Week 6 (Obstruction, Restriction and Respiratory Failure)

Question 1

Types of acute respiratory failure

Answer 1

Type I: Hypoxemia: PaO2 <60 mmHg; FIO2 >50%

Type II: Hypercapnia: PaCO2 >50 mmHg; pH < 7.35

Question 2

Causes of hypoxemic (Type I) respiratory failure

Answer 2

Ventilation/perfusion mismatch (common): high V/Q (deadspace ventilation: pulmonary embolism?), low V/Q (intrapulmonary shunt: chronic bronchitis, emphysema, asthma, bronchiectasis, CF, interstitial lung disease, pulmonary edema, pneumonia, cancer, pulmonary hemorrhage, lymphangitic spread of lung cancer, foreign body obstruction, mucous plugging, pneumothorax)

Shunt: blood shunts past/bypasses alveoli as it flows from right to left heart (intracardiac shunt from heart disease vs. intrapulmonary shunts: fluid-filled alveoli collapsed alveoli, tumor-filled alveoli, obstructed airways (listed above))

Hypoventilation: filure to ventilate causes increase in PaCO2 and causes hypoxemia

Diffusion impairment (uncommon): greater barrier to O2 transport between alveoli and blood (pulmonary edema) or greater distance for O2 to travel between alveoli and RBC (dilation of vessels)

Low PO2 (altitude)

Reduced mixed venous blood

Combinations of the above

Question 3

Calculating alveolar-arterial oxygen gradient

Answer 3

P(A-a)O2 = PAO2 - PaO2

PAO2 = PIO2 - (PACO2/R) + F (subtracts gas exchange from inspired air; this is the alveolar air equation)

PAO2 = 150 - PaCO2/0.8

Normal PAO2 = age/3

Question 4

Diagnosis for acute respiratory failure

Answer 4

If normal P(A-a)O2 (alveolar-arterial oxygen gradient), then low PO2 caused by hypoventilation

If high P(A-a)O2 (alveolar-arterial oxygen gradient), then give 100% O2, and if PaO2 increases then low V/Q (most common cause of arterial hypoxemia) and if no change after giving 100% O2 then shunting (high V/Q?; perfusion without ventilation)

Question 5

Clinical causes of acute respiratory failure

Answer 5

Acute pulmonary edema

Adult respiratory distress syndrome (ARDS)

Massive PE

Acute severe asthma

Exacerbation of COPD

Drug induced lung injury (DILI)

Acute interstitial pneumonia (AIP)

Fulminant pneumonia

Question 6

Causes of pulmonary edema

Answer 6

Cardiogenic: L heart failure, CHF

Non-cardiogenic: ARDS

Note: fluid accumulates in interstitial space and then goes into alveoli

Question 7

Definition of ARDS

Answer 7

Acute onset

Ratio of PaO2/FIO2 <200 <!--= 200 </strong--><!--= 200 </strong-->(or if between 200-300, then acute lung injury)<!--= 200 (or if betwween</p-->

PCWP not elevated (<18 mmHg)

Bilateral lung opacification

Question 8

Pathophysiology of ARDS

Answer 8

Exudative/inflammatory phase: direct or indirect injury (circulating inflammatory mediators) to pulmonary endothelial and epithelial cells leading to alveolar-capillary membrane leak and release of proinflammatory mediators; accumulation of PMNs followed by mononuclear cells

Fibroproliferative phase: chronic inflammatory cells (macrophages) continue to release cytokines, chemokines, and growth factors; angiogenesis and deposition of extra-cellular matrix; finally have fibrosis; stiff non-compliant lung with atelectasis and edema

OR

Exudative phase (1-4 days): alveolar and interstitial edema; capillary congestion; type I alveolar cells destroyed; early hyaline membrane formation

Proliferateive phase (3-10 days): increased type II alveolar cells; cellular infiltrates of alveolar septum; organization of hyaline membranes

Fibrotic phase (>7-10 days): fibrosis of hyaline membranes and alveolar septum; alveolar duct fibrosis

Summary of time table: edema then hyaline membranes then interstitial inflammation and interstitial fibrosis

Question 9

Causes of ARDS

Answer 9

Pneumonia (community acquired, nosocomial, aspiration)

Trauma (contusion)

Cardiopulmonary bypass

Fat embolism

Drug OD

Near-drowning

Toxic inhalation

Shock

Acute pancreatitis

Blood transfusions

Obstetric/surgical crisis

Hemorrhage

Question 10

Prognosis for ARDS

Answer 10

Recovery 25%

Lasting impairment (fibrosis)

Death 40-50%

Question 11

Treatment for ARDS

Answer 11

Fluid management (crucial; controversial; avoid over-hydration)

Supplemental oxygen avoiding oxygen toxicity (avoid high FiO2)

Intubation and mechanical ventilation (volume vs. pressure cycled ventilation; positive end-expiratory pressure (PEEP))

Question 12

Positive end-expiratory pressure (PEEP)

Answer 12

Makes sure alveolar presure never gets down to 0; always have some positive pressure in the alveoli to keep them open

Benefits: recruit collapsed or unstable alveoli, improves oxygenation by reducing shunt, increases FRC, improves compliance, shifts but does NOT reduce edema

Adverse effects: decreases CO becauseincreased intrathoracic pressure means decreased venous return (–> hypotension –> decreased delivery of O2 to tissues), over-inflation, increased VD/VT, barotrauma

Question 13

Alveolar ventilation equation

Answer 13

Assuming PACO2 = PaCO2

PaCO2 = 863 x VCO2/VA

Question 14

Acute ventilatory failure

Answer 14

Not ventilating/getting rid of CO2 well enough!

