CVPR-Pulmonary+LOs

//These notes were prepared by James Rose, CO 2011. Note that lecture order and content may have been (substantially) reorganized since these notes were written.//


 * Respiratory:**

Diffusion and Perfusion I + II Thursday, April 17, 2008 7:59 AM


 * Diffusion and Perfusion I + II, 4/17/08:**


 * Define arterial oxygen content
 * Recall that oxygen can exist in blood in two forms, either dissolved in blood or bound to hemoglobin.
 * The arterial oxygen content, CaO2, is just the sum of the concentrations of the dissolved and hemoglobin-bound forms in arterial blood:
 * **CaO2 = [freely dissolved O2] + [Hb-bound O2]**
 * Note that the vast majority of O2 in blood is bound to hemoglobin-- oxygen doesn’t interact very favorably with water in the blood (recall that from the discussion on surface tension).
 * Normal value of CaO2 is **20.7** mL O2 per 100 mL of blood.
 * (Note that although CaO2 is a combination of the concentrations of oxygen that's free and the oxygen that's bound to hemoglobin, PaO2 is a measure __only__ of the oxygen that's freely dissolved in the blood.)
 * Define solubility coefficient and describe how they differ for oxygen and CO2
 * Solubility coefficient: how well a gas dissolves in blood.
 * Multiplied by the partial pressure of O2 in arterial blood, this gives the concentration of O2 freely dissolved in that blood: [dissolved O2] = aO2 * PaO2
 * Obviously the above equation works for CO2 as well.
 * aO2 = 0.0013 mM/torr (very unfavorable).
 * aCO2 = 0.03 mM/torr (about 23 times more favorable than O2).
 * This means that __CO2 dissolves much better than water in blood__. This means that CO2 diffuses across alveolar membranes much faster than O2 (this becomes important later).
 * Describe the basic properties of the oxy-hemoglobin dissociation curve (ODC)
 * It's a graph of % saturation of hemoglobin over the partial pressure of O2 in blood.
 * Recall that there's a linear part of the curve (from about 20 to 50 torr PO2) and a much more flat part of the curve (above about 50 torr PO2).
 * Recall that the PO2 in arterial blood near the capillaries is about 95-- thus almost all of the hemoglobin (98%) is saturated with oxygen at normal ventilation. This becomes important later (see below). Also recall that normally deoxygenated mixed venous blood is about 75% saturated at a PO2 of about 40 torr.
 * Describe factors that promote rapid oxygen diffusion between alveoli and pulmonary capillaries in a healthy individual and how things can go wrong in disease
 * Diffusion across a membrane is determined by the following factors:
 * Pressure difference of the gas across the barrier
 * The area of the membrane (A)
 * The diameter of the membrane (d)
 * A constant (k, has to do with the properties of the medium it's diffusing thru)
 * Thus __Fick's Law__:
 * **Diffusion = (P1-P2) * (A/d) * k**
 * Another way of saying this: __things diffuse slower across thick membranes, faster across wide membranes, and faster when there's a good pressure gradient to roll down__. All of that is fairly intuitive is you think for a second.
 * Evidently you can roll the (A/d)*k stuff into a component called the "diffusing capacity." Trot that one out at the next cocktail party and see how it goes down.
 * Actually this equation is extremely important. If you understand it, then you understand how a wide variety of diseases affect gas exchange in the lungs (more on this later). So take a moment and really grok it.
 * Note that the area (A) of the alveolar membranes is really really big (about half a tennis court per lung). That helps diffusion.
 * Note that the thickness of the alveolar membranes (even when added to the water layer on the alveolus, the interstitial space between the alveolus and the capillary, and the thickness of the capillary walls) is really pretty damn thin. That helps also.
 * Note that there's a good-sized pressure gradient of O2 (PAO2 = 100, PmvO2 = 40 or so in the venous blood coming into the capillary). This, again, helps.
 * Note that the hemoglobin takes up the free oxygen in the blood and helps this gradient stay large-- as the oxygen diffuses into the blood, it's almost immediately bound to hemoglobin and doesn't affect the PO2 in the blood much, maintaining a low blood PO2 and keeping a fast rate of diffusion.
 * Because of all this, all the O2 diffusion from the alveolus into the capillary blood occurs during the first third or so of the capillary-- the rest of the capillary's length is effectively there to provide a "safety factor" that allows for the effects of disease or exercise.
 * Ie: if you've got a mild-moderate disease, or if you're exercising, O2 diffusion takes longer to occur, but you've got enough excess capillary length that by the time the blood leaves the capillary, it's still fully oxygenated.
 * However, if you've got a severe disease (interstitial fibrosis or emphysema), or if you've got a mild-moderate disease __and__ you're exercising, O2 diffusion takes long enough that it's not finished by the time the end of the capillary is reached-- thus the blood leaving the capillary is not fully oxygenated.
 * Note that CO2 diffusion is a little different. Although it also normally takes about a third of the way into the capillary to fully diffuse (for diverse reasons), CO2 diffuses __much more readily__ than O2 (due to its increased solubility in blood)-- thus even in severe fibrotic disease, CO2 diffusion generally remains sufficient to maintain a normal level of diffused clearance (though expiration can still be a hurdle to clearing that CO2 out of the alveolus).
 * Define perfusion and factors that influence it, including the effect of gravity
 * "Minute perfusion" (like minute ventilation): **Q** with a dot over it, representing the volume of blood flow through the lung in 1 minute.
 * Note that this number is the same as the cardiac output (since normally all of that CO is going through the lungs)-- thus it's normally about 5 (or 5.6) L/min.
 * Factors that affect Q:
 * __O2 tension__-- recall that low O2 causes hypoxic pulmonary vasoconstriction, which decreases local flow to the hypoxic segment.
 * __Capillary recruitment__-- recall that more blood flow through the lungs means more normally-closed capillaries open up to divert some of the increased flow. I think the point is to avoid building up increased back-pressure in the main pulmonary arteries.
 * __Gravity__-- increases perfusion at the base of the lung relative to the top of the lung (remember this from the first unit of cardio).
 * This is a fairly profound effect-- there's about __6 times__ more perfusion to the bottom than to the top.
 * Note that there's more relative perfusion at the bottom (6-fold) than there is relative ventilation at the bottom (2.5-fold). This will become significant in a bit.
 * Describe the effect of a shunt on arterial oxygen
 * **Shunt** : A portion of the blood flow which is __completely__ unventilated (not half, not two thirds; all the way shut and no exceptions). The reason for the vehemence will clear up in a bit.
 * Causes of shunts:
 * Obstructive disease (rare-- usually cause partial obstruction in alveoli, not full obstruction)
 * Heart defects (don't go to the pulmonary circulation at all)
 * Pneumonia (alveoli fill up with leukocytes, making them completely unventilated)
 * "Normal mechanisms"-- there is always a certain amount of shunting going on.
 * Bronchial circulation: a good deal of the bronchial blood goes directly into the pulmonary vein after perfusing the lung tissue, and thus forms a shunt (never oxygenated before going out into circulation).
 * This is one reason why arterial O2 levels tend to be a little lower than alveolar O2 levels.
 * The effect, as should be reasonably obvious, is to lower the total oxygen content of systemic arterial blood.
 * Think, for a moment, of two capillaries of identical sizes arising out of a single incoming vein, going to alveoli, and rejoining afterwards as arteries. Imagine for a moment that one of those alveoli is normally ventilated and that the other is completely unventilated. This is a shunting situation.
 * [I know that, technically, the channels going away from capillaries are veins, not arteries, and vice versa. Yes, yes; technicalities. We're referencing the concentration of oxygen in the systemic veins and arteries, which is what we care about for tissue perfusion. Bear with me.]
 * Ok. So basically the CaO2 in the combined artery is going to be exactly halfway between the CO2 in the ventilated arteriole (normally about 20.7 mL O2 per 100 mL blood) and the CO2 in the unventilated arteriole (which should remain the same as in mixed venous blood, normally about 15.7 mL O2 per 100 mL blood)-- about 18.2 mL O2 per 100 mL blood.
 * This means that you can calculate the fraction of the total cardiac output that is being shunted at any time by dividing the difference in oxygen concentration between the blood in the ventilated capillary and in the outgoing artery by the difference in oxygen concentration between the blood in the ventilated capillary and in the incoming vein:
 * **Qs/Qtotal = (CcapO2 - CaO2) / (CcapO2 - CmvO2)**
 * Calculate the shunted fraction of the total cardiac output
 * See above.
 * Describe the causes and effects of V/Q mismatch in arterial oxygen
 * In an ideal, weightless lung, the ventilation to an alveolus is roughly the same as the perfusion to that alveolus. (think of total alveolar perfusion and total ventilation-- about 4.2 L/min ventilation, about 5 L/min perfusion, thus a V/Q of close to 1.)
 * However, in an actual person, the ratio of V to Q in particular parts of the lung vary widely. Note that you can have a high V/Q in one place and a low V/Q in another place and still maintain the overall V/Q ratio in the lung as a whole.
 * V/Q mismatch is generally defined as a V/Q ratio that's either higher or lower than 1, within reason.
 * Causes:
 * Upright position, due to the effects of gravity:
 * Recall that ventilation at the bottom of the lung is about 2.5-times greater than the ventilation at the top of the lung ("Airway Resistance/Ventilation").
 * Recall that perfusion at the bottom of the lung is about 6 times greater than at the top of the lung (as stated above).
 * __So the V/Q ratio is going to be higher at the top of the lung at the bottom of the lung, despite the fact that both ventilation and perfusion go up at the bottom of the lung__.
 * Specifically: V/Q at the top is about (6/2.5 = ) 2.4 times higher than the V/Q ratio at the bottom.
 * This is why you get TB at the top of your lung. TB likes lots of oxygen.
 * Obstructive disease:
 * Similar to shunts, but only __partially__ unventilated alveoli.
 * Consider a situation in which you have three capillaries of identical sizes arising out a single vein, going to three different capillaries, and rejoining as a single outgoing artery. Grant for a moment that one capillary is very well ventilated (V/Q ratio of 10), one capillary is relatively normal (V/Q ratio of 1), and one capillary is partially obstructed (V/Q of 0.1).
 * [This might be expected in obstructive disease-- low ventilation in certain capillaries causes PaCO2 to rise, prompting an increase in respiratory rate, thus ventilating other alveoli extremely well and allowing slightly obstructed alveoli to rise to normal V/Q levels.]
 * We want to know the CaO2 of the outgoing artery, given the incoming CmvO2 of 15.7 mL O2 / 100 mL blood.
 * In the normal capillary, the CcapO2 should be about normal, about 20.7 mL O2 / 100 mL blood.
 * In the obstructed capillary, the CcapO2 should be quite depressed, say 16 mL O2 / 100 mL.
 * But in the very well-ventilated capillary, the CcapO2 really can't raise very much over the normally-ventilated capillary levels-- this is due to the shape of the oxy-hemoglobin dissociation curve, which shows that under normal ventilation, 98% of the binding sites for oxygen on hemoglobin are already occupied. So if you raise up the PO2 a lot (as in a high V/Q alveolus), there's only a very small increase in CcapO2-- say 20.9 mL O2 per 100 mL blood.
 * Summing these together and averaging, the arterial CaO2 is going to be (16 + 20.7 + 20.9 / 3 = ) 19.2 mL O2 per 100 mL blood.
 * What this means: you can't make up well for poorly ventilated alveoli just by ventilating other alveoli more-- the fact that you're normally binding all your hemoglobin to oxygen anyway means there's just not much more you can do that way. So V/Q mismatch in the lung always means you're going to have poorer perfusion of your blood, even if the total airflow and total perfusion stay constant.
 * That's one reason your lungs do hypoxic pulmonary vasoconstriction-- by constricting the incoming blood channels in low V/Q alveoli, you decrease Q and thus raise V/Q for that alveolus.
 * Notice also that under conditions of low CO2 (which result from over-ventilated alveoli with too high V/Q), bronchoconstriction occurs, which restricts V and thus lowers V/Q.
 * [Note that arterial CO2 levels are not affected much by normal __physiological__ V/Q mismatch because CO2 diffusion isn't dependent on hemoglobin saturation. As long as there's no change in overall ventilation or perfusion levels, the PaCO2 isn't going to change.]
 * Note, however, that in pathophysiological V/Q mismatch, in which the overall V of the lung decreases (as in interstitial lung disease or edema), arterial CO2 levels will be affected, but will be almost immediately compensated for by chemoreceptors that alter ventilation rate. See "Control of Breathing."
 * Describe how shunts and V/Q mismatch can be distinguished
 * The real difference: shunts have no ventilation at all (V/Q = 0). Low V/Qs have some ventilation, just not a normal amount ( 0 < V/Q < 1).
 * So if a patient's PaO2 is quite low, you want to figure out which one is causing it:
 * **100% O2** **ventilation** is going to be your acid test.
 * Recall that PaO2 is a measure __only__ of freely dissolved oxygen in blood, __not__ of oxygen bound to hemoglobin in the blood.
 * So if you measure PaO2 on 100% oxygen:
 * In a patient with a shunt, the 100% oxygen is not going to get to the blood in the shunt whatsoever (recall it's __completely__ unventilated). Thus the CO2 of the shunt isn't going to change. On the other hand, the 100% oxygen is going to diffuse and dissolve into the well-ventilated blood very strongly.
 * So when the two paths, ventilated and unventilated, join up again, you have a meeting of blood with completely saturated hemoglobin and lots of freely dissolved O2 (high PaO2) with blood with relatively unsaturated hemoglobin and very little freely dissolved O2 (low PaO2).
 * Because hemoglobin really likes to bind O2, when these two flows meet, the free oxygen in the one flow is going to be 'soaked up' by the depleted hemoglobin in the other flow.
 * What this means is that the PaO2 in the combined flow isn't going to be much greater than a normal flow (because all the free O2 has been picked up by hemoglobin).
 * That's for patients with shunts.
 * If you have a patient with V/Q mismatch, in the high V/Q alveolus, the hemoglobin will be completely saturated and the free oxygen in the blood will go way up, as before. In the low V/Q alveolus, however, there's enough ventilation to allow a fraction of the huge levels of oxygen to come into the blood-- which means the hemoglobin still gets completely saturated and the free oxygen goes up some as well (though not as much as the other).
 * What this means is that when the two flows mix again, there's no depleted hemoglobin in the low-V/Q channel to soak up the free oxygen in the high V/Q channel-- thus in the mixed flow, the free O2 levels are going to remain high and thus the PaO2 is elevated.
 * Bottom line: In shunts, the PaO2 doesn't go up much on 100% O2. In V/Q mismatches, the PaO2 does go up a bunch on 100% O2.

Lung Histology Thursday, April 17, 2008 8:00 AM


 * Lung Histology, 4/17/08:**


 * Describe the basic construction of the lung - lobes, segments, pleura, and branching of the conduction and vascular systems, and the relationship of the visceral and parietal pleura to ventilation.
 * You should know this by now.
 * Explain the flow of blood through the lung, both the pulmonary and bronchial systems. Be able to identify a blood vessel (as compared to a bronchus or bronchiole) in the lung.
 * Again, you should know this. Watch out for cuboidal epithelial cells in the bronchioles vs. squamous epithelial cells in blood vessels. In arterioles the squamous cells are also surrounded by a ring of smooth muscle.
 * Be able to identify the layers of the walls of the conduction system, and the functional reasons for their differences: The trachea, the bronchi, the bronchioles, and the respiratory bronchioles.
 * Mainly gone over in "Lung Microanatomy."
 * Describe the structure of alveolar septa, and the functions of their cellular and acellular components.
 * Mainly gone over in "Lung Microanatomy."
 * Outline the various defense mechanisms, both in the conduction system and alveoli, that prevent infection.
 * Mucus and lamina propria white cells in conduction system; macrophages in alveoli.
 * Describe the basic process of gas exchange at the blood-air barrier, the importance of surfactant, and be able to identify the layers of the blood-air barrier.
 * Mainly gone over in Dr. Schoppa's lectures.
 * Blood-air barrier: red cell membrane, capillary membrane (2 lipid bilayers), interstitial space, alveolar membrane (2 lipid bilayers).
 * State the underlying mechanisms for pathologies of the congestive diseases of cystic fibrosis, Kartagener's syndrome, and the particulate overload diseases such as black lung and silicosis.
 * CF: recall, defect in chloride transporter means no water output with mucus-- thus can't move the mucus.
 * Kartagener's syndrome: cilia congenitally don't work.
 * Particulate overloads: inhale particles that macrophages can't digest (soot, silicone). They die and are attempted to be ingested by other macrophages, which die in turn, etc.

