Pathophysiology: Lung
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 1 Formulas to Memorize Alveolar gas equation: If on room air: simplify it! 𝑷𝑨 𝑶𝟐 = 𝑭𝑰 𝑶𝟐 × 𝑷𝑩 − 𝟒𝟕 𝑷𝒂 𝑪𝑶𝟐 ) 𝟎.𝟖 𝑷𝑨 𝑶𝟐 = 𝟏𝟓𝟎 − ( 𝑷𝒂 𝑪𝑶𝟐 ) 𝟎.𝟖 − ( PAO2 FIO2 PB PaCO2 Use to calculate A-a difference (alveolar – arterial) Normal values: < 20 on room air (20% O2) < 100 on 100% O2 Increase: suggests venous admixture (poorly oxygenated blood reaching circulation) Alveolar O2 tension Fraction inspired O2 Barometric pressure (corrected for water pressure, - 47) Arterial CO2 Arterial Blood Gases: know normal values pH 7.35-7.45 PaO2 80-100 mm Hg PaCO2 35-45 mm Hg 2 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 o Volume at zero transmural pressure: residual volume (unstressed volume) changes with volume (less compliant at higher volumes) 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 airliquid 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 expiration 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 3 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 Laminar concentric layers of air flow slipping past each other @ different velocities (faster in middle) Turbulent molecules tumbling around (still with a net vector in flow direction) Resistance: independent of gas density Resistant: strongly dependent on gas density (↑ with ↑ density) near bifurcations; areas with eddies Transitional partially disrupt laminar flow 4 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) Distribution Upper or lower? Unilateral or bilateral? Masses (>4cm)? Nodules (<4cm)? Infiltrates? Interstitial? Mixed? Alveolar? Water Blood Cells Pus Protein Calcium Effusions? Reticular (lines) Nodular Combined Honeycomb Ground glass 5 Pulmonary Function Testing Spirometry: Inhale to TLC Exhale as rapidly/completely as you can Measure exhaled volume vs. time Results: 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 ↑ Normal or ↓ ↓ Obstructive Common Causes Of: Restriction Small / stiff lungs Pulmonary fibrosis Small / stiff chest wall Kyphoscoliosis Obstruction Respiratory muscle weakness ALS ↑ airway resistance Chronic bronchitis ↓ lung recoil Emphysema Increased airway closure 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 6 Can also have patient inhale as fast as possible at end of spirometry to generate flow-volume loop (see right) Lesion Upper airway obstruction Affects… inspiratory flow > expiratory expiratory flow > inspiratory COPD Fixed obstructions (e.g. tumor around trachea) could affect both 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) If on room air: simplify it! PAO2 = 150 – PaCO2/0.8 o Room air close to 20% oxygen Inspired [O2] changed by water vapor & CO2 PAO2 FIO2 PB Alveolar O2 tension Fraction inspired O2 Barometric pressure (corrected for water 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) 7 Causes of Hypoxemia Cause Description V/Q Mismatch Maldistribution of V relative to Q (ventilation / flow) Some areas are overventilated (↑ PaO2) but doesn’t correct for underventilated areas (↓ PaO2) Extreme V/Q mismatch A-a Response to O2 ↑ Corrects ↑ Doesn’t correct nl Good response can ↑ resp lots of venous blood gets to L heart without traversing ventilated alveoli Shunt E.g. collapsed alveoli, septal defect, etc. – can be intrapulmonary or extrapulmonary Alveolar O2 diluted by ↑ PACO2 Hypoventilation PACO2 MUST be ↑ Diffusion impairment Decreased FIO2 acidosis! Hypoxia with exercise, not at rest Red cells don’t have time to reach equilibrium on exercise Altitude, for instance ↑ with exercise 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 pH: Acidosis (<7.35) vs Alkalosis (> 7.45) Can calculate pH changes for PaCO2 changes (see table to right) Calculating pH changes due to PaCO2 changes A 1 mmHg ↑ in PaCO2 causes 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: 8 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 o o Pt inhales 0.3% CO in 10% He (both diluted equally, He is marker), holds breath 10 seconds Exhaled mixed alveolar gas sampled, exhaled [CO], [He}]measured, 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) INTERPRETING LUNG VOLUMES ↓ TLC Restriction ↑ TLC Hyperinflation ↑ RV Air trapping Key Points Patients can be pathophysiologically categorized with use of: Spirometry and Flow-volume curves ABGs DCO Lung volumes Patients can be diagnosed with H&P, PFTs, x-rays…. 9 Interstitial Lung Disease Pathogenesis of restrictive diseases: Stiff lungs (don’t expand) Stiff chest wall (or too small) Respiratory muscle weakness (diaphragm rises small lungs) Interstitial Lung Disease: STIFF LUNGS 150+ clinical entities can cause ILD “Diffuse parenchymal lung diseases” would be better o Lung is simple tubes (airways: asthma & COPD are Dz) blood vessels (pulmonary HTN) parenchyma (alveoli) – the stuff that isn’t tubes or vasculature ILD: A restrictive disorder ↓ TLC (by def’n) ↓ FVC (almost always) Normal FEV1/FVC (no flow restriction) ↓ DLCO (specific to stiff lung restrictive dz) 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 CLINICAL CLASSIFICATION OF ILD Occupational/environmental Connective tissue disorders Drug / treatment-induced dz Idiopathic disorders Hereditary / genetic “Other” disorders Pneumoconiosis (aspestos, silicosis) Toxic inhalation (ammonia, sulfur dioxide) Hypersensitivity pneumonitis (farmer’s lung, pigeon-breeder’s lung) Pretty much any autoimmune disease (scleroderma, RA, SLE, polymyositis-dermatomyositis, etc) Amiodarone, cancer drugs (bleomycin, methotrexate), radiation therapy Idiopathic pulmonary fibrosis Sarcoidosis Bronchiolitis obliterans organizing pneumonia (BOOP), Eosinophilic granuloma Various mutations: surfactant proteins B/C, ABCA transporters, telomerase mutations, Hermansky-Pudlak syndrome (all Hopkins-discovered) Lymphangitic carcinomatosis, respiratory bronchiolitis, tuberous sclerosis / lymphangiolyomatosis (LAM), 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 10 CXR: ↑ interstitial markings Fibrosis Predominantly LOWER LOBE involvement & SUBPLEURAL CT: 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?) Pneumoconiosis Accumulation of dust in the lungs; results in tissue reaction Reaction can be collagenous or non-collagenous Excludes dust exposure that results in: o malignancy, asthma, bronchitis, or emphysema Silicosis Most prevalent chronic occupational lung dz in the world! Inhalation of silica, usually in quartz form Settings (esp. if not using appropriate respiratory protection) o Types of Pneumoconiosis Silicosis Asbestosis Coal workers’ pneumoconiosis Talcosis Berylliosis Hard-metal pneumoconiosis o Tungsten carbide o Cobalt dust 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) CXR: Small rounded opacities in upper lung zones Conglomerate (>10mm) opacities o Called progressive massive fibrosis (PMF) o o Looks like tumor Small opacities can progress to PMF PFTs : identical to IPF May see airflow obstruction, ↓ FEV1/FVC occasionally Pathogenesis: 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! 