of fractures and leaving definitive osteosynthesis for a second intervention&#44; has been described in multiple trauma patients with severe bone fractures&#46;</p></span></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Monitoring</span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Recommendation 17</span><p id="par0305" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend using dynamic variables such as stroke volume variation &#40;SVV&#41; and pulse pressure variation &#40;PPV&#41; instead of static variables such as central venous pressure &#40;CVP&#41; or pulmonary artery occluded pressure &#40;PAOP&#41; to guide fluid administration in patients in sinus rhythm with severe bleeding who are receiving controlled mechanical ventilation and do not respond to initial fluid therapy&#46; &#40;1B&#41;</span></p><p id="par0310" class="elsevierStylePara elsevierViewall">Dynamic rather than static parameters should be used because they can measure preload and guide the response to fluids in patients with controlled mechanical ventilation and sinus heart rhythm&#46; Commonly used dynamic variables with a high predictive value are stroke volume variation &#40;SVV&#41; and pulse pressure variation &#40;PPV&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> although dynamic variables of volume status &#40;SVV and PPV&#41;&#44; CO<span class="elsevierStyleInf">2</span> gap&#44; and central venous oxygen saturation can also be used&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Recommendation 18</span><p id="par0315" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend performing early&#44; serial determinations of lactate and base deficit to estimate and monitor the severity of bleeding&#44; the degree of hypoperfusion&#44; tissue hypoxia&#44; and shock&#46; &#40;1B&#41;</span></p><p id="par0320" class="elsevierStylePara elsevierViewall">Serial determination of early changes in serum lactate and base deficit are among the most useful laboratory data to estimate and monitor the extent of hypoperfusion and tissue hypoxia&#44; and are a good indicator of prognosis in patients with MH&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;19</span></a></p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Recommendation 19</span><p id="par0325" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In patients with severe bleeding&#44; we recommend early monitoring of haemostasis in order to optimize the administration of blood products and prohaemostatic drugs&#46; Treatment should be individualised using algorithms based&#44; ideally&#44; on the results of viscoelastic tests &#40;1B&#41;&#44; or failing that&#44; on conventional clotting test results&#46; &#40;1C&#41;</span></p><p id="par0330" class="elsevierStylePara elsevierViewall">The most widely used viscoelastic tests &#40;VET&#41; for monitoring coagulation are Rotem&#174; &#40;Instrumentation Laboratory&#44; Bedford&#44; MA&#44; USA&#41; and TEG&#174; &#40;Haemonetics Corporation&#44; Boston&#44; MA&#44; USA&#41;&#46; Conventional clotting tests should include prothrombin time &#40;PT&#41;&#44; activated partial thromboplastin time &#40;aPTT&#41;&#44; the Clauss fibrinogen assay&#44; and platelet count&#46; There is insufficient evidence to show the superiority of one method over another&#44;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;45</span></a> but VETs provide rapid results and additional information on hyperfibrinolysis&#44; clot firmness&#44; and hypofibrinogenemia&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0335" class="elsevierStylePara elsevierViewall">In specific scenarios&#44; such as cardiac surgery and liver transplantation&#44; VETs have proven useful in reducing bleeding and transfusion needs &#40;1B in cardiac surgery&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;46</span></a> The International Society of Thrombosis and Haemostasis &#40;ISTH&#41; suggests using VETs during liver transplantation<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> and the British Society of Haematology suggests using VETs to guide transfusion in obstetric haemorrhage&#44; liver disease&#44; cardiac surgery&#44; and traumatic bleeding&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Recommendation 20</span><p id="par0340" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend basing the indication for RBC transfusion on the result of serial haemoglobin determinations&#44; taking into account both clinical and laboratory parameters&#46; &#40;1C&#41;</span></p><p id="par0345" class="elsevierStylePara elsevierViewall">The decision to administer blood should be based not only on clinical and laboratory parameters&#44; such as blood pressure&#44; heart rate&#44; SI&#44; plasma lactate levels&#44; and base deficit&#44; but also on the patient&#39;s clinical situation&#44; i&#46;e&#46;&#44; multiple trauma &#40;type of fracture or injury&#41;&#44; surgery&#44; or other scenarios&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;49</span></a></p></span></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Blood transfusion</span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Recommendation 21</span><p id="par0350" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In patients presenting massive haemorrhage&#44; we recommend considering early&#44; restrictive transfusion of RBCs&#46; &#40;1B&#41;</span></p><p id="par0355" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest using leukodepleted blood components&#46; &#40;2B&#41;</span></p><p id="par0360" class="elsevierStylePara