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Pathophysiology, COPD, Asthma: Episodic airway obstruction causing…
Pathophysiology
COPD
Results from:
Pathophysiological
Inflammatory "spill over" from the lungs and/or as an expression of COPD
Cellular
TNF-a, IL-1B, IL-6, chemokines (induce leukocyte chemotaxis)
CRP
Associated with health/exercise capacity & cardiac comorbidity to predict BMI (elevation > 2 weeks after exacerbation increases liklihood of recurrent exacerbation)
Fibrinogen
Associated with worsenned FEV1 & increased risk of COPD related hospitilization (increased by exacerbation)
Serum Amyloid
Associated with exacerbation severity
Surfactant Protein-D
Associated with disease severity & cardiac comorbidity
Cliinical Manifestations/Comorbidiies:
Skeletal muscle weakness, cachexia, ischemic heart disease, cardiac failure, osteoprosis, diabetes, normocytic anemia & depression
Bronchodilators
Inhaled anticholinergics:
Reduce muscle one & glandular mucus via inhibiion of AcH interaction with M1 & M3 receptors
Combination Inhalations:
Combination of bronchodilators & corticosteroids
Corticosteroids:
Ineffective monotherapy due to corticosteroid resistance resultant of oxidative & nitrative stress
Inhaled beta-2-adrenergic agonists:
Smooth muscle relaxation via action on beta-2-receptor & cAMP production
Other:
Methylxanthines, mucolytics
Risk factors include:
Cigarette Smoking (primary):
Occurs due to associated loss in lung function & resultant cel toxicity & impaired lung tissue repair
Enviornmental:
Occurs due to long-term inhalation exposure to occupational dust/chemicals; indoor pollution dervived from biomass fuels; and/or outdoor pollution
Genetics:
E.g. ATT deficiency or polyphorisms of TNF, surfactant, proteases & antiproteases
Other:
Severe childhood respiratory infection, asthma, airway hyperresponsiveness, nutritional compromise, impaired fetal development resultin in low boirth weight and/or infants with bronchopulmonary dysphagia
Emphysema:
Loss of lung elasticity , abnormal enlargement of airspaces distal to the terminal bronchioes & associated destruction of alveolar walls & capillary beds
Resulting from imbalance between protease & antiprotease action
Protease:
Released from neutrophils & dalveolar macropphages to breakdown elastin
Anti-protease:
Inhibit elastin breakdown [diminished]
E.g.
A-1 Antitrypsin:
Reduced by inflammation & mutations of protein inhibiting genes inherited as autosomal recessive disorders (such as in PIZ gene carriers)
Centriacinar (primary):
Upper lung
Panacinar
(primary in ind. with inherited a-1 antitrypsin deficiency): Lower lung
Associated with increased cytokine concentration
TNF-a
Adhesion molecule expression
Activation of inflammatory mediators
IL-1B
Macrophage secretion of pro-inflammatory cells (cytokines, chemokines & matrix metaloproteinase)
IL-6
Links innate & aquired immunity
Stimulates C-reactive protein release from the liver
IL-10
Inhibition of TNF-a, IL-1B, GM-CSF & matix metalloproteinase discourgaes inflammation [reduced in ind. with COPD]
IL-7
Dendritic cell programming via cytokine stimulationn for T-helper & cytotoxic lymphocytes
IL-32
Associated with disease severity but is newly defined
Treatment
Initation/increased bronchodilator therapy
Hospital admittance
Oxygen therapy
Improves pulmonary HTN
Improves exercisse capaciy
Improves mortality
Improves mental & emotional stae
Pharmacotherapy:
Beta-agonists, anticholinergics, corticosteroids, methylxanthines, antibiotics
Signs
Lab Results
CBC:
Elevated leukocytes & anemia
Elevated cytokine & acute phase protein
ABG:
Hypoxemia; hypercapnia; acidosis
Radiological Findings
Hpyerinflation
-ve (flatenning) of the hemidiaphragm
Evidence of infection
Evidence of atelectasis (collapse), pulmonary edema, caridomegaly (heart elnargement)
Physical Assessment Findings
Hypoventilation; use of accessory muscles to breathe; hyperressonant lung auscultation (indicative of air trapping); cackles (indicative of mucus secretion); hypoxemia
Fever
Tachycardia
Muscle weakness; wasting; cachexia & clubbing
Pulmonary Functions Test
Measure of:
FEV1 (ideal: > 80%)
FVC
FEV1/FVC: < 0.7 confirms airflow limitation
Triggers
Viral:
Rhinovirus (common cold) [primary]
Bacterial:
Haemophilus influenzae & related species, moraxella catarrhalis, & streptoccus pneumoniae
Other:
CHF, PE, allergn exposure, irritant exposure and/or respiratory infection [50%]
Pulmonary Rehabilitation:
Reduces symptoms, improves QOL, increases physical & emotional participation in ADL, decreased risk of hospitilization
Nutritional counselling
Patient education
Exercise training
1) Loss of lung elastic recoil
resulting from emphesyma
2) Peribronchiolar Fibrosis
resulting from imbalnces in lung repair/defence and causing airway remodelling
3) Increased Airway Secretion
resulting from mucus hyperplasia & increased expression of mucin genes
4) Airway Smooth Muscle Tone
resultnig from hyperactivity of the bronchi and causing narrowing of the airway
Chronic Bronchitis:
Airway epithelial inflammation & obstruction of major & minor airways by mucus
Diagnosis: Presnece of chronic productive cough for 3 consecutive months/2 years
Resulting from:
1) Mucus Hypersecretion:
Increased mucus tenacity, increased size/number of mucus glands & goblet cells in the airway epithelium)
2) Permanent narrowing of the airways
1) Air Trapping:
Trapping of gas in the distal portion of the lung
2) Ventilation:perfusion mismatch, polycthemia (overproduction of RBC & cyanosis), pulmonary HTN, cor pulmonale, enlargement of the right ventricle to cause right-side heart failure
Bronchiectasis:
Dilation of the bronchi & bronchioles
Results from infection and/or inflammation induced destruction of the muscle & elastic supporting tissue
1)
Inspiration: Movement of gas past site of obstruction
2)
Expiration: Decreased elastic recoical of bronchial walls causes collapse to prevent normal expiratory flow
3)
