Haemorrhagic shock (HS) is characterized by a systemic reduction in tissue oxygen delivery due to blood loss. HS is a common syndrome in veterinary patients, both in the emergency and critical care settings. It can result from a wide range of etiologies such as trauma, neoplasia, or coagulopathies. Iatrogenic injuries (surgery or procedures such as abdominocentesis or pericardiocentesis) may also lead to serious blood losses. While the initial approach in the management of HS can be similar across diseases, the underlying etiology ultimately dictates both patient management and prognosis. While it is characterized by hypovolaemia, some patients may progress to vasodilatory shock, in particular those who have undergone resuscitation. A thorough understanding of the disease mechanisms along with knowledge of current clinical evidence is of the utmost importance for acute care clinicians.

Pathophysiologic Alterations Induced by Haemorrhagic Shock

Similar to other causes of shock, haemorrhage may reduce systemic tissue oxygen delivery, ultimately leading to a cellular shift from an aerobic to an anaerobic metabolism. The hallmark of shock regardless of the underlying disease in a reduction in systemic ATP production. Cells become unable to maintain their cellular membrane integrity, which may lead to swelling (oedema). Cell death can be mediated via necrosis although apoptosis or necroptosis may also be at play.

There is a paucity of mechanistic studies of HS in veterinary patients. Furthermore, much of the human HS literature arises from trauma populations. Much of the following information is therefore derived from translational or human trauma research.

Microcirculatory Dysfunction

Despite improvement in microcirculation parameters such as heart rate, blood pressure, etc., some HS patients progress to multiple organ failure. This discrepancy is partially attributed to microcirculation anomalies. Endothelial dysfunction is a corner stone of microcirculation failure. Tight junctions between endothelial cells are under complex regulation and loss of endothelial barrier integrity is an early sign of endothelial injury. Various molecules are involved in maintaining endothelial integrity. For instance, the angiopoietin/Tie2 system mediates endothelial health and function in health and after injury. Both human and animal studies showed that while angiopoietin 1 binding to its receptor Tie2 helped maintain endothelial barrier integrity, angiopoietin 2 (which is upregulated after trauma) was associated with endothelial injury.

Endothelial Injury and Glycocalyx Shedding

The glycocalyx consists of a complex arrangement of glycoproteins, proteoglycans, and glycolipids at the apical surface of endothelial cells. The glycocalyx can be damaged following HS and endothelial injury; its components are then shed into the systemic circulation, where they promote inflammation. While the ideal resuscitation strategy for HS patients is still debated, it has been accepted that approaches based on rapid administration of large volume of isotonic crystalloids should be avoided. In dogs with HS, this approach has been associated with increased hyaluronan shedding from the endothelium and a pro-inflammatory state.

Nitric Oxide Pathway Dysregulation

The nitric oxide pathway is also a major contributor to the cascade of events occurring in HS. In the early phase of HS, red blood cell mass reduction is associated with a decrease in vascular wall shear stress, which in turn downregulates nitric oxide production and sustains capillary dysfunction. In contrast, later in the disease, nitric oxide can be overproduced and lead to vasoplegia.

Release of Damage-Associated Molecular Patterns (DAMPs or Alarmins)

Following non-specific injury, cells release endogenous mediators that not only can be used as biomarkers but also have biological functions; those are named damage-associated molecular patterns (DAMPs or alarmins). For instance, mitochondrial DNA or formyl peptides are rapidly released after trauma and incite a systemic inflammatory response. Cold-inducible RNA-binding protein (CIRP) is another DAMP of interest due to its deleterious effects. DAMPs may activate cytoplasmic inflammasomes, which are multiprotein complexes, that can upregulate inflammation and induce apoptosis; they are thought to be involved in multiple organ and immune dysfunctions observed in trauma patients. Studies in canine trauma patients have shown that in contrast to high mobility group box-1 (HMGB1) or cell-free DNA, plasma nucleosomes have prognostic value.

Trauma-Induced Coagulopathy

HS patients may suffer from various coagulopathies, whether due to consumptive processes or loss of platelet and coagulation factors through blood losses. In the subset of trauma-induced HS, patients often suffer from a continuum of coagulation disorders termed trauma-induced coagulopathy (TIC). TIC can be characterized by acute traumatic coagulopathy (ATC) and resuscitation induced coagulopathy (RIC). Disorders of fibrinolysis are an important part of ATC. While interest in hyperfibrinolysis has led to significant research in tranexamic acid in trauma patients, the trauma community has also established that some patients may also present with a state of fibrinolysis shutdown.

