Vivacast 10 – Hypoxia Classification, Delivery, Saturations

Oxygen Delivery

Classification of Hypoxia –

Think about these as different ways oxygen fails to get to the mitochondrial electron transport chain – impairing oxidative phosphorylation

Causes:

Hypoxic Hypoxia-Having a low fraction of oxygen in the alveolus

• Stood atop everest
• Hypoventilation so all the o2 is consumed in the alveolus

Anaemic Hypoxia

• Insufficient Hb going around the place so not sufficient quantity of oxygen
• Tied up Hb i.e. Carbon monoxide poisoning

Stagnant Hypoxia

• Impaired Perfusion of tissues – shock.

Histo / CytoToxic Hypoxia

• Cyanide poisoning

Delivery of Oxygen

CO x (1.39 x [Hb] x SPO₂ ) + 0.003 x P_AO₂

• 1.39 in vitro Hb Oxygen carrying capacity
• 1.34 in vivo Hb Oxygen carrying capacity 1.34 mls of O₂ per 1 Gram of Hb….

Do recall that this does not mean that the cells of the human devour all the oxygen that tottles past the capillary system, because otherwise blood returning to the heart would have spo2 of zero and Hb isn’t very good at picking up oxygen when its devoid of o2

It would also mess with oxygen delivery to the liver via the portal system….. and cause liver hypoxia if no other evolutionary changes had occurred.

As we should generally know – central venous oxygen saturations are around 75%, which would reflect a haemoglobin having 3/4 haem moieties occupied. From this you can inver that using the D02 equation, and x0.25 will tell you the amount of oxygen consumed per minute of CO output.

It will probably measure up to being about 250ml/minute – and this is one of the many ways you can calculate oxygen consumption in a human.

Plasma to Mitochrondia – Oxygen Diffusion Steps – Guyton and Hall pg 496

• Plasma PO₂ = 95mmHg
• Interstitial PO₂ = 40mmHg
• Intracellular PO₂ = 5-40mmHg depending on distance from capillary, Avg 23mmHg
• Cellular oxygen requirements are met by a pressure of 1-3mmHg

Oxy-Hemoglobin Disassociation Curve

Sigmoidal curve

• 50% SPO₂ = P_AO₂ – 3.5KPa. – AKA the p₅₀
• 75% SPO₂ = P_AO₂ – 5.3KPa
• 97% SPO₂ = P_AO₂ – 13.3KPa

This curve can be pushed to the left or right

• Left = More Affinity for Oxygen
• Right = Less affinity for Oxygen

There is a physiological element of this that favours binding in lungs and deposition in tissues. However when homeostasis is deranged by pathological occurrences affinity or deposition can be come impaired.

Haldane Effect = Deoxy Hb is better at carrying CO₂

Bohr Effect = Acid environments reduce Hb-O₂ affinity eg those with higher CO₂ levels…

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Transcript

Gas, Gas, Gas Episode 92: Hypoxia and the Oxyhaemoglobin Dissociation Curve

Introduction and Episode Overview

00:00-00:30

Please listen carefully. Hello, and welcome to Gas, Gas, Gas, the podcast that covers the FRCA primary exam. We’re going to fit into your day and give you as much of your life back as you could possibly imagine. I’m here to make your studying easier – listen to us on your commute, in the gym, in the shower, or when you’re ironing your scrubs. Expect facts, concepts, model answers and the odd tangent. Check out the show notes for all the detail, and remember to follow the show so that you never miss an episode. Let’s get on with it.

Hey hello everyone and welcome to another instalment of the Vivacast episodes with my dear colleague and co-conspirator Tom. We are looking into the depths of hypoxia, how oxygen actually might get to a cell, and the haemoglobin dissociation curve. Time naturally continues to tick on for Tom, his exam creeping ever closer, so we’ll pile straight into it. Hope you enjoy the show.

Classification of Hypoxia

01:01-02:58

Summary: Tom provides a comprehensive classification of the four types of hypoxia and their underlying mechanisms.

Oh yeah, that is time to move on. Could you classify hypoxia for me, please?

Hypoxia is the inadequate delivery of oxygen to the tissues. It can be thought of as anaemic hypoxia, histotoxic hypoxia, hypoxic hypoxia, or ischaemic hypoxia.

So, I mentioned anaemic hypoxia first. If we have reduced levels of haemoglobin in the blood, then we have less oxygen-binding capacity and less oxygen-carrying ability of the blood. And even with adequate oxygenation and gas exchange, you can still have inadequate delivery of oxygen to the tissues.

