Hyperoxia

Take home messages

• Oxygen is good if you need it, and terrible if you don't
• Aim for sats of 92-94% unless otherwise directed
• Prescribe your oxygen

Alicia Keys was right

This girl is on fire.

We all are - technically speaking - a bit on fire when you consider the fact that our cells are producing energy via the heat-generating oxidation of hydrocarbons.

Either that or we're rusting, but that doesn't sound nearly as cool.

Even at its point of discovery in 1771, Carl Wilhelm Scheele called oxygen 'fire air' such was its propensity for ignition and destruction, so you won't be surprised to discover that oxygen can end up doing rather a lot of damage if not used carefully by our intracellular mechanisms.

Using oxygen for intracellular energy generation is rather like using a nuclear reactor to heat your living room.

It works - and very well indeed - but it's rather hazardous, so you'll probably want some safety mechanisms in place.

• The key problem is those dastardly reactive oxygen species
• Unsurprisingly the lungs take the hardest hit, because they're the organ that receives the most oxygen
• It usually takes more than 24 hours for clinical effects to show up

What is Hyperoxia?

There's no specific formal definition of what constitutes hyperoxia, other than 'a state of excess oxygen in the tissues' or 'higher PaO2 than normal', but it's not a particularly complex concept to get your head around.

A key thing to note is there are two types of hyperoxia:

• Normobaric hyperoxia - normal atmospheric pressure, high inspired O2%
• Hyperbaric hyperoxia - higher than atmospheric, but can still only be 21% O2

(If you're breathing 21% oxygen at 2 atmospheres of pressure, your lungs are exposed to 42 kPa of oxygen - which is still hyperoxia)

The cascade

We know that oxygen moves down its partial pressure gradient as it moves through the body, which explains why the lungs are the most affected by high partial pressures of oxygen, because they take the biggest whiff of the ol' fire air.

• You can only really become hyperoxic by receiving a greater FiO2
• Yes, according to the alveolar gas equation, you can increase PaO2 by hyperventilating and decreasing PaCO2

But this isn't nearly as clinically significant as whacking someone on 60-100% oxygen for hours or days at a time, as you're only looking at about 16 kPa maximum by hyperventilating, and you wouldn't be able to keep that up for very long anyway.

A brief reminder

Of course you'll remember exactly how the electron transport chain works without even having to think about it, in case you'd like a quick reminder...

• Oxygen as an element is reduced to water by the electron transport chain in the mitochondria
• This process drags protons kicking and screaming across the mitochondrial membrane against their concentration gradient
• They're then allowed to fly back down their concentration gradient, driving the inner workings of ATP synthase and hey presto - energy

But there's a problem.

Some of these 'high energy' protons and electrons effectively 'leak' out and start generating all sorts of other nasties called 'reactive oxygen species' (a.k.a. oxygen free radicals).

The two to be able to list in an exam are:

• Superoxide (O2 with an extra electron)
• Hydrogen peroxide

Not only do these two do damage themselves, they then go on to produce even more free radicals as well, including:

• Singlet oxygen
• Hydroxyl radical

Like an orthopod holding an ECG, the hydroxyl radical is extremely unstable, and immediately interacts with any nearby species it can find.

This sets up a continuous cycle of free radical production, and you can imagine how that ends.

Now don't get me wrong, these free radicals are useful for their antimicrobial properties, they're just a little troublesome because they're well, anti-everything.

• They tear apart DNA and RNA
• They impair DNA repair machinery
• They damage cell membrane structure
• They mess with protein function by oxidising random amino acids

You don't live very long if they're allowed to hang around.

Antioxidants

Rather than merrily bleaching itself into oblivion, the cell has fortunately developed some rather splendid methods of defending itself from said aforementioned nuclear reactor, by producing and employing antioxidants.

These ROS-busting superheroes are the multi-talented guardian angels of the body:

• They can prevent ROS production in the first place
• They can scavenge and inactive ROS molecules
• They prevent damage to DNA and RNA
• They can also make Gwyneth Paltrow very rich indeed

That's probably all you need to know for the FRCA*

*not the Gwyneth Paltrow bit.

What happens in hyperoxia?

The main issue is that the delicate balance of oxidants and anti-oxidants is disrupted, with potentially disastrous consequences to which we probably don't pay sufficient heed.

We'll start with the pulmonary toxicity aspect of hyperoxia, as usually this is the most dangerous bit for your patient.

If you sit with an inspired oxygen concentration of greater than 60% for more than 24 hours then you start to see damage to the epithelium of the upper airways.

This can produce chest pain, shortness of breath and a sense of retrosternal tightness.

You also start to see the first measurable lung parameter changes - a drop in vital capacity.