elsevierViewall">Transfusion of RBCs is generally necessary when blood loss is between 30&#37; and 40&#37;&#46; Taking the patient&#8217;s specific situation into consideration&#44; in addition to clinical and analytical parameters&#44; will avoid performing transfusion based on isolated haemoglobin determinations&#46; A restrictive strategy reduces the need for RBC transfusion&#44; but does not have a greater impact on morbidity and mortality than a liberal strategy&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0365" class="elsevierStylePara elsevierViewall">The use of leukodepleted blood reduces the immune-related complications associated with allogeneic blood transfusion&#46;</p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Recommendation 22</span><p id="par0370" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend administering RBCs to achieve a target Hb of between 7 and 9&#8239;g&#47;dL&#46; &#40;1B&#41;</span></p><p id="par0375" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest considering a transfusion target of 9&#8722;10&#8239;g&#47;dL in high-risk patients with comorbidities&#44; such as chronic cardiovascular disease&#44; acute coronary syndrome&#44; stroke&#44; thrombocytopaenia&#44; and cancer&#46; &#40;2C&#41;</span></p><p id="par0380" class="elsevierStylePara elsevierViewall">The restrictive transfusion threshold is usually 7&#8722;8&#8239;g&#47;dL haemoglobin&#44; and therefore should be avoided in most patients with haemoglobin above that range&#46; In certain patient subgroups and clinical contexts&#44; experts suggest achieving a plasma haemoglobin level of over 9&#8239;g&#47;dL &#40;chronic cardiovascular disease&#44; acute coronary syndrome&#44; stroke&#44; or low-weight and elderly patients&#41;&#44; although there is insufficient evidence to establish recommendations on the optimal transfusion strategy in these subgroups&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#44;51</span></a></p></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Recommendation 23</span><p id="par0385" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend basing initial empirical management of massive haemorrhage on the concept of haemostatic resuscitation with a high fresh plasma-to-packed red blood cell ratio &#40;at least 1&#58;2&#41; in patients with massive haemorrhage secondary to severe trauma&#46; There is insufficient evidence to make specific recommendations in non-trauma patient&#46; &#40;1C&#41;</span></p><p id="par0390" class="elsevierStylePara elsevierViewall">Some authors suggest that transfusion strategies with fixed&#44; high plasma&#47;RBC ratios&#44; are beneficial&#44; particularly in multiple trauma patients&#44; although it has not been possible to show that the 1&#58;1&#58;1 ratio has a better risk-benefit profile than the 1&#58;1&#58;2&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;52&#8211;54</span></a></p></span></span><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0195">Plasma transfusion</span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0200">Recommendation 24</span><p id="par0395" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In massive haemorrhage follow-up&#44; we recommend administering fresh plasma using a goal-directed strategy based on clinical signs &#40;microvascular bleeding&#44; bleeding control&#41; and laboratory tests &#40;evidence of prolonged CT or R in viscoelastic tests&#44; or a high prothrombin time &#40;PT&#41; ratio and&#47;or activated partial thromboplastin time &#40;aPTT&#41; in conventional tests&#41;&#46; &#40;1C&#41;</span></p><p id="par0400" class="elsevierStylePara elsevierViewall">Plasma transfusion is still the gold standard for preventing and treating coagulopathy in MH&#44; despite its known drawbacks and the slow turnaround of laboratory tests&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0405" class="elsevierStylePara elsevierViewall">According to studies&#44; transfusion based on a pre-established higher blood product ratio provides a higher volume of plasma and platelets compared with a goal-directed strategy&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p></span></span><span id="sec0185" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0205">Platelet transfusion</span><span id="sec0190" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0210">Recommendation 25</span><p id="par0410" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend administering platelet concentrates to maintain platelets above 50&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L in all patients with active bleeding&#46; &#40;1C&#41;</span></p><p id="par0415" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest performing platelet transfusion to maintain platelets above 100&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L in patients with massive haemorrhage and brain injury or eye injury&#44; or in patients scheduled for neurosurgery or interventions involving the posterior pole of the eye&#44; or in patients with platelets above 50&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L and active&#44; refractory bleeding&#46; &#40;2C&#41;</span></p><p id="par0420" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest considering platelet concentrate transfusion to maintain a count of 50&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L in patients requiring a major invasive procedure or in multiple trauma patients&#44; even in the absence of bleeding&#46; &#40;2C&#41;</span></p><p id="par0425" class="elsevierStylePara