Quiz Yourself - Respiratory

• The FEV1 is reduced when:– airway obstruction is present as with these diseases:

• Asthma• Emphysema

• FEV1/FVC ratio is reduced when – airway obstruction is present. The normal ratio is:

• 70-75

• The FVC is reduced with – restrictive lung disease

• Pulmonary fibrosis

Lung Volumes in Disease States

What does each of these represent?

What is the alveolar gas equation?

• PAO2 = FIO2 x (PB – PH2O) – PaCO2/RQ

What is the standard version (room air/temp)?

• PAO2 = 150 – PaCO2/RQ RQ = 0.8 – 1.0

What are the 2 ways to alter V/Q ratio?

Dead space• Regions of the lung that are ventilated but not perfused

– Anatomic?• Normal. Like the trachea. About 30% of tidal volume.

– Physiologic?• Includes anatomic, but in theory, when there are unperfused

regions, as with a pulmonary embolism

Shunt • Regions of the lung that are perfused but not ventilated!

– V/Q mismatch = incomplete shunt. Responsive to O2 therapy

– Shunt is refractory to O2 therapy

Key pt: regions with a high V/Q ratio cannot compensate for regions with a low V/Q ratio b/c the high V/Q is normal!

What are the causes of hypoxemia and how do we distinguish them?

• We distinguish between them using blood gas and A-a gradient

• Hypoventilation – indicated by hypoxemia with a high pCO2, normal A-a. – Increasing frequency of breathing while lowering tidal volume

increased the proportion of dead space ventilation to alveolar ventilation

• V/Q mismatch• Shunt

– indicated by hypoxemia with a HUGE A-a difference– Common causes include intracardiac lesions, structural

abnormalities of the pulmonary vasculature, filling of alveolar spaces w/ fluid or complete alveolar collapse

• Low inspired O2 (Low altitude)

What is the diffusing capacity?

– Measured by DLCO

– Impacted by diffusion barrier and aggregate surface area of alveoli

– Measured with CO (but possible errors if the hemoglobin levels are low)

– What does emphysema do?• reduces the area reduced DLCO

– What does fibrosis do?• increases the thickness reduced DLCO

What are the volume patterns for the following diseases?

• Obstructive diseases?– larger TLCs

• Chronic bronchitis?– increased RV, increased FRC

• Emphysema?– increased RV, VERY increased TLC

• Restrictive diseases?– smaller TLCs

• Fibrosis?– all lung volumes decreased

• Obesity?– FRC reduced

• Inspiratory muscle weakness?– TLC reduced

• Expiratory muscle weakness?– RV is elevated

Mechanisms of Hypoxemia

– Hypoventilation– V/Q Mismatch– Shunt

– Low Inspired pO2

• How do we measure lung volumes?• Helium dilution

– Used to measure absolute FRC– Doesn’t work if there’s lots of obstructed airways where a

• Plethysmography – The small sealed box – Makes measurements using Boyle’s law

What patterns of impairment are associated with:

• Obstructive lung disease?– Diminished rates of expiratory flow (increased FEV1,

decreased FEV1/FVC)

• Restrictive lung disease?– Diminished lung volumes– Preserved expiratory flow

• What gives a characteristic scooped appearance in the expiratory phase of flow-volume loops?– Airway obstruction like emphysema

• When is obstruction increased during inspiration?– When it’s an extra-thoracic variable obstruction

• When is obstruction increased during expiration?– When it’s an intra-thoracic variable obstruction

What’s this?Normal Alveoli!

Bronchiectasis

Muco-Purulent Debris in Dilated Bronchi

Dilated bronchi

Bronchiectasis• What is it?

– A chronic dilation of bronchi or bronchioles secondary to inflammation or obstruction

• Pre-disposing syndromes?– Cystic fibrosis (CF)– Primary ciliary dyskinesia syndrome (Kartagener’s s.)

• Radiology?– Airway dilation which extends to the periphery

• Pathology?– Permanent dilation of bronchi– peri-bronchial inflammation and organization (fibrosis)– Can sometimes see mucopurulent debris in

bronchioles

Asthma

Charcot-Leyden crystals – eosinophil granule contents

Curschmann Spirals – mucus casts

Eosinophil

This is ASTHMA!!!!

What disease is this?

Asthma

• Clinical:– Airway hyperresponsiveness– Triggers: antigens, exercise, drugs, infections, stress– Acute, usually reversible diffuse bronchial narrowing– Sxs: Wheezing, dyspnea

• Radiology:– Alternating atelectasis and overexpansion

• Pathology:– Edema– smooth muscle thickening– BM thickening– mucous cell hyperplasia– increased submucosal eosinophils– thickened intralumenal mucus – Curschmann spirals – mucus casts– Charcot-Leyden crystals – eosinophil granule contents

Chronic Bronchitis

• A Clinical Diagnosis!– Definitional: Productive cough >

3months/year x > 2 years

• Radiology is non-specific• Pathology:

– Mucous cellular and glandular hyperplasia

– May have submucosal chronic inflammation – May have respiratory bronchiolitis

• Might look like this:

Increased numbers of mucinous glands in submucosa

Centrilobular Emphysema in COPD

Emphysema• Clinical:

– Associated with cigarette smoking (component of COPD) 1-antitrypsin deficiency, esp PIZZ mutation

• Radiology: – Increased lucency (dark region)

• Upper>lower lobe suggests centrilobular type• Lower>upper lobe suggests panlobular type

– Possible increased AP diameter– Possible flattened diaphragm

• Pathology:– Dilation of distal airspaces with septal

destruction– Locations:

• Centrilobular: Cigarette smoke • Panlobular: A1AT deficiency or cigarette smoke

– Increased elastase activity

Bronchiolitis Obliterans/Organizing Pneumonia (BOOP)

• Clinical:– Acute onset cough, dyspnea, fever, and malaise– Multiple associations, e.g. collagen-vascular

dz– Most patients respond to corticosteroids

• Radiology:– Multiple patchy airspace infiltrates

• Pathology:– Patchy fibromyxoid plugs in distal bronchioles – the

BO– Fibromyxoid plugs in alveoli, +/- endogenous lipid

pneumonia – the OP– Think bronchiolar and alveolar airspace fibroblasts

Classification of AsthmaIntrinsic Asthma-

– No allergic or (personal family) history

– Usually adult onset– Often follows severe

respiratory illness– Symptoms usually

perennial– More refractory to

treatment, become other diseases, progress to vasculitis

– Eosinophils still impt

Extrinsic Asthma-

– Strong family history of allergies

– Usually onset at a young age

– Other allergic manifestations in patients

– History of specific allergic association triggers (e.g. pollen, animal dander)

– Correlation with skin and inhalation responses to specific antigens

– Type I hypersensitivity rxn– IgE mast cell and

eosinophils

ALLERGIC SHINER: Edema/ Discoloration Around the EyeWhat does this demonstrate? What is it?

• What are the important cells in asthma?– Eosinophils (in sputum)– B lymphocytes in mediating the asthma – more impt

• What’s the point of the methacholine challenge?– It demonstrates that there’s something different in the

architecture of the asthmatic’s airways that makes them non-specifically hyperreactive

• What is a key feature of the pathophysiology of asthma that contributes to death?– Mucous plugs occluding airways

• What are Creola bodies?– Agglomerated bronchial epithelial cells, seen in asthma

• What happens when you administer a beta-agonist?– You initially decrease the O2 saturation via V/Q mismatch.

• What is AM dipping?– When peak flow is decreased in the morning; associated w/

more severe asthma• What is the late phase reaction?

– Delayed reduction in FEV1 due to IgE and influx of inflammatory cells

• What is the cornerstone of asthma therapy?– Corticosteroids (effective in reducing late phase reaction)

Findings/Diagnosing Asthma?1. Spirometry

Increase lung volumes (TLC, FRC, RV)Decreased peak flow, FVC, FEV1, FEV1/FVC

2. Auto peak end expiratory pressure (auto-PEEP)-with rate respiratory rate.

3. DLCOIncreased - useful in establishing dx

4. Methacholine challengeHyper-responsive

5. b-agonistReversible airflow obstruction when treated; albuterol

6. Eosinophils Increased in blood and found in sputum

7. ABGLow PO2, low PCO2

Treatment of Asthma

• Avoid asthmatic triggers• Use bronchodilators

– Sympathomimetics – usually B2-AR specific to increase cAMP.

• albuterol• Salmeterol is a long acting B2

– Methylxanthines – inhibits PDE increased cAMP– Anticholinergics – reserved for COPD

• Use anti-inflammatory drugs– Corticosteroids – the cornerstone of therapy– Cromolyn and nedocromil – inhaled prophylactics– Zileuton, Zafirlukast – decreases leukotrienes– Omalizumab – anti IgE antibody

General Strategy for Management of Asthma

• Infrequent attacks?– Inhaled sympathomimetics (B2)

• More frequent?– Add an anti-inflammatory as maintenance, usually a

corticosteroid

• Still not good enough?– Regular use of inhaled B2 agonists– Add methylxanthines (theophylline)

• Significant attack?– Systemic steroids

• Status asthmaticus?– IV corticosteroids– Aggressive bronchodilators

Classification of asthma?

• Mild intermittent• Mild persistent – more than 2X/week, but <1QD• Moderate persistent – daily symptoms• Severe persistent – continual symptoms

• Common precipitating stimuli of asthma?– Allergen exposure – involves histamines, leukotrienes

» Leukotrienes = why NSAIDS can precipitate asthma!

– Inhaled irritants– Respiratory tract infections– Exercise (cool air)

• When is airflow most compromised in asthmatics?– Expiration

• Why is FRC chronically increased in asthma?– Dynamic hyperinflation – can’t fully exhale all air– Persistent activity of inspiratory muscles

• What are the common symptoms of asthma?– Cough– Dyspnea– Wheezing – airflow through narrowed airways– Chest tightness

• What is the mechanism of low PO2, low PCO2 in asthmatics?– V/Q mismatch

• What are the 2 disorders under COPD? Basic defs?– Chronic bronchitis – diagnosis based on chronic cough

and sputum production– Emphysema – diagnosis based on destruction of lung

parenchyma and enlargement of air spaces distal to the terminal bronchiole

• What’s the pathogenesis of alveolar destruction?– Protease and protease inhibitors are in balance in lung– Smoking inhibits protease inhibitors– Neutrophils and macrophages in inflammation release

damaging proteases

• What are the risk factors for COPD?• Cigarette Smoking (also 2nd hand)• Hyperresponsive Airways• Occupational Factors (firemen)• Alpha1-antitrypsin Deficiency – PIZZ is BAD!

