STUDY - Technical - New Dacian's Medicine
The
Shock (2)
Translation Draft
So, we've reached septic shock. Disorder of cellular metabolism through the effects of inflammation mediators plays a leading role in the pathogenesis of septic shock and may be important in other forms of shock. These mediators include cytokines, such as tumor necrosis factor (TNF), interleukin (IL) 1, IL-2, interferon, eicosanids and platelet activation factor (PAF). TNF activates inflammatory cells, stimulates the release of other inflammatory cytokines, promotes the expression of adhesion molecules on both endothelial and neutrophil cells, activates coagulation pathways, decreases membrane potential, produces arteriolar vasodilation, increases microvascular permeability and can directly block some intracellular pathways, leading to cellular dysfunction.
IL-1 has similar effects and potentiates the effects of TNF. Interferon promotes the release of TNF and IL-1 and can act synergistically with these cytokines in achieving the cytotoxic effect. PAF also promotes the release of TNF and eicosanide and markedly increases microvascular permeability. Free radicals are reactive oxygen radicals that react with a variety of other molecules, inactivating proteins, damaging DNA and, most importantly, inducing lipid peroxidation in membranes.
Massive production of free radicals can occur after ischemia and the reperfusion that follows. In shock, cellular ischemia and intracellular calcium accumulation can activate intracellular protease and convert xanthindehydrogenase, which recycles ATP, to xanthinoxidase, which oxidizes purines with the formation of highly toxic superoxide radicals. When oxygen is reintroduced with bruschets, large amounts of superoxides can be produced and the cell's endogenous endogenous defense system can be overcome. Lipid peroxidation is a self-sustaining process that severely alters the integrity of the membrane.
Recent studies have suggested two forms of gene expression in response to stress: acute phase response and thermal shock response. Acute phase response to adverse stimuli is involved in maintaining systemic homeostasis (specific cell types express different genes). This response has as clinical correspondent the accumulation in plasma of proteins called generic acute phase reactants synthesized and secreted by the liver.
Thermal shock response is a genetic cellular response involved in maintaining systemic homeostasis (synthesized proteins act intracellularly and cannot be measured in the blood). Some proteins of this type function as "molecular carriers", which play a role in the grouping, stabilization and translocation of newly synthesized proteins.
Other "thermal shock" proteins appear to be involved in the genetic cellular death program, known as apoptosis, a physiological mechanism that normally removes aging cells. Although it has been shown that inducing these proteins makes cells more resistant to shock, new evidence suggests that their over-expression may be fateful in shock.
Inducing thermal shock response can cancel out both the acute phase and the expression of other important genes in synthetic function. The execution of this genetic cellular defense program by individual cells may not benefit the body as a whole. In addition, in addition to the cancellation of vital genetic expression programs, the induction of heat shock proteins can also initiate programmed cell death.
Let's see how to reach irreversible damage, understanding the transition from reversible cellular dysfunction to irreversible cellular damage being important for understanding shock pathogenesis. It is known that it occurs through self-amplification and self-maintenance of the inflammatory process. Typically, the activation of the inflammatory system induces inverse anti-inflammatory regulating mechanisms.
If the inflammatory stimulus is severe or prolonged enough, autocrine and paracrine responses can lead to the development of positive feedback circuits. Activation of endothelial cells usually leads to the expression of adhesion molecules and releases chemotactic and pro-inflammatory cytokines. In shock, these processes are excessive and uncontrolled.
Macrophages and adhering neutrophils, in turn, become hyperactive and release large amounts of mediators of inflammation. Similar self-maintenance mechanisms can be observed after lesions caused by free radicals, in which lipid peroxidation leads to the initiation of a self-oxidation cycle. Finally, injuries accumulated in a cell can reach a threshold at which self-destruction occurs.
How to get to organ dysfunction? Clinical manifestations of shock vary, as each organ is affected differently, depending on the severity of the infusion deficiency, the primary cause of the shock, and the already present dysfunctions of the organ. If respiratory failure persists and extensive cellular dysfunction occurs, multiorganic dysfunction results. Multiorganic insufficiency can be fatal, even without a very large number of dead cells, if cell dysfunction is severe enough to interfere with the functioning of the organ in a manner incompatible with life.
In the case of the heart, cardiac dysfunction is common in circulatory shock. In cardiogenic shock, this dysfunction usually occurs after heart attack or myocardial ischemia. Myocardial dysfunction, in turn, can exacerbate myocardial ischemia, setting up a vicious circle. Increased ventricular diastolic pressures that occur in heart failure reduce the pressure gradient for coronary infusion, and additional wall stress increases oxygen demand.
