I. Initial resuscitation and prevention of further bleeding

Minimal elapsed time

Recommendation 1

We recommend that severely injured patients be transported directly to an appropriate trauma facility. (Grade 1B)

We recommend that the time elapsed between injury and bleeding control be minimised. (Grade 1A)

Rationale

Because relatively few hospitals provide all of the services required to treat patients with multiple injuries, many healthcare systems have developed trauma networks or systems. The underlying aims of trauma care organisation is to move patients to a multi-specialist care as early as possible, yet still provide immediate critical interventions. These aims can come into conflict, and there are a number of different means with which to resolve these issues, resulting in large variations in trauma care systems both between and within countries and a consequent significant heterogeneity in the literature. The evidence is weak, but there is a general consensus that the organisation of a group of hospitals into a “trauma system” leads to about a 15 % reduction in trauma death, with about a 50 % reduction in “preventable death” [37–39]. Inter-hospital transfer of patients does not seem to change overall mortality [40], and the evidence neither supports nor refutes direct transport from the accident scene to a major trauma centre [41]. However, there is some evidence that a lower threshold for trauma centre care should be used in patients aged >65 years [42]. No definitive conclusion can be drawn about the relationship between a hospital’s trauma patient volume and outcomes [43]. Despite a lack of evidence there is a consensus that “systemised” trauma care that matches each patient to the most appropriate treatment facility is advantageous, whereby the definition of “appropriate” will depend on the patient profile, the nature of the injuries and the hospital facilities available.

Trauma patients in need of emergency surgery for ongoing haemorrhage have increased survival if the elapsed time between the traumatic injury and admission to the operating theatre is minimised. More than 50 % of all trauma patients with a fatal outcome die within 24 h of injury [6]. Despite a lack of evidence from prospective RCTs, well-designed retrospective studies provide evidence for early surgical intervention in patients with traumatic haemorrhagic shock [44–46]. In addition, studies that analyse trauma systems indirectly emphasise the importance of minimising the time between admission and surgical bleeding control in patients with traumatic haemorrhagic shock [47, 48]. Minimisation of time to surgery is an accepted principle of trauma care and is unlikely to ever be tested in a clinical trial due to lack of equipoise.

Tourniquet use

Recommendation 2

We recommend adjunct tourniquet use to stop life-threatening bleeding from open extremity injuries in the pre-surgical setting. (Grade 1B)

Rationale

When uncontrolled arterial bleeding occurs from mangled extremity injuries, including penetrating or blast injuries or traumatic amputations, a tourniquet is a simple and efficient method with which to acutely control haemorrhage [49–53]. Tourniquet application has become standard of care for the control of severe external haemorrhage following military combat injuries, and several publications report the effectiveness of tourniquets in this specific setting in adults [49–52, 54] and children [55]. A study of volunteers showed that any tourniquet device presently on the market works efficiently [53]. The study also showed that “pressure point control” was ineffective because collateral circulation was observed within seconds. Tourniquet-induced pain was not often reported by patients. No evidence or opinion supports the use of tourniquets in the context of closed injuries.

Tourniquets should be left in place until surgical control of bleeding is achieved [50, 52]; however, this time span should be kept as short as possible. Improper or prolonged placement of a tourniquet can lead to complications such as nerve paralysis and limb ischaemia [56], however these effects are rare [54]. Some publications suggest a maximum application time of 2 h [56]. Reports from military settings describe cases in which tourniquets have remained in place for up to 6 h with survival of the extremity [50].

Much discussion has been generated recently about the translation of this evidence to civilian practice, as there is little published evidence. Bleeding from most civilian wounds can be controlled by local pressure, however uncontrolled external bleeding from either blunt [57] or penetrating [58] limb injury should be controlled with a tourniquet.

Ventilation

Recommendation 3

We recommend the avoidance of hypoxaemia. (Grade 1A)

We recommend normoventilation of trauma patients. (Grade 1B)

We suggest hyperventilation in the presence of signs of imminent cerebral herniation. (Grade 2C)

Rationale

Tracheal intubation of severely injured patients is a delicate decision that involves risks and requires proper skill and training of the operator. The fundamental objective of intubation is to ensure adequate ventilation, adequate oxygenation and to guarantee the patency of the airway. There are well-defined situations in which intubation is mandatory, for example airway obstruction, altered consciousness [Glasgow Coma Score (GCS) ≤8], haemorrhagic shock, hypoventilation or hypoxaemia [59]; however, other aspects should also be considered. For example, the introduction of positive pressure can induce potentially life-threatening hypotension in hypovolaemic patients [60], and some authors have reported increased mortality associated with pre-hospital intubation [61].

Several factors influence the success of intubation and therefore a patient’s prognosis. Rapid sequence induction appears to be the best method [62], however several aspects remain to be clarified, such as who is best suited to make the decision to intubate, which drugs to use, which rescue device and the ideal infrastructure of emergency services. Most of the available data come from retrospective studies, which are open to bias, therefore controversy remains about the appropriate use of tracheal intubation in patients following traumatic injury [63].

The negative effects of hypoxaemia are well known, particularly in patients with traumatic brain injury (TBI) [64, 65], therefore, high oxygen concentrations are generally used to ensure oxygen delivery to ischaemic areas in the initial management of these patients. Some studies, however, have suggested that the achievement extreme hyperoxia is associated with increased mortality [66]. The reason for this is unclear, but may be related to increased production of free radicals or enhancement of hyperoxic vasoconstriction, hence, avoidance may be prudent. The level of hyperoxia that can become harmful in trauma patients has not been defined, but most studies consider a PaO 2 above 200–300 mmHg (27–40 kPa) to be too high [67, 68].

Adequate ventilation can affect the outcome of severe trauma patients. There is a tendency for rescue personnel to hyperventilate patients during initial resuscitation [69, 70], and hyperventilated trauma patients appear to have increased mortality when compared with non-hyperventilated patients [66]. Target PaCO 2 should be 5.0–5.5 kPa (35–40 mmHg).

The effect of hyperventilation on bleeding and outcome in patients with severe trauma without TBI is not known. There are several potential mechanisms by which the adverse effects of hyperventilation and hypocapnia could be mediated, including increased vasoconstriction with decreased cerebral blood flow and impaired tissue perfusion. Cerebral tissue lactic acidosis has been shown to occur almost immediately after induction of hypocapnia in children and adults with TBI and haemorrhagic shock [71]. In addition, an even modest level of hypocapnia [<27 mmHg (3.6 kPa)] may result in neuronal depolarisation with glutamate release and extension of the primary injury via apoptosis [72]. In the setting of absolute or relative hypovolaemia, an excessive rate of positive-pressure ventilation may further compromise venous return and produce hypotension and even cardiovascular collapse [73, 74].

The only situation in which hyperventilation-induced hypocapnia may play a potential role is imminent cerebral herniation. The decrease in cerebral blood flow produced by acute hypocapnia during hyperventilation causes a decrease in intracranial pressure that can be used for short periods of time and in selected cases such as imminent brain herniation. The presence of signs such as unilateral or bilateral pupillary dilation or decerebrate posturing are indicators for an extreme risk of imminent death or irreversible brain damage. Hyperventilation may be used under these circumstances to try to gain time until other measures are effective [75, 76]. There are no clinical studies that evaluate this practice, however, there is a clear physiological rationale. Given the extreme risk of death if no measures are undertaken, the risk–benefit balance seems favourable, however it is important to normalise PaCO 2 as soon as feasible.

Ventilation with low tidal volume (6 ml/kg) is recommended in patients with or at risk of acute respiratory distress syndrome (ARDS) [77]. In patients with normal lung function, the data is more controversial, but there is increasing evidence to support the idea that the injurious effect of high tidal volume may be initiated very early. Randomised studies demonstrate that short-term ventilation (<5 h) with high tidal volume (12 ml/kg) without positive end-expiratory pressure (PEEP) may promote pulmonary inflammation and alveolar coagulation in patients with normal lung function [78]. Although more studies are needed, the early use of protective ventilation with low tidal volume and moderate PEEP is recommended, particularly in bleeding trauma patients, who are all at risk of ARDS.

II. Diagnosis and monitoring of bleeding

Initial assessment

Recommendation 4

We recommend that the physician clinically assess the extent of traumatic haemorrhage using a combination of patient physiology, anatomical injury pattern, mechanism of injury and the patient’s response to initial resuscitation. (Grade 1C)

Rationale

While blood loss may sometimes be obvious, neither visual estimation nor physiological parameters are good guides to the degree of bleeding [79]. The mechanism of injury represents an important screening tool with which to identify patients at risk of significant haemorrhage. For example, the American College of Surgeons defined a threshold of 6 m (20 ft) as a “critical falling height” associated with major injuries [80]. Further critical mechanisms include high-energy deceleration impact, low-velocity versus high-velocity gunshot injuries, etc. The mechanism of injury in conjunction with injury severity and the patient’s physiological presentation and response to resuscitation should further guide the decision to initiate early surgical bleeding control as outlined in the Advanced Trauma Life Support (ATLS) protocol [81–84]. Table 2 summarises estimated blood loss based on initial presentation according to the ATLS classification system. The ATLS classification has been demonstrated to be a useful guide that allows the quantification of blood loss with acceptable accuracy in haemorrhagic shock [85]. However, several groups have highlighted discrepancies associated with the weight assigned each parameter when assessing blood loss that makes it difficult to classify patients using this system. Mutschler et al. analysed the adequacy of this classification and found that more than 90 % of all trauma patients could not be categorised according to the ATLS classification of hypovolaemic shock [86]. The same group analysed the validity of the ATLS classification and concluded that this system may underestimate mental disability in the presence of hypovolaemic shock and overestimate the degree of tachycardia associated with hypotension [87]. A retrospective analysis of the validity of the ATLS classification showed that increasing blood loss produces an increase in heart rate and decrease in blood pressure, but to a lesser degree than suggested by the ATLS classification. In addition, there are no significant changes in respiratory rate or in level of consciousness with bleeding [88]. Table 3 characterises the three types of response to initial fluid resuscitation, whereby the transient responders and the non-responders are candidates for immediate surgical bleeding control.

