Jennifer J. Devey, DVM, DACVECC
Research on hemorrhagic shock in dogs has been extensive and although our comprehension of what happens during shock is improving our understanding of the pathophysiology of hemorrhagic shock is far from complete. Difficulties arise from the fact that little clinical information has been published on dogs, trauma is rarely standard, and each individual's ability to compensate is different. Applying information from human clinical studies is problematic due to significant differences in physiology between species. The same applies to conclusions drawn from studies performed in laboratory rats, sheep or pigs. The research environment allows responses to be studied but it uses a model. The animals are anesthetized with drugs that may alter their baroreceptor and chemoreceptor responses. Hemorrhage is often performed by withdrawing blood from a catheter to a set endpoint at which point the 'bleeding' is stopped. Only one area of the body may be impacted during a research study, whereas in a dog hit by a car multiple areas of the body can be affected. Pain is rarely a component of the research model yet the pain response in the clinical patient plays an extremely important role. Most research models of hemorrhagic shock are terminal and only last a period of a few hours making it virtually impossible to look at longer term outcomes. Finally, although it is well recognized that hypovolemia leads to tissue hypoxia, the inflammatory pathways and why some patients develop the systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF) and some do not is not well understood.
The response to trauma is a complex interaction of catecholamines, as well as cellular and humoral mediators that help compensate for blood loss, tissue injury, pain and the increased energy demands required for healing. The degree of response by the body correlates directly with the extent of the injury and is designed to restore homeostasis. If the body's systems are overwhelmed death will result. By improving our understanding of the pathophysiology of trauma it is hoped treatment plans can be optimized.
Types of Shock
A trauma patient is usually suffering from the effects of hypovolemic shock secondary to hemorrhage; however, neurogenic shock, compressive shock, cardiogenic shock and distributive shock also may be present. Neurogenic shock, which is rare in animals, is caused by a loss of sympathetic tone due to severe spinal cord injury or severe head injury. Compressive cardiac shock occurs when pressure within the thorax causes a significant decrease in the venous return to the heart. Cardiogenic shock occurs when there is intrinsic muscle dysfunction secondary to a preexisting condition, severe hypoxemia or direct cardiac trauma. Coronary vessels may spasm secondary to direct myocardial injury and thromboses of the coronary vessels or the capillaries and small vessels of the injured heart wall may develop. Myocardial contusions characterized by subendocardial hemorrhage and interstitial edema can occur if trauma is more severe. A disturbance in the energy-dependent ion pumps as well as the release of myocardial depressant factors leads to interference with normal electrical conduction and secondary arrhythmias, as well as a decrease in cardiac muscle function. Distributive shock may be present if the patient is septic from an injury such as a lacerated bowel. The following discussion will focus on hypovolemic shock in the trauma patient.
Loss of blood leads to altered tissue perfusion and tissue hypoxia; the degree of which varies with the amount of blood lost as well as other complicating factors including the presence of other types of shock and the degree of pain being experienced. Dogs in pain need to lose far less blood than dogs not experiencing pain to experience the same degree of shock. It has been shown that dogs will tolerate a mean arterial pressure of 50 to 60 mm Hg for several hours but that a systolic blood pressure of 45 mm Hg for a short time leads to irreversible ischemia. The tissue hypoxia following hemorrhage leads to decoupling of mitochondrial respiration and oxidative phosphorylation, also known as cytopathic hypoxia.