» Normally keeps elastase in check to maintain lung elastin

Mechanisms of Airflow limitation in COPD?

• loss of alveolar attachments• obstruction of the airway due to inflammation• airway-wall fibrosis• airway smooth muscle constriction• luminal obstruction with mucus.

• Loss of elastic recoil in emphysema results in:– Decreased expiratory flow rates

• Lower driving pressure for expiratory airflow• Loss of radial traction from supporting alveolar walls

• Functional abnormalities in COPD?– Decreased FVC, FEV1, FEV1/FVC– Increased RV, FRC, TLC– Decreased DLCO in emphysema– Increased Reid index in chronic bronchitis– Hypoxia– Hypercapnia in chronic bronchitis

• Major secondary problem with COPD? Causes?– Pulmonary HTN cor pulmonale (more common in

chronic bronchitis patients)• Major Cause: Hypoxia vasoconstriction• Hypercapnia• Polycythemia• Destruction of the pulmonary vascular bed

• What is the protease-antiprotease hypothesis?– Alveolar integrity is maintained via a balancing act– Smoke increases the # of PMNs in the lung– PMNs produce elastase degrades elastin– Smoke oxidants, oxidants from inflammatory cells

impair A1AT anti-elastase activity– Neutrophil elastase stimulate mucus release– PMNs and macrophages make matrix

metalloproteinases shift balance towards degradation

Clinical Distinctions Between Blue Bloater and Pink Puffer COPD

PathophysiologyFeature Pink Puffer Blue Bloater

Pathophys. Type A Type B

Disease Association

Emphysema Chronic Bronchitis

Major Sxs Dyspnea Cough & sputum

Appearance Thin, wasted Cyantoic, obese

PO2 Decreased Decreased

PCO2 Normal or decreased

Normal or increased

Elastic recoil Decreased Normal

DLCO Decreased Normal

Hematocrit Normal Increased

Cor pulmonale Infrequent Common

Treatment of COPD

• Bronchodilators• Antibiotics• Corticosteroids

• Supplemental O2

• Exercise rehab• Chest PT, postural drainage• Surgery (last resort)

– Lung transplant– Lung volume reduction

• Vaccines: pneumovax, flu• Plasma A1AT if the patient is A1AT deficient• Mechanical ventialtion

Major Points from SmokingCessation Lecture

• Tobacco dependence is chronic and requires repeated intervention

– If at first you don’t succeed, try, try again!

• ALL pts who smoke should be offered at least ONE tobacco dependence treatment.

– Pharmacotherapy CAN be helpful– Nicotine withdrawal can be fairly severe

• Clinicians, hospitals, etc must institute consistent ID, documentation, and tx of tobacco users

• Brief tobacco dependence tx is VERY effective – all pts should be offered at least brief tx

• Strong dose-response relation between tobacco dependence tx and it’s effectiveness

Major Points from SmokingCessation Lecture

• The 3 types of counseling/behavioral therapy found to be very effective and should be used:– Social Support within treatment– Social Support outside treatment– Skills training/problem solving

• Unless contraindicated, use of effective pharmacotherapies for smoking cessation in all pts trying to quit should be used

• Tobacco dependence treatments are both clinically effective and cost-effective relative to other medical and disease prevention interventions

• Setting a quit date is IMPT!• Set up follow-up dates after quit date to see your pt.• People tend to gain weight upon quitting…

5 first line pharmacotherapies for smoking abstinence that WORK

– Bupropion SR– Nicotine gum– Nicotine inhaler – Nicotine nasal spray– Nicotine patch

2 second line pharamcotherapies for smoking:- clonidine- nortiptyline

• What is the most successful self-help format to quit smoking?– Hotline “quitlines”

• Person-to-Person contact – how much helps?– Even <3min is (moderately) better than none!– 10min or more is best

• Asking your pt to quit smoking helps/doesn’t help?– It DOES!

• What are 3 things associated with unsuccessful attempts at quitting?– Not practicing total abstinence– Drinking alcohol– Other smokers in da’ house

What disease?

Peribronchovascular spaceIs dilated

Giant cell

Sarcoidosis

Sarcoidosis• Clinical:

o Multi-system granulomatous diseaseo Adults, B>W, F>Mo Dyspnea

• Radiology:o Interstitial infiltrates in bronchovascular distribution (= lympagenic

distribution)o Usually have hilar adenopathy (picked up on routine CXR)

• Pathology:o Tight, well-formed non-caseating granulomatao Def of granulomata: Focal accumulations of epithelioid histiocytes

Peri-BronchiolarExpansion

Interstitial expansion

Loose Granulomas

Hypersensitivity Hypersensitivity PneumoniaPneumonia

Hypersensitivity Pneumonitis(Extrinsic Allergic Alveolitis)

• Clinical:o Organic dusts

Doesn’t mean carbon based Means related to organic products

o Occupational or environmental exposureo Acute and chronic: dyspnea, cough, fatigue

• Radiology:o Bilateral interstitial linear or nodular pattern

• Pathology:o Patchy peri-bronchiolar and interstitial chronic inflammation with

loosely formed granulomata

Coal-worker’s Pneumoconiosis

Coal dust macules

Patchy Sub-Pleural Fibrosis

Asbestosis

Ferruginous Body

Late Silicosis

Fibrotic Nodules

UIP

UIP: Sub-pleural fibrosis adjacent to normal lung

Usual Interstitial Pneumonia (UIP)

• Clinical:o Syn. with “Idiopathic pulmonary fibrosis (IPF)”o Adults, mean 51 yo; poor response to steroids, 66% mortality

• Radiology:o Patchy subpleural infiltrates, DDx asbestos, rheum

• Pathology:o Patchy interstitial inflammation; fibrosis alternating with

normal parenchymao Temporally heterogeneous = ongoing injury to lungo Morph overlap with rheum dzs, e.g. scleroderma

Proliferative phase DAD

Alveolus

Fibroblasts in the interstitium

Proliferative (Organizing) Phase Diffuse Alveolar

Damage (DAD)• Clinical:

o > 1-2 wks after identifiable acute lung injury (ex: MVA, septic shock, kidney stone, inhalation of noxious chemical)

o Decreased pulm compliance -> mechanical ventilationo 50% mortality

• Radiology:o Diffuse, interstitial>alveolar pattern

• Pathology:o Interstitial + intra-alveolar fibroblastic proliferationo Temporally uniform

If it’s temporally heterogeneous = UIPo You HAVE to see interstitial fibroblastic proliferation

If it’s purely intra-alveolar = BOOP

What characterizes Pulmonary function in Restrictive Lung Disease?

o Characterized by reduced FVC, normal or high FEV1/FVC ratio

ILD ObesityMuscle

WeaknessNormal

TLC

FRC

RV

TLC

FRC

RV

TLC TLC

FRC

FRC

RV

RV

Identify which is interstitial lung disease, obesity, and inspiratory & expiratory muscle weakness.

• What’s the differential diagnosis for bilateral diffuse infiltrates that mimic diffuse parenchymal disease?

o Congestive heart failureo Pulmonary infectiono Lymphangitic carcinomatosis

• What are known causes of diffuse parenchymal lung disease?o Inhaled organic dusts (asbestosis, silicosis, coal workers, berylliosiso Inhaled organic antigens hypersensitivity pneumonitiso Iatrogenic (drugs – amniodirone, radiation)

• What are unknown etiological diffuse parenchymal lung diseases?o IPF/UIPo Sarcoidosiso BOOPo Goodpasture’so Wegener’so And many more… (Connective tissue disease associated, Chronic eosinophilic

pneumonia, Lymphangioleiomyomatosis, Pulmonary Langerhan’s cell histiocytosis, Alveolar proteinosis, Pulmonary vasculitides)

Pathophysiology of Parenchymal Lung Diseases

• Decreased lung compliance (increased stiffness)o Reduced FVC, reduced FEV1, normal ratioo Reduced lung volumes TLC, FRC, RV

• Diffusion impairmento Destruction of alveolar-capillary interface by inflammation and

fibrosis, reducing the surface area for gas exchange (there is a reduced DLCO on testing)

• Pulmonary Hypertensiono Hypoxemiao Obliteration of small pulmonary vessels by fibrosis

Clinical Features ofParenchymal Lung Diseases

• Symptomso Dyspneao Cough (non-productive)

• Signso Dry crackles or rales (sound like velcro)o Clubbingo Cor pulmonale

JVD Loud P2, TR murmer edema

• What’s the major benefits of high resolution CT in diffuse parenchymal lung diseases?

o Detects sub-radiographic diseaseo Distinguishes inflammation from fibrosis

Ground glass appearance suggests inflammation

• What is thought to be the pathogenesis of sarcoidosis?o A chronic systemic granulomatous idiopathic disease where there’s

an immune response to an exogenous agent in a genetically predisposed individual

• What key cells are thought to be involved in sarcoidosis?o Macrophages

Results in increased release of TNFo T cells (specifically CD4)

BAL will reveal CD4>CD8 There may be lymphopenia on peripheral blood smears MHC II is more impt than MHC I Results in increased IL-2, INF-gamma, and other cytokines

• What are the presentations/associated diseases of sarcoidosis?

o Lofgrens Acute onset Bilateral hilar lymphadenopathy Eythema nodosum Fever Arthralgias Associated with a good prognosis

o Eye manifestations Acute or chronic uvetitis

Sjorgens – destruction of exocrine glands, specifically partoid and lacrimal Heerfordts – uvetis + uveoparotid fever, facial palsies, parotid swelling

Keratoconjunctivitis sicca – decreased tear production conjuctival and corneal inflammation

Papilledemao Lupus pernio

Associated with chronic sarcoidosis Usually on face, sometime butt and extremities

• What are common abnormalities/diagnostic test results in sarcoidosis?

o Hypergammaglobulinemia – T cells non-specifically activate B-cells lots of Igs

o Hypercalcemia, hypercalciuria – increased Ca2+ absorption from GI tract due to increased vitamin D formation

o Lymphopenia – lymphocytes involved in granuloma formationo CD4 > CD8 in BAL – CD4 plays a greater role in granuloma

formationo ACE elevated – due to vascular epithelial cells of granulomaso CXR or HRCT – parenchymal infiltrates, hilar adenopathy,

sublpleural micronodules, upper lobe predominant, honeycombing, ground glass appearance

o Gallium-67 scan – panda signo Diagnosis is one of exclusion and heavily reliant on biopsy

• How do we treat sarcoidosis?o Systemic corticosteroidso anti-TNF may be best tx (infliximab)o hydroxychloroquine

• What is the staging of sarcoidosis?o Stage I – adenopathyo Stage II – parenchymal infiltrates & adenopathyo Stage III – just parenchymal infiltrateso Stave IV – fibrosis, hilar retractionm, cysts, bullae, honeycombing

changes

UIP/IPF

• Pathogenesis?o Inflammatory process of the walls fibrosis due to dyregulated response to

damage of alveolar epithelial cellso Factors that are dysregulated fibrosis?

