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Clinical Pathophysiology Review 3 8:30 AM, March 4, 2003

Clinical Pathophysiology Review 3 8:30 AM, March 4, 2003. Fred A. Zar, MD, FACP Director, M2 Clinicopathophysiology Course Professor of Clinical Medicine University of Illinois at Chicago. Respiratory Pathophysiology. COPD: Pathophysiology and Consequences. Airway inflammation

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Clinical Pathophysiology Review 3 8:30 AM, March 4, 2003

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  1. Clinical PathophysiologyReview 38:30 AM, March 4, 2003 Fred A. Zar, MD, FACP Director, M2 Clinicopathophysiology Course Professor of Clinical Medicine University of Illinois at Chicago

  2. Respiratory Pathophysiology

  3. COPD: Pathophysiology and Consequences • Airway inflammation • Increased mucus and protease activity • Cough and sputum • Increased Airway Resistance • Wheeze and rhonchi • Pursed lip breathing • Increased Work of Breathing • Decreased exercise yet increased metabolism • Breathing may require 25–35% of energy (nml 3–5%) • Weight loss • Hyperinflation • Inspiratory muscle dysfunction • Hoover’s sign, increased AP diameter • Impaired Regional Ventilation • V/Q mismatch –> hypoxemia –> pulmonary HTN

  4. Smoking and COPD • Smoking leads to activation of macrophages and neutrophils • Pulmonary inflammation • > chronic bronchitis • Proteases released: elastase, cathepsins, metalloproteinases • > inhibited by antiproteases • alpha–1 antitrypsin, elafin, secretory leukoprotease inhibitor • > injury to extracellular matrix –> emphysema

  5. Emphysema • Definition • Airspace enlargement distal to terminal bronchiole • Due to destruction of alveolar wall • Locations • Centrilobular • Panacinar

  6. Chronic Bronchitis • Definition • Cough and sputum • Most days for 3 months • 2 consecutive yrs • Pathologic Correlate • Mucus gland hypertrophy • Goblet cell hyperplasia

  7. COPD: Therapy Drug Mechanism Clinical Effect ß2 agonists Smooth muscle relaxation Bronchodilation Decreases mast cell degran Anticholinergics Muscarinic antagonists Bronchodilation Corticosteroids Inhibit cytokine production Do not alter course Decreases eosinophils Decreases reactivity Increases ß responsiveness Decreases inflammation Theophylline Phosphodiesterase inhib. Bronchodilation Adenosine receptor inhib. Better resp. muscle function Skeletal muscle contraction

  8. Asthma • Chronic inflammatory disorder with reversible airways obstruction • Cell mediated • Mast cells, eosinophils, T lymphs, macros, PMNs, epithelial • Increased bronchial responsiveness to a variety of stimuli • Allergens, exercise, cold, pollution, infection, drugs, GERD • Symptoms and signs • Wheeze, SOB, coughing, chest tightness • Can be induced with histamine or methacholine challenge • Pulsus paridoxicus: drop of SBP with inspiration of > 10 mm Hg • Dual response • Early(5 min) due to mast cell release of histamine, LT, PG, PAF • Late (4 hr) due to eosinophil release of LT and cytokines

  9. Asthma Classification Class Symptoms Night Sx FEV1 Therapy Mild Intermittent < 2x/wk < 2x/mo > 80% PRN ß-agonist Mild Persistent 3–6x/wk > 2x/mo > 80% Daily: GC or LA or MCD PRN ß-agonist Moderate Persistent Daily > 1x/wk 60–80% Above + long– acting ß–agonist ± anticholinergic ± theophylline Severe Persistent Continuous Nightly < 60% Above + high– dose inhaled GC

  10. Asthma: Blood Gases Stage pO2 pCO2 pH I Nml Nml Nml II Nml Low High III Low Low High IV Low High Low

  11. Asthma: Therapy Drug Mechanism Clinical Effect ß2 agonists Smooth muscle relaxation Bronchodilation Decreases mast cell degran Anticholinergics Muscarinic antagonists Bronchodilation Corticosteroids Inhibit cytokine production Decreases inflammation Decrease eosinophils Decreases reactivity Increases ß responsiveness Theophylline Phosphodiesterase inhib. Bronchodilation Adenosine receptor inhib. Better resp. muscle function Skeletal muscle contraction Leukotreine inh Decrease leukotreine effect Anti–inflammatory Cromolyn/ Mast cell stabilization Anti–inflammatory Nedocromil