Tachycardia decreases the time available for diastolic filling, further compromising coronary blood flow. Ischemia also decreases diastolic compliance, further increasing ventricular diastolic pressures. In other forms of shock, especially in sepsis, ischemia is less important, with myocardial dysfunction associating with the release of myocardial depressants in circulation. Increased right ventricular hypertension and post-pregnancy may cause right heart failure after pulmonary embolism and may help limit cardiac output in sepsis. Low myocardial reactivity in catecholamines and diastolic dysfunction may also contribute to myocardial dysfunction in sepsis.
In terms of brain damage, most patients with circulatory impairment have mental disorders, generally manifested by confusion. Etiology is multifactorial, hypoperfusion, hypoxemia, acid-base abnormalities and electrolyte disorders being the main contributors. Brain self-regulation compensates to a point hypoperfusion, but when blood pressure is less than 60 mmHg, compensation begins to become insufficient and critical cerebral hypoperfusion leads to ischemic lesions.
In the lungs, pulmonary dysfunction occurs early in shock. Acute lung damage causes decreased compliance, disturbance of gas exchanges and blood shaming through unventilated areas. The clinical consequence of this lesion, severe hypoxemia with bilateral pulmonary infiltration and normal filling pressures, constitutes acute respiratory distress syndrome (ASD). Respiratory effort increases with increased oxygen needs of the respiratory muscles and the installation of tissue hypoperfusion.
Respiratory muscle fatigue and lung failure may occur, and assisted ventilation is required. Pathological markers at the onset of SDRA are aggregated by neutrophils and fibrin from pulmonary microvascularization. In evolution, an expansion of inflammation in the interstitial and alveoli occurs and the exudation of a protein liquid in the alveolar space. Fibrosis and scarring occur in the final stages.
In the kidneys, renal infusion is compromised in circulatory failure, in part due to preferential direction of blood flow to the heart and brain and less to the kidneys. The increase in the tone of the related arteriola initially compensates for the decrease in renal blood flow and maintains the glomerular infusion. When the compensating mechanism is overcome, reduced cortical blood flow can lead to acute tubular necrosis and renal failure. Associated aggressions such as nephrotoxic drugs, intravenous contrast substances or rhabdomyolysis may exacerbate renal injury in shock.
I've reached liver and gastrointestinal tract damage. Damage to the liver by hypoperfusion is frequently complicated in septic and traumatic shock by the activation of Kuppfer cells and the release of cytokines. Impairment of metabolic functions of the liver consists in the disorder of both synthesis and detoxification. Phagocytic purification in the hepatic reticuloendothelial system is also affected. Damage to the liver parenchyma is reflected by the increase in levels of transaminases, lacticdehydrogenase and bilirubin. Decrease in albumin levels and coagulation factors indicate slower synthesis capacity.
The marked increase in transaminases may be found in marked hypoxemia or hypotension ("shock liver") but these are transient and rapidly improve with reperfusion. Ischemic damage to the liver affects the center of the liver lobe (venous end) in particular, with a relative sparing of the portal end (arterial), this situation being illustrated morphopathologically by central congestion and centrotubular necrosis.
In septic shock, intrahepatic cholestasis may be present, with a marked increase in bilirubin and only a more modest increase in transaminases, these changes reflecting the dysfunction of the bile ducts due to bacterial toxins. Blood flow to the splahnic organs is compromised in circulatory shock because the blood is directed elsewhere. Intestinal ischemia occurs and the lesion can be further exacerbated by the subsequent release of free radicals during reperfusion due to resuscitation.
It has been hypothesized that ischemia/reperfusion lesion may compromise the integrity of the intestinal mucosa, leading to the translocation of bacterial toxins, although this has not been accurately demonstrated in patients. Splanhtic hypoperfusion can also cause stress ulcers, ilees and malabsorption, and occasionally alitiatic cholecystitis or pancreatitis may also occur.
I will complete this post with a few presentations about the last "important" impairment due to shock, that of the haematological system. Coagulation abnormalities are common in both septic and traumatic shock. Thrombocytopenia may occur by hemodilution associated with blood volemic overload.
Thrombocytopenia in sepsis is common, usually mediated immunologically and is frequently complicated by primary disease or medication. Activation of the clotting cascade in microvas can lead to disseminated intravascular coagulation, which causes thrombocytopenia, microangiopathic hemolytic anaemia, decreased fibrinogen and the appearance of fibrin degradation products in circulation. Microvascular consumption of clotting factors leads to a decrease in their level, with consecutive hemorrhage.
In the next post, the one on May 30, we will talk about the pathogenesis of specific forms of shock.