Alveolar:

PAO2 supposed to be 100 mmHg but is decreased

PACO2 supposed to be 40 mmHg but is increased

Question 15

Causes of acute hypercapnic (Type II) respiratory failure

Answer 15

Lung disease: asthma, emphysema, COPD, pneumonia, pneumothorax, pulmonary contusion, hemothorax, ARDS

Cardiovascular disease: pulmonary edema, stroke, arrhythmia, CHF, valvular heart disease

Respiratory muscle disease: fatigue, drug intoxication (morphine, benzodiazepines, alcohol), neurological disease

Note: only way to tell you have failure to ventilate is to measure arterial PaCO2 because could have dead space ventilation(unless person is visibly not breathing)

Question 16

Clinical physiology: chronic hypercapnia (Type II)

Answer 16

Chronic respiratory get increased PaCO2

Renal retention of HCO3-

Active transport of HCO3- across BBB

Increased CSF buffering capacity

Reduced central sensitivity to CO2

Question 17

Obstructive ventilatory defect

Answer 17

FEV1/FVC <70%

FEV1 tells you severity (>80% is mild; 50-80% is moderate; 30-50% is severe; <30% is very severe)

Question 18

Restrictive ventilatory defect

Answer 18

Low FVC and high FEV1/FVC (shouldn’t be less than 70%, or else would be obstructive) are suggestive

TLC <80% confirms

TLC for severity (65-80% is mild; 50% is moderate; <50% is severe)

Question 19

Impairment in gas exchange

Answer 19

Low DLCO <75-80%

DLCO for severity (60%+ is mild; 40-60% is moderate; <40% is severe)

Not well defined how to grade severity, but <40% considered severe

Question 20

Approach to diagnosis of restrictive lung disease

Answer 20

1) Chest wall disease: anatomic or functional
2) Pleural disease
3) Lung tissue loss: anatomical or functional
4) Diffuse parenchymal lung disease (DPLD)
5) Extrapulmonary

Question 21

Chest wall abnormalities

Answer 21

Kyphoscoliosis

Ankylosing spondylitis

Flail chest

Neuromuscular disease (ALS, myasthenia gravis, Guillain-Barre, spinal cord injury, etc)

Question 22

Pleural disease

Answer 22

Pleural effusion

Thickened pleura (fibrothorax, mesothelioma, etc)

Pneumothorax

Question 23

Loss of lung tissue

Answer 23

Anatomic or functional

Surgical resection

Airway obstruction with atelectasis (tumor, mucous, foreign body, extrinsic compression, etc)

Question 24

Diffuse parenchymal lung disease (DPLD)

Answer 24

Idiopathic interstitial pneumonias (IIP)

Sarcoidosis

Infections

Collagen vascular disease

Drug related

Pneumoconioses

Granulomatosis with polyangitis

Chronic eosinophilic pneumonia

Lipoid pneumonia

Cancer (metastatic)

Lymphangio-leiomyamatosis

Langerhan’s cell histiocytosis

Question 25

Extrapulmonary

Answer 25

Obesity

Pregnancy

Ascites: HCC with massive malignant ascites can push up against diaphragm and prevent it from being able to move

Question 26

How can you tell diffuse parenchymal lung disease apart from other restrictive ventilatory defects?

Answer 26

Diffuse parenchymal lung disease (DPLD) has decreased DLCO/VA (lung that is there is not able to exchange gas well; whereas in every other case the lung parenchyma that still exists is working well) in addition to decreased TLC (whereas others don’t have any change in DLCO/VA)

DLCO is overall ability of respiratory system to exchange gas (low even if have one normal lung and one lung was removed)

DLCO/VA is ability of respiratory system to exchange gas corrected for alveolar volume present (so normal if just one functionally normal lung)

Question 27

Differential diagnosis of hypoxemic or hypercapnic respiratory failure

Answer 27

Normal A-a PO2 but increased PaCO2: brain (drug OD, bulbar poliomyelitis, central alveolar hypoventilation), spinal cord (polio, Guillain-Barre, trauma, amyotrophic lateral sclerosis), neuromuscular (myasthenia gravis, muscular dystrophy, tetanus/botulinum toxin), thorax and pleura (massive obesity, kyphoscoliosis, flail chest, tension pneumothorax), upper airways (tracheal obstruction)

High A-a PO2 but normal/low PaCO2: lower airways (COPD, asthma, bronchiolitis), parenchymal and vascular (pulmonary edema (cardiac and ARDS), pneumonia, interstitial lung disease, pulmonary embolism)

Question 28

What things can make ARDS worse?

Answer 28

High FiO2 (fraction of inspired O2)

Overhydration

Over-expansion of alveoli

Question 29

Ventilation

Answer 29

Movement of volume of air into and out of the lungs

Minute ventilation (Ve): volume of air in and out during one minute (Vt x bpm)

Definition of ventilation that reflects gas exchange is useful and this is alveolar ventilation:

Va = Vt - Vd (dead space ventilation)

Va = (VCO2 x 863)/PACO2

Question 30

How are PACO2 and Va related?

Answer 30

Inversely proportional

If alveolar ventilation is cut in half, PACO2 will double (stop breathing as much and CO2 builds up in your alveoli)

Question 31

Acute vs. chronic hypercapnic respiratory failure

Answer 31

Acute: new onset failure to ventilate (PaCO2 >50), acidotic pH, no time for renal compensation by retention of bicarb

Chronic: long standing failure to ventilate (PaCO2 >50), but have renal compensation through bicarb retention so minimal acidosis/normal pH

Question 32

Metabolic and behavioral control systems for controlling ventilation

Answer 32

Metabolic control system: resp center stimulated directly by CO2 (peripheral chemoreceptors) or indirectly by CO2 (central chemoreceptors respond to H+ in CSF, but that comes from PCO2) or hypoxia (peripheral chemoreceptors are the only ones that sense PO2) to produce neurological impulses to stimulate respiratory muscles to produce ventilation

Behavioral control system: higher centers of brain coordinate ventilation with talking and can take over if no metabolic control (but not when you’re sleeping!)

