Lungs PDF - Respiratory System Fall 2021

The Respiratory System Cindy D. Powell, M.D., M.P.H. Fall, 2021 Byron Davis, photographed by Annie Leibovitz, 8/14/95, at the Olympic Training Center  Outline of Discussion Lung anatomy and histology...

The Respiratory System Cindy D. Powell, M.D., M.P.H. Fall, 2021 Byron Davis, photographed by Annie Leibovitz, 8/14/95, at the Olympic Training Center  Outline of Discussion Lung anatomy and histology Mechanisms of respiration, including neural control Mechanisms of defense and disorders of these (cystic fibrosis) Lung volumes and capacities Lung compliance and related disorders (interstitial lung diseases and idiopathic pulmonary fibrosis) Airway resistance and related https://www.pinterest.com/pin/ disorders (asthma, emphysema, 220324606745447976/  Outline of Discussion Gas exchange in the lung and the tissues, including the 4 mechanisms of hypoxemia Lung vascular issues and related disorders: cardiac issues including cor pulmonale, pulmonary embolism, pulmonary edema, and pulmonary hypertension Pediatric considerations, including childhood asthma https://www.nytimes.com/2021/01/26/science/coronavirus- Gerontological considerations physics-vaccine.html The Respiratory System The Pleural Space  Great Vessels of the Superior Mediastinum  Bronchial Arteries and Veins Lymph Vessels and Nodes of the Lung  Anatomy and Histology of the Airways → →  Breathing During inspiration, the contraction of the inspiratory muscles stores potential energy in the elastic tissues of the lung. Expiration occurs when the diaphragm and external intercostal muscles relax. Lung elastic recoil converts potential energy to kinetic energy, contributing to the positive pressure in the chest that drives expiration of the tidal volume. The muscles of forced expiration are the internal intercostal muscles and the abdominal muscles  Breathing Inspiration Muscles of Forced Expiration  Neural Control of Respiration The medulla contains several clusters of Other peripheral receptors detect neurons that are the source of rhythmic irritant substances (initiating outputs causing regular contractions of inspiratory muscles and initiating the coughing) or vascular congestion. respiratory cycle. Inputs from higher centers can modify the respiratory pattern for These brainstem respiratory pattern voluntary activities. generator neurons signal spinal cord (and Involuntary actions like belching, in some cases, cranial) motor neurons that stimulate the primary muscles of swallowing, and vomiting relay inspiration. Motor neurons to accessory through brainstem pathways to alter muscles of inspiration are recruited upon the pattern of breathing. physiological need. Respiratory muscles contract, providing mechanoreceptor feedback to brainstem and spinal cord. Alterations in arterial blood gases (O2 and CO2) provide chemoreceptor feedback to the brainstem respiratory nuclei.  Autonomic Nerves of the Thorax  Innervation of the Tracheobronchial Tree Nerves of the Thorax  Mechanisms of Lung Protection The mucociliary escalator protects the lung against large particles. Tight junctions between epithelial cells prevent invasion. Nonspecific defenses such as lysozyme, defensins, and antimicrobial peptides work to deter pathogens. Mucosal dendritic cells phagocytose and present antigen to T lymphocytes, activating the adaptive immune system to produce secretory immunoglobulin A (IgA). IgA provides protection by intercepting incoming pathogens and tagging them for phagocytosis and destruction. At the level of the alveoli, IgG neutralizes small particles and macrophages phagocytose them as well. Macrophages also secrete cytokines that recruit additional monocytes, neutrophils, and lymphocytes to assist. Natural killer cells are present in the alveoli and can contribute to a rapid response to invading pathogens. Finally, protective antimicrobial proteins are also components of the surfactant that lines the alveoli.  