Respiratory Exam

Dissolved and Bound Oxygen

1) Dissolved - According to Henry's Law, amount of oxygen dissolved is proportional to the partial pressure - For each 1 mmHg PaO2, there is 0.003 mL O2 per 100 mL blood - If arterial pressure (PaO2) is 100 mmHg, then there is 0.3 mL O2/100 mL blood - total dissolved O2 in the blood, multiply by CO - 0.3 mL O2/100 mL of blood x 5000 mL/min = 15 mL O2/min - delivering 15 mL of dissolved O2 per minute Oxygen demand at rest: 250 mL O2/min In extreme situations the tissue requirements maybe on the order of 300 ml O2/min - dissolved O2 is not an efficient way meet our demand. This is where hemoglobin comes in 2) Hemoglobin - 1 gram of Hb binds 1.34 mL O2 - 15 grams of Hb per dL of blood - 15g Hb/1 dL x 1.34 mL O2/1g Hb = 20 mL O2/dL - 20 mL O2/dL of blood (and 1 dL = 100 mL) - Total bound O2 in the blood, multiply by CO - 20 mL O2/dL of blood x 5000 mL/min = 1000mL O2/min - delivering 1000 mL of bound O2 per minute - more than enough to cover demand of 250 mL per minute.

Factors Influencing Static Compliance

1) Tissue Structure & Composition - Collagen fibers that lie between the alveoli and capillaries add stiffness and create final restraint at TLC (TLC, inspiration limited by max stretch of lung parenchyma) - Elastin fibers contribute to recoil properties (elasticity) - Cellularity of Interstitium - DISEASES that cause stiff lungs (restrictive lung diseases) SARCOID and INTERSTITAL FIBROSIS --> Less compliant lungs (lower TLC) 2) Vascular Distention - engorgement can increase stiffness as seen in CHF 3) Surface Tension - tendency of surface molecules to pull inward Surface tension is defined by LaPlace's Law: When there is two surfaces as in a soap bubble: P = 4T/r - smaller the radius, the higher the recoil pressure and thus higher the tendency of the bubble to collapse - In image C, the smaller bubble will collapse at the expense of the larger bubble expanding When only one surface is involved like a liquid lined alveolus: P = 2T/r Key Relationship: the recoil pressure of a bubble is inversely related to the radius of the bubble If you inflate a lung with fluid and eliminate the surface tension it becomes more compliant P=2T/R: the smaller the radius the more surface tension - If surface tension was unopposed in the lung it would lead to an unstable lung - Since our lung does not inflate uniformly, surface tension will result in smaller alveoli collapsing and larger ones over-inflating - Creating areas of hyperinflation and atelectasis - This results in shunting and low oxygen tension (hypoxemia) Surfactant: - coats the alveoli and reduces surface tension - detergent produced by Type II cells - only effects the low lung volume alveoli (which are the ones most in need of fighting surface tension, b/c small radius, high recoil pressure --> collapse) - Production begins at 24-26 weeks gestation - Composed primarily of dipalmitoyl lecithin - Lecithin:spingomyelin ratio of 2:1 is good indication of fetus lung development --> OBGYNs will perform an amniocentesis Compliance curves - The x-axis represents a change in pressure and the y axis a change in volume - If we look at the air-filled curve, notice that as we increase pressure, our volume increases until we reach a peak point (point B) - Then we release the pressure and the volume decreases back to the starting point (point A) - Compare this to a saline-filled lung. Here, we require a lot less pressure change to get up to the same volume - This is to demonstrate that if we fill the lung with fluid, we eliminate surface tension and it becomes more compliant - Hence, surface tension is one of the major factors that decreases compliance of the lung

Possible Triggers of Asthma

1. Allergens (pollens, molds, dust, cat dander) 2. Environmental agents (tobacco smoke, other air pollutants) 3. Exercise (Exercise-induced bronchoconstriction, EIB) 4. Cold, dry air 5. Medications (NSAIDs*, beta-blockers) 6. Upper respiratory infections 7. Other medical conditions (gastroesophageal reflux disease (GERD), rhinitis, upper airway cough syndrome) - must treat these also *NSAIDs can trigger asthma in some asthmatics - "aspirin sensitivity" is correlated with an excess production of cysteinyl leukotrienes brought on by NSAID-induced inhibition of cyclooxygenase - This is not an allergic reaction; it does not involve production of IgE antibodies.

Early Lung Development 6-12 weeks

1. Buds are proliferating into mesenchyme - growing caudily and laterally in Pericardioperitoneal Canals 2. Mesoderm covering the buds and bronchioles become Visceral Pleura 3. Secondary lung buds represent the future lobes of the lung a. 3 on right b. 2 on left 4. Once the Secondary buds are well formed they are anatomically known as secondary bronchioles 5. Secondary bronchioles divide dichotomously forming - 10 tertiary bronchi on the right lung - 8 tertiary bronchi on the left.

Mediastinal Disease

1. Cardiomegaly - refers to an enlarged heart - rule of thumb is that if the heart is more than a hemithorax, you call it cardiomegaly 2. Enlarged Hila - can have multiple etiologies - example shown below is of enlarged lymph nodes - not expected to ID those are lymph nodes, just recognize the hilar area is enlarged - Hilar enlargement is ID'd with yellow dotted lines. Remember the hilum is where all the major arteries, bronchi, veins, exit the root of the lung. 3. Anterior Mediastinal Mass - If there is retrosternal air space, that means there is an abnormal finding in the anterior mediastinum that will only be caused by 4 things (the 4 T's): 1. Thymoma 2. "Terrible" Lymphoma 3. Thyroid 4. Teratoma

Strategies for Treating Asthma

1. Identify and avoid exposure to (allergens, meds) or treat triggers (GERD, allergic rhinits) 2. Treat and prevent inflammatory response - anti-inflammatory agents (corticosteroids) - long-acting beta-2 adrenergic agonists (LABA) - long-acting muscarinic antagonists (LAMA) 3. Prevent immunologic response - monoclonal anti-IgE antibody; other monoclonal antibodies 4. Dilate the bronchi or prevent bronchoconstriction - bronchodilators Acute (quick relief, "rescue") treatment --> SABA vs. chronic (long-term) control (steroids, LABA)

Five Physiologic Causes of Hypoxemia: Correcting

1. Low FiO2 - normal A-a gradient of 5-10 mmHg - put patient on 100% inspired O2, the PaO2 will correct fully to >600 mmHg 2. Hypoventilation - normal A-a gradient here too (no additional shunting or thickening of alveolar membrane) - put the person on 100% FiO2, hypoxemia will correct to around 600 mmHg 3. Diffusion block - Increased A-a gradient because CO2 equilibrates easily across the membrane, but O2 does not - Putting the patient on 100% FiO2 will correct the hypoxemia but the A-a gradient will still exist. 4. V/Q mismatch/imbalance - Increased A-a gradient - PaO2 will correct to above 600 because even the areas of under ventilation will have significantly greater O2 when the patient is put on 100% FiO2 - With V/Q imbalance or mismatch if you put them on 100% FiO2 all the PAO2 rises to above 600 so again the PaO2 will be above 600 5. Shunt - Increased A-a gradient as blood is entering circulation without being oxygenated - Shunt is the only case where putting the patient on 100% FiO2 will not correct their hypoxemia to above 600 mmHg - It doesn't matter how high you crank up PAO2 if blood enters the systemic circulation without encountering the (ventilating) alveolus. First 2 the A-a gradient will be normal as the lungs are normal. Last 3: Abnormalities in the respiratory system so the A-a gradient will be increased. The first two will have a normal A-a gradient because the lungs and circulation are normal, whereas the last three have abnormalities in the respiratory system and will thus have an elevated A-a gradient.

Classifications of Asthma Severity

1. Subjective - frequency of symptoms - nighttime symptoms - use of SABA, limitation of activity 2. Objective - assessment of lung function - frequency of exacerbations requiring oral CS

Physiological Effects of Histamine at H1 receptor

1. Peripheral Actions: a) Bronchoconstriction: smooth muscle contraction b) Cardiovascular effects: i. Vasodilation primarily in arterioles and capillary vessels results in flushing, decreased TPR and BP. - H1 receptors on vascular endothelial cells cause a rapid, short-lived response mediated by release of nitric oxide - H2 receptors on smooth muscle cells mediate a slower, sustained response via cAMP ii. Increased heart rate: reflex and direct (via stimulation of H2 receptors) iii. Increased capillary permeability due to contraction and separation of endothelial cells results in edema. iv. Triple Response (wheal and flare) to intradermal injection of histamine: Localized erythema: dilation of small blood vessels at injection site - (H1- mediated response) Flare: axon reflex-mediated vasodilation of arterioles, develops more slowly and extends beyond the original spot. Wheal: increased permeability of small blood vessels resulting in localized edema - (H1-mediated response) c) Sensory nerve endings - H1 stimulation leads to itching, pain sensations, sneezing 2. Central Actions: a) Arousal and Learning/Memory (H3 receptors may also play a role) - In animal models, H1-agonists increase wakefulness and improve memory; both actions can be blocked by centrally acting H1 receptor antagonists. - In humans, sedative effects and adverse effects on cognition of centrally acting H1- antagonists have been documented. b) Effects on body temperature and appetite have also been documented.

Goals of Asthma Therapy

1. Prevent chronic and troublesome symptoms (e.g., coughing or breathlessness) 2. Require infrequent use (≤ 2 days/week) of inhaled short-acting beta2-agonist (SABA) 3. Maintain (near) normal pulmonary function 4. Maintain normal activity levels (including exercise and other physical activity) 5. Meet patients' and families' expectations of and satisfaction with asthma care 6. Prevent recurrent exacerbations of asthma and minimize the need for hospitalizations 7. Prevent progressive loss of lung function 8. Provide optimal pharmacotherapy with minimal or no adverse effects

Pathology Related to to Improper Respiratory System Development: Lungs

1. Respiratory Distress Syndrome (RDS; or hyaline membrane disease) - common cause of death in premature infants (20%) - Results from insufficient surfactant production - Alveoli collapse upon exhalation. - Treatment includes surfactant replacement therapy - Glucocorticoid treatment during pregnancy accelerates lung development and production of surfactants. 2. Oligohydramnios - Occurs from insufficient amniotic fluids in contact with lung tissues during development - Areas of lung where little or no amniotic fluid are underdeveloped 3. Congenital Lung Cysts - Form as larger bronchioles are dilated during development. - Can be large. - Viewed by radiography can give lungs a honeycombed appearance. - Drain poorly and can result in chronic infections after birth.

Mechanisms for Drug Delivery

1. Systemic: oral/IV/subcutaneous 2. To site of action (lungs) Metered-dose inhalers (MDIs) with and without spacers Dry powder inhalers (DPIs) Nebulizer: aerosolizes liquid meds Advantages of delivering drug to site of action: - rapid onset of action (except ICS: take time to produce effect) - high concentration at site of action (can ↓ dose compared to systemic dose) - reduce systemic side effects **Use of spacers can prevent systemic side effects from swallowing medication and can get more of the drug into the lungs - more in lungs, less in stomach

Canalicular Period

16-26 weeks Each terminal bronchiole divides into 2 or more respiratory bronchioles Each respiratory bronchiole divides into 3-6 alveolar ducts Purpose: 1. Tertiary bronchioles grow, divide and differentiate into respiratory bronchioles - They grow further within surrounding mesoderm 2. Some Respiratory bronchioles can differentiate into terminal alveolar sacs capable of gas exchange 3. By 5.5-6 months vascularization of lungs is well underway. Some alveolar sacs come into close contact with fetal blood and in some circumstances by 5.5 months the lungs may support the baby outside of womb

Terminal Sac Period

26 weeks - birth terminal sacs (primitive alveoli) form capillaries establish close contact Purpose: 1. firmly establish blood-air barrier - Endothelial Cells at Terminal Alveolar Sacs change their cell adhesion proteins --> These changes allow cuboidal endothelial cells to flatten. - new cells are known as Type 1 Alveolar Epithelial cells - Their flattened phenotype allow intimate association with capillaries - create a large SA for gas exchange 2-4 weeks before birth: - Another population of Endothelial cells differentiate into Type 2 Alveolar Epithelial cells. - cells remain cuboidal or become pseudostratified - Main Purpose is to produce and secrete phospholipid-rich fluids known as SURFACTANT - coats the entire terminal alveolar sac to lower the surface tension at the air-alveolar interface. - Without Surfactant the baby will undergo severe breathing problems. Known genes involved in making Surfactant - TTF-1 - HNF-3 - Glucocorticoids - Thyroxine - Surfactant A/B

Lung Volumes and Capacities

4 Lung Volumes: Basic subunit - RV (residual volume) - ERV (expiratory reserve volume) - TV (tidal volume) - IRV (inspiratory reserve volume) 4 Lung Capacities: Capacity are summations of 2 or more volumes: - TLC (total lung capacity) = RV + ERV + TV + IRV - VC (vital capacity) = ERV + TV + IRV - IC (inspiratory capacity) = TV + IRV - FRC (functional residual capacity) = RV + ERV --> Volume that you come to rest at RV, FRC and TLC cannot be measured directly (cannot measure RV of the lung) - measured indirectly

Restrictive Lung Diseases: Case 4

45 y/o woman presents with a daily chronic cough that occurs at night (daily, nocturnal) Does not respond to Albuterol, steroids or treatment for rhinitis and GERD No recent travel, exposures, infectious contacts or pets Current smoker (20 pyh) Clinical Exam: Morbid obesity Chest XRay: normal PFT: Restrictive Disease (reduced FVC, decreased DLco Bronchoscopy: - mild mucosal erythema ; no endobronchial lesions - Normal cell differential; Negative cytology Imaging: centrilobular nodules → inflammation in the distal respiratory bronchioles RB-ILD/DIP

Restrictive Lung Diseases: Case 1

47 y/o African American woman April: presents with isolated Alk Phosphatase (liver enzyme) elevation October: Presents w/ RUQ pain and weight loss July: Presents with intermittent mid-thoracic back pain Chest CT is performed - No abnormalities in lung tissue itself - Enlarged mediastinum - Enlarged R hilar lymph node - Enlarged liver and spleen Pulmonary Function Test - mildly reduced diffusion capacity (DLco) Labs - Mild leukopenia; anemia; pancytopenia - Elevated serum ACE level Note: when we see patients with pancytopenia, hepatosplenomegaly, and weightloss, we should include lymphoma in our differential. Fine needle aspiration biopsy via bronchoscopy - Granulomatous Inflammation SARCOIDOSIS

Pseudoglandular Period

5-16 weeks Branching continued to terminal bronchioles No respiratory bronchioles or alveoli present Purpose: 1. To grow and expand terminal bronchioles into surrounding mesoderm 2. Mesoderm overlying the endoderm of the lungs becomes the Visceral Pleura while the Parietal Pleura overlies the body cavity

Restrictive Lung Diseases: Case 2

51 y/o African American man has a history of sarcoidosis Sarcoid diagnosed by liver biopsy in 20s - Presented with respiratory symptoms (cough, wheezing, SOB) several years prior - Onset several years prior to confirmatory diagnosis - Treated with Prednisone twice in the years immediately following his diagnosis Today presents with NO respiratory symptoms Admits to occasional arthralgias and fatigue Chest XRay - Fibrosis in upper parts of lungs - Volume loss is evident (decreased FVC) - Hila are pulled upward due to the fibrosis (away from their normal anatomical position) Pulmonary Function Test: Reduced FVC - FVC has not changed much since his sarcoidosis diagnosis 30 years ago - Therefore, we can infer that the patient had active Sarcoid in his 20s and went into remission - His lung condition did not improve much over the years.

Alveolar Period

8 months - childhood mature alveoli have well-developed epithelial-endothelial (capillary) contacts Purpose: 1. Provide complete adaptation from aqueous/placental dependence of gas exchange to terrestrial environment. - Three adaptations must occur 1. Surfactant production 2. Proper differentiation of endothelial cells into epithelial cells capable of gas exchange 3. Establishment of pulmonary and systemic circulations Alveoli form up to age 10 17 generations of of budding division occur by month 6 which shows final shape of lungs An additional 6-7 divisions occur postnatally

Restrictive Lung Diseases: Case 3

A 72 y/o man presents with progressive exertional dyspnea and dry cough for 2 years He has no past medical history 20 pack-year history tobacco Physical Exam: Basilar Rales and Clubbing - With ambulation in the hall desaturates to 89% PFT: restrictive - Reduced FVC, DLCO, TLC CXR: - reduced lung volumes - basal and peripheral reticulation - Shaggy, haziness at the base of the lungs CT Scan - Basilar and peripheral reticulation - Thickening of interstitium due to collagen deposition - Honeycombing (irregular dilated cysts) - mostly at bases of lungs (college and cysts) IPF

Step Care Management of Asthma

Acute (quick relief) treatment vs. Chronic (long-term) control

COPD: Anatomic Classification of Emphysema

A cluster of 3-5 accini are called a lobule 1) Centriacinar (centrilobular) 2) Panacinar (panlobular) 3) Paracictricial (irregular) 4) Distal acinar (Paraseptal) Frequently there is a mixture No evidence that one evolves to the other

Respiratory Laboratory: Metastatic Carcinoma Microscopic

A focus of metastatic carcinoma from breast is seen on the pleural surface of the lung Such pleural metastases may lead to pleural effusions, including hemorrhagic effusions, and pleural fluid cytology can often reveal the malignant cells

Mechanical Ventilation for Hypoxic Failure

A ventilator is an artificial airway conduit between the machine and the person's trachea We place a tube through the mouth and into the trachea. There is a balloon around the outside of the tube to make it tight in the trachea so that all gases have to go in and out of the tube Ventilator can then hold pressure when the patient is exhaling and not let them exhale down to zero. This is called PEEP, or Positive End Expiratory Pressure. For patients in hypoxic respiratory failure, mechanical ventilation can be used to adjust the FiO2 and PEEP to improve oxygenation: 1. Increasing FiO2 - improves all physiologic causes of hypoxemia and will correct all PaO2 to over 500 mmHg for everything except for shunt - Setting FiO2 higher, such as at 100%, will increase the pressure gradient from the alveoli down. 2. Increasing PEEP can also improve oxygenation - Holding at a positive PEEP will increase FRC and increase the surface area of gas exchange, and therefore improve oxygenation --> keeps alveoli more open (so they don't collapse, acts as intrapleural negative pressure usually keeping alveoli open)

COPD: Emphysema

Abnormal permanent enlargement of air spaces distal to the terminal bronchioles accompanied by destruction of alveolar walls without obvious fibrosis - Destruction of alveolar wall damages pulmonary capillaries by tearing, fibrosis, or thrombosis - Enlarged air sacs due to destruction of alveolar walls (bullae) - Walls of individual sacs torn (repair not possible) - decrease in surface areas around the alveolar walls - Inelastic collapsible bronchioles --> loss of elastic recoil of alveoli (trouble getting air out) --> CO2 air trapping - destruction of the elastic skeleton will result in flappy airways and collapse of the airways Pathogenesis: - inhibition of a1-antitrypsin caused by mainly by smoking - leads to alveolar wall destruction (unapposed trypsin) "PINK PUFFER" - Physical appearance of a patient with severe emphysema - Oxygen levels are traditionally normal, so they are pink - doing their best to keep their CO2 normal --> requires a lot of work, so they have a thin appearance - possible and barrel chest (due to air being trapped in lungs) - usually poised, leaning forward to make it easier to breath (tripod position) - pursed lips breathing (creating own positive pressure) 1. When the patient is trying to exhale, their airways close and they cannot get the air out (They have an increased FRC) 2. On their compliance curve, due to their increased FRC, they are shifted upwards and are now at a very non-compliant part of the curve 3. Even though there is a loss of elasticity and an increase in compliance in the lungs; with all the air trapping, it is way up on the non-compliant part of the curve 4. So by pursing their lips and breathing against resistance, it can help splint the airways open on exhale to a lower volume before the airways collapse Chest X-ray - Hyperinflation of lungs (greater AP diameter) - retrosternal airspace darker than normal on lateral view - flat diaphragm due to trapped air (increase FRC) pushes down diaphragm CT Scan: Bulla and Blebs - Bulla within lung parenchyma (coalescence of destroyed alveolar sacs) - Blebs on surface b/w visceral pleura and parenchyma (if bulla pops) - If bleb pops, the air gets into the pleural space and you will have a pneumothorax Pathology Key Concepts: Emphysema - Characterized by permanent enlargement of air spaces distal to terminal bronchioles - Centriacinar is most common and associated with smoking - Smoking and pollutants cause inflammation, release of oxidants, elastases that destroy alveolar walls

Pulmonary Neoplasms: Adenocarcinoma

Adenocarcinomas are malignant, glandular epithelial tumors Gross Features Gray-white Somewhat circumscribed Most often arise from the periphery; some tumors arise from the bronchus No cavitation (tend not to cavitate) Associated w/central scarring/fibrosis - Central fibrosis retraction results in umbilication - collagen retracts creates central dimpling Lepidic growth (difficult to detect grossly) - tumors grow along the scaffolding of the alveolar septa - spread bilaterally; resembles butterfly wings microscopically Histology Adenocarcinomas have some combination of: - Glandular differentiation (cells in circle w/hole in middle) - Mucin production - Pneumocyte marker expression (secretory activity, mucin, surfactant, etc) Various patterns Tumors classified by predominant patterns: 1. Invasive Adenocarcinoma 70-90% of surgically resected cases - Prevalence of AIS (adenocarcinoma in situ) and minimally invasive adenocarcinoma - More locally confined that small cell carcinoma, can typically can be resected (diffuse lung tumors like small cell and metastatic can't be resected) - Surgeons will not resect the tumor if the cancer is metastatic - Ex. If a patient has a R-sided tumor and L-sided LNs contain mets, the surgeon will NOT remove it. Complex heterogeneous mixture of histologic subtypes - Very unpredictable Classification of subtypes is useful for identifying prognostic subsets according to the predominant pattern Patterns are measured in 5% increments STAS : spread through lung airspaces - This spread accounts for increased recurrence in patients w/ Stage 1 disease who undergo limited resection VATS Procedure: Video-Associated Thoracoscopic Surgery - Enables rapid LN biopsy for pathologic confirmation of metastasis 3 Types of Tumor removal surgery 1. Wedge Resection - remove wedge of lung lobe 2. Lobectomy - remove lung lobe 3. Pneumonectomy - remove entire lung 2. Lepidic Adenocarcinoma - Bland Type II Pneumocytes grow along alveolar walls - Invasive component present in at least 1 focus,- >5mm in greatest dimension Invasion defined as: - Histologic subtypes other than leipidic (acinar, papillary, micropapillary, solid) - Myofibroblastic stroma associated w/ invasive tumor cells - Vascular or pleural invasion - STAS 3. Acinar Adenocarcinoma - Glands with a central oval/round luminal spaces - May contain mucin - Cribriform pattern (glands w/in glands) conveys worse prognosis 4. Papillary Adenocarcinoma - Configuration of growth in which tumor forms finger-like projections ( papillae ) - Glandular proliferation along fibrovascular cells 5. Micropapillary Adenocarcinoma - Glandular cells form "florets" that lack fibrovascular cores - Vascular invasion common - Psammoma bodies: round laminated calcium deposits - Conveys POOR prognosis: associated w/ invasion and shorter survival 6. Solid Adenocarcinoma - If a suspected adenocarcinoma is solid, it must be distinguished from squamous cell carcinoma and large cell carcinoma - Tumor cells form solid sheets - Mucin present in nearly all solid tumors - If mucin is not present, the tumor must express either TFF-1 or Napsin A to be classified as a solid adenocarcinoma

Chronic Obstructive Pulmonary Disease (COPD)

Airflow limitation that is: - not fully reversible - usually progressive Chronic abnormal inflammatory response to: - environmental pollutants (worldwide, smoking inhalation from cooking) - irritants - tobacco smoke (most common cause in the USA) Two Spectrums of COPD: - Chronic Bronchitis - Emphysema - spectrum, most patients will have a bit of both

Anatomic Dead Space: Fowler's Method

Anatomic dead space: no gas exchange, gas is not coming into contact with any alveolar units Patient inhales 100% O2 - Anatomic dead space is just filled with O2 They then exhale, and expiratory CO2 concentration is measured - As "dead space" is exhaled, there should be no CO2 (Only filled with 100% O2) First part of exhalation comes from dead space—won't have CO2 - Once the O2 is expelled, the lung starts exhaling CO2 - Rapid rise in CO2 once dead space empties, the respiratory space is now exhaling Midpoint is anatomic dead space - Where dead space interfaces with respiratory space, CO2 is starting to diffuse already, that is why midpoint is used (rather than as soon as it rises)

Respiratory Laboratory: Small Cell Carcinoma Gross

Arising centrally in this lung and spreading extensively is a small cell carcinoma The cut surface of this tumor has a soft, lobulated, white to tan appearance The tumor seen here has caused obstruction of the main bronchus to left lung so that the distal lung is collapsed.