Question 33

Things that can impair metabolic control system for ventilation

Answer 33

Idiopathic (Ondine’s Curse)

CNS disease (stroke)

Disease of carotid bodies (autonomic dysfunction)

Endocrine or metabolic diseases (hypothyroidism, metabolic alkalosis)

Analgesics, sedatives, drugs are most common cause (morphine, valium, barbiturates)

Question 34

Reasons for hypercapnic respiratory failure in COPD

Answer 34

1) Respiratory muscles cannot generate enough minute ventilation to overcome inefficiency of breath to breath CO2 elimination
2) Work of breathing very high due to airway resistance
3) Muscles at mechanical disadvantage due to hyperinflation

Question 35

Sequelae of hypercapnia

Answer 35

Acidosis

Increases SNS and systemic vasodilation –> headache, cerebral edema and papilledema, cutaneous flushing and diaphoresis

Headache, confusion, coma

Question 36

Diffuse parenchymal lung diseases

Answer 36

Pneumoconioses: asbestosis, silicosis, talc, coal worders’ pneumoconiosis

Idiopathic interstitial pneumonias (IIP): interstitial pulmonary fibrosis (IPF), NSIP, COP, RB-ILD, DIP, lymphoid interstitial pneumonitis (LIP), AIP

Infections: TB, cocci, histoplasmosis, CMV, PCP

Drugs/radiation: nitrofurantoin, amiodarone, methotrexate, gold, dilantin

Hypersensitivity reactions: hay/straw (farmer’s lung), cotton (byssinosis), TDI (chemical worker’s lung), red cedar (cedar worker’s lung), sugar cane (bagassosis)

Collagen-vascular diseases: RA, SLE, systemic sclerosis, polymyositis-dermatomyositis, sjogren’s syndrome, ankylosing spondylitis and psoriatic arthritis

Vasculitis/autoimmune diseases: granulomatosis with polyangitis (GPA; Wegner’s), Churg Strauss, Goodpasture’s

Miscellaneous: sarcoid, pulmonary infiltrates with eosinophilia (PIE), chronic aspiration, pulmonary Langerhans’ cell histiocytosis (histiocytosis X)

Question 37

Non-specific findings in DPLD

Answer 37

Acute illness (days to weeks): viral infections, acute sarcoidosis or Goodpasture’s

Sub-acute illness (weeks to months): PCP, TB, sarcoidosis, alveolar hemorrhage syndromes, cryptogenic organizing pneumonia (COP), hypersensitivity pneumonitis, drug-induced lung disease

Chronic (months to years): idiopathic pulmonary fibrosis

Cough, dyspnea, abnormal PFTs, abnormal imaging

Question 38

Exposure history in DPLD

Answer 38

Hypersensitivity pneumonitis: western cedar, cotton, plastics

Pneumoconiosis: asbestos, silica

Infection: TB, coccidiomycosis

Drugs

Question 39

Extrathoracic symptoms in DPLD

Answer 39

Churg-strauss syndrome: asthma

Wegner’s/GPA: more than 50% have sinusitis, nasal complaint or otitis media

Any collagen vascular disease will have more than just pulmonary involvement

Question 40

Physical exam findings in DPLD

Answer 40

Infiltrating diseases may be silent or may have Velcro rales (dry crackles)

Sarcoidosis will have erythema nodosum, ocular manifestations, arthritis

Langerhans’ cell histiocytosis (histiocytosis X) will have lymphadenopathy and hepatosplenomegaly

Question 41

Chest X-ray in DPLD

Answer 41

Reticulonodular pattern with interstitial disease (lines all over, maybe small nodules)

Nodular changes: Wegner’s/GPA, sarcoidosis, pulmonary Langerhans’ cell histiocytosis (histiocytosis X), pneumoconiosis, granulomatous infections

Cavitation: Wegner’s/GPA, infection

Bilateral hilar adenopathy with right paratracheal nodes: sarcoid

Bilateral hilar adenopathy with hilar nodes: pulmonary Langerhans’ cell histiocytosis

Bilateral hilar adenopathy with eggshell calcifications: silicosis

Pleural disease: rheumatoid lung, asbestosis, SLE

Diffuse pulmonary disease with spontaneous pneumothorax: pulmonary Langerhans’ cell histiocytosis

Question 42

If CXR is too white, what could be causing it?

Answer 42

Blood: alveolar hemorrhage

Water: pulmonary edema (ARDS)

Pus: pneumonitis (infectious, SLE, etc)

Mass

Question 43

Where do you look for whiteness in CXR?

Answer 43

Chest wall

Pleura (costophrenic angles)

Lung parenchyma (vasculature vs. other?)

Mediastinum (look for border of aortic arch, descending aorta, left heart, RA, SVC)

Question 44

Air bronchogram

Answer 44

Finding on CXR of a dense consolidation of alveoli but clear bronchi!

Alveoli become densely consolidated then see border you don’t normally see, and see the larger airways

Question 45

How do you distinguish if consolidation is in right middle or right lower lobe?

Answer 45

Right middle lobe: see minor fissure (horizontal line); lateral subsegment if you can still see right border of heart, but medial subsegment if you cannot see right border of heart

Right lower lobe: see major fissure (diagonal/oblique line); will not be able to see diaphragm border

Question 46

Idiopathic pulmonary fibrosis (IPF)

Answer 46

This is prototypical restrictive diffuse parenchymal lung disease

Specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to lungs and associated with histopathologic and/or radiologic pattern of UIP

Pathophysiology: chronic inflammation and fibrosis leading to reduced lung compliance; involves macrophages, lymphocytes, neutrophils, eosinophils, epithelial cells, endothelial cells, fibroblasts; mediated by chemotactic factors, adhesion molecules, cytokines, arachidonic acid metabolites, ROS, growth factors, matrix proteins and enzymes

Fatal lung disease and natural history is variable and unpredictible (most develop gradual worsening of lung function over years, minority remain stable, some decline rapidly but impossible to tell who will react this way)

Diagnosis of IPF requires: exclusion of other ILDs, presence of usual interstitial pneumonia (UIP) pattern on high-resolution CT (HRCT) in patients without lung biopsy, specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy

Treatment of IPF is different from other IIPs (desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis-associated interstitial lung disease (RBILD), acute interstitial pneunomia (AIP), cryptogenic organizing pneumonia (COP), lymphocytic interstitial pneumonia (LIP)); there is no effective treatment, just supportive/symptomatic care or clinical trial or lung transplant

Peripheral involvement, honeycombing, UIP

Question 47

What determines airflow?

Answer 47

Airway size/caliber

Airway geometry

Gas viscosity

Gas density

Flow = diff in pressure/resistance

Question 48

Where is resistance to flow in the respiratory tract?