Cystic Fibrosis: a Disease in Which the Lung Protective Mechanisms Fail Autosomal recessive genetic disorder (close to 2,000 mutations have been described) with a prevalence of 1:3,500 infants who are Caucasian, 1:7,000 infants who are Latinx, and 1:17,000 in those of African ancestral origin. The genes code for the cystic fibrosis transmembrane conductance regulator (CFTR) channel, a large transmembrane protein found in cell membranes that permits movement of Cl− and HCO3− across an epithelial membrane. Normally, movement of these ions attracts water, resulting in production of fluid secretions, such as that of mucus lining the airways. IN CF the mucociliary clearance mechanism is severely impaired. Lack of Cl− transport across the epithelial cell membranes reduces the associated water movement, so the mucus layer is abnormally thin and very viscous, and the cilia are unable to properly move the mucus toward the mouth. Loss of HCO − secretion makes the mucus acidic, reducing effectiveness of white blood 3 cells in attacking pathogens. The function of an associated Na+ transporter (epithelial sodium channel, or ENaC) is increased, promoting intracellular Na+ accumulation and water retention, contributing to the thick mucus. Patients with CF have chronic lung infections that result in localized inflammation, and plug formation that leads to airway dilation, termed bronchiectasis.7,8 Cystic Fibrosis https://radiopaedia.org/cases/cystic- Pathophysiology of Cystic Fibrosis  Lung Volume and Capacity Measurements and Their Significance Tidal volume (Vt )—the volume of air inspired and expired during quiet breathing at rest; when multiplied by respiratory rate (breaths/min), resting minute ventilation is calculated. Functional residual capacity (FRC)—the volume of air in the lungs at the end of each expiration at rest. This represents the resting position of the respiratory system (lungs plus chest wall). At this point, there is an equilibrium between the intrinsic tendency of the lungs to collapse down, and the intrinsic tendency of the chest wall to expand outward. FRC is sensitive to disease processes that alter lung or chest wall mechanical properties. Vital capacity (VC)—the maximum volume of air that can be exhaled after a maximal inhalation. Depending on the context, this value can also be called forced vital capacity (FVC). This represents the greatest volume of air the respiratory system can move in response to a maximal expiratory effort. VC is sensitive to disease processes affecting the lung, the chest wall, and the neural control of muscles of respiration.  Lung Volume and Capacity Measurements and Their Significance Residual volume (RV)—the amount of air left in the lungs after a maximal expiratory effort. The RV depends on elastic recoil of the lung and is altered by diseases that affect either lung or chest wall compliance. It is measured by helium dilution or plethysmography. Total lung capacity (TLC)—the total amount of air in the lungs after a maximal inhalation; also equal to VC + RV. TLC is similarly affected by lung and chest wall disorders, as well as neuromuscular disorders affecting the muscles of respiration. Lung Volumes and Capacities  Lung and Chest Wall Relationships The volume of air inside the lungs at end-expiration (i.e., the FRC) is determined by two factors: the elastic recoil tendency of the lung to collapse down, and the tendency of the chest wall structures (ribs and intercostal muscles) to expand outward. The balance between these tendencies creates a negative pressure in the pleural space that holds the visceral and parietal pleura together. If a pneumothorax occurs, air enters the pleural space and Ppl equilibrates with atmospheric pressure. Immediately, the lung collapses down and the chest wall expands. Lung and Chest Pressures During Expiration and Inspiration  Spontaneous Pneumothorax (in a Patient with Tuberous Sclerosis) https://www.nejm.org/doi/full/10.1056/NEJMicm074098  Pneumothorax https://radiopaedia.org/cases/covid-19- https://www.britannica.com/science/ pneumothorax pneumothorax  Pleural Effusions: Fluid in the Pleural Space Imbalance of pleural fluid production vs. filtration through the visceral pleura into the lymphatics of the lung. Transudative effusions are caused by states associated with systemic fluid overload, such as pulmonary edema, nephrotic syndrome, or cirrhosis. Exudative effusions are caused by processes that directly affect the lungs, such as inflammation (ex.: pneumonia) or malignancy and cause the