Rossaint et al. Critical Care (2023) 27:80 Critical Care https://doi.org/10.1186/s13054-023-04327-7 GUIDELINES Open Access The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition Rolf Rossaint1*, Arash Afshari2, Bertil Bouillon3, Vladimir Cerny4,5, Diana Cimpoesu6, Nicola Curry7,8, Jacques Duranteau9, Daniela Filipescu10, Oliver Grottke1, Lars Grønlykke11, Anatole Harrois9, Beverley J. Hunt12, Alexander Kaserer13, Radko Komadina14, Mikkel Herold Madsen2, Marc Maegele15, Lidia Mora16, Louis Riddez17, Carolina S. Romero18, Charles‑Marc Samama19, Jean‑Louis Vincent20, Sebastian Wiberg11 and Donat R. Spahn13 Abstract Background Severe trauma represents a major global public health burden and the management of post-traumatic bleeding continues to challenge healthcare systems around the world. Post-traumatic bleeding and associated trau‑ matic coagulopathy remain leading causes of potentially preventable multiorgan failure and death if not diagnosed and managed in an appropriate and timely manner. This sixth edition of the European guideline on the management of major bleeding and coagulopathy following traumatic injury aims to advise clinicians who care for the bleeding trauma patient during the initial diagnostic and therapeutic phases of patient management. Methods The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma included repre‑ sentatives from six European professional societies and convened to assess and update the previous version of this guideline using a structured, evidence-based consensus approach. Structured literature searches covered the period since the last edition of the guideline, but considered evidence cited previously. The format of this edition has been adjusted to reflect the trend towards concise guideline documents that cite only the highest-quality studies and most relevant literature rather than attempting to provide a comprehensive literature review to accompany each recommendation. Results This guideline comprises 39 clinical practice recommendations that follow an approximate temporal path for management of the bleeding trauma patient, with recommendations grouped behind key decision points. While approximately one-third of patients who have experienced severe trauma arrive in hospital in a coagulopathic state, a systematic diagnostic and therapeutic approach has been shown to reduce the number of preventable deaths attributable to traumatic injury. Conclusion A multidisciplinary approach and adherence to evidence-based guidelines are pillars of best practice in the management of severely injured trauma patients. Further improvement in outcomes will be achieved by optimis‑ ing and standardising trauma care in line with the available evidence across Europe and beyond. *Correspondence: Rolf Rossaint RRossaint@ukaachen.de Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. 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Critical Care (2023) 27:80 Page 2 of 45 Key messages • Immediate detection and management of traumatic coagulopathy improves outcomes of severely injured patients. • This guideline follows management of the severe trauma patient in chronological order, with a focus on preven- tion of possible exsanguination. • These structured recommendations support measures that prioritise the optimisation of resources for the ben- efit of bleeding control based on scientific evidence. • Empirical management should not be implemented unless no method of monitoring bleeding and coagulation is available. • Optimal organisation of the resuscitation team for the bleeding trauma patient includes implementation of these guidelines. Keywords Emergency medicine, Trauma, Traumatic coagulopathy, Major bleeding, Haemostasis, Practice guideline, Diagnostics, Management Background of Intensive Care Medicine (ESICM), European Shock Severe trauma represents a major global public health Society (ESS), European Society for Trauma and Emer- burden. The Global Burden of Diseases, Injuries, and gency Surgery (ESTES), European Society for Emergency Risk Factors Study (GBD 2017), estimated that trauma Medicine (EuSEM) and the Network for Advancement of accounted for 8% of total deaths annually [1]. Moreover, Patient Blood Management, Haemostasis and Thrombo- among adolescents aged 10–24 years, road injuries, self- sis (NATA). harm and interpersonal violence are top causes of disabil- Following a web conference in May 2021, scientific ity-adjusted life-years; in the 25–49 year age group road queries of interest were defined by the authors and for- injuries are ranked first [2]. Post-traumatic bleeding and mulated in PICO (Population/Intervention/Comparison/ associated traumatic coagulopathy remain leading causes Outcome) format by one author (CSR) in consultation of potentially preventable multiorgan failure and death if with the methodologist (AA) (Additional file 1). Lit- not diagnosed and managed in an appropriate and timely erature search bundles and corresponding structured manner [3]. search strategies were developed and applied to Medline Approximately one-third of patients who have expe- (OvidSP), Cochrane Central Register of Controlled Trials rienced severe trauma arrive in hospital in a coagulo- (CENTRAL) and Epistemonikos databases by a Cochrane pathic state, and a systematic diagnostic and therapeutic trial search specialist. Landmark publications were used approach has been shown to reduce the number of pre- to refine literature search bundles and database searches ventable deaths attributable to traumatic injury [3–5]. were restricted to 01 Jan 2018 to 02 Dec 2021 for exist- This guideline aims to provide an evidence-based set of ing recommendations and from 01 January 2001 to 02 recommendations to advise clinicians who care for the December 2021 for new topics. Identified de-duplicated bleeding trauma patient during the initial diagnostic and abstracts were pre-screened by a subset of authors (LG, therapeutic phases of patient management. MHM, SW) and pre-selected abstracts from relevant search bundles were screened by each author (Addi- Methods tional file 2). Relevant full-text articles were retrieved and A panel of experts comprising the pan-European, mul- assessed in detail. Literature cited within identified arti- tidisciplinary Task Force for Advanced Bleeding Care cles and the previous edition of the guideline as well as in Trauma convened to assess and update the previous relevant subsequent publications were also considered. version of this guideline [6] in light of the latest avail- The authors aimed to include a restricted number of able published evidence on the management of bleeding supporting references to support each recommendation and coagulopathy following traumatic injury. The author as part of a brief accompanying rationale, with studies of group comprises experts in the fields of emergency medi- the best available quality from any publication date given cine, surgery, anaesthesiology, haematology and intensive priority. Recommendations were formulated and graded care medicine, including representatives from six Euro- according the Grading of Recommendations Assessment, pean professional societies: European Society of Anaes- Development and Evaluation (GRADE) system (Table 1) thesiology and Intensive Care (ESAIC), European Society [7]. Recommendations, grading and rationales were Rossaint et al. Critical Care (2023) 27:80 Page 3 of 45 initially drafted and critically reviewed by at least two idea that “systemised” trauma care that matches each authors and then distributed to the entire author group patient to the most appropriate treatment facility in for review prior to the live consensus process. The qual- a timely manner is advantageous, whereby the defini- ity of the literature cited to support each recommenda- tion of “appropriate” depends on patient vital status, tion was reviewed separately by the methodologist (AA), the nature of the injuries and the hospital facilities who applied Cochrane risk-of-bias assessment criteria [8] available. and/or the SIGN checklist (https://​www.​sign.​ac.​uk/​what-​ There is a consensus that trauma patients in need we-​do/​metho​dology/​check​lists/) for observational stud- of emergency intervention for ongoing haemorrhage ies to the evaluation. have increased chances of survival if the elapsed time Authors participated in a series of virtual consen- between injury and start of the intervention is mini- sus conferences in May and June 2022, during which mised. In a recent study of early haemorrhagic trauma the wording and grading of each recommendation were deaths, 34.5% were classified as potentially preventable finalised and confirmed by voting members of the expert by stopping bleeding early [11]. Time to intervention panel (RR, AA, BB, VC, DC, NC, JD, DF, OG, AH, BJH, can be lost in the pre-hospital and early in-hospital AK, RK, MM, LM, LR, CMS, JLV, DRS). Grading was settings. A retrospective analysis of a National Emer- confirmed and disagreements resolved in consultation gency Medical services Information System (NEMSIS) with the methodologist (AA). Following final revisions, with 2,018,141 patients revealed that increased scene manuscript collation and approval by the author group, time was associated with greater mortality for blunt the manuscript was peer-reviewed and approved by the and penetrating trauma [12]. A study in penetrating endorsing professional societies between September and trauma showed that every additional minute in pre- November 2022. hospital response time correlated with a 2% increase in mortality, and every additional minute in pre-hospital Results scene time correlated with a 1% increase in mortality I. Initial resuscitation and prevention of further bleeding [13]. In a systematic review of the influence of pre-hos- Minimal elapsed time pital time on outcome of trauma patients, the authors Recommendation 1 We recommend that severely found that a rapid transportation of haemodynamically injured patients be transported directly to an appropriate unstable patients with penetrating injuries was benefi- trauma facility (Grade 1B). cial [14]. In haemodynamically stable patients, mortal- We recommend that the time elapsed between injury ity did not correlate with increased pre-hospital times. and bleeding control be minimised (Grade 1B). Another study demonstrated that longer pre-hospital times in trauma patients did not increase 30-day mor- Rationale tality but were associated with an increased risk of poor Regionalisation of trauma management, with desig- functional outcome [15]. Several authors outline that it nated trauma centres that offer different levels of care is important to minimise the time from injury to inter- and that interact with both each other and pre-hospi- vention in trauma patients with ongoing bleeding, be it tal emergency medical services have improved trauma surgery or embolisation [16, 17]. This means that not care in many countries. Several have also implemented only is swift pre-hospital care of the essence, but timely trauma quality improvement programmes and con- in-hospital trauma management (door-to-needle time) tinuously evaluate their results using trauma registries. as well. In a recent systematic review and meta-analysis of 52 studies that included 1,106,431 trauma patients, the Local bleeding management effectiveness of such trauma care systems was evalu- Recommendation 2 We recommend local compression ated [9]. The study showed a significant reduction in of open wounds to limit life-threatening bleeding (Grade mortality after implementation of trauma systems and 1B). demonstrated that survival improved when systems We recommend adjunct tourniquet use to stop life- were further developed. In a retrospective multicen- threatening bleeding from open extremity injuries in tre cohort study of the Quebec trauma registry the the pre-surgical setting (Grade 1B). impact of trauma centre designation level on outcomes following haemorrhagic shock (systolic blood pres- sure < 90 mmHg) was studied [10]. Level I trauma cen- Rationale tres showed significantly lower standardised mortality Most life-threatening bleeding from open inju- rates among bleeding trauma patients compared with ries to extremities observed in the civilian setting level III and IV trauma centres. This study supports the can be controlled by local compression, either by Rossaint et al. Critical Care Table 1 Grading of recommendations after [7] Grade of recommendation Clarity of risk/benefit Quality of supporting evidence Implications 1A (2023) 27:80 Strong recommendation, high-quality evidence Benefits clearly outweigh risk and burdens, or RCTs without important limitations or over‑ Strong recommendation, can apply to most vice versa whelming evidence from observational studies patients in most circumstances without reserva‑ tion 1B Strong recommendation, moderate-quality Benefits clearly outweigh risk and burdens, or RCTs with important limitations (inconsistent Strong recommendation, can apply to most evidence vice versa results, methodological flaws, indirect or impre‑ patients in most circumstances without reserva‑ cise) or exceptionally strong evidence from tion observational studies 1C Strong recommendation, low-quality or very Benefits clearly outweigh risk and burdens, or Observational studies or case series Strong recommendation but may change when low-quality evidence vice versa higher-quality evidence becomes available 2A Weak recommendation, high-quality evidence Benefits closely balanced with risks and burden RCTs without important limitations or over‑ Weak recommendation, best action may differ whelming evidence from observational studies depending on circumstances or patients’ or societal values 2B Weak recommendation, moderate-quality Benefits closely balanced with risks and burden RCTs with important limitations (inconsistent Weak recommendation, best action may differ evidence results, methodological flaws, indirect or impre‑ depending on circumstances or patients’ or cise) or exceptionally strong evidence from societal values observational studies 2C Weak recommendation, Low-quality or very Uncertainty in the estimates of benefits, risks Observational studies or case series Very weak recommendation; other alternatives low-quality evidence and burden; benefits, risk and burden may be may be equally reasonable closely balanced RCT​ Randomised controlled trial Page 4 of 45 Rossaint et al. Critical Care (2023) 27:80 Page 5 of 45 manual compression or pressure bandages applied to intubate the trachea, rapid sequence induction appears to the wounds. Additional compression to the source of be the best method [28]. Tracheal intubation of severely bleeding can also be achieved for some penetrating injured patients is a delicate procedure that involves injuries by Foley catheter insertion directly into the risks and requires skill and proper training of the opera- wound, initially described in bleeding penetrating neck tor. A rather old study even reported increased mortality injuries [18, 19]. Compression bandages impregnated associated with pre-hospital intubation in patients with or combined with topical haemostatics enhance bleed- severe brain injury [29]. Hence, alternative methods for ing control in the pre-hospital setting [20] (see also advanced airway management may find a place in patient recommendation R22). management. However, a recent trial found that supra- In mangled extremity injuries, penetrating or blast glottic placement of a supraglottic airway device was not injuries, traumatic amputations and sometimes in more superior to endotracheal intubation after cardiac arrest limited extremity injuries, the application of a tourni- [30]. Fluid administration is usually required concur- quet is necessary to achieve complete bleeding control rently, as the introduction of positive intrathoracic pres- [20–23]. The use of tourniquets has become the stand- sure can induce a severe hypotension in hypovolaemic ard of care for severe external haemorrhage in military patients. Other questions remain, including which drugs medicine and several publications report the effective- can be recommended. Therefore, controversy remains ness of tourniquets in this specific context in adults [22] about the appropriate use of tracheal intubation in and children [23]. In the civilian setting, several small patients following traumatic injury [31]. studies and systematic reviews suggest reduced mortal- The negative effects of hypoxaemia are well known, ity with the use of pre-hospital tourniquets and a low particularly in patients with traumatic brain injury (TBI) risk of complications, although there is a lack of high- [32], therefore, high oxygen concentrations are gener- quality randomised controlled trials (RCTs) to sup- ally targeted during the initial management of these port this practice [24, 25]. Tourniquets should be left patients to ensure adequate oxygen delivery to ischaemic in place until surgical control of bleeding is achieved; areas. Some studies and meta-analyses based on high- however, time to removal should be shortened as much quality evidence [33] have suggested that prolonged as possible [20]. Improper or prolonged placement of hyperoxia ­(PaO2 well above the normal range) is associ- a tourniquet can lead to complications such as nerve ated with increased mortality [34, 35]. Extreme hyper- paralysis and limb ischaemia, but these effects are rare oxia ­[PaO2 > 487 mmHg (> 65 kPa)] should therefore be [25–27]. avoided in patients with TBI [36]. The negative effects of hyperoxia are likely related to altered microcirculation associated with high ­PaO2 [37] and increased produc- Ventilation tion of oxygen free radicals [38] and patients with severe Recommendation 3 We recommend that endotra- brain injury may be at particular risk [36]. Therefore, cheal intubation or alternative airway management although hyperoxia may increase the oxygen content and be performed without delay in the presence of airway delivery in an extremely anaemic trauma patient and be obstruction, altered consciousness [Glasgow Coma Scale associated with a benefit in this specific situation, hyper- (GCS) ≤ 8], hypoventilation or hypoxaemia (Grade 1B). oxia should be returned to normoxia as soon as the hae- We recommend the avoidance of hypoxaemia (Grade moglobin (Hb) level returns to more acceptable levels 1A). [36]. We suggest the avoidance of hyperoxaemia, except in Adequate ventilation is desirable, but there is a ten- the presence of imminent exsanguination (Grade 2B). dency for rescue personnel to hyperventilate patients We recommend normoventilation of trauma patients during initial resuscitation. The effect of hyperventilation (Grade 1B). on bleeding and outcome in patients with severe trauma We suggest hyperventilation as a life-saving measure in without TBI is not known. There are several potential the presence of signs of cerebral herniation (Grade 2C). mechanisms by which the adverse effects of hyperven- tilation and hypocapnia could be mediated, including increased vasoconstriction with decreased cerebral blood Rationale flow and impaired tissue perfusion. In the setting of abso- The fundamental objective of intubation is to ensure lute or relative hypovolaemia, an excessive rate of posi- patency of the airways and facilitate adequate ventila- tive pressure ventilation may further compromise venous tion and oxygenation. There are well-defined situations in return and produce hypotension and even cardiovascular which intubation is mandatory, including in the presence collapse [38, 39]. A target P­ aCO2 should be 5.0–5.5 kPa of airway obstruction, altered consciousness (GCS ≤ 8), (35–40 mmHg). haemorrhagic shock, hypoventilation or hypoxaemia. To Rossaint et al. Critical Care (2023) 27:80 Page 6 of 45 The only situation in which hyperventilation-induced benefit in the latter group at 30 days [49]. Mortality hypocapnia may be desirable is in the context of immi- was statistically lower per unit of pRBC and plasma. nent cerebral herniation, wherein the decrease in cer- A meta-analysis on matched trauma patients that had ebral blood flow produced by acute hypocapnia causes received pre-hospital pRBC and plasma simultane- a decrease in intracranial pressure. This should be con- ously showed a significant reduction in long-term sidered only for short