Cytokines Chemokines Matrix metallic proteases and balance with inhibitors Decreased fibrinolysis Eicosanoid imbalance: increased luekotrienes, decreased prostaglandins

• Commonly presents in?o Older adults, M>F

• Signs and Symptoms?o Exertional dyspnea that increases over timeo Non-productive cougho Possible clubbing

• What are common abnormalities/diagnostic test results in UIP?

o Velcro-like dry crackleso Peripheral edema or cor pulmonale in advanced stageso Hypoxemia, cyanosis, clubbingo CXR

Honeycombing Diffuse reticulations NO hilar enlargement

o HRCT Patchy, peripheral subpleural densities associated with small cystic spaces

• Pathology of UIP?o Honeycombingo Fibrosiso Temporal heterogeneity

What Occupational Exposure Materials can cause inflammatory reactions in

the Airways?o Secretory Inflammation

Formaldehyde – upper airways Ammonia – upper airways Particulates (coal, dust, cotton) – bronchitis Nitrogen dioxide – bronchiolitis

o Hyperreactive Airways Ozone, cotton dust – non-specific reactivity TDI – occupational asthma

What Occupational Exposure Materials can cause Parenchymal responses

Acutely? Chronically?o Acutely Pulmonary Edema due to toxic reactions

Chlorine, phosgene Acute silicosis

Hypersensitivty Pneumonia Organic materials – farmer’s lung (mold spores in hay) Inorganic materials

o Chronically Nodular fibrosis

Coal – macules Silica – collagenous lamellated nodules Beryllium – Granulomata

Diffuse Fibrosis Asbestosis

Cancer Asbestos Chloromethyl Ether, Coke oven emissions

• What are the causes/common types of pneumonoconiosis?o Nodular or diffuse fibrosis…

Silicosis Asbestosis Berylliosis Coal Worker’s

• Important things to do to make a diagnosis in occupational exposure related respiratory diseases?

o Take a detailed historyo CXR to document pneumonoconoiosiso Blood studies to document specific exposureso Lung tissue analysiso Measure peak flow throughout weeko Specific inhalational challengeso Investigation of workplace by industrial hygienist

Respiratory Diseases due to AsbestosI. Non-Malignant

A. Pleural Disease

1. Pleural Effusion

2. Diffuse Pleural Thickening

3. Localized Pleural Thickening (Plaques)

B. Diffuse Pulmonary Fibrosis (asbestosis)

II. Malignant

A. Malignant Mesothelioma- bad stuff

- cigarette smoking is NOT related

- latency is 30-40 years

B. Bronchogenic Carcinoma

C. Possibly Laryngeal Carcinoma

Asbestosis – a restrictive Lung Dz

• Latency period?o 20-30days

• Pathologic features?o Ferruginous bodies!o Peri-bronchiolar inflammation and fibrosiso May eventually honeycombo Tendency towards the lower lobes of the lungs

• Clinical Symptoms and CXR?o Dyspnea on exertiono Dry cougho Late inspiratory crackles in baseso Opacification in baseso Pleural thickening

Occupational Asthma• Definition?

o Clinically significant variable airflow obstruction due to specific workplace agent in lower [ ]s than should cause non-specific irritant response in normals or asthmatics who are not sensitized

• Risk factors? Potency of sensitizing material Level of exposure Accidental high exposures Individual patient – atopy and smoking

• Types of presentations:o Typical immediate onset – w/in 30 minutes; clears hrs after leaving work. AM

cough & sputum. Responds to bronchodilatorso Typical late onset – may not have wheezing; 4-8hrs afterwards with longer

duration. Refractory to bronchodilatorso Dual Responseo Recurrent Attacks Post Exposure – at night after exposure

• Standard Treatment:o Inhaled steroids and bronchodilators

Reactive Airways Dysfunction Syndrome (RADS)

• Characteristics:o No preceding respiratory symptoms. o Onset of symptoms after single high level exposure to an irritant. o Onset of symptoms is abrupt (without 24 hours) and symptoms

persist for at least 3 months. o Symptoms of variable airway obstruction and/or

hyperresponsiveness. o Non-specific airway hyperresponsiveness present (methacholine

challenge). o Persistent airway inflammation but lack of eosinophils

Pleural Diseases

• What is pleuritic pain?o Caused by inflammatory processes that intensify upon breathing

• What’s going on with a tension pneumothorax? o Air escapes into pleural space positive pressureo Air can’t escape on exhalation

• How can a tension pneumothorax cause shock?o By compromise of venous return

• How can ANY pneumothorax be caused?o Trauma sucking wound o Iatrogenic - Overzealous use of positive pressure ventilation,

central lines, lung biopsieso Abnormal lungs air trapping (think asthma)o Spontaneous in very tall people

• What kind of pneumothorax?o 21 y o center for BB teamo Has sudden onset of R sided chest pain & mild dyspnea o Patient is uncomfortable but vital signs are WNLo Not Sean May hopefully!

Pneumothorax disease b/c it’s a popped lung, the pneumothorax is limited and should spontaneously resolve

o 20 y o severe asthmatico Intubated & on mechanical ventilation o Suddenly becomes hypotensive & cyanotic

This is a tension pneumothorax – must decompress the patient emergently!

• What will the CXR look like on a pneumothorax?o On side of pneumothorax

Absent vascular markings Appearance of a little nub near hilum (atelectic lung) Diaphragm depressed downwards

o On side opposite of pneumothorax Mediastinum, trachea, other structures shifted over

o It’s a dark and stormy night… And a patient is brought into your ER with:

Pleuritic chest pain Dyspnea Dullness of lungs to percussion Egophony at upper level Pleural friction rub

o After you’re told he’s NOT possessed and isn’t just freaked out after watching that scary movie, you get a CXR.

o That CXR shows: Blunting of the right costaphrenic angle Elevation or flattening of right hemi diaphragm And the mediastinum shifted to the left side

o Then the scary, menacing attending asks you what does he Then the scary, menacing attending asks you what does he have. You, being the superstar that you are, reply:have. You, being the superstar that you are, reply:

“Why A Pleural Effusion, DUHDUH!”• How is normal pleural fluid made?

o Generated by Starling forces across a capillary bed

• Radiographic signs of pleural effusion include:o Blunting of costophrenic angle on upright filmo Elevation or flattening of hemi diaphragm on upright filmo Diffuse haziness of hemi thorax on supine filmo If large, will cause shift of mediastinum to contra-lateral side

• How do you relieve a massive pleural effusion?o Thoracentesis

Helpful diagnostically Helps relieve symptoms Remove 1500cc or less!

Otherwise, you might suddenly inflate the lung. Too little surfactant pulmonary edema

How do you relieve a massive pleural effusion?

• Thoracentesiso Helpful diagnosticallyo Helps relieve symptomso Remove 1500cc or less!

Otherwise, you might suddenly inflate the lung. Too little surfactant pulmonary edema

• How do you safely do a thoracentesis?o Make sure the fluid is freely flowing and not loculated

Use a lateral decubitus film

o Use ultrasound to locate effusiono Be sure to draw close to the upper part of the rib directly below the

needle you’re using, or you might hit an intercostal artery, vein, nerve

What are Lyte’s Criteria? Why do we use them in the first place?

• Helps us distinguish between an exudate and a transudate pleural effusion

o Ratio of pleural-fluid protein to serum protein > 0.5o Ratio of pleural-fluid LDH > 0.6o Pleural fluid LDH level > 2/3 upper limits of normal for serumo Any one of these characteristics means the fluid is an exudateAny one of these characteristics means the fluid is an exudate

• What other studies might you do on fluid from a pleural effusion

o cell count & differential, glucose, cytology, Gram stain, AFB stain & culture, amylase, cholesterol, triglyceride level, pH, adenosine deaminase

• What if the effusion is borderline according to Lyte? Look at albumin gradient - If difference btw albumin in serum minus pleural

fluid is > 1.2 than more likely a true transudate

What are the potential causes of a Transudate?

o CHF – due to increased pulmonary venous pressures, usually bilateral, usually resolves in 48 hours after diuresis

o Nephrosis – low oncotic pressureso Cirrhosiso Atelectasis – increased negative pleural pressureo Ascites – can preferentially form in pleural space, hepatic-

hydrothorax

• What are the potential causes of a massive exudate? Malignancy Trauma - hemothorax Empyema – bacterial infections Chylothorax – disruption of thoracic duct Rarely, TB

o Causes of bloody exudates? Cancer Pulmonary infarction Penetrating & nonpenetrating trauma Central line malplacement Chondrosarcoma S/P CABG

o Causes of turbid exudates? Chylothorax Empyema

• How do you define a hemothorax?o Defined as pleural fluid hematocrit of 50% of blood hematocrito Will coagulate & may lead to loculation with complications of

fibrothorax & possible empyemao If small, may defibrinate & remain free flowing

So the good doctor said there’s a good exam question in here…

o What kind of cell count in an exudate would make you suspect cancer or Tb?

>50% lymphocytes!o Now what additional information on this exudate

could help you decide that it’s probably NOT Tb? >5% mesothelial cells

Remember, mesothelial cells are normally found in pleural fluid to some degree since they are the cells that comprise the pleura!

Empyemas• Why should you distinguish between an empyema and a

parapneumonic effusion?o b/c empyemas need to be drained STAT!

• What the hell IS a parapneumonic effusion? Effusion secondary to a pneumonia Resolves with antibiotics. Course is usually very benign

• Great, so what about an empyema and why do I care? Implies active bacterial infection in the pleural space. Failure to recognize & drain can lead to unresolved sepsis & fibro thorax

• So how do I tell the difference between the two?o Well if it’s an empyema, there should be:

Gross pus pH < 7.1 glucose < 40 positive Gram stain or cultures

o And if it’s all borderline you need to retap that…um…lung…

Ack! It’s an Empyema! What Do I do?

o Well a tube thoracostomy for oneo Antibiotics to get those microbeso Thrombolytics if loculated or stops draining despite fluid present

on X-ray Helps combat if the thing is trying to wall itself off Don’t let it hide – go and get it!

o Decortication if unable to achieve drainage & lung is trapped in fibrinous peel

Yeah – RIP off that clot and scar tissue that I wish you saw…

o So what if I don’t and say I did? Untreated you might get empyema necessitans (where it attempts to drain

through the chest wall b/c you were too lazy to drain it) Or you might get a bronchopleural fistula causing overwhelming sepsis

Solitary PulmonaryNodule

Cartilage in excess and disarray

STOP!STOP!Hamartoma!