Pulmonary Function Tests Friday, April 18, 2008 8:05 AM


 * Pulmonary Function Tests, 4/18/08:**


 * Identify the three major components of routine pulmonary function tests and how they are performed (measured)
 * __Lung volume__:
 * Helium dilution method: allow patient to inhale a mixture of helium (inert, won't get into blood) and allow equilibration of concentrations in the patient's lungs and the external helium mixture; then measure what the concentration of helium is in the external helium mixture and back-calculate from that what total volume the helium must be distributed throughout in order for the concentration to go down to that particular level.
 * Notice that this relies on uniform distribution throughout the lungs, and that for many patients this is not the case.
 * Body plethysmography: Patient sits in a sealed box with (effectively) noseplugs and pants through a tube connected to the outside of the box. This allows pressure and volume changes within the box to be measured with a high degree of accuracy, which allows indirect measurement of lung volumes. Don't ask me, I don't really get this.
 * But it doesn't rely on uniform distribution, so it's accurate for a wider range of patients.
 * __Airflow__:
 * Recall that airflow is a measure of how rapidly air can move through a patient's airways
 * The vital capacity is measured with spirometry (make the patient inhale and exhale at maximal effort)-- lots of effort.
 * You're looking at both the total amount of air exhaled (VC, or here called FVC), but more germane to rate, you're measuring __how much__ air is being exhaled in the __first second__ of expiration. That measurement is called the FEV1 (forced expiratory volume in the first second).
 * Generally this is measured as a ratio of FEV1/FVC, to measure what proportion of the vital capacity is being exhaled in one second.
 * Normal people's ratios are around **0.7-0.8** (70-80% of FVC exhaled in the first second of expiration).
 * People with obstructive disease (recall that this means an increased compliance and decreased elastic recoil) will have a __decreased__ FEV1/FVC.
 * People with restrictive disease (recall that this means decreased compliance and increased elastic recoil) will have an __increased__ FEV1/FVC.
 * Expiratory flow-volume loops (from the data obtained by spirometry) can help distinguish what kind of disease you're looking at:
 * Both obstructive and restrictive diseases attain a lower rate of airflow during forced expiration.
 * The shape of the curves is different. See pg. 7 in her notes for graphs. Obstructive curves look less homogenous than restrictive.
 * More importantly, the flow-volume loops can help diagnose __extrathoracic vs. intrathoracic obstruction__.
 * Extrathoracic variable obstructions get better with expiration (positive pressure on sides of airways) and worse with inspiration (negative pressure on sides of airways).
 * The loop is going to show a reduced flow rate during __inspiration__.
 * Intrathoracic variable obstructions get better with inspiration (negative pressure on sides of airways) and worse with exhalation (positive pressure on sides of airways).
 * The loop is going to show a reduced flow rate during __exhalation__.
 * Fixed obstructions stay bad throughout both inspiration and expiration.
 * The loop is going to show a flow rate that's crappy all over.
 * Note that wheezing sounds during **exhalation** is usually __asthma__. Wheezing sounds during **inspiration** are called **stridor**.
 * Note that later lecturers contradict this division.
 * So after you've collected some spirometry data, you want to look at the FEV1, FVC, FEV1/FVC ratio, and the flow-volume loops.
 * __Gas Exchange__:
 * Diffusing capacity of the lung for carbon monoxide capacity (**DLCO** ):
 * Determined by surface area, membrane thickness, gas diffusion pressure gradient, and the presence of hemoglobin. This shouldn't come as a surprise (recall Fick's Law, flux is proportional to P1-P2 x A/d); remember that oxygen uptake into hemoglobin is a main factor keeping the pressure gradient large and thus driving gas exchange.
 * Measured by having the patient draw in a vital-capacity breath of a mixture of helium and carbon monoxide and hold it for 10 seconds, then expire (er, breathe out). Then you measure how much CO you have left vs. how much you started with.
 * This looks at how much CO has diffused and been able to be bound into hemoglobin, which is a measure of DLCO.
 * Emphysema results in decreased DLCO due to the widespread destruction of alveolar walls (thus reducing A).
 * Interstitial lung disease results in decreased DLCO due to the thickening of the membranes between alveolar air and the capillaries (thus increasing d).
 * The filling of alveolar spaces with debris, dead macrophages, etc also prevent oxygen from getting to the capillaries and thus decreased DLCO.
 * Lots of or too few hemoglobin molecules can also affect DLCO (more hemoglobin, more DLCO due to preserved delta-P).
 * Decreased pulmonary blood flow decreases DLCO; increased pulmonary blood flow (as in heart failure) increases DLCO.
 * Increased also in asthma (we're not sure why) or alveolar hemorrhage (bleeding into the lung tissue will certainly cause increased DLCO up until you go into hypovolemic shock).
 * Note that emphysema and asthma (two types of obstructive diseases) have opposite effects on DLCO-- thus can use this as a distinguishing test.
 * Note you can also measure compliance. See below under pressure-volume curves.
 * Note you can also measure respiratory muscle strength. Note that people with lung diseases often can't cough very well-- thus risk for pneumonia.
 * Identify components of and distinguish between volumes and capacities
 * Four "basic volumes":
 * **Tidal volume** : how much air you normally breathe in and out.
 * **Expiratory reserve volume** : how much air you could expire (beyond the normal tidal fluctuation) if you forced it with maximal effort.
 * **Inspiratory reserve volume** : how much air you could inspire (beyond the normal tidal fluctuation) if you forced it with maximal effort.
 * **Residual volume** : how much air would remain in your lungs after exhaling the tidal volume plus the expiratory reserve volume-- that is, how much air stays in your lungs even if you're exhaling for all you're worth.
 * Note that this is always measured indirectly (no direct measurement technique)
 * Four "combined capacities":
 * **Functional residual capacity** : Expiratory reserve volume plus the residual volume.
 * Note that this is how much air is in the lungs when the lungs and chest cavity are at their __equilibrium__ (after a tidal exhalation)-- thus FRC is the amount of air in the lungs when they're at rest.
 * Note another name for this is the __thoracic gas volume__ (TGV).
 * **Inspiratory capacity** : Tidal volume plus the inspiratory reserve volume.
 * **Vital capacity** : Expiratory reserve volume plus the tidal volume plus the inspiratory reserve volume (inhaling maximally after a maximal exhalation-- that is, going from the residual volume to the inspiratory capacity).
 * **Total lung capacity** : Vital capacity plus residual volume (everything added together).
 * Define the determinants of FRC (aka TGV)
 * Increased FRC is indicative of obstructive diseases (> 115% of normal)
 * Decreased FRC is indicative of restrictive diseases (< 80% of normal)
 * Identify effort dependent and independent components to pulmonary function testing
 * If you need to exert effort, that's effort dependent. Write me if you have trouble with this one.
 * Distinguish between obstructive and restrictive patterns on pulmonary function tests
 * More or less broken down in the surrounding LOs.
 * Identify the 3 major factors contributing to DLCO
 * See above (A, d, delta-P, also hemoglobin).
 * Determine how pressure - volume curves are performed and assist in interpretation of abnormal pulmonary function tests (specifically in emphysema, asthma, obesity and fibrotic lung disease) including definitions of compliance and elastance
 * This is effectively "identify the pressure-volume curve"-- we mentioned compliance a few lectures back in "Mechanisms of Breathing and Compliance."
 * Relative to the normal curve:
 * Recall that the emphysemic curve is on the left and up (more compliance).
 * Asthma is slightly up and to the left, much less dramatic.
 * The fibrotic lung disease curve is on the right and down (less compliance).
 * The decreased chest wall compliance curve (obesity) is slightly down and to the right.
 * She emphasized these curves a lot so it's probably a good idea to know them.
 * Note that the slopes of chest wall compliance and asthma curves is more or less the same as that of the normal curve, while the slopes of emphysema and fibrosis are steeper and flatter respectively.
 * Compliance is effectively the inverse of elasticity (or, here, elastance), as mentioned before.
 * Identify major disease processes by PFT patterns integrating airflow, volume, and gas exchange measurements
 * Essentially this says "look at the surrounding LOs and be able to figure out what someone's got based on PFT information." Hopefully you can do that.

Obstructive Lung Disease Friday, April 18, 2008 8:11 AM


 * Obstructive Lung Disease, 4/18/08:**

[Great lecture but kind of scattered.]


 * [My attempt at summing up this lecture:]
 * We're talking mainly about the features and differences of asthma and COPD, as well as some distinguishing features of the bronchitis vs. emphysema components of COPD. We also mention, definitionally, brochiectasis.
 * Asthma: main features are hyperreactive bronchial smooth muscle and lots of inflammation and edema. Can treat it with agents that target each of these.
 * COPD: more of a syndrome than a disease; it's something that looks like a hybrid of bronchitis (in which you get mainly conducting pathway obstruction) and emphysema (in which you get mainly alveolar destruction). You can treat the bronchitis but the emphysema is generally pretty irreversible.
 * [Recall that breathing work is the sum of airway resistance work and elasticity work. Obstructive diseases will increase airway resistance and thus airway resistance work.]
 * Identify the major types of lung diseases manifest by airflow obstruction and their anatomic correlation (i.e. bronchus vs. bronchioles)
 * Asthma (in small bronchi/large bronchioles)
 * Asthma: airway smooth muscle is hyperreactive (airways narrow too much, too easily) along with chronic airway inflammation and edema.
 * Asthma: increasing incidence/prevalence (currently prev = 5% of US population). Mortality is also increasing. See Claman from way back when about 'hygiene hypothesis:' decreased childhood exposure to allergens leads to increased incidence of asthma.
 * Extrinsic asthma: IgE-mediated response to environmental allergen
 * Intrinsic asthma: non-IgE-mediated response to some kind of virus or altered AA metabolite state. Not much known about it.
 * Note that asthma results in plugging up airways with edema and mucus clogs, causing trapped air in the distal part of those airways.
 * Bronchitis (affects bronchi)-- see under COPD below.
 * Emphysema (affects alveoli)-- see under COPD below.
 * COPD, ie. emphysema + bronchitis-- edema and thickening of airways (bronchitis), destroyed and inflated alveoli (emphysema)
 * Note that these are two relatively independent factors-- a patient can have bad emphysema and mild bronchitis, or vice versa.
 * Bronchitis: productive cough at least 3 months without any other cause. Impairs ventilation through airways.
 * Mucus gland hyperplasia (lots of mucus) and thickening of epithelial airway surfaces and smooth muscle.
 * Emphysema: loss of normal alveolar spaces (enlargement of air spaces).
 * Effectively the breakdown-to-repair balance has gone badly out of whack and resulted in irreversible destruction of alveolar septa and alveolar capillary beds.
 * Recall that this can be prompted either by smoking or by alpha-1-antitrypsin deficiency or both, along with environmental causes.
 * Note that dynamic airway collapse ("Airway Resistance/Ventilation") is more severe in emphysema patients due to a decrease in elasticity.
 * Bronchiectasis (in small bronchi/large bronchioles): abnormally large dilation of proximal bronchi due to the destruction of muscular/elastic components of those walls.
 * Shows up as chronic productive cough that doesn't respond to normal treatment. Look for purulent, foul-smelling sputum.
 * Often caused by cystic fibrosis.
 * Bronchiolitis (in large-small bronchioles)
 * Upper airway obstruction (in trachea)
 * Describe the major clinical, physiologic, and pathologic components of obstructive diseases
 * Asthma:
 * Episodic
 * Can be reversed
 * Look for response to bronchoprovocation (see below)
 * Gets worse with exercise, cold, etc.
 * Normal to increased DLCO, as mentioned in the previous lecture.
 * Emphysema: patients often have tight abdominal muscles since they're using these muscles all the time.
 * Bronchitis:
 * Cough, rhonchi (gurgling sound caused by air passage through mucus), wheezing in lungs.
 * Emphysema:
 * Diminished breath sounds, abnormally hollow sounds to percussion.
 * Low FEV1 is correlated with low survival.
 * Decreased DLCO.
 * Common to bronchitis and emphysema:
 * pursed-lip breathing (trying to expel air harder from the mouth)
 * "tripod position" (patients sit and lean forward to stabilize the auxiliary muscles they're using to breathe)
 * [How COPD kills you: respiratory failure, right ventricular failure, pneumonia, pneuomothorax.]
 * Common obstructive disease features:
 * X-rays are often fairly normal, but look for flattened-out diaphragm and big lungs with a squished pericardial sac.
 * Note that the AP thoracic diameter often grows as well (big ol' lungs).
 * Recall that the fact that the diaphragm is usually flattened out results in a decrease in the contractile strength able to be generated by that diaphragm. So inhalation is impaired, which means the patient isn't able to compensate for even mild exertion.
 * Describe how the function of the diaphragm is impaired in obstructive lung diseases and how this further contributes to decreased airflow
 * See above.
 * Note that since the diaphragm isn't working well, obstructive patients will often use their accessory muscles (scalenes, SCM) to help out.
 * Identify how bronchoprovocation testing may be helpful in evaluating suspected asthma including methacholine and exercise testing
 * Have patient inhale increasing concentrations of nebulized methacholine (or histamine) and measure FEV1:
 * The idea is to see at what bronchoconstrictive stimulation the airways will start to close up. Asthmatics will have more of a problem and will have it at lower concentrations than normal breathers.
 * Describe the major components of asthma and treatments that are aimed at controlling these
 * (1) Smooth muscle tone tending to contraction and (2) inflammation of airways.
 * Beta agonists (albuterol) treat the smooth muscle contractions.
 * Glucocorticoids treat the inflammation. Can also use leukotriene-B antagonists, anti-IgE, or mast cell stabilizers (prevent mast cell degranulation).
 * Note that long-term inflammation of the airways results in remodeling. That is, obviously, a bad idea.
 * Note also that inflammation exacerbates the smooth muscle constriction.
 * Identify clinical and historical determinants of disease severity in asthma and COPD
 * Asthma: Recurrent infections tend to make it worse. The symptoms of asthma probably also worsen its own progression.
 * COPD: Smoking. Smoking. Smoking. Also look at the FEV1 (lower is bad).
 * Describe the differences between chronic bronchitis and emphysema - both physiologic and pathologic and the predicted response to therapy
 * Airway smooth muscle tone and airway edema is a feature of bronchitis, but not of emphysema. Treating these (which you treat with beta-antagonists and steroids, like asthma) can give you an idea of how much bronchitis a patient has vs. how much emphysema.
 * This is important because different COPD patients manifest either the bronchitis or the emphysema aspect much more than other patients:
 * **"Blue bloaters"** tend to have a lot more bronchitis than emphysema (hypoventilator, hypoxic, hyperpnea, cor pulmonale (peripheral edema).
 * **"Pink puffers"** tend to have a lot more emphysema than bronchitis (hyperventilator, have less hypoxia and hyperpnea).
 * [Some things she mentioned that it was important to know back and forwards:]
 * Asthma can be reversible if treated promptly. It's episodic. It gets worse with methacholine administration. You see a normal to increased DLCO. The pressure-volume curve is shifted slightly up and left.
 * Chronic bronchitis is only minimally reversible. You see a normal to increased DLCO.
 * Emphysema is irreversible. You see a decreased DLCO. The pressure-volume curve is shifted sharply up and left. You tend to see a marked lung hyperinflation.

Restrictive Lung Disease I Friday, April 18, 2008 8:11 AM


 * Restrictive Lung Disease I, 4/18/08:**


 * Define the primary physiologic abnormalities in restrictive lung disease
 * Restrictive lung __disease__ proper is due to increase in elastic recoil of the lung. This can be thought of as lung "stiffness."
 * Dr. Lavelle: think of elasticity here as what causes a spring to regain its original shape after being stretched.
 * [Restrictive lung __physiology__ is due to chest wall restriction (excess fat, bony masses, scoliosis, etc) or respiratory muscle weakness. Different thing.]
 * Increased elasticity: Due to __fibrosis__, __edema__, and/or __alveolar dysfunction__ (surface tension problems).
 * Increased deposition of connective tissue (fibrosis):
 * Effectively, proliferation of collagen and elastin in the lung in response to injury.
 * Enlarges interstitial matrix, thus increases elastic recoil, thus leads to stiffness.
 * Surfactant depletion: increases surface tension, causing alveoli to stiffen and not be able to enlarge during inspiration.
 * Pulmonary edema: can be in the interstitium (increases elastic recoil) and/or in the alveoli themselves (decreases surfactant function).
 * Increased elastic recoil causes increased elastic work (as opposed to increasing resistance work in obstructive diseases) in breathing. Again, need to work harder to expand the overly-stiffened lungs.
 * [A couple simplifications:]
 * Obstruction: hard to exhale.
 * Restriction: hard to inhale.
 * Describe general mechanisms that lead to restrictive physiology (i.e. diseases and/or processes)
 * Acute processes:
 * Pulmonary edema
 * ARDS (lots and lots of alveolar inflammation, can lead to scarring in the alveoli)
 * Pneumonia (alveolus is full of white cells and bacteria)
 * Pleural effusion (lung is surrounded by liquid)
 * Chronic processes:
 * Idiopathic
 * Interstitial lung disease (causes: collagen vascular disease, exposure to chemicals or drugs, genetic, or idiopathic)
 * Pleural fibrosis or plaques
 * Pleural effusion again
 * Determine how PFTs can distinguish between increased lung elastic recoil vs. increased chest wall resistance (ie between restrictive physiology and restrictive lung disease)
 * Gas exchange is restricted in increased lung elastic recoil. It's not restricted in increased chest wall resistance.
 * Note that the DLCO (gas exchange measurement) needs to be corrected for total alveolar volume to be accurate
 * Can also look at the pressure-volume curve-- if the __slope__ of the line is more or less similar to normal, problem is probably restrictive physiology. If the slope of the line is flattened, problem is probably restrictive lung disease.
 * Note that patients with muscle weakness but no restrictive disease and no other restrictive physiology will have normal FRCs.
 * Determine how PFTs are interpreted in patients with mixed obstructive/restrictive lung disease
 * Look for both a decreased FEV1/FVC ratio (usually indicative of obstructive disease) and also a decreased FRC or TLC (usually indicative of restrictive disease).
 * Note smoking can give you both idiopathic interstitial fibrosis and also emphysema.
 * [Treatment: not a lot of options. Try immunosuppressive therapy, maybe antioxidants, high levels of inspired oxygen, or lung transplantation.]
 * [Summary slide:]
 * Restrictive: stiff-spring.
 * You can use the shape of the pressure-volume curve to distinguish chest wall restriction from restrictive lung disease. Can also use gas exchange (DLCO corrected for alveolar ventilation) to do the same thing.
 * Types/causes of restrictive lung disease: interstitial fibrosis, edema, alveolar dysfunction (surfactant).
 * Chest wall restriction caused by pleural disease, bony abnormalities, obesity, and respiratory muscle weakness.
 * **Four etiologies for interstitial lung disease** : Collagen-vascular disease, chemical exposure, genetics, idiopathic.
 * Remember that mixed obstructive/restrictive diseases show a low FEV1/FVC ratio (like obstructive diseases) and a low FRC (like restrictive diseases).

Pathology of Obstructive Lung Disease Monday, April 21, 2008 7:48 AM


 * Pathology of Obstructive Lung Disease, 3/21/08:**


 * Know the 3 main forms of obstructive lung disease (asthma, emphysema and chronic bronchitis)
 * Asthma, emphysema, and chronic bronchitis. Also choking on Twinkies.
 * Obstructive diseases: diseases that __trap air in the lungs__, either due to something not letting it out (eg. bronchitis/asthma mucus plugs) or due to the destruction of tissue in the alveolar septa (emphysema).
 * Know the definitions of asthma, emphysema and chronic bronchitis
 * **Asthma** - obstructive disease characterized by episodic hyperreactive bronchial smooth muscle tone, inflammation and edema of the airways with mucosal plugs in the bronchi and bronchioles, and reactivity to albuterol (short-term) and steroids (long-term). Note also a normal to increased DLCO and pressure-volume curve with the same slope as the normal curve (though slightly shifted to the left and up). Can be caused by an allergic response to just about anything, particularly fungal antigens. Can also be caused by reaction to aspirin.
 * **Emphysema** - obstructive disease characterized by irreversible destruction of alveolar septa and subsequent enlargement of the alveolar spaces, without fibrosis. Note a chronic hyperinflation of the lungs and a loss of elastic recoil due to elastin destruction. Note also a decreased DLCO (due mainly to decreased membrane area) and a P-V curve sharply skewed up and left. Mainly due to smoking and/or alpha-1 antitrypsin deficiency.
 * **Chronic bronchitis** - idiopathic obstructive disease involving edema, inflammation, increased mucosal secretion, and narrowing of the airways (that last due to smooth muscular proliferation). Only partially responsive to treatment. Shows normal to increased DLCO. Looks for respiratory rates lower and tidal volumes larger than usual (bowl curve biased towards tidal volume and away from breath rate).
 * [Note that there is a fair degree of similarity between asthma and bronchitis in the symptoms and pathology-- thickened walls, edematous, increased mucus, transition to squamous epithelium given enough time, etc. Note episodic nature of asthma vs. chronic nature of chronic bronchitis, as well as sometimes-present eosinophils in asthma but not in bronchitis.]
 * Know the differences between atopic asthma, nonatopic asthma and pharmacologic asthma
 * Atopic- IgE mediated response to specific antigens.
 * Nonatopic- non-IgE mediated response, generally in response to viral infections.
 * Pharmacologic: response to drugs (aspirin is the most common).
 * Know and be able to recognize the microscopic changes associated with asthma in the bronchi
 * Pathologic changes in asthma: look for eosinophils, thickening of basal lamina, and hypertrophy of smooth muscle in bronchial walls.
 * Also: Curschmann's spirals (mucus plugs filled with shed epithelium).
 * Also: Charcot-Leyden crystals (red, crystallized eosinophil membrane).
 * Note that eosinophils are highly reactive to steroids-- thus if you have a patient on steroids, you won't necessarily have any eosinophils in your sample.
 * [Note that pathology isn't much good at diagnosing asthma, but can confirm an existing diagnosis pretty well.]
 * Know the main types of emphysema and what they are associated with
 * **Centriacinar** (associated with smoking)-- involves mainly the upper lobes. Fairly common. Note that proximal areas of the respiratory bronchiole/alveolar ducts are preferentially affected and distal alveoli are largely spared.
 * **Panacinar** (associated with alpha-1 antitrypsin deficiency)-- involves mainly the lower lobes. Fairly rare. Note that all areas of the respiratory bronchiole, alveolar ducts, and alveoli are equally affected.
 * **Distal acinar** (idiopathic, but associated with spontaneous pneumothorax in young adults)-- involves only the distal alveoli directly under the pleura. Fairly rare.
 * Be able to recognize gross and microscopic images of emphysematous lung
 * Gross: lungs are big; usually the upper two-thirds are more severely affected (centriacinar); look for bulli under/involving the pleura ('bubble' surrounding the airspace, can rupture and cause pneumothorax).
 * Note that the emphysema is usually worst right under the pleura.. thus watch out for pneumothorax.
 * Microscopic: a whole bunch of distended airspaces with destruction of the lung tissue. Dr. Groshong: "Too much white." (white = no tissue)
 * Often see carbon deposition. Note that this is relatively benign.
 * Be familiar with alpha-1 antitrypsin deficiency and the most common phenotype associated with panacinar emphysema
 * I think he means genotype, since we covered phenotype already (lower lobes).
 * ZZ-A1AT: ZZ type is the most severe (most will get emphysema by age 40, much quicker if they smoke).
 * The genotype is called PiZZ for no immediately discernible reason; the gene is on chromosome 14.
 * [recall that the lack of A1-AT enzyme allows trypsin to dissolve the proteins in the lung with impunity. Note also that trypsin is secreted by inflammatory cells (neutrophils), so inflammation in lungs (as due to smoking) is particularly bad.]
 * Know the main microscopic changes associated with chronic bronchitis
 * Enlargement of mucus-secreting glands; increased __Reid index__ (measure of the thickness of the mucus layer relative to the thickness of the airway wall).
 * Squamous metaplasia/dysplasia (can transform to squamous-cell carcinomas)
 * Narrowing of bronchioles by inflammation, mucus plugs, and fibrosis.

