Introduction

Massive (or major) bleeding is a life-threatening emergency in hospitalized patients and occurs across most specialities including surgery, medicine (gastrointestinal), obstetrics and neonatology. These patients are not infrequently admitted to intensive care or high dependency units, for continued care and close monitoring. Even if treated outside this setting, they are often managed with input from critical care physicians. Successful haemostatic control in these situations requires the delivery of effective resuscitation, specifically transfusion therapy, in conjunction with surgical and/or radiological interventions.

Traditionally, massive (or major) haemorrhage has been defined as the loss of one blood volume within a 24-h period. Alternative definitions include a loss of 50% blood volume within 3 h or a rate of blood loss of 150 mL/min [1]. These quantitative (and retrospectively applied) definitions are fairly straightforward to understand, but from a practical standpoint are unhelpful. Early identification of severe haemorrhage, or indeed a patient at risk of major haemorrhage, is critical for improving the chances of a successful outcome. Recognition of blood loss ideally needs to be made within minutes rather than at 24 h. However, clinical evidence of blood loss can be difficult to detect, particularly in patients with good cardiovascular reserve, but a high index of suspicion in addition to parameters suggestive of shock, i.e. a systolic blood pressure (SBP) less than 70 mmHg or an SBP less than 90 mmHg after an initial fluid challenge, is a helpful tool.

This chapter will summarize haemostatic changes during major blood loss and how this knowledge has helped to drive changes to transfusion practices; it will focus on general management of major blood loss and apply these to specific clinical settings.

Massive transfusion: An outdated term?

Massive transfusion (MT) is a term that most commonly describes the transfusion of ≥10 U of red blood cells (RBC) within a 24-h period. It is an arbitrary definition and is frequently used synonymously to delineate patients with severe blood loss. However, this would artificially divide patients into different groups, while RBC transfusion should be, in fact, on a continuous spectrum. The phrase also defines a medical condition by its treatment and specifically, treatment by red cell usage rather than haemostatic interventions. Moreover, mortality has not been shown to dramatically increase at any threshold value including greater than 10 U RBC. Furthermore, the CRASH-2 study has demonstrated that tranexamic acid (TXA) when given within 3 h of injury confers mortality benefit to all trauma patients at risk of bleeding. In fact, the largest group to benefit from TXA were those who did not receive MT support, i.e. less than 10 U RBC [2].

Red cell transfusions

Patients with major bleeding need red cell transfusions urgently. Maintaining tissue perfusion and oxygenation is key to improving outcomes. Because of the direct link between tissue ischaemia and mortality, RBC transfusions are an early priority in resuscitation. As described later, hospital policies to describe access to emergency-release uncrossmatched RBCs within minutes of identification of major bleeding are essential within major haemorrhage protocols (MHPs). Intra-operative blood salvage, when selectively used for cases involving large volume blood loss such as obstetrics or surgery, may also provide a source of red cell support, but will not be considered further in this chapter.

The coagulopathy of massive haemorrhage

Coagulopathy is frequently identified in patients with life-threatening haemorrhage. Depending on the definition and patient group, it affects between 5% and 30% of patients (e.g. trauma, cardiac surgery patients and acute upper gastrointestinal haemorrhage). Coagulopathic patients, whether or not they are actively bleeding, have a worse overall prognosis. There are several causes of worsening coagulation during major blood loss:

1. Consumption. Coagulation factors and platelets are consumed during the formation of clots in an attempt to prevent blood loss through damaged vessels.
   
2. Dilution. This is a consequence of replacement of the whole blood with crystalloid, colloid and red cell transfusions. Replacement of two blood volumes with red cell concentrate alone results in a platelet count in the order of 50 × 10−9/L. Furthermore, the volume of fluid administered to a patient has been shown to be proportional to the resultant coagulopathy.
   
3. Hypoxia, acidosis and hypothermia. This triad predisposes to further bleeding. Hypothermia and acidosis impair the functional ability of both the platelets and the coagulation proteases. Haemostatic defects are most evident once pH values fall below 7.1 and temperatures below 33°C.
   
4. Ongoing bleeding. Anaemia has an effect on primary haemostasis. A low haematocrit reduces axial flow (where all the red cells flow in the middle of the vessel and platelets and plasma are pushed into close proximity to the endothelium) and thus reduces the margination of platelets and platelet–endothelial interaction.
   

   The aforementioned four effects tend to lead to increased bleeding, while the next leads to a prothrombotic phenotype and helps to explain why those patients with severe bleeding are also at increased risk of thrombotic problems including multi-organ failure:

   
   
5. Hormonal and cytokine-induced changes. Following tissue injury, hormone levels, i.e. adrenaline and vasopressin, rise, and there is an increased generation of cytokines. Vasopressin stimulates both the release of von Willebrand factor (from Weibel–Palade bodies) and expression of P-selectin on the endothelial cell surface. Cytokines, such as TNF and IL-1, as well as thrombin can cause endothelial cell activation and thus effect a slow change in endothelial cell phenotype from antithrombotic to prothrombotic.