Table 2 American College of Surgeons Advanced Trauma Life Support (ATLS) classification of blood loss* based on initial patient presentation. Table reprinted with permission from the American College of Surgeons [84] Full size table

Table 3 American College of Surgeons Advanced Trauma Life Support (ATLS) responses to initial fluid resuscitation*. Table reprinted with permission from the American College of Surgeons [84] Full size table

Specific scores to predict the risk of haemorrhagic shock may be useful to provide prompt and appropriate treatment. The shock index (heart rate divided by systolic blood pressure) may be useful in predicting critical bleeding [89] and can help to identify trauma patients that will require intervention to achieve haemostasis [90]. Paladino et al. [91] analysed the usefulness of the shock index and found that this index may be useful to draw attention to abnormal values, but that it is too insensitive to rule out disease and should not lower the suspicion of major injury. The Trauma-Associated Severe Hemorrhage (TASH) score uses seven parameters [systolic blood pressure, haemoglobin (Hb), intra-abdominal fluid, complex long bone and/or pelvic fractures, heart rate, base excess and gender] to predict the probability of mass transfusion. Maegele et al. [92] retrospectively analysed a dataset of severely multiply injured patients from the German Trauma Registry to confirm the validity of the TASH score to predict the individual probability of massive transfusion and therefore ongoing life-threatening haemorrhage. The TASH score was re-validated with 5834 patients from the same registry [93].

Immediate intervention

Recommendation 5

We recommend that patients presenting with haemorrhagic shock and an identified source of bleeding undergo an immediate bleeding control procedure unless initial resuscitation measures are successful. (Grade 1B)

Rationale

The source of bleeding may be immediately obvious, and penetrating injuries are more likely to require surgical bleeding control. In a retrospective study of 106 abdominal vascular injuries, all 41 patients arriving in shock following gunshot wounds were candidates for rapid transfer to the operating theatre for surgical bleeding control [94]. A similar observation in a study of 271 patients undergoing immediate laparotomy for gunshot wounds indicates that these wounds combined with signs of severe hypovolaemic shock specifically require early surgical bleeding control. This observation is true to a lesser extent for abdominal stab wounds [95]. Data on injuries caused by penetrating metal fragments from explosives or gunshot wounds in the Vietnam War confirm the need for early surgical control when patients present in shock [96]. In blunt trauma, the mechanism of injury can to a certain extent determine whether the patient in haemorrhagic shock will be a candidate for surgical bleeding control. Only a few studies address the relationship between the mechanism of injury and the risk of bleeding, however, and none of these publications describes a randomised prospective trial with high-level evidence [97]. We have found no objective data describing the relationship between the risk of bleeding and the mechanism of injury resulting in skeletal fractures in general or of long-bone fractures in particular.

Traffic accidents are the leading cause of pelvic injury. Motor vehicle crashes cause approximately 60 % of pelvic fractures followed by falls from great height (23 %). Most of the remainder result from motorbike collisions and vehicle-pedestrian accidents [98, 99]. There is a correlation between “unstable” pelvic fractures and intra-abdominal injuries [98, 100]. An association between major pelvic fractures and severe head injuries, concomitant thoracic, abdominal, urological and skeletal injuries is also well described [98]. High-energy injuries produce greater damage to both the pelvis and organs. Patients with high-energy injuries require more transfusion units, and more than 75 % have associated head, thorax, abdominal or genitourinary injuries [101]. It is well documented that ‘unstable’ pelvic fractures are associated with massive haemorrhage [100, 102], and haemorrhage is the leading cause of death in patients with major pelvic fractures. Vertical shear pelvic ring fractures with caudal displacement of the hemi-pelvis may disrupt the pelvic floor and pelvic vasculature far more than standard vertical shear injuries. Inferior displacement of the hemi-pelvis using X-ray imaging should therefore alert the surgeon to the possible presence of severe arterial injuries [103].

In blunt chest trauma haemothoraces >500 ml should trigger chest tube insertion. Thoracotomy is indicated for ongoing bleeding and chest tube output >1500 ml within 24 h or >200 ml for 3 consecutive hours. Acute damage control thoracotomy should be performed for refractive haemorrhagic shock due to persistent chest bleeding enhanced by initial chest tube output >1500 ml [104, 105].

Further investigation

Recommendation 6

We recommend that patients presenting with haemorrhagic shock and an unidentified source of bleeding undergo immediate further investigation. (Grade 1B)

Rationale

A patient in haemorrhagic shock with an unidentified source of bleeding should undergo immediate further assessment of chest, abdominal cavity and pelvic ring, which represent the major sources of acute blood loss in trauma. Aside from a clinical examination, X-rays of chest and pelvis in conjunction with ultrasonography [106] are recommended diagnostic modalities during the primary survey [84, 107, 108].

In selected centres, readily available computed tomography (CT) scanners [109] may replace conventional radiographic imaging techniques during the primary survey. Huber-Wagner et al. analysed the effect of the distance between the trauma room and the CT scanner on the outcome in a multicentre study involving 8004 adult major blunt trauma patients at 312 hospitals and showed that close proximity of the CT scanner to the trauma room has a significant positive effect on the survival of severely injured patients. The authors suggest that emergency department planning place the CT scanner in the trauma room or within 50 meters [110]. In their systematic literature review, Jorgensen and colleagues found no evidence that pre-hospital ultrasound of the abdomen or chest improves the treatment of trauma patients [111].

Imaging

Recommendation 7

We recommend early imaging (ultrasonography or contrast-enhanced CT) for the detection of free fluid in patients with suspected torso trauma. (Grade 1B)

Intervention

Recommendation 8

We recommend that patients with significant intra-thoracic, intra-abdominal or retroperitoneal bleeding and haemodynamic instability undergo urgent intervention. (Grade 1A)

Further assessment

Recommendation 9

We recommend CT assessment for haemodynamically stable patients. (Grade 1B)

Rationale

Blunt abdominal trauma represents a major diagnostic challenge and an important source of internal bleeding. Ultrasonography has been established as a rapid and non-invasive diagnostic approach for the detection of intra-abdominal free fluid in the emergency room [112–114]. Large prospective observational studies determined a high specificity and accuracy but low sensitivity of initial ultrasonographic examination for detecting intra-abdominal injuries in adults and children [115–121]. Liu and colleagues [122] found a high sensitivity, specificity and accuracy of initial ultrasound examination for the detection of haemoperitoneum. Ultrasonography has a high specificity but a low sensitivity for detecting free intraperitoneal fluid in penetrating torso trauma [123] and in blunt abdominal trauma in children [124]. A positive ultrasound suggests haemoperitoneum, but a negative initial abdominal ultrasound should direct further diagnostic investigations.

The role of CT scanning in acute trauma patients is well documented [125–132], and in recent years imaging for trauma patients has migrated towards multislice computed tomography (MSCT). The integration of modern MSCT scanners in the emergency room area allows the immediate assessment of trauma victims following admission [127, 128]. Using modern MSCT scanners, total whole-body scanning time may be reduced to less than 30 seconds. In a retrospective study comparing 370 patients in two groups, Weninger and colleagues [128] showed that faster diagnosis using MSCT led to shorter emergency room and operating room time and shorter intensive care unit (ICU) stays [128]. Huber-Wagner et al. [109] also showed the benefit of integration of the whole-body CT into early trauma care. CT diagnosis significantly increases the probability of survival in patients with polytrauma [110]. Whole-body CT as a standard diagnostic tool during the earliest resuscitation phase for polytraumatised patients provides the added benefit of identifying head and chest injuries and other bleeding sources in multiply injured patients.

Some authors have shown the benefit of contrast medium-enhanced CT scanning. Anderson et al. [133, 134] found high accuracy in the evaluation of splenic injuries resulting from trauma after administration of intravenous (i.v.) contrast material. Delayed-phase CT may be used to detect active bleeding in solid organs. Fang et al. [135] demonstrated that the pooling of contrast material within the peritoneal cavity in blunt liver injuries indicates active and massive bleeding. Patients with this finding showed rapid deterioration of haemodynamic status, and most required emergent surgery. Intraparenchymal pooling of contrast material with an unruptured liver capsule often indicates a self-limited haemorrhage, and these patients respond well to non-operative treatment. Tan and colleagues [136] found that patients with hollow viscus and mesenteric injuries following blunt abdominal trauma exhibited an abnormal preoperative CT scan. Wu et al. [137] showed the accuracy of CT in identifying severe, life-threatening mesenteric haemorrhage and blunt bowel injuries.

Compared to MSCT, all traditional techniques for diagnostic and imaging evaluation are associated with some limitations. The diagnostic accuracy, safety and effectiveness of immediate MSCT are dependent on sophisticated pre-hospital treatment by trained and experienced emergency personnel and short transportation times [138, 139]. If an MSCT is not available in the emergency room, the realisation of CT scanning implies transportation of the patient to the CT room, therefore the clinician must evaluate the implications and potential risks and benefits of the procedure. During transport, all vital signs should be closely monitored and resuscitation measures continued. For those patients in whom haemodynamic stability is questionable, imaging techniques such as ultrasound and chest and pelvic radiography may be useful. Peritoneal lavage is rarely indicated if ultrasound or CT are available [140]. Transfer times to and from all forms of diagnostic imaging need to be considered carefully in any patient who is haemodynamically unstable. In addition to the initial clinical assessment, point-of-care testing results, including full blood count, haematocrit (Hct), blood gases, and lactate, should be readily available under ideal circumstances.

The hypotensive patient (systolic blood pressure below 90 mmHg) presenting free intra-abdominal fluid according to ultrasonography or CT is a potential candidate for early surgical intervention if he or she cannot be stabilised by initiated fluid resuscitation [141–143]. A retrospective study by Rozycki and colleagues [144] of 1540 patients (1227 blunt, 313 penetrating trauma) assessed with ultrasound as an early diagnostic tool showed that the ultrasound examination had a sensitivity and specificity close to 100 % when patients were hypotensive.

A number of patients who present with free intra-abdominal fluid according to ultrasound can safely undergo further investigation using MSCT. Under normal circumstances, adult patients need to be haemodynamically stable when MSCT is performed outside of the emergency room [144]. Haemodynamically stable patients with a high-risk mechanism of injury, such as high-energy trauma or even low-energy injuries in elderly individuals, should be scanned after ultrasound for additional injuries using MSCT. As CT scanners are integrated in resuscitation units, whole-body CT diagnosis may replace ultrasound as a diagnostic method.