elsevierViewall">Despite the lack of solid scientific evidence&#44; there is widespread agreement that a platelet count of at least 50&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L should be maintained in patients with acute bleeding&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;7&#44;19&#44;55&#8211;57</span></a></p><p id="par0430" class="elsevierStylePara elsevierViewall">In patients with TBI or eye bleeding&#44; we recommend maintaining platelets above 100&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;19&#44;56</span></a> This threshold has been extended to include patients with persistent bleeding&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;19&#44;56&#44;57</span></a> There are no strong recommendations regarding platelet transfusion to control bleeding in patients with platelet dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a></p><p id="par0435" class="elsevierStylePara elsevierViewall">Some experts suggest administering prophylactic platelet transfusion in patients requiring major surgery or in multiple trauma patients when platelets are below 50&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;19&#44;58&#44;59</span></a></p></span><span id="sec0195" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0215">Recommendation 26</span><p id="par0440" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest avoiding platelet transfusion in patients taking antiplatelet therapy before intracerebral haemorrhage &#40;spontaneous or traumatic&#41;&#44; unless they will require neurosurgery&#46; &#40;2C&#41;</span></p><p id="par0445" class="elsevierStylePara elsevierViewall">This recommendation is derived from the PATCH study<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> in which clinical outcomes and 3-month mortality were worse in transfused patients &#40;see recommendation 41&#41;&#46;</p></span><span id="sec0200" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0220">Recommendation 27</span><p id="par0450" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest administering an initial dose of 4&#8211;8 platelet concentrates &#40;or the equivalent&#58; 1&#8211;2 units pooled&#41;&#44; or 1 apheresis unit&#44; adjusting the rate of administration to bleeding persistence&#44; the platelet count achieved with the initial dose&#44; the response to other measures to control bleeding&#44; and the results of viscoelastic tests&#44; if available&#46; &#40;2C&#41;</span></p><p id="par0455" class="elsevierStylePara elsevierViewall">The platelet transfusion dose was already suggested in the previous version of this guide&#46; If donors are available&#44; 1 apheresis unit &#40;equivalent to 4&#8722;6 platelet concentrates<span class="elsevierStyleItalic">&#41;</span> increases the count by 30&#8722;50&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L and reduces exposure to multiple donors&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;58&#44;59</span></a></p></span></span><span id="sec0205" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0225">Prothrombin complex concentrate</span><span id="sec0210" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0230">Recommendation 28</span><p id="par0460" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In the context of massive haemorrhage&#44; we recommend administering prothrombin complex concentrate and vitamin K to rapidly reverse the effect of antivitamin K oral anticoagulants in patients treated with these drugs&#46; &#40;1B&#41;</span></p><p id="par0465" class="elsevierStylePara elsevierViewall">In this context&#44; administration of prothrombin complex concentrate &#40;PCC&#41;&#44; preferably four-factor prothrombin complex concentrate&#44;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;19&#44;61&#8211;64</span></a> should be the first choice for urgent reversal of the anticoagulant effect of antivitamin-K drugs<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;5&#44;9&#44;17</span></a> &#40;Tables 4MS and 5MS&#44; supplementary material&#41;&#46; Although the optimal dosing strategy remains unclear&#44; experts recommend adjusting the dose to the patient&#8217;s weight and INR values&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a></p></span><span id="sec0215" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0235">Recommendation 29</span><p id="par0470" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We do not recommend prothrombin complex concentrate as first choice haemostatic in patients with massive haemorrhage who have not received antivitamin K oral anticoagulants&#44; although it may be used in certain patients based on the urgency of the treatment and the availability of fresh plasma&#46; &#40;1C&#41;</span></p><p id="par0475" class="elsevierStylePara elsevierViewall">There is insufficient evidence to recommend the use of PCC as first choice haemostatic in MH&#46;</p><p id="par0480" class="elsevierStylePara elsevierViewall">In specific scenarios&#44; however&#44; such as refractory bleeding&#44; cardiac surgery&#44;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">63&#44;64</span></a> liver surgery&#44; and multiple trauma&#44;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> some experts suggest the off-label use of PCC in the context of multimodal management of MH&#44; in accordance with the established legal framework&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;5&#44;9&#44;17</span></a></p></span><span id="sec0220" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0240">Recommendation 