Answer 48

Most resistance is at the 7th generation of airway (within conducting zone)

Note: narrowest place is larynx/vocal cords

Note: small airways have very little resistance in healthy people (have laminar flow) but have highest cross-sectional area

Question 49

Anatomic sites of airway resistance

Answer 49

Airway lumen: secretions, tumors, foreign bodies

Airway wall: bronchoconstriction (smooth muscle), mucous gland hypertrophy, inflammatory cell infiltration, collagen and fibrosis, loss of cartilaginous support

Peribronchial region: lymph nodes (may enlarge and collapse the RML), peribronchial edema

Upper airway: vocal cords, epiglottitis, oropharynx, nasal

Lung parenchyma: loss of elastic recoil so decreased driving pressure and loss of radial traction

Question 50

In what diseases is airway caliber/size reduced?

Answer 50

Small airway disease (COPD)

Parenchymal destruction (COPD) with less radial traction

Asthma: edema and bronchospasm

Question 51

Laminar vs. turbulent flow

Answer 51

Laminar flow: smooth, orderly with parallel currents, flow increases with increasing driving pressure, increasing size of airway, decreasing gas viscosity (thickness not density), decreasing airway length

Turbulent flow: disorganized, eddies and swirls, flow is approximately square root of laminar flow (so much lower), likely to be present with large airways, higher average velocity, higher density, lower viscosity, if Reynolds number exceeds 2000-4000

Question 52

How is He used therapeutically in severe asthma?

Answer 52

Heliox (He with 20-40% O2) used because much more likely to have laminar flow in upper airway to get more gas through (flow rate is now squared in previously turbulent airways)

Viscosity is 13% higher though so results in slightly reduced flow in small airways with laminar flow (so not as useful in COPD small airway disease)

Question 53

Driving pressure of exhalation

Answer 53

V = diff in pressure/resistance

Static elastic recoil of lung parenchyma due to elastin and collagen fibers and due to surface tension of alveoli (reduced by surfactant)

Static elastic recoil of chest wall balances lung recoil at FRC

When forced exhalation, use muscles to increase intraabdominal pressure (rectus abdominis, internal and external oblique, transversus abdominis), and to compress chest wall (internal intercostal muscles)

Question 54

What happens to elastic recoil of lung in emphysema?

Answer 54

In emphysema, elastic recoil of lung is reduced due to destruction of elastin, collagen and lung tissue in general

Lungs at bigger volume

Note: static elastic recoil tends to collapse the lung as a whole, but tends to hold airways open

Question 55

Hysteresis

Answer 55

Higher tension during inflation when surface film is being stretched

Lower tension during deflation when surface film is collapsing

Question 56

Why can’t we just continue to increase driving pressure (muscular work) if increased airflow is required?

Answer 56

There is a limit to how much you can use the muscles

As apply pressure to alveoli, you also apply that pressure to the airways so if you continue to increase pleural pressure further, you cause airway to collapse (especially if you have COPD and radial traction keeping airways open is already decreased)

Question 57

Airway collapse: equal pressure point

Answer 57

Increasing transpleural pressure is applied to alveolus, resulting in increased driving pressure but also to airways resulting in narrowing and collapse

Max expiratory flow is limited by airway collapse (if expiratory muscle strength and effort are adequate)

In emhpysema airways become more easily collapsed due to destruction of airway support structure (radial traction and cartilage) –> premature airway closure results in unexhaled air being trapped behind collapsed airways (airtrapping; increased residual volume)

Question 58

What happens if airways remain open but just have very slow flow?

Answer 58

Some lung “units” empty more slowly due to increased compliance (less recoil pressure to drive flow due to parenchymal destruction) or increased airway resistance (small airway disease)

If flow is slow then as you breathe faster and faster, get more air trapping and no time for air to be exhaled through narrow airways (new breath initiated before complete exhalation so less ventilation and air remains trapped because no time to exhale)

Overinflated lungs, high residual volume (RV)

Question 59

Physical findings of obstruction

Answer 59

Wheeze: continuous musical sounds longer than 250 ms; may be inspiratory or expiratory; oscillation of opposing walls of airways narrowed to point of near closure; pitch not related to location

Prolonged exhalation: long time constant

Hyperinflation: hyperresonance on percussion, barrel chest, low flat diaphragm

Question 60

COPD

Answer 60

Common, preventable and treatable

Characterized by persistent airflow limitation that is progressive and associated with enhanced chronic inflammatory response in airways and lung to noxious particles or gasses

Exacerbations and comorbidities contribute to severity in people

Chronic airflow limitation is mixture of small airway disease (obstructive bronchiolitis), parenchymal destruction (emphysema), and relative contributions vary from person to person

Slow and progressive with continued smoking

Measure airflow limitation by spirometry

Question 61

Respiratory symptoms of COPD

Answer 61

Cough, sputum, wheezing, dyspnea

Get cough before obstruction, but get obstruction before you’re bothered by the symptoms

Question 62

Host factors contributing to development of COPD

Answer 62

Alpha-1-antitrypsin deficiency leads to emphysema/COPD

Hyperresponsiveness to tobacco predicts accelerated rate of decline compared to non-hyperresponsive smokers

Question 63

Exposures contributing to COPD

Answer 63

Tobacco smoke by far most important

Occupational dust and chemical exposure (coal dust = airflow obstruction, cadmium fumes = emphysema)

Indoor pollution: biomas fuel, environmental tobacco smoke

Outdoor air pollution (not so much though)

Infections: lung growth, airway hyperresponsiveness, HIV infection, stepwise decline

Socioeconomic status

Question 64

Pathogenesis of COPD

Answer 64

Noxious particles and gases combined with host factors –> lung inflammation –> normal protective and/or repair mechanisms overwhelmed or defective –> oxidative stress and proteinases –> repair mechanisms –> COPD pathology

Note: inflammatory response in COPD is cytotoxic TH1 (?) cells that activate macrophages, which is markedly different from that in asthma (TH2 cells that recruit B cells)

Question 65

Protease/antiproteases

Answer 65

Proteases destroy tissue: neutrophil elastase (elastase and collagenase), neutrophil cathepsin G, neutrophil proteinase-3, cathepsins B, L, S; matrix metalloproteases (collagenase, gelatinase, elastase)

Antiproteases limit destruction by proteases: alpha-1-antitrypsinase, secretory leukoproteinase inhibitor (SLPI) and tissue inhibitors of MMPs (TIMPs)

Question 66

Alpha-1-antitrypsin deficiency

Answer 66

Alpha-1-antitrypsin is a protease inhibitor (antiprotease enzyme)

Normal allele is Pi M

Most common abnormality is point mutation where protein doesn’t make it out of the golgi in the liver (Pi Z) –> may cause liver disease in children, or cause emphysema at age 50 in a nonsmoker

Pi S allele is mutation causing decreased serum half life of alpha-1-antitrypsin, is more common in Spain/Portugal and is intermediate but if combined with Pi Z allele then increased risk for disease

Heterozygotes are fine!

