1. RESPIRATORY FAILURE Miklós Molnár Semmelweis University Institute of Pathophysiology 2005

2. Respiration Function of the respiratory system is to supply the body with oxygen for aerobic metabolism and to remove its major metabolic waste product-carbon dioxide (0.2-4 L/min). Does it by 3 Distinct Mechanisms: Ventilation: Delivery of ambient air to the alveoli Ventilation: Delivery of ambient air to the alveoli Diffusion: Movement of oxygen and carbon dioxide across the alveolar air sac and capillary wall Diffusion: Movement of oxygen and carbon dioxide across the alveolar air sac and capillary wall Circulation: Method by which oxygen is carried from site of gas exchange to the cells where active metabolism occurs Circulation: Method by which oxygen is carried from site of gas exchange to the cells where active metabolism occurs

3. Respiration Is dependent on vital links of various anatomic subcomponents

4. Central Nervous System Thorax and Pleura Neuromuscular System Spinal Cord Upper Airways Cardiovascular System and Blood Lower Airways and Alveoli Seven anatomic subcomponents whose functions are vital to the maintenance of normal respiration. Interruption in the function of any of the links has serious implications for the functioning of the system as a whole. (adapted from Bone RC: Acute Respiratory Failure: Definition and Overview. In Bone R, ed: Pulmonary and Critical Care Medicine. St. Louis: Mosby, 1997).

5. Control of Breathing Central chemoreceptors Central chemoreceptors Respiratory center – medulla oblongata Respiratory center – medulla oblongata pH (behind the blood-brain barrier)pH (behind the blood-brain barrier) Peripheral chemoreceptors – carotid bodies (carotis, arch of aorta) Peripheral chemoreceptors – carotid bodies (carotis, arch of aorta) pH/pCO 2, pO 2pH/pCO 2, pO 2 mechanoreceptors (lung, chest wall) mechanoreceptors (lung, chest wall) mechanical strech, chemical irritation,mechanical strech, chemical irritation, J-receptorsJ-receptors (juxtacapillar localization  blood volume, interstitial edema)

7. Ventilatory Responses to Physiologic Stimuli Hypercapnia Gradual increase of frequency (pCO 2 =40-70 mmHg, linear -3 l/min/mmHg) Gradual increase of frequency (pCO 2 =40-70 mmHg, linear -3 l/min/mmHg)Hypoxia normal PaO 2 =90 mmHg no effect, PaO 2 =50-55 mmHg yes normal PaO 2 =90 mmHg no effect, PaO 2 =50-55 mmHg yes Metabolic acidosis activity of the peripheral chemoreceptor ↑  hyperventilation  pCO 2 ↓, later in the CNS - 24-48 h. activity of the peripheral chemoreceptor ↑  hyperventilation  pCO 2 ↓, later in the CNS - 24-48 h. Metabolic alkalosis activity of the peripheral chemoreceptor ↓  hypoventilation  pCO 2 ↑, later in the CNS - 24-48 h. activity of the peripheral chemoreceptor ↓  hypoventilation  pCO 2 ↑, later in the CNS - 24-48 h.

8. Abnormality of the Control of Breathing

9. Abnormal Breathing Pattern normal tachypnoe Kussmaul Time (min) 6 min Air flow Apnoe: breathing stops at expiration Apneusia: breathing stops at inspiration

10. Abnormal Breathing Pattern Time (min) 1 min Cheyne Stokes Cluster Breathing (Biot Breathing)

11. Abnormal Breathing Pattern (Ataxic breathing) Voluntary Self-controlled Time (min) 1 min

12. Abnormal Breathing Pattern Sleep apnea Hypoventillation and an irregular respiratory pattern during sleep with apnea last for 15-20 sec during the REM phase, usually. Types: Central apnea (complete cessation of respiratory efforts - encephalitis, central ischemia) Obstructive apnea (intermittent upper airway obstruction, morbid obesity, redundant pharingeal soft tissue, reduced upper airway size due to enlarged lymphatic tissue) Mixed apnea (Central apnea followed by obstructive one)

13. Types of Apnea Obstructive apnea Central apnea Mixed apnea Volume Airflow Muscle activity Airflow Muscle activity Muscle activity

14. Coronal section of the head and neck showing the segment over which sleep related narrowing can occur (arrows). Anatomy of obstructive sleep apnea.