30</span><p id="par0485" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest restricting the use of activated prothrombin complex concentrate or rFVIIa to haemophiliac patients with inhibitors who present massive haemorrhage&#46; &#40;2C&#41;</span></p><p id="par0490" class="elsevierStylePara elsevierViewall">Activated PCC &#40;FEIBA&#41; and rFVIIa are specifically indicated in congenital haemophilia with inhibitor and acquired haemophilia&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">66&#44;67</span></a></p></span><span id="sec0225" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0245">Recommendation 31</span><p id="par0495" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest using prothrombin complex concentrates with caution in high thrombotic risk patients who present massive life-threatening bleeding or require surgery that cannot be delayed&#46; &#40;2C&#41;</span></p><p id="par0500" class="elsevierStylePara elsevierViewall">Although PCCs are considered safe&#44; thrombotic complications have been reported in 2&#37;&#8211;4&#37; of patients treated for MH&#46; Therefore&#44; the risk&#47;benefit balance must be individualised in patients with bleeding and high risk for thrombosis&#46;</p></span></span><span id="sec0230" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0250">Fibrinogen</span><span id="sec0235" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0255">Recommendation 32</span><p id="par0505" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend using the Clauss fibrinogen method&#44; FIBTEM in ROTEM&#174; or Functional Fibrinogen in TEG&#174; to determine fibrinogen for diagnosis or clinical management decisions in patients with massive haemorrhage &#40;1C&#41;</span></p><p id="par0510" class="elsevierStylePara elsevierViewall">This recommendation&#44; included in the previous version of the guide&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> remains valid&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;9&#44;13&#44;68</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> Fibrinogen should be quantified using the Clauss method&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0240" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0260">Recommendation 33</span><p id="par0515" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In patients with active bleeding&#44; we recommend administering fibrinogen concentrate if plasma levels &#40;Clauss functional assay&#41; are below 1&#46;5&#8211;2&#46;0&#8239;g&#47;L&#44; or A5 FIBTEM is below 7&#8211;9&#8239;mm or&#44; by equivalence&#44; the maximum amplitude on the citrated functional fibrinogen assay is less than 10&#8239;mm&#46; &#40;1C&#41;</span></p><p id="par0520" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend administering fibrinogen concentrate together with RBCs in the initial phase of massive&#44; particularly trauma-related&#44; bleeding as an alternative to haemostatic resuscitation&#44; even if VET or clotting results are unavailable &#40;1C&#41;</span></p><p id="par0525" class="elsevierStylePara elsevierViewall">The threshold for fibrinogen administration is controversial&#46; Plasma levels should not be lower than 1&#46;5&#8239;g&#47;L&#44;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;13&#44;19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#44;68&#8211;70</span></a> which corresponds to A5 FIBTEM&#8239;&#60;&#8239;7&#8239;mm&#44; although a threshold of 8&#8722;9&#8239;mm has been proposed in some clinical scenarios&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> The equivalent threshold in TEG&#174; is a maximum amplitude &#40;MA<span class="elsevierStyleInf">CFF</span>&#41; of 10&#8239;mm&#46;</p></span></span><span id="sec0245" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0265">Recommendation 34</span><p id="par0530" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest administering an initial dose of 25&#8722;50&#8239;mg&#47;kg of fibrinogen concentrate if the recommended plasma threshold is not achieved&#46; Repeat doses&#44; if required&#44; should be guided by VET&#46; &#40;2C&#41;</span></p><p id="par0535" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In adult traumatic bleeding patients&#44; we suggest administering a minimum loading dose of 3&#8722;4&#8239;grams&#46; &#40;2C&#41;</span></p><p id="par0540" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We do not recommend plasma as the first choice source of fibrinogen&#59; however&#44; it can be used if fibrinogen concentrate or cryoprecipitate is not available&#46; &#40;1C&#41;</span></p><p id="par0545" class="elsevierStylePara elsevierViewall">Although we recommend administering a loading dose of 3&#8722;4&#8239;g in patients with multiple trauma and then continuing with VET-guided administration&#44;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;19</span></a> the dose should ideally be weight-adjusted<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;19&#44;68</span></a> &#40;Table 6MS&#41;&#46;</p><p id="par0550" class="elsevierStylePara elsevierViewall">Alternatively&#44; 4&#8722;6&#8239;ml&#47;kg cryoprecipitate could be used &#40;approximately 1U&#47;5&#8722;10&#8239;kg&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;9&#44;71</span></a></p></span><span id="sec0250" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0270">Factor VIIa</span><span id="sec0255" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0275">Recommendation 35</span><p id="par0555" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Factor