Tutorial: Hypoxia 1 – Causes

“…He Tried TO Force Land ON a Cloud…”

“The captain became very talkative and resented any suggestion that he was behaving abnormally. On seeing the marker flares over the target he found he could not take his eyes off them and forced the aircraft into a steep dive…

…Afterwards he said that he could only read the large figures on the instrument panel and these appeared far away. When we realised that the aircraft was out of control the engineer trimmed the aircraft. The pilot resented this and assaulted the engineer. He then gave the order to bale out which we cancelled. He opened the window to look out, and was only prevent from falling out by the engineer who hauled him in. He said that he felt very happy, and had no feeling of fear even when he tried to force land on a cloud, thinking he was near the ground. On one occasion he informed us that we were below ground. After being forced to take oxygen from the spare helmet and mask he gradually recovered his senses and was able to fly the required course to base, although he suffered from headache which persisted after landing.”

With the boom in aviation in the early 20th Century, aircraft began to climb higher in order to travel further or to gain the military advantage. Very soon they started to run into many of the issues of altitude that we discussed in our previous tutorial. By the start of WW2 aviators were regularly flying as high as modern short haul aircraft. But unlike the (relatively!) comfortable environment found in your A320s or 737s, aviators and passengers at the time faced a rather different situation.

Unpressurised cabins meant 8-10 hour sorties in cold, hypoxic environments. Just like it was for the early balloonists, hypoxia was not an uncommon event for the first heavier-than-air aviators (and even passengers) to reach higher altitudes. The dit above, taken from ‘Into Thin Air’ by Gibson and Harrison*, highlights some of the potential outcomes of hypoxia well. But before we get into that we need to look at what hypoxia is and why it’s such a threat to the unprotected aviator.

*A much recommended, but hard to find book detailing the history of Aviation Medicine in the RAF. This story is a personal account of a sortie in an RAF Halifax during WW2. A defect in the oxygen system led to the pilot operating for around 2hrs at 20,000ft without protection!

All I NEed is the Air that I breathe?

Due to it’s key role in cellular respiration, oxygen is a fundamental requirement for (almost) all multi-cellular life. We have evolved in an environment with air that is primarily nitrogen, but has a good proportion (21%) of oxygen.

Unfortunately, the Hollies (and later Simply Red) were wrong when they sang that all that you need is the air that you breathe. In addition to just being there, if we want cellular respiration to occur, four vital steps need to be completed:

If any one of these steps doesn’t function properly then aerobic respiration cannot occur. This is what we call hypoxia.

If it helps, think of this process like any delivery service. To get your goodies from the internet to your home the company needs to acquire the product from source, package it into a van, drive that van along a pre-existing network of roads and unload it at your door. Then you need to use that product for it to have all been worthwhile.

There are four types of hypoxia; hypoxic hypoxia (I know…!), stagnant hypoxia, anaemic hypoxia and histotoxic hypoxia. The naming isn’t great and many people seem to get quite muddle at this point. However, if we look with some detail at the actions above things hopefully start to become much clearer…

Action 1: ACQUISITION

The first thing we need to do is get oxygen from the air into the body. Evolution has come up with a number of quite different systems to achieve this. Besides lungs (which we are all hopefully familiar with!) these include cutaneous respiration in roundworms, use of gills in fish, spiracles and trachae in insects or various combinations (whilst fish, amphibians and some reptiles have primary mechanisms of gas exchange, they both quite heavily relay on cutaneous respiration too*). Even animals with lungs can vary quite significantly – just compare the anatomy (and achievable altitude) of birds and humans.

*Cutaneous gas exchange even occurs in humans but it is such a tiny amount that it is rather irrelevant in the scheme of things.

Despite the myriad of different methods, all of these gas exchange systems share the same fundamental principle; diffusion. In fact some life forms with sufficient surface area:volume ratios, such as amoeba or flatworms, can rely purely on direct diffusion without any additional fancy pipework or circulation.

Time for another eponymous law!