So, we've reached septic shock. Disorder of cellular metabolism through the effects of inflammation mediators plays a leading role in the pathogenesis of septic shock and may be important in other forms of shock. These mediators include cytokines, such as tumor necrosis factor (TNF), interleukin (IL) 1, IL-2, interferon, eicosanids and platelet activation factor (PAF). TNF activates inflammatory cells, stimulates the release of other inflammatory cytokines, promotes the expression of adhesion molecules on both endothelial and neutrophil cells, activates coagulation pathways, decreases membrane potential, produces arteriolar vasodilation, increases microvascular permeability and can directly block some intracellular pathways, leading to cellular dysfunction.
IL-1 has similar effects and potentiates the effects of TNF. Interferon promotes the release of TNF and IL-1 and can act synergistically with these cytokines in achieving the cytotoxic effect. PAF also promotes the release of TNF and eicosanide and markedly increases microvascular permeability. Free radicals are reactive oxygen radicals that react with a variety of other molecules, inactivating proteins, damaging DNA and, most importantly, inducing lipid peroxidation in membranes.
Massive production of free radicals can occur after ischemia and the reperfusion that follows. In shock, cellular ischemia and intracellular calcium accumulation can activate intracellular protease and convert xanthindehydrogenase, which recycles ATP, to xanthinoxidase, which oxidizes purines with the formation of highly toxic superoxide radicals. When oxygen is reintroduced with bruschets, large amounts of superoxides can be produced and the cell's endogenous endogenous defense system can be overcome. Lipid peroxidation is a self-sustaining process that severely alters the integrity of the membrane.
Recent studies have suggested two forms of gene expression in response to stress: acute phase response and thermal shock response. Acute phase response to adverse stimuli is involved in maintaining systemic homeostasis (specific cell types express different genes). This response has as clinical correspondent the accumulation in plasma of proteins called generic acute phase reactants synthesized and secreted by the liver.
Thermal shock response is a genetic cellular response involved in maintaining systemic homeostasis (synthesized proteins act intracellularly and cannot be measured in the blood). Some proteins of this type function as "molecular carriers", which play a role in the grouping, stabilization and translocation of newly synthesized proteins.
Other "thermal shock" proteins appear to be involved in the genetic cellular death program, known as apoptosis, a physiological mechanism that normally removes aging cells. Although it has been shown that inducing these proteins makes cells more resistant to shock, new evidence suggests that their over-expression may be fateful in shock.
Inducing thermal shock response can cancel out both the acute phase and the expression of other important genes in synthetic function. The execution of this genetic cellular defense program by individual cells may not benefit the body as a whole. In addition, in addition to the cancellation of vital genetic expression programs, the induction of heat shock proteins can also initiate programmed cell death.
Let's see how to reach irreversible damage, understanding the transition from reversible cellular dysfunction to irreversible cellular damage being important for understanding shock pathogenesis. It is known that it occurs through self-amplification and self-maintenance of the inflammatory process. Typically, the activation of the inflammatory system induces inverse anti-inflammatory regulating mechanisms.
If the inflammatory stimulus is severe or prolonged enough, autocrine and paracrine responses can lead to the development of positive feedback circuits. Activation of endothelial cells usually leads to the expression of adhesion molecules and releases chemotactic and pro-inflammatory cytokines. In shock, these processes are excessive and uncontrolled.
Macrophages and adhering neutrophils, in turn, become hyperactive and release large amounts of mediators of inflammation. Similar self-maintenance mechanisms can be observed after lesions caused by free radicals, in which lipid peroxidation leads to the initiation of a self-oxidation cycle. Finally, injuries accumulated in a cell can reach a threshold at which self-destruction occurs.
How to get to organ dysfunction? Clinical manifestations of shock vary, as each organ is affected differently, depending on the severity of the infusion deficiency, the primary cause of the shock, and the already present dysfunctions of the organ. If respiratory failure persists and extensive cellular dysfunction occurs, multiorganic dysfunction results. Multiorganic insufficiency can be fatal, even without a very large number of dead cells, if cell dysfunction is severe enough to interfere with the functioning of the organ in a manner incompatible with life.
In the case of the heart, cardiac dysfunction is common in circulatory shock. In cardiogenic shock, this dysfunction usually occurs after heart attack or myocardial ischemia. Myocardial dysfunction, in turn, can exacerbate myocardial ischemia, setting up a vicious circle. Increased ventricular diastolic pressures that occur in heart failure reduce the pressure gradient for coronary infusion, and additional wall stress increases oxygen demand.