pleura to leak. https://radiopaedia.org/articles/pleural- effusion  Transudative Vs. Exudative Pleural Effusions Transudate Exudate Main Causes ↑ hydrostatic pressure/ Inflammation or ↑ ↓ oncotic pressure vascular permeability Appearance Clear to slightly yellow Cloudy Specific gravity < 1.012 > 1.012 Protein content < 2.5 g/dl > 2.9 g/dl Fluid protein/serum <.5 >.5 protein ratio Fluid LDH/serum LDH <.6 or < 2/3 >.6 or > 2/3 ratio Cholesterol content < 45 mg/dl > 45 mg/dl SAAG= serum albumin > 1.2 g/dL < 1.2 g/dL – effusion albumin Radiodensity on CT 2-15 HU 4-33 HU scan Echogenicity on US Anechoic Possibly echogenic  The pH of Parapneumonic Effusions Parapneumonic effusions come in 2 varieties: complicated and uncomplicated. Uncomplicated effusions are free-flowing and sterile. Complicated ones tend to be more viscous, loculated, and usually have been invaded by bacteria. These can become empyemas, or effusions consisting of pus. The pH of a parapneumonic effusion sheds light on whether it is complicated or not and helps determine the best therapeutic course. If the pH is > 7.30, the effusion is likely uncomplicated and will resolve with medical therapy alone If the pH is < 7.20, it is likely complicated and will need drainage. A pH between 7.20 and 7.30 is a bit of a gray zone. If the pH is < 6.0, it is likely due to esophageal rupture, although a severe empyema can have a pH this low as well.  Pleural Effusions by Ultrasound https://sjrhem.ca/pocus-pleural-effusion/ https://www.hindawi.com/journals/isrn/ 2012/676524/fig11/  Lung Compliance The relationship between the volume change of the lung with the distending pressure is termed the compliance of the lung. Diseases of decreased lung compliance create a stiffer structure —greater pressure changes are needed to maintain even normal V t. Diseases of increased lung compliance, primarily emphysema, make it easier to inflate the lungs on inspiration, but limit expiration, and also result in a much higher FRC that can limit the maximum inspired volume.  Surfactant and Surface Tension Type 1 AECs are the thin cells making up the majority of the alveolar wall. Type 2 AECs synthesize and secrete surfactant, a fluid rich in amphipathic phospholipid molecules that spread out on top of the fluid facing the alveolar air, greatly reducing surface tension and making alveolar expansion easier.  Compliance and Elastance The inverse of compliance is elastance—the ability to recoil and return to the original size after being stretched. Expiration occurs as the inspiratory muscles relax at the end of inspiration; the lung’s elastic recoil and conversion of stored energy generates pressure that drives expiration. For this reason, diseases that alter lung compliance also alter elastic recoil. Diseases of decreased compliance are associated with increased elastic recoil. Although it takes more pressure and effort to inflate the lung during inspiration, expiration occurs quickly and forcefully. Ex: multiple types of interstitial lung diseases, such as pulmonary fibrosis. Diseases of increased lung compliance reduce elastic recoil; the lungs become floppy and difficult to empty during expiration. Ex: emphysema.  Idiopathic Pulmonary Fibrosis Idiopathic pulmonary fibrosis (IPF) is diagnosed more often in adults over the age of 50. Its onset is related to environmental exposures (particularly cigarette smoke) and genetic predisposition, although it is not a monogenic disorder. Mutations in telomerase genes and mucin genes have been shown to contribute to pulmonary fibrosis susceptibility. Tissues around the alveoli accumulate fibroblasts, and extracellular matrix and collagen deposition increases. This causes: Stiffening of the lung and decreased compliance (rapid, shallow breathing) Worsening of diffusion and gas exchange causing hypoxemia (dyspnea on exertion) RV, FRC, vital capacity (VC), and total lung capacity (TLC) all decrease Treatments: nintedanib (a tyrosine kinase inhibitor that reduces fibroblast proliferation), pirfenidone (an anti-inflammatory and antioxidant treatment that slows fibrosis progression), and lung transplantation. IPF, also known as Usual Interstitial Pneumonitis (UIP) https://www.pathologyoutlines.com/topic/lungnontumorUIP.html, contributed