Hemodynamic Disorders

Hemodynamic Disorders

·       The health of cells and tissues depends not only on an intact circulation to deliver oxygen and remove wastes but also on normal fluid homeostasis.

·       Normal fluid homeostasis requires vessel wall integrity as well as maintenance of intravascular pressure and osmolarity within certain physiologic ranges.

·       Increases in vascular volume or pressure, decreases in plasma protein content, or alterations in endothelial function can result in a net outward movement of water across the vascular wall.

·       Such water extravasation into interstitial spaces is called edema; depending on its location, edema may have minimal or profound effects.

·       Thus, in the lower extremities edema fluid causes primarily swelling; however, in the lungs, edema fluid will fill alveoli and can result in life-threatening breathing difficulties.

·       Hemodynamic Disorders…..

Normal fluid homeostasis also means maintaining blood as a liquid until such time as injury necessitates formation of a clot.

Absence of clotting after vascular injury results in hemorrhage; local bleeding can compromise regional tissue perfusion, while more extensive hemorrhage can result in hypotension (shock) and death.

Conversely, inappropriate clotting (thrombosis) or migration of clots (embolism) can obstruct tissue blood supplies and cause cell death (infarction).

Abnormal fluid homeostasis (i.e., hemorrhage or thrombosis) underlies three of the most important causes of morbidity and mortality in Western society: myocardial infarction, pulmonary embolism, and cerebrovascular accident (stroke).

Hemodynamic Disorders

EDEMA

Approximately 60% of lean body weight is water, two-thirds of which is intracellular and the remainder is in extracellular compartments, mostly as interstitial fluid; only 5% of total body water is in blood plasma.

The term edema signifies increased fluid in the interstitial tissue spaces; fluid collections in different body cavities are variously designated hydrothorax, hydropericardium, or hydroperitoneum (the last is more commonly called ascites).

Anasarca is a severe and generalized edema with profound subcutaneous tissue swelling

The mechanism of inflammatory edema mostly involves increased vascular permeability

Increased Hydrostatic Pressure

Impaired venous return

Congestive heart failure  

Constrictive pericarditis

Ascites (liver cirrhosis)

Venous obstruction or compression  

Thrombosis

External pressure (e.g., mass)

Lower extremity inactivity with prolonged dependency

Arteriolar dilation

Heat

Neurohumoral dysregulation

Reduced Plasma Osmotic Pressure (Hypoproteinemia)

Protein-losing glomerulopathies (nephrotic syndrome)

Liver cirrhosis (ascites)

Malnutrition

Protein-losing gastroenteropathy

Lymphatic Obstruction

Inflammatory

Neoplastic

Postsurgical

Postirradiation

Sodium Retention

Excessive salt intake with renal insufficiency

Increased tubular reabsorption of sodium

Renal hypoperfusion

Increased renin-angiotensin-aldosterone secretion

Inflammation

Acute inflammation

Chronic inflammation

Angiogenesis

EDEMA

Clinical Correlation

The effects of edema may range from merely annoying to rapidly fatal.

Subcutaneous edema in cardiac or renal failure is important primarily because it indicates underlying disease; however, when significant it can also impair wound healing or the clearance of infection.

In contrast, pulmonary edema can cause death by interfering with normal ventilatory function and also creates a favorable environment for bacterial infection.

Brain edema is serious and can be rapidly fatal. If severe, brain edema can cause herniation (extrusion of the brain) through the foramen magnum; the brainstem vascular supply can also be compressed by edema causing increased intracranial pressure. Either state can injure the medullary centers and can cause death

HYPEREMIA AND CONGESTION

Both indicate a local increased volume of blood in a particular tissue.

Hyperemia is an active process resulting from augmented blood flow due to arteriolar dilation (e.g., at sites of inflammation or in skeletal muscle during exercise).

The affected tissue is redder than normal because of engorgement with oxygenated blood.

Congestion is a passive process resulting from impaired venous return out of a tissue.

It may occur systemically, as in cardiac failure, or it may be local, resulting from an isolated venous obstruction.

The tissue has a blue-red color (cyanosis), especially as worsening congestion leads to accumulation of deoxygenated hemoglobin in the affected tissues

Chronic passive congestion

Congestion of capillary beds is closely related to the development of edema, so that congestion and edema commonly occur together.