Put in simple terms, Fick’s Law states that the rate of diffusion (Q) relies on the surface area (SA), the concentration gradient (P1-P2), the thickness of the membrane (L) and something called the diffusion co-efficient (D)*.

*This depends on a number of factors including the substance being diffused and the environment in which this is occurring.

For our aviators (and for all us unlucky humans stuck at 0ft AGL too!) this diffusion occurs predominately at the alveoli in the lungs. Just as all the other systems of gas exchange have evolved for their purpose, alveoli are particularly well tuned to take advantage of Fick’s law.

95% of the surface area of alveoli comprises of ‘type I pneumoctyes’ which are incredibly thin squamous cells. This keeps the thickness of the membrane across which diffusion must occur to a minimum (most of the remaining surface area is made up of ‘type II pneumocytes’ which produce surfactant).

An average human lung contains approximately 300 million alveoli with a total surface area of 70-80m² (which is roughly the size of 7 parking spaces in the UK) with a dense capillary network takes advantage of as much of this area as possible.

Issues with oxygen acquisition can occur in a clinical setting if either of these factors are affected:

• Membrane thickness – increased due to fluid (pulmonary oedema) or scarring (pulmonary fibrosis)
• Surface area – This is reduced when a proximal obstruction prevents airflow to the alveoli which can occur due to a tumour, mucus plugging in an infection, airway narrowing such as in asthma etc. It can also be reduced by destruction of the alveoli as occurs in emphysema.

However, for a healthy aviator, we need to look at another part of Fick’s Law; the diffusion gradient. When talking about diffusion of oxygen in the lungs, P1-P2 refers to the difference in partial pressure of oxygen in the alveoli (P1) and the blood (P2).

The partial pressure of oxygen in the trachea is known as the P_IO₂ and can be calculated as follows:

As inspired air is usually fully humidified in the upper airways, P_H2O can be considered to be constant at 47mmHg, regardless of altitude. Similarly, unless breathing a hypoxic gas mix at the same time (which is certainly not recommended!) FO₂ will remain at 0.21 (or 21%).

So P_B is the real driving force behind the partial pressure of oxygen in the lungs of a health individual*. And herein lies the issue. As discussed in our altitude environment tutorial, barometric pressure falls exponentially as we ascend, so the higher we go, the lower P_B falls.

*Things get a bit more complicated when we look at what happens in the alveoli themselves but we’ll get into the alveolar gas equation in our next tutorial.

This has a double effect; not only is the partial pressure in the lungs reduced itself, lowering the equilibrium that can be reached at the alveoli, but the driving pressure to reach that equilibrium is also reduced.

If we reduce the diffusion gradient (P1-P2) then Fick’s Law states that the rate of diffusion will reduce. It’s important to note the wording. Diffusion will always result in an equilibrium but it just takes longer to reach this stable point.

If blood sat still long enough, the arterial partial pressure of oxygen (P_aO₂) would eventually reach the same level as the alveolar partial pressure (P_AO₂). However, our blood needs to keep moving to complete ‘Action 3’ in our list. Therefore, if the pressure gradient falls low enough, or the blood is travelling too quickly (e.g due to an increased cardiac output during exercise) that equilibrium may not be reached. This is what we call a ‘diffusion limitation‘ and it’s why hypoxia tends to be more severe as workload increases*.

*This can also occur in various clinical conditions where Fick’s Law is affected such as pulmonary fibrosis. In early stages it presents as shortness of breath on exertion (or SOBOE if you’re writing your notes quickly!)

So then, if you go high enough without any protection, or if your protection fails, a failure of oxygen acquisition will occur. It’s not really a matter of physiology, it’s a matter of physics. Unsurprisingly, this is probably the most common cause of hypoxia in aviators and where we spend a lot of time and effort as aerospace medicine specialists as a future tutorial exploring protection from hypoxia will explain.

Action 2: PACKAGING

So once we’ve got oxygen across our membranes and into the body. For single celled organisms relying on direct diffusion this is job done – the oxygen is already where it needs to be. For larger, more complex life, we need a way to distribute that oxygen. To do this, the oxygen needs to be carried by the blood.

