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Pathophysiology: Lung

Formulas to Memorize ............................................................................................................................................................ 2

Lung Mechanics Review .......................................................................................................................................................... 3
Reading a CXR ......................................................................................................................................................................... 5
Pulmonary Function Testing ................................................................................................................................................... 6
Interstitial Lung Disease ........................................................................................................................................................ 10
COPD ..................................................................................................................................................................................... 13
Pathophysiology of Asthma .................................................................................................................................................. 17
Expiratory Flow Limitation .................................................................................................................................................... 21
Pulmonary Vascular Disease ................................................................................................................................................. 24
Obesity & Breathing Disorders.............................................................................................................................................. 27
Ventilatory Failure ................................................................................................................................................................ 30
Acute Respiratory Distress Syndrome (ARDS) ...................................................................................................................... 34
Pneumonia ............................................................................................................................................................................ 37
The Pleural Space .................................................................................................................................................................. 44
Bronchopulmonary Dysplasia ............................................................................................................................................... 48
Cystic Fibrosis ........................................................................................................................................................................ 52
Disorders of the Lower Airways ............................................................................................................................................ 56
Upper Airway Disorders ........................................................................................................................................................ 61

Formulas to Memorize
PAO2 Alveolar O2 tension
𝑷𝒂 𝑪𝑶𝟐
Alveolar gas equation: 𝑷𝑨 𝑶𝟐 = 𝑭𝑰 𝑶𝟐 × 𝑷𝑩 − 𝟒𝟕 − ( 𝟎.𝟖
) FIO2 Fraction inspired O2
PB Barometric pressure
 If on room air: simplify it! 𝑷𝑨 𝑶𝟐 = 𝟏𝟓𝟎 − (
𝑷𝒂 𝑪𝑶𝟐
) (corrected for water
pressure, - 47)
Use to calculate A-a difference (alveolar – arterial) PaCO2 Arterial CO2
 Normal values: < 20 on room air (20% O2) < 100 on 100% O2
 Increase: suggests venous admixture (poorly oxygenated blood reaching circulation)

Arterial Blood Gases: know normal values

pH 7.35-7.45
PaO2 80-100 mm Hg
PaCO2 35-45 mm Hg

Lung Mechanics Review
Note: there’s probably way more to review than this lecture covered
Transmural pressure = pressure inside – pressure outside
Transpulmonary pressure (PL)= (alveolar pressure) – (pleural pressure) = elastic recoil pressure
Transdiaphragmatic pressure (Pdi) = abdominal pressure = pleural pressure
PBS = body surface pressure, Ppl = pleural pressure, PCW = chest wall pressure
So the pressure across the respiratory system is PL – PCW = (Palv – Ppl) – (Ppl – Pbs) =
 PRS = Palv - Pbs

Compliance: slope of the pressure-volume curve

 Compliance = ΔV / ΔP
 Elastance = 1/compliance
o high compliance = very distensible, high elastance means very stiff
o Compliance is better term
 Graph
o Note that compliance isn’t linear
 changes with volume (less compliant at higher volumes)
o Volume at zero transmural pressure: residual volume
(unstressed volume)

Unstressed volume (relaxation volume) Stressed volume

volume in an elastic structure when transmural pressure = 0 volume above the unstressed volume which distends the surface

Lung Compliance

 Note that RV is the volume that remains in lung at Tm = zero

 Lung is less compliant at higher volumes

Some disease processes make lung:

 more compliant (emphysema)
 less compliant (fibrosis)

What determines lung compliance?

 Tissue properties (elastin,
collagen, etc.)
 Surface tension: wherever an air-
liquid interface exists, there’s a net attractive force that tends to collapse the bubble
o Fill lung with saline: Less pressure needed to inflate (more compliant – no
surface tension)
o Surfactant: reduces surface tension & stabilizes alveoli
o ARDS: loss of surfactant = less compliant lung

Hysteresis: the compliance curve is different on inspiration vs

 Convention: compliance = expiratory compliance
 Why? Harder to inflate than keep inflated
o surfactant
o lung units close on exhalation & takes extra work to pop them back open
o tissue relaxes after time in stress & loses recoil

Chest Wall Compliance

This curve only applies when chest wall TOTALLY RELAXED

 Don’t measure in pulmonary function lab – can’t totally relax
 Less compliant at lower volumes (rib joints, etc. limiting compression)

Note: chest wall; lung compliances are similar over range of breathing pressures

Note: chest wall wants to spring open; lung wants to collapse

Chest wall compliance disorders:

 E.g. fibrothorax; scarred, thickened pleura;
obesity too (less compliant)

Respiratory System Compliance

Compliances are in series so add reciprocals
 Makes sense: blowing up a balloon inside of another balloon would be harder than blowing up either one
 1/CRS = 1/CL + 1/CCW

How does this relate to FRC, RV, TLC, and all that stuff?
 See graph – just adding the pressures of CW & lung to get RS
 FRC: inward recoil of lungs = outward recoil of relaxed thorax
o Graph: chest wall pressure is same distance from zero as lung pressure
 RV: all airways are closed
 TLC: inward recoil of RS = outward recoil of maximally contracting
inspiratory muscles

Air flow dynamics

Resistance = pressure / flow
 What pressure is needed to generate flow?
 ↑ with turbulence, tube length, and DECREASING RADIUS
 ↓ with ↑ lung volume
 80% of resistance is in LARGE AIRWAYS (bigger than subsegmental)
o Remember, small airways have large total area

Flow patterns
concentric layers of air flow slipping past Resistance:
Laminar each other @ different velocities (faster in independent of gas density
Resistant: strongly
molecules tumbling around (still with a net
Turbulent vector in flow direction)
dependent on gas density
(↑ with ↑ density)

near bifurcations; areas with eddies

Transitional partially disrupt laminar flow

Reading a CXR
Not on the exam; just a few pictures & concepts that seemed helpful

Assessing quality
 Not too much lung field above clavicle (bending over?)
 Should be able to just make out outlines of vertebrae through mediastinum (exposure good?)
Note: left hemidiaphragm “stops” (mediastinum & abdominal contents are same opacity)

Masses (>4cm)?
 Upper or lower? Infiltrates? Effusions?
 Unilateral or bilateral?
Nodules (<4cm)?

Alveolar? Mixed?
 Water
 Reticular (lines)
 Blood
 Nodular
 Cells
 Combined
 Pus
 Honeycomb
 Protein
 Ground glass
 Calcium

Pulmonary Function Testing
 Inhale to TLC
 Exhale as rapidly/completely as you can
 Measure exhaled volume vs. time

 FEV1 : Volume exhaled in 1st second
 FVC: total volume exhaled
 FEV1/FVC: fraction of total volume exhaled in 1st second (FEV1%)
o Normally ~0.8

Interpretation of Spirometry
Ventilatory defect: FVC FEV1/FVC

Restrictive ↓ Normal or ↑

Obstructive Normal or ↓ ↓

Common Causes Of:

Restriction Obstruction
Small / stiff Respiratory ↑ airway Increased airway
Small / stiff lungs ↓ lung recoil
chest wall muscle weakness resistance closure
Pulmonary fibrosis Kyphoscoliosis ALS Chronic bronchitis Emphysema Asthma

Flow-volume curves

Spirograms show expired volume and time; you can also plot
flow per time. Either way lets you calculate FEV1 and FVC

See chart to left

Can also have patient inhale as fast as possible
at end of spirometry to generate flow-volume
loop (see right)

Lesion Affects…
Upper airway inspiratory flow >
obstruction expiratory
expiratory flow >
Fixed obstructions (e.g.
could affect both
tumor around trachea)

Arterial Blood Gases

What can we assess from blood gases?
Oxygenation: hypoxia
Ventilation: hypo or hyper ventilation
Acid/base balance: nephrology
Arterial Oxygenation
Remember the oxyhemoglobin saturation curve
 Most O2 bound to Hb
 Saturation, O2 content change very little above PaO2 = 60mmHg
 Mix of blood with high and low PO2: dominated by low value
o E.g. mix 95% saturated blood ( 100mmHg) with 75% saturated blood (40 mm Hg) –
end up with 87% saturated blood (average) but because curve is sigmoidal, PO2 is
about 55 mm Hg (not an average!)

Clinically significant hypoxemia:

 Arterial Hb saturation of less than 90% (PaO2 60 mm hg)

Alveolar gas equation: memorize this: PAO2 = [FIO2 x (PB-47)] – (PaCO2/0.8) PAO2 Alveolar O2 tension
FIO2 Fraction inspired O2
 If on room air: simplify it! PAO2 = 150 – PaCO2/0.8
PB Barometric pressure
o Room air close to 20% oxygen (corrected for water
 Inspired [O2] changed by water vapor & CO2 pressure, - 47)
PaCO2 Arterial CO2
A-a gradient (i.e. who cares about the alveolar gas equation?)
 Calculate PAO2 (alveolar PO2) and compare it to arterial PO2 – are you getting oxygen from alveoli to arteries?
 Normal values: < 20 on room air (20% O2) < 100 on 100% O2
 Increase: suggests venous admixture (poorly oxygenated blood reaching circulation)

Causes of Hypoxemia
Cause Description A-a Response to
Maldistribution of V relative to Q (ventilation / flow)
V/Q Mismatch  Some areas are overventilated (↑ PaO2) ↑ Corrects
 but doesn’t correct for underventilated areas (↓ PaO2)
Extreme V/Q mismatch

 lots of venous blood gets to L heart

without traversing ventilated alveoli
Shunt ↑ Doesn’t correct
 E.g. collapsed alveoli, septal defect, etc. –
can be intrapulmonary or

Alveolar O2 diluted by ↑ PACO2 Good response

Hypoventilation nl can ↑ resp
 PACO2 MUST be ↑
Diffusion Hypoxia with exercise, not at rest ↑ with
impairment  Red cells don’t have time to reach equilibrium on exercise exercise
Decreased FIO2 Altitude, for instance nl

Ventilation: PaCO2 & pH

PaCO2 = K x VCO2 / VA (K=0.86; VA = VTidal – VDead Space)

 VCO2 = CO2 production; VA = alveolar ventilation
 Just K x CO2 production / CO2 removal

PaCO2 VERY tightly controlled (35-54 mmHg)

 >45 =HYPOventilation (VA is ↓: total ventilation ↓ or ↑ dead space)
 <35 = HYPERventilation
 Terms for actual PaCO2 findings: hyper- & hypocapnia

Hyperbolic relationship between VA and PaCO2

 If you’re hypoventilating (low part of curve), can get BIG PaCO2 changes
 Exercise (dotted curve): need more VA to maintain PaCO2

Calculating pH changes due to PaCO2 changes

pH: Acidosis (<7.35) vs Alkalosis (> 7.45)
 Can calculate pH changes for PaCO2 changes A 1 mmHg ↑ in PaCO2 causes
(see table to right) Acute (non-compensated) ↓ 0.008 in pH
Chronic (compensated) ↓ 0.003 in pH
Diffusing Capacity
Fick’s law: gas flux = (membrane diffusion coefficient X pressure gradient) / (thickness X area of membrane)
 Don’t memorize; just know that those are the things that go into flux
 Simplify everything: flux (J) = driving pressure (ΔP) X diffusing capacity (DL)
 𝐉 = 𝚫𝐏 × 𝐃𝐋 𝐃𝐋 = 𝐉/𝚫𝐏

To measure diffusing capacity:

 Can’t measure DLO2, although we’d like to – backpressure (dissociates from Hb)
 Use DLCO instead! Doesn’t have backpressure (binds really tightly to Hb)
o Pt inhales 0.3% CO in 10% He (both diluted equally, He is marker), holds breath 10 seconds
o Exhaled mixed alveolar gas sampled, exhaled [CO], [He}]measured,
o Calculate: how much CO was able to diffuse?

Interpreting DCO
 Sensitive, non-specific (something’s wrong, but huge DDx); wide normal range
 ↓ DCO: ↓ alveolar-capillary SA for gas exchange
 ↑ DCO: ↑ pulmonary capillary blood volume

Lung Volumes
How to measure residual volume?
 The rest we can get from spirometry
 Need to use GAS DILUTION (He, nitrogen, Ar, methane)

Gas dilution
 Measures only ventilated lung units
 Breathe in & out to equilibrate
 Calculate measure diluted [He]
 Use known initial volumes & initial / final [He] to figure out how
much lung capacity was around (TLC), then calculate RV by TLC-VC

Plethysmography (body box) is another option

 Uses Boyle’s Law (P1V1=P2V2)
 Measures ALL thoracic gas volume (cysts & bullae too)


↓ TLC Restriction
↑ TLC Hyperinflation
↑ RV Air trapping

Key Points
Patients can be pathophysiologically categorized with use of:
 Spirometry and Flow-volume curves
 ABGs
 Lung volumes

Patients can be diagnosed with H&P, PFTs, x-rays….

Interstitial Lung Disease
Pathogenesis of restrictive diseases:
 Stiff lungs (don’t expand) ILD: A restrictive disorder
 Stiff chest wall (or too small)  ↓ TLC (by def’n)
 Respiratory muscle weakness (diaphragm rises  small lungs)  ↓ FVC (almost always)
 Normal FEV1/FVC
Interstitial Lung Disease: STIFF LUNGS (no flow restriction)
 150+ clinical entities can cause ILD  ↓ DLCO (specific to stiff
 “Diffuse parenchymal lung diseases” would be better lung restrictive dz)
o Lung is simple
 tubes (airways: asthma & COPD are Dz)
 blood vessels (pulmonary HTN)
 parenchyma (alveoli) – the stuff that isn’t tubes or vasculature

What is the interstitium?

 Potential space with vascular components; substrate for gas exchange
 Normally should contain nothing (better for gas diffusion)

ILD / Diffuse parenchymal lung diseases (DPLD)

 Inflammation and/or fibrotic process affecting pulmonary interstitium
 Results in scarring of lung
o ↓ lung compliance
o ↓ lung volume (FVC, TLC)
o ↓ diffusion capacity (DLCO) – lets you distinguish from stiff chest wall or resp mm weakness


 Pneumoconiosis (aspestos, silicosis)
Occupational/environmental  Toxic inhalation (ammonia, sulfur dioxide)
 Hypersensitivity pneumonitis (farmer’s lung, pigeon-breeder’s lung)
Pretty much any autoimmune disease
Connective tissue disorders
(scleroderma, RA, SLE, polymyositis-dermatomyositis, etc)
Drug / treatment-induced dz Amiodarone, cancer drugs (bleomycin, methotrexate), radiation therapy
 Idiopathic pulmonary fibrosis
Idiopathic disorders  Sarcoidosis
 Bronchiolitis obliterans organizing pneumonia (BOOP), Eosinophilic granuloma
Various mutations: surfactant proteins B/C, ABCA transporters, telomerase mutations,
Hereditary / genetic
Hermansky-Pudlak syndrome (all Hopkins-discovered)
Lymphangitic carcinomatosis, respiratory bronchiolitis, tuberous sclerosis / lymphangiolyomatosis (LAM),
“Other” disorders systemic lipoidosis

Now, on to some specific examples

Idiopathic Pulmonary Fibrosis

Epidemiology: 25-30% of all cases of interstitial disease; 8-12/10k and rising, males>females (2:1), mean age 65
 Think older males; significant morbidity & mortality (≈ breast cancer)
 Distinct disease entity: not just waste basket term

Presentation: Progressive dyspnea on exertion for one year or more

 ↑ interstitial markings
 Fibrosis
 Predominantly LOWER LOBE involvement

 Architectural distortion
o (traction bronchiectasis: bronchi
pulled apart by stiffness)
 Honeycombing is diagnostic (radiographic hallmark of IPF)
o Don’t need biopsy anymore!