Host Response to Injury

It has been traditionally accepted that similar to infection-induced tissue damage, trauma is associated with a systemic inflammatory response syndrome (or SIRS) followed by a compensatory anti-inflammatory response syndrome (or CARS). Imbalances between these two responses have been associated with morbidity and mortality. Individual patient’s genetic response has been under scrutiny. Following massive blunt trauma, more than 80% of the WBC genetic expression was changed. Gene expression is not only altered in the early phase but also later in the progression of the disease. Return to pre-injury levels may range from 1 day to weeks depending on the gene of interest. Components of the innate system were upregulated while genes associated with acquired immunity were down-regulated.

Diagnosis

HS diagnosis is mostly based on the recognition of shock (which is mainly based on physical examination findings) and identifying a source of significant blood loss. Shock can be diagnosed via evidence of alteration in perfusion parameters: mentation, heart rate, mucous membrane colour, capillary refill time, extremity-to-core temperature, pulse quality (femoral and dorsal pedal being the most commonly evaluated). Patients will most often display features of hypovolaemic shock: prolonged capillary refill time, pale pink to white mucous membranes, and cold extremities. Some patients may present vasodilatory features, especially the sickest ones who have undergone resuscitation. Additional diagnostics such as plasma lactate concentration or arterial blood pressure provide further information to gauge disease severity and guide resuscitation measures.

The source of blood loss can be identified through the history or physical examination. For instance, patients that are victims of trauma may have lost a significant amount of blood at the point of injury. Furthermore, physical examination may reveal the presence of haemoptysis or epistaxis. Point-of-care ultrasound examination and cavitary fluid analysis is a rapid and inexpensive tool to further locate possible sources of blood loss.

Treatment

Source Control

While fluid resuscitation is undertaken, external sources of haemorrhage should be controlled as soon as possible. Direct pressure can be applied whenever possible. Application of haemostatic gauze on wounds with ongoing bleeding might provide additional assistance in arrest of haemorrhage.

Fluid and Vasopressor Resuscitation

Similar to other conditions, HS patients can be resuscitated with isotonic crystalloids, hypertonic crystalloids, synthetic colloids, and/or blood products. Clinicians should keep in mind the dose-dependent anticoagulant effects of synthetic colloids. Much of the literature in human medicine supports the use of blood products at a ratio of 1:1:1 (of packed red blood cell:fresh frozen plasma:platelets) for severe haemorrhagic shock. This remains an unusual scenario in veterinary medicine and is most appropriate in massive haemorrhage. The use of blood products in traumatized canines has been studied. Common reasons for blood product administration were treatment of shock, perioperative haemodynamic support, or worsening anaemia. In patients with cavitary haemorrhage without bacterial contamination, autologous blood transfusion can be considered. Patients with hypotension despite fluid resuscitation will benefit from vasopressor administration titrated to maintain arterial blood pressure within target range.

Caution should be exercised to prevent and treat hypothermia in these patients as it is a significant source of morbidity and mortality.

Tranexamic Acid

In humans, there is evidence to support the early use of fibrinolysis inhibitors after trauma to reduce the rate of bleeding-related death as well as all causes of mortality. Tranexamic acid is a lysine analog that inhibits plasminogen activation and at much higher concentrations, is a noncompetitive inhibitor of plasmin. Tranexamic acid also has anti-inflammatory effects. The currently recommended dose is 10–15 mg/kg SC, IM, or slow IV followed by 1 mg/kg/h CRI for 5–8 hours. In humans, early administration of tranexamic acid is associated with improved outcomes. The beneficial serum levels of tranexamic acid are unknown and it is still an area of active research. There is limited data in clinical veterinary medicine regarding the benefits of tranexamic acid in trauma patients. Clinicians should bear in mind that some patients may be in a fibrinolysis shutdown state.

Damage Control Resuscitation

Some patients will not respond to medical interventions and will require rapid surgical haemorrhage control. It is therefore important that acute care clinicians have protocols in place whereby patients with massive haemorrhage refractory to medical management are rapidly transferred to an operating theatre with properly trained personnel.

New Avenues

Since recent advances in the pathologic consequences of HS have identified pathways that contribute to worsening of the condition, novel therapeutic interventions have been investigated and will hopefully translate to clinical practice. Molecules such as vasculotide or histone deacetylase inhibitors have been studied as resuscitation adjuncts.

References

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