MSCT is the gold standard for the identification of retroperitoneal haemorrhage (RPH). After injection of i.v. contrast solution, CT identified RPH in all cases (100 %) and may show the source of bleeding (40 %) by extravasation of contrast media [145].

Haemodynamically unstable patients with significant intrathoracic, intra-abdominal or retroperitoneal bleeding may need urgent intervention. In these cases with thoracic trauma and chest bleeding the insertion of a chest tube is the first surgical step, usually just prior to acute damage control thoracotomy. Surgical bleeding control is necessary in unstable patients presenting with haemoperitoneum. Patients with pelvic trauma and significant retroperitoneal haematoma may need external compression, retroperitoneal packing or urgent radiologic embolisation for pelvic haemorrhage control [146–148].

Haemoglobin

Recommendation 10

We recommend that a low initial Hb be considered an indicator for severe bleeding associated with coagulopathy. (Grade 1B)

We recommend the use of repeated Hb measurements as a laboratory marker for bleeding, as an initial Hb value in the normal range may mask bleeding. (Grade 1B)

Rationale

Hb or Hct assays are part of the basic diagnostic work-up for trauma patients. Currently the use of Hb rather than Hct is widespread, and the latter is a calculated parameter derived from the Hb. However, most studies on which these recommendations are based analysed Hct rather than Hb. Because both parameters are used interchangeably in clinical practice, in these guidelines we refer to both parameters according to the parameter described by the literature to which we refer.

The diagnostic value of the Hb or Hct for detecting trauma patients with severe injury and occult bleeding sources has been a topic of debate [149–151]. A major limit of the Hb/Hct’s diagnostic value is the confounding influence of resuscitation measures on the Hb/Hct due to administration of i.v. fluids and erythrocyte concentrates [152–154]. In addition, initial Hb or Hct may not accurately reflect blood loss because patients bleed whole blood and compensatory mechanisms that move fluids from interstitial space require time and may not be reflected in initial measurements. The concept of the low sensitivity of initial Hb/Hct for the detection of severe bleeding has been challenged. In a retrospective study of 196 trauma patients, Ryan et al. [155] found that Hct at admission closely correlates with haemorrhagic shock. Other authors also recommended that the initial Hct play a greater role in the assessment of blood loss in trauma patients. In a retrospective analysis of 1492 consecutive trauma patients Thorson et al. found that the initial Hct is associated more strongly with the need for transfusion than other parameters such as heart rate, blood pressure or acidaemia, suggesting that fluid shifts are rapid after trauma and imply a more important role for Hct in the initial assessment of trauma victims [156]. An initial low Hb level is one of the predictive criteria for massive transfusion using the TASH [92] and Vandromme [157] scores.

Thorson et al. [158] analysed changes in Hct in two successive determinations and concluded that the change in Hct is a reliable parameter with which to detect blood loss. Two prospective observational diagnostic studies also showed the sensitivity of serial Hct measurements in the detection of patients with severe injury [149, 150]. Decreasing serial Hct measurements may reflect continued bleeding; however the patient with significant bleeding may maintain the serial Hct in the context of ongoing resuscitation and physiological compensatory mechanisms. Acute anaemia may play an adverse role in the clotting process because a low Hct may reduce platelet marginalisation with a potentially negative impact on platelet activation. Moreover Schlimp et al. [159] demonstrated that levels of fibrinogen lower than 150 mg/dl are detected in as many as 73 % of the patients with admission Hb lower than 10 g/dl.

Serum lactate and base deficit

Recommendation 11

We recommend serum lactate and/or base deficit measurements as sensitive tests to estimate and monitor the extent of bleeding and shock. (Grade 1B)

Rationale

Serum lactate has been used as a diagnostic parameter and prognostic marker of haemorrhagic shock since the 1960s [160]. The amount of lactate produced by anaerobic glycolysis is an indirect marker of oxygen debt, tissue hypoperfusion and the severity of haemorrhagic shock [161–164]. Similarly, base deficit values derived from arterial blood gas analysis provide an indirect estimation of global tissue acidosis due to impaired perfusion [161, 163]. Vincent and colleagues [165] showed the value of serial lactate measurements for predicting survival in a prospective study in patients with circulatory shock. This study showed that changes in lactate concentration provide an early and objective evaluation of a patient’s response to therapy and suggested that repeated lactate determinations represent a reliable prognostic index for patients with circulatory shock [165]. Abramson and colleagues [166] performed a prospective observational study in patients with multiple traumatic injuries to evaluate the correlation between lactate clearance and survival. All patients in whom lactate levels returned to the normal range (≤2 mmol/l) within 24 h survived. Survival decreased to 77.8 % if normalisation occurred within 48 h and to 13.6 % in those patients in whom lactate levels were elevated above 2 mmol/l for more than 48 h [166]. These findings were confirmed in a study by Manikis et al. [167], who showed that initial lactate levels were higher in non-survivors after major trauma and that prolongation of time to normalisation of lactate levels of more than 24 h was associated with the development of post-traumatic organ failure [167]. The determination of lactate and/or base deficit may be particularly important in penetrating trauma. In this type of trauma, triage vital signs such as blood pressure, heart rate and respiratory rate do not reflect the severity of injury and are not related to lactate or base deficit levels [168].

The reliability of lactate determination may be lower when traumatic injury is associated with alcohol consumption. Ethanol metabolism induces the conversion of pyruvate to lactate via lactate dehydrogenase, causing an increase in the level of lactate in the blood. In alcohol-associated trauma, therefore, base deficit may be a better predictor of prognosis than lactate [169], although some authors suggest that ethanol-induced acidosis may also affect base deficit, masking the prognosis of trauma patients [170]. Therefore, in the case of traumatic injury associated with alcohol consumption, the results of the lactate measurements should be interpreted with caution.

Similar to the predictive value of lactate levels, the initial base deficit, obtained either from arterial or peripheral venous blood [171] has been established as a potent independent predictor of mortality in patients with traumatic haemorrhagic shock [169]. Davis and colleagues [172] stratified the extent of base deficit into three categories: mild (-3 to -5 mEq/l), moderate (-6 to -9 mEq/l) and severe (<-10 mEq/l), and established a significant correlation between the admission base deficit, transfusion requirements within the first 24 h and the risk of post-traumatic organ failure or death [172]. The same group of authors showed that the base deficit is a better prognostic marker of death than the pH in arterial blood gas analyses [173]. Mutschler et al. [174] analysed a cohort of 16,305 severely injured patients derived from the German Trauma Registry database and concluded that the determination of base deficit upon emergency department admission predicts transfusion requirements and mortality better than ATLS classification [174]. Furthermore, the base deficit was shown to represent a highly sensitive marker for the extent of post-traumatic shock and mortality, both in adult and paediatric patients [175, 176].

In contrast to the data on lactate levels in haemorrhagic shock, reliable large-scale prospective studies on the correlation between base deficit and outcome are still lacking. Although both the base deficit and serum lactate levels are well correlated with shock and resuscitation, these two parameters do not strictly correlate with each other in severely injured patients [177]. Therefore, the independent assessment of both parameters is recommended for the evaluation of shock in trauma patients [161, 163, 177].

Coagulation monitoring

Recommendation 12

We recommend that routine practice include the early and repeated monitoring of coagulation, using either a traditional laboratory determination [prothrombin time (PT), activated partial thromboplastin time (APTT) platelet counts and fibrinogen] (Grade 1A) and/or a viscoelastic method. (Grade 1C)

Rationale

Standard coagulation monitoring comprises the early and repeated determination of PT, APTT, platelet counts and fibrinogen. Increasing emphasis focuses on the importance of fibrinogen and platelet measurements. It is often assumed that the conventional coagulation screens [international normalised ratio (INR) and APTT] monitor coagulation, however these tests monitor only the initiation phase of blood coagulation, and represent only the first 4 % of thrombin production [178]. It is therefore possible that the conventional coagulation screen appears normal, while the overall state of blood coagulation is abnormal [13, 179–183]. In addition, the delay in detection of traumatic coagulopathy can influence outcome, and the turnaround time of thromboelastometry has been shown to be significantly shorter than conventional laboratory testing, with a time saving of 30–60 min [181, 184, 185]. Viscoelastic testing may also be useful in the detection of coagulation abnormalities associated with the use of direct thrombin inhibitors such as dabigatran, argatroban, bivalirudin or hirudin. Furthermore, (early) variables of clot firmness assessed by viscoelastic testing have been shown to be good predictors for the need for massive transfusion, the incidence of thrombotic/thromboembolic events and for mortality in surgical and trauma patients [181, 186–195]. Therefore, complete and rapid monitoring of blood coagulation and fibrinolysis using viscoelastic methods may facilitate a more accurate targeting of therapy compared to conventional laboratory tests alone.

Tools such as thromboelastometry and portable coagulometers have been developed to detect coagulopathy in the emergency room or at the bedside, improving the availability of real-time data to guide patient management. Portable coagulometers that provide INR or APTT seem to provide acceptable accuracy for point-of-care INR testing in the emergency department compared with laboratory-based methods [196–198], however others have observed a lack of agreement with conventional laboratory determinations [199]. The usefulness of the parameters measured is therefore limited.

Viscoelastic methods provide a rapid assessment of coagulation to support clinical decision-making, generating a growing confidence in these methods and increased use [200, 201]. Case series using viscoelastic testing to assess trauma patients have been published. One study applied rotational thrombelastography to 23 patients, but without a comparative standard [179]. Johansson et al. [180] implemented a haemostatic resuscitation regime [early platelets and fresh frozen plasma (FFP)] guided using thrombelastography in a before-and-after study (n = 832), which showed improved outcomes. In a retrospective study of cardiovascular surgery patients (n = 3865) the combined use of thromboelastometry and portable coagulometry resulted in a reduction in blood product transfusion and thromboembolic events, but did not influence mortality [202]. Rapid thrombelastography is a new variant of viscoelastic testing in which coagulation is initiated by the addition of kaolin and tissue factor that appears to reduce the measurement time compared with conventional thrombelastography [203].