Expansion of the throax disadvantages respiratory muscles, decreasing tidal volume & causing hyperventilation & hypercapnia
4)
Barrel chest
Asthma:
Obstructive airway disease
Comorbidities:
Lung cancer, pulmonary HTN & obstructive alseep apnea
Symptoms:
SOB/dyspnea; fatigue; exercise intolerance; cough; sputum production; wheeze
Asthma:
Episodic airway obstruction causing increased resistance to airflow
Facilitates oxygen/CO2 exchnage between air & blood
1) Ventilation:
Inward & outward movement of air from the atmosphere to & from the mouth via the upper airway (nasal passages; nose; mouth; & pharynx)
2) Inspiration:
Inward movement of air achieved at the lower airway (larynx; trachea; bronchi; & bronchioles of the lung )
3) Perfusion:
Movement of blood through the lungs
4) Diffusion:
Movement of gas across the alveolar-capillary membrane
5) Expiration:
Outward movement of carbon dioxide from the mouth
Carbon Dioxide: Movement from the blood into alveoli for expuslion
Oxygen: Movement from the alveoli to the blood via pulmonary capillaries
Susceptibility is determined during fetal development and/or the first 3-5 years of life. Risk factors include:
Airborne Allergen Exposure
Tobacco Exposure
Family Hx of Allergy/Allergic Disorder
E.g. IL-4, IL-5, IL-13, IgE, eosinophil, mast cell, adrenergic receptor, leukotriene, bronchial hyperresponsiveness/Adam 33 coding genes
Other:
Low birth rate and/or respiratory distress syndrome
Risk factors include:
Exposure to infectious agents, allergens or pollution
(in the presence of additional risk factors)
Female Assignment at Birth -
Heightened by smoking; obesity; & hormonal changes
Occupational Exposure to Low Molecular Weight Sensitizers
Asthma
Extrinsic (Atopic):
Allergn related mast cell activation highly associated with elevated CD4 T-helper TH2 lymphocytes
Intrnsic (non-atopic):
Irritant related mast cell activation
Exacerbation (resulting from allergen (atopic) or irritant (non-atopic) exposure
Early/Acute Phase Response:
Occurs 10-20 min following mast cell activation, lasting hours
1)
Pre-sensitized mast cell containing IgE react to antigen binding on the mucosal surface of the airways
2)
Histamine release*
3)
Bronchoconstriction, vasodilation & increased vascular permeability
for mucosal edema & increased mucous secretions
4)
Immune activation
5)
[Sometimes] Dendritic cells facilitate immunological process for further immune response
Prostaglandin D2:
Bronchoconstriction
Vasodilation & increased vascular permeability
Cytokine
Release (from TH2 cells)*
IL-4
B-cell activation, proliferation & production of antigen specific IgE
IL-5
Eosinophil infiltration (activation/promotion)
IL-8
Activation of inflammatory resposne (eosinophils, neutrophils, basophils
IL-a
Ach concentration increase for smooth muscle contraction
Mucus secretion
B-cell activation, proliferation & production of antigen specific Ige
IL-13
Impaired mucus clearance
Bronchoconstriction
Increased fibroblast secretion
TNF-a
Adhesion molecule expression
Ach concentration increase for smooth muscle contraction
Activation of inflammatory response (eosinophils, neutrophils)
Airway remodeling via goblet cell hyperplasia & submucosal gland hypertrophy
Leukotrienne:
Mucus secretion
Epithelial damage
Airway remodelling
Platelet Activating Factor:
Vascular permeability via endothelial retraction
Activation of inflammatory response (eosinophils, neutrophils)
Platelet aggregation
Bronchospasm & Bronchial hyperreactivity
Late Phase Response:
Occurs 4-8 hrs following mast cell activation, lasting days-weeks
1)
Prolonged expiration (resulting from constriction of the airways)
3)
Autonomic stimulation of local nerve endings: Bronchoconstriction
4)
inflammtion & increased airway responsiveness
5)
Airflow limitation & heightened airway responsiveness
6)
Impaired mucociliary function; epithelial injury; & mucosal edema
Bronchospasms, vascular congestion, mucus secretion, impaired mucociliary function, thickening of the airway walls & increased contractile response of the bronchial smooth muscle with resultant bronchial hyperresponsiveness and obstruction
2) Eosinophil
release
Mucus secretion & impaired mucociliary function
Epithelial damage
2) Neutrophil
release:
First response
2) T-Lymphocyte
release:
DIfferentitation of B-cells into IgE producing plasma cells for eosinophil activation
Mast cell growth cell factor
2) Basophil
release
IgE binding releases mediators of inflammation
1) Hyperinflation:
Disadvantages the respiratory muscle
Mucus in conjuction with increased intrapleural & alveolar gas pressure impairs gas exhange
2) Alveolar hypoventilation
3) Ventilation: Perfusion missmatch
4)
Increased lung volume & alveolar hypoxia stimulates
vasoconstriction
Decreased vascular perfusion increases ventilation: perfusion mismatch
5)
Decreased [CO2] causes
respiratory alkalosis
& accopanying
hypoxia
6)
Worsenning functional residual capacity increases dyspnea, heighting the effort required to breathe & causing eventual fatigue
7) Air trapping & increased inpsiration
at high residual lung volume, worsenning the effectiveness of the cough
1 more item...
Air trapping & resultant hyperinflation of the lungs
Chest tightness
Increased mucus secretion
Cough
Productive - clear: Bacterial infection indicative of allergen/iriitant trigger
Productive - coloured: Viral infection
Non-productive: Absence of infection (generally occuring 1st)
Inadequate ventilation & abnormal ventilation: perfusion ratio
Dyspnea/SOB
Passage of air through narrowed airways
Wheezing
Inspiratory: Proximal/upper constriction
Expiratory: Distal/lower constriction (generally occuring 1st)
Labratory Values
Chest X-Ray:
Indicates absence/presence of infection. Asthmatic exacerbation is indicated by...
Hyperinflation
-ve Flattening of the hemidiaphragms
Pulmonary Functions Test:
Measurement/comparison of airway patency before & after administration of a bronchodilator to determine peak expiratory flow (PEF) [time required to exhanle] monitoring by...