Pathology of Restrictive Lung Disease Monday, April 21, 2008 8:41 AM


 * Pathology of Restrictive Lung Disease, 3/21/08:**


 * Know the main categories of acute and chronic restrictive lung disease
 * [All: inflammatory/fibrotic changes in the lung, damaging the airways and alveolar lining cells. Note that collagen deposition (fibrosis) is irreversible, while inflammatory processes up to that point can generally be reversed.]
 * Note that here, contrary to popular usage, "pneumonia" means pretty much anything that causes inflammation and consolidation (firming) of the lung, due often but not always to infection.
 * Acute:
 * **Diffuse alveolar damage** (DAD) / **Acute interstitial pneumonia** (AIP)
 * **Cryptogenic organizing pneumonia** (COP)
 * Chronic:
 * **Usual interstitial pneumonia** (UIP) / **Nonspecific Interstitial Pneumonia** (NSIP)
 * **Desquamative interstitial pneumonia** (DIP) / **Respiratory Bronchiolitis** (+ Associated Interstitial Lung Disease) (RB or RB-AILD)
 * Honeycomb lung (not really a disease but a common endpoint of all these diseases).
 * [Note a couple of things that will make this easier. One is that there are effectively two acute and two chronic disease processes, with multiple names based on extent, etiology, and patchy vs. diffuse pattern. The other is that they break down into alveolar filling (COP and DIP/RB), interstitial fibrosing (UIP/NSIP), and mixed (DAD/AIP) categories.]
 * Understand the relationship between DAD and ARDS and AIP, and the most common causes of DAD
 * ARDS: clinical pattern that corresponds to DAD/AIP.
 * DAD and AIP: they look identical. The only difference is whether or not there's a known cause for it. If a patient's got ARDS and you can trace a cause, it's DAD; if you can't trace a cause, it's AIP.
 * DAD: acute and organizing stages (see next LO), high mortality, many causes (infection, inhalants, gastric aspiration, shock, sepsis, drugs, being on a ventilator-- anything that damages alveolar surfaces).
 * Endothelial/epithelial injury causes leakage of endothelial contents into the alveolus; this causes edema and deposition of fibrin products in the alveolar spaces.
 * Note two problems going on here. One is that the alveolar septa have been severely, probably permanently, damaged; the other is that until they're repaired, you're going to have edema and fibrin deposition in those alveoli (which is what you generally look for histologically, see next LO).
 * Be able to identify the early histologic changes of DAD
 * __Acute__: also called the exudative stage (in the first week)-- edema, fibrin membrane formation in alveoli, not much inflammation yet; some thrombi forming in small vessels.
 * __Organizing__: comes after the acute stage. Involves fibroblastic proliferation in the alveolar walls and incorporation of the fibrin that was in the airspace into the wall membranes, as well as hyperplasia of alveolar type II cells as they try to repair the damage.
 * Microscopically, you see pink fibrin membranes inside the alveolar membranes (prevents O2 exchange across alveolus). As this progresses, the fibrin is taken up by the alveolar membranes themselves (organization). Eventually you can see no more fibrin inside the alveolus-- it's all been moved inside the membranes, which results in them being extremely thick.
 * Note that with persistent, repeated injury, assuming you don't fibrose, you'll eventually get squamous metaplasia in the alveolar/airway walls.
 * [I talked to him afterwards about this. It seems to happen something like this: you get damage to the blood vessels and damage to the alveolar epithelium. Fibrin leaks into the airspaces (exudative phase). This causes a proliferation of fibroblasts in the alveolar membrane, which break down the fibrin in the airspaces and moves it into the alveolar membranes, thickening them. However, because this isn't collagen but fibrin, it can be broken down, so as long as the fibroblasts aren't signaled to lay down collagen, the thickening can be reversed.]
 * [However, note that all this - at least by reading Robbins - seems to be fairly peripheral to what's actually going on with ARDS, which is that you're getting lots of alveolar damage that can't be repaired, thus leading to scarring. I'm not sure why they're fixating on this fibrinous exudate so much except that it's a good histological marker and it causes edema, which can be picked up on physical exam.]
 * Know the appearance and prognosis of COP
 * "OP" = organizing pneumonia; "COP" is when you can't find a cause (like AIP).
 * Lower mortality than DAD/AIP (treats well with steroids), subacute onset.
 * From the notes: "Alveolar filling disease [little fibrosis], but adjacent alveolar spaces may be thickened by chronic inflammatory infiltrate."
 * Look for __casts of granulation tissue__ (__fibroblasts__, __mucopolysaccharides__) filling the bronchioles and alveolar spaces.
 * Note that this is a reversible process, since no collagen is being laid down.
 * Know the common presentation, prognosis and histologic appearance of UIP and the relationship between UIP and IPF
 * Idiopathic pulmonary fibrosis (IPF)- UIP is a histological diagnosis, IPF is a clinical diagnosis-- like ARDS is the clinical counterpart to DAD.
 * Be able to identify histologic sections of DIP and know the most common risk-factor
 * DIP is not a good name; the cells in question are macrophages, not squamous cells.
 * Histology: diffuse lung disease in which yellow-brown macrophages are filling the air spaces. Note little to no fibrosis.
 * Most common risk factor is smoking.
 * Responds reasonably well to steroids and smoking cessation, but mortality is still about 25%.
 * Note Robbins sez that it's a lot better than that- "Recent studies have shown a 100% survival rate" with steroids and smoking cessation.
 * [Respiratory bronchiolitis looks like DIP-lite-- some pigmented macrophages in alveolar airspaces, but patchy instead of diffuse.]
 * Understand the difference in appearance between UIP and NSIP, and know the common risk-factors for the development of NSIP
 * Usual interstitial pneumonia-- very poor outlook, no therapy but transplant, but the disease often strikes people old enough that they don't qualify for a transplant.
 * UIP is a heterogenous, __patchy__ fibrotic process (some extremely advanced areas next to relatively unaffected areas). Fibrosis in the alveolar walls. Gets worse by the pleura and lower lobes. Robbins says that it's likely due to repeated cycles of lung injury, not chronic inflammation. Note this is in contrast to NSIP, below, which seems to be caused by a single injury.
 * Grossly, it looks like "cobblestoning"-- honeycomb lung right under the pleura.
 * Non-specific interstitial pneumonia (NSIP)-- better prognosis than UIP.
 * NSIP is __not__ heterogenous, but relatively __uniform__ in its inflammation and fibrosis-- the insult occurred at one point and is not ongoing. Note it often comes along with organizing pneumonia (alveolar filling).
 * Essentially, the more it's inflammation and the less it's fibrosis, the better the outlook is (inflammation can be reversed, collagen deposition cannot).
 * Note this distinction between UIP/NSIP and DIP/RB: in UIP/NSIP, patchy (UIP) is worse than diffuse (NSIP), while in DIP/RB, diffuse (DIP) is worse than patchy (RB).
 * Be able to recognize the gross and microscopic features of honeycomb lung
 * Honeycomb lung: end-stage pattern when the lung's been fibrosed about as much as it can be-- this is the end point of all fibrotic diseases, so you can't reason backwards from honeycomb lung to figure out the etiology.
 * Microscopically, the alveoli look like bronchioles-- thick-walled, mucus-filled cysts. The thick walls help differentiate from emphysema.
 * Grossly.. it looks like a honeycomb. Lots of large cysts; often preferentially involves pleural spaces and lower lobes.

Treatment of Obstructive Lung Disease Monday, April 21, 2008 1:30 PM


 * Treatment of Obstructive Lung Disease, 3/22/08:**


 * To understand the role of the available medications used to either relieve (quick-relief agents) or prevent (long-term control medications) symptoms of obstructive lung disease.
 * They're used to either relieve (quick-relief agents) or prevent (long-term control medications) symptoms of obstructive lung disease. Note that short-term relief has to do mainly with relieving the airway constriction (mainly beta-agonists), while long-term relief mainly has to do with treating the underlying inflammation (mainly steroids).
 * To review the current concept of asthma as an inflammatory disease with intermittent symptoms and a progressive component.
 * Asthma: chronic inflammation with periodic symptomatic episodes, which make slow inroads into progressive damage.
 * Specifically, asthma problems can be broken down as follows:
 * Acute/episodic: bronchoconstriction, airway edema, mucus plug formation.
 * Chronic: airway remodeling.
 * [upcoming poetic license alert]
 * Imagine a cliff overlooking the sea. You get recurrent episodes of stormy weather, in which the wind and water lash the rocks for a few hours and then quiet down. Between episodes it's relatively calm. But after each episode the rock is a little more eroded than before.
 * For a classical view, you can also think of the Hindu concept of a //kalpa// . A kalpa is a unit of time delineated by a number of unusual circumstances-- there's an enormous mountain, 16 miles wide and 16 miles tall. Every 100 years, an angel (or appropriate ethnic deity's messenger of choice) brushes the mountain lightly with its wings. A kalpa is the unit of time it takes to wear the mountain down to nothing.
 * Point, other than enjoying being overeducated, is that you have episodic events, each of which leaves a lasting effect that builds on the lasting effect that came before it. Depending on the severity of the episodes and their frequency, the lasting effect may be pretty mild or may even be reversible before the next attack; when the attacks are severe and/or close together, can get a buildup of irreversible airway remodeling.
 * Another example (I'm bored today) would be a sort of Prometheus redux, in which a god is chained to the top of a mountain. Every day, an eagle comes and tears out his liver. Being immortal, his body regenerates its organs over time, but by the time it's finished the next day, the eagle shows up again. Now think if the eagle set its watch ahead an hour each day, so that it showed up before his body had finished regenerating, and took the partially regenerated liver as well as (say) an ear to make up the correct amount of body mass. These (episodic) events would slowly begin to erode at the god's body, until a couple of months later there would really just be some thighs and a pelvis chained to the mountain (not sure how that would be accomplished). However, if the eagle came with sufficient time in between episodes to allow the liver to completely regenerate, the arrangement could continue indefinitely (albeit unpleasantly for the god).
 * Note that I may be overemphasizing the importance of the attacks and underemphasizing the importance of long, slow erosion and remodeling due to underlying chronic inflammation. Certainly the inflammation is what gets you in the end (which is why you don't treat with bronchodilators without treating the underlying inflammation). I think the chronic flare-ups of inflammation probably do more lasting damage than the steady-state low level of chronic inflammation.. but I could be wrong. To my recollection Dr. Szefler didn't make the distinction.
 * To provide an overview of the management principles for chronic obstructive pulmonary disease.
 * __Preferred quick relievers__: short-acting beta-2 agonists (albuterol/levalbuterol inhalers). Can use anti-cholinergics as second line drugs in COPD, but not approved in asthma. Systemic steroids are less and less used except in severely acute cases.
 * __Preferred long-term medications__: inhaled glucocorticoids. Also can use long-acting beta-2 agonists as second line drugs but you __have to combine them with a steroid__.
 * The reason for using glucocorticoids long-term is that you want to address the underlying inflammation, not the symptomatic bronchoconstriction secondary to it.
 * Recall that steroids take a while to get working, even inhaled (30 minutes to an hour).
 * Note that the preferred route of administration for most of these meds is inhalation.
 * Need to watch out for using long-acting beta-2 agonists as the only therapy for asthma. You can see an increased risk of death. **Always combine with a steroid** so that the underlying cause - the inflammation - doesn't get untreated and worsen in the face of masking its symptoms with the beta-2 agonists.
 * This was repeated several times and so bears repeating here: __never give long-acting beta 2 agonists for long-term asthma therapy without giving steroids as well.__
 * Can also use leukotriene modifiers for long term therapy: these inhibit LD4 or 5-lipoxygenase (recall leukotriene B4 is particularly implicated in asthma). Watch out for liver toxicity. They have bronchodilation and anti-inflammatory effects.
 * For long-term treatment of asthma, you can also use anti-IgE antibodies, or mast cell degranulation inhibitors. Alternatively, you can use caffeine-like drugs like theophylline, but note that these drugs have to be monitored carefully to look at blood levels, and can interact with a lot of other drugs.
 * Specifically, clarithromycin (but not azithromycin) will inhibit theophylline metabolism and certain other meds will increase it.
 * [Allergen immunotherapy (from Claman's lectures in Blood and Lymph) can induce specific allergen tolerance. This works better pre-asthma.]

Arterial Blood Gases and O2 Carriage Monday, April 21, 2008 1:31 PM


 * Arterial Blood Gases and O2 Carriage, 4/22/08:**


 * Describe the importance of oxygen "off-loading" from hemoglobin and how it can be affected by various factors
 * To be used by cells, oxygen needs to become unbound from hemoglobin (in order to diffuse into cells and mitochondria, it needs to be freely dissolved in blood). This is the "off-loading" process of oxygen from hemoglobin at tissues.
 * Affected by various factors:
 * See oxy-hemoglobin dissociation curve.
 * Right shifts:
 * Allow faster offloading of O2 at tissues (less affinity of Hb for O2).
 * Caused by increased temperature, CO2, or 2,3-DPG levels, or by decreased pH.
 * Note increased 2,3-DPG is caused by chronic hypoxia (as in a transition to high altitudes).
 * Note that a right shift caused by a drop in pH is called the __Bohr effect__.
 * Left shifts:
 * Allow greater retention of O2 in blood (more affinity of Hb for O2).
 * Caused by the reverse of all the junk just mentioned (decreased temperature, CO2, or 2,3-DPG levels, or by increased pH).
 * Note that fetal hemoglobin has a left-shifted dissociation curve.
 * Calculate oxygen delivery to tissues as a function of cardiac output and arterial oxygen content
 * Oxygen delivery is the cardiac output times the arterial oxygen content:
 * DO2 = CO * CaO2.
 * Calculate oxygen consumption from cardiac output and the difference in oxygen saturation in arterial and venous blood
 * The concept is just another application of Fick's Principle [VO2 = CO * (CaO2 - CvO2)].
 * However, say you don't have the oxygen content of the blood, just the % sats and the CO (you'll also need the hemoglobin concentration).
 * Recall from cardio that the oxygen concentration of blood can be calculated by the concentration of hemoglobin that's present, times the % saturation of its hemoglobin, times the amount of O2 that the hemoglobin could bind if it's 100% saturated (more or less a constant of 1.39). We're effectively ignoring the freely-dissolved component since it's very small relative to the hemoglobin-bound component.
 * Substituting:
 * VO2 = CO * [(SaO2 - SvO2) * [Hb] * 1.39]
 * [if you want to be really accurate and not ignore the freely-dissolved component, you also have to add 0.0013 * (PaO2 - PvO2). Generally this is, as mentioned, a small difference (given PaO2 of 100 and PvO2 of 40, about 0.078) in the light of the larger term (for a normal person, about 4.8).]
 * Describe the oxygen cascade, from air to mitochondria
 * The oxygen cascade is a graph showing how the PO2 drops depending on location. Starts (atmospheric air) at around 160 torr (dry, at sea level), drops when the air is inhaled and humidified (recall that water vapor displaces some of the O2, lowering the PIO2 to 150 torr), drops further coming into the alveolus (recall that CO2 preferentially displaces O2 in the alveolus, lowering the PAO2 depending on CO2 status), drops again in the arterial blood (due to some admixture of deoxygenated blood in the arterial flow, plus any shunting or gas exchange problems), drops substantially going into the capillaries, drops again going into the cellular cytoplasm, and finally drops going into the mitochondria to be used in metabolism.
 * Note there's a certain cutoff PO2 level below which mitochondria can no longer perform oxidative phosphorylation at their usual level of activity. This cutoff is called the Pasteur point and is organ-specific, but approximated at 1-2 torr.
 * Note that hypoxia is defined as an O2 level in mitochondria that's below this point. Caused by low CO (covered in cardio), low [Hb] (covered in B+L), or hypoxemia (low PaO2, covered below).
 * Describe how different causes of hypoxemia can be determined from arterial blood gases
 * **Hypoxemia** : Low PaO2 (recall PaO2 reflects freely dissolved O2). Distinct from __hypoxia__, which occurs at the level of the mitochondria and is thus tricky to measure.
 * The effects of low PaO2 are mainly due not to the free O2 concentration that it directly measures, but to the low % oxygen saturation of hemoglobin that that level implies.
 * 4 main arterial blood gas (ABG) measurements:
 * **PaO2**
 * **SaO2**
 * **CaO2** (in his notes, but not in his lecture)
 * **PAO2 - PaO2** (alveolar-arterial or **A-a gradient** )
 * Note you can estimate PAO2 by measuring the PaCO2 and working through the equation (PAO2 = PIO2 - PaCO2///R// ).
 * If you have a low partial pressure of oxygen in inspired air (say you're breathing mainly some inert gas or you're at high altitude), you see a low PaO2, reduced SaO2, and reduced CaO2, but no change in the A-a gradient (PIO2 is low too).
 * Similarly, if the problem is that you have a low PAO2 (say you're hypoventilating, causing CO2 to accumulate in the alveoli and displacing inspired O2), you'll see a low PaO2, reduced SaO2 and CaO2, but a normal A-a gradient, same as before (however, in this situation, you could look at arterial CO2 levels to diagnose it).
 * On the other hand, if you have a problem with O2 diffusion across the alveolar septa (as in interstitial lung disease or edema), you'll see a low PaO2, SaO2, and CaO2, and the A-a gradient will be elevated. Can test for this with the DLCO test.
 * Same thing (everything's low except for A-a gradient, which is high) if you have a shunt or V/Q mismatch, but you can distinguish between these, as mentioned in "Diffusion and Perfusion", by giving 100% O2 and measuring PaO2 levels.
 * Note that you can't, technically, diagnose hypoxemia without measuring arterial blood gases (can't wing it with a pulse oximeter).
 * Note also that you can also look at the PFT-normal, DLCO-decreased problems (anemia or carbon monoxide poisoning) with arterial blood gases:
 * In anemia, the PaO2 is normal, as is the saturation, but the CaO2 is low. The A-a gradient is also normal.
 * Recall that in carbon monoxide poisoning, the bound CO causes Hb to bind O2 more tightly (shifts dissociation curve to the left) and prevents O2 offloading at tissues, in addition to itself blocking a O2 binding site.
 * In this case, you have a normal PaO2, the SaO2 goes down, the CaO2 also goes down, and the A-a gradient stays normal.
 * Note that with pulse oximetry, you won't be able to detect the SaO2 difference (it detects bound vs. unbound hemoglobin, but doesn't do well with the difference between hemoglobin bound to O2 vs. hemoglobin bound to CO). You frequently get artificially elevated SaO2 readings through pulse oximetry with CO poisoning.
 * Note that Bob sez you often can't detect CO poisoning with standard ABGs either. A look online seems to indicate that some ABGs will directly measure the SaO2, while other will measure the PaO2 and calculate the SaO2 from that (which, in CO poisoning, will not work, since the PaO2 will be normal).