by Yale IPF/UIP with Honeycombing  IPF/UIP with Honeycombin g https:// consultqd.clevelandclinic.or g/idiopathic-pulmonary- fibrosis-what-pcps-need-to- Emphysema and Loss of Elastic Recoil and Increased Compliance (a) Normal alveoli: Elastin fibers in alveolar walls create elastic recoil upon expansion (due to inspiration). Relaxing diaphragm and external intercostal muscles promotes passive expiration proportional to the degree of lung elastic recoil. (b) Emphysema: Elastic recoil decreases when elastin fibers are destroyed by the disease emphysema. There is little elastic recoil, and air remains trapped in ever-larger spaces within the lung. Patient with Both Emphysema and Pulmonary Fibrosis (Tobacco Exposure Is a Risk Factor for Both)  Airway Resistance and Obstructive Lung Diseases https://www.researchgate.net/figure/A-scanning-electron-micrograph-of-the-cut-surface-of- human-lung-showing-small _fig1_22029871, uploaded by James Pawley  Measure of Lung Obstruction The FEV1 represents the volume of air expired in the first second of a forced expiratory maneuver. This corresponds to the time of minimal airway resistance as the maneuver begins at total lung capacity. FEV1 is generally 75% to 85% of the FVC. Flow-Volume Loops Lung Pressures During Forced Expiration Obstructive diseases alter the volume/time relationship during forced expiration. Obstructive airway pathology in asthma or COPD limits the rate of expiratory flow and promotes air trapping, increasing residual volume and decreasing FVC. Obstructive Lung Disease and the Flow Volume Loop Obstructive diseases alter the flow/volume relationship during forced expiration. COPD produces marked changes in the flow/volume loop, with reduced peak flow, increased RV and TLC due to air trapping, and a concave “scooped out” appearance of the expiratory flow decline from peak. The concave flow pattern indicates premature airway closure during forced expiration.  Neural and humoral control of bronchial smooth muscle Bronchial smooth muscle contraction is under three major influences: Vagal innervation of the airways, acting on bronchial smooth muscle cell muscarinic receptors (M). During exercise or stress, circulating Epi from the sympathetic nervous system binds to β2-adrenergic receptors (β2 Rs), causing bronchodilation. Mast cell–generated LTs bind to LTRs and cause bronchoconstriction  Asthma An obstructive airway disease characterized by acute exacerbations with dyspnea, coughing, wheezing, and airflow obstruction that usually reverts to almost- normal airway function on prompt treatment. Asthma attacks often begin in childhood, during which the most common pathogenesis is type 1 hypersensitivity (allergy). Asthma prevalence in adults  Pathophysiology of Asthma The hallmarks of allergic disorders include the following: Elevated production of T-helper 2 (Th2)-generated cytokines, including interleukin (IL)-4, IL-5, and IL-13 Class-switching by B cells that produce IgE rather than IgG Binding of IgE to mast cells, thus priming them to respond to allergen exposure by degranulation, releasing histamine and inflammatory prostaglandins Mucosal vasodilatation and edema then occurs Recruitment of eosinophils, and in some phenotypes, neutrophils and lymphocytes, to the affected tissue, perpetuating inflammatory mediator production and releasing eosinophil major basic protein, which further inflames tissues  Pathophysiology of Asthma Other triggers besides allergens: respiratory infections, exercise (particularly outdoors in cold, low-humidity conditions), aspirin in sensitive patients, and occupational exposures. Chronic changes to the airways then occur: -bronchial smooth muscle hypertrophy and hyperresponsiveness, -altered goblet cell function with mucus hypersecretion, -and airway narrowing due to muscle hypertrophy and fibroblast accumulation. Individuals with chronic asthma often has persistent airway narrowing evidenced by concavity of the expiratory flow/volume curve that becomes more pronounced during an acute asthma attack. At this point, the pathophysiology blends into COPD. https://slideplayer.com/slide/6159375/  Epithelial Damage in Asthma https://slideplayer.com/slide/6159375/  Autopsy of Patient Who Died of an