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Disease Processes I Midterm


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What are the two precursor lineages of leukemias and lymphomas?
- Myeloid: granulocytic WBC
-- Neutrophils, Eosinophils and Basophils
- Lymphoid: T and B lymphocytes
What are the basic differences between leukemias and lymphomas?
Leukemias: blood or bone marrow
Lymphomas: localized malignant lymphoid cells form solid tissue mass
What are the basic causes of leukemias/lymphomas?
- Disease of Genetic Change
- Blood cells have high susceptibility
- Cells proliferate for host protection
-- Demands on DNA synthesis/repair
-- Constantly replicating
-- Vulnerable to DNA damage
--- Point mutations, translocations…
-- Immune cells “shuffle” DNA
- Does this to produce different receptor types, gives a risk of DNA damage
What are some of the basic steps leading to leukemias/lymphomas?
1. Mutation: gives rise to oncogene.
2. Gene duplication: multiple copies.
3. Bits & pieces of chromosomes that break off and join to other pieces and are introduced into genes that have to do with cell-cycle control. Genes are overly-expressed.
What are some of the methods of diagnosis of leukemias/lymphomas?
1. Morphologic Examination- tissue architecture (eg lymph node); stained smears of blood and bone marrow. Best way of diagnosis.
2. Immunophenotypic Analysis- detect surface antigens (CD antigens); differentiation status (Table 43-4). This is important because it can help determine which type of treatment to use.
3. Cytogenetics- chromosomal abnormalities, in particular translocations (Table 43-7)
4. Molecular Genetic Analysis- DNA/RNA analysis, Southern Blotting reveal clonal populations. PCR.
What are the characteristics of Acute Lymphocytic Leukemia (ALL)?
- Majority of childhood leukemias
- Patients have cytopenia (immature cells have escaped and are now in circulation), circulating lymphoblasts
- Lymphoblasts are intermediate or large with very high nuclear:cytoplasmic ratios
- Chromosomal translocations produce active oncogene products- c-myc, abl oncogenes. These lead to specific types of treatments.
- Patients are more vulnerable to infections because they are not protected by developed WBCs.
What are the characteristics of Chronic Lymphocytic Leukemia (CLL)?
- Common leukemia in adults
- Neoplastic cell is relatively mature B cell
Disease has “indolent” clinical course
- Generally small lymphocyte with weakly expressing surface Ig
- Characteristic presence of CD5 antigen helps diagnose disease. Molecular identification.
- Transformed neoplastic cell that is more mature. Compared to ALL.
- Most instances, B-lymphocyte.
- Acute leukemias are more aggressive cancers, need immediate treatment. CLLs are indolent, slowly progressing. Patient may undergo remission for a while, but then cancer will come back.
- Smaller cell because more differentiated.
- Recognizable as B-cell.
- Chemotherapy is not as effective in treatment.
What are the characteristics of Burkitts Lymphoma?
- Endemic in Africa, sporadic elsewhere-association with EBV?
- AIDS Patients and the immunosuppressed have increased Burkitt’s incidence
- B cell lymphoma: mature phenotype, medium-size cell with low N:C ratios
- IgH enhancer drives c-myc overexpression
- Causes cancers of the jaw or face disfigurements.
- Those who are taking immunosuppressive drug therapy are more susceptible to Burkitt’s.
- Translocation of transcription factor c-myc to right next to IgH enhancer. Makes tons of immunoglobulin.
What are the characteristics of Myeloma?
- Cancer of Plasma Cells- Ig secreting B cell
- Also called plasma cell myelomas.
- Cancer produces excessive Ig which contributes to pathology
- Anemia and renal failure
- Serum electrophoresis reveals Ig “spike”
- Clonal proliferation crowds bone marrow displaying monomorphic cellularity
- Blood becomes more viscous due to increased immunoglobulin and cannot be filtered as efficiently in the kidney. Other problems arise from increased immunoglobulin.
- There is not proper production of RBCs, WBCs, due to overproduction of B-cells.
What are the characteristics of Hodgkins Lymphoma?
- About 8% of all lymphomas
- Characterized by the presence of the Reed-Sternberg (RS) cells, large malignant cells in the lymph nodes and elsewhere
- Highest incidence in young adults and in persons over 75 years
- Radiation/chemotherapy good chance for cure.
-Lymphoma is more restrictive if caught early, so radiation/chemo work well.
What are the characteristics of Myeloid Leukemias?
- Acute myelogenous leukemia (AML)- among most common leukemias in adults
- Malignant cells are large immature myeloblast forms-Auer rods help diagnose
- Chronic myelogenous leukemia (CML)- less common
- Malignant cells are more mature with better preserved functions- 95% have bcr-able gene translocation
- Specific drug available to target bcr-able
What are translocations?
- (e.g., Burkitt’s lymphoma)
- Movement of a chromosome section from one location to another.
- Was relatively rare until AIDs appeared, it is related to Burkitt’s.
- Reciprocal translocations of t(8:14)* or [t(2:8) & t(8:22)]** place c-myc into the immunoglobulin heavy chain promoter element, c-myc expression increased. c-myc is an early response gene. Lymphoid tissue proliferates.
What is amplificiation?
- Increase in the copy number of a gene.
- Prognosis for tumor therapy in several sites correlates (inversely) with copy number of amplified oncogenes.
What is insertion?
- Viral-like integration of endogenous or exogenous DNA regulatory sequences can activate proto-oncogenes.
- Specific to viral oncogenesis. HepB, HPV
What are deletions?
- Loss of a gene, a chromosomal segment or a whole chromosome.
- Deletion of a chromosomal fragment containing a wild-type (normal) tumor suppressor gene (i.e., p53 or Rb) may expose mutations in the gene on the other paired chromosome.
What are the types of carcinogens?
1. Physical
- e.g., Asbestos (more of a physical than chemical event) it is mined for its fireproofing properties. Breathing it will make it go into the respiratory tract, and then irritates the tissue and then sets off infammatory responses and then can cause cancer.
- Radiation (ionizing or UV)
2. Chemical
- e.g., Polycyclic aromatic hydrocarbons. Tars in cig. smoke.
3. Biological
- e.g., retroviruses (RNA), hepatotropic DNA viruses, papillomaviruses (DNA) (cervical cancer)
Why is the cancer rate so high when it is supposed to be a rare disease?
- Increase in the natural mutation rate due to environmental factors. Mutagens, carcinogens (sunlight, cigarette smoke, etc).
- Genetic changes which increase the rate of accumulation of subsequent mutations. (events are not independent)
- Alterations in DNA replication & repair machinery.
