**2. Physiopathology and metabolic alterations**

Early theories suggesting that hemorrhagic shock resulted from nervous system dysfunction or from a toxin released from ischemic tissue have been disproved completely. The current view for the underlying mechanism of hemorrhagic shock states that the blood loss leads to an insufficient oxygen delivery to the tissues and consequently activates several homeostatic mechanisms in order to maintain vital organ perfusion [2]. The metabolic changes observed in hemorrhagic shock sustain energy homeostasis to ensure cell vitality [16]. When looking at the cellular and

**43**

*Hemorrhagic Shock*

*DOI: http://dx.doi.org/10.5772/intechopen.82358*

thrombus in the bleeding area [27].

tissue level and if whole organism is taken into consideration, it is observed that the complexity of these events is clarified via the physical trauma-related tissue damage and by the relative effects of hypoperfusion due to hemorrhage. Sufficient oxygen to meet the metabolic requirements of the tissues cannot be supplied due to hemorrhagic shock. Cells switch from aerobic to anaerobic respiration due to hypoperfusion. Lactic acid, inorganic phosphates, and oxygen radicals begin to accumulate as a result of the mounting oxygen debt [17]. In 1877, Claude Bernard discovered that hemorrhage stimulated liver to provide glucose from the lasting glycogen stores [18]. The Second World War enforced the investigators to better understand the pathophysiology of shock. Cuthbertson described the metabolic alterations in two phases: "ebb" phase and "flow" phase. The former representing the reduction in the requirement for both oxygen and temperature followed by the latter is characterized by increase in energy and temperature requirement with consequent elevation of body temperature [19]. With fatal injuries or blood loss, a stage called "necrobiosis" occurs prior to death as defined by Stoner, where the oxygen consumption is reduced and the body temperature decreases [20–22]. Hypoxia due to shock leads to reduction in energy consumption and leads to a hypermetabolic state, where neurohumoral homeostasis increases glucose uptake to supply muscles. If shock persists, glycogen stores are depleted, and glucose is supplied by gluconeogenesis stimulated by hormones. If this process fails, the hyperglycemia turns into hypoglycemia. Pearce and Drucker suggest that glucose infusion during hemorrhagic shock is the cause for extension of life span, since homeostasis uses glucose as an energy substrate for its defense mechanisms [23]. Gann and Foster provided an alternative explanation by defining nonmetabolic role of glucose that is a critical factor. The glucose level is elevated rapidly as a result of hormonal response to injury and this causes the intracellular fluids to move to facilitate restoration of blood volume [24]. The release of damage-associated molecular patterns (DAMPs or alarmins) containing mitochondrial DNA and formyl peptides triggers systemic inflammatory response (SIRS) [25]. Eventually, the cellular homeostasis collapses by depletion of ATP resources, and membrane rupture results in necrosis, apoptosis or necroptosis and cell death [2]. At the tissue level, hypovolemia and vasoconstriction cause hypoperfusion and end organ damage in kidneys, intestines, and skeletal muscles, leading to a multiorgan failure. In the body, pulselessness occurs after a blood loss due to a severe hemorrhage and causes hypoperfusion to the brain and the myocardium, resulting in consequent cerebral anoxia and fatal arrhythmias developing in minutes [26]. Hemorrhage also causes substantial alterations in the vascular endothelium all over the body. Blood and endothelium act together for forming

Hemorrhage and shock continue, and both adaptive and maladaptive changes begin to occur in the blood. The coagulation cascade and platelets are activated to form a hemostatic plug in the hemorrhage source [28]. Probably to prevent the development of microvascular thrombosis, fibrinolytic activity increases away from hemorrhage site [29]. The mounting oxygen debt and the elevated catecholamine levels cause a sort of endotheliopathy due to the systemic degradation of the endothelial glycocalyx barrier. Autoheparinization due to increased plasmin activation and glycocalyx degradation result in hyperfibrinolysis and diffuse coagulopathy [27, 29, 30]. A hypercoagulable phenotype is present in almost half of the trauma patients [30]. Reduced platelet activity and margination contribute to hemorrhage and decreased platelet counts, increasing the mortality [31, 32]. Excessive fluid crystalloid resuscitations reduce the coagulation factor levels and decrease oxygen transfer capacity. Cold infusions increase hemorrhagic heat loss, cause energy store depletion, and reduce enzyme functions in the coagulation cascade [33]. Acidosis caused by hypoperfusion becomes more intense due to the excessive administration