periods of time until other meas- mortality but no difference in 24 h mortality [47]. Pre- ures are effective and in selected cases of imminent brain hospital use of freeze-dried plasma may have logistic herniation. The presence of signs such as unilateral or benefits over thawed/frozen plasma and retrospective bilateral pupillary dilation or decerebrate posturing are evidence has demonstrated feasibility, positive effects indicators for an extreme risk of imminent death or irre- on coagulation [50], and when administered as bolus versible brain damage. Given the extreme risk of death followed by pre-hospital pRBC, a capacity to reduce if no measures are undertaken, the risk–benefit balance pRBC requirements [51]. The multicentre phase 3 RCT seems favourable; however, it is important to normalise RePHILL (Resuscitation with pre-hospital blood prod- ­PaCO2 as soon as feasible. ucts) trial compared pre-hospital two units of pRBC Ventilation with low tidal volume (around 6 mL/kg) is and LyoPlas each (n = 209) or up to 1 L 0.9% sodium now recommended in all patients treated with mechani- chloride (n = 223) in adult trauma patients with haem- cal ventilation, including during surgery. orrhagic shock and hypotension and did not show a dif- ference for the composite endpoint mortality and/or Pre‑hospital blood product use lactate clearance [52]. The trial was stopped at 432/490 Recommendation 4 No clear recommendation or sug- patients due to the SARS-CoV-2 pandemic. gestion in favour or against the use of pre-hospital blood Due to conflicting data and the financial burden products can be provided at this time. involved in the design and implementation of pre-hospi- The pre-hospital use of blood products is technically tal pRBC and plasma transfusion programmes that may feasible; however, logistical hurdles and the scarcity of or may not provide definitive evidence, no clear recom- universal blood group donors, along with health eco- mendation or suggestion in favour or against the use nomic challenges and financial burdens, remain sub- of pre-hospital blood products can be provided at this jects of ongoing investigation and debate. The best time. The decision to commit to routine pre-hospital use evidence available to date for pre-hospital plasma of blood products requires careful consideration by all administration is derived from two pragmatic RCTs, stakeholders and must be adapted to local circumstances PAMPer (Pre-hospital Air Medical Plasma; [40]) and and settings [52]. COMBAT (Control of Major Bleeding after Trauma; [41]), which have yielded conflicting results. Secondary post hoc analyses have suggested greater benefits for II. Diagnosis and monitoring of bleeding patients who are coagulopathic, with blunt injury [42], Initial assessment a computed tomography (CT)-positive TBI [43] or with Recommendation 5 We recommend that the physician pre-hospital rescue times > 20 min [44]. A meta-analy- clinically assess the extent of traumatic haemorrhage sis of both trials including 626 patients showed reduced using a combination of patient physiology, anatomi- 24 h mortality with pre-hospital plasma but no effect cal injury pattern, mechanism of injury and the patient on 1-month mortality [45]. For pre-hospital packed red response to initial resuscitation (Grade 1C). blood cell (pRBC) concentrates, single-centre observa- We recommend that the shock index (SI) and/or pulse tional or retrospective studies have suggested improve- pressure (PP) be used to assess the degree of hypovolae- ments in both haemodynamics and survival, but are mic shock and transfusion requirements (Grade 1C). restricted to the pre-hospital phase of care with overall reduced blood product consumption [46]. In a meta- Rationale analysis of matched trauma patients, the individual use The mnemonic Advanced Trauma Life Support (ATLS) of pRBC showed no difference in long-term mortality ABCDE has been replaced by ABCDE, with or 24 h mortality [47] and consistent evidence for bene- referring to critical/catastrophic bleeding requiring ficial effects with pre-hospital pRBC is still lacking [48]. rapid bleeding control and resuscitation with blood The combined use of pre-hospital pRBC and plasma products, including massive transfusion (MT). The tra- was assessed in a secondary analysis of PAMPer among ditional ATLS classification system of hypovolaemic 407 hypotensive trauma patients divided into four pre- shock now includes physiological base excess and may hospital resuscitation groups: crystalloid only; pRBC; serve as a rough estimate for blood loss and transfusion plasma; pRBC + plasma, with the greatest survival requirements, but is not without limitations (Table 2; Rossaint et al. Critical Care (2023) 27:80 Page 7 of 45 [53, 54]). Numerous predictors of traumatic haemor- patients [58]. Further retrospective studies have used dif- rhage and scores/models have been introduced, but ferent cut-offs for MT; however, each study had thresh- with an overall low quality/variable performance [area olds between SI ≥ 0.8– ≥ 1.0 with AUROCs between 0.73 under the receiver operating characteristics (AUROC) and 0.89 [59–62]. In a prospective data collection of 1402 0.73–0.95] and a consistent lack of prospective valida- trauma patients, SI ≥ 0.8 was more sensitive than SI ≥ 0.9 tion; none are in widespread clinical use [55]. While [59]. At cut-off 0.81, SI predicted MT with a sensitivity of some models aim to predict coagulopathy, others aim 85%, specificity 64%, positive prediction 16% and negative to evaluate the risk of MT. In a meta-analysis includ- prediction 98%, with correlation to other physiological ing 84 studies describing any predictor-outcome asso- and anatomical variables [63]; at cut-off 0.91 SI predicted ciation, 47 included multivariate models and 26 were MT with a sensitivity of 81% and specificity of 0.87 [62]. specifically designed for prediction [55]. A total of 35 After adjusting for age/sex, injury severity score (ISS), distinct predictors were identified, of which systolic GCS, SI was an independent predictor for mortality and blood pressure, age, heart rate and mechanism of injury blood transfusion (OR 3.57; 3.012–4.239; [63]). A SI ≥ 1 were most frequently investigated. Only 21 multivari- retrospectively outperformed the ABC score for MT [60] ate models met the recommended sample size thresh- and clinical hypotension for significant injury and emer- old of 10 events per predictor, and seven predictors gent operation [64]. Narrow PP (< 40/ < 30 mmHg) is an were examined in at least two models: mechanism of ATLS class II haemorrhage signal and was independently injury, systolic blood pressure, heart rate, haemoglo- associated with transfusion, resuscitative thoracotomy bin, lactate and focused assessment with sonography and emergent surgery in a series of retrospective studies in trauma (FAST) [55]. Information on the mechanism [65–67]. Multivariate analysis of observational data from of injury is useful and a threshold of 6 m (20 ft) as a 957 patients confirmed a narrowed PP (< 30 mmHg) to “critical falling height” has been associated with major be significantly associated with MT (OR 3.74, 95% CI injuries, including haemorrhage [56]. Trapped patients 1.8–7.7) and emergent surgery [68]. were more likely to have time-critical injuries with sig- nificant blood loss requiring intervention [57]. Further Immediate intervention critical mechanisms include high-energy deceleration Recommendation 6 We recommend that patients with impact as well as low-velocity versus high-velocity gun- an obvious bleeding source and those presenting with shot injuries. The individual response to fluid challenge haemorrhagic shock in extremis and a suspected source may be viewed critically in the context of low-volume of bleeding undergo an immediate bleeding control pro- resuscitation and “permissive hypotension”. cedure (Grade 1B). The SI is the ratio of heart rate to systolic blood pres- sure, typically ranging between 0.5 and 0.7 in healthy Rationale adults. A SI ≥ 0.9–1.0 was retrospectively associated with The patient who presents in severe haemorrhagic shock increased MT (25%), interventional radiology (6.2%) has already lost a large volume of blood. If bleeding and operative intervention (14.7%) in bleeding trauma Table 2 American College of Surgeons Advanced Trauma Life Support (ATLS) classification of blood loss based on initial patient presentation. Signs and symptoms of haemorrhage by class Parameter Class I Class II (mild) Class III (moderate) Class IV (severe) Approximate blood loss < 15% 15–30% 31–40% > 40% Heart rate ↔ ↔/↑ ↑ ↑/↑↑ Blood pressure ↔ ↔ ↔/↓ ↓ Pulse pressure ↔ ↓ ↓ ↓ Respiratory rate ↔ ↔ ↔/↑ ↑ Urine output ↔ ↔ ↓ ↓↓ Glasgow coma scale score ↔ ↔ ↓ ↓ Base deficit* 0 to − 2 mEq/L − 2 to − 6 mEq/L − 6 to − 10 mEq/L − 10 mEq/L or less Need for blood products Monitor Possible Yes Massive transfusion protocol Table reprinted with permission from the American College of Surgeons [53] Original data from Mutschler et al. [54] *Base excess is the quantity of base ­(HCO3−, in mEq/L) that is above or below the normal range in the body. A negative number is called a base deficit and indicates metabolic acidosis Rossaint et al. Critical Care (2023) 27:80 Page 8 of 45 continues in so-called agonal patients, death is an immi- a CT scanner is not available in the emergency depart- nent risk if the source of bleeding is not rapidly con- ment, the clinician must evaluate the potential risks and trolled. In a study of 271 patients undergoing immediate benefits of patient transfer to a CT room, assuring con- laparotomy for gunshot wounds, data indicate that these tinuous monitoring and resuscitation. In a well-struc- wounds combined with signs of severe hypovolaemic tured environment and by a well-organised trauma team, shock require early surgical bleeding control [69]. The CT seems to be safe and justified even in severely injured selection of patients with severe shock for direct opera- haemodynamically unstable patients [79]. tive room trauma intervention was also beneficial for In a retrospective study between 2016 and 2019, 2694 outcomes when compared with an expected TRISS score consecutive patients were admitted to a level I trauma [70]. Similar findings have been observed in a paediat- centre and a strict emergency room algorithm followed. ric population [71]. Johnson et al. studied 16,113 trauma Injuries were missed in seven patients (0.26%; one epi- admissions, among which 628 patients sent for direct dural bleeding and six abdominal hollow organ injuries; to operation room resuscitation could be retrieved. The two died), which highlights the need for continuous clini- best predictors for the need of rapid surgical intervention cal and instrument-based examinations after completion were penetrating truncal mechanism, significant anatomy of the tertiary survey [80]. or examination findings such as amputations and major Catheter angiography should be considered in patients physiological derangements, including pre-hospital CPR with blunt pelvic trauma found to have active arterial and profound shock with a systolic blood pressure of less extravasation, regardless of bleed size or patient clinical than 90 mmHg [72]. The relationship between time and or laboratory values [81], while contrast extravasation bleeding control or “door-to-embolisation time” has also on CT, high volume pRBC transfusions and ISS ≥ 16 can been observed for complex pelvic fractures [73]. assist in identifying pelvic fracture patients for angiogra- phy with more precision [82]. Further investigation A retrospective analysis and systematic review of epi- Recommendation 7 We recommend that patients with demiology, radiologic examinations, patterns of injuries, an unidentified source of bleeding, but without a need for therapeutic measures, clinical courses and outcomes immediate bleeding control, undergo immediate further showed that visceral perfusion should be monitored clin- investigation to determine the bleeding source (Grade ically and radiologically and follow-up via magnetic reso- 1C). nance imaging or computed tomography angiography performed in order to rule out vascular complications after traumatic dissection of celiac artery [83]. Rationale Haemodynamically stable patients, or those who can be stabilised during initial resuscitation, with an uni- Imaging dentified bleeding source, but not in need of immediate Recommendation 8 We suggest the use of pre-hospital bleeding control, should undergo further investigation ultrasonography (PHUS) for the detection of haemo-/ to determine the source of bleeding. During the primary pneumothorax, haemopericardium and/or free abdomi- survey, aside from monitoring vital signs, imaging stud- nal fluid in patients with thoracoabdominal injuries, if ies (ultrasonography and CT) and laboratory blood tests feasible without delaying transport (Grade 2B). (blood gas and coagulation status) are recommended [53, We recommend the use of point-of-care ultrasonogra- 74]. phy (POCUS), including FAST, in patients with thoraco- In recent years, the accessibility of CT scanners has abdominal injuries (Grade 1C). increased dramatically, replacing the need for con- We recommend early imaging using contrast-enhanced ventional radiographic imaging [75]. The diagnostic whole-body CT (WBCT) for the detection and identi- accuracy, safety and effectiveness of these immediate fication of the type of injury and the potential source of measures are dependent on pre-hospital treatment by bleeding (Grade 1B). trained and experienced emergency personnel and short transportation times [76, 77]. The proximity of the CT Rationale scanner to the resuscitation room in the emergency The accuracy of PHUS was adequate with high sensitiv- department has been shown to have a significant posi- ity and specificity for pneumothorax, free intraabdomi- tive effect on the probability of survival for the severely nal fluid and haemoperitoneum in a systematic review injured patient [78]. The trauma workflow, comprising of three retrospective and six prospective observational immediate CT diagnosis and rapid bleeding control with- studies including 2889 trauma patients [84]. Five stud- out patient transfer, as realised in the hybrid emergency ies reported at least one change in management. A room, may improve survival in severe trauma [74]. If Rossaint et al. Critical Care (2023) 27:80 Page 9 of 45 more recent systematic review of 16 studies including requiring emergency bleeding control interventions and 3317 trauma patients confirmed the feasibility/potential found an absolute risk reduction of 11.2% (95% CI 0.3– of PHUS, with seven studies evaluating treatment and 22.7%) with immediate WBCT as the primary diagnos- transport impact, but with large inconsistencies in proto- tic modality [96]. WBCT markedly reduces time spent cols, variables and outcomes, precluding a meta-analysis in the emergency department [97] and a median 19 min of the data [85]. from admission to CT was significantly associated with In-hospital, POCUS, with its best-known application decreased mortality from exsanguination in a single- FAST, remains central to the primary ATLS survey for the centre experience [98]. A revised set of 10 clinical crite- detection of haemorrhage in pleural, pericardial and per- ria for immediate WBCT with a high-positive predictive itoneal cavities, with high specificity but overall variable value for severe injury based upon secondary analysis of to low sensitivity. Summary estimates of sensitivity and REACT-2 data is shown in Table 3 [99]. Given the post specificity for detecting/excluding free fluids, organ/vas- hoc analysis in a subset of patients on which these data cular or other injuries compared with reference imaging are based, these criteria may not apply to all patients, and and/or operative/autopsy findings were 0.74 and 0.96 in a a targeted approach may be warranted. As with POCUS, review and meta-analysis of 34 studies with 8635 patients haemodynamic factors may affect the sensitivity of con- and any type of blunt civilian injury [86]. There was sub- trast-enhanced CT [100]. stantial heterogeneity across studies and the reported accuracy of POCUS varied greatly, depending on study Haemoglobin populations and body areas affected. In general, a nega- Recommendation 9 We recommend the use of repeated tive POCUS in the context of abdominal trauma cannot Hb and/or Hct measurements as a laboratory marker for exclude injury and must be verified in any case against a bleeding, as an initial value in the normal range may mask standard reference, for example, CT. In a secondary anal- early-phase bleeding (Grade 1B). ysis of prospective data from 317 hypotensive patients (< 90 mmHg systolic blood pressure) of the Prospective, Rationale Observational, Multicentre, Major Trauma Transfusion Hb or haematocrit (Hct) assays are key parts of the basic (PROMMTT) RCT, 22 FAST-negative patients required diagnostic work-up for bleeding trauma patients. Both laparotomy within 6 h of admission; thus, in hypotensive parameters are used interchangeably in clinical practice patients with haemorrhage, significant intraabdominal and here we refer to both parameters according to the haemorrhage must be suspected [87]. From a series of parameter described by the literature cited. Recently, small studies in mixed populations, it was concluded that non-invasive Hb monitoring has also been tested and POCUS may have a higher sensitivity in the context of showed high precision compared with laboratory meas- chest and cardiac injuries [86, 88, 89]. The classic FAST urements [101]. protocol can be augmented with an additional transverse scan of the pubic symphysis (FAST-PLUS protocol), with a high CT correlation with unstable pelvic injury [90]. Rolling patients to the right may increase FAST sensitiv- Table 3 Revised criteria for immediate whole-body computed tomography in trauma patients ity by converting false-negatives into true positive exami- nations [91]. Trauma patients with one of the following parameters at hospital arrival: Observational/retrospective studies/reviews have con- Systolic blood pressure < 100 mmHg firmed the benefits of WBCT for time savings, diagnostic Estimated exterior blood loss ≥ 500 mL accuracy, localisation of bleeding sources/prioritisation Glasgow coma scale score ≤ 13 or abnormal pupillary reaction of injuries for further diagnostics/interventions and, in AND/OR part, also for survival in bleeding trauma patients [75, 92]. Patients with a clinical suspicion of one of the following diagnoses: In a multicentre study, CT identified retroperitoneal hae- Fractures of at least two long bones matoma in 100% of cases [93]; in 425 patients with abra- Flail chest, open chest, or multiple rib fractures sion/ecchymosis seat belt sign, CT was 100% sensitive for Severe abdominal injury intraabdominal injury [94]. To date, the REACT-2 trial Pelvic fracture remains the only prospective RCT to compare immedi- Unstable vertebral fractures/spinal cord compression ate WBCT versus conventional imaging/selective CT in AND/OR severe injuries with compromised vital parameters and Patients with one of the following injury mechanisms: found no survival benefit associated with WBCT, neither Fall from a height (> 4 m/> 13 ft) between groups, nor for polytrauma or TBI [95]. A sec- Wedged or trapped chest/abdomen ondary analysis (n = 172) assessed mortality in patients Criteria reprinted with permission [99] Rossaint et al. Critical Care (2023) 27:80 Page 10 of 45 The diagnostic value of the Hb or Hct for quantify- The initial base deficit, obtained either from arterial ing and/or detecting blood loss in trauma patients with or peripheral venous blood is also a potent independent severe injury and for occult bleeding sources has been predictor of mortality in patients with traumatic haemor- a topic of debate. A major limitation of the diagnostic rhagic shock [115], both in adult and paediatric patients value is the confounding influence of resuscitation flu- [116]. Base deficit values derived from arterial blood gas ids and physiological shift of interstitial fluid into the analysis provide an indirect estimation of global tissue vascular compartment [102]. Low initial Hct or Hb lev- acidosis due to impaired perfusion, provided there is no els in