Smoking increases neutrophil elastase from WBCs (increased parenchymal destruction) and smoking inactivates alpha-1-antitrypsin (less inhibition of neutropil elastase) –> MORE destruction of lung parenchyma

Question 67

Effect of oxidants and free radicals

Answer 67

Oxidants and free radicals are released by neutrophils in respiratory burst (O2-, H2O2, OH, ONOO-)

Inhaled as tobacco smoke

Damage matrix proteins, lipids, nucleic acids; activate protease precursors; inactivate antiproteases

Limited and localized by antioxidants

Question 68

Pathophysiologic changes in COPD

Answer 68

Small airway disease

Parenchymal destruction

Mucous hypersecretion

Pulmonary HTN, cor pulmonale

Systemic effects

Hypoxemia and hypercapnia

Question 69

Membranous and respiratory bronchiolitis

Answer 69

Chronic inflammation

Subsequent fibrotic repair reaction

Thickening of airway walls from inflammatory edema and cellular infiltrates

Bronchiolar fibrosis, smooth muscle hyperplasia, goblet cell hyperplasia may also be present

Airway distortion may result from fibrous scarring

Note: membranous bronchioles not supported by collagen (are small conducting airways right before respiratory alveoli)

Question 70

Parenchymal destruction in COPD

Answer 70

Condition of lung characterized by abnormal permanent enlargement of the airspace distal to the terminal bronchiole, accompanied by destruction of their walls, and without obvious fibrosis

Centrilobular emphysema: dilation and destruction (not just blowing up lung too much but actually tearing open parts of lung and getting holes!) of respiratory bronchioles and beyond (but not affecting alveolar ducts/alveoli distally)

Loss of alveolar attachments to bronchioles; decreased lung elastic recoil

Hyperinflation

Destruction of pulmonary capillary bed occurs with destruction of rest of parenchyma

Gas exchange abnormalities (decreased DLCO)

Question 71

Difference that smoking vs. alpha-1-antitrypsin cause in lungs

Answer 71

In smoking, damage starts at center of lobule (centrilobular emphysema)

In alpha-1-antitrypsin, destruction throughout entire lung (panacinar emphysema)

Note: in asthma, have no destruction of the parenchyma at all

Question 72

What is the difference between COPD and emphysema?

Answer 72

Emphysema is a TYPE of COPD, however…

Emphysema is a pathologic diagnosis: parenchymal destruction including destruction of vessels, alveolar attachments to airways, alveolar surface area

For COPD, you do not perform a biopsy! Have destruction leading to airflow obstruction and loss of gas exchange surface area and capillaries, but cannot prove whether this is emphysema histologically since no tissue sample!

Question 73

Chronic bronchitis

Answer 73

Clinical definition; mucous hypersecretion (hypertrophy and hyperplasia of the subepithelial tracheobronchial mucus glands)

Production of any sputum whether expectorated or swallowed, and in most instance accompanied by chronic cough for >3 months per year and for >2 consecutive years

Disease of small airways

Does not correlate with FEV1 or impairment but may predict future obstruction

Excludes bronchiectasis and chronic infections

Since many COPD patients cough up mucus, prior definition included chronic bronchitis in COPD but just turns out that it’s not that important in terms of functional/exercise limitation (its the small airway disease that is important in this)

Question 74

Systemic effects in COPD

Answer 74

Get pulmonary hypertension late in course of COPD: body tries to compensate for hypoxemia (poor ventilation) so get hypoxemic vasoconstriction in poorly ventilated lung units and destruction of capillaries; pathologic changes in pulmonary arteries

Get cor pulmonale due to pressure building up as a result of pulmonary hypertension and get hypertrophy and eventual failure of RV –> edema, etc

COPD associated with systemic inflammation and skeletal muscle dysfunction that may contribute to limitation of exercise capacity and decline of health status

Question 75

Hypoxemia and hypercapnia in COPD

Answer 75

Hypoxemia may develop when have 35-30% of normal FEV1 (<1L) due to V/Q mismatch: late disease parenchymal destruction reduces SA for gas exchange and capillary bed also contributing to hypoxemia during exercise

Hypercapnia may develop with even lower FEV1 (<0.75-1L) due to inspiratory muscle dysfunction: respiratory drive increased (even with hypercapnia) but respiratory muscles insufficient to overcome increased work of breathing due to airflow obstruction and increased inefficiency of ventilation

Question 76

Symptoms of COPD

Answer 76

Smoker’s cough (nonproductive) may start almost immediately with smoking (irritant effect)

COPD onset is in middle age after long latent period of progressive pathologic and physiologic changes

Chronic bronchitis: chronic productive cough due to mucous gland hypertrophy and loss of ciliated bronchial epithelium

Dyspnea, an abnormal awareness of the act of breathing: slowly progressive over years, first with moderate to strenuous exercise, then progressively with less exercise then eventually at rest; late in course get significant diffusion impairment with exercise and cor pulmonale contributes to dyspnea

Question 77

Physical findings in COPD

Answer 77

On inspection: horizontal ribs and “barrel-shaped” chest; flattening of hemi-diaphragms; use of scalene (palpable) and SCM muscles; central cyanosis; ankle or lower leg edema

On auscultation: reduced breath sounds; wheezing during quiet breathing

Question 78

Spirometry findings on COPD

Answer 78

Slow, progressively increasing obstructive ventilatory defect, without return to normal after bronchodilators

FEV1 does not correlate well with degree of emphysema

FEV1/FVC ratio <70% predicts further decline of >50 mL/yr

Prolonged exhalation time (may result in under-estimation of FVC)

Hyperinflation causes increased TLC

FRC increases due to decrease in elastic properties of lung (increased compliance)

RV increases due to premature airway closure and air trapping

Hyperinflation flattens diaphragm and results in mechanical disadvantage for ventilatory pump

