Hypoxia

Last post for PHYL3002!

Define hypoxia, hypoxemia and cyanosis.

• Hypoxia: Low oxygen content.
• Hypoxemia: Low partial pressure of oxygen in the arteries.
• Cyanosis: Discolouration of the skin due to unsaturated haemoglobin.

List the main types of hypoxia

Hypoxia can be divided into peripheral and central hypoxia. Peripheral hypoxia only affects some tissues, whereas central hypoxia affects the whole body. Peripheral hypoxia can be ischaemic (due to poor perfusion of tissue, as might happen if you tie a tourniquet too tightly), histotoxic (due to mitochondrial failure, as happens in cyanide poisoning) or in heavy exercise (oxygen supplies are depleted, causing muscle to switch to anaerobic metabolism).

Explain why there is no hypoxemia in anaemic hypoxia

Anaemia can cause hypoxia without causing hypoxemia. In anaemia, there are fewer red blood cells, and therefore less haemoglobin for oxygen to bind to. Therefore, the total oxygen concentration (oxygen dissolved in arterial blood + oxygen bound to haemoglobin) is less overall, resulting in hypoxia. Anaemia, however, does not cause oxygen dissolved in arterial blood to decrease, and therefore does not cause hypoxemia.

Identify the five causes of hypoxemia
Explain the changes in gases cause by the five types of hypoxemia

The five causes of hypoxemia are as follows:

1. Low PiO2 (partial pressure of inspired oxygen, such as in high altitudes)
2. Hypoventilation
3. Diffusion limitation (i.e. issues in gases diffusing across the alveolar wall)
4. R-L shunt (i.e. mixing of deoxygenated and oxygenated blood, as occurs in several congenital heart defects)
5. V'/Q' mismatch (the most common cause of hypoxemia)

Now let's go over each one in turn!

Low PiO2

As mentioned, this can occur at high altitudes. It can also occur due to occupational hazards (e.g. a nitrogen gas leak that displaces oxygen).

Hypoventilation

Hypoventilation = ventilation insufficient to meet respiratory demands. This can have several causes, including but not limited to the following:

• Asphyxiation- no ventilation due to a physical obstruction (strangling etc.)
• Failure of respiratory drive- can be due to CNS damage or certain drugs
• Failure of respiratory muscle- can be due to a neuromuscular disease such as muscular dystrophy
• Failure of lung ventilation- due to a restrictive or obstructive lung disease
• Drowning- as I will explain...

The effect of drowning depends on whether you are drowning in salt or fresh water. (Okay, the overall result- death- is still the same, but the path to death is a bit different.) Also most patients who die by drowning actually die by laryngospasm rather than by the water itself, but let's ignore that for now.

If you are drowning in fresh water, your blood will have a higher osmolarity than the fluid in the alveoli, so water is drawn into the blood. This causes cells to swell and then lyse. Lysed cells release a lot of potassium, so the potassium concentration of the blood goes up (which can lead to arrhythmias, heart failure etc.). Concentrations of other solutes, such as sodium, chlorine and proteins, will decrease as they have become diluted by the extra water.

If you are drowning in salt water, your blood will have a lower osmolarity than the fluid in the alveoli, so even more water is drawn into the alveoli. Therefore, salt water drowning is harder to save someone from than fresh water drowning. Since fluid is being lost from the blood, the blood is more concentrated, and so concentrations of sodium, chloride, magnesium, proteins etc. all increase.

Hypoventilation decreases oxygen concentrations and increases carbon dioxide concentrations. (This is in contrast to V'/Q' mismatch, diffusion limitation and R-L shunt, all of which cause hypoxia with little to no hypercapnia.) Therefore, hypoventilation can be distinguished from V'/Q' mismatch by use of the alveolar gas equation, but I will explain that later.

Diffusion limitation

Diffusion limitation essentially occurs to problems with gases diffusing (due to a thickened alveolar membrane etc.). This can be detected by measuring the diffusion capacity of carbon monoxide, as mentioned here. Diffusion limitation causes hypoxia with little to no hypercapnia.

R-L shunt

In a R-L shunt, there is mixture of deoxygenated and oxygenated blood. This occurs when venous blood does not get exchanged with air. There are two types of shunts: anatomical shunts, where blood fails to pass through alveoli, and physiological shunts, where air fails to get to alveoli. A normal healthy lung will have around 2% shunt, half of which is accounted for by bronchial circulation. When there is too much shunt, however, this can be problematic.

Shunt can be diagnosed by giving the patient 100% oxygen. Since 100% oxygen causes PAO2 (remember, capital A = alveolar) to increase to around 650mmHg, a normal healthy person will also have a massive increase in PaO2 (lowercase a = arteriolar). When there is a shunt involved, there is no improvement in PaO2 as the shunted blood is not exposed to the high PAO2. R-L shunt causes hypoxia with little to no hypercapnia.

V'/Q' mismatch

See earlier post: Gas Exchange and V'/Q' Ratio. Note that this is the most common cause of hypoxemia. It causes hypoxia with little to no hypercapnia.

Calculate the AaDO2 from blood gases

Since hypoventilation is the only cause of hypoxemia that causes an increase in PaCO2, it can be distinguished by using the alveolar gas equation. If you don't remember from 2nd year, the alveolar gas equation is as follows:

PAO2 = PiO2 - (PACO2/RQ)

where PAO2 is alveolar partial pressure of O2, PiO2 is inspired partial pressure of O2, PACO2 is alveolar partial pressure of CO2 and RQ is respiratory quotient, which in turn is V'CO2/V'O2 (i.e. moles of CO2 produced per moles of O2 consumed). RQ is 1 for a pure carbohydrate diet, around 0.7 for a pure fat diet, and around 0.8 for a normal Western diet.

Since we can't actually measure alveolar gases directly, we assume that they are similar to arterial gases (which they are if gas exchange is normal). Therefore, we can substitute PAO2 for PaO2 and PACO2 for PaCO2 in the above equation. PiO2 is something we can easily measure, and for RQ we can estimate 0.8 (I don't know if there are better ways to measure it though). By substituting our measured PaCO2 into the equation, we can find a theoretical PaO2, which we can then compare to the real PaO2 to find the AaDO2 (Alveolar-arterial difference in oxygen). If AaDO2 is less than 15mmHg, then hypoventilation is the cause of the hypoxemia.

Maybe this will make more sense with an example! Let's say that we have a patient with a PaO2 of 68mmHg and a PaCO2 of 50mmHg. To test whether or not they are hypoventilating, we can substitute the PaCO2 into the alveolar gas equation, find the theoretical PaO2 and compare it with the real PaO2. This gives us the following:

PAO2 = PiO2 - (PACO2/RQ)
PaO2 (theoretical) = 0.21*(760-47) - (50/0.8)
PaO2 (theoretical) = 149.73 - 62.5
PaO2 (theoretical) = 87.23mmHg

AaDO2 = PaO2 (theoretical) - PaO2 (actual)
AaDO2 = 87.23 - 68
AaDO2 = 19.23mmHg

In this case, AaDO2 is more than 15mmHg, so hypoventilation is not the cause of this patient's hypoxemia. In this case, we would have to do extra tests- a 100% oxygen test to rule out shunt and a DLCO test to rule out diffusion capacity issues. If both of those tests come back negative, then the patient has V'/Q' mismatch. Note that hypoxemia due to shunts or diffusion capacity issues are quite rare.

Shock

Shock, in a nutshell, is inadequate peripheral perfusion that can lead to cell death and, well, death of the rest of the body if left untreated. Of course, there's more to say about shock than that: enough to fill up a whole 45-minute lecture, in fact!

Understand the different types and causes of shock

There are many different types of shock:

• Hypovolemic shock: Shock due to loss of blood volume (could be due to trauma, burns, vomiting, diarrhoea and so on). I will be mainly discussing hypovolemic shock (particularly haemorrhagic shock) in this post.
• Neurogenic shock: Shock due to sudden dilation of the blood vessels, which in turn may be due to CNS damage and loss of autonomic nervous system signals to the vascular smooth muscle.
• Psychogenic shock: Shock in response to stress, pain or fright. Like neurogenic shock, there is sudden dilation of the blood vessels, but this is transient.
• Septic shock: Shock in response to a bacterial infection. Bacteria release exotoxins and endotoxins, which result in vasodilation and an increase in capillary permeability.
• Anaphylactic shock: Shock due to a severe allergic reaction. You can read more about anaphylaxis here.
• Cardiogenic shock: Shock due to some problem with the heart resulting in decreased stroke volume and decreased cardiac output. This may be due to left heart failure (which also causes pulmonary oedema) or right heart failure (which causes systemic oedema). See here for more information on heart failure.
• Obstructive shock: Shock due to obstruction of important blood vessels, causing a decrease in cardiac output. This can be due to cardiac tamponade (fluid filling the pericardial cavity), pneumothorax (air in the pleural cavity) or pulmonary embolism.