Forced Expiratory Volume in 1s (FEV1):
Air exhaled within 1 sexond of forced breath
Forced Vital Capacity/Forced Expiratory Volume (FEV):
Total air exhaled
Asthmatic Exacerbation
< 12% improvement
ABG
(primary): Measurement of pCO2 & pO2 to indicate ventilation
Normal
PaCO2:
35 - 45 mmHg
HCO3:
22 - 26 mmol/L
pH:
7.35 - 7.45
Asthmatic Exacerbation
pH:
< 7.35
PaCO2:
> 45 mmHg
HCO3:
> 22
Peak Flow Monitoring:
Measurement of PEF recorded according to the best of 3 readings
Yellow Zone:
50 - 79% - Indicates need for caution and/or short-acting broncho dilator
Red Zone:
< 50% - Indicates need for medical attention
Green Zone:
>80% - Indicates good asthma management
Controllers:
Long-term control
Leukotrienne Modifiers:
Inhibit leukotrienne action
Mast Cell Stabilizer:
Inhibit mast cell degranulation
Systemic Corticosteroids
Monoclonal Antibody SQ:
Anti IgE antibody - prevents IgE binding to basophils & mast cells to inhibit mast cell degranulation
Inhaled Corticosteroids
Relievers:
Quick-relief
Bronchodilators
Beta-2-Agonist:
Action on beta 2 adrenergic receptor increases cAMP to inhibit smooth muscle contraction
Anticholinergics:
Inhibit muscarinic cholinergic receptor to reduce airway vagal tone
Systemic Cortiosteroids (severe):
Inhibit COX & lipoxygenase pathway of inflammatory process to suppress leukocytes & fibroblasts and reduce capillary permability
Diabetes Mellitus (Part. I)
Macronutrients
Protein: Excess are converted to fatty acids, ketones or glucose - who may facilitate glucogenesis in their absence
Fat:
(1)
Glycolysis;
(2)
Fatty acid transport to all tissue c. (excluding those of the brain, NS & RBC);
(3)
The liver facilitates conversion of excess fatty acids into ketones, which then enter circulation
Glucose:
(1)
Excess initiates insulin release
(2)
2/3 undergo storage as glycogen
(3)
Liver facilitates glycogenolysis between meals to increase concentration
(4)
Saturation of skeletal muscle & liver is followed by liver facilitation of glycogenesis
Pancreas:
Located posterior to the stomach b/w the spleen & duodenum for hormonal blood glucose control
(1) Exocrine
Secretes digestive juices into the duodenum via the pancreatic duct by activation of acini cells
(2) Endocrine:
(1-2%) Secretes hormones responsible for carb metabolization via islets of Langerhans, which contain:
Alpha cells
Glucagon
(secreted in response to low BG): Increases glycogenolysis (increasing a.a. transport for glucogenesis); activates adipose cell lipase to harness energy contained in fatty acids; high levels increase bile secretion and thus reduce gastric acid (inotropic effect)
Delta cells
Somatostatin:
Reduce GI activity (increasing the time required for food absorption/extending the use of absorbed nutrients); & inhibition of insulin & glucagon release
Beta cells ...
Dysfunction - Reduced cell mass; abnormal function; or a combination of both:
Results from glucolipotoxic conditions causing apoptic death; reduced insulin synthesis due to adipokine leptin; inflammatory cytokines (toxic); & cell exhuastion due to intracellular oxidative stress & endoplasmic reticulum dysfunctio
Insulin:
Biphasic release reduces glycogenolysis & lipolysis; reduces glucogenesis (increasing protein synthesis); & increases uptake of glucose by target cells via glucose transporters (who enable direct action on blood glucose)
(1)
Entrance into circulation results from high BG;
(2)
The liver uses 1/2;
(3)
Binding to membrane receptors containing alpha & beta receptors activates kinases
(4)
Autophosphorylation of the beta receptor increases/decreases enzymes required for intracellular insulin effect (as needed)
(5)
ATP closes the K channel to cause depolarization
(6)
Opening of Ca channels causes insulin secretion
Alpha
Extends outward to form a site of attachment
Beta:
Intracellular component containing kinases
GLUT-4: Skeletal muscle & adipose tissue
GLUT-3: Neuron (highly expressed in the brain)
GLUT-2: Beta & liver cell
GLUT-1: All tisue
Amylin
(achieves hyperglycaemic & satiety effect): via gastric emptying (increasing the time required for food absorption); & inhibition of glucagon release
Counter-regulatory hormones: Counteract insulin storage during
fasting, exercise & stress
Epinephrine
(achieves transient hyperglycaemia via): glucogenesis & glycogenolysis in the liver & muscle; lipolysis; inhibition of glycogen formation; inhibition of insulin secretion (inhibiting peripheral uptake up glucose); inhibition of cholesterol breakdown into bile acids (increasing gastric acid)
Growth Hormone:
Lipolysis; increases protein synthesis; antagonizes insulin effects (decreasing cellular uptake & use of glucose); acromegaly (hypersecretion) may result in DM
Glucocorticoids:
Glucogeneogenesis; decrease tissue use of glucose; stimulate protein catabolism & reduce protein synthesis via inhibition of amino acid uptake
Counter-regulatory Mechanisms
Somogyi Effect - Insulin induced hypoglycaemia followed by rebound hyperglycaemia:
Occurs mostly in T1DM tx of hyperglycaemia or insulin resistance; hypoglycaemic state causes compensatory stimulation of counter-regulatory hormones = hyperglycaemia & slight insulin resistance
Dawn Phenomenon - Hyperglycaemia between 0500 & 0900 without preceding hypoglycaemia:
Results from abnormal circadian rhythm, which alters diabetic glucose tolerance; tx involves alteration to insulin dosage & administration time
T1DM:
Absolute lack of insulin; hyperglycaemia; substitution of fat & protein as primary energy source
Autoimmune Type 1A:
Autoimmune loss of beta cells in pancreatic islets of Langerhans (including insulin, islet cell, antibody directed at other islet autoantigens); Result of genetic-environment interaction, including:
MHC on chromosome 6: Encode leukocyte antigens HLA-DQ & HLA-DR (3 & 4 in specific are associated with 20x increase in T1DM)
Chromosome 11: Insulin gene regulation of beta cell replication & function
Other - Drugs & chemicals; nutritional intake; or viruses
Idiopathic Type 1B: (less than 10%)