Gas Transport: Waterfall Theory

As oxygen travels from ambient room air to our cells, the pressure continues to drop Room air oxygen pressure is about 160 mmHg Trachea is 150 mmHg Alveoli is 100 mmHg Blood is 98 mmHg Even lower in the cytoplasm and mitochondria. One important point to take note of is the difference in O2 pressure between the alveolar capillaries and arterial blood. - pressure drops a small amount because we all have normal anatomic shunts In a normal, healthy person, the presence of an A-a (alveolar to arterial) pressure difference is due to presence of normal shunts in the body Capillary O2 pressure - Most people would assume that it would be the average between the venous pressure (Pv = 40 mmHg) and arterial pressure (Pa = 100 mmHg) - blood equilibrates to the alveolar 100 mmHg within the first 1/3rd of the time it spends in the capillary - each RBC spends ¾ seconds in pulmonary capillary: ¼ seconds at 40 mmHg before going up to 100 mmHg for 1/2 second - our capillary pressure is closer to 85 mmHg

Obstructive Lung Diseases: Overview

Asthma Chronic Bronchitis Emphysema Bronchiectasis Can diagnose an obstructive lung disease using Pulmonary Function Test (PFT) and History - Normal: both VC and FEV1/FVC ratio are in normal range - Obstructive abnormality: FEV1/FVC ratio is below normal range (75% or 10% of Predicted ratio)

Positive End Expiratory Pressure (PEEP)

At FRC our PEEP is 0 Adding PEEP increases FRC In the supine position we lose FRC To return the sedated supine person to the normal FRC takes 5 cm PEEP "Physiologic PEEP" As the diseased lung or chest wall stiffens the pressure-volume relation of the RS curve shifts to the right and flattens and it requires higher levels of PEEP to get to a FRC Recall Compliance Curves - Ccw is the compliance of chest wall - Cl is the compliance of the lung - Crs is the compliance of the system At zero pressure, when the system comes to a resting state, we are at FRC System is most compliant at FRC, where there can be the most volume change for the least amount of pressure change - remember compliance is slope (how much change in volume for change in pressure) --> steeper the slope the better the compliance What happens if you apply PEEP? - system will be brought to a higher point on the curve (more toward the right) and will be held there - With intake of a breath, we will move further right along the curve, and the volume at the end of expiration will be larger - Essentially, PEEP increases FRC by holding us at a higher volume Wouldn't we want the original FRC where we are most compliant? Why do we apply PEEP? - If we are standing, in the system there is gravity on the diaphragm and the intercostal muscles are innervated and working - We are at the perfect FRC while standing, PEEP is 0, and the system is most compliant. What if a patient is lying on their back and sedated - gravity pushes on the abdomen and pushes the diaphragm up and the intercostal muscles are relaxed with sedation - patient is now at a lower FRC then they would have been if upright and awake - Therefore, we use PEEP. - In a person with a normal compliant lung and chest wall, it takes 5 cm (centimeters of water pressure) PEEP to return the sedated, supine patient to the FRC they usually would have while upright - Everyone on a ventilator gets 5 cm of PEEP to start with - It's often misnamed physiologic PEEP, but it's called that because it returns the patient with normal lungs and chest wall to the FRC they would have if they're upright and extubated. ***Side note: PEEP has nothing to do with overcoming the resistance of the tube. Resistance equals the change in pressure over flow. At the end of expiration, there is no flow.*** What happens when patients have pathological states that make the lungs stiff and less compliant? - Pneumonia, WBC infiltrates, pulmonary edema, fibrous tissue, etc. can make the lungs stiffer - compliance curve moves to the right and flattens, and it takes a higher change in pressure to make the same change in volume that it would in a healthy patient - Therefore, it may take higher levels of PEEP to get him to that FRC sweet spot, the most compliant part of the curve - On the graph to the right, you can see that at low pressures, it takes a lot of pressure to overcome the elastic resistance of the lungs - At some level of pressure, there is an inflection point (Pflex) where lower amounts of pressure are needed for an increase in volume - You want to set the PEEP above this inflection point in order to be at the most compliant part of the curve - This will keep the alveoli open, and allow for increased surface area, gas exchange, and oxygenation - There is also a second inflection point (Upper Pflex) past which the system will be less compliant, and you want to keep the tidal volume below this point in order to avoid popping the alveoli.

Respiratory Laboratory: Pulmonary Edema Microscopic

At high magnification, the alveoli in this lung are filled with a pink material characteristic for pulmonary edema - fluid in alveolar spaces Note also that the capillaries in the alveolar walls are congested with many red blood cells (engorging capillary spaces/dilated) Congestion and edema are common in patients with heart failure

Respiratory Laboratory: Granulomatous Disease

At low magnification, this photomicrograph reveals multiple granulomas Granulomatous disease by chest radiograph can appear as reticulonodular densities Sarcoidosis

Respiratory Laboratory: Bronchopneumonia Microscopic

At the left the alveoli are filled with a neutrophilic exudate that corresponds to the areas of consolidation seen grossly with the bronchopneumonia This contrasts with the aerated lung on the right of this photomicrograph.

Parenchymal Disease: Atelectasis

Atelectasis = Collapse of alveoli There are two main causes for atelectasis: 1. Obstructive: - endobronchial lesion preventing air to enter - something is preventing air from coming into the lungs! - Because air can't come into the lungs, the gas already inside will be absorbed and the lung will shrink and pull structures towards it 2. Compressive: - Pleural disease (effusion or PTX) with positive pressure pushing air out of alveoli - something is creating positive pressure that is pushing air out of the alveoli. - This can be caused by air (eg. pneumothorax) or fluid (eg. Pulmonary effusion) - Due to positive pressure, expect that the affected region will push structures away from it An Airless lung has the same density on the white-black scale as a soft tissue structure An atelectatic lung will silhouette the interface with diaphragm and heart Atelectasis in RUL: - Notice how the horizontal fissure is being pulled superiorly! - The atelectasis in the upper lobe is pulling the horizontal fissure UP - because there is pulling then this would be an OBSTRUCTIVE cause Atelectasis in RML: - Note how the border of the heart is obscured by the middle lobe Atelectasis in RLL: - Note that the lower lobes are on the posterior aspect of the body and in contact with the diaphragm - This is why the diaphragm is obscured Atelectasis in LUL: - Notice how you cannot see the left border of the heart OR aortic arch - You ARE able to see the diaphragm on both sides, further suggesting the upper lobe is affected. Atelectasis in LLL: - Notice that you lose the diaphragm but retain the heart border - Because structures are pulled towards the left lower lobe, this would be obstructive atelectasis.

Control of Respiration

Autonomic process of breathing originates in the brain stem located in pons and medulla Receives input from: - chemoreceptors (central, peripheral) - lung and other receptors - cortex (cortex though can always over ride the brainstem) Major output is the phrenic nerves Central chemoreceptors - Medulla - maintain pH and CO2 Peripheral chemoreceptors - carotid and aortic bodies - stimulated by hypoxia (PaO2), pH, PaCO2 Most sensitive is hypoxia, next is the pH and last is CO2 In normal person: PCO2 determines the minute ventilation - system operates well above the hypoxic trigger and the pH is maintained at 7.4 Body wants to maintain: - PaCO2 of 40 mmHg - pH at 7.4 - PaO2 above 48-50

Molecular Control of Lung Development

BMP: secreted by distal endoderm - Binds membrane receptors a. Type 1: ALK2, ALK3, ALK6 b. Type 2: BMPRII, ACTRII Noggin: secreted by mesoderm surrounding distal endoderm - Natural inhibitor of BMP4 FGF10 - Appears to maintain distal respiratory epithelia - May promote branching Sonic Hedgehog-SHH - new player - When knocked out lungs are severely underdeveloped A. BMP4 is first detected in endoderm lining pharynx B. The BMP4 site expands C and D. High concentration of BMP4 causes distal growth of respiratory diverticulum E. Lung bud forms - high concentration of BMP4 found at most distal portions of developing lungs (buds) endoderm BMP4 - autocrine --> promotes proliferation of endoderm - paracrine --> stimulates noggin in surrounding mesoderm Noggin - paracrine --> binds and inhibits BMPs, branching here because inhibits endoderm growth of lung buds at highest concentration of BMP4

Pharmacological Therapy of Asthma: Bronchodilators 1. Beta-adrenergic receptor agonists

Beta-adrenergic receptor agonists (beta2 receptor specific agonists) MOA - beta2 receptor stimulation increases cAMP, decrease in intracellular Ca++, increase in K+ conductance - relaxation of bronchial smooth muscle cells - acute inhibition of release of mediators from inflammatory cells (likely due to desensitization) --> beta2 receptors on mast cells inhibit them - inhibition of ACh release from vagal nerve endings in the lung Side effects - ↑ HR - cardiac stimulation - skeletal muscle tremor - ↓ serum K+ - ↑ serum glucose - insomnia - side effects increase with increasing dose Short-acting beta agonists (SABAs): Immediate bronchodilation ("rescue") Albuterol (Proventil®, Ventolin®, generic albuterol) - beta2 specific agonist - rapid onset (within 5 min), peak effect 15-30 min, short acting (DOA 3-4 hours) Clinical Use - as needed for quick relief ("rescue") in all stages of asthma - drug of choice to treat intermittent asthma (use as needed) - drug of choice for asthma exacerbations (use higher, more frequent doses via nebulizer) - prevent exercise-induced bronchoconstriction (EIB) - NOT for chronic or repeated use (use of SABA >2x/week usually indicates poor control of asthma - except for prevention of EIB) - As needed for intermittent dyspnea in patients with COPD Available by MDI (HFA inhaler), DPI, and for nebulization Long-acting beta agonists (LABAs) Prevention of bronchoconstriction Salmeterol - dry powder inhaler - beta2 specific agonist, potent and highly selective for beta2 receptors - slower onset (15-20 min), peak effect (> 45 min) - long-acting (12 hours) due to high lipid solubility - effective in suppressing nighttime symptoms because of long DOA Clinical Use in Asthma - in combination with inhaled corticosteroids (same inhaler) for long-term control in moderate or severe asthma (do NOT use without ICS) - use chronically but no more than twice/day because drug can accumulate - NOT used for immediate relief ("rescue") Combination product with ICS: fluticasone/salmeterol (Advair®) - makes for SAFER use for those requiring combined steroid/LABA treatment - increases patient compliance and convenience Formoterol - similar to salmeterol - faster onset of action (within 5 min) Combination products with ICS: budesonide/formoterol (Symbicort®) or mometasone/formoterol (Dulera®) OFF LABEL USE not in guidelines - budesonide/formoterol as needed for rescue (instead of albuterol) in mild asthma and in patients already taking it as control medication (based on recent data) Use of LABAs in COPD - for chronic control of dyspnea and to prevent exacerbations (once daily preps are preferred) - ***can be used as monotherapy in COPD - available in combination products with LAMAs for added bronchodilation Recommendations on use of long-acting beta agonists: - LABAs should NOT be used as monotherapy for long term control of persistent asthma - Of the adjunctive therapies available for asthma, LABA is the preferred therapy to combine with ICS in youths ≥ 12 years of age and adults - Use of LABA is not recommended to treat acute symptoms or exacerbations of asthma. NOTE: LABAs can be used safely as monotherapy in patients with COPD - use of the ICS/LABA combo did not cause an increased risk of serious asthma related events compared to use of ICS alone - ICS/LABA combination was associated with fewer severe asthma exacerbations than ICS alone - FDA removed the Black Box Warning from products containing ICS/LABA combinations - if asthma patients need more/adjunctive therapy for long term control, doing the combo is good but if the patient is good just on the ICS then do not need to add it

Structure and Function: Blood-Gas Interface

Blood gas barrier is extremely thin Surface area of 50-100 square meters Approximately 300 million alveoli. Gas is brought to one side by the airways Blood to the other side by blood vessels O2 & CO2 move between air and blood by simple diffusion (from high to low partial pressure, pressure gradient!) Blood-Gas Interface Components: - Alveoli --> Surfactant --> Epithelium --> fused BM --> Endothelium --> Plasma --> RBC Type I pneumocytes: Large flattened cells used for gas exchange Type II: Large cuboidal cells that are synthetic, secretory cells Twice as many type II cells Type I account for 90% of the surface area of the interface (take up space b/c flat and thin)

Normal CXR: PA View Structures

Bones: - Clavicles - Spine - Ribs - Scapula Vascular: - Aortic arch - Pulmonary Trunk - LA appendage - LV - RV

Normal CXR: Right Lateral View Structures

Bones: - Sternum - Spine - Ribs Retrosternal Air space - immediately ID the retrosternal air space (blue) - This is a normal finding - If there is NO space, that means there is an abnormal finding in the anterior mediastinum that will only be caused by 4 things (the 4 T's): 1. Thymoma 2. "Terrible" Lymphoma 3. Thyroid 4. Teratoma Vascular: - Aortic arch - Pulmonary Trunk and hilum Diaphragms - the diaphragm line that disappears into the heart is left diaphragm

Respiratory Laboratory: Terminology

Bronchopulmonary sequestration: - congenital anomaly - Refers to the presence of lobes or segments of lung tissue without a normal connection to the airway system. - Blood supply to the 'sequestered' area often arises from the aorta or its branches. Atelectasis: - Incomplete expansion of the lungs or part of a lung or collapse of previously inflated lung - This is a reversible problem, often occurring in post surgical patients who have pain and do not breath in fully - Atelectasis predisposes to infection. Pulmonary edema: - Accumulation of fluid within the alveolar spaces - Often occurs secondary to increased hydrostatic pressure - Appears as pink material in the alveolar space microscopically Obstructive pulmonary disease: - Also referred to as 'airway' disease - Diseases characterized by an increase in resistance to airflow - This can occur anywhere from the major bronchi distally to respiratory bronchioles These are the four main 'obstructive' diseases: - Chronic bronchitis: Clinical diagnosis in a patient who has persistent, productive cough (sputum) for at least 3 months in 2 consecutive years. - Emphysema: Characterized by abnormal permanent enlargement of the airspaces distal to the terminal bronchiole. There is destruction of the walls with fibrosis. - Asthma: Inflammatory disorder characterized by (hyper) reactive airways and reversible bronchoconstriction (bronchospasm). - Bronchiectasis: Chronic, necrotizing infection of the bronchi and bronchioles leading to or associated with abnormal dilatation of these airways. Occurs in a variety of settings including cystic fibrosis, Kartagener's and intralobar sequestration Bronchopneumonia: - Lung infection characterized by patchy consolidation of the lung parenchyma Lobar pneumonia - Acute bacterial infection of a large portion of a lobe or of an entire lobe. Consolidation: - A descriptive term for lung parenchyma when it becomes solidified by inflammation and exudates secondary to (bacterial) infection Primary atypical pneumonia/interstitial pneumonitis: - Refers to acute respiratory illness, often with fever, that is largely confined to the alveolar septa and interstitium (that potential space in the alveolar walls) - Etiologic agents include viruses, Mycoplasma and Chlamydia Pneumoconioses: - Refers to a variety of non-neoplastic lung diseases caused by inhalation of both organic as well as inorganic particulates, chemical fumes and vapors. Bronchogenic carcinoma: - Refers to primary lung cancer. There are several subtypes: squamous cell, adenocarcinoma, small cell (oat cell) carcinoma, large cell and some mixed patterns. Pneumothorax: - Air or gas within the pleural cavities; may be spontaneous, traumatic or therapeutic

Peak and Plateau Pressures

C = ΔVolume /ΔPressure Dynamic "compliance" = TV/ Peak pressure - Peep Static "compliance"= TV/ Plateau pressure - Peep - since plateau pressure is always equal to or less then peak pressure, this explains why static compliance is higher than dynamic compliance R = ΔPressure/ Flow Peak pressure: amount of pressure needed to take a volume of gas and push it into the lungs - must push against the elastic recoil of the system AND airway resistance Plateau pressure: pressure needed to keep air in the system - only need to push against the elastic recoil of the system So the difference between peak and plateau pressure is airway resistance Raw = (Peak pressure - Plateau pressure)/Flow Peak pressure: pressure needed to move the breath in to the thorax. The pressure needed to overcome the: - Elastic Resistance of the Chest wall - Elastic Resistance of the Lung ---Elasticity = 1/Crs= ΔPressure/ΔVolume - Airway Resistance ΔPressure (Peak-Peep) = (1/Crs) x Tv + Raw x Flow Four things will cause Peak Pressure to increase: 1) Decrease compliance (increased elasticity) 2) increased Raw 3) larger TV 4) Higher Flow Plateau Pressure is only the pressure needed to hold the breath During a plateau pressure gas flow is zero so: ΔPressure (Plateau-Peep) = (1/Crs) x Tv + Raw x Flow (0) Only two things will effect Plateau pressure: 1) Compliance of the Respiratory system 2) Tidal Volume In the case of a patient on a ventilator, we control TV and flow, so really there are two major factors: compliance and Raw - If the peak increases and plateau remains unchanged, we know it must be an airway resistance issue. - If the peak increases and the plateau increases, we know it must be a compliance issues (b/c that is the only factor that influences both pressures)

Measuring Diffusion in the Lung

CO is used to measure diffusion across the blood-gas barrier in the lung You give a known amount, hold your breath for 10 seconds, and measure whatever is exhaled Whatever diffuses into the blood will not be exhaled. Diffusion of the lung can be calculated as follows (don't memorize): DL = VCO / PACO The volume of CO transferred in ml/min per mmHg of partial pressure of CO in the alveolus. The more that diffuses, the better the diffusion of the lung.

Carbon Monoxide

CO interferes with the O2 transport by combining with Hb to form carboxyhemoglobin COHb which has about a 240 times the affinity of O2 - CO will bind to the same amount of Hb as O2 when the CO partial pressure is 240 less than PaO2 COHb shifts the O2 curve to the left interfering with the unloading of O2 CO is an odorless gas 240 times higher affinity for Hb than O2 --> interferes with O2 binding to Hb CO shifts the O2 dissociation curve to the left --> CO on Hb will block the unloading of O2 to tissues (lower p50 means higher affinity of Hb for O2) so whatever O2 is bound will be stuck on the Hb Two effects combine cause the dissociation curve to experience a downward and left shift Compare the dissociation curve at normal Hb = 15 and the dotted line curve, which represents 33% of Hb bound to CO The curve is shifted the left and downward. CO poisoning 1) Patients tend to look pink/cherry red 2) Saturation level will be 100% b/c the oximeter cannot tell what gas is bound to Hb, only that it is completely saturated 3) pH will be low (little to no oxygen being supplied to tissues results in production of lactic acidosis) How is CO poisoning treated? - two ways oxygen is present in the blood: dissolved and bound to Hb - If we cannot rely on hemoglobin for oxygen delivery, we must rely on dissolved oxygen - dissolved O2 contributes a very small percentage to oxygen delivery - place patient in a hyperbaric oxygen chamber that delivers extremely high atmospheric oxygen in order to achieve significant levels of dissolved O2 in the blood

Carbon Dioxide

CO2 is end product of aerobic metabolism produce entirely by mitochondria where concentration is highest. Series of tension gradients as it passes from cytoplasm (ICF) --> extravascular (ISF) --> intravascular fluid Carried in three forms: - Dissolved ( 10 %) - Bicarbonate (60%) - Carbamino Hemoglobin (30%) = Combined to proteins (carbamino compounds) Dissolved (10%) - Obeys Henry's law (the amount of CO2 dissolved is proportional to the partial pressure) - 20 times more soluble than O2 - dissolved form has a more significant contribution (10%) to total body CO2 content --> 10% evolved to the lung is in the dissolved form Bicarbonate: (60%) CO2 + H2O = H2CO3 = H+ + HCO3- - first reaction (formation of carbonic acid) is slow in plasma but fast in RBC due to carbonic anhydrase - second reaction is fast without enzyme (Carbonic acid (H2CO3) is unstable so it will rapidly breakdown to form H+ and HCO3) - ion (HCO3-) in the cell diffuses out - H+ cannot due to RBC impermeability to cation - to maintain neutrality Cl- comes into the cell in exchange for the bicarb diffusing out (Chloride Shift) - H+ ions are bound to/buffered by hemoglobin - Deoxygenated/Reduced Hb is less acidic than oxygenated and therefore binds H+ better - H+ + HbO2 = HbH+ + O2 - Haldane Effect: Presence of reduced Hb in periphery helps loading of CO2 while oxygenating hemoglobin in the lung promotes unloading of CO2 Carbamino Hemoglobin: (30%) - Carbamino compounds are formed with the binding of CO2 to terminal amine groups in blood proteins - most important protein is the globin of hemoglobin giving carbamo-hemoglobin - Deoxygenated/Reduced hemoglobin can bind more CO2 than oxygenated CO2 Dissociation Curve - oxygenated blood carries less CO2 for the same PCO2 than venous blood - curve is more linear than the O2 dissociation curve

Blood-Tissue Gas Exchange

Capillary blood in tissues has same gas composition as arterial blood - PaO2 = 95 mmHg - PaCO2 = 40 mmHg Capillary is surrounded with interstitial fluid ("Milleu") with stable O2/CO2 - PO2 = 40 mmHg - PCO2 = 45 mmHg Capillary blood equilibrates with the interstitial fluid Venous blood has same composition as interstitial fluid of organ it is draining. - PvO2 = 40 mm Hg - PvCO2 = 45 mm Hg Gas exchange in the tissue can be diffusion and perfusion limited Diffusion Limited: - Increase distance from capillary to cell OR - decreased PaO2 - can produce diffusion limitations Perfusion Limited: - Increase demand must be met with increase flow or else gas exchange will be perfusion limited

PFTs: Diffusion Capacity (DLCO)

Carbon Monoxide Diffusion Capacity Measurement - If you inhale CO, it crosses the alveolar-capillary membrane and is immediately picked up by hemoglobin (240x affinity of oxygen) - It never develops a back pressure in the capillary, so it is purely diffusion limited - To perform this test, you have the patient inhale a little CO, hold for 10 seconds, then exhale - Whatever went in that didn't come out diffused across the membrane, so this method gives us a good idea as to how the alveolar-capillary membrane is functioning. Sensitive test, but not specific for a certain disease. Low DLCO: 1. Diseases that cause decrease in surface area of membrane will result in less diffusion: - emphysema - pulmonary embolism - lung resection) . 2. Diseases that increase thickness of the membrane will also result in less diffusion - interstitial lung disease - pulmonary fibrosis - pulmonary hypertension 3. Anemia - also decreases diffusion because if you don't have hemoglobin to take up the CO then it creates a back pressure and less will come across the membrane. High DLCO - he one instance where the diffusion capacity increases is when there is alveolar hemorrhage - There is blood inside of the alveoli and its able to pick up the CO, so you can have normal diffusion but the extra blood holds on to CO resulting in what appears to be an increased diffusion capacity.