Discuss the different stages of shock

Here are the stages of haemorrhagic shock:

1. Class I haemorrhage (loss of 0-15% of blood volume): Little tachycardia. Usually no significant change in blood pressure, pulse pressure or respiratory rate.
2. Class II (15-30%): Elevated heart rate (>100bpm), tachypnea, decreased pulse pressure
3. Class III (30-40%): Tachycardia, tachypnea, decreased systolic blood pressure, oliguria
4. Class IV (>40%): Tachycardia, decreased systolic blood pressure, decreased pulse pressure, little (or no) urinary output. This stage is immediately life-threatening.

Discuss the compensatory mechanisms

Mean arterial pressure actually stays pretty constant until a fairly large amount of blood is lost (>20%), largely due to the baroreceptor reflex. The baroreceptors are maximally sensitive when mean arterial pressure is normal, which means they can easily detect even a small change in blood pressure. When blood pressure drops, the firing rate of the baroreceptors decreases. This is picked up by the nucleus tractus solitarius in the medulla, leading to sympathetic activation and parasympathetic inhibition.

Aside from the baroreceptor reflex, there are several other compensatory responses for hypovolemia. Peripheral chemoreceptors can play a role, especially when mean arterial pressure drops below 60mmHg- I suppose that less blood means less oxygen to go around. Chemoreceptor stimulation also activates the sympathetic nervous system. Due to sympathetic nervous system activation, the respiratory system may also be activated, which may enhance venous return (this all has to do with something called the "abdominothoracic pump"- maybe inflation of the lungs squishes the veins?). Yet another compensatory mechanism is an increase in circulating vasoconstrictors, such as ADH, aldosterone and catecholamines (i.e. adrenaline and noradrenaline).

Aaaaand I'm not done yet! When mean arterial pressure drops below 60mmHg, not only do peripheral chemoreceptors get activated, but the CNS ischaemic response may also be activated! The CNS ischaemic response is a very intense sympathetic response (from both sympathetic nerves and adrenal glands) that mainly exists to maintain perfusion to the brain.

Aaaaaaaand I'm still not done! Other compensatory mechanisms include redistribution of interstitial fluid (return of fluid back to the blood), stimulation of thirst (so that you drink more and get your blood volume back up) and haematopoiesis (via stimulation of EPO).

Unfortunately, in severe haemorrhage, these mechanisms may not be sufficient. A large drop in arterial pressure can create not one but two vicious cycles. In the first vicious cycle, a drop in arterial pressure causes a drop in coronary perfusion, which decreases inotropy, which decreases cardiac output, which decreases arterial pressure. In the second vicious cycle, a drop in arterial pressure decreases blood flow to the organs, which causes hypoxia, which causes release of vasodilating mediators as well as a phenomenon called "sympathetic escape" (desensitisation to sympathetic activity so that it doesn't cause as much constriction), which causes a decrease in arterial pressure.

Decompensated shock can cause cardiac failure, acidosis, CNS depression, an increase in capillary permeability, an increase in toxins (from dead cells) and blockage of small blood vessels (stagnation in blood flow can lead to clots). So, in short: you're f***ed.

Describe signs and symptoms

Signs and symptoms of shock include restlessness, anxiety, a decreased level of consciousness, dull eyes, rapid shallow respiration, nausea, vomiting, thirst, diminished urine output and usually some tachycardia. The skin may be pale, cool and clammy (in the case of hypovolemic and cardiogenic shock) or dry and flushed (in the case of septic, anaphylactic and neurogenic shock). In the case of anaphylactic shock, there may be other signs of an allergic reaction, such as hives, itching, wheezing and difficulty breathing.

Discuss treatment of shock

Treatment of shock generally comes down to treating the causes. For example, if shock is due to hypovolemia, then you need to restore blood volume by using crystalloids, colloids or blood transfusions. Furthermore, if there is bleeding, then you may need surgery to stop it. Using the same principle of "treat the cause," septic shock can be treated with antibiotics, cardiogenic shock can be treated with supports such as inotropic and chronotropic agents and anaphylactic shock can be treated with EpiPens. Vasoactive substances can be used to treat vasodilation and bicarbonate can be used to treat the acidosis that often occurs as a result of shock.

Airway Smooth Muscle

It's too late in the afternoon, I can't be bothered trying to figure out a nice introduction for this blog post. (Not like I ever do anyway.)

Describe the functional role of smooth muscle in the vascular, gastric, reproductive and urinary systems systems at a simple level.

• Arteries: Vasoconstriction, regulation of mean arterial pressure, distribution of cardiac output
• Veins: Venoconstriction, venous capacitance and cardiac filling
• Gastric: Propulsion of gut contents
• Reproductive: Contraction of the uterus pushes out the foetus
• Urinary: Contraction of bladder
• Excretory: Contraction of rectum

Recall and explain the activation of ASM.

See previous posts on smooth muscle in general:

• Physiology of Smooth Muscle
• Excitation Contraction Coupling
• Calcium Sensitisation

Mediators that activate airway smooth muscle: ACh, endothelin, LTC₄ and PGF₂

Mediators that inhibit activation of airway smooth muscle: NA, NO, VIP (vasoactive intestinal peptide) and PGE₂

Also note that unlike vascular smooth muscle, airway smooth muscle receives input from both sympathetic and parasympathetic nerves. Airway smooth muscle can also use calcium from both inside and outside of the cell (which is apparently different to other smooth muscle, such as gastric smooth muscle).

List the possible functional roles of ASM
Explain the potential function of ASM in:

We are still uncertain about the functions of airway smooth muscle. It is activated during inspiration and has phasic contractions, but the function of this is unknown. Airway resistance is decreased when ASM is inhibited, but this doesn't appear to have any beneficial effect either. There are, however, a few hypotheses about the role of ASM:

Ventilation/perfusion matching

ASM may play a role in matching ventilation to perfusion. Airways with low blood perfusion have a lower CO₂, and low CO₂ has been found to increase contraction of airway smooth muscle. Contraction of airway smooth muscle may shunt air towards areas with better perfusion. The problem with this hypothesis is that smooth muscle contraction doesn't really increase until CO₂ levels drop considerably.

Dead space regulation

Anatomical dead space, as mentioned here, here and here, consists of the conducting zone in the lungs where air passes through but is not exchanged. When we breathe in, the air that we breathe in is actually a mixture of fresh air and exhaled air from the last breath that's been sitting in the dead space. If dead space is decreased by bronchoconstriction, then the amount of rebreathed air in each breath will be reduced. The downside to this is that bronchoconstriction also increases resistance, making it harder to breathe. The optimum ratio of dead space to tidal volume is usually around 20%. It's possible that ASM can regulate the dead space volume to fit changes in tidal volume during exercise (where airways dilate, reducing resistance but increasing dead space) and other conditions.

Cough and airway stability

Even though coughing is mainly controlled by other muscles, such as the diaphragm, coughing also increases ASM tone and bronchoconstriction. While bronchoconstriction reduces air flow (the amount of volume flowing through in a given amount of time), it also increases flow velocity (which I think is the distance each of those air particles travels in a given amount of time). Increased flow velocity can increase the clearance of airways.

Another effect of an increase in ASM tone during cough is that it may also help to stabilise the airways. An increase in stiffness may reduce airway compression, which occurs during forced exhalation. (Forced exhalation occurs not only during coughing, but also crying, shouting, and so on.) A reduction in airway compression helps to keep the airways open. The overall effects of this, though, are yet to be determined.

Foetal breathing

Airway smooth muscle appears early on in foetal development. In both pig and human foetuses, airway smooth muscle shows peristaltic (i.e. contraction that moves along the length of the tube) contraction. It has been suggested that these peristaltic waves move the lung fluid and amniotic fluid into the periphery of the lung, where it is needed to help the lungs to grow. Therefore, it's possible that airway smooth muscle may have been very important in aiding lung growth in the foetus, but it may not be as useful in adults.

Comparative Physiology: Cardiovascular Systems

Understand the primary functions of the vertebrate circulatory system

The circulatory system helps deliver all kinds of things all over the body. These include nutrients, wastes, immune system cells, heat, other regulatory molecules and so on. The circulatory system is much more efficient than using simple diffusion alone- if we relied on simple diffusion, it would take roughly 9.26 minutes for something like oxygen just to get through our skin! Imagine how long it would take then for something to diffuse to the middle of our bodies!

Compare the anatomy & efficiency of open & closed circulatory systems

Many invertebrates have an open circulatory system, in which there is no separation between blood and the interstitial fluid. They have a heart to pump things around, but the blood vessels quickly end in massive sinuses. Due to the lack of separation between blood and interstitial fluid, the circulating fluid in these invertebrates is known as "haemolymph." Invertebrates with an open circulatory system still need a certain amount of pressure in order to keep the fluid moving (despite also having a heart), and thus many of these creatures have a tough exoskeleton.

All vertebrates, as well as some invertebrates, have a closed circulatory system in which blood is combined to the vessels. However, solutes can diffuse into the interstitial fluid. This system requires more energy, as the vessels offer up quite a bit of resistance. On the other hand, it is much faster than an open circulatory system and has other advantages, such as conveying blood directly to the organs and its ability to "shunt" blood to different organs via constriction of vessels etc.