Beta cell loss without evidence of autoimmunity; Associated with varying degrees of insulin deficiency, resulting in episodic ketoacidosis
Strong genetic component (especially Asian & African)
T2DM:
Insulin resistance ranging form relative insufficiency to predominant secretory effects due to insulin molecule abnormality; increased insulin antagonists; down regulation of insulin receptors; or reduced activation of post-receptor kinases & alteration of glucose transporter proteins; & abnormal insulin secretion by beta cells
Old age; obesity; hypertension; physical inactivity; family history; metabolic syndrome are considered risk factors
Obesity
High intracellular TG & cholesterol = lipotoxicity, altering insulin secretion
High cytokines = insulin resistance
High serum FFA decreases insulin sensitivity = increased production of hepatic glucose & hyperglycemia
Hyperinsulinemia
High adipokines increase PPAR gamma = increased production of serum leptin & resistin; decreased production of adiponectin
Metabolic Syndrome
is diagnosable if > 3 of the following are met: Abnormal obesity (waist circumference > 33 (women) & > 102 (men); TG > 1.7 mmol/l; HDL < 1.3 mmol/l; BP > 130/85; Fasting plasma glucose > 5.6 mmol/l
Other DM:
Genetically defined; associated with disease/disorder; induced by infection, drugs or chemicals
Gestational DM:
Any degree of glucose intolerance with onset/recognition occurring during pregnancy; insulin resistance & impaired secretion; increases maternal & fetal morbidity; Old age, family hx, hx of complication & large fetus ( > 9 lbs) are considered risk factors
Diagnostic Testing
Random Blood Glucose Test:
Diabetes > 11.0 mmol/l & clinical manifestations
Hemoglobin A1C:
Measure of hemoglobin glycosylation to provide index of blood glucose over 6-12 weeks; normla: < 7%
Capillary Blood Glucose:
Capillary blood regent & glucometer to determine glucose levels
Oral Glucose Tolerance Test (OGGT):
Measure of plasma glucose response to 75g of concentrated glucose solution after 2 hrs (diabetes: > 11.1 mmol/l)
Fasting Plasma Glucose (FBG) - 8 Hours:
Diabetes: > 7.0 mmol/l (normal < 6.0 mmol/l)
Urine Test:
Measures glucose/ketone levels
Genetic Study:
Measure of antibodies
Clinical Manifestations
Polydipsia (excess thirst):
Intracellular dehydration associated w/ hyperglycaemia pulls H20 from cells
Polyphagia (excess hunger):
[Not common in T2DM] Cellular starvation & depletion of cellular stores
Polyuria:
Glucose requiring filtration by glomeruli of kidneys > amount of glucose capable of resorption by renal tubules (ie. glucose acts as an osmotic diuretic)
Body Mass Changes:
Loss of fluid via osmotic diuresis; vomiting associated with keto-acidosis; depletion of cellular stores
Anti-diabetic agents
First Line
Biguanide:
Increase insulin sensitivity of liver & peripheral tissue; reduce hepatic glucose uptake
Second Line
SGLT-2:
Reduce renal Na-glucose co-transport of proximal convoluted tubule; increases risk of UTI;
contraindicated
in renal dysfunction, elderly & use with loop diuretics
Insulin Secretagogues:
Binding to ATP sensitive K channel receptor on beta c. causes depolarization which encourages Ca influx to initiate insulin secretion
Incretins:
Activate beta c; inhibit alpha c.
Alpha glucosidase:
Reduce carb breakdown;
contraindicated
in use with sulfonylurea, which causes hyopglycemia
TZD:
Binding to PPAR-gamma highly expressed in adipose t. increase serum leptin resistin; decreasing adipocentin, fatty acids, TG, BP & inflammatory mediators
Insulin:
Similarity to endogenous insulin reduces risk of complication; administered SQ or IV to prevent GI destruction; continuous infusion increases post-prondial glycemic control & prevents hypoglycaemia
Weight loss agents
Complications
Acute:
Hypoglycaemia; diabetic ketoacidosis; hyperosmolar hyperglycaemic nonketotic syndrome
Chronic
Microvascular disease:
Retinopathy, neuropathy, nephropathy
Macrovascular disease:
CAD, PVD, cerebrovascular disease
Fluid & Electrolyte Imbalances
1)
Capillary Hydrostatic pressure > oncotic pressure: Movement of fluid into interstitial psace
Interstitial Hydrostatic Pressure: Small negative value contributes minorly to the movement of fluid from the capillary toward the tissue
2)
High capillary osmotic pressure results from movement of fluid into the interstitial space which leaves solutes behind
3)
High capillary osmotic pressure: Encourages movement of fluid from the interstitial space to the vessel
4)
Some particles (e.g. glucose & electrolytes) move from the vessel into intersitial space, establishing colloid osmotic pressure to
5)
Lymphatic system: Facilitates drainage of extra fluid
Risk factors of infant fluid imbalance:
High metabolic rate
increases daily fluid exchange
Inability of
immature kidneys
to concentrate urine
High [H20] in extracellular compartment
results in high water ingestion/excretion,
decreasing bodily fluid reserve
Comparably
small SA of the skin
increases fluid loss through the skin
Edema:
Non-functional fuid accumulation in intersitial space
Treatment
Control underlying mechanism
Correct the problem
Treat symptoms
Supporitive measures (e.g. elevation of the legs, supportive stockings, etc.)
Third-spacing:
Non-functional fluid accumulation in transcellular space
Alterations to normal fluid movement, including:
4) Lymphatic obstruction:
Prevents excess fluid drainage
Re. Increased tissue oncotic pressure encouraging movement of fluid from the vessel or increased
1) Increased capillary hydrostatic pressure
at the venous end of the capillary increases exit of fluid from the capillary
Re. HTN resulting from increased fluid volume and/or in response to the back-up of blood
3) Increased interstitial colloid osmotic pressure:
Prevents maintence of fluid in the vessel & instead encourages movement of fluid into the interstitial space
Re. Increased capillary permeability in response to inflammatory mediators
2) Low capillary oncotic pressure:
Prevents movement of fluid from the interstitial space into the vessel
Re. Decreased [albumin] as albumin is the most prevelant colloid
Including...