Question 79

Diffusing capacity in COPD

Answer 79

Parenchymal destruction (emphysema) reduces both SA (Dm) for gas exchange and alveolar capillary bed (Vc)

DLCO correlates well with degree of emphysema (on resection or HRCT) if FEV1 >1L

Question 80

Gold 2011 staging of COPD airflow severity

Answer 80

Graded by FEV1% predicted post bronchodilator

Not all signs and symptoms correlate well with FEV1

Stage I: mild FEV1 >80%

Stage II: moderate FEV1 50-80%

Stage III: severe FEV1 30-50%

Stage IV: very severe <30% or FEV1 <50% with respiratory failure (PaO2 < 60 with or without PaCO2 > 50) or right heart failure

Note: all stages have FEV1/FVC <70%

Question 81

Exacerbations of COPD

Answer 81

Exacerbation: acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day to day variations and which leads to a change in medication

Frequent: two or more in the prior year (predictor of future exacerbations)

Question 82

Definition of asthma

Answer 82

Chronic inflammatory disorder of airways involving mast cells, eosinophils, neutrophils (less so than COPD but esp in sudden onset, fatal exacerbations, occupational asthma and patients that smoke), TH2 lymphocytes, macrophages, epithelial cells

In susceptible individuals, inflammation causes coughing (at night or early morning), wheezing, breathlessness and chest tightness

Episodes associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment

Airflow limitation due to bronchoconstriction, airway hyperresponsiveness, airway edema

Airway wall remodeling

Question 83

Asthma prevalence, risk factors

Answer 83

More common in people under 18 (whereas COPD never symptomatic in those under 18)

Risk factors: innate immunity (TH2 cytokines, IgE levels, allergic sensitization, atopy); complex genetic influence, environment (airborne allergens, viral respiratory infections, tobacco smoke in utero, air pollution, maybe diet)

Question 84

Etiology of asthma

Answer 84

Triggering symptoms: allergens, viral infections, nonspecific irritants, exercise and cold air, osmotic stimuli

Foods and medications (beta blockers, aspirin)

Emotion (rare)

Reflex bronchoconstriction (acid reflux triggers bronchospasm by NANC nerves then can get down into lung which is bad!)

Classic (Samter’s) triad: aspirin sensitivity, nasal polyps and asthma

Question 85

Early and late phase of acute inflammation of asthma

Answer 85

Early phase: rapid activation of mast cells and macrophages already in airways; release of preformed mediators (histamine, eicosanoids (leukotrienes), ROS); smooth muscle contraction, mucous secretion, vasodilation, microvascular leak; result is obstruction (bronchoconstriction, airway wall edema, luminal mucous, exudate and cells); relieved by beta agonists and related drugs

Late phase: recruitment of new cells (eosinophils, TH2 helper cells, basophils, neutrophils, macrophages); release of TH2 like cytokines (IL-2, IL-5, GM-CSF), recruitment and activation from adhesion molecules, chemokines and cytokines; enhanced nonspecific (methacholine) bronchial hyperresponsiveness; this is probably what chronic asthmatics are experiencing

Question 86

Characteristics of chronic inflammation

Answer 86

Mast cells and basophils: histamine, PGD2, LTC4, tryptase and chymase

Eosinophils: toxic granule release (major basic protein, eosinophilic cationic protein, eosinophil-derived neurotoxin, oxygen free radicals, eicosanoids (leukotrienes), TH2 like cytokines, growth factors, elastase and metalloproteases)

Lymphocytes: CD4+ T helper cells (likely control chronic inflammation by release of TH2 like cytokines (IL-4, IL-5, etc)

Macrophages, epithelial cells, neutrophils, fibroblasts and myofibroblasts

Neurogenic inflammation, eicosanoids, endothelins and NO, substance P, neurokinins (NKA, NKB)

Question 87

Chronic inflammation in asthma

Answer 87

Occurs in all “types” of asthma

Acutely increased with asthma triggers (allergens, viral infections, occupational triggers)

Occurs early in course of disease (even in mild, intermittent and in remission)

Asthma severity correlates with many inflammatory indices but inflammation does not “define” asthma subtypes/phenotypes

Question 88

Asthma symptoms

Answer 88

Variable/episodic with time and/or treatment

Dyspnea

Wheezing (more than in COPD; not always seen on physical exam)

Chest tightness (bronchoconstriction and hyperinflation)

Cough (sometimes its all it is!)

Sputum production

Nocturnal awakening

Exercise limitation

Question 89

PFTs in asthma

Answer 89

Airway obstruction

Variable with time, exposure, treatment

Decreased FEV1/FVC

Reduced FEV1, PEF, FEF25-75%

PEF variable AM/PM and day to day

May have increased TLC, FRC, RV

DLCO usually normal but may be increased in acute attacks (large intrathoracic negative pressures draw in more blood and increase pulmonary capillary blood volume; kind of blood doping effect and get DLCO up a little IF you measured during an exacerbation, but don’t usually)

Question 90

Methacholine challenge test

Answer 90

Give methacholine to people who may have asthma

If healthy, won’t do much

If severe, FEV1 will drop after having methacholine (causes bronchoconstriction because is a muscarinic agonist)

Negative test has good negative predictive value for asthma!

Question 91

Measures to determine severity of asthma

Answer 91

Can be intermittent or persistent (mild, moderate or severe)

Symptoms

Nighttime awakenings

Short acting beta2 agonist for symptom control used?

Interference with normal activity

Lung function

Exacerbations requiring oral prednisone (consider frequency and severity)?

Treatment level for initiating or after optimizing control

Question 92

Severity of asthma

Answer 92

Intrinsic intensity of disease process (impairment or risk)

Most easily measured when patient not taking long-term controller therapy

Guides initial therapy

Inferred from minimum therapy needed to maintain control

Question 93

Control of asthma

Answer 93

Well controlled, not well controlled and severe

Degree to which manifestations of asthma are minimized

Current impairment (symptoms and functional impairment)

Future risk (exacerbations, decline in lung function, adverse events from medications)

Guides treatment after initiation of long-term control medications

Question 94

Beta2 agonists for treating asthma

Answer 94

Relax airway of smooth muscle

Don’t treat the underlying problem, only treat symptoms (bronchoconstriction)

Albuterol/levalbuterol: short-acting (4h), rapid onset (15s)

Salmeterol: long-acting (12h), slower onset (15-20min)

Formoterol/arformoterol: long-acting (12h), rapid onset (<5min)

Indacaterol: long-acting (24h), slower onset

Epinephrine: has heart side effects from beta1

Question 95

Methylxanthines

Answer 95

Smooth muscle relaxation and mild anti-inflammatory (likely cause bronchodilation by inhibiting phosphodiesterase, thereby decreasing breakdown of cAMP)

Theophylline (PO) and aminophylline (IV)

Caffeine (very weak bronchodilator)

Side effects, toxicity and drug interactions (therapeutic range overlaps toxicity range, bad!)