Pathogenesis: Initiating event unknown (idiopathic!)

 Inflammatory response, epithelial cell injury, neovascularization,
repair / fibrosis all seen on path
 Genetics (telomerase defects / telomere shortening may be involved;
maybe why ↑ in older people?)

Accumulation of dust in the lungs; results in tissue reaction
Types of Pneumoconiosis
 Reaction can be collagenous or non-collagenous
 Excludes dust exposure that results in:  Silicosis
o malignancy, asthma, bronchitis, or emphysema  Asbestosis
 Coal workers’ pneumoconiosis
 Talcosis
Silicosis  Berylliosis
 Most prevalent chronic occupational lung dz in the world!  Hard-metal pneumoconiosis
 Inhalation of silica, usually in quartz form o Tungsten carbide
 Settings (esp. if not using appropriate respiratory protection) o Cobalt dust
o Mining (hard rock/ anthracite coal), foundries, brickyards, glass/ceramic
manufacturing, industrial sandblasting

Clinical Presentation:
 Dyspnea & cough (>20yrs low-moderate exposure, 5-10yrs high-level exposure)

 Small rounded opacities in upper lung zones
 Conglomerate (>10mm) opacities
o Called progressive massive fibrosis (PMF)
o Looks like tumor
o Small opacities can progress to PMF
PFTs : identical to IPF
 May see airflow obstruction, ↓ FEV1/FVC occasionally

1. Silica particles deposit in alveoli
2. Mϕ gobble them up
3. Mϕ injured / cell death happens
4. Release of intracellular proteolytic enzymes  lung injury / fibrosis
5. Silicotic nodules form!

Diagnosis of Interstitial Lung Disease
 Patient history is crucial!
o Check for exposures, how long have Sx been going on, any Hx autoimmune dz, other sx?
 Chest radiograph useful (& chest CT)
 Fiberoptic bronchoscopy
o Broncheoalveolar lavage: rule out infection, look for eosinophils
o Transbronchial biopsy: e.g. for sarcoidosis
 Thorascopic / open lung biopsy too

Treatment of Interstitial Lung Disease

Note: no FDA approved therapies for IPF: for a disease that affects 1/2M people in US & causes 40k deaths / year!

In general, for ILD: (* = not of benefit for IPF)

 Avoid exposure to causative agent
 Corticosteroids*
 Alternative immunosuppressive agents*
o Cyclophosphamide
o Azathioprine
 Anti-fibrotic drugs*
 Follow pt response to therapy with serial PFTs & pt-reported Sx
o How are they doing? Try something new if not working

COPD: chronic disease characterized by REDUCED EXPIRATORY AIRFLOW Risk factors for COPD
Diseases included in COPD: both COPD: Clinical Course  Older age
caused by cigarette smoking  Progressive ↓ in pulmonary function  Male gender (?)
 Emphysema  Punctuated by acute exacerbations  Airway hyperreactivity
 Chronic bronchitis  Low socioeconomic status
 Eventually: disability & premature death
 Others: asthma /  Alpha-1 anti-trypsin deficiency
asthmatic bronchitis / bronchiectasis / CF technically COPD too, but not in
common parlance

Emphysema Chronic Bronchitis Asthma (for comparison)

Anatomic definition (need Bx to Dx) Historical definition (Dx via phone!)
Definition: Definition: Episodic cough, wheezing, dyspnea
 Progressive destruction of alveolar  chronic mucus hypersecretion
septa & capillaries   > 3mo chronic sputum production for 2 Often considered pathophysiologically
 Airspace enlargement & bullae consecutive years separate from COPD unless chronic
development abnormalities present:
↑ airway resistance   Lung function
Destruction of septa  ↓maximum expiratory airflow  Cough
↓ elastic recoil (↑ compliance)  Sputum (“asthmatic bronchitis”)
 ↓ maximum expiratory airflow
 ↑ static lung volumes

Natural History of COPD

FEV1 normally ↓ with age; much faster in COPD
 Usually clinically recognized in older pt / 50s (Sx)
 Changes start much earlier (can detect with PFTs!)
o Just need spirometry (cheap!) to see FEV1

Only 1 in 7 smokers get COPD

 But in those who are going to get it, these changes start early

If you quit:
 Rate of FEV1 drop goes back to normal! Delay onset of Sx

Pan-Acinar vs Centrilobular Emphysema
Remember: acini / lobules are the functional unit surrounding one respiratory bronchiole

Affects Part of Lung Cause Picture

Entire Base >
Pan-Acinar antitrypsin
acinus apex

Respiratory Apex > Cigarette

bronchiole base smoking

Protease Imbalance Theory of Emphysema

Basic idea: ↑ proteases & ↓ antiproteases  imbalance  damage
 Mϕ secreting cytokines in middle of everything
 Cytokines  hyperplasia of other cells (e.g. mucus cells)
o Can lead to bronchitis too!

 Alpha-1 antitrypsin (normally inactivates proteases) deficiency leads to
premature emphysema
 Proteases such as elastase causes severe emphysema in lab animals
 Cigarette smoking causes inflammatory cells to secrete proteases (which
accumulate in the terminal airspaces)
 Cigarette smoke inactivates anti-proteases

Pink Puffers & Blue Bloaters (typical COPD pt has elements of both)
Findings Picture

 Emphysematous  Purses lips

 Dyspneic
 Hyperinflated  Shoulders elevated
Pink Puffer  Low PaCO2
 Thin physique  Leans forward
 Worse O2sat w/exercise
 Accessory mm to breathe

 Bronchitic
 High PaCO2
 Less hyperinflated
 Better O2sat w/ exercise
Blue Bloater  Obese physique
 Cyanotic
 Not dyspneic

Pathophysiologic Abnormalities in COPD
Probably good to memorize these lists of 3 things
Major pathophysiologic abnormalities in COPD
Airflow Obstruction: causes 1. Airflow obstruction (Early)
1. ↓ elastic recoil (emphysema) 2. Hypoxemia (Mid-course)
2. ↑ airway resistance (chronic bronchitis) 3. Pulmonary HTN (Late)
3. ↑ airway smooth muscle tone (asthmatic bronchitis)

Hypoxemia: causes
1. V/Q mismatch (because of non-linear Hb dissociation curve)
2. Hypoventilation (late in course; more common in chronic bronchitic)
3. Diffusion impairment (exercise or high altitude;
more common in emphysema)

Flow-volume loop:
 More curvilinear (some areas emptying very slowly – bullae, etc)
 Smaller in general (less volume)

Air trapping & hyperinflation

 Air trapping makes RV↑ (extra volume that can’t be expelled)
 Hyperinflation means TLC↑ (bigger overall volumes)

Operating lung volumes (rest vs. exercise)

 Normally ↑ VT by blowing out more during exercise
 In COPD:
o can’t blow out fast enough
o take another breath before fully exhaled
o ↑ end expiratory volume
o VT ↑ to keep up with metabolic demands
o Reach TLC – need to stop exercise
(can’t ↑ VT any more)

CXR findings (not good for screening vs. spirogram)

 ↑ A-P diameter
 Flat diaphragms (less efficient)
 ↓ vascular markings
 ↑ size of central pulmonary arteries
 ↑ anterior air space
 ↑ sterno-phrenic angle

CT findings with
density masking:
 better for Dx
 Too much air
(↓ density)

Pulmonary Hypertension: due to chronic alveolar hypoxia

 Give O2 to prevent
 Maybe contribution from destruction of pulmonary capillary bed too

Gas exchange: problems progress over course of disease

Consequences of pulmonary HTN

 RV dilatation
 ↑ venous pressure (↑ RA pressure too)
o Peripheral edema
o Can’t ↑ CO with exercise or stress
 Decreased survival
 50% 5-year mortality with cor pulmonale (RH failure)

Treatment of COPD
Chronic oxygen improves survival in pts with hypoxemia
 Concentrator or liquid O2 
 deliver with nasal cannula, Venturi mask (control concentration), or transtracheal catheter (high flow) as needed

Smoking cessation slows progression

 ASK ABOUT SMOKING & give forceful encouragement to quit (↑ quit rate 50%)
 Encourage unambiguous quit date
 Follow up progress
 Nicotine replacement (transdermal patch, gum, lozenge, spray)
 Bupropion or varenicline
 Refer to group program
 1-800-QUIT-NOW – have somebody else do the counseling for you!

Long-acting bronchodilators & inhaled corticosteroids

 ↓ exacerbations & ↑ survival

Influenza vaccination & pneumococcal vaccination might have benefit too?

Advanced treatment:
 Lung transplant
 Alpha-1 antitrypsin replacement therapy ($30K/yr, not known if benefit, only for pan-acinar)
 Lung volume reduction surgery
 Long-term mechanical ventilation

Exacerbations in COPD
 Increase in cough, phlegm, dyspnea
 Occur on average 2-3/year
 50-75% caused by bacterial infection
 Treated with antibiotics, steroids Treatment for Acute Respiratory Failure
 Impair quality of life  Non-invasive positive pressure ventilation
 May result in acute respiratory failure  Intubation & mechanical vent if needed
 Can be prevented by inhaled bronchodilators, inhaled steroids

Pathophysiology of Asthma
Definition: Chronic lung disease characterized by Epidemiology
1. Chronic airway inflammation  20M (7%) in US
2. Airway hyperresponsiveness  M>F in kids; F>M in adults
 Most common childhood chronic dz
3. Variability in outflow obstruction
 Prevalence, mortality rate ↑
Cause: UNKNOWN  ↑ mortality in AA pts (big gap!)
 Genetic factors (clusters in families, ↑ in atopic pts - ↑ ability to generate IgE after allergen exposure)
 Environmental exposures (tobacco smoke, occupational agents, air pollutants)
 Respiratory infections? Controversial: exacerbates but no good data for causation

Chronic Airway Inflammation

Triggers: lots!
 Cockroaches, mice, irritants, infections, etc. (more later)
 EOSINOPHILS major player
 Mast cells (IgE) too
 Histamine, prostaglandins, etc. released

Leads to:
 Bronchoconstriction
 Airway edema
 Goblet cell hyperplasia (↑ mucus)

Eventually results in ↑ AIRWAY RESISTANCE and AIRFLOW OBSTRUCTION (wheezing, shortness of breath)

Airway Hyperresponsiveness
Exaggerated bronchoconstriction after environmental exposures or response to stimuli
 We all do it; just more in asthma pts
 Allergens (e.g. dust mite), irritants (e.g. tobacco smoke), methacholine (diagnostic)
 Mechanism unclear: airway inflammation? Abnormal neural control of airways? ↓ ability to relax smooth mm?

Methacholine (MCh) challenge

 MCh: cholinergic agonist  bronchoconstriction
 Inhale progressively higher [MCh] & record FEV1 after each dose
o Precipitous drop in asthma pts
 Provocative Dose 20 (PD20): dose needed to provoke 20% fall in FEV1
o PD20 < 8 in asthma
 NOT PREDICTIVE of sx severity
 Sensitive but NOT SPECIFIC: all pts with low PD20 don’t have asthma
o COPD, CF, other resp disorders
o 10-15% normal pts
o Can’t use by itself to Dx asthma

Variability in Airflow Obstruction
Obstructive ventilatory defect present

Can at least partially reverse with bronchodilator therapy

 Usually FEV1 ↑ >12%, 200mL

Obstruction VARIES TEMPORALLY: within and between days

 Often worse in early AM
 Symptoms are episodic
o COUGH (can be only
presenting symptom!)
 Can see fluctuation in FEV1 with time

Obstruction VARIES SPATIALLY as well

 Radiolabeled aerosol deposits: patchy deposition mostly in
large & proximal airways; some airways less obstructed

Asthma Exacerbations
Acute ↑ in airway resistance from: bronchoconstriction, airway edema, mucus / cell debris
 Usually over days-weeks but can be sudden
 60% asthmatics: 1+ severe exacerbation/yr
Clinical Presentation
 VIRAL INFECTIONS (most common cause; rhinovirus, influenza)
Hx: ↑ SOB, chest tightness, wheezing, cough
 Inhaled irritants (cig smoke, ozone, particulates)
PE: tachypnea, wheezing, prolonged expiration
 Inhaled allergens (dust mites, animal dander – cats, mice, etc)
Radiology: hyperinflated, flattened diaphragms
 Exercise or cold air (irritates!)
 Occupational exposures
Physiological alterations in exacerbation:
Hyperinflation: Specific to patient (need to test & find out).
Can have delayed symptoms too – exposure, get Sx hours later!
 Diaphragms flattened  mechanical
disadvantage (hard to flatten more to breathe!)
 ↑ work breathing
o abdominal paradox: use less efficient intercostals to breathe, so abdomen goes in instead of out on inspiration
o Can lead to respiratory failure
 Pulmonary HTN: alveolar capillaries compressed (↑ alveolar pressure)

Signs of a severe asthma exacerbation

1. Pulsus paradoxus: > 10 mmHg drop in SBP with inspiration, caused by ↑ pleural pressure swings (↓ LH filling)

2. Respiratory muscle fatigue: from being hyperinflated

o Can’t speak in full sentences
o Accessory mm of respiration (sternocleidomastoid, intracostals) retracting
o Paradoxical abdominal movement (abdomen in instead of out on inspiration)

3. Hypercarbic Respiratory Failure (↑ PaCO2)
o Diaphragm fatigued (↑ work of breathing)  alveolar hypoventilation with ↑ PaCO2
o Normally asthma pts hyperventilate during exacerbation so PaCO2 should be low (<40mmHg)
o A NORMAL PaCO2 is therefore a bad sign in asthma exacerbation

Treatment of Asthma
Patient education: what it is, how to manage, what drugs are, etc.
Avoid triggers: needs to be comprehensive Goals of treatment
 Smoke avoidance, Pet avoidance, Roach control, Mouse control
 Dust mite modifications: 1. Control symptoms
o Allergy proof covers, Wash linens in hot water weekly 2. Prevent exacerbation
o Vacuum/sweep weekly, Carpet/curtain removal, Humidity control 3. Maintain lung function as close to
Asthma management plan normal as possible
 Can have pt measure peak expiratory flow rates at home • Use objective measures: pt
may not realize how bad it is!
 Plan with pt: what actions to take based on peak flow
 Helps with appropriate medication use (not overuse), can have pt call &
4. Avoid adverse effects from
schedule appt or prescription refill if drastic decline, etc. medications
5. Prevent irreversible airway
Pharmacologic treatment: obstruction
• Is asthma predisposition for
1. Bronchodilators: relax bronchial smooth muscle COPD?
a. Short & long-acting β2 agonists, anticholinergic meds 6. Prevent asthma mortality
b. Inhaled
c. Short-acting meds for RESCUE ONLY
2. Inhaled corticosteroids: anti-inflammatory 3. Oral corticosteroids
a. Cornerstone of daily control therapy a. If can’t control with inhaled meds
b. Add if pt needs their bronchodilator b. ↑ side effects
>2x/wk, for instance
4. Others: if refractory to tx
Drug Description
Cromolyn sodium / nedocromil Anti-inflammatory, Mast cell stabilizer (↓ degranulation)
Anti-inflammatory, less effective than corticosteroids
Leukotrine modifiers
(can use if mild asthma or corticosteroids contraindicated)
Theophylline Methylxanthine bronchodilator
Anti-IgE Really expensive; IV; only in very severe cases

Acute Exacerbations:
 ↑ frequency of short-acting bronchodilators with ↑ Sx
 Often needs oral corticosteroids, may need subQ or parenteral β-agonists if severe
 Monitor for respiratory failure

Inhaled drug delivery:

 Aerosolized spray with a propellant, currently with hydrofluoroalkane
Metered-Dose Inhalers (MDI)
 Requires slow deep inhalation with 10 sec breathhold to be most effective
 Minimizes oropharyngeal deposition with MDI
Spacers with MDIs  Requires less coordination
 Can deliver drug as effectively as with nebulizer, even during exacerbation
 Rapid inhalation
Dry-powder Inhalers
 Dose lost if exhales into the device
 Expensive
Nebulized Solutions
 Depends less on patient coordination

How to use MDIs & Spacers

MDI: don’t put it the whole way into

mouth (just coat back of throat!)