Lungs
Re. Insufficient gas exchange/hypoinflation of the lungs
Dyspnea; restlessness; deminished breath sounds; and/or cackles on auscultation
Abdomen
Re. Increased IHP due to portal vein injury by liver cirrhosis or inflammatory reponse
Ascites: Third-spacing in the peritoneal cavity
Airway
Re. inflammatory response to allergn/microorganism
Dysphagia; anxiety; stridor; airway obstruction; and/or asphyxia
Intestines
Third-spacing occuring in lumen & intestinal wall
Brain
Re. inflammatory response to infection/trauma
Headache; altered LOC or coma; abdnormal pupil size or reflexive responses; changes in respiratory pattern; changes in muscle tone; and/or abnormal posturing
Peripheral
Re. Obstruction of venous blood flow results from increased CHP or lymphatic obstruction
Dependent: Immobility
Pitting: Salt retention
Balance is maintained via...
ADH
[hypothalamus/Post. Pit.]
Acts in response to low blood volume or increased osmolarity
Increases H20 retention
RAAS
Acts in response to juxtaglomerular cells [kidney] which meausre BV stretch
Renin: Synthesize antigotensinogen into angiotensin II
Increase Na reabsorption
Aldosterone synthesis: Acts on distal tubule to reabsorb Na (and H20) & lose K
Thirst
Occurs in response to small changes in fluid volume or osmolarity
Natriuretic Peptide
Acts in response to blood volume
Increase Na/H20 excretion via:
Decreased aldosterone
Vasodilation
Supression of renin levels
Baroreceptors
[BV wall & kidneys]
Measure of BV stretch via blood volume/pressure
SNS
Acts in response to changes in blood volume or BP
Na reabsorption
Renin release
Constriction/relaxation of afferent/efferent artioles in the kidneys (constriction = increased H20 retention)
Osmoreceptors
[hypothalamus]
Meausre of blood osmolarity
Proportiante Changes in Na/H20 (Isotonic)
Gains:
Isotonic fluid excess
Re. Excess flluid intake or insufficient elimination
Clinical Manifestations (unusal):
Weight gain, increased urine output edema, neck vein distension, bounding pulse, respiratory distress (cough or crackles), decreased HCT & BUN
Tx:
Discontinue fluid inatake, decrease volume via diuretic therapy, cause tx
Lossess:
Isotonic fluid defifict
Re. Insufficient fluid intake or excess elimination
Clinical Manifestations:
Thirst, weight loss, decreased urine output, increased SG & osmolality, sunken eyes, loss of skin tugor, tearing in infants, reduced BP or pulse, increased HCT & BUN
Tx:
Fluid replacement, cause tx
Disproportiante Changes in Na/H20
Gains:
Hypernatremia
Greater than 145 mmol/L Re. loss of H20 or excess Na in ECF
Clinical Manifestations (unsual):
Thirst, sunken cells, neuromuscular excitability, volume depletion cuasing orthostatic HTN & dry mucus membrane
Tx:
Decrease [salt], increased [fluid], slow correction
Lossess:
Hyponatremia
Less than 135 mmol/L Re. Excess H20 or loss of Na in ECF
Clinical Manifestations:
Cellular fluid shift causes brain swelling, GI fluid shift causes diarrhea, neuromuscular changes, low serum osmolality, HCT & BUN
Tx:
Decrease fluid excess, Na replacement, monitroing, cause tx
Potassium
Normal: 140-150 mmol/L (normal cell ) & 3.5 - 5 mmol/L (ECF)
Hypokalemia:
< 3.5 mmol/L Re. insufficient K intake
Clinical Manifestations
(slow)
GI:
Inhibition of normal peristalsis causes nausea, vomiting and/or diarrhea
Skeletal:
Decreases smooth muscle activity causes constipation & paralytic ileus
Renal:
Poor urine concentration increases plasma osmolarity to stimulate thirst
Caridovascular:
Abnormal electrical activity/contractility encourages postural hypotension & cardiac arrhythmias
Tx:
Prevention, oral K supplements
Hyperkalemia:
> 5 mmol/L Re. excess K intake
Clinical Manifestations
(unusual)
GI:
Nausea, vomiting, cramping, diarrhea
Skeletal:
Abnormal sensation, paresthesia, weakness, dizziness
Caridovascular:
Reduced conductivity causing ventricular afribilation and/or cardiac arrest
Regulation: Vitamin D, PTH & Calcitonin
Normal [Ca]: 2.1 - 2.6 mmol/L
Clinical Manifestations:
Neuromusuclar & cardiovascular
Inflammation (Part. I)
Human Defence Mechanisms
Inflammation:
Humoral (ie. blood or plasma derived processes) OR cellular (ie. cell derived processes)
Immunity
(Acquired, specific & adaptive): Invokes memory, humoral OR cellular processes
Natural Barriers:
Epithelial layers lining the GI, genitourinary & respiratory tracts
Mechanical:
Eliminates pathogens (e.g. sneezing)
Chemical:
E.g. Mucous, tears, ear wax, etc.
Clinical Manifestations
Pain (Dolar):
Result of increased capillary permeability; prostaglandin action on nerve endings; & final product of kinin system
Pus:
Result of neutrophil death
Clot:
Result of thrombus activated by clotting cascade
Redness (Rubour):
Result of vasodilation & increased blood flow to injury site
Loss of function (Function Lossa):
Edema & pain
Heat (Calor):
Result of vasodilation & increased blood flow to injury site
Edema (Tumour):
Result of vasodilation; increased blood flow to injury site; & increased capillary permeability
Acute Inflammation:
Short-duration; self-limiting; non-specific; leads to healing & chronic inflammation
Cellular:
Leukocyte (and additional c.) migration from circulation to tissue for elimination of offending agents & release of chemical mediators (mast c. & macrophages) from tissue to promote leukocyte adhesion
Vascular:
Changes in vessel diameter increase blood flow to the site of injury...