VIIa should not be first-line therapy in massive haemorrhage&#46; &#40;1B&#41;</span></p><p id="par0560" class="elsevierStylePara elsevierViewall">We suggest considering factor VIIa only in patients refractory to conventional haemostatic measures&#46; &#40;2B&#41;</p><p id="par0565" class="elsevierStylePara elsevierViewall">Factor VIIa is not indicated for the treatment of MH&#46; The few studies investigating factor VIIa in massive haemorrhage have reported equivocal results and a high incidence of thrombotic events&#44; particularly arterial&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;9&#44;17</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;72</span></a></p><p id="par0570" class="elsevierStylePara elsevierViewall">We suggest using factor VIIa only if all other haemostasis measures have been ineffective and fibrinogen&#44; platelet count&#44; pH&#44; and temperature have been optimized<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;68&#44;72</span></a> &#40;Table 7MS&#41;&#46;</p></span></span><span id="sec0260" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0280">Antifibrinolytics</span><span id="sec0265" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0285">Recommendation 36</span><p id="par0575" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend administering tranexamic acid &#40;TXA&#41; within 3&#8239;hours of the onset of massive traumatic haemorrhage and in patients with TBI&#46; &#40;1A&#41;</span></p><p id="par0580" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest treating severe perioperative bleeding with tranexamic acid&#44; ideally under VET guidance&#46; &#40;2B&#41;</span></p><p id="par0585" class="elsevierStylePara elsevierViewall">The recommendation to use TXA in multiple trauma and TBI patients is based on the CRASH-2<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> and CRASH-3 studies&#44; respectively&#46; However&#44; it is important to bear in mind that late administration does not provide benefits and increases complications&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> The recommended loading dose is 1&#8239;g over 10&#8239;min&#44; followed by infusion of 1&#8239;g over 8&#8239;h&#46;</p><p id="par0590" class="elsevierStylePara elsevierViewall">In the perioperative context&#44; some authors suggest administering TXA to treat active bleeding&#44; although this is not supported by evidence from randomised trials&#46; TXA should be administered when hyperfibrinolysis has been confirmed&#44; except in cardiac surgery&#44; where there is a high level of evidence &#40;1A&#41; to recommend it as a prophylactic&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p></span></span><span id="sec0270" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0290">Other measures</span><span id="sec0275" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0295">Recommendation 37</span><p id="par0595" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest evaluating the administration of desmopressin &#40;0&#46;3&#8239;&#956;g&#47;kg&#41; in bleeding patients with von Willebrand disease&#46; &#40;2C&#41;</span></p><p id="par0600" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest evaluating the administration of desmopressin &#40;0&#46;3&#8239;&#956;g&#47;kg&#41; in uraemic bleeding patients treated with aspirin or patients with critical bleeding and known platelet dysfunction&#46; &#40;2C&#41;</span></p><p id="par0605" class="elsevierStylePara elsevierViewall">Desmopressin &#40;DDAVP&#41; is effective in the treatment and prevention of mild to moderate bleeding in patients with congenital or acquired disorders of primary haemostasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;9</span></a></p></span><span id="sec0280" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0300">Recommendation 38</span><p id="par0610" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend using topical haemostatics in combination with conventional surgery-specific measures in patients presenting massive haemorrhage&#46; &#40;1B&#41;</span></p><p id="par0615" class="elsevierStylePara elsevierViewall">Topical haemostatics are effective when the source of bleeding can be accessed directly&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;7&#44;9</span></a></p></span><span id="sec0285" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0305">Recommendation 39</span><p id="par0620" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend considering mechanical control measures&#44; such as angioembolization&#46; &#40;1B&#41;</span></p><p id="par0625" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest using endovascular procedures &#40;e&#46;g&#46;&#44; REBOA&#41; to treat massive haemorrhage in certain patients&#44; if available&#46; &#40;2C&#41;</span></p><p id="par0630" class="elsevierStylePara elsevierViewall">Angioembolization is an effective alternative to early open surgery<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> in certain patients &#40;nonvariceal or lower upper gastrointestinal bleeding&#44; or pancreatitis-induced arterial bleeding&#41;&#44; and in patients with pelvic fracture&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0635" class="elsevierStylePara elsevierViewall">The use of aortic balloon occlusion can be considered under extreme circumstances in multiple trauma patients to gain time until bleeding can be controlled&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> in patients with a ruptured abdominal aortic aneurysm&#44; and in those with severe gastrointestinal