Despite the widespread use of viscoelastic methods, the usefulness has recently been questioned. In a recent systematic review Hunt et al. [204] found no evidence of the accuracy of thrombelastography and very little evidence to support the accuracy of thromboelastometry and were therefore unable to offer any advice about the use of these methods [204]. In another systematic review Da Luz et al. [205] concluded that only limited evidence from observational studies support the use of viscoelastic tests to diagnose early traumatic coagulopathy, but while these tests may predict blood-product transfusion, mortality and other patient-important outcomes may be unaffected [205]. A number of other limitations to the use of viscoelastic methods have been described. Larsen et al. [206] found that thrombelastography was unable to distinguish coagulopathies caused by dilution from thrombocytopenia, whereas thromboelastometry was indeed capable of distinguishing these two different types of coagulopathy and suggesting the correct treatment [206]. The use of thrombelastography may thus lead to unnecessary transfusion with platelets, whereas the application of thromboelastometry may result in goal-directed fibrinogen substitution. Although use is rapidly increasing, controversy remains at present regarding the utility of viscoelastic methods for the detection of post-traumatic coagulopathy.

The agreement between viscoelastic methods and standard coagulation test also remains a matter of debate. Some studies find acceptable agreement [207–209], however a number of other studies found significant discrepancies [25, 199, 210, 211] even among different viscoelastic methods (thrombelastography and thromboelastometry). Hagemo et al. [212] found that the correlation was highly variable at different stages of the clotting process and between centres, highlighting the need for clarification and standardisation of these techniques. One limitation of viscoelastic tests is the lack of sensitivity to detect and monitor platelet dysfunction due to antiplatelet drugs. If platelet dysfunction is expected, point-of-care platelet function tests, for example whole blood impedance aggregometry, should be used in addition to viscoelastic tests [213, 214]. More research is required in this area, and in the meantime physicians should use their own judgement when developing local policies.

It is theoretically possible that the pattern of change in measures of coagulation such as D-dimers may help to identify patients with ongoing bleeding. However, a single publication showed that the positive predictive value of D-dimers is only 1.8 % in the postoperative and/or post-traumatic setting [215], therefore traditional methods of detection for ongoing bleeding, such as serial clinical evaluation of radiology (ultrasound, CT or angiography) should be used.

III. Tissue oxygenation, type of fluid and temperature management

Tissue oxygenation

Recommendation 13

We recommend a target systolic blood pressure of 80–90 mmHg until major bleeding has been stopped in the initial phase following trauma without brain injury. (Grade 1C)

In patients with severe TBI (GCS ≤8), we recommend that a mean arterial pressure ≥80 mmHg be maintained. (Grade 1C)

Restricted volume replacement

Recommendation 14

We recommend use of a restricted volume replacement strategy to achieve target blood pressure until bleeding can be controlled. (Grade 1B)

Vasopressors and inotropic agents

Recommendation 15

In the presence of life-threatening hypotension, we recommend administration of vasopressors in addition to fluids to maintain target arterial pressure. (Grade 1C)

We recommend infusion of an inotropic agent in the presence of myocardial dysfunction. (Grade 1C)

Rationale

In order to maintain tissue oxygenation, traditional treatment of trauma patients used early and aggressive fluid administration to restore blood volume. This approach may, however, increase the hydrostatic pressure on the wound, cause dislodgement of blood clots, a dilution of coagulation factors and undesirable cooling of the patient. The concept of “damage control resuscitation” aims to achieve a lower than normal blood pressure, also called “permissive hypotension”, and thereby avoid the adverse effects of early aggressive resuscitation using high doses of fluids while there is a potential risk of tissue hypoperfusion during short periods [216]. The general effectiveness of permissive hypotension remains to be confirmed in randomised clinical trials, however, two studies published in the 1990s demonstrated increased survival when a low and delayed fluid volume resuscitation concept was used in penetrating [217] or penetrating and blunt [218] trauma. However, in contrast to these studies, no significant differences in survival were found in two further trials in patients with either penetrating and blunt trauma [219] or blunt trauma alone [220].

Several retrospective analyses published in the last few years demonstrated that aggressive resuscitation techniques, often initiated in the pre-hospital setting, may be detrimental for trauma patients [9, 28, 221, 222]. One of these studies showed that this strategy increased the likelihood that patients with severe extremity injuries developed secondary abdominal compartment syndrome (ACS) [221]. In that study, early large-volume crystalloid administration was the greatest predictor of secondary ACS. Moreover, another retrospective analysis using the German Trauma Registry database, including 17,200 multiply injured patients, showed that the incidence of coagulopathy increased with increasing volume of i.v. fluids administered pre-clinically [9]. Coagulopathy was observed in >40 % of patients with >2000 ml, in >50 % with >3000 ml and in >70 % with >4000 ml administered. Using the same trauma registry, a retrospective matched pairs analysis (n = 1896) demonstrated that multiply injured trauma patients with an Injury Severity Score (ISS) ≥16 points and a systolic blood pressure ≥60 mmHg at the accident site who received pre-hospital low-volume resuscitation (0–1500 ml) had a higher survival rate than patients in whom a pre-hospital high-volume strategy (≥1501 ml) was used [28]. These results are supported by another retrospective analysis of patients from the US National Trauma Data Bank [222]. In this study the authors analysed 776,734 patients, of whom about 50 % received pre-hospital i.v. fluid and 50 % did not. The group of patients receiving preoperative i.v. fluids were significantly more likely to die (OR 1.11, 95 % CI 1.05 to 1.17), an association which was especially marked in patients with penetrating mechanisms of injury (OR 1.25, 95 % CI 1.08 to 1.45), hypotension (OR 1.44, 95 % CI 1.29 to 1.59), severe head injury (OR 1.34, 95 % CI 1.17 to 1.54) and patients undergoing immediate surgery (OR 1.35, 95 % CI 1.22 to 1.50). The authors concluded that the routine use of pre-hospital i.v. fluid for all trauma patients should be discouraged. It should be noted that this study, and especially its conclusion, has been criticised [223].

Initial use of a restrictive volume replacement strategy is supported by a prospective randomised trial that analysed the consequences of an initial intra-hospital hypotensive resuscitation strategy in trauma patients with haemorrhagic shock [224]. In this study, with nearly all of the 90 patients suffering from penetrating trauma, patients who had at least one documented in-hospital systolic blood pressure ≤90 mmHg were randomised to a target minimum mean arterial pressure of 50 mmHg or 65 mmHg. One major drawback to this study was that no statistically significant difference between the actual mean arterial pressure was observed between the two groups over the duration of the study (64.4 mmHg vs. 68.5 mmHg, P = 0.15). Although the authors could not demonstrate a survival difference for the two treatment strategies at day 30, 24 h postoperative death and coagulopathy were increased in the group with the higher target minimum pressure. The patients in this group received not only more i.v. fluids overall, but also more blood product transfusions. Another study that supports a restrictive volume replacement strategy was reported by Brown et al. [225]. In this study 1216 trauma patients with an ISS >15 were included; 51 % suffered from hypotension, defined as a systolic arterial blood pressure (SAP) <90 mmHg. 68 % of the patients received a volume load of >500 ml crystalloid solution. The authors demonstrated that administration of >500 ml pre-hospital crystalloid was associated with worse outcome in patients without pre-hospital hypotension but not in patients with hypotension. The administration of >500 ml crystalloid was associated with a correction of hypotension. The authors suggested that pre-hospital volume resuscitation should be goal-directed based on the presence or absence of hypotension. Recently, Schreiber et al. [226] assessed the feasibility and safety of controlled resuscitation (n = 97) in hypotensive trauma patients compared to standard resuscitation (n = 95). Patients were enrolled and randomised in the pre-hospital setting. Eligible patients had a pre-hospital systolic blood pressure ≤90 mmHg. Controlled resuscitation patients received 250 ml fluid if no radial pulse or an SAP <70 mmHg was present and additional 250 ml boluses to maintain a radial pulse or a systolic blood pressure ≥70 mmHg. The mean (SD) crystalloid volume administered during the study period was 1.0 l (1.5) in the controlled resuscitation group and 2.0 l (1.4) in the standard resuscitation group. ICU-free days, ventilator-free days, renal injury and renal failure did not differ between the groups.

A meta-analysis by Kwan et al. analysed randomised trials that investigated the timing and volume of i.v. fluid administration in bleeding trauma patients [227]. The authors identified three trials that addressed the timing of administration and that included a total of 1957 patients. Three studies investigated volume load, but included only 171 patients. In contrast to the retrospective analysis described above, the meta-analysis failed to demonstrate an advantage associated with delayed compared to early fluid administration nor of smaller compared to larger volume fluid administration in this small group of prospective studies that included only a very limited number of patients. A further meta-analysis that assessed seven retrospective observational studies that included a total of 13,687 patients and three prospective studies that included 798 patients estimated a small benefit in favour of a restricted volume replacement strategy [228], however, the authors cautioned that the available studies were subject to a high risk of selection bias and clinical heterogeneity.

It should be noted that a damage control resuscitation strategy using restrictive volume replacement is contraindicated in patients with TBI and spinal injuries, because an adequate perfusion pressure is crucial to ensure tissue oxygenation of the injured central nervous system [229]. Rapid bleeding control is of particular importance in these patients. In addition, the concept of permissive hypotension should be carefully considered in the elderly patient, and may be contraindicated if the patient suffers from chronic arterial hypertension [230].

In conclusion, a damage control resuscitation strategy that aims to achieve a lower than normal systolic blood pressure of 80–90 mmHg using a concept of restricted fluid replacement in patients without TBI and/or spinal injury is supported by the literature, however strong evidence from RCTs is lacking.

Vasopressors may also be required transiently to sustain life and maintain tissue perfusion in the presence of life-threatening hypotension, even when fluid expansion is in progress and hypovolaemia has not yet been corrected. Norepinephrine (NE) is often used to restore arterial pressure in septic and haemorrhagic shock and is now recommended as the agent of choice for this purpose during septic shock [231]. Although NE has some β-adrenergic effects, it acts predominantly as a vasoconstrictor. Arterial α-adrenergic stimulation increases arterial resistance and may increase cardiac afterload; NE exerts both arterial and venous α-adrenergic stimulation [232]. Indeed, in addition to its arterial vasoconstrictor effect, NE induces venoconstriction at the level of the splanchnic circulation in particular, which increases the pressure in capacitance vessels and actively shifts splanchnic blood volume to the systemic circulation [233]. This venous adrenergic stimulation may recruit some blood from the venous unstressed volume, i.e., the volume that fills the blood vessels without generating intravascular pressure. Moreover, stimulation of β 2 -adrenergic receptors decreases venous resistance and increases venous return [233].