(1)
Brief vasoconstriction;
(2)
Vasodilation & increased blood flow;
(3)
Decreased blood flow & increased vascular permeability;
(4)
Increased hydrostatic pressure & increased leukocyte movement;
(5)
Heat, redness & CAM expression
Mast Cell Degranulation (primary)
-- Mast Cells -immature prior to departing circulation - contain preformed granules & are located in CT adjacent to blood vessels]
Long-term
(Synthesis)
Leukotrienes:
Dilation & increased permeability for exudatio
Cytokines:
Release of IL-4 & TNF-a
IL-4:
B cell proliferation & antibody production
TNF-a:
Increase permeability & leukocyte migration
Prostaglandins:
Dilation & increased permeability for exudation & pain
Growth Factors:
Release VEGF & PDGF
VEGF:
Endothelial cell proliferation
TNF-a:
Increase permeability & leukocyte migration
Immediate
(Degranulation)
Tryptase:* Release of chronroitin sulfate
Cytokines:* Release of IL-4 & TNF-a
IL-4:
B cell proliferation & antibody production
TNF-a:
Increase permeability & leukocyte migration
Histamine:
Dilation & increased permeability for exudation
*Neutrophil Chemotactic Factor:
Neutrophil attraction to injury site for phagocytosis
Eosinophil Chemotactic Factor:
Neutrophil attraction to injury site for phagocytosis & inhibition of vascular effects
Release of
Cell Derived Mediators
Liver-plasma Derived Mediators
Acute-phase proteins: Fever & inflammation
Factor XII (Hageman Factor Action): Clotting/fibrinolytic system & kinin system
Cell Derived Mediators
Preformed Mediators
Platelets: Serotonin
Neutrophils & Macrophages: Lysosomal enzymes
Mast Cells: Histamine
Newly Synthesized
Leukocytes: Prostaglandins, leukotrienes & platelet activating factor
Leukocytes & Macrophages: NO & O2 derived free radicals
Macrolymphaendothelial cells: Cytokines
Plasma Protein System
-- Stimulation of 1 cascade stimulates activation of additional cascades located in the liver
Clotting System:
Release of
thrombin
elicits formation of fibrin clots
Extrinsic: External T. damage
Intrinsic: Endothelium damage
Kinin System:
Release of
bradykinin
elicits Vasodilation; vascular permeability; & pain
Complement System:
Release of
CB3
(opsonization),
C5A
&
C3A
(chemotaxis & anaphylaxis) elicits cell lysis
Leptin: Mannose binding activates enzymatic activity
Alternate: Immediate inflammation
Classic: Pathogen entrance
Margination: Decreased leukocyte migration encourages tight adherence to endothelium for pseudopod formation
Phagocyte plasma membrane extends in finger-like projection
Diapedesis: Leukocyte movement through widened junction b/w endothelial & tissue c. followed by (migration) movement across endothelial walls for tight adherence to endothelium
Opsonization: Increases invader recognition & binding
Surrounding pseudopods engulf bacteria/cell disease causing lyosome fusion wth phagosome for formation of a phagolysosome
Degradation by lysosomal enzymes
Endothelial injury increases adhesion molecules = leukocyte adherence & LDL oxidation
Macrophage signal triggers inflammatory response: Release of mediators & cytokines
Communication b/w innate & adaptive immune response: Process/presentation of pathogen to immune cells; T-cell communicating w/ innate system for partial destruction & b-cells for lineage formation
Platelet & sub-endothelial activation: Increased adhesion molecules & smooth m. proliferation
Formation of lipid core forms fibrous cap responsible for vessel occlusion
MI
Ischemic Disease
Ischemic Disease (80%): Cerebrovascular obstruction
Hemorrhagic (20%): Brain bleeding resulting from BV rupture, aneurysm & injury
Childhood Obesity
Complications
Colon cancer:
Results from increased BMI, waist circumference & visceral/central adiposity
Osteoarthritis:
Results from weight gain which causes stress on bone/ankles
Liver disease:
Results from fat deposition in the liver = fibrosis
Acanthosis Nigricans:
Hyperpigmentation resulting from insulin resistance
Vascular disease:
Results from dyslipidemia & inactivity = atherosclerosis
POCS & NAFLD:
Hyperandrogegism & hyperinsulinemia associated with increased body hair, acne & testosterone resulting from insulin resistance
T2DM:
Results from dysregulation of lipid metabolism which causes hyperglycaemia & changes in blood flow due to insulin resistance = retinopathy
Hypertension:
Results from effects of angiotensin
Stroke:
Results from visceral adiposity (esp > 65)
Excess TNF-a:
High fatty acid concentration causes fat breakdown in adipose tissue; high VLDL from the liver & reduced HDL encourages arterial deposition
Causes interference in insulin signalling of muscle & liver tissue, decreasing insulin binding to cause compensatory increase in insulin secretion & thus beta cell exhaustion = hyperglycaemia
Feedback Mechanism
Ghrelin
(low in obesity): Excretion is facilitated primarily by the stomach & secondarily by the small intestine in response to low BG (during fasting state); hypothalamus transmits hunger signal to increase fat storage & orexigenic effects
GLP-1:
Released by distal illeum & colon in response to glucose; thalamus promotes satiety, which stimulates insulin release
CCK:
Released by enteroendocrine cells in response to fat in the duodenum; promotes satiety
Insulin:
Released by pancreatic cells in response to glucose; promotes satiety
Stomach distension:
Activation of stretch receptors by food; promotes satiety
Measurable by
BMI
: Weight (kg) / Height (m^2)
Ideal:
18.5 - 24.9 kg/m^2
Overweight:
25 - 29 kg/m^2
Obese:
> 30 kg/m^2
Paediatric: Determined by growth charts that factor gender & age
Overweight:
> 85th percentile but below the 97th
Obese:
> 97th percentile
Adipocytes: Size increases due to increased caloric intake
Leptin
(high in obesity - due to pro inflammatory cytokines): Energy regulation & glucose homeostasis reduces appetite; Action on hypothalamus activates SANS for peripheral vasoconstriction & increased BP = hypertension
Angiotensinogen
(synthesized in proportion to adiposity): Passage through kidneys & lungs synthesizes angiotensinogen II which increases BP via vasoconstriction & increased H20 retention = hypertension
Resistin
(high in obesity): Associated with atherosclerosis, cardiovascular disease, fatty liver disease, etc.
Adiponectin
(levels are negatively correlated with HDL): Normally produce insulin-sensitizing effects which reduce TNF-a and increase VLDL clearance
Key terms
Appetite: Desire for particular food
Satiety: Discourages food-seeking behaviour
Hunger: Promotes food-seeking behaviour
Children's Exercise & Nutrition Centre:
Measures success by reduced body fat percentage; & mathematical index (actual & expected weight x10)
Exercise: (45m - 60m/day)
Increases insulin sensitivity; reduces gluconeogenesis; improves lipid profile
Failure of Diets:
Occurs because metabolic rate increases quickly following return to previous food levels - suggests 20m food rule instead
Physiological Testing
Hemoglobin A1C:
< 6.0%
Body fat measurement; electrocardiogram; BP; Pulmonary function; & fitness test
Glucose 2hrs following meal:
5 - 8 mmol/l
Fasting glucose
: 4 - 6 mmol/l
TG
: 1.7 mmol/l
Total cholesterol:
< 5.2 mmol/l
HDL:
> 1.0 mmol/l
LDL:
< 3.0 mmol/l
Stress & Adaptation
Involves individual responses to stress, dependent on ....