11 Diagnosis of Interstitial Lung Disease Patient history is crucial! Chest radiograph useful (& chest CT) Fiberoptic bronchoscopy o o o Check for exposures, how long have Sx been going on, any Hx autoimmune dz, other sx? Broncheoalveolar lavage: rule out infection, look for eosinophils 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 o Cyclophosphamide 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 12 COPD COPD: chronic disease characterized by REDUCED EXPIRATORY AIRFLOW Risk factors for COPD CIGARETTE SMOKING Diseases included in COPD: both caused by cigarette smoking Emphysema Chronic bronchitis COPD: Clinical Course Progressive ↓ in pulmonary function Punctuated by acute exacerbations Eventually: disability & premature death Others: asthma / asthmatic bronchitis / bronchiectasis / CF technically COPD too, but not in common parlance Emphysema Anatomic definition (need Bx to Dx) Definition: Progressive destruction of alveolar septa & capillaries Airspace enlargement & bullae development Destruction of septa ↓ elastic recoil (↑ compliance) ↓ maximum expiratory airflow ↑ static lung volumes Chronic Bronchitis Historical definition (Dx via phone!) Definition: chronic mucus hypersecretion > 3mo chronic sputum production for 2 consecutive years ↑ airway resistance ↓maximum expiratory airflow Older age Male gender (?) Airway hyperreactivity Low socioeconomic status Alpha-1 anti-trypsin deficiency Asthma (for comparison) Episodic cough, wheezing, dyspnea Often considered pathophysiologically separate from COPD unless chronic abnormalities present: Lung function Cough Sputum (“asthmatic bronchitis”) Natural History of COPD FEV1 normally ↓ with age; much faster in COPD 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 13 Pan-Acinar vs Centrilobular Emphysema Remember: acini / lobules are the functional unit surrounding one respiratory bronchiole Affects Part of Lung Pan-Acinar Entire acinus Base > Centrilobular Respiratory bronchiole Apex > apex base Cause Picture Alpha-1 antitrypsin deficiency Cigarette 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! Evidence: 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 Pink Puffer Blue Bloater Emphysematous Hyperinflated Thin physique Bronchitic Less hyperinflated Obese physique Not dyspneic Picture Dyspneic Low PaCO2 Worse O2sat w/exercise Purses lips Shoulders elevated Leans forward Accessory mm to breathe High PaCO2 Better O2sat w/ exercise Cyanotic 14 Pathophysiologic Abnormalities in COPD Probably good to memorize these lists of 3 things Airflow Obstruction: causes 1. ↓ elastic recoil (emphysema) 2. ↑ airway resistance (chronic bronchitis) 3. ↑ airway smooth muscle tone (asthmatic bronchitis) Major pathophysiologic abnormalities in COPD 1. Airflow obstruction (Early) 2. Hypoxemia (Mid-course) 3. Pulmonary HTN (Late) 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 o o o o can’t blow out fast enough take another breath before fully exhaled ↑ end expiratory volume VT ↑ to keep up with metabolic demands 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 15 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 Impair quality of life May result in acute respiratory failure Can be prevented by inhaled bronchodilators, inhaled steroids Treatment for Acute Respiratory Failure Non-invasive positive pressure ventilation Intubation & mechanical vent if needed 16 Pathophysiology of Asthma Definition: Chronic lung disease characterized by 1. Chronic airway inflammation 2. Airway hyperresponsiveness 3. Variability in outflow obstruction Epidemiology 20M (7%) in US M>F in kids; F>M in adults Most common childhood chronic dz Prevalence, mortality rate ↑ ↑ mortality in AA pts (big gap!) Cause: UNKNOWN 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) Effectors 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 o o COPD, CF, other resp disorders 10-15% normal pts Can’t use by itself to Dx asthma 17 Variability in Airflow Obstruction Obstructive ventilatory defect present LOW FEV1/FVC RATIO (<0.7) 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 DYSPNEA o CHEST TIGHTNESS o WHEEZING 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 Hx: ↑ SOB, chest tightness, wheezing, cough PE: tachypnea, wheezing, prolonged expiration Radiology: hyperinflated, flattened diaphragms Triggers VIRAL INFECTIONS (most common cause; rhinovirus, influenza) Inhaled irritants (cig smoke, ozone, particulates) Inhaled allergens (dust mites, animal dander – cats, mice, etc) Exercise or cold air (irritates!) Occupational exposures Physiological alterations in exacerbation: Specific to patient (need to test & find out). Hyperinflation: 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 o o Can’t speak in full sentences Accessory mm of respiration (sternocleidomastoid, intracostals) retracting Paradoxical abdominal movement (abdomen in instead of out on inspiration) 18 3. Hypercarbic Respiratory Failure (↑ PaCO2) o o Diaphragm fatigued (↑ work of breathing) alveolar hypoventilation with ↑ PaCO2 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: o Allergy proof covers, Wash linens in hot water weekly o Vacuum/sweep weekly, Carpet/curtain removal, Humidity control Asthma management plan Can have pt measure peak expiratory flow rates at home Plan with pt: what actions to take based on peak flow • Helps with appropriate medication use (not overuse), can have pt call & schedule appt or prescription refill if drastic decline, etc. Pharmacologic treatment: 1. Bronchodilators: relax bronchial smooth muscle a. Short & long-acting β2 agonists, anticholinergic meds b. Inhaled c. Short-acting meds for RESCUE ONLY 2. Inhaled corticosteroids: anti-inflammatory a. Cornerstone of daily control therapy b. Add if pt needs their bronchodilator >2x/wk, for instance 1. Control symptoms 2. Prevent exacerbation 3. Maintain lung function as close to normal as possible Use objective measures: pt may not realize how bad it is! 4. Avoid adverse effects from medications 5. Prevent irreversible airway obstruction • Is asthma predisposition for COPD? 6. Prevent asthma mortality 3. Oral corticosteroids a. If can’t control with inhaled meds b. ↑ side effects 4. Others: if refractory to tx Drug Cromolyn sodium / nedocromil Leukotrine modifiers Theophylline Anti-IgE Description Anti-inflammatory, Mast cell stabilizer (↓ degranulation) Anti-inflammatory, less effective than corticosteroids (can use if mild asthma or corticosteroids contraindicated) Methylxanthine bronchodilator 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: Metered-Dose Inhalers (MDI) Spacers with MDIs Dry-powder Inhalers Nebulized Solutions Aerosolized spray with a propellant, currently with hydrofluoroalkane Requires slow deep inhalation with 10 sec breathhold to be most effective Minimizes oropharyngeal deposition with MDI Requires less coordination Can deliver drug as effectively as with nebulizer, even during exacerbation Rapid inhalation Dose lost if exhales into the device Expensive Depends less on patient coordination 19 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. 