CO2 Carriage and Acid/Base Balance Tuesday, April 22, 2008 11:02 AM


 * CO2 Carriage and Acid/Base Balance, 4/22/08:**


 * Describe the ways in which CO2 is carried in blood
 * __Freely dissolved__ in blood-- in arterial blood, this is at a concentration of 1.2 mM.
 * Carried in __bicarbonate ions__ (HCO3-)-- in arterial blood, this is at a concentration of 24 mM.
 * Recall that carbon dioxide reacts with water to form bicarbonate and a proton:
 * **CO2 + H2O <--> HCO3- + H+**
 * This is catalyzed by //carbonic anhydrase//.
 * Carried in __carbamino compounds__ (CO2 bound to an amino acid or protein, mainly hemoglobin)-- in arterial blood, this is at a concentration of 1.2 mM.
 * Describe the reaction in red blood cells that converts CO2 to bicarbonate and protons
 * See previous LO.
 * Note the basic principle: more CO2, drives equation to the right (le Chatelier's principle) and drives up [H+], lowering pH. Less CO2, drives equation to the left, thus less [H+], raising pH. By contrast, if you have lots of H+ in the system, the equilibrium shifts left, increasing conversion with bicarbonate to CO2, and if you have a paucity of H+ in the system, it shifts to the right and favors breakdown of CO2. Lots of fun, you bet. This is going to be important later.
 * Calculate the blood pH as a function of blood bicarbonate and CO2 (the Henderson-Hasselbalch equation)
 * I bet you all remember this one. I think DJ got it tattooed on his back during M2M.
 * H-H equation: pH = pKa + log ([A-]/[HA]). Here, pKa of the acid is 6.1. Thus:
 * **pH = 6.1 + log ([HCO3-]/[CO2])**
 * Recall that you can get the concentration of free CO2 in the blood (that is, [CO2]) by the solubility coefficient of CO2 times the partial pressure of CO2 in the blood:
 * [CO2] = PaCO2 * aCO2 (about 0.03).
 * Thus:
 * **pH = 6.1 + log ([HCO3-]/(PaCO2 * 0.03))**
 * Describe factors that can influence blood pH (CO2, fixed acids and bases, and buffers)
 * More CO2 drives the equilibrium towards lower pH (increased [H+]). You can also see this just from plugging the numbers in the equation above.
 * If you add bicarbonate (HCO3-) to the system, the concentration of HCO3- goes up, thus log ([HCO3-]/[CO2]) goes up, thus the pH goes up.
 * If you add H+ to the system (acids), the pH obviously goes down. But note buffering effects on this:
 * Buffer systems against influx of protons:
 * (1) Bicarbonate ions (HCO3-). Given a reservoir of HCO3-, an influx of H+ can be neutralized by reacting with HCO3- to form CO2 in the blood. What makes this work is that it's an open system-- that is, blood-borne CO2 can be exhaled from the lungs. Effectively you're exchanging some of your protons + HCO3- for CO2 and exhaling the CO2, thus kind of 'ventilating' the excess protons.
 * This is a handy concept for understanding all the stuff that's about to come down. The more HCO3- you've got, the more the pH is going to rise and the [H+] is going to drop, and the more CO2 is going to be generated.
 * (2) Proteins, mainly hemoglobin, can 'absorb' protons in the blood. This becomes important when you're considering chemoreceptors in the vasculature and comparing their sensitivity to that of chemoreceptors in the brain (which has no hemoglobin floating around in its CSF). See "Control of Breathing."
 * Describe the causes of metabolic and respiratory disturbances in acid/base balance, as well as mechanisms of compensation for each
 * Four classes of acid/base disturbances:
 * (1) **Respiratory acidosis** : defined as a __low blood pH due to a high CO2 level__.
 * Caused by __hypoventilation__ at the alveoli (as due to severe obstructive disease or drug overdose that override the breathing-control centers in the brain).
 * __Compensated for by the renal system__ with transport of protons into the urine from the blood and transport of HCO3- into the blood from the urine. Bicarbonate reabsorption seems to be the main mechanism. This takes place in the proximal tubule.
 * The extra bicarbonate shifts the H-H equation towards a higher pH.
 * Note that this compensation is __slow__ (3-4 days).
 * (2) **Respiratory alkalosis** : defined as a __high blood pH due to a low CO2 level__.
 * Caused by __hyperventilation__ at the alveoli (as due to high altitude tachypnea when trying to increase VAO2).
 * __Compensated for by the renal system__ by a decreased reabsorption of HCO3- in the proximal tubule.
 * The decreased bicarbonate shifts the H-H equation towards a lower pH.
 * This compensation is __slow__ (3-4 days).
 * (3) **Metabolic acidosis** : defined as a __low blood pH due to a high level of non-CO2 acid(s)__.
 * Can be caused by increased levels of keto acids in diabetes (diabetic ketoacidosis), or increased levels of lactic acid in hypoxia, or diarrhea (in which you lose a lot of HCO3-).
 * __Compensated for by the respiratory system__ by increasing the alveolar ventilation.
 * This lowers CO2 levels, which raises blood pH to compensate.
 * This compensation is __very fast__ (all the blood passes through your lungs in a short span of time, and CO2 diffusion out of the blood is extremely rapid).
 * (4) **Metabolic alkalosis** : defined as a __high blood pH due to a low level of non-CO2 acid(s)__.
 * Can be caused by an overdose of antacid tablets (increased level of HCO3-) or vomiting (loss of gastric acid).
 * __Compensated for by the respiratory system__ by decreasing the alveolar ventilation.
 * This raises CO2 levels, which lowers blood pH to compensate.
 * Again, this compensation is __very fast__.
 * But note that it is also often //__incomplete__// -- the respiratory centers in your brain aren't going to allow the alveolar ventilation to drop below a certain point.
 * Describe how acid/base status can be determined from arterial blood gases
 * Look at pH, PaCO2, [HCO3-], and PaO2:
 * (1) If you have a respiratory problem with no renal compensation, the PaCO2 should be either high or low (depending on if it's acidosis or alkalosis), and the pH should be the opposite (high for low PaCO2, low for high PaCO2).
 * (2) If you have a respiratory problem with complete renal compensation, the PaCO2 should be affected as above, but instead of the pH changing, it'll be the [HCO3-] (due to altered renal reabsorption). Note that the HCO3- levels should track the PaCO2 levels (high PaCO2, high [HCO3-]; low PaCO2, low [HCO3-]).
 * (3) If you have a metabolic problem with complete respiratory compensation, there should be an affected level of [HCO3] and an affected PaCO2 (due to altered ventilation). Note that, again, the HCO3 levels should track the PaCO2 levels (both go up or both go down).
 * Summarize:
 * Compensated respiratory acidosis: PaCO2 up, leading to HCO3- up.
 * Compensated respiratory alkalosis: PaCO2 down, leading to HCO3- down.
 * Compensated metabolic acidosis: HCO3- down, leading to PaCO2 down.
 * Compensated metabolic alkalosis: HCO3- up, leading to PaCO2 up.
 * Specific numbers:
 * (1) Uncompensated respiratory acid/base imbalance:
 * A PaCO2 change of **10** torr results in a change in pH of **0.08**.
 * (2) Compensated respiratory acid/base imbalance:
 * A PaCO2 change of **10** torr results in a [HCO3-] change of **5-10** mEq/L.
 * (3) Compensated metabolic acid/base imbalance:
 * A [HCO3-] change of **10** mEq/L results in a PaCO2 change of **10-15** torr.
 * Note that in compensated respiratory acidosis, the PaCO2 will go up causing the [HCO3-] to go up; in compensated metabolic acidosis, the [HCO3-] will go down, causing the PaCO2 to go down. So although both acidotic scenarios show linked changes in CO2 and HCO3- levels, the direction of the change can tell you whether it's originally a metabolic or a respiratory dysfunction.
 * That said, note that with compensated respiratory acidosis and compensated metabolic __alk__alosis, both should show increased HCO3- and CO2 levels. You may still be able to tell the difference by looking at the pH (is it acidosis or alkalosis?), but in well-compensated patients the pH shouldn't budge much.

Pulmonary Circulation I + II Tuesday, April 22, 2008 2:16 PM


 * Pulmonary Circulation I + II, 4/23/08:**


 * Define the major functions of the pulmonary circulation
 * Bronchial circulation gets oxygenated blood to the lung tissue. Pulmonary circulation gets deoxygenated blood to the alveoli to get reoxygenated.
 * Note that the bronchial circulation is under systemic pressure (comes off the aorta), while the pulmonary circulation is under very low pressure (mean arterial pressure about 1/6th of the MAP of the systemic circulation).
 * Note also that the pulmonary circulation isn't a fixed system; when the cardiac output increases dramatically (as during exercise), the lung can recruit additional (unused) vessels to keep the overall pulmonary circulation low-- can accommodate an increase of 4-fold in the cardiac output while only increasing the pulmonary MAP to 18 or 20 mm Hg (from 15). Recall that this process is called recruitment.
 * The pulmonary vessels are also way more compliant and distensible than the systemic vessels, with much less elastic fiber and smooth muscle-- this also helps restrict pulmonary pressure by decreasing pulmonary resistance (increased radius) under conditions of increased flow.
 * The right side of the heart is therefore relatively thin and not terribly strong. Recall that its shape isn't really designed for strong contraction, either. This becomes a problem when you get pulmonary hypertension, since you can't compensate well by ratcheting up right ventricular pressure.
 * Recall that hypoxia causes vasoconstriction in the lung. This winds up being important in a variety of pathologies.
 * From the notes, I thought this was nicely succinct: "When the pulmonary circulation screws up, it is usually manifest in 3 ways:"
 * **Abnormal gas exchange**
 * **Pulmonary edema**
 * **Pulmonary hypertension**
 * Define the major determinants of blood flow distribution in the lung
 * Hypoxic pulmonary vasoconstriction shifts blood away from malfunctioning alveoli (thus correcting V/Q at those alveoli).
 * In the opposite direction, recall that NO and prostacyclin are produced in response to shear stress in order to vasodilate vessels with increased flow.
 * Also recall that gravity means that the vessels at the base of a lung in an upright person will be about 6x more perfused than the vessels at the top.
 * [Recall that in a normal person, the tidal volume is about 450 mL and the anatomic dead space is about 150 mL (1/3 of the tidal volume at rest isn't used for gas exchange). As tidal volume goes up (example cited here is during exercise), this ratio shrinks (since dead space in a healthy person shouldn't increase during exercise). More on this in "Assessment of V/Q."]
 * Describe the zones of the lung
 * Zone I - no flow, at apex of lung
 * Zone II - intermittent flow, in middle of lung
 * Zone III - constant flow, at bottom of lung.
 * Recall that if a person is supine, the zones are going to change orientation (they're based on gravity effects, not anatomic spaces).
 * We went over this in cardio. Essentially the alveolar pressure is greater than either the arterial or venous pressure in Zone I (no flow, completely collapsed vessel); the alveolar pressure is greater than the venous pressure but not the arterial pressure in Zone II (pulsatile or intermittent flow depending on the vicissitudes of the flow); in Zone III, the alveolar pressure is less than either the venous or arterial pressures (thus constant flow).
 * Note that this means if you're putting in a Swann-Ganz catheter, you want to make sure it's in a Zone III vessel (need to have an open connection to venous side of vessel in order to measure back pressure).
 * A word about V/Q matching: they really seem very fond of this idea. It would be a good idea to know it well. Again, V/Q tends to be higher at the apex, since the perfusion drops faster than the ventilation as you go up the lung. But V/Q mismatch anywhere in the lung, even if it's corrected in the total lung perfusion and ventilation, is going to impair the reoxygenation of pulmonary blood. For ideal reoxygenation, the V/Q needs to be the same throughout the lung (generally at about a level of 0.9).
 * If you'll pardon a metaphor (and if you won't, who needs ya?), it's as if you're putting cookies out for well-behaved kids. Say there's twenty rooms (alveoli) and twenty kids (vessels), each of which only goes to one room. Suppose further that since the kids are well-behaved, they'll only take one cookie apiece (obviously not based in the reality of either children or med students).
 * Now if you have twenty cookies (oxygen) and twenty kids (vessels) and twenty rooms in which to give the cookies to the kids (alveoli), in principle you haven't got a problem as long as exactly one cookie is in each room. But if you put two cookies in one room and none in another, the kid going to the room with both cookies will only take one, while the kid going to the room with no cookies will go hungry, and you'll have a wasted, spare cookie (oxygen) sitting in its room (alveolus) all by itself and a hungry kid on the other end.
 * If you think about it for a second, you'll see that there is no other way of parceling out the cookies than one-cookie-to-one-room that doesn't end up with at least one hungry kid and no kids that are any fuller with cookies than they would otherwise be. So you're making kids hungry and not even benefiting other kids while you do it. Shame on you.
 * Similarly, V/Q mismatch is always a bad idea, even if the total V and total Q of the lung stays the same, because the hemoglobin in the blood can't absorb much more oxygen than normal at a high V/Q, but will go oxygen-hungry if its V/Q is low.
 * Define the determinants of water and solute balance in the lung and the different types of pulmonary edema
 * This gets back to Starling's Law (not the one about muscle length and force of contraction, the one about transmural fluid flow in a capillary)-- fluid filtration is determined by the difference in hydrostatic pressure inside and outside the capillary, balanced by the difference in oncotic pressure inside and outside the capillary.
 * Pulmonary edema, and edema in general, is caused by:
 * (1) **Increased hydrostatic pressure**, as due to left-sided heart failure.
 * Note hydrostatic edema can occur very rapidly, and responds rapidly to treatment.
 * In hydrostatic pulmonary edema you can also see Kerley B lines (enlarged lymphatic channels along the interlobular septa that are engorged with edematous fluid).
 * (2) **Increased permeability of the capillary membrane**, as due to endothelial damage.
 * Note permeability edema generally happens more slowly, and responds slowly, if at all, to treatment.
 * Increased permeability pulmonary edema due to ARDS:
 * Alveolar/endothelial damage causes fluid to leak into the alveoli, leading to a shunt past fluid-filled alveoli or a V/Q mismatch with very poorly ventilated alveoli.
 * Notice that it's possible to distinguish between hydrostatic or ARDS-related increased permeability edema by treatment with diuretics and measurement of left atrial pressure. Hydrostatic should respond to diuretics and have a high LA pressure. ARDS won't respond to diuretics and will have a fairly normal LA pressure.
 * Note that there are enough corrective factors in the lung capillaries that you virtually never get edema due to disturbances in oncotic pressure (as in hypoalbuminemia).
 * Describe the risk factors, clinical presentation, diagnostic procedures, and treatment of acute pulmonary embolism
 * As covered before, risk factors include immobilization, pregnancy, hormones, malignancy, etc. Recall Virchow's Triad: injury, stasis, hypercoagulable states. Use an ultrasound to pick it up and maybe a D-dimer test (thrombin breakdown product)-- if the D-dimer is negative, probably isn't PE.
 * PE: kills more people than AIDS + breast cancer together each year. So a big deal.
 * Clinically, look for __chest pain, shortness of breath, hemoptysis, and right ventricular heave__.
 * Can also use EKG, chest x-ray, V/Q scan, CT angiogram, and a standard angiogram (the current gold standard for finding PEs) in addition to ultrasound.
 * Note that on EKG you normally just pick up sinus tachycardia (maybe some inverted T waves).
 * Chest X-rays show up normal or with some atelectasis (collapse of part of lung).
 * V/Q scans have been gone over already-- the ventilation is normal to a section but its perfusion is poor.
 * Treatment:
 * Stable: give heparin/warfarin
 * Unstable (failing right ventricle, hypotensive): heparin, maybe tPA, and an IVC filter; possibly take out part of the lung containing the thrombus (thrombectomy).
 * Define pulmonary hypertension and what causes it
 * Pulmonary hypertension (PHTN) is defined as a mean pulmonary arterial pressure of **above 25** mm Hg.
 * Causes:
 * Increases in left atrial pressure (left-sided heart failure is the most common cause of right-sided heart failure).
 * Increases in pulmonary vascular resistance:
 * **__Post__-capillary** : pulmonary venous hypertension
 * **__Pre__-capillary** : pulmonary arterial hypertension ( **PAH** )
 * [Note that his notes are a little confused on whether pre-capillary pulmonary hypertension is the same thing as pulmonary arterial hypertension or not. I'm going with yes, since the various other causes listed for PHTN lead to PAH anyway, but be aware.]
 * Post-capillary PHTN is usually caused by CHF or mitral disease (can also, more rarely, be venous occlusive disease). Note that this tends to cause hydrostatic pulmonary edema, as above, and can lead to right ventricular failure, particularly if acute.
 * Pre-capillary PHTN (PAH) can be caused by a number of factors:
 * __Pulmonary embolus__ (PE) from DVT, tumor, marrow fat, etc. This can cause sudden death due to right ventricular overload.
 * Note a theme: acute pulmonary hypertension is a serious deal, whether it's post-capillary from a blocked mitral valve or pre-capillary from a PE. If the right heart doesn't have time to adjust, you can go into right-sided failure very quickly.
 * Note that right heart failure due to pulmonary arterial hypertension alone, without left heart involvement, is called __cor pulmonale__.
 * Further: I'm fairly sure you're supposed to pronounce the 'e' on the end of 'pulmonale' since it's a Latin derivation and not from the French (which would be 'coeur pulmonale' or something similar). Please, don't embarrass your profession by pronouncing the 'e' as 'ee' and not 'eh' (the 'ee' sound is spelled 'i' in Latin).
 * Note also that what kills you in PEs isn't hypoxia but the right heart failure.
 * __Congenital heart disease__ (Tetrology of Fallot, or VSD/ASD gone into Eisenmenger's) or __chronic hypoxia__ (pulmonary hypoxic vasoconstriction reflex).
 * __Chronic alveolar hypoventilation__: chronically elevated PaCO2 causes decreased PAO2-- A-a gradient is normal on ABGs, but ongoing hypoxia causes vasoconstriction and can lead to PAH as well.
 * __Certain chronic obstructive diseases__ (like chronic bronchitis) cause chronic hypoxia, leading to pulmonary artery hypertension and venous backup-- which is why blue bloaters are blue.
 * Note also that the chronic hypoxia in sleep apnea also presumably causes PAH.
 * Symptoms of PAH: chest pain, orthopnea, exercise intolerance, lower extremity edema (but not in the lungs).
 * Note that __post-capillary PHTN causes pulmonary edema__, while __pre-capillary PHTN does not__ (they can __both cause peripheral edema__). Thus listen for rales in lungs to indicate pulmonary edema and thus post-capillary problems.
 * Note also that many pre-capillary problems with PHTN are caused by problems completely outside the lung parenchyma (ie. pulmonary emboli). So if you have normal PFTs but abnormally low DLCO, start looking for problems originating from the pulmonary vasculature.
 * Treatment of PHTN: O2, warfarin, vasodilators (prostacylin and CCBs), endothelin blockers, PDE inhibitors (Viagra). Lung transplant works if you've got a spare or two lying around.