But there’s a problem. Oxygen isn’t very soluble (particularly at body temperature). At a P_aO₂ of 100mmHg, only 15ml of oxygen can be carried in the 5L of blood an average human has. As our resting oxygen consumption is around 3.5ml/min per kg of tissue we don’t need to get into more complex considerations of cardiac output to know this isn’t going to be enough. Indeed, only about 2% of oxygen is carried in the plasma.

So luckily we have those handy red blood cells packed with haemoglobin (Hb)* to do this for us.

*To avoid going down a further rabbit hole, I won’t go into haemoglobin in detail, suffice to say it is one of the brilliant outcomes of evolution. If you need a bit of a refresher on the function of Hb and the oxygen dissociation curve, there are some decent videos online such as here or here .

Time for some number soup…Each molecule of Hb has four haem groups, each of which can carry a molecule of oxygen. This means that 1g of Hb can carry 1.39ml of oxygen. With approximately 15g Hb per 100ml blood, our 5L of circulation could now carry 1042.5ml of oxygen rather than a measly 15ml.

The numbers are not important to remember. What is important is that without Hb, our blood clearly cannot hold enough oxygen to get it to where it needs to be in sufficient quantities. The amount of oxygen in our blood can carry can be calculated by the following equation:

At first glance this may appear confusing. But if you notice that everything to the left of the ‘+’ is oxygen packaged into Hb (with 1.34 being the ml of O₂ carried per g of Hb) and everything to the right of the ‘+’ is oxygen packaged directly into the plasma (with the 0.003 being the solubility of oxygen at body temperature per 100ml per mmHg) it gets a bit clearer*

*You may see slightly different versions of this equation. Normally this is due to the units chosen for Hb concentration and pressure but the numbers should come out the same at the end.

If we plug in some standard numbers we can see that C_aO₂ = ((15 x 1.34) x 0.98) + (100 x 0.003) = 20.0vol%.

An Hb of 8g/dL (or 80g/L) is where severe anaemia starts according to the WHO. If our Hb drops to this level we can see that vol% falls to 10.8%. So…not having enough Hb (or anaemia) will reduce the amount of oxygen that can be carried by the blood.

But there’s more…

Think back to Fick’s Law – given a set SA and membrane thickness, the force driving oxygen across the alveolar membrane is the diffusion gradient, or P1-P2. We’ve already stated that this is the difference between P_AO₂ (alveolar partial pressure, P1) and P_aO₂ (arterial partial pressure. P2). What is worth some clarification is that the arterial partial pressure of oxygen is the partial pressure of oxygen carried in the plasma, not the total oxygen content of the blood.

When oxygen binds to Hb in the pulmonary capillaries it ‘removes’ it from the plasma, lowering the P_aO₂. This keeps P2 as low as possible and helps to maintains a high concentration gradient along the capillary, ensuring the rate of diffusion is maintained.

So with fewer Hb molecules, not only would there be less oxygen carried to the peripheries but there could very well be a diffusion limitation, lowering the P_aO₂ futher.

I’ve Got Enough Hb…I’m Alright, JAck

Anything that affects the ability for blood to carry oxygen can cause hypoxia. These causes are is traditionally termed anaemic hypoxia. This can be found in a wide range of clinical conditions at ground level. Any limitation in acquiring oxygen that occurs at altitude will be exacerbated by anaemia, with lower carriage of oxygen to tissues and an increased risk of a diffusion limitation.

But there’s another way an aviator can get hypoxic from failure of oxygen packaging which highlights why anaemic hypoxia may not be the best term.

Piston engines can create high concentrations of carbon monoxide (CO) due to incomplete combustion (when fuel is too rich or the air supply is limited) or with aging parts. If there is inadequate sealing from the engine or exhaust in a piston powered aircraft, CO can enter the cabin. Furthermore, many aircraft heat external air by running it over warm engine parts to condition it for the cabin. Any slight breaks or leaks in the engine form another route for CO to enter the cabin. On a side note, aircraft with turbine engines (turbojets, turbofans or turboprobs) have a very low risk of generating significant quantities of CO in cabin air unless there is another cause such as an on board fire.

