Generally cytokines help to notify that an enemy pathogen has entered our body; however, when they are released in larger quantities they become destructive and create an over-reactive response. The effects of spreading inflammatory reaction include endothelial damage, organ damage, adult respiratory distress syndrome ARDS , progression to shock, and progression to death.
The endothelium is involved in the control of vascular tone, platelet reactivity, coagulation, and permeability. The transition from a normal to a dysfunctional endothelium is associated with abnormal vasomotor activity, the development of a pro-coagulant surface, and an acceleration of the inflammation process Bacon et al.
An early indicator of sepsis is damage to these vascular endothelial cells and can manifest in hypotension. A normal inflammatory reaction activates local endothelial cells but it also damages those same cells. Sepsis multiplies this effect by activating and damaging endothelial cells in patches throughout the entire vascular system. Damage to the vascular endothelium causes edema and the collection of neutrophils and macrophages.
In damaged regions, gas exchange is reduced, nutrients cannot diffuse into the tissues, and waste products cannot diffuse out. An organ with significant damage to its vascular endothelium ends up poorly perfused and ischemic. Such an organ will function poorly organ dysfunction or it will fail altogether. As sepsis continues, it causes increasing organ dysfunction and then organ failure, and the risk of the patient dying doubles for each organ that fails Shapiro et al.
The lungs are usually an early casualty in sepsis, regardless of the location of the initial infection. The surface area of the vascular endothelium of the lungs is large, and when a septic reaction begins disrupting endothelial areas in the body the lungs are likely to suffer significant damage.
The surface area of one lung has been said to be the size of a tennis court! This can help you visualize the potential surface area for gas exchange but also potential tissue damage. Regions of the lung with damaged endothelia become filled with neutrophils and macrophages, as if the dead soldiers of a lost battle spread across a battlefield. Interstitial spaces develop edema, fibrin is deposited, and surfactant is reduced.
These regions of the lung become heavy and poorly compliant and local gas exchange is minimal. To make matters worse, the phenomenon of hypoxic pulmonary vasoconstriction HPV is damaged in sepsis. As a protective mechanisms, your amazing lungs have the ability to close off circulation to any damaged areas to conserve energy. HPV is a protective mechanism that normally redirects arterial blood away from any nonfunctioning parts of the lung to better ventilated areas Wang et al.
In sepsis, however, circulating inflammatory molecules reduce the ability of lung arterioles to constrict. Increasing lung dysfunction eventually leads to lung failure. In sepsis, lung failure takes the form of acute respiratory distress syndrome, or ARDS. Acute respiratory distress syndrome is sudden-onset pulmonary edema caused by endothelial injury in the lungs. Other causes, such as cardiac failure or pneumonia, can produce pulmonary edema, but in ARDS the edema occurs as a direct result of lung injury.
During ARDS, leaky pulmonary capillaries allow alveoli to be flooded, and the lungs get heavy and are poorly compliant. Chest films of ARDS patients show diffuse or patchy infiltrates bilaterally, as if a white out in a snow storm.
Gas exchange is reduced, and the patient becomes dyspneic and hypoxemic. One characteristic of hypoxemia in ARDS is a low arterial oxygen level that remains low despite oxygen supplementation. Management of ARDS includes mechanical ventilation, treatment of the cause of the lung injury, and supportive care. A : She had a smoking history that had already damaged endothelial tissue of the lungs. The surface area of her lungs was less effective due to smoking.
ARDS comes on quickly; it can appear in minutes to hours after the onset of sepsis. The condition presents as the sudden appearance of severe hypoxemia. The lungs become fluid-filled and poorly compliant, making breathing more difficult. A chest x-ray will show new bilateral diffuse or pulmonary infiltrates, and mechanical ventilation is usually required Jui, The most frequent etiology is pneumonia, followed by nonpulmonary infections.
There is no specific preventive treatment against the development of ARDS in patients with sepsis. Novel therapies are being studied, but no promising results have been reported. It seems that early detection of patients with sepsis who are at risk of developing ARDS is one way to achieve better results in the earliest phase. Indeed, one of the most important preventive strategies is to ensure adequate management of sepsis, including source control and early appropriate antibiotic therapy de Haro, In a patient without pre-existing cardiac problems, the heart can generally endure a bout of sepsis.