Control of Breathing Thursday, April 24, 2008 8:01 AM


 * Control of Breathing, 4/24/08:**


 * Describe the function of the main respiratory center in the medulla.
 * Recall from anatomy that the medulla sits in the brainstem just above the spinal cord and just below the pons. This is basic, reptile-brain stuff.
 * The respiratory center is a decision-making locus in the medulla that integrates information about blood O2/CO2/pH status and provides an output that modulates respiration.
 * More specifically, its output runs along motor neurons that control respiratory muscles to increase either or both of the breathing rate or the tidal volume.
 * Its inputs can be broken down into two classes and a bunch of other junk:
 * (1) **peripheral chemoreceptors** in the vasculature
 * (2) **central chemoreceptors** in the brainstem
 * (3) a hodgepodge of other inputs from a variety of locations
 * Describe the locations and functions of peripheral chemoreceptors.
 * They're located in the carotid and aortic bodies, and include:
 * __Peripheral O2 receptors__ (activated by low levels of oxygen)-- send a signal to the respiratory center to increase respiratory rate/tidal volume (and thus VA) when PaO2 is decreased.
 * Notice this function isn't linear-- there's a point at which the curve becomes very steep and you start getting large increases in VA for relatively small decreases in PaO2. Similarly, the area around normal PaO2 levels is fairly flat (small decreases away in PaO2 won't change the VA much).
 * Notice also that if a patient is having trouble because of low PaO2 levels in the blood (or some manner of dysfunction in his peripheral chemoreceptors), their respiratory rate and tidal volume should respond dramatically to 100% O2.
 * __Peripheral CO2 receptors__ (activated by high PaCO2).
 * __Peripheral proton receptors__ (activated by low arterial pH).
 * It may not be important, but these are only found in the carotid bodies and not in the aortic bodies.
 * Note a couple things about peripheral chemoreceptors:
 * (1), they're __mostly responding to CO2 and pH__. O2 levels usually aren't an issue until you get to high altitude.
 * (2), they're __very fast__ (respond in seconds).
 * (3), they (and all of these receptors) are functioning more on the 'tone' level than the 'absolute' level. That is, how rapidly they fire determines the response from the respiratory center, and if (say) the pH goes up, the proton receptors will fire more slowly, modulating the respiratory response. The point is that they're __activated__ by increases in CO2 or H+ or decreases in O2, but they __can respond__ to the reverse (decreased CO2 or H+ or increased O2) by altering their rate of activation. Email me if that doesn't makes sense.
 * Describe the location and functions of central chemoreceptors. Understand the relative importance of peripheral or central chemoreceptors under different conditions.
 * They're located in the medulla, nearby to but distinct from the respiratory center:
 * There's only one type we're discussing here, and that's the **central CO2 sensors** (measure PaCO2). Note that these are called sensors, not receptors. The reasons for this should become clear in a minute.
 * Recall that the blood-brain barrier has a very low permeability to charged particles (like H+) due to the very-tight junctions in its endothelia. This means that proton receptors in the brain can't directly measure the pH of the blood, since protons can't cross the barrier to activate them.
 * So what happens is that the CO2 in blood diffuses across the BBB and dissolves into HCO3- and H+. Then the H+ just created binds to a proton receptor on the CO2 sensor, activating it.
 * So the central CO2 sensors measure CO2 but are actually triggered by H+-- the central CO2 __sensor__ is activated by a proton __receptor__.
 * The central sensors are __slow-acting__ (take minutes) but are much more central to the regulation of VA to adapt to high chronic PaCO2 than the peripheral CO2 receptors.
 * The reason for this is that when CO2 dissolves in blood and dissociates into H+ and HCO3-, the protons are bound by blood-borne proteins (particularly hemoglobin, as mentioned earlier). However, in the CSF, there's much less protein around, providing less buffering capacity for H+ in the brain and allowing the CO2 sensors in the brain to be much more sensitive in detecting small changes in PaCO2.
 * Note, however, that the peripheral receptors are the more important in reacting to sudden, large changes in CO2 levels, as during rapid exercise (have seconds, not minutes, to respond).
 * Guiding principle: except at high altitude, **CO2 is the most important factor controlling ventilation** . (At altitude, O2 becomes more important.)
 * Note that the peripheral chemoreceptors are the only ones directly measuring PaO2 and arterial pH (so they're the only ones that 'see' metabolic acidosis, for example, since the proton receptors in the central sensors only pick up CO2 levels).
 * [Note the following examples. See if these make sense.]
 * In ketoacidosis, you get a response mainly from the peripheral H+ receptors (metabolic acidosis).
 * When sprinting, you get a response mainly from the peripheral CO2 receptors (acute large change in PaCO).
 * With pathophysiological V/Q mismatch, you get a response mainly from the central CO2 sensors.
 * This seems to be because the overall ventilation of the lung decreases in pathophysiological V/Q mismatch (as opposed to the physiological V/Q mismatch described in "Diffusion and Perfusion," in which the overall ventilation stays constant while that of certain areas goes up and that of others goes down), thus increasing CO2 levels in the blood and triggering the proton receptors in the medulla.
 * On Mount Everest, you get a response mainly from the O2 receptors.
 * Describe the role of the blood-brain barrier in determining the function of central chemoreceptors.
 * See above. That's why the central sensors can't directly measure pH-- the protons can't diffuse well through the BBB. But they can measure the protons generated by CO2 that's diffused through and has broken down in the CSF into HCO3- and H+.
 * Describe other types of inputs into the respiratory center.
 * Cortex (voluntary control of breathing)
 * Limbic system (emotional control of breathing)
 * Pulmonary irritant receptors (respond to, yes, irritants-- smoke, gas, cold air, etc.)
 * (many more that he didn't mention in class. They're in the notes.)
 * Describe the integrated response to exercise, with respect to oxygen delivery and CO2 elimination.
 * Recall that oxygen delivery equals the cardiac output times the arterial oxygen concentration.
 * During exercise, the cardiac output goes up. This, along with an increase in the tissue's oxygen extraction efficiency, allows an increase in oxygen consumption by tissues. This big increase in VO2 means a corresponding increase in CO2 production (VCO2).
 * The increased CO2 triggers arterial CO2 receptors, which increases VA dramatically to compensate.
 * Note that at a certain point of exercise (the anaerobic threshold), VA increases even more dramatically. This is because lactic acid builds up and triggers activity from the peripheral pH receptors as well.
 * [Integrated response at altitude:]
 * Initially:
 * PIO2 goes down, followed by PaO2; this activates peripheral PaO2 receptors to increase VA.
 * This leads to an increase in PaO2, but it also leads to a decrease in PaCO2.
 * The decrease in PaCO2 increases arterial pH (respiratory alkalosis).
 * The alkalosis triggers the central chemoreceptors to fire slower, thus causing the respiratory center in the brain to tell the respiratory muscles to lower respiratory rate and tidal volume, thus lowering VA (in contrast with the peripheral PaO2 receptor signals). So you can only compensate for the decreased PIO2 so far, at first, because it's opposed by the central chemoreceptors.
 * After you've been at altitude for a while, the renal compensation for the respiratory alkalosis kicks in, decreasing [HCO3-] in the blood to compensating for the blood's high pH. This decreases PaCO2, which in turn stimulates the central chemoreceptors to ease off their VA depression and allows greater ventilation to compensate for the low PIO2.

Pulmonary Defense Mechanisms Thursday, April 24, 2008 9:03 AM


 * Pulmonary Defense Mechanisms, 4/24/08:**


 * Describe the Environmental Protection Agency (EPA) criteria air pollutants, their sources, the acceptable levels, and ambient concentrations in Denver
 * Carbon monoxide: formed by incomplete oxidation of carbon (as from internal combustion engines). You know a fair bit about CO already.
 * Particulate matter: see next LO. Come from car exhaust, cigarette smoke, industrial products, etc.
 * Ozone: formed by UV light catalyzing 3O2 -> 2O3. Doesn't penetrate to body fluids to a significant degree, since it's very reactive and gets taken out by endogenous antioxidants.
 * The rest of this information is just freakin' stupid to assign. Memorize it if you want.
 * Standards:
 * CO: 1 hr = 35 ppm, 8 hr = 9 ppm
 * PM (24 hr): < 10 micron = 150 mcg/m3, < 2.5 micron = 25 mcg/m3
 * Ozone (1 hr): 0.125 ppm
 * Denver:
 * CO: 1 hr = 5.7 ppm, 8 hr= 3.1 ppm
 * PM (24 hr): < 10 micron = 115 mcg/m3, < 2.5 micron = 25 mcg/m3
 * Ozone (1 hr): 0.112 ppm
 * Describe the properties of ambient air particles and gases that affect their deposition and retention. Focus on particles, pollen grains, and gases, such as ammonia, chlorine, carbon monoxide, and ozone
 * Particles: size does, in fact, matter (although so does the motion of the cilia), specifically the aerodynamic diameter (note this means that long, thin fibers can penetrate the lung pretty deeply):
 * Large size particles (d > 10 microns) don't enter the lung (trapped in nose and upper airways). Note pollens are usually > 10 microns.
 * Coarse (d < 10 microns) can enter the lung and are implicated in lung cancer and airway disease.
 * Fine (d <2.5 microns) (combustion of fossil fuels) are implicated in lung cancer as well.
 * Ultrafine (d < 0.1 micron) have systemic effects-- they get out of the lungs and can be found in the organ. Particulate automobile combustion products are often ultrafine.
 * Gases: the major factor that determines a gas's deposition is its aqueous solubility. If it's very soluble (like ammonia), it gets mainly absorbed before it reaches the lower airways. If it's not, it can make it down into the alveoli easier. CO and O3 are insoluble (though recall that O3 is mainly neutralized before reaching body fluids).
 * Describe the major functions of the nose and upper airway. What happens if you have to breathe solely through your mouth?
 * Functions: air conduction, obviously, but also to filter the inhaled air and control temperature and water content of the incoming/outgoing air.
 * Temperature control and particulate filtration don't take place if you breathe through your mouth (or an endotracheal tube).
 * Describe the properties of mucus and the physiology of mucocilliary clearance. What happens in ciliary dyskinesia syndromes? What other organs are affected? What happens to the mucus in cystic fibrosis? Why aren't the bacteria cleared?
 * Mucus seems predominantly composed of mucin, secreted by goblet and submucosal glands, and inorganic salts (Wiki). It's cleared by unidirectional beating of ciliary arms in the airways. Note that there are also a bunch of irritant receptors in the airways to prompt a cough response to clear mucus and particles.
 * Ciliary dyskinesia is the absence of ciliary function and is linked to Kartagener's Syndrome (sinusitis, bronchiectasis, dextrocardia). It can affect sperm motility, the orientation of organs (from Wiki), and "other organs" (our ever-precise notes).
 * CF: Chlorine transporter deficiency. Mucus doesn't expand or get watery, causing respiratory blockages and infections due to an inability to get the mucus cleared (it's too viscous).
 * Describe the function and properties of pattern recognition molecules in innate immunity. What are the roles of collectins (surfactant protein A, surfactant protein D, and mannose binding lectin) in host defense? What are the functions of toll-like receptors on epithelial cells and inflammatory cells?
 * PRRs are more or less as we learned them in B+L, a 'built-in' response to certain common pathogenic molecular patterns. They don't directly involve the adaptive immune system (although recall dendritic cells are a bridge between them).
 * Surfactant turns out to play a major role in the immune system as well as being important for surface tension. Surfactant proteins A and D and mannose binding lectin are all pattern recognition molecules in the alveolus-- they bind to specific pathogen molecular patterns and __agglutinate__ them so that they are able to be cleared much more easily by macrophages or mucus removal. Note that they also __decrease__ the pro-inflammatory effects of macrophages (to avoid unnecessary inflammation due to macrophage scavenging).
 * Note this really sucks when combined with mucus clearance problems, because the pathogens effectively has free reign to hang out in your mucus (which isn't being cleared) while your collectins are simultaneously suppressing the inflammatory response that would otherwise mount.
 * TLRs are pattern-recognition molecules on the actual cell surfaces themselves, instead of being in the extracellular fluid (surfactant). These, when bound, activate local inflammation (by activating NF-kB, if you think all the way back to Cohen's first lecture and "the mother of all inflammatory processes").
 * Describe the epithelial barrier in the conducting airways and the alveolar compartments. What cells are involved? What type of intercellular junctions account for the barrier? If the barrier is disrupted by epithelial injury, how do the epithelial cells reestablish the barrier?
 * I have no idea how to answer this question from his notes other than to refer to Bendiak's notes on lung histology and microanatomy. Epithelial barriers restore themselves - assuming the stem cells are uninjured - in the normal fashion, by adjacent sections growing out to cover the injured area and differentiating into mature epithelium. Epithelial cells in the airway are joined by tight junctions just like any other epithelial cells.
 * Describe how viruses infect cells, trigger an innate immune response, and the ways viruses avoid the immune response. Why does pneumococcal pneumonia commonly follow influenza infection?
 * Most of this was already covered in D+D. Viruses target particular receptors on particular cells to attach to and enter those cells. They trigger innate responses from NK cells (through interferon or decreased MHC-I expression). They avoid those responses in a wide variety of ways, including directly infecting leukocytes, downregulating apoptosis pathways, having very rapid replication/lysis cycles, altering their surface antigens, swapping around their viral genomes, etc.
 * Influenza deactivates certain scavenger receptors on alveolar macrophages to allow secondary infections to take root (which, in turn, helps influenza get itself more firmly rooted). This is why pneumococcus has a leg up in an influenza-infected lung.
 * Note, in passing, that alveolar macrophages are not that great at antigen presentation-- they're better at clearing than stimulating an immune response.
 * This is generally good-- you want to be able to stimulate an immune response to infection, but you don't want to stimulate an immune response to every particle that winds up in the lungs.
 * Describe how pulmonary host defense mechanisms might be altered by alcohol and by chronic lung disease, such as asthma, COPD, and cystic fibrosis
 * Alcohol:
 * Blunted cough/gag reflexes (decreased mucociliary clearance, increased risk of aspiration)
 * Decreased macrophage/neutrophil function
 * Low reduced-glutathione (GSH, an antioxidant) levels, leading to oxidative stress in the lung
 * Altered flora in oropharyngeal tract, leading to increased rates of URI
 * Asthma:
 * With asthma attacks, more prone to get infections (disrupted epithelial surface, mucus clogs); with infections, more prone to asthma attacks.
 * COPD:
 * Well, you're destroying alveolar septa, cilia, and capillaries, and creating large airspaces that are constantly filled with oxygen. That predisposes you to colonization by aerobic bacteria.
 * CF:
 * In CF you see chronic infection and brochiectasis of the conducting airways but not much infection below that, evidently.. perhaps due to normal/increased immune function below that point?

Sleep Disordered Breathing/Obstructive Sleep Apnea Friday, April 25, 2008 7:31 AM


 * Sleep Disordered Breathing/Obstructive Sleep Apnea:**


 * Discuss the etiology of obstructive sleep apnea
 * "The hallmark of an obstructive apnea event is a pharyngeal occlusion during sleep."
 * Notice that obesity is associated with sleep apnea-- the upper airways narrow due to lipid deposition, and during REM sleep the skeletal muscles of the pharynx relax, predisposing to airway collapse, leading to hypoxemia and wakening in order to breathe.
 * The airway blockage can be due to tongue relapse, or inflamed tonsils, or anything else that obstructs it.
 * Alcohol is a selective depressor of upper airway-dilator motor neurons. More ethanol, less upper airway dilation, more snoring/apnea.
 * Describe the pathophysiology of apnea including cardiovascular changes during an apneic event
 * Snore: partial collapse of upper airways. Breathing gets more and more muffled until the airflow shuts completely - apnea - and partial wakening with deep ragged breathing results.
 * Pulmonary hypertension: probably caused by pulmonary vasoconstriction reflex episodes during hypoxic apneas throughout the night.
 * Systemic hypertension: probably caused by sympathetic hyperstimulation during hypoxic episodes, causing systemic vasoconstriction.
 * Note that the sympathetic system remains ramped up in the day after the apnea as well-- which means the hypertension remains high as well. Note also that this hyperstimulation during the day can be prevented by preventing apnea at night.
 * Outline the epidemiology of apnea
 * As mentioned, obesity is an issue. However, facial anatomy also appears to be extremely important. Evidently, people with underdeveloped jaws and an overbite are predisposed to develop sleep apnea.
 * In terms of statistics, apnea with more than five episodes per hours of sleep occurs in about 25% of normal, working adult men and 9% of normal, working adult women. (I wonder how this stacks up against BMI data?)
 * About 4% of men and 2% of the women in the cited study had clinically significant symptoms from their apnea.
 * If you've got obstructive sleep apnea, you're about 5 times more likely to crash your car than someone who doesn't.
 * Discuss the clinical features and complications of OSA (i.e. sleepiness, hypertension, etc.)
 * Sleepiness occurs because you don't get much uninterrupted deep/REM sleep.
 * Cycling through stage 3 and 4 non-REM sleep seems to provide the most restfulness. Waking (back to stage 0) a lot before stages 3 and 4 are reached causes daytime sleepiness.
 * The cardiovascular complications include cerebral vascular events, CHF, and CAD, as well as systemic and pulmonary hypertension, endothelial dysfunction, and insulin resistance. Notice cor pulmonale is also a possibility.
 * Notice most of these effects can be attributed to the __pulmonary vasoconstriction response to hypoxia__ (right-side) or the __sympathetic stimulation and corresponding hypertension__ (left-side). Recall that chronic hypertension causes endothelial dysfunction, which causes more vasoconstriction and thrombogenesis. Hypertension causes left ventricular hypertrophy and cause lead to CHF; thrombogenesis can lead to stroke.
 * Note that if you have obstructive sleep apnea, you're more likely to suffer sudden cardiac death in your sleep.
 * Describe the therapeutic approach to apnea
 * What you'd like to do is maintain pharyngeal patency. You can do this by inducing your patients to lose weight (works well but, obviously, difficult to do or maintain), or with devices that pull the tongue or jaw forward, or with a tracheostomy (bypass the obstruction, but somewhat dramatic).
 * Most common form of therapy is a continuous positive airway pressure (CPAP) mask. This is a device to, no kidding, deliver positive pressure to the airways: it's a mask hooked up to a small compressor and a fan that plugs into the wall. This pushes the tongue forward and keeps the narrowed airways from collapsing. Not terribly comfortable to wear all night, though; compliance is an issue.

Assessment of V/Q Friday, April 25, 2008 8:50 AM


 * Assessment of V/Q, 4/25/08:**


 * Identify the differences between shunts and dead space anatomically and physiologically
 * Shunt: Perfusion, no ventilation.
 * Dead space: Ventilation, no perfusion.
 * Anatomic dead space: the air volume in the conducting pathways.
 * Physiologic dead space: the air volume going into unperfused respiratory pathways or alveoli with a very high V/Q.
 * List the major causes of increased dead space including how different patterns of ventilation can influence the amount of dead space
 * [Most dead space is normal-- anatomic dead space is simply the conducting airways that don't have potential for gas exchange. Recall that the typical ratio of the anatomic dead space to the tidal volume is about 1/3 (150 mL ADS/450 mL TV).]
 * [The following equation for determining dead space-to-tidal volume ratio isn't on the test but is on the boards:]
 * Vd/Vt = (PaCO2 - PexpiredCO2) / PaCO2
 * (I think the point is that in dead space, there's not going to be any CO2 accretion, since there's no gas exchange. Thus by measuring how much the CO2 levels are diluted when you exhale, you can figure out how much dead space was filled on the previous inhale.)
 * [Note that VA = tidal volume minus dead space-- thus more dead space leads to a stimulus to increase VA to compensate.]
 * (1) __Shallow breathing__ can cause an increased dead space ratio, since the volume in the conducting airways isn't changing (if you take 250 mL breaths, 150 mL of it is still going to stick in the conducting airways, leaving only 100 mL to do gas exchange).
 * (2) __Obstructive pulmonary emboli__ block blood flow to well-ventilated alveoli, creating more dead space.
 * (3) __Decreased cardiac output__ decreases perfusion to the lungs, causing increased dead space.
 * (4) __Mechanical ventilation__ (ventilator tubing increases anatomic dead space, positive pressure preferentially inflates the more compliant vessels, leading to increased physiologic dead space)
 * (5) __Emphysema__ (decreased perfusion due to capillary destruction).
 * [Note that dead space doesn't directly alter gas exchange, but does result in wasted respiratory work. Most people can compensate well, so increased dead space is generally asymptomatic until it becomes severe or until compensatory mechanisms fail for other reasons.]
 * List the major causes of low V/Q and shunt
 * Shunt:
 * Anything that completely occludes the alveolus (eg. transudate due to left heart failure or exudate due to ARDS or pneumonia)
 * Congenital heart defects (right-to-left shunts)
 * Atelectasis (airway collapse)
 * Etc. Any situation in which blood flow is receiving no ventilation.
 * Low V/Q:
 * Hypoventilation
 * Asthma
 * Chronic bronchitis (mucus plugging, increased airway resistance)
 * Late emphysema (increased perfusion to the few remaining capillaries)
 * Interstitial lung disease
 * Calculate the A-a gradient using the alveolar gas equation
 * Alveolar gas equation: PAO2 = PIO2 - PaCO2///R//
 * Subtract the PaO2 (measured by ABGs) from the PAO2 and you've got the A-a gradient.
 * Define the five causes of hypoxemia and how the A-a gradient is used to distinguish these from one another
 * **Altitude** (normal A-a gradient)
 * **Hypoventilation** (normal A-a gradient)
 * Due to: obesity, sleep or waking apnea, neuromuscular disease, drugs that depress the respiratory center
 * **Diffusion limitation** (increased A-a gradient)
 * Due to extreme exercise (blood isn't in the capillary long enough to diffuse), or interstitial lung disease during exertion (blood leaves the capillary before it can diffuse through the thickened membrane), or edema.
 * **Low V/Q** and **shunt** (increased A-a gradient).
 * [Note that, as mentioned before, pulse oximetry is not good at picking up CO poisoning. Methemoglobinemia isn't well detected by PO either (drops to about 85%, tends to stay stable regardless of O2 infusion).]
 * Note methemoglobinemia can be caused by certain anesthetics used to sedate patients for intubation and relieved by methylene blue (at low doses). As in B+L, watch out for G6PD deficiency-- methylene blue is an oxidative stressor and can cause hemolysis.