2. 3. 4. 5. 6. 7. 8. 9. Asthma is more common in children (↑ mortality in African-Americans) Three cardinal features: airway inflammation, airway hyperresponsiveness, variable airflow obstruction Genetics, respiratory infections, and environmental exposures all likely contribute to developing asthma Asthma Sx: wheeze, dyspnea, cough, chest tightness Bacterial infections rarely trigger asthma exacerbations Airway hyperresponsiveness (positive methacholine challenge) is not specific for asthma Airflow obstruction is due to bronchoconstriction, airway edema, and inflammatory exudates in airway lumen Pulsus paradoxus, a rising PaCO2, and respiratory muscle fatigue indicate a severe asthma exacerbation Treatment should include patient education, environmental control practices, an asthma management plan and medications based upon symptom severity. 20 Expiratory Flow Limitation Expiratory Flow Limitation (defn): ↑effort to exhale does NOT cause ↑ expiratory flow rate PATHOPHYSIOLOGY OF RESPIRATORY FUNCTION: BASIC CATEGORIES Restrictive ventilatory defects Obstructive ventilatory defects Gas exchange defects Difficulty getting air into the lungs Difficulty getting air out of the lungs Difficulty with efficient movement of 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) 21 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 1. Airway resistance (bronchi) 2. Tendency of airway to close (or resist closure) Contributing factors Picture Diameter Length Bronchi have cartilage, smooth mm to resist closure, but will still shut if pressure across them is more than slightly negative Smooth muscle tone (↑ with asthma so ↑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) 22 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 23 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 PVR = PA𝑸 LA o o 𝒕 Resistance = pressure gradient over flow. 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) LOWEST PVR at FRC 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 Definition: MEMORIZE THIS Mean Ppa > 25 mm Hg Can be measured non-invasively with electrocardiography Causes of Pulmonary Hypertension Remember R=ΔP/Q, so PVR = PPA− PLA 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 24 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 ARDS, positive pressure ventilation, others o + distorting capillaries mechanically, some dropping out ↑ arterial resistance: primarily vascular IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION (PRIMARY PULMONARY HYPERTENSION) Looking at more central, larger arteries Pulmonary Arterial Hypertension o Idiopathic, Familial, or associated with CVD / HIV / Liver disease /Drugs Chronic thromboembolic disease o Needs to be chronic o throwing lots of clots, ↑ resistance over time (occluding vessels downstream) No cause or association identifiable o Rule out other causes Women 20-45 yo Dyspnea >1 yr PPA markedly elevated at dx Median survival = 3 yrs (before Tx) TGF-β involved in vascular remodeling (definitely in familial forms, probably in sporadic form too) 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 25 Consequences of pulmonary HTN ACUTE (e.g. Acute PE) CHRONIC (e.g. chronic lung dz, PAH) RV not hypertrophied; fails quickly (pushing against ↑ resistance) RA pressure ↑ as RV fails ↑ catecholamines to ↑ mean systemic pressure, ↑ HR ↓ Venous return / CO shock, sudden death Acute PEs have 10-15% mortality RH has time to hypertrophy o See BIG RV and RA RA pressure ↑ over time (can’t eject everything) pulmonary hypertension Venous return, CO maintained (↑ sympathetics, ↑ 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 Prognosis: Correlates with mean pulmonary arterial pressure! o See graph: ↑ PPA = ↑ mortality Similarly: o o o ↑ RA pressure (RH failing!) = 3 mo median survival ↓ CO (failing) = bad prognosis Hyponatremia (compensatory mechanisms failing) = bad prognosis Treatment of pulmonary HTN Goals of treatment: UNLOAD the RV o Vasodilation Reverse hypoxia & active vasoconstriction O2 is a vasodilator! Reverse remodeling Avoid in situ thrombosis & embolism from deep veins (anticoagulants) VASCULAR MODIFIERS Prostaglandin I2 (prostacyclin) Vasodilation & inhibition of remodeling Requires chronic perfusion but improvement in survival (50% at 5yrs vs 20% w/o Tx) Endothelin receptor antagonists (e.g. Bosentan) Endothelin usually leads to vasoconstriction, proliferation, migration of smooth mm (reverse!) Can give orally; good functional data (six minute walk) but not good data for survival (should correlate?) PDE5 inhibition (e.g. sildenafil / Viagra®) ↑ cGMP vasodilation, inhibition of remodeling Can give orally, again good functional data but not good data for survival Lung transplant: cures PAH but has significant problems in its own right 5yr survival is ~50% (worst of transplants) Summary: 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 26 Obesity & Breathing Disorders Obesity: BMI kg/m2; >25 overwt, >30 obese. Growing problem (ha!). More obesity in Missisippi. (mentally recreate obesity epidemic maps) Obstructive ↓ 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 Snoring Choking, gasping Alterations during sleep Excessive movements Insomnia Cardiopulmonary dysfunction Hypertension Glucose Intolerance MI / Heart Failure / Arrhythmias Cor Pulmonale Alterations in daytime function Excessive hypersomnolence Intellectual deterioration Fatigue What do you see on overnight sleep study? 1. Periods of no ventilation 2. ↓ O2sat as a result 3. ↑ esophageal pressure variations (trying to inspire: asphyxic response) 4. Microarousals: waking up from sleep (although not the whole way – patient doesn’t fully awaken) Interruptions in sleep Daytime hypersomnolence, etc. 4 1 2 3 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) 27 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 Obesity: More common in upper body obesity (“apples” – mostly males) o o o Fat encroaching on neck / pharyngeal tissues ↑ collapsibility Fat ↑ load on resp system / impedes gas exchange 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: AE = ↑ 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 28 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 o o o Below closing volume (where airway closure starts): some of your airways are going to be closed Microatelectasis too (small areas of collapse; worsens shunt) V/Q mismatch & hypoxemia can result Hypercapnia: ↑ 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 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 ↓ VCO2 (produce less carbon dioxide!) WEIGHT LOSS (even moderate loss ~ 5% helps!) Maintain oxygenation o o ↑ PIO2 (supplemental oxygen) Treat sleep apnea (repeated ↓ in oxygen sat) 29 Ventilatory Failure Lung failure Primary feature Clinical syndromes Pump failure Hypoxia Hypercarbia Pneumonia, Asthma, COPD, 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 I Slow (S) IIa Fast-fatigue-resistant (FR) IIb Fast-fatigable (FF) Oxidative capacity High Medium Glycolic Fatigue Slowly Moderate Quickly Strength Low Medium 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 Remember that TIDAL EXPIRATION is PASSIVE o Use active expiration during exercise, obstruction, dyspnea, pulmonary function testing Abdominal muscles & internal intercostals Essential for STRONG COUGH (clear mucus!) 