Spacer: discharge before inspiration

(MDI alone – simultaneous)

Step Care
Sx, severity depend on:
 frequency of exacerbations
 frequency of nocturnal symptoms
 variability in lung function (FEV1 / PEFR)

Step up if: frequent need for β-agonist

Step down (remove treatments) if 1-6mo symptom control

Summary (from slides)

1. Asthma is more common in children (↑ mortality in African-Americans)

2. Three cardinal features: airway inflammation, airway hyperresponsiveness, variable airflow obstruction
3. Genetics, respiratory infections, and environmental exposures all likely contribute to developing asthma
4. Asthma Sx: wheeze, dyspnea, cough, chest tightness
5. Bacterial infections rarely trigger asthma exacerbations
6. Airway hyperresponsiveness (positive methacholine challenge) is not specific for asthma
7. Airflow obstruction is due to bronchoconstriction, airway edema, and inflammatory exudates in airway lumen
8. Pulsus paradoxus, a rising PaCO2, and respiratory muscle fatigue indicate a severe asthma exacerbation
9. Treatment should include patient education, environmental control practices, an asthma management plan
and medications based upon symptom severity.

Expiratory Flow Limitation
Restrictive ventilatory defects Difficulty getting air into the lungs
↑effort to exhale does NOT cause Obstructive ventilatory defects Difficulty getting air out of the lungs
↑ expiratory flow rate Difficulty with efficient movement of
Gas exchange defects
gases between alveoli & blood

A spirogram (left) is any

graph of exhaled
volume vs time.

The slope is the

expiratory flow
(volume per time); can
be graphed against total
exhaled volume (right)
as expiratory flow –
volume relationship

The pleural pressure generated is analogous to the effort exerted.

 ↑ effort  ↑ expiratory flow: but only to a point.
 The curves all superimpose on their way back down

Isovolume effort-flow relationship:

 At a given volume, there’s a relationship
between % max effort and flow
 ↑ max flow at ↑ volume still in lung (earlier,
before you’ve exhaled the volume) – e.g. A vs B
 Flow restriction: there’s a point of effort at
which ↑effort doesn’t translate to ↑flow
o Normally about 60% max effort is
where flow restriction happens

What Causes Flow Limitation?

For the following, pretend that this is all isovolume (lung volume constant despite expiratory effort & airflow)

Picture What’s going on

 Ppl is about -8 if you hold your breath with glottis open after inspiration
 That makes Pel (elastic recoil) 8 (positive = lung wants to recoil)

Expiratory muscles contract
 Isovolumic so Pel has to be the same (8)
 ↑Ppl (contraction of expiratory muscles), so ↑Palv too (keep Pel same)
 ↑Palv now creates a gradient, and ↑airflow out

At the same time, Ppl pushes in on bronchus, causing it to narrow

 esp. distal bronchus – where pressure is lower (gradient with Patm=0)
 ↑resistance so ↓airflow out

Flow limitation:
 airflow stops increasing at some point (60% max effort in normal)
 resistance from ↑ Ppl cancels out ↑ airflow from ↑ Palv

But if totally occluded, ↑ pressure inside bronchus (>Ppl)

 forces airway open again

Airway opens up again  now the pressure is greater outside (forces closed)

Paradox: if closed, pops open; if open, forced closed

Resolved by either:
 Bronchus fluttering open & closed
 Bronchus doesn’t really close; self-adjusts diameter to maintain it just
open enough to balance opening & closing

What determines max expiratory airflow?

Determinant Contributing factors Picture

1. Airway resistance  Diameter

(bronchi)  Length

Bronchi have cartilage, smooth mm to resist closure, but will

still shut if pressure across them is more than slightly negative
2. Tendency of airway to
 Smooth muscle tone (↑ with asthma so ↑closure)
close (or resist closure)  Mucosal thickness
 Tethering effect of parenchyma

 Lung volume (↑volume  ↑ recoil)

 Elastic properties of lung tissue
3. Elastic recoil of lung
Emphysema: ↓elasticity, ↓ elastic recoil  ↓ flow at any
volume. Opposite for IPF (↑elasticity  ↑elastic recoil  ↑
flow at any volume)

Why is this a problem in chronic obstructive lung disease?

Normally: lots of reserve at rest

 Exhalation happens far underneath maximal envelope

COPD: reserve lost

 ↓ volumes, ↓ maximal expiratory flow
 Even at rest, operating on your maximal envelope
 Try to exert  can’t ↑ expiratory flow

What does this have to do with other systems?

Bladder like lung, urethra like bronchus

 ↑ abdominal pressure to try to force urine out (like ↑ pleural pressure)
 Prostate squeezes urethra like pleural pressure on bronchus
o ↓ flow with prostatic hypertrophy
 Flow limitation happens during micturition – can’t get it out!

Similar Flow Limitation in:

 Expiratory airflow
 Inspiratory airflow
 Vena cava blood flow
 Micturition
 Blood flow during CPR

Pulmonary Vascular Disease
Review from last year: pulmonary circulation
Key points about the pulmonary circulation:
 Entire cardiac output goes through it
 Low pressure drop (25-5)
 Low resistance (low pressure drop!)
P −P
o Resistance = pressure gradient over flow.
o Pressure gradient (pulmonary artery to LA) divided by the flow
(cardiac output = venous return)

Passive: Pulmonary circulation not a rigid tube:

 ↓ PVR with ↑ CO (passively!)
 Capillaries are recruitable & distensible
 No active processes needed
 Maintains pressure gradient over CO range

Active: Vascular tone can be modified to adapt to changing Qt (=CO)

 Change along curve = passive adaptations
 Shifting between parallel curves = vasoconstriction or vasodilation

PVR is U-shaped curve (passive mechanisms)

o ↑ lung volume: compress alveolar vessels (↑ PVR)
o ↓ lung volume: compress extra-alveolar vessels (↓ PVR)
 Hyperinflation (e.g. asthma): ↑ PVR (above normal FRC)
 ARDS: lowers FRC (↑ PVR too)

Pulmonary Hypertension: Definition

Abnormal elevation of pulmonary artery pressure, the gradient
between pulmonary artery & pulmonary vein, or increase in PVR Mean Ppa > 25 mm Hg
Can be measured non-invasively with electrocardiography

Causes of Pulmonary Hypertension

Remember R=ΔP/Q, so PVR = 𝑸𝒕
Rearranging to find things that can affect P PA:

PPA = Cardiac Output × Resistancedownstream + PLA

So ↑ PPA with
1. ↑ left atrial pressure
2. ↑ downstream resistance
3. ↑ cardiac output

1. ↑ LA pressure
 LV or mitral valve disease (cardiomyopathy, mitral regurgitation or stenosis, etc)
 ↑ LA pressure  ↑ backpressure so ↑ pulmonary arterial pressure
 Most common cause of pulmonary hypertension (because LH dz very common)
 Treatment: unload left heart (treat underlying condition to ↓ LA pressure)

2. ↑ downstream resistance
 Very uncommon to raise resistance in veins – usually arteriolar or arterial

↑ arteriolar resistance: primarily hypoxic

 Hypoxia causes ACTIVE pulmonary arteriolar vasoconstriction
(↑ resistance)
o Altitude, hypoventilation, etc.
o Why? Hypoxic Pulmonary Vasoconstriction to match V/Q
o shut down blood flow to underventilated lobe; reduce shunt
o Good locally but bad globally (leads to pulmonary HTN)
+ +
o Mechanism: maybe from inhibition of K channels (see K channels shut down
in hypoxic PA cells but not endothelial cells from other areas of the body –
would want to vasodilate there!)

 COPD: both hypoxia & distortion of alveoli & capillaries

 Interstitial disease: sarcoid, IPF, etc
o distorting capillaries mechanically, some dropping out
 ARDS, positive pressure ventilation, others IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION
↑ arterial resistance: primarily vascular  Women 20-45 yo
 Looking at more central, larger arteries  Dyspnea >1 yr
 Pulmonary Arterial Hypertension  PPA markedly elevated at dx
o Idiopathic, Familial, or associated with CVD / HIV /
 Median survival = 3 yrs (before Tx)
Liver disease /Drugs
 TGF-β involved in vascular remodeling
(definitely in familial forms, probably in
 Chronic thromboembolic disease sporadic form too)
o Needs to be chronic  No cause or association identifiable
o throwing lots of clots, ↑ resistance over time o Rule out other causes
(occluding vessels downstream)

3. ↑ cardiac output
 ↑ pulmonary blood flow  ↑ PPA
o Anemia, hyperthyroidism (↑ CO); generally not severe; reversible
 Chronic ↑ flow  vascular remodeling  ↑ resistance (more fixed form)
o L-to-R shunt (ASD/VSD), Sickle cell anemia too

Consequences of pulmonary HTN
ACUTE (e.g. Acute PE) CHRONIC (e.g. chronic lung dz, PAH)
 RV not hypertrophied; fails quickly  RH has time to hypertrophy
(pushing against ↑ resistance) o See BIG RV and RA
 RA pressure ↑ as RV fails  RA pressure ↑ over time (can’t eject everything) 
 ↑ catecholamines to ↑ mean systemic pressure, ↑ HR pulmonary hypertension
 ↓ Venous return / CO  shock, sudden death  Venous return, CO maintained (↑ sympathetics, ↑
 Acute PEs have 10-15% mortality mean systemic pressure to augment return)

Cor pulmonale: RH failure due to pulmonary disease

 These are patients with COPD or CHRONIC HYPOXIA, for instance
 RH has to keep pushing against diseased lung, eventually fails
 Findings: Edema, ↑JVP, loud P2, right S3, RV heave, tricuspid regurg, hepatic congestion, big pulmonary arteries, ↓DLCO
 Dx with echocardiogram or right heart cath

 Correlates with mean pulmonary arterial pressure!
o See graph: ↑ PPA = ↑ mortality
 Similarly:
o ↑ RA pressure (RH failing!) = 3 mo median survival
o ↓ CO (failing) = bad prognosis
o Hyponatremia (compensatory mechanisms failing) = bad prognosis

Treatment of pulmonary HTN

Goals of treatment:
o Vasodilation
 Reverse hypoxia & active vasoconstriction
 O2 is a vasodilator!
 Reverse remodeling
 Avoid in situ thrombosis & embolism from deep veins (anticoagulants)

Prostaglandin I2 (prostacyclin) Endothelin receptor antagonists PDE5 inhibition
(e.g. Bosentan) (e.g. sildenafil / Viagra®)
 Endothelin usually leads to
 ↑ cGMP  vasodilation, inhibition of
 Vasodilation & inhibition of remodeling vasoconstriction, proliferation,
migration of smooth mm (reverse!)
 Requires chronic perfusion but
 Can give orally, again good functional
improvement in survival (50% at 5yrs  Can give orally; good functional data
data but not good data for survival
vs 20% w/o Tx) (six minute walk) but not good data
for survival (should correlate?)

Lung transplant: cures PAH but has significant problems in its own right
 5yr survival is ~50% (worst of transplants)

 Pulmonary hypertension can arise via various physiologic or pathophysiologic mechanisms (most still unclear)
 Harder to diagnose than systemic HTN / often presents late
 Major clinical importance of pulmonary HTN: effect on the RV (acute vs. chronic)
 Strategies to decrease PVR and unload the RV have beneficial effects on patients with pulmonary hypertension
Obesity & Breathing Disorders
Obesity: BMI kg/m2; >25 overwt, >30 obese. Growing problem (ha!).
More obesity in Missisippi. Obstructive
 (mentally recreate obesity epidemic maps) ↓ Sleep Apnea↓

Obesity can cause a range of breathing disorders

 Some while awake, some while asleep
 Various clinical significances

Sleep apnea
Clinical Features
Upper Airway Obstruction Alterations during sleep
 Snoring  Excessive movements
 Choking, gasping  Insomnia
Cardiopulmonary dysfunction
Alterations in daytime function
 Hypertension
 Excessive hypersomnolence
 Glucose Intolerance
 Intellectual deterioration
 MI / Heart Failure / Arrhythmias
 Fatigue
 Cor Pulmonale

What do you see on overnight sleep study?

1. Periods of no ventilation
2. ↓ O2sat as a result
3. ↑ esophageal pressure variations 4
(trying to inspire: asphyxic response)
4. Microarousals: waking up from sleep (although not 1
the whole way – patient doesn’t fully awaken)

Interruptions in sleep Daytime hypersomnolence, etc.