Phosphodiesterase IV specific inhibitors: raflumilast approved for COPD 3/1/11

Question 96

Anticholinergics for treating asthma

Answer 96

Not used as commonly in asthma because don’t work as fast as beta agonists, but use ipratropium if have beta2 tremor

Used in COPD primarily (tiotropium)

Relaxation of cholinergic (muscarinic) induced bronchoconstriction

Ipratropium is short acting (6h) and tiotropium is long acting (24h) and selective for M3 and M1 receptor

Atropine has systemic side effects

Question 97

Corticosteroids as treatment for asthma

Answer 97

Local broad airway anti-inflammatory

Beclomethasone HFA (dry powder inhaler)

Fluticasone HFA or DPI, also with salmeterol (beta agonist)

Budesonide DPI or nebulizer, also with formoterol

Mometasone DPI, also with formoterol

Ciclesonide HFA

For rescue: oral prednisolone, methylprednisolone, IV methylprednisolone, hydrocortisone

Question 98

Antileukotriene agents for asthma

Answer 98

Only help 15-20% of people (can tell who won’t respond genetically)

Specific reduction in leukotriene mediators

Acute bronchodilation and limited anti-inflammatory

Montelukast: antagonizes LTD4 and LTE4 receptors (CysLT type 1)

Zafirlukast: antagonizes LTD4 and LTE4 receptors

Zileuton: inhibits 5 lipoxigenase

Question 99

Other agents to treat asthma

Answer 99

Cromolyn nebulizer (doesn’t actually work that well)

Omalizumab: anti IgE antibody; helpful in severe cases to reduce exacerbation

Question 100

How do we reduce risk factors for asthma

Answer 100

Trigger avoidance: environmental modification, pneumococcal and influenza vaccination (because infection can cause exacerbation?), occupational assessment

Cigarette smoking: reduces anti-inflammatory action of corticosteroids

Question 101

Management of asthma

Answer 101

Step up as needed if adherent and step down if possible if asthma well controlled for 3 months

1) PRN beta2 agonist
2) Low-dose inhaled corticosteroid (ICS)
3) Medium dose ICS or low-dose ICS + long acting beta2 agonist (LABA)
4) Medium dose ICS + LABA
5) High dose ICS + LABA and consider omalizumab
6) High dose ICS + LABA + oral corticosteroids and consider omalizumab

Quick relief medication for all patients: short-acting beta2 agonist as needed for symptoms up to 3 doses at 20 minute intervals depending on severity of symptoms

Question 102

Risk reduction for COPD

Answer 102

Reduce exposure to tobacco smoke, occupational dusts and chemicals and indoor and outdoor air pollutants

Smoking cessation is single most effective (and cost effective) way to reduce risk of developing/progressing COPD

Test for alpha-1-antitrypsin deficiency in non-smokers with COPD, family history of AAT and early presentation of COPD

Question 103

Oxygen administration for COPD

Answer 103

O2 administration is only way (other than smoking cessation) to improve survival in patients with COPD

Question 104

COPD management by GOLD category

Answer 104

Group A: few symptoms, low risk = PRN beta agonists or anticholinergics

Group B: many symptoms, low risk = long-acting beta agonists (LABA) or anticholinergics (LAMA)

Group C: few symptoms, high risk = LABA/ICS or LAMA or LABA/LAMA

Group D: many symptoms, high risk = LABA/ICS or LAMA, LABA/LAMA, LABA/LAMA/ICS, LABA/raflumilast

Question 105

Difference in how inhaled steroids are used in COPD vs. asthma

Answer 105

Purpose of ICS in COPD is to reduce exacerbations so if no exacerbations then no need for ICS

Purpose of ICS in asthma is to reduce inflammation and disease as well as symptoms (so can take steroid daily)

Question 106

Management of asthma and COPD exacerbations

Answer 106

Bronchodilators: continuous nebulized albuterol and ipratropium or frequent high dose MDI until improved then converted to metered dose inhaler; if come into the ER, may give 20 puffs of albuterol to try to relieve bronchospasm

Corticosteroids: IV at hospital or PO at home; steroids take 8 hours to work so have to get them through that time with bronchodilators and potentially temporary ventilation; use methylprednisone once followed by prednisone usually tapered from 60 mg/d

Oxygen to maintain SpO2 >92% but don’t want to give too high O2 or else will suppress respiratory drive

Rule out PE

In asthma, consider magnesium, heliox (FiO2 0.3 with He), montelukast

Consider IV terbutaline, IV aminophylline (but make sure haven’t already taken theophylline), intubation and mechanical ventilation with permissive hypercapnia, paralytic agents

Discharge: oral steroid burst, good long-term medication regimen, rescue medication, plan for exacerbations, good follow-up

Question 107

Causes of asthma or COPD exacerbations

Answer 107

Exposure

Infection

Didn’t take their medications

Question 108

Causes of wheeze and obstruction

Answer 108

Extrathoracic upper airway: post nasal drip, Klebsiella rhinoscleroma, hypertrophied tonsils, laryngeal edema, laryngocele, epiglottitis (supraglottitis), retropharyngeal abscess, vocal cord dysfunction, bilateral vocal cord paralysis, vagus nerve compression due to increased ICP, postextubation granuloma, hemorrhagic vocal cord obstruction, abnormal arytenoid movement, cricoarytenoid arthritis, malignancy, obesity, Wegner’s granulomatosis (GPA), anaphylaxis, sleep apnea