#### *Hemorrhagic Shock DOI: http://dx.doi.org/10.5772/intechopen.82358*

*Clinical Management of Shock - The Science and Art of Physiological Restoration*

the jarring (shock and agitation)" in his article in 1743 [7].

ment has become the principal therapy for circulatory shock.

definitive care at a trauma center [15].

**2. Physiopathology and metabolic alterations**

**1.1 Brief history**

and so tissues and organs in case where the control cannot be assumed. Crystalloid solutions do not have superiority over each other, and there is not any type of treatment which is absolutely recommended apart from that they are kept limited.

As proposed by the historians, the first written definition of shock is made by Celsus (AD 20) after a penetrating heart injury as "The pulse fades away, the color is extremely pallid, cold and malodorous sweats break out the body as if the body has been wetted by dew, the extremities become cold and death quickly follows" [6]. LeDran, a military surgeon, derived a word from shock as "The bullet thrown from the gunpowder acquires such rapid force that the whole animal participates in

The emergence of biochemistry at the beginning of the twentieth century started serious scientific studies on the pathogenesis of circulatory shock. A number of physiologists agreed on the existence of a toxin released in response to injury, and it was identified to be histamine by Walter Cannon in the US and by Sir Henry Dale in England [8, 9]. However, neither histamine nor other identified vasoactive amines could successively mimic the picture of shock. In the late 1920s and 1930s, Blalock suggested an alternative hypothesis for shock and defined it as direct fluid loss from blood circulation culminating in peripheral vascular failure, a persistence of poor peripheral perfusion. After the proposal of this hypothesis, fluid replace-

Compilation of Artz and Fitts on that blood and fluids with salt are needed for closing the volume gap occurring after hemorrhage was not commonly appreciated [10]. This concept was supported by highlighting that saline solution should be given in ongoing hemorrhage later [11]. Kinney and Wells criticized the current immediate therapeutic attention to the many problems associated with trauma without regard to the patient's ventilation. Their article established a new objective: therapy in all injured patients should look beyond blood pressure so as to ensure provision and maintenance of effective gas exchange of tissues [12]. While Lansing et al. defended the need for vasoactive medicines for perfusion of vital organs, Nickerson and Gourzis defended the disadvantages of vasoconstriction [13, 14]. The term "golden hour" is widely attributed to R. Adams Cowley, founder of Baltimore's renowned Shock Trauma Institute, who in a 1975 article stated, "the first hour after injury will largely determine a critically injured person's chances for survival"—this was in an era characterized by a lack of an organized trauma system and inadequate prehospital care. The validity of this concept remains controversial. An analogous concept, the "platinum 10 minutes" places a time constraint on the prehospital care of seriously injured patients: no patient should have more than 10 min of scene-time stabilization by the prehospital team prior to transport to

Early theories suggesting that hemorrhagic shock resulted from nervous system

dysfunction or from a toxin released from ischemic tissue have been disproved completely. The current view for the underlying mechanism of hemorrhagic shock states that the blood loss leads to an insufficient oxygen delivery to the tissues and consequently activates several homeostatic mechanisms in order to maintain vital organ perfusion [2]. The metabolic changes observed in hemorrhagic shock sustain energy homeostasis to ensure cell vitality [16]. When looking at the cellular and