Epidemiology: measure apnea / hypopnea index (AHI)

 # of episodes per hour (<5/night is normal)
 <10% in general pop, but ↑↑ in obese men, snorers

Sleep Apnea: Pharyngeal Obstruction

Pharyngeal obstruction is key component (critical pressure)
 Normally, negative pharyngeal pressure keeps airway open
 Apneic patient: throat closes! Positive critical pressure

Spectrum of critical pressures: more negative keeps things open

 Snoring, obstructive hypopnea can result even at - pressures (more closed)
 Positive critical pressure: sleep apnea (totally obstructing)

Neuromuscular activity:
 Normally, when upright, genioglossus contracts
(to pull tongue forward on inspiration to open airway)
 Normally, when supine, have more genioglossus activity
(tonic activity too to keep tongue out of the way)
 Apneic patients have ↓ / absent genioglossal nerve firing

In adults: combination of
 structural problems and
 this neuromuscular dysfunction

 More common in upper body obesity (“apples” – mostly males)
o Fat encroaching on neck / pharyngeal tissues  ↑ collapsibility
o Fat  ↑ load on resp system / impedes gas exchange
o Fat  cytokines / humoral factors that ↓ CNS reflexes to keep things open

Therapy for Obstructive Sleep Apnea

Change either the nasal or critical pressure

↑ Nasal Pressure: CPAP

↓ Critical pressure:
 weight loss
 structural approaches
 ↑ neuromuscular activity

CPAP: change nasal pressure

 continuous positive airway pressure
 How it works: wear mask, force air in through nose, inflates throat,
push airway open
 Mainstay of treatment
 Sleep study: AE = ↑ CPAP pressures
o smaller esophageal pressure swings (not trying to breathe
as hard); no obstruction, airflow normal
o Arrows: inspiratory airflow limitation (snoring)
 Partial obstruction so limit flow at a point

 Linear relationship between airway pressure & flow

o Below Pcrit, still obstructed
o Find point where flow is normal & prescribe CPAP at / above that pressure

Changing Critical Pressure

1. Weight loss (good way, even small reductions help)
2. Structural approach
a. Body positioning
b. Uvulopalatopharyngoplasty (surgical – open things up)
c. Hyoid / mandibular repositioning (not done much anymore)
3. Increase neuromuscular activity
a. protriptyline (not great results) or direct electrical hypoglossal stimulation (experimental)
4. Bypass obstruction (tracheostomy) if really severe

Daytime Respiratory Complications of Severe Obesity
Hypoxemia & hypercapnia  cor pulmonale

Hypoxemia: from mechanical alterations

 ↓ TLC & ↓ FRC (↓ chest wall compliance)

 ↓ FRC  ↓ oxygenation (breathing at lower lung volume)

o Below closing volume (where airway closure starts):
 some of your airways are going to be closed
o Microatelectasis too (small areas of collapse; worsens shunt)
o V/Q mismatch & hypoxemia can result

 ↑ metabolic demand (more CO2 produced) if obese
 Should ↑ alveolar ventilation (VA) to compensate
o Blow off extra CO2
 If ventilatory drive depressed, ↑↑PaCO2
(not getting rid of the extra you’re producing)

Why hypoventilation? (see hypercapnia above)

 Won’t breathe (CNS problems)
o Impaired ventilatory drive, metabolic alkalosis,
CNS-depressing meds
 Can’t breathe (mechanical problems)
o Neuromuscular disorders, restrictive chest abnormalities (OBESITY),
parenchymal lung dz, upper airway obstruction

In obesity: alterations in drive to breathe

 Blunted ventilatory response to CO2 challenge
 Leptin deficiency blunts response in mice in and of
itself (ob/ob mice) – restored with giving leptin

Therapy for Hypoventilation in Obesity

Treat Hypoxemia!

 ↓ PaCO2
o ↑ VA (alveolar ventilation): blow off more CO2
 Stimulant (progesterone)  ↑ VA (the same way ↑ metabolic demands dealt with in pregnancy)
 Mechanical ventilation / CPAP to ↑ VA if needed
o ↓ VCO2 (produce less carbon dioxide!)
 WEIGHT LOSS (even moderate loss ~ 5% helps!)

 Maintain oxygenation
o ↑ PIO2 (supplemental oxygen)
o Treat sleep apnea (repeated ↓ in oxygen sat)

Ventilatory Failure
Lung failure Pump failure
Primary feature Hypoxia Hypercarbia
Pneumonia, Asthma, COPD,
Clinical syndromes interstitial lung disease, myopathies, neuropathies,
PE, ARDS spinal cord lesions
Note: hypercarbia is LATE in pump failure: don’t miss stuff that comes before!

Muscles of Respiration: Review

Fiber types & fatigue
 Tendency to fatigue related to oxidative capacity
Type Oxidative capacity Fatigue Strength
I Slow (S) High Slowly Low
IIa Fast-fatigue-resistant (FR) Medium Moderate Medium
IIb Fast-fatigable (FF) Glycolic Quickly High

Diaphragm: usually mostly slow & fatigue resistant

 As ↑ ventilatory demand: recruits more strong fast-fatigable fibers

The Diaphragm: “C-3/4/5 keeps the diaphragm alive!”

 Vertical fibers (contract = pull down)
o Curvature is mostly the central tendon
o Costal and pleural attachments
 Actions:
o Piston-like: pull down, ↓ pleural pressure (upper ribs sucked in)
o Appositional: ↑ abdominal pressure (lower ribs pushed out)
 What passes through diaphragm where?
o “I ate ten eggs at twelve” = I 8 (IVC @ C8) 10 Egs (esophagus @ C 10) AT 12 (azygous & thoracic duct @C12)

Intercostal muscles & scalene

 Really active with every breath (not just accessory muscles)
 External = inspiration; Internal = expiration (backwards)

Accessory muscles:
 Inactive in relaxed breathing; active during exercise or disease
 Sternocleidomastoid is big one
 Pectoralis major / minor, trapezius, serratus anterior too

Expiratory muscles
o Use active expiration during exercise, obstruction, dyspnea, pulmonary function testing
 Abdominal muscles & internal intercostals
 Essential for STRONG COUGH (clear mucus!)

Mechanisms of Respiratory Muscle Failure
↑ demand, ↓ capacity, or both

RM demand: how much are you breathing and how hard is it to breathe?
↑ demand with … Because…
↑ CO2 production Need to get rid of CO2 (e.g. obesity)
Alveolar ventilation is needed to get rid of CO2:
Minute ventilation ↑ Dead space
↑ total ventilation if ↑ dead space to preserve VA
↑ respiratory drive By definition
↓ lung compliance
Harder to breathe if stiffer
Respiratory system mechanics ↓ chest wall compliance
↑ airway resistance Pushing against more

RM Capacity: what determines it?

 Intrinsic muscle function
 Neural function FRC
 Lung volume
o Remember: muscles have maximum in the tension-length relationship
o At point of ideal actin/myosin overlap (length), can get most force
generated (tension)
o FRC: muscles are at length to generate maximum tension
 Metabolic substrate: Oxygen supply & blood supply to resp mm

When things go wrong: Hyerinflation

 Diaphragm “piston” descended, fibers oriented more medially
o flattened so away from maximum on length-tension curve
 ↓ zone of apposition (less effectively turning ribs outward)
 Ribs more horizontal (intercostals, scalene less effective)
 ↓ outward recoil of chest wall (harder to inspire)

Results of hyperinflation: ↑ work of breathing

 Compliance ↓: at a higher volume so lung is less compliant
o For the same VT, you now need to generate a bigger ΔPPL
 Intrinsic (auto) PEEP: need to isovolumetrically contract t o get
pressure down to zero before next breath!

When things go wrong: COPD

RM demand ↑↑ (RM pressure output ↑↑ 3x normal)
 Hyperinflated, ↑ resistance, ↑ resting ventilation (↑ dead space)
 In COPD, O2 consumption shoots up with ↑ ventilation much faster than in normal subjects

RM capacity ↓↓
 Hyperinflation (worse with exercise)
 Malnutrition (esp. protein)  ↓ diaphragm mass END RESULT IN COPD
 Steroids (COPD Tx)  chronic myopathy ↑ demand + ↓ capacity = failure
 Myopathy  ↓ oxidative capacity
When things go wrong: Critical Illness

Cardiogenic or septic shock: ↓ cardiac output

 Hypoxia (because ↓ CO)
o ↓ delivery & ↑ demand (↑ ventilation because hypoxic!)
 People in shock die when they STOP BREATHING (hypoxia  arrhythmias)

Faster progression to lactic acidosis if have to use muscles to breathe

 Expt: dogs with blood loss on vent or breathing on own
 Use mechanical ventilation if patient in shock even if nothing wrong with lungs

Recovery phase (problems after critical illness)

Critical illness polyneuropathy Critical illness myopathy
 MOF after sepsis
 After corticosteroids or neuromuscular blockade
 Demylenation or axonal degeneration
Occur in up to 25% of patients on mechanical vent > 1 wk
Usually but not always recover; often prolongs period of time on ventilation

When things go wrong: Neuromuscular Disorders

Many conditions cause ↓ capacity (stroke, spinal cord injury, ALS, phrenic nerve injury, Guillan-barre, myasthenia gravis, MD)

Spinal cord injury: C-3-4-5…

Site of cervical cord injury Muscles affected Results
Accessory / expiratory muscles
Lower Weak cough  pneumonia
Diaphragm spared
Higher Diaphragm affected (+others) Need long-term ventilation

Diaphragmatic Paralysis
Causes Features
Cardiac surgery, trauma,  Relatively Asx (DOE)
tumor, stroke, herpes zoster  ↓ max voluntary vent (25%)
 Severe dyspnea & ORTHOPNEA (really bad)
Neuropathies, herpes zoster,
Bilateral  ↓ VC and max voluntary vent (50%)
vasculitis, Lyme dz
 Diagnose by Pdi (transdiaphragmatic pressure – balloon in esophagus vs stomach)

↓ respiratory drive: either won’t breathe or can’t breathe

 Drug OD or CNS disorders of central drive can cause

When things go wrong: Obesity

What’s wrong? Why’s it bad?

 RM oxygen consumption ↑↑ (can reach 15% total) Makes you less tolerant:
o ↑ work of breathing, have to move all that extra mass  Of any lung disease
 RM force ↓ (especially supine – same as above)  Of low respiratory drive
 RM endurance ↓

Assessment of RM Function
Simple clinical observation: “TAP”
 Tachypnea
 Accessory muscle use
 Paradoxical breathing
o Put one hand on abdomen, other on chest: should rise & fall together. If diaphragm can’t contract, not raising
abdominal pressure. Accessory muscles contract, suck abdominal contents in  abdomen falls
o Respiratory alternans: periods of alternating paradoxical & normal breathing
 Diaphragm works for a while, takes a break & lets accessory muscles work, etc.

Blood gases: hypercarbia (but a LATE sign! Very ominous if rising – some pts can have chronic hypercarbia)

Maximum inspiratory / expiratory pressure (MIP/MEP)

 Measurement of global inspiratory or expiratory strength
 Inhale / exhale against occluded airway
 Varies with lung volume
o Max MIP at RV (the whole way down, easiest to inhale)
o Max MEP at TLC (totally expanded, easiest to exhale)

Transdiaphragmatic Pressure (Pdi)

 MIP/MEP measure all muscles together
 Pdi is specific for diaphragm
Treatment of RM failure

Muscle training (exercise) – works for skeletal muscle but NOT for resp muscle Treatment strategies
 Works in normals (↑ strength / endurance) but not patients  Exercise
 Problem: already exercising resp MM all the time (e.g. COPD)  Rest
 Medications
Rest (mechanical ventilation)  Pacing
 Allow respiratory muscles to recover from constant load  Surgery
 Mechanical ventilation
o Non-invasive (nasal / facial mask with positive pressure), invasive (if intubated)
o Temporary (endotracheal tube) or permanent (tracheostomy)

Medications: don’t really have any good ones! Respiratory muscle surgery : Lung volume reduction
 Bronchodilators (dilate airways, ↓  Used infrequently these days
hyperinflation)  Severe emphysema:
 Theophylline (↑ strength, ↑ resistance to ↑RM strength by ↓ hyperinflation
fatigue)  ↑ lung fxn, sx, survival in some pts, but
 Androgenic steroids (mixed results) unpredictable outcomes

Diaphragmatic pacing: rarely useful

 Traumatic or resp. center injury, NOT for fatigue
 Need intact phrenic nerves

Key Points (from slides)

 RM failure manifested by hypercarbia
 Diaphragm is main inspiratory muscle
 Inspiration is impaired by hyperinflation
 RM failure due to demand/capacity imbalance
 Treated by restoring balance
o ↓ workload or rest muscles with ventilator
Acute Respiratory Distress Syndrome (ARDS)
Biopsy: Diffuse Alveolar Damage (thickened alveolar/capillary septae, hyaline membranes)
What is ARDS?
 Acute lung injury of the alveolar-capillary membrane, 1. Acute respiratory distress.
characterized by: 2. Diffuse alveolar infiltrates on CXR
o Permeability pulmonary edema
o Acute respiratory failure 3. Severe hypoxemia (PaO2/FIO2 ≤ 200 mmHg)
Example: PaO2 of 200 mm Hg on FIO2 = 1.0
 A syndrome (see box to right) 4. Absence of left heart failure
(pulmonary capillary wedge pressure < 18 mmHg)

Routes of Injury
Inhalation Blood-borne Direct injury to lung
 Sepsis
 Aspiration of gastric contents  Trauma
 Pneumonia (diffuse bilateral)  Drug overdose (narcotics, ASA)  Lung contusion
 Smoke inhalation  Multiple transfusions  Radiation
 Near-drowning  Pancreatitis
 Venous air embolism

Predisposing factors
Other risk factors for ARDS
 SEPSIS / trauma /gastric acid
 40% pts with sepsis develop ARDS; 40% ARDS pts had sepsis as factor aspiration
 Sepsis / trauma / gastric acid aspiration = 75% of cases  Older age
 Severity of associated illness
Multiple factors multiply risk of ARDS development  Cig smoking / chronic lung dz
 Chronic alcohol abuse

Clinical Course of ARDS

Variable onset of signs / symptoms
 Direct lung injury (gastric aspiration, etc): explosive course (resp distress over min-hrs)
 Blood-borne causes (sepsis, trauma, drug OD): gradual onset (hrs to days)

Risk factor exposure  90% develop sx, on vent within 3 days

 If you’re exposed to risk and don’t get sx within 3 days, you’re probably ok

Mortality: currently 30-40%; Most deaths within 2-3 wks (90%)

 Early (<3 days): underlying illness
 Late (>3 days): multi-system organ failure / nosocomial sepsis
 few (15%) from failure to oxygenate / ventilate (good at management)

Survivors: mostly NOT severely impaired

 Pulmonary function: spirometry & lung volume nl by 6mo; DLCO stays at 70% by 12mo
 Functional recovery is slower (peripheral muscle weakness common @ 12mo)

Pathphysiology of ARDS
1. Injury to capillary endothelium (activated PMNs, Mϕ)  cytokines, oxygen radicals, etc.)
2. Pulmonary Edema
o Protein rich (both water & protein leaking)
o Sensitive to small increases in capillary pressure
o Insensitive to changes in blood oncotic pressure

 fluid drains out (depends on Kf = conductance constant & driving pressure,
combination of hydrostatic pushing out minus oncotic sucking into capillary)
 Lymph channels drain lung, keep the alveolus dry

ARDS: damaged capillary endothelium

 ↑ Kf (leaky)
 ↓ σ (oncotic pressure keeps fluid in capillary less because proteins are leaking through )
 ↑ fluid filtration (Qf) as a result (Starling equation)  edema

Pulmonary edema: leads to hypoxemia & ↓ lung compliance (CL)

 Hypoxemia: Right to left intrapulmonary shunt

o Refractory to oxygen; caused by alveolar flooding & collapse
 Airway resistance ↑ (extra weight pushing on them, less tension pulling airways open)  regional hypoventilation
 Alveolar instability: abnormal surface tension forces?
o V/Q mismatch too (same mechanisms as above, just not complete) – in transition zone
o NOT contributing: diffusion impairment or hypoventilation

 ↓ Lung compliance: lung is smaller & stiffer

o Why?
 ↓ ventilated lung volume (alveoli compressed / closed)
 ↑ surface forces (surface tension ↑)
 ↑interstitial edema (heavier weight of lung itself)
 Fibrosis (later)
o All this means respiratory muscles have to work harder

Findings: CXR, CT, biopsy

 tons of Area of compression

interstitial (shunt – no ventilation) with
edema on CXR transition zone above (V/Q

 Diffuse alveolar damage on biopsy

 Thickened alveolar/capillary membranes
 Hyaline membranes
 Diffuse inflammatory infiltrate

Management of ARDS: Oxygen Therapy
Oxygen Therapy: main strategy for ARDS treatment
PEEP: essentially raising FRC  Arterial O2sat = 90%
 Keep positive airway pressure at end expiration o (too high is toxic!)
 Recruits more lung: stents open compressed airways & alveoli w/ +pressure  Keep FIO2 ≤ 0.60
o ↑ FRC, ↓ shunt fraction, ↑ compliance  Maintain cardiac output


 ↓ venous return  ↓ cardiac output (↑ FRC  ↑ resistance)  Mechanical ventilation
 Barotrauma (volutrauma) – overinflate lung (pneumothorax!)  PEEP (positive end-expiratory pressure)
 ↑ dead space (ventilated but not perfused)
o squeezing shut alveolar capillaries; same reason why ↓ venous return)

Mechanical ventilation
 Study: reducing tidal volume in mechanical vent lead to ↓ mortality, ↑ vent-free days, ↓ organ failure
 Can cause more damage with overstretching!