Occupational Lung Diseases/Exposures Monday, April 28, 2008 7:51 AM


 * Occupational Lung Diseases/Exposures, 4/28/08:**


 * Define the role of the physician in identifying occupational and/or environmental hazards
 * I think what he's getting at is to consider these hazards when you're getting a history from your patients and forming a differential.
 * His other point seems to be that instead of accepting a diagnosis of 'idiopathic' you should dig and see if you can't turn up an occupational etiology.
 * There's also a public health component: once you've identified a disease as occurring due to an occupational exposure, something can be done about preventing that exposure in the future.
 * Note that there's a Preventative Medicine specialty.
 * Describe the different types of respiratory system diseases that may occur due to occupational and/or environmental exposures and relate these to the anatomy of the respiratory system
 * **Pneumoconioses** (fibrotic diseases caused by inhalation of dust):
 * Asbestosis-
 * Lung fibrosis; 8-fold increased risk of lung cancer, pleural plaques/effusion/cancer.
 * Asbestos fibers get lodged in bifurcations in the respiratory bronchioles; macrophages attempt to engulf them, and die.
 * Show up as __reticular opacities__ in the middle and lower lung zones.
 * Slowly-progressing fibrosis over decades. No cure.
 * Restrictive physiology.
 * Silicosis-
 * International problem, everywhere you do hard-rock mining (also sand-blasting, gravestone-carving, etc).
 * Silicotic nodules show up in lungs-- __scattered irregular__ birefringent particles.
 * Over times, nodules coalesce and patients develop progressive fibrosis.
 * Restrictive physiology.
 * Coal worker's pneumoconiosis (Black lung)-
 * Slowly progressive lung scarring due to coal or hard rock mining.
 * Effectively the lung begins to look like a lump of coal. Like silicosis, begins with individual bundles of coal that coalesce into larger areas of fibrosis.
 * Restrictive or mixed physiology.
 * **Granulomatous** disorders:
 * Beryliosis (inhaled berylium)-- test by seeing if lymphocytes specifically react with berylium particles.
 * Hypersensitivity pneumonitis
 * Various chemicals, aerosols, molds, etc, etc.
 * [Note that pneumoconioses are more or less free of adaptive immune response, while granulomatous disorders are heavily involved with the adaptive response, possibly because you need T cells to activate the macrophages.]
 * Infections (mycobacteria), cancers (tobacco smoke, etc)
 * Outline the key features of the occupational and/or environmental history to obtain from all patients
 * Where do you work? For how long and what kinds of hours? What do you do there? Are you exposed to dust, fumes, radiation, loud noise, etc? Do you use protective equipment? Is anyone else at your work having similar problems?
 * [Repeat for previous jobs]
 * Recognize the major categories of occupational disorders including the lung
 * Airway diseases- asthma (exposure to irritants-- about __15%__ of adult-onset asthma is caused by occupational exposures)
 * Diffuse lung diseases- sarcoidosis (9/11 dust), COPD/chronic bronchitis (inhaled fibers), carbon monoxide poisoning, inhaled stuff related to methamphetamine production, beryllium exposure.
 * [Cancer/infection- not mentioned extensively here but clearly significant.]

Pulmonary manifestations of systemic disease Monday, April 28, 2008 9:09 AM


 * Pulmonary Manifestations of Systemic Disease, 4/28/08:**


 * Identify the pulmonary manifestations associated with the different systemic diseases
 * (1) __Amyotrophic lateral sclerosis__ (ALS/Lou Gehrig's disease): (ALS = progressive neurodegenerative disease causing muscular weakness and uncoordination)
 * **Chronic aspiration** (pharyngeal muscle weakness)
 * **Chest wall/diaphragm weakness** -- low VA and thus hypercapnia (can cause lethargy and confusion), weak cough, SOB, orthopnea
 * Look for:
 * Lung infiltrates, particularly in the right middle lobe (aspirations tend to accumulate there due to main bronchial anatomy), and an inability to flatten the diaphragm on chest X-ray
 * Restrictive physiology pattern on a P/V graph, and a decreased FVC despite a normal FEV1/FVC ratio on PFTs.
 * Hypercapnia and maybe compensatory increased HCO3- on ABGs.
 * (2) __Rheumatoid arthritis__:
 * Can cause pleural inflammation/effusion/thickening, pneumothorax, ILD, pulmonary HTN, organizing pneumonia, vasculitis.
 * (3) __Goodpasture's syndrome__:
 * Recall that Goodpasture's is a type II immunopathology (antibodies against normal tissue) that affects mainly the kidneys and the lung (so keep it in mind when you're thinking about renal failure). Look for **alveolar hemorrhage**.
 * [Note other causes of alveolar hemorrhage + renal disease:]
 * SLE
 * Scleroderma
 * Wegener's granulomatosis
 * Henoch-Schonlein purpura (IgA-mediated type III disease, most common form of systemic vasculitis in children)
 * Cryoglobulinemia
 * Look for hemoptysis, patchy ground-glass infiltrates throughout lung (alveolar hemorrhage), get a Coomb's test and maybe a bronchoscopy to make sure it's blood (not pus or edematous fluid) in the alveoli.
 * Look for an **__increased__ DLCO** (blood is actually in the alveolar space and can take up the CO directly) but has a restrictive effect on lung function.
 * __Inflammatory Bowel Disease__ (IBD):
 * **Inflammation of trachea, bronchi, bronchioles** . Can get bronchiectasis as well due to repeated infections. Also look for **pleural effusion** and **ILD**.
 * X-ray: look for airway thickening (better on CT scan)
 * Note that pleural effusion or ILD result in restriction, where airway inflammation tend to cause obstructive disease.
 * __Sickle-cell disease__:
 * Infection (URIs are common triggers for sickle-cell)
 * Thrombosis of sickled cells can lead to infarctions (lots of chest pain, can lead to hypoventilation due to inability to inhale deeply).
 * "**Acute Chest syndrome** :" Infection leads to oxygen stress, causing worsening of sickling, which then leads to increased microocclusion of lung vessels and hence increased dead space and worsening of dyspnea.
 * Look for hypoxia, alveolar/interstitial infiltrates (edema due to endothelial damage from sickled cells) on X-ray. Note that the damage (increased permeability edema) can back blood up into the pulmonary arteries (causing pulmonary hypertension).
 * Identify whether the pulmonary manifestations of the systemic diseases are associated with obstructive or restrictive lung physiology
 * Infiltrate as due to aspirations in ALS: restrictive lung disease
 * Pleural effusion as due to rheumatoid arthritis: restrictive lung disease
 * Alveolar hemorrhage due to Goodpasture's syndrome: restrictive, but look for increased DLCO.
 * Bronchitis/bronchiectasis due to IBD: obstructive disease
 * Pleural effusion/ILD due to IBD: restrictive disease
 * Infiltrate/edema due to sickle-cell disease: restrictive disease

ALS: muscle weakness (chronic aspiration, diaphragmatic weakness)

RA: all kinds of crap.

Goodpasture's: alveolar hemorrhage (hemoptysis) and renal disease. Look for increased DLCO and positive Coomb's test, but no pus (no infection).

IBD: repeated airway inflammation, bronchiectasis; also pleural effusion and ILD.

Sickle-cell: watch for acute chest syndrome after infection: endothelial injury/vaso-occlusion in alveolar capillaries (edema, pulmonary hypertension).

Upper Airway and Larynx: Anatomy, Function, Disorders Monday, April 28, 2008 3:32 PM


 * Upper Airway and Larynx: Anatomy, Function, Disorders, 4/29/08:**

Once again, lecture notes are a little scattered. Best guess:
 * Describe the major anatomical and functional relationships of the upper airway
 * 5 layers covering the vocal folds (really 3):
 * Epithelium
 * Lamina propria (superficial, intermediate, deep)
 * Lamina propria allows vocal folds to vibrate (which is what allows speech).
 * Smooth muscle
 * Her notes also point out that the airway is lined with psuedostratified ciliated columnar epithelium.
 * Note abdominal muscles are significant in that they allow steady control of air intake and exhalation (which then determines loudness and duration of sound).
 * Note males have longer vocal folds; children/women have shorter (larynxes sit higher).
 * Define how speech is generated and the major categories of speech disorders
 * Vibration of lamina propria in vocal folds; change pitch by altering length of cords by altering position of thyroid cartilage. Also shape air with shape of mouth, tongue, and lips.
 * Note voice is dependent on enough air volume to vibrate vocal folds with sufficient amplitude. If you can't breathe in or out well, can't speak either.
 * Disorders:
 * Hoarseness: abnormal voice changes: breathy, raspy, strained, weak.
 * **Dysphonia** : general alteration of voice quality, usually from a laryngeal source.
 * **Dysarthria** : defect in rhythm, enunciation, articulation, usually from a neurological or muscular source. (stroke patients)
 * **Stridor** : high-pitched noise from large airway, due to obstruction during respiration.
 * (Inspiratory: look for epiglottal malasia, epiglottitis, epiglottal cancer)
 * (note she says stridor can be expiratory, unlike previous lecturers, and Wiki backs her up. If the stridor is both inspiratory and expiratory, look for a fixed obstruction such as subglottal stenosis, scarring behind the glottis after prolonged intubation, or croup inflammation in kids.)
 * **Stertor** : snoring sound from nose, nasopharynx, or throat (upper airways).
 * **Wheezing** : high-pitched sound (generally during exhalation) from smaller airways.
 * Define the major symptom complexes that indicate disorders of the upper airway and larynx
 * Hm. See the list above and the list at the bottom.
 * Define how the complex of symptoms called hoarseness is characterized and evaluated
 * Be concerned about:
 * Hoarseness that lasts longer than 2-3 weeks, particularly with smoking/drinking history (may indicate cancer).
 * Referred pain can occur (ear pain due to throat injury)
 * Hemoptysis, difficulty swallowing, lumps in neck
 * Complete loss or severe change in voice lasting more than a couple days
 * Define the major infectious and non-infectious causes of hoarseness
 * Infectious: __Viral laryngitis__ (most common- second most common is bacterial infection)
 * Non-infectious: __Chronic reflux__ (gastric acid in the larynx)
 * Everything else is more or less what you'd expect (vocal abuse, allergies or post-nasal drip, chronic cough, trauma, age, neoplasia, smoking, etc, etc).
 * [Also can get polyps, cysts, granulomas, and nodules in vocal folds themselves; frequently have to be surgically removed, sometimes can dealt with by vocal therapy.]
 * [Reinke's edema: 'bags of water on the vocal cords that flop in and out.' Occur in female smokers and will recur if taken out.]
 * [Vocal fold hemorrhage: popped a blood vessel in vocal folds. Patient needs to stay on strict voice rest to avoid scarring (and permanent hoarseness).]
 * [Age: vocal folds get slack with age, causing the voice to get softer.]
 * [After radiation therapy, get a lot of dead mucosa clogging up throat.]
 * [Arytenoid dislocation: recall that the vocal cords are stuck to the arytenoids. They can get dislocated during intubation, extubation, or trauma (particularly when the patient yanks out his tube without deflating it) and need to be put back in place quickly.]
 * [Left recurrent laryngeal nerve: goes down the neck, under the aortic arch, then back up the neck into the thyrocricoid cartilage. Long course. Look for nearby cancers with CT scan. Can also do electromyography (checking to see if muscles have normal innervation) to check for vocal fold paralysis. Note that if the nerves are pushed out to the side (as in spinal surgery through the neck) they can take a long time to resume their normal course and become more fully functional.]
 * [Reflux: can cause interarytenoid edema.]
 * [Can get recurrent papillomas growing in airway (on squamous cells).]
 * [Leukoplakia: white plaque in larynx, usually indicates a pre-malignant change.]
 * [Laryngeal cancer: can remove larynx completely and effectively provide a 'breathing hole' separate from esophageal pathway.]

Cough as Defense Mechanism and Symptom Monday, April 28, 2008 3:37 PM


 * Cough as Defense Mechanism and Symptom, 4/29/08:**


 * Understand the function and physiological mechanisms of cough
 * Cough: clears gunk out of airways (mucus, pathogens, particles, particles trapped in mucus, mucus doing a little two-step around the pathogens, etc).
 * Mostly controlled by vagus nerve (although can be voluntarily controlled by cortex).
 * Note that the vagus gets input from all sorts of places: ear, lungs, heart, esophagus, as well as the expected larynx/pharynx/tracheobronchial tree.
 * 4 phases:
 * Inspiratory phase: inhale; at end of inhalation, glottis closes.
 * Compressive phase: thoracic/abdominal muscles contract against a fixed diaphragm and a fixed glottis (a kind of isovolumetric contraction of the airspaces).
 * Expiratory phase: glottis opens, air comes shooting out.
 * Relaxation phase: relax thoracic/abdominal muscles.
 * Be able to classify cough according to its duration (acute, subacute, chronic)
 * Acute: cough lasting less than 3 weeks.
 * [Things to worry about: pneumonia, severe asthma or COPD exacerbation, pulmonary embolisms, heart failure.]
 * [More usually: URIs, lower respiratory tract infections, environmental or occupational exposures.]
 * Subacute: cough lasting 3-8 weeks.
 * [Think about postinfectious mucus drip proceeding to bacterial infection, asthma, etc. If it's not post-infectious, it's worked up as a chronic cough.]
 * Chronic: cough lasting more than 8 weeks.
 * [Generally due to either upper airway cough syndrome (the renamed post-nasal drip), asthma, or GERD. Also, less commonly, non-asthma eosinophilic bronchitis.]
 * [Notice that an impaired ability to cough can indicate a number of problems, including restrictive/obstructive lung diseases, sedatives, supine position, etc. This is a problem because you can aspirate bacteria, food, etc into the airway, resulting in obstruction or pneumonia, leading to abscess, ARDS, bronchiectasis, fibrosis, etc.]
 * Know the most common causes of acute and chronic cough in adults
 * As mentioned:
 * Acute cough: URIs, LRIs, acute exacerbation of existing asthma/COPD, environmental or occupational exposure.
 * Chronic cough: UACS, asthma, GERD, NAEB.
 * Note that maybe a quarter of patients with a cough have more than one etiology behind it.
 * Understand the role of antibiotics in the treatment of acute cough
 * URIs should not be treated with antibiotics (viral infections).
 * With LRIs, don't treat routinely with antibiotics, but consider //Bordatella pertussis// and //Mycoplasma/Chlamydia// exposure. Also consider bacterial infection secondary to COPD and bronchiectasis.
 * Obviously you don't treat asthma or particulate exposures with antibiotics.
 * Know the symptoms, signs, and empiric treatment for the 4 most common causes of chronic cough in adults (UACS, asthma, GERD, NAEB)
 * UACS: as mentioned, this is new-speak for post-nasal drip. Effectively you get a mucus drip from the nose or paranasal sinuses, triggering upper airway cough receptors. Can also get inflammation directly on those cough receptors.
 * Symptoms: 'tickle' in throat and throat clearing, as well as things you'd expect from a cough: hoarseness, nasal congestion, mucusal drainage.
 * Signs: 'cobblestoned' oropharyngeal mucosa, mucus in oropharynx or nasal passages.
 * Treatment: Antihistamine/decongestant combination for at least 2 weeks.
 * Note that if it persists after this treatment, then need to start looking at non-viral causes.
 * Asthma: we've covered this. Cough stimulated by irritant receptors near the inflamed site.
 * Symptoms: Intermittent wheezing (expiration), dyspnea, cough. Note sometime cough is the only symptom.
 * Signs: When present, wheezing on expiration. Test for improvement in FEV1/FVC with an albuterol inhaler. Also can use bronchoprovocation with methacholine to support diagnosis.
 * Treatment: Inhaled bronchodilator and an inhaled corticosteroid for at least 8 weeks.
 * GERD: Gastro-esophageal reflux disease (backflow of stomach contents into the esophagus, and up from there). Cough stimulated by the irritation of any part of the airway by stomach contents (aspiration of gastric acids) or irritant receptors in the esophagus alone. Note that the cough can also stimulate more reflux.
 * Symptoms: Generally, cough alone. Sometimes have heartburn or regurgitation.
 * Signs: None specific. Test esophageal pH over 24 hours.
 * Treatment: Proton pump inhibitor for at least 2 months, plus lifestyle modifications (weight loss and altered eating habits).
 * NAEB: Non-asthma eosinophilic bronchitis (a similar inflammation to asthma but lacking airway muscular hyperreactivity); develops frequently from environmental or occupational exposures. Cough stimulated by irritation by inflammation.
 * Symptoms: cough without wheezing or dyspnea (note this can also be asthma).
 * Signs: No wheezing on expiration. Asthma tests mentioned above are negative. Induced sputum analysis shows increased eosinophils.
 * Treatment: inhaled corticosteroids for at least 4 weeks.
 * [Important: note that you always get a chest X-ray with a chronic, unexplained cough.]
 * [Also recall that __ACE-inhibitors__ and smoking are frequent causes of coughing as well.]
 * Be aware of some important differences between chronic cough in children and adults
 * Chronic cough in children: lasting more than __4__ weeks (as opposed to 8 in adults). Less known about etiologies, although asthma, sinus disease, or GERD can cause chronic cough in children as well.
 * Consider chronic tobacco smoke exposure as a cause of cough in children as well.

Pharmacotherapy of the Upper Airway Tuesday, April 29, 2008 9:00 AM


 * Pharmacotherapy of the Upper Airway, 4/29/08:**

Note, as per French's style, that a lot of this isn't LOs but just good useful information:
 * __Glands__: activation of muscarinic receptors causes increased secretion, particularly here in mucus and gastric gland cells.
 * __Blood vessels__: activation of muscarinic/H1/bradykinin receptors causes dilation by NO production (counters alpha-1/sympathetic innervation constriction)
 * __Smooth muscle__: activation of muscarinic/H1 receptors causes constriction.
 * __Cough center__: irritants activate bradykinin receptors near the irritant site; these send a signal through sodium channels to the cough center, which sends efferent signals through sodium channels to cough muscles.
 * Note that increased levels of bradykinin following ACE-inhibitor administration can cause increased irritant receptor stimulation, causing the cough that's often seen with ACE-i use.
 * Note also that mu opioid receptors can block outgoing signals from the cough center to the muscles.
 * Note that inflammation (as from post-nasal drip) triggers bradykinin receptors, causing pain stimulus and cough.