**42**

tissue level and if whole organism is taken into consideration, it is observed that the complexity of these events is clarified via the physical trauma-related tissue damage and by the relative effects of hypoperfusion due to hemorrhage. Sufficient oxygen to meet the metabolic requirements of the tissues cannot be supplied due to hemorrhagic shock. Cells switch from aerobic to anaerobic respiration due to hypoperfusion. Lactic acid, inorganic phosphates, and oxygen radicals begin to accumulate as a result of the mounting oxygen debt [17]. In 1877, Claude Bernard discovered that hemorrhage stimulated liver to provide glucose from the lasting glycogen stores [18]. The Second World War enforced the investigators to better understand the pathophysiology of shock. Cuthbertson described the metabolic alterations in two phases: "ebb" phase and "flow" phase. The former representing the reduction in the requirement for both oxygen and temperature followed by the latter is characterized by increase in energy and temperature requirement with consequent elevation of body temperature [19]. With fatal injuries or blood loss, a stage called "necrobiosis" occurs prior to death as defined by Stoner, where the oxygen consumption is reduced and the body temperature decreases [20–22]. Hypoxia due to shock leads to reduction in energy consumption and leads to a hypermetabolic state, where neurohumoral homeostasis increases glucose uptake to supply muscles. If shock persists, glycogen stores are depleted, and glucose is supplied by gluconeogenesis stimulated by hormones. If this process fails, the hyperglycemia turns into hypoglycemia. Pearce and Drucker suggest that glucose infusion during hemorrhagic shock is the cause for extension of life span, since homeostasis uses glucose as an energy substrate for its defense mechanisms [23]. Gann and Foster provided an alternative explanation by defining nonmetabolic role of glucose that is a critical factor. The glucose level is elevated rapidly as a result of hormonal response to injury and this causes the intracellular fluids to move to facilitate restoration of blood volume [24].

The release of damage-associated molecular patterns (DAMPs or alarmins) containing mitochondrial DNA and formyl peptides triggers systemic inflammatory response (SIRS) [25]. Eventually, the cellular homeostasis collapses by depletion of ATP resources, and membrane rupture results in necrosis, apoptosis or necroptosis and cell death [2]. At the tissue level, hypovolemia and vasoconstriction cause hypoperfusion and end organ damage in kidneys, intestines, and skeletal muscles, leading to a multiorgan failure. In the body, pulselessness occurs after a blood loss due to a severe hemorrhage and causes hypoperfusion to the brain and the myocardium, resulting in consequent cerebral anoxia and fatal arrhythmias developing in minutes [26]. Hemorrhage also causes substantial alterations in the vascular endothelium all over the body. Blood and endothelium act together for forming thrombus in the bleeding area [27].

Hemorrhage and shock continue, and both adaptive and maladaptive changes begin to occur in the blood. The coagulation cascade and platelets are activated to form a hemostatic plug in the hemorrhage source [28]. Probably to prevent the development of microvascular thrombosis, fibrinolytic activity increases away from hemorrhage site [29]. The mounting oxygen debt and the elevated catecholamine levels cause a sort of endotheliopathy due to the systemic degradation of the endothelial glycocalyx barrier. Autoheparinization due to increased plasmin activation and glycocalyx degradation result in hyperfibrinolysis and diffuse coagulopathy [27, 29, 30]. A hypercoagulable phenotype is present in almost half of the trauma patients [30]. Reduced platelet activity and margination contribute to hemorrhage and decreased platelet counts, increasing the mortality [31, 32]. Excessive fluid crystalloid resuscitations reduce the coagulation factor levels and decrease oxygen transfer capacity. Cold infusions increase hemorrhagic heat loss, cause energy store depletion, and reduce enzyme functions in the coagulation cascade [33]. Acidosis caused by hypoperfusion becomes more intense due to the excessive administration

of the acidic crystalloid solutions. This eventually impairs the functioning of the coagulation factors and results in a vicious cycle, where coagulopathy, hypothermia, and acidosis occur [34].

The valid opinion is that the first response to a serious injury and shock is a robust and innate SIRS followed by a relative immunosuppression state called as compensatory anti-inflammatory response syndrome (CARS), bringing along a period of recovery. If a complication occurs, the cycle will repeat with a newly formed SIRS followed by CARS. While the innate proinflammatory and antiinflammatory immunity genes are upregulated after the injury, the adaptive immunity genes are downregulated simultaneously. During the recovery period of patients without complications, these responses rapidly decrease to baseline. On the other hand, in patients with complications, the reduction of the excessive response to normal levels occurs more slowly [35].