Hamartomao It’s BENIGN!!!!o Clin:

Adolescence adulthood None in newborns - not congenital

o Rad: Solitary nodule +/- popcorn calcification Peripheral > central

o Path: Gross: solitary, lobulated, cartilagenous Micro: normal tissues in excess/disarray

If it’s calcified, it’s comforting b/c it tends to be non-malignant!

What are the Malignant epithelial neoplasms (Carcinomas)?

o Squamous cell carcinomao Adenocarcinomao Large cell undifferentiated carcinomao Small cell undifferentiated carcinoma

One of these things is not like the others.One of these things is not like the others.

One of these things just doesn’t belong…One of these things just doesn’t belong…

Small cell is treated differently and has a much Small cell is treated differently and has a much more severe progression!more severe progression!

Normal

Keratin

Desmosomes

Squamous Cell CarcinomaSquamous Cell Carcinoma

Squamous cell carcinoma• Clin:

o Smokers association? YES

o Prevalence? 20-30% of common carcinomas

o May secrete PTH-like compound

• Radiology:o central > > peripheral

• Path: o Bronchi > Larynx > Trachea

KEY CHARACTERISTICS?o +/- Desmosomes (intercellular bridges)+/- Desmosomes (intercellular bridges)

+/- Keratin production, e.g. keratin pearls +/- Keratin production, e.g. keratin pearls

Primary

Pleural effusion

Gland formation

Mucin production (red on PASd stain)

AdenocarcinomaAdenocarcinoma

Adenocarcinoma• Clin:

o 30-40% of common carcinomas o Smoking association?

Most common carcinoma in non-smokers, but 80% of adenoCAs occur in smokers

• Rad: o peripheral > central

• Path: o +/- glands +/- glands o +/- mucin+/- mucino Bronchiolo-alveolar carcinoma subset

Bronchiolo-alveolar carcinoma- Note the mucin in the alveoli. Gas exchange is gonna suck in this patient!

Bronchioloalveolar carcinoma (BAC)

• Subset of?o Adenocarcinoma

• Incidence?o Rising incidence (presently 20-25%)o Associated w/ smoking?

Not associated with cigarette smoking

• Rad: o Peripheral, can be multifocal and bilateral

• Path: o Lepidic (butterfly-like) growth patterno Mucinous or non-mucinouso Unifocal or multifocal

Large cell undifferentiated carcinoma

Large cell undifferentiated carcinoma

o Clin: 10% of common carcinomas

o Rad: non-specific

o Path: H&E: Undifferentiated cDNA microarrays: distinct disease

Basically, it’s a carcinoma with no distinguishing features

At diagnosis Response to therapy

Viable carcinoma

Necrotic carcinoma

Normal lymphocytes

Small Cell Carcinoma

Small cell carcinoma• Clin:

o Smokers? YES

o 20 % of common carcinomaso Paraneoplastic Syndromes:

Ectopic ACTH, ADH, Eaton-Lambert, carcinoid s.

o Commonly high stage at presentationo Responsive to chemo/RT, but low 5 yr survival

• Rad: o Central in >90%o Frequent metastases to LNs and distant sites

• Path: o Malignant cytology; high N:C ratioo No nucleoli; punctate salt and pepper nucleolio High mitotic activity and tumor cell necrosis

o Think small round blue cells!

VisibleC-PAngle

Loss of C-P Angle= Pleural effusion or mass

Thickened pleura Normal thickness pleura

Thin delicate microvilliThin delicate microvilli

Associated w/ ferruginous bodies

MesotheliomaMesothelioma

Most Common Metastatic carcinomas in the Lung?

Breast adenoCA GI adenoCA Renal adenoCA Head/neck squamous cell CA

Lung Cancer - Basics• What are the 2 most impt risk factors for lung cancer?

o Geneticso Smoking (15% smokers will get lung cancer; 85% CA in smokers)

• What types of molecules are the predominant carcinogens in cigarettes?

o Polycyclic hydrocarbons• What sex is more susceptible to lung CA? Theories why?

o WOMENo Differences in metabolism, CYP450o Hormonal effects in lungs

• What are some mutations that have been implicated?o 3p – NSCLCo Ras – adenocarcinomao Myc – small cello NSCLC – p53o Rb – small cello Random breaks in 1, 3, 5, 7, 15, 17

More Lung Cancer Basics

• Most common sites of metastases:o Livero Boneo Braino Adrenals

• What are the paraneoplastic syndromes associated w/ NSCLC?

o Clubbing, Hypertrophic orthropathy (adeno), Hypercalcemia (squamous)

• What are the paraneoplastic syndromes associated w/ SCLC?

o SIADH (hyponatremia), Cushings, Lambert-Eatons, peripheral neuropathy, cerebellar degeneration

Diagnostic Tools for Lung CA• The Basics

o Detailed hx and physical (esp lungs and supraclavicular nodes)o CXRo Chest CTo Lab tests: CBC, liver fxn, alkaline phosphatase, serum Ca2+

• The Good, Special Stuffo For central, endobronchial lesions

Sputum cytology (3+ specimens for 90% yield) Bronchoscopy

Can also do transtracheal needle aspirate of nodes near trachea and bronchi

o For peripheral lesions Transthoracic needle biopsy (CT guided) Thoracentesis (effusions)

Malignant (w/ CA cells in exudate) or paramalignant

Staging Lung CA

• SCLCo What’s Useful? Limited stage disease vs. extensive stage disease

Limited stage - confined to hemithorax; within a radiation port Extensive - Tumor beyond a radiation port, includes malignant pleural

effusion; what most pts present with

o What’s not so useful? TNM system (which is used in NSCLC)

T – location, size N – nodes M – metastases

- Stage I – no nodes involved- Stage II – nodes on the same side/hilum of CA- Stage III – nodes/mediastinum- Stage IV – another organ involved or a second lesion in the lung

EARLY

IIIA, IIIB = locally advancedIIIB, IV = advanced, effusion

• Tricks to help us stage NSCLC?o Intrathoracic

Chest CT FDG PET Scan Mediastinoscopy

o Extrathoracic Bone scan CT/MRI of brain Abdominal CT (liver, adrenals) Biopsies of extrathoracic lesions

• Treating NSCLCo Early – surgical resection + chemoo Locally Advanced – chemo + surgery or radiationo Advanced – chemo

Can help improve sxs, cost effective, increases 1yr survival

• Treating SCLCo Limited – chemo + radioo Extensive – chemo, w/ palliative radio as needed

Adenocarcinoma Most common NSCLC in US Smokers and non-smokers Peripheral (in the lung parenchyma) May arise in area of previous scarring More likely to spread to lymph nodes and outside of the chest Hypotrophic orthopathy or clubbing alone may be present

Bronchioloalveolar carcinoma Subtype of adenocarcinoma More common in women More common in non-smokers than smokers for poorly defined

reasons Cough and bronchorrhea (frothy sputum production) Variable radiographic presentation: solitary nodule, multiple

nodules, infiltrate/consolidation with air-bronchograms

Squamous cell carcinoma Exclusively in smokers Generally arise in proximal airways May cause obstruction of the airway with distal atelectasis, post obstructive

pneumonia May cavitate Hypercalcemia due to PTH like substance (weakness, dehydration, mental

status changes), clubbing

Small Cell Lung Cancer 15-20% of all lung CAs (decreasing) The least common lung CA Exclusively in smokers Generally originate within bronchial wall Bulky central tumor with extensive mediastinal lymph node involvement Rapid grown and early distant metastases Paraneoplastic syndromes especially SIADH (low sodium or hyponatremia

associated with mental status changes)

Got Your Sound On?

Time to Take a Study Break!!!

Is it close to midnight?And that exam is lurking in the morn

Types of inflammatory responses/cells in infections and

likely disease processNeutrophils

Acute pneumonia (usually bacterial) Usually in alveoli

Lymphocytes Usually viral or atypical pneumonia Usually in interstitium

Granulomatous inflammation (epitheloid histiocytes, lymphocytes, giant cells)

Usually mycobacterial or fungal pneumonia

Neutrophils filling alveolar space in acute pneumonia

Interstitial lymphocytes in viral pneumonia

Histiocytes and multinucleated giant cells (granulomatous inflammation) in mycobacterial pneumonia

Giant Celll

Common bacterial pneumonia microbes

• Community acquirednormal flora, common agents

Pneumococcal (streptococcus pneumoniae) Klebsiella Hemophilus, Staph aureus, other strep

• Nosocomial (hospital acquired)Pseudomonas aeruginosa

especially in cystic fibrosis patientsMethicillin resistant staphylococcus aureus (MRSA)

• Types of pneumonia patterns on CXRLobar (entire lobeBronchopneumonia (patchy in more than one lobe

surrounding a bronchus

What is the agent of Pneumococcal pneumonia? How do you get it? Sxs?

Pathology?• Streptococcus pneumoniae is the prototype of bacterial

pneumoniaEncapsulated gram + cocci (diplococcus)Normal resident of the nasopharynxOften preceded by a viral infection sets you up for

bacterial pneumoniaClinical: fever, chills, chest pain, purulent or bloody

sputum, opacified chest X rayPathology

Early: pulmonary edema and proliferation of bacteria, intra-alveolar accumulation of neutrophils and erythrocytes (“red hepatization”)

Later: serum and fibrinous exudates, intra-alveolar organization, macrophages (“gray hepatization”)

What are the sxs of Legionella pneumonia?

• “Legionnaires’ disease”Acute onset of malaise, fever, pneumonia, myalgias,

abdominal pain, diarrhea

• Type of bact? Gram stain? How do you see it?Small gram negative bacillusNeed special stains to visualize

• What does CXR look like?Pathology: bronchopneumonia with multiple lobes

involved, alveoli filled with fibrin and inflammationX ray is frequently more worrisome than clinical

symptoms would suggest

What patients are susceptible to pneumonias caused by anaerobic bacteria?

Anesthetized patientsAlcoholicsSeizure disorder

• What are characteristics of anaerobic pneumonias?Normal inhabitants of oral cavityStreptococci, fusobacteria, bacteroides Often cause necrosisFoul smelling sputumMay develop abscess formation

What are common complications ofbacterial pneumonias?