trauma patients closely correlate with haemor- other cause of metabolic acidosis such as renal failure or rhagic shock [103, 104]. In a retrospective analysis of hyperchloremia. Although both blood lactate levels and 1492 consecutive trauma patients, Thorson et al. found base deficits are well correlated with shock and resusci- that the initial Hct was associated more closely with the tation, these two variables do not strictly correlate with need for transfusion than other parameters such as heart each other in severely injured patients and lactate levels rate, blood pressure or acidaemia [105]. Serial measure- more specifically reflect the degree of tissue hypoperfu- ments increase the sensitivity of these parameters to sion [117, 118]. detect blood loss in patients with severe injury [106, 107]. Holstein and co-workers showed that a Hb level below Coagulation monitoring 80 g/L in patients with pelvic trauma was associated with Recommendation 11 We recommend the early and non-survival [108] and there was also a close correlation repeated monitoring of haemostasis, using either a tra- between Hb and fibrinogen levels [109]. Because initial ditional laboratory determination such as prothrombin Hb values close to the normal range may mask early- time (PT)/international normalised ratio (INR), Clauss phase serious bleeding [110], repeated measurement is fibrinogen level and platelet count and/or point-of-care prudent. (POC) PT/INR and/or a viscoelastic method (Grade 1C). In summary, initial Hct and Hb value changes over time represent simple and reliable bedside parameters with Rationale which to detect blood loss, despite several limitations. It is generally accepted that traumatic coagulopathy is defined using the prothrombin time ratio (PTr); where a Blood lactate and base deficit PTr > 1.2 is the threshold for detecting traumatic coagu- Recommendation 10 We recommend blood lactate as a lopathy and PTr > 1.5 is indicative of severe coagulopathy. sensitive test to estimate and monitor the extent of bleed- Thresholds for other conventional clotting tests (CCTs) ing and tissue hypoperfusion; in the absence of lactate are less well-established and no consensus values defin- measurements, base deficit may represent a suitable alter- ing traumatic coagulopathy have been agreed, despite native (Grade 1B). low Clauss fibrinogen (< 1.3 g/L) and markers of fibrinol- ysis, such as elevated D-dimers, being commonly found in bleeding patients and associated with increased mor- Rationale tality [119, 120]. In contrast, platelet counts tend to fall In hypovolemic shock, the amount of lactate is primar- late during trauma haemorrhage and poorly reflect the ily produced by anaerobic glycolysis and is therefore an platelet dysfunction found after injury. indirect marker of cellular hypoxia. Altered liver perfu- POC PT testing has obvious attractions as a diag- sion can also prolong the lactate clearance. Blood lactate nostic entity. Adding to the published data is a retro- has been used as a diagnostic and prognostic marker of spective study of 522 patients comparing POC-PTr haemorrhagic shock since the 1960s [111] and is consid- tests to laboratory PTr [121]. The authors reported ered to reflect the severity of haemorrhagic shock. Stud- good reliability and accuracy for POC-PTr when val- ies have shown the value of serial lactate measurements ues were < 2.0, but, like previous studies [122, 123], for predicting survival in shock [112] and also provide an precision fell as PTr rose. Despite these limitations, the early and objective evaluation of patient response to ther- authors reported that thresholds of POC-PTr of 1.2 and apy [113]. The determination of lactate may be particu- 1.4 could be used to detect moderate and severe trau- larly important in penetrating trauma, where vital signs, matic coagulopathy, respectively [121]. such as blood pressure, heart rate and respiratory rate, Viscoelastic measures (VEM) are commonly used do not reliably reflect the severity of injury [112]. The to detect traumatic coagulopathy. Up to now, VEM- reliability of lactate determination may be lower when guided transfusion algorithms have been devel- traumatic injury is associated with alcohol consumption oped at single centres. A recent study reported the [114]. Rossaint et al. Critical Care (2023) 27:80 Page 11 of 45 development of three pragmatic algorithms detecting Rationale key coagulation defects (PTr > 1.2, fibrinogen < 2 g/L, Current platelet function POC devices measure differ- platelets < 100 × ­109/L) and defining simple transfu- ent parameters of platelet activation and have different sion thresholds, using data prospectively collected levels of sensitivity, therefore, they are not interchange- from six European sites [n = 968 thromboelastography able in the assessment of platelet reactivity. Moreover, (TEG); 2019 rotational thromboelastometry (ROTEM); results may be of limited value if platelet counts are low. 2287 CCT] [124]. A multicentre RCT (iTACTIC; Different POC platelet function tests (PFTs) were used NCT02593877) subsequently tested these algorithms in several observational studies to detect antiplatelet in 690 adults, comparing empiric transfusion therapy agents (APAs) and induced platelet inhibition in trauma vational study that prospectively compared ­Multiplate®, guided by either: CCT or VEM (ROTEM/TEG) [125]. patients, with mixed results [130–133]. In a small obser- ­TEG®-PM® and V ­ erifyNow® in populations treated or No difference in the primary outcome (alive and free from MT at 24 h) was reported VEM 67%, CCT 64%, OR 1.15 (95% CI 0.76–1.73). Notably, in a pre-specified not with APAs, the three devices detected APA use with ­ ultiplate® < 40 U as a refer- subgroup of 74 TBI patients, a significant difference an area under the curve (AUC) of 0.90, 0.77 and 0.90, ® ® ­ erifyNow® detected platelet dys- was seen in 28-day mortality: VEM 44%, CCT 74%, OR respectively [134]. With M 0.28 (95% CI 0.10–0.74). An important limitation to ence, ­TEG -PM and V this study was the small number of included coagulo- function with an AUROC of 0.78 and 0.89, respectively. pathic patients (29%)—the group deemed to have the The utility of POC-PFTs in the detection or exclusion most to gain by the intervention [125]. of pre-injury APA treatment is limited, as several obser- TBI is an area of increasing focus with VEM. In a retro- vational studies found that trauma patients, especially spective study, a distinct r-TEG pattern was reported for those with TBI, had therapeutic assay results or values TBI, characterised by prolonged activated clotting time below the reference interval, independent of APA intake (> 128 s), reduced α-angle (< 65°), low functional fibrino- history [135–138]. In a prospective observational study gen levels (< 365 mg/dL), normal maximum amplitude and that included 824 adult trauma patients with suspected no increased fibrinolysis (Ly30 1.2%) [126]. Added to this, pre-injury APA treatment and who were tested using a systematic review of 31 studies concluded that TEG can thromboelastography with platelet mapping (TEG-PM), readily detect the coagulopathy of TBI and indeed a vari- AA inhibition accurately detected pre-injury APA and ety of coagulopathy subtypes can be described according aspirin use (AUROC, 0.89 and 0.84, respectively); how- to TBI severity [127]. Notably, increased % inhibition of ever, ADP inhibition performed poorly (AUROC, 0.58). the TEG-platelet mapping cartridges for arachidonic acid Neither AA nor ADP inhibition was able to discern spe- (AA) and adenosine diphosphate (ADP) was consistently cific APA regimens or entirely rule out APA use [132]. reported in the TBI cohorts [127]. However, a second sys- As diagnostic cut-offs for pathologic platelet dysfunc- tematic review was more reserved in its findings, conclud- tion after traumatic injury have not been established, dis- ing that more data are required before it is possible to state tinguishing pharmacologic from trauma-induced platelet that VEM assays are useful for the detection of TBI-related receptor hypofunction is not easy. Moreover, the in vivo coagulopathy and its subsequent treatment [128]. platelet response to the individual agonists utilised in One major concern around the use of VEM for detect- POC-PFTs to induce activation and aggregation may not ing coagulopathy/guiding therapy is the inter-and intra- be adequate for detecting traumatic platelet dysfunction. variability of results between hospitals and operators. Consequently, the role of POC-PFTs in predicting Cartridge-based ROTEM and TEG devices have been outcome or stratifying trauma patients at a higher risk brought to market in part to address this. A multicentre of bleeding who may subsequently benefit from platelet study across 12 US trauma centres was conducted com- transfusion has not been established. Several observa- paring reliability of the TEG 6S with TEG 5000 [129]. The tional studies using different POC-PFTs found conflicting two devices gave results that were well correlated and results regarding the severity of trauma and prognostic importantly, a strong within-device reproducibility for information that various tests may provide [134, 136– the TEG 6S machine [129]. 138]. In a prospective study including 221 patients with traumatic intracranial haemorrhage (TICH), patients Platelet function monitoring with nonresponsive platelets had similar in-hospital Recommendation 12 We recommend that the routine mortality [3 (3.0%) vs. 6 (6.3%), p = 0.324], TICH pro- use of POC platelet function devices for platelet function gression [26 (27.1%) vs. 24 (26.1%), p = 0.877], inten- monitoring in trauma patients on antiplatelet therapy or sive care unit admission rates [34 (34.3%) vs. 38 (40.0%), with suspected platelet dysfunction be avoided (Grade p = 0.415] and length of stay [3 (interquartile range, 2–8) 1C). vs. 3.2 (interquartile range, 2–7) days, p = 0.818] as those Rossaint et al. Critical Care (2023) 27:80 Page 12 of 45 with responsive platelets [136]. In contrast, a systematic prospective and retrospective studies showing reduced review including 16 studies on adult patients with TBI mortality in comparison to traditional aggressive vol- (isolated or polytrauma) indicates that TEG-PM assays ume replacement targeting normotension [49, 145, 146]. are associated with mortality and bleeding complica- Several retrospective studies demonstrated that aggres- tions, but points to the low quality of current evidence in sive resuscitation techniques, often initiated in the pre- this population [127]. hospital setting, not only increased mortality, but also The role of POC-PFTs in guiding haemostatic therapy more often resulted in damage control laparotomy, is also uncertain. While there is some evidence that plate- coagulopathy, multiorgan failure, nosocomial infec- let transfusion can correct platelet dysfunction in TBI tions, a need for transfusions and prolonged intensive [131, 138] and limit the overall administration of blood care unit (ICU) and length of hospital stays [147–149]. products [139, 140], other studies have failed to confirm A recently published retrospective analysis of the effect the improvement of platelet function [130, 137] or out- of aggressive volume resuscitation confirmed the poten- come [131]. In an observational study that retrospectively tial harm associated with this strategy in comparison included 157 patients with TICH, a platelet reactivity test to a restrictive volume strategy in a paediatric trauma and guided platelet transfusion strategy were not associ- population [150]. ated with a difference in intracranial haemorrhage (ICH) It should be noted that the concept of permissive hypo- worsening [133]. It also seems that platelet transfusion tension and restrictive volume resuscitation is contrain- may enhance platelet function via AA receptor-mediated dicated in patients with TBI and spinal injuries. This is pathways but has little impact on ADP receptor-medi- because an adequate perfusion pressure is crucial to ated pathways [135]. ensure tissue oxygenation of the injured central nervous In summary, there is weak scientific evidence of a system. However, it remains unclear how to attain the clinically meaningful influence of POC-PFTs in trauma best balance between volume resuscitation and vaso- patients and an urgent need for future studies to eluci- pressor administration in order to achieve an adequate date their potential clinical benefits. perfusion pressure. Therefore, rapid bleeding control is of particular importance in these patients. In addition, III. Tissue oxygenation, volume, fluids and temperature the concept of permissive hypotension should be care- Volume replacement and target blood pressure fully considered in elderly patient [151] and may be con- Recommendation 13 In the initial phase following traindicated if the patient suffers from chronic arterial trauma, we recommend the use of a restricted volume hypertension. replacement strategy with a target systolic blood pressure In conclusion, a damage control resuscitation strat- of 80–90 mmHg (mean arterial pressure 50–60 mmHg) egy using a concept of restricted fluid replacement that until major bleeding has been stopped without clinical aims to achieve a reduced systolic blood pressure of evidence of brain injury (Grade 1B). 80–90 mmHg in patients without TBI and/or spinal In patients with severe TBI (GCS ≤ 8), we recommend injury is supported by the literature. However, the cur- that a mean arterial pressure ≥ 80 mmHg be maintained rently available data should be interpreted with caution; (Grade 1C). reported RCTs are limited by a low number of patients included and poor-to-moderate quality. The retrospec- tive data suffer from inherent limitations as well as meth- Rationale odological weaknesses such as a high risk of selection The initial treatment of trauma-induced hypotension bias and clinical heterogeneity. Therefore, further con- uses the concept of a restricted volume replacement firmation in adequately powered prospective RCTs is and permissive hypotension. This strategy was mainly needed. triggered by a RCT published in the 1990s demonstrat- ing increased survival in penetrating trauma [141]. In the meantime, this strategy is replacing conventional Vasopressors and inotropic agents aggressive fluid resuscitation. A recent meta-analysis of Recommendation 14 If a restricted volume replacement RCTs analysed mortality in trauma patients without TBI strategy does not achieve the target blood pressure, we receiving either traditional aggressive fluid resuscitation recommend the administration of noradrenaline in addi- or following a restricted volume replacement and per- tion to fluids to maintain target arterial pressure (Grade missive hypotension concept found a decrease in mortal- 1C). ity when the latter concept was used [142, 143]. We recommend infusion of dobutamine in the pres- This concept is supported by several meta-analyses of ence of myocardial dysfunction (Grade 1C). retrospective studies alone [144] as well as combined Rossaint et al. Critical Care (2023) 27:80 Page 13 of 45 Rationale to resuscitative fluid [161]. Patients were administered Several retrospective studies describe an increase in mor- fluid alone or fluid plus vasopressin (bolus 4 IU) and i.v. tality [152–155] or no benefit [156] when noradrenaline infusion of vasopressin (0.04 IU/min) for 5 h. The fluid vasopressors are used in the trauma setting. Another plus vasopressin group needed a significantly lower total study found no independent association between mor- resuscitation fluid volume over 5 days than the control tality and vasopressor use in trauma patients, except for group (p = 0.04). The rates of adverse events, organ dys- the use of epinephrine [157]. A systematic review of early function and 30-day mortality were similar. In summary, vasopressor use in trauma published in 2017 was unable additional research is needed to determine whether to conclude whether vasopressors cause more harm or including low-dose arginine vasopressin improves mor- benefit when administered to patients with severe hypo- bidity or mortality. tension [158]. However, all previous studies, including Cardiac dysfunction could be altered in the trauma the recent systematic review, comprise studies of very patient following cardiac contusion, pericardial effusion low quality and a high risk of bias; most notably, patients or secondary to brain injury with intracranial hyperten- receiving vasopressors were systematically more severely sion. The presence of myocardial dysfunction requires ill than those not receiving vasopressors. The threshold treatment with an inotropic agent such as dobutamine for hypotension in most studies was defined as a systolic or epinephrine. In the absence of an evaluation of cardiac blood pressure of < 85 or 90 mmHg, without stating a function or cardiac output monitoring, as is often the precise threshold at which vasopressors were used. How- case in the early phase of haemorrhagic shock manage- ever, a systolic blood pressure of 80–90 mmHg in most ment, cardiac dysfunction must be suspected if there is patients does not represent life-threatening hypotension. a poor response to fluid expansion and norepinephrine. In these cases, the use of vasopressors raises concerns about altering organ perfusion by potentiating vasocon- Type of fluid striction and consequently causing a further reduction of Recommendation 15 We recommend that fluid therapy organ perfusion, which may inflict harm to the patient. using a 0.9% sodium chloride or balanced crystalloid Therefore, in the early stages of resuscitation the pre- solution be initiated in the hypotensive bleeding trauma sent evidence supports a strategy of restricted volume patient (Grade 1B). replacement and permissive hypotension until the bleed- We recommend that hypotonic solutions such as ing is controlled without the use of a vasopressor if a Ringer’s lactate be avoided in patients with severe head target systolic blood pressure of 80–90 mmHg can be trauma (Grade 1B). achieved. However, if these measures fail to achieve the We recommend that the use of colloids be restricted target blood pressure and if severe haemorrhage-induced due to the adverse effects on haemostasis (Grade 1C). hypotension with a systolic blood pressure < 80 mmHg occurs, transient noradrenaline is recommended to Rationale maintain life and tissue perfusion. Whereas the use of crystalloids is widely accepted as part Nevertheless, it is well known that the pathophysiol- of an initial restrictive fluid replacement strategy in the ogy of acute blood loss consists of two phases, an initial bleeding trauma patient, the type of crystalloid is still vasoconstriction, a sympathoexcitatory and later a vaso- under discussion. In most trauma studies 0.9% sodium dilatory, sympathoinhibitory phase, which during haem- chloride was used as the crystalloid solution. However, orrhagic shock may cause a further reduction in vascular there exist concerns that saline as the main i.v. fluid tone in the severely bleeding trauma patient [159]. There- results in harm to patients, such as hyperchloraemic aci- fore, in order to achieve an appropriate balance between dosis or increased incidence of kidney injury, which may intravascular volume and vascular tone, it may be ben- reduce survival. In contrast to 0.9% sodium chloride, eficial to counteract vasodilation in the presence of balanced electrolyte solutions comprise physiological or haemorrhage [159]. Following the hypothesis that severe near-physiological concentrations of chloride and may haemorrhagic shock is associated with a state of arginine therefore be advantageous [162]. Whereas a large RCT vasopressin deficiency, Sims et al. performed a RCT in including 15,802 critically ill patients comparing bal- 100 trauma patients with haemorrhagic shock to assess anced crystalloids versus 0.9% sodium chloride showed the effect of supplementation of this hormone [160]. This a lower rate of the composite outcome “death from any small but well-designed study showed that low-dose argi- cause, new renal-replacement therapy or persistent renal nine vasopressin (bolus of 4 IU followed by 0.04 IU/min) dysfunction” when balanced crystalloids were used [163], decreases blood product