Asthma: Laboratory Findings

Charcot-Leyden Crystals: in the sputum - formed from membranes of Eosinophils (Due to an excess amount in the airway) Curschmann Spirals: condensed mucus Creola Bodes: Clusters of shed epithelial cells

Respiratory Laboratory: Emphysema Gross

Chest cavity is opened at autopsy to reveal numerous large bullae apparent on the surface of the lungs in a patient dying with emphysema Bullae are large dilated airspaces that bulge out from beneath the pleura Emphysema is characterized by a loss of lung parenchyma by destruction of alveoli so that there is permanent dilation of airspaces.

Asthma: Pathogenesis

Chronic disorder of conducting airways Usually immunologically driven (caused by an immunologic reaction) Marked by episodic bronchoconstriction due to increased airway sensitivity to a variety of stimuli - hyperactive bronchoconstriction Inflammation of bronchial walls Increased mucus production and wheezing Airways obstruction is reversible - maybe not entirely reversible - either spontaneously or with treatment Pathophysiology - Airway hyper-responsiveness (AHR): exaggerated bronchoconstrictor response to many physical changes, chemical or pharmacologic agents - Type 1 Hypersensitivity Reaction - Reversibility in airflow limitation: 12-15% improvement in FEV1 following B-agonist Pathogenesis: - Fundamental abnormality of asthma is an exaggerated TH2 response to normally harmless environmental antigens - TH2 cells cytokines stimulate B cells to produce IgE and other antibodies - IL-4 and 5 are important in recruitment of eosinophils - Il-13 stimulates increased mucus secretion Immediate phase reaction - Triggered by Ag-induced cross-linking of IgE bound to Fc receptors on mast cells - Pre-formed mediators induce bronchospasm, increased vascular permeability, mucus production, recruitment of leukocytes - within minutes of allergen exposure Late phase reaction - Leukocytes release additional mediators that also increase mucus production and may cause epithelial damage (TH2 and eosinophil mediated) Key Concepts: - Asthma is characterized by reversible bronchoconstriction caused by airway hyper-responsiveness to a variety of stimuli - Atopic asthma is caused by a TH2 and IgE mediated immunologic reaction to environmental allergens - Eosinophils are found in almost all subtypes of asthma - Airway remodeling may occur and includes sub basement membrane fibrosis, bronchial gland hypertrophy and smooth muscle hypertrophy

Idiopathic Interstitial Pneumonias (IIPs): Nonspecific Interstitial Pneumonia (NSIP)

Clinical Features - Onset: 40-50 y/o - Predominantly females - Seen in nonsmokers - Strong association with connective tissue disease (CTD) - these patients tend to have (+) serology markers for autoimmunity despite the fact that they're not diagnosed with major conditions such as Lupus - UCTD: 43% ANA (+), 23% RF (+) Symptoms milder, onset 6 -7 mos prior to diagnosis Better prognosis compared to IPF 2 Subtypes/Progressions Cellular/Inflammatory NSIP: treatable with immunosuppressants, better outcomes - Histopathology: Inflammatory infiltrate w/ some collagen deposition, more inflammatory cells Fibrotic NSIP: less responsive to immunosuppressive therapy; more progressive - Histopathology: collagen deposition - Tends to follow IPF trajectory CT Findings - Peripheral distribution - NO HONEYCOMB cysts

Respiratory Laboratory: Pulmonary Embolism Gross

Closer view of a thromboembolus filling a main pulmonary artery reveals a layered appearance - typical of a thrombus that formed in a large vein of the pelvis or lower extremity

Structure and Function of Airways

Combined cross section of daughter branches is always greater than mother bronchus, resulting in a flaring of the airways as the bronchi and bronchioles divide Graph illustrates how total cross section area relates to the airway generation - around 8-9th generation, the cross sectional area starts to increase exponentially The 4th division is the narrowest portion, so most of the resistance occur in the 4th-7th division As the airway generation increases, diseases of increased resistance become harder and harder to detect due to the low baseline resistance.

Histamine Receptors

Coupled to G-proteins

Respiratory Laboratory: Normal Lung Gross

Cross-section of normal lung Minimal posterior congestion at the lower right Hilar lymph nodes are small and have enough anthracotic pigment to make them appear grayish-black - from dusts in the air breathed in, scavenged by pulmonary macrophages, transferred to lymphatics, and collected in lymph nodes

Compliance Overview

Compliance and elasticity are inversely related: Compliance = ΔV/ΔP Elasticity = ΔP/ΔV Lung Compliance: - As distending force (pressure) is increased, the tension in the lung is increased - The result is a force (tension) that when released, recoils the lung toward a resting volume (recoil pressure or elastic pressure: Pel) - The slope of the pressure volume curve is the lung compliance (C = ΔV/ΔP) Elastic recoil (elasticity) is the tendency of the lung to collapse from an inflated volume Elasticity is the inverse of compliance (1/C) Highly compliant lung will expand easily Low compliant lung (stiff lung) does not expand well Static vs Dynamic Properties of the Lungs Static state: - no motion or time component - there is no dynamic forces (all muscles are to be relaxed) - You take a certain volume and measure the pressure needed to hold that volume - Then you repeat for different volumes - Thus, we are taking snap shots/one point in time of the lung pressure and volume - Dynamic properties occur over time Dynamic state - measuring pressure changes continuously as volume changes - element of time - dynamic properties take into consideration airway resistance because there is flow of gas occurring during measurements - In static states, there is no flow of gas and thus we are not taking airway resistance into consideration

Laryngeal Development 4-12 weeks

Concomitantly w/respiratory diverticulum development the Primordial Pharynx developing A. Esophagotracheal Ridges grow B. Esophagotracheal Ridges fuse resulting in 2 structures 1. Esophagotracheal septum 2. Laryngotracheal Orifice (laryngeal Inlet) C. Internal Side of Developing Larynx form Arches 1-6 - Entire lining is comprised of endoderm - Underlying cartilage and muscle is derived from Mesoderm and Neural Crest - Arytenoid Swellings come from mesoderm proliferation between arches 4-6 around Laryngotracheal orifice - By week 6-7 the laryngotracheal orifice is transformed into a T-shaped opening bordered by the Primordial epiglottis D. Underlying Mesoderm and Neural Crest - Signals the overlying endoderm of larynx to proliferate - Endoderm proliferation of Primordial Epiglottis closes the laryngotracheal orifice at week 7.5. - AT week 10 the laryngotracheal orifice is recanalized and is now the Primordial Glottis Development of Hypobranchial Eminence (Epiglottis) - Occurs by proliferation of Arches 3-4 - Caudal portion of H.E. line primordial glottis (P.G.) until week 10 - During Apoptosis of tissue lining the P.G., the Mesoderm and Endoderm of H.E. proliferate and swell - by week 10-11 the eminence forms the typical epiglottis-the tissue that folds over the trachea when you swallow E. Innervation of Future Musculature of Larynx - 10th Cranial Nerve (vagus) innervates derivatives of 4th Arch -- Superior Laryngeal Branch of 10th Cranial Nerve -- Recurrent Laryngeal Branch of 10th Cranial Nerve innervates derivatives of 6th Arch

Conducting and Respiratory Zones

Conducting Zone: All the structures air passes through before reaching the respiratory zone - Trachea --> Bronchi --> Terminal Bronchioles Warms and humidifies inspired air. Filters and cleans: - Mucus secreted to trap particles in the inspired air. - Mucus moved by cilia to be expectorated Respiratory Zone: - Region of gas exchange - Includes respiratory bronchioles and alveolar sacs. - Must contain alveoli

Structure and Function: Airways

Conductive system: - conducting airway or anatomic dead space - About 150 ml - Trachea --> Main (Primary) Bronchi --> Lobar (Secondary) Bronchi --> Segmental (Tertiary) bronchi --> Terminal bronchioles: (first 16 generations) - 16 generations of branching in the conductive system before we reach the gas exchange system - no gas exchange (there are no air sacs, gas is either moving in or out) - portion of the lung we are only ventilating air Serves several purposes: - Warms/humidifies air - Filters and cleans inspired air -- Mucus is secreted to trap particles in inspired air -- Mucus is moved by cilia to be expectorated (coughed up) Gas Exchange/Alveolar System - Respiratory bronchioles --> alveolar ducts --> alveoli: (last 7 generations) - respiratory zones where gas exchange occurs - called the acinus - 2.5-3 liters of volume - much larger cross-sectional area than the conductive system Trachea: - Mean diameter of 1.8 cm - length of about 11 cm - Supported by U shaped cartilage - **part in the neck is not subjected to intra-thoracic pressure changes Bronchi have incomplete cartilage Bronchioles have no cartilage, only smooth muscle (resistance here) - 70,000 terminal bronchioles Distal to bronchiole are the acini Combined cross section of the daughter branches is generally greater than the mother bronchus Resulting in a flaring of airways with the narrowest part being 4th generation

Genetic Mutations in Lung Development

Cystic Fibrosis Cystic fibrosis transmembrane conductance regulator (CFTR) - Most common mutation: ΔF508 - change of one aa phenylalanine at 508th position on protein Use crispr to remove mutation, provide donor DNA with no mutation - problem is that there is not yet a good delivery system, can be done in lab

Body Plethysmography

DIRECT MEASUREMENT "Body Box" Most accurate measurement of FRC Boyle's law: Pressure x Volume is constant (at constant temp) P1*V1 = P2*(V1 - ΔV) P3*V2 = P4*(V2 + ΔV) We can measure pressure in the box, and we know the volume of the box Patient is in air-tight box and begins to breath - P1*V1: initial conditions of box - P2*(V1 - ΔV): no air is leaving/entering box, but chest is expanding - As chest is expanding, the pressure in box will go up - Can measure new pressure: P2 - ΔV: Volume chest has expanded by/inhaled - We don't know new volume (V1 - ΔV), but we can calculate using Boyle's law - P3*V2 = P4*(V2 + DV) - P3: We know pressure at mouth tube (when patient is at FRC) - We do not know FRC (V2) - P4: pressure at mouth tube during breathing - Can calculate V2 by using ΔV from first equation Will account for all gas in thorax --> even those that do not ventilate - This is because it is a pressure/volume system rather than a volume/concentration system Issues: Flatulence (more gas in box) or air escaping through ears (Scuba divers with blown out ears)

Alveolar Gas Pressure

Dalton's Law of partial pressures: - in a mixture of gases, each gas exerts a partial pressure proportional to its fraction Fraction (F)iO2 in atmosphere is 0.21 At Sea Level = 1 Atm of pressure = 760mmHg 760mmHg x 0.21 = 160 mmHg of O2 Water Vapor is a gas = 47 mm HG In the trachea: (760-47) x 0.21 = 150 mmHg O2 Alveolar Oxygen Equation: - In the alveolus we have to make room for CO2 - For every 5 molecules of O2 used there are 4 molecules of CO2 produced - 4/5 = 0.8 respiratory quotient Alveolar Oxygen Tension (PalvO2): PAlv O2 = (760 -47) x FiO2 - PaCO2/0.8 PAlv O2 = 713 x 0.21 - PaCO2/0.8 PAlv O2 Equation - PAlvO2 = (760-47) x 0.21 = 150 mm Hg - PAlvO2= (760-47) x 0.21 - (PaCO2/0.8) - PAlvO2 = 150 - 40/0.8 = 100 mmHG

Ventilation-Perfusion Relationships: V/Q Ratios/Mismatch

Dead Space V/Q = Infinity Normal Lung V/Q = 1 V/Q imbalance V/Q < 1 Shunt V/Q = 0 Note that as you go from low V/Q ratio to high, the O2 pressure in the alveolus rises and the CO2 pressure in the alveolus falls. This is because the less you perfuse the alveolus, the less the CO2 will be able to diffuse out of the capillary

Lung Embryology Summary Key Points

Definitive endoderm arises from ectoderm that has engressed through the primitive streak Embryonic folding 3 dimensionally gives rise to the tube in-tube body plan The inner tube becomes the gut endoderm The gut endoderm gives rise to not only the lungs but also the GI tract, tongue, liver, pancreas, gall bladder, and parts of the pharyngeal arches The lungs develop from a specified region of the foregut as a diverticulum that becomes bilobed and quickly develops a proximal-distal axis This axis is important for developing the initial Proximal Bronchiolar Epithelium and Distal Respiratory Epithelium. The larynx forms concomitantly with the initial and later development of the lung buds. The Tenth Cranial Nerve innervates the derivatives of the larynx Maturation of the lungs occurs beginning as early as week 5 of development and proceeds through early adolescence. Congenital lung pathologies are not uncommon. The balance of amniotic fluid within the lungs is important. Too much or too little fluid can cause major lung defects. VACTERL Defects can cause atresias. KNOW what the acronym VACTERL stands for. This is something you could see on the Step 1 exams

COPD: Chronic Bronchitis

Defintion: - Presence of chronic productive cough for 3 months in 2 successive years in a patient in whom other causes of chronic cough have been excluded Proximal disease: - Airways contain a lot of mucus that impede action of respiratory cilia - Air passage narrowed by mucus plugging and swelling of the airways - Alveolar/capillary membranes are completely normal and fine --> distal respiratory epithelium is fine (gas exchange) "BLUE BLOATER" - Physical appearance of a typical patient with chronic bronchitis - patients respiration driven by hypoxic drive - chronic CO2 retainers --> obstructive disease, difficult to expire CO2 - PaO2: 55mHg --> blue - alveolar hypoventilation due to a loss of their CO2 drive due to chronic CO2 retention - This makes their body acidic and their metabolic system compensates by retaining buffer --> chronic respiratory acidosis with metabolic compensation - As this continues the O2 levels will continue to decrease - Eventually our O2 levels will decrease so much that Hypoxic drive kicks in and forces our bodies to breath (PaO2<55 and O2 Sat <90%) - This makes a person cyanotic/hypoxic and they will have blue lips Pathology Key Concepts: Chronic Bronchitis Dominant pathologic features include: - mucus hypersecretion - persistent inflammation Histology - Enlargement of mucous-secreting glands - Goblet cell hyperplasia - Chronic inflammation - Bronchiolar wall fibrosis Pathologic hallmark: - mucous gland enlargement - chronic inflammation of the airway wall - thickened bronchial basement membrane - squamous metaplasia - goblet cell hyperplasia of surface epithelium Bronchial mucous glands are greatly enlarged Reid index is 0.6 which is double the normal

Idiopathic Interstitial Pneumonias (IIPs): RB-ILD/DIP

Desquamative Interstitial Pneumonia (DIP) Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RB-ILD) Onset age 30-40 y/o M > F (2:1) Common in smokers: both associated w/ smoking Treatment: - smoking cessation - corticosteroids Biopsy: pigmented alveolar macrophages - Observe a smudgy brownish/red material Two conditions differ in region of the lung affected: RB-ILD: Peribronchial inflammation and fibrosis DIP: Affects alveolar spaces (rather than bronchiolar)

COPD: Anatomic Classification of Emphysema 3) Paracictricial (Irregular)

Dilated airspaces are often seen on the edge of pulmonary scars Incidental finding without clinical significance

Bronchiectasis

Disease state where a focal area of bronchus that has been chronically infected becomes dilated and does not clear mucus very well This is a group of diseases are infectious in origin The chronic infection will destroy cilli, resulting in mucus plugging There will then be airway dilation and recurrent chronic infections Common causes: - Cystic Fibrosis, Pneumonia, and TB

Pulmonary Neoplasms: Metastatic Carcinoma

Distinguished from primary carcinoma in that there are numerous, randomly distributed tumors on the lung parenchyma - primary tends to be a solitary mass Tumors typically vary in size

Pressure Distribution Across the Thorax

During ventilatory cycle a pressure gradient applied across the thorax drives gas to the terminal bronchioles and expands the lungs and chest wall Because the lung is a passive structure the effective transpulmonary pressure driving ventilation is: Palv-Ppl - This is the ΔP that is used in the compliance equation (ΔV/ΔP) Difference between Passive patient vs. Active patient inflation 1) Active respiration - In this situation, we use our muscles to pull down the diaphragm and expand the thorax forward and upward (recall: bucket handle) - This expands the chest wall and creates a negative pressure in the lungs, which causes air from the environment to be pulled in 2) Passive respiration - In this situation, rather than generating a negative pressure to pull air in, we are using a machine to push positive pressure into the lungs.

Diffusion

FICK's law Diffusion across a tissue sheet Amount of gas transferred is: - proportional to area (A), a diffusion constant (D), and the difference between the partial pressures (P1-P2) - inversely proportional to the thickness CO2 and O2 have a similar MW but CO2 is much more soluble in plasma. For this reason, the diffusion constant will be about 20 times that of O2, and CO2 will diffuse much more rapidly across the alveolar membrane. Diffusion and Perfusion Limitations on Gas Exchange - Nitrous Oxide is perfusion limited - CO is diffusion limited - O2 is both perfusion and diffusion limited Under normal conditions - RBC typically spends about ¾ of a second in the alveolar capillary (time for gas exchange) - some gases are better able to diffuse across the membrane than others Carbon monoxide is an example of a gas that is diffusion limited - it does not diffuse fast enough to reach a significant concentration in the plasma - mopped up by hemoglobin which binds strongly to it - diffusion-limitation analogy: "Imagine a train being loaded up with boxes as it goes through a station. In the case of diffusion-limited gas exchange, the train is slowly loaded by a single person. Loading the train is slow, so no matter how fast you send the train through, you won't be able to load more boxes." Nitrous Oxide (N2O) is an example of a perfusion-limited gas - It is perfusion-limited because it diffuses across the alveolar wall extremely quickly and the blood flow is what limits the amount of Nitrous Oxide exchanged - the boxes are loaded onto the train almost instantly by a super quick loading robot as it comes through the station - In perfusion-limited gas exchange, the only way to load more boxes is to speed up the train, or perfusion, as the speed of train limits the loading of the boxes

Patterns of Flow

Flow of air, like fluid, is driven by a pressure differential, which depends on the rate and pattern of flow At low rates of flow (low velocity), the streamlines are parallel, and flow is laminar At higher flows, there may be disturbances and disorganization leading to turbulent flow. Laminar flow is characterized by movement of fluid in smooth, parallel layers, where the velocity is greatest at the center of the tube Turbulent flow is irregular, chaotic, and contains lateral mixing and eddies. Character of air flow is defined by Reynold's Number (Re): Re = 2rvd/n r = radius, v = velocity, d = density, η = viscosity Higher Re (>2000) means that your flow is more likely to be turbulent Physical character of the flow is important because the pressure differential that drives the movement of air in and out of the lung is dependent on the rate and pattern of flow Clinical significance of Flow Property - patient with asthma who has small, tight airways due to inflammation, and is having trouble getting oxygen because of turbulent flow of the air - Solution: hook patient up to Heliox, which contains helium instead of nitrogen - helium is less dense than nitrogen, decreasing Re --> less turbulent flow - patient can now get more oxygen in and out of their lungs due to reduced turbulence, thereby improving oxygenation

Dynamic Compression of Airways

Flow volume loop - plot of inspiratory and expiratory flow (y-axis) vs volume (x-axis) during performance of maximally forced inspiratory and expiratory maneuvers At total lung capacity (TLC), there is less resistance since the airways are wide open (elastic skeleton stretches and pulls the airways wide open) so a high peak expiratory flow rate can be generated As exhalation continues, airways shrink, resistance increases, and flow tapers off At residual volume (RV), flow stops The descending slope of all three curves line up because flow is effort independent, while peak flow is effort dependent. Note: Vital Capacity (VC) = TLC - RV Reason that expiratory flow is effort independent is because of the presence of a physiological choke point, which limits expiratory flow (A) Preinspiration: - Intrapleural pressure of -5 - Alveolar and airway pressure of 0 - Creating a transpulmonary pressure (PA - Pip) of +5 keeping the airway open - There is currently no flow (B) During inspiration: - Drop diaphragm and expansion of thoracic cage/volume generates greater negative pressure in the intrapleural space (-7), which is transmitted to the alveolus (-2) - This creates a pressure gradient (negative pressure in alveoli, 0 pressure outside) causing air to flow into the alveolus - Transpulmonay pressure of +6 keeping the airway open. (C) End-inspiration: - Alveolus is filled with air, and the pressure gradient between the alveolus and the atmosphere has dissipated (0 alveolar pressure, 0 outside) - Intrapleural pressure is -8, Transpulmonay pressure of +8 keeping the airway open (D) Forced expiration: - Air is forced out of the lungs using expiratory muscles, which applies a positive pressure of +38 (expiratory muscles + elastic recoil drive pressure) to the alveoli - Intrapleural pressure is +30 - Pressure gradient/difference from +38 in the alveolus to 0 in the atmosphere - In this large pressure gradient, there is a point where the +30 intrapleural pressure causes the airway to collapse, creating a physiological choke point that moves with dynamic exhalation, thus leading to the effort-independent portion of the curve. Note: This choke point phenomenon is worsened by anything that increases airway resistance, like obstructive lung disease

Respiratory Laboratory: Bronchiectasis

Focal area of dilated bronchi typical of bronchiectasis Bronchiectasis tends to be localized with disease processes such as neoplasms and aspirated foreign bodies that block a portion of the airways. Widespread bronchiectasis is typical for patients with cystic fibrosis who have recurrent infections and obstruction of airways by mucus throughout the lungs.

Respiratory Laboratory: Primary Tuberculosis Gross

Ghon complex is seen here is this case of primary tuberculosis (peripheral nodule and draining lymph node) Primary tuberculosis is the pattern seen with initial infection with tuberculosis, most often in children. Reactivation or reinfection to produce secondary tuberculosis is more typically seen in adults.