Understand the evolutionary changes in the vertebrate heart from primitive fish to amphibians, reptiles, birds & mammals in terms of structure & overall circulatory efficiency

Flatworm

The flatworm is probably the simplest in terms of getting its nutrients: it can be over a metre long, but is very flat (hence its name). Its "flatness" means that it can get everything it needs via simple diffusion alone.

Hagfish

The hagfish is a primitive eel-like fish. Its circulatory system is considered to be partially open: while it has closed blood vessels, it also has several sinuses. It has five hearts: a main heart that pumps to the gills and four accessory hearts. This is probably necessary because the gills offer up a lot of resistance which slows down the blood considerably. The four accessory hearts (but not the main heart) are under direct neural control and can increase their output under sympathetic stimulation. When their output increases, venous return to the main heart increases, increasing the cardiac output of the main heart.

Elasmobranchs and teleosts

Elasmobranchs and teleosts are kinds of fish. They have a single heart with four chambers, but the four chambers are in a row (kind of like the foetal human heart before it folds and divides), so it is considered to be 2-chambered. These four chambers are called the sinus venosus, atrium, ventricle and conus arteriosus (a.k.a. "bulbus cordis").

Lungfish

Lungfish are, well, fish with lungs. As opposed to hagfish, lungfish only have one heart. The atrium and ventricle of this heart are partly divided, but not entirely (i.e. the lungfish heart still only has two chambers). This heart pumps into five "branchial arteries," three of which pass through gills and two which do not. From here, blood can either go to the lungs or to the rest of the body. Two veins return blood to the heart: one from the lung and one from the body. There is some mixing of the oxygenated blood from the lungs and deoxygenated blood from the body, but this is relatively limited as there are spiral folds in the bulbus cordis that separate the blood.

Amphibians

Amphibians have a 3-chambered heart (two atria and one ventricle) as opposed to the two-chambered hearts of fish. Even though the ventricle is not fully divided, it has a functional division called the "dense trabeculation of the spongy myocardium" and a spiral fold in the conus arteriosus (just like the spiral folds in the bulbus cordis of lungfish).

The artery that leaves the amphibian heart splits into two: a pulmocutaneous artery that goes to the lungs and skin (which is also an accessory breathing organ in amphibians) and a systemic artery that goes to the rest of the body. The left atrium receives oxygenated blood from the lungs, whereas the right atrium receives a mixture of oxygenated blood from the skin and deoxygenated blood from the tissues (so there is some mixing of blood).

Reptiles (except for crocodiles because they're special)

Unlike amphibians, reptiles only use their lungs for gas exchange, so their circulatory system must be simpler too, right? Wrong.

The atria of reptiles are divided completely, so that part's easy. The ventricle, however? Not so easy. The ventricle of reptile hearts is divided incompletely into three chambers: the cavum venosum (CV), cavum arteriosum (CA) and cavum pulmonale (CP). These connect into two systemic arteries (the right and left systemic arch) and the pulmonary artery.

During ventricular systole, the pressure in the pulnonary artery is relatively low, allowing blood to flow in from the CP and CV. (The intercaval canal- the passage between the CA and CV- is still closed at this point.) As the pressure increases, the intercaval canal opens, allowing blood from the CA to enter the CV, while a muscular ridge forms between the CV and CP (preventing blood from flowing between these two sections). Blood from the CV then enters the systemic arches.

Well, that was confusing. Why are reptiles so confusing? Well, this confusing system allows reptiles to bypass the lungs, which is useful when diving. During diving, PA resistance increases, causing a right-to-left cardiac shunt (i.e. deoxygenated blood gets to flow to the rest of the body too). When they're back on land, they have a left-to-right shunt.

Crocodiles

Crocodiles are different to other reptiles in that they have a proper four-chambered heart. Just like in humans, the right atria receives deoxygenated blood from the body, whereas the left atria receives oxygenated blood from the lungs. Output from the ventricles is a bit more complicated: the right ventricle is connected to a pulmonary artery and to the left systemic arch, whereas the left ventricle is only connected to the right systemic arch. The two systemic arteries are connected by the foramen of Panizza. Usually, there is a higher pressure in the left systemic arch, which prevents the valve from the right ventricle to the left systemic arch from opening. However, when crocodiles are diving, pulmonary vasculature resistance increases, closing off the valve from the right ventricle to the pulmonary artery, which shunts blood from the right ventricle into the left systemic arch instead. This results in a right-to-left shunt. (Note that crocodiles can't have a left-to-right shunt as the valve from the left ventricle to the right systemic arch is pretty much always open.)

Birds

Birds also have a four-chambered heart. Oxygenated and deoxygenated blood are completely separated (unlike in crocodiles when they can mix during diving).

Mammals

I've already spoken a lot about humans, so not much to say here. Fun fact though: the sinus venosus, which I mentioned back when I wrote about elasmobranchs and teleosts, still remains in the mammalian heart: it's the sinoatrial node.

Comparative Physiology: Respiratory Systems

This week we're learning about comparative physiology, which is basically comparing the physiology of different animals. Enjoy!

Insects

Insects don't have a circulatory system as they have a highly branching tracheal system that can take air all the way to the cells. The tracheal system begins at one of many spiracles, which are little "air holes" on the outer surface (for lack of a better word) of the insect. These spiracles connect to tracheae, which branch out into tracheoles, and so on. Reliance on this system limits insect size. That being said, around 300 million years ago there was a giant dragonfly called Meganeura with a 70cm wingspan. It's been suggested that it was able to survive because atmospheric oxygen then was higher then than it is now (~30% as compared to ~21%).

Fish

As you probably know, fish have gills on the outside of their bodies, which allow them to breathe underwater. Gills are made up of highly vascularised thin parts known as lamellae, which create a very large surface area for gas exchange. Blood travels in the opposite direction to water, creating a "counter-current system" that is very efficient at absorbing oxygen. Despite the large surface area and high efficiency, lots of water needs to be moved past the gills in order for adequate oxygen to be obtained. Lamellae collapse when exposed to air, which is why fish can't breathe when out of water.

Amphibians

Amphibians have lungs, but they look quite different to ours. They are simple inverted bags and don't have as much folding as mammal lungs. Amphibians use "positive pressure" ventilation, which I think means that they mechanically pump something (the buccal cavity, which is like the mouth cavity of the frog) in order to move air around.

More "primitive" amphibians use 4-stroke ventilation which, as you may guess, has four steps. Steps 1 and 2 are for inspiration, whereas steps 3 and 4 are for expiration.

1. Nostrils open and buccal cavity expands, allowing air to enter the buccal cavity.
2. Nostrils close, glottis opens and buccal cavity contracts, pushing air into the lungs.
3. Lungs contract, pushing air back into the buccal cavity.
4. Glottis closes, nostrils open and buccal cavity contracts, pushing air out.

More "modern" amphibians use 2-stroke ventilation:

1. Buccal cavity expands. Air is drawn in from outside and from the lungs.
2. Buccal cavity contracts. Air is forced out outside and into the lungs.

One of the downsides to 2-stroke ventilation is that there is some mixing of old and new air.

Reptiles

Reptiles have a "negative pressure" ventilation, just like us. However, most do not have a diaphragm which can contract in order to produce this "negative pressure." Instead, many have muscularised ribs that can do this job. Because of this, some reptiles can't walk and breathe at the same time. Crocodiles are a bit different: they do have a diaphragm-like structure called the diaphragmaticus, which connects the pelvic girdle to the liver (which is connected to the lungs). (Crocodile hearts are also a bit different to those of other reptiles, as I'll talk about in a later post.)

More primitive reptiles have "bag-like" lungs, just like amphibians. More modern ones, however, have folding in order to increase the surface area for gas exchange. Hence we're starting to get closer to the mammalian lung... yay I guess?

Oh and one more thing. Crocodiles and some lizards have something called "unidirectional airflow." Air coming down the trachea can go from the trachea into the dorsobronchi (an air sac), through some parabronchi (where gas exchange happens) and then into the ventrobronchi (another air sac) before leaving. In short, air goes around in one direction (rather than going down into the lungs and then back up the way it came). Birds also have something similar, as I'll talk about later.

Mammals

I won't talk too much about mammals, as I've already spoken quite a lot about the lungs of one mammal in particular (*cough*humans*cough*). They have "negative pressure" ventilation and alveolar lungs. One of the "cons" of the mammalian lung is that it has dead space, which is where air passes through but is not exchanged. There are two types of dead space: alveolar dead space and anatomic dead space. Alveolar dead space occurs when there is no blood flowing through the surrounding capillaries of an alveolus, whereas anatomic dead space occurs in the conducting zones of the lung where air passes through but is not exchanged.

Birds

Bird lungs are kind of weird in that they are calcified. They also have the parabronchial structure and unidirectional airflow that I talked about when talking about reptiles. They do not have a diaphragm but they do have some air sacs that help in pushing the air around. Their blood-gas barrier is very thin, making gas exchange efficient, while the calcification of the lung prevents tearing. Birds have a "cross-current" system where the blood runs perpendicular to the direction of airflow. This is not as efficient as the counter-current system in fish, but it's a lot more efficient than gas exchange without a fancy current system. In fact, they can more efficiently extract oxygen as the oxygen content of the air decreases. (They do this by taking big, slow breaths.)