- Alterations in the feedback controls which detect damage.
What are the dominant and recessive patterns of gene expression in cancer?
- “Dominant” genetic change
oncogenes (and their normal counterparts, the proto-oncogenes).
-- Usually a gain of function (i.e., an increase in signal transduction, transcription factors, etc.).
- “Recessive” genetic change
-- tumor suppressor genes
-- loss of function (replicative control, brakes).
What are the oncogene families?
- ras proteins active in signal transduction (GTP binding domains of a GTPase) coupled to cell surface receptors; activated by point mutations.
- myc proteins function as transcription factors; activated by amplifications or translocations
- neu gene codes for a transmembrane protein with homology for EGF receptor; activated in breast tumors by amplification [protein tyrosine kinase?].
What are tumor suppressor genes?
- p53 and rb : Roles in surveillance for DNA damage and as brake on cell cycle-dependent transcription factors.
What is the role of angiogenesis in tumor growth?
- In the absence of vessel formation, tumors grow only to a size limited by nutrient diffusion.
- After angiogenesis, linear tumor cell growth accelerates to exponential growth.
- The tumor bed effect:
pre-irradiation of a site of experimental tumor implantation reduces the rate of subsequent tumor growth.
- Due to sterilization of vascular endothelial cells, preventing angiogenesis
What are the steps of vessel formation in tumors?
1. Endothelial cell induced basement membrane degradation (in parent venule).
2. Endothelial cell locomotion.
3. Endothelial mitosis.
4. Lumen formation.
5. Generation of a basement membrane.
6. Recruitment of pericytes.
How are capillaries different in tumors than normal tissue?
- Tumor vessels often have more endothelial cells per lumen than normal vessels.
- Tumor vessels are often dilated and “leaky” [highly permeable].
-- Contributes to high interstitial pressure in tumors.
- Tumor vasculature does not follow the normal “artery - arteriole - capillary - venule - vein” organization.
- AV shunts & irregular, chaotic flow.
What are angiogenic stimulatory factors in tumors?
- Endothelial Cell (EC) Mitogens
-- Acidic FGF [fibroblast growth factor], Basic FGF, VEGF [vascular endothelial GF]
- Induces DNA synthesis in ECs:
-- PD-ECGF [platelet derived endothelial cell GF].
- Chemotaxins for ECs
-- Angiotropin
- Macrophage Recruitment
-- TGF-ß (also inhibits EC proliferation).
What are angiogenic inhibitory factors in tumors?
- Interferon alfa-2a
-- suppresses bFGF formation by tumor cells
- Collagenase inhibitors
-- Tissue Inhibitors of Metalloproteinases (TIMPs)
- Angiostatic Steroids [cortisol, tetrahydrocortisol + heparin or ß-cyclodextrin]
-- degrades newly formed basement membrane components of growing capillaries.
- Angiostatin, Endostatin
-- Specific anti-angiogenesis factors elaborated by tumors.
How is tumor angiogenesis initiated?
- Expression of new angiogenic molecules
-- Production of bFGF by tumor cells
- Recruitment of macrophages & mast cells
-- acidic, hypoxic environment of tumors stimulates angiogenic activity of macrophages.
- Suppression of pericyte inhibition of EC proliferation (?).
-- Factors from tumors suppress inhibition leading to endothelial cell replication supporting angiogenesis.
What are consequences of angiogenesis in tumors?
- Leaky vessels (and lack of a lymphatic drainage system) leads to increase interstitial pressure within tumor.
-- Tumors don’t “outgrow” their blood supply - they collapse it.
- Accelerated growth of solid tumors.
- Greatly increased risk of metastasis.
What are the characteristics of metasisis of cancer?
- Tumors are cellularly heterogeneous
-- Selection pressure for metastatic phenotype via hypoxia resistance.
- Metastatic subpopulation becomes dominant early in the growth of the primary tumor mass.
- Common sites of metastatic spread include regional lymph nodes, lung, liver, brain, bone.
What are the steps in a metastatic cascade?
- Local invasion.
- Intravasation (penetration into the local lymphatic or blood vessel)
- Circulation.
- Extravasation.
- Colony formation at distant site.
What are the steps of invasion in the metastatic cascade?
1. Attachment: Involves laminin, fibronectin & other factors and adhesion molecules: integrins, cadherins,etc. Ability to attach to basement membrane structures may separate heterogenous subclones within primary tumor.
2. Proteolysis: Proteolysis is a normal process under strict regulatory control; in tumors an imbalance favors invasion. Metalloproteinases, urokinase-type plasminogen activator involved.
3. Migration (motility): Utilize chemotaxis factors [incl. complement materials, collagen] Autocrine motility factor stimulates migration of cohort of tumor cells.
What are some tumor specific antigens?
- Oncofetal antigens
-- Carcinoembryonic antigen (CEA),
-- alpha feto-protein (AFP).
- Surface glycolipid & glycoprotein antigens
-- Prostate specific antigen (PSA).
- Oncogene products.
- All these antigens have been more helpful in following the progress of therapy than in detecting occult neoplasms or in direct therapy
What are the "7 warning signs" of early cancer?
- Change in bowel/bladder habits.
- A sore that does not heal
- Unusual bleeding or discharge
- Thickening or lump
- Indigestion or difficulty in swallowing
- Obvious change in wart or mole
- Nagging cough or hoarseness.
How are tumors graded?
- Qualitative assessment based on the degree of differentiation in tumor.
-- Since tumors are composed of heterogenous populations of cells, some may be well-differentiated and others poorly differentiated.
- Grades are assigned based on the appearance of differentiation characteristics.
-- Grade 1 (well differentiated) to Grade 4 (poorly differentiated) with
--(GX=unable to assess)
What are the general characteristics of the 2 categories of lung disease?
1. obstructive lung disease (COPD, asthma)
- increased airway resistance
- increased lung compliance
- decreased flow
2. restrictive lung disease (pulmonary fibrosis)
- airway resistance unchanged
- decreased lung compliance
- flow normal/increased at given lung volume
What is COPD?
- Abnormal permanent enlargement of the airspaces distal to the terminal bronchioles with destruction of their walls without obvious fibrosis (no scar tissue). Lung becomes more compliant. Surface area of the gas exchange decreases.
- There is a loss of elastin and collagen in the lungs (CT in the lungs). There is a permanent enlargement of the alveolar region of the lungs. Not in the airways.
- Chronic bronchitis is in the airways.
- COPD affects both gas exchange areas and conducting airways.
What are pink puffers?
- predominantly emphysema
- chief complaint is dysema (labored breathing, sensation of difficult breathing)
- expanded chests
- thin, wasting
- cough rare
- accessory muscles of respiration very active
What are blue bloaters?
