1. Anasarca -severe systemic edema

2. Noninflammatory(protein poortransudates) causes ofedema

1) Increased hydrostatic pressure-systemic edema is most commonly due to CONGESTIVE HEART FAILURE (CHF)

2) Reduced plasma osmotic pressure-occurs with ALBUMIN LOSS-the reduced plasma volume --> diminished renal perfusion and resultant renin production (anddownstream effects on angiotensin and aldosterone), but the subsequent salt and water retention cannotcorrect the plasma volume due to the underlying protein deficit

3) Sodium and water retention-primary salt retention with obligatory associated water retention, causes BOTH increased hydrostaticpressure and reduced osmotic pressure-sodium retention can occur with any renal dysfunction-PRIMARY water retention can occur with release of ADH either due to increased plasma osmolarity,diminished plasma volume, or inappropriately in the setting of malignancy; lung or pituitary pathology canalso cause inappropriate ADH secretion

4) Lymphatic obstruction-blocks removal of interstitial fluid-obstruction is usually localized and related to inflammation or neoplastic processes

3. Morphology -edema is most easily appreciated grossly-Micro: only as subtle cell swelling and separation of the extracellular matrix

*Subcutaneous edema-may be diffuse or occur where hydrostatic pressures are greatest (e.g. influenced by gravity, calledDEPENDENT EDEMA [legs when standing, sacrum when recumbent]-Finger pressure over substantial subcutaneous edema typically leaves and imprint, called PITTINGEDEMA

*Edema resulting from hypoproteinemia is GENERALLY MORE SEVERE and DIFFUSE. It is most evidentin loss connective tissue (e.g. eyelids, causing periorbital edema)

*Pulmonary edema - can result in lungs that are 2-3 times their normal weight. Sectioning reveals a frothy,blood-tinged mixture of air, edema fluid, and erythrocytosis

*Brain edema - may be localized to sites of injury or may be generalized (e.g. encephalitis, hypertensivecrises, or obstruction of venous outflow)-when generalized, the brain is grossly swollen with narrowed sulci and distended gyri flattened against theskull

4. Clinical consequences -Subcutaneous edema - can IMPAIR WOUND HEALING or INFECTION CLEARANCE-Pulmonary edema IMPEDES GAS EXCHANGE and INCREASES THE RISK OF INFECTION-brain edema within the confined space of the skull can impede cerebral blood flow or cause HERNIATION,compromising critical medullary centers

5. Hyperemia -an active process due to augmented blood inflow from arteriolar dilation (e.g. skeletal muscle duringexercise or at sites of inflammation).-Tissues are red (erythema) owing to engorgement with oxygenated blood

6. Congestion -a PASSIVE PROCESS-caused by impaired outflow from a tissue; it can be systemic (e.g. CHF) or local (e.g. an isolated venousobstruction)-tissues are blue-red (cyanosis) as worsening congestion leads to an accumulation of deoxyhemoglobin-long standing stasis of deoxygenated blood can result in hypoxia severe enough to cause ischemic tissueinjury and fibrosis

111-132Study online at quizlet.com/_8h6pj

7. Morphology *Acute Congestion - vessels are distended, and organs are grossly HYPEREMIC-capillary bed congestion is also commonly associated with interstitial edema

*In CHRONIC CONGESTION - capillary rupture may cause focal hemorrhage. Subsequent erythrocyte breakdownresults in HEMOSIDERIN-LADEN MACROPHAGES-Parenchymal cell atrophy or death (with fibrosis) may also be present -Grossly tissues appear BROWN, CONTRACTED, and FIBROTIC-lungs and liver are commonly affected

*IN LUNGS - capillary engorgement is associated with interstitial edema and airspace transudates-chronic manifestations = hemosiderin-laden macrophages (heart failure cells) and fibrotic septa

*IN LIVER - acute congestion manifests as central vein and sinusoidal distention and occasionally with centralhepatocyte degeneration-in chronic congestion, the central regions of the hepatic lobules are grossly RED-BROWN and slightly depressed(loss of cells) relative to surrounding uncongested tan liver (called nutmeg liver)-Micro: there is CENTRILOBULAR NECROSIS with heptatocyte dropout and hemorrhage, including hemosiderin-laden macrophages-Since the centrilobular area is at the distal end of the hepatic blood supply, it is most subject to necrosis wheneverliver perfusion is compromised