or peripartum haemorrhage&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0290" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0310">Recommendation 40</span><p id="par0640" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend monitoring plasma calcium levels in bleeding patients &#40;1C&#41;&#44; particularly if massive transfusion is required&#46; &#40;1B&#41;</span></p><p id="par0645" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend maintaining plasma calcium levels in the normal range and administering calcium in case of hypocalcaemia &#40;ionic Ca &#60;3&#46;6&#8239;mg&#47;dl&#44; or corrected serum calcium &#60;7&#46;5&#8239;mg&#47;dl&#41;&#46; &#40;1B&#41;</span></p><p id="par0650" class="elsevierStylePara elsevierViewall">It is important to control calcium whenever large volumes of blood components are administered&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">75&#8211;77</span></a></p></span><span id="sec0295" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0315">Recommendation 41</span><p id="par0655" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In cases of severe or massive haemorrhage&#44; we recommend ascertaining whether the patient is under treatment with antiplatelet drugs or anticoagulants&#46; If so&#44; reversal agents should be administered&#44; provided an individual analysis has shown that the benefit outweighs the risk of thrombosis&#46; &#40;1B&#41;</span></p><p id="par0660" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We recommend administering prothrombin complex concentrate plus vitamin-k in patients treated with vitamin K-dependent oral anticoagulants&#46; &#40;1B&#41;</span></p><p id="par0665" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest performing early platelet transfusion in patients with bleeding clearly associated with antiplatelet drugs&#44; ideally after monitoring platelet function&#46; &#40;2C&#41;</span></p><p id="par0670" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In patients treated with dabigatran&#44; we suggest administering idarucizumab instead of non-specific haemostatic agents such as prothrombin complex concentrates&#46; &#40;2A&#41;</span></p><p id="par0675" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">We suggest administering andexanet alpha or prothrombin complex concentrate in patients receiving oral factor-Xa inhibitors &#40;&#8220;xabans&#8221;&#41; who present life-threatening or uncontrolled bleeding&#46; &#40;2C&#41;</span></p><p id="par0680" class="elsevierStylePara elsevierViewall">Platelets may be the best option in patients with bleeding clearly associated with antiplatelet drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> The effectiveness of this treatment will depend on certain factors&#44; such as the antiplatelet drug involved&#44; the time since the last dose&#44; the mechanism and site of bleeding&#44; and the criteria of efficacy&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> Dosage is equally uncertain&#44; with some authors suggesting 0&#46;7&#8239;&#215;&#8239;10<span class="elsevierStyleSup">11</span>&#47;10&#8239;kg &#40;equivalent to approximately one unit of platelet concentrate per 10&#8239;kg&#44; or 2 pools in a 70&#8722;80&#8239;kg patient&#41; in bleeding associated with aspirin use&#44; up to double when associated with clopidogrel&#44; or even more in the case of prasugrel&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;78</span></a></p><p id="par0685" class="elsevierStylePara elsevierViewall">A systematic review of platelet transfusion in patients with brain haemorrhage was inconclusive due to methodological limitations of the studies reviewed&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;79&#44;80</span></a></p><p id="par0690" class="elsevierStylePara elsevierViewall">Specific reversal agents are recommended in patients treated with anticoagulant drugs<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> &#40;Table 8MS&#41;&#46; The use of idarucizumab to reverse dabigatran anticoagulation does not appear to be associated with a clear reduction in mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> The recommended doses are 5&#8239;g in 2 intravenous doses of 2&#46;5&#8239;g over 15&#8239;min&#46; Andexanet-alpha has been approved to reverse anticoagulation in patients treated with apixaban and rivaroxaban&#46;</p></span></span></span><span id="sec0300" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0320">Discussion</span><p id="par0695" class="elsevierStylePara elsevierViewall">Management of MH is extremely complex&#44; and patient survival can be improved by using the multiple tools and strategies included in clinical guidelines&#44; consensus documents&#44; and massive transfusion protocols&#46;</p><p id="par0700" class="elsevierStylePara elsevierViewall">This multidisciplinary document&#44; endorsed by SEDAR&#44; SEMICYUC and SETH&#44; updates the recommendations of the original HEMOMAS document&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> This version&#44; like the previous edition&#44; omits specific scenarios such as obstetrics&#44; paediatrics&#44; and gastrointestinal bleeding&#44; because the specific measures required deviate from the purpose of this update&#46;</p><p id="par0705" class="elsevierStylePara elsevierViewall">We used a methodology based on a review of relevant articles published since the previous edition &#8212; a strategy that allowed us to update the previous recommendations without amending the fundamental structure of the