Sepsis causes leaky capillaries, which reduces blood volume and lowers blood pressure. At first, the vascular system responds with arterial constriction and increased vascular tone. This helps the heart to maintain a normal cardiac output.
As the sepsis continues however, the heart muscle begins to weaken due to the depressant effect of some of the circulating inflammatory molecules; however, the weakened ventricles also stretch, so the dilated ventricles pump extra blood with each stroke.
In this way, the cardiac output blood volume pumped per minute can remain fairly constant or even increase during a bout of sepsis. In a patient with existing cardiac problems, however, the heart is not as able to endure this stress, often causing complete heart failure. Like the lung, kidney function is entirely dependent on maintaining a significant area of intact vascular endothelium.
When the septic reaction invades the kidneys, neutrophils and macrophages begin to fill the interstitial tissue and the endothelial cells of the blood vessels are activated and damaged. At the same time, the kidneys, like all body tissues, become underperfused and hypoxic. At first, kidney dysfunction appears as a reduced glomerular filtration rate and an increase in serum creatinine levels. If the sepsis continues, acute tubular necrosis develops, which can eventually lead to acute renal failure Neviere, a.
The spreading hypoperfusion of sepsis limits the oxygen supply to the intestines. Without oxygen, anaerobic metabolism is activated releasing ketones and lactate, which causes a drop in pH inside the gut. Hypoxia and acidosis stress the epithelium that lines the gastrointestinal tract, and its natural barrier functions including protection against gut microbes are weakened.
Bacteria and toxic molecules from the gut lumen slip through the gut wall and into the bloodstream and the lymphatics spreading throughout the rest of the body. This is why the normal flora, which once was helpful to the body, can become the enemy. Sepsis typically causes small painless erosions in the mucosa especially in the upper GI tract , resulting in a continual seepage of blood. In severe sepsis or septic shock, the hypoperfusion can also immobilize the intestines, which then develop paralytic ileus Neviere, a.
What nutrition guidelines are important for the sepsis patient in ICU while controlling blood glucose levels? What protocols does your facility use? One of the main functions of the liver is clearance of infectious agents and their products, but sepsis can induce liver damage.
Just as sepsis destroys the endothelial cells of all organs, sepsis damages hepatocytes and the hypotension through the body can disrupt blood flow to the liver itself, creating hypoxia and cell death. The sepsis-induced liver dysfunction leads to a spillover of bacteria, bacterial toxins, and debris into the circulation.
Elevated liver enzymes and coagulation defects may occur. A decreased ability to excrete toxins such as ammonia can lead to encephalopathy Nesseler et al. In sepsis with so many chemicals and molecules of inflammation in the bloodstream, the brain can become toxic.
Sepsis often causes acute brain dysfunction, characterized by fluctuating mental status changes, inattention, and disorganized thinking. The effects on the brain are caused by both inflammatory and non-inflammatory processes, which may induce significant alterations in vulnerable areas of the brain Sonneville, The problems begin when circulating inflammatory molecules disrupt the endothelium of the blood vessels along the blood—brain barrier BBB.
The leaky BBB lets inflammatory molecules, along with infiltrating white cells, into the neural tissue.
Subsequently, edema and collections of cells around arterioles hinder the entry of oxygen and nutrients and the exit of metabolic wastes. In this situation, neurons shut down and cerebral functions slow. Brain dysfunction during sepsis is frequently complicated with other factors from previous conditions including withdrawal syndrome, drug overdoses, and severe metabolic disturbances.
Severe sepsis occurs when organ dysfunction progresses to organ failure. If arteries fail to constrict, septic shock occurs. In septic shock, episodes of hypotension cannot be reversed by giving more fluids.
Severe sepsis often progresses to shock. Of every 4 patients in the emergency department with sepsis, 1 patient will develop shock within 72 hours, even after having received appropriate and timely antibiotic therapy Glickman et al. In septic shock, blood vessels can no longer constrict sufficiently to maintain an adequate blood pressure. Three processes contribute to the unresponsiveness of the arterial wall muscles in septic shock which cause hypotension:.