15. An obese young woman with the short, thick neck typically seen in patients with obstructive sleep apnea. Pathophysiology

16. Enlarged uvula resting on the base of the tongue (large arrow), along with hypertrophied tonsils (small arrows). The posterior pharyngeal erythema may be secondary to repeated trauma from snoring or gastroesophageal reflux Pathophysiology

17. Elongated soft palate (arrows). In this patient, an increased anteroposterior dimension caused the soft palate to rest on the base of the tongue in the relaxed position. Pathophysiology

18. Family members or partners complaint that the patient has loud snoring, nocturnal gasping or choking. Clinical Manifestation

19. Sleep Apnea Syndrome is profoundly associated with hypertension independent of all relevant risk factors. Arrhythmias from mild to severe. Motor vehicle accident : Six time increased accident rate compared to the general population. Pathophysiologic Consequences

20. Treatment

22. Carbon dioxide Water vapour Oxygen Nitrogen

23. Stephen Hawking “A Brief History of Time”: 1988. Someone told me that each equation I included in the book would halve the sales.

24. Pulmonary Gas Exchange Alveolar O 2 tension (PAO 2 =100 mmHg ) Capillary blood leaving the alveolus (Pc’O 2 =100 mmHg ) Arterial O 2 tension (PaO 2 =90 mm Hg ) Ideal Alveolar Gas Equation Calculation of PAO 2 (considering ideal alveolus): PAO 2 = PIO 2 – PACO 2 x FIO 2 + (1-FIO 2 ) R FIO 2 : fraction of inspired O 2 (0.21 in room air) R: gas exchange ration – metabolic respiratory quotient (CO 2 production/O 2 consumption=0.7-1.0, typical value of about 0.8) PIO 2 : pO 2 of the inspired gas (PIO 2 = 0.21x(760-47)=150 mmHg) PAO 2 = PIO 2 – PaCO 2 x 1.25

25. Representation of the Decrease in Partial Pressure of O 2 from Inspired Air

26. Effectiveness of Oxygene Exchange in the Lung (Alveololar-Arterial oxygen difference) Alveolo-arterial gragient Ideal situation P(A-a)=0 Right-to-left shunt (2-4 %), ventilation-perfusion mismatch. P (A – a) = 2.5 + 0.21 x (age in years) If P (A - a) > 20 mmHg on room air is abnormal usually due to a parenchymal abnormality of the lung

27. Oxygen Content of Blood (CaO 2 ) Bound to hemoglobin (major part) Dissolved in plasma (small amount) CaO 2 = Hb x 1.39 x + 0.0031 x PaO 2 SaO 2 100 Hb: hemoglobin (g/100ml) 1.39 : oxygen-carrying capacity of Hb (ml O 2 /g Hb) SaO 2 : % of Hb that is bound to O 2 = (oxygen saturation) 0.0031: solubility coefficient for O 2 in plasma (ml O 2 /100 ml/mmHg) PaO 2 : partial pressure of O 2 in arterial blood

28. Dissociation Curve of Oxyhemoglobin % of SO 2 PO 2 (mmHg) Physiologicly important Clinically important Adaptations Right shift: acidosis fever, 2,3-DPG Left shift: alkalosis cold

29. Why the O 2 content is so important ? += Hb=15 g% 100 ml 200 ml PaO 2 30 mmHg PaO 2 96 mmHg PaO 2 ? mmHg ??? (30 + 96 )/2 = 63 mmHg ??? !! WRONG !!

30. Right Answer % of SO 2 PO 2 (mmHg) O 2 content (ml/100 ml blood) (12.4 + 19.8) / 2 = 16.1 ml O 2 / 100 ml  PaO 2 = 42 mmHg

31. Respiratory Failure Impaired gas exchange: Hypoxia with or without hypercapnia Can be subclassified into acute and chronic presentations

32. Acute respiratory failure occurs when: pulmonary system is no longer able to meet the metabolic demands of the body pulmonary system is no longer able to meet the metabolic demands of the body Hypoxemic respiratory failure: PaO 2  60 mmHg when breathing room air PaO 2  60 mmHg when breathing room air Hypercapnic respiratory failure: PaCO 2  50 Hgmm PaCO 2  50 Hgmm Definitions of Respiratory Failure Hypoxemia

33. Classification of Respiratory Failure Predominant Hypercapnic a Hypoxemia b Type Acute Chronic Minutes to hours; no compensatory changes Minutes to hours; no compensatory changes Days to months; compensatory changes present  pH and  HCO 3 Days to months; compensatory changes present  hemoglobin a PaCO 2 > 50 mmHg b PaO 2 < 60 mmHg

34. Respiratory Failure Pump failureLung failure Nervous System Thoracic cage Resp. muscle Nervous System Thoracic cage Resp. muscle HypercapniaHypoxemia Breakdown of respiratory failure into its two major components: Pump failure and lung failure. The end results of pump failure is hypercapnia, and the end result of lung failure is hypoxemia.