There are two cycles in bird breathing. In cycle 1, air goes from outside to the posterior air sac during inspiration, and into the lung during exhalation. In cycle 2, air goes from the lung to the anterior air sac during inspiration, and leaves the body during expiration.

Air breathing

A random note on the issues with breathing air (as opposed to water, like fish). Even though air is usually not saturated with water vapour, gas exchange surfaces are moist and water is required in order for diffusion capacity to reach a suitable level. Additionally, inspired air is usually cooler than the body, so heating is also required. The other challenge is that the amount of water required to dissolve oxygen increases as temperature increases, so lots of water needs to be added. This water can be recuperated by decreasing the temperature of the air during expiration, allowing the water to condense out. Thankfully, we have a "nasal turbinate" system in our noses, which acts as a kind of "air-con."

"Arse breathing"

Basically what it says on the box. Some animals, like the Fitzroy River turtle, can breathe through their arses. Yay!

Airway Hyperresponsiveness

This lecture was mostly a recap of the PHAR3303 lectures on asthma, which I've written about here and here.

What is airway hyperresponsiveness?

Airway hyperresponsiveness means that the airway responds more strongly to a bronchoconstrictor like histamine or to some other respiratory challenge as compared to a healthier airway. Respiratory challenges can be direct, such as when you use histamine or methacholine (an acetylcholine analogue) that directly stimulates H1 or M3 receptors, respectively. Respiratory challenges can also be indirect, such as when you provoke bronchoconstriction through inflammatory pathways. Inhaling hypertonic saline or exercising can do this as these stimuli cause the airways to dry out.

How is it measured? Can you calculate a PC20?

One measure of airway hyperresponsiveness is a PC20, or the provocative concentration of agonist producing a 20% fall in FEV₁. To calculate a PC20, first calculate what the patient's FEV₁ will be after a 20% decrease (e.g. if your patient's FEV₁ is 3.4L, multiply that by 0.8 to get 2.72L). Next, find out what concentration of agonist you need to decrease the FEV₁ to that level.

What are the broad factors that determine airway narrowing?

There are several factors, including the density and affinity of receptors that might trigger airway narrowing and the prevalence of smooth muscle that can produce force. There are also factors that provide mechanical opposition to airway narrowing. For example, parenchymal tethering is the phenomenon in which the alveoli "tether" the airways open (i.e. when the alveoli are inflated, they tug on and open the airways).

Name potential mechanisms producing airway hyperresponsiveness?

Thickening of the ASM layer?

See previous post: Airway pathology in asthma. Thickness of the airway smooth muscle can also be compared to the perimeter of the basement membrane (Pbm), which gives a standard index of airway size.

Poor bronchodilatory response to deep inspiration?

See previous post: Smooth muscle response to stretch

Gravitational Effects on Circulation

This lecture covered quite a bit of high school physics level stuff, but unfortunately I didn't do high school level physics (at least not year 11/12). Oh well.

Energy and its Impact on Blood Flow

You've probably had it drilled into you over and over again (possibly a few times by this blog) that blood flows from a region of higher pressure to a region of lower pressure. Well, now I'm going to blow your mind by telling you that that's not strictly true. Blood actually flows down an energy gradient rather than a pressure gradient. If the pressure gradient was the be-all-and-end-all, then certain phenomena would not be possible, as we will soon explore.

Energy loss and pressure loss often come hand in hand, as pressure is a form of energy. When fluid flows against a resistance, energy is lost as heat, manifesting as a decrease in pressure. When resistance is increased, like in stenosis (narrowing of the arteries), pressure decreases further. Pressure goes back up once you get past the stenosis, but blood is still able to flow up the pressure gradient as the energy gradient is still decreasing (provided that the vessel is not completely blocked). But how?

Well, we need to consider another interesting thing that happens in stenosis. Kinetic energy increases in stenosis, as velocity of a fluid increases as cross-sectional area of the vessel decreases, and kinetic energy is equal to (1/2)mv². This means that even though the pressure in a stenosis decreases, the rise in kinetic energy is enough to give the stenotic area more energy than the area after the stenosis. Therefore, blood can keep flowing past the stenotic area.

Effects of Gravity on Blood Pressure

Hydrostatic pressure, or pressure in the fluid due to gravity, is equal to (rho)gh, where rho is the density of the fluid in kg/m³, g is the gravitational constant (roughly 9.8 m/s²) and h is the depth in m. Applying this formula, the pressure at the bottom of a 1m column of water is 1000 kg/m³ * 9.8 m/s² * 1m = 9800Pa (Pascals). As 1Pa = 0.0075mmHg, this can be converted into 73.6mmHg.

Now, we don't study biology just to look at columns of water, so let's look at animals and humans! Let's start off with giraffes with their long necks. The head of a giraffe is roughly 1.5m above its heart, which equates to a pressure difference of around 115mmHg. The significance of this is that the heart needs to pump blood at a high enough pressure to keep the brain perfused as well. It's no good for the heart to provide a pressure of 115mmHg, because while the blood would be able to leave the heart, it would have a pressure of 0mmHg by the time it reached the brain, which is clearly not enough to keep a giraffe's brain going. Hence, a giraffe's arterial pressure is quite high (around 200mmHg). Fun fact: you can also get an idea of an animal's blood pressure by looking at the size and thickness of the left ventricle. So if you can't be bothered using your knowledge of physics to make an estimated guess, cut out their hearts instead :P

Consequences of Gravity on the Dependent Vasculature

"Dependent vasculature" refers to basically all the vessels below the heart. This is particularly important to us as bipeds, as quite a large proportion of our vasculature is below the level of the heart.

First, let's consider a U-shaped tube lying flat on a table. If it has an inlet pressure of 100mmHg and an outlet pressure of 0mmHg (all relative to atmospheric pressure), the pressure halfway along the tube will be 50mmHg.

Second, let's consider a U-shaped tube that is upright, with inlet and outlet pressures of 0mmHg (again, all relative to atmospheric pressure). The pressure at the bottom of the tube (where the bend is) will depend on the hydrostatic pressure equation (P = (rho)gh). For the sake of this example, let's just pretend that this pressure is 80mmHg.

Now, let's combine our two examples by simply adding the two together! This gives us a new, upright tube with an inlet pressure of 100mmHg, an outlet pressure of 0mmHg and a pressure of 130mmHg in the bend (50mmHg + 80mmHg). Note, however, that despite this higher pressure at the base, the pressure difference (100mmHg to 0mmHg) is still the same, meaning that the flow is still the same.

The increased pressure at the base is not insignificant, however. Our feet have a higher venous pressure than our legs, which have a higher venous pressure than our heart, and so on. This means that our blood will tend to pool in the veins (and I say the veins specifically as they are more compliant and better at storing blood than the arteries). This has two main effects.

Firstly, as I mentioned here, the main force pushing blood out of the capillaries is the hydrostatic pressure of the capillaries. If this increases, then much more fluid will leak out of the capillaries, causing oedema over time. (This can be prevented by wriggling your feet and lower limbs a little bit.)

Secondly, a combination of blood pooling in the lower limbs and blood leaking out of the capillaries leads to a reduction in venous return. Reduced venous return leads to reduced stroke volume, which leads to reduced cardiac output, which leads to reduced blood pressure, which would lead to fainting if our bodies didn't do anything. Thankfully, our bodies have a trick up their sleeves!

Physiological Response to Potentially Detrimental Effects of Gravity

BARORECEPTOR REFLEX.

Also just a note on how our bodies respond to an increased/decreased gravitational force as compared to usual. These are conditions that might be experienced by astronauts and/or stunt pilots. When G (gravitational force) is negative, blood moves to the head, causing "redout" from broken capillaries in the eyes. When G is larger than usual, blood moves to the feet, causing "blackout" from loss of blood to the head.

High Altitude and Ventilation

In this post we'll be talking about the effects of high altitude on ventilation, including stuff like mountain sickness.

Describe the ∆ PB at high altitude (HA)

As you are probably aware, barometric pressure (PB) decreases as altitude increases. Barometric pressure drops by half with every 5500m increase in altitude. Generally "high altitude" is classified as 1500-3000m, very high altitude as 3000-5000m and extreme altitude as greater than 5000m.

Understand the stress of HA
Describe the effect of HA on gas exchange

Since the barometric pressure is lower at high altitudes, so too is the partial pressure of oxygen. This means that there is a reduced pressure gradient, and therefore a reduced "driving pressure" for oxygen as you go up. Saturation of haemoglobin also decreases with altitude, so you have even less oxygen in the blood than usual. Heart rate can also increase with altitude, leaving less time for the blood in the pulmonary capillaries to equilibrate with the air. All of these factors combined can lead to hypoxemia (low blood oxygen) and hypoxia at high altitudes.