  12. Pulmonary Fibrosis • Pathogenesis • Initial insult –> immune response –> alveolitis –> WBC/macro cytokine release–> injury to epithelial cells and alveolar basal lamina –> repair with fibrosis • Associated Diseases • Idiopathic (cryptogenic fibrosing alveolitis) • CTD: RA, scleroderma, PMS • Sarcoidosis • Occupational lung disease: silicosis, asbestosis • Hypersensitivity pneumonitis • Eosinophilic granuloma • Drugs

  13. Pulmonary Fibrosis: Manifestations • Dyspnea • Rapid shallow breathing • Inspiratory crackles (Velcro®) • Digital clubbing • Later right heart failure

  14. Pressure–Volume CurveObjectively assesses elastic recoil • Parameters • X–axis = lung volume • Y–axis = pleural (esophageal) pressure • Compliance = slope (∆Y/∆X or ∆P/∆V) • Vmax = maximum expiratory flow rate • Dependent on recoil and airway resistance • Alterations in disease states • Emphysema: loss of elastic recoil • Increased slope, shift to left, higher volumes • Pulmonary fibrosis: increased elastic recoil • Decreased slope, shift to right, lower volumes

  15. Pressure–Volume CurvesObstructive vs. Restrictive Disease ObstructiveRestrictive Example Emphysema Pulmonary fibrosis Elastic recoil Decreased Increased Compliance Increased Decreased P–V slope Increased Decreased Curve shift Left Right Volumes Higher Lower

  16. Pathophysiologic Consequences(Emphysema, Decreased Elastic Recoil) • Increased lung compliance • Increased lung distension • Increased airway collapse • Decreased Vmax • Increased work of breathing • Increased ventilatory drive • Increased FRC and RV • V/Q mismatch • Decreased diffusion capacity

  17. Pathophysiologic Consequences(Pulmonary Fibrosis, Increased Elastic Recoil) • Decreased lung compliance • Decreased lung distension • Increased Vmax • Increased work of breathing • Increased ventilatory drive • Decreased TLC, FRC, RV • V/Q mismatch • Decreased diffusion capacity

  18. Respiratory Muscles • Inspiratory • Diaphragm • Contracts–> increased intra–abd pressure –> pushes abd out –> pushes lower rib cage and chest wall out • Contractility best with low lung volumes • Accessory muscles (SCM) • Recruited during increased ventilatory demands • Elevate rib cage • Expiratory • Abdominal muscles • Increase abd pressure, displace diaphragm upward

  19. Pulmonary Function Testing • Dynamic Lung Function • Spirometry • Flow loops • Maximum voluntary ventilation • Static Lung Function • Lung volumes • Lung capacities • Gas exchange • Diffusion capacity (CO) • Arterial blood gases

  20. Indications For Pulmonary Function Testing • Assess SOB • Determine presence/degree of pulmonary disease • Determine pathophysiology of pulmonary disease • Assess course, prognosis and response to therapy • Assess disability

  21. Obstructive Lung Diseases Decreased FEV1/FVC Decreased Vmax (FEF25–75,FEF50) Inward–bowed decrease slope of exp flow–volume loop Restrictive Lung Disease Decreased FVC and FEV1 Normal to high FEV1/FVC Preserved Vmax (FEF25–75,FEF50) Outward–bowed increase slope of exp flow–volume loop Dynamic Lung Function Abnormalities

  22. Obstructive Lung Disease Chronic Bronchitis Emphysema Asthma Acute Bronchitis Bronchiectasis Bronchiolitis Obliterans Restrictive Lung Disease Pulmonary Pulmonary Fibrosis Pulmonary Edema Focal Lung Disease Tumor Pneumonia Atelectasis Lung Resection Extra–Pulmonary Obesity Kyphoscoliosis Neuromuscular Disease Pleural Effusion PFT Classification of Pulmonary Diseases

  23. Spirometry in Pulmonary Diseases ObstructiveRestrictive FVC FEV1 FEV1/FVC FEF50 MVV

  24. Lung Volumes in Pulmonary Diseases ObstructiveRestrictive TLC VC FRC RV DLCO

  25. Respiratory Failure • Definitions • Hypoxemic respiratory failure = PaO2 < 50 mmHg • Hypercapnic respiratory failure = PaCO2 > 50 mmHg • Mechanisms of Hypoxemia • Hypoventilation • V/Q Mismatch • Pulmonary Shunts

  26. Hypoventilatory Respiratory Failure • Due to inappropriate volume and/or frequency of respirations • Increased PaCO2 with concomitant decrease PaO2 • Acutely causes: acidosis, pulmonary hypertension • Causes • CNS disease: any destructive process • Endocrine/metabolic: hypothyroidism, metabolic alkalosis • Neuromuscular: lesions of anterior horn cells, peripheral nerves, motor end plate, muscle itself • Structural: COPD, kyphoscoliosis, obesity