requirements. These findings one recently published RCT [164] and two meta-analy- are in line with an earlier double-blind randomised trial ses comparing the effect of balanced crystalloids versus that assessed the safety and efficacy of adding vasopressin 0.9% saline for resuscitation of critically ill adults did not Rossaint et al. Critical Care (2023) 27:80 Page 14 of 45 show a difference in mortality, acute kidney failure or concentrate, depending on the type of colloids and con- length of hospital stay [165, 166]. Nevertheless, know- centration of fibrinogen concentrate being used [175, ing that further studies in trauma patients are warranted 176]. However, if bleeding is excessive and if crystalloids to clarify which crystalloid solution is the best for ini- in combination with vasopressors are unable to support tial trauma management, the authors of this guideline maintenance of basic tissue perfusion, colloid infusions favour a balanced electrolyte solution as the initial crys- represent a further option to restore perfusion. talloid solution in trauma patients. However, if a 0.9% sodium chloride solution is used, it should be limited to Erythrocytes a maximum of 1–1.5 L. Saline solutions should not be Recommendation 16 If erythrocyte transfusion is neces- used in severe acidosis, especially when associated with sary, we recommend a target haemoglobin of 70–90 g/L hyperchloremia. (Grade 1C). Hypotonic solutions, such as Ringer’s lactate or hypo- tonic albumin should be avoided in patients with TBI in Rationale order to minimise a fluid shift into the damaged cerebral pRBC transfusion improves volume status and restores tissue. A secondary analysis from the PROMMTT study arterial oxygen transport during haemorrhagic shock revealed that Ringer’s lactate solutions were associated resuscitation. Although pRBC transfusion is extensively with higher adjusted mortality compared with normal used in trauma patients to replace blood loss until bleed- saline [167]. Hypertonic solutions, on the other hand, did ing is controlled, few studies have compared different not influence survival or 6-month neurological outcome haemoglobin levels relative to pRBC transfusion. In a in patients with and without TBI [168–170]. recent Cochrane database analysis that assessed haemo- Colloid solutions have been used more effectively to globin thresholds to guide pRBC transfusion, there was restore intravascular volume, as would be expected from no evidence of harm associated with targeting a restric- basic physiologic concepts of fluid exchange across the tive threshold between 70 and 80 g/L as compared to a vasculature. A review of RCTs indicated that colloid solu- threshold greater than 90–100 g/L in 48 trials involving tions can result in lower fluid requirements than crystal- 21,433 patients [177]. However, high-quality data were loids in all types of patients, including trauma victims, only available in cardiac, orthopaedic surgery and critical with a ratio of 1.5/1 [171]. However, it is still unclear care patients and no study on acute bleeding in trauma whether colloids really have a beneficial effect on mor- patients was included in the analysis. In a small-sample- bidity or mortality. Two recently published meta-analyses size before–after study (n = 131 patients) in which the comparing colloids such as starch solutions, gelatine and transfusion threshold was decreased from 70 to 65 g/L albumin with crystalloids failed to demonstrate a benefit in a trauma centre, no difference was reported in hospi- on survival of colloids in surgical patients [172, 173]. Nei- tal length of stay or organ failure [178]. Above all, physi- ther meta-analysis revealed an increase in renal failure or cians should keep in mind that haemorrhagic shock may replacement therapy when colloids were administered in be a rapidly evolving situation in which anticipation of surgical patients in need of hypovolemic resuscitation. transfusion is essential to prevent an excessive decrease However, the most recent meta-analysis by Chappell in arterial oxygen transport and the decision to transfuse et al. demonstrated improved haemodynamic stability, should not be based on haemoglobin levels alone. a reduced need for vasopressors and reduced the length Brain-injured patients may be especially at risk of of hospital stay by 9 h in surgical patients treated with ischaemia during acute anaemia. For this reason, differ- starches in addition to crystalloids [174]. The present ent transfusion thresholds may apply for these patients. data in trauma resuscitation do not allow a recommen- In a recent meta-analysis compiling 4 studies (3 ran- dation as to which of the different colloids is best for domised controlled trials and one retrospective study) the initial management of the bleeding trauma patient. in TBI patients, a haemoglobin threshold of 70 g/L was Moreover, neither the timepoint of fluid resuscitation nor associated with a better neurological outcome than a the duration and dose of fluid resuscitation have been haemoglobin threshold of 100 g/L [179]. However, 55% analysed to date. of patients included in the meta-analysis were from a ret- In conclusion, for the initial phase of traumatic haem- rospective study exposing to a high risk of bias since the orrhagic shock, a restrictive volume strategy using crys- amount of packed pRBC administered may reflect patient talloid solutions is generally accepted. The main rationale severity rather than a threshold-guided transfusion. for the primary use of crystalloids is that coagulation Neurologic outcome data were similar in the retrospec- and platelet function are impaired by all hydroxyethyl tive study [180] and the largest prospective randomised starch and gelatine solutions. These negative effects on study [181], both favouring a restrictive transfusion trig- coagulation might be partially improved using fibrinogen ger of ≤ 70 g/L. Interestingly, progressive haemorrhagic Rossaint et al. Critical Care (2023) 27:80 Page 15 of 45 injury was also less frequent in patients randomised to a and halved the number of pRBC units and fresh frozen restrictive transfusion threshold (Hb < 70 g/L) [182]. In plasma (FFP) [188]. A feasibility study was conducted a feasibility study, Gobatto et al. randomised 44 moder- in 130 patients with combat-related injuries, with 27 ate or severe TBI patients in 2 ICUs in Brazil to a restric- receiving MT (defined as 10 pRBC in 12 h), among tive (< 70 g/L) or a liberal (100 g/L) transfusion strategy whom ICS was used in 17 cases. Autologous blood [183]. The restrictive strategy led to a haemoglobin level accounted for only 7.6% of blood products transfused. of 84 ± 10 g/L versus 93 ± 13 g/L and hospital mortality The best ratio of recovered to required pRBC mass was lower in the liberal transfusion group (7/23 vs. 1/21). was 39%, in patients undergoing laparotomy or thora- Neurological outcome at 6 months tended to be better cotomy after a gunshot wound [189]. Another review using the liberal strategy. This is in contrast to the much of 179 patients with penetrating and blunt abdominal larger prospective randomised study by Robertson et al. trauma compared one group receiving only allogeneic with 200 patients showing similar mortality but a more blood (n = 108) to another receiving additional recov- favourable neurologic outcome in the restrictive haemo- ered blood (n = 71). Bleeding was significantly higher globin transfusion (Hb < 70 g/L) group [181, 182]. In the in the ICS group and the reinfused volume doubled. meantime, following the haemorrhagic phase, an optimal A logistic regression revealed that ISS > 25, systolic transfusion threshold may be individualised according to blood pressure < 90 mmHg and estimated blood loss brain multimodal monitoring in TBI patients. > 2000 mL predicted mortality [190]. In acute unstable haemorrhagic pelvic trauma, ICS Cell salvage may be indicated when management involves an ante- Recommendation 17 We suggest that cell salvage be rior approach and/or an open reduction internal fixa- considered in the presence of severe bleeding from an tion through an infraumbilical laparotomy or with abdominal, pelvic or thoracic cavity (Grade 2B). preperitoneal pelvic packing (PPP) [191]. Observational studies in deferred osteosynthesis of complex frac- Rationale tures of the acetabulum concluded that greater fracture The use of intraoperative cell salvage (ICS) during traumatic complexity is associated with more bleeding (anterior haemorrhage is not widespread and the evidence is limited approach as a risk factor [192]) and the use of ICS more [184]. Reinfusion of autologous blood can become a poten- cost-effective [193], although in other evaluations no tial driver for worsening impaired coagulation, endothelial differences in allogeneic transfusion were found [194]. disbalance and immunomodulation. Bleeding may originate Blood from the thoracic cavity could be recovered and from multiple injuries and large processed volumes may re-transfused from chest drains after haemothorax or after exacerbate haemodilution. When haemostatic measures thoracotomy. In a multi-institutional retrospective study, involve damage control by thoracotomy or laparotomy, a 272 trauma patients were allocated to two groups based on physical cavity, preferably uncontaminated, may be available transfusion of salvaged blood from the haemothorax. There from which to retrieve blood. Washing and optional double- was no significant difference in in-hospital complications, suction can lead to removal of contaminants and micro- mortality or 24 h post-admission coagulation. Patients who organisms [185]. Salvaged blood can be passed through had received autologous blood had lower requirements for individual or double filters or with leukoreduction capac- allogeneic blood and platelet concentrates and the cost of ity. The immunological benefit of salvaged blood is not well transfusions was significantly lower [195]. defined; however, preliminary experimental studies suggest There is no evidence that emergency autologous that the procedure may be advantageous [186]. transfusion in trauma worsens clinical outcomes; how- To date, the only randomised controlled trial in ever, the lack of quality randomised trials precludes a trauma patients, who underwent ICS during 44 lapa- general recommendation. ICS could offer advantages rotomies for penetrating injuries, showed a decrease of for patients who refuse transfusion and in a resource- 4.7 allogenic pRBC units within the first 24 h without constrained environment, potentially including pre- increasing postoperative infection rates and no signifi- hospital blood salvage, when transport and access to cant difference in survival [187]. Several retrospective blood products are challenging [196]. studies also demonstrated efficacy in reducing alloge- Temperature management neic transfusion, but no difference in mortality. One cohort compared the use of ICS in 47 trauma patients Recommendation 18 We recommend early applica- undergoing emergency surgery (83% laparotomies) tion of measures to reduce heat loss and warm the hypo- with 47 serving as the control group. The use of ICS thermic patient to achieve and maintain normothermia accounted for 40–45% of transfusion requirements (Grade 1C). Rossaint et al. Critical Care (2023) 27:80 Page 16 of 45 Rationale civilian sector for active re-warming of trauma patients Hypothermia in trauma patients has been consistently [207]. shown to increase mortality [197, 198] and blood product Because coagulopathy in trauma increases mortality, transfusions [198]. The effects of hypothermia include normothermia with core temperatures between 36 and altered platelet function, impaired coagulation factor 37 °C should be targeted to create optimal pre-conditions function (a 1 °C drop in temperature is associated with a for coagulation. 10% drop in function), enzyme inhibition and fibrinoly- sis. Often, the coagulation effects can only be detected IV. Rapid control of bleeding using lab values when coagulation tests (PT and activated Damage control surgery partial thromboplastin time [APTT]) are performed at Recommendation 19 We recommend damage control the low temperatures present in patients with hypother- surgery in the severely injured patient presenting with mia, but not when assessed at 37 °C, as is routine prac- haemorrhagic shock, signs of ongoing bleeding, coagu- tice for such laboratory tests. Hypothermia in severely lopathy and/or combined abdominal vascular and pan- affected trauma patients with a core body temperature creatic injuries (Grade 1B). < 35 °C is often associated with acidosis, hypotension and Other factors that should trigger a damage control coagulopathy and is one of the key factors of so-called approach are hypothermia, acidosis, inaccessible major trauma-induced coagulopathy [199]. anatomic injury, a need for time-consuming procedures Hypothermia in trauma patients not only causes a (Grade 1C). higher morbidity and mortality, but also leads to higher We recommend primary definitive surgical manage- blood loss and transfusion requirements [198]. This ment in the absence of any of the factors above (Grade has been shown in a retrospective study of 604 trauma 1C). patients who required MT [200]. The authors performed a logistic regression analysis, which demonstrated that Rationale a temperature lower than 34 °C was associated with a The severely injured patient with continuing bleeding or greater independent risk of mortality greater than 80% deep haemorrhagic shock generally has a poor chance of after controlling for differences in shock, coagulopathy, survival. Without early control of bleeding and proper injury severity and transfusion requirements. A further resuscitation, these patients exhaust their physiological study performed a secondary analysis using 10 years of reserves, with resulting profound acidosis, hypothermia data from the Pennsylvania Trauma Outcome Study and coagulopathy, also known as the “lethal triad”. (PTOS), which showed in more than 11,033 patients In 1983, Stone et al. described the techniques of abbre- with severe TBI that spontaneous hypothermia at hospi- viated laparotomy [208] and ten years later Rotondo et al. tal admission was associated with a significant increase defined the abbreviated laparotomy in three different in the risk of mortality [201]. In addition, induced hypo- stages (immediate laparotomy for control of bleeding and thermia in TBI with temperatures between 32 and 35 °C contamination, temporary closure of the abdomen for for at least 48 h was associated with either no improved further resuscitation in the ICU before definitive repair) outcome [202–204] or higher mortality in a general pop- and coined it “damage control” (DC) [209]. The concept ulation with TBI [205, 206]. Nevertheless, one meta-anal- became widely accepted despite the lack of prospective ysis showed that hypothermia in patients with increased randomised studies and DC techniques were described intracranial pressure is beneficial, if used therapeutically for other injuries outside the abdomen [210]. In addi- rather than prophylactically [206]. tion, DC resuscitation became an entity and an essential In order to reduce the risk of hypothermia and of adjunct to the surgical DC in achieving coagulation and hypothermia-induced coagulopathy wet clothing should reducing secondary complications [210, 211]. The situa- be removed, additional heat loss should be avoided and tion for the severely traumatised patient in shock there- the ambient temperature should be increased. Forced fore changed and the indications for DC surgery required air warming, warm fluid therapy and, in extreme cases, clarification, especially as DC surgery side effects became extracorporeal re-warming devices are further helpful better known. In a systematic review of DC surgery in measures. Another option might be the use of a hypo- civilian trauma patients, several indications were identi- thermia prevention and management kit, which is a fied, but few showed evidence of validity or were asso- low-cost, lightweight, low-volume commercial product ciated with better outcomes when DC was performed that sustains 10 h of continuous dry heat. Although this compared to definitive repair. The study concluded that kit was designed to prevent hypothermia during tactical DC surgery should be used only when definitive sur- casualty evacuation, its application is also feasible in the gery cannot be performed [212]. The application of a DC Rossaint et al. Critical Care (2023) 27:80 Page 17 of 45 surgical approach should therefore be limited to patients mortality observed between AE and PPP in patients with in which the “lethal triad” of physiological parameters is traumatic pelvic haemorrhage [223]. present and definitive surgery not feasible. In selected patients, REBOA may serve as a bridge between haemodynamic collapse and definitive bleeding Pelvic ring closure and stabilisation control. REBOA may also be used as an adjunct to PPP Recommendation 20 We recommend the adjunct use to stem temporary bleeding [224, 225]. The available data of a pelvic binder in the pre-hospital setting to limit life- suggest that REBOA can temporarily improve haemo- threatening bleeding in the presence of a suspected pelvic dynamics [226, 227]. The evidence demonstrating that fracture (Grade 1C). REBOA improves survival is conflicting [228–230] and We recommend that patients with pelvic ring disrup- REBOA is associated with potentially significant compli- tion in haemorrhagic shock undergo pelvic ring closure cations [224, 230]. A systematic review and meta-analysis and stabilisation as early as possible (Grade 1B). concluded that no valid conclusions on the superiority of REBOA can be drawn compared with resuscitative Embolisation, packing, surgery and resuscitative thoracotomy or non-REBOA treatment in uncontrolled endovascular balloon occlusion of the aorta (REBOA) haemorrhagic shock [228]. Quality evidence to support Recommendation 21 We recommend temporary extra- the clinical use of REBOA is lacking [230]. Further stud- peritoneal packing when bleeding is ongoing and/or when ies should therefore be performed within specific train- angioembolisation cannot be achieved in a timely man- ing programmes and experimental settings. ner. Extra-peritoneal packing can be combined with open abdominal surgery when necessary (Grade 1C). Local haemostatic measures We suggest that REBOA be considered in patients with Recommendation 22 We recommend the use of topical noncompressible life-threatening traumatic haemorrhage haemostatic agents in combination with other surgical to bridge the gap between haemodynamic collapse and measures or with packing for venous or moderate arte- haemorrhage control (Grade 2C). rial bleeding associated with parenchymal injuries (Grade 1B). Rationale External emergency stabilisation of unstable pelvic fractures reduces haemorrhage associated with bleed- Rationale ing pelvic fractures in most situations [213]. The use of A wide range of local haemostatic agents is currently a non-invasive pelvic binder, invasive external fixation available for use as adjuncts to traditional surgical tech- or C-clamp depends on the individual injury pattern niques to obtain haemorrhagic control. These topical according to the principles of damage control orthopae- agents can be particularly useful when access to the site dics [214–216]. of bleeding is challenging. The use of topical haemostatic Kim et al. reported that among 148 patients with pelvic agents should consider several factors, such as the type fractures using the OTA/AO fracture classification 58.8% of bleeding, severity, coagulation status and each agent’s had type A, 34.5% type B and 6.7% type C fractures. Arte- specific characteristics. Relatively extensive experience rial bleeding seen on CT angiography was observed in in humans is now available [231–240]. In a retrospective 18.9%. Independent risk factors for bleeding included database review of the UK Joint Trauma Registry, it was type B and C fractures, body temperature < 36 °C and concluded that the application of haemostatic dressings blood lactate > 3.4 mmol/L [217]. in severely war-injured patients increased survival [238]. Despite the use of a multidisciplinary treatment The many different