The alveolar gas equation was also brought up in these slides. The alveolar gas equation, as you may recall, is PAO2 = PIO2 - (PACO2/RQ), where PAO2 is the partial pressure of alveolar oxygen, PIO2 is the partial pressure of inspired oxygen, PAO2 is the partial pressure of alveolar carbon dioxide and RQ is the respiratory quotient (usually around 0.8). On the summit of Mt Everest, the barometric pressure is around 253mmHg, giving a PIO2 of around (253-47)*0.21 = 43mmHg. Plugging this into our equation, along with a "normal" PACO2 of 40mmHg, gives us 43 - (40/0.8) = -7 mmHg. But how can this be? Well, turns out that PACO2 is much lower than 40mmHg at high altitudes due to hyperventilation, as I'll discuss later.

Discuss short- & long term acclimatisation

Acclimatisation to high altitudes depends on several factors: the severity of hypoxic stress (which depends on altitude), the rate of onset of hypoxia (which depends on how quickly you're going up) and individual factors such as genetics. We can look at acclimatisation in both the short and long term. Let's look at the short term first:

Short-term acclimatisation

When we are hypoxic, the peripheral chemoreceptors pick this up and stimulate respiratory centres in the medulla. These centres stimulate an increase in ventilation, which results in a decrease in PACO2 (which is why PACO2 is often lower at high altitudes). A low PACO2 then suppresses the respiratory centres in the medulla, keeping things somewhat in check. Overall, though, ventilation increases by around 1.65 times.

If hypoxia is prolonged, carotid bodies increase their sensitivity to PO2, sending even more signals to the medulla to increase ventilation. Furthermore, the kidneys will eventually start to increase their secretion of bicarbonate ion, balancing out the decrease in PACO2 (and hence stopping low PACO2 from suppressing the medulla). This leads to a roughly 5x increase in ventilation.

Aside from ventilation changes, low PO2 can also cause vasodilation in the systemic circulation. Cardiac output can also increase. This leads to an increase in pulmonary blood flow and sustained oxygen delivery to the tissues.

The problem with short-term acclimatisation is that these processes tend to be very energy-hungry. Thankfully there are also long-term acclimatisation processes!

Long-term acclimatisation

Over a long time, HIF (hypoxia-induced factor) and EPO (erythropoietin) can cause polycytaemia, or an increase in red blood cells. This increases haematocrit and haemoglobin, and therefore oxygen-carrying capacity as well. Polycytaemia raises the O2-Hb dissociation curve (as the extra haemoglobin means that there is more oxygen in the blood at a given partial pressure of blood oxygen), but this all comes at a cost. Polycytaemia causes the blood to become more viscous (resistant to flow), increasing the workload for the heart.

The diffusing capacity of the lung can also increase. Normal diffusing capacity is around 21mL/mmHg/min, but this can increase 2-3 times with acclimatisation. This increase occurs due to an increase in pulmonary arterial blood pressure, pulmonary capillary blood volume and lung air volume.

The cells themselves can acclimatise to high altitudes. They do this by increasing their amounts of mitochondria and oxidative enzymes.

Angiogenesis, or development of new blood vessels, is another important method of acclimatisation. When there is sufficient oxygen, HIF (hypoxia-inducible factor) gets hydroxylated and degraded. When oxygen is low, however, HIF can translocate into the nucleus, where it can upregulate vascular endothelial growth factor, fibroblast growth factor and angiogenin. These factors can lead to increased angiogenesis.

Discuss mountain sickness & treatments

Mountain sickness is, well, sickness from climbing mountains (due to the increase in altitude). Some of the more severe problems at high altitude include high altitude pulmonary oedema and high altitude cerebral oedema.

High altitude pulmonary oedema occurs when hypoxia causes uneven pulmonary vasoconstriction, so that some vessels get hardly any blood and others get way too much. The vessels that get way too much blood get an increase in capillary pressure, causing damage to the capillary wall and oedema. Inflammatory mediators may also be produced, further contributing to oedema.

High altitude cerebral oedema occurs when hypoxia causes brain vasodilation, increased sympathetic activity and the production of factors such as cytokines that increase the permeability of the blood-brain barrier. All of these factors combined can lead to increased capillary pressure in the brain, which leads to leakage and therefore oedema. Symptoms of high altitude cerebral oedema include severe disorientation, seizures and coma.

Now, back to mountain sickness. Mountain sickness can be classified as acute (from climbing a mountain or whatever) or chronic (from living in a high place for a while). Symptoms of acute mountain sickness include headache, dizziness, sleep disturbance, nausea and loss of judgement. Symptoms of chronic mountain sickness, also known as Monge's disease, include the symptoms of acute mountain sickness, as well as pulmonary oedema and heart failure. Heart failure can occur due to polycytaemia (which, as mentioned before, puts extra work on the heart), as well as the increase in blood pressure due to pulmonary artery constriction (as occurs during hypoxia). The right ventricle is usually most likely to be affected, as that's the ventricle that pumps blood to the lungs.

The #1 treatment for mountain sickness is pretty logical: descend to a lower altitude. If that's not possible due to bad weather, you can use a Gamow bag, which is a bag that can be filled to a pressure higher than what you'd be getting on the mountain. In a similar vein, you can use supplemental oxygen. Another treatment option is removal of excess red blood cells via phlebotomy. There are also some drugs that can be used to help: acetazolamide increases ventilation by increasing bicarbonate secretion (this makes the blood more acidic, which increases the drive to breathe) and vasodilators such as nifedipine and sildenafil can help decrease pulmonary hypertension. Steroids, such as dexamethasone, can also aid in treatment.

Respiratory Diseases

First post for PHYL3002 after the study break! This post will touch on a lot of topics that I've spoken about before.

Types of Lung Disease

Lung diseases can be classified into several different categories: infections, tumours, chronic and pulmonary vascular diseases. For this post, we will be mainly looking at chronic lung diseases, like asthma and COPD.

There are also several other types of respiratory disease that don't necessarily involve the lung. For example, haematological disorders such as anaemia can reduce the oxygen-carrying capacity of the blood. Neuromuscular diseases can also impact the diaphragm and other muscles involved in breathing.

Back to chronic lung diseases! Chronic lung diseases can be broken down into two main categories: restrictive disease (in which compliance is reduced and changes in lung volume are reduced) and obstructive disease (in which resistance is increased and flow rate is reduced). Obstructive disease can then be broken down into reversible (i.e. responds well to bronchodilators) and non-reversible. An example of a restrictive disease is pulmonary fibrosis, an example of a reversible obstructive disease is asthma and an example of non-reversible obstructive disease is COPD. (I'll go into all of these in more detail).

Lung Function Tests

As mentioned above, restrictive diseases are marked by reduced compliance and obstructive diseases are marked by increased resistance. To directly measure compliance, you need to know intrapleural pressure, whereas to directly measure resistance, you need to know alveolar pressure. Unfortunately, these parameters are difficult to measure. Plethysmography, which uses a "body box," can measure these, but plethysmographs are expensive and not commonly found. Hence, we have to use other measures to help us monitor these diseases.

Firstly, we can use spirometry to measure different volumes. I've explained spirometry and the values that it can measure here. I've also described the pattern of lung volume changes in obstructive vs. restrictive diseases here.

Spirometry can't measure all lung volumes- we need to use the helium dilution technique to measure functional residual capacity (and by extension residual volume and total lung capacity), as explained here. Sometimes a little bit of CO is used at the same time in order to determine the diffusion capacity of the lung. This is because CO has similar diffusion properties to O₂. (The amount of CO used is obviously low so we don't kill the patient while we're at it.) This gives us a value called D_LCO, or the CO diffusion capacity of the lung.

Commonly used indices for resistance include PEF (peak expiratory flow), FEV₁, FEV₁/FVC ratio and flow-volume loops. I've discussed PEF and flow-volume loops, as well as how they change in disease states, here. FEV₁ was discussed here.

Blood gases can also be tested in order to test lung function. pH, arteriolar O₂ and CO₂ can all be measured. These measurements can also be used to calculate AaDO₂, or the alveolar-arterial oxygen difference.

Yet another test that can be done is the nitrogen washout test. This tests whether or not the alveoli have filled up relatively evenly. In the nitrogen washout test, the patient inspires 100% oxygen and then exhales. Normally, the graph of expired N₂ will start pretty flat, as the alveolar dead space will still be filled with the 100% oxygen that was just inhaled. As exhalation continues, though, the expired N₂ will increase. Eventually, when the alveoli are reached, a plateau phase will be reached in which the exhaled N₂ remains constant for a bit. If there is non-uniform ventilation, however (i.e. the alveoli do not fill up evenly), there will be no plateau phase: instead the expired N₂ will increase steadily.

Examples of Lung Diseases

Asthma

See previous post: The Respiratory System

Asthma is a reversible obstructive disease marked by airway wall thickening, smooth muscle thickening, mucus production and infiltration by inflammatory cells, such as eosinophils. As mentioned above, it is considered to be reversible because it can be helped by bronchodilators.

Bronchitis

See previous posts: COPD and Respiratory Pathophysiology 1

Another thing to be aware of is that broncholitic asthma is a type of chronic bronchitis that can see some improvements via a bronchodilator. It is possible, however, that broncholitic asthma is simply chronic bronchitis and asthma together in the same person.