Asthma Attack A cross-section of a bronchiole from a subject who died during an asthma attack. a) Luminal occlusion caused by muscle constriction, thickening of the airway wall, increased smooth muscle mass and a marked inflammatory process in the airway wall, mainly characterized by eosinophils. b) Detail from a). The distribution of the inflammatory process is more obvious: there is a greater density of eosinophils in the area outside the smooth muscle (“outer” region) than in that inside it (“inner” region). (Haematoxylin and eosin staining). https://erj.ersjournals.com/content/  Airway Remodeling in Long-standing Asthma. An airway from a 70-year- old patient with asthma is shown. Examples of the structural and functional changes of chronic asthma are highlighted and are discussed throughout the text. MMP, Matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinases; bFGF, https://www.jacionline.org/article/ S0091-6749(05)01648-9/fulltext  Risk Factors for Death from Asthma History of severe exacerbations Poor perception of severity History of intubations or critical of airflow limitation care admissions Co-morbid conditions 2 or more hospital admissions per year Psychiatric disease, 3 or more emergency room visits psychosocial issues per year Lower socioeconomic status, Hospital or emergency room visit urban residence within the last year > 2 cannisters per month of Illicit drug use inhaled beta-2 agonists Sensitivity to Alternaria Chronic use of systemic mold corticosteroids Lack of written asthma plan  COPD 2 Main Types: Emphysema and Chronic Broncitis Before Covid, COPD was the 3rd leading cause of death in the United States, and the 4th leading cause of death worldwide. Defined by reduced expiratory airflow (particularly FEV1 and FEV1/FVC) that is not reversible (unlike asthma), along with exertional dyspnea, cough, and sputum production. Some patients with COPD do have features of asthma, with a portion of their airflow obstruction that is reversible, and this is called asthma overlap syndrome. Longstanding asthma is a risk factor for the development of COPD. COPD is a complex disorder with overlapping disease processes that include air space enlargement due to tissue destruction (as in emphysema), and chronic inflammation with cough and sputum production (chronic bronchitis).  COPD Caused by smoking, smoke exposure in the environment, including cooking indoors with biomass fuels without ventilation, and exposure to other pollutants, such as toxic fumes, and urban air pollution. Genetics play a role, as described in Molfino, N.A. The Genetics of COPD, Chest, V. 125, issue 5, 2004, pp. 1929-1940. Alpha-1-antitrypsin deficiency is an inherited disease that predisposes patients to COPD, usually when the person is homozygous for 2 defective genes. Alpha-1-antitrypsin is a protein produced by the liver that helps to inactivate enzymes such as elastase and trypsin, which are often released in inflammation, but which can also damage the lung tissue itself if their activity is not kept in check.  Pathophysiology of COPD In emphysema, airflow limitation is due to the loss of tissue over time, which results in decreased elastic recoil and an increase in lung compliance (elastance, or elastic recoil, is the inverse of compliance). Airways are prone to collapse because of the loss of adjacent tissue that would normally exert a tethering function, helping to keep airways open. Pursed lip breathing can help by generating PEEP. The diagnosis of chronic bronchitis is based on the clinical history of persistence of productive cough for at least 3 months that is documented in at least 2 consecutive years. Associated factors, many of which contribute to airway narrowing: Chronic inflammation with neutrophil and macrophage infiltration Increased mucus production Edema of the mucosa Fibrotic changes over time in the bronchial walls Types of Emphysematous Destruction  Clinical Manifestations of COPD Air trapping, which can chronically increase RV, FRC, and TLC Chest anterior–posterior dimension may be visibly increased (visible as a barrel-shaped chest) and identifiable on chest x-ray. With progression of disease, hypoxia and hypercapnia Recurrent infections, which are the most common cause of exacerbations Other things that may present similar to exacerbations: exposure to allergens, cardiac events (such as pulmonary edema), pulmonary emboli, mechanical issues such as pneumothorax, and medication noncompliance. An investigation for the presence of one of the above causes of an exacerbation should be conducted whenever a patient presents with a flare of COPD.  