8. Hemorrhage -a release of blood into the extravascular space-rupture of a large artery or vein is usually due to vascular injury-capillary bleeding can occur with chronic congestion-a tendency to hemorrhage from insignificant injury is seen in a variety of disorders called HEMORRHAGICDIATHESES

9. Hemorrhageclassifications

*can be external or ENCLOSED WITHIN A TISSUE (=HEMATOMA)

*Petechiae - are minute, 1-2 mm hemorrhages in skin, mucous membranes, or serosal surfaces. These occur withincreased intravascular pressure, low platelet counts (thrombocytopenia), or defective platelet function

*Purpura - are greater than or equal to 3 mm hemorrhages. These occur for the same reasons as petechiae, as wellas with trauma, local vascular inflammation (vasculitis), or increased vascular fragility (e.g. amyloidosis)

*Ecchymoses - are greater than or equal to 1-2 cm subcutaneous hematomas (i.e. bruises). Typically associatedwith trauma but are also exacerbated by other bleeding disorders. The characteristic color changes in a bruise aredue to progressive metabolism of extravasated hemoglobin by tissue macrophages

*Large accumulations of blood in body cavities are called HEMOTHORAX, HEMIPERICARDIUM,HEMOPERITONEUM, or HEMARTHROSIS (joint), depending upon the location. Patients with extensivehemorrhage occasionally develop jaundice from massive erythrocyte breakdown and systemic bilirubin release

10. Clinicalsignificance ofhemorrhagedepends on ____

-the volume and rate of blood loss*rapid loss of less than 20%, or slow losses of even larger amounts, may have little impact*Greater losses --> hemorrhagic (hypovolemic) shock

11. Hemostasis vs.Thrombosis

*Hemostasis - normal, physiologic process maintaining blood in a fluid, clot-free state within normal vesselswhile inducing a rapid, localized hemostatic plug at sites of vascular injury

*Thrombosis - represents a pathologic state - it is the inappropriate activation of hemostatic mechanisms inuninjured vessels or thrombotic occlusion after relatively minor injury

12. NormalHemostasis

*After injury there is a characteristic hemostatic response

-transient reflex neurogenic arteriolar vasoconstriction augmented by endothelin (a potent endothelial-derivedvasoconstrictor)-platelet adhesion and activation (i.e., shape change and secretory granule release) by binding to exposedsubendothelial ECM. Secreted products (ADP, TxA2) recruit other platelets to form a temporary hemostatic plug(primary hemostasis)-Activation of the COAGULATION CASCADE by release of TISSUE FACTOR (aka THROMBOPLASTIN or FACTORIII), a membrane-bound lipoprotein procoagulant factor synthesized by endothelium; coagulation culminates inTHROMBIN GENERATION and conversion of CIRCULATING FIBRINOGEN TO INSOLUBLE FIBRIN; thrombinalso induces additional platelet recruitment and granule release-Polymerized fibrin and platelet aggregates together form a solid, permanent plug (secondary hemostasis)-Activation of counter-regulatory mechanisms (e.g. tissue plasminogen activator [t-PA] restricts the hemostatic plug tothe site of injury

13. Endothelium(EC)antithromboticproperties

-intact endothelium blocks platelet access to thrombogenic subendothelial ECM-Prostacyclin (PGI2) and nitric oxide (NO) inhibit platelet binding -Adenosinediphosphatase degrades adenosine diphosphate (ADP), and inducer of platelet aggregation -membrane-associated thrombomodulin converts thrombin to an anticoagulant protein-tissue factor pathway inhibitor (TFPI) blocks intermediates in the coagulation cascade-Heparin-like surface molecules facilitate plasma antithrombin III inactivation of thrombin-t-PA cleaves plasminogen to form plasmin, which, in turn, degrades fibrin

14. Endotheliumprothromboticproperties

-EC produce von Willebrand factor (vWF); EC damage allows platelet to bind the underlying ECM through interactionwith vWF-TISSUE FACTOR production is the major activator of the extrinsic clotting cascade-Plasminogen activator inhibitors (PAIs) limit fibrinolysis and favor thrombosis