30 Mechanisms of Respiratory Muscle Failure IMBALANCE between DEMAND and CAPACITY ↑ demand, ↓ capacity, or both RM demand: how much are you breathing and how hard is it to breathe? ↑ demand with … Because… Need to get rid of CO2 (e.g. obesity) ↑ CO2 production Minute ventilation Respiratory system mechanics ↑ Dead space ↑ respiratory drive ↓ lung compliance ↓ chest wall compliance ↑ airway resistance Alveolar ventilation is needed to get rid of CO2: ↑ total ventilation if ↑ dead space to preserve VA By definition Harder to breathe if stiffer Pushing against more RM Capacity: what determines it? Intrinsic muscle function Neural function Lung volume o o FRC Remember: muscles have maximum in the tension-length relationship 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 Hyperinflation: 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 Steroids (COPD Tx) chronic myopathy Myopathy ↓ oxidative capacity END RESULT IN COPD ↑ demand + ↓ capacity = failure 31 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 MOF after sepsis Demylenation or axonal degeneration Critical illness myopathy After corticosteroids or neuromuscular blockade 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 Lower Higher Diaphragmatic Paralysis Causes Unilateral Cardiac surgery, trauma, tumor, stroke, herpes zoster Bilateral Neuropathies, herpes zoster, vasculitis, Lyme dz Muscles affected Accessory / expiratory muscles Diaphragm spared Diaphragm affected (+others) Results Weak cough pneumonia Need long-term ventilation Features Relatively Asx (DOE) ↓ max voluntary vent (25%) Severe dyspnea & ORTHOPNEA (really bad) ↓ VC and max voluntary vent (50%) 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? RM oxygen consumption ↑↑ (can reach 15% total) o ↑ work of breathing, have to move all that extra mass RM force ↓ (especially supine – same as above) RM endurance ↓ Why’s it bad? Makes you less tolerant: Of any lung disease Of low respiratory drive 32 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 Works in normals (↑ strength / endurance) but not patients Problem: already exercising resp MM all the time (e.g. COPD) Rest (mechanical ventilation) Allow respiratory muscles to recover from constant load Treatment strategies Exercise Rest Medications Pacing 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! Bronchodilators (dilate airways, ↓ hyperinflation) Theophylline (↑ strength, ↑ resistance to fatigue) Androgenic steroids (mixed results) Respiratory muscle surgery : Lung volume reduction Used infrequently these days Severe emphysema: ↑RM strength by ↓ hyperinflation ↑ lung fxn, sx, survival in some pts, but 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 33 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, characterized by: o Permeability pulmonary edema o Acute respiratory failure A syndrome (see box to right) CLINICAL DEFINITION OF ARDS 1. Acute respiratory distress. 2. Diffuse alveolar infiltrates on CXR 3. Severe hypoxemia (PaO2/FIO2 ≤ 200 mmHg) Example: PaO2 of 200 mm Hg on FIO2 = 1.0 4. Absence of left heart failure (pulmonary capillary wedge pressure < 18 mmHg) Routes of Injury Inhalation Aspiration of gastric contents Pneumonia (diffuse bilateral) Smoke inhalation Near-drowning Blood-borne Sepsis Trauma Drug overdose (narcotics, ASA) Multiple transfusions Pancreatitis Venous air embolism Predisposing factors SEPSIS IS #1 40% pts with sepsis develop ARDS; 40% ARDS pts had sepsis as factor Sepsis / trauma / gastric acid aspiration = 75% of cases Multiple factors multiply risk of ARDS development Direct injury to lung Lung contusion Radiation Other risk factors for ARDS SEPSIS / trauma /gastric acid aspiration Older age Severity of associated illness Cig smoking / chronic lung dz Chronic alcohol abuse Clinical Course of ARDS Variable onset of signs / symptoms Direct lung injury (gastric aspiration, etc): Blood-borne causes (sepsis, trauma, drug OD): explosive course (resp distress over min-hrs) 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) 34 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 o Sensitive to small increases in capillary pressure Insensitive to changes in blood oncotic pressure Normally: 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 o o Airway resistance ↑ (extra weight pushing on them, less tension pulling airways open) regional hypoventilation Alveolar instability: abnormal surface tension forces? V/Q mismatch too (same mechanisms as above, just not complete) – in transition zone NOT contributing: diffusion impairment or hypoventilation ↓ Lung compliance: lung is smaller & stiffer o o Why? ↓ ventilated lung volume (alveoli compressed / closed) ↑ surface forces (surface tension ↑) ↑interstitial edema (heavier weight of lung itself) Fibrosis (later) All this means respiratory muscles have to work harder Findings: CXR, CT, biopsy Area of compression (shunt – no ventilation) with transition zone above (V/Q mismatch) tons of interstitial edema on CXR Diffuse alveolar damage on biopsy Thickened alveolar/capillary membranes Hyaline membranes Diffuse inflammatory infiltrate 35 Management of ARDS: Oxygen Therapy Oxygen Therapy: main strategy for ARDS treatment PEEP: essentially raising FRC Keep positive airway pressure at end expiration Recruits more lung: stents open compressed airways & alveoli w/ +pressure o ↑ FRC, ↓ shunt fraction, ↑ compliance Risks of PEEP: ↓ venous return ↓ cardiac output (↑ FRC ↑ resistance) Barotrauma (volutrauma) – overinflate lung (pneumothorax!) ↑ dead space (ventilated but not perfused) o GOALS OF O2 THERAPY FOR ARDS Arterial O2sat = 90% o (too high is toxic!) Keep FIO2 ≤ 0.60 Maintain cardiac output METHODS Mechanical ventilation PEEP (positive end-expiratory pressure) 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 o Ventilator-induced injury o Nosocomial infections (keep FIO2 ≤ 0.60) (keep tidal vol ≤ 6 ml/kg) pneumonia, catheters 36 Pneumonia Significance th 7 leading cause of death in US Leading cause among nosocomial infections M. tb is most deadly bacteria in world Pandemic influenza major geopolitical death Generally, patients with pneumonia do well (only 25% CAP hospitalized; 