CO binds to Hb but does so with 210 times more affinity than oxygen. Once it’s there, it’s hard to get rid of (the half life of carboxyhaemoglobin or COHb is around 4-6 hours). Exposure to even low concentrations of CO will, over time, reduce the amount of Hb available for oxygen. If we look back at the oxygen carriage equation, effectively the 1.34 starts to get smaller and smaller. So there may be the same amount of Hb molecules, but they no longer able to carry oxygen.

Whilst this might sound like a ‘toxic’ form of hypoxia, CO poisoning is all about oxygen packaging and hence is classed as an ‘anaemic’ hypoxia. It is a big risk in aircraft as it can cause incapacitation rapidly in high quantities or over a long exposure, or can affect performance in smaller exposures which may affect performance and cause accidents. You can read more about CO poisoning in aviation here.

Action 3: Delivery

So now we’ve got our oxygen into the body and packed neatly in our red blood cells and it’s ready for delivery to where it is needed. This next step relies on three things; circulation, propulsion and offloading.

CIRCULATION

If we can extend our metaphor, consider the body as a city. The cells are houses that need regular deliveries of food (oxygen) and the road network is the circulation.

If a road is blocked the delivery vans cannot get to the houses distal to that blockage (unless there are other routes, or ‘collaterals’). The houses run out of food and, after a period of working in a non-ideal starvation mode (anaerobic respiration), they start to die off.

This sort of blockage is what we classically think of when we talk about stagnant hypoxia and it is the cause of myocardial infarctions and ischaemic strokes. The blockage can be caused by local pathology (such as plaque rupture and thrombosis in a coronary artery or compression by a tumour) or migratory pathology (such as an embolism from a distant clot).

The blockage doesn’t need to be complete, either. If you’re driving down a three lane road and it rapidly narrows to one lane (I’m looking at you A3!) the traffic starts to build up as the onward flow reduces. The same happens in the circulation. When vasoconstriction occurs, distal flow is reduced.

The relationship between flow and radius is described by Poiseuille’s Law:

As radius is raised to the forth power, a small change in radius results in a large change in flow. If this constriction is severe enough – such as extremities in prolonged cold exposure or extended use of vasopressors – tissue hypoxia can result.

There are a number of reasons that a failure of oxygen delivery can occur in aviation. Clearly any of the clinical causes at ground level could happen in flight (although it is a key role of Aviation Medicine to help avoid this risk) but there are specific causes too.

Rapid or prolonged reductions of pressure produce nitrogen bubbles in the circulation (remember Henry’s Law?) that obstruct smaller vessels and lead to reduced flow and hence oxygen delivery downstream. This is one of the causes of the clinical picture of decompression sickness or ‘evolved gas disease’. If the pressure change is quick and large enough to damage lung tissue sometime bubbles of air can enter the arterial circulation as arterial gas emboli. We will discuss these more when we talk about Decompression Illnesses in another tutorial.

PROPULSION

A working circulatory system relies not only on open roads but also on an adequate propulsion system. Unlike in our metaphor, this propulsion does not come from the blood itself but from the heart acting as a pump. How well this pump is working can be expressed as Cardiac Output (CO) which is the amount of blood per beat (Stroke Volume, SV) multiplied by the number of beats a minute (Heart Rate, HR) to give us a value in L/min.

To work out how much oxygen is being delivered (if all roads are working properly!), we can use the following equation:

This is quite a nice way of showing that if we increase our stroke volume or our heart rate we increase the amount of oxygen delivered to the tissues. The inverse is obviously also true and this forms the second key reason oxygen delivery fails – pump failure.