- predominantly bronchitis
- overweight
- chronic productive cough
- cyanotic (bluish appearance)
- cor pulmonale: right heart enlargement (or failure)
What is the clinical presentation of COPD?
- cough, mucous production, wheezing, shortness of breath, flared chest, pursed-lip breathing
- increased lung compliance, work of breathing
-- changes in lung volumes/capacities/mechanics
-- atelectasis
- airflow obstruction: decr. FEV1, FVC, FEV1/FVC
- VE/Q mismatching: hypoxemia, hypercapnia
-- decreased O2sat, hematocrit > 55%
- cor pulmonale
What are the changes in mechanical properties with COPD?
- compliance: ∆V/∆P
- normal: ~ 200 ml/cmH2O
- COPD: > 200 ml/cm H2O
-- increased compliance
-- loss of connective tissue matrix in lung
-- atelectasis: air trapping
--- collapse of lung tissue/airways during expiration
How are the muscles of ventilation different in COPD?
- inspiration: diaphragm, external intercostals
-- exercise: accessory muscles
- expiration: passive
-- exercise: forced expiration, abdominals, internal intercostals
- inspiration: scalenes, sternocleidomastoids, pectoralis minor, serratus anterior
- expiration: abdominals, internal intercostals
What are the factors affecting airway resistance in COPD?
- mucous secretion
-inflammatory mediators affecting bronchiolar smooth muscle tone
-- parasympathetic (muscarinic) vs. sympathetic (b2)
-- direct or indirect (reflex) action
- dynamic compression of airways
What happens during maximal expiratory effort pertaining to dynamic compression of airways?
- pleural/alveolar pressure become positive
- downstream airway transmural pressure temporarily becomes negative causing temporary airway collapse
-- called equal pressure point
-- driving force for flow becomes elastic recoil pressure, not pressure created by expiratory muscles
- pressure within airway builds, airway opens; cycle starts over
- called dynamic compression or Starling resistor
What happens with dynamic compression in COPD?
- airways have radial traction due to connective tissue "tethering"
- radial traction lost as connective tissue matrix breaks down in COPD
-- airways collapse easier (at lower pressures) limiting flow
-- steel pipe (low compliance) vs. rubber pipe (high compliance)
- pursed-lip/slow breathing
What is the pathophysiology of COPD?
- irritants cause airway inflammation
-- macrophages release chemotactic factors, proteases; neutrophils recruited
-- cellular changes
--- hyperplasia of mucous glands
--- loss of cilia on airway epithelium
- protease/anti-protease theory
-- protease inhibitor: a1-antitrypsin
--- inhibited by lung oxidants like smoke
- increased proteases, loss of lung tissue
What is the pathophysiology of asthma?
- Type I hypersensitivity
-- IgE mediated
- responsible allergens
- TH2 subset releases:
-- IL-3, 4, 10: mast cell production
-- IL-4: B cell IgE production
-- IL-5: eosinophil activation
What does the IgE+ allergen do?
- mast cell secretion
-- histamine, eosinophil chemotactic factor
- eosinophil secretion
-- major basic protein, leukotrienes
- macrophage secretion
-- proteases, leukotrienes
What are the consequences of airway inflammation?
- stimulation of afferent nerves
- vasodilation
- bronchoconstriction
- mucous secretion
- basement membrane thickening
- peribronchialar fibrosis
- hyper-reactive airways
What is the clinical presentation of IPF?
- cough, dyspnea
- decrease in lung compliance
-- reduction in volumes/capacities
-- flow measures normal or elevated
- increased work of breathing
-- rapid, shallow breathing
- hypoxemia w/hypocapnia
-- pulmonary capillary bed changes
- cor pulmonale
What are the changes in mechanical properties with IPF?
- compliance: ∆V/∆P
- normal: ~ 200 ml/cm H2O
-- compliance due to: 1) connective tissue matrix and 2) surface tension forces
- restrictive disease: decreased compliance
-- < 200 ml/cm H2O
-- inward elastic recoil greater than normal due to increase in collagen
-- FRC (mechanical balance point) is reduced
What are the changes in airway resistance with IPF?
- airway resistance same or reduced in fibrotic disease
- radial traction "tethering" increases as connective tissue matrix is increased
-- steel pipe (low compliance) vs. rubber pipe (high compliance)
What is the pathophysiology of IPF?
- result of inflammation: regeneration OR repair
- inflammatory response in lung w/repair
-- alveolar macrophages respond to initial insult
-- neutrophils, eosinophils, etc., recruited; release cytokines; inflammation amplified
-- fibroblasts activated by TGF-b; collagen production
- proliferation of abnormal type II cells
-- abnormally functioning cells; surfactant production
- capillary bed destruction
What are the defense barriers of the lung?
- aerodynamic filtration
- epiglottis closure
- cough, sneezing
- rapid, shallow breathing
- mucociliary transport (escalator) system
- resident phagocytes: PMNs and macrophages
What is the clinical presentation of influenza?
- whole body
-- fever, chills, headache, myalgia, malaise
- respiratory
-- dry cough, nasal discharge, sore throat
- respiratory complications
-- viral/bacterial pneumonia
influenza → pneumonia → pulmonary edema → ARDS
What is the biological structure of influenza?
- bilayer membrane w/glycoprotein projections
-- hemagglutinin (HA)
-- neuraminidase (NA)
-- protein coat surrounds 8 strands of RNA
- major strains (A, B, C)/subtypes (HA/NA)
- antigenic drift: minor variation in HA/NA
-- yearly epidemics/vaccines
- antigenic shift: major variation in HA/NA
-- 1918 pandemic; SARS?
What is the pathophysiology of influenza?
- spread via respiratory droplets
- epithelial cell death
- humoral mediated response
-- IgA
- cell mediated response
-- CTL/Type I MHCs
What are the types of pneumonia?
- Community acquired: streptococcus pneumonia (pneumococcus)
- Hospital acquired: staphylococcus aureus
What are the symptoms of community acquired pneumonia?
- productive cough, chest pain, fever, myalgia
- rapid, shallow breathing (reduced compliance)
- increased WBC count (>11,000 cells/ml)
- tachycardia
- hemoptysis, bubbling rales
What are the 4 stages of pneumonia?
- engorgement
- red hepatization
- gray hepatization
- resolution
What are the mechanisms of pulmonary edema?