• Lung abscesses Walled off area of infection with destruction of pulmonary

parenchyma destruction of all normal architecture Clinical: fever, cough, foul smelling sputum, mortality 5-10%

• Pyothorax/empyema Infection of pleural fluid with purulent material within the

pleural space. May become loculated (fibrous walls around the inflammation),

which requires drainage as well as antibiotics to treat. A clinical problem b/c it doesn’t have normal blood flow for

tx with antibiotics AND it doesn’t drain normally w/ a chest tube

• Bacteremia Bacteria within the bloodstream May seed distant sites Endocarditis, meningitis, pericarditis

What does this demonstrate?

Alcoholics on the rightlung b/c that’s where

aspiration goes!

An abscess.

Who’s likely to get it and where?

Center of pulmonary abscess showing acute inflammation with destruction of

Normal pulmonary architecture (no alveolar walls)

Peripheral focus of granulomatousInflammation (Ghon focus)

Granulomatous inflammationIn hilar lymph node

Initial tuberculous infection: Ghon complex(Ghon focus + involved hilar nodes)

necrotizing granulomatous inflammation

Positive AFBBeaded look to the bact

Tuberculosis• Primary tuberculosis

Inhalation of aerosolized droplets settle in periphery of lower lobes Ghon complex: Peripheral focus of infection (granuloma, Ghon

focus, often in a lower lobe) and the infected hilar/ mediastinal lymph node

Pathology: caseous (cheese like) necrotizing granulomatous inflammation

90% of primary infections are asymptomatic; 10% progressive primary Tb (enlarged lesion >6cm, spread to other parts of the lung, children or immunosuppressed patients)

• Secondary tuberculosis Reactivation of primary Tb OR a new infection in previously sensitized

pt Clinical: fever, fatigue, weight loss, sweats, cough, hemoptysis Numerous caseating granulomas most common in the apical

and posterior segments of upper lobes (highest aeration) These may heal and calcify, but some may erode into a bronchus,

leading to tuberculosis cavity Usually 3-10 cm, often in apex of lung Communication with bronchus allows dissemination of organisms

throughout lung

Complications of tuberculosis

• Miliary Tb Multiple small (millet seed size) granulomas in many organs Results from hematogenous dissemination Kidneys, adrenals, bone marrow, spleen, liver lymph nodes are

common sites• Hemoptysis

Erosion of inflammatory response/Tb granuloma into a pulmonary artery

• Bronchopleural fistula Erosion of inflammatory response/granuloma into the pleural

space, resulting in Tb empyema• Unusual complications – you cough up Tb and swallow it, and it’s

happy to colonize somewhere else Tuberculous laryngitis Intestinal tuberculosis

Other mycobacterial diseases• Mycobacterium avium-intracellulare

Found in soil, water, foodCauses disease in immunocompromised patients,

particularly HIV+ (HIV Tb)

• Mycobacterium kansasiiAssociated with Hairy cell leukemia

• Mycobacterium bovis Infection from ingested milk (the bow Tb)

Histoplasmosis• Found in:

in infected dust, bird droppings

• Appearance: dimorphic fungus with tiny yeast forms

• Common location: Endemic in midwest and southeast US, particularly Mississippi and

Ohio valleys

• Clinical and pathologic findings Similar to Tb Yeast phagocytosed by macrophages and PMNs result in focal infections with parenchyma and hilar lymph

nodes granulomas and caseating necrosis Old granulomas frequently calcify Immunosuppressed patients may have disseminated disease involving

lungs, liver, adrenals, intestines

Coccidioidomysis

• Appearance: dimorphic fungi with large thick walled sporangia 30-60

microns filled with endospores 1-5 microns

• Geography/location: Endemic in southwestern US, particularly San Joaquin

valley.

• Clinical and pathologic findings Similar to Tb and histoplasmosis, Immunocompromised patients may have release of

endospores into lung causing with fulminant disease with purulent response

Meningeal and MSK involvement possible

Cryptococcosis• Appearance?

yeast 4-9 microns with mucinous capsule• Found in?

pigeon droppings• Clinical and pathological presentation?

Clinical disease almost exclusively in immunocompromised patients

Lung is the portal of entry CNS is the most common symptomatic site (especially

cryptococcal meningitis) Organism may be demonstrated in CSF, lung

washings/BAL and biopsy with special stains (India Ink, mucin stains). Cryptococcus is one of the few fungi with mucicarmine positive capsule.

Cryptococcus on GMS stain showing narrow based buddingCryptococcus: mucicarmine positive capsule

Blastomycosis• Appearance:

a large dimorphic fungus with broad based budding.

• Geography/location: In US in Mississipi and Ohio River valleys and Great

Lakes regions

• Pathology:Disease usually confined to lungs, causes mixed

granulomatous and suppurative inflammation

Blastomycosis: Large yeast with broad based budding

Aspergillosis• Appearance:

septate hyphae with acute angle branching, found in soil and decaying plant material

• Diseases/Presentation Aspergilloma (Mycetoma, “fungus ball”)

Grows with preexisting cavity, often Tb cavity Tangled mat of hyphae within cavity, X-ray may show

mass and air within cavity Allergic-Bronchopulmonary aspergillosis (ABPA)

Asthmatics develop immunological reaction to Aspergillus, w/ infiltrates on CXR, eosinophilia of blood/sputum, wheezing, cough and sputum production

Treatment with steroids to control immune response It’s not the fungus that hurts you, it’s your body’s

response Invasive aspergillosis – usually fatal

Almost exclusively in immunocompromised hosts Invasion of pulmonary blood vessels with

organismcausing infaction, thrombosis, exsanguination

Aspergilloma (fungus ball) within pre-existing cavityAspergilloma showing non-invasive fungus within granulation tissue linedcavity

Aspergillus: septate hyphae with 45 degree branching

Invasive aspergillus

Aspergillus within blood vessel wall

Mucormycosis (Zygomycosis)• Caused by inhalation of spores of several fungi

(Mucor, Rhizopus, Absidia) ubiquitous in soil, food, decaying vegetable material

• Appearance?grow as non-septate hyphae

• Common patients?patients with underlying illness, particularly

diabetics

• Common presentation? rhinocerebral (nasal sinuses and brain) and

pulmonary. Causes vascular invasion, septic infaction, hemorrhage

Mucomycosis

Pneumocystis carinii

• What is it?A common pulmonary pathogen causing pneumonia

in immunosuppressed patients, especially HIV

• What do you see?Trophozoites and cysts, latter identifiable with GMS

stain, fills alveolar spaces with organisms and proteinaceous fluid, preventing gas exchange

• Bronchoalveolar lavage useful for diagnosis• Causes dyspnea and CXR with infiltrates• Dx by cytology

Pneumocystis on GMS stain: cup shaped organisms within alveolar spaces

Viral pneumonias• Cytomegalovirus – most common viral infxn

Interstitial pneumonia in infants and immunocompromised patients, especially organ transplant patients, now we screen (donor & recipient)

Large cell, big nucleus w/ large, single basophilic intranuclear inclusion

• Measles Multinucleated giant cells with nuclear inclusions

• Varicella (chicken pox and herpes zoster) are usually asymptomatic Interstitial mononuclear cell pneumonia, may

produce focal necrosisNuclear eosinophilic viral inclusions, may be

mutlinucleated• Herpes simplex

necrotizing tracheobronchitis and diffuse alveolar damage• Other viruses (especially in children)

Adenovirus Respiratory syncytial virus

Measles pneumonia: multinucleated giant cells with viral inclusions

Cytomegalovirus pneumonia

Herpes virus on cytology specimen

Viral inclusion

Mycoplasm pneumonia: sparse lymphocytic interstitial inflammation

Mycoplasma

• Small free-living prokaryote, common cause of acute self-limited pneumonia and tracheobronchitis,

• milder than usual bacterial pneumonia (“walking pneumonia”)

• Highly transmissible through airborne droplets• Cause of 15-20% of pneumonias in developed countries• Pathology: patchy consolidation, mononuclear

infiltrate, usually of a lower lobe • Very common but not very bad• You’ll see something on CXR but not lots of sxs

Really common at college/in dorms

What are common host defenses to respiratory infection?

ANATOMIC Upper Airway (nose) Epiglottis/Larynx Epithelial Tight Junctions

MECHANICAL (“INNATE”) Mucociliary and Cough Clearance

IMMUNE “Innate” (lysozyme; lactoferrin; “defensins”) Immune Response

Secretory IgA (nasal/bronchial) Humoral Antibody Cellular

GENERAL Alveolar Macrophages (AM) Inflammatory Response (PMNs, etc.) Anti-Proteases

• What defenses are protecting the proximal airways and nose? Primary Components: cilia, liquid/mucus, submucosal gland

secretions Mucociliary clearance – respond to neurohormonal and

mechanical stimuli Secretions of the submucosal glands – what’s in this?

Lysozymes IgA – neutralizing; secreted as a dimer IgG – opsonizing

• What are the defenses in the alveoli/distal airways? No cilia or mucus Macrophages – they can seek and phagocytose pathogens, as

well as coordinated the cellular response via chemotactic factors and cytokines

IgG

• Secondary defense mechanisms thoughout the lung? Neutrophils and other inflammatory cells

Lung Defense Failures

• Common: viral infection - after influenza, other infxns can occurcigarette smokingCOPDpatients w/ underlying lung disease

• Severe failures of lung defense include: AIDSMedications (corticosteroids like prednisone, other

immunosuppressives, chemotherapyMalignancies (leukemia, lymphoma) – can lower cell

and antibody mediated immunityEndotracheal tubes – HAP

Routes of Infection of Lung

• AspirationMicroaspiration of pathogens colonizing the

oropharynx (your upper away)Gross aspiration of mouth/GI tract contents

into lungs

• InhalationAmbient droplets/particles entrained (e.g. TB,

fungi)

• Hematogenouse.g. Staph. aureus with IVDA, endocarditis, or

a catherter

Typical Pneumonia• Rapid onset• Ill appearing• High fever, rigors (shaking

chills), chest pain, purulent sputum

• Consolidation, rales on exam• Leukocytosis (15-20K)

• Airspace filling/lobar infiltrate on CXR with air bronchograms

• Meant to describe: S. pneumo, S. aureus, GN bacilli like Klebsiella

Atypical Pneumonia• Indolent onset (7-10days)• Less ill appearing• Low-grade fever, malaise,

headache, dry cough

• Rales without consolidation• Mild/no leukocytosis;

negative cultures

• Patchy/interstitial infiltrates on CXR

• Meant to describe: Mycoplasma, or Chlamydia

Typical vs Atypical Pneumonia

NOT HIGHLY PREDICTIVE OF SPECIFIC PATHOGENS!!!