Emphysema

See previous posts: COPD and Respiratory Pathophysiology 1

COPD

COPD is basically an umbrella term that covers bronchitis and emphysema. Both can cause fun stuff like obstruction, V'/Q' mismatch, pulmonary hypertension and right heart failure.

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis, in contrast to the diseases covered above, is a restrictive disease. As the name suggests, it is the formation of scar tissue (fibrosis) in the lung for no apparent reason ("idiopathic" is a fancy term for saying "we don't know"). While many lung volumes, like TLC, FRC, RV and FVC can fall, FEV₁/FVC ratio is often increased in this group (due to a normal FEV₁ and reduced FVC).

CO2 Transport and Acid/Base Balance

Discuss CO₂ transport in blood

See earlier post: Composition of the Blood

Describe the CO₂ dissociation curve

CO₂, just like O₂, can bind to haemoglobin. It binds to a different part of haemoglobin (the amino group as opposed to the haem group), but O₂ and CO₂ both cause structural conformations such that the two can't bind at the same time. In fact, there's a name for this: the Haldane Effect refers to increased binding of CO₂ when less O₂ is bound.

The CO₂ dissociation curve has a very different shape to the O₂ dissociation curve. As you should know, the O₂ dissociation curve is sigmoidal: it has a steeper part and a plateau phase. The CO₂ curve, however, is just a simple curve, like the slope of a hill. In fact, when you get within the range of CO₂ concentrations that you would normally see, the slope is pretty much linear.

Over normal ranges, the CO₂ dissociation curve is steeper than that of the O₂ dissociation curve. This is because the CO₂ dissociation curve lacks a plateau phase.

Discuss the link between CO₂ and pH

Increased CO₂ causes H⁺ concentration to increase (which means that pH decreases), due to the buffer system mentioned here. Decreasing CO₂ has the opposite effect: the pH will increase.

The pH change can be quantified by using the Henderson-Hasselbalch Equation, which you might remember from CHEM1004 (assuming that you haven't shut the pain out of your mind). As you may (or may not) remember, the Henderson-Hasselbalch equation is pH = pKa + log([A^-]/[HA]). We will now apply this equation to the bicarbonate buffer, which I mentioned here and will mention again later on in this post. The pKa of this buffer is 6.1, allowing us to make the following substitution:

pH = 6.1 + log([HCO₃^-]/[CO₂])

The issue with using this formula as it is is that we usually don't measure the concentration of carbon dioxide, but rather the partial pressure of carbon dioxide. Not to worry, however, as Henry's Law tells us that [CO₂] = 0.03 * P_CO2. We can then make this substitution:

pH = 6.1 + log([HCO₃^-]/(0.03*P_CO2))

Understand the importance of acid-base homeostasis in the body

Acid-base homeostasis is important because if your blood gets too acidic, you die, and if your blood gets too alkaline, you die. So please ignore any quack that tells you to make your blood more alkaline.

Discuss the regulatory systems contributing to acid-base homeostasis

The main regulatory systems are buffers in the blood, the respiratory system and the renal system.

Buffers

The main pH buffering system of the blood is the bicarbonate system, which I mentioned here. Phosphates (HPO₄^2- and H₂PO₄^-) can also serve as buffers. Proteins can also serve as a buffer, as detailed here. Proteins have a high buffering capacity, but are slow to respond.

Respiratory System

The respiratory system controls pH by regulating the concentration of CO₂. This can take a few minutes to hours to kick in.

Renal System

The renal system takes longer (hours-days) to regulate pH. It mainly regulates the concentration of HCO₃^- via affecting its reabsorption or producing more of it in renal tubule cells. The renal system can also increase the secretion of H⁺. The problem with the latter, however, is that less K⁺ can be secreted when this happens, causing an increase in serum K⁺ concentrations, leading to hyperkalemia. This causes a range of problems in the cardiovascular, neuromuscular and gastrointestinal systems. HCO₃^- reabsorption is described in more detail here.

Discuss the Davenport diagram

Ew, diagrams. Diagrams = drawing, and drawing = effort. Oh well then, if I must...

The Davenport diagram has three main features: pH on the x-axis, plasma bicarbonate on the y-axis and a set of curved lines called isocapnia lines. Each isocapnia line represents a different partial pressure of carbon dioxide. Higher isocapnia lines represent higher partial pressures of carbon dioxide.

I've also drawn a whole bunch of random dots on the diagram. Well, they're not totally random, though now looking at it I've decided that I haven't used the best lettering system. Oh well.

Let's start from point D, which is pretty much in the middle. Let's pretend for now that point D is the normal state of bicarbonate concentration, carbon dioxide pressure and pH.

In respiratory acidosis, represented by point A on the graph, CO₂ increases and pH decreases. Respiratory acidosis may be due to hypoventilation (too little breathing), which causes a buildup of CO₂. This hypoventilation, in turn, may be due to damage to the respiratory centres or some kind of obstruction. The kidneys can compensate for this by increasing bicarbonate, leading us to point B, where the pH is back to normal.

In respiratory alkalosis, represented by point G on the graph, CO₂ decreases and pH increases. This is usually due to hyperventilation, which can occur due to the effects of drugs, CNS disorders and so on. The kidneys can compensate by getting rid of bicarbonate, leading us to point F.

In metabolic acidosis, too little bicarbonate is available, causing pH to drop from point D to point C. This may be due to alcohol abuse, diabetes, lactic acidosis, salicylate (aspirin) poisoning or renal tubular dysfunction. This can be compensated for by blowing off more carbon dioxide, leading us to point F.

In metabolic alkalosis, too much bicarbonate is available, causing pH to rise from point D to point E. This may be due to vomiting, hyperaldosteronism or exogenous steroids. This can be compensated for by blowing off less carbon dioxide, restoring pH to point B.

Gas Exchange and V'/Q' Ratio

I can't be bothered thinking up an introduction for this post, so let's just get into it!

Recall the blood pressures in the pulmonary circulation.

Blood pressures in the pulmonary circulation are lower than those in the systemic circulation. The pressure in the pulmonary arteries is around 22/8. The capillary pressure is also around 10mmHg less than in the systemic capillaries.

Explain how the Starling equilibrium is altered in pulmonary capillaries.

Firstly, you might want to refresh your memory on the Starling equilibrium by looking here. In pulmonary capillaries, one of the outward driving pressures (blood pressure) is greatly reduced as compared to the systemic circulation. How, then, is this compensated for?

Alveoli affect the Starling equilibrium as well. Air pressure within the alveoli pushes outwards (i.e. towards the blood), whereas the surface tension pulls stuff inwards (i.e. out of the blood). Everything's usually all nicely balanced so that pulmonary oedema (fluid in the lungs) doesn't occur (though obviously this can change in disease states).

Define V'/Q' mismatch

First some quick definitions: V' (which is sometimes displayed as V with a dot on top) is airflow, whereas Q' (again, Q with a dot on top) is blood flow. Blood flow and airflow are not uniform throughout the lung- some areas have better blood flow than airflow, and some areas have the opposite problem. For optimal gas exchange, blood flow should equal airflow, but this isn't possible everywhere in the lung. All of this can be expressed as the Ventilation-Perfusion ratio, or V'_A/Q'.

Now I'll give a quick overview on the main factors controlling pulmonary blood vessel resistance and air pressure (both of which ultimately control flow, as flow is equal to (change in pressure)/resistance):

For blood flow, we need to look at how many pulmonary vessels are open or closed. At rest, many vessels are closed. When blood pressure increases, more blood vessels are open, and those that are open may distend. This causes a reduction in pulmonary resistance. When blood pressure decreases, more vessels close off, increasing pulmonary resistance.

For air flow, see my earlier post: Mechanics of Breathing. In particular, read the part about compliance and the LaPlace equation.

Explain how V'/Q' mismatch produces hypoxia

As I just mentioned, airflow and blood flow are not equal everywhere in the lung. To understand the consequences of this, let's consider the two gases separately.

Oxygen

In underventilated alveoli (i.e. alveoli with more blood flow than airflow), the blood will arrive and leave with a smaller than usual increase in O₂ due to the limited amount of airflow. In overventilated alveoli (i.e. alveoli with more airflow), there will be a larger than usual increase in O₂.

However, these do not cancel each other out! Remember, haemoglobin saturation plays a large role in oxygen content of the blood. When blood flow and air flow are well-matched, you'll get a normal increase in airflow, and haemoglobin saturation will go back up to 95-100% (after becoming unsaturated during oxygen transfer to the cells of the body). When there is a larger than usual increase in O₂, haemoglobin saturation won't change much (as you can't get more than 100% haemoglobin saturation), so you're really not changing the oxygen concentration much at all! Hence, V'/Q' mismatch produces hypoxia.

Carbon Dioxide

Carbon dioxide is the opposite to oxygen: underventilated alveoli will not remove as much CO₂ as an over-ventilated one. These do, however, cancel out, as saturation is not an issue here. Hence, V'/Q' mismatch will produce little (if any) hypercapnia.