- pressure (cardiogenic)
-- increased pulmonary
-- venous/capillary pressures
-- mitral valve disease, left ventricular failure, chronic renal failure, liver failure (hypo-albuminemia)
- permeability (non-cardiogenic)
-- increased permeability in pulmonary capillary endothelium
-- pneumonia, sepsis, high altitude pulmonary edema, inhaled toxins
What are the clinical symptoms of pulmonary edema?
- dyspnea; eventually productive cough; rapid, shallow breathing; rales/crackles
- reduction in lung compliance; increased work of breathing
- sputum
- hypoxemia
* edema fluid causes lung surface tension to increase: reduced lung compliance
What are RARs?
- RARs (rapidly adapting receptors or irritant receptors)
-- lie between airway epithelial cells
-- stimulated by inhaled irritants, reductions in lung compliance
-- reflex response is bronchoconstriction, rapid shallow breathing, cough
What are pulmonary C-Fibers?
- aka J receptors
- believed to be located between capillaries and alveolar walls
- sensitive to edema, mediators of inflammation
- reflex response is rapid shallow breathing, bradycardia, hypotension
What are the symptoms of ARDS?
- tachycardia, tachypnea
- pulmonary infiltrates (nerve stimulation)
- reduced compliance (nerve stimulation)
- severe hypoxemia
- edema
- reduced release of surfactant
- high or low fever
- mechanical ventilation
What is the pathenogenesis of ARDS?
- sepsis
-- normal leukocyte count
4,000-11,000 cells/ml
-- sepsis
>12,000 or <4,000 cells/ml
- inflammatory damage to endothelium
-- macrophages, neutrophils
-- release inflammatory mediators
-- endotoxin (lipopolysaccharide)
What is the treatment for ARDS?
- no effective treatment for ARDS
- O2 therapy for hypoxemia
-- increase FIO2 to keep O2sat > 88%
-- mechanical ventilation
--- increased ventilation
--- use of PEEP
- antibiotics?
- ~ 50% death rate
- recovery: fibrosis, reactive airways
What is the pathophysiology of tuberculosis?
* primary Tb
- initial infection from human w/active Tb
- lung apex (over ventilated, aerobic)
- immune response: inflammation, cell-mediated immunity
- Ghon complex (granuloma tubercle)
- PPD hypersensitivity reaction
* reactivation Tb
- time course; most common cause of clinical Tb
- cause: endogenous organisms?
- miliary Tb
What is the treatment for tuberculosis?
- BCG vaccine
-- attenuated strain of myobacterium bovis
-- positive PPDs
-- anergy and (-) PPDs
- chemotherapy (drug cocktail example)
-- daily isonizid, streptomycin, ethambutol, pyrazinamide: 2 months
-- daily isonizid, rifampin: 4 more months
What is the clinical presentation of pulmonary embolism?
- dyspnea, chest pain, hemoptysis, rapid, shallow breathing
- increased pulmonary arterial pressure
What is the pathophysiology of pulmonary embolism?
- stasis leading to clot formation/increased PPA
-- component of clot
-- PPA ∆s proportional to circulation occluded
- reflex vaso-/bronchoconstriction secondary to lung collapse
-- RARs, C- fiber stimulation
-- consequences
- acute decreases in lung compliance
What is the treatment for pulmonary embolism?
* hemodynamically unstable patients
- thrombolytic therapy
-- streptokinase
-- urokinase
-- tissue plasminogen activator (t-PA)
* anticoagulation therapy
- heparin IV for 1-2 days
- heparin + warfarin for 5-7 days
- oral warfarin for 3 months
What are the signs and symptoms of CVD?
- Chest pain
- Dyspnea (resting and post-exertional)
- Fatigue (at rest and post-exertional)
- Palpitations
- Cough
- Edema
- Syncopy
What are the American Heart Association Category I CVD risk factors?
* Proven to lower risk if modified:
- Cigarette smoking
- Hypertension
- High-fat/cholesterol diet
- High LDL cholesterol level
What are the American Heart Assoc. Category II CVD risk factors?
* Modifications are “likely” to lower risk
- Diabetes
- Physical inactivity
- Low HDL cholesterol
- Obesity
- Post-menopausal status
What are the American Heart Assoc. Category III CVD risk factors?
* Modifications “might” lower risk
- Psychosocial factors
- Oxidative stress
- No alcohol consumption
What are the American Heart Assoc. Category IV CVD risk factors?
* No intervention can lower risk (nonmodifiable; but compensatory activities can be taken!)
- Age
- Male gender
- Low socioeconomic status(???)
- Family history of early-onset CVD
What are the effects of viruses on CVD?
- In the past several years, research has shown that viruses may be linked to the atherosclerosis process.
- Several studies have shown that heart disease patients are more likely to be infected with chlamydia pneumoniae than individuals without heart disease
- A recent Finnish study suggested that both chlyamydia pneumoniae and herpes simplex 1 can increase the risk of heart disease
What is the mechanism by which viruses affect CVD?
- Chlamydia has a surface peptide that resembles a peptide found in myosin, a protein found in muscle.
- Chlamydia can ‘sneak by’ the body’s initial immune defenses and invade muscle tissue.
- The body eventually mounts an immune response, attacking both the chlamydia virus AND the muscle tissue, causing inflammation and thickening of blood vessel walls.
What are the "artery-opening" techniques?
- Angioplasty: “balloon” flattens plaque
- Atherectomy: cuts away plaque
- Stents: wire mesh tube props open the artery (used after angioplasty or after atherectomy)
- Lasers: use heat or light to destroy plaque
What are the surgical procedures used to treat CAD?
- “Traditional” Coronary Artery Bypass Graft (CABG) Surgery
- Transmyocardial Revascularization: a laser is used to cut a series of channels in the heart muscle to increase blood flow
- Cardiomyoplasty: skeletal muscles from the back or abdomen are wrapped around the ventricle to improve heart’s pumping ability
- Heart Transplant: used only when the heart is irreversibly damaged
What is artherosclerosis?
Atherosclerosis is a slow, progressive condition in which the inner layers of the artery walls become thick, irregular and rigid (‘plaque’ formation).
What is the life history of an artherosclerotic lesion?
1. Atherogenesis begins in early life.
2. Lesion evolution usually occurs slowly over decades, often asymptomatic.
2. eventually causes stable symptoms such as embarrassment of flow, angina pectoris or intermittent claudication. 3. For the first part of the life history of the lesion, growth proceeds abluminally, in an outward direction preserving the lumen (compensatory enlargement or “positive remodeling”).
4. A minority of lesions will produce thrombotic complications, leading to unstable coronary syndromes, thrombotic stroke, or critical limb ischemia.
What is the pathophysiology of artherosclerosis?
- As atherosclerotic plaques grow, arteries narrow and blood flow is decreased, there is greater likelihood that the plaque will dislodge and create a blood clot.