#### **2.1 Volume restoration**

For restoration of impaired energy metabolism, reduced intravascular volume should be replaced immediately. Baue et al. have found out that both colloidal and erythrocyte free fluids meet the requirements for the oxidative metabolism to take place; however, the rapid dilution of hematocrit increases the cardiac output, cardiac workload, and the peripheral circulation [36]. The intravascular circulating volume is more effective in maintaining the energy metabolism compared to the circulating erythrocyte mass [37]. An acute loss in the circulating volume of less than 25% requires an urgent attention since the hematocrit level can be reduced more than 50% before a critical shortage of red blood cells becomes evident. The restoration of the plasma volume after a long duration of hemorrhage has been attributed to the osmotic activity in the capillary bed, induced by the hyperglycemia occurring as a result of hypovolemic shock; however, this has not been proven to be true because a transcapillary osmotic gradient does not develop. Monitoring the cardiac output is a reliable method to evaluate the reduction in the blood flow and to observe the effects of the oxidative metabolism and catecholamine response [38]. Consistent with the observations of Blalock, at the beginning of the shock, blood pressure is an insufficient parameter to demonstrate the status of the circulation. Similarly, no correlations have been found out among the blood glucose levels, hemodynamic changes, and the levels of plasma insulin during hypovolemia [16].

Maintaining the blood volume after the hemorrhage occurs in two phases. The first is initiated by a fall in the capillary of hydrostatic pressure, stopping until when the sum of the capillary hydrostatic pressure and the oncotic pressures equals the sum of interstitial hydrostatic and oncotic pressures. In the second phase, albumin is moved to the capillaries in response to the increase in interstitial pressure. This increase of osmotic pressure in the interstitial space is maintained by the osmotic gradient in the cell membrane caused by the presence of extracellular glucose. While glucose is produced due to the effects of counter-regulatory hormones including cortisol, glucagon, catecholamines, vasopressin, and angiotensin, insulin secretion is inhibited concomitantly. Blockage of any of these hormones will impair the restoration of blood volume. Cortisol is the most critical hormone because the absence of it, the restoration of the blood volume will fail completely [39].

In order for blood volume to be completely restored, all cardiovascular variables, including the cardiac output, are required to be reestablished [40, 41]. In hemorrhage up to a blood loss of 25% of the whole volume, reestablishment of the parameters takes approximately 48 hours. If the hemorrhage-associated blood loss exceeds 26% or more of the blood volume, the restoration of the blood volume will fail [42]. Na/K ATPase pump is essential for the sustainability of the cellular transmembrane potential;

**45**

**Figure 1.**

*Physiopathologic alterations in hemorrhage and hemorrhagic shock.*

*Hemorrhagic Shock*

erythrocytes as well [43, 44].

*DOI: http://dx.doi.org/10.5772/intechopen.82358*

however, the activity of this pump is inhibited in all kinds of circulatory shock. This inhibition is considered to be associated with the impairment in the oxygen delivery. The disturbances in the Na/K ATPase activity cannot only be due to the impairments in the oxygen delivery since erythrocytes do not consume oxygen. The findings of Shire show that intravascular volume loss more than 26% indicates the same threshold value as that of an experimental reduction in the transmembrane potential. This phenomenon is initially observed in the muscle cells followed by the observation in the

## *Hemorrhagic Shock DOI: http://dx.doi.org/10.5772/intechopen.82358*

*Clinical Management of Shock - The Science and Art of Physiological Restoration*

and acidosis occur [34].

**2.1 Volume restoration**

to normal levels occurs more slowly [35].

of the acidic crystalloid solutions. This eventually impairs the functioning of the coagulation factors and results in a vicious cycle, where coagulopathy, hypothermia,

The valid opinion is that the first response to a serious injury and shock is a robust and innate SIRS followed by a relative immunosuppression state called as compensatory anti-inflammatory response syndrome (CARS), bringing along a period of recovery. If a complication occurs, the cycle will repeat with a newly formed SIRS followed by CARS. While the innate proinflammatory and antiinflammatory immunity genes are upregulated after the injury, the adaptive immunity genes are downregulated simultaneously. During the recovery period of patients without complications, these responses rapidly decrease to baseline. On the other hand, in patients with complications, the reduction of the excessive response