V'/Q' mismatch is a very common cause of hypoxia in disease states. V'/Q' mismatch is particularly marked in disease states such as asthma, where air will flow into healthy alveoli, whereas blood will flow to affected alveoli.

Describe the cause of orthostatic V'/Q' mismatch

When we are standing, airflow goes to the bottom of the lung. This is because gravity causes alveoli to stretch and become less compliant, particularly those towards the top (apex) of the lung. Blood flow also goes to the bottom of the lung when we're standing, as the higher blood pressure at the base causes vasodilation (as explained above). That sounds great, right? Airflow and blood flow increase in the same places!

Not quite. It's true that gravity does have an effect on both blood flow and ventilation, but it has more of an effect on blood flow than on ventilation. Hence, there is still some V'/Q' mismatch in most places in the lung. Towards the base of the lung, there will be more perfusion than ventilation; towards the apex, there will be more ventilation than perfusion. Ventilation and perfusion are relatively even at around the third rib.

Explain how V'/Q' mismatch is minimized in the normal lung 

In this post, I described how local metabolites can affect vasoconstriction and vasodilation. I also mentioned that O₂ is a vasoconstrictor everywhere except for in the pulmonary circulation, where it is a vasodilator. Well, that's relevant again: well-ventilated alveoli will cause vasodilation, whereas poorly perfused alveoli are hypoxic and cause vasoconstriction. In severe hypoxia, all of the pulmonary vessels can constrict, increasing blood pressure in the pulmonary circulation. This causes pulmonary hypertension, which can lead to oedema, right heart failure and death.

At really low levels of CO₂ (like really low), the airways may constrict to prevent more CO₂ from leaving. This generally isn't very important, however: most of our V'/Q' mismatch compensation is done by the blood vessels, rather than by the airways.

Respiratory Reflexes

This lecture had a fair bit of new content. It's not as difficult conceptually as that last cardiovascular lecture, but it is still way too much for a Monday afternoon IMO :P (Okay, it wasn't that bad, but I feel like there were a few little bits and pieces that just slid past me.)

Describe the inputs to the central rhythm generator.

As mentioned in my previous post, respiratory rhythm arises largely from the medulla. The centres in the medulla involved in control of respiration can be influenced by a variety of factors, such as feedback from peripheral receptors, emotion and temperature. (Temperature doesn't really have a massive effect on ventilation in humans, but in some animals, such as dogs, it can cause panting.) Voluntary control of ventilation is separate to the rhythm control in the medulla.

List the three types of lung receptors

The three types of lung/lower airway receptors include slowly adapting receptors (SARs), rapidly adapting receptors (RARs) and C-fibres. I'll describe them in more detail soon.

Describe the Hering-Breuer reflex.

As mentioned here, the Hering-Breuer reflex prevents overinflation of the lungs. It does this by suppressing inhalation when the lungs are already inflated. The vagus nerve is vital to this reflex- if you cut it, the reflex disappears. The Hering-Breuer reflex is not particularly strong in conscious humans, but it is important in animals (and may also be important in anaesthetised humans).

Explain the role of SAR and their stimulation and effects.

SAR, or Slowly Adapting Receptors, help detect the volume of the lungs. They are activated when the lungs are stretched, and as they do not adapt to the stretch (or at least they adapt very slowly, hence their name), they keep firing while the lungs are inflated. These may contribute to the Hering-Breuer reflex, which I just described.

SARs are myelinated fibres which have a conduction velocity of 15-30m/s (which is pretty standard for myelinated fibres). As mentioned above, they are stimulated by stretch. They do not respond to deflation, unlike RARs as I'll discuss shortly. The effects of SAR activation include reduced tidal volume, shorter respiratory time and bronchodilation.

Describe the reflex effects of RAR and the stimuli that activate them

RAR, or Rapidly Adapting Receptors, help detect changes in volumes of the lungs. Located within or near the epithelium, they are activated when stretching occurs, but their response is rapidly "switched off." They respond in response to both inflation and deflation, and the frequency of their impulses depends on the rate of change of volume of the lung (which is also related to inspiratory flow rate).

RARs, like SARs, are myelinated fibres with a conduction velocity of 15-30m/s. As well as being stimulated by stretch, they are also stimulated by irritants such as acid, smoke and dust. They produce reflexes such as coughing, tachypnea (abnormally rapid breathing), hyperventilation and bronchoconstriction.

Describe the activation and reflexes produced by C-fibres.

C-fibres, unlike RARs and SARs, are unmyelinated and thus their conduction velocity is much slower (1m/s). They come in two flavours: bronchial and pulmonary. They are present in the airway epithelium, as well as in other places around the lung.

Stimulants of C-fibres include capsaicin (as I'll explain shortly), acid and/or hypertonic saline (for bronchial C-fibres) and oedema and/or large amounts of inflation (for pulmonary C-fibres). It should be noted, however, that they are generally not very responsive to inflation. Activation of C-fibres produces bronchoconstriction, bradycardia, and sometimes cough. Initially, C-fibre activation can produce apnoea, but later on hyperpnea can be produced instead. (See here if you don't remember what these terms mean.)

One thing that is kind of unique about C-fibres is that they contain both afferent and efferent fibres, allowing the signal to branch out more easily (I think... there were quite a few tidbits in this lecture that I didn't quite get). C-fibres also contain neurotransmitters, including peptide neurotransmitters such as tachykinins. These can cause vascular leak (contraction of endothelial cells, increasing the amount of space between them), mucous production and bronchoconstriction. (I think. As I said, there were quite a few bits in this lecture that slid over me. I blame the time in the afternoon.)

Recall the receptors activated by capsaicin.

C-fibres can be activated by capsaicin, the component of chilli that makes it hot. Capsaicin activates vallinoid receptors (VR1), which are TRP (transient receptor potential) channels. Activation of VR1s produces the sensation of heat. Over long periods of time, capsaicin can actually kill off C-fibres, making you more tolerant to hot foods.

Explain the detection of cough.

This was hardly covered in the lecture, but the summary slide says that RARs and maybe C-fibres can detect cough. Receptors in the upper airways might help as well.

Describe the effects and activation of upper airway cool receptors.

Receptors in our upper airways can respond to changes in temperature, such as what happens when we exhale air from outside. Stimulation of these receptors makes us feel like we are breathing, so receptor stimulation suppresses further ventilation. On the other hand, when these receptors are blocked, we can feel like we can't breathe even though our blood gas concentrations might be normal.

Aside from cool receptors, there are quite a few other receptors in the upper airway (nose and larynx). These can cause laryngospasm (closing off of the larynx). These receptors can respond to flow, temperature, pressure, upper airway muscle contraction, snoring and obstruction.

Describe the effects of menthol.

Menthol stimulates cool receptors, making it feel like you are getting more airflow than you actually are.

Explain the muscle proprioception reflexes including the spindle and tendon organ

Muscles have a couple of different proprioception reflexes. We didn't go into too much detail on them in the lecture though. Apparently this was covered to some extent in PHYL2002, which I didn't do, so...

Muscle spindles can measure muscle length, and sudden change in spindle length (as might happen when you tap someone on the knee) can cause a reflex contraction. The Golgi apparatus can also play a role in measuring force on the tendon. Such receptors are present in a lot of skeletal muscles, but the diaphragm has few of them. Hence, a lot of the proprioception reflexes involved in breathing actually come from the abdominal muscles and intercostal muscles.

Define dyspnea.

Dyspnea is the feeling that you can't breathe, even though blood gases might be normal. There are several different mechanisms that might trigger this, such as mucus covering the cool receptors (as happens during a cold).

Control of Ventilation

Now we're moving onto learning about respiration! Yay...? Also, this lecture has a hell of a lot of aims, so hold onto your hat!

Describe the central generation of respiratory rhythm, including the three common hypothesis.

As mentioned here, generation of respiratory rhythm originates from centres in the medulla of the brain. There are several different hypotheses about how these centres interact:

1. Off-switch model: In this model, inspiratory motor neurons stimulate inspiration. Inspiration then feeds back onto some integrating neurons, which then stimulate an "off-switch" to stop inspiration. Eventually, the lack of inspiration stops the "off-switch" neurons, causing the inspiratory neurons to start up again.
2. Oscillator model: In this model, both inspiratory and expiratory neurons are constitutively activated. Inspiratory neurons can activate interneurons that turn the expiratory neurons off, and vice versa. If the timing is right, they can inhibit each other at the right times, generating a rhythm.
3. Pacemaker kernel model: This model suggests that there are some cells that act as a pacemaker. Indeed, some cells in the pre-Bötzinger complex do show synchronised pacemaker spikes. Glutamate inhibitors can block this synchrony.

The off-switch model and oscillator models are also known as "distributed network models," as they require multiple different groups of cells to work together.

Define apnoea, hyperpnea, hypopnea, gasping, apneusis.