35. Examples of Disease that Causes Respiratory Failure BRAIN Drug overdose Drug overdose Cerebrovascular accident Cerebrovascular accident SPINAL CORD, NEUROMUSCULAR Myastenia Gravis Syndrome Myastenia Gravis Syndrome Polio Polio Guillian-Barre’ Guillian-Barre’ Spinal cord trauma or tumor Spinal cord trauma or tumor CHEST WALL Flail Chest Flail Chest Kyphoscoliosis Kyphoscoliosis UPPER AIRWAYS Vocal cord paralysis or paradoxicalmotion Vocal cord paralysis or paradoxicalmotion Tracheal stenosis, laryngospasm Tracheal stenosis, laryngospasm LOWER AIRWAYS & LUNGS Asthma Asthma Bronchitis Bronchitis Chronic Obstructive Pulmonary Disease Chronic Obstructive Pulmonary Disease Pulmonary Embolism Pulmonary Embolism Acute Respiratory Distress Acute Respiratory Distress Preumonia Preumonia Alveolar Hemorrhage Alveolar HemorrhageHEART Congestive Heart Failure Congestive Heart Failure Valvular Abnormalities Valvular Abnormalities Pump Failure Lung Failure

36. Pathophysiology of Respiratory Failure Diffusion abnormalities: disturbances in gas transfer across the alveolar capillary bed Ventilation-perfusion imbalance and intrapulmonary shunt: problems with matching pulmonary blood flow and ventilation Alveolar hypoventilation: decreased alveolar ventilation Pathophysiologic mechanisms for respiratory failure include:

37. Diffusion Abnormalities The process by which O 2 and CO 2 move passively across the alveolar capillary membrane that depends upon its physical properties (thickness, area, and diffusibility) and solubility of the gas Problem mainly in chronic, less so in acute respiratory failure

38. Problems with Matching Pulmonary Blood Flow and Ventilation Ideally each alveolar capillary exchange unit would have perfect matching of ventilation and perfusion to ensure optimum gas exchange across each unit This does not happen even in normal individuals where V/Q ranges in different lung regions from 0.6 to 3.0, mean overall is 1.0 In disease states, balance of ventilation and perfusion may be disturbed further: ventilation-perfusion inequality - imbalances of V/Q ventilation-perfusion inequality - imbalances of V/Q intrapulmonary shunt: mixed venous blood not exposed to the alveolus intrapulmonary shunt: mixed venous blood not exposed to the alveolus

41. Problems with Matching Pulmonary Blood Flow and Ventilation In disease states, balance of ventilation and perfusion may be disturbed further: ventilation-perfusion inequality - imbalances of V/Q ventilation-perfusion inequality - imbalances of V/Q intrapulmonary shunt: mixed venous blood not exposed to the alveolus intrapulmonary shunt: mixed venous blood not exposed to the alveolus

43. Hypoventilation To prevent the development of respiratory acidosis, the carbon dioxide produced each day (17,000 meq acid) must be exhaled by the lungs at the same rate The relationship among alveolar ventilation (VA), carbon dioxide production (VCO 2 ) and the partial pressure of carbon dioxide in the blood (PaCO 2 ) is expressed using a modification of the Fick principle of mass balance that quantitates VCO 2 as the product of VA and the fractional concentration of CO 2 in the alveolar gas

44. Diagnosis of Respiratory Failure History and Physical Examination patient symptoms patient symptoms physical examination physical examination Laboratory Tests

45. Patient Symptoms in Respiratory Failure Mental function: headache, visual disturbances, confusion, memory loss, hallucinations, loss of consciousness. Dyspnea (resting vs. exertional). Cough, sputum production, chest pain.