If the heart is unable to maintain an adequate circulation then there is a bit of a double hit. Not only is delivery to the tissues reduced, but also the amount of blood that can be oxygenated by the lungs in any given time period is reduced. In the most extreme cases – where circulation ceases entirely – the oxygen that is carried by the blood will rapidly be used up. As we will come to see when we talk about G-Forces, the brain can only continue to maintain consciousness for about 4 seconds when after blood flow stops.

OFFLOADING

Just as it would be no good if your delivery driver got to your house but carried on driving with your package still in their van, oxygen delivery also relies on offloading the product at the target cells. Offloading at the cells is a similar process to absorption at the lungs. It is driven by diffusion and hence Fick’s Law*.

On this end, however, the factors that affect this are related to the other actions. If you absorption or carriage are affected, P1 is reduced and diffusion will slow. If there is a blockage of some routes of circulation, the surface area reduces and if your cells can’t use the oxygen they already have, P2 will increase and diffusion will slow. In turn then, offloading of oxygen relies upon and can be affected by all the other actions.

*There are some important caveats however. Some clinical conditions (such as oedema) can increase the diffusion distance locally, resulting in local tissue hypoxia (or ischaemia).

How easily oxygen will detach from Hb is determined by the type of haemoglobin and the various factors that affect the oxygen dissociation curve (pH, Temperature, 2,3-DPG). As mentioned before, this is outside the scope of this tutorial, save to say that these factors are not generally directly affected by the aviation environment (although 2,3-DPG may play a role in altitude acclimatisation for long duration exposures such as mountain climbing).

Action 4: Utilisation

This action is the least likely to be affected by aviation and as its been a long time since my pre-clinical med school days I won’t risk attempting to go into the details of citric acid cycles or electron transport chains. Suffice to say that you can get as much oxygen into a cell as you want, but if the cell can’t use it then it’s all been for nought. This primarily happens in certain metabolic conditions or in the face of toxins like cyanide that block parts of the cellular machinery.

This tends to only occurs in aviation in the presence of fire. Alongside carbon monoxide and a lot of other nasty chemicals such as hydrogen chloride and benzene vapours, aircraft fires can produce hydrogen cyanide to to burning plastics and nylons. If this is inhaled it is readily absorbed through the respiratory tract and mucosa. At a cellular level, an enzyme in the mitochondria called cytochrome C oxidase is inhibited, preventing aerobic respiration and causing cellular hypoxia. If the quantities absorbed are enough to affect multiple cells quickly this can result in a widespread, and potentially fatal, hypoxia.

As you can guess, there are plenty of life-threatening risks if an aircraft is on fire. Furthermore, detecting accurate blood levels of cyanide post mortem is difficult, in part due to its short half-life. It is hard to tell, therefore, how likely this is to be the cause of fatalities in aircraft fires. However, if we are aware of this risk then things can be done to minimise the production of cyanide during fires by avoiding certain material types or using fire-proof coverings where possible.

The FOUr MUSKETEERS

That’s all well and good, but I promised an easy way to remember the four types of hypoxia. So here it is:

As you may have noticed during my ramblings, the four actions needed to prevent hypoxia line up really quite nicely with the four types of hypoxia. This also highlights why the current naming convention causes so much confusion. CO poisoning does not cause anaemia in the colloquial sense, but it does affect carriage of oxygen in the blood. A tourniquet doesn’t really cause stagnation of the blood (it will just go another way!) but it does affect the delivery of it to downstream tissues.

In other words, whilst the four types of hypoxia are phrased like a pathology they are actually classified according to which of the four required actions has failed.

“On One Occasion HE Informed Us We Were Below Ground…”

So we’ve learnt about the types of hypoxia and how they can occur in the air. Three of the four types of hypoxia will only occur in aviation in certain scenarios (fumes events, fires, DCS). However if you go high enough without protection, hypoxic (or hypobaric) hypoxia will definitely occur because it isn’t to due to physiology, it’s to due to pure physics.

But what does this really mean and why does it matter? Unfortunately you’ll have to wait until our next tutorial to find out…

Until then…

Yours,

JB

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Check out this tutorial on the causes of hypoxia by #NGAM at NextGenAsM.wordpress.com

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