• Apnoea: Lack of breathing. May result from damage to the medulla.
• Hyperpnea: Increased breathing
• Hypopnea: Reduced breathing
• Hyperventilation: Increased breathing that goes beyond what your body actually needs. (Note that hyperpnea and hyperventilation both involve increased breathing, but hyperventilation is inappropriate to the situation, whereas hyperpnea is totally appropriate.)
• Apneusis: Prolonged inspirations with short expirations. May occur due to damage to the pons. (This is where the pneumotaxic centre is, as I'll explain in a bit.)
• Gasping: The opposite of apneusis: prolonged expirations with short inspirations.

Describe the brain regions involved in the respiratory rhythm.

See earlier post: Control of Ventilation

Explain the function of the pneumotaxic centre.

See earlier post: Control of Ventilation. Also, as mentioned earlier in this post, the pneumotaxic centre is located in the pons, so damage to the pons causes apneusis.

Identify simple respiratory patterns and how they arise

I'm not really sure what I'm meant to know for this. Apneusis maybe? But I just wrote about that...

Describe the location of the central and peripheral chemoreceptors.

The central chemoreceptors are located in the ventral medulla, whereas the peripheral chemoreceptors are located in the carotid body and aortic arch.

Describe the stimuli that these receptors respond to.

Central chemoreceptors respond to the pH of the cerebrospinal fluid, which actually allows them to respond to CO₂ in a very roundabout way. CO₂ can diffuse through the blood-brain barrier, where it can form H⁺ and HCO₃^- by reacting with water. An increase in H⁺ decreases the pH, which is detected by the central chemoreceptors. It's unclear exactly how the central chemoreceptors are activated. To add even more confusion, there are many cells in the brain that can detect pH: aside from the chemoreceptors in the ventral medulla, cells in the dorsal and ventral respiratory groups, pons and hypothalamus can all respond to pH. Le sigh.

Peripheral receptors can respond to CO₂, H⁺ and O₂, though to my understanding they respond mostly to O₂. Also, carotid bodies may be better at sensing H⁺ than aortic bodies.

Peripheral receptors can respond more rapidly than central chemoreceptors as they don't have to worry about gases diffusing through the blood-brain barrier and whatnot.

Recall the sensory input into control of ventilation, the effectors controlled and where control occurs.

Not sure what exactly I'm supposed to put here that I haven't put under another heading, so I'm just going to shove a link to my old post on ventilation control here and call it a day.

Explain how the peripheral chemoreceptors sense P_O2 and P_CO2

The cells of the peripheral chemoreceptors that detect O₂, CO₂ and pH are called glomus cells. Glomus cells are excitable and can release neurotransmitters, just like nerve cells.

CO₂ can diffuse into glomus cells and cause a change in pH, just like they do in the brain. The increased H⁺ ions can protonate and close calcium-activated potassium channels in the membrane of these cells. As potassium can no longer leave, the cell becomes more and more depolarised, eventually leading to action potentials.

O₂ is detected via a different mechanism. O₂ can be converted into carbon monoxide by an enzyme called haemoxygenase. Carbon monoxide is usually known as a poisonous gas, but it can also serve as a signalling molecule in the cells. In this case, carbon monoxide causes CO-gated potassium channels to open. This keeps the membrane potential low, inhibiting action potentials. If O₂ levels drop, CO levels also drop, allowing these channels to close. (This usually happens when P_O2 < 60mmHg.) As mentioned before, stopping potassium from leaving causes the cell to depolarise and action potentials to be produced.

Explain the response to changes in blood oxygen, carbon dioxide and pH.

As alluded to before, low levels of oxygen (<60mmHg) cause a large increase in ventilation. Aaaaand I don't really have much else to say here.

Most of the response to carbon dioxide (60-80%) occurs via central chemoreceptors, though peripheral receptors play a part too, as discussed above.

Another interesting phenomenon to take note of is that of "synergistic drives." Essentially, this means that when oxygen levels are low, your cells become more responsive to high CO₂, and vice versa. This is because the detection of oxygen and carbon dioxide occur through similar mechanisms: the opening or closing of potassium channels of glomus cells.

Venous Pressure and Vascular Function Curves

This lecture was more complicated than it looked at first, which isn't all too helpful given that I can feel a headache coming on :P Oh well. This will be our last lecture on cardiovascular physiology for this unit for a little while.

Explain how central venous pressure determines cardiac pre-load and output.

As you should hopefully know by now, blood flows from a place of higher pressure to a place of lower pressure until the pressures are equal. Hence, blood will flow from the veins into the ventricles of the heart during diastole until the pressures are equal. The central venous pressure thus determines the amount of filling, which determines cardiac pre-load. As covered here and here, increased end-diastolic volume/increased pre-load increases stroke volume and, by extension, cardiac output.

Understand how central venous pressure is regulated through the vascular function curve, including the actions of blood volume, vasotone and veno-tone.

Blood volume alters venous pressure pretty much the same way it alters arterial pressure: increasing blood volume increases pressure and decreasing blood volume decreases pressure. So far, so good.

The effects of vasotone (arterial contraction) on central venous pressure are less intuitive. If vasotone increases, less blood can get through to the venous side. (Remember, flow is inversely proportional to resistance, and resistance increases as you constrict the blood vessels). Hence, increased vasotone will actually decrease venous pressure.

The effects of venotone (venous contraction) are a bit easier to grasp. Increased venous constriction will increase the pressure, and vice versa.

The relationship between cardiac output and central venous pressure can be plotted on the vascular function curve:

This graph can be a bit tricky to interpret. For starters, you actually have to read it the "wrong way around": you have to find a venous pressure from a given cardiac output, not the other way around. It's done this way so that both the vascular function curve and the cardiac function curve can be plotted on the same axes, as you shall soon see.

Another thing you'll notice about this graph is that the graph levels out below a certain venous pressure. This is because ventricular filling depends on a pressure gradient between the veins and the ventricles, and if venous pressure drops to the same pressure or lower than ventricular pressure, then the ventricles cannot fill any more and cardiac output cannot be increased. One more thing to point out is the x-intercept at the graph: this point represents the venous pressure if there was no cardiac output (i.e. if the heart had stopped and the blood pressure was allowed to simply equilibrate throughout the entire system of blood vessels). This pressure is also known as the mean circulatory (MC) pressure, and is usually around 7mmHg.

When blood volume is increased, such as during a blood transfusion, the entire graph shifts up and right. A greater cardiac output can be produced, and the MC pressure is higher. (Remember, if you have more "stuff" in what is essentially the same amount of space, you're going to have a higher pressure.) The reverse is true for when blood volume is decreased.

Now, blood vessels are not just passive: they can constrict and relax. How does that affect the vascular function curve?

Venoconstriction has a similar effect to increasing the blood volume: it raises the curve up and right. It also changes the slope of the curve slightly (the above picture is possibly exaggerated), leading to a higher possible venous pressure at zero cardiac output. This makes sense: pressure is inversely proportional to volume, so if you constrict the veins, thereby reducing the space inside, you'll increase the pressure. Vasoconstriction, on the other hand, does not change venous pressure when cardiac output is zero. (I'm not sure why- I'm thinking it's because arteries are smaller than veins and thus vasoconstriction has less of an overall effect on volume than venoconstriction? That's something I'll have to check.) Maximum cardiac output is greatly reduced- as mentioned here, MAP = CO*TPR. Rearranging this equation gives CO = MAP/TPR, so it follows that an increased peripheral resistance, as occurs during vasoconstriction, will decrease cardiac output.

Understand how cardiac output is set by the interaction between the vascular and cardiac function curves.

Some of the stuff in this post might seem a bit unintuitive, especially given the relationship between diastolic volume (and venous pressure) and cardiac output. In previous posts, I've said that stroke volume, and therefore cardiac output, is dependent on ventricular filling, which in turn is dependent on venous pressure. However, venous pressure is also dependent on cardiac output! Increasing cardiac output increases the amount of blood taken out of the veins and put into the arteries, and thus decreases venous pressure. So how can we put all of this together into a coherent picture?

The answer is simply to use two graphs: the vascular function curve, which I mentioned above, as well as the cardiac function curve (the one I showed you when talking about the Frank-Starling Law). These two graphs can be plotted on the same axes. The place at which they overlap gives the cardiac output and central venous pressure at steady state.

When there is a deviation from steady state, the cardiac output and venous pressure will gradually adjust until steady state is reached. As an example, let's say that we have some venoconstriction, raising the venous pressure:

Venoconstriction raises the venous pressure to point A. From the cardiac function curve, that venous pressure will cause the cardiac output to increase to point B. However, from the vascular function curve, that cardiac output should cause the venous pressure to decrease to C'. Because of the conflicting results from these curves, the venous pressure decreases a bit, causing cardiac output to decrease, and then venous pressure decreases a bit more, and so on until steady state is reached again.

Any stimulus that causes one or both of these curves to change can change the steady state. For example, as mentioned here, increased inotropy will raise the cardiac function curve:

As can be seen in the graph above, changing the cardiac function curve will also change the intercept between the vascular and cardiac function curves.

Of course, there are many different stimuli that can affect the curves, but I feel like I've already drawn more than my fair share of crappy Paint diagrams for this post. If you want to see how a particular stimulus will affect steady state, why not draw a diagram for yourself and find out?