Pulmonary toxicity occurs in four stages:

• To start with, in the initiation phase, the increased partial pressure of oxygen starts churning out enormous quantities of reactive oxygen species, setting up an oxidant:antioxidant imbalance
• This triggers the inflammatory phase, featuring surfactant disruption as well as epithelial and endothelial damage in the alveolus and capillary respectively, leading to pulmonary oedema, increased cytokine production and activation of the immune system
• We then saunter gracefully into the proliferative phase, with increased type II pneumocyte secretions and activation of the clotting cascade and widespread production of microthrombi
• Finally we end up in the fibrotic phase, where permanent lung damage is caused by deposition of collagen and fibrotic lung changes

Other organs

So here it gets rather interesting, because there's a strange paradoxical phenomenon where hyperoxia induces both hyperventilation and vasoconstriction in much of the systemic vasculature.

As a result, the resulting DO2 to vital organs including brain and heart can actually end up being lower than if you hadn't given any supplemental oxygen in the first place.

So what's the highest safe dose?

We don't know, but we do know that early space craft used hypobaric pure oxygen, giving a PaO2 of around 35kPa for several days without any issue.

Interestingly the fact that we can't produce our own vitamin C means we've had to develop other enzymatic antioxidant processes, and as a result humans are pretty good at tolerating high partial pressures of oxygen when compared to other species.

Sometimes it's helpful

As with many things in medicine, there is the odd occasion when bad becomes good and we can actually use something harmful as a useful therapeutic intervention (as long as it's done properly).

Why is the surgeon telling me to give more oxygen?

So some early evidence suggested that an FiO2 of 80% reduced postoperative nausea and vomiting, but this has subsequently been shown to not be a thing.

Apparently a very small subset of patients, who'd had a gas induction and no other antiemetics found a bit of benefit, but that's it.

Certainly not worth all the damage it does.

Some others thought that lots of oxygen helped reduce wound infections, and this chain of thought even reached the point where the WHO in 2016 advised that every intubated patient having surgery should be treated with hyperoxia, and we should all ignore the adverse effects of the oxygen.

As you can imagine this has been widely criticised, and more recent studies disagree vehemently with this conclusion.

The only thing that maybe benefits from hyperoxia is anastomotic integrity, with some evidence suggesting fewer cases of dehiscence and breakdown in patients given more oxygen, but it's not solid evidence and you really want to consider whether it's worth all the potential harm.

A vascular surgeon might ask you to give lots of oxygen to a patient with chronic diabetic foot ulcers to try and reduce the risk of amputation, but with all the harmful side effects and the lack of power in these studies - probably best not.

Interestingly, cancer patients seem to survive better (at 3 years) if given 30% oxygen compared to 80%, suggesting the oxygen might have an impact on seeding of metastatic cells.

What about ICU?

Yeah there are no surprises here either - avoid hyperoxia wherever possible.

Essentially, unless there are extenuating circumstances or a very weird and wonderful pathology that requires a specific oxygen target - you should aim for oxygen levels of 94-96% or 9-13 kPa.

I can still preoxygenate though right?

YES.

Using 100% (or 95% if you're one of them) to denitrogenate the lungs before high risk airway interventions such as intubation and extubation remains crucially important, and the benefits of having an FRC full of oxygen massively outweigh any potential harms of a few minutes of hyperoxia.

This is largely because you're doing it for a matter of minutes rather than hours, and 100% oxygen is considered safe if you're giving it for less than a few hours.

Check out this brilliant infographic from Novice Anaesthesia

Kids too?

Maybe not...

The infant respiratory system is a tricky pickle.

They have very compliant chests and very bouncy lungs, meaning there's an increased tendency for their airways to collapse, so their apnoeic FRC's are even more tiny than you'd expect.

This means they don't benefit nearly as much as adults from solid preoxygenation prior to induction of anaesthesia.

Because they collapse their airways with such enthusiasm, they're much more reliant on effective V/Q matching, and much more sensitive to atelectasis, both of which are made worse by lots of oxygen.

A word to the wisened

There are some key things to be aware of in elderly patients.

Older lungs produce more free radicals and express more pro-inflammatory cytokines, and develop permanent fibrotic damage sooner than younger lungs.

Older skeletal muscle deteriorates due to myofibril damage over time, and this process is worsened by hyperoxia - the diaphragm is no exception to this rule, so they suffer worse diaphragmatic contractile dysfunction.

And then there's the brain.

This is particularly important in elderly patients who already have an impaired NO-mediated cerebral vasodilatation response, and reduced cerebral blood flow to begin with.

So their finger sats can be great, but their cerebral sats not so much.

There are also suggestive studies that link hyperoxia with worsening and even development of Alzheimer's and other neurodegenerative disorders.

Useful Tweets and Resources

Check out this awesome infographic on pre-oxygenation from Novice Anaesthesia

References and Further Reading

Perioperative use of oxygen: variabilities across age

Abstract. Enormous interest has emerged in the perioperative use of high concentrations of inspired oxygen in an attempt to increase tissue oxygenation and ther

OUP Academic*

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