  27. V/Q Mismatch Respiratory Failure • The most common respiratory failure • Usually with some hypoventilation • Ideal gas exchange occurs with a V/Q ratio of 0.8 • 4L/min alveolar ventilation and 5l/min cardiac output • If V/Q decreases • Less air reaches alveoli per given amount of perfusion • Less exchange of O2 and CO2 • Alveolar end–capillary PO2 drops and PCO2 increases • “Healthier” alveoli can compensate for CO2 but not O2 • ABG shows low PaO2 and low PaCO2 • If V/Q increases • More air reaches alveoli per given amount of perfusion • More exchange of O2 and CO2 • Alveolar end–capillary PO2 increases and PCO2 drops • O2 dissociation curve flat at high levels, can’t compensate

  28. Pulmonary Shunt Respiratory Failure • Completely unventilated alveoli (extreme V/Q mismatch) • Causes • Atelectasis, edema, consolidation, ARDS • Venous blood is “shunted” from pulmonary into systemic arterial system without getting oxygenated • V/Q ~ 0 (no ventilation to a perfused alveolus) • Results in hypoxemia and hypocapnia like V/Q mismatch

  29. Clinical Approach to Respiratory Failure • What’s the PaCO2? • If normal or low –> excludes hypoventilation • If high, compute alveolar–arterial O2 gradient • Calculating the A–a gradient • PaO2 is measured via an arterial blood gas • PAO2 is calculated • (Pb – PH2O)FIO2 – PACO2/r • (747 – 47)0.21 – PaCO2 x 1.2 • 147 – (PaCO2 x 1.2) • Normal gradient is 10–15 mmHg • If increased = poor gas exchange = V/Q mismatch or shunt

  30. Treatment of Respiratory Failure By Type TypeTreatment Hypoventilation Mechanical ventilation V/Q mismatch Controlled increased FIO2 Target PAO2 = 50–60 mmHg Bronchodilators, antibiotics, Rx CHF Shunting Mechanical ventilation Positive End–Expiratory Pressure (PEEP) Target PAO2 = 50–60 mmHg Target FIO2 < 60%

  31. Respiratory Acidosis and Alkalosis • Acute Respiratory Acidosis • pH decreases 0.08 pH units / 10 mmHg PCO2 increase • HCO3– increases 1 meq/L / 10 mmHg PCO2 increase • Compensated (Chronic) Respiratory Acidosis • pH decreases 0.03 pH units / 10 mmHg PCO2 increase • HCO3– increases 3.5 meq/L / 10 mmHg PCO2 increase • Acute Respiratory Alkalosis • pH increases 0.08 pH units / 10 mmHg PCO2 decrease • HCO3– decreases 2 meq/L / 10 mmHg PCO2 decrease • Compensated (Chronic) Respiratory Alkalosis • pH usually normal • HCO3– decreases 5.0 meq/L / 10 mmHg PCO2 decrease

  32. Consequences of Acute CO2 Retention • Acidosis • Impaired tissue metabolism • Cerebral Vasodilation • Cerebral edema • Pulmonary Vasoconstriction • Pulmonary hypertension • CO2 Narcosis • Lethargy –> coma • Hypoxemia • Organ dysfunction

  33. Dyspnea • Definition • Synonyms: Breathlessness, shortness of breath (SOB), difficulty in breathing (DIB) • Uncomfortable awareness of breathing difficulty • Pathophysiologic Cause • Discrepancy between the drive to breath and the level of ventilation achieved.

  34. Acute Dyspnea Pulmonary edema Asthma Chest wall injury Pneumothorax Pulmonary embolism Pneumonia ARDS Pleural effusion Pulmonary hemorrhage Chronic, Progressive Dyspnea COPD CHF Interstitial Fibrosis Asthma Effusions Thromboembolic disease Pulmonary vascular disease Psychogenic dyspnea Anemia (Hb < 7.0) Tracheal stenosis Hypersensitivity disorders Acute And Chronic Dyspnea

  35. Systemic vs. Pulmonary Circulation • Systemic Circulation • Normal pressures = 120/80 • SVR = 19.6 torr/L/min • Pulmonary Circulation • Normal pressures = 25/15 • SVR = 2.6 torr/L/min

  36. Normal parameters Pressures = 25/15 Vascular resistance = 2.6 torr/L/min Decreased vascular resistance Parasympathetic tone Acetylcholine Beta–2 agonists Bradykinin Prostaglandins: PGE1, PGI2 Nitric oxide Increased vascular resistance Sympathetic tone Prostaglandins: PGF2a, PGF2 Thromboxane Angiotensin Histamine Serotonin Alveolar hypoxia or hypercapnia Acidosis Pulmonary Vascular Resistance