46. Arterial Blood Gas Analysis The most important lab test to subclassify respiratory failure Provides an indication of the duration and severity of respiratory failure Gives 3 Types of Information: presence and degree of hypoxemia (PaO 2 ) presence and degree of hypoxemia (PaO 2 ) presence and degree of hypercapnia (PaCO 2 ) presence and degree of hypercapnia (PaCO 2 ) arterial Acid-Base Status (pH) arterial Acid-Base Status (pH)

47. Hypoxemia Reduction of partial pressure of oxygen in the blood Resting PaO 2 normally 75-80mmHg, 60mmHg lower limit of safety Oxygenation failure considered if PaO 2 < 50-60mmHg on FiO 2 40% or greater Decreases in PaO 2 Occur Secondary To: intracardiac or intrapulmonary shunting of blood intracardiac or intrapulmonary shunting of blood V/Q mismatch V/Q mismatch alveolar hypoventilation alveolar hypoventilation Alveolar gas equation is helpful in sorting out causes of hypoxemia

48. Hypercapnia Hypercapnia in an increase PaCO 2 > 50 mmHg. PaCO 2 = KVO 2 * VA VCO 2 (carbon dioxide) is produced by the oxidative metabolism of carbon containing food products. Any increase in VCO 2 or decrease in VA will result in hypercapnia.

49. Respiratory Failure Examples of Lung vs. Pump Failure Disorders causing respiratory failure can usually be divided into those causing lung failure (impaired oxygenation) vs. pump failure (hypercapnia). Adult Respiratory Distress Syndrome (ARDS) is an example of lung failure, drug overdose is an example of pump failure.

50. ARDS - Clinical Case 43 year old respiratory therapists with asthma, develops acute exacerbation and aspirates during endotracheal intubation. Following intubation, progressive severe hypoxemia refractory to 100% O 2 develops. Lab Data ABG on 100% FiO 2, shows PaO 2 114, PaCO 2 32, pH 7.47 on VT 600cc, RR 18. A-a gradient=56mmHg. ABG on 100% FiO 2, shows PaO 2 114, PaCO 2 32, pH 7.47 on VT 600cc, RR 18. A-a gradient=56mmHg. CXR shows diffuse alveolar infiltrates. CXR shows diffuse alveolar infiltrates.Management mechanical ventilation, AC ventilation, high FiO 2 with increasing levels of PEEP to decrease shunting. mechanical ventilation, AC ventilation, high FiO 2 with increasing levels of PEEP to decrease shunting. Aggressive use of bronchodilators to alleviate bronchospasm. Aggressive use of bronchodilators to alleviate bronchospasm. Diuresis, enteral feeding, DVT and GI bleed prophylaxis.` Diuresis, enteral feeding, DVT and GI bleed prophylaxis.`

51. Respiratory Failure: Pump Failure Case Case: 24 year old white female injected heroin 1/2 hour prior to presentation and presents comatose with shallow irregular respirations. Needle tracks are present, gag reflex is absent. Labs: ABG shows PaO2 40, PaCO 2 80, and pH 7.01. Alveolar - arterial gradient = 10mmHg. CXR - clear lungs. ABG shows PaO2 40, PaCO 2 80, and pH 7.01. Alveolar - arterial gradient = 10mmHg. CXR - clear lungs.Therapy: Endotracheal intubation assisted ventilation Naloxone infusion Endotracheal intubation assisted ventilation Naloxone infusion

52. Diffusion abnormalities Factors influencing diffusion thickness of membrane (inverse) thickness of membrane (inverse) area (linear) area (linear) constant of diffusion constant of diffusion pressure gradient (linear) pressure gradient (linear) V gas =A x D x P 1 - P 2 T A: area of membrane D: constant T: thickness of membrane P 1 -P 2 : pressure gradient

53. Possible causes of abnormal diffusion Increase the thickness or decrease of area fibrotic tissue or alveolar cell proliferation fibrotic tissue or alveolar cell proliferation thickening of capillary membrane thickening of capillary membrane interstitial edema, exudates interstitial edema, exudates intraalveolar edema or exudates intraalveolar edema or exudates Shorter contact time 1/3 is enough for the normal diffusion so PaO 2 normal generally 1/3 is enough for the normal diffusion so PaO 2 normal generally CO increases  PaO 2  if diffusion is effected CO increases  PaO 2  if diffusion is effected FIO 2   (P 1 - P 2 )  FIO 2   (P 1 - P 2 ) 

54. Changes of Gas exchange by exercise 60 at rest CO 

55. Summary Abnormal diffusion: PAO 2 normal but PaO 2 decreased P(A - a)O 2 >10 mmHg Usually triggered by exercise FIO 2 ↑ improves Rarely the cause of hypoxia

57. Mechanical component of breathing Mechanisms influencing inspiration and expiration elasticity elasticity Lung parenchyma Lung parenchyma Cavity of chest Cavity of chest resistance of airways resistance of airways other forces against the mechanism of respiration other forces against the mechanism of respiration