In hypoxic hypoxia, that’s the most straightforward type. If you have inadequate oxygen delivery to the blood within the pulmonary vascular bed, then that will lead to reduced oxygen delivery to the tissues. That can either be from reduced fraction of inspired oxygen or through impaired gas exchange within the lungs.

Cytotoxic hypoxia can be caused by various substances such as cyanide or by sulphur dioxide gas. Both of these cause irreversible binding of oxygen to haemoglobin so that it can’t be released into the tissues from capillary beds. So despite good oxygen gas exchange and adequate delivery of blood to the tissues, you still have reduced oxygen delivery at a cellular level.

So we’re talking about cytotoxic, hypoxic, histotoxic hypoxia. I think I may have mentioned ischaemic hypoxia as well was the other one that I mentioned. So ischaemic hypoxia relates to inadequate perfusion of tissue in order to deliver oxygen to it. So most commonly this could be caused by a thrombus or something such as a PE.

All of these really – the hypoxia itself means that mitochondria aren’t getting adequate oxygen delivery at a cellular level and so cannot produce ATP at sufficient rates and cause stress at a cellular level.

Mechanism of Cyanide Toxicity

03:23-04:00

So just for clarity, could you just tell me the mechanism of action of cyanide again, please?

So I mentioned that cyanide has an effect on oxygen binding to haemoglobin, but I was confusing it with carbon monoxide, whereas I believe cyanide is toxic to mitochondria and stops the production of ATP at a mitochondrial level.

ATP. Sorry, did I say ADP? I beg your pardon. ATP. Did you say ATP? Adenosine triphosphate. Yeah, you did, yeah, mate. Adenosine triphosphate, yeah. Excellent.

Oxygen Delivery Formula and Mechanisms

04:01-06:17

Summary: Discussion of the oxygen delivery formula and how oxygen transfers from plasma to mitochondria.

So you mentioned the phrase delivery of O₂ quite a few times there. There’s a formula that brings all that together. Could you tell me?

Yes. Oxygen delivery is equal to the cardiac output multiplied by the haemoglobin concentration, multiplied by the oxygen saturations. These can be modified with some numbers to give you millilitres per litre number at the end of it. So I think oxygen saturations normally multiplied by 0.003 and haemoglobin levels are multiplied by 1.34 if the number is given in grams per litre.

Okay, so what does delivery of oxygen really tell you?

Oxygen delivery tells us how much oxygen is being made available to the tissue in order to use for respiration.

But then tell me, how does oxygen transfer from plasma to the mitochondria? What governs that?

So once we reach a capillary level, oxygen has to be first of all released from haemoglobin, where it’s primarily carried, under the influence of 2,3-DPG and under the influence of local pH. So lower pH and high 2,3-DPG levels cause release of oxygen from haemoglobin. And presence of CO₂ being released from the cells also causes some conformational changes in the haemoglobin – as CO₂ binds to haemoglobin, it helps release oxygen as well.

This then has to diffuse out of capillaries, which are specially designed essentially to be leaky at a very microscopic level and allow fluid to pass out into the interstitial space. Oxygen then diffuses across this space and across cell walls, being a small nonpolar molecule and diffuses into mitochondria within the cell. It’s the mitochondria that then utilise oxygen in the oxygen transport chain in order to produce ATP.

The electron transport chain, Tom, is somewhere we’re going to leave for next time.

The Oxyhaemoglobin Dissociation Curve

06:17-08:30

Summary: Tom explains the sigmoid relationship between oxygen saturation and partial pressure, and the factors that shift the curve.

But what is the – tell me about the relationship between saturation and plasma oxygen content?

You can draw a sigmoid graph representing the partial pressure of oxygen and oxygen saturations known as the oxygen saturation curve, I believe. The terminology escapes me currently. But this sigmoid shape will shift to the right or left under the influence of various factors.

So under normal conditions, the higher the partial pressure of oxygen within plasma, the higher the oxygen saturation. As we mentioned earlier, under the influence of lower pH or 2,3-DPG, oxygen is more easily given up. So for a lower partial pressure, you have a – for the same partial pressure of oxygen you have a lower oxygen saturation, i.e. a shift of that curve to the left. Increased temperature will also cause a similar shift to the left.

Some things can cause a shift to the right, so increasing plasma pH and reduced 2,3-DPG levels.

For instance, okay, so just so we’re super clear, the presence of 2,3-DPG at a higher amount, let’s call it lots of 2,3-DPG. Does that increase or decrease haemoglobin’s affinity for oxygen?