The decrease in circulating blood volume decreases the hydrostatic pressure in the vessels and allows fluids to shift from the interstitium to the intravascular space. Up to 50% blood volume expansion can occur in a short period of time. The decrease in hemoglobin causes significant alterations in the amount of oxygen that is being carried in the blood. Under normal conditions only approximately 1.5% of the oxygen delivered to the tissues is in a dissolved form, the remainder is carried by hemoglobin. The lack of oxygen from decreased circulating blood volume as well as decreased hemoglobin leads to anaerobic metabolism and lactate build up. This in conjunction with accumulation of waste products especially carbon dioxide contribute to the tissue acidosis. Hypoxia, as well as some of the inflammatory cytokines, increases production of autocoids which along with lactate and other tissue factors such as nitric oxide (whose release appears to be impaired in severe trauma) cause loss of autoregulation and worsen vasodilation. The baroreceptor and chemoreceptor response is altered by hypoxia, ischemia, acidemia and hypothermia which also contributes to the poor microcirculatory blood flow. Acidemia, hypoxemia and cytokines decrease hemoglobin's affinity for oxygen and decrease red blood cell deformability. Sludging of blood flow leads to formation of rouleaux and clogging of the microcirculation. Cell pump dysfunction needs to cell swelling. Mitochondrial decoupling occurs.
Changes in arterial and venous pressure and volume, osmolality, pH, arterial oxygen concentration, pain, and toxic mediators of inflammation such as cytokines all serve to trigger the hypothalamus to relay messages to the sympathetic nervous system and the pituitary gland. The sympathetic nervous system releases epinephrine and norepinephrine. The resulting vasoconstriction helps to shunt the blood to the brain, heart and lungs and away from the splanchnic organs, kidneys, muscle and skin leading to a worsening of the regional ischemia. Sympathetic stimulation causes contraction of the spleen and liver in the dog, which can infuse up to 30% of the dog's blood volume into the circulation, and release of cortisol from the adrenal glands. The pituitary gland releases adrenocorticotropic hormone (ACTH) leading to increased synthesis and release of cortisol. Cortisol causes an increase in circulating glucose by stimulating gluconeogenesis, insulin resistance, lipolysis, and protein catabolism. Cortisol, along with catecholamines, promotes sodium retention in the kidneys which leads to water retention and an improvement in blood volume. The renin-angiotensin-aldosterone system is activated secondary to decreased renal blood flow leading to sodium and water retention. Antidiuretic hormone (ADH) is also released by the pituitary gland in response to a decreased blood volume. Both ADH and angiotensin are also potent vasoconstrictors and help to maintain blood pressure via their pressor effects.
Pain is an important activator of the stress response. The hypothalamus receives input from pain fibers which leads to activation of the hypothalamic-pituitary axis. Endogenous opioids are released by the pituitary, and endorphins are released by the adrenal glands. These opioids also may serve as counterregulatory hormones decreasing the production of ACTH, increasing the secretion of insulin and modulating neutrophil and lymphocyte function.
Cytokines are produced from tissue trauma which enhance the inflammatory response along with arachidonic acid metabolites such as leukotrienes and thromboxane, and activation of the complement system. Trauma is associated with a loss of immunocompetence with a loss of both numbers and function of T and B lymphocytes. Abnormalities include decreases in antibody response, neutrophil chemotaxis and adherence, serum opsonic activity and fibronectin. Levels of granulocyte colony-stimulating factor are decreased leading to decreased granulopoiesis and phagocytosis becomes ineffective.
The Metabolic Response
The metabolic response to trauma has been divided into two phases - the ebb phase, or a hypometabolic phase and a flow phase or hypermetabolic phase. The ebb phase lasts about 8 to 12 hours post injury and the flow phase peaks at 3 to 4 days and lasts about 7 to 10 days unless the recovery period is complicated by organ failure. During the flow phase there is an increase in glucose production, protein catabolism, and energy consumption at the cellular level. There is a dramatic increase in oxygen consumption and a resultant increase in carbon dioxide production. Epinephrine and inflammatory cytokines play a major role in the hypermetabolic response. Epinephrine increases the rate of glycogenolysis, gluconeogenesis (via conversion of amino acids and glycerol) and conversion of skeletal muscle glycogen to lactate. Epinephrine inhibits insulin release, increases glucagon release and increases lipolysis. Protein catabolism is markedly increased during the flow phase and a negative nitrogen balance ensues. Hepatic synthesis of the acute phase proteins, such as C-reactive protein, complement proteins, and fibrinogen, is increased. Acute phase proteins help regulate the inflammatory process, inhibit proteases, and modulate coagulation.