Individual Judgement:
Conscious appraisal of change, challenging one's ability to cope (ie. Demand:resource imbalance)
Physiological Response:
Dependent on personal interpretation which may heighten/reduce physiological outcomes
Mineralocorticoids:
Primarily aldosterone, - produced in zona glomerulosa
Catecholamines:
Primarily epinephrine & norepinephrine - produced in zona fasciculata & reticularis
Glucocorticoids:
Primarily cortisol - produced in zona fasciculata
External Stimuli
Quality:
Severity of stressors (e.g. daily, major change affecting many, etc.)
Duration:
E.g. Acute, sequential, chronic-intermittent, etc.
Quantity:
Sum of negative consequences (pos/neg)
HPA Axis
1) Stress response activates the
thalamus
for stimulation of the
cerebral cortex
2)
Limbic System:
Facilitates emotional response
3)
Hypothalamus:
Facilitates CRH (CRF) secretion
4)
Locus Ceruleus:
NE secretion activates the
ANS
; increasing NE & EPI secretion
Stimulation of the
Adrenal Medulla
EPI:
Gluoconeogenesis; lipolysis; contractility; HR (thus CO); & bronchodilation
NE
(fight vs flight): Increases BP; coagulation; vigilance, arousal & anxiety; sweat production; goosebumps; & pupil dilation
4)
Ant. Pituitary:
ACTH secretion activates the
Adrenal Cortex
; stimulating cortisol secretion
Cortisol:
Decreases inflammatory immune response; altering glucose, fat & protein metabolism via binding to specimen & albumin; inhibition of hippocampus function
4)
Post. Pituitary:
ADH secretion
Na/H20 retention stimulates input from cortisol & catecholamines
High SRF increases ACTH to promote the synthesis of aldosterone and further encourage Na/H20 retention
2)
Reticular Activating System
Increases alertness, arousal & muscle tension (via action on spinal cord reflexes)
ACUTE stress:
Achieved at the hypothalamus & anterior pituitary - negative feedback decreases ACTH, inhibiting cortisol
CATECHOLAMINE Effects:
High HR & BP; glycogenolysis; bronchodilation; changes to blood flow low GI motility & increase urinary retention; heightened metabolic rate improves nutrient absorption
CHRONIC Stress:
Negative feedback system is blunted, prolonging activation of the HPA
CORTICOID Effects:
Na/H20 retention by kidneys, increasing BV & BP; lipolysis & gluconeogenesis, causing hyperglycemia & immune suppression
Negative:
Gluconeogenesis decreases muscle mass; nitrogen depletion; t-cell reduction decreases immune response; hyperglycaemia; catecholamine release causes cardiovascular strain
Impaired Hippocampal function:
Neuronal atrophy & destruction of dendrites; decreased short-term memory; decreased accuracy of contextual memories & impaired reliability; & impaired ability to recognize threat
Emotional symptomology:
Nervousness, anxiety & butterflies; phobias; depression & moodiness; irritability & frustration; substance abuse; desperation for control
Healing:
Decreased immune response to vaccines; depression of adaptive immune system decreases identification/eradication of pathogens, decreasing wound healing; decreased response to inflammatory stimuli; cortisol inhibition of vascular endothelial growth factor reduces angiogenesis; suppression of killer cells increases susceptibility to infection
Clinical Interventions
Eliminate/inhibit stressors: Avoidance; acceptance; plan of action; positive reappraisal
Response Management: Adequate diet; limits; exercise; healthy coping; relaxation; imagery; or exercise
Delirium
Hypothesis of
pathophysiology
NT Dysregulation/Cholinergic:
Acetylcholine responsible for memory & cognition is inhibited by dopamine; dopamine agonists thus induce delirium while antagonist treat delirium
Physiological Stressors
Neuroinflammatory:
Cytokines increase peripheral c. production, weakening the blood-brain barrier & encouraging entrance of inflammatory agents. Inflammatory agents enter blood tissue & interact with microglia responsible for modulation of endothelial cells to influence cerebral blood flow, signal propagation & neuron excitability
Metabolic Derangement
Electrolyte Disorders
Genetic Factors
Diagnostic Criteria
C) Cognition disturbance
D) Disturbances in criteria A/C cannot be justified by pre-existing neurocognitive disorders AND didn't occur in the context of reduced arousal
B) Baseline deviation is quick (hrs - days) & fluctuating in severity
E) Evidence that the disturbance has resulted from direct physiological consequences of another medical condition; substance intoxication/with-drawl; toxin exposure or multiple aetiologies
A) Attention disturbance (reduced awareness)
Clinical Features:
Acute onset; fluctuating course; inattention; disorganized thinking; altered LOC; cognitive deficits; perceptual disturbances; psychomotor disturbances; emotional disturbances; altered sleep-wake cycle
Hyperactive:
Restlessness; agitation; insomnia; vigilance; rapid speech; mistaken for schizophrenia, bipolar disorder and/or agitated dementia
Hypoactive
(primary): Slowed & lack of movement; speech paucity; unresponsiveness; associated with high mortality
Mixed:
Alternating hyper-/hypo- active states
Risk Factors
Predisposing
(Client specific baseline present upon admission): Demographic characteristics; cognitive status; functional status; sensory impairment; reduced oral intake; drug use; & co-existing medical conditions
Precipitating
(Factors related to hospitalization): Primarily neurologic diseases; incurrent illness; surgery; drugs; & prolonged sleep deprivation
Dementia (Primary):
Associated with reduced cerebral blood flow; cholinergic deficiency; & inflammation
Clinical Tx
Targeted Risk Factor:
Cognitive impairment (requires orientation & therapeutic activity); sleep deprivation (especially non-pharmacological); immobility; visual impairment; hearing impairment; dehydration
Pharmacological Management:
Antipsychotics (e.g. low dose Haloperidol) highly associated with mortality
Mood Disorders
Genetic Etiology:
Associated with polymorphisms of genes responsible for...