It decreases haemoglobin’s affinity for oxygen. So a lack of it means that oxygen is held on to by the haemoglobin – holds onto the oxygen when there’s not as much.

And then, how does temperature influence it?

So, hot environments lead to hyperthermia causes a shift of the haemoglobin dissociation curve to the right. Yeah, the right. So the affinity of haemoglobin decreases. Yeah. ‘Cause it’s just there’s more energy in the system, so the oxygen’s more like, “Let me go.” At least that’s how I imagine it.

So just to clarify there, James, so I think I was right the first time over that. I think decreased affinity is a left shift.

Host Summary and Clarification

08:46-13:28

Summary: James provides a comprehensive review of the key concepts covered, with corrections and additional detail.

So everyone, that was Tom, pounding his way through these topics. But just so that we are all singing from the same hymn sheet, I’m going to go over the show notes very quickly here.

Classification of Hypoxia Revisited

So I asked Tom about the classification of hypoxia, and I think about this classification as the different ways that oxygen fails to get from the atmosphere to the electron transport chain. You could even go as far as to imagine someone stood atop Everest.

They are experiencing hypoxic hypoxia because there’s a low fraction of oxygen available in the alveolus. This can also come about if someone is hypoventilating and the fraction of oxygen deteriorates in the alveolus over time as it is taken up by blood flow crossing the alveolus.

Or perhaps they have anaemic hypoxia, because there’s either insufficient haemoglobin going around the place – i.e., they’ve fallen off Everest and they’re quietly bleeding to death. Or perhaps they were cooking inside their tent and they have now got carbon monoxide poisoning and their haemoglobin is dysfunctional.

Perhaps they’ve been atop Everest, and they’ve had a spot of myocardial infarction, and now they have cardiogenic shock. They’re just not pumping enough oxygen around their body to their tissues – they have stagnant hypoxia.

Or perhaps, for some inexplicable reason, someone has poisoned them on top of Everest with cyanide, and now they have histotoxic or cytotoxic hypoxia.

So the classification of hypoxia, guys, is either:

• Hypoxic hypoxia: not enough oxygen in alveolus
• Anaemic hypoxia: either a lack of haemoglobin in the plasma or dysfunctioned haemoglobin
• Stagnant hypoxia: i.e. shock, a failure of the haemoglobin you have to get where it needs to go
• Cytotoxic hypoxia: the mitochondria is dysfunctioned, cyanide poisoning

Oxygen Delivery Formula

We then go on to delivery of oxygen. This brings together two concepts. One, your cardiac output – i.e., how much blood is going round and round – and is multiplied by the amount of oxygen currently carried in your blood, which is worked out by knowing the saturations of that blood, your haemoglobin concentration of that blood, as well as the partial pressure of oxygen in blood, because there is a dissolved quantity of oxygen in blood, as we all know.

And this is all multiplied together in a manner which is in the show notes. And the critical bit of information we need to know is how much oxygen is carried per unit of haemoglobin, or gram of haemoglobin, and that is, in reality, 1.34 millilitres of oxygen per one gram of haemoglobin. Important number to remember.

Oxyhaemoglobin Dissociation Curve Summary

We then touched on the oxyhaemoglobin dissociation curve, and Tom described a sigmoidal structure that shifts to the right or the left depending on the environment the haemoglobin finds itself in. A shift to the left yields a greater affinity for oxygen, whereas a shift to the right yields a lesser affinity for oxygen – i.e., left shifts the haemoglobin holds on to oxygen, right shifts in this curve, it releases oxygen.

There are a bunch of factors on either side of this situation that can cause these events.

A left shift, classically:

• A raised pH – i.e. a slightly more alkaline environment
• A cooler temperature
• Less 2,3-DPG levels
• And for example, if you’re using foetal haemoglobin, which we know has a higher affinity for oxygen, and that’s how foetuses get their oxygen across that placenta

Drivers to the right – i.e. things that reduce oxygen affinity:

• Acidic environments
• Environments with an increased temperature
• Environments with a greater level of 2,3-DPG

Have a read of the show notes. Get on the internet and look at these curves. Try and fix them in your mind and try and think of something that works for you that helps you remember which way left and right is for this, because I’ve not thought of a good one. Maybe you can email me and I can put it on the show notes as well.

Closing

13:46-14:04

Thanks for listening to the episode, guys. If you found it useful or awful, please like and subscribe and rate the show. Definitely, go check out their show notes on gasgasgas.uk. We all know that this is a bucket of content. I want you to take some time for yourself and don’t overcook it. Don’t freak out. Keep studying.