12% of those die) Need to recognize, assess risk, Dx, Tx Pathogenesis 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 Inhalation Micro-aspiration Aspiration Macro-aspiration Mucosal spread Hematogenous Organisms M. TB, Legionella, endemic fungi, viruses (e.g. flu), anthrax S. pneumo, H. flu, GNB, S. aureus Anaerobes (esp. those found in mouth) – not as pathogenic (need more!) People with seizure disorders, drug users, alcoholics, neuromuscular disorders, etc. – need big aspiration! Respiratory viruses 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 Endotracheal intubation Viral infection & smoking (knocks out mucociliary escalator) Immunodeficiency Antigenic drift / shift (Influenza virus) Capsule (resist phagocytosis) (S. pneumo, Cryptococcus) Evasion of phagolysosome killing (M. TB, Legionella) Clinical Presentation Symptoms: Fevers, chills, rigors (shaking) – cytokines, etc. Cough, sputum production, dyspnea, pleuritic pain (sharp with inspiration / coughing) – when more established Signs: Infiltration crackles Consolidation dull to percussion, tubular breath sounds Pleurisy (friction rub – scratchy sound on insp.) CXR: INFILTRATE (diagnostic!) 37 Pneumonia vs Acute bronchitis: important for treatment Pneumonia Bronchitis Cough & Fever Cough + Fever Sx PE VS: P >100,RR >24, BP Crackles, consolidation X-ray Etiology Antibiotics? Infiltrate BACTERIAL YES Normal VS Rhonchi, wheezes (except flu) Negative VIRAL NO Infiltrate: hallmark of pneumonia Diagnosis: CXR Patterns Lobar = restricted by fissure Consolidation Air bronchogram: outline of bronchi stand out against fluid-filled alveoli Lobar No normal airflow: alveoli filled w/ fluid pneumonia Pneumococcal; other bacterial pneumonias especially Spotty, patchy infiltrate around central airways Bronchopneumonia Not a homogenous lobular pattern Viral / atypical pneumonias especially Linear, reticular patterns (“web like”) Less dense, fluffier infiltrates Interstitial pneumonia Inflammation in interstitium (fluid, not pus) No air bronchograms Viral / atypical pneumonias especially Necrosis debris discharged via connection to airway (leaves cavity) Lung abscess or cavity Air-fluid levels (if still some pus around) – means pyogenic bacteria (S. aureus, Klebsiella, oral anaerobes) limited Ddx: GNR, S. aureus, M. TB, fungi 38 Diagnosis: Sputum & Culture Quality of sputum: Good: Bad: Polys Lots Few Squamous epithelial cells Few Lots Grossly From Thick mucus Saliva Lower resp tract 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 Likely pathogen isolated from resp secretion that… Is screened to distinguish sputum with saliva Gram stain: predominant pathogen c/w culture result Culture: Moderate to heavy growth Definitive Cause Likely pathogen isolated from normally sterile site (blood, pleural fluid) OR Definite pathogen isolated from resp secretion – these guys are never incidental! o Bacteria: Legionella, mycoplasma, M. TB, B. anthracis o Viruses: Influenza, paraflu, RSV, SARS o Fungi: Pneumocystis, endemic fungi Can’t call it definitive if it could be there for other reasons! Other rapid ID techniques: Antigen detection / IF (urine, resp. secretions, blood), Nucleic acid amplification (resp secretions), Ab detection (blood) Clasisfying Pneumonia Acute Sub-acute / Chronic Acute vs Chronic evolves over hours / days (S. pneumo, H. flu, Legionella – fast growers) 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 S. aureus, Pseudomonas/GNRs, Enterobacteriaceae Hospital-acquired Onset >48h after admission Community-acquired pneumonia Causes: Bacterial (80%) > Viral (15-20%) ≫ Fungal (1-2%) > parasites ( < 1%) See chart: * = not commonly isolated from sputum / blood Treatment: often EMPIRIC (and successful) Common Strep pneumoniae H. flu Legionella * Mycoplasma pneumoniae* Chlamydia pneumoniae* Viruses* Less common Staphylococcus aureus Moraxella catarrhalis Gram-negative bacilli Anaerobic bacteria* Respiratory syncytial virus* Parainfluenza* Adenovirus* Metapneumovirus* SARS coronavirus* 39 Classification of CAP: typical vs. atypical “Typical” pneumonia Onset Acute Symptoms Fever / chills / Rigors Cough Lung exam findings CXR Leukocytosis Etiology Productive of purulent sputum Consolidation Dense infiltrate YES (WBC > 15k) Strep pneumoniae, H. flu “Atypical” pneumonia Subacute Nonspecific, systemic, more viral: Headache, pharyngitis, myalgias Non-productive cough Few findings Patchy / interstitial infiltrate Modest (WBC < 15k) 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 Legionellosis Epidemiology: At-risk: Dx: Treatment: MORTALITY: 2-5% of CAP, sporadic in general pop, epidemics (hotels, hospitals) age > 40, COPD, immunosuppressed (old, smoking / drinking too much – like a Legionnaire) urinary antigen detects 80% (doesn’t grow well) macrolide or fluoroquinolone 10-20% ! Influenza Epidemiology: Mortality: Sx: Dx: Rx: Prevention: common (seasonal), also pandemic (drift/shift) 36k/yr, esp. elderly elderly high fever, myalgia, headache, cough clinical Dx > Ag test > culture amantadine / neuraminidase inhibitors (give w/in 36hrs) 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 + subacute course + putrid sputum (anaerobes) + compatible CXR + no other pathogens ID’d Treatment: Clindamycin, β-lactam + metronidazole, β-lactam / β-lactamase 40 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 Aspiration pneumonia, etc. Often see air-fluid levels Cavity M. TB, etc. – infectious, need respiratory isolation 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 Treatment Empiric: BROADER spectrum than CAP (more possible causative agents) Pathogen directed when you figure out what it is Prevention Proper infection control (↓ transmission) Identify aspiration-prone patients, ↑ HOB Avoid unnecessary antacid therapy (↑ bacterial contents in stomach ↑ infection if aspirate) Limit ventilator time 41 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 TYPE OF DEFECT Humoral Asplenia EXAMPLE(s) MAJOR PATHOGENS agammaglobulinemia Sickle cell disease, traumatic or surgical asplenia Neutrophil dysfunction chronic granulomatous dz Neutropenia Aplastic anemia, cancer chemotherapy, congenital AIDS, steroids, organ transplant recipients, cancer chemotherapy, lymphoma S. pneumoniae, H. influenzae (N. meningitidis) S. pneumoniae, H. influenzae (N. meningitidis) S. aureus, Serratia, Burkholderia, Aspergillus, Nocardia Gram-negative bacilli, Aspergillus sp. Pneumocystis, Mycobacteria, Nocardia, Fungi, Legionella sp. Herpesviruses (CMV, HSV) Cell-mediated immunity HIV: CD4 count what kind of infection you’re susceptible to (table for future reference too) CD4+ >500 200-500 50-200 <50 Pathogens S. pneumoniae, H. flu S. pneumoniae, H. flu, M. TB S. pneumoniae, Pneumocystis jiroveci, H. flu , M. TB, Histoplasma, Cryptococcus S. pneumoniae, P. jiroveci, M. TB, Other mycobacteria, 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 