In long-standing congestion, called chronic passive congestion, the stasis of poorly oxygenated blood causes chronic hypoxia, which in turn can result in degeneration or death of parenchymal cells and subsequent tissue fibrosis.

Capillary rupture at such sites of chronic congestion can also cause small foci of hemorrhage; phagocytosis and catabolism of the erythrocyte debris can result in accumulations of hemosiderin-laden macrophages.

Morphology

Cut surfaces of hyperemic or congested tissues are hemorrhagic and wet.

Microscopically, acute pulmonary congestion is characterized by alveolar capillaries engorged with blood; there may also be associated alveolar septal edema and/or focal minute intra-alveolar hemorrhage.

In chronic pulmonary congestion the septa become thickened and fibrotic, and the alveolar spaces may contain numerous hemosiderin-laden macrophages ("heart failure cells").

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In acute hepatic congestion the central vein and sinusoids are distended with blood, and there may even be central hepatocyte degeneration; the periportal hepatocytes, better oxygenated because of their proximity to hepatic arterioles, undergo less severe hypoxia and may develop only fatty change

In chronic passive congestion of the liver the central regions of the hepatic lobules are grossly red-brown and slightly depressed (because of a loss of cells) and are accentuated against the surrounding zones of uncongested tan, sometimes fatty, liver ("nutmeg liver").

Microscopically, there is centrilobular necrosis with hepatocyte drop-out, hemorrhage, and hemosiderin-laden macrophages.

In long-standing, severe hepatic congestion (most commonly associated with heart failure), hepatic fibrosis ("cardiac cirrhosis") can develop.

It is important to note that because the central portion of the hepatic lobule is the last to receive blood, centrilobular necrosis can also occur whenever there is reduced hepatic blood flow (including shock from any cause); there need not be previous hepatic congestion.

Liver with chronic passive congestion & hemorrhagic necrosis.

HEMORRHAGE

Hemorrhage is extravasation of blood from vessels into the extravascular space.

Capillary bleeding can occur under conditions of chronic congestion; an increased tendency to hemorrhage (usually with insignificant injury) occurs in a wide variety of clinical disorders collectively called hemorrhagic diatheses.

Rupture of a large artery or vein results in severe hemorrhage, and is almost always due to vascular injury, including trauma, atherosclerosis, or inflammatory or neoplastic erosion of the vessel wall.

Hemorrhage can be external or can be confined within a tissue; any accumulation is referred to as a hematoma.

Hematomas can be relatively insignificant (e.g., a bruise) or can involve so much bleeding as to cause death (e.g., a massive retroperitoneal hematoma resulting from rupture of a dissecting aortic aneurysm;

Types of Hemorrhage

Minute (1- to 2-mm) hemorrhages into skin, mucous membranes, or serosal surfaces are called petechiae  and are typically associated with locally increased intravascular pressure, low platelet counts (thrombocytopenia), defective platelet function, or clotting factor deficiencies

 

Slightly larger (3- to 5-mm) hemorrhages are called purpura and can be associated with many of the same disorders that cause petechiae; in addition, purpura can occur with trauma, vascular inflammation (vasculitis), or increased vascular fragility

Larger (1- to 2-cm) subcutaneous hematomas (bruises) are called ecchymoses.

The erythrocytes in these local hemorrhages are phagocytosed and degraded by macrophages; the hemoglobin (red-blue color) is enzymatically converted into bilirubin (blue-green color) and eventually into hemosiderin (golden-brown), accounting for the characteristic color changes in a hematoma.

Large accumulations of blood in one or another of the body cavities are called hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis (in joints).

Patients with extensive hemorrhages occasionally develop jaundice from the massive breakdown of red blood cells and systemic increases in bilirubin

Clinical Significance

Depends on the volume and rate of blood loss.

Rapid removal of around  20% of blood volume or slow losses of even larger amounts may have little impact in healthy adults;

Greater losses, however, can cause hypovolemic shock.

The site of hemorrhage is also important; bleeding that would be trivial in the subcutaneous tissues may cause death if located in the brain.

Finally, chronic or recurrent external blood loss (e.g., a peptic ulcer or menstrual bleeding) causes a net loss of iron, leading to iron deficiency anemia.