Animal studies that investigated uncontrolled haemorrhage have suggested that NE infusion reduces the amount of fluid resuscitation required to achieve a given arterial pressure target, is associated with lower blood loss and significantly improved survival [234, 235]. However, the effects of NE have not been rigorously investigated in humans during haemorrhagic shock. An interim analysis performed during an ongoing multicentre prospective cohort study suggested that the early use of vasopressors for haemodynamic support after haemorrhagic shock may be deleterious in comparison to aggressive volume resuscitation and should be used cautiously [236]. This study has several limitations, however. First, this was a secondary analysis of a prospective cohort study and was not designed to answer the specific hypothesis tested, and second, the group receiving vasopressors had a higher rate of thoracotomy. Thus, a prospective study to define the effect of vasopressors on patients during haemorrhagic shock is clearly needed.

A double-blind randomised trial to assess the safety and efficacy of adding vasopressin to resuscitative fluid has been performed [237]. Patients were given fluid alone or fluid plus vasopressin (bolus 4 IU) and i.v. infusion of 200 ml/h (vasopressin 2.4 IU/h) for 5 h. The fluid plus vasopressin group needed a significantly lower total resuscitation fluid volume over 5 days than the control group (P = 0.04). The rates of adverse events, organ dysfunction and 30-day mortality were similar.

Vasopressors may be useful if used transiently to sustain arterial pressure and maintain tissue perfusion in the face of life-threatening hypotension. If used, it is essential to respect the recommended objectives for SAP (80–90 mmHg) in patients without TBI.

Because vasopressors may increase cardiac afterload if the infusion rate is excessive or left ventricular function is already impaired, an assessment of cardiac function during the initial ultrasound examination is essential. Cardiac dysfunction could be altered in the trauma patient following cardiac contusion, pericardial effusion or secondary to brain injury with intracranial hypertension. The presence of myocardial dysfunction requires treatment with an inotropic agent such as dobutamine or epinephrine. In the absence of an evaluation of cardiac function or cardiac output monitoring, as is often the case in the early phase of haemorrhagic shock management, cardiac dysfunction must be suspected in the presence of a poor response to fluid expansion and NE.

Type of fluid

Recommendation 16

We recommend that fluid therapy using isotonic crystalloid solutions be initiated in the hypotensive bleeding trauma patient. (Grade 1A)

We suggest that excessive use of 0.9 % NaCl solution be avoided. (Grade 2C)

We recommend that hypotonic solutions such as Ringer’s lactate be avoided in patients with severe head trauma. (Grade 1C)

We suggest that the use of colloids be restricted due to the adverse effects on haemostasis. (Grade 2C)

Rationale

Although fluid resuscitation is the first step to restore tissue perfusion in severe haemorrhagic shock, it is still unclear whether crystalloids or colloids, and more specifically which crystalloid or which colloid, should be used in the initial treatment of the bleeding trauma patient.

In most trauma studies 0.9 % sodium chloride was used as the crystalloid solution. However, recent studies suggest that this crystalloid may increase acidosis and the incidence of kidney injury in healthy volunteers or critically ill adults [238, 239]. In contrast to 0.9 % sodium chloride, balanced electrolyte solutions contain physiological or near-physiological concentrations of electrolytes. Recently, in a small prospective randomised trial in 46 trauma patients a balanced electrolyte solution improved acid-base status and caused less hyperchloraemia at 24 h post injury compared to 0.9 % sodium chloride [240]. A secondary analysis of this study demonstrated that the use of a balanced electrolyte solution resulted in a net cost benefit in comparison to the use of 0.9 % saline chloride [241]. Therefore, if 0.9 % sodium chloride is used it should be limited to a maximum of 1–1.5 l.

If crystalloids are used, hypotonic solutions such as Ringer’s lactate should be avoided in patients with TBI in order to minimise a fluid shift into the damaged cerebral tissue. In addition, the use of solutions with the potential to restore pH may be advantageous, since a recent study demonstrated that Ringer’s acetate solution more rapidly ameliorated splanchnic dysoxia, as evidenced by gastric tonometry, than Ringer’s lactate [242]. Whether an advantage for certain isotonic balanced crystalloids with respect to a reduced morbidity or mortality exists is not clear and remains to be evaluated [241, 243].

The most recent Cochrane meta-analysis on the type of fluid, colloids or crystalloids, failed to demonstrate that colloids reduce the risk of death compared to resuscitation with crystalloids in critically ill patients treated in an ICU [244]. The authors compared the use of albumin or plasma protein fraction with crystalloids, performing an analysis of 24 trials that included a total of 9920 patients, and demonstrated a pooled risk ratio (RR) of 1.01 (95 % CI 0.93 to 1.10). Twenty-five trials compared hydroxyethyl starch (HES) to crystalloids in a total of 9147 patients, demonstrating a beneficial effect in favour of crystalloids [RR 1.10 (1.02 to 1.19)], and modified gelatin was assessed in 11 trials that included a total of 506 patients showing neither a beneficial nor a deleterious effect [RR 0.91 (0.49 to 1.72)]. The authors concluded that there is no evidence that resuscitation with colloids has any beneficial effect on survival, and HES may even cause harm. However, neither the time point of fluid resuscitation nor the duration and dosages of fluid resuscitation were analysed or discussed. Nevertheless, at the present time good data demonstrating the benefit of colloids are lacking.

Since colloids are also more expensive than crystalloids, if fluids are used during the initial treatment phase as part of the restricted volume replacement strategy, administration of crystalloids rather than colloids to treat the hypotensive bleeding trauma patient seems to be justified. Also in later stages of resuscitation, large volume crystalloid administration is not independently associated with multiple organ failure [245]. In addition, if high ratios of FFP:RBC (red blood cells) cannot be administered to trauma patients, a retrospective study showed that resuscitation with at least 1 l crystalloid per unit RBC seems to be associated with reduced overall mortality [246].

At present it is not clear whether, and if, which colloids should be used if crystalloids fail to restore target blood pressure. Bunn et al. published a Cochrane meta-analysis with the aim of comparing the effects of different colloid solutions in a total of 5484 patients thought to require volume replacement [247]. From this review, there is no evidence that one colloid solution is more effective or safer than any other, although the confidence intervals were wide and do not exclude clinically significant differences between colloids. Nevertheless, there are conflicting meta-analysis data showing on the one hand increased kidney injury and increased mortality in critically ill patients treated with HES [248, 249] and on the other hand no differences in the incidence of death or acute kidney failure in surgical patients receiving 6 % HES [250]. It seems doubtful whether any conclusions can be drawn from these studies performed mostly under completely different conditions than are present in the acute hypovolaemic trauma patient. In addition to these conflicting results, a recent in vitro study using blood from healthy volunteers demonstrated that coagulation and platelet function are impaired by all HES and gelatin solutions [251]. However, gelatin-induced coagulopathy was reversible with the administration of fibrinogen, whereas HES-induced coagulopathy was not. So far, only one small RCT described a benefit for a HES solution in trauma patients. HES (130/0.4) provided significantly better lactate clearance and less renal injury than saline in 67 penetrating trauma patients [252]. Because only 42 blunt trauma patients were included in the study, no differences in these parameters could be observed using the different solutions. Therefore, if colloids are administered in patients in whom crystalloids fail to restore target blood pressure, dosing should be within the prescribed limits and, if HES is employed, a modern HES solution should be used.

A number of studies have investigated hypertonic solutions. In 2008, a double-blind RCT in 209 patients with blunt traumatic injuries analysed the effect of treatment with 250 ml 7.5 % hypertonic saline and 6 % dextran 70 compared to lactated Ringer’s solution on organ failure [253]. The intent-to-treat analysis demonstrated no significant difference in organ failure and in ARDS-free survival. However, there was improved ARDS-free survival in the subset (19 % of the population) requiring 10 U or more of packed RBC [253]. A clinical trial with brain injury patients found that hypertonic saline reduced intracranial pressure more effectively than dextran solutions with 20 % mannitol when compared in equimolar dosing [254]. However, Cooper et al. found almost no difference in neurological function 6 months after TBI in patients who had received pre-hospital hypertonic saline resuscitation compared to conventional fluid [255]. Moreover, two large prospective randomised multicentre studies by Bulger and co-workers [256, 257] analysed the effect of out-of-hospital administration of hypertonic fluids on neurological outcome following severe TBI and survival after traumatic hypovolaemic shock. These studies were not able to demonstrate any advantage compared to normal 0.9 % saline among the 2184 patients included. In contrast, a recent study demonstrated that hypertonic solutions interfere with coagulation in this group of patients [258].

In conclusion, the evidence suggests that hypertonic saline solutions are safe, but will neither improve survival nor improve neurological outcome after TBI. So far only one study reported that initial fluid resuscitation with hypertonic saline dextran was beneficial and improved survival compared to normal saline [259].

Erythrocytes

Recommendation 17

We recommend a target Hb of 7 to 9 g/dl. (Grade 1C)

Rationale

Oxygen delivery to tissues is the product of blood flow and arterial oxygen content, which is directly related to the Hb concentration, therefore decreasing Hb might be expected to give tissue hypoxia. However, compensatory responses to acute normovolaemic anaemia occur, including macro- and microcirculatory changes in blood flow, so the clinical effects of low Hb are complex.

RCTs that have evaluated Hb thresholds for transfusion in critically ill patients have consistently found that restrictive transfusion strategies (Hb thresholds between 7 and 9 g/dL) are as safe as, or safer than, liberal strategies (thresholds ≥9 g/dL) [260–263], with the possible exception of patients following cardiac surgery [264] or with acute coronary syndrome. These studies have excluded patients with massive bleeding. No prospective RCT has compared restrictive and liberal transfusion regimens in trauma patients. A subset of 203 trauma patients from the Transfusion Requirements in Critical Care (TRICC) trial [260] was re-analysed [265]. A restrictive transfusion regimen (Hb transfusion trigger <7.0 g/dl) resulted in fewer transfusions compared with the liberal transfusion regimen (Hb transfusion trigger <10 g/dl) and appeared to be safe. However, no statistically significant benefit in terms of multiple organ failure or post-traumatic infections was observed. It should be emphasised that this study was neither designed nor powered to answer these questions with precision. In addition, it cannot be ruled out that the number of RBC units transfused merely reflects the severity of injury. Nevertheless, RBC transfusions have been shown in multiple studies to be associated with increased mortality [266–270], lung injury [270–272], increased infection rates [273, 274] and renal failure in trauma victims [269].