This is the most important test that needs to be done in diagnosing pneumonia?

• Chest Radiography May distinguish pneumonia from other problems (bronchitis,

CHF, TB, PE, cancer) Assesses severity/distribution (multilobar) of disease and

identifies complications (pleural effusion, abscess, empyema)

Many patterns observed Airspace filling processes (lobar; patchy

“bronchopneumonia”) Interstitial patterns Location, cavitation, adenopathy…

CXR will ESTABLIGH THAT YOU HAVE CXR will ESTABLIGH THAT YOU HAVE PNEUMONIA…PNEUMONIA…

But CXR won’t tell you what the But CXR won’t tell you what the responsible pathogen isresponsible pathogen is

Since CXR and clinical presentation only tells you the patient has pneumonia, do

you even care what the causative microbe is?• YES

The pathogen determines how you treat it (and in my case, how much I freak out)

• Great, so how do I figure out WHAT the pathogen is then? Sputum Gram’s stain and culture: used but utility debated

due to high false+ and false- rates Blood cultures: for hospitalized patients (specific, but not

sensitive); much better. Strep pneumoniae causes the most + blood cultures

Ancillary testing for specific organisms Legionella: Urinary antigen immunoassay

(serotype 1) DFA, selective media Chlamydia, Mycoplasma: serologies, but these

are relatively unhelpful in the acute setting TB: AFB smear/culture Fungus: KOH/culture

So when is this sputum Gram stain & Culture

going to be worth me missing sleep?• When you’ve got…

Large numbers of bacteria with a single morphology observed in setting of many PMN’s and few/no squamous epithelial cells (i.e. lower airway specimen)

Obtained before antibioticsDetection of a non-colonizer (mycobacteria, endemic

fungi, Legionella, PCP) That’s when I go:

Yeeeeeeeearrrrrrhhhhh!!!(yes I know I’m a dork, but you’re laughing – admit it.

And I have to entertain myself SOMEHOW!)

This is a sputum sample and it tells us?

That it was probably an incompetent med student who this specimen, b/c it SUCKS. Look at all the squamous epithelial cells and where are the inflammatory cells?!?!?

So after you fix that previous person’s mistake, you see this. What are you thinking?

Besides thinking “damn, I’m good” you should be thinking STREP!!!

When Do I give up on the whole idea of a bacterial pneumonia and consider TB/fungal

agents?

• CXR: Upper lobe cavitary infiltrate: TB!!

• Clinical course: Indolent course x weeks/monthsNon-resolving on treatment

• Exposure history:Outdoorsman (Blastomycosis)Desert southwest (Coccidioidomycosis)TB contacts or from endemic area

The patient asks you to predict how bad the infxn is. You’ll assess the severity looking at

what? And what’ll make you panic?

Demographics: Age >60 years, comorbidities (cancer, “organ failures”, immunosuppressed

conditions, CHF)

• Clinical findings: altered mental status severe vital sign abnormalities

(RR>30; SBP < 90; T>40 or <35; HR >125)• Lab data:

WBC >30k or <4k; hypoxemia; acidosis

• CXR: multilobar involvement, fulminant progression

or you could just use a magic eight ball…

Pathogens ~ Modifying Risk Factors• Aerobic GN bacilli Alcoholism, nursing home, cariopulmonary disease like Klebsiella

• Anaerobes Loss of consciousness (alcohol, seizure), swallowing dysfunction, poor dental hygiene, airway obstruction

• H. influenzae COPD, smoker

• S. aureus Nursing home, post-influenza, IVDA, bronchiectasis

• P. aeruginosa Structural lung disease (bronchiectasis, CF), recent broad spectrum antibiotics therapy, malnutrition, chronic steroids

• DRSP Age > 65; -lactam therapy within 3 months; exposure drug resistant S. pneumoniae to child in daycare; underlying medical co-morbidities

What are your basic Treatment Groups for Pneumonia?

Outpatient1. No underlying. disease

or modifying factors

2. Underlying comorbidities or modifying factors (COPD, CHF, alcoholism,…)

Inpatient3. Inpatients not needing ICU

carea. No comorbiditiesb. Underlying comorbidities

4. Severe pneumonia requiring ICU carea. Low risk for

pseudomonasb. Risk for pseudomonas

How do you treat each group?

Outpatient: No cardiopulmonary disease or

modifying factors

Advanced generation macrolide (azithromycin, clarithromycin)

OR Antipneumococcal fluoroquinolone (levofloxacin, moxifloxacin)

Outpatient: With Cardiopulmonary Disease/Modifying Risk Factors

Antipneumococcal fluoroquinoloneOR

2nd/3rd generation cephalosporin + macrolide

Inpatient: Not needing ICU IV 3rd generation cephalosporin + macrolide

ORIV antipneumococcal fluoroquinolone

Inpatients: ICU requiring IV 3rd generation cephalosporin + macrolide

ORIV antipneumococcal fluoroquinoloneConsider Vancomycin (MRSA and PRSP)If there is a Pseudomonas risk, add these:

Anti-pseudomonal B-lactam + cipro

HAP Pathogens and Treatment• Treatment based upon the local hospital flora

Commonly available along w/ the drug resistances!

• Common pathogens: P. aeruginosa, Enterobacter, E. coli, Klebsiella, Proteus, Serratia, S. aureus, Acinetobacter, anaerobes

• HAP more likely to be polymicrobial • Resistant GN’s and S. aureus (MRSA) more common,

and may spread rapidly to at risk patients

So in the Immunocompromised Host, what is reflective of the specific immune deficit?

• Risk for pathogens reflect specific immune deficitNeutropenia:

bacteria, aspergillus, candida

Splenectomy: encapsulated organisms

T-cell number (HIV) or function (immunosuppressives):

fungi, mycobacteria, viruses (CMV, EBV), bacteria

HIV lung infections reflect what?

• Risk for infection proportional to CD4 count:>500: lower risk (M. tuberculosis, bacterial

pneumonia)<200: Pneumocystis carinii<50: disseminated M. avium complex

• Higher frequency of bacterial pneumonia, esp. S. pneumoniae and H. influenzae, and tuberculosis at all CD4 counts

• How do you avoid PCP in HIV+ patients?Prophylactic therapy in compliant patients quite

effective trimethoprim/sulfa – also used to treat Dapsone inhaled pentamidine – also used to treat

AIDS and Pneumocystis carinii• Clinical Presentation

Dyspnea, dry cough, fever – insidious onset Diffuse infiltrates typical (normal in 5%; atypical with

inhaled pentamidine)Hypoxemia prominent feature

• DiagnosisVisualization (DFA, silver stain) of organisms in lower

resp. secretions (induced sputum; bronchoalveolar lavage 85-95% sensitive in HIV)

• Treatment:Trimethoprim-Sulfamethoxazole (Bactrim) IV pentamidineCorticosteroids: for pO2 < 70 mmHg or A-a grad >35

mmHg (reduces risk of resp. failure and death)

AIDS and Non-TB mycobacteria

• Primary species are within M. avium complex• Risk when CD4 count < 50 (prophylaxis with

clarithromycin)• Primarily cause disseminated disease, rather

than pulmonary diseaseFever, weight loss, anemia/leukopenia, diarrhea,

hepatitis, adenopathyMAC cultured from blood, bone marrow, stool

• Treated with Clarithromycin + ethambutol

AIDS and Fungal Pneumonia

• Cryptococcus neoformans: Common cause of meningitis, usually without

pneumoniaMay cause local or diffuse pulmonary disease;

disseminate

• Histoplasmosis, Coccidiodomycosis: Usually disseminated disease in HIV

• Invasive Aspergillosis:End-stage (CD4 < 50) disease, concomitant

neutropenia (e.g. meds…) are risk factors

AIDS and Non-infectious Lung Diseases

• Kaposi’s sarcoma: infiltrates, nodules, pleural effusions, adenopathy, and airway lesions all possible (Gallium scan negative) human herpesvirus-8

• Lymphocytic interstitial pneumonitis (LIP) especially children with HIV

• Non-specific interstitial pneumonitis (NSIP)• Pulmonary Hypertension

Pathology identical to primary pulmonary hypertension

What is bronchiectasis? 2 modes of pathogenesis? Its vicious cycle?

“Irreversible dilation of airways caused by inflammatory destruction of airway walls”Pathogenesis Infection/Inflammation

bacterial pneumonia, tuberculosis, measles, pertussis

Airway obstruction Cystic Fibrosis (CF) Primary Ciliary Dyskinesia (PCD; Kartagener’s

Syndrome) Hypogammaglobulinemia (total; IgG2/IgG4; IgA)• Airway obstruction/Infection

Airway wall damage/dilation Impairment of mucus clearance

Promotion of Airway Infection

Other Etiologies of Bronchiectasis“Traction bronchiectasis” - ILDAirway obstruction (e.g. foreign body)ABPA (Allergic bronchopulmonary aspergillosis)1-antitrypsin deficiencyCOPDRheumatologic diseases (Sjogren’s syndrome, RA)Young’s syndrome (bronchiectasis, obstructive

azoospermia, sinusitis; normal sweat Cl- and CFTR genotype)

• What happens to the bronchial arteries in bronchiectasis and why?Marked hypertrophy of bronchial arteries due to

chronic inflammatory stimuli

Clinical features of bronchiectasis

• Chronic cough • copious purulent sputum production

~10% with “dry bronchiectasis”

• Periodic hemoptysisMay be massive, as source is hypertrophied bronchial

arteries, which are at system blood pressure

• Abnormal lung sounds and clubbing variably present

What is suggestive history of bronchiectasis?How do we diagnose bronchiectasis?

HRCT – procedure of choice to demonstrate presence, location, and extent of disease

So you have a pt and the HRCT shows bronchiectasis. Now what?

• Figure out what the cause is! CF:

Sweat chloride or CFTR genotyping Immunoglobulin deficiency:

IgG/subclasses, IgA PCD:

nasal scrape for cilia structure; exhaled NO level 1-antitrypsin ABPA:

immediate aspergillus skin test; IgE• Treatment?

Antibiotics aimed at airway flora Airway clearance

Chest percussion (manual, devices), exercise -agonists

Reduces reversible airway obstruction and promotes mucociliary clearance

Surgery For refractory symptoms/hemoptysis from localized

disease

Cystic Fibrosis

• What are the major defects? Production of thick, tenacious secretions from exocrine glands Elevated concentrations of Na2+, K+, and Cl- in sweat

• What are the major clinical problems from CF? Pancreatic insufficiency Recurrent episodes of tracheobronchial infections Bronchiectasis

• What is the genetic basis of CF? Most common lethal genetic disease in Caucasian population

Affects 1 : 3,300 Caucasian births Monogenetic, autosomal recessive Affected gene is called “Cystic Fibrosis Transmembrane

Conductance Regulator”, or CFTR. >1000 individual CFTR mutations identified, but DF508

mutation accounts for 2/3 of CF alleles worldwide

What is the Cascade to Lung Disease in CF?What is the Cascade to Lung Disease in CF?