In contrast, when red cells are retained (e.g., with hemorrhage into body cavities or tissues), the iron can be reutilized for hemoglobin synthesis.

A, Punctate petechial hemorrhages of the colonic mucosa, a consequence of thrombocytopenia.
B, Fatal intracerebral hemorrhage.

HEMOSTASIS AND THROMBOSIS

Normal hemostasis is a consequence of tightly regulated processes that maintain blood in a fluid, clot-free state in normal vessels while inducing the rapid formation of a localized hemostatic plug at the site of vascular injury.

The pathologic form of hemostasis is thrombosis; it involves blood clot (thrombus) formation in uninjured CVS or thrombotic occlusion of a vessel after relatively minor injury.

Both hemostasis and thrombosis involve three components: the vascular wall, platelets, and the coagulation cascade.

Normal Hemostasis

Contribution of Endothelial Cells to Coagulation

Intact endothelial cells maintain liquid blood flow by:

Actively inhibiting platelet adherence,

Preventing coagulation factor activation,

Lysing blood clots that may form.

Endothelial cells can be stimulated by direct injury or by various cytokines that are produced during inflammation.

Such stimulation results in expression of procoagulant proteins (e.g., tissue factor and vWF) that contribute to local thrombus formation.

Loss of endothelial integrity exposes underlying vWF and basement membrane collagen, both substrates for platelet aggregation and thrombus formation.

Platelet Aggregation

Endothelial injury exposes underlying basement membrane ECM;

Platelets adhere to the ECM and become activated by binding to vWF through GpIb platelet receptors.

Platelets secrete granule products that include calcium (activates coagulation proteins) and ADP (mediates further platelet aggregation and degranulation).

Also synthesize TXA2 (increases platelet activation and causes vasoconstriction).

Expose phospholipid complexes that provide an important surface for coagulation -protein activation

Released ADP stimulates formation of a primary hemostatic plug by activating platelet GpIIb-IIIa receptors that in turn facilitate fibrinogen binding and cross-linking.

The formation of definitive secondary hemostatic plug requires the activation of thrombin  to cleave fibrinogen and form polymerized fibrin via coagulation cascade

SUMMARY: Coagulation Factors

Coagulation occurs via the sequential enzymatic conversion of a cascade of circulating and locally synthesized proteins.

Tissue factor elaborated at sites of injury is the most important initiator of the coagulation cascade; at the final stage of coagulation, thrombin  converts fibrinogen into insoluble fibrin, which helps to form the definitive hemostatic plug. Coagulation is normally constrained to sites of vascular injury by:

Limiting enzymatic activation to phospholipid complexes provided by activated platelets

Natural anticoagulants elaborated at sites of endothelial injury or during activation of the coagulation cascade

Induction of fibrinolytic pathways involving plasmin through the activities of various PAs

Thrombosis

There are three primary influences on thrombus formation (called Virchow's triad):

(1) endothelial injury, (Alteration in wall)

(2) stasis or turbulence of blood flow (Alteration in flow)

(3) blood hypercoagulability (Alteration in cougulability)

Endothelial Injury

This is a dominant influence, since endothelial loss by itself can lead to thrombosis.

It is particularly important for thrombus formation occurring in the heart or in the arterial circulation, where the normally high flow rates might otherwise hamper clotting by preventing platelet adhesion or diluting coagulation factors.

Thus, thrombus formation within the cardiac chambers (e.g., after endocardial injury due to myocardial infarction), over ulcerated plaques in atherosclerotic arteries, or at sites of traumatic or inflammatory vascular injury (vasculitis) is largely a function of endothelial injury.

Endothelial Injury….

Clearly, physical loss of endothelium leads to exposure of subendothelial ECM, adhesion of platelets, release of tissue factor, and local depletion of PGI2 and plasminogen activators.

However, endothelium need not be denuded or physically disrupted for thrombosis; any imbalance between prothrombotic and antithrombotic activities of endothelium can influence local clotting events

Significant endothelial dysfunction (in the absence of endothelial cell loss) may occur with hypertension, turbulent flow over scarred valves, or by the action of bacterial endotoxins.

Even relatively subtle influences, such as homocystinuria, hypercholesterolemia, radiation, or products absorbed from cigarette smoke, may be sources of endothelial dysfunction

Alterations in Normal Blood Flow

Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents and local pockets of stasis; stasis is a major contributor to the development of venous thrombi.