- Disruption in blood flow in the arteries leads to ischemia (oxygen deprivation) within the tissue supplied by the vessels.
Where can ischemia occur in the body?
- Coronary Arteries → Angina or Heart Attack
- Carotid Arteries → Transient Ischemic Attack or Stroke
- Peripheral Arteries → Claudication (pain in the muscles of the lower legs)
What is the histology of normal elastic arteries?
- Elastic artery (large arteries) have concentric laminae of elastic tissue that form sandwiches with successive layers of smooth muscle cells. Each level of the elastic arterial tree has a characteristic number of elastic laminae.
What is the histology of normal muscular arteries?
- Muscular artery (smaller arteries and arterioles) have smooth muscle cells that are surrounded by a collagenous matrix but lack the concentric rings of well-organized elastic tissue characteristic of the larger arteries.
What are the steps in artherosclerotic evolution?
1. Accumulation of lipoprotein particles in the intima. Modifications include oxidation and glycation.
2. Oxidative stress including products found in modified lipoproteins can induce local cytokine elaboration.
3. The cytokines induce increased expression of adhesion molecules for leukocytes that cause their attachment and chemoattractant molecules that direct their migration into the intima.
4. Blood monocytes, on entering the artery wall in response to chemoattractant cytokines such as monocyte chemoattractant protein 1 (MCP-1), encounter stimuli such as macrophage colony stimulating factor (M-CSF) that can augment their expression of scavenger receptors.
5. Scavenger receptors mediate the uptake of modified lipoprotein particles and promote the development of foam cells. Macrophage foam cells are a source of mediators such as further cytokines and effector molecules such as hypochlorous acid, superoxide anion (O2–), and matrix metalloproteinases.
6. Smooth muscle cells in the intima divide, and other smooth muscle cells migrate into the intima from the media.
7. Smooth muscle cells can then divide and elaborate extracellular matrix, promoting extracellular matrix accumulation in the growing atherosclerotic plaque. In this manner, the fatty streak can evolve into a fibrofatty lesion.
8. In later stages, calcification can occur
What are some of the complications of artherosclerosis?
- Arterial stenosis: narrowing of the lumen
-- Exertional angina, or claudication
-- “compensatory enlargement”
- Thrombosis: critical mechanism of pathology
-- Plaque disruption leading to clotting (hypertension)
-- Enhanced clotting surface: migratory thrombus
What is cyanosis?
- Both a symptom and a physical sign
- 2 types
1. Central Cyanosis: decreased oxygen saturation – impaired pulmonary function
2. Peripheral Cyanosis: low cardiac output or cutaneous vasoconstriction (due to cold)
- Neonatal – usually congenital defect (like PDA or septal defect)
What are some of the types of edema?
- Unilateral: DVT
- Bilateral: heart failure
“my shoes are tight”
Weight gain 3-5 kg
- Rule out renal or hepatic disease
- Edema + dyspnea = left ventricular dysfunction
What are some signs of CV problems?
- Cough: dry or with hemoptysis (expectoration of blood or of sputum)
- Fatigue
- Nocturia: frequent night urination
- Anorexia
- Vision changes
- Hoarse voice
What does an ECG detect?
- Cardiac valves morphology & chamber enlargement , hypertrophy ?
- LV systolic and diastolic function & regional wall motion abnormality
- Valves function : stenosis & regurgitation
- Congenital heart disease : ASD,VSD,PDA
- Aortic dissection
- Doppler Enhanced: shows movement of blood
-- Valve function
What is nuclear cardiography?
- Used to visualize myocardial perfusion
- Used for quantifying ischemia
- Radiopharmaceuticals accumulate propotional to regional myocardial blood flow
-- Thallium-201
-- Technetium-99
What are the renal causes of hypertension?
- Renal parenchymal disease
- Acute glomerulonephritis
- Chronic nephritis
- Polycystic disease
- Diabetic nephropathy
- Hydronephrosis
What are some of the renalvascular causes of hypertension?
- Renal artery stenosis
- Intrarenal vasculitis
- Renin-producing tumors
- Renoprival
- Primary sodium retention (Liddle syndrome, Gordon syndrome)
What are some endocrine causes of hypertension?
- Acromegaly
- Hypothyroidism
- Hyperthyroidism
- Hypercalcemia (hyperparathyroidism)
- Adrenal Cortical Cushing syndrome
- Primary aldosteronism
- Congenital adrenal hyperplasia
What are some medullary causes of hypertension?
- Pheochromocytoma
- Extraadrenal chromaffin tumors
- Carcinoid
What exogenous hormones are causes of hypertension?
- Estrogen
- Glucocorticoids
- Mineralocorticoids
- Sympathomimetics
- Monoamine oxidase inhibitors
What are some other 2ndary causes of hypertension?
- Coarctation of the aorta
- Pregnancy-induced hypertension
- Neurological disorders
- Increased intracranial pressure
- Brain tumor
- Encephalitis Respiratory acidosis
- Sleep apnea
- Acute stress, including surgery
- Psychogenic hyperventilation
- Hypoglycemia
- Burns
- Pancreatitis
- Alcohol withdrawal
What are the target organs affected by hypertension?
* Target organ damage
- Eyes
-- Hypertensive retinopathy
- Heart
- Kidneys
- Brain
What are the effects of hypertension on the heart?
- Increased tension and stiffness of left ventricle
-- Accelerates atherosclerosis in coronary vessels
-- Increased likelihood of:
--- myocardial ischemia
--- Arrhythmias
--- Sudden death
--- Congestive heart failure
- Changes in left ventricular function
-- Enhanced contractility
- Left ventricular hypertrophy
-- Thicker muscle with smaller ventricular cavity
-- Decreased SV (increased afterload)
--- Dyspnea
--- Pulmonary congestion
What are the effects of hypertension on the kidneys?
- Kidneys – cause and effected
- Intraglomerular hypertension results in microalbinuria (impaired renal function)
-- Microalbinuria is correlated with insulin resistance
- Nephrosclerosis – reduced blood flow to nephrons
-- Uremia develops
*Hypertension is the leading cause of end-stage renal disease
What are the effects of hypertension on the brain?
- Accelerated cognitive decline
- Increased risk:
-- Stroke (esp. hemorrhagic)
-- Transient ischemic attacks (TIA)
What are the mechanisms of hypertension?
- BP = Q x PR
- Slow and gradual (insidious) increases
-- Makes predisposing factors hard to indentify
- 3 main mechanisms
-- Increased pumping action of heart
-- Increased vascular resistance
-- Increased blood volume (viscosity)
What is the role of sodium in hypertension?