Respiratory Laboratory: Adenocarcinoma Microscopic

Glandular structures formed by this neoplasm are consistent with a moderately differentiated adenocarcinoma Peripheral lung cancers that have not metastasized can be easily resected

COPD: Summary Recommendations from The Medical Letter 2017

Goals of Therapy 1. Relieve symptoms 2. Improve exercise tolerance 3. Improve health status 4. Prevent disease progression 5. Prevent and treat exacerbations 6. Reduce mortality

Respiratory Laboratory: Secondary Tuberculosis Gross

Gross lung demonstrates extensive caseous necrosis This pattern of multiple caseating granulomas primarily in the upper lobes is most characteristic of secondary (reactivation) tuberculosis.

Respiratory Laboratory: Pulmonary Embolism Microscopic

Here a thromboembolus is packed into a pulmonary artery Over time, if the patient survives, the thromboembolus will undergo organization and dissolution

Mechanisms of Histamine Release from Storage Granules

Histamine Synthesis - Histidine - (L-histidine decarboxylase) -> Histamine 1. Immunologic release: - Antigen-antibody (IgE) interaction on the mast cell or basophil surface causes histamine release resulting in an immediate hypersensitivity or allergic reaction - This process is called degranulation and requires energy 2. Physical disruption of mast cells - due to tissue injury causes histamine release 3. Direct (nonspecific) release by drugs or other compounds - not IgE mediated. a) Morphine b) Contrast dye c) Succinylcholine d) Vancomycin (red man syndrome)

Respiratory Laboratory: Necrotizing Bronchopneumonia Gross

Histologically there would be focal destruction of alveolar walls liquefactive necrosis seen

Ventilation-Perfusion Relationships: Hypoventilation

Hypoventilation is when we are not moving air in and out of the alveoli effectively Hypoventilation causes hypoxemia because we are not adequately exhaling CO2 - This will lead to a high partial pressure of PACO2 in the alveoli, and lower partial pressure of PAO2 - Hypoventilation always causes an increase in alveolar CO2 and therefore arterial PaCO2 If you halve alveolar minute ventilation, you will double PACO2 If you double alveolar minute ventilation, you will halve the PACO2 **Doubling/halving alveolar minute ventilation is not the same as doubling/halving respiratory rate - shortcut only works for alevolar minute ventilation because this is where the CO2 is ventilated - referring to alveloar ventilation!!! (not overall ventilation) - in diseased states with higher overall dead space, there ventilation rate might be normal but their alveolar ventilation is hypovenitlating VeCO2 x 0.86/ (1-Vd/Vt) = PaCO2 x f x Vt

Ventilation-Perfusion Relationships

Hypoxemia: Low oxygen tension in the arterial blood (low PaO2) Normal PaO2 is about 100 mmHg Significant hypoxemia can lead to hypoxic tissue damage Five Physiologic Causes of Hypoxemia/low PaO2 1) Low Inspired PiO2 2) Hypoventilation 3) Diffusion limitations 4) Shunt 5) V/Q imbalance

Nitrogen Washout

INDIRECT MEASUREMENT of RV, FRC, TLC Same principle as helium dilution, but instead we use a gas that is already in FRC and can be washed out Use 100% O2 to wash out all the N2 (80% of air is nitrogen gas) Patient is at FRC When they exhale, we can get concentration of N2 (or CO2) Collect exhaled gas—washing out N2 and CO2 (Flooding lake with 100% O2) Exhaled gas in bag: we can measure concentration of either in the bag FiN2 at FRC is 0.8 (80% of air) FRC * 0.8 = Volume of bag * FN2 in bag Nitrogen washout/Helium dilution are very accurate unless someone has a disease of the lung - N2/CO2 do not leave space or helium doesn't get in there - Emphysema (obstructive lung disease) or Asthma (poor ventilation) - We will underestimate true FRC because it will not take into account space that is not ventilating well (Green circle)

Spirometry: Helium Dilution

INDIRECT MEASUREMENT of RV, FRC, TLC C1 * V1 = C2 * (V1+V2) Helium is inert: won't cross alveolar membrane Start with helium in system, but it is not entering body Valve is opened, have patient breathe in and out until equilibration (when they reach FRC) Helium is diluted throughout system and the new concentration is measured Patient comes to rest at FRC (V2) Can subtract ERV from FRC to get RV

Idiopathic Interstitial Pneumonias (IIPs): Idiopathic Pulmonary Fibrosis (IPF)

IPF is the most common of the idiopathic diseases Clinical Features - Onset > 50 y/o: "Disease of aging" - RARE onset before 50 y/o, more prevalent those over 75 - Male predominant - Smoking may be a risk factor - Insidious onset of dyspnea and cough: Patients have a hard time pin-pointing when symptoms began - Progressive/fatal within 3-5 years - Inevitably fatal w/o a lung transplant - around same incidence as pancreatic cancer and ovarian cancer, leukemia Histopathology - Heterogeneous: normal lungs w/dense areas of collagen deposition - Patchy interstitial FIBROSIS - Most pronounced in subpleural regions - Early and late lesions - HONEYCOMB fibrosis : Dense fibrosis lined by bronchiolar epithelium - Patchy alveolar septal infiltrate of lymphocytes, plasma cells, mast cells, and eosinophils Pathophysiology - Environmental factors injure alveolar epithelial cells - Injury induces inflammation and cytokine release, triggering the recruitment and infiltration of myofibroblasts - Myofibroblasts lay down collagen - In IPF patients, this process is dysregulated --> excess collagen deposition and fibrosis - Fibrosis decreases lung compliance, inducing a restrictive lung phenotype Risk Factors - Cigarette smoking - Environmental exposures (affect lung wound healing) ○ Gastroesophageal Reflux (GERD) ○ viral infections - Genetics ○ Telomerase mutations ○ Surfactant mutations ○ MUC5B infections (35% cases) Treatment - We used to think that inflammatory reactions triggered interstitial fibrosis - treated IPF with the same immunosuppressants used to treat sarcoidosis - A 2011 trial demonstrated that immunosuppressant IPF treatment led to increased mortality (perhaps due to increased infections) - 2 new antifibrotic drugs were approved by the FDA Pirfenidone, Nintedanib - drugs modulate cytokine responses that contribute to fibrosis - modestly slow disease progression; they do not reverse any present damage nor stop progression Management - Patients with mild to moderate illness can start Pirfenidone or Nintendanib - also need to assess comorbidities (GERD, OSA) - Pulmonary rehabilitation, Influenza and Pneumococcal vaccination, and supplemental O2 must also be considered - Important to remember that disease progression is inevitable - Lung transplant evaluation if appropriate - Enroll in a clinical trial if eligible

Allergic reactions Mediated by Histamine

IgE-mediated hypersensitivity reactions can occur as a result of antigen presentation through: - the skin (insect bite) - mucous membranes (pollen, molds) - GI tract (foods such as nuts or shellfish or drugs such as penicillin) - parenterally (drugs) The reaction can lead to one or all of the following: 1. Allergic rhinitis - rhinorrhea (runny nose), nasal itching, sneezing, congestion - can be seasonal or perennial 2. Allergic conjunctivitis - itchy, watery eyes, often associated with allergic rhinitis 3. Acute urticaria (hives) - disseminated wheal and flare response that results in red, itchy patches on the skin 4. Anaphylaxis - systemic mast cell and basophil degranulation releases histamine and other mediators and results in severe hypotension, edema, severe bronchoconstriction and epiglottal swelling, which impedes breathing.

Rhinitis

Inflammation of the nasal mucous membranes. Symptoms: - rhinorrhea (runny nose) due to mucous gland stimulation - sneezing and nasal itching due to histamine release and sensory nerve stimulation - nasal congestion due to dilation and engorgement of nasal blood vessels Types: 1. allergic - IgE mediated reactions, Th2 cell mediated mucosal inflammation (can be seasonal or perennial), nasal mucosa can become hyper-responsive Treatment options: a. decongestants - oral or intranasal b. antihistamines - oral or intranasal c. corticosteroids - intranasal d. cromolyn - intranasal e. leukotriene antagonist - oral f. anticholinergic - intranasal 2. non-allergic - due to cold virus infection Treatment - decongestants only - oral or intranasal Strategies to counteract effects of histamine and other mediators: 1. Prevent release of mediators - corticosteroids (intranasal) - mast cell stabilizer (cromolyn) 2. Block receptors for mediators and transmitters (pharmacological antagonists) - H1 receptor antagonists (antihistamines) - leukotriene receptor antagonists - muscarinic receptor antagonists (anticholinergics) 3. Administer physiological antagonist - alpha1-adrenergic receptor agonists (decongestants) - epinephrine - for systemic reactions (anaphylaxis) 4. Allergen immunotherapy Pathophysiology of Allergic Rhinitis - Diagram Treatment strategies (depend on whether it's allergic or non-allergic): 1. Decongestants Allergic and non-allergic rhinitis - alpha1-adrenergic receptor stimulants cause vasoconstriction and decrease nasal congestion; improve nasal airflow phenylephrine (oral OTC cold preps or nasal spray - Neo-Synephrine) has recently been shown to be no more effective than placebo at relieving nasal congestion pseudoephedrine is more effective but available "behind the counter" only Oral administration - side effects related to alpha1 receptor stimulation (↑ BP, urinary retention) Intranasal application - limit use to 3-5 days to avoid rebound congestion (rhinitis medicamentosa) - a1 receptor down regulate from being over stimulated 2. Antihistamines allergic rhinitis only - prevent/treat histamine's effects (sneezing, runny nose, itching) - 2nd generation agents are preferred especially for long-term use 1st line drugs for mild to moderate nasal and ocular symptoms - act quickly but are even better if administered before symptoms occur oral or intranasal preparations - intranasal has faster onset, better relief of nasal congestion, but bitter taste Loratadine (Claritin®, oral) Azelastine (intranasal or ophthalmic) Loratadine/pseudoephedrine - Oral preps available alone or in combination with decongestant: (Claritin-D®) Azelastine/fluticasone intranasal - Intranasal preps available alone or in combination with CS fluticasone - combo produces better symptom relief than either drug alone Side effects of intranasal preps - nasal discomfort, nosebleeds 3. Intranasal corticosteroids allergic rhinitis only - prevent production/release of mediators from mast cells - prevent all symptoms of inflammation 1st line: most effective prophylactic treatment against moderate to severe symptoms - reduce both nasal and ocular symptoms Dosing :once/day Onset of action within 12 h Maximal effect may take 7 days or longer Fluticasone (Flonase®) - also available in combo with intranasal antihistamine Fluticasone/azelastine - additive effects Side effects are mild - dryness/irritation of nasal mucosa 4. Intranasal Cromolyn sodium allergic rhinitis only - prevents release of mediators from mast cells - use prophylactically before exposure to known allergen - not as effective as intranasal corticosteroids 5. Leukotriene receptor antagonist allergic rhinitis only Montelukast (oral) - modest effect - less effective than intranasal corticosteroids or H1 antihistamines - can use in combination with antihistamine in patients who can't tolerate or won't take intranasal CS 6. Intranasal anticholinergic Ipratropium bromide (Atrovent®) - use to reduce rhinorrhea - does not relieve other symptoms - use as adjunct medication - anticholinergic side effects 7. Anti-IgE antibody Omalizumab (subcutaneous injection) - reduces symptoms of allergic rhinitis in patients taking it for asthma - not approved by the FDA for allergic rhinitis (is approved for chronic urticaria) 8. Allergen Immunotherapy - allergen extracts of grass pollen and ragweed pollen - sublingual administration at least 12 weeks before and during pollen season - reduces symptoms of allergic rhinitis - side effects: allergic reactions in mouth area including oropharyngeal edema - expensive

Pharmacological Therapy of Asthma: Anti-inflammatory drugs for chronic control 1. Corticosteroids

Inhaled steroids (ICS) - most potent and effective of anti-inflammatory drugs - first-line treatment for all levels of persistent asthma MOA Inhibit the inflammatory response by: - preventing production and release of inflammatory mediators by suppressing transcription of inflammatory genes - preventing recruitment of inflammatory cells into the airway - inducing apoptosis in eosinophils and TH2 lymphocytes Increase transcription of beta2 receptors and prevent receptor desensitization - good reason for combining to LABA so we dont get receptor densizization Overall effect is a suppression of late inflammatory response and reduction in airway hyperresponsiveness, but not a cure of the underlying disease Lung damage from airway remodeling is not reversed by steroids Cessation of treatment leads to return of symptoms Outcomes: - improve pulmonary function - prevent symptoms - reduce frequency of exacerbations - reduce Emergency Department visits - decrease asthma-related deaths Fluticasone (Flovent®) - other agents (beclomethasone, flunisolide, triamcinolone, budesonide, mometasone, ciclesonide) are all equally effective Combination products: fluticasone/salmeterol (Advair®), budesonide/formoterol (Symbicort®) Use in asthma - chronic control for all levels of persistent asthma - NOT for immediate relief - take days to weeks to become fully effective OFF LABEL USE not in guidelines - recent data has shown that as-needed use of ICS/LABA budesonide/formoterol is effective in reducing asthma symptoms when used for rescue (instead of a SABA) in mild asthma and in patients already taking it as control medication (no data on other ICS/LABA combos) Dosing - low, medium, high - use lowest dose that will control symptoms, step down if well-controlled - higher doses increase extent of systemic absorption and risk of systemic effects Side effects (low-medium doses) - increased susceptibility to thrush (oropharyngeal yeast infection) due to local suppression of immune response - dysphonia (hoarseness) - cough *Incidence is reduced with use of spacer and by rinsing mouth after taking drug Side effects (high doses) - above plus - increased systemic effects - should monitor for possible changes in bone density, cataract formation, development of glaucoma, HPA axis suppression - no increase in risk of pneumonia in asthma patients Side effects (children) - long-term treatment with ICS (budesonide) causes an initial reduction (first 2 yrs of treatment) in growth that persists into adulthood as reduced attained height (on average, attained height is 0.5 inch less than expected) - Choose preparations with the least systemic absorption at the lowest dose. Use in COPD - Steroids are not as effective in COPD - do NOT use as monotherapy in COPD - use as adjuncts to long-acting bronchodilators for patients with moderate-to-severe COPD experiencing frequent exacerbations - Patients who respond are more likely to have concomitant asthma Oral or parenteral steroids Prednisone, Prednisolone Uses - chronic use in some cases of severe persistent asthma - can consider for short term use (5-10 days oral course) during exacerbations in all patients - fewer side effects with short-term use - short course can be given, if needed, to control symptoms when initiating long-term treatment with ICS Effects occur in 6-12 hours (faster than with inhaled CS) Many toxicities - to reduce try alternate day dosing Side effects related to the metabolic effects of the corticosteroids - ↑ BP, ↑ diabetes, weight gain, osteoporosis, cataracts, glaucoma, facial swelling, Cushingoid habitus, adrenal suppression, psychiatric disturbances Side effects related to the suppression of the immune response - ↑ risk of infections (no evidence of ↑ in lung infections when used in asthma patients), impaired wound healing Longer-term use can cause adrenal suppression --> cortisol negative feedback loop, no endogenous production of cortisol - do not stop treatment suddenly or patient will experience acute adrenal insufficiency - Patient must be weaned slowly to allow recovery of adrenal function - No dose-tapering is necessary with short course (5-10 day) treatment.

Structure and Function: Ventilation

Inspiration Diaphragm contracts and descends - Increase in superior-inferior volume External Intercostal muscles contract causing ribs like a bucket handle to swing out - Increase in anterior-posterior diameter - Increase in transverse diameter Action draws air into the lung - increased thoracic volume, decreased intrathoracic pressure --> air moves from high to low pressure Air travels to terminal bronchus by bulk flow Beyond that point the cross-sectional area is so large that the forward velocity of the gas becomes slow and diffusion of gas in the airways takes over as dominant mechanism of ventilation in the respiratory zone Expiration - The lung is elastic (alveoli) and returns passively to pre-inspiratory volume - diaphragm and external intercostal muscle relax (abdominal organs passively recoil on diaphragm) - Decrease in thoracic volume - Normal breath of 500ml requires distending pressure of less than 3 cm water Compliance = V/P Elasticity = P/V Compliance = 1/Elasticity Compliance of a system is the ease to which a structure can be stretched Elasticity of a system is the ease to which a structure that is stretched can be shrunk back. Our lungs need the right balance of compliance and elasticity to be healthy We want our lungs to be compliant enough that we can expand them easily But we also want our lungs to be elastic enough that they can return to their resting volume after we take a breath

Flow Volume Loops in Pathologic Airway Obstruction

Inspiration: Intrathoracic airway (lungs) expands Extrathoracic airway (trachea) narrows - As you're inhaling, there is a negative pressure within the airway, which causes the extrathoracic portion to narrow because the atmospheric pressure is 0, which is greater than the pressure in the airway. Expiration: Intrathoracic airway narrows Extrathoracic airway expands - As you're exhaling, there is a positive pressure within the airway, causing the extrathoracic portion to expand, because the atmospheric pressure is 0. If there is flattening of a portion of the flow-volume loop, that means that there is an obstruction in the portion of the airway that narrows during that phase of breathing A) Fixed (Intra- or Extrathoracic) - Both inspiration and expiration loops are flattened - obstruction is so large that regardless of the airway, both inspiration and expiration are affected - This happens with vocal cord paralysis, or a large tumor B) Variable extrathoracic: - Normal expiratory loop - flattened inspiratory loop - obstruction in the extrathoracic airway, since that narrows during inspiration (negative pressure inside, positive pressure outside) - This can be due to vocal cord paralysis. C) Variable intrathoracic: - Normal inspiratory loop - flattened expiratory loop - obstruction in the intrathoracic airway, since that narrows during expiration - This can be due to obstructive lung disease.

H1-Antihistamines

Mechanism of Action - act as inverse agonists at the H1 receptor - stabilize the histamine receptor in the inactive state, inhibiting its activity Simplified two-state model of H1 receptor. - H1 receptors coexist in two conformational states - the inactive and active states - which are in conformational equilibrium with one another - Histamine acts as an agonist for the active conformation of the H1 receptor and shifts the equilibrium toward the active conformation - Antihistamines act as inverse agonists that bind and stabilize inactive conformation of the H1 receptor, thereby shifting the equilibrium toward the inactive receptor state. Categories of H1-Antihistamines 1. First Generation Antihistamines Diphenhydramine Chlorpheniramine Promethazine Dimenhydrinate - generally are more lipid-soluble and can easily penetrate blood-brain barrier - In addition to inhibiting H1-receptors, some antihistamines are antagonists at other receptors including muscarinic cholinergic, alpha-adrenergic and serotonergic receptors - these actions may contribute to their therapeutic and adverse effects - They usually cause sedation and autonomic (particularly anticholinergic) effects 2. Second Generation Antihistamines Fexofenadine Cetirizine Loratadine Desloratadine Azelastine - ionized at physiologic pH and penetrate the blood-brain barrier poorly - more selective for the H1 receptors - They are less sedating and have fewer autonomic effects. Pharmacokinetics - easily absorbed from the GI tract with peak plasma concentrations occurring 1-3 hours after oral administration - In general, the 2nd generation agents are longer acting and require less frequent dosing (once daily) - dosing regimen of some agents does not always correspond to their half-life or duration of action. Metabolism and Drug Interactions a) Loratadine is metabolized by CYP3A - increased side effects if given with CYP3A inhibitors. b) Fexofenadine is excreted primarily in feces. c) Cetirizine is primarily renally eliminated. Pharmacological Properties - Table Therapeutic Uses of H1 Antihistamines: - Clinical use sometimes depends on the individual agent's actions at receptors other than the H1 receptor. 1. Allergies - especially acute ones (both 1st and 2nd generation antihistamines) - allergic rhinitis (oral or intranasal preparations) - allergic conjunctivitis (oral or topical (eye drops) preparations) - acute urticaria (oral preparations) Effect: - drugs reduce histamine-mediated rhinorrhea, sneezing, lacrimation and itching of eyes, nose, throat and skin - Better response is obtained if the drug is given prior to or at the beginning of exposure to the allergen - Oral agents are not as effective at relieving nasal congestion (therefore, combine with a1-adrenergic agonists = decongestants; combination products such as Claritin-D = loratadine + pseudoephedrine are available) 2. Sedation - found to be a side effect of many 1st generation antihistamines so some are approved for use as sedatives. - Diphenhydramine and doxylamine (ingredient in Nyquil) are the only H1 antagonists approved for use as sedatives - Available OTC 3. Motion Sickness - 1st generation antihistamines - Greater efficacy if drug is given prior to onset of symptoms - block a step in the histaminergic and cholinergic pathway from the inner ear to the emetic center - Prevention of nausea and vomiting may be due to both antihistaminergic and anticholinergic (antimuscarinic) actions. - Dimenhydrinate - Promethazine - strong antiemetic action - Cyclizine - less sedating 4. Common cold - Although included in OTC cold preparations - antihistamines are of little use against the common cold - anticholinergic effect of some H1 antihistamines may help reduce nasal secretions. Adverse Effects 1. Sedation/Cognitive Impairment - more likely with 1st generation H1 antagonists - Even when the drugs are taken at bedtime, drowsiness may linger in the morning - These drugs may also interfere with learning and memory, performance on examinations and psychomotor performance, even without sedation. Driving is impaired - Tolerance to the sedating and performance effects can occur with chronic use. 2nd generation H1 antagonists: - Fexofenadine: non-sedating even in high doses - Loratadine/Desloratadine - sedation can occur at higher doses or in situations where clearance is reduced - elderly patients, patients with hepatic impairment, or when taken with drugs that inhibit its metabolism (i.e., CYP 3A inhibitors). - Cetirizine: causes sedation at recommended doses 2. Anticholinergic Effects - dry mouth, blurred vision, urinary retention, constipation - more prominent with 1st generation H1 antagonists 3. Postural Hypotension - likely due to a1-adrenergic receptor blockade Toxicity in Overdose - CNS excitation - hallucination, ataxia, convulsions - Anticholinergic symptoms - dilated pupils, flushed face, tachycardia, urinary retention, dry mouth, fever - Coma, cardiorespiratory collapse, death - Treatment is symptomatic and supportive Drug Interactions (mainly 1st generation H1 antagonists) 1. CNS depressants - alcohol, barbiturates, opioids, benzodiazepines 2. Drugs with anticholinergic properties - atropine-like drugs - tricyclic antidepressants - some antipsychotic drugs

Parenchymal Disease: Alveolar and Interstitial (Parenchymal Infiltrates)

Interstitial Disease: - disease remains between the alveoli and capillaries in the interstitium - (CC: pulmonary fibrosis, sarcoidosis) - alveoli still have air in them - disease is between the alveoli and capillaries there will still be air in the alveoli so the lungs will look mostly BLACK Alveolar/Airspace Disease: - disease extends into the alveoli filling them - (CC: pneumonia, pulmonary edema) - diseases will present with air bronchograms and loss of vascular markings (obscured because of the infiltrate, changing density of the alveoli to match vasculature) - alveoli are filled, expect the lungs to look mostly WHITE - Air bronchograms = darker lines that represent the outline of the bronchi that are not affected, not filled with fluid (still air) do not change density - NOTE: you normally cannot see the horizontal fissure, but when there is pathology present, the horizontal fissure is highly apparent! - Dense Alveolar/airspace is also called consolidation or white out

COPD: Anatomic Classification of Emphysema 4) Distal acinar (Paraseptal)

Involve the periphery of the acinus adjacent to pleura upper lobe Most frequently associated with spontaneous pneumothorax in young persons Coalesce into bulla

COPD: Anatomic Classification of Emphysema 1) Centriacinar (Centrilobular)

Involves mid portion of acinus surrounding respiratory bronchioles Distal often spared unless severe More upper lobe Men more predominant although less so Even in severe form there is almost always a rim of normal alveola surrounding the emphysematous area MOST COMMON FORM OF EMPHYSEMA Most common among smoker (inhibition of a1-antitrypsin)

Pulmonary Neoplasms Overview

Leading cause of cancer deaths Each year about 200,000 in US are told they have lung cancer Each year about 150,000 people die from lung cancer 80% to 90% of lung cancer cases are linked to cigarette smoking - Strongest associated with squamous cell carcinoma and small cell carcinoma About 7,300 people who have never smoked die from lung cancer due to secondhand smoke exposure each year Radon is the 2nd most common known cause of lung cancer - Other risk factors include genetics, asbestos exposure, diesel fuels, particulate matter, and air pollution Smoking can cause cancer in other sites (risk factor for many other neoplastic diseases) Screening is recommended for people at high risk

Pharmacological Therapy of Asthma: Anti-inflammatory drugs for chronic control 2. Leukotriene receptor antagonists

Leukotriene receptor antagonists (available for oral use only) Montelukast (Singulair®, once/day) Zafirlukast (Accolate®, 2x/day) MOA - block leukotriene (cysLT) receptors preventing all deleterious effects mediated by leukotrienes (bronchoconstriction, chemotaxis of inflammatory cells, mucus production, increased vascular permeability) Use - alternative to ICS (but not preferred) for chronic treatment of mild asthma - can combine with ICS for chronic treatment of moderate asthma (however, ICS/LABA combination is preferred); addition of a leukotriene modifier may allow for a reduction in dose of inhaled steroid - useful in patients with both asthma and allergic rhinitis - approved for prevention of exercise-induced bronchoconstriction (can take daily or 2 hours before exercise) - not all patients respond to these drugs Side effects - hepatic injury (rare)

Respiratory Laboratory: Bronchopneumonia Gross

Lighter areas that appear to be raised on cut surface from the surrounding lung are the areas of consolidation of the lung Upon closer inspection, the pattern of patchy distribution of a bronchopneumonia is seen Consolidated areas here very closely match the pattern of lung lobules (hence the term "lobular" pneumonia).

