Pharmacological adjuncts to stop bleeding: options and effectiveness

Severe trauma and massive haemorrhage represent the leading cause of death and disability in patients under the age of 45 years in the developed world [1‐5]. Because of the disproportionate incidence of trauma in younger people, the burden to society is even bigger. Haemorrhage in the setting of trauma is responsible for 30–40 % of trauma mortality [5, 6], with 33–56 % of these deaths occurring in the pre-hospital period [5, 6], whilst one-third of these deaths occur in-hospital [7, 8]. Additionally, haemorrhage represents an important contributory factor for increased mortality of a different aetiology, particularly multi-organ failure and head injury [7, 9].

During the last decades, many advancements have been made in our understanding of the pathophysiology of trauma, the availability of diagnostic adjuncts and the introduction of new resuscitation protocols [10]. Nevertheless, outcomes from massive haemorrhage remain poor, especially in the background of massive blood transfusion and significant coagulopathy [11].

The present review discusses the current literature with regard to the management of haemorrhage following trauma, with a special reference to the use of pharmacological adjuncts. Novel insights, concepts and treatment modalities are also discussed.

The haemodynamic response triggered by trauma is biphasic, with the systemic arterial pressure initially maintained, followed by a sudden decrease in the systemic arterial pressure with increasing blood loss [12]. If the resuscitation is not adequate, this haemodynamic redistribution can compromise the blood flow to vital organs, therefore further increasing mortality and morbidity [12].

Another significant factor contributing to increased mortality and morbidity following trauma is that of acute coagulopathy [11, 13, 14]. The development of coagulopathy is multifactorial and if not rapidly reversed, it results in a vicious circle often referred to as “acute traumatic coagulopathy” or “acute coagulopathy of trauma shock” [11]. It is usually a combination of the inadequate tissue perfusion because of the resulting hypovolemia and the subsequent cell hypoxia, anaerobic respiration and metabolic acidosis, the thrombin–thrombomodulin-complex generation resulting from the tissue injury and the activation of anticoagulant and fibrinolytic pathways [6, 14]. The resulting state of hyperfibrinolysis is believed to play a central role in the initial coagulopathy, since the maintenance of clot stability is equally important in clot formation [13]. Moreover, the associated hypothermia, which is very common in the traumatised and especially unconscious/sedated patient, leads to a reduced clotting enzymatic activity and a decreased platelet function, a process that further impairs coagulation [6].

Coagulopathy, acidosis and hypothermia are collectively known as the “lethal triad” of trauma and their role in increasing trauma mortality and morbidity is well established [6, 9, 11]. Understanding the pathophysiology of the lethal triad, as well as the importance of its rapid recognition, should serve as the cornerstone for the management of the bleeding trauma patient.

Failure to promptly recognise bleeding and commence appropriate early management is the leading cause of preventable death following trauma [15]. A multidisciplinary approach aiming to the prompt recognition of shock due to haemorrhage following trauma (defined as loss of 20 % or more of the total blood loss) is of paramount importance, preferentially before the decompensation. The correct management, targeting at preventing or reversing any associated metabolic derangement, should be followed by timely interventions to control bleeding, restore tissue perfusion and achieve haemodynamic stability (Table 1) [5, 9, 14, 16].

In the pre-hospital setting, the adherence to the fundamental principles of Advanced Trauma Life Support (ATLS^®) is emphasised, including the rapid transportation of patients to the hospital and limiting therapy to what is necessary to maintain adequate tissue perfusion, such as use of tourniquets to stop life threatening bleeding [14].

In-hospital, provided that ATLS^® principles are adhered to, the source of bleeding should be rapidly identified. Multi-sliced computed tomography and ultrasound scans can be used as adjuncts to the clinical examination in the haemodynamically stable patient [14]. In the haemodynamically unstable patient, early control of significant bleeding in the abdomen and/or pelvis can be managed with surgical exploration, packing, angiographic embolisation and stabilisation of pelvic ring [14, 16]. Moreover, serial measurements of serum lactate and base deficit measurements can be used for estimating/monitoring the extent of bleeding and shock, whereas post-traumatic coagulopathy should be monitored and promptly corrected [14]. Additionally, techniques/modalities which have been proved effective for resuscitating the trauma patients include: permissive hypotension (targeting a systolic blood pressure of 80–90 mmHg, until any major bleeding has been stopped) and maintenance of minimally acceptable perfusion to prevent vasoconstriction, dislodgement of the early thrombus and therefore increase of blood loss [4, 5, 14]; minimising the use of crystalloid intravenous fluids during resuscitation, therefore minimising the effect of clotting factors dilution [4, 5, 14]; the use of crystalloid solutions with neutral pH, avoiding hyperchloremic metabolic acidosis associated with resuscitation with large-volume normal saline solutions [4, 5]; the use of blood products including packed red blood cells (RBC), fresh frozen plasma (FFP) and platelets [4]; aggressive prevention of heat loss using heat blankets, blood warming devices and warm intravenous (IV) fluids [4, 16]; and providing adequate analgesia to minimise movement and surges in blood pressure that can increase bleeding [16]. Most recently, attention has been shifted to the pathophysiology at a cellular level, with less sensitive parameters (systolic blood pressure and response to volume resuscitation) being de-emphasised [4].