- “sodium sensitivity”: resetting of the pressure-natriuresis after salt intake
- Increased driving pressure to filter sodium at the kidney
- Sodium may “drive” the sympathetic nervous sytem (indirect effect)
What are causes sympathetic hyperactivity?
* Heart
- Increased circulating catecholamines (epi)
- Bind to beta-1 adrenoceptors – increase inotropic and chronotropic activity
* Arterial Tree
- Increased release of norepinephrine binds to alpha-1 receptors and causes vasoconstriction and venocontriction
* Kidney
- Renal efferents stimulates renin release (PRA) and increases angiotensinergic vasoconstriction
What occurs with excess sodium intake?
- Increase osmotic effect of sodium (inc. vascular volume)
- Increases efferent activity to the kidney which increases angiotensin II levels (but not always PRA)
- Increased filtration pressure produces nephrosclerosis
How does hyperinsulemia affect hypertension?
- Obese are hyperinsulinemic secondary to insulin resistance
- Insulin “drives” the SNS (like salt, but in a different mechanism)
* Lack of vasodilatory effect by involve NO
How does endothelial cell dysfunction affect hypertension?
Impaired insulin resistance may influence endothelial derived relaxing factors.
How does Nitric Oxide affect hypertension?
- Impaired NO mediated vasodilation
*vascular responsiveness in restored with antihypertensives
How does endothelin affect hypertension?
- Endothelial derived constricting factors (E-1)
- Adrenal link?
What is myocardial ischemia?
- An imbalance between the supply of oxygen and the myocardial demand resulting in myocardial ischemia.
- Ischemia: low oxygen state, lack of arterial blood
Obstruction of flow
- Hypoxia: lack of O2 (despite adequate blood flow)
- Hypercapnia: excess CO2
What are the 2 types of IHD?
- Patients with overt IHD show at least a couple of symptoms e.g. chest pain, dyspnea (often unnoticed). Angina is the primary symptom of IHD.
- Patients with silent type ischemia don’t show any symptoms. The first indication of heart problems is usually a severe heart attack. in this cases where patients have silent ischemia it’s very important to identified early.
What are the manifestations of IHD?
- Sudden death
- Myocardial infarction
- Acute coronary syndrome
- Stable angina pectoris
- Heart failure
- Arrhythmia
- Asymptomatic
What are some of the medical treatments for IHD?
- Nitrates
-- Increase myocardial oxygen supply, systemic vasodilation
- Beta blockers
-- Inhibit increases in heart rate and contractility
-- Decrease myocardial oxygen demand
- Calcium channel agonists
-- Coronary vasodilators
-- Lipid lowering agents
- Lifestyle modification
-- Smoking, diet, physical activity, stress, alcohol
What are the qualifications for coronary artery bypass grafting surgery?
- Symptomatic without exertion
- Left coronary artery is involved
- Left ventricular function is at risk
- 50% occlusion is considered significant
- Failed PTCA
What are some agents used to prevent restenosis in IHD?
* Platelet inhibitors
- Aspirin
* Antithrombins
- Heparin analogs
- Warfarin
* Vasodilators
- NO donors; linsidomine, molsidomine
* Antiproliferative agents
- Growth factor inhibitors; Angiopeptin, trapidil
* Antiinflammatories and antioxidants
- Vit A, C, E, Dexamethasone
* Lipid lowering agents
- Statins: Lovaststin, pravastatin, fluvastatin
- Fish oils prevent restenosis
What is ischemic stroke?
- Ischemic stroke is the most common one and it can be divided in to two groups.
-- Thrombotic: clot forms at site and occludes blood flow
-- Embolic stroke: clot forms somewhere in the body and gets clogged in the brain
--- embolic stroke is often a result of heart disease and occurs without any signs
What is hemorrhagic stroke?
- Hemorrhagic stroke occurs when a blood vessel that supplies the brain with blood ruptures and leaks out in to the brain.
- Hemorrhagic stroke has also two types,
-- Intracerebral hemorrhage
--- Hypertension
-- Subarachnoid hemorrhage
--- Head injury
What is intracerebral hemorrhage?
-- An intracerebral hemorrhage occurs when blood vessels bleed into surrounding brain tissue. In addition to damage caused by blood itself, ischemic damage may occur due to impaired blood flow.
-- Main cause: High blood pressure
-- Other possible causes: head injury or aneurysm rupture
What is subarachnoid hemorrhage?
- Subarachnoid hemorrhage describes bleeding between the skull and the brain, and often results from an aneurysm.
-- Main causes: Head injury and high blood pressure rupture existing aneurysm.
-- Complications: Hemorrhage can also cause vasospasm – blood vessels surrounding the ruptured blood vessels constrict, restricting blood flow to parts of the brain and causing further brain tissue damage.
What are the symptoms of stroke?
- If you have ischemic stroke the symptoms may be blindness in one eye or hearing problems in one ear, confusion, loss of balance/coordination, trouble of speaking or muscle paralysis.
- The symptoms in cerebral hemorrhage occurs suddenly and continue worsening. This are headaches, confusion and vomiting.
- Subarachnoid hemorrhage has similar symptoms but it has also pain in looking into light and stiff neck/headache.
What are the AHA signs and symptoms of stroke?
- Sudden numbness or weakness of the face, arm or leg, especially on one side of the body
- Sudden confusion, trouble speaking or understanding
- Sudden trouble seeing in one or both eyes
- Sudden trouble walking, dizziness, loss of balance or coordination
- Sudden, severe headache with no known cause
What are the mechanisms of stroke?
- Primary mechanism of nearly all cerebrovascular incidents is “abnormal autonomic nervous system function, primarily a markedly increased sympathetic and output”
- Stroke patients can present with:
-- ECG abnormalities
-- Prolonged QT interval, inverted T waves, odd QRS
-- Arrythmias
-- Ventricular tachycardia or fibrillation
-- Cause and Effect may be difficult to separate
What are the treatments for stroke?
- Thrombolysis or surgical removal of clot
- Rehabilitation
- Prevention of future strokes
-- Aspirin
-- Heparin
-- Coumadin (warfarin)
How can heart failure be acquired?
1. Loss of muscle e.g., through coronary occlusion and subsequent myocardial infarction.
2. Chronically elevated work load on the heart, e.g., in hypertension.
3. Myopathic diseases of the heart, e.g., in dilated cardiomyopathy.
4.Infectious diseases.
* Usually due to a loss of contractility of the muscle itself but can be caused acutely by valvular dysfunction.
What are the causes of heart failure?