Clinical Manifestations: Emphysema http://www.radtechonduty.com/2018/04/ respiratory-disease-emphysema.html https://www.startradiology.com/ internships/gynecology/thorax/x-  Clinical Manifestations: Emphysema https://radiopaedia.org/articles/chronic- https://www.wikidoc.org/index.php/ obstructive-pulmonary-disease-1 Alpha_1-antitrypsin_deficiency_x_ray Bullae Formation in Emphysema https://www.alamy.com/chest-x- ray-emphysema-  More on Emphysema https://www.ncbi.nlm.nih.gov/books/NBK482217/ PA, alveolar pressure; Ppl, pleural figure/article-21034.image.f2/ pressure; PT, transpulmonary pressure. Chronic Bronchitis Mucus gland hyperplasia in chronic bronchitis https://www.medscape.com/answers/ 297664-7339/what-is-the- pathophysiology-of-chronic-bronchitis- in-chronic-obstructive-pulmonary- disease-copd Bronchiectasis  n Lung Disorders PFT Findings in Common Lung Disorders Disorder FEV1/FVC FVC RV, TLC, FRC DlCO COPD/emphysema ↓ ↓ ↑ ↓ Pulmonary fibrosis –, ↑ ↓ ↓ –, ↓ COPD/chronic bronchitis ↓ ↓ RV, FRC ↑ – TLC – Asthma (acute phase)* ↓ ↓ ↑ –  Obstructive Sleep Apnea Apnea: complete airflow cessation despite inspiratory muscle contraction. Hypopnea: decreased depth or duration of a breath. Apnea/hypopnea index (AHI): how many of these events occur per hour. These events are caused by upper airway obstruction during sleep. Cause decreased O2 and CO2 levels, arousals, and sympathetic surges. OSA diagnosed by polysomnograms: AHI > 5 with signs of sleep loss, or AHI > 15 regardless of signs of sleep loss. Gray zone: AHI 5-15. In addition to excessive daytime sleepiness, pathophysiological consequences of repeated arousals, nocturnal spikes of sympathetic activity, intermittent hypoxia, and oxidative stress include cardiovascular pathology—heart disease, hypertension, and atrial fibrillation. Treated with cpap, airway surgery, weight loss, avoidance of supine position, avoidance of alcohol and smoking.  Three Areas of Obstruction in OSA https://www.metrohealth.org/otolaryngology/sleep-surgery/about-obstructive-sleep- apnea---osa  Central Sleep Apnea Central sleep apnea (CSA) is due to a failure of the neural regulation of breathing, either due to a primary brain abnormality or due to a delay in blood circulation time (as in heart failure) that causes a lag between blood gas levels in the lungs and those that the brain sees. Central sleep apnea with Cheyne-Stokes Respirations (CSA-CSR) often occurs in heart failure. https://www.researchgate.net/figure/ Polysomnogram-showing-crescendo-decrescendo- pattern-of-breathing-as-shown-by-the-  Gas Exchange in the Lung and the Oxygen-Hemoglobin Dissociation Curve Oxygen is poorly soluble in plasma, and the dissolved O2 in the blood is not enough to supply the body’s needs. Hemoglobin solves this problem by binding O2 efficiently at the PO2 at the alveolus and releases it as efficiently at the PO2 of the tissues. Average alveolar PO2 is 100 mm Hg, and average tissue PO2 is 40 mm Hg. Hemoglobin is a tetrameric protein consisting of 2 alpha + 2 beta chains, and each chain has a central iron atom where the O2 binds.  The Oxygen-Hemoglobin Dissociation Curve The relationship between the local Po2 and percent saturation of hemoglobin (Hb % sat) is a nonlinear relationship graphically depicted in the oxygen–Hb (oxyhemoglobin) dissociation The Bohr Effect curve. When the PO2 rises and the 1st O2 molecule binds to Hb, the shape of the hb molecule changes, its O2 binding affinity increases, the slope of the O2-Hb dissociation curve increases. The curve starts to flatten out at ~ 75% hb saturation, and at a PO2 of 100 mm Hg, the saturation is 100%. The greater the Hb concentration, the greater will be the oxygen-carrying 2,3-diphosphoglycerate is produced by capacity. If a person has anemia, s/he RBCs during glycolysis. Its production is  4 Causes of Hypoxemia Hypoxia is a deficiency of Cause of