Simple Spirometry

Limitation: - cannot measure RV, FRC, and TLC Inverted bucket inside another bucket of water As patient inhales—bucket goes down (pen goes up, red lines) As patient exhales—bucket goes up (pen goes down, showing red lines drawn) We cannot measure: - Residual Volume: never leaves the mouth - Functional Capacity (need to know residual volume) - Total Lung Capacity (need to know residual volume)

Respiratory Laboratory: Foreign Body Response

Localized foreign body giant cell response to the aspirated material seen here at high magnification - granuloma - foreign body Aspirated material may also produce inflammation from chemical irritation, as with gastric contents Aspiration pneumonia stroke, cva patients at risk (lose control of muscles used to swallow Giant cell response to foreign body Acute inflammatory response (neutrophils) to bacteria/irritants on foreign body

Static: Pressure-Volume Relationship

Lung compliance: - Under static conditions the pressure gradient across the lung Palv-Ppl counterbalances the elastic forces of lung recoil (elasticity) Thoracic Cavity Compliance: - For spontaneous breathing patient (Active patient) the pressure distending the chest wall can not be measured because these pressures are generated by the muscles in the chest wall itself and not represented by Ppl - Only when the chest wall is passively inflated can it's distensibility be assessed. (Patmos-Ppl = 0-Ppl) Volume change: - Under a normal condition, the lung and inner chest wall occupy an identical volume determined by lung compliance (TLC) and trans-structural pressures (RV) RV is limited by chest wall recoil TLC is limited by lung compliance/distensability FRC is place on curve of optimal compliance Although P-V curve is linear over usual tidal volumes, convexity becomes apparent at higher volumes The limits of distensibility are reached at TLC. The compliance is best close to FRC Lung Line: - At a pressure of 0, the lungs will sit at a certain volume - If positive pressure is applied, the lung will inflate and move up along the dotted line - Eventually, the lungs will reach a point of maximum inflation where adding more pressure will not increase the volume - Thus, the top of the dotted line starts to flatten (it's not illustrated very well here) Chest Wall Line: - chest wall will rest at a certain volume when the pressure is 0 - Notice that this resting volume is larger than the lung's resting volume - Again, if we add positive pressure, the volume will increase along the dotted line - Notice that the compliance curve for the chest wall remains steep up top - This is because the diaphragm has the ability to go all the way down to the pelvis and thus the thorax can hold a very large volume - One the opposite spectrum, if we added negative pressure (so that air leaves the thorax), we eventually reach a point where no matter how much negative pressure we apply, we cannot compress the thorax anymore (this is because of the ribs) - Here we see flattening of the dotted line at the bottom of the compliance curve (at Residual Volume) Lung and Chest Wall Line - these two systems together, we end up with the solid middle compliance curve - At 0 pressure, it will come to rest at a volume that is higher than where the lung wants to be (so it takes +5 cm of pressure on the lungs) but lower than where the chest wall wants to be (so it takes -5 cm of pressure on the chest wall) - This is the system at rest and is also the functional residual capacity (FRC) and happens to be where the lung is most compliant - The pleural pressure at this resting state is -5 cm water - Notice that this line has flattened both at the bottom and top of the curve - This is because the lungs limit inflation while the chest wall limits deflation - TLC (total lung capacity) is a function of the lung - RV (residual volume) is a function of the thorax Pneumothorax occurs when there is an uncoupling of the lung and chest wall - poke a hole in the pleura of the lungs --> Air enters the pleural space and we lose the negative pressure that was keeping the lung distended - The lung will return to its resting volume, as will the thorax (they are now uncoupled) - A sucking-blowing chest wound describes a situation in which air is moving into the intrapleural space during inspiration and moving out during expiration - A sucking chest wound describes a situation in which air is moving into the chest wall during inspiration but is not leaving during expiration - More and more air enters the pleural space and compresses the lungs, causing a tension pneumothorax - So, a sucking chest wound is more dangerous than a sucking-blowing chest wound. Hysteresis: - To achieve a particular volume, more pressure must be applied on the inflation limb of the P-V curve than on the deflation limb: - In depletion of surfactant this effect is more pronounced Compliance curve: Pressure Volume Loop - Increasing pressure causes increase lung volumes - Conversely increasing lung volumes increases the recoil pressure

Ventilation-Perfusion Relationships: V/Q Ratios of the Lung

Lung has an overall V/Q of 1 If some alveoli are not ventilating as well The CO2 in those alveoli will be higher than the normal 40 mmHg Therefore, the oxygen will be lower than 100 mmHg, and the blood that flows through will equilibrate and be hypoxemic to an extent Lower the V/Q, the more hypoxemic the arterial O2 will be and higher the CO2. V/Q ratio varies in different areas of the lung V/Q ratio at the bottom of the lung is less than 1 V/Q at the top of the lung is greater than 1

Respiratory Laboratory: Squamous Cell Carcinoma Microscopic

Microscopic appearance of squamous cell carcinoma with nests of polygonal cells with pink cytoplasm and distinct cell borders The nuclei are hyperchromatic and angular

Respiratory Laboratory: Small Cell Carcinoma Microscopic

Microscopic pattern of a small cell carcinoma in which small dark blue cells with minimal cytoplasm are packed together in sheets Small cell carcinomas, which are a highly malignant form of neuroendocrine tumor, are often associated with paraneoplastic syndromes

Respiratory Laboratory: Emphysema Microscopic

Microscopically at high magnification, the loss of alveolar walls with emphysema is demonstrated - loss of lung elastic recoil - loss of SA for gas exchange Remaining airspaces are dilated

Minute Ventilation

Minute ventilation (Ve): Tidal volume (TV) x rate (f) Ve = TV x f Both tidal volume and rate will directly alter the PaCO2. Minute ventilation = dead space ventilation + alveolar ventilation - alveolar ventilation is what really determines the PaCO2 because dead space does not exchange gas - If you increase the minute ventilation and dead space is fixed, we will only increase the alveolar ventilation One can increase the minute ventilation (Ve) by increasing the rate or increasing the TV Clinically, however, we only change the minute ventilation by changing the rate Once we set the TV we usually don't change it because we don't want to overstretch the lung.

Factors Influencing Airway Resistance

Most of the factors influencing airway resistance come down to the radius of the airway and how various factors expand and constrict the airway: Airway Caliber: bigger = decreased resistance, smaller = increased resistance - Bronchi are held open by the elastic skeleton of the lung --> As the lung expands, the elastic skeleton stretches and pulls the airways even wider open (bigger = larger radius = less resistance) - Bronchi are supported by radial traction of surrounding tissue (Caliber increases as lung expands) - At very low volumes, small airways may close completely, which traps air in the lung (closing volume) Autonomic activity: - Parasympathetic activity causes bronchoconstriction via constriction of smooth muscle. - Sympathetic activity (β-agonists) causes bronchodilation via relaxation of smooth muscle Inflammation of bronchial walls reduces radius of airways and thus increases resistance Density and viscosity of the gas - Viscosity: Increased viscosity increases resistance - Density: Decreased density decreases Re leading to more laminar flow (less resistance)

Respiratory Laboratory: Metastatic Carcinoma Gross

Multiple variably-sized masses are seen in all lung fields. These tan-white nodules are characteristic for metastatic carcinoma. Metastases to the lungs are more common even than primary lung neoplasms simply because so many other primary tumors can metastasize to the lungs Even the hilar nodes in this photograph demonstrate nodules of metastatic carcinoma. The nodules are usually in the periphery and do not cause major obstruction

Pharmacological Therapy of Asthma: Bronchodilators 2. Muscarinic receptor antagonists (anticholinergics)

Muscarinic receptor antagonists (anticholinergics) MOA - block muscarinic receptors in bronchial smooth muscle and mucus glands - block direct and reflex vagus nerve mediated bronchoconstriction and mucus secretion Side Effects - anticholinergic: dry mouth, urinary retention, constipation Short-acting muscarinic antagonists (SAMAs) Ipratropium bromide (Atrovent®) - FDA approved for COPD, not asthma - used off-label for asthma - 4° ammonium compound --> reduces systemic absorption and CNS penetration - onset of action 15 minutes, peaks in 1-2 hours, lasts 6-8 hr Clinical Use - less effective in producing bronchodilation in asthma than the more potent beta agonists. Patient response is variable. - used (off-label) in patients who do not respond to or should not take beta agonists (patients with bronchoconstriction due to beta blockers or patients with serious cardiac arrhythmias or unstable angina) but has slower onset of action - can use in combination with SABA (additive effects) in moderate-severe asthma exacerbations (in nebulizer) - for intermittent (acute) dyspnea in COPD and chronic bronchitis patients - can use in combination with SABA (same inhaler) in COPD and chronic bronchitis Available as MDI and for nebulization Long-acting muscarinic antagonists (LAMAs) Tiotropium (Spiriva®) - duration 24 h - FDA approved for COPD and for maintenance treatment of asthma Clinical Use - high efficacy for long-term treatment of COPD - available alone or in combination with a LABA for use in COPD - use with ICS/LABA in patients with moderate-to-severe COPD - ICS/LABA/LAMA combination now approved for COPD (contains a different LAMA) Current asthma recommendations based on more recent studies - use in combination with ICS as alternative to adding LABA (noninferior study) - add to ICS/LABA in patients with severe asthma - improves lung function

Granulomatous Inflammatory Diseases: Sarcoidosis

Non-caseating granulomatous inflammatory response resulting from environmental/occupational exposures in genetically susceptible individuals Slide (A) shows a high magnification image of a lung granuloma - The granuloma is composed of epithelioid histiocytes and multinucleated giant cells - Lymphocytes line the periphery of the granuloma - Often, this diseased tissue is surrounded by a rim of collagen - hyalinization often occurs in older granulomas Slide (C) shows a granuloma from lower magnification - We can observe the granuloma's peribronchovascular distribution i.e. it is near the airways, lymphatics, and blood vessels Pathogenesis - pulmonary antigen-presenting cells (APC), namely macrophages and dendritic cells, phagocytose inhaled antigens in alveoli - APCs degrade, process and then present the antigen in the context of MHC II - CD4 T cells interact with membrane-bound MHC-Ag complexes - This interaction prompts T cell production of cytokines, especially IL-2 - IL-2 acts in autocrine fashion: stimulates the T cell to produce TNF (proliferation/activation) and IFN-y (further stimulating macrophages which release IL-12) - These cytokines drive granuloma formation --> alveolitis Progression - Sarcoidosis is typically a self-limiting disease - Several years post-diagnosis 60-70% of patients see resolution of chest X-Ray abnormalities - About 30% of patients do not see resolution; these patients live with chronic sarcoid, probably going to have the chronic form of the disease if it doesn't self resolve over 3-4 years Clinical Characteristics - Lung involvement: 90% of patients' CXRs show evidence of disease - Eyes and skin - Onset: 20-40 y/o - Second peak in onset: women over 50 y/o - Genetics play a role in disease phenotype - Caucasians commonly present w/ abnormal Ca 2+ metabolism and erythema nodosum - African Americans frequently present w/ peripheral lymphadenopathy, liver, bone marrow, and skin involvement - Phenotype and outcome may be influenced by HLA genes ○ HLA DRB*0401 → ocular involvement ○ HLA DPB1*0101 → hypercalcemia, whites Diagnosis - If we sarcoidosis suspected --> almost always need a tissue biopsy for conformation - Can biopsy the lung (via bronchoscopy) or conjunctiva - If biopsy is negative, we can rule out sarcoidosis (high sensitivity snOUT) - Even in suspected cases, biopsies containing granulomas are not diagnostic - Sarcoid diagnosis is truly a diagnosis of exclusion - Must consider sarcoid mimics when we see granulomatous inflammation --> large differential diagnoses for granulomas - Key differentials include infections and malignancies - Once we exclude sarcoid mimics AND find evidence of multisystem involvement, we can diagnose the patient with sarcoidosis Two clinical syndromes can make sarcoid diagnosis w/o a biopsy : 1. Lofgren Syndrome - Hilar and mediastinal lymphadenopathy - Erythema Nodosum: Tender subcutaneous nodules - patient may present with arthralgias and low-grade fever 2. Heerfordt Syndrome - Uveitis - Parotitis: Parotid gland inflammation - Cyclical fevers Predicting Disease Course and Resolution: Scadding Score Stage I - Hilar and mediastinal adenopathy alone - NO parenchymal disease - Frequency: 25-65% - Resolution: 60-90% Stage II - Hilar and mediastinal lymphadenopathy - Parenchymal infiltrates - CXR: Reticular nodules Frequency: 20-40% - Resolution: 40-70% Stage III - NO adenopathy - Pulmonary infiltrates - CXR: shadowing in lungs w/o LN involvement - Frequency: 10-15% - Resolution: 10-20% Stage IV - Fibrosis - Frequency: 5% - Resolution: 0% :( - Patients will live with a chronic condition; this doesn't necessarily mean that they will have severe functional impairments Characteristics Associated with Poor Prognosis - Age > 40 at onset - African American - Requirement for steroids - Extrapulmonary involvement ○ cardiac or neurologic involvement ○ Lupus pernio: skin rash on the face ○ Splenomegaly, hypercalcemia, osseous disease - Highly symptomatic pulmonary involvement (poor PFTs) ○ Stage III-IV Scadding Score CXR ○ Pulmonary Hypertension ○ Significant physiologic impairment ○ Moderate to severe dyspnea Treatment - Treat to avoid danger (ex. prevent cardiac and ocular damage) and improve quality of life - If a patient has normal PFTs and no symptoms, it's recommended that providers watch and wait - Previously used Prednisone to treat Sarcoidosis - treatment was problematic as corticosteroids have MANY side effects: weight gain, bone loss, HTN, diabetes, and glaucoma - steroid-sparing immunosuppressants such as Methotrexate, Cyclophosphamide and Hydroxychloroquine - Hydroxychloroquine is an antimalarial - helps treat sarcoid patients' fatigue, Ca + imbalances, joint issues - Anti-TNF agents (Infliximab and Adalimumab): reserved for 3rd line treatment of severe disease.

COPD: Anatomic Classification of Emphysema 2) Panacinar (Panlobular)

Non-selective destruction of entire acinus Associated with Alpha 1 antitrypsin Seen in women as well as men Tends to be in lower lobes May be see in association with centrilobar form Seen with alpha 1 antitrypsin deficiency where it will be lower lobe

Respiratory Laboratory: Normal Lung Microscopic

Normal lung microscopically Alveolar walls are thin and delicate Alveoli are well-aerated and contain only an occasional pulmonary macrophage Pneumocytes (epithelial) and endothelial cells (capillaries) that surround the alveolar air sacs Mostly empty space as it should be (there are very rare alveolar macrophages in some spaces if you look close enough)

PFTs: Spirometry: Severity of Obstructive and Restrictive Diseases

Obstructive - If FEV1/FVC Ratio is 10% below normal predicted ratio, then there is an obstructive disease - The FEV1/FVC Ratio only tells you if there is an obstruction or not (diagnosis) - Does not give any insight on the degree of severity of obstruction - Severity of obstruction is determined based on comparing absolute FEV1 with predicted normal FEV1 Physiologic variant represents someone like Michael Phelps with such a large FVC that it's not possible to get 80% of that volume out in 1 second - original FEV1/FVC Ratio is low, but there isn't really an obstruction. In terms of obstructive disease - asthma obstruction can be reversed - whereas COPD obstruction cannot be reversed - A bronchodilator (b2 agonist) inhaler is given and then the testing is repeated - Reversibility: Improvement of FEV1 or FVC by 12% (at least 200c) with the use of bronchodilators Restrictive - The FEV1/FVC Ratio can indicate a restrictive disease - TLC allows for determination of severity - TLC is reduced and determines severity - Restrictive lung diseases result in stiff lungs with diminished ability to expand, resulting in a lower TLC Since RV, FRC, and TLC cannot be measured directly through spirometry the following methods can be used to measure indirectly: - Helium Dilution - Nitrogen Washout OR - Body Plethysmography When reading PFTs, the FRC will inform you of which technique was used (FRC He, FRC N2, FRC Pleth)

Obstructive vs. Restrictive Lung Disease

Obstructive lung disease: - characterized by airway obstruction. Asthma: - inflammation and muscle constriction - reduces the radius of the airway and increases resistance Chronic Obstructive Pulmonary Disease (COPD): - Diseases in this class lie on a spectrum between: - Emphysema: airways and alveoli are floppy and closed (loss of elastic recoil) - Chronic bronchitis: airways are full of mucus, increase resistance - Patients often have a condition that is comprised of a mix of the two. 3 classes of drugs that can be used for these diseases: - Anti-cholinergics - Anti-inflammatory agents - β2 Agonists Interstitial/Restrictive lung disease: - lung itself is stiffer and less compliant Pulmonary fibrosis: lung tissue becomes damaged and scarred Sarcoidosis: immune reaction to lung resulting in inflammation and lung stiffness.

Pharmacological Therapy of Asthma: Anti-IgE Antibody

Omalizumab (Xolair®) MOA - IgG monoclonal antibody that binds to IgE - prevents IgE binding to mast cells and release of mediators Use - administered SQ every 2-4 weeks over months improves symptoms and reduces asthma exacerbations. - adjunctive therapy in patients (greater than 6 yrs) with documented perennial allergen-induced, moderate to severe asthma whose symptoms are inadequately controlled by ICS - added benefit - improves symptoms of allergic rhinitis (but not FDA approved for this) Side effects - anaphylaxis (rare but has Black Box warning) - increase risk of infections, etc. - bruising and pain at injection site (most common) Very expensive - true of all monoclonal antibodies

Idiopathic Interstitial Pneumonias (IIPs): Cryptogenic Organizing Pneumonia (COP)

Onset ~ 55 y/o no gender predominance Symptoms - Cough, SOB, fever, and constitutional symptoms - Patients present acutely with systemic systems - May mimic non-resolving pneumonia - Patients often have been treated w/ several rounds of ABX for incorrectly diagnosed infectious pneumonia Diagnosis of exclusion: rule out other causes of organizing pneumonia - drug/environmental exposures - connective tissue disease Histology - Affects distal respiratory bronchioles, and some alveolar spaces - Polyps of immature connective tissue and proliferating fibroblasts - "Plug" the respiratory bronchioles - Masson bodies: stain blue with Pentachrome Stain - Surrounded by interstitial infiltrate of mononuclear cells CT Findings - Peripheral and peribronchovascular consolidation - Resembles pneumonia! Clinical Course and Treatment - Responds quickly to corticosteroids - Treat for several months then slowly taper dose - ⅓ of patients have recurrent or persistent disease, Fairly high relapse rate

Restrictive Lung Diseases: Overview

Over 150 distinct clinical entities "Interstitial lung disease" misnomer - Restrictive lung diseases can affect the interstitium, alveolar spaces, pulmonary vasculature, and/or pleura Decrease in lung compliance PFTs: smaller TV, TLC Common clinical presentation - Dyspnea, cough - Restrictive physiology Extrapulmonary manifestations - many also overlap with autoimmune diseases 15% of all pulmonologist appointments Pulmonary interstitium - alveolar wall is made of Type I and II pneumocytes - neighboring capillary lumen is surrounded by a single endothelial cell layer - These structures facilitate efficient gas exchange - Gases diffuse from the alveolar air sac, across the pneumocyte (epithelial), into the interstitium, across the endothelial cell, and into the capillary - This normally thin barrier facilitates rapid gas exchange - When patients develop interstitial diseases, this barrier is altered and diffusion is compromised (increased thickness, decreases Ficks rates of diffusion) Histological Slides - difference between normal, healthy alveoli and alveoli of a patient with interstitial lung disease - Appreciate the thin alveolar septa in the healthy lung - Also note the thin interstitial layer surrounding the alveoli - This layer's thinness contributes to the distensibility and compliance of the lung (lower Pel) - Contrast the normal lung to the diseased lung - diseased lung contains alveolar septa filled with inflammatory infiltrate and collagen - This lung is stiffer and therefore less compliant (higher Pel)

Oxygen Delivery and Consumption

Oxygen Carry Content (CaO2): CaO2 = (Hb x SaO2 x 1.34) + (PaO2 x 0.003) - number gives us content: mL of O2/volume of blood - if the SaO2 is 100%, then our CaO2 would be the oxygen carry capacity Oxygen Delivery (DO2): DO2 = CaO2 x CO x 10 - 15 mL/min (from dissolved) + 1000 mL/min (bound to Hb) = 1015 mL O2/min Oxygen consumption (VO2): VO2 = CO x 10 x (a-v)O2 - formula relies on arterio-venous difference to figure out how much O2 was consumed - arterial O2 content: 20 mL O2/dL blood (dissolved O2 is 0.3 mL/dL blood, we are going to ignore its small contribution) - Mixed venous oxygen has a pressure (PaO2) of 40 mmHg and Hb is 75% saturated - Hb x SaO2 x 1.34 = 15 mL O2/dL blood - (a-v)O2 = 20 - 15 = 5 mL O2/dL blood - VO2 = 250 mL O2/min You can use this equation to estimate CO (Q) in a patient assuming VO2 is 250 and you measure the blood arterial and venous gas. CO2 consumption (VCO2): VCO2 = CO x 10 x (a-v)CO2 - arterio-venous difference for CO2 = 4 mL CO2/dL blood - VCO2 = 200 mL CO2/min Ratio of the two consumptions: VCO2/VO2 = 200/250 = 0.8 respiratory quotient of 0.8 Graph: Relationship between DO2 (delivered oxygen) and VO2 (consumed oxygen) in both a normal and a septic patient: Point A: normal resting point Point B: - consuming the same amount - less oxygen is being delivered - bodies extract a higher amount of sxygen from the blood (hemoglobin) - So instead of Hg coming back in veins 75% saturated, they might come back 50% saturated Point C: represents our maximum extraction ratio (ERc) which is 66% - at best, we can extract 66% of the O2 from hemoglobin, leaving venous O2 saturation level at 34%. Point D: past ERc - reached a point where we are not getting the 250 mL O2/min that is needed - delivery is not meeting the demand and we enter a state of shock Red line represents a state of sepsis In sepsis, our body is attempting to fight off an infection and thus requires higher O2 consumption levels VO2 is at 300 rather than 250. In order to meet this higher demand, we need higher oxygen delivery point E represents a higher level of both demand and delivery Notice that the point where consumption exceeds delivery occurs more quickly in sepsis ERc is much lower, at 30%2.