types of local haemostatic agents approach, the mortality rate associated with haemody- are based on collagen, sometimes combined with a pro- namic instability due to severe pelvic fracture remains coagulant [233], gelatine alone or combined with a pro- 30% [218, 219]. Ongoing bleeding after external emer- coagulant [231, 234, 235, 237], absorbable cellulose [236] gency stabilisation can be managed using either tem- or oxidised cellulose impregnated with polyethylene porary retroperitoneal/PPP combined with laparotomy glycol or salts to achieve more rapid haemostasis. Other when needed and/or angioembolisation (AE) [220–222]. products based on fibrin and synthetic glues or adhesives The critical decision to transfer a patient to the OR ver- have sealant and haemostatic properties [232]. In addi- sus interventional radiology suite can be managed using tion, poly-N-acetyl-glucosamine derived from chitin, intraoperative AE with C-arm digital subtraction angi- minerals such as kaolin and zeolite have demonstrated ography [221]. There was no significant difference in haemostatic effects [238–240]. Rossaint et al. Critical Care (2023) 27:80 Page 18 of 45 V. Initial management of bleeding and coagulopathy three routes: no additional TXA, 1 g infusion, 1 g bolus Antifibrinolytic agents followed by a 1 g infusion, with 30-day mortality rates of Recommendation 23 We recommend that tranexamic 9.3%, 7.8%, 7.3%, respectively (10% for placebo only) [49]. acid (TXA) be administered to the trauma patient who is Participants administered TXA within 1 h of injury and bleeding or at risk of significant bleeding as soon as pos- a shock index < 0.9, had a 65% lower likelihood of 30-day sible, if feasible en route to the hospital, and within 3 h mortality (HR 0.35, 95% CI 0.19–0.65), as well as a lower after injury at a loading dose of 1 g infused over 10 min, incidence of multiorgan failure and 24 h transfusion followed by an i.v. infusion of 1 g over 8 h (Grade 1A). requirements compared with those with delayed (> 1 h We recommend that the administration of TXA not from injury) TXA treatment [248]. await results from a viscoelastic assessment (Grade 1B). There have been questions raised about whether TXA should be administered only to those patients with evi- Rationale dence of hyperfibrinolysis, following concerns that some TXA has become one of the mainstays of therapy for the patients are in a state of fibrinolytic shutdown (TEG injured patient at risk of bleeding [241]. Since publication LY30 < 0.9%). In the pre-hospital TBI RCT described of the CRASH-2 trial, which showed a reduction in mor- above, 700 of the 966-strong cohort had TEG samples tality of 1.5% and a reduction in bleeding deaths by one- analysed at 0 and 6 h [249]. There was an equal spread third, there have been further trials evaluating TXA in of fibrinolytic TEG phenotypes, in particular shutdown TBI [242–245], different TXA dosing regimens [49, 243] across the 3 groups, with no increased incidence in those and TXA in the pre-hospital setting [49, 243]. treated with TXA. VEM measures did not change over The largest TBI study, CRASH-3 (n = 12,737), com- 6 h, despite changes to CCT measures of lysis. This find- pared 1 g bolus TXA followed by 1 g 8 h infusion i.v. TXA ing led the authors to suggest that TEG may be poorly with matched placebo. In patients treated within 3 h of sensitive to fibrinolysis [249]. injury (n = 9202), the risk of head injury-related death was 18.5% (TXA) versus 19.8% [placebo; risk ratio (RR) Coagulation support 0.94, 95% CI 0.86–1.02]. Early treatment was shown to Recommendation 24 We recommend that monitoring reduce death in mild and moderate head injury (RR 0.78, and measures to support coagulation be initiated imme- 95% CI 0.64–0.95) but not in severe head injury (RR 0.99, diately upon hospital admission (Grade 1B). 95% CI 0.91–1.7) [246]. TXA was highly cost-effective for mild and moderate head injury and in patients in which Rationale both pupils reacted [246]. Participants with milder head While several general pathophysiological mechanisms injury may have benefited more from TXA because of have been described that result in traumatic coagulopa- a smaller baseline bleed volume [247]. Two RCTs pub- thy, including low fibrinogen levels and hyperfibrinoly- lished recently investigating patients with TBI were sis [6, 124, 250], it is essential to quickly determine the small (n = 100 [244]) and (n = 149 [245]), single-centre type and degree of coagulopathy in the individual patient and found no difference between TXA and placebo for to identify the most prominent cause or causes, includ- primary endpoints of intracranial haemorrhage [244] ing the presence of anticoagulants, to be treated spe- or intracerebral haematoma growth over 24 h [245], cifically and in a goal-directed manner [6]. Early and respectively. goal-directed therapeutic intervention improves coagula- Two RCTs examined pre-hospital TXA, using varying tion [251, 252], which can reduce the need for transfusion drug dosing [49, 243]. In a RCT investigating patients of pRBC, FFP and platelets [5, 251–253], decrease post- with TBI, 966 patients (GCS < 12) were treated with TXA traumatic multiorgan failure [251], length of hospital stay or placebo using an out-of-hospital bolus and an in- [252] and improve survival [4, 5, 253–255]. In contrast, hospital infusion regimen. Two different doses of TXA no general survival benefit could be found in other stud- were used: 1 g bolus and 1 g infusion, or 2 g bolus and ies [6, 125]. However, in most of the studies decisions on placebo infusion. No difference was reported in the pri- therapeutic interventions were primarily based on tradi- mary endpoint, the Glasgow Outcome Scale-Extended tional laboratory values such as PT, APTT and platelet score > 4 at 6 months, 65% combined TXA group vs. count, and treatment limited to FFP and platelet trans- 62%, placebo [243]. In a general trauma RCT (n = 927), fusions. In the study by Baksaas-Aasen et al., all patients pre-hospital TXA (1 g over 10 min in 100 mL saline) received initial treatment according to empiric massive was compared with matched placebo, given within 2 h haemorrhage protocols (pRBC:plasma:platelets in a 1:1:1 of injury [49]. Mortality at 30 days was 9.9% with pla- ratio) and were then randomised into augmented viscoe- cebo versus 8.1% with TXA (no difference) [49]. Sub- lastic or conventional coagulation testing-guided inter- sequent in-hospital dosing for the TXA arm followed ventions. Despite a somewhat higher early fibrinogen Rossaint et al. Critical Care (2023) 27:80 Page 19 of 45 administration in the viscoelastic testing group, no over- failure and mortality within 30 days post-injury, although all difference in outcome (24 h after injury alive or free with a higher rate of ventilator-associated pneumonia of MT) was observed, with the exception of patients with and wound infections [261]. Similarly, in a large trauma TBI who showed a reduced 28-day mortality in the vis- database early platelet transfusion within 6 h was associ- coelastic testing group, a predefined secondary outcome ated with decreased 24 h mortality both in patients with [125]. The overall outcome in this study is not surprising massive and non-massive transfusion [262]. since the treatment algorithm defined very similar treat- Contrasting with empirical treatment using fixed FFP/ ment in terms of blood products, cryoprecipitate and platelet/pRBC ratios, and to avoid the adverse effects fibrinogen concentrate, irrespective of augmented vis- associated with FFP transfusion, several European cen- coelastic or conventional coagulation testing [256]. tres strongly support the use of coagulation factor con- centrates (CFCs) for first-line coagulation resuscitation Initial coagulation resuscitation in patients with significant bleeding and coagulopathy Recommendation 25 In the initial management of [263]. Critical fibrinogen levels (< 1.5 g/L) are reached in patients with expected massive haemorrhage, we recom- many massively injured patients at admission, and initial mend one of the two following strategies: fibrinogen levels below normal predict in-hospital mor- tality in major trauma patients. FFP is impractical for • Fibrinogen concentrate or cryoprecipitate and pRBC increasing fibrinogen levels > 1.5 g/L; modelling shows (Grade 1C) that levels > 1.8 g/L are extremely difficult, if not impos- • FFP or pathogen-inactivated FFP in a FFP/pRBC sible, to achieve, as the volume required increases expo- ratio of at least 1:2 as needed (Grade 1C) nentially as the targeted fibrinogen level approaches that in therapeutic plasma (≈2 g/L) [264]. In addition, we suggest a high platelet/pRBC ratio Apart from dilutional effects and poor efficacy in (Grade 2B). increasing fibrinogen levels > 1.5–2.0 g/L in massively bleeding patients, transfusion of plasma cannot be ini- Rationale tiated at the same time as pRBC transfusion and delays For initial resuscitation between hospital arrival and in achieving the targeted plasma/pRBC ratio may occur. results from coagulation monitoring, early transfusion For initial coagulation support, while awaiting viscoelas- with FFP, platelets and pRBC in fixed ratios may improve tic or laboratory tests, the administration of 2 g fibrino- survival and haemostasis, but data are equivocal. The gen based on clinical criteria at admission (systolic blood PROPPR trial randomised 680 trauma patients to early pressure < 100 mmHg, lactate ≥ 5 mmol/L, base excess FFP:platelets:pRBC administered 1:1:1 (platelets admin- ≤ − 6 or haemoglobin ≤ 9 g/dL) has been proposed, to istered as part of first transfusion pack) or 1:1:2 (platelets mimic the 1:1 ratio corresponding to the first 4 units of with second pack). Mortality was comparable, but the pRBC and potentially correct hypofibrinogenemia [265]. 1:1:1 group showed improved haemostasis and reduced A randomised comparison of fibrinogen concentrate exsanguination deaths [257]. A recent literature review and cryoprecipitate in hypofibrinogenaemic trauma suggested that MT protocols in adult trauma patients patients (FEISTY) found that both treatments effectively should utilise ratios between 1:1:1 and 1:1:2 [258]. increased plasma fibrinogen, with greater elevation in The pre-emptive administration of platelets as part of a fibrin-based clot amplitude after the first administration fixed-ratio blood product strategy in massive bleeding is with fibrinogen concentrate [FIBTEM A5 mean differ- controversial. Further analysis of the PROPPR trial data ence 2.6 mm (95% CI 1.1–4.1 mm), p = 0.001] [266]. Pla- suggests that transfusion of platelets in bleeding patients cebo-controlled trials have also demonstrated improved is associated with significantly decreased 24 h (5.8% vs. clot stability and fibrinogen levels in trauma patients 16.9%; p < 0.5) and 30-day mortality (9.5% vs. 20.2%; receiving fibrinogen concentrate. In a prospective trauma p < 0.5), more patients achieving haemostasis (94.9% vs. registry, fibrinogen concentrate administration within 73.4%; p < 0.1) and fewer deaths as a result of exsanguina- the first 6 h of traumatic haemorrhagic shock did not sig- tion (1.5% vs. 12.9%; p < 0.1), without an increase in com- nificantly reduce 24 h all-cause mortality [267]. plications such as acute respiratory distress syndrome (ARDS), multiorgan failure and acute kidney injury [259]. VI. Further goal‑directed coagulation management Receiving higher ratios of platelets and plasma relative Goal‑directed therapy to pRBC hastens haemostasias in subjects who have yet Recommendation 26 We recommend that resuscitation to achieve haemostasis within 3 h after hospital admis- measures be continued using a goal-directed strategy, sion [260]. In patients with MT, early platelet transfusion guided by standard laboratory coagulation values and/or within 4 h was associated with lower rate of multiorgan VEM (Grade 1B). Rossaint et al. Critical Care (2023) 27:80 Page 20 of 45 Rationale a survival benefit with VEM. The known transfusion-lim- Multiple sources of retrospective evidence have con- iting effect with VEM was confirmed across four of these firmed the benefits of goal-directed strategies guided by five studies [279–282]. TEG/ROTEM‐guided transfu- POC viscoelastic monitoring (VEM, e.g. TEG/ROTEM; sions were also associated with fewer additional invasive [268, 269]) or conventional coagulation assays (CCAs; haemostatic interventions (angioembolic, endoscopic or [270, 271]) to augment damage control resuscitation surgical) in surgical patients [280] and reduced the risk of in bleeding trauma patients. VEM is highly specific for acute kidney injury in mixed patient groups [280–282]. hyperfibrinolysis, the most lethal and resource-intensive However, the Cochrane review [282], the three meta- phenotype of fibrinolysis in trauma, and is more sensitive analyses [279–281] and the one subgroup meta-analysis in the detection of coagulopathy than CCAs [272]. POC of two RCTs [127] were of overall low to moderate qual- VEM-based treatment algorithms, including thresholds ity, including risk of bias on the use of TEG/ROTEM to to initiate goal-directed therapies with blood products, monitor and guide haemostatic treatment/transfusion coagulation factors and haemostatic agents, have been versus non-TEG/ROTEM- or standard-of-care with/ introduced [273, 274] and their successful implemen- without CCA-guided blood transfusion in patients with tation demonstrated ([272]. The introduction of POC bleeding [282]. ROTEM has altered blood product transfusion practices for major trauma patients [275], with faster decision- Fresh frozen plasma‑based management making/initiation of therapies to correct coagulopathy Recommendation 27 If a FFP-based coagulation resusci- [272], improvement in functional blood clotting param- tation strategy is used, we recommend that further use of eters [276, 277] and safer transfusion strategies [269], FFP be guided by standard laboratory coagulation screen- including better survival [255] and cost savings [254, 269, ing parameters (PT and/or APTT > 1.5 times normal and/ 278]. or viscoelastic evidence of a coagulation factor deficiency) ­EG® was explored Early goal-directed haemostatic resuscitation of trau- (Grade 1C). matic coagulopathy guided by T We recommend that the use of FFP be avoided for the ­ EG® group was signifi- in a single-centre, pragmatic prospective RCT in 111 correction of hypofibrinogenemia if fibrinogen concen- patients, and survival in the T trate and/or cryoprecipitate are available (Grade 1C). cantly higher than in the CCA group with less use of plasma and platelets [253]. In the prospective RETIC Rationale study, an indirect benefit in favour of VEM was noted, as Plasma (thawed FFP or pathogen-inactivated plasma) is its use was precondition to demonstrate a survival ben- used in many countries to treat traumatic coagulopathy. efit resulting from targeted coagulation factor supple- However, although plasma contains all pro- and antico- mentation [251]. The iTACTIC trial was a multi‐centre agulant factors, FFP contains only ~ 70% the normal level RCT that compared outcomes defined as alive and free of of all clotting factors. The transfusion of plasma might MT (≥ 10 pRBC) at 24 h after injury among 396 trauma have protective effects on haemorrhage-induced glycoca- patients treated according to empiric massive haem- lyx disruption [283], but is also associated with increased orrhage protocols, augmented by optimised VEM or risk of several adverse events [284]. A retrospective study CCA‐guided interventions [125]. While there was no dif- identified FFP transfusion as an independent risk factor ference between groups in the intention-to-treat analysis, for mortality after severe TBI [285]. there was a trend towards improved survival in the pre- When a FFP-based coagulation resuscitation strategy specified subgroup that was coagulopathic (INR > 1.2), is used, retrospective analysis [286] and the randomised which became significant in the subgroup with TBI (OR PROPPR study [257] have suggested that early transfu- 2.12, 95% CI 0.84–5.34). In a single-centre pre- and post- sion of plasma in a balanced ratio of 1:1 with pRBC is implementation study that included 201 patients with associated with higher rates of haemostasis and lower major haemorrhage mortality was significantly lower in rates of mortality and exsanguination in patients with the post-TEG group at 24 h (13% vs. 5%; p = 0.006) and critical haemorrhage when compared with a ratio of 1:2, 30 days (25% vs. 11%; p = 0.002), with significantly less although the optimal ratio has not yet been established. blood product wastage [254]. In isolated TBI with VEM- A subsequent analysis of the PROPPR study showed that identified coagulopathy and treatment requiring crani- earlier time to haemostasis was independently associated otomy, the rate of progressive haemorrhagic injury and with decreases in 30-day mortality, acute kidney injury, for neurosurgical re-intervention was significantly lower ARDS, multiorgan failure and sepsis in bleeding trauma [277]. Blood transfusion due to bleeding [279] or acutely patients [287]. Despite limited scientific evidence, FFP bleeding trauma [280], TBI [127] or in patients undergo- administration should be guided by evidence of coagula- ing surgical procedures [281] consistently demonstrated tion factor deficiency, as indicated by PT or APTT > 1.5 Rossaint et al. Critical Care (2023) 27:80 Page 21 of 45 times the normal control or by prolongation of viscoelas- Provided that fibrinogen levels are normal, we sug- tic parameters such as clotting time or reaction time. gest that prothrombin complex concentrate (PCC) is Different plasma preparations show wide variabil- administered to the bleeding patient based on evidence ity; FFP contains a variable amount of fibrinogen and of delayed coagulation initiation using VEM (Grade 2C). other coagulation factors [284]. A prospective cohort We suggest that monitoring of FXIII be included in study found no consistent correction of clot function or coagulation support algorithms and that FXIII be supple- increases in procoagulant factor concentrations following mented in bleeding patients with a functional FXIII defi- FFP transfusion during the acute phase of ongoing bleed- ciency (Grade 2C). ing [288]. Ex vivo the use of CFCs for the reconstitution of blood achieves higher haematocrit and fibrinogen con- Rationale tent compared with FFP [289]. The RETIC randomised Traumatic coagulopathy is characterised by a low fibrin- trial showed that FFP was insufficient to correct hypofi- ogen concentration and often an increased fibrinolytic brinogenemia or significantly improve clot strength vs. activity [6, 124, 250]. Besides early administration of TXA fibrinogen concentrate in adult trauma patients [251]. A (see recommendation R23) early fibrinogen administra- high proportion of patients in the FFP group required tion (see recommendation R29) is also of key importance, crossover rescue therapy using CFCs, whereas rescue ideally guided by a fibrinogen concentration < 1.5 g/L therapy was much less frequent in the CFC group [23 or viscoelastic evidence of a functional fibrinogen defi- patients (52%) vs. 2 patients (4%), respectively; OR 25.34 ciency [6]. Since the specific coagulation situation varies (95% CI 5.47–240.03), p < 0.0001] [251]. In another ran- between patients and over time, the exact needs of each domised comparison, patients with traumatic coagulopa- individual patient must be determined based on standard thy received fibrinogen concentrate, FFP or no product; laboratory coagulation parameters and/or viscoelastic the need for pRBC, intravenous fluid in the first 24 h of evidence of a functional coagulation factor deficiency [6]. hospitalisation and ICU admission, as well as the rates The usefulness of PCC has been demonstrated, with of sepsis and mortality, were all significantly lower in the evidence of reduced haematoma formation in patients fibrinogen concentrate group [290]. with head injury [295], and is preferable to FFP for the Pathogen-inactivated plasma has a more standard- rapid reversal of the effects of vitamin K antagonists ised fibrinogen content and minimises the risk of trans- (VKAs) [296] (see recommendation R33). In a recent fusion-related acute