Overall Therapy of ARDS: Summary

 No direct anti-ARDS treatment
 Treat underlying problem (if possible)
 Maintain O2 delivery and systemic organ fxn

 Avoid complications:
o Oxygen toxicity (keep FIO2 ≤ 0.60)
o Ventilator-induced injury (keep tidal vol ≤ 6 ml/kg)
o Nosocomial infections pneumonia, catheters

7 leading cause of death in US Generally, patients with pneumonia do well
 Leading cause among nosocomial infections  (only 25% CAP hospitalized; 12% of those die)
 M. tb is most deadly bacteria in world  Need to recognize, assess risk, Dx, Tx
 Pandemic influenza major geopolitical death

Pneumonia: infection of the lung parenchyma
 Not one disease, but many common ones that share a common anatomic location
 Some non-infectious processes also are called “pneumonia” – e.g. eosinophilic pneumonia

Route of Infection
 Many people think it’s inhaled respiratory transmission – but not most common way!
 Most: colonization (oropharynx / endotrach tube)  establish there  aspirated into lung!

Route of transmission Organisms

Inhalation M. TB, Legionella, endemic fungi, viruses (e.g. flu), anthrax
Micro-aspiration S. pneumo, H. flu, GNB, S. aureus
Anaerobes (esp. those found in mouth) – not as pathogenic (need more!)
Macro-aspiration  People with seizure disorders, drug users, alcoholics, neuromuscular disorders, etc. –
need big aspiration!
Mucosal spread Respiratory viruses
Hematogenous S. aureus (from R-sided endocarditis)

Pathogens need to overcome host defenses

 Angle of airways can change airflow  problems!

 Mucociliary escalator: sweep mucus upwards, cleared
 Cough reflex (prevents aspiratory pneumonia)
 Lots of stuff secreted; cellular components

 If this gets messed up, you have ↑ susceptibility

↓ Host & ↑ Microbe: the “arms race”

Lowered host defenses Microbial virulence
 Impaired consciousness
 Antigenic drift / shift (Influenza virus)
 Endotracheal intubation
 Capsule (resist phagocytosis) (S. pneumo, Cryptococcus)
 Viral infection & smoking (knocks out mucociliary escalator)
 Evasion of phagolysosome killing (M. TB, Legionella)
 Immunodeficiency

Clinical Presentation
Symptoms: Signs:
 Fevers, chills, rigors (shaking) – cytokines, etc.  Infiltration  crackles
 Cough, sputum production, dyspnea, pleuritic  Consolidation  dull to percussion,
pain (sharp with inspiration / coughing) – when tubular breath sounds
more established  Pleurisy (friction rub – scratchy sound on insp.)

CXR: INFILTRATE (diagnostic!)

Pneumonia vs Acute bronchitis: important for treatment
Pneumonia Bronchitis
Sx Cough & Fever Cough + Fever
Normal VS
VS: P >100,RR >24, BP
PE Rhonchi, wheezes
Crackles, consolidation
(except flu)
X-ray Infiltrate Negative
Antibiotics? YES NO Infiltrate: hallmark of pneumonia

Diagnosis: CXR Patterns

 Lobar = restricted by fissure

 Air bronchogram: outline of bronchi stand

out against fluid-filled alveoli

Lobar  No normal airflow: alveoli filled w/ fluid

 Pneumococcal; other bacterial
pneumonias especially

 Spotty, patchy infiltrate around central

pneumonia  Not a homogenous lobular pattern

 Viral / atypical pneumonias especially

 Linear, reticular patterns (“web like”)

 Less dense, fluffier infiltrates

 Inflammation in interstitium
(fluid, not pus)
 No air bronchograms

 Viral / atypical pneumonias especially

 Necrosis  debris discharged via

connection to airway (leaves cavity)

Lung  Air-fluid levels (if still some pus around) –

abscess or means pyogenic bacteria (S. aureus,
cavity Klebsiella, oral anaerobes)

 limited Ddx:
GNR, S. aureus, M. TB, fungi

Diagnosis: Sputum & Culture
Quality of Squamous
Polys Grossly From
sputum: epithelial cells
Good: Lots Few Thick mucus Lower resp tract
Bad: Few Lots Saliva Upper resp tract

Can be mixed too: believe type III, consider type II, throw out type I
 Graded by lab
 Picture: left is good (thick sputum with polys); right is bad (saliva with epithelial)

Is what you isolated the cause?

Probable Cause Definitive Cause
 Likely pathogen isolated from normally sterile site
Likely pathogen isolated from resp secretion that… (blood, pleural fluid)
 Is screened to distinguish sputum with saliva  Definite pathogen isolated from resp secretion –
 Gram stain: predominant pathogen c/w culture result these guys are never incidental!
 Culture: Moderate to heavy growth o Bacteria: Legionella, mycoplasma, M. TB, B. anthracis
 Can’t call it definitive if it could be there for other reasons! o Viruses: Influenza, paraflu, RSV, SARS
o Fungi: Pneumocystis, endemic fungi

Other rapid ID techniques:

 Antigen detection / IF (urine, resp. secretions, blood), Nucleic acid amplification (resp secretions), Ab detection (blood)

Clasisfying Pneumonia
Acute vs Chronic
Acute evolves over hours / days (S. pneumo, H. flu, Legionella – fast growers)
Sub-acute / Chronic evolves over weeks-months (M. TB, fungi, anaerobic abscesses, PCP – slow growers)

Community acquired vs Nosocomial (hospital-acquired) – for acute pneumonias

Community-acquired no significant exposure to healthcare system S. pneumo, mycoplasma, chlamydia, H. flu
Hospital-acquired Onset >48h after admission S. aureus, Pseudomonas/GNRs, Enterobacteriaceae

Community-acquired pneumonia

Causes: Common Less common

 Bacterial (80%) > Viral (15-20%) ≫  Staphylococcus aureus
Fungal (1-2%) > parasites ( < 1%)  Strep pneumoniae  Moraxella catarrhalis
 H. flu  Gram-negative bacilli
 Anaerobic bacteria*
 See chart:  Legionella *
 Respiratory syncytial virus*
* = not commonly isolated from sputum / blood  Mycoplasma pneumoniae*  Parainfluenza*
 Chlamydia pneumoniae*  Adenovirus*
Treatment: often EMPIRIC (and successful)  Viruses*  Metapneumovirus*
 SARS coronavirus*

Classification of CAP: typical vs. atypical
“Typical” pneumonia “Atypical” pneumonia
Onset Acute Subacute
Nonspecific, systemic, more viral:
Symptoms Fever / chills / Rigors
Headache, pharyngitis, myalgias
Cough Productive of purulent sputum Non-productive cough
Lung exam findings Consolidation Few findings
CXR Dense infiltrate Patchy / interstitial infiltrate
Leukocytosis YES (WBC > 15k) Modest (WBC < 15k)
Etiology Strep pneumoniae, H. flu M. pneumoniae, Legionella sp., Chlamydia sp, viruses

Mycoplasma & Chlamydia Sp

 Symptoms relatively mild (“walking pneumonia”); mortality basically nil
 Won’t ID agents with routine studies
 Mycoplasma: can cause extrapulmonary dz (hemolytic anemia, neuro sequelae)
 NOT RESPONSIVE to β-LACTAMS: cover with tetracycline, macrolide, fluoroquinolone

 Epidemiology: 2-5% of CAP, sporadic in general pop, epidemics (hotels, hospitals)
 At-risk: age > 40, COPD, immunosuppressed (old, smoking / drinking too much – like a Legionnaire)
 Dx: urinary antigen detects 80% (doesn’t grow well)
 Treatment: macrolide or fluoroquinolone
 MORTALITY: 10-20% !

 Epidemiology: common (seasonal), also pandemic (drift/shift)
 Mortality: 36k/yr, esp. elderly elderly
 Sx: high fever, myalgia, headache, cough
 Dx: clinical Dx > Ag test > culture
 Rx: amantadine / neuraminidase inhibitors (give w/in 36hrs)
 Prevention: vaccine (70-90% efficacy, ↓ severity), antiviral px, respiratory isolation, good resp precautions

Influenza can lead to bacterial superinfection (bacterial pneumonia 2° to influenza)

1° influenza pneumonia Bacterial superinfection
Course Progressive Transient recovery from influenza, then relapse
Sputum High titers of virus S. pneumo, H. flu, S. aureus, GAS
Rx Antivirals, supportive care Pathogen-directed Abx

Aspiration Pneumonia
Frequency: ≈ 10% CAP, common cause of HAP
At-risk: Macro-aspiration (alcoholism, drug abuse, seizure disorder, neuromuscular disorder)
Sx / signs: Cough, fever, infiltrate in dependent segment (GRAVITY)

Dx: usually clinical:

 at-risk host +  compatible CXR +
 subacute course +  no other pathogens ID’d
 putrid sputum (anaerobes) +

Treatment: Clindamycin, β-lactam + metronidazole, β-lactam / β-lactamase

Where’s it coming from? Gingival crevice!
 Anaerobes, etc.
 See polymicrobial flora on gram stain but nothing grows on Cx (anaerobes!)

Chemical pneumonia involved too (acid!)

 Organisms in aspiration pneumonia take a while to establish themselves
 Acid burn of gastric contents  rapidly develop pneumonitis
o If no bacterial involvement: transient, no Abx needed

Aspiration pneumonia:
if bacterial agents get involved, ends up in dependent locations (GRAVITY)
 Lower lobe if standing up
 Right middle lobe if laying down / on back
 Often lead to abscesses!

Abscess vs Cavity

Aspiration pneumonia, etc. M. TB, etc. – infectious, need respiratory isolation

Often see air-fluid levels Upper lobe, esp. apical location; No air fluid levels

Nosocomial Pneumonia
Hospital pathogens: Gram (-) bacilli, S. aureus

Hosts are compromised:

 HIV, cancer Rx, neutropenia, elderly
 Mechanical defenses impaired: NG tubes / ventilators
↑ aspiration risk: impaired consciousness (anesthesia), procedures
↑ exposure to other pts: Legionella, RSV, influenza, TB, SARS

 Empiric: BROADER spectrum than CAP (more possible causative agents)
 Pathogen directed when you figure out what it is

 Proper infection control (↓ transmission)  Avoid unnecessary antacid therapy
 Identify aspiration-prone patients, ↑ HOB (↑ bacterial contents in stomach  ↑ infection if aspirate)
 Limit ventilator time

Immunocompromised pts
Type of defects depend on what kind of immune compromise you have (what usually clears the infection?)
 Table for reference; probably wouldn’t memorize
 Asplenia  ↑ susceptibility to encapsulated organisms


Humoral agammaglobulinemia S. pneumoniae, H. influenzae (N. meningitidis)
Asplenia Sickle cell disease, traumatic or surgical asplenia S. pneumoniae, H. influenzae (N. meningitidis)
S. aureus, Serratia, Burkholderia, Aspergillus,
Neutrophil dysfunction chronic granulomatous dz
Neutropenia Aplastic anemia, cancer chemotherapy, congenital Gram-negative bacilli, Aspergillus sp.
AIDS, steroids, organ transplant recipients, cancer Pneumocystis, Mycobacteria, Nocardia, Fungi,
Cell-mediated immunity
chemotherapy, lymphoma Legionella sp. Herpesviruses (CMV, HSV)

HIV: CD4 count  what kind of infection you’re susceptible to (table for future reference too)
CD4+ Pathogens
>500 S. pneumoniae, H. flu
200-500 S. pneumoniae, H. flu, M. TB
S. pneumoniae, Pneumocystis jiroveci, H. flu , M. TB,
50-200 Histoplasma, Cryptococcus
S. pneumoniae, P. jiroveci, M. TB, Other mycobacteria,
<50 H. capsulatum, C. neoformans, Aspergillus sp.,
Nocardia sp., Rhodococcus equi, CMV, Kaposi’s sarcoma

Pneumocystis jiroveci (formerly carinii)

 Frequency: up to 90% AIDS-associated pneumonia
 Sx: Cough, dyspnea, fever (x 3+ weeks)
 Dx: Induced sputum, bronchoscopy, open lung Bx
 Rx: TMP/SMX, then HAART
 Mortality: 100% w/o Abx; 17% hosp pts + Abx
 Prevention: Abx px, HAART

CXR in Immunocompromised Patients (another one not to memorize but future reference)
CXR Finding Associated pathogens
Diffuse interstitial infiltrate Pneumocystis, CMV, Kaposi sarcoma, respiratory viruses
Diffuse nodular infiltrate (miliary) Mycobacteria, Histoplasmosis, other fungi, Pneumocystis
Localized infiltrate Typical bacteria, Nocardia, Fungi, Mycobacteria
Large nodular/cavitary infiltrate Staph aureus, Mycobacteria, Nocardia, GNR, Aspergillus, other fungi, anaerobes (aspiration)
Hilar adenopathy Mycobacteria, fungi, Kaposi sarcoma, lymphoma

Etiology by Age
Newborn Children Young adults Middle age** Elderly**
(0-6 wks) (6 wk–18 yrs) (18-40 yrs) (40-65 yrs) (> 65 yrs)
 Group B strep  H. flu  Mycoplasma  S. pneumoniae  S. pneumoniae
 GNR  Mycoplasma  C. pneumoniae  Anaerobes  Anaerobes
 Chlamydia trachomatis  Viral***  S. pneumoniae  H. influenzae  H. influenzae
(4-6 wks)  Pneumocystis  GNR
 carinii (AIDS)  Viral***
Agents are listed in rank order
** Major causes of nosocomial pneumonia: *** Major viral pathogens
 GNR (Klebsiella sp., P. aerug, Enterobacter sp., and E. coli),  RSV, parainfluenza, and adenovirus
 S. aureus, anaerobes  middle-aged adults: only common viral cause is influenza.