Oxygen Uptake Along the Pulmonary Capillary

Oxygen is both perfusion and diffusion-limited under normal conditions As shown in the diagram: - oxygen is diffusion limited for the first ~0.25 seconds before PAO2 and PaO2 equilibrate - then perfusion limited for the next ~0.5 seconds O2 uptake along the capillary is challenged by: 1. Exercise - blood is pumped faster and spends less time in the capillary (move left down the x-axis) - normally not an issue but can be more serious in diseased lung states (graph A to the right) 2. Alveolar hypoxia - According to Fick's Law, diffusion is proportional to the pressure gradient across the capillary - Alveolar hypoxia will lower the PAO2 - PaO2 pressure difference, decreasing diffusion of O2 into the blood. 3. Interstitial disease - Thickening of blood-gas barrier decreases diffusion (also according Fick's law, where diffusion is inversely related to T) - Interstitial fibrosis and sarcoidosis are the two main interstitial diseases of the lung

Lung Cancer Clinical Behaviors

Paraneoplastic/Endocrine Syndromes - Organ or tissue dysfunction at sites remote from the primary and the metastases - May be endocrine, neurologic, dermatologic, rheumatologic, other - Cancer-produced hormones and hormone-like substances that act at a distance to produce symptoms that are not associated with the tumor itself (ACTH, PTH) Metastases - LNs - Liver - Adrenals - Brain - Pleura - Bone - Lung cancer can metastasize to the other lung! --> If contralateral pulmonary LNs are involved, the patient may not be a candidate for resection Causes of Death 30% Tumor burden i.e. the amount of both primary tumor and metastases present - Tumors act as a metabolic sink → metabolic dysfunction - invades blood vessels --> hemorrhage - larger tumor burden also cuases cachexia - energy consuming 20% Infection 17% Metastatic complications 12% Pulmonary Hemorrhage → shock 10% Pulmonary Embolism 7% Diffuse Alveolar Disease <5% Miscellaneous

Ventilation-Perfusion Relationships: Low Inspired PiO2

Partial pressure of Oxygen in inspired air (FiO2) is low PAO2 = (760-47) x FiO2 - PaCO2/0.8 PAO2 = 713 x FiO2-PaCO2/0.8 Normal: PAO2 = (713) x 0.21 - 40/0.8 PAO2 = 150 - 50 PAO2 = 100 mmHg If FiO2 is only 15% PAO2= 713 x 0.15 -PaCO2/0.8 PAO2 = 107 -40/0.8 PAO2 = 57 mm Hg Will result in a maximum PaO2 of 57 mmHg, which is significantly hypoxemic

Optimal Peep

Peep is designed to bring the patient to the FRC where they are the most compliant: C = Δ V/Δ P When using a fixed tidal volume (Vt), then static compliance is: Cs = Vt /(Plateau - Peep) Why is it not Peak - Peep? - Because that would be dynamic compliance, where there is flow - With flow, airway resistance is a force that PIP must overcome. To find the optimal PEEP, adjust to the level that makes the difference between Plateau-Peep the smallest - If the denominator is the smallest, the static compliance will be the best

Respiratory Laboratory: Adenocarcinoma Gross

Peripheral adenocarcinoma of the lung. Adenocarcinomas and large cell anaplastic carcinomas tend to occur more peripherally in lung Adenocarcinoma is the one cell type of primary lung tumor that occurs more often in non-smokers and in smokers who have quit

Pulmonary Neoplasms: Signs and Symptoms of Lung Cancer

Persistent cough last several months Hemoptysis **If patients present with these key symptoms, work to rule lung cancer out Chest pain: worsens with deep breathing, coughing or laughing Hoarseness SOB, Dyspnea New onset of wheezing Fatigue Recurrent infections Loss of appetite and weight loss: - metabolic sink, trap energy (tumor burns energy) --> caloric depletion of metastatic cancer - Inanition: calorie depletion related to metastatic cancer

Restrictive Lung Diseases: Common Clinical Features

Physical Exam Findings - Fine "velcro" crackles heard at base of the lung - Inspiratory Squeaks: Due to inflammation in distal respiratory bronchioles - Clubbing of digits - Prominent P2, RV heave: sign of Cor Pulmonale, higher pulmonary vascular resistance (because lower O2 diffusion) - Wheezing is UNCOMMON because restrictive diseases don't affect the large airways Pulmonary Function Testing Restriction (common but not universal) - Reduced lung volumes: ↓ FVC, TLC, FRC (RV) - Lungs lose compliance and can't expand - Normal or Increased FEV1 /FVC ratio: lungs are NOT obstructed, high elasticity, elastic recoil Impaired gas exchange - Reduced diffusion capacity DLco and PaO2 - Increased P(A-a)O2 gradient: As disease progresses, you will see a reduced resting arterial O2 tension and an increased arterial Aa gradient - Desaturation on exercise oximetry i.e. exertional hypoxemia

Physiologic Dead Space: Bohr's Method

Physiologic dead space: no gas is being exchanged Physiologic dead space is always equal to or greater than anatomic dead space In Bohr's method, you have a patient exhale a volume of gas into a box and from this we can calculate physiologic dead space: - volume of the box gives us Tidal volume (TV) - PCO2 in the box gives us expired CO2 pressure (PeCO2) - blood draw can give us arterial CO2 pressure (PaCO2) Bohr's Equation: (Phys. Dead Space Volume/TV) = (PaCO2 - PeCO2)/PaCO2 - PaCO2 = arterial CO2 pressure - PeCO2 = expired CO2 pressure (Vd/Vt) = (PaCO2 - PeCO2)/PaCO2

Pleural Disease: Pleural Effusion

Pleural effusion: collection of fluid between the layers of pleura (visceral and parietal) that line the lungs. This is a potential space and anything here would be considered pathology. PA view on first CXR shows a meniscus that indicates fluid build up around the right lung! Note that you also lose the costovertebral angle If you lay the same patient on their side, the fluid will pool downwards with gravity This is called a "decubitus view" and will allow you to determine how much fluid is present

Pleural Disease: Pneumothorax

Pneumothorax is when there is air inside the thoracic cavity b/w the pleura (pleural space) When this happens, air in the thorax creates a positive pressure that pushes down on structures and will collapse your lung 1. Iatrogenic traumatic Pneumothorax - Ex of a unilateral pneumothorax - resident punctured the pleura while trying to insert a central line - When the pneumothorax is due to injury, it's referred to as an "iatrogenic or traumatic pneumothorax" 2. Spontaneous Tension Pneumothorax - More advanced pneumothorax - Notice how the left diaphragm is pushed down much farther than the right! 3. Tension Pneumothorax on Ventilator - completely lose any structures normally seen because the air has expanded the thoracic cavity into the abdomen!

Magnetic Resonance Imaging (MRI)

Pros Best for soft tissue resolution No ionizing radiation Much safer to use (fetal) Cons Takes a long time (>45 min) Limits for patients that cannot sit still (sedation) Contrast (Gadolinium) can deposit in your tissues (brain) - particular concern for the brain and limits the number of MRIs one person can have in their lifetime MRIs do not use x-rays Instead, a machine with a very strong magnet is used to align all of the hydrogen atoms in a patient's body with the magnetic field The way these hydrogen atoms behave can be visualized in even more detail than can be seen on a CT scan, and MRIs are great for soft tissue visualization Filters can be applied to look at various tissue types, like in a CT scan Each filter requires an additional scan The magnet is always on! Don't wear a watch into the room and ruin the machine on the first day of your rotation with radiology because you really can't afford to fix that mistake. Use 'intensity' not 'density' to describe MRIs.

Computed Tomography (CT)

Pros Fast < 2 min Readily available Great spatial resolution Eliminates overlapping densities like in X-ray Best for looking at bones Cons Much higher ionizing radiation IV Contrast is nephrotoxic CT scans utilize x-ray technology with a detector shaped like ring that spins around the patient's body When looking at a slice, it is as if you are standing at the feet and looking towards the head - your left = patient's right Planes Viewed: Transverse Coronal Sagittal CT scans allow you to follow structures as they move through the body due to the multiplanar capability of the scan Filters can be applied to CT images to provide enhanced images of bone vs. soft tissue - MPI, maximum intensity projection, or VRI, volume rendered images, can be used to highlight structures

Maturation of Lungs

Pseudoglandular Period - 5-16 weeks - branching continued to terminal bronchioles (2^23) - no respiratory bronchioles or alveoli present Canalicular Period - 16-26 weeks - each terminal bronchioles divides into 2 or more respiratory bronchioles - each respiratory bronchiole divides into 3-6 alveolar ducts Terminal Sac Period - 26 weeks - birth - terminal sacs (primitive alveoli) form - capillaries establish close contact Alveolar Period - 8 months - childhood - mature alveoli have well-developed epithelial-endothelial (capillary) contacts

Structure and Function: Blood Vessels and Flow

Pulmonary Circulation - Pulmonary artery --> Capillary --> Pulmonary Vein - Diameter of capillary = 10 mm, just large enough for a single RBC - Pulmonary artery receives entire CO from the right side of the heart but the resistance is small compared to systemic circulation - Pulmonary Circulation: low pressure, low resistance system - large volume, low pressure --> lung is very compliant - Each RBC spends 3/4 sec in the capillary - So efficient that there is virtually complete equilibration of O2 and CO2 Bronchial Circulation: - supplies oxygenated blood to conducting airways to terminal bronchioles - Receives only 1% of cardiac output and is nonessential for lung function - bronchial flow is a mere fraction of pulmonary arterial flow - lung can function well without it for example in a lung transplant - The resistance in the bronchial circulation is high as it is part of the systemic circulation Hemoptysis (coughing up blood) is usually caused by rupture of bronchial arteries, since these are high pressure vessels - Hemoptysis is seen in people with TB as these vessels can become damaged when TB causes areas of the lung to become necrotic - To alleviate hemoptysis, an interventional radiologist would want to get to the site of bleeding through the aorta, NOT the pulmonary trunk

Respiratory Laboratory: Pulmonary Edema Macrophages

Pulmonary congestion with dilated capillaries and leakage of blood into alveolar spaces leads to an increase in hemosiderin-laden macrophages Brown granules of hemosiderin from break down of RBC's appear in the macrophage cytoplasm.

Structure and Function: Fick's Law of Diffusion

Rate of Diffusion: Area/Thickness x D x (P1 - P2) D = Solubility/MW Diffusion is: - directly proportional to SA which the gas is diffusing across, the pressure gradient and diffusion constant (solubility) - indirectly proportional to the thickness of the membrane which is is diffusing across CO2 has a higher solubility than O2

Pharmacological Therapy of Asthma: Anti-inflammatory drugs for chronic control 3. Phosphodiesterase inhibitor for COPD

Roflumilast - for COPD - available for oral use only MOA - specific PDE4 inhibitor increases cAMP in inflammatory cells leading to an antiinflammatory effect but NOT bronchodilation Use - adjunct therapy to reduce the risk of exacerbations in adults with severe COPD associated with chronic bronchitis and a history of exacerbations Side effects - nausea and diarrhea; weight loss - CNS effects - insomnia, depression, anxiety

Pathophysiology of Asthma

Re-exposure to antigen induces a two-phased response: 1. Early asthmatic response - characterized by bronchoconstriction - occurs immediately - reversible - antigen-antibody (IgE) crosslink on surface of mast cells or basophils leads to release of mediators (leukotrienes, histamine, prostaglandins) that cause bronchoconstriction, increased vascular permeability (edema), mucus gland secretion and activation of sensory nerve endings. 2. Late asthmatic response - occurs 2-8 hours after exposure - cytokines (IL-4, IL-5, IL-13) released by T-helper type 2 (TH2) and basophils lead to infiltration by inflammatory cells (i.e., eosinophils) which release proinflammatory mediators (including proteases and growth factors) that result in further bronchoconstriction, edema, mucus hypersecretion, smooth muscle hyperplasia and epithelial damage - If this cascade of events occurs repeatedly, it can lead to irreversible airway remodeling Asthma is a chronic inflammatory disorder characterized by: - Airway hyperresponsiveness - Airway inflammation - Bronchoconstriction Bronchial smooth muscle: ANS Control 1. Adrenergic (not innervated) - beta-2 adrenergic receptors mediate bronchodilation 2. Cholinergic - vagus nerve releases Ach, which acts on a muscarinic receptor leading to: - bronchoconstriction - mucus production (increased glandular secretion) Signs and Symptoms of Reduced Airflow: - Bronchospasm --> wheezing - Mucous secretion --> dry cough, thick sputum - Increased vascular permeability --> edema (inflammation) --> chest tightness Long-term Effects of Chronic Inflammation: AIRWAY REMODLING - Respiratory tract epithelial cell damage - Subepithelial fibrosis (BM thickening) and smooth muscle hyperplasia - Gland hyperplasia and mucus hypersecretion - Increased vascularity (angiogenesis

Ultrasound

Real Time Imaging Lexicon: Echogenicity Pros Readily accessible No ionizing radiation Much safer to use (fetal) Real time imaging Doppler is excellent for assessing blood flow Cons: Operator dependent Poor spatial resolution Suboptimal imaging in obese patients Air/bowel gas prevents US beams from penetrating and seeing structures Ultrasounds use soundwaves to create an image based on how far an object is away from the source of the waves - an image is created based on this time difference The waves that hit the head of the fetus in the picture to the right took less time to return to the transducer than those that hit the back of the fetus

Fluoroscopy and Conventional Angiography

Real time imaging allows us to analyze the function of structures X-ray technology For example, if you want to see if a patient who was being fed via tube still has the ability to swallow, you could use fluoroscopy to visualize the structures involved in swallowing using contrast Similarly, angiography allows us to see contrast moving through the coronary vasculature in real time - In the image, you can see that the contrast was unable to move past an obstruction - The 'after' photo shows that flow has been restored following a procedure to remove/bypass the obstruction, allowing the contrast to travel through the vessels

Lung Cancer Molecular (Biomarker) Testing

Recommended for all patients with advanced (i.e. Stage 4) non-small cell cancers Biomarkers are a useful adjunct: - they add to the positive predictive value of who will respond to a particular treatment At a minimum, testing should be performed for mutations/fusions for: ○ EGFR ○ ALK ○ ROS1 ○ PD-L1 - When expressed by tumor cells, Programmed Death Ligand 1 interacts with PDL on T cells - This interaction induces T cell death - If the tumor highly expresses PD-L1, patients can be treated w/ Pembrolizumab - Low/no PD-L1 expression: Platinum-based chemotherapy FDA-approved therapies are available for patients with mutations above - These therapies are very $$$$$ Other mutations to screen for: - RET rearrangements - BRAF mutations - MET exon 14 alterations

Respiratory Laboratory: Honeycomb Lung

Regardless of the etiology for restrictive lung diseases, many eventually lead to extensive fibrosis The gross appearance, as seen here in a patient with organizing diffuse alveolar damage, is known as "honeycomb" lung because of the appearance of the irregular air spaces between bands of dense fibrous connective tissue.

Oxygen-Hemoglobin Dissociation Curve

Relationship between pressure (PaO2) and hemoglobin saturation (SaO2) Relationship is sigmoidal not linear (due to nature oxygen cooperatively binding to hemoglobin) Flat upper portion - if PalvO2 decreases a bit it will have little effect on the SaO2 --> loading of O2 will be stable - In the alveoli and arteries, a decrease in PO2 will not significantly impact hemoglobin saturation Steep lower portion - peripheral tissues can withdraw large amounts of O2 - small drops in PaO2 encountered at the tissue level which occur at tissue level, result in large unloading of O2) During times of exercise or stress, the curve can shift and facilitate more unloading of O2 at PaO2 levels encountered at the tissue level Right shift Increased P50 (oxygen tension at 50% saturation) means decreased hemoglobin affinity for O2 --> better unloading of O2 --> will allow increased O2 unloading with oxygen pressure/tension changes, which allows us to get more oxygen to tissues - this allows for less up-take at the alveolar-capillary level, it allows for greater degree of unloading at the tissue level. Thus more O2 delivered to tissues - Decreased pH (acidosis) - Increased PaCO2 (Bohr effect) - Increased 2,3-DPG (a molecule that binds deoxygenated Hb with high affinity - high levels in Sherpas) - Increased temperature Left shift Decreased P50 (oxygen tension at 50% saturation) means increased hemoglobin affinity for O2 --> will cause decreased O2 unloading with pressure changes, which means less oxygen to tissues - Increased pH (alkalosis) - Decreased PaCO2 - Decreased 2,3-DPG - Decreased temperature - CO poisoning

Structure and Function: Overview

Respiration - Biochemist: define respiration as metabolic process that utilizes O2 and produces CO2 - Physiologist: describe respiration as transport of Oxygen from air to the cells and CO2 from the cells to the air Single cellular organism relied on diffusion for transport of O2 which is dependent on SA As organisms became larger, needed to develop circulatory system. - Medium to carry O2 (blood) - Pump (heart) - Component with large surface area to exchange gas (lung) Lung: Primary function is gas exchange - Secondary: Metabolizes some compounds - Filters unwanted material from circulation - Acts as a reservoir of blood

Initial Formation of Lung Buds 4-6 weeks

Respiratory diverticulum (endoderm) protrudes from foregut - Sets up the proximal-distal axis 1. Consists of two distinct epithelial cell subpopulations: - Proximal Bronchiolar Epithelium - Distal Respiratory Epithelium 2. P-D axis is very important in signaling - In a few days the tip of R.D. has enlarged followed by division into right and left lung buds (primary lung buds)

Respiratory Laboratory: RSV

Respiratory syncycial virus (RSV) in a child Note the giant cells that are part of the viral cytopathic effect - cell fusion, syncytia formation, cell-mediated immunity required The inset demonstrates a typical giant cell with a round, pink intracytoplasmic inclusion Interstitial inflammation Desquamation of pneumocytes RSV accounts for many cases of pneumonia in children under 2 years, and can be a cause for death in infants 1 to 6 months of age or older

Mechanical Ventilation Indications

Respiratory system's two main jobs are to remove carbon dioxide and take in oxygen Two types of respiratory failure: 1. Hypercapnic (too much CO2) 2. Hypoxic (not enough O2). Ventilatory Support: Hypercapneic Respiratory Failure - occurs when CO2 builds up due to a failure in ventilation - mechanical ventilation provides ventilatory support to the patient - hypercapneic respiratory failure can occur due to: 1. Depressed Drive: respiratory drive has decreased - Ex: A patient gets hit over the head with a baseball bat and loses neural control of respiration. - Ex: A patient has taken a medication that slows down breathing 2. Overloaded muscles: respiratory drive is intact but muscles cannot keep up with the work of ventilation need - Excessive loads: Ex: Asthma or COPD make the airways too tight and the muscles become fatigued. - Weakened muscles: Ex: Neuromuscular disorders, such as ALS, weaken the muscles. Oxygenation Support: Hypoxic Respiratory Failure - occurs when there is not enough O2 due to a failure in oxygenation - mechanical ventilation provides oxygenation support to the patient - Hypoxic respiratory failure can occur due to: 1. Gas exchange abnormalities: - Ex: 5 physiological causes of hypoxemia: low inspired PiO2, hypoventilation, diffusion limitations, V/Q imbalance, shunt 2. Low perfusion states - Ex: Low perfusion states, such as shock or decreased cardiac output, in which the O2 is still loaded into the blood but cannot get to the tissues

Restrictive Lung Diseases Classification/Categories

Restrictive Lung Diseases can be divided into 3 broad categories: 1. Diseases of Known Causes 2. Idiopathic Interstitial Pneumonias (IIPs) 3. Granulomatous Inflammatory Diseases Numerous subtypes within each category Restrictive lung diseases can be caused by: - drugs - connective tissue disorders (CTD) - occupational/environmental exposures - unknown agents Nearly ½ of restrictive lung diseases have an unidentifiable cause

Pathological Flow Volume Loops

Restrictive airway disease - high expiratory peak flow rate, and fast descent - Due to stiffening of the lung, the vital capacity is small (width of the curve) - The airways themselves are wide open, so high peak flows (8 L/s) can be generated (and increased elastic recoil of lungs can generate higher expiratory pressures) but there is not a whole lot of air in the lungs. Obstructive lung disease: - low peak expiratory flow rate, slow descent - Peak flow rate here is only 4 L/s because of the narrowed airways (increased resistance) - flow rate drops off quickly due to the airway obstruction, which leads to the hallmark concavity of the flow-volume loop - slower descent because choke point worsening due to airway obstruction/resistance

Changes in PIP and Pplat

Scenario A: Elevated PIP and normal PPlat: - If someone's PIP has gone up and the Pplat remains the same, then the difference is the Raw, airway resistance. Diseases or situations of increased Raw include: - Bronchospasm (such as in asthma) - Secretions in the airway - Kink or biting tube - Endobronchial partial obstruction When this occurs, there is increased pressure that is going to airway resistance and the alveoli is not seeing that high pressure The high pressure is due to something proximal to the alveoli You have to fix the problem but don't have to worry about the lung popping. Scenario B: Elevated PIP and elevated PPlat: - Both PIP and Pplat are elevated such that the difference between them is the same as before - Airway resistance has not changed - Compliance problem. Diseases of worsening compliance include: - Either lung compliance - Chest wall compliance (The most compliant part of the entire system is the diaphragm. If there is too much air in the stomach from a misplaced ventilator, ascites, or intra-abdominal problems, chest wall compliance can go down.)