Hypoxemia Such as That Observed in: oxygen at the tissue level. It 1. Generalized OSA/OHS, hypoventilation Opioid/drug overdose, can result from: Central nervous system Situations of low inspired disease, Neuromuscular weakness oxygen, such as high altitude Anemia 2. Ventilation/perfusion COPD/asthma, A lack of perfusion to the tissue mismatch and regional hypoventilation Pneumonia, Pulmonary embolism, Poisoning Pulmonary fibrosis, Pulmonary edema A lack of oxygen in the blood due to lung disease Hypoxemia refers to low 3. Shunt Anatomical: Cyanotic congenital levels of oxygen in the blood. heart defects, Physiological: ARDS 4. Diffusion abnormality Interstitial lung disease (many types),  1. Hypoventilation The conducting airways of the lungs have no Variable Respira Volumes (mL) Ventilation: alveoli and are unable to conduct gas s tory exchange; thus, they are collectively known Rate Volume × Rate (mL/min) as dead space. (breath s/min) As a general rule, a person’s dead space (in Tidal Dead Alveola Total Dead Alveola Space r Space Space r Space milliliters) is about the same as his or her weight (in pounds); thus, a man with average body composition and weighing 150 pounds Before 12 500 150 350 6,000 1,800 4,200 would have about 150 mL of dead space. injury Volume tidal x RR = Volume alveolar X RR + Volume dead space X RR. Immedia 12 200 150 50 2,400 1,800 600 tely after With hypoventilation, not only dose the injury minute ventilation fall, but the fraction of dead space ventilation increases. Shortly 30 200 150 50 6,000 4,500 1,500 after Examples: other neuromuscular disorders, injury opioid overdoses, obesity hypoventilation syndrome, restrictive thoracic disorders such as scoliosis, etc. Hypoventilation Example: Data From a Hypothetical Patient With Spinal Cord Injury  2. Ventilation/Perfusion (V/Q) Mismatch Optimal gas exchange depends on both the rate of ventilation reaching the alveoli and the rate of blood flow (perfusion) traveling through the alveolar capillaries. In clinical situations, imbalance between ventilation and perfusion of the alveoli (ventilation/perfusion mismatch) is the most common cause of hypoxemia in chronic lung disease as well as in acute conditions such as pulmonary edema and pneumonia. Partially oxygenated blood decreases final PO2 of blood leaving the lungs. Hypoxemia caused by ˙V/˙Q mismatch is typically responsive to Normal V//Q matching  2. Ventilation/Perfusion (V/Q) Mismatch The airway on the left is partially blocked, providing a region of low ventilation, whereas adjacent regions have normal ventilation. Blood flowing through the underventilated region is unable to pick up sufficient O2 or remove sufficient CO2. When mixed with blood perfusing units with better ˙V/˙Q matching, the resulting pulmonary venous blood has lower O2 and higher CO2 than normal.  Supplemental Oxygen and Hypoxic Vasoconstriction Help to Correct for V/Q Mismatch Oxygen administration improves hypoxemia in (˙V/˙Q) mismatch. CO2 levels vary with the degree of regional hypoventilation, but CO2 and pH levels may remain relatively normal due to stimulation of respiratory rate and depth by CO2- sensitive central chemoreceptors. Hypoxic vasoconstriction is a physiological response to regional hypoxia within the lung using constriction of the pulmonary vasculature. It returns V/Q matching toward normal.  3. Shunt In a shunt, a region of lung is receiving no airflow at all, for example, due to atelectasis, mucus plugging, or flooding due to pneumonia or pulmonary edema. Blood flowing through these lung regions has no addition of O2 or removal of CO2, creating more severe hypoxemia and hypercapnia of the mixed pulmonary venous blood. It can be considered an extreme form of V/Q mismatch. Oxygen administration is less effective at improving blood gases, as inspired air can never reach the affected regions.  