lung injury (TRALI) and infection meta-analysis comparing the treatment of patients with compared with FFP. The use of readily transfusable liq- trauma-induced coagulopathy with FFP alone vs. FFP uid plasma has been shown to enable a higher plasma/ plus PCC, the addition of PCC was found to decrease the pRBC ratio within the first hour of transfusion [291], thus transfusion of pRBC and FFP and to decrease mortality potentially increasing the efficacy to prevent coagulopa- significantly without increasing thromboembolic adverse thy. A recent metanalysis and retrospective data found events [297]. This meta-analysis, however, was limited to no difference in mortality when using liquid or thawed 3 retrospective studies in 840 patients. PCC may also be plasma in trauma patients [292, 293]. used in the treatment of trauma patients anticoagulated With a relative shortage of type AB plasma, to allow with Xa inhibitors (see recommendation R34). transfusion of plasma for resuscitation of patients whose VEM is useful to guide individualised goal-directed blood type is unknown, the use of ABO-incompati- coagulation therapy in patients with traumatic coagu- ble plasma in the form of group A plasma for trauma lopathy [6]. In the initial phase, a low fibrinogen con- patients of unknown ABO group is increasingly being centration is expected. However, thrombin generation investigated. The majority of available studies were retro- is preserved or even increased [298]. Initial treatment spective and showed no significant increases in morbid- should therefore comprise fibrinogen administration, ity or mortality. A secondary analysis from the PROPPR which not only increases the maximum clot firmness in trial showed that MT of incompatible type A plasma to FIBTEM, but also shortens the clotting time in EXTEM patients with blood group B or AB was not associated [276]. Only if the EXTEM clotting time remains pro- with significantly increased morbidity [294]. longed, despite a fibrinogen level > 1.5 g/L should PCC be administered to normalise the EXTEM clotting time Coagulation factor concentrate‑based management [299]. Recommendation 28 If a CFC-based strategy is used, we It is important to avoid the overly liberal use of PCC recommend treatment with factor concentrates based on in trauma patients, because PCC administration results standard laboratory coagulation parameters and/or vis- in increased thrombin potential over days that is not coelastic evidence of a functional coagulation factor defi- reflected by standard laboratory tests and might expose ciency (Grade 1C). the trauma patient to an increased risk of delayed Rossaint et al. Critical Care (2023) 27:80 Page 22 of 45 thrombotic complications [300]. Therefore, the risk of RCTs are available [290, 304–307] for FC. For three stud- thrombotic complications resulting from PCC treatment ies, the primary outcome was feasibility in a restricted should be weighed against the need for rapid and effec- time frame, which was only reached for two of them [305, tive correction of coagulopathy [296]. 306]. One study selected clot stability with FIBTEM as a Coagulation factor XIII (FXIII), formerly known as a primary outcome and confirmed the feasibility of early “fibrin stabilising factor” is circulating in tetrameric form pre-hospital administration [307]. Of these four stud- consisting of two A and two B subunits. The A subunit of ies, none was powered to assess any difference in trans- FXIII is activated to FXIIIa by thrombin and FXIIIa cataly- fusion requirements, even if no difference was observed ses the cross-linking of fibrin. Strong cross-linking of fibrin between the control groups and the FC groups. One prevents fibrinolysis and FXIII activity seems to be an study compared the effect of FC, FFP and no plasma-no important independent modulator of clot firmness [301]. FC (control) on the mortality of trauma patients [290]. Low levels of FXIII have been found in patients with The difference was highly in favour of FC and there was major trauma and coagulopathy. If cryoprecipitate is not also a significant difference in transfusion amounts and available, as in most European countries, and a CFC- other major outcomes, but this study was not blinded based strategy is used, very little if any factor XIII is and had major biases, imprecision and inconsistency. administered. Monitoring factor XIII levels and replace- Two retrospective registry studies with injury severity ment below a certain threshold therefore is suggested as score-matched control groups and a propensity analy- part of coagulation support algorithms. At present, how- sis showed no difference between FC-treated patients ever, the need for and a defined optimal level of FXIII and control patients for all-cause mortality or transfu- replacement in major trauma patients has not been deter- sion [267, 308]. Finally, a systematic review and meta- mined. The updated ESA guidelines for the management analysis showed that there was no difference between FC of severe perioperative bleeding suggest the administra- and control for mortality, pRBC, FFP or platelet transfu- tion of FXIII concentrate in the presence of bleeding and sion requirements or thromboembolic events, with a low a FXIII level < 30% [302]. The use of FXIII concentrate quality of evidence [309]. at a FXIII level < 60% was part of multimodal algorithms *Based on the weak level of the evidence, the proposed in two recent studies in major trauma patients, result- grading of this recommendation was 2B. However, fol- ing in major reductions in transfusion requirements and lowing in-depth discussion, some authors suggested that improvements in clinical outcomes, including a reduc- either 2B or 1C might be appropriate. The voting results tion in the duration of stay in the ICU, organ dysfunction were split: 50% objected to and 39% supported a grading and hospital mortality in one study [5, 251]. of 2B, while 11%, representing the non-voting authors, abstained. The group therefore decided to revert the Fibrinogen supplementation grading to 1C, as in the previous edition of the guideline, Recommendation 29 We recommend treatment with because several authors felt that downgrading to a sug- fibrinogen concentrate or cryoprecipitate if major bleed- gestion might risk misinterpretation to the detriment ing is accompanied by hypofibrinogenemia (viscoelastic of fibrinogen concentrate use as part of daily clinical signs of a functional fibrinogen deficit or a plasma Clauss practice. fibrinogen level ≤ 1.5 g/L) (Grade 1C)* We suggest an initial fibrinogen supplementation of Platelets 3–4 g. This is equivalent to 15–20 single donor units of Recommendation 30 We suggest that platelets be admin- cryoprecipitate or 3–4 g fibrinogen concentrate. Repeat istered to maintain a platelet count above 50 × ­109/L doses should be guided by VEM and laboratory assess- in trauma patients with ongoing bleeding and above ment of fibrinogen levels (Grade 2C). 100 × ­109/L in patients with TBI (Grade 2C). If administered, we suggest an initial dose of four to Rationale eight single platelet units or one aphaeresis pack (Grade Cryoprecipitate and fibrinogen concentrate (FC) have 2B). now been prescribed to trauma patients for more than 10 years without any evidence-based support. Up to now, Rationale no large double-blind RCT has confirmed the validity While a low platelet count has been consistently asso- of this strategy. A randomised controlled feasibility trial ciated with both morbidity and mortality in trauma showed that early fibrinogen supplementation with cryo- patients, the threshold and timing of platelet transfusion precipitate was feasible in trauma patients [303]. No dif- remains controversial [6]. Although the platelet count ference in transfusion was observed; however, the study at admission was found to be a biomarker for trauma was not adequately powered. Only five very small recent severity and predictive of outcome, including bleeding Rossaint et al. Critical Care (2023) 27:80 Page 23 of 45 intensity and transfusion requirements [262], platelet different platelet products with different storage times, counts are frequently within the normal range at hospi- administered at different time intervals. As such, a spe- tal admission, but may decrease sharply in the following cific platelet/pRBC ratio for empiric transfusion cannot 1–2 h of haemostatic resuscitation and decline continu- be recommended at present. ously thereafter, suggesting an important role for the The optimal timing of platelet transfusion in associa- treatment administered [310]. tion with traumatic bleeding also requires clarification. No randomised trials have investigated specific platelet Further analysis of the PROPPR study showed that the transfusion thresholds in trauma patients. Several obser- impact of transfusion ratios on haemostasis is dynamic vational studies have investigated associations between and the longer it takes to achieve haemostasis, the more platelet transfusion and outcome; however, these are sub- likely high blood product transfusion ratios, including ject to an inherent risk of bias such as immortal time bias platelets, may be beneficial in terms of both haemosta- as well as bias from residual confounding. Accordingly, sis and survival [260]. Others observed increasing effects there is currently weak scientific evidence to support a of platelet transfusion on platelet aggregation over time, specific platelet transfusion threshold in the bleeding identifying a potential early period of resistance to plate- trauma patient. In a sub-study of a RCT, patients ran- let transfusion that resolves by 72–96 h [315]. Late trans- domised to receive first-line coagulation factors or FFP fusions (after 48 h) resulted in a larger increase in platelet were also transfused with platelets to maintain platelet numbers. counts between 50 and 100 × ­109/L [310]. Platelet trans- fusion did not substantially improve platelet count and Calcium contributed to poor clinical outcome. Recommendation 31 We recommend that ionised cal- In patients with TBI, the benefit of platelet transfu- cium levels be monitored and maintained within the nor- sion is also controversial [133, 136]. However, in patients mal range following major trauma and especially during with severe TBI, if ADP response improved after platelet massive transfusion (Grade 1C). administration, the need for neurosurgical intervention We recommend the administration of calcium chloride decreased, as well as mortality [138]. to correct hypocalcaemia (Grade 1C). The therapeutic dose of platelets is four to six units of pooled platelets, equivalent to one aphaeresis plate- Rationale let product, which contains approximately 3–4 × ­1011 The normal range of ionised calcium ­ (Ca2+) is 1.1– platelets [311]. This dose is usually sufficient to provide 1.3 mmol/L and is pH-dependent, with a 0.1 unit haemostasis in a thrombocytopenic bleeding patient and increase in pH decreasing ionised calcium concentration should increase the platelet count by > 30 × ­109/L. How- by approximately 0.05 mmol/L [316]. Ionised calcium is ever, the recovery rate in peripheral blood may be lower essential not only for the formation and stabilisation of under conditions associated with increased consumption fibrin polymerisation sites but also for many platelet- and transfusion of one unit of platelets may be insuffi- related functions, with a reduction in the concentration cient to improve haemostasis in trauma patients. of calcium negatively impacting both processes [316]. The effect of higher platelet doses as well as empiric In addition, cardiac contractility and systemic vascular platelet transfusion in trauma patients without throm- resistance are impaired in the presence of reduced ion- bocytopenia as part of a balanced transfusion strat- ised calcium levels. Importantly, laboratory tests do not egy with other blood products is controversial. Data accurately reflect the detrimental effect of hypocalcaemia from French [262] and US [312] trauma registries sup- on the coagulation cascade, as blood samples are citrated port platelet transfusion despite a normal platelet count and then subsequently recalcified prior to being analysed. [262] and maintenance of a platelet/pRBC ratio closer Acute hypocalcaemia is both a common finding in to1:1, respectively. Recent systematic reviews also found trauma patients and frequently complicates MT [317, that higher platelet/pRBC ratios result in a significant 318]. Low calcium concentrations at admission are asso- decrease in short-term (24 h) and long-term (28–30 day) ciated with platelet activation, aggregation, decreased mortalities [313, 314], lower ICU length of stay (LOS) clot strength, blood transfusions and increased mortal- and higher ICU-free days [314], without influencing the ity [319–321]. In patients receiving blood transfusions, occurrence of thromboembolic events or organ failure hypocalcaemia results from the citrate-mediated chela- [313] when compared with lower platelet/pRBC ratios. tion of serum ­Ca2+. Each unit of pRBC or FFP contains These results should be interpreted with extreme cau- approximately 3 g of citrate used as a preservative and tion, as many source studies are prone to various types of anticoagulant. This citrate is normally metabolised by bias, including various definitions of high and low plate- mitochondria in the liver to bicarbonate in a matter of let/pRBC ratios, severity of bleeding and MT, as well as minutes. However, in the context of haemorrhagic shock Rossaint et al. Critical Care (2023) 27:80 Page 24 of 45 requiring massive transfusion, liver function is often mortality [325]. A Cochrane systematic review concluded impaired due to hypoperfusion. The resulting hypocal- that the efficacy of rFVIIa outside its current licensed caemia is detrimental chiefly because of the pivotal role indications is unproven and even associated with an ­Ca2+ plays in the coagulation cascade. C ­ a2+ acts as a increased incidence of arterial thromboses, therefore cofactor in the activation of factors II, VII, IX and X, as rFVIIa should only be used for licensed indications or in well as proteins C and S. It is also necessary for platelet the context of a study [326]. In the context of bleeding adhesion at the site of vessel injury. Remarkably, hypoc- major trauma patients, rFVIIa should be considered only alcaemia within the first 24 h of critical bleeding can if treatment with a combination of surgical approaches, predict mortality and the need for multiple transfusions best-practice use of blood products, antifibrinolytics and with greater accuracy than the lowest fibrinogen concen- correction of severe metabolic acidosis, hypothermia and tration, acidosis and the lowest platelet count [322]. Ion- hypocalcaemia fail to control bleeding. Best-practice use ised calcium levels are also easily monitored, as they are of blood products includes pRBC, platelets, FFP and cryo- included as a standard part of a blood gas analysis by the precipitate/fibrinogen targeting to Hct above 24%, plate- majority of blood gas analysers available on the market. lets above 50 × ­109/L and fibrinogen above 1.5–2.0 g/L. Transfusion-induced hypocalcaemia, with ionised In patients with isolated head injury and TICH, the use ­Ca2+ levels below 0.9 mmol/L or serum total corrected of rFVIIa was shown to have no positive effect on patient calcium levels of 7.5 mg/dL or lower, should be cor- outcomes, and even found to be harmful [327, 328]. rected promptly, as ionised C­ a2+ levels below 0.8 mmol/L Accordingly, a Cochrane systematic review found no sup- are associated with cardiac dysrhythmias. Importantly, port in favour of rFVIIa treatment for reducing mortality however, it should be noted that while an association or disability in patients with TBI and related ICH [329]. between admission ionised hypocalcaemia and mortality, The use of rFVIIa to treat traumatic coagulopathy increased blood transfusion and coagulopathy has been represents an "off-label" indication and its administra- identified, no data demonstrate that the prevention or tion was associated to increased risk of thromboembolic treatment of ionised hypocalcaemia reduces mortality in complications [330, 331]. However, the recent evidence patients with critical bleeding requiring MT. did not find elevated thromboembolic complications in The preferred agent to correct hypocalcaemia is cal- severe trauma patients receiving rFVIIa [325, 332]. cium chloride, 10 mL as a 10% solution contains 270 mg of elemental calcium. In comparison, 10 mL of 10% cal- VII. Management of antithrombotic agents cium gluconate contains only 90 mg of elemental calcium Reversal of vitamin K‑dependent oral anticoagulants [323]. Calcium chloride may also be preferable to calcium Recommendation 33 In the bleeding trauma patient, we gluconate in the setting of abnormal liver function, where recommend the emergency reversal of vitamin K-depend- decreased citrate metabolism results in the slower release ent oral anticoagulants with the early use of both PCC and of ionised calcium. 5–10 mg i.v. phytomenadione (vitamin K ­ 1) (Grade 1A). Recombinant activated coagulation factor VII Rationale Recommendation 32 We do not recommend the use of VKAs such as warfarin, are still prescribed, despite the recombinant activated coagulation factor VII (rFVIIa) as increasing use of direct oral anticoagulants (DOACs) first-line treatment (Grade 1B). [333], for the prevention of thromboembolism in atrial We suggest that the off-label use of rFVIIa be consid- fibrillation, previous venous or arterial thromboembo- ered only if major bleeding and traumatic coagulopathy lism and/or mechanical heart valves. There are three persist despite all other attempts to control bleeding, sys- therapeutic options for the reversal of VKAs: vitamin K, temic homeostasis and best-practice use of conventional PCC and FFP. Modern guidelines advise the rapid res- haemostatic measures (Grade 2C). toration of a normal INR, although evidence that this improves clinical outcome is limited to case series [295, Rationale 334–338], one suggesting more improvement if PCC was rFVIIa acts on the endogenous coagulation system, but administered rapidly [337]. its effect depends on adequate numbers of platelets and For the immediate reversal of VKAs, the missing fibrinogen, pH and body temperature near normal lev- coagulation factors, FII, FIX and FX, are replaced with els. Primary predictors of a poor response to rFVIIa PCC [339]. However, correction of INR is particularly treatment are pH < 7.2 (p < 0.0001) and platelet count dependent on FVII and there are low levels of FVII in < 100 × ­109/L (p = 0.046) [324]. three-factor PCC. Unfortunately, some countries only Administration of rFVIIa as an adjunct to standard have access to three-factor PCC [340]; however, the use care in severely bleeding trauma patients did not affect of three-factor PCC is not recommended if four-factor Rossaint et al. Critical Care (2023) 27:80 Page 25 of 45 PCC is available. Because the half-life of administered apixaban, edoxaban or rivaroxaban in patients treated FVII is only about six hours, it is important that vita- or suspected of being treated with one of these agents min K1 (phytomenadione) is co-administered with (Grade 2C). PCC to stimulate production of the vitamin K-depend- We suggest that measurement of anti-Xa activity be ent coagulation factors after the initial effect of PCC. calibrated for the specific agent. If not possible or avail- FFP contains the missing coagulation factors diluted able, we suggest low molecular weight heparin (LMWH)- among all the other constituents of plasma. However, calibrated anti-Xa assays as a reliable alternative (Grade large volumes of FFP are required to replace the miss- 2C). ing factors, thus reversal is often not achieved and there If bleeding is life-threatening in the presence of an are risks of transfusion-associated circulatory overload apixaban or rivaroxaban effect, especially in patients with and TRALI [339]. Indeed a review of 19 studies that TBI, we suggest reversal with andexanet alfa (Grade 2C). included 2878 patients showed that PCC provides more If andexanet alfa is not available, or in patients receiv- rapid and complete factor replacement for PCC versus ing edoxaban, we