In addition, in severe trauma, damage control surgery has been proven to be of vital importance [5]. According to this concept, a staged approach is followed with initial abbreviated surgical interventions to control bleeding, contamination and fracture stabilisation, which followed definitive surgical procedures when the patient conditions are improved [5]. Patients that should be considered for this approach are those in deep haemorrhagic shock with signs of ongoing bleeding and established coagulopathy, as well as patients with severe hypothermia, acidosis, major anatomic injuries that cannot be accessed, need for multiple lengthy procedures or presence of major concomitant injuries [14].

It has been reported that more than 50 % of polytrauma patients are transfused, whilst in several developed countries over 15 % of these patients receive massive transfusions (variably defined as transfusion of more than 10 units of packed red blood cells or transfusion of more than 50 % of total blood volume in 24 h, or transfusion of more than 5 units in 4 h) [17, 18]. Balanced and early use of blood components including red blood cells, platelets, plasma [fresh frozen plasma (FFP) or pathogen-inactivated plasma], fibrinogen and cryoprecipitate has been reported to be effective in major bleeding [14, 19]. In addition, several risk factors have been identified to contribute to an increased blood loss in trauma patients, including use of anticoagulant medications, coagulation disorders, advanced age, use of a pneumatic tourniquet, critical illness and pre-existing anaemia [20‐22]. Generally, a haemoglobin (Hb) target between 7 and 9 g/dl is considered to be satisfactory for achieving adequate oxygen delivery to the tissues [14].

Even though the safety of allogeneic blood product transfusion has considerably improved over the last decades, transfusion is still associated with significant morbidity and mortality. Potential hazards of allogenic blood transfusion include the risk of infection (HIV, HBV, HCV) [23‐25], non-infectious complications such as ABO incompatibility [26], haemolytic reactions, immunosuppression and even death [27, 28]. Historical transfusion risks such as transfusion errors (incorrect blood component transfused) and other acute transfusion reactions happen very rarely.

A recent meta-analysis on the risks associated with blood transfusion suggests that there is an association between increasing transfusion and mortality, sepsis, multi-organ system dysfunction and acute respiratory distress syndrome (ARDS) [17, 29]. Additionally, a Cochrane review reported that in-hospital mortality of patients receiving restrictive transfusion strategies was reduced, compared to patients managed with liberal transfusion strategies [25]. Therefore, the clinician should always balance the benefits of transfusion against the possible risks, especially in patients who are not unstable, but had haemorrhage. Another facet that should be considered is that blood remains a scarce and costly resource; it has been previously reported that the cost of a unit of red blood cells to the National Health Service in 2011 was £125 [23], whereas this cost is constantly rising.

A wide range of pharmacological agents has been used as adjunct in traditional techniques to obtain haemorrhagic control. These can generally be categorised into two major groups: topical (local) and systemic haemostatic agents.

Severe trauma and massive haemorrhage remains the leading cause of death and disability in the young population. Even though much advancement has been made in the management of these patients with the introduction of complex resuscitation protocols, the outcomes remain poor. The use of anti-fibrinolytic agents is one of the most promising interventions, but their benefits should be balanced with the risk of complications, especially thrombosis. Based on the available evidence and our experience, our recommendations are outlined in Table 2.

Following the publication of the CRASH-2 trial results, TXA has been incorporated into most trauma management protocols worldwide, both in the pre-hospital and hospital environment. The World Health Organization (WHO) has also included TXA into the List of Essential Medicines, whereas the National Institute for Health and Care Excellence (NICE) is expected to publish a Clinical Guideline on the assessment and management of major trauma in February 2016 including the off-label use of TXA [58, 59].

The benefits of this easy-to-use molecule are also likely to be greater in the elderly population who have a higher baseline risk of death from haemorrhage and thromboembolic events, an observation based on the reduction of the arterial events in this patient group [35]. Pererl et al. have developed and validated a prognostic model for risk of mortality based on clinical parameters such as age, Glasgow Coma Score (GCS), systolic blood pressure and geographic area [8]. This protocol could potentially be used as an additional tool for deciding whether or not to use lifesaving interventions such as TXA. In any case, the treating physician should use all the available information and their clinical judgment to the best interest of their patient.

Finally, it has been estimated that every year up to 128,000 deaths worldwide can be averted if TXA is administered within 1 h from injury, whereas when administered within 3 h, up to 112,000 deaths can be averted [60]. This potential is more significant in low and middle income countries [60], whereas TXA is likely to be highly cost-effective in any income setting as reflected by the life years saved [61].

Pre-hospital care should be improved with TXA been incorporated in the management of bleeding trauma patients, whereas advanced trauma resuscitation protocols should be in place in order to reduce time to definitive haemorrhage control. Future research should aim into investigating trauma coagulopathy and the effect of interventions such as that of TXA. Finally, further pharmacokinetic and pharmacodynamic studies are required to clarify the exact mechanism of action of TXA, as well as the optimal doses in both the adult and paediatric populations.