58. Lung volumes Spirometer TV: tidal volume ERV: expiratory reserve capacity RV: residual volume VC: vital capacity FRC: functional reserve capacity TLC: total lung capacity

60. Measurement of lung volumes Spirometer – RV can not be determined body plethysmograph Inert gas dilution test FRC can be estimated. FRC can be estimated. RV = FRC-ERV TLC = RV + VC

61. Static expiratory pressure-volume curves Disruption of alveolar walls FRC , RV  elasticity  Interstitial or infiltration problem FRC , RV , elasticity 

62. Factors influencing the elastic recoil Surface tension (surfactant -dipalmitodylphosfatidilcholin, other lipids and proteins- produced by type II. alveolar cells Tissue elasticity (amount of elastin and collagen)

63. The importance of surface tension. If two connected alveoli have the same surface tension, then the smaller the radius, the greater the pressure tending to collapse the sphere. This could lead to alveolar instability, with smaller units emptying info larger ones. Alveoli typically do not have the same surface tension because surface forces vary according to surface area, due to the presence of surfactant. Since the relative concentration of surfactant in the surface layer of the sphere increases as the radius of the sphere falls, the effect of surfactant is increased at low lung volumes. This tends to counterbal­ance the increase in pressure needed to keep alveoli open at diminished lung volume and adds stability to alveoli which might otherwise tend to collapse info one another. Surfactant thus protects against regional col­lapse of lung units, a condition known as atelectasis, in addition to its other functions.

64. Pathological conditions respiratory distress syndrome in newborns Inadequate biosynthetic pathways Inadequate biosynthetic pathways Inactivation of surfactant Inactivation of surfactant Pathologic mechanical forces used up surfactant Pathologic mechanical forces used up surfactant metabolic problems: acidosis, hypoxia, decreased venous circulation metabolic problems: acidosis, hypoxia, decreased venous circulation Alveoli collapse, TLC , RV  and FRC , elastic effort 

65. (ARDS) -atelectasy, lung edema shock shock trauma: burning, fat embolism, crash of lung tissue, water aspiration trauma: burning, fat embolism, crash of lung tissue, water aspiration Infections - Sepsis Infections - Sepsis Inhalation of toxic gas Inhalation of toxic gas Overdose of drugs: barbiturates, salycylates, heroin, thiazids Overdose of drugs: barbiturates, salycylates, heroin, thiazids Metabolites: ketoacidoses, uremic toxins Metabolites: ketoacidoses, uremic toxins Others: pancreatitis, DIC, amnion-embolism, paraquat- toxication Others: pancreatitis, DIC, amnion-embolism, paraquat- toxication Adult Respiratory Distress Syndrome

66. Decreased in elasticity Elasticity of lung parenchyma decreases lung fibrosis lung fibrosis emphysema emphysema Elasticity of chest cavity decreases obesity obesity Deformity of chest wall (ankylo spondilitis, scoliosis) Deformity of chest wall (ankylo spondilitis, scoliosis) Elastic effort increases, TLC , FRC .

67. Changes of airflow Central obstructions Acute obstruction between the glottis and carina. Allergic reaction triggered by bite of insects Acute obstruction between the glottis and carina. Allergic reaction triggered by bite of insects Slowly developing chronic forms: Slowly developing chronic forms: Constant obstruction e.g. tumor Constant obstruction e.g. tumor Temporary Laryngeal spasm Temporary Laryngeal spasm

68. Maximal expiratory volume Measures the mechanical status of airways FVC - Forced Vital Capacity expiration: expiration: P alv = P pl + P el P pl : pleural pressure, muscle work P el : pressure of elasticity Important: The expiratory flow at the ¾ of the vital capacity dose not depend on muscle forces, elasticity dependent

69. Forced Vital Capacity(FVC)

71. Asthma

72. Volume-time curves FVC plotted this way usually FEF 25-75

73. Functions of breathing muscles Diaphragm: tidal volume (breathing at rest) Intercostali muscles outer: inspiration outer: inspiration inner: expiration inner: expiration Scalenus muscle (lifting ribs) tidal breathing Sternocleidomastoid muscle – lifting the sternum (forced respiration) Frontal longitudinal muscles - (forced respiration)