suggest the administration of PCC (25– FFP [341], and thromboembolic complications were 50 U/kg) (Grade 2C). less frequent in PCC recipients (2.5%) than FFP recipi- ents (6.4%). However, similar poor clinical outcomes Management of direct oral anticoagulants—direct thrombin were seen in both groups [341]. inhibitors Four-factor PCC is administered intravenously in a Recommendation 35 We suggest the measurement of dose of 25–50 U/kg simultaneously with vitamin K and dabigatran plasma levels using diluted thrombin time in there are algorithms to calculate the most appropri- patients treated or suspected of being treated with dabi- ate dose based on body weight and INR level [339]. A gatran (Grade 2C). stepwise dosage is recommended, e.g. 25 U/kg if INR If measurement is not possible or available, we suggest is 2–4.0, 35 U/kg if INR is 4–6.0 and 50 U/kg if INR measurement of the standard thrombin time to allow is > 6.0 [342]. With difficult i.v. access, intraosseous a qualitative estimation of the presence of dabigatran infusion of PCC has been used with no apparent det- (Grade 2C). rimental effects [343]. After reversal, INR should be If bleeding is life-threatening in those receiving dabi- monitored regularly over the next week, as a minority gatran, we recommend treatment with idarucizumab (i.v. of patients take over a week to clear warfarin from their 5 g) (Grade 1C). blood and require additional vitamin K [344]. A rare and unpredictable, but important, side effect of i.v. vita- min K is an anaphylactic reaction, which can result in Rationale cardiac arrest, with an incidence of 3 per 100,000 doses The DOAC plasma concentration is the most important via a non-immunoglobulin E (IgE) mechanism, possibly factor that determines whether an active reversal of med- due to the solubiliser in the vitamin K solution [345]. ication is necessary. Increasing DOAC plasma levels pro- We recommend a 5–10 mg dose of vitamin K because gressively affect laboratory and viscoelastic coagulation less may not fully correct the INR and conversely more tests. Early assessment of both laboratory coagulation than 10 mg vitamin K ­ 1 can prevent re-warfarinisation tests and direct measurements of DOAC levels, there- for days and may create a prothrombotic state, which fore, is crucial in trauma patients receiving or suspected could lead to further thromboembolism [339]. of having received a DOAC [347]. The use of PCC is associated with an increased risk Measurement using three commonly available labora- of venous and arterial thrombosis during the recov- tory tests, PT, antifactor Xa and thrombin time, allows ery period, due to pre-existing risk and possibly the use for the assessment of whether a patient is anticoagu- of PCC itself [339]. In addition, higher incidences of lated, and if so, by which agent, VKA, a FXa inhibitor or thromboembolic events have been reported in trauma a thrombin inhibitor, respectively. If it is unknown with patients with the use of three-factor PCC compared with which DOAC the patient has been treated or the anti-Xa four-factor PCC [346]. Therefore, in patients who have assay calibrated for the specific agent is not available, a received PCC, thromboprophylaxis must be considered universal, LMWH-calibrated, anti-Xa assay is a reliable as early as possible after bleeding has been controlled. alternative. This assay accurately determines rivaroxa- ban, apixaban and edoxaban concentrations and cor- Management of direct oral anticoagulants—factor Xa rectly predicts relevant drug concentrations [348]. An inhibitors anti-Xa activity of 0.35 U/mL thereby corresponds to a Recommendation 34 We suggest the measurement of DOAC cut-off value of 30 µg/L, 0.58 U/mL corresponds plasma levels of oral direct antifactor Xa agents such as to 50 µg/L and 1.14 U/mL corresponds to 100 µg/L [348]. Rossaint et al. Critical Care (2023) 27:80 Page 26 of 45 Viscoelastic coagulation tests may also be helpful, since suggest an initial dose of 25 U/kg, as this dose has been most DOACs prolong the clotting time (ROTEM or Clot- shown to provide effective haemostasis without increased Pro) progressively [349]. Apixaban has only a low impact rates of thromboembolic events [357]. Repeated PCC on the clotting time even at high plasma concentrations; doses may be necessary in special cases, but caution however, if the patient has a traumatic coagulopathy should be used due to the possible thrombotic potential with a prolonged clotting time, it will not be possible to of PCC products. discriminate between this effect and the presence of a In the presence of life-threatening bleeding and anti- DOAC prior to treatment [350]. FIIa activity due to dabigatran, treatment with idaruci- Andexanet alfa acts as a decoy target for the urgent zumab (5 g i.v.) should be initiated [358, 359]. Repeated reversal of rivaroxaban and apixaban [351]. The US Food doses of idarucizumab may be necessary in patients and Drug Administration (FDA) approved andexanet with high dabigatran plasma levels [360]. Once idaruci- alpha in May 2018, followed by the European Medicines zumab has been administered coagulation tests should Agency (EMA) in 2019. Andexanet alfa is administered be repeated within 5–10 min (laboratory and viscoelastic as an intravenous bolus of 400 mg over 15 min followed tests). Only after dabigatran neutralisation, they are able by a continuous infusion of 480 mg over 2 h (low dose) to show the underlying coagulopathy usually present in or 800 mg over 30 min followed by a continuous infu- patients following major trauma [361]. sion of 960 mg over 2 h (high dose) [351]. The dose and The co-administration of tranexamic acid (15 mg/ time since the last DOAC intake determine whether the kg or 1 g) is indicated in trauma patients independ- low- or high-dosage protocol is applied. A propensity ent of the present DOAC and reversal strategy (see score-matched analysis showed that the adjusted 30-day recommendation R23). mortality rates were lower for patients treated with andexanet alfa than in matched patients receiving PCC [352]. In patients suffering from an intracerebral haem- Antiplatelet agents orrhage andexanet alfa reduced anti-FXa activity with Recommendation 36 We recommend that routine plate- a high rate of haemostatic efficacy and a beneficial out- let transfusion be avoided in patients with ongoing bleed- come [353]. Another comparison of andexanet alfa versus ing who have been treated with APAs (Grade 1C). four-factor PCC reversal showed no significant differ- ence regarding thrombotic events, but larger studies are Rationale required to confirm this finding [354]. In patients with Conflicting data exist with respect to the effects of APAs acute major bleeding treated with edoxaban, initial evi- on bleeding and outcome in trauma patients, with or dence shows, that andexanet alfa significantly decreases without TBI [6]. One meta-analysis that included 24 anti-Xa activity with good haemostatic efficacy and may observational studies and 5423 participants with early be considered as a reversal strategy [355]. Use in this con- surgery for hip fracture found a higher risk of bleeding text is, however, currently still off-label and further data and higher blood transfusion requirements, but similar are necessary to confirm this finding. outcomes in patients taking APAs compared to those Plasma levels of antifactor Xa agents following the without antiplatelet therapy [362]. administration of andexanet alfa cannot be reliably meas- In mild TBI patients treated with APAs, two meta- ured with standard anti-Xa assays because the level of analyses have demonstrated a small increased risk of dilution causes dissociation of andexanet alfa from the immediate ICH, especially if concomitant with another anticoagulant, resulting in an overestimation of the anti- risk factor for ICH such as GCS < 15 or age > 65 years coagulant concentration. Thus, modified anti-Xa assays [363] and a very low risk of delayed ICH [364], respec- with reduced dilution are available in some coagulation tively. However, the subgroup of patients on dual anti- laboratories [356]. VEM tests such as ROTEM or ClotPro platelet therapy had an increased delayed bleeding risk, still can provide additional information about residual compared with single APA patients [364]. Another meta- antifactor Xa activity [349, 350]; however, ROTEM tests analysis that included 20 observational studies compar- are only minimally impacted by low DOAC levels [350]. ing 2447 TBI patients on pre-injury APAs with 4814 Four-factor PCC antagonises the anticoagulant effect controls revealed no statistically significant difference in of factor X inhibitors. PCC increases prothrombin and early mortality, need for neurosurgery or LOS between factor X levels inducing a compensatory prohaemostatic the two groups, with similar results for subgroup analy- effect with increased thrombin generation potential. ses of aspirin and clopidogrel users [365]. Therefore, if antifactor Xa activity has been detected and The discrepant results on the risk of bleeding in patients andexanet alfa is not available or patients are on edoxa- taking APAs may be explained by the insufficient analysis ban, PCC (25–50 U/kg) treatment may be initiated. We Rossaint et al. Critical Care (2023) 27:80 Page 27 of 45 of confounding factors that may influence the effects of We recommend combined pharmacological and IPC different APAs in specific groups of patients. Evaluation thromboprophylaxis within 24 h after bleeding has been of platelet function in bleeding trauma patients treated controlled and until the patient is mobile (Grade 1B). with suspected or confirmed pre-injury APAs may be We do not recommend the use of graduated compres- useful to guide reversal therapies [139], but the role of sion stockings for thromboprophylaxis (Grade 1C). current POC-PFTs is not yet established (see recommen- We do not recommend the routine use of inferior vena dation R12). Whether bleeding in the setting of APA use cava filters as thromboprophylaxis (Grade 1C). warrants platelet transfusion is also controversial. Two meta-analyses of ten [366] and twelve [367] stud- Rationale ies, respectively, mainly retrospective and including The risk of hospital-acquired venous thromboembo- mostly aspirin-treated patients, showed a lack of evi- lism (VTE) after multiple trauma is high; a prospective dence of survival benefit following platelet transfusion study showed that without thromboprophylaxis 18% had in TICH while on APAs. While there was no significant proximal deep vein thrombosis (DVT) and 11% pulmo- overall reduction in haemorrhage progression or need nary embolism (PE) while PE is the third leading cause for neurosurgical intervention, sensitivity analysis dem- of death in those who survive beyond the third day [372]. onstrated that among studies with larger sample sizes, There are few RCTs assessing thromboprophylaxis in platelet transfusion was associated with a reduced risk trauma patients alone. Of particular note, there are none of haemorrhage progression but increased mortality assessing the use of graduated compression stockings [367]. The lack of survival benefit associated with platelet (GrCS) in trauma patients; indeed, there is no evidence transfusion in patients with severe TBI on APAs was con- to show that GrCS reduce the risk of death due to a PE firmed in a further prospective multicentric study [368]. in any hospitalised patients. Recently the GAPS study However, in a single-institution study administration of [373] failed to show any evidence of benefit with the use two units of pooled platelets improved outcomes com- of GrCS in an RCT of over 2000 surgical patients with pared with one unit [369]. moderate VTE risk; while the CLOTS (Clots in Legs Or Another meta-analysis that included 16 clinical trials in Stockings) studies in stroke patients showed that GrCS both spontaneous and TICH patients on APAs found a could cause harm [374]. significant difference for haematoma expansion in favour In contrast to GrCS, there is good evidence to suggest of platelet transfusion compared with standard of care, that IPC is associated with a benefit in reducing hospi- but no difference in mortality and severe disability, and tal-associated VTE. A recent Cochrane review [375] on a slight increase in the odds for adverse thromboembolic the use of combined IPC and pharmacological thrombo- events following platelet transfusion [370]. prophylaxis compared with either alone, based mainly Importantly, potential confounding factors in the stud- on surgical and trauma patients, concluded that combin- ies on platelet transfusion in patients on APAs are the ing IPC with pharmacological prophylaxis, compared dose, the timing and the type of platelet product adminis- with pharmacological prophylaxis alone, reduces the tered, as well as the type of APAs administered. However, incidence of both PE (low-certainty evidence) and DVT few studies have specifically investigated the reversal of (high-certainty evidence). In those with a bleeding risk, P2Y12 inhibitors after TICH. In a cohort of 243 patients IPC alone is preferable until the bleeding risk recedes. with isolated TBI and ICH on pre-injury P2Y12 inhibitor, A systematic review and meta-analysis [376] showed platelet transfusion was associated with a 32% decrease that thromboprophylaxis with heparins decreases DVT in the rate of progression of ICH, a 20% decrease in neu- and PE in critically ill medical and surgical patients, and rosurgical intervention, and a survival benefit on multi- LMWH compared with twice daily unfractionated hepa- variate regression analysis [371]. rin (UFH) decreases both the overall rate and sympto- Data on desmopressin as a potential alternative to matic rate of PE. Furthermore, a large study in the elderly platelet transfusion for reversal of APA effects in trauma [377] showed LMWH was more efficacious than UFH patients are scarce, therefore, we have not made a recom- and had a lower bleeding risk in a geriatric population mendation on the use of desmopressin in this setting. of over 93,000. Weight-adjusted LMWH is widely used although good RCTs comparing standard versus weight VIII. Thromboprophylaxis adjusted are awaited. A 289-patient study of those who Thromboprophylaxis developed VTE during or after a critical care stay showed Recommendation 37 We recommend early initiation of that thromboprophylaxis failure was more frequent mechanical thromboprophylaxis with intermittent pneu- with elevated body mass index, a personal or family his- matic compression (IPC) while the patient is immobile tory of VTE and those administered vasopressors [378]. and has a bleeding risk (Grade 1C). However, there are inadequate data to suggest routine Rossaint et al. Critical Care (2023) 27:80 Page 28 of 45 Table 4 Adherence to the following quality standards may be assessed to evaluate the quality of care provided the bleeding trauma patient Parameter Time from injury to the initiation of intervention to stop bleeding (surgery or embolisation) in hypotensive patients who do not respond to initial resuscitation Time from hospital arrival to availability of a full set of blood results [full blood count, prothrombin time, fibrinogen, calcium, viscoelastic testing (if avail‑ able)] Proportion of patients receiving the correct treatment according to the blood results Proportion of patients receiving tranexamic acid within 3 h after injury Damage control surgical techniques used in accordance with recommendation R19 Thromboprophylaxis commenced in accordance with recommendation R37 monitoring of LMWH with anti-Xa levels improves clini- IX. Guideline implementation and quality control cal outcome [378, 379]. Guideline implementation Contraindications to pharmacological thromboprophy- Recommendation 38 We recommend the local imple- laxis include patients who are already receiving full-dose mentation of evidence-based guidelines for management anticoagulation, those with significant thrombocytopenia of the bleeding trauma patient (Grade 1B). (platelet count < 50 × ­109/L), an untreated inherited or acquired bleeding disorder, evidence of active bleeding, uncontrolled hypertension (blood pressure > 230/120), Assessment of bleeding control and outcome a lumbar puncture/spinal analgesia expected within the Recommendation 39 We recommend that local clinical next 12 h or performed within the last 4 h (24 h if trau- quality and safety management systems include param- matic), procedures with a high bleeding risk or a new eters to assess key measures of bleeding control and out- haemorrhagic stroke. come (Grade 1B). The optimal timing for the initiation of pharmacological thromboprophylaxis remains inadequately investigated, Rationale especially after TBI. Retrospective studies looking at TBI Implementation of treatment guidelines in complex show that there are fewer VTE if thromboprophylaxis is areas of clinical care, such as the management of trauma started sooner (within 24–72 h of injury) rather than later, patients, is challenging [6]. However, repetitive edu- without increased bleeding risk [380], but how much ear- cational activities addressing all healthcare providers lier thromboprophylaxis can be used with efficacy and involved, and in particular training in the simulation cen- safety is the subject of future clinical trials. We suggest that tre, have been shown to be successful in increasing guide- pharmacological VTE prophylaxis be initiated with either line adherence [383, 384]. The evaluation of healthcare LMWH, or low-dose UFH in patients with renal failure, as provider perspectives on guideline quality also plays an early as possible, only after a head CT confirms that ICH is important role in a successful implementation process. stable and in the absence of persistent bleeding. High guideline credibility, as well as a strong and well- The use of prophylactic inferior vena cava (IVC) filters communicated leadership commitment to the guidelines, has been shown to be of no benefit in reducing a com- can increase adherence [383]. Once guidelines are intro- posite end point of symptomatic PE and death compared duced, guideline adherence needs to be monitored with with no filter [381]. Moreover, a meta-analysis concluded feedback [385] of the results to the involved health care that while IVC filters in this setting may reduce non-fatal providers. PE they do not affect overall mortality [382]. Further- In addition, clinical debriefing is very useful during the more, there is also no evidence of added benefit when implementation of recommendations to favour clinical IVC filters are used in combination with pharmacological decision-making, situational awareness, communication, thromboprophylaxis. PE still occur despite the presence enhanced teamwork, team leadership and optimisation of a filter. Filters have short- and long-term complication of resources (space, equipment and environment) [386, rates and are associated with high cost and often pro- 387]. Oral debriefing allows healthcare professionals to vide a false sense of security, delaying the use of effective anticipate or review medical interventions, emphasise pharmacological thromboprophylaxis. Lastly, a further psychological safety and thus provide quality assurance problem with IVC filters is that they require a second of facilitation strategies and skills with the prevention of invasive procedure to remove. cognitive biases and personality traits and their potential Rossaint et al. Critical Care (2023) 27:80 Page 29 of 45 Fig. 1 Summary of treatment modalities for the bleeding trauma patient included in this guideline. APTT Activated partial thromboplastin time, CT Computed tomography, FFP Fresh frozen plasma, GCS Glasgow coma scale, Hb Haemoglobin, Hct Haematocrit, INR International normalised ratio, LMWH Low molecular weight heparin, MAP Mean arterial pressure, PCC Prothrombin complex concentrate, PT Prothrombin time, pRBC Packed red blood cells, REBOA Resuscitative endovascular balloon occlusion of the aorta, TBI Traumatic brain injury Rossaint et al. Critical Care (2023) 27:80 Page 30 of 45 Fig. 1 continued Rossaint et al. Critical Care (2023) 27:80 Page 31 of 45 Fig. 1 continued impact on decisions, medical errors, behaviour and indi- with TBI with a Glasgow Coma Scale score of 4–12 [390]. vidual-level patient outcomes [388]. In this detailed analysis, it could be shown that the more Higher guideline adherence in turn results in improved often physiologic parameters were outside the corridors survival in patients suffering from TBI [389]. This was described for goal-directed treatment, the higher the per- confirmed in a recent study on the impact of guideline centage of poor neurologic outcome and mortality [390]. adherence on morbidity and mortality in 882 patients Rossaint et al. Critical Care (2023) 27:80 Page 32 of 45 Additionally, in general trauma, adherence to these under appropriate circumstances. This edition also dis- European guidelines on the management of bleeding cusses the potential pre-hospital use of blood products trauma patients resulted in higher patient survival [4, but does not include a recommendation or suggestion for 391]. These early and small studies were recently con- or against this practice. firmed by an analysis of the treatment and outcome in This guideline is associated with several limitations. 