15. Platelets -after vascular injury, platelets encounter ECM constituents (collagen, proteoglycans, fibronectin, and other adhesiveglycoproteins), which are normally sequestered beneath an intact endothelium. Then, platelets undergo ACTIVATIONinvolving adhesion and shape change, secretion (release reaction), and aggregation

*Platelet-ECM adhesion is mediated through vWF, thereby acting as a bridge between platelet receptors (mostlyglycoprotein Ib) and exposed collagen.-Genetic deficiencies of vWF or glycoprotein-Ib (i.e. Bernard-Soulier syndrome) result in bleeding disorders

*Platelet granule secretion (release reaction) -occurs shortly after adhesion. ALPHA GRANULES express P-selectinadhesion molecules and contain coagulation and growth factors; dense bodies or delta granules contain ADP,calcium, and vasoactive amines (e.g. histamine)-ADP is a potent mediator of PLATELET AGGREGATION, and calcium is important for the coagulation cascade-The release reaction also results in surface expression of PHOSPHOLIPID COMPLEX, providing a locus for calciumand coagulation factor interactions in the CLOTTING CASCADE

*Platelet aggregation-platelets adhering to other platelets is promoted by ADP and thromboxane A2-ADP activation changes platelet GpIIb-IIIa receptor conformation to allow FIBRINOGEN BINDING. FIBRINOGENbridges multiple platelets, forming large aggregates (GpIIb-IIIa deficiencies result in GLANZMANNTHROMBASTHENIA bleeding disorder)-platelet derived TxA2 activates platelet aggregation and is a potent vasoconstrictor (recall that EC-derived PGI2inhibits platelet aggregation and is a potent vasodilator)

16. CoagulationCascade

*Intrinsic Pathway-classically initiated by activation of HAGEMAN FACTOR (factor XII)*Extrinsic cascade-activated by TISSUE FACTOR

17. Prothrombintime (PT)

-screens for the function of the proteins in the extrinsic pathway (VII, X, II, V, and fibrinogen)

18. Partialthromboplastintime (PTT)

-screens for the function of the proteins in the intrinsic pathway (XII, XI, IX, VIII, X, V, II, and fibrinogen)

19. Controlmechanisms

*factor activation can only occur at sites of exposed phospholipids. Also, activated clotting factors are diluted by flowan are cleared by the liver and tissue macrophages

*Antithrombins (e.g. antithrombin III), complexed with heparin-like cofactors on endothelium, inhibit thrombin andother serine proteases - factors IXa, Xa, XIa, and XIIa

*Endothelial THROMBOMODULIN modifies thrombin so that it can cleave PROTEINS C and S; these, in turn,inactivate factors Va and VIIIa

*TFPI (Tissue factor pathway inhibitor) inactivates tissue factor-factor VIIa complexes

*Thrombin induces endothelial t-PA release; t-PA generates active PLASMIN from circulating PLASMINOGEN -Plasmin can also be generated by a factor XII-dependent pathway. Plasmin cleaves fibrin and interferes with itspolymerization; the resulting FIBRIN SPLIT PRODUCTS also act as weak anticoagulants

*Functional plasmin activity is restricted to sites of thrombosis-t-PA activates plasminogen most effectively when bound to fibrin meshwork-Free plasmin is rapidly neutralized by serum a2-plasmin inhibitor

*Endothelium modulates anticoagulation by releasing PLASMINOGEN ACTIVATOR INHIBITORS (PAIs), whichinhibit t-PA binding to fibrin. Thrombin and certain cytokines increase PAI production; cytokines released in thesetting of severe inflammation can therefore cause intravascular thrombosis

20. Virchow's triad *3 primary influences on thrombus fomation

1) Endothelial injury - is dominant and can independently cause thrombosis (e.g. endocarditis or ulceratedatherosclerotic plaque). Injury can be due to hemodynamic stresses (e.g. HT or turbulent), endotoxin, radiation, ornoxious agents. thrombosis results from exposed subendothelial ECM, increased platelet adhesion or procoagulantproduction (i.e. tissue factor, PAI) or reduced anticoagulant activity

2) Alterations in normal blood flow -can promote thrombosis. normal blood flow is LAMINAR (i.e. cellular elementsflow centrally in the vessel lumen, separated from endothelium by a plasma clear zone). *Stasis and turbulence (the latter forms eddy currents with local pockets of stasis):-disrupt laminar flow and bring platelets into contact with the endothelium-prevent dilution of activated clotting factors by flowing blood-retard the inflow of clotting inhibitors-promote endothelial cell activation