- Inappropriate reduction in therapy
-- Ie: sodium or fluid restriction, discontinue meds
- Arrythmias
-- Tachycardia, bradycadia or a-v dissociation
- Myocardial ischemia or infarction
- Systemic infection
- Emotional or physical stress
- Cardiac infection
- Administration of cardiac depressants
-- beta-adrenergic antagonists, calcium antagonists (verapamil, diltiazem), many antiarrhythmic agents. Estrogens, corticosteroids, and nonsteroidal antiinflammatory agents can cause salt and water retention.
What are the symptoms of heart failure?
- Respiratory Distress: Breathlessness, a cardinal manifestation
- Exertional Dyspnea: “how much activity is required”
- Orthopena: Dyspena is a recumbent position that is alleviated by sitting upright
- Paroxysmal Nocturnal Dyspnea: “The patient awakens, often quite suddenly, and with a feeling of severe anxiety and suffocation, sits bolt upright and gasps for breath”
- Non productive cough, cough during recumbency (improves with diuretics)
What are the FACES of heart failure?
F - fatigue
A - activities limited
C - Chest congestion
E - Edema or ankle swelling
S - Shortness of breath
What are the physical manifestations of heart failure?
- Increased sympathetic activity
-- peripheral vasoconstriction, pallor and coldness of the extremities and cyanosis of the digits, sinus tachycardia
- Pulmonary rales: bubbly wheezing lung sounds
- Increased venous pressure:
-- Jugular distention that is relieved on inhalation
- Congestive hepatology: enlarged liver
- Edema: up to 4 liters of retention before edema occurs
- Ascites: accumulation of serous fluid in the abdominal cavity
Why does venous pressure rise?
1. A loss of contractility shifts the cardiac output curve to the right and down which raises venous pressure (A to B)
2. The reduced cardiac output causes a lowered aortic pressure that causes renal retention of fluids and sympathetic reflex venoconstriction. Both effects move the venous function curve up and to the right again raising venous pressure. (B to C to D)
3. The healthy (rt) ventricle actively pumps blood into the venous side of the depressed (lt) ventricle raising venous pressure further on the diseased side of the heart.
What are the compensations in heart failure?
* Compensation: If failure is mild the elevated sympathetic drive to the heart and moderately elevated venous pressure may restore cardiac output and allow for near normal activity.
* Decompensated: With more severe failure cardiac output even at rest may be inadequate. The venous congestion damages other organs such at the kidney and the healthy ventricle.
What is dilation of the heart?
- When the fall in contractility occurs suddenly such as with a myocardial infarction, the acute elevation in diastolic pressure may cause the muscle fibers to rearrange (fiber slippage) so that the internal diameter of the heart increases dramatically over a matter of hours. The increased diameter with no increase in muscle mass is termed dilation (as opposed to hypertrophy).
- The wall tension is elevated in the dilated ventricle due to the diameter effect in the law of LaPlace and puts the compromised ventricular fibers under even more strain.
How does hypertrophy lead to heart failure?
1. Heart muscle responds to increased workload with hypertrophy.
2. Increased expression of muscle proteins makes the heart bigger (remodeling) but not better. The new muscle is less efficient in generating force.
3. The hypertrophied heart has less compliance during diastole which reduces its stroke volume.
4. The coronary circulation does not seem to develop along with the hypertrophy so that oxygen delivery is poor to hypertrophied heart.
5. If the heart responds to the increased workload by hypertrophy, which if unable to compensate, heart failure will eventually result. As the heart fails it is under more drive to hypertrophy. The only way to stop this positive feedback situation is to eliminate the overload.
6. Humoral factors, particularly angiotensin II, contribute to the detrimental remodeling. Reducing angiotensin by angiotensin converting enzyme (ACE) inhibitors greatly reduces remodeling with equivalent workloads.
How does the nature of stress affect the pattern of hypertrophy?
1. Factors that increase the wall tension, e.g., hypertension or aortic stenosis cause concentric hypertrophy. Diastolic compliance is reduced.
2. Factors that increase the stroke volume such as regurgitant valves, septal defects, or arterial-venous fistulas cause eccentric hypertrophy. Diastolic compliance is unaffected or even increased.
3. The heart may not tolerate fixing a volume overload in advanced failure because the afterload on the heart will often be increased after repair. Fixing the lesion in the high wall tension heart is usually well tolerated because the afterload decreases after the repair.
What are treatments for heart failure?
1. If possible remove the underlying lesion, e.g., correct the hypertension.
2. Treatment in heart failure is often aimed at reducing the venous congestion with diuretics.
a. Elevated systemic venous pressure causes swelling, kidney damage, etc.
b. Elevated left atrial pressure causes life-threatening pulmonary edema.
3. Positive inotropic agents, e.g., digitalis temporarily improve symptoms but do not prolong life.
4. Beta adrenergic blockers improve symptoms and prolong life.
a. Reduce background beta-1 adrenergic drive at rest.
b. Prevent down-regulation of beta-1 receptors so that under exercise norepinephrine can compete with the blocker and stimulate the heart.
5. ACE inhibitors reduce remodeling following myocardial infarction.
6. In severe cases such as extensive infarction or cardiomyopathies the lesion cannot be eliminated and transplant may be the only alternative.
What is re-entry in arrythmias?
- Caused by unidirectional block, usually in diseased tissues
- Probably the cause of many arrhythmias
- Can occur in atria, ventricles and nodal tissue
AP’s conducted only one-way, but conduction is slower
- Causes a constant loop of AP’s re-exciting repeatedly (Circus Rhythm)
- The tissue begins to beat independently of input
What is abnormal pacemaker activity?
- Occurs under pathological conditions such as increased catecholamine levels and ischemia
- Areas of the heart that are normally quiescent can take on a spontaneous rhythm
- Catecholamines increase depolarisation rate
- Ischemia causes increased release of adrenaline from adrenal medulla and produces partial depolarisation by decreasing activity of the Na+/K+ ATPase
- This depolarisation leads to an AP
What is heart block?
- Damaged nodal tissues (e.g. infarction) cannot conduct properly
- If the AV node is blocked (or another major part of the conduction system), then atria and ventricles beat independently.
What are the signs and symptoms of arrythmias?
- Palpitations
- Syncope
- Lightheadedness: Presyncope
- Congestive heart failure
*Patient may be unaware or keenly aware of symptomology
What are the types of arrythmias?