4. Diffusion Defect Diffusion limitation has several Fick’s law of diffusion: potential mechanisms and causes. J (flux) = DA(C1-C2) Decreased surface area can occur (thickness of the membrane) with: Where Alveolar loss as in emphysema J = the rate of movement of the Removal of all or part of a lung for gas cancer surgery D = the diffusing constant of the Atelectasis (complete alveolar collapse) molecule that reflects the unique Complete alveolar flooding due to properties making it easier or pulmonary edema or inflammatory fluid in pneumonia harder to move through a barrier Thickness of the alveolar–capillary A = the surface area for diffusion interface may increase due to Δc = the concentration Fibroblast accumulation and collagen difference across the barrier deposition due to idiopathic pulmonary fibrosis Δx = the thickness of the barrier Fluid accumulation along the alveolar walls in early pulmonary edema or pneumonia  4. Diffusion Defect DLCO: diffusing capacity of the Normal DLCO: lung is measured during pulmonary function testing, Uncomplicated asthma usually by giving a single Uncomplicated chronic breath of carbon monoxide and measuring its uptake. bronchitis Diffusion limitation responds well to supplemental O2. As Reduced DLCO: oxygen therapy raises the alveolar PO2, the partial Emphysema, pressure difference across the Severe fibrotic lung membrane barrier increases and promotes greater diffusion disease, rate, as predicted by the Fick Pulmonary hypertension equation.  The Lungs and Their Vasculature The lungs, weighing about 850 g, receive the entire output of the right side of the heart, with a flow rate averaging 5 L/min. Pulmonary vascular resistance is substantially lower than systemic resistance, so pulmonary vascular pressures are much lower than systemic vascular pressures, despite receiving an equal cardiac output. Mean pulmonary artery pressure averages 15 to 20 mm Hg in adults younger than 50 years.25 Owing to lower pressures, gravity has a substantial effect on blood flow distribution from the top to the bottom of the lungs (or dependent and non-dependent regions), with the smallest amount of blood flow reaching the apex of each lung in the upright position, and the greatest amount of flow to the bases.  The Lungs and Their Vasculature In addition to gravity, lung blood flow is modified by local tissue Po 2. A vascular adaptation to lung regions that are hypoxic due to poor ventilation is vasoconstriction. This hypoxic vasoconstriction limits blood flow to poorly ventilated alveoli and maximizes blood flow to well- ventilated alveoli. As previously noted, optimal oxygenation is achieved when blood flow (perfusion) matches ventilation at each level of the lung. Although this mechanism is protective in patients with limited, focal areas of consolidation, it is problematic in patients with progressive, generalized lung disease. In such disorders, widespread hypoxia and hypoxic vasoconstriction may be present, leading to chronic elevations in pulmonary arterial pressures, termed pulmonary arterial hypertension. Increased pressures in the pulmonary vasculature damage vessel integrity, stress the heart, and spill over into negative effects on the systemic circulation that empties into the right side of the heart.  Cor Pulmonale Lung diseases cause hypoxic vasoconstriction, resulting in ↑ PVR and secondary pulmonary hypertension and ↑ RV afterload. Severity of pulmonary htn (mean PAP) http://www.yalepath.org/edu/path100/Lab%205/ Normal is 12-16 mmHg page14.html Mild = 25-40mmHg Moderate = 41-55mmHg Severe = > 55mmHg The RV hypertrophies and ultimately enlarges and fails, a condition called cor pulmonale. https://www.internationaljournalofcardiology.co m/article/S0167-5273(07)01375-7/fulltext →  Pulmonary Embolism Pathologic material can arrive in the pulmonary circulation from the systemic veins, including blood clots (thromboembolism), air, tumor cells, and septic emboli. Fat and amniotic fluid can also embolize. When it is one of the 1st 4 materials above, the bulk action of the blockage of perfusion is the issue. When it is fat or amniotic fluid, damage to the endothelial cells often results in ARDS. RV ← Virchow’s triad for thromboembolism: Endothelial injury Venous stasis Hypercoagulability PE is subdivided clinically with respect to anatomical location and presence or absence of hemodynamic stability. https://pmj.bmj.com/content/92/1090/487  Pulmonary Embolism Stratified definitions of PE: Massive PE, characterized as persistent hypotension lasting more than 15 minutes or necessitating inotropic support, with systolic blood pressure