Diffuse interstitial infiltrate Diffuse nodular infiltrate (miliary) Localized infiltrate Large nodular/cavitary infiltrate Hilar adenopathy Associated pathogens Pneumocystis, CMV, Kaposi sarcoma, respiratory viruses Mycobacteria, Histoplasmosis, other fungi, Pneumocystis Typical bacteria, Nocardia, Fungi, Mycobacteria Staph aureus, Mycobacteria, Nocardia, GNR, Aspergillus, other fungi, anaerobes (aspiration) Mycobacteria, fungi, Kaposi sarcoma, lymphoma 42 Etiology by Age Newborn (0-6 wks) Children (6 wk–18 yrs) Group B strep GNR Chlamydia trachomatis (4-6 wks) H. flu Mycoplasma Viral*** Young adults (18-40 yrs) Middle age** (40-65 yrs) Elderly** (> 65 yrs) Mycoplasma S. pneumoniae S. pneumoniae C. pneumoniae Anaerobes Anaerobes S. pneumoniae H. influenzae H. influenzae 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 Co-morbidities (malignancy, cardiopulmonary dz) Alterations in host defense (don’t use bacteriostatic abx!) Marked derangements in vital signs Multiple lobe involvement Bacteremia Treatment Often empiric, usually successful Narrow spectrum when pathogen-directed ↑ need to identify specific pathogens if: o o o o Severe disease Host immunosuppressed Unusual features (e.g. cavity) Failure to improve Summary of Important Points Role: Agents: Distinctive pathogens: Diagnostic evaluation: Treatment: Most important infectious disease! Pneumococcus, Legionella, Influenza, mouth flora, M. tuberculosis Age, CAP, HAP, Compromised host Poor yield, colonizers in respiratory specimens, few rapid diagnostics Usually empiric abx and usually successful 43 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 o o Parietal: intercostals, internal mam. arteries Visceral: bronchial & pulmonary arteries 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 (lungscollapse, 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 ] Basically: ↑ with ↑ surface area, permeability of membrane to H2O, pressure difference between capillary & pleural space. ↓ with ↑ oncotic pressure difference (& ↑ impermeability of membrane to proteins Qf Lp A P/π σd • • = = = = = liquid movement filtration coefficient (H20 conductivity of membrane) surface area of membrane hydrostatic and oncotic pressures solute reflection coefficient ability of membrane to restrict large molecules 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 ↑ intravascular pressure / interstitial fluid o LV / RV failure, PE, pneumonia, SVC syndrome, pericardial effusions ↓ pleural pressure o Atelectasis, ↑ elastic recoil pres. ↑ pleural fluid protein ↑ permeability o pleural inflammation, VGEF ↑ peritoneal fluid Disruption of thoracic duct / intrathoracic vessels Iatrogenic Decreased Clearance lymphatic obstruction is #1 o 28 fold capacity for drainage vs normal production ↑ systemic vascular pressures o SVC syndrome, RV failure ? disruption of aquaporins o 4 types found in the lung; o AQP1 important in peritoneal fluid transport 44 Epidemiology: 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 Thoracentesis (taking fluid out of pleural effusion) Indications Contraindications Unless you know why it’s there, take it out! Absolute & relative Especially if: Unilateral effusions, particularly L-sided* Bilateral effusions of unequal size* Normal cardiac silhouette on CXR* Febrile, evidence of pleurisy Bleeding, infection pneumothorax (1.3-20%, 2% need chest tube placed) Also: o o o o (* = indicates that effusion’s less likely to be transudate) For relief of dyspnea too o vasovagal episodes / arrhythmia, tumor seeding of needle tract, puncture of other organs, re-expansion pulmonary edema death (rare) Visualize the effusion CXR (can lay down in lateral decubitus to help see level) Ultrasound o o good for ICU, small effusions, trauma, teaching U/S is really the standard of care these days Go OVER THE RIB 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 Major causes CHF, PE, cirrhosis (almost all cases!) Pneumonia, malignancy, PE, GI disease (>90% cases are one of these 4) Other causes Nephrosis, peritoneal dialysis, pericardial disease, hypoalbuminemia, Glomerulonephritis, sarcoid, SVC syndrome, urinothorax, myxedema Tons (huge DDx) CHF:can produce exudative effusion post-diuresis 45 Is it an exudate? Get both peritoneal fluid & serum LDH + protein compare. Need one of the following (looking for ↑ leakage into pleural fluid) o o Fluid : Serum protein >0.5 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) PPE, can treat by draining Hours later: air pockets develop with gas production, would need surgery After days / weeks: can rupture, requiring thoracotomy (major surgery) Therapy for PPE ABX: based on local prevalence, resistance DRAIN IT: 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 not identified in 6% BAD SIGN: Die in average of 4 months – PALLIATE by treating effusion o Primary tumor is most important predictor; performance status too 1° tumor GI CA Lung CA Breast CA / unknown Mesothelioma Survival 2.3 mo 3 mo 5 mo 6 mo Pathogenesis: tumor emboli visceral pleura, 2° seeding of pleural space / parietal pleura (or via diaphragm) 46 Work-up of malignant effusions: Thoracentesis (cytology beter than closed pleural Bx) Thorascopy (95% sensitivity) NOT Bronchoscopy (little value!) Treatment: for palliation Don’t use much sedation – no nerves in visceral pleura Go in and remove malignant nodules Talc blown in (acts as glue to hold lung to chest wall; Paramalignant Effusions (not all effusions in cancer are malignant effusions) related to primary tumor but not direct neoplastic involvement of pleura Etiologies: Post-obstructive pneumonia PPE, obstruction of thoracic duct chylothorax, PE, SVC syndrome, post-obstructive atelectasis ↓ PPL, low Ponc from cachexia, pneumonitis/trapped lung, cancer Rx, more also prevents re-accumulation of fluid) Pneumothorax Moving from fluid (effusion) to air (pneumothorax) in pleural space Pneumothorax: Physical Exam ↓ breath sounds ↓ fremitus Hyperresonance Tracheal deviation Hypotension Tachycardia Pneumothorax: AIR in the pleural space Spontaneous o Primary (tall, thin males – paraseptal emphysema?) o Secondary (HIV, other underlying disease) Traumatic (stab wound, etc) Presentation: depends on size & co-morbidities Small pneumothorax Tension pneumothorax R. apical pneumothorax; white line is visceral pleura; more radiolucent above (no lung features) R. tension pneumothorax; lung collapses entirely filled with air (more radiolucent), mediastinum shifts away from 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: imbalance in hydrostatic / oncotic pressure Lymphatics are important for drainage Drain effusions EARLY! Prior to getting a chest CT! Drain ‘em dry! Malignant effusion palliate early! Pneumothorax: can be life threatening 47 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 Common features of BPD high mortality rate Premature births in US 11% all US births < 37 wks (premature) 308k with low BW (<2500g), 58k with very low BW (<1500g) Abnormal CXR Respiratory symptoms Hx of supplemental O2 and/or mech vent in neonatal period Complications of prematurity: not just lung problems in these infants! BPD intraventricular hemorrhage periventricular leukomalacia necrotizing entercolitis retinopathy of prematurity 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 ATELECTASIS, OVER-INFLATION, CYSTIC CHANGES Hyperinflation, interstitial changes, cystic development “Mosaic changes” on CT: dense areas, hyperinflation Histology: areas of atelectasis, other areas with alveolar enlargement; fibrosis rxn Treatment 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 radicalsimpairs 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!) 