 * Allergies: histamine from degranulated mast cells acts at H1 receptors in vessels, causing dilation.
 * Dilation causes both congestion and rhinorrhea.
 * Anaphylaxis: histamine from degranulated mast cells acts at H1 receptors in smooth muscle in throat, causing bronchoconstriction. Note that you treat this with epinephrine (a physiological antagonist) to dilate bronchial smooth muscle and also treat vascular dilation; synergistic with antihistamines in both of these actions.
 * In the body's inflammatory response to a respiratory viral infection, bradykinin causes the same symptoms as allergies - congestion and rhinorrhea due to vasodilation - as well as pain (sore throat) and cough stimulation.

--Begin actual LOs--
 * Describe the primary storage sites of histamine and the major stimulants of histamine release.
 * Histamine is primarily stored in sites of potential injury or infection: nose, mouth, feet, anything exposed to the outside world (GI tract, lungs, skin), and vessels.
 * Histamine release is, in immunologic situations, caused by two cross-linked IgE + antigen complexes to the mast cell, but can be caused by a wide variety of inflammatory mediators as well.
 * [Note that certain agents (cromolyn sodium) stabilize mast cell membranes, decreasing their degranulation. Epinephrine and glucocorticoids also affect degranulation.]
 * Explain the major physiological actions of histamines on the vascular system, edema, gastric secretions, and nonvascular smooth muscle.
 * As mentioned above: vasodilation (leading to edema), increased gastric secretions, and constriction of bronchial muscle.
 * List the major classes or generations of antihistamine (H1 antagonists) and describe their primary pharmacological actions, as well as the advantages and disadvantages (uses - side effects) of each.
 * 1st-generation agents cross the BBB and block H1, muscarinic, alpha-1, and sodium channels.
 * They block H1:
 * This causes relief of peripheral symptoms of congestion and rhinorrhea.
 * They also cause mild sedation in the CNS.
 * They block muscarinic receptors in the periphery: cause "dry mouth."
 * Also block sodium channels: lowers efferent cough stimulus from cough center.
 * Also block alpha-1 channels: block vasoconstriction, can predispose to orthostatic hypotension.
 * [2nd generation agents __do not__ cross the BBB (don't cause sedation, no good for motion sickness).]
 * They're also highly selective for H1 receptors-- no muscarinic, alpha-1, or sodium channel blockade.
 * Note that this means they can't suppress a cough, but also don't cause orthostatic hypotension and dry mouth.
 * For the antihistamine drugs listed below describe: mechanism and site of action (receptors and effector organs involved), pharmacokinetic factors (central vs peripheral activity, organ of elimination, duration of action - short vs long), major clinical uses, most common and most severe side effects, significant contraindications.
 * Metabolized by liver. First generation agents have peak levels in 1-2 hours, while second generation agents (loratadine, fexofenadine, cetirizine) have slower onsets and longer durations (12-14 hours).
 * Side effects: as noted, first generation drugs tend to have sedation, dry mouth, and postural hypotension issues. Second generation drugs seem to be generally well tolerated.
 * Some random notes on antihistamines:
 * 1st generation: __Diphenhydramine__, __Chlorpheniramine__, __Meclizine__, __Dimenhydrinate__.
 * Diphenhydramine (Benadryl):
 * Moderate cough suppressant. Also a topical anesthetic due to Na-channel blocking.
 * Meclizine: good for motion sickness, safe for use during pregnancy.
 * 2nd generation: __Loratadine__/__Fexofenadine__ (terfenadine)/__Cetirizine__.
 * Note that the FDA recommends not to use decongestants or antihistamines in kids under 6 (overdose danger).
 * For the various agents used in respiratory conditions (esp. colds and allergies) listed below describe: their role in treating symptoms (MOA), relative efficacy, route of administration, side effects, and their relative advantages / disadvantages.
 * Decongestants (sympathomimetics):
 * [The point is to use these as physiological antagonists to counter vasodilation in allergies/inflammation.]
 * __Phenylephrine__: Direct alpha-1 agonist. Very useful as a topical solution such as Afrin (avoids extensive MAO degradation). Watch out for overuse (in which vasoconstriction can lead to tissue necrosis). Watch out also for rebound congestion (tolerance to direct stimulation leads to withdrawal symptoms).
 * __Pseudoephedrine__: Systemic, indirect alpha-1 agonist (causes increased release of norepinephrine). Don't get rebound congestion, but, since it's used systemically, NE is released all over the body-- thus danger of elevated blood pressure.
 * __Oxymetolazine__: (topical) like phenylephrine, but longer-acting and thus only used twice a day, avoiding some of the rebound congestion.
 * Antitussive (anti-cough) agents:
 * __Codeine__: controlled substance, but it works really well. The definitive antitussive. Agonist of mu opioid receptors at the cough center.
 * __Dextromethorphan__ (in Robitussin DM): Like codeine, works as an agonist of receptors at cough center to suppress outgoing cough signals.
 * [Diphenhydramine: seems to be useful here mainly for its anti-muscarinic effects (dries out mucus glands to prevent the post-nasal drip that's irritating the cough receptors)]
 * Expectorants:
 * Guaifenesin: (seems to not work any better than improved hydration.)
 * Mucolytics:
 * N-Acetylcysteine: (not covered, but watch out for it exacerbating COPD)

Pediatric Lung Disease Tuesday, April 29, 2008 9:42 AM


 * Pediatric Lung Disease, 4/29/08:**

[As I mentioned, the listed LOs - and the notes - have nothing to do with her actual LOs (below).]

---
 * Understand the difference between pediatric and adult pulmonary physiology.
 * The pediatric airway is smaller. Recall that airway resistance is proportional to the inverse of the radius to the fourth power; thus there's much more airway resistance even without pathophysiology. Thus kids are more susceptible to obstruction (inflammation, edema, etc) causing problems with airflow.
 * Note that children are 'obligate nose breathers' due to soft palate proximity to epiglottis. Thus if they're clogged up with nasal mucus, they can't breathe well or at all.]
 * Note also that the pediatric diaphragm is flatter and fatigues more quickly. Also pediatric ribs are more or less horizontal, so they can't rotate upwards much to help expand the lungs during inspiration.
 * This means that in sick kids, you see a lot of abdominal muscle use during respiration, tachyhypnea, and grunting at the end of expiration (trying to keep the airways open).
 * Understand how to apply pulmonary physiology to pediatric illness/pathology.
 * (Hodgepodge follows.)
 * Note 4 main causes of hypoxia: V/Q mismatch, shunt, hypoventilation, diffusion problems (our other lecturer also cited high altitude). Most common one in kids is V/Q mismatch, often because the blood winds up going to poorly ventilated alveoli in infectious pulmonary disease.
 * Note also that wheezes are caused by lower-airway problems, usually with exhalation (recall that intrathoracic obstructions get worse with expiration) whereas stridor is caused by upper-airway problems, usually with inhalation (recall that extrathoracic obstruction gets worse with inhalation).
 * Acute inspiratory stridor in kids: usually caused by any etiology of the croup syndrome, or a foreign body in the larynx.
 * Bronchiolitis: most common cause of hospitalization of children under 1 year (usually caused by viral infection)-- tachypnea, retractions, wheezing. Secretions and edema in small airways is a bigger problem in kids due to the smaller diameter of their airways (as noted above).
 * Understand the signs of respiratory distress in an infant: tachypnea, retractions, grunting, fatigue.
 * These are outlined above. Remember that they can't expand their ribs much and their diaphragm tires quickly.
 * [Other notes on pediatric lung disease:]
 * [Differentiate the different croup syndromes:]
 * Croup syndrome: acute inflammatory disease of the larynx.
 * Viral croup: generally caused by parainfluenza and shows up with barking cough, stridor, and often low-grade fever. Is seasonal; treat acutely with inhaled epinephrine, chronically with corticosteroids. Mostly improves in a few days.
 * Epiglottitis: A medical emergency constituted by rapid swelling of the epiglottis and severe airway obstruction, usually due to infection by //H. influenzae// . Presents with high fever, loss of appetite, drooling, soft stridor, cyanosis. Kid must be intubated immediately and IV antibiotics started. Generally resolves quickly.
 * Bacterial tracheitis: mucosal bacterial invasion of patients with viral croup, causing pseudomembrane formation in the trachea. Presents as unimproving viral croup with higher fever, and severe progressive upper airway obstruction. Again, kid needs to be intubated and started on IV antibiotics. Resolution generally takes longer than epiglottitis or croup.
 * [Define bronchopulmonary dysplasia in terms of risk factors, prevention and treatment, and long-term sequellae:]
 * Brochopulmonary dysplasia (BPD) seems to be more of a clinical syndrome than a disease. Here's what it looks like:
 * ARDS in first week of life
 * O2 therapy or mechanical ventilation required past 36 weeks
 * Unresolved respiratory abnormalities that continue after the acute episode has been resolved
 * (this seems to be a catch-all term for "kid has ARDS, we fix it but something in ARDS plus something in how we fixed it leads to long-term damage.")
 * Risk factors:
 * Premature birth (the big one)-- immature lungs haven't finished developing either alveolar area or surfactant coverage, thus are more susceptible to both getting ARDS and receiving injury from positive pressure and high O2 content.
 * Note full-term babies with lots of aspiration or pulmonary hypertension can also develop BPD.
 * Prevention and treatment:
 * Administration of steroids to the mother 24 hours before the birth helps with the surfactant deficiency. Surfactant therapy also seems to help this a lot.
 * Long-term sequellae: mainly, increased risk for asthma, pulmonary hypertension, COPD, airway obstruction, and various nervous and feeding problems.

Inflammatory Lung Disease Wednesday, April 30, 2008 7:51 AM


 * Inflammatory Lung Disease, 4/30/08:**

zKnow the 3 main findings in hypersensitivity pneumonia o Caused by an allergic reaction to antigens driving a granulomatous reaction in the lung. Effectively a chronic overreaction to antigen stimulation. Causes fibrosis and irreversible lung damage if untreated, which is why it's important to catch it early. o Findings: · (1) Non-necrotizing granulomas: loosely formed, not very dense balls of macrophages. · (2) Bronchiolocentric chronic interstitial pneumonia: chronic inflammation of the alveolar septa with more and more inflammation near the airways (site of antigen presentation). · (3) Organizing pneumonia: recall that this causes fibroblastic mucus plugs in the airspaces.
 * Know the cell types involved in chronic, acute and granulomatous inflammation
 * Chronic inflammation: Predominantly **lymphocytes** (T + plasma cells).
 * Notice that the lung doesn't generally have lymph nodes-- it has 'lymphoid aggregates' that live in the walls of airways. So when you see a well-defined cluster of lymphocytes that doesn't extend up into the airway itself, that's probably an aggregate (bronchial-associated lymphoid tissue, or BALT).
 * However, when you see a less-defined cluster of lymphocytes infiltrating through various layers of the airway, particularly when it's completely encircling the airway, you think chronic inflammation, specifically cellular bronchiolitis (see below).
 * Acute inflammation: Predominantly **neutrophils** . One consequence of this is that, since neutrophils die fairly rapidly, there's a lot of cellular debris in the area.
 * Granulomatous inflammation: Predominantly **macrophages** -- granulomas are mainly clusters of activated macrophages trying to 'wall off' the site of inflammation.
 * Note that in granulomatous infections, you see macrophages that look weird-- pink, elongated, epithelioid. They tend to form round structures encircling the center of the granuloma.
 * You also see 'giant' macrophages (bunch of macrophages fused together).
 * Know the features and causes of cellular bronchiolitis
 * __Lymphocytes__ infiltrating and encircling small airways. Some causes:
 * Infection: generally mycoplasma or chlamydia (relatively __indolent__ organisms)
 * Chronic aspiration
 * Collagen vascular disease or autoimmune disease
 * Inflammatory bowel disease (late complication, possibly due to similarity between mucin-secreting cells in bronchioles and in small intestine)
 * [Note contrast with cellular interstitial pneumonia, which involves the alveolar septa-- look for thickened septa filled with lymphocytes (caused by viral infections or as part of interstitial lung disease).]
 * Know the differences between capillaritis, acute bronchiolitis and bronchoalveolar pneumonia
 * Acute bronchiolitis: neutrophils in __lumen__ and __bronchiole wall__.
 * Nearly always caused by infection, although can be acute aspiration or inhalation of fumes or toxins. Can also be part of a larger bronchopneumonia or an acute episode of inflammatory bowel disease.
 * Capillaritis: neutrophils in the __alveolar septa__, particularly the capillaries. Causes red cells to leak into the air space.
 * Usually caused by the response to a viral infection or an autoimmune reactions. Note that it may be indicative of a larger vasculitis (like Wegener's).
 * Bronchoalveolar pneumonia: neutrophils in the airspaces (possibly a sequellae of capillaritis). Look for patchy alveolar consolidation with bronchial and bronchiolar involvement.
 * [To briefly review: Chronic (lymphocytes) = cellular bronchitis, cellular interstitial pneumonia. Acute (neutrophils) = acute bronchiolitis, capillaritis, bronchoalveolar pneumonia.]
 * Review the features of lobar pneumonia and its classic stages of development
 * __Lobar pneumonia__: Classically pneumococcal.
 * Uniform involvement of 1 or more lobes (pneumonia __doesn't cross lobar boundaries__).
 * Stages:
 * Edema and congestion in 12-14 hours. Not many inflammatory cells yet.
 * "Red hepatization" stage for 1-3 days: Increased neutrophils, firm lung (looks and feels like liver), red cell-, fibrin-, and pus-filled alveolar spaces.
 * "Gray hepatization" stage for 3-4 days: disintegration of the neutrophils and red cells; fibrin-filled alveolar spaces.
 * Resolution in 2-5 days afterwards.
 * Note complications: bacteria can get into the blood stream, the lung can scar, or you can get bronchiectasis (see next LO).
 * [Note that one reason that it's worse to get varicella as a child than an adult is that there's a very unpleasant AIP complex that's associated with varicella infection in adults.]
 * Know the definition of bronchiectasis
 * Airways tend to dilate in response to infection. With enough recurrent infections, the airways can get scarred up and stuck in this dilated form-- bronchiectasis.
 * The permanently dilated airways sets up the lungs for further infections (vicious cycle).
 * Know what a granuloma is, and the difference between necrotizing granulomas and non-necrotizing granulomas
 * Granulomas are very long-lived things-- they form as a 'last-ditch' effort to wall off the things or organisms that the body can't destroy.
 * Granuloma: "a prison [made] of macrophages and collagen."
 * Necrotizing: in the center of the granuloma, there's a lot of dying tissue.
 * Almost always caused by infections, usually **mycobacterial** (particularly **TB** ) and fungal (though Wegener's causes this as well).
 * Non-necrotizing: in the center of the granuloma, there's no dying tissue.
 * Can be caused by a bunch of crap. Sarcoidosis, beryliosis, hypersensitivity, or an early necrotizing granuloma before it's had a chance to necrotize.
 * Understand the common causes of necrotizing granulomatous infections (mycobacteria, fungus)
 * As mentioned, mainly tuberculosis. Note TB has a very rapid resistance adaptation mechanism.
 * TB: peripheral caseous necrosis forms, get walled off into granulomas; collagen forms around them. Note that viable organisms can survive inside these granulomas for decades, and become reactivated at a later point.
 * TB tends to __localize in the upper lobes__ rather than the lower lobes.
 * Fungal infection: show granulomas that look exactly the same as TB. Have to stain for fungi to differentiate.
 * Can be particularly pathogenic fungi or opportunistic, normally commensal fungi.
 * Pathogenic:
 * Histoplasmosis: picked up from bird/bat poop. Very small budding yeast (half the size of a red blood cell).
 * Coccidiomycosis: picked up from rodents. Largest fungi around. This is the most common cause of 'coin lesions' on x-rays (looks like lung cancer).
 * Blastomycosis: picked up from soil. Medium-sized fungi; "wide-necked buds."
 * Know the findings of sarcoid and chronic beryllium disease
 * Sarcoidosis: main source, if you can call it that, of non-necrotizing granulomatous disease. Effectively "idiopathic" at least for the moment. Note that the granulomas can involve nearly every organ of the body and spread along lymphatic channels.
 * Note that if you find granulomas sitting out in the airspaces, that's probably not sarcoidosis (almost always near lymph).
 * Beryliosis: Pathologically indistinguishable from sarcoidosis. History is the only clue to differentiation. Occurs mainly in genetically susceptible population (delayed hypersensitivity reactions).

Chronic: Lymphocytes in/around the airways: **cellular bronchiolitis** Lymphocytes in the alveolar septa: **cellular interstitial pneumonia**

Acute: Neutrophils in/around the airways: **acute bronchiolitis** Neutrophils in the alveolar septa: **capillaritis** Neutrophils in the alveolar airspaces: **bronchoalveolar pneumonia**

Lobar pneumonia: edema/congestion, hemorrhage/pus in alveoli, fibrin in alveoli, resolution.

necrotizing: infectious (mycobacteria/fungal), Wegener's non-necrotizing: sarcoid, beryliosis, etc

Lung Carcinogenesis and Cancer Wednesday, April 30, 2008 9:00 AM


 * Lung Carcinogenesis and Cancer, 4/30/08:**

[Again: best guess.]
 * Describe three major etiologic agents that cause lung cancer.
 * Tobacco (active 85-87%, passive 3-5%)
 * Radon (uranium breakdown product) in home (3-5%)
 * Industrial pollution (0-5%)
 * List the two major clinical classes of lung cancer.
 * Small-cell and non-small cell.
 * Non-small cell includes squamous cell carcinomas, adenocarcinomas, and undifferentiated large-cell carcinomas.
 * Small-cell: also called "oat cell carcinoma." Most metastatic tumor around and hence bad news.
 * What genetic regions or genes have been shown to be important in lung cancer susceptibility?
 * Chromosome 6q23-25: increased susceptibility.
 * Chromosomal aneusomy (abnormal chromosomal number or structure) seems to indicate increased risk.
 * Gene promoter methylation (gene silencing): if you have certain regulatory genes silenced, also an increased risk.
 * (Notice that a family history of lung cancer is an increased risk factor, as you'd think.)
 * Describe two mechanisms of tumor suppressor gene inactivation in lung cancer.
 * Methylation and aneusomy, as mentioned?
 * [Note 2/3 of presenting patients with cancer come in with Stage IIIA or worse (non-surgical); only 16% of them will survive the next five years.]
 * [Good predictor of lung nodule malignancy: its size. Maybe biopsy it above 8 mm?]
 * [Note also that spiral CT seems much better at picking up early lung cancer than X-ray.]
 * Understand the role of autocrine growth factors in lung carcinogenesis.
 * Evidently the tumors often secrete their own growth factors, or the individual is secreting increased amount of them. Obviously this helps the cancer grow.
 * To understand the concept of growth factor or oncogene addiction in lung cancer, particularly in relation to EGFR tyrosine kinase inhibitors.
 * I think the idea here is that certain tumors are dependent on an increased expression of growth factors (like EGF, epithelial growth factor) or oncogenes, particularly in people whose EGF receptors have mutations that make them susceptible to being unregulated. If you can block those receptors, the cancer can regress dramatically. This seems particularly true of EGF receptor tyrosine kinase inhibitors in lung cancer.
 * What factors predict response or lack of response to EGFR tyrosine kinase inhibitors?
 * Response: never-smokers, East Asian ethnicity, female gender, with adenocarcinoma histology. Also people with overexpressed EGF receptors.
 * Lack of response: everyone else, I suppose.
 * To understand the concept of field cancerization and some of its underlying mechanisms.
 * Field cancerization: the idea that cancer can cause a change in surrounding/other tissues that makes them more susceptible to becoming new cancers themselves.
 * Could come about due to a mutation in an epithelial stem cell that later dispersed throughout the tissue. See similar patterns of tumor suppression gene loss of heterozygosity and epigenetic modification in fields of tissue near cancer.
 * Describe the effects of beta carotene and retinol supplementation on lung cancer development.
 * Generally, existing studies suggest that high fruit and vegetable intake produces a drop in lung cancer.
 * However, beta-carotene and retinol supplementation seem to be neutral or increase risk of lung cancer.