74. Mechanism of respiratory muscles Length - stretch correlation Inspiratory muscles have the highest stretch at rest Inspiratory muscles have the highest stretch at rest Expiratory muscles have the highest stretch at TLC Expiratory muscles have the highest stretch at TLC Hyperinflation obstruction  inflates  efficacy increases during expiration; however more work needed during inspiration obstruction  inflates  efficacy increases during expiration; however more work needed during inspiration O 2 equilibrium (substituted/needed) Similarly to brain and heart muscles needs oxygen. The inspiratory muscles are more sensitive because there are no other help  hypercapny, hypoxemy Similarly to brain and heart muscles needs oxygen. The inspiratory muscles are more sensitive because there are no other help  hypercapny, hypoxemy

75. Evaluation of mechanical forces Spirometer FVC, FEV 1, FEF 25-75, FVC, FEV 1, FEF 25-75, Diseases influence the mechanical forces of lung decrease air ventilation and cause  Obstructive lung diseases Decreases the amount of air holding unit of lung cause  Restrictive lung diseases Mixed form (few) FEV 1 FVC

76. Restrictive pulmonary diseases FVC , FEV 1 /FVC normal FVC , FEV 1 /FVC normal Obstructive pulmonary diseases, asthma, emphysema etc. FVC , FEV 1 /FVC  FVC , FEV 1 /FVC 

78. “COPD”Emphysema Chronic Bronchitis Asthma Cystic Fibrosis Interstitial Lung Disease (ILD). Obstructive Pulmonary Diseases

79. Chronic Obstructive Pulmonary Disease (COPD) COPD is an accumulation of symptoms produced by respiratory diseases that result in a diagnosis if COPD. Chronic bronchitis and emphysema. COPD is a respiratory disorder or syndrome rather than a disease state.

80. COPD Fourth leading cause of death in US. Approximately 18 million individuals. Results in $440 billion in health care costs annually. Surge of COPD in recent years.

81. COPD Symptoms COPD is characterized by two concepts: Decreased expiratory air flow pressure, and Decreased expiratory air flow pressure, and Increased resistance to expiratory air flow. Increased resistance to expiratory air flow. These problems are caused by airway obstruction, determined by specific respiratory disease.

82. Chronic Obstruction Pulmonary Diseases (COPD) Increased bronchial fluids inflammations, thickening of brochial wall, hypertrophy of smooth muscles inflammations, thickening of brochial wall, hypertrophy of smooth muscles Thickening of Acini, discrepancy between protease – antiproteases  alveolar damage Narrowing of small airways, inflammation, fibrosis  resistance of airways increase Usually mixed form

83. Hypercapnia in COPD PaCO 2 = K x CO 2 produced alveolar gas exchange PaCO 2 = K x BMR + respir work respir volume - residual Respiratory work less then 2 % of BMR. can exceed 20%, in pathologic conditions. Hyperventilation can not decrease PCO 2, because the rate of CO 2 production is more

85. Progression of COPD and Asthma Normal Failure Time in Weeks, Months, Years

87. Possible compensatory mechanisms With and increased a pCO 2 alveolar hypoventillation pCO 2   CSF [HCO 3 ] -   stimulation decreases  hypoxia, cyanosis  pulmonal hypertension, polycythaemia, cor pulmonale, edema  “Blue bloater” alveolar hypoventillation pCO 2   CSF [HCO 3 ] -   stimulation decreases  hypoxia, cyanosis  pulmonal hypertension, polycythaemia, cor pulmonale, edema  “Blue bloater” Tachypnoe  pCO 2, PACO 2 normal, non cyanotic, there is no polycythaemia nor edema  “Ping puffer” Tachypnoe  pCO 2, PACO 2 normal, non cyanotic, there is no polycythaemia nor edema  “Ping puffer”

89. Chronic Bronchitis Chronic cough associated with sputum production more than 90 days on 2 successive years. Rule out TBC, tumor, congestive heart failure Cause: smoking, air pollution. Occupational exposure, etc. smoking, air pollution. Occupational exposure, etc. Pathologic changes: Increase in mucous glands in airways Increase in mucous glands in airways Mucus accumulation in small airways Mucus accumulation in small airways Small diameter, <2mm, airways narrowing Small diameter, <2mm, airways narrowing Recurrent inflammations, infection, and subsequent scaring in the terminal airways  R aw  (resistance) Recurrent inflammations, infection, and subsequent scaring in the terminal airways  R aw  (resistance) Blue bloater type: Hypoxaemic, right heart failure Blue bloater type: Hypoxaemic, right heart failure (clinical diagnosis)