48 Surfactant review Surfactant: 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 2×tension LaPlace’s Law: Pressure = radius 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 Steroids – double-edged sword o o consider high frequency ventilation (smaller volumes) and permissive hypercapnia 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 49 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 Cough with gagging / emesis (breathing really fast – hard to take bottle) Cyanosis with exertion Fast breathing Wheezing Ronchi / crackles Retractions and/or head bobbing (bad sign) Medical treatment Meds consider if need supplemental O2 Diuretics Inhaled steroids β-adrenergic bronchodilators Anticholinergics (nebulized ipratroprium, etc) Preterm > 3wks – acute / chronic distal diuretics may improve pulmonary mechanics BPD infants have ↑ airway resistance & inflammation use PRN (can develop tolerance) can help in respiratory aspiration IRDS – kind of like COPD lungs in a mechanistic sense Supplemental Oxygen Hypoxia in BPD infants (formerly thought was ↑ SIDS) o o ↑ number of central apneas ↑ 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 Gastroesophogeal reflux GER + aspiration Bronchomalacia / tracheomalacia (resolves by 2-3 yrs) Vocal cord dysfunction / subglottic stenosis Recurrent insults to lungs can worsen underlying BPD & prevent compensatory lung growth Growth continues through 2 years – window for catching up! 50 Pulmonary Outcomes in BPD infants Respiratory Sx in 25% young adults / adolescents who had BPD: Wheezing (↓ small airway flows) Recurrent pneumonia Chronic need for resp meds ↓ exercise tolerance Radiographic abnormalities ↑ risk of airway obstruction & reactivity (↓ FEV1) Course: 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 51 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 Systemic! Lungs Pancreas GI Repro glands Skin Chronic obstructive pulmonary disease Pancreatic exocrine insufficiency (↓ enzymes to digest fat) CFTR channel helps in stool transit Can’t develop (e.g. vas deferens) Sweat electrolytes ↑ (sweat test, messed up salt balance) Diagnosis by CLINICAL TRIAD: ↑ SWEAT CHLORIDE PANCREATIC INSUFFICIENCY CHRONIC PULMONARY DISEASE Respiratory Manifestations Chronic cough and bronchitis at first Bronchiectasis (no matter how well you treat) Recurrent pneumonia (staph aureus, pseudomonas aeruginosa) Chronic sinusitis, nasal polyps Hemoptysis, pneumothorax (↑ pressure cysts can pop!) Chronic airways obstruction, irreversible CF lung disease starts as endobronchial infection Max prevalence 50% age 5-17 yrs Staph aureus 25% age 2-5 H. flu Pseudomonas aeruginosa peaks age 18 & remains throughout life Burkholderia cepacia Progression of lung infections: Other notes now vaccine so ↓ incidence mucoidy, makes biofilms feared, very hard to treat 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, antiinflammatories 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 52 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) Nasal polyps + asthma in child: 99% of time it’s CF! 3% CF pts; tx with topical steroids, surgical excision Pan-sinusitis: maldevelopment opacifiction, erosion All CF pts; Tx with abx, surgery 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 Can densely adhere to wall intussusception, currant jelly stools, blood Tx with pancreatic enzymes, osmotic laxatives, enemas, even surgery o Esp if pt out in heat, gets a little dehydrated 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 o Block islets ↓ insulin and ↓ glucagon (so ketoacidosis rare) 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 53 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 Jaundice in infancy Hypochloremic alkalosis in infancy Heat prostration Infancy/adulthood (males) Failure to thrive Infancy/childhood Rectal prolapse in childhood Nasal polyposis in Childhood/adulthood Panopacification of sinuses/pansinusitis in childhood Pancreatitis in late childhood/early adulthood Unexplained cirrhosis in childhood/adolescence Gallstones in late childhood/early adulthood CBAVD/Azoospermia at any age (but becomes more obvious in adults) Recurrent or persistent pneumonia any age Staphylococcal pneumonia at any age (especially infants) Mucoid Pseudomonas in lung at any age 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 o o 44% homozygous 45% heterozygous 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 54 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 Idiopathic pancreatitis Allergic bronchopulmonary aspergillosis Disseminated bronchiectasis Diffuse bronchiectasis associated with rheumatoid arthritis Sinusitis (Sarcoidosis) CF Treatments Aspect of CF High Sweat Chloride Thick Airway Mucus Chronic Lung Infections Inflammation Respiratory Failure Pancreatic Insufficiency Meconium Ileus Islet Cell Loss Male Infertility, CBAVD Biliary tract insufficiency Treatment Dietary Salt (a disease you ↑ salt for!) Chest Physiotherapy/DNase Hypertonic Saline Antibiotics Anti-Inflammatories BiPAP Lung Transplant Pancreatic Enzymes PEG, stool softeners Insulin, Pancreatic Transplants In Vitro Fertilization 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!) 