CFTR Gene Mutation

Altered Ion Transport

Abnormal airway surface liquid (volume depletion)

Impaired airway defenses (reduced mucociliary clearance)

Chronic airway infection/inflammation

Progressive bronchiectasis

Sodium is reabsorbed WAY too much from the airways. Water follow inwards. This leads to the collapse of mucociliary clearance.

How do you diagnose CF?

• 1+ typical phenotypic features and evidence of CFTR malfunction CFTR malfxn:

Sweat Chloride Test – gold standard; > 60 mmol/L CFTR Mutation Analysis – genotyping; 2 mutations required Nasal Potential Difference (PD) testing – demonstrates ion transport

abnormalities Phenotypic features:

Chronic Sinopulmonary Disease: Persistent infection with P. aeruginosa, S. aureus Chronic cough/sputum PFTs (obstruction) Radiographs: bronchiectasis (upper lobe) Nasal Polyps, sinusitis Digital Clubbing

GI: Meconium ileus, rectal prolapse, Distal Intestinal Obstruction Syndrome (DIOS) Pancreatic insufficiency Malnutrition Fat soluble vitamin deficiency Focal biliary cirrhosis

Others: Salt loss syndromes: acute salt depletion, chronic metabolic alkalosis Obstructive azoospermia (CBAVD)

How do you get pseudomonas in CF?

Impaired mucociliary clearanceStatic, hypoxic mucus layerPseudomonas growth in biofilms by altering

metabolism from aerobic anaerobic Intense inflammation with resolution of infection

• What are serious complications of CF?PneumothoraxMassive hemoptysis due to dilation of bronchial

arteriesRespiratory insufficiencyCor pulmonale

What is the standard maintenance therapy for CF?

• Airway obstruction from thick secretions Airway clearance DNase, mucolytics Hypertonic saline – speeds up clearance of mucus Bronchodilators

• Infection Inhaled and oral antibiotics

• Inflammation Ibuprofen Corticosteroids Azithromycin – also an antibiotic! Shown to slow disease

• Nutritional Support High fat/calorie diet Pancreatic enzyme supplementation Fat soluble vitamin supplementation (A,D,E,K)

• Screening for other complications CF-related diabetes Liver disease Bone disease

Pulmonary Thromboembolism

Occluded artery

Parenchymal infarctwith hemorrhage

Pulmonary Thromboemboli (pulmonary embolism, PE)

• Clinical:Dyspnea, hemoptysisCommonly due to lower extremity thrombi

• Radiology:Decreased flow, V/Q mismatch abnormal V/Q

scan

• Pathology:Pulmonary arterial thromboemboliSurvivors may have peripheral wedge-shaped

infarction

Medial and intimal hypertrophy

Plexiform lesion

Pulmonary Artery Hypertension

• Clinical: Sporadic Primary PH: Idiopathic; young adults; 5% Familial Primary PH: Autosomal dominant; 5% Secondary PH: Identifiable cause of increased pulmonary

blood flow and/or increased resistance; 90%

• Radiology: Non-specific

• Pathology: Medial hypertrophy intimal proliferation intimal fibrosis plexiform vascular lesions

Hemosiderin-laden macrophages = prior hemorrhageElastica disruption = vascular injury

Wegener’s Granulomatosis

Necrotizing Granulomatous Vasculitis

What are the 2 Mechanisms That are Used when there’s increased blood flow

through the lungs?

What’s going on with the pulmonary vasculature resistance as you inhale?

• Total pulmonary vasculature resistance increases as you inhale/increase lung volumesAlveolar components increase with inspirationExtra-alveolar components decrease w/ inspiration

• How do you define pulmonary hypertension?Defined as mean pulmonary artery pressure >25 mm

Hg at rest or 30 mm Hg during exercise

• What is the general progression of disease w/ increased pulmonary vasculature resistance?Pulmonary vascular obstruction increased

pulmonary vascular resistance pulmonary HTN increased RV work cor pulmonale

What is the vicious cycle of pulmonary HTN?

Pulmonary HTN

Vascular ChangesIntimal proliferation

Medial hypertrophy

Angiomatoid transformation

Fibrinoid necrosis

Decreased Cross-

Sectional Area

What are the Mechanisms of Pulmonary Hypertension

• Passive: increased left atrial pressure, e.g. mitral

stenosis, mitral regurgitation, LV failure

• Hyperkinetic: high flow states: VSD, ASD

• Occlusive: Chronic PE

• Obliterative: emphysema, interstitial lung disease,

vasculitis, sarcoidosis

• Vasoconstrictive: hypoxia, scleroderma

What is the basis of Primary Pulmonary Hypertension

• Potential etiologies PGIS, endothelin, Kv-channels, eNOS, mutant BMPR2, ANP

• Mean age at diagnosis is 36• More common in females than males• No racial predilection• Familial Disease accounts for ~10% of cases• Disease progresses to cor pulmonale and

premature death if not treated with median survival of 2.5-3 years

Symptoms of PPH Progressive exertional dyspnea—virtually 100%

Patient may faint upon exercise Fatigue Chest pain—due to right ventricular Ischemia Exercise syncope or near syncope Hemoptysis Hoarseness Peripheral edema

• Physical Exam Findings Jugular venous distention Accentuated second heart sound (P2) Right ventricular heave @ left sternal border Right sided gallops (S3, S4) @ sternal border Tricuspid regurgitation murmur (systolic) or pulmonic (diastolic)

murmur Peripheral edema due to RHF

Therapy of Pulmonary Hypertension

Anticoagulation– improves survivalOxygen – in hypoxemic patientsCa2+ channel blockers – may improve exercise

tolerance and hemodynamics in patients (~25%) with mild-moderate disease

Prostacyclin—intravenous/subcutaneous administration improves hemodynamics, exercise tolerance, and prolongs survival in severe PPH

Bosentan—endothelin receptor antagonist that improves exercise tolerance.

Transplantation – the last resort

What are the Pathophysiological Consequences of Pulmonary Embolism

• Pulmonary consequences Increased alveolar deadspace Pneumoconstriction—described in animals Hypoxemia—shunt, V/Q mismatch Hyperventilation Depletion of alveolar surfactant—takes ~24 hr Pulmonary infarction

• Hemodynamic consequences Decrease in x-section area of pulmonary vascular bed:

50-60% reduction significant pulmonary HTN, RHF, hypotension

Humoral reflex mechanisms—hypoxic vasoconstriction, mediator release (like 5HT)

Diagnostic Tests for DVT

• Venography• Impedance Plethysmography• Duplex Scanning• Dopper flow velocity• MRI scans

Diagnosis of Acute Pulmonary Embolism• Symptoms

Dyspnea Pleuritic pain Apprehension Cough Hemoptysis Syncope

• Signs Tachycardia Increased P2 Thrombophlebitis – in lower extremeties S3,S4 gallop Diaphoresis Edema Murmur Cyanosis

• Laboratory Studies ECG- non-specific, sign of Right heart strain S1Q3 pattern in precordial leads CXR Blood Gases D-Dimers – more useful to r/o

• Ventilation Perfusion Scanning – w/ good sxs, it’s fairly reliable• Spiral or helical CT scanning• Pulmonary Angiography

Contraindications to Heparin Therapy

• Absolute: Recent (w/in two weeks) hemorrhagic CVA.Recent neurosurgery, ocular or spinal surgery

• Relative:Recent major surgeryMajor trauma Intracranial neoplasmRecent gastrointestinal bleedingConcurrent guaiac positive stoolMild to moderate hemostatic defectsSevere uncontrolled hypertension >200mm Hg

Systolic or >110mm Hg diastolicHematuria

• In these situations, you would use an IVC!

So you’ve got edema in the distal airwaysand alveolar epithelium. What cell helps you

deal?• TYPE II pneumocytes (main cell)

By increasing Na-K ATPase on basolateral surface, you can increase influx of Na+ from the airspaces via ENaC

Water follow Na+

Na-K ATPase is inhibited by oubain ENaC is inhibited by amiloride This process is accelerated by beta-agonists Can upregulate in at risk infants w/ corticosteroids

to mom and infant more type II cells more surfactant and more efflux

Dexamethasone also helps increase expression of ENaC

• How can you measure the efficacy of alveolar fluid clearance in the lung? Inject a mix of regular and radioactive albumin

Alveolar filling pattern with air bronchograms

Fibrin-rich “hyaline membranes”

Exudative (Acute) Phase Diffuse Alveolar Damage (DAD)

• Clinical: Adult respiratory distress syndrome (ARDS) Identifiable lung injury 0-2 wks beforeAcute dyspnea, hypoxemia, decreased

compliance

• Radiology:Diffuse alveolar filling pattern

• Pathology:Endo- or epithelial injury, Type II cell

hyperplasiaFirst 2 wks after injury: edema fibrin

Respiratory distress syndrome of newborns

• Clinical:PrematurityTachypnea, intercostal muscle retraction,

hypoxemia

• Radiology:Diffuse alveolar filling pattern with air

bronchograms

• Pathology: Insufficient surfactant production by type II cellsAtelectasis hypoxia/acidosis epith necrosisDiffuse intra-alveolar hyaline membrane

formation (exudative DAD)

Alveolar Hemorrhage Syndrome

RBCs filling alveolar spaces

Causes of Alveolar Hemorrhage Syndrome

• Goodpasture’s syndrome• Acute lupus pneumonitis• Wegener’s granulomatosis

Goodpasture’s syndrome

• Clinical:Young adults, M>F

• Radiology:Diffuse alveolar pattern

• Pathology:Anti-basement membrane IgG antibodies

damage pulmonary and renal basement membranes

Linear IgG and C’ deposition by ImmunoFluorescence and Electron microscopy

Anti-GBM IgG is detectable in serum

Acute lupus pneumonitis

• Clinical:Component of systemic lupus erythematosus

(SLE)Children & adults, F>M

• Radiology:Diffuse alveolar pattern

• Pathology:Necrotizing capillaritis due to immune complexesGranular IgG/C’ deposition by IF and EMANA or anti-dsDNA Ab detectable in serum

Aspiration of cooked fat

Lipid

Aspiration• Clinical:

Children - foreign bodiesAdults - gastric acid, food

Lipids, e.g. mineral oil laxatives or nasal drops (“exogenous lipid pneumonia”)

• Radiology:Focal alveolar pattern typically RLL

• Pathology:Gastric acid DADForeign material foreign body giant cell

reaction with exogenous material

Endogenous lipoid pneumonia(“post-obstructive”, “golden” pneumonia)

• Clinical:Central major airway obstruction

• Radiology:Peripheral infiltrates +/- central mass

• Pathology: Increased numbers of foamy alveolar

macrophages distal to an airway obstruction, +/- cholesterol clefts, without foreign material

Endogenous (Post-Obstructive) Lipid Pneumonia

Foamy Macrophages

Severe Pulmonary Edema

Transudate in interstitium and alveolar airspaces

Capillary congestion

Pulmonary Edema

• Clinical:Cardiogenic: LV pump failure, mitral valve

stenosis

• Radiology: Incr. vascular markings, reticular +/- nodular Think Kerley B lines

• Pathology:Venous and capillary congestion Incr. free water in the interstitium +/- alveoli

Define ARDS• Acute Respiratory Distress Syndrome

– A clinical definition– Acute onset– Bilateral infiltrates on CXR– Pulmonary Artery wedge pressure <18 or no evidence of

left atrial hypertension• PaO2/FIO2 < 300: Acute Lung Injury• PaO2/FIO2 < 200: ARDS

• Common Causes? Most Common Cause?Direct Lung Injury

Pneumonia

Aspiration

Pulmonary Contusion

Fat Emboli

Inhalational Injury

Near Drowning

Indirect Lung InjurySepsisMultiple TraumaOther ShockAcute PancreatitisMultiple TransfusionsDrug Toxicity

Septic Shock

Inflammatory Cytokines

Nitric Oxide from Vasc. Endothelium

Low Systemic Vascular Resistance

High Cardiac Output Hypotension

Wide pulse pressure ex: (90/30)

Brisk capillary refill

Hyperdynamic

Decreased urine output

Decreased mental status

Lactic Acidosis – b/c all these tissues are underperfused

Continuum and Definitions of Septic Shock

• Infection– Inflammatory response to microorganisms, or– Invasion of normally sterile tissues

• Systemic Inflammatory Response Syndrome (SIRS)– Systemic response to a variety of processes

• Fever, • tachypnea, • tachycardia, • Leukocytosis

– Be careful; there are some infections that resemble sepsis but AREN’T despite the overlap with SIRS

– It all comes down to is it multiorgan?!?!

• Sepsis– Infection plus 2 SIRS criteria

• Severe Sepsis– Sepsis – Organ dysfunction (ex: hypotension, hypoxemia)

• Septic shock– Sepsis – Hypotension despite fluid resuscitation

• Multiple Organ Dysfunction Syndrome (MODS)– Altered organ function in an acutely ill patient– Homeostasis cannot be maintained without intervention

Acute or Exudative Phase of ARDS

Exposure to a Risk Factor

Alveolar Capillary Injury Epithelial Cell Injury

Leak of Protein Rich Fluid into Interstitium and Alveolus

Arterial hypoxemia refractory to oxygen = SHUNT!SHUNT!

Bilateral patchy infiltrates

VERY Decreased lung compliance (need PEEP)

Rapid onset respiratory failure

Proliferative or Fibrotic Phase of ARDS

• Fibrosing AlveolitisFibrosing Alveolitis– Procollagen III peptide present day 1 or 2– Histologic changes day 5-7

• Clinical Evidence Day 5-10Clinical Evidence Day 5-10– Persistent hypoxemia– Increased alveolar dead space– Further decrease in compliance– Pulmonary hypertension - Obliteration of pulmonary

capillary bed

• Steroids are helpful in this stage (but not in the Steroids are helpful in this stage (but not in the acute/exudative phase)acute/exudative phase)

• When ventilating a patient, make sure you don’t When ventilating a patient, make sure you don’t overdo itoverdo it– You don’t want to injure the healthy parts of the lungYou don’t want to injure the healthy parts of the lung– Use a low tidal volume at a higher frequency (despite the inability to Use a low tidal volume at a higher frequency (despite the inability to

get rid of COget rid of CO22))

2 General Classes of Respiratory Failure

Hypoxemic - inadequate O2 delivery

Hypercapnic - respiratory acidosis (high PCO2)secondary to failure to adequately ventilate

Hypoxemic Failure

Physiological CausesA. Decreased PIO2

B. Decreased VA

C. Ventilation/Perfusion [V/Q] Mismatch

D. RL Shunt

E. Diffusion Limitation only problematic during exercise

Physiologic Causes of Hypoxemic Physiologic Causes of Hypoxemic FailureFailure

• Decreased PIO2

– As with high altitude

• Decreased VA

– Hypoxia (PAO2) secondary from hypercapnia (PACO2)

• V/Q Mismatch– Can be corrected by supplemental O2

• RL Shunt– Refractory to O2 treatment

• Diffusion Limitation– Only a problem under exercise stress due to

increased CO (common in pulmonary fibrosis)

Physiologic Causes of Hypercapnic Failure

• Increased VE 2o VCO2 – fever, trauma

• Increased VE 2o VD/VT

– pulmonary embolism, emphysema

• Decreased VA

– Many, many causes

• Causes of Decreased Minute Ventilation1. Respiratory drive

(e.g., narcotic overdose)2. Nerve conduction

(e.g., cervical cord trauma, Guillain-Barre syndrome)3. Neuromuscular (e.g., myasthenia gravis, muscle

atrophy)4. Chest wall (e.g., flail chest, kyphoscoliosis)5. Lung disease (e.g., asthma, COPD)6. Upper airway obstruction

Arterial blood gases and diagnosis

pH pCO2 HCO3-  

7.40 40 24 Normal

7.30 55 26 Acute Failure

7.37 55 31 Compensated Failure

7.25 85 36 Acute and Chronic Failure

Clinical signs of respiratory muscle weakness

1. Tachypnea

2. Decreasing Vital Capacity

3. Decreasing Maximum Inspiratory Force

4. Ineffective cough

Note: Hypercapnea is a late sign of respiratory failure due to neuromuscular limitations.

Support ventilation prior to Resp. Failure

How do you TREAT Hypercapnic Failure?A. Diagnose and treat underlying cause

B. Consider respiratory stimulants

1. Naloxone (opioid antagonist)2. Controlled hypoxemia (in proper clinical settings)3. Chemicals (rarely effective; xanthines, progesterone)

C. Assist devices

1. Negative pressure - Iron lung, Cuirass ventilator2. Nasal/Face Mask CPAP - Continuous Positive Airway Pressure3. Cycled CPAP (BiPAP) - Bilevel Positive Airway Pressure

D. Threshold for tracheal intubation and positive pressure ventilation -usually low pH.

E. Mechanical ventilation techniques1. Breath initiation/Respiratory Rate2. Tidal volume 3. Patient regulation of VE

-Spontaneous breaths- Tidal volume

4. PEEP = Positive End Expiratory Pressure

Damage to these parts of the brain are associated with what types of

breathing patterns?• Forebrain

– Post hyperventilation apnea– Cheyne Stokes Respiraton:

• crescendo-decrescendo• Due to problems w/ CNS or HF

• Hypothalamus– Central reflex hypernea

• Pons– Apneustic breathing – pause btw inspiration and

expiration– Cluster breathing– Ataxic breathing

• Medullary– Ondine’s Curse – no involuntary control of breathing– Ataxic breathing

What is Sleep Apnea?• Repetitive episodes of diminished air flow associated with oxygen

desaturation or arousal• Patients may have hundreds of events per night• Two types:

– Obstructive• You try to breath, but the airway is closed• Relaxation of upper airway muscles

– Central• There is no stimulus to breath• Relaxation of lower airway muscles

• Associated w/:– Snoring– Obesity (can still occur in normal body habitus)– Mixed w/ Cheyne-Stokes or hypoventilation– HTN– Tachycardia– Narrow airway, edema, large neck– Risk factors: smoking, alcohol, GERD, brain disease, heart disease,

ADHD (any kid who snores, evaluate!)– IS a risk factor for: HTN, MI, Stroke, RHF, pulmonary HTN, Diabetes,

Motor vehicle accidents, HA, Depression, Shorter life span by 7-10yrs

Who needs evaluated for OSA ?

• Snoring associated with HTN, obesity, DM, or any vascular disease.

• Snoring in individuals with unrefreshing sleep, excessive sleepiness or insomnia.

• All children who snore (American Academy Pediatric).

OSA Treatment• Continuous Positive Airway Pressure (CPAP,

BiPAP)• Surgery – 50-50 chance of success• Dental Device• Weight Loss• Medication• Avoidance of alcohol• Sleep on side

Respiratory Failure

Lung Failure

Gas Exchange FailureHypoxemia

Shunt

Diffusion Limit

VQ Mismatch

Low Inspired O2

Ventilation Failure

Hypercapnia

CNS Depression

Muscular Fatigue

Mechanical FailurePoor VA

Causes of Hypercapnic Failure

• Normal Ventilation – Increased Production of CO2 (fever,

tramua)• Normal Ventilation with Increased

Deadspace (VQ Mismatch) – Pulmonary Embolus– Emphysema

• Decreased Ventilation (lots of causes)– Breath Holding– Obesity– Drugs

What’s the Poor Mans Rule of Thumb for Acute versus Chronic

Respiratory Acidosis?

• Acute Respiratory Acidosis-HCO3 rise by 1 mEq/L for each 10 mmHg

PCO2

• Chronic Respiratory Acidosis-HCO3 rise by 4 mEq/L for each 10 mmHg

PCO2– The body has had time to renally/metabolically

compensate for the respiratory acidosis by increasing HCO3

- amts to counteract the drop in pH.

What are the causes of dyspnea?

• Abnormal gas exchange or acidosis– Hypercapnia – sensed in medulla, carotid

bodies– Hypoxemia – sensed in carotid bodies– Low pH - sensed in medulla, carotid bodies

• Increased neuromuscular stimuli– Chest wall muscle receptors– Parenchymal and airway receptors

• Abnormal perception/psychogenic

If given these Sxs in the history, what diseases should you be thinking about?

If given these findings in the physical exam, what diseases should you be thinking about?

If given these findings in the physical exam, what diseases should you be thinking about?

If given these findings in the physical exam, what diseases should you be thinking about?

If given these diagnostic results, what diseases should you be thinking about?

What are these diagnostic tests useful for in making diagnoses?

Congrats! You’re Done!Good luck on the exam

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