Tachycardia decreases the time available for diastolic filling, further compromising coronary blood flow. Ischemia also decreases diastolic compliance, further increasing ventricular diastolic pressures. In other forms of shock, especially in sepsis, ischemia is less important, with myocardial dysfunction associating with the release of myocardial depressants in circulation. Increased right ventricular hypertension and post-pregnancy may cause right heart failure after pulmonary embolism and may help limit cardiac output in sepsis. Low myocardial reactivity in catecholamines and diastolic dysfunction may also contribute to myocardial dysfunction in sepsis.
In terms of brain damage, most patients with circulatory impairment have mental disorders, generally manifested by confusion. Etiology is multifactorial, hypoperfusion, hypoxemia, acid-base abnormalities and electrolyte disorders being the main contributors. Brain self-regulation compensates to a point hypoperfusion, but when blood pressure is less than 60 mmHg, compensation begins to become insufficient and critical cerebral hypoperfusion leads to ischemic lesions.
In the lungs, pulmonary dysfunction occurs early in shock. Acute lung damage causes decreased compliance, disturbance of gas exchanges and blood shaming through unventilated areas. The clinical consequence of this lesion, severe hypoxemia with bilateral pulmonary infiltration and normal filling pressures, constitutes acute respiratory distress syndrome (ASD). Respiratory effort increases with increased oxygen needs of the respiratory muscles and the installation of tissue hypoperfusion.
Respiratory muscle fatigue and lung failure may occur, and assisted ventilation is required. Pathological markers at the onset of SDRA are aggregated by neutrophils and fibrin from pulmonary microvascularization. In evolution, an expansion of inflammation in the interstitial and alveoli occurs and the exudation of a protein liquid in the alveolar space. Fibrosis and scarring occur in the final stages.
In the kidneys, renal infusion is compromised in circulatory failure, in part due to preferential direction of blood flow to the heart and brain and less to the kidneys. The increase in the tone of the related arteriola initially compensates for the decrease in renal blood flow and maintains the glomerular infusion. When the compensating mechanism is overcome, reduced cortical blood flow can lead to acute tubular necrosis and renal failure. Associated aggressions such as nephrotoxic drugs, intravenous contrast substances or rhabdomyolysis may exacerbate renal injury in shock.
I've reached liver and gastrointestinal tract damage. Damage to the liver by hypoperfusion is frequently complicated in septic and traumatic shock by the activation of Kuppfer cells and the release of cytokines. Impairment of metabolic functions of the liver consists in the disorder of both synthesis and detoxification. Phagocytic purification in the hepatic reticuloendothelial system is also affected. Damage to the liver parenchyma is reflected by the increase in levels of transaminases, lacticdehydrogenase and bilirubin. Decrease in albumin levels and coagulation factors indicate slower synthesis capacity.
The marked increase in transaminases may be found in marked hypoxemia or hypotension ("shock liver") but these are transient and rapidly improve with reperfusion. Ischemic damage to the liver affects the center of the liver lobe (venous end) in particular, with a relative sparing of the portal end (arterial), this situation being illustrated morphopathologically by central congestion and centrotubular necrosis.
In septic shock, intrahepatic cholestasis may be present, with a marked increase in bilirubin and only a more modest increase in transaminases, these changes reflecting the dysfunction of the bile ducts due to bacterial toxins. Blood flow to the splahnic organs is compromised in circulatory shock because the blood is directed elsewhere. Intestinal ischemia occurs and the lesion can be further exacerbated by the subsequent release of free radicals during reperfusion due to resuscitation.
It has been hypothesized that ischemia/reperfusion lesion may compromise the integrity of the intestinal mucosa, leading to the translocation of bacterial toxins, although this has not been accurately demonstrated in patients. Splanhtic hypoperfusion can also cause stress ulcers, ilees and malabsorption, and occasionally alitiatic cholecystitis or pancreatitis may also occur.
I will complete this post with a few presentations about the last "important" impairment due to shock, that of the haematological system. Coagulation abnormalities are common in both septic and traumatic shock. Thrombocytopenia may occur by hemodilution associated with blood volemic overload.
Thrombocytopenia in sepsis is common, usually mediated immunologically and is frequently complicated by primary disease or medication. Activation of the clotting cascade in microvas can lead to disseminated intravascular coagulation, which causes thrombocytopenia, microangiopathic hemolytic anaemia, decreased fibrinogen and the appearance of fibrin degradation products in circulation. Microvascular consumption of clotting factors leads to a decrease in their level, with consecutive hemorrhage.
In the next post, the one on May 30, we will talk about the pathogenesis of specific forms of shock.
Let us have only good
understanding, love and gratitude!
Dorin, Merticaru