Normal blood flow is laminar, such that platelets flow centrally in the vessel lumen, separated from the endothelium by a slower moving clear zone of plasma. Stasis and turbulence therefore:

Disrupt laminar flow and bring platelets into contact with the endothelium

Prevent dilution of activated clotting factors by fresh-flowing blood

Retard the inflow of clotting factor inhibitors and permit the buildup of thrombi

Promote endothelial cell activation, resulting in local thrombosis, leukocyte adhesion, etc.

Hypercoagulability

Generally contributes less frequently to thrombotic .

It is loosely defined as any alteration of the coagulation pathways that predisposes to thrombosis, and it can be divided into primary (genetic) and secondary (acquired) disorders .

Of the inherited causes mutations in the factor V gene and the prothrombin gene are the most common:

Acquired thrombotic diatheses: multifactorial and complicated

In some situations (e.g., cardiac failure or trauma), stasis or vascular injury may be most important.

Hypercoagulability due to use of oral contraceptive use and hyperestrogenic state of pregnancy, related to increased hepatic synthesis of coagulation factors and reduced synthesis of antithrombin III.

In disseminated cancers, release of procoagulant tumor products predisposes to thrombosis.

Hypercoagulability in advancing age has been attributed to increasing platelet aggregation and reduced endothelial PGI2 release.

Smoking and obesity promote hypercoagulability by unknown mechanisms

Hypercougulability

Morphology

Thrombi can develop anywhere in the cardiovascular system (in cardiac chambers, on valves, in arteries, veins, capillaries).

The size and shape of a thrombus depend on the site of origin and the cause.

Arterial or cardiac thrombi begin at sites of endothelial injury or turbulence; venous thrombi occur at sites of stasis.

Thrombi are focally attached to the underlying vascular surface.

Arterial thrombi tend to grow in a retrograde direction from the point of attachment,

Venous thrombi extend in the direction of blood flow (thus both tend to propagate toward the heart).

The propagating portion of a thrombus is poorly attached and therefore prone to fragmentation, generating an embolus.

Morphology

Thrombi can have grossly (and microscopically) apparent laminations called lines of Zahn; these represent pale platelet and fibrin layers alternating with darker erythrocyte-rich layers.

Such lines are significant only in that they represent thrombosis in the setting of flowing blood; their presence can therefore potentially distinguish antemortem thrombosis from the bland nonlaminated postmortem clots

Thrombi occurring in heart chambers or in the aortic lumen are designated mural thrombi.

Morphology

Arterial thrombi are frequently occlusive and are produced by platelet and coagulation activation; they are typically a friable meshwork of platelets, fibrin, erythrocytes, and degenerating leukocytes.

Venous thrombosis (phlebothrombosis) is almost invariably occlusive, and the thrombus can create a long cast of the lumen; venous thrombosis is largely the result of activation of the coagulation cascade, and platelets play a secondary role.

Because these thrombi form in the sluggish venous circulation, they also tend to contain more enmeshed erythrocytes and are therefore called red, or stasis, thrombi.

Postmortem clots

Postmortem clots can sometimes be mistaken at autopsy for venous thrombi.

Postmortem "thrombi" are gelatinous, with a dark red dependent portion where RBCs have settled by gravity, and a yellow "chicken fat" supernatant, and they are usually not attached to the underlying wall.

In contrast, red thrombi are firmer and are focally attached, and sectioning reveals strands of gray fibrin. 

Specific types of Thrombi

Thrombi on heart valves are called vegetations.

Bacterial or fungal blood-borne infections can cause valve damage, subsequently leading to large thrombotic masses (infective endocarditis,).

Sterile vegetations can also develop on noninfected valves in hypercoagulable states, so-called nonbacterial thrombotic endocarditis

Less commonly, sterile, verrucous endocarditis (Libman-Sacks endocarditis) can occur in the setting of systemic lupus erythe

Fate of the Thrombus

Propagation: accumulation of additional platelets and fibrin, eventually causing vessel obstruction.

Embolization: Thrombi dislodge or fragment and are transported elsewhere in the vasculature.

Dissolution: Thrombi are removed by fibrinolytic activity.

Organization and recanalization.