Treatment of Pneumonia
Who should I be worried about? (Predictors of BAD OUTCOME)
 Older age  Marked derangements in vital signs
 Co-morbidities (malignancy, cardiopulmonary dz)  Multiple lobe involvement
 Alterations in host defense (don’t use bacteriostatic abx!)  Bacteremia

 Often empiric, usually successful
 Narrow spectrum when pathogen-directed
 ↑ need to identify specific pathogens if:
o Severe disease
o Host immunosuppressed
o Unusual features (e.g. cavity)
o Failure to improve

Summary of Important Points

Role: Most important infectious disease!
Agents: Pneumococcus, Legionella, Influenza, mouth flora, M. tuberculosis
Distinctive pathogens: Age, CAP, HAP, Compromised host
Diagnostic evaluation: Poor yield, colonizers in respiratory specimens, few rapid diagnostics
Treatment: Usually empiric abx and usually successful

The Pleural Space
Anatomy Review
 Lined by parietal & visceral pleural (merge @ hilum)
 Pleural cavities separated by mediastinum
 2000 cm2 of surface area, 10-20 μ in diameter (thin)

Villi on mesothelial cells (very metabolically active), stroma too

Visceral pleura: NO SENSORY FIBERS (if patient says “ow”, it doesn’t mean you hit the lung)

Pleural fluid: generally produced on parietal side

 From: Pleural capillaries primarily
o Parietal: intercostals, internal mam. arteries
o Visceral: bronchial & pulmonary arteries
o Some from interstitium too
 Intrathoracic lymphatics important for draining
 Peritoneal cavity: can have peritoneal fluid go up into pleural fluid in some disease states

Normally: slightly negative pleural pressure (lungscollapse, chest expand) – suck fluid in

Starling Equation: what determines movement of liquid into pleural space from capillaries??

 𝑄𝑓 = 𝐿𝑝 × 𝐴[ 𝑃𝑐𝑎𝑝 − 𝑃𝑝𝑙 − 𝜎𝑑 𝜋𝑐𝑎𝑝 − 𝜋𝑝𝑙 ] Qf = liquid movement

Lp = filtration coefficient (H20 conductivity of membrane)
A = surface area of membrane
 Basically: ↑ with ↑ surface area, permeability of
P/π = hydrostatic and oncotic pressures
membrane to H2O, pressure difference between
σd = solute reflection coefficient
capillary & pleural space. ↓ with ↑ oncotic pressure
• ability of membrane to restrict large molecules
difference (& ↑ impermeability of membrane to • capillary permeability (VEGF)

What causes ↑ pleural fluid?

 Normally produce 0.01 cc/kg/hr
 Lymphatics: can take up ≈ 0.28 cc/ kg/ hr (28x production!)
 So you need either ↓↓ lymphatic flow or another process to get pleural fluid build up

Normally 8 cc pleural fluid per side

 1-2 g protein / 100cc; 1400-4500 cells / μL, mainly Mϕ, monos, lymphs
 Need optimal amount for normal respiration (transpulmonary pressure maintenance, easy sliding)

Pleural effusions
Causes of Pleural Effusions
Increased Production Decreased Clearance
 ↑ intravascular pressure / interstitial fluid
 lymphatic obstruction is #1
o LV / RV failure, PE, pneumonia, SVC syndrome, pericardial effusions
o 28 fold capacity for drainage vs normal
 ↓ pleural pressure
o Atelectasis, ↑ elastic recoil pres.
 ↑ systemic vascular pressures
 ↑ pleural fluid protein
o SVC syndrome, RV failure
 ↑ permeability
 ? disruption of aquaporins
o pleural inflammation, VGEF
o 4 types found in the lung;
 ↑ peritoneal fluid
o AQP1 important in peritoneal fluid transport
 Disruption of thoracic duct / intrathoracic vessels
 Iatrogenic

 CHF (500k), Parapneumonic (300k), Malignant (200k), PE (150k), Viral (100k) are big ones
o Parapneumonic = related to pneumonia!
 Also: Cirrhosis/ascites, post-CABG, GI dz, TB, mesothelioma, asbestos exposure

Clinical features: due to underlying cause of effusion

 DYSPNEA: 57%
o 1° due to large effusion:  alteration in chest wall PV curve
o Like emphysema
 Cough, chest pain (dull in malignant, pleuritic in benign)
 Fever: more in benign disease

(taking fluid out of pleural effusion)
Indications Contraindications
Unless you know why it’s there, take it out! Absolute & relative
Especially if:  Bleeding, infection
 Unilateral effusions, particularly L-sided*  pneumothorax (1.3-20%, 2% need chest tube placed)
 Bilateral effusions of unequal size* Also:
 Normal cardiac silhouette on CXR* o vasovagal episodes / arrhythmia,
 Febrile, evidence of pleurisy o tumor seeding of needle tract,
(* = indicates that effusion’s less likely to be transudate) o puncture of other organs,
o re-expansion pulmonary edema
For relief of dyspnea too
o death (rare)

Visualize the effusion

 CXR (can lay down in lateral decubitus to help see level)
 Ultrasound
o good for ICU, small effusions, trauma, teaching
o U/S is really the standard of care these days


 Superior side – avoid intercostal vessels / nerve
 Go more laterally (avoid intrathoracics, etc)

Transudates & Exudates

Two types of pleural effusions: transudates / exudates; different clinical significance & etiology
Transudate Exudate
Cause Hydrostatic or colloid pressure imbalance Inflammation / disease of pleura
Pleura Intact Damaged
CHF, PE, cirrhosis Pneumonia, malignancy, PE, GI disease
Major causes
(almost all cases!) (>90% cases are one of these 4)
Nephrosis, peritoneal dialysis, pericardial disease,
Tons (huge DDx)
Other causes hypoalbuminemia, Glomerulonephritis, sarcoid, SVC
syndrome, urinothorax, myxedema CHF:can produce exudative effusion post-diuresis

Is it an exudate? Get both peritoneal fluid & serum LDH + protein compare.
 Need one of the following (looking for ↑ leakage into pleural fluid)
o Fluid : Serum protein >0.5
o Fluid : Serum LDH >0.6
o Fluid LDH >200 IU/L or > 0.45 upper limit nl for lab
 If no serum labs: can use pleural fluid protein / LDH levels alone (not as good)
o (protein > 2.9, LDH > 60% upper limit nl, chol > 45 mg/dL)

If you suspect a transudate, check serum – fluid albumin gradient

 Transudate if > 1.2 g (not leaking albumin)

Other things to do:

 Check the appearance of the fluid: serous, serosanguinous, purulent (empyema), etc?
 Closed pleural biopsy is good for TB (stick needle in, try to rip off some pleura)

Parapneumonic Effusions (PPE) & Empyema

Parapneumonic effusion = effusion after pneumonia (40-57% pts with bacterial pneumonia develop PPE)
 No clinical difference but ↑ mortality (3.4-7x), especially with delayed drainage (16x)
 DON’T WAIT to treat – “never let the sun set on a pleural effusion”

PPE  empyema (pus in pleural space) in 10-20% PPE

 Up to 58% overall mortality!

Don’t wait to treat a pleural effusion! These can move quickly (e.g. PPE  air pockets rupture)

Hours later: air pockets develop with After days / weeks: can rupture,
PPE, can treat by draining
gas production, would need surgery requiring thoracotomy (major surgery)

Therapy for PPE

 ABX: based on local prevalence, resistance
o Chest tube ± fibrinolytics
o Thorascopy, thoracotomy, open drainage

Malignant Effusions
#2 cause of exudative effusions (200k/yr in US), #1 for exudative effusions that need thoracentesis

Lung cancer, breast cancer, lymphoma responsible for 75% 1° tumor Survival
 1° tumor not identified in 6% GI CA 2.3 mo
 BAD SIGN: Die in average of 4 months – PALLIATE by treating effusion Lung CA 3 mo
o Primary tumor is most important predictor; performance status too Breast CA / unknown 5 mo
Mesothelioma 6 mo
 tumor emboli  visceral pleura, 2° seeding of pleural space / parietal pleura (or via diaphragm)
Work-up of malignant effusions: Paramalignant Effusions
 Thoracentesis (cytology beter than closed pleural Bx) (not all effusions in cancer are malignant effusions)
 Thorascopy (95% sensitivity)
 NOT Bronchoscopy (little value!)  related to primary tumor but
 not direct neoplastic involvement of pleura
Treatment: for palliation
 Don’t use much sedation – no nerves in visceral pleura Etiologies: Post-obstructive pneumonia  PPE, obstruction of thoracic duct
 Go in and remove malignant nodules  chylothorax, PE, SVC syndrome, post-obstructive atelectasis  ↓ PPL,
 Talc blown in (acts as glue to hold lung to chest wall; low Ponc from cachexia, pneumonitis/trapped lung, cancer Rx, more
also prevents re-accumulation of fluid)

Moving from fluid (effusion) to air (pneumothorax) in pleural space

Pneumothorax: AIR in the pleural space Pneumothorax: Physical Exam

 Spontaneous  ↓ breath sounds
o Primary (tall, thin males – paraseptal emphysema?)  ↓ fremitus
o Secondary (HIV, other underlying disease)  Hyperresonance
 Traumatic (stab wound, etc)  Tracheal deviation
 Hypotension
Presentation: depends on size & co-morbidities  Tachycardia

Small pneumothorax Tension pneumothorax

R. tension pneumothorax; lung collapses entirely  filled

R. apical pneumothorax; white line is visceral pleura; more
with air (more radiolucent), mediastinum shifts away from
radiolucent above (no lung features)
air (to left in this case)

Tension pneumothorax:
 Tachycardic: shock  death
 Need needle decompression HR returns to normal immediately!

PTX Treatment: depends on signs, symptoms / 1° vs 2°

 Observation
 100% O2  4-6x ↑ in rate of absorption
 Tube thoracostomy

Take Home Points

 Pleural fluid accumulation results from:  Drain effusions EARLY!
imbalance in hydrostatic / oncotic pressure Prior to getting a chest CT! Drain ‘em dry!
 Lymphatics are important for drainage  Malignant effusion  palliate early!
 Pneumothorax: can be life threatening
Bronchopulmonary Dysplasia
BPD Definition: Premature infants who require oxygen or ventilatory support beyond 36-wks post-conceptional age
 A.k.a. “premature lung disease of infancy”

Relatively new disease (1967), pulmonary disease after resp therapy of IRDS (↑ O2 conc, mechanical vent)
 airway inflammation, fibrosis, smooth muscle hypertrophy
 high mortality rate Common features of BPD
 Abnormal CXR
Premature births in US  Respiratory symptoms
 11% all US births < 37 wks (premature)  Hx of supplemental O2 and/or
 308k with low BW (<2500g), 58k with very low BW (<1500g) mech vent in neonatal period

Complications of prematurity: not just lung problems in these infants!

 BPD  periventricular leukomalacia  retinopathy of prematurity
 intraventricular hemorrhage  necrotizing entercolitis

In US, bronchopulmonary dysplasia is the leading cause of chronic lung disease in infants
 BPD can also occur in up to 20% of mechanically ventilated FULL TERM infants
Pathological Findings

Hyperinflation, interstitial changes, “Mosaic changes” on CT: Histology: areas of atelectasis, other areas
cystic development dense areas, hyperinflation with alveolar enlargement; fibrosis rxn

Has really ↑ survival for very early gestation infants
 Use of bovine surfactant
 Tertiary care centers take care of infants
 Better ventilator techniques (less damage)
 Prudent supplemental O2 use
o (high concentrations  free radicalsimpairs alveolar growth)
o Remember lung keeps growing & developing (until 2 yo)

Exogenous surfactant: made huge change in these infants

 ↓ airway surface tension
 ↓ IRDS incidence in premature infants
 Can work really fast (6 hrs in picture to right!)

Surfactant review

 Formed in lamellar bodies in type II pneumocytes

 Secreted, forms monolayer in air-liquid interface
 ↓ surface tension

Surface tension: directly proportional to pressure needed to open & keep open alveoli
 LaPlace’s Law: Pressure =
 If ↑ surface tension, need ↑ pressure to keep open (newborn with RDS: collapse!)

BPD in Extremely Low Birth Weight Infants

Exogenous surfactant: doesn’t ↓ incidence of BPD in extremely low birth weight infants
 BPD extremely common in extremely low birth weight infants (52% 500-750g, ↓ with ↑ wt)

“New BPD”: FEWER & LARGER alveoli (alveolar hypoplasia)

 Secondary to developmental arrest in canalicular stage
(16-24 wks gestation)
 Fewer alveoli, smaller SA of lungs (see picture)  problems
 Extremely premature infants have ↓ surface area

BPD Risk Factors

1. Positive pressure ventilation
a. causes inflammation, problems in lung

2. Infection
a. Immune systems not developed
b. pre/post-natal infections

3. Inhibition of alveolar growth

a. nutrition (malnutrition)
b. steroids / oxygen (double-edged swords)

How to prevent PBD

 Prevent premature delivery
 Avoid mechanical ventilation in preemie infants when possible
o consider high frequency ventilation (smaller volumes) and permissive hypercapnia
 Steroids – double-edged sword
o Prenatal –OK
o Avoid postnatal when possible (esp. first week of life)
 Avoid infections in mother and infant
 Maximize calories in preemie infants to prevent malnutrition

Diagnostic Criteria (severity of BPD)

If born ≤32 wks gestation & got >21% O2 for 28+ days: assess at 36 wks PMA or at time of discharge
Mild BPD Breathing room air
Moderate BPD Need < 30% O2
Severe BPD Need ≥ 30% O2 and/or positive pressure (nasal CPAP / PPV)

↑ need for pulm meds, hospitalization in follow up studies if more severe BPD

Respiratory Syncitial Virus: RSV

 Infection  High morbidity & ↑ mortality, especially in BPD infants
 Out to 2-3 yrs, ↑ RSV hospitalizations in BPD infants

Respiratory Symptoms of BPD

 Fast breathing  Cough with gagging / emesis
 Wheezing (breathing really fast – hard to take bottle)
 Ronchi / crackles  Cyanosis with exertion
 Retractions and/or head bobbing (bad sign)

Medical treatment
consider if need supplemental O2
 Preterm > 3wks – acute / chronic distal diuretics may improve pulmonary mechanics
Inhaled steroids BPD infants have ↑ airway resistance & inflammation
β-adrenergic bronchodilators use PRN (can develop tolerance)
Anticholinergics can help in respiratory aspiration
(nebulized ipratroprium, etc)  IRDS – kind of like COPD lungs in a mechanistic sense

Supplemental Oxygen
 Hypoxia in BPD infants (formerly thought was ↑ SIDS)
o ↑ number of central apneas
o ↑ central apneas, hypoxia  bradycardias, severe hypoxemia, inability to auto-resuscitate (death)
 Maintain O2 sat: better growth / development, prevent central apneas / oxygen
o ↓ risk of sudden death from acute hypoxia
 Want O2Sat 92% or greater during sleep, with feeds, during activities

Weaning off O2:

 Consider if O2sat > 93%
 Wean off during day first, assess growth over several weeks
 Consider overnight sleep study before discontinuing at night

Nutrition: need 120-150 kcal/day for adequate growth, supplemental tube feeding if needed

Exacerbation of respiratory Sx in BPD

 Aspiration during feeds  Bronchomalacia / tracheomalacia (resolves by 2-3 yrs)
 Gastroesophogeal reflux  Vocal cord dysfunction / subglottic stenosis
 GER + aspiration

Recurrent insults to lungs can worsen underlying BPD & prevent compensatory lung growth
 Growth continues through 2 years – window for catching up!