Because anaemia is a possible cause of secondary ischaemic damage, concerns have been raised about the safety of restrictive transfusion strategies in the subpopulation of patients with TBI. Most early clinical information comes from retrospective observational studies with important methodological limitations. These data have yielded inconsistent results on the effects of RBC transfusion on markers of cerebral perfusion and metabolism in patients with isolated severe TBI. Two systematic reviews published in 2012 stressed the lack of high-level scientific evidence for a specific Hb transfusion trigger in this setting [275, 276]. More recently, two studies have focused on the effect of anaemia and RBC transfusion on neurological outcome after TBI [277, 278]. A retrospective review of data collected prospectively in 1158 patients with a GCS ≤8 in the absence of haemorrhagic shock found that RBC transfusion was associated with worse outcomes (28-day survival, ARDS-free survival, 6-month neurological outcome) when the initial Hb was >10 g/dl [277]. No relationship between RBC transfusion and outcomes was found in patients with an initial Hb ≤10 g/dl [277]. In a 2 × 2 factorial design RCT of 200 patients with TBI at two clinical sites, Robertson et al. compared two Hb transfusion thresholds (7 or 10 g/dl), and separately compared administration of erythropoietin (EPO) or placebo [278]. Patients were enrolled within 6 h of injury and 99 patients were assigned to the 7 g/dl transfusion threshold and 101 patients to the 10 g/dl threshold. The main outcome was neurological recovery at 6 months that was assessed using the Glasgow Outcome Scale dichotomised as favourable or unfavourable. No advantage was found in favour of the 10 g/dl Hb level. In the 7 g/dl threshold group, 42.5 % of patients had a favourable outcome, compared to 33.0 % in the 10 g/dl threshold group (95 % CI for difference −0.06 to 0.25). There was no difference in mortality. More thromboembolic events were observed in the 10 g/dl threshold group [278]. Overall, patients with severe TBI should not be managed with a Hb transfusion threshold different than that of other critically ill patients.

Erythrocytes contribute to haemostasis by influencing the biochemical and functional responsiveness of activated platelets via the rheological effect on platelet margination and by supporting thrombin generation [279]. The effects of the Hct on blood coagulation have not been fully elucidated [280]. An acute reduction of the Hct results in an increase in the bleeding time [281, 282], with restoration upon re-transfusion [281]. This may relate to the presence of the enzyme elastase on the surface of RBC membranes, which may activate coagulation factor IX [283, 284]. However, an animal model showed that a moderate reduction in Hct does not increase blood loss from a standard spleen injury [282], and an isolated in vitro reduction of the Hct did not compromise blood coagulation as assessed by thromboelastometry [285].

Alternative methods of raising Hb have been little studied. The erythropoietic response is blunted in trauma patients [286] and therefore the administration of epoetin alpha appears an attractive option. In a first prospective randomised trial in ICU patients (n = 1302, 48 % being trauma patients) a significant reduction in RBC transfusion percentage from 60.4 to 50.5 % (P < 0.001) and reduction in the median number of RBC units transfused from two to one (P < 0.001) was observed [287]. In the subgroup of trauma patients 28-day mortality was also reduced [OR 0.43 (0.23 to 0.81)] [287]. In a subsequent prospective randomised trial in ICU patients (n = 1460, 54 % being trauma patients) no significant reduction in RBC transfusions was found [288]. Thrombotic complications were higher in epoetin alpha-treated patients [HR 1.58 (1.09 to 2.28)], however this difference was observed exclusively in patients without heparin prophylaxis [288]. Nevertheless, a trend towards a reduced mortality was found in the entire group of ICU patients, and trauma patients had a lower 29-day [adjusted HR 0.37 (0.19 to 0.72)] and 140-day mortality [adjusted HR 0.40 (0.23 to 0.69)] when treated with epoetin alpha. A third prospective randomised trial enrolled patients (n = 194) with major blunt orthopaedic trauma [289], and no significant effect of epoetin alpha was found, however this study was characterised by a nearly 50 % drop-out rate during the study and a non-significant result is therefore not surprising.

The relatively limited effect of epoetin alpha treatment on transfusion needs may be surprising given the blunted EPO response in trauma patients [286]. However, iron metabolism is also altered after trauma, with iron not being fully available for haematopoiesis [286]. Neither iron metabolism nor availability are fully understood following traumatic injury and complicated by the fact that certain proteins such as ferritin are massively upregulated after trauma as part of the acute-phase response [286]. Intravenous iron may therefore represent another attractive option with which to foster haematopoiesis. Indeed, studies that assess the effect of i.v. iron (with [290, 291] or without [292] concomitant epoetin alpha) showed reduced RBC transfusions [290–292], postoperative infections [290–292], length of hospital stay [291] and mortality in patients with hip fractures [291]. While i.v. iron appears to be promising, oral iron is largely ineffective [293]. In the near future, the Efficacy of Ferric Carboxymaltose With or Without EPO Reducing Red-cell Transfusion Packs in Hip Fracture Perioperative Period (PAHFRAC-01) project, a prospective randomised multicentre study (NCT01154491), will provide further insight into the benefit of i.v. iron and epoetin alpha treatment in patients with hip fracture [294].

In non-trauma patients a meta-analysis showed that preoperative i.v. iron administration was efficacious in correcting preoperative anaemia and in lowering RBC transfusion rates in elective surgery, but found an increased infection rate [295]. This potential risk has not been evaluated for postoperative i.v. iron administration or in trauma patients. Interestingly, i.v. iron treatment in 20,820 haemodialysis patients was associated with a trend towards lower infection rates, lower mortality and a shorter hospital stay [296]. Similarly, i.v. iron treatment equally in anaemic mice with sepsis did not cause increased mortality and corrected anaemia [297]. Short-term preoperative treatment with iron carboxymaltose and epoetin alpha also resulted in a highly significant decrease in postoperative infectious complications (12.0 to 7.9 %) and a shortening of hospitalisation by approximately 1 day in anaemic patients undergoing orthopaedic surgery [291]. In addition, 30-day mortality decreased from 9.4 to 4.8 % in patients with hip fractures [291]. The potential adverse effect of i.v. iron administration in trauma patients may thus be overestimated and certainly remains to be investigated further.

Temperature management

Recommendation 18

We recommend early application of measures to reduce heat loss and warm the hypothermic patient in order to achieve and maintain normothermia. (Grade 1C)

Rationale

Hypothermia, a core body temperature <35 °C, is associated with acidosis, hypotension and coagulopathy in severely injured patients. The effects of hypothermia include altered platelet function, impaired coagulation factor function (a 1 °C drop in temperature is associated with a 10 % drop in function), enzyme inhibition and fibrinolysis [298–300]. Body temperatures below 34 °C compromise blood coagulation, but this has only been observed when coagulation tests (PT and APTT) are carried out at the low temperatures seen in patients with hypothermia, and not when assessed at 37 °C as is routine practice for such tests.

The profound clinical effects of hypothermia ultimately lead to higher morbidity and mortality [301], and hypothermic patients require more blood products [302]. In a retrospective study of 604 trauma patients who required massive transfusion, a logistic regression analysis demonstrated that a temperature lower than 34 °C was associated with a greater independent risk of mortality of more than 80 % after controlling for differences in shock, coagulopathy, injury severity and transfusion requirements (OR 1.87; 95 % CI 1.18 to 3.0; P = 0.007) [303]. A recent study performed a secondary data analysis of 10 years of the Pennsylvania Trauma Outcome Study (PTOS), which analysed 11,033 patients with severe TBI and demonstrated that spontaneous hypothermia at hospital admission was associated with a significant increase in the risk of mortality in patients with severe TBI [304]. Steps to prevent hypothermia and the risk of hypothermia-induced coagulopathy include removing wet clothing, covering the patient to avoid additional heat loss, increasing the ambient temperature, forced air warming, warm fluid therapy, and, in extreme cases, extracorporeal re-warming devices [305–307].

Whereas accidental or induced hypothermia should clearly be avoided in patients without TBI, contradictory results have been reported in patients with TBI. In this trauma setting several large multicentre clinical trials failed to show an effect of therapeutic hypothermia [308–310], while a recent meta-analysis by Crossley et al., which also included several single-centre studies, demonstrated an overall reduction in mortality and poor outcomes [311]. Earlier meta-analyses that examined mortality and neurological outcomes associated with mild hypothermia in TBI were not able to demonstrate such a benefit, which might be explained by the use of different exclusion and inclusion criteria for the analysis [312, 313]. Another reason for controversial results could be differences in the speed of induction and duration of hypothermia, for example it has been shown that 5 days of long-term cooling is more efficacious than 2 days of short-term cooling when mild hypothermia is used to control refractory intracranial hypertension in adults with severe TBI [314, 315]. Moreover, the situation might be different if hypothermia in TBI is compared to conventional treatment that allows fever episodes or compared to strict temperature control between 35.5 and 37 °C [310]. Therefore, at the present time no recommendation can be made in favour of the therapeutic use of whole-body hypothermia in TBI patients.

IV. Rapid control of bleeding

Damage control surgery

Recommendation 19

We recommend that damage control surgery be employed in the severely injured patient presenting with deep haemorrhagic shock, signs of ongoing bleeding and coagulopathy. (Grade 1B)

Other factors that should trigger a damage control approach are severe coagulopathy, hypothermia, acidosis, inaccessible major anatomic injury, a need for time-consuming procedures or concomitant major injury outside the abdomen. (Grade 1C)

We recommend primary definitive surgical management in the haemodynamically stable patient and in the absence of any of the factors above. (Grade 1C)

Rationale

The severely injured patient arriving at the hospital with continuing bleeding or deep haemorrhagic shock generally has a poor chance of survival without early control of bleeding, proper resuscitation and blood transfusion. This is particularly true for patients who present with uncontrolled bleeding due to multiple penetrating injuries or patients with major abdominal injury and unstable pelvic fractures with bleeding from fracture sites and retroperitoneal vessels. The final common pathway in these patients is the exhaustion of physiological reserves with resulting profound acidosis, hypothermia and coagulopathy, also known as the “bloody vicious cycle” or “lethal triad”.