90. Emphysema Abnormal permanent enlargement of the airspaces distal to the terminal bronchiole, with destruction of the wall,without obvious fibrosis Site of injury is the septa- Elimination of pulmonary capillary bed Elimination of pulmonary capillary bed Increase volume in acinus, with the development of blebs (air spaces near pleura) and bulae (large air spaces) Increase volume in acinus, with the development of blebs (air spaces near pleura) and bulae (large air spaces) Mechanical decrease in airway caliber (compression of acini) Mechanical decrease in airway caliber (compression of acini) Loss of elastic recoil Loss of elastic recoil

91. Types of Emphysema Centrilobular (centriacinar) emphysema Upper lobes and superior segments of the lower lobes. Upper lobes and superior segments of the lower lobes. Highly associated with smoking Highly associated with smoking Panlobular (panacinar) emphysema Entire acinus, even in its earliest stages. Associated with homozygous alpha1-antitrypsin deficiency Entire acinus, even in its earliest stages. Associated with homozygous alpha1-antitrypsin deficiency Distal aciner (periacinar, paraseptal, subpleural) emphysema Involves distal alveolar sacs and ducts, usually in the upper lobes and often subpleurally or along fibrous interlobular septa. Typically seen in a young adult with history of spontaneous pneumothorax Involves distal alveolar sacs and ducts, usually in the upper lobes and often subpleurally or along fibrous interlobular septa. Typically seen in a young adult with history of spontaneous pneumothorax

92. Emphysema

94. Pathogenesis of Emphysema Inbalance between naturally occuring proteases and atiproteases Alveolar destruction occurs by the proteases liberated from neutrophils, elastase Alveolar destruction occurs by the proteases liberated from neutrophils, elastase Smoking inhibits  1 -antitrypsin Smoking inhibits  1 -antitrypsin General alveolar hyperventilatio General alveolar hyperventilatio “Pink puffer type”

96. Emphysema Pathogenesis

97. Asthma Reversible air flow obstruction manifested by wheezing and caused by combinaton of airway mucosal edema and inflammation Increased secretions and smooth muscle constriction. Increased secretions and smooth muscle constriction. Inflammatory Mechanism in Asthma Early (<15 min), IgE-mediatedó and late (4-8 h), mechanism unknown Early (<15 min), IgE-mediatedó and late (4-8 h), mechanism unknown Multiple cells (macrophages, eosinophils, hystiocytes and T-lymphocytes) and many mediators (cytokines, groth factors, enzymes and superoxides) are involed following various airway challenges (antigenes, chemical exposure, exercise). At least six separate steps in this complex chain of events have been identified Multiple cells (macrophages, eosinophils, hystiocytes and T-lymphocytes) and many mediators (cytokines, groth factors, enzymes and superoxides) are involed following various airway challenges (antigenes, chemical exposure, exercise). At least six separate steps in this complex chain of events have been identified

98. Allergen Mast Cell Degranulates Histamine Bradykinin Leukotriene Prostaglandins Thromboxane Chemotactic factor Releases Mediators *Airway smooth muscle contraction *Increased vascular permeability *Increased mucous secretions Peden, 2003

99. Histamine Bradykinin Leukotriene Prostaglandins Thromboxane Recruits Eos Eosinophils release Mediators Trashes Airway Epithelium and destroys cilia!!! Loss of epithelium... 1. Exposes nerve endings 2. Increased cytokine production 3.More inflammation. 4.Bronchospasm—inc. parasympathetic Late asthmatic response—4-8hrs later Peden, 2003

100. Lung Remodeling Jeffery Am J. Resp. Crit Care Med. 2001

106. Severity of Asthma  Total dilatation

107. Pathophysiology of Asthma Triggering spec. antigen  IgE  hystiocytes  tryptase, PGD 2, LTC 4 spec. antigen  IgE  hystiocytes  tryptase, PGD 2, LTC 4Signaling cytokins  T-lymphocytes (intermediate messenger)  IL-2  IL-2 receptors  kemotaxis, activation of immunsystem  IgE cytokins  T-lymphocytes (intermediate messenger)  IL-2  IL-2 receptors  kemotaxis, activation of immunsystem  IgE Migration macrophages, eosinophils, lymphocytes, monocytes  LTB4, PAF, IL- 5, IL-8; IL-1, TNF  ELAM-1, ICAM-1, Mac-1 adhesion molecules  inflammation macrophages, eosinophils, lymphocytes, monocytes  LTB4, PAF, IL- 5, IL-8; IL-1, TNF  ELAM-1, ICAM-1, Mac-1 adhesion molecules  inflammation Inflammatory Cell Activation cytokines  LTC4  brochospasm, increased permeability cytokines  LTC4  brochospasm, increased permeability Inflammation Causes Bronchoconstriction Damage of epithelial cells  az antigen penetrates into deeper layer  stronger bronchospasm, smooth muscle cell ploriferation. Inhibits mediators inducing dilatation (PGE 2, NO) Damage of epithelial cells  az antigen penetrates into deeper layer  stronger bronchospasm, smooth muscle cell ploriferation. Inhibits mediators inducing dilatation (PGE 2, NO) Resolution Although usually the episodic disease fully reversible, chronic form becoming evident Although usually the episodic disease fully reversible, chronic form becoming evident