Thrombi induce inflammation and fibrosis (organization). These can eventually recanalize (re-establishing some degree of flow), or they can be incorporated into a thickened vessel wall

Low-power view of an artery with an old thrombus.
A, H&E-stained section.
B, Stain for elastic tissue.

EMBOLISM

An embolus is a intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin (Formation or entry).

Virtually 99% of all emboli represent some part of a dislodged thrombus, hence the term thromboembolism.

Rare forms of emboli include fat droplets, bubbles of air or nitrogen, atherosclerotic debris (cholesterol emboli), tumor fragments, bits of bone marrow, or foreign bodies such as bullets.

EMBOLISM

However, unless otherwise specified, an embolism should be considered to be thrombotic in origin.

Inevitably, emboli lodge in vessels too small to permit further passage, resulting in partial or complete vascular occlusion.

The consequences of thromboembolism include ischemic necrosis (infarction) of downstream tissue.

Depending on the site of origin, emboli may lodge anywhere in the vascular tree; the clinical outcomes are best understood from the standpoint of whether emboli lodge in the pulmonary or systemic circulations

Embolus derived from a lower extremity deep venous thrombosis and now impacted in a pulmonary artery branch

Pulmonary Embolism

They are carried through progressively larger channels and pass through the right side of the heart before entering the pulmonary vasculature.

Depending on the size of the embolus, it may occlude the main pulmonary artery, impact across bifurcation (saddle embolus), or pass out into the smaller, branching arterioles.

Frequently, there are multiple emboli, perhaps sequentially, or as a shower of smaller emboli from a single large thrombus; in general, the patient who has had one pulmonary embolus is at high risk of having more.

Rarely, an embolus can pass through an interatrial or interventricular defect, thereby entering the systemic circulation (paradoxical embolism).

Pulmonary Embolism

Sudden death, right ventricular failure (cor pulmonale), or cardiovascular collapse occurs when 60% or more of the pulmonary circulation is obstructed with emboli.

Embolic obstruction of medium-sized arteries can cause pulmonary hemorrhage but usually not pulmonary infarction because the lung has a dual blood supply and the intact bronchial arterial circulation continues to supply blood to the area

Many emboli occurring over a period of time may cause pulmonary hypertension with right ventricular failure.

Systemic Thromboembolism

Systemic thromboembolism refers to emboli in the arterial circulation.

Most (80%) arise from intracardiac mural thrombi, two-thirds of which are associated with left ventricular wall infarcts and another quarter with dilated left atria (e.g., secondary to mitral valve disease).

The remainder originate from aortic aneurysms, thrombi on ulcerated atherosclerotic plaques, or fragmentation of valvular vegetations

Arterial emboli can travel to a wide variety of sites; the site of arrest depends on the point of origin of the thromboembolus and the relative blood flow through the downstream tissues.

The major sites for arteriolar embolization are the lower extremities (75%) and the brain (10%), with the intestines, kidneys, and spleen affected to a lesser extent

INFARCTION

An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage in a particular tissue.

Tissue infarction is a common and extremely important cause of clinical illness.

More than half of all deaths in the United States are caused by cardiovascular disease, and most of these are attributable to myocardial or cerebral infarction.

Pulmonary infarction is a common complication in several clinical settings, bowel infarction is frequently fatal, and ischemic necrosis of the extremities (gangrene) is a serious problem in the diabetic population.

INFARCTION

Nearly 99% from thrombotic or embolic events, and from arterial occlusion.

Infarction may also be caused by other mechanisms:s local vasospasm, expansion of an atheroma secondary to intraplaque hemorrhage, or extrinsic compression of a vessel (e.g., by tumor).

Uncommon causes include vessel twisting (e.g., in testicular torsion or bowel volvulus), vascular compression by edema or entrapment in a hernia sac, or traumatic vessel rupture.

Although venous thrombosis can cause infarction, it more often merely induces venous obstruction and congestion.

Usually, bypass channels open rapidly after the occlusion forms, providing some outflow from the area that, in turn, improves the arterial inflow.

Infarcts caused by venous thrombosis are more likely in organs with a single venous outflow channel (e.g., testis and ovary).

Infarction…

Morphology

Infarcts are classified on the basis of their color (reflecting the amount of hemorrhage) and the presence or absence of microbial infection.