3) Hypercoagulanility

*Heritable hypercoagulable states-Factor V gene mutations = most common; 2-15% of caucasians (and 60% of patients with recurrent DVT) carry theso-called LEIDEN MUTATION, thereby rendering factor V resistant to protein C inactivation-Deficiencies of ANTITHROMBIN III, protein C, or protein S

*Acquired hypercoagulable states-oral contraceptives or the hyperestrogenic state of pregnancy may cause hypercoagulability by increasing hepaticsynthesis of coagulation factors and reduced synthesis of antithrombin III-Certain malignancies can release procoagulant tumor products

*Heparin-induced thrombocytopenia syndrome -occurs when heparin products (unfractioned more commonly thanlow molecular weight heparin) induces circulating antibodies that activate platelets and injure ECs

*Antiphospholipid antibody syndrome - occurs in patients with antibodies against anionic phospholipids thatactivate platelets or interfere with protein C activity

21. MorphologyofThrombosis

*Venous thrombi characteristically OCCUR IN SITES OF STASIS and are OCCLUSIVE

*Arterial or cardiac thrombi usually begin at sites of endothelial injury (e.g. atherosclerotic plaque, endocarditis) orturbulence (vessel bifurcation)-Aortic or cardiac thrombi- these thrombi are typically NONOCCLUSIVE (mural) as a result of rapid and high volumeflow-smaller arterial thrombi can be OCCLUSIVE

*Thrombi are generally FIRMLY ATTACHED at their site of origin and typically PROPAGATE TOWARD THE HEART-thus arterial thrombi extend RETROGRADE from the attachment point, whereas venous thrombi extend in thedirection of blood flow

*Arterial and cardiac mural thrombi have gross and microscopic laminations (lines of Zahn) produced by pale layers ofplatelets and fibrin alternating with darker erythrocyte-rich layers

*Venous thrombi (phlebothrombosis) -typically occur in a relatively static environment, resulting in a fairly uniform castcontaining abundant erythrocytes among sparse fibrin strands (red or stasis thrombi). Phlebothrombosis mostcommonly affects the veins of the lower extremities (more than 90% of cases)

*Valve thrombosis-infectious endocarditis - organisms form large, infected thrombotic masses (vegetations) with associated valve damageand systemic infections-Nonbacterial thrombotic endocarditis: non-infected, sterile vegetations develop in hypercoagulable states, typicallywithout valve damage-Verrucous (Libman-Sacks) endocarditis (sterile vegetations) - this occurs in SLE due to immune complex deposition;inflammation can cause valve scarring

22. Fate ofThrombus

*Propagation*Embolization: thrombi dislodge an travel to other sites*Dissolution - by fibrinolytic activity*Organization and recanalization - ingrowth of endothelial cells, smooth muscle cells, and fibroblasts to create vascularchannels, or incorporate the thrombus into the vessel wall*Mycotic aneurysm - rarely, microbial seeding of a thrombus leads to a mycotic aneurysm

23. Clinicalconsequences

*Thrombi can:

1) obstruct vessels

2) embolize

24. Venous thrombosis(Phlebothrombosis)

-occurs most commonly in deep or superficial leg veins

*superficial thrombi usually occur in varicose saphenous veins, causing local congestion and pain but rarelyembolizing. Local edema and impaired venous drainage predispose to skin infections and VARICOSE ULCERS

*DEEP THROMBI in larger leg veins above the knee (e.g. popliteal, femoral, and iliac veins) can result in painand edema, as well as increased risk for embolization. Venous obstruction is usually offset by collateral flow, anddeep vein thromboses are asymptomatic in approximately 50% of patients, being recognized only afterembolization

*DVT occurs in multiple clinical settings-advanced age, bed rest, immobilization, thereby diminishing the milking action of muscles in the lower leg andslowing venous return-CHF-trauma, surgery, and burns --> reduced physical activity, injury to vessels, release of procoagulant substancesfor tissues, and reduced tPA-The puerperal (period of 6 weeks after childbirth) and postpartum states are associated with amniotic fluidembolization and hypercoagulability-tumor-associated procoagulant release (migratory thrombophlebitis or Trousseau syndrome)