Intrathoracic upper airway: tracheal stenosis due to prior intubation, acquired tracheomalacia, relapsing polychondritis, tracheobronchealmegaly, intrathoracic goier, right sided arotic arch, malignancies, tracheal chondroma, tracheal leiomyoma, herpetic tracheobronchitis, benign bronchial tumors, tracheal adenoma (HPV), malignancies, foriegn body aspiration

Lower airway obstruction: asthma, COPD, bronchiectasis, CF, malignancies, bronchiolitis, pseudomembranous aspergillus tracheobronchitis, lymphangioleimyomatosis (LAM), lymphangitic carcinomatosis, aspiration, pulmonary embolism, anaphylaxis, carcinoid syndrome, parasitic infections, pulmonary edema

Question 109

Summary of COPD vs. asthma

Answer 109

Both obstructive

COPD: small airway disease and parenchymal destruction due to tobacco/AAT deficiency/chronic bronchitis; preventable (early) mortality, treatable morbidity (only treating symptoms)

Asthma: inflammation of airways treatable with inhaled corticosteroids and bronchospasm relieved with beta2 agonist (treating underlying inflammation)

Question 110

Causes of chronic neuromuscular respiratory failure

Answer 110

Neurological disease: postinfectious polyneuropathy (Guillain-Barre syndrome), motor neuron disease (ALS), poliomyelitis

Muscular disease: muscular dystrophy, myopathy (metabolic or structural), connective tissue disease (SLE)

Chest wall deformity: kyphosis, scoliosis, gibbus, secondary to muscle disease (muscular dystrophy, poliomyelitis)

Question 111

What happens to TLC and RV in neuromuscular disease?

Answer 111

TLC decreases

RV increases

Lungs cannot expand as much and chest wall cannot shrink as much

Question 112

How do you assess breathing muscle endurance?

Answer 112

Maximum voluntary ventilation (MVV)

Breathe deep and quickly for 12 seconds to calculate MVV

Can estimate MVV by doing FEV1 x 40 because you exhale for 40 seconds out of every minute

Question 113

How do you assess strength of breathing muscles?

Answer 113

Maximum inspiratory and expiratory mouth pressures (PImax and PEmax)

Better inspiratory force at lower lung volumes

Better expiratory force at higher lung volumes

Question 114

Measuring oxygen diffusion in the lung

Answer 114

Use DLCO: uses CO to determine diffusion characteristics of the lung

CO goes through alveolar duct to alveolar space across alveolar epithelium into tissue interstitium across capillary epithelium and into plasma

From plasma gets across RBC membrane, into RBC cytoplasm and onto hemoglobin

Measure CO content of air breathed out to figure out how much diffused into the lung

Question 115

Factors influencing diffusing capacity

Answer 115

Factors increasing DLCO: body size (SA, Vc), lung volume (SA), exercise, supine (Vc, more uniform distribution of blood throughout lung)

Factors decreasing DLCO: age, anemia (less Hb to bind CO), diffusion impairment, resection (SA)

Question 116

What happens to PCO2 and PO2 in muscular disease?

Answer 116

In muscular disease, get hypoventilation which causes higher PCO2 and lower PO2

See these levels in both acute and chronic muscular disease

Question 117

What happens in patient with chronic ventilatory failure?

Answer 117

Chronic hypoxemia causes reflex pulmonary vasoconstriction and with chronicity get remodeling of pulmonary vasculature so resistance increases and get secondary pulmonary hypertension as a result of hypoxemia

Pulmonary HTN causes right heart failure (cor pulmonale) which causes hypoxemia, cyanosis, peripheral edema, large pulsatile liver, JVD

In chronic hypercapnia, get respiratory acidosis but renal compensation by retaining bicarb

PO2 is low so can provide some supplemental O2 (if PO2 <50) but don’t want to give too much because that will cause decreased ventilatory drive and worsen hypercapnia via DeJours effect

Question 118

Estimations of how pH changes with PCO2 and bicarb

Answer 118

Increase of PCO2 1 mmHg will decrease pH 0.01 units

Retention of 0.5 mEq/L of bicarb will restore pH 0.01 units toward normal

Question 119

What happens to central chemoreceptors in chronic hypercapnic ventilatory failure?

Answer 119

1) High PCO2 in blood diffuses into CSF so you get high PCO2 in CSF
2) In the CSF, CO2 combines with water, forms carbonic acid then dissociates to form H+
3) Kidney has retained bicarb to compensate for hypercapnia in peripheral blood and that bicarb is actively transported into CSF to balance the increased CO2 (increased CSF buffering capacity)
4) This bicarb in the CSF restores pH of CSF toward normal so there is less H+ in CSF to stimulate central chemoreceptors and drive from central chemoreceptors is now diminished

Overall have less active central chemoreceptors in presence of high PCO2 in peripheral blood –> must be more reliant on peripheral chemoreceptor

Question 120

What happens when person with chronic hypercapnia breathes 100% O2?

Answer 120

Peripheral chemoreceptors sense high O2 and low CO2 and decrease ventilation and get increased end tidal CO2

High PO2 makes carotid body disinterested in ventilatory control

If you give oxygen you correct hypoxemia a little but PCO2 rises even higher and pH becomes more acidotic because hypoventilating! Want to maintain adequate O2, don’t need it to be too high because you can manage with slightly high CO2

Question 121

Complications of chronic neuromuscular respiratory failure

Answer 121

Progressive loss of ventilatory muscle strength: worsening dyspnea then impaired cough then worsening hypercapnia

Increasing difficulty swallowing: aspiration pneumonia

Question 122

Clinical management of chronic neuromuscular respiratory failure

Answer 122

Clinical considerations: chronic ventilatory support (noninvasive positive pressure ventilation (NIPPV) has higher pressure on inspiration and lower on expiration to make breathing easier), tracheostomy for PPV (removes half of dead space so get more alveolar ventilation), percutaneous gastrostomy (PEG) for nutrition

Ethical considerations: advance directive, durable power of attorney

Question 123

FiO2 with different modes of oxygenation

Answer 123

Nasal cannula: 24-35% (each L/min raises FiO2 3-4% from 21%)

Face mask: 35-60%

Non-rebreather face mask: 70-95%

Intubation: 100%

Question 124

Normal A-a gradient

Answer 124

10-15 mmHg

PAO2 - PaO2 (measured)

Calculate PAO2: 150 - (PaCO2/0.8)