1169 severely injured patients treated at the Royal Lon- First, only a few of the recommendations are based on don Hospital Major Trauma Centre from 2008 to 2017 high-quality evidence, a fact that highlights the need for according to their major haemorrhage protocol. During future research in this area. Second, in order to support this period, the MT rate dropped from 68 to 24%, median a more general approach to the trauma patient, spe- pRBC transfusion from 12 to 4 units and mortality from cific recommendations for special populations such as 45 to 27% [3]. paediatric patients or patients with TBI have not been Training in trauma care should emphasise the key role included. Third, these guidelines are limited to recom- of coagulation in determining outcome. Increasing clini- mendations for which implementation is likely to be cian knowledge and understanding in this area should be feasible within most European healthcare systems. Nev- an integral part of the implementation of the algorithm. ertheless, we are confident that adherence to these Euro- All trauma care centres should evaluate their own per- pean guidelines for the management of the bleeding formance using a routine institutional quality manage- trauma patient will result in higher patient survival [4, 5]. ment programme. An audit of adherence to best practice, In publishing the sixth edition of this guideline, our aim including feedback and practice change where needed, continues to be improvement of outcomes in severely should be included as part of the local implementation of injured trauma patients by optimising and standardis- these guidelines. To evaluate the quality of care provided ing trauma care in line with the available evidence across to the patient who is bleeding after major trauma, we Europe and beyond. suggest that adherence to the following quality standards be assessed (Table 4). Abbreviations AA Arachidonic acid Discussion ADP Adenosine diphosphate AE Angioembolisation Severe traumatic injury continues to challenge health- AIS Abbreviated injury scale care systems around the world and post-traumatic bleed- APA Antiplatelet agent ing remains a leading cause of potentially preventable APTT Activated partial thromboplastin time ARDS Acute respiratory distress syndrome death among injured patients. Therefore, it is important ATLS Advanced trauma life support to provide guidance on the management of major bleed- AUC​ Area under the curve ing and coagulopathy following traumatic injury. This AUROC Area under the receiver operating characteristics CCA​ Conventional coagulation assay sixth edition of the European guideline (summarised in CCT​ Conventional clotting test Additional file 3) on the management of major bleeding CFC Coagulation factor concentrate and coagulopathy following traumatic injury represents CPR Cardiopulmonary resuscitation CT Computed tomography an update of the editions published by the same core DC Damage control author group in 2007, 2010, 2013, 2016 and most recently DOAC Direct oral anticoagulant in 2019 [6]. The format of this edition has been adjusted DVT Deep vein thrombosis eFAST Extended focused assessment with sonography in trauma to reflect the trend towards concise guideline docu- EXTEM Extrinsically activated test with tissue factor ments that cite only the highest-quality studies and most FAST Focused assessment with sonography in trauma relevant literature rather than attempting to provide a FFP Fresh-frozen plasma FIBTEM Fibrin-based extrinsically activated test with tissue factor and the comprehensive literature review to accompany each rec- platelet inhibitor cytochalasin D ommendation. Additional older literature citations and GCS Glasgow coma scale an extended discussion around some of the recommen- GrCS Graduated compression stockings Hb Haemoglobin dations included here can therefore be found in previous Hct Haematocrit editions of this guideline. ICH Intracranial haemorrhage The nine chapters of this guideline continue to fol- ICS Intraoperative cell salvage ICU Intensive care unit low an approximate temporal path for management of IgE Immunoglobin E the bleeding trauma patient, with recommendations INR International normalised ratio grouped behind key decision points (Fig. 1; Additional IPC Intermittent pneumatic compression ISS Injury severity score file 4). New to this edition of the guideline is a recom- IVC Inferior vena cava mendation and discussion around the use of cell salvage LMWH Low molecular weight heparin Rossaint et al. Critical Care (2023) 27:80 Page 33 of 45 LOS Length of stay Donat R. Spahn serves as co-chair of the ABC-T European Medical Education MAP Mean arterial pressure Initiative. MT Massive transfusion Arash Afshari represented the European Society of Anaesthesiology and OR Odds ratio Intensive Care (ESAIC) on the ABC-T Task Force. PCC Prothrombin complex concentrate Bertil Bouillon is a member of the ABC-T European Medical Education Initiative PE Pulmonary embolism faculty. PFT Platelet function test Vladimir Cerny is a member of the ABC-T European Medical Education Initia‑ PHUS Pre-hospital ultrasonography tive faculty. POC Point-of-care Diana Cimpoesu represented the European Society for Emergency Medicine POCUS Point-of-care ultrasonography (EuSEM) on the ABC-T Task Force. PP Pulse pressure Nicola Curry is a member of the ABC-T European Medical Education Initiative PPP Preperitoneal pelvic packing faculty. pRBC Packed red blood cells Jacques Duranteau represented the European Society of Intensive Care Medi‑ PT Prothrombin time cine (ESICM) on the ABC-T Task Force. PTr Prothrombin time ratio Daniela Filipescu represented the European Society of Anaesthesiology and RCT​ Randomised controlled trial Intensive Care (ESAIC) on the ABC-T Task Force. REBOA Resuscitative endovascular balloon occlusion of the aorta Oliver Grottke is a member of the ABC-T European Medical Education Initiative rFVIIa Recombinant activated coagulation factor VII faculty. ROTEM Rotational thromboelastometry Lars Grønlykke served as an adjunct member of the ABC-T European Medical RR Risk ratio Education Initiative faculty. SI Shock index Anatole Harrois is a member of the ABC-T European Medical Education Initia‑ TBI Traumatic brain injury tive faculty. TEG Thromboelastography Beverley J. Hunt is a member of the ABC-T European Medical Education Initia‑ TEG-PM Thromboelastography with platelet mapping tive faculty. TICH Traumatic intracranial haemorrhage Alexander Kaserer is a member of the ABC-T European Medical Education TRALI Transfusion-related acute lung injury Initiative faculty. TXA Tranexamic acid Radko Komadina represented the European Society of Trauma and Emergency UFH Unfractionated heparin Surgery (ESTES) on the ABC-T Task Force. VEM Viscoelastic monitoring/measures Mikkel Herold Madsen served as an adjunct member of the ABC-T European VKA Vitamin K antagonist Medical Education Initiative faculty. VTE Venous thromboembolism Marc Maegele represented the European Shock Society (ESS) on the ABC-T WBCT Whole-body computed tomography Task Force. Lidia Mora is a member of the ABC-T European Medical Education Initiative faculty. Supplementary Information Louis Riddez is a member of the ABC-T European Medical Education Initiative The online version contains supplementary material available at https://​doi.​ faculty. org/​10.​1186/​s13054-​023-​04327-7. Carolina S Romero served as an adjunct member of the ABC-T European Medi‑ cal Education Initiative faculty. Additional file 1. Summary of PICOs. Charles-Marc Samama represented the Network for Advancement of Patient Blood Management, Haemostasis and Thrombosis (NATA) on the ABC-T Task Additional file 2. Search bundles, structured literature search strategies Force. and results. Jean-Louis Vincent is a member of the ABC-T European Medical Education Additional file 3. Summary of recommendations. Initiative faculty. Sebastian Wiberg served as an adjunct member of the ABC-T European Medi‑ Additional file 4. Summary of treatment modalities for the bleeding cal Education Initiative faculty. trauma patient included in this guideline (A0 poster). Funding Costs incurred for medical writing support and publication were supported Acknowledgements by unrestricted Grants from CSL Behring GmbH (Marburg, Germany), LFB The development of this guideline was initiated and performed by the Biomédicaments (Courtaboeuf, France) and Alexion Pharma Germany GmbH authors as members of the Task Force for Advanced Bleeding Care in Trauma. (Munich, Germany). The grantors had no authorship or editorial control over Meeting organisation and medical writing support for literature searches the content of the meetings or any subsequent publication. and manuscript preparation were provided by Ashfield MedComms GmbH (Mannheim, Germany), an Inizio company. Structured literature searches were Availability of data and materials designed and performed by Janne Vendt (Copenhagen University Hospital, All of the publications cited in this guideline were identified in publicly avail‑ Herlev, Denmark). This publication has been endorsed by the European able databases using the search strategies listed in Additional file 2. Society of Anaesthesiology and Intensive Care (ESAIC), European Society of Intensive Care Medicine (ESICM), European Shock Society (ESS), European Society for Trauma and Emergency Surgery (ESTES), European Society for Declarations Emergency Medicine (EuSEM) and the Network for Advancement of Patient Blood Management, Haemostasis and Thrombosis (NATA). Ethics approval and consent to participate Not applicable. Author contributions All of the authors participated in the formulation of questions to be addressed Consent for publication in the guideline, screening of abstracts and literature, the remote consensus- Not applicable. finding processes, and drafting, review, revision and approval of the final manuscript. All authors read and approved the final version of the manuscript. Competing interests RR: In the past 5 years, RR has received honoraria for consulting or lecturing Author’s information from CSL Behring, Boehringer Ingelheim and Fresenius. In fields related to Rolf Rossaint serves as chair of the Advanced Bleeding Care in Trauma (ABC-T) this work RR received research grand funding from the German Research European Medical Education Initiative. Foundation. AA has no competing interests to declare. BB has no competing Rossaint et al. Critical Care (2023) 27:80 Page 34 of 45 interests to declare. VC has no competing interests to declare. DC: In the past Kenilworth, New Jersey, USA, Novo Nordisk Health Care AG, Zurich, Switzer‑ 5 years, DC has received funding from the European Union Competitive‑ land, PAION Deutschland GmbH, Aachen, Germany, Pharmacosmos A/S, Hol‑ ness Operational Program; UEFISCDI (Unitatea Executiva Pentru Finantarea baek, Denmark, Pfizer AG, Zürich, Switzerland, Pierre Fabre Pharma, Alschwil, Invatamantului Superior a Cercetarii Dezvoltarii si Inovarii), the Romanian Switzerland, Portola Schweiz GmbH, Aarau, Switzerland, Roche Diagnostics National Plan for Research, Development, and Innovation; NATO-SPS (North International Ltd, Reinach, Switzerland, Sarstedt AG & Co., Sevelen, Switzer‑ Atlantic Treaty Organisation—Science for Peace and Security); Erasmus+ First land and Nümbrecht, Germany, Shire Switzerland GmbH, Zug, Switzerland, Aid Improve Survival (TIRAMISU)" and COST Action CA19137. NC: In the last Takeda, Glattpark, Switzerland, Tem International GmbH, Munich, Germany, 5 years, NC has received honoraria for consulting from LFB, Bayer and Sobi and Vifor Pharma, Munich, Germany, Neuilly sur Seine, France and Villars-sur-Glâne, institutional research grant support from CSL Behring and Sobi. JD: In the last Switzerland, Vifor (International) AG, St. Gallen, Switzerland, Zuellig Pharma 5 years, JD has received honoraria for symposium lectures from Octapharma Holdings, Singapore, Singapore. and LFB Biomédicaments. DF: In the past 5 years, DF has received honoraria for lecturing from the University of Continuing Education, Department for Health Author details 1 Sciences and Medicine and Research, Krems, Donau University & Eurasia Heart Department of Anaesthesiology, University Hospital Aachen, RWTH, Aachen Foundation, Austria, the 2019 International Congress of Cardiothoracic and University, Pauwelsstrasse 30, D‑52074 Aachen, Germany. 2 Department Vascular Anesthesia & Asian Society of Cardiothoracic Anesthesia Organizing of Paediatric and Obstetric Anaesthesia, Rigshospitalet, University of Copenha‑ Committee, the American Society of Anesthesiologists, and the Instrumenta‑ gen, Blegdamsvej 9, DK‑2100 Copenhagen, Denmark. 3 Department of Trauma tion Laboratory Company (Werfen). DF received institutional support from and Orthopaedic Surgery, Cologne‑Merheim Medical Centre (CMMC), Vifor Pharma Romania SRL. DF is the deputy chair of the Romanian Anaemia University of Witten/Herdecke, Ostmerheimer Strasse 200, D‑51109 Cologne, Working Group and chair of the Romanian Patient Blood Management imple‑ Germany. 4 Department of Anaesthesiology, Perioperative Medicine and Inten‑ mentation group. OG: In the past 5 years, OG has received research funding sive Care, Masaryk Hospital, J.E. Purkinje University, Socialni pece 3316/12A, from Astra Zeneca (Hamburg, Germany), Alveron (Amsterdam, The Nether‑ CZ‑40113 Usti nad Labem, Czech Republic. 5 Department of Anaesthesiology lands), Bayer AG (Wuppertal, Germany), Boehringer Ingelheim (Ingelheim, Ger‑ and Intensive Care Medicine, Charles University Faculty of Medicine, Simkova many), CSL Behring (Marburg, Germany), Octapharma (Lachen, Switzerland), 870, CZ‑50003 Hradec Králové, Czech Republic. 6 Department of Emergency Portola (San Francisco, California), Werfen (Munich, Germany) and the German Medicine, Emergency County Hospital “Sf. Spiridon” Iasi, University of Medicine Research Foundation (DFG). He has also received honoraria for lectures and and Pharmacy ”Grigore T. Popa” Iasi, Blvd. Independentei 1, RO‑700111 Iasi, consultancy from Baxalta (Unterschleißheim, Germany), Bayer AG (Wuppertal, Romania. 7 Oxford Haemophilia and Thrombosis Centre, Nuffield Orthopaedic Germany), Boehringer Ingelheim, CSL Behring (Marburg, Germany), Ferring Centre, Oxford University Hospitals NHS Trust, Windmill Road, Oxford OX3 7HE, (Kiel, Germany), Octapharma (Lachen, Switzerland), Pfizer (Berlin, Germany), UK. 8 Radcliffe Department of Medicine, Oxford University, Oxford, UK. 9 Depart‑ Takeda (Zurich, Switzerland), Portola (San Francisco, California), Sanofi (Berlin, ment of Anesthesiology, Intensive Care and Perioperative Medicine, Assistance Germany) and Werfen (Munich, Germany). LG has no competing interests Publique Hôpitaux de Paris, Paris Saclay University, 78 rue du Général Leclerc, to declare. AH: In the past 5 years, AH has received honoraria for consulting F‑94275 Le Kremlin‑Bicêtre Cedex, France. 10 Department of Cardiac Anaesthe‑ or lecturing from LFB Biomédicaments, Edwards Lifesciences, AOP Orphans sia and Intensive Care, “Prof. Dr. C. C. Iliescu” Emergency Institute of Cardio‑ Pharmaceuticals and Mindray. BJH has no competing interests to declare. vascular Diseases, Carol Davila University of Medicine and Pharmacy, Sos AK: In the last 5 years, AK has received honoraria for lecturing from Bayer Fundeni 256‑258, RO‑022328 Bucharest, Romania. 11 Department of Thoracic AG, Zürich, Switzerland. RK: In the past 5 years, RK has received honoraria for Anaesthesiology, The Heart Centre, Rigshospitalet, University of Copenhagen, consulting or lecturing from CSL Behring. MHM: In the past 5 years, MHM Blegdamsvej 9, DK‑2100 Copenhagen, Denmark. 12 Thrombosis and Haemo‑ has received institutional research grant support from the Department of philia Centre, Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Anaesthesia, Nordsjaellands Hospital, University of Copenhagen, Hilleroed, Road, London SE1 7EH, UK. 13 Institute of Anaesthesiology, University Hospital Denmark. MM: In the past 5 years, MM has received honoraria and support for Zurich, Raemistrasse 100, CH‑8091 Zurich, Switzerland. 14 Department of Trau‑ speaker bureaus, lectures, advisory boards, conference travels and research matology, General and Teaching Hospital Celje, Medical Faculty, Ljubljana activities from Abbott Inc, Alexion Pharma, AstraZeneca, Bayer, Biotest, CSL University, Oblakova ulica 5, SI‑3000 Celje, Slovenia. 15 Department of Trauma Behring, IL Werfen/Instrumentation Laboratories and LFB Biomédicaments. and Orthopaedic Surgery, Cologne‑Merheim Medical Centre (CMMC), LM has no competing interests to declare. LR has no competing interests to Institute for Research in Operative Medicine (IFOM), University of Witten/ declare. CSR has no competing interests to declare. CMS: In the last five years, Herdecke, Ostmerheimer Strasse 200, D‑51109 Cologne, Germany. 16 Depart‑ CMS’ department has received an honorarium from Norgine and three grants ment of Anaesthesiology, Intensive Care and Pain Clinic, Vall d’Hebron Trauma, from i-SEP, Octapharma and Sanofi India. From 2019 to 2022 CMS served as Rehabilitation and Burns Hospital, Autonomous University of Barcelona, chair of NATA, with several contacts with industry and some grants to NATA Passeig de la Vall d’Hebron 119‑129, ES‑08035 Barcelona, Spain. 17 Department from CSL Behring, Hemosonics, i-SEP, Masimo, Medtronic, Nordic pharma of Surgery and Trauma, Karolinska University Hospital, S‑171 76 Solna, Sweden. 18 Octapharma, Pharmacosmos, Sysmex, Vifor, Werfen (no personal benefit). Department of Anaesthesia, Intensive Care and Pain Therapy, Consorcio JLV has no competing interests to declare. SW has no competing interests Hospital General Universitario de Valencia, Universidad Europea of Valencia to declare. DRS: In the past 5 years, DRS’s academic department has received Methodology Research Department, Avenida Tres Cruces 2, ES‑46014 Valencia, grant support from the Swiss National Science Foundation, Berne, Switzerland, Spain. 19 Department of Anaesthesia, Intensive Care and Perioperative Medi‑ the Swiss Society of Anesthesiology and Perioperative Medicine (SSAPM), cine, GHU AP-HP Centre - Université Paris Cité - Cochin Hospital, 27 rue du Berne, Switzerland, the Swiss Foundation for Anesthesia Research, Zurich, Faubourg St. Jacques, F‑75014 Paris, France. 20 Department of Intensive Care, Switzerland, Vifor SA, Villars-sur-Glâne, Switzerland and Vifor (International) AG, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, St. Gallen, Switzerland. DRS is co-chair of the ABC-Trauma Faculty, sponsored B‑1070 Brussels, Belgium. by unrestricted educational grants from Novo Nordisk Health Care AG, Zurich, Switzerland, CSL Behring GmbH, Marburg, Germany, LFB Biomédicaments, Received: 16 November 2022 Accepted: 20 January 2023 Courtaboeuf Cedex, France and Octapharma AG, Lachen, Switzerland. DRS received honoraria/travel support for consulting or lecturing from: Alliance Rouge, Bern, Switzerland, Danube University of Krems, Austria, European Society of Anesthesiology and Intensive Care, Brussels, BE, Korean Society for Patient Blood Management, Seoul, Korea, Korean Society of Anesthesiologists, References Seoul, Korea, Network for the Advancement of Patient Blood Management, 1. 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