In 1983, Stone et al. described the techniques of abbreviated laparotomy, packing to control haemorrhage and of deferred definitive surgical repair until coagulation has been established [316]. Several articles have since described the beneficial results of this approach, now referred to as “damage control” [317–320]. This approach should be considered in patients with major abdominal injury and a need for adjunctive use of angioembolisation, major abdominal injury and a need to evaluate as early possible other injuries, major abdominal injury and traumatic amputation of a limb. Factors that should trigger a damage control approach in the operating theatre are temperature ≤34 °C, pH ≤7.2, an inaccessible major venous injury, a need for time-consuming procedures in a patient with suboptimal response to resuscitation or inability to achieve haemostasis due to recalcitrant coagulopathy [321, 322].

Damage control surgery of the abdomen consists of three components: the first component is an abbreviated resuscitative laparotomy for control of bleeding, the restitution of blood flow where necessary and the control of contamination. This should be achieved as rapidly as possible without spending unnecessary time on traditional organ repairs that can be deferred to a later phase. The abdomen is packed and temporary abdominal closure is performed. Packing aims to compress liver ruptures or exert direct pressure on the sources of bleeding and abdominal packing may permit further attempts to achieve total haemostasis through angiography and/or correction of the “lethal triad”. The removal of packs should preferably be deferred for at least 48 h to lower the risk of re-bleeding.

The second component of damage control surgery is intensive care treatment, focused on core re-warming, correction of the acid-base imbalance and coagulopathy as well as optimising the ventilation and the haemodynamic status. If complementary angiography and/or further injury investigation is needed, it should be performed during this phase.

The third component is the definitive surgical repair that is performed only when target parameters have been achieved [95, 317–320, 323, 324]. Although the concept of “damage control” intuitively makes sense, no RCTs exist to support it. Retrospective studies support the concept showing reduced morbidity and mortality rates in selective populations [320].

The same “damage control” principles have been applied to orthopaedic injuries in severely injured patients. Scalea et al. were the first to coin the term “damage control orthopaedics” [325]. Relevant fractures are primarily stabilised with external fixators rather than primary definitive osteosynthesis [325–327]. The less traumatic nature and shorter duration of the surgical procedure aims to reduce the secondary procedure-related trauma. Definitive osteosynthesis surgery can be performed after 4–14 days when the patient has recovered sufficiently. Retrospective clinical studies and prospective cohort studies seem to support the concept of damage control. The only available randomised study shows an advantage for this strategy in “borderline” patients [327]. The damage control concept has also been described for thoracic and neurosurgery [328, 329]. In addition to damage control surgical approaches, damage control anaesthesia or resuscitation comprises a number of important measures described in the other recommendations within this document.

Pelvic ring closure and stabilisation

Recommendation 20

We recommend that patients with pelvic ring disruption in haemorrhagic shock undergo immediate pelvic ring closure and stabilisation. (Grade 1B)

Packing, embolisation and surgery

Recommendation 21

We recommend that patients with ongoing haemodynamic instability despite adequate pelvic ring stabilisation receive early pre-peritoneal packing, angiographic embolisation and/or surgical bleeding control. (Grade 1B)

Rationale

The mortality rate for patients with severe pelvic ring disruptions and haemodynamic instability remains high [330, 331]. The early detection of these injuries and initial efforts to reduce disruption and stabilise the pelvis as well as containing bleeding is therefore crucial. Markers of pelvic haemorrhage include anterior-posterior and vertical shear deformations on standard roentgenograms, CT “blush” (active arterial extravasation), bladder compression pressure, pelvic haematoma evident by CT and ongoing haemodynamic instability despite adequate fracture stabilisation [332–334].

The initial therapy for pelvic fractures includes control of venous and/or cancellous bone bleeding by pelvic closure as a first step [335]. Some institutions use primarily external fixators to control haemorrhage from pelvic fractures [332], but pelvic closure may also be achieved using a pelvic binder, a pelvic C-clamp or improvised methods such as a bed sheet [335, 336]. In addition to the pelvic closure, fracture stabilisation and the tamponade effect of the haematoma, pre-, extra or retroperitoneal packing will reduce or stop the venous bleeding [337–339]. Pre-peritoneal packing is used to decrease the need for pelvic embolisation and may be performed simultaneously, or soon after, initial pelvic fracture stabilisation. The most commonly embolised vascular bed and therefore the most studied is the pelvis [340]. Pelvic packing could potentially aid in early intrapelvic bleeding control and provide crucial time for more selective haemorrhage management [337, 339].

Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been used in patients in end-stage shock following blunt and penetrating trauma together with embolisation of the vascular bed in the pelvis. Descriptions of REBOA are few and there are no published trials. Some combined approaches are reported and the technology is evolving [331]. These techniques can be combined with a consecutive laparotomy if deemed necessary [337]. This may decrease the high mortality rate observed in patients with major pelvic injuries who have undergone laparotomy as the primary intervention, however non-therapeutic laparotomy should be avoided [341]. Time to pelvic embolisation for haemodynamically unstable pelvic fractures may affect survival [331, 342].

Angiography and embolisation are currently accepted as highly effective means with which to control arterial bleeding that cannot be controlled by fracture stabilisation [146, 332, 336, 339, 341, 343, 344]. Radiological management can also be usefully applied to abdominal and thoracic bleeding [345–349]. Martinelli et al. [350] report the use of intra-aortic balloon occlusion to reduce bleeding and permit transport to the angiography theatre. In contrast, Morozumi et al. suggest the use of mobile digital subtraction angiography in the emergency department for arterial embolisation performed by trauma surgeons themselves [351]. A number of authors argue that permissive hypotension while obtaining pelvic stabilisation and/or angiography (damage control resuscitation, hypertonic solutions, controlled hypothermia) could achieve better survival. Institutional differences in the capacity to perform timely angiography and embolisation may explain the different treatment algorithms suggested by many authors. Reports on transcatheter angiographic embolisation suggest a 100 % higher mortality during off-hours due to lack of radiological service [352], therefore a multidisciplinary approach to these severe injuries is required.

Local haemostatic measures

Recommendation 22

We recommend the use of topical haemostatic agents in combination with other surgical measures or with packing for venous or moderate arterial bleeding associated with parenchymal injuries. (Grade 1B)

Rationale

A wide range of local haemostatic agents are currently available for use as adjuncts to traditional surgical techniques to obtain haemorrhagic control. These topical agents can be particularly useful when access to the site of bleeding is difficult. Local haemostatic agents include collagen, gelatin or cellulose-based products, fibrin and synthetic glues or adhesives that can be used for both external and internal bleeding while polysaccharide-based and inorganic haemostatics are still mainly used and approved for external bleeding.

The use of topical haemostatic agents should consider several factors such as the type of surgical procedure, cost, severity of bleeding, coagulation status and each agent’s specific characteristics. Some of these agents should be avoided when autotransfusion is applied, and several other contraindications need to be considered [353, 354]. The capacity of each agent to control bleeding was initially studied in animals, but increasing experience in humans is now available [353–369].

The different types of local haemostatic agents are briefly presented according to their basis and haemostatic capacity.

Collagen-based agents trigger platelet aggregation, resulting in clot formation when in contact with a bleeding surface. They are often combined with a procoagulant substance such as thrombin to enhance the haemostatic effect. A positive haemostatic effect has been shown in several human studies [360–363].

Gelatin-based products can be used alone or in combination with a procoagulant substance [353]. Swelling of the gelatin in contact with blood reduces the blood flow and, in combination with a thrombin-based component, enhances haemostasis [357–359]. The products have been successfully used for local bleeding control in brain or thyroid surgery when electrocautery may cause damage to nerves [356] or to control bleeding from irregular surfaces such as post-sinus surgery [355].

Absorbable cellulose-based haemostatic agents have been widely used to treat bleeding for many years, and case reports as well as a prospective observational human study support their effectiveness [368]. The oxidised cellulose-based product can be impregnated with polyethylene glycol and other salts and achieve comparable and more rapid haemostasis compared to the combined products described below [367].

Fibrin and synthetic glues or adhesives have both haemostatic and sealant properties, and their significant effect on haemostasis has been shown in several randomised controlled human studies involving vascular, bone, skin and visceral surgery [364–366].

Polysaccharide-based haemostatics can be divided into two broad categories [353]: N-acetyl-glucosamine-containing glycosaminoglycans purified from microalgae and diatoms and microporous polysaccharide haemospheres produced from potato starch. The mechanism of action is complex and depends on the purity or combination with other substances such as cellulose or fibrin. A number of different products in the form of pads, patches or bandages are currently available and have been shown to be efficient for external use and for splanchnic bleeding in animals. An observational study showed that haemorrhage control was achieved using a poly-N-acetyl glucosamine-based bandage applied to ten patients with severe hepatic and abdominal injuries, acidosis and clinical coagulopathy [369].

Although the evidence is mainly observational, these agents have become widely used.

V. Initial management of bleeding and coagulopathy

Coagulation support

Recommendation 23

We recommend that monitoring and measures to support coagulation be initiated immediately upon hospital admission. (Grade 1B)

Rationale

Some means with which to evaluate trauma-related coagulopathy have been developed [370], however, these largely confirm the main pathophysiological mechanisms described above [371, 372]. While several general pathophysiological mechanisms can be described that result in trauma-related coagulopathy, it is essential to quickly determine the type and degree of coagulopathy in the individual patient in order to determine the most prominent cause or causes to be treated specifically in a goal-directed manner [373].

Early monitoring of coagulation is essential to detect trauma-induced coagulopathy and to define the main causes, including hyperfibrinolysis [13, 25, 179, 183, 374]. Early therapeutic intervention does improve coagulation tests [375], reduce the need for transfusion of RBC, FFP and platelets [12, 376], reduce the incidence of post-traumatic multi-organ failure, shorten length of hospital stay [12] and may improve survival [377, 378]. Interestingly, the success of early algorithm-based and goal-directed coagulation management in reducing transfusions and improving outcome, including mortality, has also been shown in cardiac surgery [202, 379–381]. Therefore, early algorithm-based and goal-directed coagulation management treatment is likely to improve the outcome of severely injured patients [382, 383]. This has indeed been shown in a prospective randomised study [384] and in a large study assessing the introduction of such a concept in two large Italian trauma centres [385]. However, there are also studies in which no survival benefit could be shown [375, 386, 387]; variation in published results may be due to choice of coagulation monitoring tests (negative trials tended to use traditional laboratory values such as PT, APTT and platelet count) and type of therapy used (negative trials tended to use only FFP and platelets [379–381, 384].