Pulmonary Neoplasms: Small Cell Carcinoma

Small Cell Carcinoma (13% of all lung cancers) - one of the four variants of Neuroendocrine carcinomas - other variants are: large cell neuroendocrine carcinoma, atypical carcinoid tumors, and typical carcinoid tumors - Neuroendocrine carcinomas arise from embryonic neural crest cells Deadly tumor most commonly associated with cigarette smoking, especially heavy smoking - Out of all of the lung cancers, small cell carcinoma shows the strongest association w/ cigarette smoking - Continued smoking multiplies risk of a second cancer up to four times! - Small Cell Carcinoma is rarely seen in nonsmokers Tumors arise from the bronchial epithelium Cells are microscopically small Tumors themselves are large Gross Features Large gross perihilar mass → subsequent peribronchial obstruction - Grossly large tumors in central part of lung Considered metastatic at time of diagnosis - Always order a brain CT Scan - Tumors often metastasize and/or embolize to brain - Tumors are initially radiosensitive - they respond to external beam radiation, overtime become less sensitive Conspicuous LN involvement: Bulky LNs No cavitation Typically presents as a large hilar mass with bulky lymph nodes Cavitation is rare Histology - Malignant epithelial tumor that consists of small cells with scant cytoplasm - Extensive Necrosis typically - High mitotic count - Neuroendocrine markers ○ Chromogranin ○ Synaptophysin

Respiratory Laboratory: Peripheral Pulmonary Embolism Microscopic

Small peripheral pulmonary artery thromboembolus Such a small PE would probably not be noticed or cause problems unless there were many of them showered into the pulmonary circulation at once or over a period of time This could lead to pulmonary hypertension.

Major Types of Lung Cancer

Squamous cell carcinoma Adenocarcinoma Small cell carcinoma (variant of neuroendocrine carcinoma) Metastatic carcinoma

Pulmonary Neoplasms: Squamous Cell Carcinoma (SCC)

Squamous cell carcinoma (SCC) is a malignant epithelial tumor - strongly associated with smoking - Some oncologists consider Human Papilloma Virus a SCC risk factor, however this idea is controversial Gross Features - Tumors tend to be large, soft, and friable - Tumors typically arise from a mainstem (primary) or lobar (secondary) bronchus - Proximity to carina is an important element in planning treatment - Central cavity due to necrosis Two requirements for cavity formation: 1. Significant necrosis 2. Carcinoma and necrotic tissue must "communicate" with the bronchus: As a patient coughs, the necrotic tissue is expelled into the bronchus; it is then spit up into the sputum Can you tell which side of the lung the tumor is on? - tracheal cartilage lines the anterolateral tracheal walls - The trachealis muscle lines the posterior side - Therefore, this image is a posterior view of the trachea/bronchi - You can see the carcinoma growing on the L mainstem bronchus Histology Squamous cell carcinoma must include either (or both): - Keratinization - Intercellular bridges If neither Keratinization nor intercellular bridges are present, the tumor must express immunohistochemical markers of squamous cell differentiation - Staining for detection of: p40, p63, CK5, or CK5/6 - TTF-1 (-, negative) Prognosis depends on: - patient's performance score (i.e. how healthy the patient is when the tumor is identified) - stage

Respiratory Laboratory: Squamous Cell Carcinoma Gross

Squamous cell carcinoma of the lung that is arising centrally in the lung (as most squamous cell carcinomas do) It is obstructing the right main bronchus The neoplasm is very firm and has a pale white to tan cut surface

Structure and Function: Stages of Respiration

Stage I: VENTILATION: Ambient air --> alveolus - Moving O2 from the environment into the lung - Moving CO2 from the lung into the environment Stage II: PULMONARY GAS EXCHANGE: Occurs at alveolar - capillary membrane (DIFFUSION) - O2 diffuses from alveoli into blood - CO2 diffuses from blood into alveoli Stage III: GAS TRANSPORT: Alveolar capillaries to periphery/general circulation (CIRCULATION PUMP) - Getting O2 from alveolar capillaries to general circulation - Getting CO2 from general circulation to alveolar capillaries Stage IV: PERIPHERAL GAS EXCHANGE: Periphery to cell/mitochondria (DIFFUSION) - O2 diffuses from general circulation into cells/mitochondria - CO2 diffuses from cells/mitochondria into general circulation

Static vs. Dynamic Compliance

Static pressure-volume curve - inflate the lung, hold the volume, and measure the pressure (and do this repeatedly for different volumes) - Again, each point is a snapshot in time and there is no movement of gas Dynamic pressure-volume curve - inspiratory loop (bottom) and expiratory loop (top) - line between the two end points (slope): compliance - Notice that dynamic compliance is lower than static compliance - (Recall: compliance is ΔV/ΔP so it would be slope of the curve - slope of the dynamic curve is lower than that of the static curve - This is because airway resistance is a factor in dynamic compliance Elasticity (1/compliance) of the Lung and Chest wall are additive. - respiratory system includes the chest wall and the lung - equation for elasticity requires both Cl (compliance of lungs) and Ccw (compliance of chest wall): 1/Crs = 1/Cl + 1/Ccw In a normal, up-right individual at FRC: - Cl = 200 - Ccw = 200 Crs = 100 mL/cm H2O So when added together, the respiratory system is less compliant than its individual components As the lung or chest wall stiffens (lung becomes diseased/restrictive physiology), the compliance curve (pressure-volume relation) will shift to the right and become flatter - takes more pressure to get out of the low volume zone and it takes less pressure to move into the damage zone - more distending pressure must be applied to achieve adequate lung volumes (for ventilation) - This makes it that much more important to stay in the middle part of the curve, where compliance is high

Acid-Base Disorders: 6 Step Process

Step 1: Is the primary disorder acidosis or alkalosis? Look at the pH - Acidemia is blood pH <7.4 --> Acidosis - Alkalemia is blood pH >7.4 --> Alkalosis Step 2: What is the respiratory derangement and is it primary? - primary respiratory disorder is when change in pH is due to changes in the PCO2 levels - If a pH decrease (acidosis) is due to PaCO2, HH equation would predict an ABG of a high PaCO2 (>40) - If a pH increase (alkalosis) is due to PaCO2, HH equation would predict an ABG of a low PaCO2 (<40) - If pH and PaCO2 match HH predictions then the primary disorder is Respiratory in nature - If they do not match, then the primary disorder is metabolic Step 3: If the primary disorder is Respiratory is it Acute or Chronic? Acute: D PaCO2 of 10mmHg = D pH of 0.08 Chronic: D PaCO2 of 10mmHg = D pH of 0.03-0.05 Acute: no metabolic compensation (uncompensated) Chronic: metabolic compensation - problem has been going on a while (hours/days) and - kidneys have begun to regulate the bicarb and H+ in order to compensate pH towards 7.4. - With pure compensation changes, there is never a correction fully back to a pH of 7.4 because as you get closer to 7.4 there is less stimulus to drive the correction. Step 4: If the primary disorder is Metabolic, is the respiratory derangement compensatory? Winters: pred PaCo2 = (1.5 x HCO3) + 8 (+2) Metabolic Acidosis - Occurs with drastic reduction in HCO3 (or gain in H+) leading to an acidemia - Lungs are quick to react and will hyperventilate in order to partially correct this, and blow off acid in form of CO2 - pH remains low (Acidemia) - HCO3 is low (metabolic acidosis) - PCO2 is low (respiratory compensation) Metabolic Alkalosis - Occurs with an increase in HCO3 (or loss of H+) leading to an alkalosis - Lungs are quick to react and will hypoventilate in order to partially correct this, retain acid in form of CO2 - pH remains high (Alkalemia) - HCO3 is high (metabolic alkalosis) - PCO2 is high (respiratory compensation) Step 5: If Primary is metabolic acidosis is there an elevated gap or a normal gap/Non-gap ? Normal Gap: Na -(Cl+HCO3) = 6-12 Elevated Anion Gap (Gap Acidosis) Metabolic Acidosis: Adding Acid - Consuming Buffer • M-Methanol • U-Uremia (renal failure: PO4, SO4) • D-DKA Starvation both lead to formation of ketones and acid • P-Propylene glycol (Paraldehyde) • I-Iron, INH • L-Lactic Acidosis • E-Ethylene glycol • S-Salicylates • (Metformin, Sulfates, Rhabdo, Formaldehyde) Normal Gap (Non-Gap) Metabolic Acidosis: Loss of Buffer • GI losses: Diarrhea (vomiting causes contraction alkalosis) • Renal Losses: RTA, Acetazolamide • Hyper alimentation In these situations in addition to low HCO3 there is either low Na or high Cl Step 6: If there is a gap acidosis does it account for all the acidemia ? Delta Delta: (Measured gap - normal gap) + Measured HCO3 = normal HCO3 --> primary elevated gap metabolic acidosis =/normal HCO3 --> also a non gap metabolic derangement in addition to gap acidosis --> THE DREADED TRIPLE DISORDER

Anaphylaxis

Systemic allergic reaction involving mast cell and basophil degranulation, which releases mediators into the circulation resulting in: - Hypotension - Extravasation of fluid: contraction of endothelial cells leads to increased capillary permeability and movement of fluid to the intercellular space - Severe bronchoconstriction - Epiglottal swelling: impedes airflow Treatment - use a physiological antagonist (epinephrine, EpiPen auto-injector, dose -0.01 mg/kg IM (maximum 0.5 mg)) Alpha1-adrenergic receptor stimulation - causes vasoconstriction - increasing BP - counteracting edema and epiglottal swelling Beta1-adrenergic receptor stimulation - causes cardiac stimulation leading to increased cardiac output and BP Beta2-adrenergic receptor stimulation - causes bronchodilation and decreases mediator release

Total Lung Capacity (TLC)

TLC is determined by the lung's elastic skeleton, or the limit to which it can be stretched - At TLC, the elastic recoil of the healthy lung is 30-35 cm H2O - If you expose an alveoli to more than this, it will rip. - Remember that plateau pressure, where there is no flow of gas, represents what the alveoli is seeing. - When patients are on mechanical ventilation and their lungs are sicker, we measure the plateau pressure to make sure that we're keeping it less than 30-35 cm - If the lungs are getting stiffer (increased elastic recoil, decreased compliance), and the plateau pressure starts to rise, we need to decrease it by using smaller TVs so we don't overdistend the lungs Residual volume is determined by thoracic cavity, not the lung - The thoracic cavity can accommodate way more air than the lungs - We are stuck at TLC because the elastic skeleton of the lung is stretched to the maximum - The lung's elasticity is what determines TLC. Why aren't we concerned with peak pressure, which is higher? - The extra pressure is to overcome the airway resistance, and this pressure does not get to the alveoli.

Respiratory Laboratory: Bronchopneumonia Microscopic High Magnification

The alveolar exudate of mainly neutrophils is seen The surrounding alveolar walls have capillaries that are dilated and filled with RBC's Such an exudative process is typical for bacterial infection (endothelial contraction and vasodilation to allow extravasation of WBCs to fight off bacteria) This exudate gives rise to the productive cough of purulent yellow sputum seen with bacterial pneumonias

Respiratory Laboratory:

The dense white encircling tumor mass is arising from the visceral pleura and is a mesothelioma These are big bulky tumors that can fill the chest cavity. The risk factor for mesothelioma is asbestos exposure. Asbestosis more commonly predisposes to bronchogenic carcinomas, increasing the risk by a factor of five. Smoking increases the risk for lung cancer by a factor of ten. Thus, smokers with a history of asbestos exposure have a risk 50 fold greater likelihood of for developing bronchogenic lung cancer

Pharmacological Therapy of Asthma: Bronchodilators 3. Phosphodiesterase (PDE) Inhibitor

Theophylline - methylxanthine like caffeine (available for oral use only) MOA - various mechanisms leading to bronchodilation and anti-inflammatory effects - nonspecific phosphodiesterase inhibition leads to increased cAMP in bronchial smooth muscle (relaxation) and inflammatory cells (↓ release of mediators) - adenosine receptor antagonism (may lead to arrhythmias and seizures) Narrow therapeutic range - must monitor serum drug levels to stay in therapeutic range and avoid toxicit - start with lower dose and increase progressively to reduce risk of toxicity Many Toxicities - GI (increased HCl secretion, nausea, vomiting) - cardiac (tachycardia, arrhythmias) - CNS excitation (insomnia, headache, seizures) Many Drug Interactions - metabolized by P450-1A2 so inhibition or induction of 1A2 can result in increased or decreased theophylline blood levels Clinical Use - only as add-on to ICS/LABA for long-term control of asthma (sustained release prep) - more widely used in developing countries because it is inexpensive - once used as rescue medication in ER - (intravenous) - used as add-on to LABA in COPD

Respiratory Laboratory: Asbestosis

This is the causative agent for asbestosis This long, thin object is an asbestos fiber Many houses and offices still contain building materials with asbestos, particularly insulation, so care must be taken when doing remodeling or reconstruction.

Normal Lung Histology

Top Left: Bronchi vs. bronchiole

Pathology Related to to Improper Respiratory System Development: TEFs

Tracheoesophageal Fistulas (TEFs) Fistula: abnormal connection between two parts inside of the body Anatomy of most common TEF - Baby swallows and fluids spills over into trachea and into lungs - Fixed with surgery TEFs are associated with family of defects called VACTERL DEFECTS 1. Vert. Anomalies 2. Anal Atresias 3. Cardiac Defects 4. TEFs 5. Esophageal Atresias 6. Renal Anomalies 7. Limb Defects Atresia w/distal fistula (86%) Isolated esophageal atresia (7%) Atresia w/double fistula (4%) Isolated tracheoesophageal fistula (H type) (2%) Atresia w/proximal fistula (1%)

Acid-Base Status

Transport of CO2 has a powerful effect on the acid-base balance of the blood Henderson-Hasselbach equation pH = 6.1 + log (HCO3-)/ 0.03 x PCO2 Alkalemia/Acidemia: pH of blood (Normal 7.4) Alkalosis/Acidosis refers to the disorder Rise in CO2 leads to a respiratory acidosis Fall in CO2 leads to a respiratory alkalosis Rise in HCO3 leads to a metabolic alkalosis Fall in the HCO3 leads to a metabolic acidosis

Immune Responses to Allergens

Types of allergic reactions: - Asthma: bronchioles - Allergic rhinitis: nasal passages - Allergic conjunctivitis: eyes - Urticaria (hives): skin - Anaphylaxis: systemic allergic reaction Allergic individuals react to allergen exposure by mounting an exaggerated antibody-mediated response initiated by T-helper type 2 (TH2) lymphocytes IgE-mediated hypersensitivity reaction - Allergen-induced mast cell degranulation requires two separate exposures to the antigen - On initial exposure, the allergen must penetrate mucosal surfaces so that it can encounter cells of the immune system - Activation of the immune response causes B lymphocytes to secrete allergen-specific IgE antibodies - IgE molecules bind to Fc receptors on mast cells, leading to sensitization of the mast cell - On subsequent exposure, the multivalent allergen crosslinks two IgE/Fc receptor complexes on the mast cell surface causing the mast cell to degranulate - Local histamine release results in an inflammatory response, shown here as edema. IgE antibodies attach to cells that contain mediators of inflammation and immune reactions: - Mast cells: skin and tissues (mucous membranes, lungs, GI tract, vasculature) - Basophils: blood - Eosinophils: lungs Antigen-antibody cross-linking causes release of mediators including: - Histamine - Leukotrienes - Prostaglandins - Cytokines and chemokines Physiological Effects of Mediators 1. Histamine (H1 receptors → ↑IP3, ↑Ca++) - bronchoconstriction - vasodilation (via NO) --> flushing, decreased peripheral resistance --> ↓BP - increased capillary permeability due to contraction of endothelial cells results in movement of fluid to the intercellular space → edema - triple response (wheal and flare) to intradermal injection of histamine - sensory nerve endings - stimulation leads to itching and pain sensations 2. Leukotrienes (cysLT receptors → ↑IP3, ↑Ca++) - bronchoconstriction, bronchospasm (longer lasting than histamine) - increased mucus secretion in lungs - vasodilation (via NO) - increased vascular permeability - wheal and flare response 3. Cytokines (kinase-linked receptors, regulate gene expression) - stimulate formation of inflammatory mediators - cause proliferation and activation of immune cells, ex. Th2 cells, eosinophils (IL-5) - chronic asthma mediators, second phase response - stimulate B cells to produce antibodies (IL-4, IL-13) - cause infiltration of inflammatory cells Strategies to counteract effects of allergen-induced mediators: 1. Prevent release of mediators: - corticosteroids - mast cell stabilizer (cromolyn) 2. Block receptors for mediators or transmitters (pharmacological antagonists): - histamine - H1 receptor antagonists (antihistamines) - leukotrienes - leukotriene receptor antagonists - acetylcholine - muscarinic receptor antagonists (anticholinergics) 3. Administer physiological "antagonist": - alpha1-adrenergic receptor stimulants (decongestants) - beta2-adrenergic receptor agonists (bronchodilators) - epinephrine - use for systemic reactions (anaphylaxis)

Pulmonary Neoplasms: Malignant Mesothelioma

Uncommon Malignant disease arising in mesothelial cells of pleura, peritoneum, or tunica vaginalis (surrounds testis) 80% of pleural and peritoneal mesotheliomas are associated with asbestos exposure - Especially amphibole forms Poor prognosis in pleural or peritoneum Highly aggressive, rapid, and painful death

Airway Resistance

Under Laminar flow, Poiseuille's Law defines resistance: R = R = 8nL/pir^4 Flow = ΔP/R R = Resistance, η = Viscosity, L = length, r = radius, ΔP = pressure differential So putting it all together: Flow = ΔP pi r^4/8nL You can see that as different variables like length, viscosity, and radius change, the flow and delivery of air changes as well As radius of tube/airway increases, Resistance drops severely, and consequently, flow increases greatly Physiologically, airway resistance is defined as: R = ΔP/flow

PFTs: Bronchoprovocation

Use this method in a patient with suspected asthma with normal baseline PFTs Induce bronchoconstriction using Methacholine inhalation - Have the patient inhale a bronchoconstrictor (i.e., methacholine) in small doses to provoke an asthma attack Looking for a 20% decline in the FEV1 for a positive study - Patient must start out at 100% FEV1 - Then give the patient saline. - Administer a small dose of methacholine, then check the FEV1. - If the FEV1 did not change or drops by less than 20%, then administer another dose and keep going. - If the during the process, the FEV1 drops by 20% then administer a bronchodilator. A negative study rules out asthma with 95% certainty - If you get to the maximum methacholine dose and FEV1 has not dropped by 20%, then asthma is ruled out with 95% certainty. - This test isn't actually used to diagnosed asthma, but rather to rule it out. Can then use the graph to see what dose resulted in the drop and then use that to extrapolate the PC20, provocative challenge 20%. Higher PC20 indicates more stable asthma Lower PC20 means that the asthma control is worse Asthma is diagnosed through history, physical exam, response to therapy, etc.

Time Constants and V/Q Imbalance

V/Q Imbalance or V/Q mismatch happens when a part of the lung receives blood flow perfusion (Q) without alveolar ventilation (V), or alveolar ventilation (V) without blood flow perfusion V/Q Imbalance can lead to hypoxemia, or low oxygen tension in the blood Example: V/Q < 1 (normal perfusion, insufficient alveolar ventilation) Presence of an airway obstruction in setting of normal alveoli with normal elasticity/compliance impairs oxygenation of blood Diagram illustrates differing time constants between alveoli, where some alveoli inflate faster than others. (A) Airway to alveoli 2 has an obstruction, narrowing it. (B) As you breath in, flow preferentially goes to alveoli 1 because it is the path of least resistance. A1 will ventilate, A2 will not ventilate as well, leading to a V/Q imbalance. (C&D) If you hold the breath/slow down the breathing rate, the volumes of A1 and A2 will equilibrate. With a normal breathing rate in the above situation, A2 will not be ventilating properly, leading to a V/Q imbalance, meaning that the blood coming from that alveolus has comparatively higher levels of carbon dioxide, and lower levels of oxygen. Clinical Correlate: - Ventilators can hold inspiratory time longer, and alter the ratio of inspiratory time to expiratory time so that patients spend more time inspiring in order to give the alveoli time to equilibrate

Ventilation and Gas Exchange

V/Q ratio: 1 matching perfusion to ventilation ~1 Q = perfusion V = ventilation Total Ventilation = Vt x RR (f) - VE = (500 ml/breath)*(15 breaths/minute) = 7500 ml/min Alveolar ventilation = (Vt - Vd) x f Volume reaching alveoli = 350 ml Tidal Volume (500) - Anatomical Dead space (150) Alveolar minute ventilation = (350 ml/breath)* (15 breaths/minute) = 5250 ml/min of air Pulmonary blood flow = Cardiac output = (70 ml/b)*(70 b/min) ≈ 5000 ml/min of blood Ventilation/Perfusion ratio is roughly 1:1 (5250 ≈ 5000) Anatomic Dead Space (Vd) is the volume of conducting airways = 150 ml - Fowler's method Physiologic dead space is the volume of gas that does not eliminate CO2 (ventilation w/no perfusion) - Bohr's Method The two are almost the same in normal subjects, but physiologic can be increased in many lung diseases (areas that do not participate in gas exchange due to poor perfusion) Regional Differences of Ventilation: - Better ventilation in the lower zone of the lung compared to the upper zone - Most air goes to lower zone, least goes to upper zon - most ventilation occurs in lower zone (Gravity dependent) Regional Differences of Perfusion - Gravity takes most of blood to lower zone (same principle as ventilation) - Gradient is much steeper for perfusion than for ventilation Ventilation-Perfusion Relationships Absolute: - More V and Q in the bottom (gravity dependent) Relative: - Top of lung V higher than Q - Bottom of lung Q is higher than V Two lines of perfusion and ventilation intersect at 3rd rib (V/Q = 1) - Upper ribs (1-2): relatively more ventilation than perfusion, V/Q > 1 - Lower ribs (4-5): relatively more perfusion than ventilation, V/Q < 1 - Sum of all eventually lead to a 1:1 ratio of perfusion : ventilation Remember that both ventilation (V) and perfusion (Q) are greater at the bottom of the lung compared to the top, but that the relatively there is more perfusion at the bottom of the lung (V/Q < 1) and more ventilation at the top of the lung (V/Q > 1)

Ventilator Modes

Variety of modes that you can set for a ventilator - essentially it comes down to whether you want your patient to have full support, partial support, or a salvage mode - You can adjust how the ventilator does 1) cycling on, its 2) target, and how it does 3) cycling off 1) Cycling on: event which triggers the breath. You can cycle on by: a) Control which is time cycled (set on the machine) - If you set a rate of 10, every 6 seconds the machine will set a breath. b) Assist pressure of flow cycled on - which cycles on after sensing a change in pressure or flow. It senses the patient starting a breath. ***These are the only two ways the machine can start a breath. You can even set it to do both*** 2) Target: goal of the breath once the machine fires. You can set for: a) Volume targeted: gives a set tidal volume - If you set a TV, it will give the whole TV - However, say you give a patient a set TV of 500 cc (normal TV) but their lung progressively becomes diseased so that half of it is diseased and half of it is normal - The diseased lung isn't inflating. The whole TV will go to the normal lung, overinflate it, and possibly rip it due to high pressures. In this scenario you want to set to pressure targeted. b) Pressure targeted: gives a set inspiratory pressure - When the machine fires a breath it immediately goes to a pressure and holds it there for the whole inspiratory time - If the lung gets stiffer, the pressure will remain the same, but the volumes will go down 3) Cycling off: event that terminates the ventilator breath a) Volume: terminates once the tidal volume is delivered - This is the most standard for a full support mode or a volume targeted breath - Once the volume has been given it, the ventilator terminates the breath b) Flow: terminates once inspiratory flow diminishes - This is the standard for an assist mode - Once the flow drops off, the ventilator stops pushing c) Time: terminates once inspiratory time or I:E ratio is achieved - This is used in salvage modes to hold in the air so the patient has a better chance of oxygenating