For restoration of impaired energy metabolism, reduced intravascular volume should be replaced immediately. Baue et al. have found out that both colloidal and erythrocyte free fluids meet the requirements for the oxidative metabolism to take place; however, the rapid dilution of hematocrit increases the cardiac output, cardiac workload, and the peripheral circulation [36]. The intravascular circulating volume is more effective in maintaining the energy metabolism compared to the circulating erythrocyte mass [37]. An acute loss in the circulating volume of less than 25% requires an urgent attention since the hematocrit level can be reduced more than 50% before a critical shortage of red blood cells becomes evident. The restoration of the plasma volume after a long duration of hemorrhage has been attributed to the osmotic activity in the capillary bed, induced by the hyperglycemia occurring as a result of hypovolemic shock; however, this has not been proven to be true because a transcapillary osmotic gradient does not develop. Monitoring the cardiac output is a reliable method to evaluate the reduction in the blood flow and to observe the effects of the oxidative metabolism and catecholamine response [38]. Consistent with the observations of Blalock, at the beginning of the shock, blood pressure is an insufficient parameter to demonstrate the status of the circulation. Similarly, no correlations have been found out among the blood glucose levels, hemodynamic changes, and the levels of plasma insulin during hypovolemia [16]. Maintaining the blood volume after the hemorrhage occurs in two phases. The first is initiated by a fall in the capillary of hydrostatic pressure, stopping until when the sum of the capillary hydrostatic pressure and the oncotic pressures equals the sum of interstitial hydrostatic and oncotic pressures. In the second phase, albumin is moved to the capillaries in response to the increase in interstitial pressure. This increase of osmotic pressure in the interstitial space is maintained by the osmotic gradient in the cell membrane caused by the presence of extracellular glucose. While glucose is produced due to the effects of counter-regulatory hormones including cortisol, glucagon, catecholamines, vasopressin, and angiotensin, insulin secretion is inhibited concomitantly. Blockage of any of these hormones will impair the restoration of blood volume. Cortisol is the most critical hormone because the

absence of it, the restoration of the blood volume will fail completely [39].

In order for blood volume to be completely restored, all cardiovascular variables, including the cardiac output, are required to be reestablished [40, 41]. In hemorrhage up to a blood loss of 25% of the whole volume, reestablishment of the parameters takes approximately 48 hours. If the hemorrhage-associated blood loss exceeds 26% or more of the blood volume, the restoration of the blood volume will fail [42]. Na/K ATPase pump is essential for the sustainability of the cellular transmembrane potential;

**44**

however, the activity of this pump is inhibited in all kinds of circulatory shock. This inhibition is considered to be associated with the impairment in the oxygen delivery. The disturbances in the Na/K ATPase activity cannot only be due to the impairments in the oxygen delivery since erythrocytes do not consume oxygen. The findings of Shire show that intravascular volume loss more than 26% indicates the same threshold value as that of an experimental reduction in the transmembrane potential. This phenomenon is initially observed in the muscle cells followed by the observation in the erythrocytes as well [43, 44].

Evans et al. have reported a protein, which occurs in the first 20 minutes of serious hemorrhage in the rats, depolarizing several cells in a number of species [45]. Boulanger et al. have confirmed this finding in dogs with serious hemorrhage [46]. Jones et al. noted that this substance reduced both the contractility and velocity in the isolated and perfused rat hearts, reporting that this depolarizing protein was potentially effective in the development of cardiogenic shock [47]. This led to the conclusion that this hypothetical protein should be the similar underlying cause for three types of circulatory shock.

The experiments testing this hypothesis and looking for the significant consequences of cell depolarization isolated adenosine as the stimulating factor [48]. It was demonstrated that adenosine enhanced the ATPase activity and provided survival for hours during the experimental hemorrhagic shock in rats. Following these results, the stimulation of the Na/K ATPase pump showed the significance of inhibition in shock states. The inhibition of the pump should have a critical effect on mortality [49] (**Figure 1**).