25. Arterial andCardiacThrombosis

-Atherosclerosis is the major cause of arterial thrombi due to abnormal and endothelial damage-MI with dyskinesis and endocardial damage can cause mural thrombi-RHEUMATIC VALVULAR DISEASE resulting in mitral valve scarring and stenosis, with left atrial dilation,predisposes to atrial thrombus formation; concurrent atrial fibrillation augments the blood stasis and propensityto thrombose-cardiac and aortic mural thrombi can embolize peripherally; brain, kidneys, and spleen are prime targets

26. DIC -reflected by widespread fibrin microthrombi in the microcirculation-caused by disorders ranging from obstetric complications to advanced malignancy-DIC is not a primary disease, but rather it is a complication of any diffuse thrombin activation*Microthrombi can cause diffuse circulatory insufficiency, particularly in the brain, lungs, heart and kidneys-there is also concurrent consumption of platelets and coagulation factors (consumption coagulopathy), withfibrinolytic pathway activation, thereby leading to uncontrollable bleeding

27. Pulmonaryembolism

-greater than 95% come from DVT-PE can occlude the main pulmonary artery, impact across the bifurcation (saddle embolus), or pass into smallerarterioles*In general, ONE PE PUTS A PATIENT AT RISK FOR MORE*Rarely, emboli pass through atrial or ventricular defects into the systemic circulation (PARADOXICALEMBOLISM)

-Most PE (60-80%) are small and clinically silent. They eventually organize and get incorporated into the vesselwall or leave a delicate, bridging fibrous WEB-Sudden death, right sided heart failure (cor pulmonale), or CV collapse occur when 60% or more of thepulmonary circulation is obstructed with emboli-PE in medium-sized arteries can cause pulmonary hemorrhage but usually not pulmonary infarction due tocollateral bronchial artery flow; however, with left-sided cardiac failure, infarcts can result-PE in SMALL END-ARTERIOLAR vessels typically cause hemorrhage or infarction-MULTIPLE EMBOLI over time can cause pulmonary hypertension and right ventricular failure

28. SystemicThromboembolism

-refers to emboli in the arterial circulation~80% arise from intracardiac mural thrombi-2/3 are secondary to myocardial infarcts, and 25% arise in the setting of dilated left atria and fibrillation-can also originate from AORTIC ANEURYSMS, THROMBI ON ULCERATED ATHEROSCLEROTIC PLAQUES,OR VALVULAR VEGETATIONS-they rarely originate from PARADOXICAL EMBOLI-10-15% are unknown origin

*Major sites for arteriolar embolization are the LOWER EXTREMITIES (75%) and brain (10%)-consequences depend on collateral circulation, tissue vulnerability to ischemia, and vessel caliber-most arterial emboli cause tissue infarction

29. Fat and Marrowembolism

*PE of microscopic fat globules-occurs after FRACTURES of long bones or, rarely, after burns or soft tissue trauma-occur in 90% of severe skeletal injuries; less than 10% have any clinical findings

*FAT EMBOLISM SYNDROME-fatal in 10%-heralded by sudden pulmonary insufficiency 1-3 days after injury-20-50% of patients have a diffuse petechial rash and may have neurologic symptoms (irritability andrestlessness) that progress to delirium or coma-thrombocytopenia and anemia can also occur-fatty acid release --> toxic injury-edema and hemorrhage can be seen micro

30. Air embolism -gas bubbles within the circulation-obstruct vascular flow and cause ischemia*small amounts in the coronary or cerebral circulation (introduced following surgery) can be catastrophic-100 cc required

*DECOMPRESSION SICKNESS-special form of air embolism caused by sudden changes in atmospheric pressure; deep-sea divers and individualsin unpressurized aircraft during rapid ascent are at risk-Air breathed at high pressure causes increasing amounts of gas (particularly nitrogen) to be dissolved in bloodand tissues-Subsequent rapid ascent (depressurization) allows the dissolved gases to expand and bubble out of solution toform gas emboli-formation of gas bubbles in skeletal muscles and joints causes painful BENDS-In lungs and, edema, hemorrhage, and focal emphysema --> resp distress, or CHOKES. Has emboli may alsocause focal ischemia in a number of tissues, including brain and heart

-a more chronic form of decompression sickness is CAISSON DISEASE; persistent gas emboli in poorlyvascularized portions of the skeleton (heads of the femurs, tibia, and humeri) lead to ischemic necrosis