108. Pathophysiology of Asthma

109. Bronchiectasis Pathogenesis Bronchial obstruction → Atelectasis Dilatation of walls of patent airways Infection → Bronchial wall inflammation → weakened walls → further dilation Cystic fibrosis: squamous metaplasia with impaired mucociliary action, infection, necrosis of bronchial and bronchiolar walls Kartagener’s syndrome: absent dynein arms in cilia → lack of ciliary activity

110. Function of Cytoplasmic Dynein

111. Bronchiectasis Morphology Gross Usually both lower lobes May be localised Dilated airways CylindroidFusiformSaccular Cystic pattern on cut surface of lungs Histology Acute and chronic inflammation Desquamation of epithelium Necrotising ulceration Squamous metaplasia Necrosis → lung abscess Fibrosis

112. Bronchiectasis Computed Tomography

113. Bronchiectasis Gross

114. Bronchiectasis Histology

115. Bronchiectasis Complications Pneumonia Lung abscess EmpyemaSepticaemia Cor pulmonale Metastatic cerebral abscesses Secondary Amyloidosis

116. Cystic Fibrosis Genetic deficiency disease characterized by recurrent respiratory tract infections. Estimated 1 in 20 individuals carry trait for CF. Typically diagnosed by age of 6 months. Limits life expectancy to ~29 years.

117. Cystic Fibrosis Improper cellular retention of sodium chloride – lungs, pancreas. NaCl draws water from airways, resulting in dry mucus. Airway obstruction, resulting in respiratory infection and tissue damage.

118. Cystic Fibrosis Individuals can go asymptomatic until adolescence. Later trigger, however, indicates more rapid decline in health. Typically will also involve heptatic system, including cirrhosis and jaundice.

119. Diagnosis PE and history of respiratory infections during infancy/childhood. Sweat test – increased sodium marker. DNA analysis. Currently, genetic engineering is attempting to develop way to modify gene.

120. Pathomechanism Cl - transport abnormality of bronchial cells on the luminal site Cl - diffuses into the cells normally. Influenced Cl - transport  sodium accumulation  Viscosity of mucus increases, plugging airways  infections (Pseudomonas aeruginosa)  Respiratory failure, brochiectasis  death

121.  1 – antitrypsin Deficiency (AAT) Autosomal disease (more than 75 allels have been identified), decreased amount of antitrypsin produced. Antiprotease activity decreases  elastase activity ↑ emphysema by age of 40, develops earlier in smokers.

122. Interstitial Lung Disease Inflammation of the alveolar walls inside the lungs. Almost exclusively from industrial irritants and agricultural byproducts. Numerous conditions coined in occupational health to describe ILD.

123. Black lung – coal dust from mining. Farmer’s lung – fungi exposure in moldy hay. Bird breeder’s lung – inhalation of avian proteins. Silicosis – inhalation of silicon dust. Asbestosis – inhalation of asbestos. Exposure to wood products, detergents, metals, and other animal proteins. Interstitial Lung Disease

124. Diagnosis PE. Evaluation of job site. X-ray of lungs. Spirometry

125. Pathomechanizmus Interstitium is involved. Injury occurs initially to thype I alveolar epitelial cells or capillary endothelium  edema, haemorrhage  fibrin is deposited along alveolar walls (hyalin membrán)  Inflammatory phase  infiltration of neutrophils, macrophages and lymphocytes  cytokines  influence the subsequent intensity and duration of disease process and fibrosis and repair process Inflammatory process subsides, proliferation of type II alveolar cells and organization of the fibrinous exudate occur  collagen is deposited  distortion of lung architecture and enlargement of alveolar air spaces Subsequent inflammatory process promote lung damage

126. This should be enough for to day