  37. Pulmonary Hypertension: Etiologies • Increased Left Atrial Pressure • Congestive heart failure • Mitral stenosis • Increased Pulmonary Flow • Left to right shunt • Increased Pulmonary Vascular Resistance • Vasoconstriction • Hypoxia • Obstructive • Primary pulmonary hypertension • Pulmonary embolism (clot, tumor, fat, parasite) • Obliterative • Emphysema • Pulmonary fibrosis

  38. Pulmonary Hypertension: Signs • Heart Exam • Increased P2 • Wide split of S2 • R ventricular heave • S4 • Pressures • Increased R ventricular end–diastolic pressure • Increased RA pressure • Increased CVP

  39. Risk Factors for DVT/Pulmonary Embolism • Venous Stasis • Immobility: age, obesity, bed rest, trauma, surgery, neuro Dx • Heart disease: CHF, atrial arrhythmia, myocardial infarction • Pregnancy • Vein Wall Injury • Prior DVT • Pelvic, hip, leg fracture or surgery • Hypercoagulable States • Malignancies • Estrogen: pregnancy, exogenous • Nephrotic syndrome • Hereditary: Ptn C and S deficiencies, factor V Leiden, homocystinemia, prothrombin gene mutations, high factor levels, antiphospholipid Ab

  40. Pulmonary Embolism: Pathophysiology • Release of Platelet Factors • Serotonin and thromboxane A2 • Vasoconstriction –> pulmonary HTN, RV dysfunction, chest pain, low BP, hypoxemia • Decreased alveolar perfusion • Increased dead space (increased V/Q) –> hypoxemia and hypocapnia • Reflex bronchoconstriction –> wheezing • Loss of surfactant • Atelectasis, alveolar edema and bleed –> SOB, crackles, chest pain • Decreased V/Q –> hypoxemia • Irritant and J receptor stimulation –> hyperventilation and SOB

  41. Pulmonary Embolism: Symptoms • Dyspnea • Pleuritic chest pain • Cough • Hemoptysis • Syncope

  42. Pathophysiology of Chronic Pulmonary HTN Phenomenon Physical Exam (Sx) Increased pulmonary artery pressure –> Increased P2 Right ventricular hypertrophy –> RV S4 Right heart failure –> RV S3 Increased JVP, edema Hepatomegaly (Fatigue and dyspnea)

  43. Sleep Medicine

  44. Sleep Architecture(Cycles every 90–120 minutes) • Non–Rapid Eye Movement (NREM) Sleep • Stage 1: Transition from wakefulness • EEG fast theta (4–7 Hz); easily aroused and deny being asleep • Stage 2: Intermediate sleep, 40–50% of total sleep time • EEG: slower and higher amplitude, sleep spindles: 12–14 Hz bursts, k–complexes: double negative wave • Stage 3 and 4: Deep sleep, 20% of sleep • EEG: High amplitude, slow (1–3 Hz) • Rapid Eye Movement (REM) Sleep • EEG: Low voltage, high frequency ~ wakefulness • EMG: atonic • EYE: rapid eye movements

  45. Determinants of Sleep • Homeostasis • Enough sleep = amount that allows alertness for the day • ~ 8 hours, yet highly variable • Circadian Rhythms • Suprachiasmatic nucleus near hypothalamus • Receives input via the retino–hypothalamic tract • Changes With Age • Arousals increase, deep sleep decreases, latency increases

  46. Obstructive Sleep Apnea • Definition • Repetitive episodes of upper airway obstruction • Frequent apnea and hypoxemia • Symptoms • Nighttime symptoms • Snoring, apnea/gasping, flailing of limbs, frequent awakenings, GE reflux urination • Daytime symptoms • Tiredness upon awakening, morning HA, excessive sleepiness, loss of libido/impotence • MVA, work accidents, school/work problems, social embarrassment, marital problems, memory/concentration trouble, depression

  47. OSA: Predisposing Factors • Age • Obesity • M>F 2:1 • Upper airway obstruction • Craniofacial anomalies • Medications • Alcohol • Smoking • Genetics

  48. OSA: Physical Exam • Short fat neck • Obesity • Upper airway narrowing • Large tonsils • Enlarged uvula • Long soft palate • Micrognathia/retrognathia

  49. Sleep Apnea: Clinicopathologic Effects • Acute • Brady/tachyarrhythmias • Chronic • Systemic HTN • Pulmonary HTN • CHF • Myocardial infarction • Stroke • Hypercapneic respiratory failure

  50. OSA: Polysomnographic Findings • Apneas • > 30 per hour • Terminated by arousal • Often occur over 50% of sleep time • Architecture • Destroyed • Decreased Stage 3 and 4 • Decreased REM

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