The Endothelial Response
The endothelium is responsible for controlling coagulation, regulating vascular tone, controlling vascular permeability, and regulating leukocyte adherence and migration. Tissue injury leads to disruption of the endothelium with subsequent activation of the arachidonic acid cascade. Hypoxia leads to an increase in intracellular calcium, and adhesion and activation of leukocytes and platelets due to hypoxia-induced expression of cellular adhesion molecules. Increased intracellular calcium may lead to leukocyte dysfunction.
During inflammatory processes the endothelium becomes predominantly procoagulant which if uncontrolled can lead to a disseminated intravascular coagulation. Endothelial injury causes release of tissue thromboplastin which activates the extrinsic coagulation system, and exposure of subendothelial collagen which activates the intrinsic coagulation system via Factor XII (Hageman factor). Activation of factor XII causes conversion of kininogen to bradykinin, which leads to increased vascular permeability, pain, vasodilation, margination of granulocytes, and additional injury to the endothelium. The complement cascade is triggered in response to activation of Factor XII and the presence of kinins. The reticuloendothelial system may be impaired by the presence of fibrin and glucocorticoids, which may help predispose to microthromboses. Trauma causes changes in the fibrinolytic system, which in combination with the loss of coagulation proteins, also contributes to coagulation abnormalities.
Trauma Triad of Death
The trauma 'triad of death' is acidosis, hypothermia and coagulopathy. The acidosis can have a respiratory component secondary to pulmonary contusions, pneumothorax, diaphragmatic hernia or pain from blunt or penetrating trauma to the chest wall. Metabolic acidosis develops secondary to poor tissue perfusion and the ensuing hypoxia. Below a pH of 7.2 enzyme systems in the body start to become affected. These enzyme systems drive everything from muscle contraction to coagulation. Hypothermia can develop secondary to environmental conditions, alterations in perfusion and from treatment with cold intravenous fluids. Hypothermia may lead to further complications by decreasing the metabolic rate, causing a decrease in sinoatrial node automaticity, an increase in ventricular irritability, a decrease in enzyme reactions, in increase in membrane permeability, and a failure of ion pumps. Mild hypothermia can be protective during shock but significant hypothermia is associated with higher morbidity and mortality. Coagulopathy results from loss of clotting factors, alterations in the coagulation cascade secondary to inflammatory mediators, acidemia and hypothermia as well as dilution from fluid therapy. All efforts should be made clinically to avoid this triad.
The goal of therapy should be directed towards improving the microcirculation through a combination of measures to improve hemodynamic and ventilatory homeostasis. Blood volume, blood pressure and urine output should be normalized; however despite normalization of vital signs it has been shown in severe hemorrhage that there is an ongoing oxygen debt. Because of the decoupling of the mitochondria therapeutic strategies are being developed to support mitochondrial function. A target of a mean arterial pressure (which means diastolic pressure must be measured) of at least 60 mm Hg has been suggested to ensure adequate central nervous system perfusion as well as renal perfusion. Ideally monitoring should include assessment of regional tissue beds, something which is generally still impractical. Lactates and base deficits will provide indicators of tissue perfusion but will rarely reflect what is occurring in all tissues. During initial resuscitation oxygen extraction should increase and central venous oxygen pressures will decrease. Ideally they should return to at least 40 mm Hg. Patients who are having trouble oxygenating or ventilating should be intubated and provided with positive pressure ventilation. Patients should be monitored to ensure perfusion goals are being realized but also to ensure the patient is not hypothermic, hemoglobin remains close to 30%, oncotic pressure is adequate, electrolytes are normal and the patient is not becoming coagulopathic.
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