Ventilation-Perfusion Relationships: Dead Space

Ventilation-Perfusion (V/Q) ratio: 𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑎𝑖𝑟 𝑒𝑛𝑡𝑒𝑟𝑖𝑛𝑔 𝑎𝑙𝑣𝑒𝑜𝑙𝑖 𝑝𝑒𝑟 𝑚𝑖𝑛𝑢𝑡𝑒 / 𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑏𝑙𝑜𝑜𝑑 𝑝𝑒𝑟𝑓𝑢𝑠𝑖𝑛𝑔 𝑎𝑙𝑣𝑒𝑜𝑙𝑎𝑟 𝑐𝑎𝑝𝑖𝑙𝑙𝑎𝑟𝑖𝑒𝑠 𝑝𝑒𝑟 𝑚𝑖𝑛𝑢𝑡𝑒 A person with a normal, healthy lung breathes in approximately 5 L alveolar minute ventilation Normal Cardiac Output is also about 5 L/min Normal V/Q ratio is 1 Dead Space occurs when there is ventilation with no perfusion V/Q = infinity Dead Space: is normal ventilation but no perfusion Anatomic Dead Space: - amount of air in conducting airways that does not participate in gas exchange - anatomic dead space is normal! Physiologic Dead Space: - lack of perfusion is due to a physiologic or pathologic condition such as pulmonary embolism or under-perfused alveoli

Ventilation-Perfusion Relationships: Shunt

Ventilation-Perfusion (V/Q) ratio: 𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑎𝑖𝑟 𝑒𝑛𝑡𝑒𝑟𝑖𝑛𝑔 𝑎𝑙𝑣𝑒𝑜𝑙𝑖 𝑝𝑒𝑟 𝑚𝑖𝑛𝑢𝑡𝑒 / 𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑏𝑙𝑜𝑜𝑑 𝑝𝑒𝑟𝑓𝑢𝑠𝑖𝑛𝑔 𝑎𝑙𝑣𝑒𝑜𝑙𝑎𝑟 𝑐𝑎𝑝𝑖𝑙𝑙𝑎𝑟𝑖𝑒𝑠 𝑝𝑒𝑟 𝑚𝑖𝑛𝑢𝑡𝑒 A person with a normal, healthy lung breathes in approximately 5 L alveolar minute ventilation Normal Cardiac Output is also about 5 L/min Normal V/Q ratio is 1 Shunt occurs when there is perfusion, but no ventilation V/Q = 0 Anatomic Shunt: blood that enters the arterial system without coming in contact with an alveolar-capillary membrane Normal Shunts: Bronchial circulation - blood comes off the aorta, perfuses the bronchioles, then gets dumped back into the pulmonary veins (deoxygenated into oxygenated) and back out to the systemic vasculature without being reoxygenated Thebesian Circulation - blood supplying the left ventricle dumps right into the left ventricle after perfusing the muscle tissue Abnormal Shunts: - Ventricular-septal defects - Patent Ductus arteriosus w/right to left flow - Arterial-Venous Malformation Alveolar-arterial Gradient - For this reason, we all actually have a small degree of hypoxemia - blood leaving the left ventricle and traveling systemically has slightly less O2 saturation the PAO2 in the alveoli - difference is referred to as the A-a gradient - Because of normal shunts there will normally be a PAO2-PaO2 difference or gradient of 0-10 mm Hg when breathing room air - this is normal! - normal A-a gradient is due to shunts that are a normal part of our circulation Diseases that cause more shunting (perfusion w/no ventilation) will increase the A-a gradient Normally on room air at sea level PAO2= 100 mm Hg Normally on room air at sea level the PaO2 = 95 mm Hg

Asthma: Histology

Yellow arrow: eosinophils Blue arrow: Smooth muscle hypertrophy Green arrow: Goblet cell hyperplasia and mucus production Black arrow: Basement membrane thickening

Volume vs. Pressure Targeted Ventilators

Volume Targeted Ventilators Seen as A: "Assist-Control" on the graph - In these modes, the volume given is constant, but the airway pressure is variable and will depend on compliance - This is an "assisted breath" because if you look at the second pressure wave there is a negative pressure due to the patient taking a breath - Observe how the pressure is variable. - In volume targeted ventilators, if compliance goes down, then pressure goes up. PiP - peep = (1/ Crs) x TV + (Raw x Flow) Crs = compliance of respiratory system (Lung + Thoracic Cavity) Pressure Targeted Ventilators - Seen as C: "Pressure Support" on the graph - In these modes, the pressure given is constant but the volume is variable and will depend on compliance. - Observe how the volume is variable. - In pressure targeted ventilators, if compliance goes down, then volume will also go down to keep the pressure constant PiP - peep = (1/ Crs) x TV + (Raw x Flow)

Airway Resistance: Inspiratory-Expiratory Cycle

Volume: Lung volume increases during inspiration (decrease in pressure) Lung volume decreases during expiration (increase in pressure) Intrapleural Pressure: As intrapleural pressure drops during inspiration, this pulls open the alveoli, creating a negative pressure within the alveoli, which pulls air into the lung. - Solid line represents pressure actually measured during the maneuver (dynamic measurement) - Dashed line represents pressure difference if you were merely stretching lung to the various volumes (pressure of elastic recoil of the lungs) - difference between the two lines is the airway resistance, and indicates that the drop in inspiratory pressure (pressure difference) generated is to work against both the elastic recoil and airway resistance --> you are not only stretching the lung—you're also overcoming the resistance of the airway --> therefore larger pressure difference required than just the dashed line At the end of inspiration where there is no flow, the two curves line up to be the same (just the elastic recoil, no flow so no airway resistance) On exhalation, intrapleural pressure increases, creating positive pressure in the alveoli pushing air out of the lung - There is airway resistance that is opposing flow of the air out requiring a greater increase in intrapleural pressure (still negative, but less negative, greater pressure change) This is the airway resistance that a ventilator needs to overcome along with the elasticity/compliance of the lungs and chest wall Flow and Alveolar Pressure: - Inhalation, or inward flow is defined as negative by convention - Exhalation, or outwards flow is defined as positive. - Inspiration: alveolar pressure drops, creating a pressure differential allowing for air to flow into the alveoli - At the end of inspiration, alveolar pressure returns to 0, and now that the pressure gradient is gone, flow ceases as well - Exhalation: Pressure is released from lung recoil, leading to positive pressure in the alveoli (and 0 outside the mouth), which causes gas to leave the lungs

PFTs: Spirometry and Flows

Volumes: - Tidal Volume (TV) - Inspiratory Reserve Volume (IRV) - Expiratory Reserve Volume (ERV) - Residual Volume (RV) --- cannot be directly measured Capacities: - Total Lung Capacity (TLC): TV + IRV + ERV + RV --- cannot be directly measured - Vital Capacity (VC): TV + IRV + ERV - Inspiratory Capacity (IC): TV + IRV - Functional Residual Capacity (FRC): ERV + RV --- cannot be directly measured Forced Vital Capacity Maneuver When trying to assess if the airways are wide open or if there's a problem with airflow with increased resistance, have the patient do the vital capacity maneuver If maneuver is done as rapid forceful than it is referred to as forced vital capacity (FVC) - ask them to blow it out as fast and hard as they can - known as the forced FVC maneuver - Can not measure RV, TLC and FRC directly FVC: - amount of gas exhaled during the forced vital capacity maneuver - This represents an absolute volume FEV1: - amount of gas that comes out in the first second of the FVC maneuver - represents a true flow: ΔV/ΔT FEV1/FVC Ratio: - Predicted ratio based on patient's height, race, age, and gender - Ratio value is normally 75-80%, meaning that the patient is blowing out 75-80% of their VC during the first second of the FVC maneuver Obstructive Diseases (i.e., COPD, asthma): - Difficulty with exhaling air - FEV1 is reduced much more than the FVC - decreased FEV1/FVC Ratio (less than 10% of the predicted ratio) Restrictive Diseases (i.e., pulmonary fibrosis, sarcoidosis) - Difficulty with inhaling air - Both FEV1 and FVC are reduced - normal or increased FEV1/FVC Ratio (may even reach 100%) - airways are very elastic can just force that air out, but not a lot of air to start with because of decreased compliance (VC is lower)

Normal Lung Physiology: Overview

Weight 900-1000g - 40-50% of weight is blood at a normal state - Lung is a great reservoir of blood → mobilized when you needed for LV to improve your strove volume - 300,000,000 Alveoli Airway division: Trachea → Main Bronchi → Lobar Bronchi → Segmental Bronchi → Subsegmental Bronchi → Membranous Bronchiole → Terminal Bronchiole up to 16th division - Terminal bronchiole: most distal bronchiole that is completely lined with epithelium - These are the conducting airways, where no gas exchange occurs (Dead Space) - 70,000 Terminal Bronchioles Distal to the Terminal Bronchiole are the acini where gas exchange occurs - Portion distal to terminal bronchiole forms anatomical unit called the acinus - gives rise to three generation of respiratory bronchioles that have alveoli extending from the walls - Transitional and Respiratory Zones - At end of the alveolar ducts (around the 23rd division) are the alveoli Bronchi: cartilage containing conducting tubes Bronchioles: Non-cartilage airways (only SM) Alveoli are lined by two types of cells - Type 1 Pneumocytes: Large flattened cells that are used for gas exchange - Type 2 Pneumocytes: Large cuboidal cells that are synthetic, secretory cells - twice as many Type 2 cells as there are Type 1 - BUT Type 1 cells account for 90% of the surface area

Normal CXR: Lung Structures

When looking to ID what lobe of the lung is affected, it's essential to look at a lateral CXR because lower lobes are in the posterior aspect of the body Because of this, if you suspect a mass in the lung, you always want to get a lateral view to parse out what lobe is affected. Three lobes on the right Two lobes on the left Both lungs have an oblique fissure but only the RIGHT lung has a horizontal fissure You should NOT normally be able to visualize dense fissures on CXR unless there is some sort of pathology

Basic Settings for Mechanical Ventilation

When starting a ventilator: Set a MODE Select settings for 4 parameters: 1. FiO2: - When initially starting a ventilator, we usually put FiO2 at 100% - We "shoot high" and then come down because we want to protect the heart and brain from irreversible damage - don't really have to worry about oxygen toxicity, or too much O2, outside of neonatal care. 2. Rate: - set the rate usually to about 12 breaths/min. - We usually breath about 12-20 times a minute 3. TV (tidal volume): - TV is based on ideal body weight - give about 6-8 cc/kg - 0.5 L or 500 cc. 4. PEEP: - For supine patients, start with 5 cm of PEEP. One can increase the Ve by changing the rate or the TV but clinically only by changing the rate

Ventilation-Perfusion Relationships: Diffusion Abnormality

When the blood-gas barrier thickens, O2 will not be able to equilibrate with blood as effectively, which can lead to hypoxemia Fick's law states that diffusion is inversely related to membrane thickness Although the PAO2 is normal, thickening of the blood gas barrier limits diffusion of O2 and the PaO2 may not reach the PAO2 PAO2= 100 mmHg PaO2 = 50 mm Hg

Pleural Disease: White-Out Hemithorax

White-Out Hemithorax: entire section of the lungs is white on CXR Three possible causes that you should consider - Each can be differentiated from each other based on whether you see a shift in the mediastinum No shift = Consolidation (alveolar air space disease) - has progressed so far that fluid has gotten into the pleural space - no shift of structures because you're not changing any volume: just replacing air with fluid. Pushes AWAY = Hydrothorax (severe pleural effusion) - as fluid builds up, this adds a positive pressure that pushes structures away from the affected area - compressive atelectasis?? Pulls TOWARDS = Obstructive atelectasis - affected area of the lung shrinks in on itself due to obstruction and pulls everything towards itself a) alveolar air space disease Notice there is no shifting of any identifiable structures b) pleural effusion is creating positive pressure that's pushing the trachea and heart into the R chest - Tension Hydrothorax with mediastinal shift c) Obstructive atelectasis is shrinking the left lung due to endobronchial obstruction, pulling the trachea and heart towards the left chest.

PFTs: Flow Volume Loops

X-axis: volume Y-axis: flow (expiratory = positive; inspiratory = negative) You have the patient blow everything out, so what's remaining is the RV Then the patient inspires to reach TLC Next, the patient expires as fast and hard as possible until the loop is back to the RV. Comparing Flow Volume Loops 1st = restrictive 2nd = normal 3rd = obstructive) In restrictive diseases: - expiratory flow rate is able to be maintained at 8 L/s - however, since the vital capacity is so small (could not inspire much air because of loss of compliance) the flow rate tapers off quickly, resulting in a narrow flow volume loop In the normal flow volume loop, flow is 8 L/s during expiration. In obstructive diseases: - the airways are narrowed so the expiratory flow rate cannot be maintained, resulting in a short flow volume loop - There is also a concavity of the expiratory loop due to the narrowing requiring increased time to expire air. Flow volume loops of large obstructive lesions During inspiration, there is flow from zero pressure in the room to the negative pressure in the alveoli drawing air in (pressure gradient) - intrathoracic airways get bigger (transpulmonary pressure negative pressure) - extrathoracic airways get smaller (higher pressure outside, negative pressure in airways) During expiration, it's reversed - intrathoracic airways get smaller (transpulmonary positive pressure) - extrathoracic airways get bigger (positive pressure inside, zero pressure outside) Panel A: Fixed Obstructive Loop - There is flattening of both the inspiratory and expiratory loop - indicating a severe obstruction that is not able to be overcome Panel B: Variable Extrathoracic Loop - flattening of the inspiratory loop, meaning there is an obstruction of the extrathoracic airway - Expiratory loop is normal - Causes include paralyzed vocal cords and stenosis of vocal cord due to an airway tube Panel C: Variable Intrathoracic Loop - flattening of the expiratory loop, meaning there is an obstruction of the intrathoracic airway - Inspiratory loop is normal - Seen in obstructive lung diseases

X-ray

X-ray beams - electromagnetic waves - short wavelengths, lot of energy - makes the waves carcinogens Creating the Image To create x-ray images, an object is placed between the beam source and a detector - beam source directs waves at the object - detector measures how much energy passes through the object and makes it to the other side The images are a sum of all of the structures that are directly in the line between the beam source and the detector - this means there can be a high degree of overlap in the images 3D --> 2D This leads us to one of the challenges of using x-rays: perspective - Imposing a 3D object onto a 2D image means we need more than one view/angle to determine how objects' positions relate to one another Factors Affecting the Image 1. Density - Objects with a higher density will look whiter on the image: metal > bone > fluid, soft tissue, muscle > fat > air - Since fluid, muscle, and soft tissue are about the same density, hard to tell them apart - One trick is to look for a straight line, Our bodies don't have perfectly straight lines, so if you notice one, it is probably fluid - to describe densities, use the terms 'hypodense, isodense, and hyperdense' 2. Thickness - if you take two objects made of identical material, but one is thicker than the other, the thicker object will appear whiter Positioning/Orientation Importance of positioning: - When your hand is far from the wall and close to the flashlight, the shadow is (a) huge and (b) fuzzy - If you move your hand closer to the wall (detector) and farther from the light (beam) the shadow will have (a) a more realistic size and (b) clear borders Concept is applied to x-rays Chest x-rays are always taken with a PA (posterior anterior) view (exception to this is that AP views can be taken for patients with limited mobility) - patients are oriented so that the beams enter their body through the back and exit through the chest anterior before hitting the detector - Using AP views creates images that do not artificially increase the size of the heart - We want the heart to be as true to size as possible and making sure that the heart looks true to size is more important than the apparent size of the lungs Lateral views the left side of the body should be placed closest to the detector to avoid false magnification of the heart - beam enters through the right, left side on detector - This positioning will result in an image with overlapping ribs - right ribs will look larger and have poorly defined borders compared to the left ribs in lateral views

Chest X-Rays (CXR): Overview

X-ray will differentiate structures by density - structures of the same density (ie: heart and diaphragm) will to blend together - aka Gradation Density as related to the color on CXR, listed from brightest to darkest: - metal = bright white - bone = white - soft tissue = gray/white - fat = gray - air = black Orientation of the patient is described by the direction of radiation - Posterior-Anterior view: radiation beam is going into their back and out the anterior chest and the patient is standing with the film/detector on their chest - Views can be anterior, posterior, lateral, AND oblique. - *You can also describe something as a "frontal view" if you have no idea what orientation the patient is in* Frontal view: - AP: Anterior-posterior - PA: Posterior-anterior Lateral view: - Left Lateral - Right lateral Decubitus views: Left or Right Oblique View Preferred view is PA (posterior - anterior: beam is going into their back and film is against the chest) This is for two reasons: 1. The scapula are retracted off the chest, allowing for easier visuals of the lungs 2. The heart is closer to the film (film against the chest) so it's not making a huge shadow. - Not all patients can stand for a CXR so an AP view might be necessary so they can lay in bed - A good clue to see if it's an AP CXR is to see if there are EKG leads, tubes, etc. in the CXR which likely indicates the patient was not standing for the imaging

Peak and Plateau Pressures

You can program a one second inspiratory pause to obtain a plateau pressure (Pplat) - During this maneuver, there is no flow so the pressure at the alveoli is the same as the ventilator end alveolar distention pressure - Pplat = end alveolar distention pressure Graph: - time: x axis - airway pressure: y axis. At inspiration, the breath is started and pushes against 2 resistive forces: 1. elastic recoil of the respiratory system (inverse of compliance) (flow independent) 2. airway resistance (flow dependent) Once the breath is in, you can program the ventilator to hold the breath in. Peak pressure at the end of inspiration, or peak inspiratory pressure (PIP), followed by a drop in pressure that reaches a plateau, or plateau pressure (Pplat). Plateau pressure represents the pressure the ventilator needs to generate just to keep the breath in - no flow of gas, so the plateau pressure equals the pressure that the alveoli is experiencing - only having to overcome the elastic recoil of the respiratory system because there's no flow of gas - If there's no flow of gas, airway resistance is not a factor Peak pressure is the pressure needed to move the breath into the thorax. It is the pressure needed to overcome the two resistive forces: 1) Elastic resistance of the chest wall and the lung - Elasticity = 1/Compliance = ΔP/ΔV 2) Airway Resistance - Raw = ΔPressure/Flow Δ Pressure (Peak - Peep) = (1/Crs) x Tv + Raw x Flow If the peak pressure on the ventilator is getting higher, then one of four possibilities has happened: 1. Decreased compliance 2. Increased Raw 3. increased TV (this is fixed on a ventilator) 4. increased flow (this is fixed on a ventilator) - Either the elastic resistance has gone up, which means that compliance has gone down OR - the airway resistance has gone up Plateau Pressure is only the pressure needed to hold the breath. During a plateau pressure, flow is zero so: Δ Pressure (Plateau - Peep) = (1/Crs) x Tv + Raw x Flow (0) If the plateau pressure on the ventilator is getting higher, then there are only two aspects that could have changed: 1. Decreased compliance 2. Increased TV (this is fixed on a ventilator) Graph demonstrates the difference between peak and plateau pressure - area under PIP and above the red dotted line represents the additional force of airway resistance that PIP must overcome in addition to the elastic recoil (represented by transthoracic pressure) - area under Pplat represents that it only needs to overcome the elastic recoil of the respiratory system. Side note: You would not get a graph like this if you were taking static compliance by inflating the lungs slowly and stopping and taking measurements. Why? Because there would be no flow when you stopped to take measurements and thus no airway resistance

West Zones of the Lung

Zones of the lung are defined by the alveolar pressure (PA) in relation to the pulmonary arterial/capillary (Pa) and vein (Pv) pressure As we move up in the lung PA increases relative to the pressure in the vasculature (Pa and Pv) At the bottom of the lungs, vascular pressure exceeds airway pressure Zone 1: top - alveolar pressure (PA) exceeds the vascular pressure and the capillaries are occluded Zone 2: middle - alveolar pressure equals the vascular pressure at some point between the artery and vein where the vasculature will be occluded Zone 3: bottom - vascular pressure exceeds alveolar pressure and the vasculature is wide open Clinical correlate Pulmonary Capillary Wedge must be placed in zone 3 to get a measure of pressure in the left atrium. The vessels in zones 1 or 2 will be occluded downstream of the probe so rather than LA pressure, you will be measuring airway pressure.

Minute Ventilation and PaCO2

oVeCO2: minute expiratory CO2 - amount of CO2 that's coming out of your mouth per minute - In steady state, that should be the amount of CO2 that is in the alveoli that are being eliminated per minute - Therefore, oVeCO2 is a product of the alveolar minute ventilation times the alveolar CO2 concentration 0.86: conversion factor for Standard Temperature and Pressure PACO2: alveolar partial pressure of CO2 - cannot measure PACO2 but CO2 diffuses so quickly that you can measure the arterial CO2 (PaCO2) and use that in its place oVΑ minute: alveolar minute ventilation - percent of alveolar volume that is undergoing ventilation per minute Vt: tidal volume Vd: dead space volume f: rate of breaths per minute. oVeCO2 x 0.86 = PACO2 x oVΑ minute - minute expiratory CO2 times the conversion factor 0.86 equals PACO2 times alveolar minute ventilation - Another way to write alveolar minute ventilation is 1-Vd/Vt - Vd/Vt is the percent of tidal volume that is dead space - If you subtract Vd/Vt from 1, you will get the percent of tidal volume that is alveolar and not dead space. oVeCO2 x 0.86 = PaCO2 x oVe x (1 - Vd/ Vt) (oVeCO2 x 0.86)/(1-Vd/Vt) = PaCO2 x (f x Vt) If we don't change the tidal volume If the person's CO2 production doesn't change If the percent that is dead space doesn't change The rate (f) x PaCO2 will be constant If the PaCO2 in the artery is 60 and the rate is 10 10 x 60 = 600 If I want the PaCO2 to be 30, then I raise the rate to 20 20 x 30 = 600 If you double the respiratory rate, then the PaCO2 will decrease by half This is how you can adjust PaCO2 through mechanical ventilation Why don't we double the tidal volume? Because the tidal volume is on the other side of the curve and is not linear What happens if a patient is in the ICU is being ventilated with a constant rate and the CO2 changes? - For example, imagine that initially CO2 is 40 and respiratory rate is kept 15 (40 x 15 = 600, perfect!) - Later on, the respiratory rate is still at 15 but the CO2 is 60. What the heck happened? This means that either: 1) the patient is making more CO2 (septic shock, hypermetabolic syndrome, etc.) or 2) lung disease has progressed and more of it is dead space (more specifically, physiologic dead space). Recall that anatomic dead space is air that never comes in contact with areas of gas exchange while physiologic dead space is anatomic dead space plus extra dead space from diseases (for example in a pulmonary embolism there is ventilation of air that does not come in contact with perfusion).