The best available information suggests that death in sepsis most often results from the irreversible failure of a number of organ systems rather than from the failure of any one particular organ or system. However, in those cases where death can be attributed to the failure of a single system, it is usually the cardiovascular, respiratory, or central nervous system Vincent et al. Q : What additional risk factors did our case study patient have for sepsis?
A : She had additional toxins in her body from daily cigarette and alcohol use, which compounded the stress and infection of pneumonia. If you are attending a virtual event or viewing video content, you must meet the minimum participation requirement to proceed. If you think this message was received in error, please contact an administrator. Return to Course Home. Sepsis: Immune Response Meltdown Page 6 of One of the physiological functions of NO is to provide an intrinsic response to alterations in peripheral blood flow myogenic control.
When NO is formed in the endothelium, it diffuses into the vascular smooth muscle cells where it activates the enzyme guanylyl cyclase. This increases concentrations of cyclic GMP levels which lead to a reduction in intracellular calcium levels and activation of potassium channels. This leads to vascular smooth muscle relaxation.
Peripheral vascular dysfunction during sepsis is mediated by excessive production of NO by the enzyme iNOS. Increased NO concentration leads to hyperpolarization of potassium channels and persistent relaxation of smooth muscle. In addition to vasodilatation, there is a failure of the cardiovascular reflexes, which normally control arterial pressure. The sympathetic and neuroendocrine responses to shock cause vasoconstriction, which is mediated by G-proteins and second messenger systems, in turn activating intracellular pathways.
These responses to sympathetic activity and angiotensin II are decreased due to the increased production of NO, which decreases the cellular activity of signal transduction mechanisms. The right ventricle RV differs embryologically, structurally, and functionally from the LV.
The principle function of the RV is to facilitate efficient gas exchange. It has a thin wall with a low muscle mass, ejecting into the pulmonary circulation, which has a low resistance and a high compliance. The pressures generated on the right side are low; mean pulmonary artery pressure is 15 mm Hg.
The RV depolarizes and then contracts in a longitudinal manner from the inflow tract to the outflow tract and produces a wave which is peristaltic in manner. This contrasts with the circumferential pressure generating contraction of the left side of the heart.
Like the LV, the cardiac output of the RV is determined by changes in preload, afterload, and contractility. The changes in ventricular function in sepsis are similar to those on the left side. The function is compromised by changes in contractility and afterload.
The free wall of the RV has a low muscle mass and can respond to increases in preload by dilating, but it responds poorly to afterload because of its relative inefficiency as a muscle pump. The onset of sepsis leads to a change in contractility due to effects of circulating inflammatory mediators which are the same as those outlined above. There is a decrease in RVEF similar to that in the systemic circulation. The stresses imposed by sepsis on the RV muscle mass and the changes in afterload can ultimately lead to right ventricular failure.
The pulmonary circulation is a low-pressure system, which can respond to an increased cardiac output during exercise or after a physiological stress. The ability of the pulmonary circulation to respond to a large cardiac output without a major change in pressure ensures that effective gas exchange can take place.
It is important to consider the concept of blood flow in addition to generated pressure when considering the physiology of the pulmonary circulation. The right-sided circulation responds to changes in cardiac output by recruitment of pulmonary vessels which have low perfusion during stable conditions. In addition to recruitment, distension of these vessels allows an increase in blood flow which will support the need for improved gas exchange. These processes occur without vasomotor control.
The major stress imposed on the RV during sepsis is an increase in the afterload due to pulmonary hypertension. Hypoxic pulmonary vasoconstriction HPV is a response of the small arterioles of the pulmonary circulation to a decrease in alveolar or mixed venous oxygen content.
The greater influence is from alveolar hypoxia. The function of this response is to divert blood from the hypoxic areas of the lungs to those which are ventilated, thus attempting to maintain optimum ventilation and perfusion ratios and ensure efficient gas exchange.
It is a rapid response and occurs within seconds of induced hypoxia. The reflex occurs in the isolated lung and is independent of neural connections.
The precise mechanism has not been proven, but NO is implicated. During sepsis, unregulated NO production in the systemic circulation leads to vasodilatation. In the presence of hypoxia, NO production decreases in the pulmonary circulation and local vasoconstriction occurs. It is also thought that local release of the potent vasoconstrictor endothelin occurs due to hypoxia.