55 Disorders of the Lower Airways “When noisy breathing is not asthma” Clinical Approach History Onset Alleviating / exacerbating factors Physical Exam of the Chest Inspection: Vital signs (resp rate, SaO2), retractions, contour Percussion (dullness vs hyperinflation) o o Position o Occurrence: sleep or activity o Response to therapy Diaphragmatic domes normally w/in 1-2 finger breadths of scapular tips Palpation Auscultation is the big one o Inspiratory or Expiratory o Airway disease = narrowing (laminar vs turbulent air flow depending on radius) Other associated symptoms: COUGH (never normal in babies!) Something pushing in from outside! Position Above thoracic output Sound Stridor Ins/Exp Inspiratory Below thoracic output Wheezing Expiratory More detail High pitched Coarse sound Peripheral (e.g. asthma) 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 NORMAL ABNORMAL Bronchial (tubular): equal loudness I/E Vesicular: I>E, soft expiratory phase Respiratory phase o Inspiration (stridor) or end-inspiration (crackles) 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) 56 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 persists o Acquired: focus of infection/scarring develops systemic blood source Anatomy of pulmonary sequestration Intralobar 75% Extralobar 25% Extralobar extrathoracic Rare (w/in parenchyma, usually L posterior basal) (beneath L. lower lobe; perfused by abnormal artery coming from below diaphragm) Asx until infected (adolescence) (recurrent “pneumonia”, abscess formation, abnormal CXR) Detected in infancy (associated malformations) Diaphragmatic lesions, gut anomalies, polyhydramnios Treatment: surgical excision Congenital large hyperlucent lobe Formerly “Congenital lobar emphysema” (CLE) Incidence: Etiology: 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) 57 Tracheoesophageal Fistula Incomplete mesodermal separation of primitive foregut Esophagus connected to trachea More common: 1st and twin pregnancies; ↑ with ↑ maternal age 2/3 have other associated abnormalities Presents around birth (feeding / breathing abnormalities) o See barium swallow to right 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 58 Bronchoscopy: 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 59 Bronchiolitis INFLAMMATION of BRONCHIOLES usu. occurring in children UNDER 2 YRS OLD resulting from VIRAL INFECTION Disease of WINTER, infectious in nature Pathophysiology Ventilation / perfusion mismatching Airway obstruction o o o Airway wall edema Mucous plugging Bronchospasm Increased airway resistance o o o Air trapping Decreased compliance Increased work of breathing o Hypoxemia Paradoxical breathing o o Decreased tidal volume Decreased minute ventilation Path: large mucus plug, fairly loose, some cellularity Related to CERTAIN INFECTIONS 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 Therapy:SUPPORTIVE CARE Remember: not all that wheezes is asthma… but most of it is 60 Upper Airway Disorders Anatomy Review Nasal Cavity Nasopharynx Oropharynx Hypopharynx Larynx Turbinates and sinus ostia (ethmoid, maxillary, frontal) Airway posterior to the nasal passages, adjacent to soft palate Posterior to the tongue Superior to and including the vocal cords 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 INFANTS are OBLIGATE NASAL BREATHERS o o If you block the nose, hard to breathe! 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 o Adults: larynx drops down (C5) o o more efficient breathing with nursing ↓ aspiration risk Better for speech (longer passage) Older, better coordination, can handle aspiration risk Neanderthals were somewhere in between (some capacity for speech) Airway Obstructions: Overview Nasopharyngeal obstruction Choanal atresia Adenoid hypertrophy Oropharyngeal obstruction Tonsillar hypertrophy Micrognathia Macroglossia Laryngopharyngeal obstruction Laryngomalacia Vocal cord paralysis Subglottic stenosis Infection Croup Epiglottitis Diphtheria Nasopharyngeal Obstruction Choanal atresia Nasal cavities extend poteriorly during development, directed by palatal process’ fusion st 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 61 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! Complications: 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 Cause airway obstruction o Also depends on airway tone is with sleep! 62 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 o mostly between 2-6 years old (tonsils growing, airway smaller) or adolescents (heavier more soft tissue) Treatment: Tonsillectomy (80-90% successful) Micrognathia 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) Therapy: Mild micrognathia: Severe micrognathia: may improve by school age 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 o prevents tongue from being posteriorly displaced temporary (until child grows) Macroglossia 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 Laryngomalacia Most common cause of stridor in infants o Inspiratory noise, implies extrathoracic obstruction o (Wheezing = expiratory, intrathoracic – e.g. asthma) Pathophysiology: Dynamic anomaly, cartilage collapses into airway Etiology unclear (no tissue anomalies, no differences in muscle bulk – maybe muscle dyscoordination, structural variation) Presentation: 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) 63 Vocal Cord Paralysis #2 common congenital laryngeal abnormality Bilateral VCP usually idiopathic Etiology Presentation can be from CNS lesions (anything pressing on brainstem Diagnosed late Mild stridor, hoarse phonation, occasional aspiration Unilateral VCP usually recurrent laryngeal nerve damage birth trauma or with cardiac surgery too (e.g. PDA ligation) Normal phonation & stridor Occasionally as airway emergency (if on top of cough, cold, etc) Improves (↓ inflammation, other VC compensates) Correct CNS lesions, may need tracheostomy Treatment 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 rd Epidemiology 3 most common laryngeal anomaly Related to airway inflammation Incomplete recanalization of larynx Inflammatory factors: prolonged intubation, traumatic Pathophysiology intubation, oversized endotracheal tube used, GE reflux during gestation 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 Diagnosis: 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 Laryngomalacia Epiglottis somewhat omega-shaped Can see that it’s dynamic (collapsed on picture to right) Unilateral vocal cord paralysis Vocal cord paralysis (lack of bulk on paralyzed side in L picture, doesn’t completely close in R picture) Opening: should close completely (aspiration risk) Subglottic stenosis Very narrow opening (all subglottic stenosis closing it up) 64 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 Infections 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) Pathophysiology: 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) Presentation: 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 Therapy: Nebulized epinephrine (α-adrenergic effects vasoconstriction, ↓ edema) o o beta-agonists don’t help 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 65 Epiglottitis Cellulitis of supraglottic structures Typically 2-7 yo in autumn / winter Incidence ↓↓ with HiB vax Pathophysiology of Epiglottitis HiB 99% of cases historically o o Other bacteria & some viruses since vaccine HiB still in non-immunized, vaccine failure (trisomy 21, prematurity, malignancy, immunodeficiency) Presentation 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 X-ray: THUMB SIGN (looks like large thumb on epiglottis - inflammation) Getting X-rays before airway secured = controversial Therapy: MEDICAL EMERGENCY 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 Diptheria 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 66
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