Tuberculosis: Worldwide Control and Testing Wednesday, April 30, 2008 10:00 AM


 * Tuberculosis: Worldwide Control and Testing, 4/30/08:**

[Latent TB: temporary "draw" between host and mycobacteria tuberculosis.] (Solid caseous necrosis in the center of a granuloma: activated macrophages destroy escaping TB bacteria but serve more of a containment role. (Note that if the caseous center liquefies (surrounding macrophages breaking down), the TB can escape out of the granuloma and into the airway (to be coughed out). [Note that in immunocompetent individuals, TB infection (almost always occurs through the respiratory tract) is usually a latent phenomenon.] [Numbers: 2 billion worldwide infected, 7-8 million new cases/year, 2-3 million deaths/year.] [TB resurgence in 80's and 90's: HIV, less funding for TB public health infrastructure, increased immigration from TB-endemic regions, emergence of drug resistance.]


 * Identify individuals who should be targeted for tuberculin skin testing to diagnose latent tuberculosis infection
 * __Immigrants from TB-endemic countries__ and __HIV-positive__ individuals; also people who have recent contact with TB patients, immunosuppressed patients, homeless, IV drug users, diabetes, end-stage renal disease, silicosis patients, etc.
 * Note that there's different size criteria for different risk groups. HIV is in the highest risk group (> 5 mm induration = latent TB indication), health care workers and recent immigrants = medium risk (> 10 mm induration = latent TB indication)
 * Note that HIV and TB accelerate each others' progression. TB is responsible for about 1/3 of all deaths from AIDS. HIV depletes killer T cell count (CD4+), which degrades the body's ability to activate macrophages and retain granuloma integrity.
 * Notice that TB skin test is still a cheap, easy, reliable way to distinguish latent TB infection from uninfected individuals. (inject TB proteins, measure the diameter of induration or hardness after 48-72 hours.) Notice that vaccinated individuals can also cause a positive TB skin test.
 * [Note that detection based on tuberculin skin test and treatment based on the results is very effective at preventing reactivation of TB. That said, there is a certain false-positive rate due to prior TB vaccination or non-infectious mycobacteria, and there's a certain false-negative rate due to immunosuppression (organ transplants, HIV, etc).]
 * [Note also that there's another test, the interferon-gamma assay. It provokes memory T cells with a TB-specific antigen; if they're seen it before, they produce a lot of interferon gamma. Quicker, more sensitivity, more specific (no vaccination false positives).]
 * Know the optimal pharmacologic regimen for treatment of latent tuberculosis infection
 * Preferred treatment: 9 months of isoniazid. Can also do 6 months for more mature of less immunosuppressed patients.
 * Notice that //active// tuberculosis is not treated with isoniazid, but treated with a multi-drug regimen of at least 4 drugs.
 * Note that vitamin D seems to be important in immune function (induces antimicrobial peptides, among other things vs. tuberculosis).
 * Note also that rifampin-pyrazinamide treatment cannot be recommended for treatment of //latent// TB, due to liver toxicity.
 * Understand the public health implications of identifying and treating latent tuberculous infection
 * Treating latent infection can stop it from becoming reactivated, thus prevent spread.

Diseases of the Mediastinum and Pleura Wednesday, April 30, 2008 11:03 AM


 * Diseases of the Mediastinum and Pleura, 4/30/08:**


 * Identify the anatomic relationships of the cardiovascular, respiratory, endocrine, and GI systems within the mediastinum and the compartments of the mediastinum
 * CV: Heart and great vessels.
 * Respiratory: trachea and main bronchi.
 * Compartments:
 * Anterior: Behind sternum, anterior to heart/great vessels.
 * Contains the thymus, lymphatic vessels, connective tissues, and abnormally located thyroid/parathyroid tissue.
 * Middle: Behind that; includes trachea and heart/great vessels.
 * Contains the heart, pericardium, great vessels, SVC, trachea, major bronchi, hila of lungs, lymph nodes, phrenic and upper vagus nerves, connective tissue.
 * Posterior: Behind that.
 * Contains the esophagus, descending aorta, azygous/hemiazygous veins, thoracic duct, lymph nodes, lower vagus nerves, sympathetic chains, connective tissue.
 * Define the major symptoms and clinical syndromes associated with mediastinal diseases and how they relate to the mediastinal compartment
 * Mass lesions:
 * See below.
 * Pneumomediastinum:
 * Pneumomediastinum: air/gas in the mediastinum, usually asymptomatic but can present with chest pain, dyspnea, fever, and a crunching sign on auscultation. Generally a radiographic diagnosis. Note that positive pressure can cause this.
 * Mediastinitis:
 * Collection of etiologies of inflammation in the mediastinum.
 * Acute inflammation has a dramatic presentation (septic) and frequently lethal consequences. Compression of mediastinal structures (see superior vena cava syndrome, below) can follow.
 * Can be caused acutely by perforation of esophagus as due to lots of vomiting, perforation of trachea, post-surgical infection, or anthrax.
 * Treated by surgical debridement and drainage, followed by antibiotics.
 * Chronic inflammation is generally due to ongoing granulomas (often tuberculosis).
 * **Superior vena cava syndrome** : results from obstruction/impingement of superior vena cava.
 * Obstruction of blood flow: dilated veins in upper thorax, neck, and head; edema in face/neck/upper torso; headache, altered mental status, and vision changes.
 * Get a chest X-ray to evaluate mediastinal space.
 * List the types of masses found in the mediastinum including frequency and clinical evaluation of these masses
 * 80% of asymptomatic masses are benign.
 * 50% of symptomatic masses are malignant (thus 50% benign).
 * Local symptoms tend to be related to compression or invasion of local structures; systemic symptoms tend to be fever, anorexia, weight loss, endocrine/autoimmune factors.
 * Anterior mediastinal mass:
 * Thymic neoplasm
 * Germ cell tumor (teratoma)
 * Hodgkin's or non-Hodgkin's lymphoma
 * Thyroid neoplasm
 * Middle mediastinal mass:
 * Lymphadenopathy due to inflammation/granulomas, metastasis, [Castleman's disease]
 * Lymphoma
 * Cysts formed during development in pericardium/bronchi
 * Vascular enlargements (aortic dissection, etc)
 * Diaphragmatic hernia [Morgagni or right-sided herniation]
 * Posterior mediastinal mass:
 * Neurogenic tumors of peripheral nerves/sympathetic ganglia, or paraganglionic tissue.
 * Meningocele (protrusion of meninges into mediastinum)
 * Esophageal lesions
 * Diaphragmatic hernia (Bochdalek or left-sided herniation, less common)
 * Use chest X-rays, elevated levels of proteins for germ cell tumors, spiral CT, MRI (mainly for neurogenic lesions), ultrasound (for cysts), radionuclide scanning for thyroid or PET scans to evaluate metabolic activity in tumors.
 * Usually require a tissue biopsy/aspiration:
 * Can use transbronchial needle aspiration, endoscopic ultrasound-guided aspiration, or percutaneous aspiration.
 * Note you can also do surgery: scoping through artificial holes in the chest, pretty much.
 * List the diagnostic procedures used to evaluate abnormalities of the pleural space
 * Note that site-specific chest pain is often pleural rather than mediastinal.
 * X-rays work good for initial diagnosis.
 * Do pleurocentesis (needle draw in thorax near dullness to percussion), look for protein/LDH content, look at cellularity, Gram stain, etc.
 * Identify the difference between transudative and exudative pleural effusions
 * Transudate: effectively, hydrostatic edema. Recall that transudates are non-protein-rich and hypocellular.
 * Can be caused by CHF, cirrhosis, nephrotic syndrome.
 * Exudate: generally inflammation. Recall that exudates are protein-rich and can be hypercellular.
 * Can be caused by neoplasms, infections, pulmonary embolism, GI disease, systemic inflammation due to collagen vascular disease.
 * Measure the serum LDH/protein content and compare it to that of the pleural fluid.
 * Stupid numbers:
 * A pleural-fluid LDH content that's more than 60% of the serum level, or a protein content that's more than 50% of the serum level, means exudate.
 * List the types of tumors found in the pleural space
 * Most common: lung, breast, lymphoma, GI, genitourinary.

Adaptation to Extreme Environments/Exercise Thursday, May 01, 2008 10:01 AM


 * Adaptation to Extreme Environments and Exercise, 5/1/08:**


 * Determine the inspired PO2 based on barometric pressure and how this related to human exploration at altitude and at depth
 * Recall that PIO2 = (PB - 47) * FIO2.
 * PB (and thus PIO2) goes up as you go deeper and down as you go higher.
 * Define the normal ventilatory and cardiac adaptation to altitude and depth
 * First response to altitude:
 * Increase __cardiac output__ by increasing heart rate (increase O2 delivery to tissues). Occurs within minutes of exposure to altitude.
 * Note this is an acute mechanism only. After a little while, this goes back to normal. However, note the chronic effect on erythropoietin (below).
 * Hypoxia causes systemic vasodilation, reducing afterload on the heart, and thus also allowing the heart to increase its stroke volume without sympathetic stimulation.
 * There's also an increase in __minute ventilation__ (and thus also VA) by increasing respiratory rate and tidal volume, due to stimulation of low-PO2 receptors in the periphery. This increases CO2 clearance and increases PaO2.
 * Over a long period of time, adaptation to chronic high altitude results in a couple of interesting things:
 * You see an exaggerated response to hypoxia: the respiratory centers will increase ventilation with a much milder stimulus (higher PaO2) than at low altitude.
 * So if at a normal altitude you'd start to hyperventilate at PaO2 = 50, at chronic high altitude you might start to hyperventilate at PaO2 = 70.
 * Note that with chronic hypoxia, the level of erythropoietin secreted by the kidneys goes up. This __increases hemoglobin levels__, which allows the heart to resume a fairly normal cardiac output while still improving O2 delivery to tissues.
 * Note that the increase in Hb is matched by a reduction in plasma volume, which presumably has consequences for viscosity.
 * You also see a left shift in the oxy-hemoglobin dissociation curve. This is due to the hyperventilation: the low CO2 causes alkalosis (high pH), which causes a Bohr effect and shifts the curve left.
 * Note you have also an increase in 2,3-DPG (slight shift to right, maybe increased offloading at tissues?). This effect is generally small compared to the left-shift due to CO2.
 * The muscles adapt as well: they increase myoglobin content (increase O2 binding capacity) and capillary density (increase perfusion).
 * Note also that in extreme low PIO2 situations the oxygen diffusion into capillary RBCs can be slow enough that it can be incomplete by the time the blood leaves the capillary.
 * Note that small differences in barometric pressures can make big differences in physiology (recall that oxy-hemoglobin dissociation curve has a zone at which small changes in PaO2 have larger impacts on the % hemoglobin saturation, and % saturation
 * Define the major pathologic clinical syndromes associated with exposure to altitude
 * __Acute Mountain Sickness__- headache, nausea, malaise, anorexia. Starts about 6 hours after going to altitude (altitude can be just about anything, but mostly over 6600 feet). Symptoms generally peak in 2-3 days and resolve spontaneously after that. Can also treat with __acetazolamide__ (diuretic that wastes bicarbonate-- reduces blood CO2). Note that fitness is not protective and AMS frequently recurs in individuals upon recurrent exposure to altitude.
 * __High Altitude Pulmonary Edema__ - extreme pulmonary hypertension, dyspnea, cough, hypoxia, bilateral infiltrates on chest X-ray. Seems to be involved with a decreased ventilatory drive response to hypoxia, causing the lungs to become increasingly hypoxic, causing organ-wide vasoconstriction, causing pulmonary hypertension and pulmonary edema. Note that this can kill you. Genetic factors predispose. First treatment is descent. Can't be a sherpa.
 * I want to write a blues song about a Nepalese guy who wants to be a sherpa but gets HAPE whenever he goes up there. Note, however, that Nepalese and Tibetans seem to have a blunted hypoxic vasoconstriction reflex. So much for art.
 * __High Altitude Cerebral Edema__: similar to AMS but progresses quickly to ataxia (uncoordination), hallucinations, and coma. Rare but very bad.
 * __Other junk__: Living at high altitude tends to result in increased infant mortality and lower birth weights; also higher rates of pre-ecclampsia. Note also the possibility of polycythemia or cor pulmonale due to pulmonary arterial hypertension.
 * Define the major clinical syndromes associated with exposure to depth with either breathholding or breathing of gas
 * Breath-holding:
 * __Pulmonary barotrauma__: the high pressure in the trachea pushes the gas out of it and into the interstitium, whence it can get into the pleural space (causing pneumothorax) or the mediastinum (pneumomediastinum).
 * __Air embolus__: same idea, but the gas in the alveoli gets pushed into the blood vessel; can cause stroke.
 * __Shallow water blackout__: diving while holding your breath can cause a loss of consciousness. This seems to be mainly in people that hyperventilate before diving-- this lowers CO2 levels, which if you recall is the main mechanism for the urge to breathe. So their brains begin to get hypoxic but their CO2 levels are still normal-- so they black out in the water without knowing that they're hypoxic at all.
 * Breathing gas:
 * __The bends__: rapid ascent decreases pressure on inert gases like nitrogen in the blood, causing them to supersaturate and precipitate out of solution in the form of bubbles-- these bubbles expand into emboli and can cause organ damage. Don't go diving and then go to the mountains, that makes it worse.
 * __Nitrogen narcosis__: breathing compressed air that's largely nitrogen at depth increases PaN2 and can cause ataxia, poor decision-making, and unconsciousness. (This is why __helium__ is generally used instead.)
 * Identify clinical situations (i.e. gas exchange limitations and airflow limitations) which increase the risk of exposure to extreme environments.
 * Diving: Note that the air becomes more viscous, the airways are slightly narrowed, the work of breathing is harder, and the dead space is increased (SCUBA tubing).
 * Asthmatics having attacks should probably not go diving. COPD is also a problem.

Influenza, SARS, and Bird Flu Thursday, May 01, 2008 4:29 PM


 * Influenza, SARS, and Bird Flu, 5/2/08:**


 * Define the clinical syndromes of SARS including epidemiology, clinical presentation, mortality, and containment
 * Note that SARS was spread largely through exposure in hospitals.
 * Clinical presentation:
 * Week 1: fever, muscle pain, headache, sore throat, and cough, sometimes diarrhea (looks very much like H5N1).
 * Week 2: rapid progression dyspnea, cough, and hypoxia, sometimes ARDS; high LDH and low white cell counts
 * Week 3: resolution, one way or the other.
 * Epidemiology: can be airborne spread, but more often spread in large droplets from close contact.
 * Note that, unlike traditional influenza, maximal viral shedding in SARS occurs around day 10 - right around the time they're in the hospital.
 * Mortality: seems to be from 10-20%.
 * Note that despite similarity in initial clinical presentation, SARS is not related to influenza-- it's caused by a coronavirus.
 * Define how bird flu and influenza epidemics differ with respect to epidemiology and public health risk
 * Honestly, I don't get this one. Influenza is influenza whether it's human or avian. Both varieties can mutate into something very unpleasant for which there's no herd immunity. I think that perhaps what she was trying to get across is that human influenza tends to cause fairly mild outbreaks (some partial-immunity exists) with some frequency, whereas avian influenza seems to cause really nasty outbreaks (no partial immunity exists) but it doesn't happen as often, because avian flu needs to acquire several changes before it can become a pandemic source in humans (more below on this).
 * Recall that we worry specifically about human Influenza A, both because it's very pathogenic and because it can cross-infect other species. Recall also that "antigenic shift" refers to a major alteration in the virus (viral genome swapping, or interspecies crossing, or both) that potentiates an effectively completely new set of antigens, while "antigenic drift" refers to minor changes in surface antigens.
 * Influenza pandemic: outbreak of a newly emerged type of flu (antigenic shift)-- there is no pre-existing immunity in human populations. After a pandemic, you generally get immunity punctuated by small, more local epidemics as the virus undergoes minor, but clinically significant, variations.
 * Unsurprisingly, pandemics tend to kill a bunch of people (though a lot of that is blunted these days due to antivirals, antibiotics vs. post-influenza pneumonia, improved public health conditions, etc).
 * Note that a disproportionate number of those people seem to be younger (24-34) than you'd expect. This, recall from B+L, has something to do with systemic cytokine activity due to systemic T cell activation. Younger people have a lot more T cells to be activated, thus a stronger and more lethal response.
 * Avian influenza: Again, recall that generally the avian flu needs to have a couple of changes in order to actually cause a pandemic-- one to cross over to humans, another to be able to be contagious through airborne transmission from human to human (to attach to sialic acid receptors in the upper respiratory tract). Generally, so far, primary exposure has resulted only from extensive exposure (ie. you're a chicken farmer).
 * Note that the reconstructed 1918 flu virus shows it to be entirely an avian flu, with no interpolation from human viruses.
 * H5N1 clinical presentation:
 * Incubation usually 2-5 days
 * High fever, symptoms of LRI
 * Sometimes diarrhea, pleuritic chest pain, dyspnea, vomiting
 * Multifocal consolidation (like pneumonia) and pleural effusions
 * Progress to ARDS, usually by day 6
 * Oseltamivir is the treatment of choice but notice that it doesn't really seem to do any good; maybe administered too late?
 * Understand the importance and potential impact of emerging infectious diseases in your role as a physician
 * Oh, for God's sake.

Pulmonary Physical Exam Thursday, May 01, 2008 4:30 PM


 * Pulmonary Physical Exam, 5/2/08:**


 * Know the components of a complete pulmonary physical exam
 * Inspection, palpation, percussion, auscultation-- not necessarily in that order.
 * Inspection: vital signs (HR, BP, temp, RR); also ox saturation and cyanosis, clubbing, etc.
 * Palpation: areas of tenderness, assess skeletal abnormalities, tactile fremitus, palpation of the trachea to assess deviation.
 * Percussion: look for dullness or hyperresonance.
 * Auscultation: listen for breath sounds.
 * Understand the pathophysiologic reasons for abnormal percussion, palpation, and auscultation of the chest
 * Abnormal percussion findings:
 * Dullness: fluid- or solid-filled spaces, frequently due to pleural effusions, lobar pneumonia, or atelectasis.
 * Hyperresonance: anything that increases air in the lung, frequently due to pneumothorax, emphysema, or air-filled bullae.
 * Abnormal palpation findings:
 * Decreased fremitus: caused by excess air in the lungs, a pleural effusion, or atelectasis.
 * Increased fremitus: caused by consolidation (replacement of air with fluid), as in pneumonia or pulmonary edema.
 * Abnormal auscultation findings:
 * __Crackles/rales__: Disruptive airflow through the small airways, caused by pulmonary edema, pneumonia, and ILD.
 * __Rhonchi__: continuous rumbling sounds caused by airflow through an airway partially obstructed by mucus or secretions.
 * __Wheezes__: continuous high-pitched sounds during inspiration or expiration, caused by high airflow through a narrowed airway.
 * Identify major physical exam findings associated with pneumonias, pleural effusions, atelectasis, pneumothorax, asthma, COPD, etc.
 * Pneumonia: rales in the affected lung, dullness to percussion, increased tactile fremitus.
 * Pleural effusion: decreased/absent breath sounds over the affected portion of the lung, dullness to percussion, decreased tactile fremitus.
 * Atelectasis: Absent breath sounds over the affected portion of the lung, dullness to percussion, decreased tactile fremitus.
 * Pneumothorax: Absent breath sounds, hyperresonance to percussion
 * Asthma: Wheezes, generally expiratory, on auscultation, normal fremitus, normal percussion.
 * COPD: Rhonchi in lungs, hyperresonance to percussion, decreased tactile fremitus.
 * [Don't forget to look at the required equations on Blackboard.]