original document&#46;</p><p id="par0710" class="elsevierStylePara elsevierViewall">The number of recommendations has been reduced to 41 &#8211; fewer than the 2016 edition &#8211; containing a total of 61 statements&#44; of which 38 are recommendations and 23 suggestions&#46; The only recommendations with the highest level of evidence refer to the early use of isotonic crystalloids and tranexamic acid in patients with traumatic MH&#46; During the update process&#44; we found it necessary to change the grade of recommendation or level of evidence and wording of certain statements&#46; Table 2MS lists all these modifications&#46;</p><p id="par0715" class="elsevierStylePara elsevierViewall">The document highlights the importance of damage control surgery&#44; transfusion of blood products based on appropriate RBC&#47;plasma&#47;platelet ratios&#44; guiding haemostatic therapy by VET or conventional coagulation tests that give a better picture of coagulopathy and allow clinicians to individualize treatment&#44; and specific measures required in patients treated with antiplatelets and anticoagulants&#46;</p></span><span id="sec0305" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0325">Conclusions</span><p id="par0720" class="elsevierStylePara elsevierViewall">MH is associated with a high rate of mortality&#46; It is vital to regularly update recommendations for the multidisciplinary management of MH in order to allow clinicians to promptly diagnose patients with MH and at risk of MH&#44; implement strategies to control bleeding&#44; replace lost blood volume&#44; and avoid the associated coagulopathy&#46;</p></span><span id="sec0310" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0330">Financial support</span><p id="par0725" class="elsevierStylePara elsevierViewall">The present study has been funded by an unrestricted grant from CSL-Behring&#46;</p></span><span id="sec0315" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0335">Acknowledgements</span><p id="par0735" class="elsevierStylePara elsevierViewall">The authors wish to thank Fernando Rico-Vilademoros for methodological support&#44; Isabel San Andr&#233;s for the literature search&#44; and Ampersand Consulting for logistics in preparing the manuscript&#46; In the years since publication of the first document&#44; some of the original authors have retired from their professional practice&#46; Their generosity in giving way to other colleagues who have joined the panel of experts of the present document must be acknowledged&#46; This new version would not have been possible without the publication of the first HEMOMAS document&#46;</p></span><span id="sec0320" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0340">Author contributions</span><p id="par0785" class="elsevierStylePara elsevierViewall">JVL&#58; general coordination&#44; review of the recommendations&#44; writing of the manuscript&#44; review and approval of the manuscript&#46; CA&#44; EG&#44; PM&#44; PMN&#44; PP&#46; JAP&#44; MQ&#44; FJRM&#44; AS&#58; review of the recommendations&#44; writing of the manuscript&#44; review and approval of the manuscript&#46;</p></span></span>"
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                1 => array:2 [
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                  "titulo" => "Recommendation 9"
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                  "titulo" => "Recommendation 12"
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                  "titulo" => "Recommendation 14"
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              "titulo" => "Monitoring"
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                  "titulo" => "Recommendation 18"
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                2 => array:2 [
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                  "titulo" => "Recommendation 19"
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                  "titulo" => "Recommendation 20"
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              "titulo" => "Blood transfusion"
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                  "titulo" => "Recommendation 22"
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                  "titulo" => "Recommendation 26"
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                  "titulo" => "Recommendation 27"
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              "titulo" => "Prothrombin complex concentrate"
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                  "titulo" => "Recommendation 29"
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                2 => array:2 [
                  "identificador" => "sec0220"
                  "titulo" => "Recommendation 30"
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                3 => array:2 [
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                  "titulo" => "Recommendation 31"
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              "titulo" => "Fibrinogen"
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                  "titulo" => "Recommendation 33"
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              "titulo" => "Recommendation 34"
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              "titulo" => "Antifibrinolytics"
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              "titulo" => "Other measures"
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