There is evidence that the active control of the pulmonary circulation is influenced by ligands of systemic origin which lead to receptor activation. There are both cholinergic and adrenergic receptors in the pulmonary vascular tree, which allow changes in pulmonary vascular tone and resistance. The predominant response is vasoconstriction. Cholinergic parasympathetic nerves cause vasodilatation by stimulation of muscarinic M3 receptors, with NO acting as a mediator for cholinergic transmission.
Other circulating humoral factors can induce a local vasoconstrictor response, including endothelin, angiotensin, and histamine. Pulmonary hypertension is thus a multifactorial consequence of sepsis and is probably due to inhibition of NO production due to hypoxia and also an enhanced vasoconstriction due to acidosis, increased adrenergic stimulation, and local mediators such as endothelin Table 2.
The mediators involved in the active control of the pulmonary circulation 6. Ventricular interdependence is defined as the forces that are transmitted from one ventricle to the other ventricle through the myocardium and pericardium, independent of neural, humoral, or circulatory effects. Ventricular interdependence is a result of the close anatomical correlation of the ventricular cavities within the pericardium. The ventricles can be considered in series.
Stroke volume of systolic contraction of one cavity creates the preload of the next Fig. This is an oblique transverse section of the heart taken through the mid-cavity. It demonstrates the thick walled LV and the thinner wall of the RV. It demonstrates the crescentic shape of the RV in comparison with the round ventricular cavity on the left. The septum is noted.
The failing RV can impede left-sided performance by decreasing LV preload. This severe RV diastolic dysfunction can be seen in sepsis Fig. This is a four-chamber view of the heart observed with transoesophageal echocardiography.
It is taken during end-diastole. The atrioventricular TV and MV valves are open. There is volume overload of the RV which has moved the septum towards the left side of the heart. The pericardium normally allows free movement of the ventricular cavities even in the presence of a dilated heart; however, this may itself be compromised by pericardial disease during sepsis or high intrathoracic pressures caused by mechanical ventilation.
Supraventricular tachyarrhythmias are commonly found in patients with sepsis, especially atrial fibrillation. The voltage-dependent L-channels which are responsible for calcium flux in phase 2 of the cardiac action potential have a specific heteromeric structure.
It is a known site of channel regulation by second messenger systems. Animal studies have demonstrated that during sepsis, NO decreases the influx of calcium by alteration of the activity of this channel during phase 2 of repolarization. The potassium channel is also affected during sepsis and an increased influx of potassium occurs in myocytes during repolarization.
These two mechanisms are responsible for the timing of repolarization. Action potential duration APD is decreased during sepsis in atrial myocytes. There is no change in resting membrane potential. A decrease in influx of calcium during phase 2 of repolarization is one of the electrophysiological changes associated with the genesis of tachyarrhythmias in sepsis Fig. The phases of the action potential are shown. Phase 0, depolarization; phase 1, partial repolarization; phase 2, plateau phase; phase 3, repolarization.
The APD is ms in the ventricle and ms in the atrium. The green line demonstrates how sepsis alters phase 2 and leads to a decrease in APD. This is due to a direct effect on the calcium channels and predisposes to atrial fibrillation. There is no evidence that global ischaemia leads to myocardial dysfunction in sepsis, with no alteration in coronary artery perfusion. There is a change in the metabolic activity of the heart during sepsis, as it develops an increased capacity to metabolize lactate as a substrate in preference to glucose and free fatty acids.
High energy phosphate levels are maintained in the presence of normal arterial oxygen tension. If a patient has pre-existing coronary artery disease then the increased work of the heart can lead to myocardial ischaemia. The oxygen demand is increased by the tachycardia and the supply may be limited by decreased subendocardial perfusion due to increased end-diastolic pressure.
It is important to consider sepsis as a risk factor in patients with diagnosed coronary atheroma. The increased work of the RV in the presence of pulmonary hypertension and systemic hypotension can alter the supply—demand ratio of the RV. This may worsen RV failure due to increased oxygen demand in the presence of impaired coronary artery perfusion. The reflex response to shock is the activation of the sympathetic system.
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