Pulmonary Outcomes in BPD infants
Respiratory Sx in 25% young adults / adolescents who had BPD:
 Wheezing (↓ small airway flows)  Radiographic abnormalities
 Recurrent pneumonia  ↑ risk of airway obstruction & reactivity
 Chronic need for resp meds (↓ FEV1)
 ↓ exercise tolerance

 Hospitalizations for resp problems ↓ by 4-5 yo
 ↑ frequency of chronic resp problems (esp. obstruction)
 Wheezing ↑ smaller kids (in BW < 1500g
 ↓ resp reserve, ↑ O2 desaturation with exercise

Non-respiratory issues too!

 1/3 require physical, occupational therapy, technical aids
 One of most costly chronic childhood diseases
 Impact on everyday family function (big problem esp. if ↓ socioeconomic class)
 Severe disabilities (22% @ 6 yrs) – e.g. cerebral palsy, blindness, profound deafness
o Boys > girls
 Cognitive impairment in 41% at 6 yrs

Cystic Fibrosis
Genetics of CFTR
 1:2750 Caucasians, carrier rate 1:25
 ↓ in African Americans (1:17k), ↓↓ in Asians (1:70k)
 CFTR : Single gene mutation
o (chromosome 7, most common mutation is ΔF508)
o cAMP-regulated chloride channel
o Autosomal recessive

Manifestations of CFTR
Lungs Chronic obstructive pulmonary disease Diagnosis by CLINICAL TRIAD:
Pancreas Pancreatic exocrine insufficiency (↓ enzymes to digest fat)  ↑ SWEAT CHLORIDE
GI CFTR channel helps in stool transit
Repro glands Can’t develop (e.g. vas deferens)
Skin Sweat electrolytes ↑ (sweat test, messed up salt balance)  CHRONIC PULMONARY DISEASE

Respiratory Manifestations
 Chronic cough and bronchitis at first  Chronic sinusitis, nasal polyps
 Bronchiectasis (no matter how well you treat)  Hemoptysis, pneumothorax (↑ pressure  cysts  can pop!)
 Recurrent pneumonia (staph aureus,  Chronic airways obstruction, irreversible
pseudomonas aeruginosa)

CF lung disease starts as endobronchial infection

Max prevalence Other notes
Staph aureus 50% age 5-17 yrs
H. flu 25% age 2-5 now vaccine so ↓ incidence
Pseudomonas aeruginosa peaks age 18 & remains throughout life mucoidy, makes biofilms
Burkholderia cepacia feared, very hard to treat
Progression of lung infections:
Findings in Lung
1. Bacterial endobronchial colonization

2. Intense inflammatory rxn

3. Obstructive lung dz with superimposed

pulmonary exacerbations
o (↑ cough, sputum, dyspnea, ↓ PFTs;
wt loss, fatigue, rarely fever)

Can require intermittent abx

 Oral / IV / inhaled
 Airway clearance, bronchodilators, anti-
inflammatories too

Don’t let it progress – INTERVENE EARLY

Need to be able to clear mucus

(multidimensional treatment approach) Submucosal glands dilated, hypertrophied. Airways are the problem –
mucus plugs, surrounding inflammation in response.
CXR: patchy, white, interstitial inflammation; Lungs: bronchiectasis

Complications of CF lung disease

Hemotypsis: bronchiectasis, dilation of brachial arteries

 Control with abx, embolization

Pneumothorax: dilated peripheral airways + mucus plugging / air trapping, rupture of pleura
 Chest tubes, pleural sclerosis involved too
 50% recurrence rate
See these more frequently in adults now: about 1/3 CF pts are adults these days

CF Upper airway disease

Nasal polyposis (shouldn’t see nasal polyps in child) Pan-sinusitis: maldevelopment  opacifiction, erosion
 Nasal polyps + asthma in child: 99% of time it’s CF!  All CF pts; Tx with abx, surgery
 3% CF pts; tx with topical steroids, surgical excision

CF GI disease
GI Sx start early: pancreas blocked, no good in utero production of fat metabolizing enzymes
 Meconium ileus (newborn) ≈ Distal intestinal obstruction syndrome (postnatal) – GI blockage
o Can lead to intussusception (telescoping of bowel into itself, can cause death)
 Meconium peritonitis too
 Pancreatic insufficiency is lifelong (malabsorption)
 Hepatic cirrhosis, portal HTN, neonatal direct hyperbilirubenemia, gall bladder obstruction
 Nutritional aspects (edema, hypoalbuminemia, hypovitaminosis A/K/E) – more rare these days

DIOS: Distinal Intestinal Obstruction Syndrome

 Not secreting chloride  stool accumulates at ileal/cecal junction
o Esp if pt out in heat, gets a little dehydrated
 Can densely adhere to wall intussusception, currant jelly stools, blood
 Tx with pancreatic enzymes, osmotic laxatives, enemas, even surgery

Pancreatic Disease
 ↓ volumes & bicarb content of pancreatic fluid
 15% have milder mutation pancreatic sufficiency (longer life span but ↑ risk pancreatitis!)
 Can lead to CF-related diabetes (3% kids, 14% adults)
o Block islets  ↓ insulin and ↓ glucagon (so ketoacidosis rare)
o Stresses can trigger hyperglycemia: pregnancy, corticosteroids, pulmonary exacerbation

Hepatobiliary Dz
 Eosinophilic concretions in bile ducts  ↑ gall bladder dz, gall stones, microgallbladder
 Cirrhosis in 3%: portal HTN, splenomegaly, esophageal varices

Congenital Absence of Vas Deferens

 Most CF males  absent / atretic vas deferens  azoospermia, infertility
o Even with mildest mutations
 Dx with palpation or U/S

Diagnosis of CF
Sweat Test
 Classic test; still used as primary test

 Pilocarpine to stimulate cholinergic pathway of sweat generation

o collect w/ filter paper, measure salt
 CFTR: reabsorb chloride to protect from dehydration
o So if there’s too much chloride (very salty sweat), CF
o ≥ 60 meq / L chloride is high

 Other causes too! (but usually CF)

Varies with age: up to 80 in some adults, ≥ 30 meq/L suspsicious in young infants

When should I get a sweat test? (these things mostly make sense)
 Meconium ileus, meconium peritonitis  Panopacification of sinuses/pansinusitis in  CBAVD/Azoospermia at any age (but
 Jaundice in infancy childhood becomes more obvious in adults)
 Hypochloremic alkalosis in infancy  Pancreatitis in late childhood/early  Recurrent or persistent pneumonia any age
 Heat prostration Infancy/adulthood (males) adulthood  Staphylococcal pneumonia at any age
 Failure to thrive Infancy/childhood  Unexplained cirrhosis in (especially infants)
 Rectal prolapse in childhood childhood/adolescence  Mucoid Pseudomonas in lung at any age
 Nasal polyposis in Childhood/adulthood  Gallstones in late childhood/early adulthood  Bronchiectasis at anyage
 Family history (sibling, first cousin)
Immunoreactive Trypsin
 Most CF patients develop ↑ immunoreactive trypsin, but 80% false positive rate

Dx by Genotyping
 1000x mutations in CFTR; internet databases; don’t know significance of all
 Commercial genotyping available

CFTR: an ABC Transporter

 ΔF508 is the classic mutation (European)
o 44% homozygous
o 45% heterozygous
o 11% non-ΔF508

Classes of Mutations in CFTR

I-III: more serious
I. Stop codons (no synthesis)
II. ΔF508 (block in processing, both not fully
constructed & doesn’t make to surface)
III. Regulation: can’t open with cAMP
(pancreatic insufficiency CF if 2 serious mutations

IV-V: milder mutations (If one serious, one milder: mild dominantes - milder phenotype)
IV. Altered conductance
V. Reduced synthesis

CFTR has a spectrum of pheonotypes

 Heterozygous, / mild mutation – maybe asthma modifier
 CF Syndrome: maybe mild mutations only  sinusitis alone (atypical CF phenotype)
 Cystic fibrosis: Severe/Severe genotype

Organ-Specific Vulnerabilities
 Organs that make lots of protein & secrete slowly through long tortuous passages
 Genotype: predictive of pancreatic sufficiency but not other diseases (meconium ileus, liver dz, diabetes)

Pulmonary Status
 Variable rate of decline (even with identical genotype)
 Complex structure / function, main cause of morbidity / mortality

↑ CFTR carrier frequency in…

 Obstructive azoospermia  Disseminated bronchiectasis  Sinusitis
 Idiopathic pancreatitis  Diffuse bronchiectasis associated with  (Sarcoidosis)
 Allergic bronchopulmonary aspergillosis rheumatoid arthritis

CF Treatments
Aspect of CF Treatment
High Sweat Chloride Dietary Salt (a disease you ↑ salt for!)
Chest Physiotherapy/DNase
Thick Airway Mucus
Hypertonic Saline
Chronic Lung Infections Antibiotics
Inflammation Anti-Inflammatories
Respiratory Failure
Lung Transplant
Pancreatic Insufficiency Pancreatic Enzymes
Meconium Ileus PEG, stool softeners
Islet Cell Loss Insulin, Pancreatic Transplants
Male Infertility, CBAVD In Vitro Fertilization
Biliary tract insufficiency Bile acid salts

Some Data and Stuff

Better survival with more recent birth cohorts

 ↑ with nutrition, vitamins, enzymes, abx, better tx / analaysis of data / use of registries (best practices)

FEV1 ↓ with age but ↑ with BMI

 Try to keep BMI of CF pts up!

Respiratory severity ↑ with age (more normal lung fxn in children)

 Once you lose it, won’t get it back

Bacterial infections vs time

 Pseudomonas: 80% pts from 25-34 yo
 ↑ MRSA these days
 B. cepacia – especially bad

Lung transplant: not a good solution; limited organs available, tons of side effects, risk of death
 Trading one disease for another

Median predicted survival now 38 years (↑ but still – only 50% live to be 38!)

Disorders of the Lower Airways
“When noisy breathing is not asthma”

Clinical Approach
Physical Exam of the Chest  Onset
 Inspection: Vital signs (resp rate, SaO2), retractions, contour  Alleviating / exacerbating factors
 Percussion (dullness vs hyperinflation) o Position
o Diaphragmatic domes normally w/in 1-2 finger breadths of scapular tips
o Occurrence: sleep or activity
 Palpation o Response to therapy
 Auscultation is the big one  Other associated symptoms:
o Inspiratory or Expiratory COUGH (never normal in babies!)
o Airway disease = narrowing
(laminar vs turbulent air flow depending on radius)
 Something pushing in from outside!
Position Sound Ins/Exp More detail
Above thoracic output Stridor Inspiratory
High pitched Peripheral (e.g. asthma)
Below thoracic output Wheezing Expiratory
Coarse sound Central (larger airways)

Where do sounds come from? THE AIRWAY!

 Turbulent = loud, laminar = quiet
 Most from trachea, medium sized bronchi
 Peripheral airways: nearly silent; contribute little to total resp resistance
o Unless asthma / narrowing

Describing breath sounds

 Respiratory phase
 Bronchial (tubular): equal loudness I/E o Inspiration (stridor) or end-inspiration (crackles)
 Vesicular: I>E, soft expiratory phase o Expiration (wheezes)
 Location (e.g., central or peripheral)
 Quality (e.g., monophonic or polyphonic)

Lower Airway Lesions in Newborns & Infants

“Wheezing since birth” – noisy on 1st day of life
 Think congenital lesions (vascular ring, tracheal web, absent pulm valve, congenital lobar emphysema)
o All result in tracheal compression – can see expiratory flow reduction

Congenital Thoracic Malformations:

old nomenclature separated; now lumped together
 Affected lobes remain filled with fluid at birth (radiodense), then later air
 Recurrent infection is common complication, often with abscess formation (periphery)
 Unaffected lobes: usually normal, can be compressed
 Get an electrocardiogram (associated with cardiac abnormalities)

CTM: foregut cysts:

 Not pathogenic in and of themselves but press on other things; can get infected
 Most common cyst in infancy (Sx = compression) but
50% diagnosed >15yo (Sx = chest pain, dysphagia)

o Small incidence of malignancies
 Tx: often lobectomy (no recurrence with complete excision)

CTM: Congenital cystic adenomatoid malformations

 Often solid / fluid filled at birth  air filled with time
o Can see air-fluid level on CXR
 Classification: related to location and potential for malignancy
o Associations with other syndromes & malignancies
 Tx: resection (esp. infection)  most surgeons remove

CTM: Pulmonary sequestration

 Pulmonary tissue separated from functioning lung and
supplied by SYSTEMIC circulation
 Etiology: 2 theories

o Congenital: accessory lung bud;

primitive perfusion from systemic circ

o Acquired: focus of infection/scarring

 develops systemic blood source

 Anatomy of pulmonary sequestration

(w/in parenchyma, Asx until infected (adolescence)
Intralobar 75% usually L posterior basal) (recurrent “pneumonia”, abscess formation, abnormal CXR)
(beneath L. lower lobe; perfused by
Detected in infancy (associated malformations)
Extralobar 25% abnormal artery coming from below
diaphragm) Diaphragmatic lesions, gut anomalies, polyhydramnios
Extralobar extrathoracic Rare
 Treatment: surgical excision

Congenital large hyperlucent lobe

Formerly “Congenital lobar emphysema” (CLE)

Incidence: 1:20k-30k
 Mechanical obstruction in utero(25%) – mucosal flap, lobar twisting on pedicle
 Airway collapse (25%) – bronchial atresia, deficient bronchial cartilage
 No clear etiology (50%)

CXR: over inflated lobe

 compressing trachea
 pushes everything over to right
 Hyperlucent(over inflated) – can get V/Q mismatch
 Upper lobe disease: here LUL, most common, > RUL > RML, LL rare)

Pathology: ↓ # alveoli, ↓ bronchial wall cartilage

Treatment: expectant management (see if improves) – previously more excision
 Some mechanical vent techniques might help (oscillatory vent if ventilated)