Initial coagulation resuscitation

Recommendation 24

In the initial management of patients with expected massive haemorrhage, we recommend one of the two following strategies:

Plasma (FFP or pathogen-inactivated plasma) in a plasma – RBC ratio of at least 1:2 as needed. (Grade 1B)

Fibrinogen concentrate and RBC according to Hb level. (Grade 1C)

Rationale

We define “initial resuscitation” as the period between arrival in the emergency department and availability of results from coagulation monitoring (coagulation screen, fibrinogen level and/or viscoelastic monitoring and platelet count). There are still conflicting opinions about use of plasma as the initial strategy to support coagulation, and several authors, mainly in Europe, strongly disagree with the initial transfusion of patients based on an empirical ratio rather than guided by concurrent laboratory data (goal-directed therapy) [388]. In the absence of rapid point-of-care coagulation testing to facilitate goal-directed therapy, initial treatment with blood components in a fixed ratio may constitute a reasonable approach. If concurrent coagulation results are available, they should be used to guide therapy.

In May 2005, based on reports from the ongoing conflict in Iraq, an international expert conference on massive transfusion hosted by the US Army’s Institute of Surgical Research introduced a new concept for the resuscitation of patients with massive bleeding and recommended the immediate administration of coagulation components with a 1:1:1 ratio for RBC, plasma and platelets [389–391] until laboratory measurements to adjust therapy were available. In the following few years retrospective evidence from both military and civilian practice suggested improved outcomes in patients with massive bleeding after the adoption of a massive transfusion protocol, including the early administration of high-dose plasma therapy [392]. Several subsequent studies focused on this strategy to determine whether standard doses of plasma and platelets in a fixed ratio relative to RBC were able to improve survival. Notwithstanding a large number of studies, the evidence with respect to the use of high ratios shows conflicting results. Although many authors suggested that early and aggressive plasma transfusion may reduce mortality [393], the optimal FFP:RBC and platelet:RBC ratio was controversial because of the possible survival bias that flaws most studies [394, 395]. Survival bias is the bias resulting from the fact that surviving patients are more likely to receive more plasma and platelets compared with non-survivors, because they live long enough to receive those blood products. A prospective multicentre study that included a large population of patients undergoing massive transfusion showed that high FFP:RBC and platelet:RBC ratios are associated with a survival benefit, also when time-dependency is accounted for [225], however other authors have come to opposite conclusions [396]. Khan et al. were unable to confirm significant increases in procoagulant factor levels or consistent correction of any measure of clot function when FFP was delivered during the acute phase of ongoing bleeding [396]. The recent Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomised clinical trial in 680 trauma patients who were suspected to sustain or had experienced massive blood loss [397, 398] reported that there was no difference in overall survival between early administration of plasma, platelets and RBC in a 1:1:1 ratio (FFP:platelets: RBC) compared to 1:1:2. However more patients in the 1:1:1 group achieved “anatomic” haemostasis and fewer experienced death due to exsanguination by 24 h. The early use of platelets and high level of FFP use in the 1:1:1 group was not associated with a significantly increased rate of complications. The early administration of platelets as described in Recommendation 29 is important, however from a practical standpoint platelets may not be readily available during the initial resuscitation period described here.

As with all products derived from human blood, the complications associated with FFP treatment include circulatory overload, ABO incompatibility, transmission of infectious diseases (including prion diseases) and mild allergic reactions. Transfusion-related acute lung injury (TRALI) [399, 400] is a severe adverse effect associated with the presence of leucocyte antibodies in transfused plasma. The risk of TRALI has been greatly reduced by avoiding the use of plasma from women with a history of pregnancy [401]. Transmission of infectious diseases can be minimised by the use of pathogen-inactivated plasma (industrial purified plasma).

Further controversy concerns the use of plasma to correct the decreased fibrinogen levels associated with haemorrhagic shock. Haemostasis is critically dependent on fibrinogen as a substrate for clot formation and the ligand for platelet aggregation. Fibrinogen is the single coagulation factor that is affected more and earlier in association with trauma-induced coagulopathy. Many bleeding trauma patients with trauma-induced coagulopathy present with a fibrinogen depletion, below levels currently recommended for therapeutic supplementation. Recently Schlimp et al. [159] demonstrated that levels of fibrinogen lower than 1.5 g/l are detected in as many as 73 % of patients with an admission Hb lower than 100 g/l and in 63 % of those with a BE lower than -6. Moreover, Rourke et al. [402] found low fibrinogen in 41 % of the patients who were hypotensive on admission. In this study, hypotension, increasing shock severity and a high degree of injury (ISS ≥25), were all associated with a reduction in fibrinogen levels. Fibrinogen depletion is associated with poor outcomes and survival improves with administered fibrinogen [403]. Fibrinogen is by far the coagulation protein with the highest plasma concentration. One litre of plasma contains on average 2 g of fibrinogen. Therefore for very initial coagulation support, while waiting for the results of viscoelastic or laboratory tests, it has been proposed to administer 2 g of fibrinogen to mimic the expected 1:1 ratio corresponding to the first four units of RBC and potentially correct hypofibrinogenaemia if already present [385, 404]. Recent experimental data show that administration of fibrinogen does not suppress endogenous fibrinogen synthesis [405].

Administration of plasma to bleeding patients may stabilise fibrinogen levels, avoiding a further decrease, but plasma transfusions cannot contribute to a significant increase in fibrinogen level unless very high volumes are infused [406]. The Activation of Coagulation and Inflammation in Trauma (ACIT) study [396] confirmed these findings, showing that the percentage of coagulopathic patients increased with a standard near 1:1 FFP:RBC transfusion protocol. Similar results were recently reported by Khan et al. [15]. Again, a 1:1 FFP:RBC transfusion protocol did not alleviate coagulopathy; the percentage of coagulopathic patients even increased the longer this treatment lasted. Interestingly, in the same study it was shown that only high-dose fibrinogen administration resulted in improved coagulation and a reduction in coagulopathy. Furthermore, both FFP and pathogen-inactivated plasma need to be group-matched, thawed and warmed prior to administration. Therefore, unless pre-thawed plasma is available, plasma transfusion cannot be initiated at the same time as universal RBC transfusion. An average delay of 93 min was reported by Snyder et al. [394] and recently confirmed by Halmin et al. [407], possibly explaining why a real-life targeted plasma:RBC ratio is achieved only a few hours after treatment initiation. During this interval the fibrinogen level is likely to be lower than desired.

Antifibrinolytic agents

Recommendation 25

We recommend that tranexamic acid be administered as early as possible to the trauma patient who is bleeding or at risk of significant haemorrhage at a loading dose of 1 g infused over 10 min, followed by an i.v. infusion of 1 g over 8 h. (Grade 1A)

We recommend that tranexamic acid be administered to the bleeding trauma patient within 3 h after injury. (Grade 1B)

We suggest that protocols for the management of bleeding patients consider administration of the first dose of tranexamic acid en route to the hospital. (Grade 2C)

Rationale

Tranexamic acid (trans-4-aminomethyl cyclohexane-1-carboxylic acid; TXA) is a synthetic lysine analogue that is a competitive inhibitor of plasminogen. TXA is distributed throughout all tissues, and the plasma half-life is 120 min [408]. The Clinical Randomisation of Antifibrinolytic therapy in Significant Haemorrhage (CRASH-2) trial [409] assessed the effects of early administration of a short course of TXA on death, vascular occlusive events and the receipt of blood product transfusion in trauma patients who were bleeding or at risk of significant bleeding. The trial randomised 20,211 adult trauma patients with or at risk of significant bleeding to either TXA (loading dose 1 g over 10 min followed by infusion of 1 g over 8 h) or matching placebo within 8 h of injury. The primary outcome was death in hospital within 4 weeks of injury. All analyses assessed the intention-to-treat population. All-cause mortality was significantly reduced with TXA by 1.5 %, and the risk of death due to bleeding was significantly reduced by 0.8 % and a reduction in bleeding deaths by one-third, mainly through preventing exsanguination within the first 24 h [410, 411]. One retrospective study has suggested that TXA is of no benefit in patients with viscoelastic hyperfibrinolysis [412] and another found TXA to reduce multiple organ failure and mortality in severely injured shocked patients [413]. This discrepancy is probably attributable to methodological limitations.

The risk of precipitated thrombosis with the use of the lysine analogues TXA and ε-aminocaproic acid had been of major theoretical concern; however CRASH-2 showed that the rate of venous thromboembolism (VTE) was not altered, while post-traumatic arterial thromboses, especially myocardial infarction, were lower with the use of TXA. No adverse events were described with the use of TXA in CRASH-2, although an increased rate of seizures has been described in patients receiving a high-dose TXA undergoing cardiac surgery [414], probably reflecting the role of fibrinolytic molecules as neurotransmitters.

An unplanned subgroup analysis of the CRASH-2 data [415] showed that early treatment (≤1 h from injury) significantly reduced the risk of death due to bleeding by 2.5 %. Treatment administered between 1 and 3 h also reduced the risk of death due to bleeding by 1.3 %. Treatment given after 3 h increased the risk of death due to bleeding by 1.3 %; therefore we recommend that TXA not be given more than 3 h following injury. In order to ensure that TXA is given early, the administration of TXA at the pre-hospital site of injury needs to be planned, and we suggest that protocols for the management of bleeding patients consider administration of the first dose of TXA at the site of injury. If TXA is restricted to massive transfusion protocols or only used in patients clinically judged to be at “high risk”, it is estimated that only 40 % of the potential benefit from this treatment will be achieved [416]. For the full benefit, TXA should therefore be administered to all patients with trauma and significant bleeding. Thus TXA should be included as part of each institutional “trauma management protocol” not the “massive blood loss” or “major haemorrhage” protocols.

The cost-effectiveness of TXA in trauma has been calculated in three countries [417, 418]: Tanzania as an example of a low-income country, India as a middle-income country and the UK as a high-income country. The cost of TXA administration to 1