31. Amniotic fluidembolism

-embolization of amniotic fluid into the maternal pulmonary circulation is a serious (80% mortality) butuncommon (1 in 40,000 deliveries) complication of labor and postpartum period*syndrome = sudden severe dyspnea, cyanosis, and hypotensive shock, followed by seizures and coma. Pulmonaryedema, DIFFUSE ALVEOLAR DAMAGE, and DIC ensue from release of toxic (fatty acid) and thrombogenicsubstances in amniotic fluid-Classic histologic findings include fetal squamous cells, mucin, lanugo hair, and fat from vernix caseosa in thematernal pulmonary microcirculation

32. Red Infarct *occur in:-venous occlusions (e.g. ovarian torsion)-loose tissues-tissues with dual circulations-tissues previously congested b/c of sluggish venous outflow-site of previous occlusion and necrosis when flow is reestablished

33. Whiteinfarcts

-occur in SOLID ORGANS with end arterial circulations (i.e. few collaterals)-i.e. spleen, kidney

34. Infarction -all tend to be WEDGE-SHAPED; the occluded vessel marks the apex, and the organ periphery forms the base. Lateralmargins may be irregular, reflecting the pattern of adjacent vascular supply-dominant histo feature: COAGULATIVE NECROSIS followed temporally by an inflammatory response (hours to days)and by a reparative response (days to weeks) beginning in the preserved margins-most infarcts are ultimately replaced by scar tissue

*Infarction in the CNS --> LIQUEFACTIVE NECROSIS

35. Shock *systemic HYPOPERFUSION resulting from reduction in either CARDIAC OUTPUT of the effective circulating bloodvolume

1) Cardiogenic shock -low cardiac output due to outflow obstruction (i.e. PE) or myocardial pump failure (arrythmia,tamponade, MI)

2) hypovolemic shock - low cardiac output due to hemorrhage or fluid loss (e.g. burn)

3) Septic shock - results from vasodilation and peripheral blood loss pooling caused by microbial infection

*rarer - neurogenic (loss of vascular tone and peripheral pooling (anesthetic accident or spinal cord injury), andANAPHYLACTIC

36. Septicshock

-most commonly caused by gram-positive bacteria - gram neg - bacteria - fungi

-procoagulant EC phenotype develops (DIC in up to 50% of cases)

-Metabolic abnormalities - insulin resistance and hyperglycemia are characteristic of the septic state, attributable toinflammatory cytokines and the early production of stress-induced hormones such as glucagon, GH, and cortisol. Withtime, adrenal insufficiency may supervene

-Immune suppression

-Organ dysfunction - reduced perfusion to tissues; myocardial contractility may be directly impacted, and endothelialdamage underlies the dev. of ACUTE RESP DISTRESS SYNDROME

37. Stages ofShock

1) Nonprogressive phase - phase during which reflex neurohumoral compensatory mechanisms are activated andperfusion of vital organs is maintained

2) Progressive phase - tissue HYPOPERFUSION and worsening circulatory and metabolic abnormalities including lacticacidosis due to anaerobic glycolysis. The acidosis also blunts the vasomotor response, causing vasodilation

3) Irreversible phase-damage is so severe that, even if perfusion is restored, survival is not possible-Renal shutdown due to ACUTE TUBULAR NECROSIS and ischemic bowel leaking microbes into the bloodstream(sepsis) can be terminal events

38. Morphologyof shock

*acute tubular necrosis --> oliguria, anuria, and electrolyte disturbances*lungs are seldom affected in hypovolemic shock but can be and lead to DAD in septic or traumatic shock*brain, heart, lungs, kidneys, adrenals, and GI tract are particularly affected

39. Clinicalconsequences

*Hypovolemic and cardiogenic shock - there is hypotension with a weak, rapid pulse; tachypnea; and cool, clammy,cyanotic skin

*Septic shock - skin may be initially warm and flushed owing to peripheral vasodilation

*pts. surviving the initial complications enter a SECOND PHASE DOMINATED BY RENAL INSUFFICIENCY andmarked by a progressive fall in urine output, as well as severe fluid and electrolyte imbalances

*prognosis: varies with the origin and duration of shock: cardiogenic and septic shock carry worse mortality rates thanhypovolemic shock