Metabolic control of NTs & their receptors
Intracellular transduction of neuronal signals
Population control of neurons & their synaptic connections
the speed at which all above processes occur in response to environmental changes
Etiological Theories
Neurobiological:
Attributes MDs to deficiency/dysregulation in CNS concentration of NT which impedes NT synthesis by presynaptic neuron; storage in synaptic vesicles; release of NT via axonal terminals; binding of NT to post synaptic membrane receptors; removal of the NT from the synaptic cleft
NE & E
(DA): Excitatory or inhibitory action via adrenergic pathway which stimulates cerebral cortex to activate limbic system & then brain stem (locus coeruleus)
5-HT
(tryptophan): Inhibitory action via adrenergic pathway which stimulates cerebral cortex to activate limbic system & then brain stem (raphe nucleus) - eg. Depression, OCD
DA
(tyrosine): (Mostly) Excitatory action on motivation & emotional regulation (substantia nigra/ventral segmental midbrain) - eg. Psychotic disorders
GABA, Glycine, Glutamate:
Glutamate - Excitatory
|
Gaba & Glycine - Inhibitory
Ach
(choline): Excitatory or inhibitory (basal ganglia/motor cortex) - eg. Alzheimers
Biogenic Amine:
Attributes MDs to deficiency in 5-HT, NE & DA in the synaptic cleft (decreased presynaptic release OR postsynaptic sensitivity)
Chicken & egg phenomenon
BDNF:
(Responsible for neuronal cell growth, synaptic changes occurring throughout a person's lifespan & promotion of the cyclic process) Synthesized in response to activation of serotonin receptors & secreted by "Val" & "Met" alleles following activation of DNA-binding factors responsible for the stimulation of genes involved in serotonin function [low]
Cyclic Process:
Promotes outgrowth, synapse formation, survival of serotonin neurons & eventual innervation of multiple brain regions
Met-allele
: Associated with small gestational hippocampus; hippocampal hyper activation during learning; poor hippocampus-dependent memory function
Hippocampus:
Modulates cognitive aspects - eg. Memory impairment, hopelessness/doom, guilt, suicidality (associated with high risk of depression if found in conjunction w/ short allele of the serotonin transporter & psychomotor stress)
Other
Result (generally) from over stimulation of the HPA axis
Developmental:
Loss of parent/emotionally adequate parenting to cause delay in appropriate developmental milestones
Family Distress:
Disruption in family dynamics involving maladaptive circular patterns in family interactions
Behavioural:
Severe reduction in rewarding activities OR increased unpleasant activities
Social Factors:
Adverse/traumatic life event (especially involving the loss of an important relationship/role)
Psychodynamic:
Distorted -ve beliefs/thoughts about self, environment & the future
Serotonin Transport Gene:
(Responsible for 5-HT transport) Contains polymorphism giving rise to short & long alleles (an ind. may be homozygous for either short or long alleles OR heterozygous for for one of ea)
Short-allele:
Slow synthesis of serotonin transporter reduces speed with which serotonin neurons can adapt to changes in their stimulation
Neurophysiology of Symptoms
Prefrontal/Cerebral Cortex:
Planning/insight, problem solving, judgement, emotional expression - pruned during underuse that results from 5-HT & NE deficiency
Hypothalamus:
Autonomic regulation --> Sleep & appetite changes; fatigue; & anhedonia
Temporal lobe:
Integration & interpretation of somatic, bodily, visual or auditory info to recognize & respond appropriately - decreased function during underuse that results from 5-HT & NE dysregulation
Amygdala:
Modulates behaviour, fear, aggression & sexual arousal in response to signalling from the temporal lobe, occipital lobe, hypothalamus & limbic structures --> Anhedonia, vigilance/fear, exaggerated stress, increased NE & CRF
HPA Axis:
Corticotropin secretion in response to CRF stimulates corticotropin receptors to release cortisol in the blood --> Erratic cortisol spikes & activation of the Amygdala & NE system
Symptoms:
Cytokine Dysregulation:
Abnormal mediation between immune & nerve cells causing adverse effects that manifest as symptoms of major depression (and related symptoms)
Physical Pain:
Accumulation of 5-HT at the nerve synapse
Circadian Dysfunction:
Deep sleep reached early in the sleep-cycle, temperature dysregulation, abnormal hormone secretion due to changes in circadian rhythm (sleep pattern integrated into 24h light-dark solar day, associated with monthly rhythms of the moon to provide temporal organization & promote environmental adaptation)
|
Tx: Sleep hygiene teaching, sedative meds
Decreased thyroid function:
Requires thyroid replacement therapy to reverse the process & increase speed of tx metabolization/response
Key Features
Airway Remodeling
resulting from:
Increased [goblet cell]; Hyperplasia & hypertrophy of smooth muscle cells causing thickenning of smooth muscle and increased airway deposition of collagen & additional proteins, contributing to thickenning of the lamina reticularis with subepithelial fibrosis & increases vascularity of the airway wall
Outcomes:
Mast cell activation
Epithelial changes
Submucosal infiltration of lymphocytes & eosinophils
Thickening of the basement membrane
Bronchospasm
resulting from:
Increases responsiveness to cholinergic receptors
Alteration of muscarinic receptor function
Mucus Hypersection
resuting from:
Goblet cell hyperplasia & submusoal gland hypertophy
Outcomes:
(In combination with increased plasma exudation) Formation of mucus plugs causes airway obstruction
Increased airway hyperresponsiveness
Impaired mucocilliary function causes worsenned ability to clear mucus
Regulators of Blood Glucose
Counter Regulators
Clinical Tx
Regulatory Mechanisms
Tx
TX
Regulatory Mechanisms
Consequences
Tx
Regulators
Inflammatory Mediators
Mechanism of Action
Atherosclerosis
Childhood Etiology
Respiratory System
Adult Etiology
Subtype
Clinical Manifestations
Pharmacological Therapy
Etiology
Mechanism of Airflow Limitation
Phenotypes
Mechanism of Air Trapping & Hyperinflation
Mechanism of Systemic Inflammation
Acute Exacerbation (AECOPD)
Clinical Manifestations
Treatment
Capillary Fluid Balance
Capillary Fluid Imbalance
Infant Etiology
Clinical Manifestations
Na/H20 Regulation
Disorders of Na/H20 Balance
Disorders of Potassium Imbalance
Calcium, Phosphorus & Magnesium Imbalance