- Bradycardia: slower than 60 bpm or lower than expected during exertion
- Tachycardia: ~90-100 bpm at rest or faster than expected during exertion
- Flutter: 200-350 bpm
- Fibrillation: up to 500/min Irregular, uncoordinated contractions, fragmentary, ventricles beat at one fifth the rate of the atria, but not regularly. If chronic, then the condition is serious
- Atrial: Originating or occupying the atria
- Supraventricular: originating somewhere after the SA node
- Ventricular: Originating or occupying the ventricles
What is superventricular tachycardia?
- It is common - requires only atrial and/or atrioventricular (AV) nodal tissue for its initiation and maintenance.
- It is usually a narrow-complex tachycardia that has a regular, rapid rhythm.
What is atrial flutter?
- Rhythm disturbance of the atria that results in regular tachycardic ventricular waveforms. Atrial rates in atrial flutter are generally 240-400 beats per minute. The QRS complexes are uniform in shape but irregular in rate. P waves may have saw-toothed configurations.
What is premature ventricular contraction?
- PVC: Ectopic beat in the ventricle that can occur singly or in clusters
- Caused by electrical irritability
- Factors influencing electrical irritability
-- Ischemia
-- Electrolyte imbalances
-- Drug intoxication
What is ventricular tachycardia?
- Originates in the ventricles
- Can be life threatening
- Most patients have significant heart disease
-- Coronary artery disease
-- A previous myocardial infarction
-- Cardiomyopathy
What are the types of ventricular tachycardia?
* Sustained VT
- Episodes last at least 30 seconds
- Commonly seen in adults with prior:
-- Myocardial infarction
-- Chronic coronary artery disease
-- Dilated cardiomyopathy
* Non-sustained VT
- Episodes last at least 6 beats but < 30 seconds
What is ventricular fibrillation?
- Heart rate: Chaotic, random and asynchronous
- Rhythm: Irregular
- Mechanism: Multiple wavelets of reentry
- Recognition: No discrete QRS complexes
- Treatment: Defibrillation
What are antiarrythmic agents?
- Class I - Na+ - channel blockers (direct membrane action – Flecanide)
- Class II - Sympatholytic agents (β blockers)
- Class III - Prolong repolarization (K+ blockers)
- Class IV- Prolong depolarization (Ca++ channel blockers
- Purinergic agonists
- Digitalis glycosides
What are the causes of shock?
1. Reduced blood volume as occurs in burns or hemorrhage.
2. Loss of autonomic tone to the peripheral vessels.
3. Impaired cardiac function as occurs in severe heart failure.
4. Increased peripheral demand for blood flow as occurs in sepsis.
What are signs of shock?
- Tachypnea
-- Shallow, irregular, labored
- Blood Pressure
-- Normal, Low or Falling
- Hypotension is a late finding: why?
-- Compensatory mechanisms work at first to maintain MAP
- Due to hypoperfusion:
-- Decreased “mentation” - confused, sluggish, anxious
-- Skin cold, mottled
How do burns cause shock?
Burns cause hypovolemia due to fluid loss at the burned tissue (evaporation and oozing). In addition the capillaries become permeable to plasma proteins causing shift of fluid out of the vascular compartment and into the tissues due to altered Starling forces.
What is cardiogenic shock?
Cardiogenic shock occurs when the heart is in acute severe failure. It is hard to treat because in many cases the cardiac function is not easily restored.
What is neurogenic shock?
Neurogenic shock occurs when there is a loss of sympathetic tone in the periphery.
a. Common in spinal cord injury - After a week or two of denervation the tone returns spontaneously.
b. Trauma, physical or psychological
What is anaphylactic shock?
Anaphylactic shock occurs when there is an antigen-antibody reaction in the blood such as occurs with transfusion of an incompatible blood type, severe reaction to an insect bite, or severe food allergy. Massive production of histamine causes dilation of blood vessels and increased capillary permeability to proteins.
What are the classifications of shock?
* Low Output Circulatory Failure
- Hypovolemic shock (too little volume)
- Cardiogenic shock (pump failure)
- Obstructive shock
- Distributive shock: Venous pooling
* High Output Circulatory Failure
- Distributive Shock: Sepsis, toxic shock, anaphylaxis
What is hypovolemic shock?
- CO reduced due to loss of intravascular VOLUME
-- Reduced venous return
- Causes
-- Most often, blood loss (hemorrhage)
-- Dehydration
-- Burns
-- Fluid lost into peritoneal cavity w/ pancreatitis
What are the causes of cardiogenic shock?
- Myocardial Infarction (most frequent cause)
- Acute Valvular Dysfunction – e.g. papillary muscle rupture post-MI
- Arrhythmia – e.g., heart block, ventricular tachycardia
What is obstructive shock?
- CO reduced by vascular obstruction:
-- Obstruction of Venous return (vena cava syndrome – usually neoplasms)
-- Compression of the heart (pericardial tamponade*)
-- Outflow from heart (Massive pulmonary embolism, aortic dissection)
What is pericardial tamponade?
- Life threatening condition caused by fluid (blood, effusion fluid) under pressure around the heart.
- Decreases CO by decreasing filling
- Causes include pericarditis and MI
What is distributive shock?
- Maldistribution of flow
- Two Categories:
-- Low Output - Venous pooling due to loss of venous tone
-- High Output Circulatory Failure
What is venous pooling?
- A Low Output Circulatory Failure
- Often due to spinal shock or drug overdose
- Behaves like hypovolemic shock
-- CO severely reduced because blood is pooled in peripheral veins, rather than returned to heart
What is high output distributive shock?
- CO is normal or elevated; distribution inappropriate
- Shock is due to loss of vascular resistance
- Examples:
-- Sepsis, Toxic Shock: Bacterial endotoxin triggers vasodilation
-- Anaphylaxis
What does lack of blood flow in the periphery due to shock lead to? (Cycle)
1. Lack of blood low to the periphery injures the tissues (releases local vasodilatory factors) and converts a baroreceptor mediated constriction into a massive dilation.
2. Dilation increases venous capacitance which reduces filling pressure and cardiac output.
3. Tissues release cytokines which maintain dilation and attack other tissues.
- Histamine
- Kinins
- Nitric oxide
- Tumor necrosis factor alpha
- Prostaglandins
- Interleukins
4. Once the irreversible phase is entered correcting the lesion will not eliminate the shock state. That is largely due to dead or dying tissues in the periphery.
Why is blood pressure a poor indicator of the shock state?
1. The baroreceptors reflex can maintain blood pressure for short periods even while cardiac output is dangerously low.
2. Symptoms of low cardiac output include: cold and pale skin, pale mucous membranes, low urine volume (oliguria), incessant thirst, and impaired cerebration.
3. In septic shock the cardiac output may be normal but the peripheral oxygen demand is greatly elevated by the fever, and circulating cytokines.

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