Therefore, infarcts may be either red (hemorrhagic) or white (anemic) and may be either septic or bland.

Red infarcts occur;

(1) with venous occlusions (such as in ovarian torsion);

(2) in loose tissues (lung) that allow blood to collect in the infarcted zone;

(3) in tissues with dual circulations e.g. lung and small intestine, permitting flow of blood from an unobstructed parallel supply into a necrotic area

(4) in tissues that were previously congested because of sluggish venous outflow;

(5) when flow is re-established to a site of previous arterial occlusion and necrosis (e.g., fragmentation of an occlusive embolus or angioplasty of a thrombotic lesion).

Infarction….Morphology

White infarcts occur with:

1. Arterial occlusions or in solid organs (such as heart, spleen, and kidney), where the solidity of the tissue limits the amount of hemorrhage that can seep into the area of ischemic necrosis from adjoining capillary beds

       

        All infarcts tend to be wedge shaped, with the occluded vessel at the apex and the periphery of the organ forming the base; when the base is a serosal surface there can be an overlying fibrinous exudate.

        At the outset, all infarcts are poorly defined and slightly hemorrhagic. The margins of both types of infarcts tend to become better defined with time by a narrow rim of congestion attributable to inflammation at the edge of the lesion

Infarction…Morphology

The dominant histologic characteristic of infarction is ischemic coagulative necrosis.

An inflammatory response at the margins of infarcts within a few hours and is usually well defined within 1 to 2 days.

Inflammatory response is followed by a reparative response beginning in the preserved margins.

In stable or labile tissues, parenchymal regeneration can occur at the periphery, where underlying stromal architecture is spared.

However, most infarcts are ultimately replaced by scar.

The brain is an exception to these generalizations; ischemic tissue injury in the central nervous system results in liquefactive necrosis .

Infarction….Morphology

Septic infarctions occur when bacterial vegetations from a heart valve embolize or when microbes seed an area of necrotic tissue.

        In these cases the infarct is converted into an abscess, with a correspondingly greater inflammatory response.

        The eventual sequence of organization, however, follows the pattern previously described.

Factors That Influence Development of an Infarct

Vascular occlusion can have no or minimal effect, or can cause death of a tissue or even the individual.

The major determinants of the eventual outcome include the;

nature of the vascular supply,

the rate of development of the occlusion,

vulnerability to hypoxia,

and the oxygen content of blood.

Red and white infarcts. A, Hemorrhagic, roughly wedge-shaped pulmonary infarct (red infarct). B, Sharply demarcated pale infarct in the spleen (white infarct).

Kidney infarct, now replaced by a large fibrotic scar.

SHOCK

Shock is the final common pathway for a number of potentially lethal clinical events, including severe hemorrhage, extensive trauma or burns, large myocardial infarction, massive pulmonary embolism, and microbial sepsis.

Regardless of the underlying pathology, shock gives rise to systemic hypoperfusion; it can be caused either by reduced cardiac output or by reduced effective circulating blood volume.

The end results are hypotension, impaired tissue perfusion, and cellular hypoxia.

Although the hypoxic and metabolic effects of hypoperfusion initially cause only reversible cellular injury, persistence of shock eventually causes irreversible tissue injury and can culminate in the death of the patient.

Types of Shock

Other types of Shock

Less commonly, shock may occur in the setting of an anesthetic accident or a spinal cord injury (neurogenic shock), as a result of loss of vascular tone and peripheral pooling of blood.

Anaphylactic shock represents systemic vasodilation and increased vascular permeability caused by an immunoglobulin E hypersensitivity reaction. In these situations, acute severe widespread vasodilation results in tissue hypoperfusion and cellular anoxia.

Cardiogenic shock

Results from failure of the cardiac pump:

Myocardial damage (infarction),

Ventricular arrhythmias,

extrinsic compression (cardiac tamponade,),

or outflow obstruction (e.g., pulmonary embolism).Hypovolemic shock results from loss of blood or plasma volume. This may be caused by hemorrhage, fluid loss from severe burns, or trauma.

Septic shock

Is caused by microbial infection.

Most commonly this occurs in the setting of gram-negative infections (endotoxic shock), but it can also occur with gram-positive and fungal infections.

Notably, there need not be systemic bacteremia to induce septic shock; host inflammatory responses to local extravascular infections may be sufficient.