Tracheoesophageal Fistula
 Incomplete mesodermal separation of primitive foregut
 Esophagus connected to trachea
o See barium swallow to right
 More common: 1st and twin pregnancies; ↑ with ↑ maternal age
 2/3 have other associated abnormalities
 Presents around birth (feeding / breathing abnormalities)

4-5 different kinds:

 H-type fistula: small connection between trachea & esophagus
o Can present later: recurrent pneumonia / wheezing but rare
 Esophageal etresia is most common (esophagus stops as blind pouch, distal esophagus connects to trachea)

Can all be repaired surgically

 Local tracheomalacia & brassy cough common after TEF repair
o Malacia = “softening”
 Esophogeal dysmotility (vagal disruptions)  recurrent aspiration
 TEF can recur after repair (very rare)

Vascular Rings
 Can show up early but often later in life
 Extrinsic obstruction of trachea & esophagus
 Most common: double aortic arch; can see others too
o Wraps around trachea, compresses
o Just sever one of arches (smaller one)  everything OK

CXR: look for right sided arch (sensitive but not specific – common variant)

Pulmonary swing:
 Left PA originates from Right PA, courses posterior to trachea (see CT)
 Results in tracheomalacia

Tracheomalacia / Bronchomalacia

Dynamic collapse of trachea secondary to increased compliance of tracheal rings

 Worse on exparation
 Most common in distal 3rd
 Can get kinking (transition from malacic segment to normal segment)
 Babies: spells of apnea (collapse airway with crying, etc.) - dangerous

Laryngeomalacia Tracheo/ bronchomalacia

stridor, inspiratory, upper airway wheeze, louder on expiration
Many people have combo! Biphasic noise (may indicated fixed narrowing)
Most gets better over time if not repeated injury from aspiration, other probs

Parents often aware of noisy breathing early but often don’t present until 6-12 mo
 Fremitus is uniform, normal lung volumes (obstructing), lack of retractions, poor bronchodilator response
 ALWAYS present if you have a TEF

 Left mainstem bronchus has keyhole appearance
 Right mainstem bronchus has a lip (airway flopping into lumen)

Tracheal Bronchus
If airway not built right (e.g. aberrant RUL bronchus coming off of trachea instead of bronchus)
 Picture: ignore arrow, actually the top bronchus branching off early

 Normal variant, predisposes to chronic RUL atelectasis

o Pigs are all like this, so called “pig bronchus” too

 Don’t need to do anything about it unless causing problems

Foreign body aspiration

 Can occur in any age, frequently toddlers / preschoolers (stick stuff in mouth)
 Choking Hx often negative
 Unilateral / “monophonic” WHEEZE
(same tone throughout)
o Phase delay on differential stethoscope

CXR often doesn’t help: most are radiolucent

 may be difficult in younger pts to get insp/exp films
 L-R decubitis films show absence of deflation

Lack of response to all medical therapy

Chronic Congestion
 CHRONIC WET COUGH IS A RED FLAG – something else is going on! (wheezing + cough)
o Beyond just narrowing of airways
o CF / primary/acquired dyskinesia, passive smoking, humoral immunodeficiency, retained foreign body

Gastroesophageal Reflux Disease

 Recurrent croup is often a sign of GERD (“spasmodic” with no sign of URI)
 Hoarseness
 Can lead to laryngomalacia (acid)
 Poorly controlled asthma

INFLAMMATION of BRONCHIOLES usu. occurring in children UNDER 2 YRS OLD resulting from VIRAL INFECTION
 Disease of WINTER, infectious in nature

 Airway obstruction  Ventilation / perfusion mismatching
o Airway wall edema o Hypoxemia
o Mucous plugging
o Bronchospasm  Paradoxical breathing
 Increased airway resistance o Decreased tidal volume
o Air trapping o Decreased minute ventilation
o Decreased compliance
o Increased work of breathing

Path: large mucus plug, fairly loose, some cellularity


 RSV: causes lower airway dz in infants (cold in adults)
 Also: influenza A, metapnuemo, paraflu, adenovirus, mycoplasma pneumonia

Clinical manifestations of RSV:

 Rhinorrhea
 Cough
 Low grade fever
 Apnea (CNS-related)
o Early: RSV-specific
o Later: sign of resp failure
 Tachypnea
 Hypoxemia
 Wheezes / Crackles


Remember: not all that wheezes is asthma… but most of it is

Upper Airway Disorders

Anatomy Review
Nasal Cavity Turbinates and sinus ostia (ethmoid, maxillary, frontal)
Nasopharynx Airway posterior to the nasal passages, adjacent to soft palate
Oropharynx Posterior to the tongue
Hypopharynx Superior to and including the vocal cords
Larynx Airway inferior to the vocal cords

Where are potential sites of obstruction?

Upper Airway Development

Birth: large epiglottis

 covers soft palate, forming channel that encourages nasal breathing


o If you block the nose, hard to breathe!
o Cleaning out the nose (congestion) helps with many problems

 If epiglottis closed, straight shot to esophagus:

o but everything close to each other: easy to aspirate!

Laryngeal Position
 Infants: have high larynx (C3)
o more efficient breathing with nursing
o ↓ aspiration risk

 Adults: larynx drops down (C5)

o Better for speech (longer passage)
o Older, better coordination, can handle aspiration risk

 Neanderthals were somewhere in between (some capacity for speech)

Airway Obstructions: Overview

Nasopharyngeal obstruction Oropharyngeal obstruction Laryngopharyngeal obstruction Infection
 Choanal atresia  Tonsillar hypertrophy  Laryngomalacia  Croup
 Adenoid hypertrophy  Micrognathia  Vocal cord paralysis  Epiglottitis
 Macroglossia  Subglottic stenosis  Diphtheria

Nasopharyngeal Obstruction
Choanal atresia
 Nasal cavities extend poteriorly during development, directed by palatal process’ fusion

Membrane separates nasal cavitiy from oral cavity  thins & ruptures (mid 1 trimester)
 Rupture failure = choanal atresia
o Remember infants are nasal breathers: 1° route of breathing obstructed

Epidemiology: most common cause of true nasal obstruction (1:10k)

 2:1 unilateral:bilateral
Associated with other congenital anomalies in 50%, including CHARGE
 Colomba, heart, choanal atresia, retarded growth, genital hypoplasia, ear defects
Choanal atresia, cont.

Presentation: can cause cardirespiratory failure on 1st day after birth

 Apnea, cyanosis, respiratory distress – relieved with crying / mouth breathing
o Re-establishing an airflow via mouth!

Dx: try to pass a #8 French catheter through each nostril to see if it’s patent!

 Aspiration from dyscoordination (2° to ↑ nasal airway resistance)
 Severe hypoxemia with sleep (trying to breathe through nose  obstructive apnea)

Treatment: INTUBATION is most effective initial treatment

 Surgical excision with stent (4+ wks) to prevent recurrence is definitive

Waldeyer’s Ring
 “adenoids & tonsils”

 Pharyngeal tonsils = adenoids

 Lingual tonsils too
 Palatine tonsils = normal tonsils
 Tubal tonsils – back side

Tonsils have strategic placement

 Where particles should drop out of air
 Lymphoid tissue picks it up

But if they get inflamed, they can cause instruction

Adenoid Hypertrophy
 Long face
 Open mouth breathing (blocked nasal passage)
 “Nasal” voice
 ↓ development of maxilla over time

Maxillary development is dependent on nasal breathing

 Some weird oxygenation effect?
 Chronic obstruction  ↓ maxillary growth

Treatment: adenoidectomy

Oropharyngeal Obstruction
Tonsilar hypertrophy
 “kissing tonsils” – see pictures
 Can be graded but airway obstruction doesn’t correlate directly
o Also depends on airway tone is with sleep!
 Cause airway obstruction

Presentation (Tonsilar hypertrophy)
 Snoring is most common
 Muffled voice, drooling, trouble swallowing, choking on solids (more rare)
 Obstructive sleep apnea: no airflow movement during breathing (dx with sleep study)
o mostly between 2-6 years old (tonsils growing, airway smaller)
o or adolescents (heavier  more soft tissue)
Treatment: Tonsillectomy (80-90% successful)

 often associated with underlying genetic disorders

Pathophysiology: Mandibular hypoplasia of unclear etiology

 often associated with cleft palate
o (small jaw  tongue displaced ↑  palate shelves can’t fuse)

 Mild micrognathia: may improve by school age
 Severe micrognathia: can require intubation / tracheostomy

 Better breathing in prone position (tongue flops forward out of airway)

 Mandibular distraction  mandibular remodeling (pic)

 Labiolingual suturing (“tongue-lip adhesion”)
o prevents tongue from being posteriorly displaced
o temporary (until child grows)

 Big tongue
Associated with: angioedema, congenital syndromes (e.g. Beckwith-Wiedemann), lymphangioma
Pathophysiology: Tongue displaced into hypopharynx  obstructive apnea
Therapy: prone positioning, tongue debulking (rarely done)

Laryngopharyngeal obstruction
 Most common cause of stridor in infants
o Inspiratory noise, implies extrathoracic obstruction
o (Wheezing = expiratory, intrathoracic – e.g. asthma)

 Dynamic anomaly, cartilage collapses into airway
 Etiology unclear (no tissue anomalies, no differences in muscle bulk – maybe muscle dyscoordination, structural variation)

 Stridor onset since birth, minimal respiratory distress
 Worse in supine position and when agitated / active
 ↓ noise when at rest (↑ flow  ↑ turbulence – kind of like cardiac murmurs)
 Normal voice quality & pitch

Treatment: usually no therapy required (resolves by 12 mo)

Vocal Cord Paralysis
 #2 common congenital laryngeal abnormality
Bilateral VCP Unilateral VCP
Etiology  usually idiopathic  usually recurrent laryngeal nerve damage
 can be from CNS lesions (anything pressing on  birth trauma or with cardiac surgery too (e.g. PDA
brainstem ligation)
Presentation  Diagnosed late  Normal phonation & stridor
 Mild stridor, hoarse phonation, occasional aspiration  Occasionally as airway emergency
(if on top of cough, cold, etc)
Treatment Correct CNS lesions, may need tracheostomy Improves (↓ inflammation, other VC compensates)
 Signs of birth trauma: think VCP possibly
 VCP: can be early sign of brain stem / spinal cord compression
 Acquired too: local neck trauma, head trauma, viral compression (more rare in kids)

Subglottic Stenosis
Congenital Acquired
Epidemiology 3 most common laryngeal anomaly Related to airway inflammation
Incomplete recanalization of larynx Inflammatory factors: prolonged intubation, traumatic
during gestation intubation, oversized endotracheal tube used, GE reflux
Presentation Recurrent / persistent croup Hx of prior intubation, airway instrumentation
If Severe stenosis: biphasic stridor, dyspnea, labored breathing
 Gets much worse if they have a cough or cold  already obstructed
If you’re having trouble with expected ET tube size, be careful!

Treatment: frequently requires tracheostomy or airway surgery (more than other two)

Laryngopharyngeal Obstructions: Approach

 X-rays correlate poorly with actual degree of airway narrowing
 Flexible laryngoscopy for Dx
 Pulmonary function tests  upper airway obstruction (need > 6yo kid)

Laryngoscopy: looking down into the airway

Epiglottis somewhat omega-shaped

Laryngomalacia Can see that it’s dynamic (collapsed on picture
to right)

Unilateral vocal cord paralysis

(lack of bulk on paralyzed side in L picture, doesn’t
Vocal cord
completely close in R picture)
Opening: should close completely (aspiration risk)

Subglottic Very narrow opening

stenosis (all subglottic stenosis closing it up)

Laryngopharyngeal Obstructions: Complication
Inability to coordinate feeding
 Growth failure, aspiration
 Treatment: occupational therapy or feeding tube (worst-case scenario)

Obstructive apnea (GET A SLEEP STUDY)

 Hypoxemia  growth failure, neurodevelopmental delay, pulmonary HTN & cor pulmonale
o Sleep study for snoring kids!
 Treatment: CPAP / BiPAP (stent open airway), airway surgery and/or tracheostomy

Viral Croup (Laryngotracheobronchitis)
 Most common infectious cause of upper airway obstruction in pediatrics
o Peak 18-24 mo
o Often post-URTI (coryzal prodrome)

Most common agents (75% cases): parainfluenza viruses (esp. PIV1)

 Edema  narrowing; stridor from turbulence
 Smaller airway, poor cell-mediated immunity  predisposition of airway obstruction
 Cricoid cartilage: complete ring (not C-shaped like lower down in trachea, bronchi)
o Bigger reduction in lumen (so more predisposition to obstruction) (resistance ↑ with r4)

 Barking cough, hoarse voice, inspiratory stridor (exertion / agitation), restlessness
o Drooling / resp distress in severe cases
 Symptoms worse at night
 Hypoxemia / hypercarbia: severe upper airway obstruction
 Hx of recurrent croup suggests underlying abnormality
(more than 3-4x in same kid)

X-ray: STEEPLE SIGN is classic

 Supposed to be open airway but blocked!
 Doesn’t correlate with severity of obstruction

 Nebulized epinephrine (α-adrenergic effects vasoconstriction, ↓ edema)
o beta-agonists don’t help
o Doesn’t affect duration of croup
o REBOUND can occur – keep watching the kid for a while!
 Heliox mixtures  ↓ turbulence but no large studies
 Most studies: no benefit with humidified air
 Corticosteriods: supported by evidence but type, route, dosing regimen debated


Cellulitis of supraglottic structures

 Typically 2-7 yo in autumn / winter
 Incidence ↓↓ with HiB vax

Pathophysiology of Epiglottitis
 HiB  99% of cases historically
o Other bacteria & some viruses since vaccine
o HiB still in non-immunized, vaccine failure
(trisomy 21, prematurity, malignancy, immunodeficiency)

 Rapid for HiB, more gradual for strep
Sore throat / dyspnea  muffled voice, drooling, tripod position, toxic appearance
o Picture: kid tripoding (leaning forward, on hands; retractions too)
 Stridor isn’t prominent but can occur with worsening obstruction


 (looks like large thumb on epiglottis - inflammation)
 Getting X-rays before airway secured = controversial


 Call ENT or anesthesia IMMEDIATELY
 Inhalational induction of anesthesia, intubation:
but be ready to do tracheostomy

 Abx: cover HiB & Strep

 Some evidence for empiric use of steroids

Prognosis: Intubation time: 1.3 days for HiB, 6d for Strep

 Incidence ↓↓↓ with vaccination
 Exudative material clogs / blocks airway (gray films)
 Antitoxin is mainstay of therapy

Important Points
Upper airway obstruction can present as a medical emergency
 Secure the airway first, then worry about diagnoses
 Nasal obstruction can pose significant problems for obligate nasal breathers (infants)
Obtain polysomnography (sleep study) to assess severity of obstructive apnea
 Pulse-oximetry alone is not adequate
 Asymptomatic examination while awake can be misleading
Why we treat:
 Obstructive apnea can lead to growth failure, developmental delays, and right ventricular failure